COMPOUNDS THAT INHIBIT

MCL-1 PROTEIN

This application claims the benefit of U.S. Provisional Application No. 62/300,013, filed on February 25, 2016, which is hereby incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit myeloid cell leukemia 1 protein (Mcl-1 , also abbreviated as MCL-1 or MCL1); methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds.

BACKGROUND OF THE INVENTION

One common characteristic of human cancer is overexpression of Mcl-1. Mcl-1 overexpression prevents cancer cells from undergoing programmed cell death (apoptosis), allowing the cells to survive despite widespread genetic damage.

Mcl-1 is a member of the Bcl-2 family of proteins. The Bel -2 family includes pro-apoptotic members (such as BAX and BAK) which, upon activation, form a homo-oligomer in the outer mitochondrial membrane that leads to pore formation and the escape of mitochondrial contents, a step in triggering apoptosis. Antiapoptotic members of the Bcl-2 family (such as Bcl-2, Bel -XL, and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK, and BAD) exhibit additional regulatory functions.

Research has shown that Mcl-1 inhibitors can be useful for the treatment of cancers. MCi-1 is overexpressed in numerous cancers. See Beroukhim et al. (2010) Nature 463, 899-90. Cancer cells containing amplifications surrounding the Mcl-1 and Bcl-2-1-1 anti-apoptotic genes depend on the expression of these genes for survival . Beroukhim et al. Mcl-1 is a relevant target for the re-iniation of apoptosis in numerous cancer cells. See G. Lessene, P. Czabotar and P.

Colman, Nat. Rev. Drug. Discov., 2008, 7, 989--- 1000; C. Akgul Cell. Mol. Life Sci. Vol. 66, 2009; and Arthur M. Mandelin II, Richard M. Pope, Expert Opin, Ther. Targets (2007) l l (3):363-373.

New compositions and methods for preparing and formulating Mcl-1 inhibitors would be useful.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides compounds of Formula I,

or a pharmaceutically acceptable salt thereof,

wherein;

a, b, and c, each represented by the symbol is a single or double chemical bond which may be cis or trans, wherein one of a, b, c, d and e is a double bond, or each of a, b, c, d and e is a single bond, or a and c are double bonds and b, d, and e are single bonds;

A is CR ^9A or N; wherein when A is CR ^9A , R ⁹ and R ^9A together may form

Cl b:

Q is selected from C or S; wherein R ⁵ and R- ^lA may both be absent if Q is S; or R ⁵ and R ^5A together may form =0 when Q is C or S; or R ⁵ and R ^5A together may form =CH2 or =N when Q is C;

T is CH, CR ¹ or N;

9 V is selected from C, O, or N; wherein if V is O, then R ⁷ and R ^7A are absent; further wherein if V is N, then R ^7A is absent; and further wherein if V is C, then R ^" and R ^7A together may form a =0;

W is selected from C, O, or N; wherein if W is O, then R ⁸ and R ^8A are absent; and further wherein if W is N, then R ^8A is absent;

Z is selected from C, O, or N; wherein if Z is O, then R ⁶ and R ^faA are absent; and further wherein if Z is N, then R ^6A is absent;

a and b are single bonds if Z is O or N;

a is a single bond if Q is S;

R ⁵ and R ^6A are absent when a is a double bond;

R ^6A and R ^7A are absent when b is a double bond;

R ^/A and R ^SA are absent when c is a double bond;

R ^SA and R ^10A are absent when d is a double bond;

R ^10A and R ^9A are absent when e is a double bond;

R ^s is H, Ci-ealkyl, Ci-ealkenyl, Ci-e.alkynyl, or -Y-R ^{3 3} ;

Y is independently O, or NR ¹⁴ ;

R ^5A is H;

p is 0 or 1 ;

q is 0, 1 , or 2; wherein if q is 0, then d and e represent the same bond; v is 0, 1 , or 2;

w is 0, 1, or 2;

z. is 0 or 1 ; wherein z is 0 only if q is 0; wherein if z. is 0 and q is 0, then c and e represent the same bond;

each of R ¹ and R ³ is independently selected from halo, -Ci-ealkylhalo, -C i- 6aikyl, -Ci-ealkenylene, -ίΠ K 1 Η ) |„Κ ^:! . -SG ₂ R ^a , -C(=0)R ^a ,-C(=0)OR ^a , or - C(==0)NR ^a R ^b ;

each of R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , l ⁹ , and R ^lu is independently selected from H, halo, -Ci-ehaloalkyl, -Ci-ealkyl, -O-Ci-ealkyl, -Ci-ealkenyl, -Ci-ealkenylene, -Ci- e.alkyl-O-Ci-ealkyl, -( ( 1 hC! K))„R ^:! -SO2R ³ , -CN, -( ( 0 )R ^:! ,-C(-0)OR ^a , - OC(=0)R ^a , -C(=0)NR ^a R , a 5- to 10-membered aryl or heteroaryl a 5- to 10- mernbered spirocycioalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycioalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a -C=0 group , and the spiroheterocycloalkyl, or heterocycloalkyl may include a -S=0 or -SO?.;

R ¹¹ is independently selected from H, Ci-ehaloalkyi, -Ci-ealkyl, -Ci- ealkenylene, -(CH ₂ CH ₂ 0)nR ^a , -SQ ₂ R ^a , -C(=0)R ^a ,-C(=0)OR ^a , -C(=0)NR ^a R , -Ci- 6alkyl-Q-Ci-6aikyl, a 5~ to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycioalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycioalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a -C=0 group , and the spiroheterocycloalkyl, or heterocycloalkyl may include a -S=0 or SO?.;

each of R ^2A , R ^5A , R ^6A , R ^7A , R ^8A , R ^9A and R ^i0A is independently H, OH, halo, -Ci-6alkyl;

alternatively R ⁶ and R ⁷ together may form a 3- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;

alternatively R ⁶ and R ⁹ together may form a 5- to 8-membered ring, optionally containing a heteroatom selected from , O or S atom, which may contain a double bond;

alternatively R ⁶ and R ¹⁰ together may form a 5- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond; alternatively R ⁸ and R ⁹ together may form a 4- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;

alternatively R ⁸ and R ^{! 0} together may form a 3- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;

alternatively R ⁹ and R ^!0 together may form a 3- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond; and the ring optionally may be substituted by R ¹⁴ ;

wherein the -Ci-ealkyl of any of the R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^!0 , R ¹¹ , R ^2A , R ^6A , R ^7A , R ^8A , R ^9A and R ^!0A substituents is substituted by 0, 1 , 2 or 3 R ¹² substituents independently selected from OH, -OCi-6alkyl, -Ci-ealkyl-O-Ci-ealkyl, halo, -O-haloCi-ealkyl, -CN, -NR ^a R ^b , ^•• { \ R"R ^il R - ^" . -S0 ₂ R ^a , - i i i i ί GU I k - ( ^' ! ()}R ^a . ··()( { 0) -'. ·( { <)}<>R ^: ' -C(=0)NR ^a R ^b , ··() ·{ - io 10-membered heterocycloakvi), a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocycloalkyi group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyi group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyi group may include a -C=0 group , and the spiroheterocycloalkyl, or heterocycloalkyi may include a -S=0 or SO2;

wherein the aiyl, heteroaryl, cycloalkyl, heterocycloalkyi, spirocycloalkyl or spiroheterocycloalkyl group of any of the R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R", and R ¹² substituents can be unsubstituted or substituted with from 1 to 4 R ¹³ substituents independently selected from OH, halo, -NR ^c R ^a , -Ci-ealkyl, -OCi- ealkyi, -Ci-ealkyl-OH, -Ci~6alkyi-0-C i~6alkyl, -Ci-Aaloalkyl, -0-haloCi-6alkyl, - SO?.R ^c , -CN, -C(=0)NR ^c R ^d , ^■■ ( ^' ( )R ^■ ()(. ( () ) ^:: . -C(=0)OR ^c , a 5- to 10- membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or

spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bi cyclic heterocycloalkvl group, wherein the heteroaryl, spiroheterocvcloalkyl, or heterocycloalkvl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocvcloalkyl, or heterocycloalk l group may include a - OO group , and the spiroheterocvcloalkyl, or heterocycloalkvl may include a - S=0 or -SO?.:

wherein each R ^a , R ^b , R ^c , and R ^d is independently hydrogen, OH, -Ci- e.alkyl, -Ci-6alkyl-NR ^l4 R ¹⁴ , NR ¹⁴ R ¹⁴ , -SO2R ¹⁴ , -(CH ₂ CH ₂ 0)nCH3, -C(=0)R ^]4 , -CN, -OC(=0)R ¹⁴ , -C(=0)OR ¹⁴ . -C(=0)NR ¹ R ¹⁴ , -C.-ehaloalkyl, -O-haloC.-ealkyl, -Ci- 6alkyl~0-Ci-6alkyl, benzyl, phenyl, a -Ci-ealkyl-heterocycloalkyl, a 5- to 10- membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or

spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl, heterocycloalkyl group of the -Ci-6alkyl--- heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, or the heterocycloalkyl group of the -Chalky 1-heterocycloalkyl group may include a -C O group , and the spiroheterocycloalkyl, or

heterocycloalkyl may include a -S=0 or SO2; and

the aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl or the heterocycloalkyl group of the -Ci-6alkyl--heterocycloalkyl group of R ^a , R , R ^c , and R ^d can be unsubstituted or substituted with from 1 to 4 R ¹⁴ substituents independently selected from H, OH, halo, -Ci-ealkyl, -OCi-ealkyl, -Ci-6haloalkyl, -CN, -O-haloCi-ealkyl, phenyl, tolyl, -C(0)Ci-6alkyl, -C(0)OCHs and -SO -NiCi I . )··.

wherein is independently in each instance an integer from 1 to 4; and wherein at least one of the following is true:

a) A is N; or

b) Z is O or N; or

c) Q is S; or d) V is O or N; or

e) W is O or N; or

f) at least one of R ² and R ^2A is independently OH, halo, -Ci-eaikyl: or g) v is 1 or 2; or

h) w is 0; or

i) w is 2; or

j) w is 1 and R ^J is -Ci-bhaloalkyl, -Ci-6alkyl, -Ci-6alkenylene, -

(CH ₂ CH ₂ 0)nR ^a , -S0 ₂ R ^a , -C(=0)R ^a ,-C(=0)OR ^a , or ~C(==0)NR ^a R ; or

i) R ⁸ is independently selected from alo, -Ci-ehaloalkyl, -Ci-ealkyi, -Ci- 6alkenylene, -(CH ₂ CH ₂ 0)„R ^a , -S0 ₂ R ^a , -C(=0)R ^a ,-C{ <))<>ΗΛ - C(=0)NR ^a R , a 5- to 10-membered aryl or heteroarv'l, a 5- to 10- membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10- membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalk}'! or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a -Ο group , and the spiroheterocycloalkyl, or heterocycloalkyl may include a -S=0 or S0 ₂ ; or

m) R ^8A is independently selected from OH or halo; or

n) z is 0; or

o) q is 0; or

p) q is 2; or

q) when q is 1, R ¹⁰ is independently selected from halo, -Ci-ealkyl-OH, - Ci-ehaloalkyl, -Ci-ealkenylesne, -(CH ₂ CH ₂ 0) _n R ^a , -S0 ₂ R ^a , -C(==0)R ^a ,- C(=0)OR ³ , -C(=0)NR ^a R , a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkvl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the spirocvcloalkyl, spiroheterocycloalkyl, or heterocycloalkvl group may include a -C=0 group, and the spiroheterocycloalkyl, or

heterocycloalkyi may include a -S ^:: =0 or SO2; or

r) when q is 1, R ^10A is independently selected from OH or halo; or s) when A is C, R ^9A is independently selected from OH or halo; or t) R ⁹ is independently selected from halo, -Ci-ealkyl-OH, -Ci-ehaloalkyl, - Ci-ealkenylene, -(CH ₂ CH ₂ 0)nR ^a , -S0 ₂ R ^a , -C(=0)R ^a ,-C(=0)OR ^a , - C(=Q)NR R ^b , a 5- to 10-membered and or heteroaryl, a 5- to 10- membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10- cycloalkenyl, monocyclic or bi cyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyi group, where the heteroaryl,

spiroheterocycloalkyl or heterocycloalkyi group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyi group may include a -C=0 group, and the spiroheterocycloalkyl, or

heterocycloalkyi may include a -S=0 or SO2; or

u) a is a double bond; or

v) c is a double bond; or

w) d is a double bond; or

x) e is a double bond; or

y) a and c are each double bonds; or

z) R ⁷ and R ^7A together represent =0; or

aa) when Y is (), then R ⁿ is not H, Ci-ealkyl, or -((;¾<□¾.())£¾; or bb) Q is S; or

cc) when A is CR ^9A , R ⁹ and R ^9A together form =CH ₂ or R ⁷ and R ^7A

together form a =0; or

dd) each R ⁵ and R' ^A is H; or ee) when R ^u is H, unsubstituted Ci-oaikyl, or ~(CH ₂ CH20)nC¾ at least one of R ⁸ , R ⁹ , R ¹⁰ , R\ R ^{? A} . R ^6A , R ^7A , R ^8A , R ^9A and R ^10A is not H, Ci- c.alkyi, 3-6- membered cycloalkvl, or (CH2)n-3-6-membered cycloalkyl.

In another embodiment, the present invention provides compounds having the Formula Π:

or a pharmaceutically acceptable salt, thereof; wherein R ¹ , R , R ^J , R ⁴ , R ⁶ , R\ R ⁹ , R ¹⁰ . R ¹¹ , R" ^A , R ^SA , R ^9A and R ^10A are defined above.

In another embodiment, the present invention provides compounds having the Formula I la:

or a pharmaceutically acceptable salt thereof; w herein R R ² , R ³ , R ⁴ , R'\ R ⁷ . R ⁸ , R ⁹ . R ¹⁰ . R ^u , R ^2A , R ^SA , R ^9A and R ^10A are defined above.

In another embodiment, the present invention provides compounds having the Formula III:

or a pharmaceutically acceptable salt thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^{5 i} , R ^2A , R ^6A , R ^7A , R ^8A , R ^9A and R ^10A are defined above.

in another embodiment, the present invention provides compounds havine the Formula Ilia:

or a pharmaceutically acceptable salt thereof; wherein R ¹ , R- , R\ R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R"\ R ^6A , R ^7A , R ^8A , R ^9A and R ^30A are defined above.

In another embodiment, the present invention provides compounds having the Formula IV:

or a pharmaceutically acceptable salt thereof; wherein RA R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁵ , R ⁹ , R ¹⁰ , R ^6A , R ^9A and R ^l0A are defined above.

In another embodiment, the present invention provides compounds having the Formula V:

or a pharmaceutically acceptable salt thereof; wherein R ¹ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ^y , R ⁱ⁰ , R ¹¹ , R ^8A , and R ^10A are defined above. In another embodiment, the present invention provides compounds having

R ¹¹ , R ^8A , and R ^10A are defined above.

In another embodiment, the present invention provides compounds other than a compound of Formula I, wherein the compounds have the Formula VI:

or a pharmaceutically acceptable salt thereof;

wherein g, represented by the symbol ------ is a single or double chemical bond which may be cis or trans;

R ^B is a halo;

R ^1B is H, Ci-ealkyi , or -(CH2CH20)jCH3, wherein j is an integer from 1 to

4;

R ^B is H or Ci-6alkyl;

R- ^c - is H or Ci-ealkyl;

R ^3B is H or C i-6alky and

R ^3C is H, Ci-6alkyl, Cs-6 cycloalkyl, or (CH2)k-C3- Cycioalkyl, wherein k is ait integer from 1 to 4.

in another embodiment, the present invention has a structure selected from:

or a stereoisomer thereof; a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof and a pharmaceutically acceptable excipient.

In another embodiment, the present invention has a structure selected from:





and or a stereoisomer thereof; a pharmaceutically acceptabie salt thereof, a pharmaceuti cally acceptable salt of the stereoisomer thereof.

In another embodiment, the present invention has a pharmaceutical composition comprising the compound of the present invention or a

pharmaceutically acceptable stereoisomer thereof, or pharmaceutically acceptable salt thereof or stereoisomer of the salt thereof, and a pharmaceutically acceptable carrier or diluent.

In another embodiment, the present invention is a method of treating cancer, the method comprising: administering to a patient in need thereof a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a method of treating cancer, wherein the cancer is a hematologic malignancy.

In another embodiment, the present invention is a method of treating cancer, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

In another embodiment, the present invention is a method of treating cancer, wherein the cancer is multiple myeloma.

In another embodiment, the present invention is a method of treating cancer, further comprising administering to the patient in need thereof a therapeutically effective amount of an additional pharmaceutically active

compound.

In another embodiment, the present invention is a method of treating cancer, wherein the additional pharmaceutically active compound is carfilzomib.

In another embodiment, the present invention is a use of a compound of the present invention for treating cancer in a subject.

In another embodiment, the present invention is a use of a compound of the present invention in the preparation of a medicament for treating cancer.

In another embodiment, the present invention is a method of treating cancer, wherein the cancer is a hematologic malignancy .

In another embodiment, the present invention is a method of treating cancer, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

In another embodiment, the present invention is a method of treating cancer, wherein the cancer is multiple myeloma.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitabl e methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the disclosure will be apparent from the following detailed description and figures, and from the claims.

DETAILED DESCRIPTION

The symbol "-" represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol - is commonly used to represent a methyl group in a molecule.

As used herein, chemical structures which contain one or more

stereocenters depicted with dashed and bold bonds (i.e., and -— ) are meant to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure. As used herein, bonds symbolized by a simple line do not indicate a stereo-preference. Unless otherwise indicated to the contrary, chemical structures that include one or more stereocenters which are illustrated herein without indicating absolute or relative stereochemistry encompass all possible stereoisomeric forms of the compound (e.g., diastereomers, enantiomers) and mixtures thereof. Structures with a single bold or dashed line, and at least one additional simple line, encompass a single enantiomeric series of all possible diastereomers.

As used herein, the term "about" is meant to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term "about," whether or not the term is explicitly used, unless explicitly stated otherwise. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "alkyl" means a straight or branched chain hydrocarbon.

Representative examples of aikyi groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyi, sec-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as C i-s alkyl.

The term "compound", as used herein is meant to include all

stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates).

The term "cycloalkyl" means a cyclic, nonaromatic hydrocarbon.

Representative examples of cycloalkyl groups include cyc!opropy!, cyclobutyl, cyciopentyl, cyciohexyi and cycloheptyl. A cycloalkyl group can contain one or more double bonds. Representative examples of cycloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and

cyclobutadienyl. Common cycloalkyl groups are C3-8 cycloalkyl groups.

The term "excipient", as used herein, means any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient. Handbook of Pharmaceutical Excipients, 5 ^th Edition, R.C. Rowe , P.J. Sheskey, and S.C. Owen, editors, Pharmaceutical Press, 2005, Hardback, 928, 08536961 87.

For the terms "for example" and "such as" and grammatical equivalences thereof, the phrase "and without limitation" is understood to follow unless explicitly stated otherwise.

The term "halogen" or "halo" means F, CI, Br or I The term "oxo", when used as a substituent, means the =0 group, which is typically attached to a carbon atom.

The term "patient" means subjects including animals, such as dogs, cats, cow's, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.

The term "patient in need" means a patient having, or at risk of having, one or more diseases or conditions where the Mcl-l protein is involved, such as cancers. Identifying a patient in need can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

The phrases "parenteral administration" and "administered parenteraily" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, i traarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection, and infusion.

Compositions suitable for parenteral injection may comprise

physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The term "pharmaceutically acceptable" is employed herein to refer to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical j udgment, suitable for administration to a patient, commensurate with a reasonable benefit/risk ratio.

The phrase ^" 'pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein the language "pharmaceutically acceptable carrier" includes buffer, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (! ) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted β- cyciodextrin; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (1 1 ) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol ; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyroge -free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions provided herein are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

The term "pharmaceutically acceptable salt" refers to the relatively nontoxic, inorganic and organic acid addition salts of a compound provided herein. These salts can be prepared in situ during the final isolation and purification of a compound provided herein, or by separately reacting the compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1 -19. )

The term "substituted" means that a hydrogen atom on a molecule or group is replaced with a group or atom. Typical substitutents include: halogen, Ci-salkyl, hydroxyl, Ci -salkoxy, -NR ^X R ^X , nitro, cyano, halo or perhaloCi-ealkyl, Osalkenyl, Osalkynyl, -SR ^X , S{ <)}:R". C( ()}( )R\ C< (»R\ wherein each R ^x is independently hydrogen or Ci-Cs alkyl . It is noted that when the substituent is -NR ^X R ^X , the R ^x groups may be joined together with the nitrogen atom to form a ring.

A group or atom that replaces a hydrogen atom is also called a substituent.

Any particular molecule or group ca have one or more substituent depending on the number of hydrogen atoms that can be replaced.

The phrases "systemic administration", "administered systemically", "peripheral administration", and "administered peripherally" as used herein mean the administration of a ligand, drug, or other material via route other than directly into the central nervous system, such that it enters the patient's system and thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

The term "therapeutically effective amount" means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular di sease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.

The terms "treating", "treat" or "treatment" and the like include preventative (e.g., prophylactic) and palliative treatment. The methods provided herein include the manufacture and use of pharmaceutical compositions, which include one or more of the compounds provided herein. Also included are the pharmaceutical compositions themselves.

In some embodiments, a compound provided herein may contain one or more acidic functional groups and, thus, is capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term

"pharmaceutically acceptable salts" in these instances refers to the relatively nontoxic inorganic and organic base addition salts of a compound provided herein. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethvlamine, ethvlenediamme, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives and antioxida

Examples of pharmaceutically acceptable antioxidants include: ( ! ) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl paimitate, butyiated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gall ate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

A pharmaceutical composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include tonicity - adjusting agents, such as sugars and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of one or more compounds provided herein, it is desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. For example, delayed absorption of a parenteral!}' administered compound can be accomplished by dissolving or suspending the compound in an oil vehicle.

The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal deliver '. The dose of the compound or composition can be varied over time. All combinations, deliver}' methods and administration sequences are contemplated.

The compounds of the present invention and in some embodiments, other additional pharmaceutically active compounds, can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally, mtravaginaily, intraperitoneally,

intravesica!ly, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.

Compositions prepared as described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art. For example, where the compositions are to be administered orally, they may be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, they maybe formulated as injections (intravenous, intramuscular, or subcutaneous), drop infusion preparations, or suppositories. For application by the ophthalmic mucous membrane route, they may be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means in conjunction with the methods described herein, and, if desired, the acti ve ingredient may be mixed with any conventional additive or excipient, such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, or a coating agent.

Formulations suitable for oral administration may be in the form of capsules (e.g., gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, troches, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes, and the like, each containing a predetermined amount of a compound provided herein as an active ingredient. A composition may also be administered as a bolus, electuary, or paste. Oral compositions generally include an inert diluent or an edible carrier.

Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of an oral composition. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient can be mixed with one or more pharmaceutically acceptable carriers, s uch as sodium citrate or dicalcium phosphate, and/or any of the following: (1 ) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, saccharin, glucose, mannitol, and/or silicic acid: (2) binders, such as, for example, carboxymethylcellulose, microcrystalline cellulose, gum tragacanth, alginates, gelatin, polyvinyl pyrrolidine, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato, com, or tapioca starch, alginic acid, Primogel, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, Sterotes, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) a glidant, such as colloidal silicon dioxide; (11) coloring agents; and (12) a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycol ate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.

Tablets, and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known i the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, microspheres, and/or nanoparticles. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opaciiying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.

Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, soiubiiizmg agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compound(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols,

poiyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Pharmaceutical compositions suitable for parenteral administration ca include one or more compounds provided herein in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. In one embodiment, the intravenous (IV) formulation consists of a composition containing hydroxypropyl beta cyclodextrin within a pH range between 8 - 10 as a buffered or unbuffered solution. The IV formulation can be formulated as a sterile solution ready for injection, a sterile solution ready for dilution into an IV admixture or a sterile solid for reconstitution. The API in the IV formulation may exist as a free acid/base or an in situ salt.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions provided herein include water for injection (e.g., sterile water for injection), bacteriostatic water, ethanol, polyois (such as glycerol, propylene glycol, polyethylene glycol such as liquid polyethylene glycol, and the like), sterile buffer (such as citrate buffer), and suitable mixtures thereof, vegetable oils, such as olive oil, injectable organic esters, such as ethyl oieate, and Cremophor EL™ (BASF, Parsippany, NJ). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The composition should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum raonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are freeze-diying (Ivophiiization), which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Injectable depot forms can be made by forming microencapsule or nanoencapsule matrices of a compound provided herein in biodegradable polymers such as polylactide-polyglycoiide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employ ed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes, microeniulsions or nanoemulsions, which are compatible with body tissue.

For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant (e.g., a gas such as carbon dioxide) or a nebulizer. Such methods include those described in U.S. Patent No. 6,468,798. Additionally, intranasal delivery can be accomplished, as described in, inter alia, Harnajima et al, Clin. Immunol Immunopathol., 88(2), 205-10 (1998). Liposomes (e.g., as described in U.S. Patent No. 6,472,375, which is incorporated herein by reference in its entirety), microencapsulation and nanoencapsulation can also be used. Biodegradable targetable microparticie deliver}' systems or biodegradable targetable nanoparticle delivery systems can also be used (e.g., as described in U.S. Patent No. 6,471,996, which is incorporated herein by reference in its entirety).

Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means. Dosage forms for the topical or transdermal administration of a compound provided herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active component may be mixed under sterile conditions with a

pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. For transmucosal or transdermal

administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The ointments, pastes, creams, and gels may contain, in addition to one or more compounds provided herein, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound provided herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohvdrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

A compound provided herein can be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing a compound or composition provided herein. A nonaqueous (e.g., fluorocarbon propeilant) suspension could be used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol can be made by formulating an aqueous solution or suspension of the agent together with con v entional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particul ar composition, but typically include nonionic surfactants (TWEEN ^® (polysorbates), PLURONIC ^® (poloxaraers), sorbitan esters, lecithin, CREMGPHOR ^® (polyethoxylates)), pharmaceutically acceptable co- solvents such as polyethylene glycol, innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

Transdermal patches have the added advantage of providing controlled delivery of a compound provided herein to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

The pharmaceutical compositions can also be prepared in the form of suppositories or retention enemas for rectal and/or vaginal delivery. Formulations presented as a suppository can be prepared by mixing one or more compounds provided herein with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, glycerides, polyethylene glycol, a

suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent. Formulations which are suitable for vaginal

administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and

microencapsulated deliver) _' - systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, poly gly colic acid, collagen, poiyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially (e.g., from Alza Corporation and Nova Pharmaceuticals, Inc.). Liposomal suspensions (including liposomes iargeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,81 1 , which is incorporated herein by reference in its entirety for all purposes.

The compounds of the present invention are used in the treatment of diseases, disorders or symptoms mediated by Mcl-1 inhibition. Examples of diseases, disorders or symptoms mediated by Mcl-1 inhibition include, but are not limited to, cancers. Non-limiting examples of cancers include breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myelogenous leukemia.

The cancers can include carcinomas (originating in the outer layer of cells of the skin and internal membranes, e.g., breasts, kidneys, lungs, skin): sarcomas (arising from connective tissue such as bone, muscle, cartilage, and blood vessels), and hematologic malignancies (e.g., lymphomas and leukemias, which arise in the blood or blood-forming organs such as the spleen, lymph nodes, and bone marrow). Cancer cells can include, for example, tumor cells, neoplastic cells, malignant cells, metastatic cells, and hyperplastic cells.

In an embodiment, the disease, disorder or symptom is a hyperproliferative disorder, e.g., a lymphoma, leukemia, carcinoma (e.g., renal, breast, lung, skin), multiple myeloma, or a sarcoma. In one embodiment, the leukemia is acute myeloid leukemia. In one embodiment, the hyperproliferative disorder is a relapsed or refractor}' cancer.

Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The specific dosage and dosage range depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. In some embodiments, the compositions provided herein can be provided in an aqueous solution containing about 0. 1 -10% w/v of a compound disclosed herein, among other substances, for parenteral

administration. Typical dose ranges can include from about 0.01 to about 50 mg/kg of body weight per day, given in 1 -4 divided doses. Each divided dose may contain the same or different compounds. The dosage will be a

therapeutically effective amount depending on several factors including the o v erall health of a patient, and the formulation and route of administration of the selected compound(s).

Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about G.001%-100% active ingredient, in one embodiment from about 0.1 to about 95%, in another embodiment from about 75 to about 85%. Although the dosage will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, in general, a daily dosage of from about 0.01 to about 3,000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose or in divided doses. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

The pharmaceutical composition may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular patient specific dosage regimens should be adj usted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

The precise time of administration and/or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc. However, the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the patient and adjusting the dosage and/or timing

The compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds or agents. The other pharmaceutically active compounds/agents can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds or agents, the compounds can be administered simultaneously, or sequentially .

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used in combination with one or more additional pharmaceutically active compounds/agents.

One or more additional pharmaceutically active compounds or agents may be administered separately, as part of a multiple dose regimen, from the compound of Formula T (e.g., sequentially, e.g., on different overlapping schedul es with the administration of one or more compounds of Formula I (including any subgenera or specific compounds thereof). In other embodiments, the one or more additional compounds/agents may be part of a single dosage form, mixed together with the compound of Formula I in a single composition. In still another embodiment, the one or more additional compounds/agents can be given as a separate dose that is administered at about the same time that one or more compounds of Formula I are administered (e.g., simultaneously with the administrati on of one or more compounds of Formula I (including any subgenera or specific compounds thereof). Both the compound of Formula I and the one or more additional compounds/agents can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

In a particular embodiment, the additional pharmaceutically active compound/agent is a compound or agent that can be used to treat a cancer. For example, the additional pharmaceutically active compound/agent ca be selected from antineoplastic agents, anti-angiogenic agents, chemotlierapeutic agents, and peptidal cancer therapy agents. In another embodiment, the antineoplastic agents are selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, kinase inhibitors, proteasome inhibitors, and combinations thereof. It is noted that the additional pharmaceutically active compound/agent may be a traditional small organic chemical molecule or can be a macromolecule such as a protein, antibody, peptibody, DNA, R A or a fragment of such macroniolecules.

Examples of additional pharmaceutically acti v e compounds/agents that can be used in the treatment of cancers and that can be used in combination with one or more compounds of the present invention include: acemannan; aclarubicin; aldesleukin; ali tretinoin; amifostine; amrubicin; amsacrine; anagrelide; argiabin; arsenic trioxide; BAM 002 (Novelos); bicalutamide; broxuridine; celmoleukin; cetrorelix; c!adribine; clotrimazole; DA 3030 (Dong- A); daclizumab; denileukin diftitox; deslorelin; dilazep; docosanol; doxercalciferol; doxifluridine;

bromocriptine; cytarabine; HIT diclofenac; interferon alfa; tretinoin; edelfosine; edrecoiomab; eflornithine; emitefur; epirubicin; epoetin beta; etoposide phosphate; exisulind; fadrozole; finasteride; fludarabine phosphate; formestane; fotemustine; gallium nitrate; gemtuzumab zogamicin; gimeracil/oteracil/tegafur combination; glycopine; gosereim; heptapiatin; human chorionic gonadotropin; human fetal alpha fetoprotein; ibandronic acid; interferon alfa; interferon alfa natural; interferon alfa-2; interferon alfa-2a; interferon alfa-2b; interferon alfa-Nl ; interferon alfa~n3; interferon alfacon-l ; interferon alpha natural; interferon beta; interferon beta-la; interferon beta-lb; interferon gamma natural; interferon gamma- la; interferon gamma- l b; interleukin-1 beta; iobenguane; irsogladine; lanreotide; LC 9018 (Yakult); leflunomide; lenograstim; lentinan sulfate;

letrozole; leukocyte alpha interferon; leuproreim; levamisole+fluorouracil;

liarozole; lobaplatin: lonidamine; lovastatin; masoprocol: melarsoprol;

metoclopramide; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitoxantrone; molgramostim; nafarelin; naloxone+pentazocine; nartograstim: nedaplatin; nilutamide; noscapine; novel eiythropoiesis stimulating protein; NSC 631570 octreotide; oprelvekin; osaterone; paciitaxel; pamidronic acid; peginterferon alfa-2b; pentosan polysulfate sodium; pentostatin; picibanil; pirarubicin; rabbit antithymocyte polyclonal antibody; pol ethylene glycol interferon alfa-2a; porfimer sodium; raltitrexed; rasburicase; rhenium Re 186 etidronate; RII retinamide; romurtide; samarium (153 Sm) lexidronam; sargramostim; sizofuran; sobuzoxane; sonermin; strontium-89 chloride; suramin; tasonermin; tazarotene; tegafur; temoporfin: teniposide;

tetrachlorodecaoxide; th malfasin; thyrotropin alfa; toremifene; tositumomab- iodine 1.31 ; treosulfan; tretinoin; trilostane; trimetrexate; triptorelin; tumor necrosis factor alpha natural; ubenimex; bladder cancer vaccine; Maruyama vaccine; melanoma lysate vaccine; valrubicin; verteporfin; virulizin; zinostatin stimalamer; abarelix; AE 941 (Aeterna); ambarnusiine; antisense oligonucleotide; bcl-2 (Genta); APC 8015 (Dendreon); dexaminoglutethimide; diaziquone; EL 532 (Elan); EM 800 (Endorecherche); enil uracil; etanidazole; fenretinide;

galocitabine: gastrin 17 immunogen; HLA-B7 gene therapy (Vical); granulocyte macrophage colony stimulating factor; histamine dihydrochloride; ibritumomab tiuxetan; ilomastat; IM 862 (Cytran); interleukin-2; iproxifene; LDI 200

(Milkhaus); leridistim; lintuzumab; CA 125 monoclonal antibody (MAb)

(Biomira); cancer MAb (Japan Pharmaceutical Development); HER-2 and Fc MAb (Medarex); idiotypic 105AD7 MAb (CRC Technology); idiotypic CEA

MAb (Trilex); LYM-1 -iodine 13.1 MAb (Technic] one); polymorphic epithelial mucin-yttrium 90 MAb (Antisoma); marimastat: men og aril: mitumomab;

motexafin gadolinium; MX 6 (Galderma); noiatrexed; P 30 protein; pegvisomant; porfiromycin; prinomastat; RL 0903 (Shire); rubitecan; satraplatin; sodium phenylacetate; sparfosic acid; SRL 172 (SR Pharma); SU 5416 (SUGEN); TA 077 (Tanabe); tetrathioniolvbdate; thaiiblastine; thrombopoietin; tin ethyl etiopurpurin; tirapazamine: cancer vaccine (Biomira); melanoma vaccine; melanoma oncolysate vaccine; viral melanoma cell lysates vaccine; valspodarl; fluorouracil; 5- fluorouracil; paeitaxel ; imatinib; altretamine; ciadibrine; cyclophosphamine; decarazine; irinotecan; mitosmycin; mitoxane; topotecan; vinoreibme; adriamycin; mithram; imiquimod; alemtuzmab; exemestane; hevacizumah; cetuximab;

azacitidine; clofarabine; decitabine; desatinib; dexrazoxane; docetaxel; epirubicin; oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole; gefitimb; gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatinib; lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib; nilotinib; pegasparga.se; pemetrexed;

rituximab; dasatinib; thalidomide; bexarotene; tenisirolimus; bortezomib;

carfilzomib(published in WO2006017842); oprozomib (WG2007056464);

vorinostat; capecitabine; zoledronic acid; anastrozole; sunitinib; aprepitant and nelarabine, or a pharmaceutically acceptable salt thereof.

Additional pharmaceutically active compounds/agents that can be used in the treatment of cancers and that can be used in combination with one or more compound of the present invention include: epoetin alia; darbepoetin alfa;

panitumumab; pegfilgrastim; paiiferniin; filgrastim; denosumab; ancestim; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951 ; and AMG 706, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a composition provided herein is conjointly administered with a chemotherapeutic agent . Suitable chemotherapeutic agents may include, natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vmorelbine), paclitaxei, epidipodophyilotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithrarttycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine), antiplatelet agents,

antiproliferative/antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethyienimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dmaciciih, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busuifan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative/antimitotic antimetabolites such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum

coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium buly ate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zaiypsis), PI3K delta inhibitor (e.g., GS-1 10 ! and TGR-1202), PI3K delta and gamma inhibitor (e.g., CAL-130), multi-kinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists such as leutinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF- neutralizing antibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GR 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), aiiti-CSl (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P 13K / Akt inhibitors (e.g., perifosine), Akt inhibitor (e.g., GSK- 2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD .138 (e.g., BT062), Torcl/2 specific kinase inhibitor (e.g. , INK128), kinase inhibitor (e.g., GS-1101), ER/UPR targeting agent (e.g., MKC-3946), cFMS inhibitor (e.g., ARRY-382), JAK1/2 inhibitor (e.g., CYT387), PARP inhibitor (e.g., olapanb and veliparib (ABT-888)), BCL-2 antagonist. Other chemotherapeutic agents may include mechlorethamine, camptotheein, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafemb, or any analog or derivative variant of the foregoing.

The compounds of the present in vention may also be used in combination with radiation therapy, hormone therapy, surgery and immunotherapy, which therapies are well known to those skilled in the art.

in certain embodiments, a pharmaceutical composition provided herein is conjointly administered with a steroid. Suitable steroids may include, but are not limited to, 21 -acetoxy regnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deffazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortoione, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisoiide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone,

fluorometholone, fluperolone acetate, flupredmdene acetate, fluprednisoione, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, haiometasone, hydrocortisone, loteprednol etabonate, raazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25- diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and/or derivatives thereof. In a particular embodiment, the compounds of the present invention can also be used in combination with additional pharmaceutically active agents that treat nausea. Examples of agents that can be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and

prochlorperazine; or a pharmaceutically acceptable salt thereof.

As one aspect of the present invention contemplates the treatment of the disease/conditions with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium,

tetraethyiammomum, methyiamine, dimethylamine, trimetliyiamine,

triethyl amine, ethylamine, and the like. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1 -19 (1977).

The term "prodrug" means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drags as Novel Deliver}' Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

To illustrate, if the compound of the invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-Ce alkyl, (C ₂ - Cl ₂ )alkanoyloxy methyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms,

alkoxycarbonyloxy methyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkOxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C ₂ )alkylamino(C ₂ - C ₃ )alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C ₂ )alkyl, N,N-di(Ci- C2)alkylcarbaraoyl-(Ci-C2)alkyl and piperidino-, pyrrolidine- or morpholino(C2- 3)alkyl. Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-Cr alkanoyloxymethyl, l-((Ci- C6)alkanoyloxy)ethyl, l-memyl-l-((Ci-C6)alkanoyloxy)e1hyl, (Ci- Cejalkoxycarbony oxymethyl, N-(Ci-C6)alkoxycarbonylarrunomethyl, succinoyl, (Ci-C6)alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and ot-aminoacyi, or a- aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(0)(OH) ₂ , -P(0)(0(Ci-C6)alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxy! group of the hemiacetal form of a carbohydrate).

The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both th e cis and trans forms (designated as Z and E, respectively), as well as mixtures, are contemplated.

Mixture of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods such as chromatography and/or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding re enantiomers.

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms. It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. Those skilled in the art will recognize that the compound names and structures contained herein may be based on a particular tautomer of a compound. While the name or structure for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the present invention, unless stated otherwise.

It is also intended that the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

The compounds of the present invention may exist in various solid states including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.

EXAMPLES

The examples presented below illustrate specific embodiments of the present invention. These examples are meant to be representative and are not intended to limit the scope of the claims in any manner.

The following abbreviations may be used herein:

DBU l,8-diazabicydoj 5A0]undec-7-ene

DCE Dichloroethane

DCM Dichloromethane

DEA Diethylamine

Dess-Martin 1,1,1 -triacetoxv- 1 , 1 -dihydro- 1 ,2-benziodoxol-3 - penodinane; (lH)-one

DIEA or DIPEA Dii sopropy lethy lamine

DMAP 4-dimethylaminopyridme

DMF N,N-dimethylforniamide

DMSO dimethyl sulfoxide

N-ethyl-N'-(3-

EDC

dimethylaminopropyl)carbodiimide

ee or e.e. enantiomeric excess

eq Equivalent

ESI or ES electrospray ionization

Et Ethyl

EtoO diethyl ether

EtOAc ethyl acetate

Em triethylamine

EtOH ethyl alcohol

g gram(s)

GC gas chromatography

h hour(s)

Ή NMR proton nuclear magnetic resonance spectroscopy

Ih hydrogen gas

] ! ·■() Water

H2SO4 sulfuric acid

l-fBis(dimethylamino)methylene]-lH-l,2,3-

HATU

triazo3o| 4,5-b|pyridinium 3-oxid hexafluorophosphate

HC1 hydrochloric acid

Hex hexane(s)

HPLC high performance liquid chromatography

IP intraperitoneal

IPA isopropyl alcohol

IPAc isopropyl acetate

K2CO3 potassium carbonate

K3PO4 potassium phosphate

F Karl Fischer titration

KHMDS potassium hexamethyldisilazide

KOAc potassium acetate

KOH potassium hydroxide

L liter(s)

LAH lithium aluminium hydride

LCMS, LC-MS or

liquid chromatography mass spectrometr ' LC/MS

LiHMDS lithium hexamethyldisilazide

LiOH lithium hydroxide

M mol ar (mol L ^"1 )

Me methyl

MeCN acetonitrile

Mel iodomethane

MeOH methyl alcohol

MeTHF methy Itetrahy drof uran

mg miliigram(s)

MgS04 magnesium sulphate

min minute(s)

mL milliliter(s) MS mass spectrometry

MSA methanesulfonic acid

MsCl meth anesulfony 1 chl oride

MTBE methyl tert-butyl ether

m/z mass-to-charge ratio

N Normality (Eq/L)

N2 nitrogen gas

NaCl sodium chloride

Na ..< () :. sodium carbonate

NaHCOs sodium bicarbonate

NaH ₂ P0 ₄ sodium dih drogen phosphate

NaNO sodium nitrite

NaOH sodium hydroxide

NaQtBu sodium tert-butoxide

\a -Sih sodium sulfate

Na ₂ S ₂ 0 ₃ sodium thiosulfate

NH3 ammonia, azane

NH4CI ammonium chloride

NH4OH ammonium hydroxide

NMP 1 -methyl-2-pyrrolidinone

NMR nuclear magnetic resonance spectroscopy

PO per oral

POCI3 phosphor}"! chloride

PhMe toluene

ppm parts per million

QD once daily

QNMR quantitative NMR

BF round-bottomed flask

RT or rt or r.t. room temperature sat. or sat'd or satd Saturated

SFC supercritical fluid chromatography

Ss0 ₂ silicon dioxide, silica

SOC12 thion l chloride

tBu tert but 4

TEMPO (2,2,6,6-tetramethylpiperidin-l-yl)oxidanyl

TFA triflouroacetic acid

THF Tetrahydrofuran

TLC thin layer chromatography

TsOH toluene sulfonic acid

v/v volume per volume

It is noted that when a percent (%) is used with regard to a liquid, it is a percent by volume with respect to the solution. Mien used with a solid, it is the percent with regard to the solid composition.

The following synthetic schemes show generally how to make intermediates and compounds of the present invention.

Compounds of the present invention generally can be prepared combining and further elaborating common advanced synthetic intermediates generated from commercially available starting materials, using synthetic techniques known to those of skill in the art. The syntheses of these common advanced intermediates are outlined below and further exempliiication is found in the specific examples provided. Common Advanced Intermediates

intermediate AA intermediate EE

Intermediate AA11A

(S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3',4 ₅ 4'.5-TETRAHYDRO-

2Η 2Ή-8ΡΙΚΟ[ΒΕΝΖΟ[Β] [1 ,4]ΟΧΑΖΕΡΙΝΕ-3, 1'-ΝΑΡΗΤΙ-ΙΑΙ,ΕΝΕ]-7- CARBOXYLIC ACID

STEP 1 : 6-CHLORO-3 ,4-DIHYDRONAPHTHALEN - 1 (2H)-ONE

A 1L beaker was charged with 6-amino-3,4-dihydro-l(2H)-naphthalenone (47.5 g, 1 eq), H ₂ 0 (250 mL), and concentrated HC1 (57 mL). The mixture was stirred with a plastic straw until dissolution and cooled to <0 °C. NaN0 ₂ (22.4 g) solution in H2O (45 mL) was added dropwise to the 6-aminotetralone HCT solution, while manually stirred, maintaining the temperature below 0 °C to give a dark red solution, which was used directly for chlorination. To a 2L 4-necked round bottom flask with open necks was added cuprous chloride (99 g, 1002 mmol) and concentrated HC1 (393 mL, 4715 mmol) to give a dark solution which was cooled to 0 °C. The diazotized solution (starting with 6- aminotetraione 95 g) was added portion-wise into the CuCl/HCl solution, maintaining the temp below 10 °C. The resulting dark reaction mixture was allowed to warm to ambient temperature, stirred for 1 li and poured into a separately funnel with DCM (150 mL). After partition, the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with H2O (75 ml,). To the DCM stream was added saturated NaHCCb (100 mL) and Darco (15 g), the mixture was stirred for 15 min and then filtered through a celite pad. The layers were separated and the aqueous was washed with DCM (30 mL). The organic la ers were combined and concentrated to give a brown oil, which could be used directly in the next step. The batch could be further purified by filtration through a plug of sili ca gel (~ 100 g) rinsing with 10-50% EtO Ac/heptane followed by concentration to give the product as a brown oil (87.5 g, 82 % yield).

STEP 2: (R)-6-CHLORO-3,4-DmYDRO-2H-SPlRO[NAPHTHALENE-l ,2'- OXIRANE] AND (R)-6-CHLORO-3,4-DIHYDRO-2H-

SPIRO [NAPHTHALENE- 1 ,2"-OXIRANE]

A 2L 4-necked RBF was charged 6-chloro-3,4-dihydro-l(2H)- naphthalenone (123 g, 681 mmol), trimethylsulfonium iodide (143 g, 701 mmol) and DMSO (1100 mL, 8.94 mL/g). Potassium hydroxide (76 g, 1362 mmol) (pellets) was added. The suspension was stirred at ambient temperature for 2 days after which time crude ¾ NMR showed no remaining starting material. The solution was poured into 800 g of crushed ice, rinsed with MTBE (200 mL) and an additional portion of MTBE (700 mL) was added. The resulting mixture was stirred for 5 min. and after partition the bottom aqueous layer was extracted with MTBE twice (500 mL, 300 mL) and combined with the main MTBE extract. The combined organic stream was washed with brine (2X600 mL) and 330 g of AI2O3 (neutral) was added. The resulting suspension was stirred for 5 min. at 22 °C, filtered and washed with MTBE (400 mL). The filtrate was concentrated to give the title compound as a red viscous oil (125 g , 94%).

STEP 3: (S)-6-CHLORO- 1 ,2,3 ,4-TETRAHYDRONAPHTH ALENE- 1 - C ARB ALDEHYDE AND (R)-6-CHLORO- 1 ,2,3,4-

TETRAHYDRON APHTHALENE-1 -C ARB ALDEHYDE

A 3L 3-necked RBF was charged with racemic 6-chloro-3,4-dihydro-2H- spiro| naphthalene- l,2'-oxirane] (160 g, 822 mmol) and THF (1760 mL, 1 1 niL/g).

After the batch was cooled to -8 °C with a dry ice/IP A bath, boron trifluoride diethyl etherate (5.07 mL, 41.1 mmol) was added over ~ 3 min. An exotherm raised the batch temp to 10 °C instantly. The batch was stirred at -5 to 0 °C for 5 min, and LC analysis of a sample (quenched into coid NaHCCb solution) showed complete conversi on. The reaction was quenched by the addition of saturated NaHCOs (300 mL) at -5 °C followed by MTBE (400 mL, 2.5 mL/g) and the mixture was transferred to a separatory funnel and rinsed with MTBE (240 mL, 1 .5 mL/g). After partition, the aqueous layer was discarded along with some white solid (likely boric acid or borax). The organic layer was washed with brine (350 mL) and concentrated under reduced pressure to give a red oil. The crude material was used directly in the next step. STEP 4: (6-CHLORO- 1 ,2,3,4-TETRAHYDRONAPHTH ALENE- 1 , ! - DIYL)DIMETHANOL H

Racemic 6-chloro- 1 ,2,3,4-tetrahy dro- 1 -naphthalenecarbaldehy de was charged onto a 3L 3-necked RBF and rinsed with di ethylene glycol (1000 mL, 5.88 mL/g). Formaldehyde 37% solution (652 mL, 8757 mmol) was added and the resulting biphasic emulsion was cooled to 5 °C with a dry ice/IP A bath.

Potassium hydroxide (45% aqueous solution, 652 mL, 11.9 mol) was added over -30 min, maintaining the temperature below 20 °C. After complete addition, the batch (20 °C) was slowly heated to 45 °C (Caution: Exothermic reaction) and aged for 1 h. HPLC showed complete conversion. Note: Some viscous insoluble iar was formed and it was removed prior to aqueous workup. To the hatch was added brine (500 mL) and the mixture was extracted with DCM until the product content in the aqueous phase was less than 5%. The combined DCM extract was concentrated to -750 mL as a red oil, washed with H2O (500 mL), and the product started to crystallize out. Separated the suspension + DCM and discarded the clear top aqueous layer. The bottom layer was stirred in ice/H^O bath for 30 mm, filtered and washed with DCM (-100 mL) and H2O (100 mL). The product was dried under dr ' air/vacuum to give a first crop (113 g, 498 mmol, 57 % yield). The DCM layer from the resulting mother liquor was separated and concentrated to 200-300 g (KF = 0.5%), seeded, and stirred in ice 1 120 bath for 30 min. The product was filtered, washed with DCM (-50 mL), and dried in dry air/vacuum to give a second crop (14.3 g, 63.1 mmol, 7 % yield) for a combined total yield of 6- chloro-L2,3,4-tetrahydronaphthalene-l,l-diyl)dimethanol of 127 g (64%).

STEP 5: (S)-(6-CHLORO-l-(HYDROXYMETHYL)-l,2,3,4- TETRAHYDRONAPHTHALEN- 1 -YL)METHYL 4-BROMOBENZO ATE

To a solution of 2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2- yl)pyridine (R,R-K g Catalyst) (1.57 g, 2.64 mmol) in dry DCM (450 mL), copper(II) chloride (0.355 g, 2.64 mmol) was added and the resulting green colored solution was stirred at room temperature for 1 h. This solution was added via cannula to solution of (6-chloro-l,2,3,4-tetrahydronaphthalene-l,l- diyl)dimethanol (30 g, 132.73 mmol) in dry DCM (800 mL). The resulting mixture was cooled to -78 °C and a light green colored precipitation was observed in the reaction after some time. A solution of 4-bromobenzoyl chloride (34.77 g, 158.79 mmol) in DCM (500 mL) was then added slowly followed by the dropwise addition of N-ethyl-N-isopropylpropan-2-amine (20 g, 154 mmol). The resulting reaction mixture was stirred at -78 °C for 3 h then it was quenched with pH 3 phosphate buffer (1 L) and warmed to ambient temperature with vigorous stirring. The mixture was then diluted with DCM (2 L) and the layers were separated. The organic phase was washed with pH 3 buffer (1 L), sat. NaHCCh (1 L), and brine (2 L) then it was dried over sodium sulfate, filtered and concentrated. The crude material thus obtained was purified by column chromatography over silica gel (100-200 mesh, 80% DCM in hexane) afforded pure (S)-(6-chloro-l- (hydroxymethyl)-l,2,3,4-tetrahydronap]vthalen-i-yl)methyl 4-bromobenzoaie (45 g, 84 %; e.r = 91.4:8.6 ChiralCel OD-H (250 mm x 4,6 mm); Mobile Phase: n- Hexane: IPA: 90: 10; Run Time: 20 min; flow rate: lml/min; sample preparation: IPA, Retention time (major peak)- 9.32 min; Retention time (minor peak)-! 1 .46 mm). R _f : 0.6 in 100% DCM.

STEP 6: (R)-(6-CHLORO-l-FORMYL-i,2,3,4-

TETRAHYDRONAPHTHALEN- 1 - YL)METHYL 4-BROMOBENZO ATE

To a stirred solution of (S)-(6-chloro- 1 -(hy droxymethyl)- 1 ,2,3,4- tetrahydronaphthalen-l-yl)methyl 4-bromobenzoate (100 g, 244.5 mmol) in DCM (2.5 L), Dess-Martin periodinane (121.4 g, 293.3 mmol) was added at 10 °C. The cooling bath was removed after addition and the reaction mixture was stirred for 30 min at ambient temperature. Water (9 mL) was then added and the resulting biphasic mixture was stirred further at ambient temperature for 30 min. The reaction mixture was then cooled to 0 °C and quenched with 2 L of a 1 : 1 mixture of 10% Na ₂ S ₂ 03 / Saturated NaHCCh solution. The reaction mixture was stirred further at ambient temperature for 10 min then the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 1,5 L). The combined organic layer was washed with 1 L of 10% Na_S ₂ 03 / Saturated NaHCCh solution and 1 L of brine then it was dried over sodium sulfate, filtered, and concentrated.

Purification of the residue by column chromatography over silica gel (100-200 mesh, 5% ethyl acetate/hexane) afforded (R)-(6-chloro-l -formyl-l , 2,3,4- tetrahydronaphtha]en-l -y])methyl 4-bromobenzoate (80 g, 81 %). Rf ; 0.7 in 10% ethyl acetate in hexane.

The enantiomeric purity of the title compound could be improved by the following procedure: (R)-(6-chloro- 1 -formyl-1 ,2,3,4-tetrahy dronaphthalen- 1 -yl)methyl 4- bromobenzoate (190 g) was added in toluene (950 mL) and heated to 50 °C to complete dissolution. The homogeneous solution was cooled to ambient temperature and seeded with racemic compound. The solution was cooled to -

25 °C and aged overnight. The mother liquor was then decanted and concentrated to afford 160 g of enantiomerically enriched (R)-(6-chloro-l-formyl-l,2,3,4- tetrahydronaphthalen~l-}'l)methyl 4-bromobenzoate (94% ee as determined by chiral HPLC). Chiral HPLC conditions: Column: ChiralCel OD-H (250 mm x 4.6 mm); Mobile Phase: n-Hexane:IPA : 90: 10. Run Time: 20 min. Flow rate: l ml/min. Sample preparation: ethanol. Retention time (major peak)- 8.488 min. (96.97%);

Retention time (minor peak)-9.592 min. (3.03%).

STEP 7: (R)-(6-CHLORO-l-(pIMETHOXYMETHYL)-l ₅ 2,3,4- TETRAH YD RON APHTH AL EN- 1 -YL)METH ANOL

To a solution of (R)-(6-chloro-l-formyl-l,2,3,4-tetrahydronaphthalen-l- yl)methyl 4-bromobenzoate (75 g, 183.8 mmol) in anhydrous MeOH (1 L\ p- toluene sulfonic acid (1 g, 9.2 mmol) and trimethyl orthoformate (58.4 mL, 551 mmol) were added and the reaction mixture was refluxed until the starting material was completely consumed (~ 4 h). The reaction mass was concentrated to 50% volume and diluted with THF (1 L) and IN NaOH (1 L, 1 mol). The resulting reaction mixture was stirred at 40 °C overnight then it was concentrated under reduced pressure and the residue was diluted with ethyl acetate (1 ,5 L). The aqueous layer was separated and extracted with ethyl acetate (2 x 500 mL) and the combined organic layers were washed with IN NaOH (1 L) and brine (1 L), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography over 100-200 mesh size silica gel (10% ethyl acetate/hex ane) affording pure (R)-(6-chloro-l-(dimethoxymethyl)-l , 2,3,4- tetrahydronaphthalen-l -yl)methanol as a light brown thick oil (44 g, 89%). Rr : 0. 5 in 30% ethyl acetate in hexane.

STEP 8: TERT-BUTYL-4-FLUORO-3-NITROBENZOATE

To a solution of 4-fluoro-3-nitrobenzoic acid (100 g, 540.2 mmol) in t- butanol (2.5 L), DMAP (13.18 g, 108.04 mmol) and di tert-butyl dicarbonate (248 mL, 1080.4 mmol) were added and the reaction mixture was heated at 40 °C overnight. On completion, the reaction mixture was diluted with water and the aqueous phase was extracted with ethyl acetate (3 x 1.5 L). The combined organic layer was washed further with water (Ix IL), brine (lx IL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography (100-200 mesh size silica gel, eluting with a gradient of 100% hexanes to 5% Ethyl acetate in hexanes) affording pure ¾ri-butyl-4-fluoro-3-nitrobenzoate (70 g, 54%) as light yellow solid. Rf: 0.5 in 5% ethyl acetate in hexane. STEP 9: (R)-TERT-BUTYL 4~((6~CHLORO~ l~(DIMETHOXYMETHYL)~ 1 ,2, 3 ,4-TETRAHYDRON APHTH ALEN- 1 -YL)METHOXY)-3-

NITROBENZOATE

A solution of (R)-(6-chloro-.l -(dimethoxymethyl)-l , 2,3,4- tetrahydronaphthalen-l-yl)rnethanol (70 g, 259.2 mmol) in dry THF (3.5 L) was cooled to 0 °C and LiHMDS (1 M in THF) (363 inL, 363 mmol) was added dropwise. After 5 min, a solution of tert-butyl 4-fluoro-3-nitrobenzoate (74.9 g, 311 mmol) in THF (500 ml.) was added dropwise via dropping funnel and the resulting mixture was warmed to ambient temperature. Upon completion (~1 h), the mixture was cooled to 0 °C, quenched with saturated NH4CI solution (1 L) and extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with MHUCl (1 L) and brine (1 L), dried over sodium sulfateand concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography using 100-200 mesh size silica gel (5% ethyl acetate/hexane) to afford (R)-tert-butyl 4-((6-chloro-l-(dimethoxymethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)methoxy)-3-nitrobenzoate as yellow thick oil (110 g, 87%» yield). Rf: 0.6 in 10% ethyl acetate in hexane

STEP 10A: (R)-4-((6-CHLORO-l-FORMYL-l,2,3 ₅ 4-

TETRAHYDRONAPHTH ALEN- 1 -YL)METHOXY)-3-NITROBENZOIC ACID

To a solution of (R)-tert-butyl 4-((6-chloro-l -(dimethoxymethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)methoxy)-3-nitrobenzoate (35 g, 71.25 inmol) in acetonitrile (1 L) erbium inflate (4.3 g, 7.1 mmol) and water (13 mL) were added. The resulting mixture was heated to 80 °C overnight. The solvent was then removed under reduced pressure and the residue was dissolved in diethyl ether (1.5 L) and washed with IN HCl (500 mL) and brine (500 mL). The organic layer was dried over NazSC t, filtered, and concentrated to afford (R)-4-((6-chloro-l- formy]-l ,2,3,4-tetrahy dronaphthalen- 1 -yl)methoxy)-3-nitrobenzoic acid (30 g) which was used without further purification. Rf: 0.15 in 30% ethyl acetate in hexane.

Alternatively, (R)-4-((6-chloro-l-formyl-l,2,3,4-tetrahydronaphthalen-l- yl)methoxy)-3-nitrobenzoic acid could be prepared from (6-chloro-l, 2,3,4- tetrahydronaphthalene-l,l-diyl)dimethanol (Step 4) as follows:

A 250 ml, 3-necked-round bottom flask was charged with copper (II) chloride (0.095 g, 0.02 equiv), 2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5- dihydrooxazol-2-yl)pyridine (0.42 g, 0.02 equiv) and THF (28.5 g, 4V). After inertion with N ₂ , the batch was stirred at 20 °C for 0.5 h. To the homogenous green solution was added (6-chloro-l,2,3,4-tetrahydronaphthalene-l,l- diyl)dimethanol (8.0 g, 1.00 equiv) followed by THF (14.2 g, 2V) and 4- methylmorpholine (3.75 g, 1.05 equiv). The reaction mixture was cooled to -

20 °C, and a solution of 1-napthoyl chloride (7.06 g, 1.05 equiv) in THF (21.3 g, 3 V) was added to the batch over 0.5 h maintaining the temperature below -15 °C. After aging at -20 °C for 20 h, an aliquot of the reaction slurry was sampled and assayed by HPLC (result in the table). The slurry was directly filtered through a glass-fritted funnel while maintaining the temperature at -20 °C. The filter cake was washed with two portions of cold (<-10 °C) THF (2 x 14.2 g, 2V) rinsed through the reaction vessel. The filter cake (4-methylmoipholine ^s HCl) was transferred to an appropriately labeled container. The mother liquor and washes were concentrated to a minimum volume and distiilative solvent swap by charging toluene until the batch volume is 6V and toluene/THF ratio is >98:2 (v/v) as measured by qNMR. To the batch at 20 °C was added heptane (11 g, 2V) and the slurry was heated to 85 °C (dissolution observed). The solution was cooled to 75 °C and charged with seed (0.27 g, 0.02 equiv). The slurry was cooled to 20 °C over 3 h and aged for >1 h. The batch was filtered through a glass-fritted filter and the cake was washed with toluene/heptane (3: 1 v/v) (11 g, 2 V) then toluene/heptane (1 : 1 v/v) (11 g, 2V). The cake was dried under N?. for 12 h at ambient temperature and the cake was assayed dry by QNMR (<! wt% toluene and heptane). The product was obtained as an off-white solid (8.75 g, 63% after wt adjustment).

A 60L jacketed reactor vented with a bleach scrubber was charged with (S)-(6-chloro-l -(hydroxymethyl)-l ,2,3,4-tetrahydronaphthalen-l -yl)m 1 - naphthoate (2.693 Kg, 88.6 wt%, 6.3 mol) followed by DCM (17,9 Kg, 5 vol) and EtN/ ^' Pr? (2.84 Kg, 3.5 equiv). After N ₂ inertion, the batch was agitated and cooled to 0 °C. To the alcohol slurry mixture in the reactor was added a solution of freshly prepared SCb'pyridine (2.10 Kg, 2.5 equiv of SCb'pyridine in 7.43 Kg, 3 vol. DMSO) over 30 min while maintaining the batch temperature below 15 °C. After addition, HPLC assay showed >99% conversion. The batch was quenched by the addition of water (14 L, 5 vol) over -20 min. maintaining the batch temperature below 15 °C and then toluene (16.8 L, 6 vol) was added. After partition, the organic layer was treated with water (14 L, 5 vol) and toluene (16.8 L, 6 vol). The top organic layer was washed wdth 2 N HC1 twice (14 L each, 5 vol) and brine (14 L, 5 vol). The organic layer was drained to a clean container, assayed by HPLC and then transferred back to the clea 60L reactor through an inline filter. The batch w¾s concentrated to a minimal volume and solvent switched to MeOH until the batch volume was 28 L (10 vol) and MeOH/toluene ratio was 3: 1 (v/v) as measured by QNMR. The batch was then transferred to a 30L jacketed reactor through an inline filter. After adjustment of the batch temperature to 30 °C, the batch w¾s seeded with the aldehyde (51 g, 0.02 equiv) as a slurr ' in MeOH (400 ml.). After the slurry was aged for 30 min at 30 °C, the batch was solvent switched by distillation with MeOH until the batch volume is 11 L (4 vol) and MeOH/toluene ratio is >99: 1 (v/v). The batch was then cooled to 5 °C and MeOH H ₂ 0 mixture (3.70 Kg MeOH + 1.34 Kg water) was added over 1 .5 h to bring the total solvent volume to approximately 5.5 vol and final

MeQH/H?0 to 90/10 (v/v). The batch was heated to 65 °C over 30 min. and cooled to 20 °C over 2 h and aged for ~ 2 h. The batch was filtered through an Aurora filter fitted with < 25 μπι filter cloth. The cake was washed with

MeOH/water (10: 1) (1 X2 vol)., then MeOH/water (2: 1 ) ( 1X2 vol). The cake was dried under N ₂ at ambient temperature for > 4 h until dry to give the product as an off-white solid (1.99 Kg, 72% after wt% adjustment).

A 3-necked 25( ⁾ mL RBF was charged with (R)-(6-chloro- 1-formy 1-1, 2,3,4- tetrahydronaphthalen-l -yl)methyl 1-naphthoate (10 g, 94,4 wt%, 95.3% LCAP, >99% ee), methanol (100 mi , }, trimethyl orthoformate (7 mL), and TsOH monohydrate (0.24 g). The RBF was inerted with ₂ , and started agitation. ^r riie batch was heated to 60 °C and aged for 2 h and HPLC assay showed >98% conversion.

The batch was concentrated under vacuum (-150-190 torr, external temp -40 °C) to minimal volume using a rotoevaporator. The batch was turned over to THF by charging THF three times (50 mL each time) and distilling under vacuum (-165 torr, external temp -40 °C). After each of the first two THF charges, the batch was concentrated down to a minimal volume, and after the last THF charge and distillation QNMR analysis of a sample showed the target ratio of >20/l THF/MeOH (v/v). LiOH monohydrate (10.46 g, 10 eq) and water (50 mL) were charged to the 3-necked 250mL RBF. The reaction mixture was heated to 65 °C and aged for 18 h. HPLC assay showed >99% conversion. The batch was cooled to 20 °C and transferred to a 500-mL separator}' funnel. MTBE (106 mL) was charged to the separatory funnel and shaken well. After settling for 5 min, the bottom aqueous layer was drained. The top organic layer was washed with 20%) K2CQ3 twice (32 mL and 11 mL). The batch was transferred to a 250mL RBF. Assay by HPLC showed <2% naphthanoic acid by-product. The batch was concentrated to a minimal volume at reduced pressure on the rotoevaporator (300 mbar, external temp -40 °C). The batch was turned over to THF using a rotoevaporator (-250 mbar, external temp -40 °C) by adding and distilling of THF (-50 mL, -50 mL). After each THF charge, the batch was distilled down to a minimal volume. THF (50 mL) was charged to the 250mL RBF. KF of a sample showed 0%, water (<0.1% acceptable). The batch was polish filtered (60mL medium-frit funnel) into a clean and dr ' 3 -necked 250mL RBF using THF (50 mL) for rinsing and volume adjusting. To the batch was added 4-fluoro-3- nitrobenzoic acid (4.61 g, 1.0 eq), the mixture was cooled to -20 °C and 20% potassium tert-butoxide THF solution (40 mL) was added over 1.5 h maintaining the batch temperature at - 20 ± 10 °C (exothermic). After complete addition, the batch was aged at -20 °C and an aliquot assayed by HPLC after 1.5 h showed 98% conversion. To the batch in the flask was added saturated NH4CI solution (10 mL) maintaining the temperature at -20 ± 10 °C followed by addition of water (20 mL) and MeTHF (34 mL) at -20 ± 20 °C, The mixture was warmed to 20 °C and agitated for 13 h. The batch was transferred to a separately funnel, allowed to settle for -5 min, and the bottom aqueous layer was removed keeping the rag with the organic stream. The top organic stream was washed with saturated NH4CI solution (10 mL) and water (20 mL) at 20 °C. After -5 min of settling, the aqueous layer was separated. To the total crude organic stream (KF=14%) was added MSA (4 mL) in a 250mL 3-necked RBF. The batch was heated to reflux (65 °C) for 25 h and LC assay showed full conversion (>97%).

The batch was cooled to <20 °C and Κ ₃ Ρ04Ή ₂ 0 (4.5 g) and water (7 mL) were added. The batch was transferred to a separatory funnel and the bottom aqueous layer was drained to give the aldehyde product crude solution. The combined organic crude stream was concentrated to minimum volume using a rotary evaporator. To the batch in a 500mL RBF was charged AcOH (-50 mL, -50 mL) and distilled using a rotary evaporator at reduced pressure (30 mbar, external temp -40 °C). The THF level was measured by qNMR and none was observed. The mixture was transferred to a 250mL 3-necked RBF and HO Ac was added to adjust the total volume to -40 mL, when ciystallization occurred. To the batch was added H2O (12 mL) over ~ 1 h. After aging for >1 h, LC assay of supernatant concentration was 9 mg/mL. If concentration is >10 mg/mL then a small portion of water (0.2 vol) can be added; after checking by LC, repeat if necessary. The batch was filtered, washed with 20% H ₂ 0/AcOH (23 mL) and dried under N ₂ /vacuum for 3.25 h to give the title compound (8.22 g) as an off- white solid (82% yield corrected for purity).

STEP 10B: (R)-TERT BUTYL 4-((6-CHLORO-l-FORMYL-l , 2,3,4- TETRAHYDRONAPHTHALEN-l-YL) ETHOXY)-3-NlTROBENZOATE

To a solution of (R)-tert-butyl 4-((6-chloro-l-(dimethoxymethyl)-l,2,3,4- tetTahydronaphthalen-l -yl)methoxy)-3-nitrobenzoate (lg, 2,033 mmol) in anhydrous acetone (41 ml.) was added amberlyst-15 (lg, 2.033 mmol; prewashed with 2 x 10 mL dry acetone). The mixture was heated to 50 °C for 3.5 h, then it was filtered and rinsed with DCM. The filtrate was concentrated and dried under high vacuum overnight (it turned a dark red color). LC/MS and NMR analysis suggested ~ 10% of corresponding carboxylic acid was present as well as 0.5 eq mesityl oxide. The mixture was advanced to the next step without further purification.

STEP 11 : (S)-6'-CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYL IC

ACID

A solution of crude (R)-4-((6-chloro-l-formyl-l,2,3,4- tetrahydronaphthalen-l -yl)methoxy)-3-nitrobenzoic acid (30 g, 77.10 mmol) in acetic acid (i L) was heated to 70 °C and iron powder (28 g, 500 mmol) was added. The resulting mixture was heated for 4 h at 70 °C. Acetic acid was then removed under reduced pressure and the residue was dissolved in DCE (1 L). Sodium triacetoxy borohydride (46.5 g, 740 mmol) was added portion-wise and the reaction mixture was stirred at ambient temperature for i h. The reaction was then quenched with water followed by 10% aqueous citric acid (500 mL). The aqueous phase was extracted with DCM (2 x 1 L) and the combined organic layer was washed with brine (500 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using 100-200 mesh size silica gel (40% ethyl acetate/hexane) to afford pure (S)- 6'-chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene] -7-carboxylic acid as white solid (24 g, 99% after two steps). RJ: 0.3 in 40% ethyl acetate in hexane.

Alternatively, (S)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][i,4]oxazepme-3, ~naphthalene]-7-carboxylic acid with ((1 S,4R)- 7 7-dimethyl-2-oxobicyclo|2.2.1]heptan-l-yl)niethanesuifonic acid (1 : 1) could be prepared as follows:

A pressure reactor was charged with (R)-4-((6-chloro- l -formyl- 1 ,2,3,4- tetrahydronaphthalen-l -yl)methoxy)-3-nitrobenzoic acid (20 g, 94 wt%), 5%Pf ^' S/C wet ( 2,2 g), THF (400 mL) and Ti( ()i Pr) . (0.5 mL). The reactor was then sealed, purged with inert gas (3 cycles, at least once with stirring) and then it was purged with H ₂ (1 cycle). The reactor was then pressurized with Hi to 70 psig, stirring (950 rpm) was initiated and the temperature was increased to 90 °C maintaining the H ₂ pressure in the reactor (70 psig at 22-30 °C, 80 psig at 50-60 °C and 90 psig at 88-91 °C). After 16 h the reactor was cooled to ambient temperature and purged with inert gas (3 cycles). HPLC analysis of the reaction confirmed > 98% conversion.

The reaction mixture was filtered through a Celite pad (2 inch) using additional THF for rinses, and the filtrate was concentrated under reduced pressure at 40 °C. To the residue was added IPA (60 mL) and 2-4% aqueous MeOH (10 mL), the mixture was stirred for 10 minutes and then it was filtered through a pad of Celite (2 inch). MeOH was evaporated under reduced pressure at 40 °C and to the concentrated IPA solution cooled to ambient temperature was added a solution of (+)-camphor-10-sulfonic acid (CSA, 56.0 g) in IPA (200 mL) dropwise over 2 h. After 10% of the CSA solution has been added, the mixture was seeded with crystals of CI (10 - 1 3 mg) foll owed by the addition of the remaining CSA solution. After stirring at ambient temperature overnight the mixture was filtered, the filter cake was washed with 100 mL of IPA and dried under vacuum/N ₂ at ambient temperature. The product is isolated as a white solid:(S)-6 ^, -chloro-3 4,4^5 etrahydro-2H,2H-spiro[benzo[b] [l,4]oxazepine-3, - naphthalene]-7-carboxylic acid with ((l S,4R)-7,7-dimethyl-2- oxobic clo[2.2.1 ]heptan-l-yl)methanesulfonic acid (1 : 1) (85 - 88% yield, 99 - l OO LCAP, > 99.5% ee).

STEP 12A: (S)- METHYL 6'-CHLORO-3',4,4 ^f ,5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE~3, 1 '-NAPHTHALENE]-7- CARBOXYLATE

To a solution of (S)-6 ^! -chloro-3;4,4',5 etraliydiO-2H,2'H- spiro[benzo[b] [l,4]oxazepme-3, ~naphthalene]-7-carboxylic acid (130 g, 379 mmol) in methanol (6 L) was added amberlyst-15 (130 g, pre-washed with anhydrous methanol) and heated to reflux for 10 h. Amberlyst was then removed by filtration and rinsed with methanol (3 x 300 mL). The combined filtrate was concentrated and the residue was purified by column chromatography affording pure (S)- methyl 6' ^» chloi -3',4,4',5~tetrahydro-2H,2'H~

spiroj benzoj bj [ L4 |oxazepine-3, -naphthalene]-7-carboxylate as a white solid (105 g, 77%). f: 0.7 in 10% ethyl acetate in hexane. Chiral HPLC conditions: Column: ChiralCel OD-H (250 mm x 4.6 mm, 5 μπι); Mobile Phase: n- Hexane:EiOH : 95:05. Run Time: 25 min. Flow rate: l ml/min. Retention time (minor peak)- 10.162 min. (1.98%); Retention time (major peak}- 12.292 min. (98.02%). STEP 12B: (S)-TERTBUTYL 6 ^! -CHLORO-3 ^! ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE j -7- CARBOXYLATE

To a solution of (R)-tert-butyl 4-((6-chloro-l-formyl-l,2,3,4- tetrahydronaphthalen~l -yl)methoxy)~3-nitrobenzoate (0.9g, 2.018 mmol) in acetic acid (20.22 ml, 353 mmol) at 70 °C was added iron (0.676 g, 12.11 mmol). The mixture was stirred vigourously for 4 h, then it was concentrated and the residue was diluted with 20 mL 1 ,2 DCE. Sodium triacetoxyhydroborate (1.7 ! 1 g, 8.07 mmol) was added and the mixture was stirred at ambient temperature for 20 min. Upon quenching by addition of 20 mL water a very thick slurry formed, 20 mL 10% citric acid solution was added and the mixture became much lighter in color. The layers were separated and the aqueous layer was extracted with 2 x 20 mL dichloromethane. The combined organics were washed with 10 mL 10% citric acid and 0 ml, brine, dried over MgS0 ₄ , filtered, and concentrated. The residue was deposited on 3 g silica gel and purified using 5-10% ethyl acetate in hexanes to eiute (S)-tert-butyl 6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy 1 ate (557 mg, 1 , 393 mmol, 69.0 % yield). Further elution with 30% ethyl acetate in hexanes provided (S)-6'-chloro-3^4,4^5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine-3,r- naphthalene]-7-carboxylic acid (132 mg, 0,384 mmol, 19.02 % yield)

STEP 13 : ( 1 R,2S )- 1 ,2-C YCLOBUT ANEDIYLDIMETH ANOL

To a rapidly stirred solution of lithium aluminum hydride (1.0m solution in THF, 1000 mL, 1000 mmol) at ambient temperature in a 3000 mL 3-necked flask under a stream of Argon was added gradually over 2 hours solid (lR,5S)-3- oxabicyclo[3.2.0]heptane-2,4-dione (40 g, 3 7 mmol), maintaining the internal temperature of the reaction mixture below 50 °C. Upon completed addition of the anhydride the reaction was stirred overnight at ambient temperature under argon. After 16 hours the reaction mixture was cooled by an ice bath to 10 °C internal temperature and, under a fast stream of argon, a solution of 36 mL water was added drop wise by addition funnel at a rate that maintained the internal temperature between 12 - 15 °C, approximately 1 ml/min, with vigorous stirring (500 rprn). Upon completed addition the mixture was vigorously stirred (500 rpm) in the ice-bath for 1 hour then removed from the bath and stirred to room temperature for 1 hour before cooling again with an ice bath to 5-10 °C internal temperature. To the mixture was added 36 mL of a 15% sodium hydroxide aqueous solution over a period of 45 minutes, maintaining the internal temperature between 10 - 20 °C. To the thick mixture was added 108 mL water drop wise by addition funnel, maintaining the internal temperature between 10 - 20 °C, over approximately 1 hour. Upon completed addition of the water the flask was removed from the ice bath, equilibrated to room temperature and left to stir vigorously under argon overnight. After stirring for 16 hours the mixture was filtered and the filtrate concentrated under reduced pressui'e to afford a colorless, slightly opaque oil. The oil was taken up in diethyl ether and stirred over anhydrous magnesium sulfate, filtered through a pad of C ^' el ite and the filtrate concentrated under reduced pressure to afford 32.8 g of a colorless oil, which was used in the next step without further purification (89% yield).

STEP 14 : ( 1 R,2S )-C YCLOBUTANE- 1 ,2-DIYLBTS (METHYLENE)

DIACETATE Acetic anhydride (2.59 mL; 3.0 equiv.) was added to the (1R,2R)-1,2- cyclobutanediyldimethanol (1.06 g, 9.15 mmol) and the resulting solution heated to 50 °C. After stirring overnight, the mixture was assayed by GC and showed complete conversion. The mixture was then diluted with 15mL of heptane and concentrated under vacuum to give a clear oil. The oil was dissolved in 15mL heptane and concentrated back down to an oil (azeotropic removal of acetic anhydride) to give thetitle compound as an oil L827g; 88.3% purity by quantitative NMR using benzyl benzoate as an internal standard. (88% yield).

STEP 15: ((lR,2S)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL

ACETATE

A 12 L 3-neck RBF equipped with mechanical stirrer was charged with a 1M sodium citrate solution (prepared by mixing sodium citrate tribasic dihvdrate (682 g, 2320 mmol) and water to reach total volume -2.3L) and 3.48L water (Tintemal was ~25°C). The mixture was briefly cooled with ice/water bath to

Tinternai ~20.2°C. pH~-8.46 (measured with pH probe). Amano Lipase from Pseudomonas fluorescens (41.8 g, 1547 mmol) was then added in one charge (pH ~ 8.12) and the mixture was vigorously stirred at ambient temperature for ~5min. (lR,2S)-cyclobutane-l,2-diylbis(methylene) diacetate (348 g, 1547 mmol) was then added in one charge and the resulting mixture was stirred vigorously at ambient temperature monitoring Tinternai and pH. After stirring the mixture overnight (Tinternal~20.9°C and pH~5.45) an aliquot was collected, extracted with IP Ac, diluted with ACN and analyzed by GC and the reaction was deemed complete (1.21% SM leftover, 0.17% of enantiomer, 1.8% of diol). Celite (70g) added to the reaction mixture and the slurry was filtered through a pad of celite on a medium porosity glass filter (fast filtration, ~15-20min), rinsing with 2.5 L IP Ac. The biphasic mixture was transferred into a 12L-extractor and stirred for -lrnin. The aqueous layer was separated and extracted with IP Ac (lx 4L), and the combined organic extract was concentrated in vacuo obtaining 337.28g (99.6 % ee; -50-60 mol% of residual IP Ac by 1H-NMR; qN MR: 37.63mg + benzyl benzoate (Aldrich catalog#B6630, lot# MKBG9990V, 61.27mg; Result: ~65wt%; corrected yield 89%). The crude product was used as such for the next step.

STEP 16: ((lR,2R)-2-FORMYLCYCLOBUTYL)METHYL ACETATE A 2-L Atlas reactor was charged with ((l R,2S)-2- (hydroxymethyl)cyclobutyl)methyl acetate (126.39 g, 79.6wt% by QNMR; 636 mmol) and 1L of DCM and the jacket temperature was set to 2()°C. Iodobenzene di acetate (225 g, 700 mmol) was then added as a solid (endothermic addition: the temperature decreased to 15 °C). TEMPO (3.97 g, 25.4 mmol) was then added as a solid in one portion resulting in a cloudy orange solution which became clear over the course of 20 mm. After stirring at 20 °C overnight an aliquot was collected, diluted with MeOH and analyzed by GC and the reaction was deemed complete. NOTE: An Additional kicker charge of iodobenzene diacetate and TEMPO can be used to push the reaction to completion if necessary. The reaction mixture was then cooled to Tint ernal= 1.8 °C (ice/ dry ice/ water bath) and diisopropylethylamine { 1 4ml .; 1 1 13mol) was added drop-wise via addition funnel over 65 min keeping Tinternal<5°C. The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring. After 48 h an aliquot was collected, diluted with methanol and analyzed by GC showing a 12: 1 ratio of trans: cis isomers. The reaction mixture was then cooled to Tinternal

<5°C (ice/water bath) and water (230mL) was added over -lOmin (Tinternal reached 14°C). The organic layer was separated, washed with water (125mL) and 1 M aqueous NaH2 _. P04 (90mL) and concentrated in vacuo to afford 273.4g of ((lR,2R)-2-formylcyclobutyl)methyl acetate (qNMR: 68.85mg + benzyl benzoate (Aldrich catalog* B6630, Lot#MKBG9990V, 72.36mg). Result: 32wt%-contains iodobenzene as major contaminant; corrected yield 88.6%). The crude product was used as such for next step.

STEP 17 : ( ( 1 R,2R)-2-((R)-( 1 H-BENZO [D] [ 1 ,2,3] TRI AZOL- 1 - YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL ACETATE To a solution of crude ((lR,2R)-2-formylcyclobutyl)methyl acetate (5 g, 10.27 mmol; 32.07 wt% -contains iodobenzene) in 8 mL MTBE was added benzotriazole (1.296 g, 10.00 mmol) as a solid (slightly exothermic). The clear solution became increasingly cloudy and a precipitate formed. The mixture was allowed to equilibrate overnight at ambient temperature then heptane was added (6 mL). After aging for 6 h the mixture was filtered at ambient temperature and washed with lOmL of 1 : 1 MTBE / heptane. The white solid was air dried on the frit under vacuum obtaining 2.48g of ((.lR,2R)-2-((R)-(lH-benzo[d][ l,2,3]triazol- l-yl)(hydiOxy)methyi)cyclobutyl)methyl acetate; 89% yield (uncorrected) STEP 18: (S)-METHYL 5-(((l S,2R)-2-ACETOXYCYCLOBUTYL)METHYL)- 6'-CHLORO-3',4,4',5"TETRAHYDRO-2H,2'H- SPTRO[BENZO[B][l ₅ 4]OXAZEPTNE-3, l '-NAPHTHALENE]-7- CARBOXYLATE

((lR,2R)-2-Formylcyclobutyl)methyl acetate (4.36 g, 27.9 mmol) (steps

16) was added to a solution of (S)-methyl 6 ^, -chloro-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carboxylat e (5.0 g, 13.97 mmol) (step 12) in DCM (78 mL) and AcOH (38.8 mL). The solution was stirred at ambient temperature for 10 minutes, then it was cooled to 0 °C and sodium cyanoborohydride (1.463 mL, 27.9 mmol) was added slowly portion by portion over 1 hour. After complete addition the mixture was stirred at 0 °C for 10 minutes then it was poured slowly into cold NaOH solution and extracted with EtOAc (120ml). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 220 g ISCO Gold column and eluted with 0 % to 10 % EtOAc /hexane, to provide the title compound, 6.0 g, as a white solid, m/z (ESI +ve ion) 498.1 (M+H) ⁺ . STEP 19 A: (S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-

(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H.2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

CARBOXYLATE

Potassium hydroxide (0.278 ml, 10.14 mmol) was added to a solution of (S)-methyl 5-(((lR,2S)-2-(acetoxymethyl)cyclobu1\'l)methyl)-6 ^, -chloro-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate

(1.530 g, 3.07 mmol) in MeOH (99 ml). The mixture was stirred at ambient temperature for 4 h, then it was neutralized with IN HQ to pH = 7 and concentrated under reduced pressure. The aqueous residue was then extracted with EtOAc (400ml) and the organic extract was washed with brine, dried over anh drous sodium sulfate and filtered through a short plug of silica gel to afford the title compound as a white solid, 1.354 g, was obtiained. m/z (ESI, +ve ion) 456.2 ( M i l)

Alternatively, (S)-methyl 6'-chloro-5-(((lR,2R)-2- (hydroxyme†hyl)cyclobutyi)methyl)-3',4,4',5-tetrahydro-2H, 2 ^f H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate could be prepared as follows: To a slurry of (S)-6'-chloro-3',4,4 ^, ,5-tetrahydi -2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid with ((1S,4R)- 7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l -y] )methanesulfonic acid (1 : 1) (step 1 1 ) (32,22 g, 52.5 mmol) and ((lR,2R)-2-((R)-(lH-benzo[d] [l,2,3]triazol-l- yl)(hydiOxy)methyl)cyclobut 'i)methyl acetate (step 17) (15.89 g, 57.7 mmol) in CH2CI2 (226 mL, 7 mL/g) was added sodium triacetoxylborohydride (13.90 g, 65,6 mmol) in 4 portions over 30 min. Additional ((lR,2R)-2-((R)-(lH- benzo[d] [ 1 ,2,3 ]triazol-l -yl)(hy droxy)niethyl)cy clobutyl)methyl acetate (2.89 g, 10.50 mmol) and sodium triacetoxyborohydride (2.78 g, 13.12 mmol) were added to drive the reaction to completion (HPLC assay). 80 mL of water was then added and the resulting mixture was agitated for 5 min. The layers were then separated and the organic phase was washed with 60ml water and 20 mL of brine then it was concentrated to an oil under reduced pressure. The residue was dissolved in 50 mL of MeOH and 40mL of 5N NaOH were then added at ambient temperature (exothermic). Upon reaction completion (determined by HPLC assay) the reaction mixture was partitioned between 133 mL of MTBE and 35mL of 1.5 M citric acid. The organic phase was transferred to a round bottom flask and the solvent was exchanged to MeCN via atmospheric distillation. This solution was seeded at 62 °C (a slum' developed) then it was allowed to reach ambient temperature and aged o vernight. The slurry was then filtered at 20.5 °C through a coarse frit glass sinter funnel and the filter cake was washed using 60 mL of MeCN, then dried in a vacuum oven at 40 °C to constant weight. Final mass: 21.87g (96.4 w t% by HPLC).

A 100 mL 3-necked-round bottom flask was charged with (S)-6'-chloro-5- (((l R,2R)-2-(¾ydroxyme l)cyc]obutyl)me l)-3 4,4^5-tetTahydro-2H,2'H- spiro[benzo[b] [i,4]oxazepine-3, ~naphthalene]-7-carboxylic acid (4.53 g, 1.0 equiv), MeOH (45 mL, 10 vol), and then a prepared solution of SOC . (11.28 mL, 1.0M in MeCN, 1.1 equiv). Under an atmosphere of N ₂ , the batch was heated to 55 °C and stirred for 18 h (or until >99% conversion as determined by HPLC). The reaction mixture was then allowed to cool to 20 °C over 2 h. To the resulting white slurry was added Hunig's base (3.94 mL, 2.2 equiv) and after aging for 0.5 h, water (9.0 mL, 2 V) was added as antisolvent over 1 h. The white slurry was aged for >2 h and the batch was filtered through a glass-fritted filter and the cake was washed with MeOH/water (5: 1 v/v) (9.0 mL, 2V) then MeOH/water (2: 1 v/v) (9.0 mL, 2V). The cake was dried under N ₂ with vacuum for 12 h at ambient temperature. The product was obtained as a white solid (4.36 g, 92% yield). STEP 19B: (S)-TERTBUTYL 6'-CHLORO-5-(((lR,2R)-2-

(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2H.2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

CARBOXYLATE

The title compound was synthesized from (S)-tertbutyl 6'-chloro-3',4,4',5 tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylat

(Intermediate AA11A, Step 12B) following the procedures described for Intermediate AA1 1 A, Steps 1 8- 19A).

STEP 20A: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2- FORMYLCYCIi3BUTYL)METHYL)-3',4,4',5-TETRAI-I ^T DRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE

To a cooled (-70 °C) solution of DMSO (7.12 mL, 2.5 equiv) and DCM

(183 mL, 10 vol) in a 1 L 3-necked-round bottom flask inerted with N? was added oxalyi chloride (26.1 mL, 1.0M in DCM, 1.3 equiv) at a rate to maintain temperature below -70 °C. The batch was aged at <-70 °C for 30 min and then a prepared solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2- (hydiOxymethyl)cyclobuf}'i)methyl)-3',4,4',5-tetrahydro-2H,2 'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (18.3 g, 1.0 equiv) in DCM (183 ml., 10 vol) was added at a rate to maintain reaction temperature <- 70 °C. The batch was aged for 1.5 h and then EtsN (22.4 mL, 4.0 equiv) was added at a rate to maintain batch temperature <-70 °C. After aging for 1 h, the batch was allowed to warm to -20 °C and water (366 mL, 20 vol) was added. The batch was agitated at 20 °C and the phases separated. The organic layer was washed with 2 x IN HQ (183 mL, 10 vol) and brine (183 mL, 10 vol). The organic layer was polish filtered and concentrated m vacuo to afford (S)-methyl 6'-chloro-5-(((lR,2R)-2~formylcyxfc

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyla te (19.91 g, 94% yield corrected for wt%) as a tan foam.

STEP 20B: (S)-TERTBUTYL 6'-CHLORO-5-(((lR,2R)-2- FORMYIX;YCIi3BUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'I-I- SPIRO[BENZO[B] [1 ,4]OXAZEPINE~3, 1 '-NAPHTHALENE]-7- CARBOXYLATE

The title compound was synthesized from (S)-tertbutyl 6'-chloro-5- (((lR,2R)-2-(hydroxymethy1)cyclobutyl)methyl)-:r,4,4V5-tetr

spiro [benzo | b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Intermediate AA 11 A, Step 19B) following the procedure described for Intermediate AA11 A, step 20A.

STEP 21 : (S)-METHYL

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4 ₅ 4 ^, ,5-TETRAHYDRO- 2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE

An oven dried three-neck round bottom flask equipped with a pressure- equalizing addition funnel, thermocouple and magnetic stirbar was cooled to ambient temperature under a purge of argon gas. The flask was charged with (li?,2S)-2-morpholmo~l~phenylpropan-l~ol (40.2 g, 182 mmol; prepared according to the literature procedure by Brubaker, J.D.; Myers, A.G. Org. Lett. 2007, 9, 3523-3525) against a positive pressure of argon. The addition funnel was charged with toluene (450 mL), which was dropped into the reactor. The solution was cooled in an ethylenegiycol-CCb. bath (~ -12 °C) and treated with butyliithium solution, 2.5m in hexanes (72.6 mL, 182 mmol), causing a white solid to precipitate that gradually went into solution as it was stirred over 30 minutes. Divinylzinc solution, (605 mL, 182 mmol ; prepared according to the literature procedure by Brubaker, J.D.; Myers, A.G. Org. Lett. 2007, 9, 3523-3525; The concentration of di vinylzinc solution was determined by titrating against iodine (Krasovskiy, A,; Knochel, P. Synthesis 2006, 890-891 ); concentration was generally -0.25M)) was added, and the solution was aged with stirring in the cold bath for an hour; the internal temperature was -15 °C. (<S)-methyl 6'-chloro-5- (((l ?,2 ?)-2-fbrmylcyclobutyl)methyl)-3^4,4',5-ietrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate (48.5 g, 107 mmol) (azeotroped thrice with toluene) was added as a solution in toluene (200 mL, 150 mL + 2 x 25 mL cannula/vial rinse) via cannula (16G), over about 20 minutes. The internal temperature rose to -10 °C. The mixture was stirred for 90 minutes while maintaining the internal reaction temperature below -5 °C. The addition funnel was charged with 30% w/w aqueous citric acid (450 mL), then the reaction was quenched by adding the solution to the reaction mixture. The reactor was removed from the bath and permitted to stir at ambient temperature. The solution was transferred to a separatory funnel and the flask was rinsed with toluene and 30% aq citric acid (50 ml each). The layers were mixed and then separated. The organic layer was washed with water (250 mL), then brine (250 mL), and finally dried with MgS0 ₄ . The solution was filtered and concentrated to yield a yellow oil, ~90g after vacuum overnight, 20; 1 dr. This was split into 3 batches and purified by column chromatography 10 to 20% EtOAe/hexanes 1.5kg SiCte, to provide (S)-methyl~6 ^! "Chloro-5-(((li?,2i?)~2~((5)-l - hydroxy ally l)cyclobutyl)methyl)-3',4,4',5-tetrahydfo-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (43.3 g, 84%). The aqueous layer and washings were placed in an ice-water bath and basified to pH > 13 by addition of 8N aqueous NaOH. This solution was then extracted with toluene (3 x 250 mL). The combined organic extracts were washed with water (250 mL) and brine (250 mL), then dried with MgS0 ₄ . The solution was filtered and concentrated to recover the ligand in >95% yield. If desired the ligand could be recrystailized from heptanes. STEP 22: (S)-6'-CHLOR()-5-(((l R,2R)-2-((S)-l -

HYDROXYALLYL)CYCLOBUTYL)METI-IYL)-3 ^f ,4,4',5-TETRAI-IYDRO- 2H,2H-SPlRO[BENZO[B] [l,4]OXAZEPlNE-3,r~NAPHTHALENE]~7- CARBOXYLIC ACID

To a solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)c>'clobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate (4.59 g, 9.52 mmol) in a mixture of THF (18 ml), MeOH (6.00 ml) and water (6.00 ml) was added lithium hydroxide monohydrate (0.799 g, 19.05 mmol) and the reaction was stirred at 50 °C for 4 hours. The reaction mixture was then concentrated to ~ 15 mL, cooled to 0 °C and acidified with 2N HC1 to pH = 3. The resulting viscous oil was diluted with 20 mL of water and 50 mL of EtOAc and a clear two-layer mixture was obtained. More EtOAc (ca. 200ml) was added and the organic layer was separated, washed with brine, dried with MgS0 ₄ , filtered and concentrated under reduced pressure. The crude material was loaded onto a column (220g), and purified with EtOAc in hexanes using the following gradient: 0-2.5 minutes 0% of EtOAc, 2.5 m-6 m 0-20% EtOAc, 6m-35m 20-60% EtOAc, 35m-40 m 70% EtOAc to give (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)c 'clobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepme-3, ~naphthalene]-7-carboxylic acid (4.22 g, 9.02 mmoi, 95 % yield) as a white solid.

Intermediate AA11B

(S)-6'-CHLORO-5-(((lR,2R)-2-((R)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2H-SPlRO[BENZO[B] [l,4]OXAZEPlNE-3,r-NAPHTHALENE]-7- CARBOXYLIC ACID

STEP 1 : (S)-TERTBUTYL 6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METHYL)-3',4 ₅ 4 ^, .5-TETRAHYDRO- 2H,2'H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3, l'-NAPI-iTI-IALENE]-7-

CARBOXYL ATE AND (S)-TERTBUTYL 6'-CHLORO-5-(((lR,2R)-2-((R)-l- HYDROXYALLYL)CYCLOBOTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2Η,2Ή-8ΡΚ()|;ΒΕΝΖΟ[Β| [ 1,4]ΟΧΑΖΕΡΙΝΕ-3,1·-ΝΑΡΗΤΗΑΕΕΝΕ]-7- CARBOXYLATE AND

To a solution of (S)-tert-bulyl 6'-chloro-5-(((lR,2R)-2- formylc ' ^, clobutyl)rnethyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7-carbox late (Intermediate AA11A, Step 20B, 0.754 g, 1.520 mmol) in THF ( 19.00 ml) cooled to 0 °C was added vinylmagnesium chloride solution (1.425 ml, 2.280 mmol) dropwise. The mixture was stirred at 0 °C and upon completion it was quenched with water and sat. NH4CI solution and extracted with EtOAc (200ml). The organic phase was washed with brine, dried with anhydrous sodium sulfate and concentrated.

Purification of the residue on a 220 g silica gel column eluting with 10% EtOAc in hexanes over 80 min provided (S)-tert-butyl 6'-chloro-5-(((l R,2R)-2-((S)-l - hydroxyallyl)cyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (3 12 mg). Rf 0.60 in 1 :4 EtOAc in hexan.es.

Further elution provided (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((R)-l~ hydrox\'allyl)c lobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4 |oxazepine-3, -naphthalene]-7-carboxyiate (270 mg). Rf 0.60 in 1 :4 EtOAc in hexanes. (S)-tertbutyi 6'-chloro-5-(((l R,2R)-2-

(hydroxymethyl)eyclobutyl)me^

spiro [benzo [b I [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Intermediate AA 1 1A, Step 19B, 91 mg) was also isolated. STEP 2: (S)-6'-CHLORO-5-(((l R,2R)-2-((R)-l-

HYDR0XYAL;LYL)CYCL0BU L)METHYL)-3V4,4',5-TETRAHYDR0- 2Η,2Ή-8Ρ11 0[ΒΕ ΖΟ[Β] [1,4]ΟΧΑΖΕΡ1ΝΕ-3, Γ-ΝΑΡΗΊΉΑΕΕΝΕ]-7- CARBOXYLIC ACID

10 mL of a 25 % TFA in DCM solution was addded to (S)-tert-butyl 6'- chloro~5-(((lR,2R)-2-((R)-l-hydro^^

2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy late (315 mg, 0.601 mmol). The reaction mixture was stirred at ambient temperature overnight then it was concentrated under reduced pressure. The residue was directly purified by on silica, eluting with 0-35 % EtOAc (containing 0.3% HOAc) in hexanes to give (S)-6'-cMoro-5-(((lR,2R)-2-((R)-l½droj^allyl)cyclobu1yl)met iiyl)-3 ^, ₅ 4 _s 4 ^, ,5- tetrahy dro-2H,2'H-spiro| benzoj b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (271 mg, 0.579 mmol, 96 % yield). Intermediate A A12A

(S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5~TETiL HYDRO-2H,2'H-

SPIRO [BENZO [B][ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7 - C ARB OXYLI C

ACID

STEP 1A: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYHEX-

2-EN-l-YL)CYCLOBUTYL)METI-r ^;" L)-3',4,4',5-TETRAJiYDRO-2H,2'H-

SPIRO[BENZO[B][l ,4]OXAZEPINE-3,l'-NAPHTHALENEl-7-

CARBOXYLATE

Under argon atmosphere, a dry three-neck flask charged with dry hexane (27 mL) was cooled to 0 °C. To this solution was added borane-methyl sulfide complex (3.29 ml, 34,6 mmol) and cyclohexene (7.01 ml, 69.3 mmol) and the mixture was stirred at 0 °C for 2 h. To the resulting white suspension was added 1-pentyne (3.41 ml, 34.6 mmol) and the mixture was stirred at ambient temperature for 0.5 h. The mixture was then cooled to -78 °C and diethylzinc, 1.0m solution in hexanes (32.3 ml, 32.3 mmol) was added. After addition the mixture was warmed to 0 °C, stirred for 3 minutes then recooled to -78 °C. This solution was named solution A. A separate flask was charged with a mixture of ((S)-methyl 6'-chiorc 5 ((li?,2i?)-2-formylcyclohuiy])methyi)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylate (Intermediate AAl lA, Step 20 A, 5.24g, 11.54 mmol) and (2s)-3-exo- (morpholino) isoborneal (0.486 g, 2.032 mmol) in n-hexane (50.9 ml) and toluene (16.97 ml). The mixture was stirred at ambient temperature until all solid was dissolved then it was cooled to 0 °C. Under argon atmosphere 54 ml of solution A was added slowly via syringe during 1.6 h. After stirring for 5 min at 0 °C the mixture was quenched with saturated NH4CI solution (70 ml), diluted with water

(30 ml) and extracted with EtOAc (3 x 270 ml), washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 330g ISCO Gold column and eluted with 0 % to 5 % EtOAc / exane, to provide the title compound, 3.8 g as a white solid, m/z (ESI, +ve ion) 524.1 (M+H) ⁺ .

STEP IB: (S)-TERTBUTYL 6'-CHLORO-5-(((l R,2R)-2-((S,E)-l- HYDROXYHEX-2-EN-l~YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO|;BENZO[B] [ 1 ,4]OXAZEPINE-3, 1

NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERTBUTYL 6'-CHLORO-5- (((lR,2R)-2-((R,E)-l-HYDROXYHEX-2-E -l-YL)CYCLOBUTYL)METHYL)- S'^^'j-TETR-^HYD O^H^'H-SPl OtBE ZOtBll l^iOXAZEPI E-S,!'- NAPHTHALENE1 -7-CARBOXYLATE

The title compound was synthesized from (S)-tert-butyl 6'~chloro~ (((lR,2R)-2-formylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, l '-naphthalene]-7-carboxylate (3.19 g.

Intermediate AA11A, Step 20B). The crude material was absorbed onto a plug of silica and purified on a 330 g ISCO Gold column eluting with 0 to 15 % EtOAc in heptanes over 45 min to provide (S)-tertbutyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l - hy droxyhex-2-en- 1 -yl)cyclobutyl)methyl)-3 ^! ,4,4',5 -tetrahy dro~2H,2 ^! H~ spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (2.36 g).

Further elution provided (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((R,E)-l- hydroxyhex-2-en-l -yl)cyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (0.45 g). STEP 2: (S)-6'-CHLORO-5-(((l R,2R)-2-((S ₅ E)-l -HYDROXYHEX-2-EN-l -

YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETR/ HYDRO-2H,2 ^! H-

SPIROI ;BENZO[B] [I ,4 ]OXAZEPINE-3, l '-NAPHTHALENE] -7-CARBOXYLIC

ACID

A mixture of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en- 1 -yl)cy clobut\d)methyl)-3',4,4',5-tetrahy dro~2H,2 ^! H~

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (4.6 g, 8.78 mmol) and lithium hydroxide monohydrate (3.68 g, 88 mmol) in MeOH (98 ml) and THF (98 ml) (with a few drops of water) was stirred at 50 °C overnight. The solvent was then removed and the residue was acidified with IN HC1 to pH 2-3. The mixture was extracted with EtOAc (80 ml x 3) and the combined organic layer was washed with brine (10 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydiOxyhex-2-en-l-yl)cyclobut 'i)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (4.25 g, 8.34 mmol, 95 % yield).

Alternatively, the title compound could be synthesized as follows:

To a solid mixture of (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l - hydrox 'hex-2-en-l -y])c clobutyl)methy])-3 4,4',5-tetrahydro-2H,2'H- spiro [benzo | b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carbox late (Intermediate AA12A, Step IB, first eluting isomer, 4.50 g 7.95 mmol) and lithium hydroxide monohydrate (1.66 g, 39.7 mmol) was added solvent Dioxane/MeOH (1 : 1) (159 ml). The mixture was heated to 65 °C and stirred overnight. The mitxure was then diluted with water and acidified with 1.0 N HC1 to pH~4. The organic sovents were evaporated under reduced pressure and to the residue was added water. The aqueous mixture was then extracted with EtOAc thrice, and the combined organic extract was concentrated. The residue was purified on a 120 g silica gel column eluting with a gradient of 0-70% EtOAc in hexanes to provide (S)-6'-chloro-5- (((l R,2R)~2-((S,F ~ iydroxyhex~2-e^

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxy lie acid (3.80 g, 7.45 mmol, 94 % yield).

Intermediate AA12B

(S)-6'-CHLORO-5-(((l R,2R)-2-((R,E)- 1 -HYDROXYHEX-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^f H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID

The title compound was synthesized from (S)-tertbutyl 6'~chloro~S~ (((1 R,2R)-2-((R,E)- 1 -hydroxyhex-2-en-l -yl)cyclobutyl)niethyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4 ] oxazepine-3, 1 '-naphthalene] -7-carboxy late (Intermediate AA12A, Step IB, second eluting isomer) following the procedure described for Intermediate AA12A, Step 2. Intermediate A A 13 A

(S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT-3-EN-l- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID

STEP LA: (S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-((S)-l-HYDROXYBUT-3- EN-l-YL) CYCT.A3BUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2I-L2'H- SPIRO[BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- C ARB OXYL ATE

An oven-dried 200-mL flask charged with a suspension of (1R,2R)-N- methyl-l-phenyl-l-(((lS,5S,10R)-10-(1rimethylsilyl)-9-borabi cyclo[3.3.2]decan- 9-yl)oxy)propan-2-amine (5.40 g, 14.54 mmol) in Et-20 (73 niL) under argon was cooled to -78 °C and treated with allylmagnesium bromide (13.22 ml, 13.22 mmol) solution, dropwise. The mixture was allowed to warm to ambient temperature and stirred for 1 h. The solution (~ 0. 17 M; solution A) was then recooled to -78 °C.

A separate 200 ml flask charged with ((5 -methyl 6'-chloro-5-(((li?,2i?)-2- formylcyclobu1yl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3,r-naphthalene]-7-carboxylate (Intermediate AA1 1 A, Step 20A, 2.0 g, 4.4 ! mmol) in Et ₂ 0 (22.03 ml) under argon was cooled to -78 °C. To this solution was added 40 niL of the above solution A and the resulting mixture was stirred at -78 °C for 40 minutes. 4-methylmorpholine 4- oxide (3.10 g, 26.4 mmol) was then added and the mixture was allowed to warm to ambient temperature for 10 minutes. Methanol (10ml) was then added and the volatile organics were evaporated under reduced pressure at ambient temperature. Additional methanol (100ml) was then added and after stirring at ambient temperature for 1 h the mixture was concentrated. The residue was diluted with EtOAc (450ml), washed with IN HC1 (15 ml), Ν¾€Κ>3 solution (10 ml), and brine (6 ml), dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 220g ISCO Gold column and eluted with 0 % to 5 %

EtOAc/hexane, to provide the title compound, 1.88 g as a white solid, m/z (ESI, +ve ion) 496.0 ( V! R )

STEP IB: (S)-TERTBUTYL 6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYBUT-3-EN-l -YL) CYCLOBUTYL)METHYL)-3' ₅ 4.4 ^, ,5- TETRAHYDRO-2H,2 ^* H-SPIRO[BENZO[B] [1 ,4] OXAZEPTNE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

The title compound was synthesized from (S)-tert-butyl 6'-chloro-5- (((lR,2R)-2-forntylcyclobutyl)me ])-3\4 ₅ 4^5-tetrah dro-2H ₅ 2H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (3.0 g, Intermediate AA11A, Step 20B) following the procedure described for Intermediate AA13A, Step 1 A. The crude material was purified on a 220 g silica gel column eluting with 5% EtOAc in hexanes over 60 rain to provide (S)-tert-butyl 6'-chloro-5-(((l.R,2R)- 2-((SH½droxybut-3-en -yl)cyclob spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (2.19 g). Rf ^: = 0.5 in 1 :4 EtOAc in hexanes.

STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT-3-EN-l- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID

A mixture of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en- l-yl)cyclobut54)methyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (1.88 g, 3.79 mmol) and lithium h droxide solution (I M) (34. 1 ml, 34. 1 mmol) in MeOH (34 ml) and THF (50 ml) was stirred at 65 °C for 50 minutes. After cooling to ambient temperature, the mixture was acidified with IN HC1 to pH 2-3, extracted with EtOAc (350ml), dried over anhydrous sodium sulfate and concentrated to provide the title compound, 1.82 g as a white solid, m/z (ESI, +ve ion) 482.0 (M+H) ⁺ . Alternatively, the title compound could be synthesized as follows:

To a solution of (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((S)-l -hydroxy but- 3-en-l-yl)c xlobut 'l)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Intermediate AA13A, Step I B, 250 mg, 0,465 mmol) in CH2CI2 (3.717 ml.) at ambient temperaure, TFA (0,929 mL) was added and the reaction mixture was stirred for 4 h. The crude reaction mixture was then concentrated, the residue was taken up in EtOAc, washed once with sat. NaHCC , dried over MgS04, filtered and concentrated to give a white foam. The crude material was used as such, without further purification. Intermediate AA13B

(S)-6'-CHLORO-5-(((lR,2R)-2-((R)-l-HYDROXYBUT-3-EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^f H- SPIRO [BENZO [B][ ;i,4]OXAZEPINE-3,l'-NAPHTHALE E]-7-CARBOXYLIC

ACID

STEP 1 : (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-l-HYDROXYBUT-3- EN- 1 -YL) CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO [B] [ 1 ,4] OXAZEPINE-3, Γ -NAPHTHALENE] -7- CARBOXYLATE

To a mixture of ally 1 iodide (0,824 mL, 8.95 mmol) and (S)-methyl 6'- chloro-5~(((lR,2R 2~formyl^^

spiro [benzo | b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Intermediate AA11A, Step 20A, 1016 mg, 2.238 mmol) in DMF (40.700 mL) was added indium powder (0. 106 mL, 6.71 mmol) in one portion. The mixture was stirred at ambient temperature for 30 min then it was diluted with water (50 ml) and extracted with EtOAc (2 x 80 mL). The combined organics were dried over anhydrous magnesium sulfate and concentrated. The crude material was loaded onto a cartridge and purifed via column chromatography (80 g ISCO gold) eluting with a gradient of 0-10-20% EtOAc/hexane over 30 min. to obtain (S)-methyl 6'- cWoro-5-(((l R,2R)-2-((S)-l -hydroxybut-3-en-l-yl)cyclobutyl)me l)-3 ^, ,4 ₅ 4 ^, ,5- tetTahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthale ne]-7-carboxylate (450 mg, Intermediate AA13A, Step 1A) as the first eluting isomer. Futher el u lion provided (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)-l- hydro j'but-S-en-l-y cj lobul methy -S'^^'^-tetrahydro- H^' l- spiroj benzoj bj[ L4|oxazepine-3, -naphthalene]-7-carboxylate (431 nig) as the second eluting isomer.

STEP 2: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((R)-l -HYDROXYBUT-3-EN-l-

Yl. VCi ()!¾!. !Ύ!.}\Π·. ! 11Y!.)-3'.4. I .5- Π·. ! RAI !YI>RO-2l i.2'1 !-

SPIRO [BENZO [B ] [ 1,4] OXAZEPINE-3 , l'-N APHTHALENE] -7-C ARBOXYL1C

ACID

The title compound was synthesized from (S)-methyl 6'-chloro-5- (((lR,2R)-2-((R)-l-hydroxybut-3-en-l-yl)cyclobutd)me l)-34,4',5-tetrahydro- 2H,2'H-spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy late (431 mg, 0.869 mmol) following the procedure described for Intermediate AA11 A, Step 22. The crude material was used as such without further purification.

Intermediate AA16

(S)-6'-CHLORO-8-FLUORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYPENT-2- EN-l-

YL)CYCLOBUlTL)METHYL)-3',4,4',5~TETiL HYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLI C

ACID

STEP 1 : (R)-METHYL 4-((6-CHLORO- 1 -(DIMETHOXYMETHYL)- 1 ,2,3,4- TETRAHYDRONAPHTHALEN- 1 -YL)METHOXY)-2-FL UORO-5 - NITROBENZOATE AND (R)-METHYL 2-((6-CHLORO-l- (DIMETHOXYMETHYL)- 1 ,2,3,4-TETRAHYDRON APHTHALEN- 1 - YL)METHOXY)-4-FLUORO-5-NITROBENZOATE

To a 0 °C solution of methyl 2,4-difluoro-5-nitrobenzoate (2406 mg, 1 1 ,08 mmol, Ace Synthesis, LLC) and (R)-(6-chl oro-l-(dimethox methyl)- 1,2,3, 4- tetrahydronaphthalen-l-yl)methanol (Intermediate AA1 1 , Step 7; 2000 mg, 7.39 mmol) in THF (37 mL) under N ₂ atmosphere was added LiHMDS (8.86 ml., 8.86 mmol, 1.0 M solution in THF) dropwise over 5 mm. The resulting solution was allowed to warm to ambient temperature and stirred for 5.0 hr. The reaction mixture was slowly poured into a saturated aqueous NH4CI solution (30 mL) and diluted with water (20 mL). The organic layer was separated and the aqueous layer was back extracted with EtOAc (2 50 mL). The organic layers were combined, washed with water (15 mL) and brine (10 mL), and dried over MgSCk After removal of organic solvents under reduced pressure, the residue was purified by flash chromatography on 40 g IS CO Gold silica gel column with 0-50% EtOAc/Hexanes to provide the title compound as a 1 : 1 mixture (2.78 g, 5.94 mmol, 80% yield).

STEP 2: (R)-METHYL 5-AMINO-4-((6-CHLORO-l-(DTMETOOXYMETOYL)- 1 ,2,3,4-TETRAHYDRONAPHTHALEN- 1 -YL)METHOXY)-2- FLUOROBENZOATE AND ((R)-METHYL 5-AMINO-2-((6-CHLORO-l- (DIMETHOXYMETHYL)- 1 ,2,3,4-TETRAHYDRONAPHTHALEN- 1 - YL)METHOXY)-4-FLUOROBENZOATE

A mixture of (R)-methyl 4-((6-chloro-l-(dimethoxy methyl)- 1,2,3, 4- tetrahydronaphthalen-1 -yl)methoxy)-2-fluoro-5-nitrobenzoate and (R)-methyl 2- ((6-chloro-l-(dimethox 'methyl)-l,2,3,4-tetrahydronaphthalen-l-yl)m

fluoro-5-nitrobenzoate (1 : 1 mixture, 1.98 g), and Pt0 ₂ (98 mg, Sigma-Aldrich) in

EtOAc (15 mL) was left stirring under H ₂ atmosphere at rt for 3.0 h. The resulting reaction flask was purged with 2 for 5 min, and the solid was removed by filtration and washed with EtOAc. After removal of organic solvents under reduced pressure, the cmde material was taken on to the next step without further purification.

STEP 3: METHYL 6'-CHLORO-8-FLU()RO-3',4'-DIHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

A mixture of (R)-methyl 5-amino-4-((6-chloro-l -(dimethoxymethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)methoxy)-2-fluorobenzoate and ((R)-methyl 5- amino-2-((6-chloro-l-(dimethoxymethyl)-l,2,3,4-tetrahyclrona phthalen-l- yl)methoxy)-4-fluorobenzoate (1 : 1 mixture) and HC1 (4.0 N in 1,4-dioxane,

Sigma Aldrich, 10.0 mL) was stirred at ambient temperature for 1.5 hr. The mixture was then slowly poured into saturated aq. NaHC03 (10 mL), diluted with water (10 mL), and extracted with DCM (2 * 20 mL). After removal of organic solvents under reduced pressure, the crude material was taken on to the next step without further purification

STEP 4: (S)-METHYL 6'-CHLORO-8-FLUORO-3',4,4',5-TETRAHYDRO-

2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

CARBOXYLATE

To a solution of (methyl 6'-chloro-8-fluoro-3',4 ^, -dihydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate in DCM (12 mL) was added sodium triacetoxyborohydride (1 .0 M in THF, Sigma- Aldrich; 5.0 mL, 5.0 mmol). The mixture was allowed to stir at 0 °C to rt for 4.0 h. The solution was then treated with saturated aqueous NH ₄ C1 (5 mL) and saturated aqueous citric acid solution (0.2 mL), diluted with water (15 mL), and extracted with CH2CS2 (2 x 16 mL). The organic solutions were combined. After removal of organic solvents under reduced pressure, the residue was purified by flash chromatography on 12 g ISCO Gold silica gel column eluting with 20-70%»

EtOAc/Hexanes to provide the title product as a white foam (980 mg, 2.61 mmol, 61,6% yield for the three steps).

STEP 5: ((S)-METHYL 5-(((lR,2R)-2-(((TERT-

BUTYLDIMETHYLSlLYL)OXY)METHYL)CYCLOBUTYL)METHYL)-6'- CHL()R()-8-FLUORO-3 ^! ,4,4',5-TETRAHYDRO-2H,2TI-

SPIRO[BENZO[B][l,4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE.

To a mixture of (S)-methyi 6'-chloro-8-fluoro-3',4,4',5-tetrahydro-2H,2'H spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (900 mg, 2.395 mmol) and (lR,2R)-2-(((tert- butyldimethylsilyl)oxy)methyl)cyclobutanecarbaldehyde (Intermediate AA14, Step 7; 830 mg, 3.63 mmol) in AcOH CH ₂ Cl ₂ (l :4) (8 mL) in ice bath was added solution of sodium borocyanohydride (2.395 mL, 1.0 N, 2.395 rnmol, Sigma- Aldrich) in THF (2.5 mL) via syrmge pump over 1.0 h. The resulting mixture was allowed to stir at ambient tempeature for 10 more minutes, TLC (20% EtOAc in hexanes) of the crude reaction mixture indicated complete conversion of the starting material and clean formation of a less polar product. The mixture was quenched with saturated aq. NH4CI (8 mL), diluted with water (10 mL) and aq. citric aid solution (10 mL, 4.0 N), and extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with brine (5 mL) and dried over MgS€>4. Removal of the organic solvents under reduced pressure provided the crude title product as a brown syrup. This material was taken on to the next step without further purification.

STEP 6: (S)-METHYL 6'-CHLORO-8-FLUORO-5-(((lR,2R)-2- { RY DROXY Y! h ! 1 1 Y I . ) ( V ( ^' ί ( ) B ί. I ^' Y I . } \ Π ·. ! 1 1 Υ ! . )-3'.4. ·Γ.5- Π ·. 1 R..\! !Y DRO- 2H,2'H-SPIRO [BENZO [B] [ 1 ,4] GXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE

The title compound was prepared as a white solid starting from (S)-methyi 5-(((l R,2R)-2-(((tert-butyldimethylsilyl)oxy)methyl)cj ⁷ clobutyl)methyl)-6'-chloro- 8-fluoro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '- naphthalene] -7-carboxylate following the procedure described for Intermediate AA14, Step 10. Purification of the crude material by flash chromatography on 40 g ISCO Gold silica gel column with 20-70% EtOAc/Hexanes provided the title products as a colorless solid (920 mg, 1.94 rnmol, 81% yield for the two steps). MS m/z (ESI, +ve ion) 474.0 (M+H) ^"h . STEP 7: (S)-METHYL 6'-CHLO O-8-FLUORO-5-(((l R,2R)-2- F01 AiYLCYCLOBUlTL)METHYL)"3',4,4',5-TETiL HYDRO-2H,2'H- SPIRO BENZO[B] [1 ,4 ]OXAZEPINE-3, 1 '-NAPHTHALENE]-7-

CARBOXYLATE

To a solution of (S)-methyl 6'-chloro-8-fluoro-5-(((l R,2R)-2- (hydroxymelhyl)cyclobutyl)methyl)-3 4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7 -carboxy 1 ate (790 mg, 1.667 mmol) in CH2CI2 (10 mL) was added Dess-Martm periodmane (Advanced Chenii blocks; 848 mg, 2.000 mmol). The mixture was left stirring at ambient temperature for 2 h then it was directly injected onto a 40 g silica gel column and purified eluting with 20-60% EtOAc/Hexanes to provide the title compound (670 mg, 1.42 mmol, 85% yield).

STEP 8: (S)-METHYL 6'-CHLORO-8-FLUORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN- 1 -YL)CYCLOBUTYL)METHYL)-3',4,4',5- ΙΈΤ^ΑΗΥΟ^Ο-2Η,2Ή-8Ρ¾0[ΒΕΝΖΟ[Β][1,4]ΟΧΑ� �ΕΡΙΝΕ-3, 1 '- APHTH ALENE] -7 - C ARB OXYL ATE

The title compound was prepared as a white solid starting from (S)-methyi 6'-chloro-8-fluoro-5-(((lP 2R)-2-formylcyclobutyl)memyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7-carboxylate (670 mg, 1.42 mmol) following the procedure described for Intermediate AA12, Step 1. Purification of the crude material on a 24 g column eluting with 20-60%

EtOAc/Hexanes provided the title compound (670 mg, 1.23 mmol, 87% yield). MS m (ESI, +ve ion) 542.0 ( M i ! ) .

STEP 9: (S)-6'-CHLORO-8-FLUORO-5-(((l R,2R)-2-((S,E)-l -HYDROXYHEX- 2-EN-l -YL)CYCLOBUTYL)METlWL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

The title compound was prepared as a colorless solid starting from (S)- methyl 6'-chloro-8-fluoro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l- yl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxylate (670 mmol, 1.23 mmol) following the procedure described for Intermediate AA12, Step 2. Purification of the crude material on a 24 g column eluting with 40-100% EtOAc/Hexanes provided the title compound (431 mg, 0.816 mmol, 66% yield). MS rrv'z (ESI, +ve ion) 528.0 (M+H) .

Intermediate AA17

(S)-6'-8-DICHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYPENT-2-EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _j! 4HYDRO-2H,2 ^, H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID

STEP 1 : ETHYL 2-CHLORO-4-FLUORO-5-NITROBENZOATE A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (14.80 ml, 1 14 mrnol, Combi-Blocks Inc.), ferric sulfate hydrate (0.952 g, 2.277 mrnol, Sigma-Aidrieh Chemical Company, Inc.) and ethanol (398 ml, 6832 mrnol, 200 proof , GOLD SHIELD CHEMICAL COMPANY ) with 1 ml, of cone, H2SO4 was reflux for 6,0 h, and then heated at 50 °C for 72 h. To the mixture was added cone. H2SQ4 (2.0 rnL), additional ferric sulfate hydrate (1.12 g), and water (3 mL). The mixture was reffuxed for a further 12 h. After removal of organic solvents under reduced pressure, the residue was dissolved in EtOAc (700 mL), washed with water, brine, and dried ove Na ₂ S04, After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on 24 g silica gel column with 0-50% EtOAc in hexanes provided the title compound as a pale yellow solid

(14.39 g).

STEP 2: (R)-ETHYL 2-CHLORO-4-((6-CHLORO- 1 -(DIMETHOXYMETHYL)- l,2,3,4-TETRAHYDRONAPHTHALEN-l-YL)METHOXY)-5- NITROBENZOATE

The title compound was prepared from (R)-(6-chloro-l- (dimethoxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)methanol (Intermediate ΑΑΓΙΑ, Step 7; 1 ,5 g, 5.54 mrnol) and ethyl 2-chloro-4-fluoro-5-nitrobenzoate (Intermediate AA17, Step 1; 1.5 g, 6.09 mmol) following the procedure as described for the synthesis of (R)-methyl 4-((6-chloro-l-(dimethoxymethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)methoxy)-2-fluoro-5-nitrob enzoate

(Intermediate AA16, Step 1 ), except that the crude product was purified by flash chromatography on a 40 g ISCO Gold silica gel column with 0-40% EtOAc in hexanes to provide the title products (2.4 g, 4.81 mmol, 83% yield) as a single isomer. STEP 3: (R)-ETHYL 5-AMINO-2-CHLORO-4-((6-CHLORO-l - (DIMETHOXYMETHYL)- 1 ,2,3,4-TETRAHYDRON APHTHALEN- 1

YL)METHOXY)BENZOATE

The title compound was prepared from (R)-ethyl 2-chloro-4-((6-chloro-l-

(dimethoxyniethyl)-l,2,3,4-tetraliydronaphtlialen-l-yl)me thoxy)-5-nitrobenzoate (Intermediate AA17, Step 2; 2.4 g, 4.81 mmol) following the procedure as described for the synthesis of (R)-methyl 4-((6-chloro-l-(dimethoxymethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)methoxy)-2-fluoro-5-nitrob enzoate

(Intermediate AA16, Step 2) and the crude product was used directly in the next step without purification.

STEP 4: (S)-ETHYL e'^-DICHLORO-S'^'-DIHYDRO^H^'H- SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l '-NAPHTHALENEl-7-

CARBOXYLATE

The title compound was prepared from (R)-ethyl 5-amino-2-chloro-4-((6- chloro- 1 -(dimethoxy methyi)-l ,2, 3,4-tetrahy dronaphthaien- 1 -yl)methoxy)benzoate (Intermediate AA17, Step 3) following the procedure as described for the synthesis of (R)-methyl 4-((6-chloro-.l -(dimethoxy methyl)-! ,2,3,4- tetrahydronaphthalen-l-yl)rnethoxy)-2-fluoro-5-nitrobenzoate (Intermediate AA16, Step 3) and the crude product was used directly in the next step without purification. MS m/z (ESI, +ve ion) 404.0 ( VI I I ) . STEP 5: (S)-ETHYL 6',8-DICHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7

CARBOXYLATE

The title compound was prepared from (S)-ethyl 6',8-dichloro-3',4'- dihydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalene] -7-carboxylate (Intermediate AA 17, Step 4) following the procedure as described for the synthesis of (R)-methyl 4-((6-chloro-l-(dimethoxymethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)methoxy)-2-fluoro-5-nitrobenzoate (Intermediate AA16, Step 4), except that the crude product was purified by flash

chromatography on a 40 g ISCO Gold silica gel column eluting with 20-70% EtOAc in hexanes to provide the title compound (1.35 g, 3.32 mmol, 79% for th three steps) as a white solid. MS m/z (ESI, +ve ion) 406.0 (M+H) ⁺ .

STEP 6: ( 1R,2R)-CYCL0BUTANE-1 ,2-DIYLD IMETH ANOL H

To a solution of (lR,2R)~cyclobutane-l,2-dicarboxylic acid (20.0 g, 138.8 mmol) in THF (200 mL) was added Btb.DMS (29.0 mL, 305.5 mmol) dropwise at 0 °C. The reaction mixture was stirred at ambient temperature for 12 h. After the completion of reaction (monitored by TLC), the reaction mixture was cooled to 0 °C and methanol (50 mL) was added dropwise. The resulting reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure to get crude material. The crude material was again diluted with methanol (200 mL) and concentrated under reduced pressure to afford the title compound (15.0 g, 93.0%) which was carried forward to the next step without purification. Rf _: 0.1 in 50% ethyl acetate in hexane.

STEP 7: ((1R, 2R)-2-(HYDROXYMETHYL) CYCLOBUTYL) METHYL BENZOATE

To a suspension of sodium hydride (60-65% suspension in oil, 4.9 g, 129.3 mniol) in THF (100 mL) at 0 °C was added a solution of (lR,2R)-cyclobutane- 1,2-diyldimethanol (15.0 g, 129.3 mmol) in THF (50 mL) dropwise. The resulting mixture was stirred at ambient temperature for 30 min, heated at 50 °C for 2.5 h, then cooled to ambient temperature and left stirring at ambient temperature for 12 h. The reaction mixture was cooled to -50 °C and a solution of benzoyl chloride (15,0 mL, 129.3 mmol) in 50 mL THF was added to it over 30 min. The mixture was stirred at ambient temperature for 2 h. After the completion of reaction (monitored by TLC), the reaction mixture was quenched with saturated NH ₄ C1 solution (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to get crude material, which was purified by column chromatography (silica: 100- 200 mesh size: elution: 0-30% ethyl acetate) to obtain the title compound (21.7 g, 76,4%). f: 0,4 in 30% ethyl acetate in hexane.

STEP 8. (( 1 R,2R)-2-FORMYLC YCLOBUTYL)METHYL BENZOATE

To a 500mL 3 necked round-bottomed flask equiped with a mechanical stirrer, a nitrogen gas inlet and a temperature probe was charged ((1R, 2R)-2- (hydroxyniethyl) eyclobutyi) methyl benzoate (13 g, 59.0 mmol) and DCM (130 mL). The solution was cooled to 0-5°C in an ice/water bath, and (diacetoxyiodo) benzene (Sigma Aidrich; 20.57 g, 63.9 mmol) was added followed by 2,2,6,6- tetramethylpiperidinooxy (Sigma Aidrich; 0.475 g, 3.04 mmol), and water (0.106 mL, 5.90 mmol). The reaction was stirred at 0-5 °C briefly then it was warmed up to ambient temperature slowly in 1 hour, and kept stirring at room temperature. After 4 h 0.05 eq. of 2,6,6-tetramethylpiperidinooxy (0.475 g, 3.04 mmol) was added and after 23 h 0.1 eq. of (diacetoxyiodo)benzene (1.960 g, 6.08 mmol) was added. After 46 h the reaction was quenched with 50 mL Na2S2(>3 solution and 150 mL sat. NaHCCb solution. The mixture was stirred for 30 mill, extracted with DCM, concentrated and loaded on silica gel. The material was purified by- column (Heptane:EtOAc = 10: 0 to 1.5:8.5) to afford ((1 R,2R)~2~

foimylcyclobutyl)methyl benzoate (12.08g, 55.3 mmol, 94 % yield).

STEP 9. ((lR,2R)-2-((S,E)-l-HYDROXYHEX- YL)CYCLOBUTYL)METHYL BENZOATE

The title compound was prepared from ((lR,2R)-2- formylcyclobutyl)methyl benzoate (1.00 g), following the procedure as described for the synthesis of Intermediate AA16, Step 8, except that the crude product was purified by flash chromatography on IS CO Gold silica gel column using 0-20% EtOAc/Hexanes as eluent to provide the title compound as a white solid (845 mg, 2,93 mmol, 64% yield). STEP 10. ((lR,2R)-2-((S,E)-l-((TERT-BUTYLDIMETHYLSILYL)OXY)HEX- 2-EN-l -YL)CYCLOBUTYL)METHYL BENZOATE

To a 0 °C solution of ((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l- yl)cyclobutyl)methyl benzoate (828 mg, 2.87 mmol), imidazole (Acros Organics 99+%, crystalline; 0.284 mL, 4.31 mmol,) in CH2CI2 (20 mL) under N?. was added 2,6-dimethylpyridine (Sigma- Aldrich Chemical Company, inc.; 1.334 mL, 11.48 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (Sigma- Aldrich Chemical Company, Inc.: 1.319 mL, 5.74 mmol, The cloudy mixture was allowed to warm with the ice bath to ambient temperature and stirred for 24 h. The mixture was then quenched with saturated aqueous NaHCCb (10 mL), diluted with water (15 mL), and extracted with CH2CI2 (3 ^χ 15 mL). After removal of organic sol vents under reduced pressure, purification of the residue by flash

chromatography on ISCO Gold silica gel column eluting with 0-20%

EtOAc/Hexanes provided the title compound as a white solid (1.155 g, 2.87 mmol, 100% yield).

STEP 1 1. (lR,2R)-2-((S,E)-l -((TERT-BUTYLDIMETOYLSILYL)OX^ )HEX- EN- i - YL)C YCLOBUTANEC ARB ALDEHYDE

To a solution of ((l R,2R)-2-((S,E)- l -((tert-butyidimeihylsilyi)oxy)hex-2- en-l-yl)cyclobutyl)methyl benzoate (1 , 100 g, 2.73 mmol, Step 7) in MeOH (4.55 ml) at ambient temperature was added sodium methylate (2.56 ml, 30% w/w, 13.66 mmol, Acros Organics). The solution was allowed to stir at ambient temperature for 45 min, and then treated with saturated aquous NaHCCb (5 mL) and water (5 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The organic layers were combined and washed with water (3 mL) and brine (3 m L). Removal of organic solvents under reduced pressure provided the crude title compound as a white solid (710 mg, 2.38 mmol, 87% yield). STEP 12. (lR,2R)-2-((S,E)-l -((TERT-BUTYLDIMETHYLSILYL)OXY)HEX-2- EN- 1 - YL)C YCLOBUTANEC ARB ALDEHYDE

To a -78 °C solution of dimethyl sulfoxide (675 μΐ, 9,51 mmol, Sigma-

Aldnch Chemical Company, Inc.) in CH2CI2 (6.8 mL) under N2 was added oxalyl chloride (2.38 mL, 2.0 M in CH2CI2, 4.76 mmol) dropwise over 4 min. The mixture was allowed to stir in the cold bath for 45 min. To the solution was slowly added a solution of ((lR,2R)-2-((S,E)-l-((tert-butyldimethylsilyl)oxy)hex-2-en-l - yl)cyclobutyl)methanol (710 mg, 2.378 mmol) in CH2CI2 (3 mL) over 2 mm. The mixture was allowed to stir in the bath for 1.5 h, followed by slow addition of anhydrous triethylamine (2.0 mL, 14.27 mmol, Sigma- Aldrich Chemical

Company, liic) dropwise. The resulting mixture was removed from ice bath and left stirring at ambient temperature for 45 min. To the cloudy mixture was added saturated aqueous NaHCCb (5 mL) and water (10 m L). The resulting mixture was extracted with CH2CI2 (2 ^χ 25 mL). The organic solution was combined and washed with water (8 mL). Removal of organic sol vents under reduced pressure provided crude title compound as a white solid (695 mg, 2.34 mmol, 99% yield). STEP 13: ((S)-ETHYL 5-(((lR,2R)-2-((S,E)-l-((TERT- BUTYLDIMETHYLSTLYL)OXY)HEX-2-EN- i -

YL)CYCLOBUTYL)METHYL 6^8 1ICHLORO-:r,4,4',5-TETRAHYDRO- 2H,2'H-SPIRO [BENZO [B] [ 1 ,4] GXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE

To a solution of (l R,2R)-2-((S,E)-l-((tert-but ddimethylsilyl)oxy)hex-2- en-l-yl)cyclobutanecarbaldehyde (Intermediate ΑΑΓ7 Step 12; 147 mg, 0.495 mmol) and (S)-ethyl 6',8-dichloro-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox date (Intermediate A A 17 Step 5; 201 mg, 0,495 mmol) in 20% AcOH/CH ₂ Cl ₂ (4 mL) under N ₂ in 0 °C ice bath was added a solution of sodium borocyanohydride (2.395 mL, 1.0 N in THF, 2.395 mmol, Sigma-Aldrich Chemical Inc.) drop wise using a syringe pump over 50 min. The resulting mixture was allowed to warm to ambient temperature and left stirnng for 30 min. The reaction solution was then treated with saturated aqueous NH ₄ C1 (10 mL) and water (8 mL) and the resulting mixture was extracted with EtOAc (3 ^χ 12 mL). The organic layers were combined and after removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on 1SCO Gold silica gel column with 0-50% EtOAc Hexanes provided the title compound as white solid (221 mg, 0.322 mmol, 65% yield).

STEP 14: (S)-ETHYL 6',8-DICHLORO-5-(((lR,2R)-2-((S.E)-l-

HYDROXYHEX-2-EN-!-YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-C ARBOXYLATE

A solution of (S)-ethyl 5-(((l R,2R)-2-((S,E)-l-((tert- butyldimethy]silyl)oxy)hex-2-en~l~yi^

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylat (220 mg, 0.320 mmol, Step 10) in THF (2 mL) was added tetrabutylammonium fluoride (0.641 mL, 1.0 M in THF, 0.641 mmol, Sigma-Aldrich Chemical Company, Inc.). The mixture was allowed to stir at ambient temperature overnight, and then treated with water (6 ml.) and extracted with EtOAc (3 8 mL). The organic layers were combined and after removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-50% EtOAc/Hexanes provided the title compound as white solid (114 mg, 0.199 mrnoi, 62% yield).

STEP 15: (S)-6'-8-DICHLORO-5-(((lR,2R)-2-((S,E)-l-ilYDROXYPENT-2-EN- l~YL CYCLOBUTYL)MF;raYL -3V^ l\5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , l'-N APHTHALENE] -7-C ARBOXYLIC ACID

A mixture of (S)-ethyl 6',8-dichloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en-l-yl)cyciobuty3)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late (114 mg, 0.199 mmol) in THF/water (1 : 1) (3.98 mL) was treated with lithium hydroxide (23.84 mg, 0.996 mmol). The mixture was stirred at 50 °C for 30 min. The mxture was then quenched with HO Ac (0.1 mL), diluted with water (8 mL) and extractd with EtOAc (3 ^χ 12 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on 24 g silica gel column with 0-100% EtOAc in hexanes provided (S)-6'-8-dichloro-5-(((lR,2R)-2-((S,E)-l- hydroxypent-2-en-l-yl)c lobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy lie aci d as col orless solid. MS m/z (ESI, +ve ion) 544.0 (M+H) ⁺ .

Intermediate AA18

(S)-6'-CHLORO-4V^-DIFLUORO-5-(((lR,2R)-2-((S,E)-l -HYDROXYHEX-2- EN-l-YL)CYCLOBUlTL)METHYL)-3 ^! ,4,4',5-TEmAHYDRO-2H,2'H- SPIRO| BENZO[B;| |;i,4|OXAZEPINE-3, l '-NAPHTHALENE]-7-CARBOXYLIC ACID

STEP 1 : 5 ΗΕΟΚΟ-2-ΡΕυθΚΟ- "ΜΕΊΉΟΧΥ-Ν-ΜΕΤΉΥΕΒΕΝΖ/ Μ1ΒΕ

To a stirred solution of 5-chloro-2-fluorobenzoic acid (900 g, 5. 17 mol) in DCM (10 L) was added oxalyl chloride (990 g, 7,8 mol) at 0 °C. After addition, DMF (3 mi_) was added and the reaction mixture was stirred at ambient temperature overnight. On completion, the solvent was removed under reduced pressure, the residue was dissolved in DCM (2 L) and the solution was concentrated again to dryness. The acid chloride thus obtained (900 g, 4.66 mol) was dissolved in DCM (6 L) and N,0-dimethylhydrox lamine hydrochloride

(682,27 g, 7 mmol) was added followed by a solution of triethylamine (2.7 L, 19.4 mol) in DCM (4 L) dropwise at 0 °C. The reaction mixture was warmed slowly to ambient temperature, and stirred overnight. The mixture was then quenched with ice water and the layers were separated. The aqueous layer was extracted with DCM (2 x 3 L) and the combined organic layer was washed with 0.5 N HCl (4 L), I NaOH (4 L), water (5 L) and brine (5 L) then it was dried over Na ₂ S0 ₄ and concentrated to afford 5-chloro-2-iluoro-N-methoxy-N-methy3benzarriide (900 g, 80% yield).

STEP 2: DIETHYL 6-CHLORO-4-OXO-3,4-DIHYDRONAPHTHALENE- 1 , 1 (2H)-DIC ARBOXYL ATE

5-chloro-2-fluoro-N-methoxy-N-methylbenzamide (900 g, 4.15 mol) was dissolved in THF (10 L) and the solution was cooled to -78 °C and

vinylmagnesium bromide (1.0 M solution in THF, 6.2 L, 6.2 mol) was added over 1 h. After the addition, the reaction mixture was warmed to ambient temperature slowly and allowed to stir for 2 h. The resulting suspension was cooled to -78 °C and diethyl malonate (1980 mL, 12.4 mol) was added. The mixture was then allowed to reach ambient temperature and stirred for ! h. The reaction was then quenched with saturated Ni hil solution (8 L) and extracted with ethyl acetate (3 x 8 L). The combined organic layers were washed with brine (5 L), dried over Na ₂ S04 and concentrated to afford a yellow oil. The above obtained oil was dissolved in DMSO (2.3 L) and potassium carbonate (288 g, 2.09 mol) was added. The mixture was heated to 70 °C overnight and upon completion, the reaction was cooled to ambient temperature and diluted with ice cold water (10 L). The aqueous layer was extracted with ethyl acetate (2 x 10 L) and the combined organic layer was washed with brine (3 x 5 L), dried over Na ₂ S04 and

concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography over silica gel (60-120 mesh, 4% ethyl acetate/hexane) affording pure diethyl 6-chloro-4-oxo-3,4-dihydronaphthalene- l,l(2H)-dicarboxylate (900 g, 67% yield).

STEP 3: DIETHYL 6~CHI,ORO~4,4-DTFLUORO~3,4- -1 , 1 (2H)-DiC ARBOXYLATE

A solution of diethyl 6-chloro-4-oxo-3,4-dihydronaphthalene-l ,l(2H)- dicarboxylate (4.5 g, 13.86 mmol) in bis(2-methoxyethyi)aminosulfur trifluoride (Deoxo-Fluor ® , Signia-Aklnch, St. Louis, MO, USA) (10.22 ml, 55.4 mmol) was treated with ethanol (0.064 g, 1.386 mmol) and heated at 60 °C for 2d. The reaction was then cooled to room temperature and quenched by careful addition into a saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with IN HC1, sat. NaHCOs solution, and brine. The organic phase was dried over MgS04, filtered and concentrated. Purification by normal phase silica gel column chromatography (5% ethyl acetate in hexanes) afforded diethyl 6-chloro-4,4-difluoro-3,4-dihydronaphthalene-l, l (2H)-dicarbox date (4.0 g, 11.54 mmol, 83 % yield) and recovered diethyl 6-chloro-4-oxo-3,4- dihydronaphthalene-l,l(2H)-dicarboxylate (420 mg, 1.293 mmol, 9.33 % yield). STEP 4: (6-CHLORO-4,4-DIFLUORO-l,2,3,4-

TETRAHYDRONAPHTHALENE- 1 , 1 -ΌΙΥ L)DIMETH AN OL

To a solution of diethyl 6-chloro-4,4-difluoro-3,4-dihydronaphthalene- l,l(2H)-dicarboxylate (1.05 g, 3.03 mmol) in THF (9.18 ml.) at 0 °C was added lithium aluminum hydride (1.0 M in THF, 9.08 mL, 9.08 mmol). The reaction was allowed to warm to ambient temperatui'e and stir for 1.5 h. The reaction was cooled back to 0 °C and quenched with 1 ml. water followed by 20 mL 2N HC1. To the mixture was added 75 mL ethyl acetate and sufficient solid NaCl to saturate the aqueous layer. The phases were separated and the aqeuous layer was extracted with 25 mL of ethyl acetate. The combined organics were washed with brine and dried over Na ₂ S0 ₄ , filtered, and concentrated. Purification by silica gel column chromatography using a gradient of 15-30% acetone in hexanes afforded (6-chloro-4,4-difluoro-l ,2,3,4-tetrahydronaphthalene-l , 1 -diyl)dimethanol (600 mg, 2,284 mmol, 75 % yield). Additional or alternative purification can be effected by washing or slurrying the solid product with dichloromethane.

STEP 5: (S)-(6-CHLORO-4,4-DIFLUORO-l-(HYDROXYMETHYL)-l ,2,3,4- TETRAHYDRONAPHTHALEN-l-YL)METHYL 4-BROMOBENZOATE

Copper(ll) chloride (0.134 g, 0.995 mmol) and 2,6-bis((R)-5,5-dibutyl-4- phenyl-4,5-dihydrooxazol-2-yl)pyridine (0.612 g, 1.031 mmol, prepared according to the procedure described in Li, J.Y; You, Y.S.; Kang, S. H. J. Am. Chem. Soc, 2011, 133, 1772) were combined in 50 mL anhydrous DCM under argon and stirred at ambient temperature for 3 h. The catalyst solution so prepared was added to a solution of (6-chloro-4,4-difluoro- 1,2,3,4- tetrahydronaphthalene-l,l-diyl)dimethanol (4.75 g, 18.08 mmol) in 250 ml, anhydrous DCM and rinsed with 25 mL anhydrous DCM. The reaction was cooled to -78 °C and treated with 4-bromobenzoyl chloride (4.76 g, 21.70 mmol) in 25 mL DCM and rinsed with 25 mL of DCM. The reaction was then treated with N-ethyl-N-isopropylpropan-2-amine (3.46 mL, 19.89 mmol) and held between -78 °C to -45 °C overnight. The reaction was then quenched with 250 mL 10% citric acid solution. The layers were separated and the organic phase was washed with 100 mL 10% citric acid solution, 200 mL sat. NaHCCb solution and 200 mL brine. The organic phase was dried over MgS0 ₄ , filtered, and concentrated. Purification by silica gel colunm chromatography using 10-15%) acetone in hexanes (330g Redisep Gold ® column, Teledyne Isco, Lincoln NE, USA) followed by repunfication of mixed fractions (220g Redisep Gold ® column, Teledyne Isco, Lincoln NE, LISA) afforded 6.5 g of (S)-(6-chloro-4,4- difluoro- 1 -(hydroxymethy 1)- 1 ,2,3,4-tetrah dronaphthalen- 1 -yl)methyl 4- bromobenzoate. The enantiomeric excess was found to be 87% (15% IPA in hexanes, Chiralcel OD-H.) If desired, the enantiomeric excess may be improved by recrystaliization from toluene as follows: 3.8 g of (S)-(6-chloro-4,4-difluoro-l - (hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)methyl 4-bromobenzoate (-80% ee) was heated in sufficient toluene to dissolve in a 90 °C bath. The solution is cooled to ambient temperature with stirring and seeded with racemic (6-chloro-4,4-difluoro-l -(hydroxymethyl)-l ,2,3,4-tetrahy dronaphthalen-I - yl)methyl 4-bromobenzoate. After 1 h at ambient temperature (crystallization occurred), the solution was cooled to 0 °C and stirred for 30 min, then warmed to ambient temperature and stirred for 1 h. The resultant solids were filtered and rinsed with 2 x 5 mL 0 °C toluene to afford 500 mg of racemic (6-chloro-4,4- difluoro- 1 -(hydroxy methyl)- 1 ,2,3,4-tetrahy dronaphthalen- 1 -yl)methyl 4- bromobenzoate. The mother liquor was concentrated to afford 3,3 g of 94% ee (S)-(6-chloro-4,4-difluoro- 1 -(by droxymethyl)- 1 ,2,3,4-tetrahy dronaphthalen- 1 - yl)methyl 4-bromobenzoate. STEP 6: (R)-(6~CHLORO-4,4 >IFLLORO-l-FORMYL-L2,3,4-

TETRAHYDRONAPHTHAL - 1 -YL)METHYL 4-BROMOBENZOATE

The title compound was synthesized from (S)-(6-chloro-4,4-difluoro-l- (hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)methyl 4-bromobenzoate following the procedure described for Intermediate AA 11, Step 6.

STEP 7: (R)-(6-CHLORO- 1 -(DIMETHOXYMETHYL)-4,4-DIFLUORO- 1 ,2,3,4- TETRAH YDRONAPHTHALEN- 1 - YL)METH ANOL

The title compound was synthesized from (R)-(6-chloro-4,4-difluoro-l formyl-1 ,2,3,4-tetrahydronaphthalen-l -y])methyi 4-bromobenzoate following procedure described for Intermediate AA 11, Step 7.

STEP 8: (R)-TERT-BUTYL 4-((6-CHLORO-l-(DIMETHOXYMETHYL)-4,4- DIFLUORO-l,2,3,4-TETRAHYDRONAPHTHALEN-.l -YL)METHOXY)-3- NITROBENZOATE

The title compound was synthesized from (R)-(6-chloro- .l - (dimethoxymethyl)-4,4-difluoro- 1 ,2,3,4-tetrahy dronaphthalen- 1 -yl)methanol and tert-butyl-4-fluoro-3-nitrobenzoate (Intermediate AA 1 1, Step 8) following the procedure described for Intermediate AA I I , Step 9.

STEP 9. (R)-TERT-BUTYL 4-((6-CHLORO-4,4-DlFLUORO-l-FORMYL- 1 ,2, 3 ,4-TETRAH YDRON APHTH ALEN- 1 - YL)METHOXY)-3- NITROBENZOATE

The title compound was synthesized from (R)-tert-butyl 4-((6-chloro-l-

(dimethoxymethyl)-4,4-difluoro- 1 ,2,3,4-tetrahy dronaphthalen- 1 -yl)methoxy)-3- nitrobenzoate following the procedure described for Intermediate AA 11 , Step 10.

STEP 10: (S)-6'-CHLORO-4',4 ^f -DIFLUORO-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2H,2H- SPIRO[BENZO[B] [ l,4]OXAZEPI E-3,r-NAPHTHALENE]-7-CARBOXYLIC ACID

The title compound was synthesized from (R)-tert-butyl 4-((6-chloro-4,4- difluoro-l-formyl-l,2,3,4-tetrahydronaph&

following the procedure described for Intermediate AA 1 1 , Step 1 1.

STEP 11 : 1 -ETHOXYCYCLOPROPANOL

OH

IX OEi (1-ethoxycyclopropoxy) trimethylsilane (Wonda, 500 g, 2,866 mol) was dissolved in methanol (1.4 L) and the resulting solution was stirred at ambient temperature for 2 days. The reaction was monitored by NMR and upon completion, methanol was removed in vacuo, yielding the title compound (266 g, 90.8% yield).

STEP 12: BENZYL 2-CYCLOPROPYLIDENEACETATE

CO,Bn

>-'

A solution of l-ethoxycyciopropanol (266 g, 2.61 mol) and benzoic acid (63.7 g, 0.52 mol) in anhydrous chloroform (3 L), under an atmosphere of nitrogen, was refluxed for 10 min and then a solution of benzyl 2-

(triphenylphosphoranylidene)acetate (Wonda, 1 ,07 kg, 2.61 mol) dissolved in the minimum volume of chloroform was added dropwise. The reaction was monitored by TLC and upon completion, the mixture was allowed to cool to room

temperature and the solvent was removed on a rotary evaporator. The residue was directly loaded onto the column (60-120 mesh silica gel; pure hexane to 5% ethyl acetate in hexane) to afford the title compound (331 g, 67,4%). Rr : 0,65 in 10% ethyl acetate in hexane. STEP 13: (S)-BENZYL 2-HYDROXY-2-(l-HYDROXYCYCLOPROPYL)

ACETATE

To an ice-cooled solution of benzyl 2-cyclopropylideneacetate (331 g, 1.76 mol) in a mixture of t-butanol (8.8 L) and water (8.8 L) was added AD-mix β (Aldrich, 2.45 kg). The resulting orange suspension was vigorously stirred at 0 °C. Ten minutes later, methanes ulfonamide (Alfa Aesar, 167 g, 1.76 mol) was added to the reaction in a single portion. The reaction mixture was stirred at 0 °C for 16 h. Upon completion, solid sodium sulfite (830 g, 6.58 mol) was added and the mixture was stirred at 0 °C for 15 minutes. The reaction mixture was diluted with ethyl acetate (10 L), the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 3 L). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude material which was purified by column chromatography (60-120 mesh silica; pure hexane to 40% ethyl acetate in hexane) affording the title compound as a translucent oil (260 g, 66.5%). Rr : 0.1 in 10% ethyl acetate in hexane. Chiral HPLC conditions: Column: Chiral pak IC (250 mm x 4.6 mm); Mobile Phase: n- Hexane:EtOH : 90: 10. Run Time: 20 rain. Flow rate: lml/min. Retention time (minor peak)- 9.35 (5.4%); Retention time (major peak)- 1 1.67 {9-1.6%).

STEP 14: (R)-l -(l -HYDROXYCYCLOPROPYL) ETHANE- 1 ,2-DIOL

A solution of (S)-benzyl 2-hydroxy-2-(l -hydrox cyclopropyl)acetate (260 g, 1 .17 moi) in THF (5 L) was cooled to 0 °C and lithium borohydride (98 g, 4.68 mol) was added portion- wise. After addition of lithium borohydride, the reaction mixture was stirred at 10 °C for 2 h. Upon completion, the reaction was cooled to 0 °C and quenched carefully with methanol (2.02 L). Ammonium acetate solution in methanol (1.5 kg in I L of methanol) was then added followed by the addition of acetic acid ( 30 ml,). The reaction mixture was filtered and the filtrate was concentrated at 30 °C at rotavapor. The residue thus obtained was diluted with THF (3 L) and filtered to remove the solid. The solid cake was washed with copious amount of THF. The filtrate was concentrated by rotary evaporator (temperature of the waterbath was kept at 30 °C) to obtain the crude material (300 g) which was used as such in next step. Rf : 0.1 in 40% ethyl acetate in hexane. STEP 15: (R)-l-(2-((TCRT-BUTYLDIPHENYLSILYL)OXY)-l -

HYDROXYETHYL) CYCLOPROPANOL The crude material from step 4 (300 g) was dissolved in THF (5 L) and imidazole (556 g, 8.19 mol) was added. The resulting reaction mixture was cooled to 0 °C and tert-butyl diphenylsilyl chloride (1.07 L, 4.1 mol) was added dropwise over a period of 1 h. The resulting reaction mixture was stirred at rt for 4 h. Upon completion, the reaction was quenched with saturated NH C1 solution at 0 °C. The aqueous layer was extracted with ethyl acetate (3 x 3 L) and the combined organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography (60-120 mesh; pure hexane to 10% ethyl acetate in hexane) affording pure title compound (240 g, 57.5% yield) as a thick oil. Rf : 0.45 in 30% ethyl acetate in hexane.

STEP 16: (S)-2-(((TERT-

BUTTLDIPHENYLSILYL)OXY)M )CYCLOBUTANONE

(R)-l -(2-((tert-butyldiphenylsily l)oxy )-l -hydroxy ethyl) cyclopropanol

(240 g, 0.673 mol) was dissolved in anhydrous pyridine (6 L), under an atmosphere of nitrogen, and the resulting solution was cooled to 0 °C in an ice/water bath. Neat methanesulfonyl chloride (78.5 mL; 1.01 mol) was added dropwise via dropping funnel over a period of 1 h. The reaction mixture was then allowed to slowly warm to room temperature and it was stirred at room temperature for 4 h. Upon completion, the reaction mixture was quenched with ice-water and the aqueous layer was extracted with ethyl acetate (3 x 5 L). The combined organic layers were washed with 15% citric acid solution to removed pyridine, then with brine and finally dried over sodium sulfate. The solvent was removed under reduced pressure to obtain the crude material which was purified by column chromatography (60-120 mesh size silica; eiuting with a gradient of 0- 5% ethyl acetate in hexanes) affording pure title compound (163 g, 71.5% yield). Rf : 0.55 in 10% ethyl acetate in hexane. STEP 17: (R)-TERT-BUTYL((2-

(METH0XYMETHYLENE)CYCL0BIJTYL)METH0XY)-D1PHENYL" SILANE

TB

A suspension of (methoxymethyl) triphenylphosphonium chloride (dried under high vacuum for 3 h while heating at 60 °C, 578 g, 1.685 mol, 3.5 equiv.) in anhydrous THF (vigorously purged with Argon for over IS minutes immediately prior to use, 5.5 L) was cooied to -78 °C in a dry ice/acetone slum' and n-butyl lithium (2.5 M solution in hexanes, 540 mL,1.35 mol, 2.8 equiv.) was added dropwise via cannula, giving a yellowish suspension. The diy ice slurry was immediately replaced with an ice-water bath, and the ylide suspension rapidly became dark red upon warming to zero degree. After 15 minutes, a solution of (S)-2-(((iert-butyldipheny3silyl)oxy)methyl)cyc3obutanone (163 g, 0.481 mol) in THF (1 .5 L) was added to the above prepared ylide solution in a dropwise manner over a period of 30 min. After complete addition, the reaction was stirred at rt for 16 h (the color persisted). The reaction was monitored by TLC and upon completion, the mixture was cooled to 0 °C and quenched by the cautious addition of saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (3 x 3L) and the combined organic layer was washed with brine, dried o ver sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography (60-120 mesh silica gel, pure hexane to 2% ethyl acetate in hexanes) affording the title compound (mixture of diastereomers, 105 g, 59.5%). A small amount of hydrolyzed product (described in the following step) was also observed by TLC and NMR. Ri : 0.6 and 0.65 (diasteromers) in 10% ethyl acetate in hexane.

STEP 18: (l S,2R)-2-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)

CYCLOBUTANECARBALDEHYDE TB

To a stirred solution of (R)-tert-but 'l((2- (nietlioxymethylene)cyclobui d)methoxy)-diphenyl"Silane (105 g, 0.286 mol) in DCM (2.1 L), water (53 mL) was added and the resulting solution was cooled to - 78 °C, Then a solution of trichloroacetic acid (84 g, 0.51 mol) in DCM (500 ml.) was added at -78 °C dropwise over a period of 1 h. The solution was allowed to warm to 0 °C and it was stirred at 0 °C for 15 min and then at ambient temperature for 2 h. The reaction was monitored by TLC and upon completion, the mixture was cooled to 0 °C and quenched by the addition of saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted with DCM (3 x 1 L). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the title compound (97 g, 96.2%) which had partially (-30%) epimerized to (lR,2R)-2- ((tert-butyldiphenylsilyloxy)methyl)cyclobutane-carbaldehyde (described below). This mixture was used as such in the following step. Rr: 0.55 in 10% ethyl acetate in hexane.

STEP 19: (lR,2R)-2-((TERT-

BUTYLDIPHENYLSILYLOXY)METHYL)CYCLOBUTANE

CARBALDEHYDE

A solution of (1 S,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl) cy clobutanecarbaldehyde (97.0 g, 0.275 mol,) in MeOH (1.94 L) was cooled to 0 °C and potassium tert-butoxide (Aldrich, 1 M in THF, 1 10.0 mL, 0.1 10 mol) was added to it dropwise. The reaction mixture was stirred for 6 h at ambient temperature. The reaction was monitored by ^! H NMR and upon completion, the mixture was quenched with pH 7 phosphate buffer solution (700 mL) and the aqueous phase was extracted with ethyl acetate (3 x 1.5 L). The combined organic layer was washed with brine (1.5 L), dried over anhydrous Na2S04 and concentrated under reduced pressure affording the title compound (95.0 g, 97.9%) as yellowish thick oil. The crude compound was used in the next step without further purification. Nearly 4-5% of the other isomer ((1 S,2R)-2-(((tert- butyldiphenyisilyl)oxy)methyl) cyclobutanecarbaldehyde) is also observed by NMR. Rf: 0.55 in 10% ethyl acetate in hexane.

The enantiomeric purity of this material could be improved as follows: To a solution of (lR,2R)-2-((tert-butyldiphenylsilyloxy)methyl)cyclobutane- carbaldehyde (95.0 g, 0.269 mol,) in EtOH (950 mL) was added sodium acetate (44.2 g, 0.539 mol) and the reaction mixture was stirred at rt for 15 min. Then the reaction mixture was cooled to 0 °C and semicarbazide hydrochloride (Aldrich, 33.1 g, 0.296 mol) was added portion-wise and the reaction mixture was stirred at rt for 2 h. Upon completion, the reaction was quenched with sat. sodium bicarbonate solution (500 mL) and the aqueous layer was extracted with DCM (2 x 2.0 L). The combined organic layer was washed with water (1.0 L), followed by brine (1.0 L), dried over anhydrous Na?.S04 and concentrated under reduced pressure affording a yellowish thick gel (98.0 g, 89%). The crude semicarbazone thus obtained was dissolved in 430 mL of hot methyl tert-butyl ether (MTBE) and then 6.4 L of boiling hot n-heptane was added to the resulting solution. The mixture was allowed to stand at ambient temperature for 3 days. The crystalline product was collected and washed with a small amount of hexane (50 mL) affording 60 g of enantio-ennched material (enantiomeric excess was 89%). This material was recrystalhzed as described above using 263 mL MTBE and 3.94 L hot n-heptane, aging at ambient temperature for 15 h delivering 55 g of enantio- enriched material (enantiomeric excess was 96%, Column: Chiral pak ADH (250 mm x 4.6 mm); Mobile Phase: n-Hexane:EtOH : 97:3. Run Time: 25 min. Flow rate: lml/min. Retention time (major peak)- 11.65 (98.04%); Retention time (minor peak)-! 6.79 (1.96%). This material was dissolved in acetone (1.13 L), cooled to 0 °C and Amberlyst-15 ion exchange resin, wet (Aldrich, 55.0 g) was added. Aqueous formaldehyde (1 10 mL, 37% solution) was added to the reaction mixture rapidly via dropping funnel at 0 °C over a period of 10 min. The reaction mixture was stirred at ambient temperature for 3 h then it was filtered through a celite bed and concentrated under reduced pressure below 35 °C. The residual turbid aqueous suspension was dilute with brine and extracted with pentane (3 x 1 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ S04 and concentrated under reduced pressure affording the enantio-enriched title compound (43.1 g, 91.1 %) as colourless but opaque oil .

STEP 20: (S)-5-(((lR,2R)-2-(((TERT-

BUTYLDIPHEr^LSILYL)OXY)METHYL)CYCLOBU L)METHYL)-6'-

CHLORO-4^4 ^, 3rFLUORO-:r,4,4^5-TETRAHYDRO-2H,2 ^! H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , l'-N APHTHALENE] -7-C ARBQXYLIC

ACID

To a solution of (lR,2R)-2-(((tert- bulyldiphenylsiiyl)oxy)methyl)cyclobutai'iecarbaldehyde (Intermediate AA18, Step 19; 4.73 g, 13,43 mmol) and (S)-6 ^, -chloro-4 ^, ,4'-difluoro-3',4,4',5-tetTahydro- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (step 10, 3.4 g, 8.95 mmol) in acetic acid (29.8 ml) and DCM (59.7 ml) at 0 °C (stirred for 15 minutes) was added sodium cyanoborohydride (0.281 g, 4.48 mmol) as a 1M solution in THF slowly over 2 h. The reaction appears mostly complete by TLC. The mixture was poured into ~ 3M NaOH (25.06 g, 627 mmol in 200 mL of water) and 300 mL of ethyl ether. The aqueous phase was extracted with ethyl ether (200 mL) and the combined organic phase was washed with 100 ml.

10%Na ₂ CO3/200 mL brine, followed by IN HC1, and again brine, then it was dried over MgS04, filtered, and concentrated. The crude material was purified on a 330 g silica gel column, eluting with 15-20% ethyl acetate in hexanes. The desired product dragged and did not separate well from ((l R,2R)-2-(((tert- but 'ldiphenylsilyl)ox\')methyl)cyclobutyl)methanol (1.75 g, 4.94 mmol, 55.1 % yield) also formed in the reaction. The mixed fractions (~ 4g) were collected and repurified on a 220 g silica gel column using 10-20% acetone in hexanes leading to the isolation of desired (S)-5-(((lR,2R)-2-(((tert- buty diphenyisilyl)oxy)methyl)cyclobut> )methyl)"6'"Chloi -4',4'~difluoro- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1,4 joxazepine-3,1 '-naphthalene j-7- carboxylic acid (4.6 g, 6.42 mmol, 71.7 % yield) and ((lR,2R)-2-(((tert- butyldiphenylsilyl)ox ')rnethyl)cyclobutyl)methanol (1.75 g, 4.94 mmol, 55.1 % yield) The product only appeared 85% pure by NMR, but it was taken on to the next step.

STEP 21 : (S)-METHYL 5-(((lR,2R)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCXOBUTYL)METHYL)-6'-

CHLQRQ-4',4'-DlFLUQRO-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

To a solution of (S)-5-(((l R,2R)-2-(((tert- butyldiphenylsilyl)ox niethyl)cyclobuty )methyl)-6'-chloro-4',4'-difluoro- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid (4.6 g, 6.42 mmol) in 75 ml toluene and 25 mL methanol was added TMS-diazomethane 2M in hexane (3.85 ml, 7.71 mmol) dropwise with stirring. After stirring for lh LC/MS showed 80% conversion and an additional charge of 1 mL TMS-diazomethane was added. After 10 mm the mixture w ^? as quenched by addition of acetic acid and concentrated under rotary evaporation (in the hood, for safety). The material thus obtained was dried under high vacuum overnight. TLC in 1% acetone in hexanes or 2% ethyl acetate in hexanes did not show separation of a significant amount of impurities, so the material was taken on crude to the next step.

STEP 22: (S)-METHYL e'-CHLORO^'^'-DIFLUORO-S-^l ^R)^- (HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2H-SPlRO[BENZO[B] [l,4]OXAZEPlNE-3,r-NAPHTHALENE]-7- CARBOXYLATE

To a solution of (S)-methyl 5-(((l R,2R)-2-(((tert- butyldiphenylsilyl)oxy)methyl)cyclobuty^

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate (4.7 g, 6.44 mmol) in THF (25.7 ml) was added TBAF (8.04 ml, 8.04 mmol) and the mixture was stirred at ambient temperature for 6 h. The mixture was then diluted with ethyl ether and washed with 2 x 50 mL of 50% brine, then 50 mL brine, then it was dried over MgSC , filtered, concentrated. The residue was deposited on silica gel (25g) and purified on a 330 g silica gel column eluting with 20% ethyl acetate in hexanes leading to partial separation of the desired product. Note: it is necessary to remove -15% impurity that had been carried since the reductive animation— likely a diasteroemeric product resulting from low ee of the cyclobutane. The mixed fractions (700 mg) were recycled through a 120 g column eluting with 20% ethyl acetate in hexanes and the purified (S)-methyl 6'- chloro-4V4'-difluoro-5-(((lR,2R)-2~(hydroxymethyl)cycl^

tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate

(combined total yield of 2.3 g, 4.68 mmol, 72.7 %) was obtained cleanly, as a white solid.

STEP 23: (S)-METHYL e'-CHLORO^'^'-DTFLUORO-S-^lR^R)^- (HYDROXYMETHYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO- 2H,2'H-SP1R0 [BENZO [B] [ 1 ,4] OXAZEP1NE-3, Γ -NAPHTHALENE] -7- CARBOXYLATE

A solution of dess-martinperiodinane (1.345 g, 3.17 mmol) in 26 mL dichlorornethane was filtered through a 0.45 uM membrane. To this solution was added (S)-methyl 6 ^, -chloro-4 ^, ,4 ^, -difluoro-5-(((lR,2R)-2- (hydiOxymethyl)cyclobut d)methyl)~3',4,4',5~tetrahydro-2H,2'H~

spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (1.2 g, 2.439 mmol) in 15 mL dichlorornethane dropwise over 10 min. After 30 rain, water (0.048 ml, 2.68 mmol) in 20 mL dichlorornethane was added dropwise over 30 minutes. The mixture was then quenched with 50 mL of dess martin extractor (1 : 1 10% Na ₂ S ₂ 03/sat. NaHCOs) and stirred for 20 min. The organic layer was separated and washed with 50 ml dess martin extractor, then 25 mL sat. NaHCCte, dried over MgS0 ₄ , filtered, and concentrated. Crude NMR showed -5% of dess martin byproduct. The semipure material was passed through a 40 g silica gel column eluting with 100% DCM. The desired product dragged on the column but could be efficently isolated (1.12 g, 94% yield).

STEP 24: (S)-METHYL 6'-CHLORO-4',4'-DIFLUORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN-l~YL)CYCLOBUTYL)METHYL)-3^4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE j -7-C ARBOXYLATE

The title compound was synthesized from (S)-methyl 6'-chioro-4',4'- difluoro-5-(((lR,2R)-2-fonnylcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiroj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate following the procedure described for Intermediate AA 12, Step 1. STEP 25: (S)-6 ^, -CHLORO-4' ₅ 4 ^, -DIFLUORO-5-(((l R,2R)-2-((S,E)-l - HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-3'.4,4 ^, ,5- TETRAHYDRO-2H,2^SPIRO[BENZO[B][l,4]OXAZEPIN&3, l '- NAPHTHALENE] -7-CARBOXYLIC ACID

The title compound was synthesized from (S)-methyl 6 ^! ~chloro~4 ^! ,4'- difluoro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l-yl)cyclobu tyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spifo[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylate following the procedure described for Intermediate AA 12, Step 2.

Intermediate AA19

(S)-7'-CHLORO-5-(((lR,2R)-2-((S)-l - HYDROXY ALL YL)CYCLOBUTYL)METHYL)-4,5-DIHYDRO-2H-

SP1RO [BENZO [B] [ 1 ,4] OXAZEP1NE-3 ^'-CHROMAN] - 7- CARBOXYLIC

ACID

STEP I : (2-(2-BROMO-5-CHLOROPHENOXY)ETHOXY)(DIMETHYL)(2- METHYL-2-PROPANYL)SILANE

To a solution of 2-bromo-5-chlorophenol (50 g, 241 mmol) in NMP (500 mL) was added K2CO3 (66.51 g, 482 mmol), (2-bromoethoxy)-tert-butyl- dimethylsilane (56,8 mL, 265.1 mmol) and catalytic amount of KJ (800 mg, 4.80 mmol), and the suspension was heated to 90 °C for 5 h. On completion, the suspension was cooled to room temperature and diluted with water (500 mL). Aqueous phase was extracted with ethyl acetate (3 x 250 mL). Combined organic layer was washed with water (500 mL), brine (500 mL) and dried over sodium sulphate. Solvent was removed under reduced pressure to afford crude material which was purified by column chromatography (100-200 mesh size silica gel, eluting with a gradient of 100% hexanes to 5% ethyl acetate in hexanes) affording pure (2-(2-bromo-5-chlorophenoxy)ethoxy)(dimethyl)(2-m.ethyl~2-pr opanyl)silane (72 g, 83.5%) as light yellow oil. Rf : 0.8 in 5% Ethyl acetate in hexane.

STEP 2: DIETHYL 2-(2-(2-((TERT- BUTYLDIMETHYLSlLYL)OXY)ETHOXY)-4'

CHLOROPHENYL)MALONAT

To a solution of potassium phosphate (70 g, 329.6 mmol) and Pd(tBu3P) ₂ (3.98 g, 7.8 mmol) (both weighed under nitrogen) in toluene (70 mL), was added 2-(2-bromo-5-chlorophenoxy)ethoxy)(dimethyl)(2-methyl-2-prop anyl)silane (40 g, 109.8 mmol) dissolved in dry toluene (70 mL) (plus 2 x 20 mL rinses with toluene) followed by the addition of diethyl malonate (19.3 mL, 120.8 mmol). The resulting suspension was heated at 85 °C for 6 h under an atmosphere of argon. The reaction monitored by LCMS and upon completion, the suspension was cooled to room temperature and then directly loaded over silica gel and purified by column chromatography (100-200 mesh size silica gel, eluting with a gradient of 100% hexanes to 10% ethyl acetate in hexanes) to afford pure diethyl 2-(2-(2-((tert-buty ldi methy lsily l)oxy )ethoxy )-4-chloropheny l)mal onate (28 g, 60%) as a clear oil. Rf : 0.5 in 10% ethyl acetate in hexane

STEP 3: DIETHYL 7-CHLOROC -4.4-DICARBOXYLATE To a solution of diethyl 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4- chlorophenyl)malonate (31 g, 69.96 mmol) and DBU (20.7 ml, 139.9 mmol) in MeCN (700 ml), under N?. atmosphere, 4-nitrobenzene-l-sulfonyl fluoride (28.7 g, 139.9 mmol) was added and the resulting solution was heated to 70 °C for 24 h. The reaction was monitored by TLC and upon completion, the solution was concentrated under reduced pressure to remove the MeCN at 35°C and the residue was diluted with water (400 mL) and aqueous phase was extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with water (400 mL), IN HCl (500 ml.) followed by NaHCCb (500 mL) solution and finally with brine (500 mL). Organic layer was dried over NazSCn, filtered, and concentrated under vacuum to get the crude material which was purified by column

chromatography (100-200 mesh size silica gel, eluting with a gradient of 100% hexane to 10% ethyl acetate / hexanes). The fractions containing the product were combined and concentrated under vacuum to provide diethyl 7-chlorochroman- 4,4-dicarboxylate (17 g, 78%) as colorless oil. Rx : 0.4 in 10% ethyl acetate in hexane.

STEP 4: (7-CHLOROCHROMAN-4,4-DIYL)DIMETHANOL

To a solution of 7-chlorochroman-4,4-dicarboxylate (15 g, 47.96 mmol) in

THF (250 mL) was added DIBAL-H (1 M in THF, 480 mL, 480 mmol) dropwise at 0 °C. The reaction mixture was stirred at ambient temperature for 4 h then it was quenched by the addition of saturated solution of NH4CI (500 mL) and extracted with 700 ml, of ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated. The crude material thus obtained was dissolved in THF (250 mL) and water (150 mL), and sodium borohydnde (10.64 g, 287.76 mmol) was added. The reaction was stirred at ambient temperature for 3 h then it was quenched with saturated NH4CI solution (300 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (100-200 mesh size silica gel, eiuting with a gradient of 100%» Hexane to 70% ethyl acetate / hexanes) affording pure (7- chlorochroman-4,4-diyl)dimethanol (10 g, 91 %). Rr. 0.3 in 70% ethyl acetate in hexane.

STEP 5 : (S)-(7-CHLORO-4-(HYDROXYMETHYL)CHROMAN-4- YL)METHYL 4-BROMOBENZOATE

To a solution of 2,6-bis((R)-5,5-dibutyl-4-phenyl-4,5-dihydrooxazol-2- yl)pyridine (RR-K g Catalyst) (1.29 g, 2.186 mmol) in dry DCM (40 mL), copper(II) chloride (293.90 mg, 2.186 mmol) was added and the resulting green solution was stirred at ambient temperature for 3 h. This solution was added via cannula to a solution of (7-chlorochroman-4,4-diyl)dimethanol (10 g, 43.72 mmol) in dry DCM (1.7 L). The resulting solution was cooled to -78°C and light green colored precipitation was observed in the reaction after some time. A solution of 4-bromobenzoyl chloride (14.3 g, 65.52 mmol) in DCM (70 mL) was then added slowly followed after 10 mm by the drop wise addition of N-ethyl-N- isopropylpropan-2-amine (8.37 mL, 48.09 mmol). The resulting reaction mixture was stirred at -78°C for 2 h then it was quenched with pi I - phosphate buffer (500 mL) and warmed to ambient temperature with vigorous stirring. The reaction was diluted with ethyl acetate (3 L) and the layers were separated. The organic phase was washed with pH~3 buffer (1 x 500 mL), saturated NaHCCb (2 x 500 mL), and brine (1 x 500 mL), dried over sodium sulfate, filtered and concentrated. The crude material thus obtained was purified by column chromatography (100-200 mesh size silica gel, eiuting with 100% DCM) affording pure (S)-(7-chloro-4-(hydroxymeihyl)chroman~4-yl)methyi 4- bromobenzoate as a white solid (15 g, 83.4%; e.r. = 92:8). This material was dissolved in 23 mL of acetone and 127 mL of hexane was added with continuous stirring. The precipitate thus obtained was filtered and washed with hexane to obtain the enantioenriched (e.r. ^:=: 98.4: 1.6; ChiralCel OD-H (250 mm x 4.5 mm); mobile phase: n -hexane: TP A: 95 :5; run time: 20 rain; flow rate: 1 ml/min; sample preparation: IP A; retention time (major peak)-l 2.483 min. ; retention time (minor peak)-15.681 min.) title compound. Re: 0.5 in 100%.

STEP 6: ( )-(7-CHLORO-4-FOR]VIYLCHROMAN-4-YL)METHYL 4- ENZOATE

To a stirred solution of (S)-(7-cWoro-4-(hydroxymethyl)chroman-4- yl)methyl 4-bromobenzoate (i i g, 26.71 mmol) in DCM (700 mL), Dess-Martin periodinane (13.59 g, 32.06 mmol) was added at 10 °C, Cooling bath was removed after addition and the reaction mixture was stirred for 30 min at ambient temperature. Water (577 mg, 32.06 mmol) was then added slowly and the reaction mixture was stirred further at ambient temperature for 30 min. The reaction was then cooled to 0 °C, quenched with a 1 : 1 mixture of 10% NaaS^C saturated NaHCCb (200 mL) solution and stirred further at room temperature for 1 h. The solution was then diluted with ethyl acetate (700 mL) and the aqueous phase was separated. The organic phase was washed with 200 mL of 1 : 1 mixture of 10% Na ₂ S ₂ 03 / saturated NaHCCb solution, saturated NaHCCb solution (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography (100-200 mesh size silica gel, eluting with 10% ethyl acetate in hexanes) to afforded (R)-(7-chloro-4- formylchroman-4-yl)methyl 4-bromobenzoate as light yellow solid (9 g, 82%). Rf : 0.7 in 10% ethyl acetate in hexane. STEP 7: (R)-(6-CHLORO - 1 -(DTMETHOXYMETHYL)-l

TETRAHYDRONAPHTHALEN-l-YL)METHANOL

To a solution of (R)-(7-chloro-4-formylchroman-4-yl)methyl 4- bromobenzoate (9 g, 21.96 mmol) in anhydrous MeOH (450 mL), /j-toluene sulfonic acid (185 mg, 1.076 mmol) and trimethyl orthoformate (7.20 mL, 65.88 mmol) were added and the reaction mixture was refiuxed for 4 h. The reaction mass was then concentrated to 50% volume and diluted with THF (225 mL) and IN NaOH (225 ml,, 66 mmol). The resulting mixture was stirred at room temperature overnight then it was concentrated under reduced pressure and the residue was diluted with diethyl ether (500 mL). The aqueous layer was separated and the organic layer was washed with IN NaOH (300 mL). The combined aqueous layers were extracted with diethyl ether (200 mL) and the combined organic layers were washed again with IN NaOH (200 mL) and brine then dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (100-200 mesh size silica gel, eluting with 20% ethyl acetate/hexane) to afford pure (R)-(6-chloro-l- (dimethoxymemyl)-l ,2,3,4-tetrahydronaphthalen-l -yl)methanol as a colorless thick oil (5.39 g, 100%). Rf : 0.5 in 30% ethyl acetate in hexane.

STEP 8: (R)-TERT-BUTYL 4-((7-CHLORO-4-

(DIMETTHOXYMETHYL)CHROMAN-4-YL)METHOXY)-3-

NITROBENZOATE

A solution of (R)-(6~chl oro- -(dimethoxymethyl)-l, 2,3,4- tetrahydronaphthalen-l-yl)methanol (5.3 g, 19.43 mmol) in dry THF (150 mL) was cooled to 0 °C and LiHMDS (1 M in THF, 25.2 mL, 25.2 mmol) was added dropwise. After 5 min, a solution of tert-butyl 4~fluoro-3~nitrobenzoate

(Intermediate AA11, Step 8; 5.15 g, 21.37 mmol) in THF was added dropwise via syringe and the resulting mixture was warmed to room temperature. After 1 h the reaction was cooled to 0 °C, quenched with saturated NH4CI solution (100 mL) and extracted with ethyl acetate (500 mL). The combined organic layers were washed with NH4CI (100 mL), brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude material thus obtained was purified by column chromatography (100-200 mesh size silica gel, eiuting with 5% ethyl acetate/hexane) to afford (R)- tert-butyl 4-((7-chloro-4-

(dimethox 'methy])chroman-4-yl)methoxy)-3-nitrobenzoate as a yellow semi-solid (9 g, 93.8% yield). Rf : 0.5 in 10% ethyl acetate in hexane.

STEP 9: (R)-TERT-BUTYL 4-((7-CHLORO-4-FORMYLCHROMAN-4- YL)METHOXY)-3-NITRO

To a solution of (R)-tert-butyl 4-((7-chloro-4-(dimethoxymethyl)chroman- 4-yl)methoxy)-3-nitrobenzoate (9 g, 18.22 mmol) in anhydrous acetone (100 mL) was added amberlyst-15 (9 g, 18.22 mmol) (prewashed with 2 x 100 mL dry acetone) and the solution was heated to 50 °C for 12 h. Upon completion, the reaction mixture was filtered and rinsed with acetone and the combined filtrate was concentrated. LCMS analysis of crude material showed 30% of the benzoic acid. The crude material was then dissolved in tert-butanol (200 mL), di tert-butyl dicarbonate (4.8 mL, 8.22 mmol) and DMAP (222 mg, 1.82 mmol) were added and the reaction mass was heated at 40 °C overnight. The mixture was then diluted with water (400 mL) and the aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over sodium sulfate and concentrated and the crude material was purified by column chromatography (100-200 mesh size silica gel, eluting with 5% ethyl acetate/hexane) to afford pure (R)-tert-butyl 4-((7-cMofo-4-formylchroman-4-yl)methoxy)-3-nitrobenzoate as light yellow semi solid (6 g, 77.3%). Rf : 0.45 in 10% ethyl acetate in hexane.

STEP 10: (S)-TERT-BUTYL 7'-CHLORO-4,5-DIHYDRO-2H- SPIR0[BENZ0|;B][ 1,4]0XA -3,4'-CHR0MAN]-7-CARB0XYLATE

A solution of (R)-tert-butyl 4-((7-chloro-4-formylchroman-4-yl)methoxy)- 3-nitrobenzoate (6 g, 13.41 rnmol) in acetic acid (148 raL) was heated at 70 °C and iron powder (4.5 g, 80.51 mmol) was added. The resulting mixture was heated for 4 h at 70 °C. Acetic acid was then removed under reduced pressure and the residue was dissolved in DCE (150 mL). Sodium triacetoxy borohydride (1 1 .36 g, 53.64 mmol) was then added portion wise and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was then quenched with water (200 mL) followed by 10% citric acid solution (400 mL). The aqueous phase was extracted with DCM (3 x 150 mL) and the combined organic layer was washed with brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (100-200 mesh size silica gel, 5% ethyl acetate/hexane) to afford pure (S)-tert-butyl 7'-chloro-4,5- dihydro-2H-spiro[benzo[b] [1 ,4]oxazepme-3,4'-cnroman]-7-carboxylate as a white solid (3.5 g; e.r. = 97.4:2.6; CluralCei OD-H (250 mm x 4.5 mm); mobile phase: n-hexane:ethanol: 90: 10; am time: 20 min; flow ⁷ rate: lml/min; Sample preparation: IP A; retention time (major peak)-I0.518 min; retention time (minor peak)-8.667 min). Rf : 0.6 in 10% ethyl acetate in hexane.

STEP 11 : (S)-7'-CHLORO-4,5-DIHYDRO-2H-

SPIRO|;BENZO[B][l,4]OXAZEPINE-3.4'-CHROMAN]-7-CARBOXYLIC

ACID

(R)-tert-butyl 4-((7-chloro-4-formylchroman-4-yl)methoxy)-3- nitrobenzoate (3.35 g, 7.48 mmol) was dissolved in acetic acid (64.2 ml, 1122 mmol) and to this was added iron (2.506 g, 44.9 mmol). The solution was heated at 70 °C for 4 hours. The solution was cooled to ambient temperature and then concentrated under vacuum The residue obtained was purified on a 8( ⁾ g si ca gel column (dry loaded), eluting with a gradient of DCM to 2% MeOH / DCM to provide the partially purified title compound as the second eluting major component. This material was repurified on a 40g silica gel column (dry loaded), eluting with a gradient of 100% Hexanes to 8% iPrOH / Hexanes and again on a 40g silica gel column (dry loaded), eluting with a gradient of 0.5% MeOH / DCM to 1% MeOH / DCM to provide (S)-7'-chloro-4,5-diliydro-2H- spiroj benzoj b] [ 1,4 ]oxazepine-3,4'-chroman]-7-carboxylic acid (1.12 g, 3.24 mmol, 43.3 % yield) as a white solid.

STEP 12: (S)-5-(((lR,2R)-2-

((BENZOYLOXY)METHYL)CYCLOBUT ^r L)METHYL)-7'-CHLORO-4,5- DIHYDRO-2H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3,4'-CHROMAN]-7- CARBOXYL1C ACID

(S)-7'-chloro-4,5-dihydro-2H-spiro[benzo[b][ l,4]oxazepine-3,4'- chroman]-7-carboxylic acid (1.1 g, 3.18 mmol) was dissolved in DCM (28.3 ml) and acetic acid (3.53 ml). The solution was cooled in a ice bath under an atmosphere of N ₂ . To this was then added ((lR,2R)-2-formylcyclobutyl)methy benzoate (Intermediate AA17, Step 8) 1M in DCM (3.50 ml, 3.50 mmol) and the solution was stirred for 10 rnin. Sodium cyanoborohydride 1 M in THF (1.591 ml, 1.591 mmol) was then slowly added dropwise. The solution was then stirred in the ice bath for 20 minutes. To this was then slowly added an ice cold solution of NaOH (3.05 g, 76 mmol) dissolved in 40 ml of water (pH of the solution was -13). The suspension was then trasferred to a separator}' funnel, diluted with 6ml of acetic acid and washed with EtOAc. The aqueous layer was washed again with EtOAc. The combined organics were dried over MgS(>4, filtered and

concentrated under vacuum. The residue obtained was purified on a 40g silica gel column (dry loaded), eiuting with a gradient of 0 to 50% EtOAc in Hexanes to provide (S)-5-(((lR,2R)-2-((benzoyloxy)methyl)cvxlobutyl)methyl)-7'- chloro-4,5- dihydro-2Hspiro[benzo[b][l ,4]oxazepine-3,4'-chroman]-7-carboxylic acid (0.732 g, 1.336 mmol, 42.0 % yield) as a white foam.

STEP 13: (S)-5-(((lR,2R)-2-

(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-7'-CHLORO-4,5- DIHYDRO-2H-SPIRO[BENZO[B] [ i .4 | (. ⁾ X Λ /! I \ i -.-3. ·!'-( Ί I ROM Λ \

CARBOXYLIC ACID

To a solution of (S)-5-(((l R,2R)-2-

(^enzoyloxy)memyl)cyclobu d)methyl)-7'-chloro-4,5-dihydro-2H- spiro[benzo[b][l,4]oxazepine-3,4'-chroman]-7-carbox lic acid (725 mg,

1.323 mmol) in anhydrous methanol was added sodium (45.6 mg, 1.984 mmol). The mixture was allowed to stir over the weekend and it was then quenched with 3 mL IN HCL and 10 mL water. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate, washed with brine, dried over MgS04, filtered, and concentrated. The crude material was purified using 20-40% acetone in hexanes to afford (S)-7'-chloro-5-(((lR,2R)-2- (hydroxymethyl)cyclobutyl)methyl)-4,5-dihydro~2H- spiro[benzo[b] [l,4]oxazepine-3,4'-chroman]-7-carboxylic acid (490 mg, 1. 104 mmol, 83 % yield).

STEP 14: (S)-METHYL 5-(((l R,2R)-2-

(HYDR0XYME;THYL)CYCL0BU1TL)METHYL)-7'-CHL0R0-4,5- DIHYDRO-2H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,4'-CHROMA ]-7-

CARBOXYLATE

To a solution of (S)-7'-chloro-5-(((lR,2R)-2- (hydroxymethyl)cyclobutyl)methyl)-4,5-dihydro-2H- spiro[benzo[b] [l,4]oxazepine-3,4'-chroman]-7-carboxv'lic acid (460 mg, 1.036 mmol) in 20 mL anhydrous toluene and methanol (4192 μΐ, 104 mmol) was added TMS-diazomethane (Aldrich, 2 M; 674 μΐ, 1.347 mmol). After I h, the mixture was concentrated to dryness and dried under high vacuum overnight. Isolated (S)- methyl 7'~chloro-5-(((lR,2R)-2~(hydroxymethyl)cyciobut d)methyl)~4,5-dihydro- 2H-spiro| ^" benzo| ^" b] |T,4]oxazepine-3,4'-chroman]-7-carboxylate (500 mg, 1.092 mmol; contaminated by ~ 0.33 equivalents of toluene).

STEP 15: (S)-METHYL 7'-CHLORO-5-(((lR,2R)-2- FORMYLCYCLOBUTYL)METHYL)-4,5-DIHYDRO-2H-

SPIRO [BENZO [B ] [ 1 ,4]OXAZ -3,4'-CHROMAN]-7-CARBOXYLATE

To a solution of (S)-rnethyl 7'-chloro-5-(((lR,2R)-2- (hydroxymethyl)cyclobut d)methyl)~4,5~dihydro-2H- spiro[benzo[b] [l,4]oxazepine-3,4'-chroman]-7-carboxylate (500 mg , 1.024 mmol) in 5 mL dichioromeihane was added a solution of Dess-Martin periodinane (Cheni lmpex International; 500 nig, 1.178 mmol) in 5 mL dichloromethane, filtered through a 0.45 uM filter. After 30 minutes, water (18.45 μΐ, 1.024 mmol) in 5 mL dichloromethane was added dropwise over 30 minutes. After lh an additional charge of 2 x 100 mg dess martin periodinane was added and after 5 minutes, more water (18.45 μΐ, 1.024 mmol) was added. After 10 minutes the reaction was quenched by addition of 20 mL dess-martin extractor (50% sat.NaHCC , 50% 10% Na ₂ S ₂ 03) and stirred for lh. The aqueous phase was with DCM and the combined organic phases were washed with sat. ?.C03 (emulsion occurred. Added water to separate layers) and brine, then dried over MgSC filtered, and concentrated. The crude material was purified by column chromatography using 20-30% ethyl acetate in hexanes to afford (S)-methyl 7'- chloro-5-(((lR,2R)-2-formylcyclobut 'l)methyl)-4,5-dihydro-2H- spiro[benzo[b] [l,4]oxazepine-3,4'-chroman]-7-carboxylate (350 mg, 0.768 mmol, 75,0 % yield),

STEP 16: (S)-METHYL 7'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-4,5-DIHYDRO-2H- SPIRO[BENZO[B][l,4]OXA -3,4'-CHROMAN]-7-CARBOXYLATE

To a solution of (S)-methyl 7'-chloro-5-(((l.R,2R)-2- foImylc^ lobu1 d)memyl)-4, -dihydro-2Hspiro[benzo[b][l,4]oxazepine-3,4 ^, - chromanj-7-carboxylate (350 mg, 0.768 mmol) in tetrahydrofuran (7677 μΐ) at - 10 °C under argon was added vinylmagnesium bromide (Aldrich, 1 M in THF; 998 μΐ, 0,998 mmol) dropwise. After 2h the reaction was quenched by addition of sat. NH4CI and extracted with ethyl ether and washed with brine. The combine organics were dried over MgSi filtered, and concentrated. The crude material was purified by column chromatography using 20-30%) ethyl acetate in hexanes to afford (S)-methyl 7'-chloro-5-(((l R,2R)-2-((S)-l- hydrox\'allyl)c lobulyl)methyl)-4,5-dihydro-2Hspiro[benzo[b] [l,4]oxazepine- 3,4'-chroman]-7-carboxylate as the second eluting major isomer (150 mg, 0.310 mmol, 40,4 % yield).

STEP 17: (S)-7'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METHYL)-4,5-DIHYDRO-2H- SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3,4'-CHROMAN]-7-C ARBOXYLIC

ACID

The title compound was synthesized from S)-methyl 7'-chloro-5- (((l R,2R)-2-((S)-l-hydroxydlyl)cyclobut 'l)methyl)-4,5-dihydro- 2Hspiro[benzo[b][l,4]oxazepine-3,4'-chroman]-7-carboxylate as the second eluting major isomer (135 mg, 0.279 mmol) following the procedure described for Intermediate AA 12, Step 2. Purification by column chromatography eluting with 20 to 25% acetone in hexanes provided (S)-7'-chloro-5-(((lR,2R)-2-((S)-l- hydroxya31yl)cyciobuty3)methyi)-4,5-dihydro-2H-spiro[benzo[b | [ l,4joxazepine- 3,4'-chroman]-7-carboxylic acid (87 mg, 0.185 mmol, 66,4% yield). Intermediate AA20

(S)-5'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)C^CLOBUTYL)METHYL)-2',3',4,5-TETRAHYDRO-2H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-INDENE] ~7 -C ARBOXYLIC ACID

STEP 1 : (S)-5-CHLORO-2,3 -DIHYDRO- 1 H-I DEN- 1 -OL AND (R)-5-

CHLORO-2,3-DIHYDRO- 1 H-INDEN- 1 -OL To a solution of 5-chloro-2,3-dihydro-lH-inden-l-one (50.0 g, 301.2 mmol) in THF (500 mL) was added sodium borohydride solution (23.0 g, 602.4 mmol) in water ( 100 mL) at 0 °C drop-wise in 1 h. The resulting reaction mixture was stirred at ambient temperature for 12 h. After completion, the reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3 x 1500 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain a racemic mixture of (S)-5-chloro-2,3-dihydro-lH-inden-l-ol and (R)-5-chloro-2,3-dihydro-lH-inden- l-ol (48.0 g, 94.8 % yield), which was used in next step without purification.

STEP 2: (S)-l,5-DlCHLORO-2,3-DIHYDRO-lH-INDENE AND (R)-l,5- DICHLORO-2,3-DIHYDR -lH-INDENE

To a solution of racemic 5-chloro-2,3-dihydro-lH-inden-l-ol (45.0 g, 267.8 mmol) in 1 ,4-dioxane ( 200 mL) was added thiony chloride (45 mL) at ambient temperature dropwise in 10 minutes. The resulting reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was poured into wet ice (1 kg) and stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate (3 x 1000 mL). The organic layer were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain a racemic mixture of (S)-l,5-dichloro-2,3-dihydro-lH-indene and (R)-L5-dichloro- 2,3-dihydro-lH-indene (46.0 g, 93.8 % yield), which was used in next step without purification. STEP 3: (S)-5-CHLORO-2,3-DIHYDRO-lH-INDENE-l-CARBONITRILE

AND (R)-5-CHLORO-2,3-DIHYDRO-l H-INDENE-l -CARBONITRILE To a suspension of racemic 1 , 5-dichloro-2,3-dihydro-lH-indene (45.0 g, 241.9 mmol) in DMF (780 mL) was added sodium cyanide (15.4 g, 314.0 mmol) in one portion. The reaction mixture was stirred at 50 °C for 12 h. After completion, the reaction was diluted with water (1000 mL) and aqueous layer was extracted with ethyl acetate (3 x 1000 mL). The organic layer were combined, dried over sodium sulphate and concentrated under reduced pressure to get to get crude compound which was purified by column chromatography (silica 100-200 mesh; elution: 0-2 % ethyl acetate in hexane in DCM) to obtain a racemic mixture of (S)-5-chloro-2,3-dihydro-lH-indene-l-carbonitrile and (R)~5-ehloro-2,3~ dihydro-lH-indene-l-carbonitrile (19.0 g, 45.2 % yield).

STEP 4: (S)-METHYL 5-CHLORO-2, 3 -DIHYDRO- 1H-INDENE- 1 - CARBOXYLATE AND (R)-METHYL 5-CHLORO-2,3-DIHYDRO-lH- - 1 -CARBOXYLATE

To a suspension of 5-chloro-2, 3-dihydro-lH-indene-l-carbonitrile (19 g, 107.0 mmol) in MeOH (63 mL) and water (126 mL) was added sulfuric acid ( 95 mL) dropwise at 0 °C. The reaction mixture was heated at 120 °C for 12 h. After completion (on TLC), the reaction mixture concentrate upto water layer and extracted with ethyl acetate (3 x 500 mL). The organic layer were combined, dried over sodium sulphate and concentrated under reduced pressure to get crude product which was purified by purified by column chromatography (silica 100- 200 mesh; elution: 0-2 % ethyl acetate in hexane ) to obtain a racemic mixture of (S)-methyl 5-chloro-2,3-dihydro-lH-indene-l-carbox late and (R)-methyl 5- chloro~2,3-dihydro-lH-indene-l~carboxylate (12.6 g, 55.5 % yield).

STEP 5: (R)-l -ETHYL 1 -METHYL 5-CHLORO-2,3-DlHYDRO-lH-TNDENE- 1 , 1 -DIC ARBOXYLATE AND (S)-l-ETHYL 1 -METHYL 5-CHLORO-2.3- DIHYDRO - 1 H-INDENE-1 , 1 -DIC ARBOXYLATE

To a solution of 5-chloro-2, 3-dihycLro-lH-indene-l-carboxylate (12.6 g, 60.0 mmol) in THF (130 mL) was added LiHMDS 1.0M (78 mL, 72.0 mmol) dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. Ethyl cyanoformate (7.7 mL, 78.0 mmol) was added to reaction mixture dropwise at - 78 °C in 30 minutes. After completion (on TLC), the reaction mixture was quenched with aq. NITiCl (200 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layer was combined, dried over sodium sulfate and concentrated under reduced pressure to get crude product, which was purified by column chromatography (silica 100-200 mesh; elution: 0-2 % ethyl acetate in hexane ) to obtain pure 1 -ethyl 1 -methyl 5-chloro-2,3-dihydro-l H-indene-l ,l -dicarboxylate (15,3 g, 90.5 % yield).

STEP 6: (5-CHLORO-2, 3 -DIHYDRO- 1H-INDENE- 1 , 1 -DIYL)DTMETH ANOL

To a solution of racemic 1 -ethyl 1 -methyl 5-chloro-2,3-dihydro-lH- indene-l,l-dicarboxylate (60 g, 212.0 mmol) in THF (600 mL) was added LiBH ₄ (27.8 g, 1276.5 mmol) portion wise at ambient temperature. The reaction mixture was stirred at 70 °C for 12 h. After completion (on TLC), the reaction mixture was quenched with aq. NH4CI (250 mL) and extracted with ethyl acetate (3 x 1000 mL). The organic layer were combined, dried over sodium sulphate and concentrated under reduced pressure to get crude product, which was purified by crystallization in DCM and hexane to obtain (5-chloro-2,3-dihydro-l H-indene- l,l -diyl)dimethanol (29.0 g, 64.4 % yield).

STEP 7: (S)-TERT-BUTYL 4-((5-CHLOR()-l-(HYDROXYMETHYL)-2,3- DIHYDRO-l H-INDEN-l-YL)METHOXY)-3-NITROBENZOATE AND (R)- TERT-BUTYL 4-((5-CHLORO-l-(HYDROXYMETOYL)-2,3-DIHYDRO-l H- INDEN-l-YL)ME -3-NlTROBENZOATE

To a solution of (5-chloro-2,3-dihydro-lH-indene-l,l-diyl)dimethanol (29.0 g, 136,0 mmol) in THF (600 mL) was added LiHMDS 1.0 M (150 mL, 150.0 mmol) at -78 °C drop-wise in 20 minutes and then /-butyl 4~fluoro-3- nitrobenzoate (32.9 g, 136.0 mmol) was added. The resulting reaction mixture was stirred at -78 °C for 30 minutes and then at ambient temperature for 12 h. After completion (on TLC), the reaction mixture was quenched with aq. NH ₄ C1 (200 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layer were combined, dried over sodium sulphate and concentrated under reduced pressure to get crude product, which was purified by column chromatography (silica 100-200 mesh; elution: 0-30 % ethyl acetate in hexane ) to obtain a racemic mixture of (S)- tert-butyl 4-((5-chloro-l-(hydroxyme1hyl)-2,3-dihydro-lH-inden-l-yl)met hoxy)- 3-nitrobenzoate and (R)-tert-buty 1 4-((5-chloro- 1 -(hydroxymeihyl)-2,3-dihydro- lH-inden-l -yl)methoxy)-3-nitrobenzoate (36.1 g, 61% yield).

STEP 8: (R)-TERT-BUTYL 4-((5-CHLORO-l-FORMYL-2,3-DIHYDRO-lH- INDEN- 1 -YL)METHOXY)-3-NITROBENZO ATE AND (S)-TERT-BUTYL 4- ((5 - CHLORO - 1 -FORMYL-2,3 -DIHYDRO - 1 H-INDEN- 1 - YL)METHOXY)-3- NITROBENZOA

To a solution of racemic tert-butyl 4-((5-chloro-l-(hydroxymethyl)-2,3- dro-.lH-inden-l -y])methoxy)-3-nitrobenzoate (36.1 g, 83.37 mmol) in DCM (360 mL) was added Dess-martin periodinane (46.8 g, 1 10.3 mrnol) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with aq. NaHCC (200 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain a racemic mixture of (R)-tert-butyl 4-((5-chloro-l-formyl-2,3-dihydro-lH-inden-l-yl)methoxy)-3- nitrobenzoate and (S)-tert-butyl 4-((5-chloro-l-formyl-2,3-dihydro-lH-inden-l - yl)methoxy)-3-mtrobenzoate (50 g, 61 .0 %), which was carr ' forward for next step without purification.

STEP 9: (S)-TERT-BUTYL 5'-CHLORO-2',3',4,5-TETRAHYDRO-2H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-INDENE]-7-CARBOXYLATE AND (R)-TERT-BUTYL 5'-CHLORO-2',3',4,5"TETRAHYDRO-2H"

SPIRO[BENZO -3,r-INDE E]-7-CARBOXYLATE

To a solution of racemic tert-butyl 4-((5-chloro-l-formyl-2,3-dihydro- lH- inden-l-yl)methoxy)-3-nitrobenzoate (50.0 g, 116.0 mmol) in THF (500 mL) and acetic acid ( 250 mL) was added iron powder (76.0 g, 1357 mmol ) in one portion. The reaction mixture was heated at 70 °C for 3 h then it was cooled at ambient temperature and sodium cyanoborohydide (72.8 g, 1160.0 mmol) was added portion wise at ambient temperature. The reaction mixture was stirred at ambient temperature for 30 minutes then it was passed through a pad of celite and the celite pad was washed with ethyl acetate (2 x 100 mL). The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product, which was pun i led by column

chromatography (silica 100-200 mesh; elution: 0-2 % ethyl acetate in hexane) to obtain a racemic mixture of the title compound (18.0 g, 40.9 %). The enantiomers were separated by SFC (Sample preparation: 9.5 g/500 mL (19 mg/mL) sample solution in MeOH:DCM (4: 1); Column: Chiralpak OJ-H, 50 X 150 mm, 5 μιτι; Mobile Phase A: CO2; Mobile Phase B: MeOH(20 mM NH3) Isocratic: 48% B; Flow Rate: 250 g/min; Loading: 5.0 mLof sample solution prepared as above (-95 mg); Detection: UV @ 232 nm; Cycle Time: 7.8 rain; Total Elution Time: 10 min; Instmment: Thar 350 SFC) providing (S)-tert-butyl 5'-chloro-2',3',4,5-tetrahydro- 2H-spiro[benzo[b] [l,4]oxazepine-3, -indene]-7-carboxylate as the first eluting isomer and (R)-tert-butyl 5'-chloro-2',3',4,5-tetrahydro-2H- spiro[benzo[b] [l,4]oxa?.epine-3, -indene]-7-carbox late as the second eluting isomer.

STEP 10: (S)-TERT-BUTYL 5-(((l ,2R)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTYL)METHYL)-5'-

CHLORO-2',3',4,5-TETl AHYDRO-2H-SPlRO[BENZO[B] [l,4]OXAZEPlNE- 3,1 '-INDENE] -7-C ARBOXY

A mixture of (S)-tert-butyl 5 ^! -ΰ1ι1θΓθ-2',3',4,5-ΐ6ίΓ3ΐι ^Γθ-2Η- spiro[benzo[b] [l,4]oxazepine-3,r-indene]-7-carbox late (intermediate AA20, step 9, first eluting isomer; 0.930 g, 2.411 mmol) and (l ,2R)-2-(((tert- but 'ldiphenylsilyl)oxy)methyl)cyclobutanecarbaldehyde (Intermediate AA18, Step 19; 0.85 g, 2.41 1 mmol) in 20%AcOH/DCM (12 ml) was allowed to stir in an ice bath for 15 min. To the solution was added sodium cyanoborohydride (1.218 ml, 1.0 M in THF, 1.218 mmol, Sigma- Aldrich Chemical Company, Inc.) drop wise via syringe pump over 80 min. The resulting mixture was left stirring in the bath for 75 min. TLC (20%EtOAc/Hexanes) indicated reaction completion. The reaction solution was slowly poured into a cold aqueous NaOH solution (1.0 N, 20 mL), and the resulting mixture was allowed to stir at ambient temperature for 30 min. The organic lay er was separated, and the aqueous layer was back extracted with EtOAc (3 x 15 mL). Organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on 1SCO Gold silica gel column with 0-25%

EtOAc/Hexanes provided the title compound as a colorless syrup. STEP 11 : (S)-TERT-BUTYL 5 '-CHLORO-5 -((( 1 R,2R)~2-

(HYDROXYMETHYL)CYCLOBUTYL)METHYL)-2',3',4,5"TETRAHYDRO- 2H-SPIRO[BENZO Bj l,4;| -3,r-INDENE]-7-CARBOXYLATE

To a flask charged with (S)-tert-butyl 5-(((lR,2R)-2-(((tert- butyldiphenylsilyl)ox niethyl)cyclobutyl)methy])-5'-ch]oro-2',3',4,5-tetrahydro- 2H-spiro[benzo[b] [1 ,4]oxazepine-3, 1 '-indene]-7-carbox>'late (1.5 g, 2.076 mmoi, Step 1) was added tetrabutylammonium fluoride (7.50 ml, 1.0 M in THF, 7.50 mmoi, Sigma-Aldrich chemical Company Inc.). The solution was allowed to stir at rt for 2.0 h till TLC (20%EtOAc/Hexanes) indicated reaction completion. The resulting mixture was diluted with water (13) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with water (5mL) and brine (5 mL), and dried over MgSCk After removal of organic solvents under reduced pressure, the residue was purified by flash chromatography on ISCO Gold silica gel column with 0-55% EtOAc/Hexanes to provide the title products as a white foam.

STEP 12: (S)-TERT-BUTYL 5'-CHLORO-5-(((l R,2R)-2- FORMYLCYCLOBUTYL)METHYL)-2',3',4,5-TETRAHYDRO-2H- SPIRO[BENZO[B][ l,4]OX -3, l'-INDENE]-7-CARBOXYLATE The title compound was prepared from ((S)-tert-butyl 5'-chloro-5- (((lR,2R)-2-(hydrox 'me l)cyclobutyl)me l)-2^3^4,5-tetrahydro-2H- spiro benzo b] | ,4]oxazepine-3,r-mdene]-7-carboxylate as a white foam, following the procedure described for the synthesis of Intermediate AA16, Step 7. rrv'z (ESI, +ve ion) 482.2 { Yi - H ) .

STEP 13: (S)-TERT-BUTYL 5 ^! -CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METilYL)-2 ^f ,3',4,5-TETRAI-IYDRO-2H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , T-INDENE] -7 - C ARBOXYL ATE

To a -78 °C solution of (S)-tert-butyl 5'-chloro-5-(((l R,2R)-2- formylcyclobutyl)memyl)-2',3',4,5-tetrahydro-2H-spiro[benzo[ b] [l,4]oxazepine- 3,l '-indene]-7-carboxylate (1509 mg, 3.13 mmol) in THF (16 mL) under N ₂ was add vinylmagnesium bromide (6261 μΐ, 1.0 M in THF, 6.26 mmol, Sigma- Aldrich chemical Company Inc.) drop wise over 4 mm. After stirring in the - 78 °C bath for 2.0 hr, the reaction solution was allowed to warm with the bath to ambient temperature over 105 min. To this solution was added saturated aqueous NH4CI (12 mL) and water (12 m) and the mixture was left at ambient temperature overnight. The organic layer was separated, and the aqueous layer was back extracted with EtOAc (3 ^χ 15 mL). The organic solutions were combined, washed with brine (5 mL), and dried over MgS0 ₄ . After removal of organic solvents under reduced pressure, the residue was purified by flash

chromatography on I SCO Gold silica gel column with 0-30%» EtOAc/Hexanes. The first eluting fraction was collected as the title product as a white foam. STEP 14: (S)-5'-CHLORO-5-(((lR,2R)-2-((S)-l -

HYDROXYALLYL)CYCLOBUWL)METHYL)~2\3',4,5-TETl AHYDRO-2H- SPIRO I BENZO [B] [ 1 ,4 j OXAZEPINE-3 , 1 '-INDENE ] -7-C ARBOXYLIC ACID To a solution of (S)-tert-but l 5'-chloro-5-(((l R,2R)-2-((S)-l - hydroxyallyl)c^ lobu1\d)methyl)-2',3',4,5-tetrahydro-2H- spiro[benzo[b] [l,4]oxazepine-3,l'-indene]-7-carboxylate (655 mg, 1.284 mmol, Step 4) in CH2CI2 (8 inL) at ambient temperature was added trifluoroacetic acid (2 mL, Sigma-Aldrich chemical Company Inc.). The resulting mixture was allowed to stir at rt for 3.0 hr. After removal of organic solvents under reduced pressure, the residue was purified by flash chromatography on I SCO Gold silica gel column with 0-60% EtOAc/Hexanes (EtOAc contained 0.3% HO Ac) to provide the title compound as a white foam.

Intermediate EE 11

N,N-BIS(4-METHOXYBENZYL)

A solution of 4-methoxybenzaldehyde (100 g, 734.5 mmol, Spectrochem) and 4-methoxy benzyl amine (100 g, 734.5 mmol, G.L.R.) in toluene (0.8 L) was refluxed at 130 ^° C using a Dean Stark apparatus for 6 h. The reaction was monitored by TLC and uponn completion, excess solvent was removed under reduced pressure and the residue was dissolved in methanol (0.8 L). The resulting solution was cooled to 0 °C and sodium borohydride (36.12 g, 954.8 mmol) was added in portions. After complete addition the reaction mixture was stirred for 3 h at ambient temperature. Methanol was then removed, and the residue was diluted with water (1.0 L) and ethyl acetate (2.0 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layer was washed with water, brine and dried over sodium sulfate. Solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography over silica gel (100-200 mesh size) eluting with a gradient of 100% hexanes to 25% ethyl acetate in hexanes affording the title compound (160 g, 84.6%) as colorless but opaque liquid. Rf : 0.5 in 30% Ethyl acetate in hexane.

Intermediate EE 12

N,N-BlS(4-METHOXYB^ZYL) Em NESULFONAMIDE

A mixture of methanesulfonamide (Sigma- Aidnch, 5 g, 52.6 mmol), p- niethoxy benzyl chloride (14.98 mL, 1 10 mmol), potassium carbonate anhydrous (36.3 g, 263 mmol) and potassium iodide (0.873 g, 5.26 mmol) in anhydrous 2- butanone (175 ml) was refluxed (75 °C) overnight. The reaction was monitored by TLC and LC/MS and upon completion, the mixture was cooled to ambient temperature, filtered, washed with diethyl ether and concentrated. The crude material (17.54 g, 52.3 mmol, 99 % yield) was used with no further purification. MS (ESI, positive ion) m/z: 358.1 (M+Na).

Intermediate EE 13

N,N-BIS(4-METHOXYBENZY FONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 200 g, 775.19 mmol) in DCM (2.5 L) was added tnethylamine (336.17 mi, 2325.5 mmol), and the reaction mixture was cooled to 0 ^° C. Ethanes ulfonyl chloride (95 mL, 1007.75 mmol, Aldrich) was then added in drop-wise manner followed by DMAP (19.0 g, 155.03 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min. The reaction was monitored by TLC and upon completion, the mixture was diluted with water and the layers were separated and the aqueous phase was extracted with DCM (3 x 1.5 L), The combined organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography over silica gel (100-200 mesh), eluting with a gradient of 0-12% ethyl acetate in hexanes affording the title compound (145 g, 53.4%) as white fluffy solid. RJ: 0.5 in 20% Ethyl acetate in hexane.

Intermediate EE 14

N,N-BIS(4-METHQXYBENZY: )PRQPANES ULFON AMIDE

To a solution of N,N-bis(4-methoxybenzyl)amine (Intermediate EE11; 405 g, 1569.7 mmol) in DCM (4.0 L) was added tnethylamine (681.0 ml, 4709.3 mmol), and the reaction mixture was cooled to 0 ^° C. Propanesufonyl chloride (231 mL, 2040.6 mmol, Aldrich) was then added in a drop-wise manner followed by DMAP (38.3 g, 313.9 mmol). The resulting mixture was stirred at ambient temperature for 30 mm. The reaction was monitored by TLC and upon completion, the mixture was diluted with 2.0 L of water, the layers were seprated and the aqueous phase was extracted with DCM (3 x 2.0 L). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressui'e to afford the crude material which was purified by column chromatography over silica gel (100-200 mesh), eluting with a gradient of 0-12% ethyl acetate in hexanes affording the title compound (300 g, 52.44%) as w hile fluffy solid. Rf. 0.5 in 20% Ethyl acetate in hexane.

BUT-3-ENE- 1 -SULFONAMIDE

STEP 1 : SODIUM BUT-3-ENE-1 -SULFONATE

A mixture of 4-bromo- 1 -butene (3,01 ml, 29,6 mmol, LLBChem) and sodium sulfite (4.11 g, 32,6 mmol) in water (20 ml) was stirred at 1 10 °C overnight. The reaction was monitored by TLC and upon completion, water was removed under reduced pressure and the residue was triturated with acetone. The solid obtained was filtered to afford the title compound as a white solid (4.53 g) which was used as such in next step.

STEP 2: BUT-3-E E-1 -SULFONAMIDE

A mixture of sodium but-3-ene-l -sulfonate (4.50 g, 28.5 mmol) and phosphorus oxy chloride (70 mL) was stirred at 135 °C for 7 h. After this time, phosphorus oxy chloride was removed under reduced pressure to obtain a dark residue containing a white solid. This residue was diluted with acetonitrile (20 ml), and then filtered to remove the precipitate. The filtrate was cooled to 0 °C and then treated with ammonia solution (30% aqueous) (30 mL) drop-wise. After complete addition, the reaction was stirred at 0 °C for 30 min. The mixture was then diluted with ethyl acetate (300 mL), washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography over silica gel (100-200 mesh; eluting with 1 : 1 EtOAc/hexane), affording the title compound as white solid, 1.55 g, (yield: 40%). R 0.3 in 30% ethyl acetate in hexane. MS (ESI, positive ion) m/z: 1 17.1 (M+l).

Intermediate EE 16

Ν,Ν-ΒΙ8(4-ΜΕΊΉΟΧΥΒΕΝΖ )ΒϋΤ-3-ΕΝΕ-Ι-8υίΡΟΝΑΜΙΟΕ

A mixture of but-3-ene-l -sulfonamide (Intermediate EE 15; 1.5 g, 1 1 .10 mmol), p-methoxybenzyl chloride (3.76 mL, 27.7 mmol), potassium carbonate anhydrous (7.67 g, 55.5 mmol) and sodium iodide (0.166 g, 1.110 mmol) in anhydrous 2-butanone (55.5 ml) was refluxed (75 °C) overnight. The reaction was monitored by TLC and LC/MS and upon completion, the mixture was cooled to ambient temperature, filtered and concentrated. The crude material was absorbed onto a piu of silica gel and purified by chromatography through silica gel ( 100-200 mesh), eluting with 0 to 30 % EtOAc in hexane, to provide the title compound (4.10 g, 10.92 mmol, 98 % yield) as a colorless oil. Rf 0.7 in 30% ethyl acetate in hexane. MS (ESI, positive ion) m/z: 376.2 (M+l).

Intermediate EE 17

(R)-PENT-4-ENE-2-SULFONAMI

STEP 1 : (8)-Ν,Ν-Βί8(4-ΜΕΊΉΟΧΥΒΕΝΖΥΙ,)ΡΕΝΤ-4-Ε� �Ε-2-

SULFONAMIDE AND (R)-N,N-BIS(4- ETHOXYBENZYL)PENT-4-ENE-2- SULFONAMID

N,N-bis(4-methoxybenzyl)but-3-ene-l -sulfonamide (Intermediate EE! 6; 50.0 g, 133.2 mmol) was azeotroped with toluene and dried under vacuum for lh. THF (890 mL) was added and the mixture was cooled to -78 °C. n-butyi lithium (2.5M in hexanes, 63.9 mL, 159.9 mmol) was then added and the reaction mixture was stirred at -78 °C for lh. This anion solution was added slowly to a solution of iodomethane (16.8 mL, 266.5 mmol) in THF (300 mL) cooled to -78 °C. The resulting reaction mixture was stirred for another 15 min at -78 °C. On completion of the reaction (monitored by TLC), the mixture was quenched with saturated NH4CI solution and extracted with ethyl acetate. The organic layer was dried over Na ₂ S04 and concentrated under reduced pressure to obtain crude material which was purified by column chromatography over silica gel eluting with 5-10% ethyl acetate in hexane to provide the title compound as a racemic mixture (22.0 g) of semisolid nature. Separation of the enantiomers by SFC (Column: Chiralpak AD- H, 50 X 250 mm, 5 μ ηι: Mobile Phase A: ("().·: Mobile Phase B: Ethanol;

Isocratic: 40% B with C02 recycler on; Flow Rate: 200 g/min; Loading: 2.0 mL of sample prepared as above (-100 mg); Detection: UV @ 230 nm; Cycle Time: 5 min; Total Elution Time: 10 min; Instrument: Thar 350 (Lakers)) provided (S)- N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide as the first eluting isomer (retention time 2.22 min) and (R)-N,N-bis(4-methoxybenzyl)pent-4-ene-2- sulfonamide as the second eluting isomer (retention time 2,57 min).

STEP 2: (R)-PENT-4-ENE-2-SULFO AMIDE

To a solution of (R)-N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide (Intermediate EE! 7, Step 1, second eluting isomer; 221 mg, 0.567 mmol) in

CH2CI2 (2.8 mL), was added trifluoroacetic acid (1.7 mL, 22.70 mmol) dropwise (the clear solution very rapidly turned dark). After stirring for 7 h (TLC 30% EtOAc/hexanes showed complete loss of starting material) the mixture was diluted with EtOAc, washed with sat. NaHCCb, back extracted with EtOAc, dried over MgS04 and concentrated. The crude material was purified via

chromatography (12 g ISCO Gold column; 0-40%, EtOAc hexanes) to provide (R)-pent-4-ene-2-sulfonamide (70 mg, 0.469 mmol, 83 % yield)

Intermediate EE 172

(S)-PENT-4-ENE-2-SULFONAMl

This intermediate was synthesized from (S)-N,N-bis(4- methoxybenzyl)pent-4-ene-2-sulfonamide (Intermediate EE 17, Step 1 , first eluting isomer) using the procedure described for Intermediate EE 17, Step 2. Intermediate 8

(R)-HEX-5-ENE-3-SULFONAMI

STEP 1 : (S)-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-3-SULFONAMlDE AND (Κ)-Ν^Ν-Β -ΜΕ1ΉΟΧΥΒΕΝΖΥΕ)ΗΕΧ~5"ΕΝΕ-3-8υΕΡΟΝΑΜ ΙΟΕ

N,N-bis(4-methoxybenz l)but-3-ene-l -sulfonamide (Intermediate EE ! 6) (40.0 g, 106.6 mmol) was azeotroped in toluene under vacuum for 2 h. THF (700 mL) was added under argon atmosphere and the reaction mixture was cooled to - 78 °C. Butyl lithium (2.5M in hexanes; 71.6 mL, 127.9 mmol) was added and the reaction mixture was stirred at -78 °C for lh. This anion solution was added slowly to a solution of ethyl iodide (36.44 mL, 340.1 mmol) in THF (40 mL) cooled to -78 °C. The resulting reaction mixture was then quenched with saturated NH ₄ C1 solution, allowed to reach ambient temperature and extracted with ethyl acetate. The organic layer was dried over Na_S04 and concentrated under reduced pressure to obtain crude material which was purified by column chromatography over silica gel eluting with 5-10% ethyl acetate in hexane to provide the title compound as a racemic mixture (24 g) of semisolid nature. MS (ESI, positive ion) m/z; 404.03 (M+l). Separation of the enantiomers by SFC

(Sample preparation: 14.4 g/200 mL (72 mg/mL) sample solution in MeOFLDCM (3: 1); Column: Chiralpak AD-H, 30 X 250 mm, 5 μηι; Mobile Phase A: CO2; Mobile Phase B: MeOH(20mM M L): Isocratic: 50% B , Flow Rate: 100 mL/min: Outlet Pressure: 100 bar; Loading: 1.0 mL of sample solution prepared as above (72 mg); Detection: UV @ 227 nm; Cycle Time: 8 min; Total EJution Time: 17 min; Instrument: Thar 350 SFC) provided (S)-N,N-bis(4-methoxybetizyl)hex-5- ene-3-sulfonamide as the first eluting isomer and (R)-N,N-bis(4- methoxybenzyl)hex-5-ene-3 -sulfonamide as the second eluting isomer.

STEP 2: (R)-HEX-5-ENE-3-SULFONAMIDE

This intermediate was synthesized from (R)-N,N-bis(4- methoxybenzyl)hex-5-ene-3-sulfonamide (Intermediate EE18, Step 1, second eluting isomer) using the procedure described for Intermediate EE 17, Step 2.

(S)-HEX-5-ENE-3-SULFONAMIDE

H, -S"

This intermediate was synthesized from (S)-N,N-bis(4- methoxybenzyl)hex-5-ene-3 -sulfonamide (Intermediate EE18, Step I, first eluting isomer) using the procedure described for Intermediate EE! 7, Step 2,

N,N-BIS(4-METHOXYBEN -SULFONAMIDE

STEP 1 : SODIUM PENT-4-ENE- 1 -SULFONATE

© Θ %o

Na ο·

To a 3L 3 necked round-bottomed flask equiped with a mechanical stirrer, a nitrogen gas inlet, a condenser, and a temperature probe was charged 5-bromo- 1-pentene (Sigma Aldrich, 200 g, 1342 mmol), sodium sulfite (Strem Chemicals; 186 g, 1476 mmol), and water (400 mL). The mixture was heated to reflux (set at 100 °C and refluxed at 93-94 °C) 4 hours; aliquot N.V1R showed >95% conversion. The mixture was concentrated and azeotroped with acetone to remove water. The crude solid was washed with acetone and filtered to afford sodmm pent-4-ene-l -sulfonate (350 g, 2033 mmol).

STEP 2: PENT-4-ENE-1 -SULFONAMIDE

To a 3L 3 necked round-bottomed flask equiped with a mechanical stirrer, a nitrogen gas inlet, a condenser, and a temperature probe was charged sodium pent-4-ene-l -sulfonate (100 g, 581mmol) (-150 g of crude material from step 1) and phosphorus oxy chloride (Sigma Aldrich; 532 ml, 5808 mmol). The mixture was heated to 90 °C for 18 hours after which, the reaction was filtered and the solid was washed with CFbCN. The organic solution was concentrated and azeotroped with CH3CN to remove POCh to afford 85 g pent-4-ene-l -sulfonyl chloride intermediate. This material (solution in 300 mL CHsCN) was charged onto a 1L 3 necked round-bottomed flask equiped with a mechanical stirrer, a nitrogen gas inlet, a condenser, and a temperature probe. The reaction was cooled to Q~5°C and ammonium hydroxide (Sigma Aldrich; 28 % Nl¾; 404 ml, 2904 mmol) was added slowly over 30 min. The reaction was stirred at 0-5°C for 1 hour, after which EtOAc (300mL) was added and the mixture was extracted with EtOAc and concentrated to afford pent-4-ene-l -sulfonamide (50 g, 335 mmol, 57,7 % yield) as a brown oil

STEP 3: N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-l -SULFONAMIDE

The title compound was synthesized from pent-4-ene- 1 -sulfonamide (4.5 g, 30.2 mmol) following the procedure described for Intermediate EE16.

Purification of the crude material provided N,N-bis(4-methoxybenzyl)pent-4-ene- 1 -sulfonamide (1 1.4 g, 29.3 mmol, 97% yield) as a colorless oil.

Intermediate EE20

(R)-HEX-5-ENE-2-SULFONAMlDE

STEP 1 : (S)-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2-SULFO AMIDE AND (R)-N,N- FONAMIDE

A solution of N,N-bis(4-methoxybenzyl)ethanesulfonarnide (Intermediate

EE13; 140.0 g, 400.64 mrnoi) in THF (1.4 L, THF was purged with argon for 15 rnin before using) was cooled to -78 °C and butyl lithium solution (2.6 M in hexanes, 200.0 ml, 520.83 mmol) was added drop-wise. The mixture turned dark pink after complete addition. The resulting solution was stirred at -78 °C for 10 rnin, and 4-bromo- 1 -butene (73.2 ml, 721.15 mmol) was added over 2 min. The solution turned colorless or light brown upon addition of 4-bromo- 1 -butene. After 5 min, the reaction was allowed to reach ambient temperature and stir for 1 h. The reaction was monitored by TLC and upon completion, the mixture was quenched with saturated NH Cl solution (400 mL) and the resulting aqueous layer was extracted with ethyl acetate (2 x 1.0 L). The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude material which was purified by column chromatography (silica gel 100-200 mesh) eluting with a gradient of 0- 4% acetone in hexanes affording the title compound (racemic mixture, 80.0 g, 49.5%) as a colorless thick oil. R 0.5 in 10% Acetone in hexane. MS (ESI, positive ion) m/z: 404.25 (M+1). Separation of the enantiomers by SFC (Sample preparation: 75 g/1.5 L (50 mg/mL) sample solution in MeOH; Column: Chiralpak IF, 21 X 250 ram, 5 μτη; Mobile Phase A: CO2; Mobile Phase B: MeOH(0.2% DEA); Isocratic: 40% B; Flow Rate: 80 niL/min; Outlet Pressure: 100 bar; Loading: 3.0 mLof sample solution prepared as above (150 mg); Detection: UV @ 225 nm; Cycle Time: 3.9 min; Total Elution Time: 6 min; Instrument: Thar 80 SFC) provided (S)-N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide as the first eluting isomer and (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide as second eluting isomer.

STEP 2: (R)-HEX-5-ENE-2-SULFONAMIDE

The title compound was synthesized from (R)-N,N-bis(4- methoxybenzyl)hex-5-ene-2-sulfonamide (Intermediate EE20, Step 1, second eluting isomer) using the procedure described for Intermediate EE 17, Step 2.

(S)-HEX-5-ENE-2-SULFONAMIDE

H,N-S' r~ ^f

The title compound was synthesized from (S)-N,N-bis(4- methoxybenzyl)hex-5-ene-2-sulfonamide (Intermediate EE20, Step 1 , first eluting isomer) using the procedure described for Intermediate EE1 7, Step 2.

(R)-HEPT-6-ENE-3 -SULFONAMIDE i-s' '

STEP 1 : (S)-N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE"3- SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-

SULFONAMID

The title compound was synthesized from N,N-bis(4- methoxybenzyl)propanesulfonamide (Intermediate EE 14) using the procedure described for Intermediate AA20, Step 1. Rf : 0.5 in 10% acetone in hexane. Separation of the enantiomers by SFC (Sample preparation: 40.55g/170mL (238. mg/mL) sample solution in MeOH; Column: Chiralpak AD-H, 50 X 150 mm, 5 μηι; Mobile Phase A: CO2; Mobile Phase B: MeOH (20mM NH3); Isocrahc: 50% B; Flow Rate: 190 mL/min; Outlet Pressure: 100 bar; Loading: 1.5 mLof sample solution prepared as above (357.8 mg); Detection UV @ 227 nrn; Cycle Time: 17.5 min; Total Elution Time: 21 min; Instrument: Thar 350 SFC) provided (S)- N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide as the first eluting isomer and (R)-N,N-bis(4-methoxybenz 'l)hept-6-ene-3-sulfonamide as the second eluting isomer. STEP 2: (R)-HEPT-6-ENE-3-SULFONAMIDE

The title compound was synthesized from (R)-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide (Intermediate EE21, Step 1 , second eluting isomer) using the procedure described for Intermediate EE 17, Step 2. Intermediate ££212

(S)-HEPT-6-E E-3-SULFONAM

Thetitle compound was synthesized from (S)-N,N-bis(4- memoxybenzyl)hept-6-ene-3-sulfonamide (Intermediate EE21, Step 1, first eluting isomer) using the procedure described for Intermediate EE17, Step 2.

Intermediate ££22

(2R,3S)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

STEP 1 : (4S,5S)-4,5-DIMETHYL-I, ~DIOXATHIOLANE 2,2-DIOXIDE To a 500-mL, 3-necked round-bottomed flask (equipped with a water- cooled reflux condenser and an HC1 trap) was added (2s,3s)-(+)-2,3-butanediol (Aldrich, Milwaukee Wisconsin)(15.00 ml, 166 mmol) and CCU (120 ml).

Thion l chloride, reagentplus (14.57 ml, 200 mmol) was then added drop wise via a syringe over a period of 20 minutes and the resulting mixture was heated to 98 °C for 45 minutes, then it was allowed to cool to room temperature. Rf of intermediate = 0.42 eluting with 50% EtOAc in heptanes; use KMNO4 to visualize compound. The reaction mixture was then cooled in an ice-water bath, MeCN (120 mL) and water (150 mL) were added followed by ruthenium(lll) chloride (0.035 g, 0.166 mmol). Sodium periodate (53.4 g, 250 mmol) was then added slowly portion wise over 30 minutes. The resulting biphasic brown mixture was stirred vigorously while all owed to reach room temperature for a period of 1.5 hour (internal temperature never increased above room temperature). TLC (50% EtOAc in heptanes) show¾d complete conversion. The crude mixture was then poured into ice water and extracted twice with 300 ml of diethyl ether. The combined organic layers were washed once with 200 ml of saturated sodium bicarbonate, washed once with 200 ml of brine, dried over sodium sulfate and concentrated by rotary evaporation to give (4S,5S)-4,5-dimethyl-l,3,2- dioxatliio!ane 2,2-dioxide (21.2 g, 139 mmol) as a red oil.

STEP 2: (2S,3S)-3-METHYLHEX- -EN-2-OL

To a 500 ml flask was added (4S,5S)-4,5-dimethyi-l,3,2-dioxathiolaiie 2,2-dioxide (from Intermediate EE22, Step 1 ; 21.2 g, 139 mmol) and THF (220 mL) at which time the solution was cooled to - 78 °C and was subjected to 3 cycles of evacuation/back-filiing with argon. To the solution was then added dilithium tetrachlorocuprate(ii), 0.1m solution in tetrahydrofuran (69.7 mL, 6.97 mmol). The resulting mixture was stirred at -78 °C for 30 minutes and then allylmagnesium bromide, 1.0m solution in diethyl ether (397 mi,, 397 mmol) was added slowly via cannula over 80 minutes. The resulting mixture was stirred at 0 °C for 4 hours. The mixture was then quenched carefully with 200 mL water and allowed to reach room temperature at which time the volatiles were removed by rotary evaporation. To the aqueous residue was then added 50% H2SO4 (150 mL), the mixture was stirred for 5 minutes, Et ₂ 0 was then added (400 mL) and the mixture was stirred vigorously at room temperature overnight. The layers were then separated, the aqueous layer was extracted with 300 ml Et?,0 and the combined organic layers were washed with 300 ml of saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated by rotary evaporation to give (2S,3S)-3-methylhex-5-en-2-ol (6.7 g, 58.7 mmol) as a clear oil. Rf = 0.60 eluting with 50% EtOAc in heptanes.

STEP 3: 2^((2R,3S)-3-METHY -5-EN-2-YL)TfflO)PYRIMIDINE

To a 2000 ml dry round bottom flask containing a stirring solution of tributylphosphine (57.7 ml, 231 mmol) in 1000 mL degassed THF (sparged with argon for 30 minutes plus 5 cycles of pump/add argon) at 0 °C was added diethyl azodicarboxylate, 40 wl.% solution in toluene (103 ml, 262 mmol) drop wise un der an atmosphere of argon. Note: the orange color of DEAD was quenched almost immediately. Then a solution of (2S,3S)-3-methylhex-5-en-2-ol (from Intermediate EE22, Step 2; 17.6 g, 154 mmoi; dried over sodium sulfate) was added drop wise as a solution in 50 ml of THF to the solution of phosphine/DEAD complex, via syringe-filter (0.45 um). The resulting RQH/DEAD/Bu3p mixture was aged at zero degrees for 15 minutes (solution turned light orange), at which time pyrimidine-2-thiol (49.3 g, 439 mmol) was added gradually to the top of the reaction vessel (as a solid) under positive argon pressure. The reaction was stirred at 0 °C for lhour then at room temperature 15 hours (Reaction not done at 12 hours by LCMS). Note: The reaction cannot be monitored by the disappearance of starting material. Use toluene as an internal standard. The crude reaction was ihen filtered to remove excess pyrimidine-2-thiol, diluted with 1000 ml of EtOAc, extracted twice with 500 ml of 1 N K2CO3 and once with 500 ml of brine. The aqueous layer was back extracted with 300 ml of EtOAc and the combined organic layers were dried over sodium sulfate. The organic solution was then filtered, the solvent removed by rotary evaporation and the crude filtered to remove the (E)-di ethyl diazene-l,2-dicarboxylategenerated in the reaction . The filtrate (125 g) was passed through a silica plug (500 g silica, eluting with 2 L of DCM) to give 75 g of crude product after solvent removal. The crude product was purified again on a Combiflash (125 g gold silica column), eluting with 10% EtOAc in heptanes to give 2-(((2R,3S)-3-methylhex-5-en-2-yl)thio)pyrimidine (20.37 g, 98 mmol) as a light yellow oil.

STEP 4: 2-(((2R,3S)-3"METHY -5-EN-2~YL)SULFONYL)PYl lMlDINE

To a 500 ml three neck flask with a reflux condenser was added phenylphosphonic acid (3.95 g, 24.96 mmol), sodium tungstate oxide dihydrate (8.23 g, 24.96 mmol), tetrabuiyl ammonium sulfate, 50 wt. % solution in water (28.7 ml, 24.96 mmol), a catalytic amount of hydrogen peroxide 30% in water (12.75 ml, 125 mmol), toluene (200 ml) and 2-(((2R,3S)-3-methylhex-5-en-2- yl)thio)pyrimidine (from Intermediate EE22, Step 3; 52 g, 250 mmol). The reaction was stirred at 45 °C for 5 minutes at which time hydrogen peroxide 30% in water (58.6 ml, 574 mmol) was added portion wise (10 ml at a time). Five minutes after the first portion of hydrogen peroxide was added, an exotherm was observed (65 °C), the reaction was taken out of oil bath, the addition was stopped and the flask placed in a water bath until temperature stabilizes. The flask was taken out of the water bath and the portion wise addition of hydrogen peroxide was continued at a rate in which the internal temperature stayed between 45 °C and 55 °C (about 40 minutes). Note: an ice bath was utilized if the temperature went above 60 °C and an oil bath was used if the temperature fell below 45 °C. The reaction was then stirred at 45 °C for one hour. The reaction was diluted with 1400 ml of EtOAc and extracted two times with 500 ml of water and once with 500 ml of brine. The organic layer was dried o ver sodium sulfate, filtered, concentrated and the crude purified on a Combiflash (330 g gold silica column per 30 grams of crude), eluting with 0% - 50% EtOAc in heptanes to give 2-

(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)pyrimidine (55.7 g, 232 mmol) as a light yellow oil.

STEP 5: SODIUM (2R,3S)-3-METHYLHEX-5-ENE-2-SULFINATE

To a solution of 2-(((2R,3S)-3-methylhex-5-en-2- yl)sulfonyl)pyrimidine (from Intermediate EE22, Step 4; 52 g, 216 mmol) in MeOH (400 mL) at room temperature was added sodium methoxide solution (51.0 mL, 223 mmol) over 70 minutes. Note: sodium methoxide was added portion wise, the internal temperature was monitored and the addition was slowed or the reaction was cooled in a water bath, never letting the internal temperature exceeded 30 °C. The mixture was then concentrated by rotary evaporation and the waxy solid was triturated with MTBE (add 200 ml MTBE, stir for 1 hour using a spatula to break up clumps), filtered (use a stream of nitrogen over filter cake) and washed with 100 ml of cold MTBE to obtain sodium (2R,3S)-3-methylhex-5-ene- 2-sulfinate (46 g, 250 mmol) as a an off white solid.

STEP 6. : (2R,3S)-3-METHYLHEX-5-ENE-2-SULFONAMIDE

To a 1000 ml three neck flask was added sodium (2R,3S)-3-methylhex-5- ene-2-sulfmate (from Intermediate EE22, Step 5; 46 g, 225 mmol), 500 ml of water and potassium acetate (44.1 g, 449 mmol) at room temperature. The pH was checked (should be around pH = ^: 8.5) at which time the flask was place in a 45 °C oil bath and hydroxylamine-o-sulfonic acid (21.09 g, 187 mmol) was added portion wise over 90 minutes. Hie internal temperature of the reaction was monitored and the reaction was removed from the oil bath (if needed) to control exotherm (Tmax = 55 °C). Note: the reaction was monitored by LCMS every 10 minutes and was done after 0.83 eq. of hydroxylamine-o-sulfonic acid was added. The mixture was then cooled to room temperature and was extracted with 1000 ml of EtOAc. The organic phase was extracted three times with 500 ml of 1 HC1, two times with 300 ml of saturated sodium bicarbonate, once with 200 ml of brine, dried over sodium sulfate, filtered and concentrated by rotary evaporation to provide (2R,3S)-3-methylhex-5-ene-2-sulfonamide (32 g, 181 mmol) as a white solid.

EXAMPLE I . (l S,3'R,6'R,7 ^f S,8'E, I l 'R, i2'R)-6-CHLORO-l 1 '- (HYDROXYMETHYL)-7'-METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]()XA[ 13 |THIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ - ⁶ .0 ^l9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

STEP 1 : (S)-ETHYL 2-((,S)-l-I-r>T)ROXYETHYL)PENT-4-ENOATE

The following procedure was adapted from: Prater, G.; Muller, U.; Gunther, W.

Tetrahedron 1984, 40, 1269-1277. A 2 L 3 -neck flask and addition funnel were dried overnight in an oven. The joints were greased, then assembled hot, and cooled under a flush of argon. The center neck was equipped with a pressure equalizing addition funnel, one side was fitted with a septa and an argon inlet line, while the other side was equipped with an adaptor connected to an oil bubbler to monitor flow of argon through the reaction system. Once cooled, lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (830 mL, 830 mmol) was charged to the addition funnel, and then to the reactor. The reaction flask was cooled in an acetone/CC bath, and then a solution of (&)-(+)-3-hydroxy-n-butyric acid ethyl ester (49.4 mL, 378 mmol) in THF (50 mL) was added via cannula to the cooled reactor. This mixture stirred for 30 minutes, then was treated with ally! bromide (36.0 mL, 416 mmol). 10 minutes after the addition was complete, the reactor was removed from the bath and permitted to equilibrate to ambient temperature over 3 hours, when it was quenched by addition of saturated aqueous NH ₄ C1 (300 mL). The solution was transferred to a separator}' funnel . Water was added to dissolve the precipitated solids. The layers were mixed and then separated. The aqueous phase was extracted with EtOAc (2 x 250 mL). The combined extracts were washed with water (300 ml.) and then brine (300 mL). The solution was dried over MgSCH, filtered and concentrated. ^" Ή NMR analysis of the crude mixture showed that a considerable amount of HMDS was present. The concentrate was taken up in EtOAc (500 mL) then washed with IN HC1 (2 x 250 mL.), water, and brine. The solution was dried with MgS€>4, filtered and concentrated to afford a yellow oil. The oil was distilled at reduced pressure (4 mmHg, 60-70 °C) to yield a clear liquid, (S)-ethyl 2-((<S)-l-hydroxyethyl)pent-4-enoate (55 g, 319 mmol, 84 % yield). ^l H NMR (400 MHz, CDCh) δ 5.83 - 5.69 (m, 1 H), 5.14 - 5.07 (m, 1H), 5.07 - 5.02 (m, 1H), 4.19 (q, ./ 7. 1 Hz, 2H), 3.99 - 3.89 (m, 1H), 2.59 (d, ./ 7.4 Hz, i l l ). 2.51 - 2,36 (m, 31 1 1.28 i i. J 7. 1 Hz, 3H), 1.25 i d. ./ 6.5 Hz, 3H).

STEP 2: (2 ?,3S)-2-ALLYLBUTANE-l,3-DIOL

Lithium aluminum hydride, 1.0 M solution in THF (300 mL, 300 mmol) was cannulated to an oven dried 1 L Schlenk flask equipped with a nitrogen inlet through the side-arm. The flask was cooled in an ice-water hath. A solution of (S)-ethyl 2-((5 l -hydroxy ethyl)pent-4-enoate (25.9 g, 150 mmol) in THF (30 mL) was added dro wise via cannula to the stirring cold solution, over 15 minutes. The cannula and solution flask were rinsed with 15 mL of THF. The solution was stirred and the reaction progress was monitored by TLC Upon completion, the cold solution was slowly quenched with water (11.5 mL), 15% w/v aqueous NaOH (1 1.5 mL) and then more water (34 mL). Once the solution had warmed to RT, the solution was treated with Na2S04, and was then filtered. The solids were washed twice with hot EtOAc (2 x 100 mL). Concentration of the solution yielded a clear oil, characterized as (2 ?,35)-2-allylbutane-l,3-diol by ¾ NMR, of about 90% purity. The material was not purified further. ^" Ή NMR (400MHz, CDCb) δ 5.80 (tdd, J=17.2, 10.0, 7.1 Hz, 1H), 5.12 - 5.00 (m, 2H), 3.96 - 3.86 (m, 2H), 3.67 (dd, ./ Π .2. 6.3 Hz, H i ). 2.80 (br. s., 2H), 2.29 - 2.18 (m. 11 1 ). 2, 16 - 2.05 (m, I I I ). 1 .61 - 1.51 (m, i l l ). 1 ,28 !dd. ./ 6.3. 1.0 FIz, 3H).

STEP 3: (25 3i¾~3"(((77ii?J'-BUTYLDIMETHYLSlLYL)OXY)METHYL)HEX- 5-EN-2-OL

A solution of (2R,3S)-2-allylbutane-l ,3-diol (3.1 i g, 23.89 mmol) in DCM (50 ml) was treated with imidazole (2.00 ml, 30.4 mmol) and then tert- butyldimethylsilyl chloride (3.988 g, 26.5 mmol) causing the clear homogenous solution to become opaque white. The solution was stirred at ambient temperature (ca. 2 h) then quenched with water (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (25 mL). The combined organic layers were washed with brine, dried over Na ₂ S04, filtered and concentrated to yield clear oil. The oil was purified by column chromatography eluting with a gradient of 5 to 20% EtOAc/hexanes, on a 80g S1O2 column, to yield ( 2.V. ? A')-3-{ ( { /*.·/-/- butyldimethylsilyl)oxy)niethyl)hex-5-en~2~ol (4.47 g, 18.29 mmol, 77 % yield). ¾ NMR (400MHz, CDCh) δ 5.78 (dddd, j 1 .8. 10.0, 7.8, 6.3 Hz, 1H), 5.10 - 5 ,01 (m, 2H), 3.93 (dd, J=10.2, 3 ,7 Hz, ! ! ! }. 3.85 (qdd, 6.3. 6. 1 , 5. 1 Hz, 1 1 1 ). 3.65 (dd, J=10.2. 6.1 Hz, IH), 3.58 (d, J=5. l Hz, IH), 2.28 - 2.20 (m, I I I ). 2.14 - 2,05 (m, IH), 1.59 - 1.50 (m, IH), 1.25 (d,■/ 6, 3 Hz, 3H), 0.91 (s, 9H), 0.09 (s, 6H).

STEP 4: 2-(((2R,3R)-3-(((TERT- BUTYLDIMETHYLSILYL)OXY)METHYL)HEX-

YL)THIO)PY IMIDINE

A cold (0 °C) stirred solution of (25 ^, ,3iR)-3-(((ter/- butyldimethylsilyl)oxy)methyl)hex-5-en-2-ol (4.77 g, 19.51 mmol) and triethylamine (3.5 ml, 25.2 mmol) in DCM (40 mL) was treated with

methanesuifonyl chloride (2.0 mL, 25.8 mmol), added dropwise via syringe, which yielded an opaque mixture by the end of the addition. The solution was removed from the bath after 1 hour and stirred while equilibrating to ambient temperature. Water was added to the reaction mixture, and the lay ers were separated. The aqueous layer was extracted with DCM (2 x) then the combined organic layers were washed with I N HC1 (2 x 25 mL) and then saturated aqueous NaHCCb (25 mL), which caused the formation of an emulsion that could not be broken by addition of brine, additional NaCl, water, or hexane. Finally, the mixture was diluted with -300 mL EtOAc, and separation was observed. The layers were separated, and then the organic layer was washed with brine (50 mL), dried over MgS(>4, filtered and concentrated to give a clear oil. The oil was taken up in DMF (65 ml.) and treated with 2-mercapto- pyrimidine (2.22 g, 19.79 mmol) and potassium carbonate (2.73 g, 19.75 mmol) then the reaction mixture was stirred at ambient temperature for 18 hours. ^" Ή NMR analysis of an aliquot revealed minimal conversion. The reaction mixture was heated to 60 °C; within 5 hours the reaction failed to reach completion. More K2CO3 (300 mg) and 2-mercapto-pyrimidine (200 mg) were added and the solution stirred overnight (16 h). After cooling to room temperature, the reaction mixture was partitioned between water and EtO Ac. The layers were separated, and the aqueous layer was extracted once with EtO Ac. The combined organic extracts were washed thrice with brine, then dried over MgS0 ₄ , filtered and concentrated to yield an oily yellow residue. The residue was purified by column chromatography eiuting with a gradient of 10 to 30% EtOAc/hexanes on a 80g S1O2 column to afford 2-(((2/?,3/?)-3-(((teri-butyldimethylsilyl)oxv')iiiethyl)hex -5- en-2-yl)thio)pyrimidine (4.76 g, 14.06 mmol, 9: 1 mixture of thioether to

mesylate). ¾ NMR (400MHz, CDCh) δ 8.50 (d, ,7=4,9 Hz, 2H), 6.92 (t, J=4,8 Hz, 1H), 5.84 (ddt, ./ 1 7. 1 . 10.1, 7.0 Hz, IH), 5.12 - 5.02 (m, 2H), 4.22 (qd,

./ 74 . 4.2 Hz, i l l . 3.75 - 3.66 (m, 2H), 2.34 - 2. 1 7 (m, 2H), 2.02 - 1.93 (m, IH), 1.45 (d, J 7.0 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H); MS (ESI) mlz 339 3 ! VI H i . STEP 5: 2-(((2R,3R)-3-(((TERT-

BUTYLDIMETHYLSILYL)OXY)METHYL)HEX-5-EN-2- YL) S ULFON Y L)P YR1MIDINE

A solution of 2-(((2^,3^)-3-(((teri-butyldimethylsilyl)ox ')methy])hex-5- en-2-yl)thio)pyrimidine (4.76 g, 14.1 mmol) in DCM (75 mL) was cooled in an ice bath, then treated with 3-chlorobenzoperoxoic acid (6.62 g, 29.5 mmol) in a single portion. DMF (3 mL) was added causing the heterogeneous cloudy mixture to become clear. The solution was stirred in the ice-water bath and equilibrated to ambient temperature while stirring overnight. The mixture was quenched with saturated aqueous NaHCCb. The layers were separated, and the aqueous layer was extracted with DCM (2x). The combined extracts were washed twice with brine and then dried over MgS04, filtered and concentrated, yielding a yellow oil. The oil was purified by column chromatography on a 80g SiO?. column, eluting with a gradient of 0 to 100%, EtOAc/hexanes to yield 2-(((2R,3R)-3-(((fcrf- butyldimethylsilyl)oxy)methyl)hex-5-en-2-yl)sulfonyl)pyrimid ine (3.8g, 10.3 mmol, 73% yield). ¾ NMR (400 MHz, CDCb) δ 8.91 (d, .7=4.7 Hz, 2 H), 7.50 (t, ./ 4.9 Hz, 1 H), 5.67 (dddd, J=16.6, 10.4, 7.6, 6.8 Hz, 1 H), 4.98 - 5.07 (m, 2 H), 3.98 (qd, ./ 7.2. 3.3 Hz, 1 H), 3.89 (dd, ./ 10.4. 4.3 Hz, 1 H), 3.75 (dd,■/ i O.4. 5.7 Hz, I H), 2.44 - 2,53 (m, I H), 2.26 - 2,35 (m, I H), 2. 10 - 2, 19 (m, 1 H), 1.30 (d,

7.2 Hz, 3 H i. 0.83 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H); MS (ESI) m!z = 37 .2 | Μ · Π | .

STEP 6: (2.¾,3R)-3-(((TERT-BUTYLDIMETHYLSILYL)OXY)METHYL)HEX- 5-ENE-2-S ULF ON AMIDE

2-(((2^,3^)-3-(((tert-butyldimethylsi]yl)oxy)methyl)hex-5-en -2- yl)sulfonyl)pyrimidine (3.8 g, 10.25 mmol) was dissolved in MeOH (103 mL). The solution was treated with 25 wt% MeONa/MeOH (7.03 mL, 30.8 mmol). After stirring for 45 minutes, the reaction mixture was concentrated to yield a yellow foam. The foam was dissolved in water (100 mL) and treated with sodium acetate (1.73 g, 21.09 mmol) and hydroxylamine-o-sulfonic acid (1.160 g, 10.25 mmol). The solution was stirred at 50 °C for 5 hours, and was then cooled to ambient temperature. EtOAc (100 mL) was added and the layers were vigorously mixed. The organic layer was separated, and the aqueous layer was extracted twice more. The combined extracts were dried with MgSC , filtered and concentrated yielding a pale yellow residue. The residue was purified by column chromatography eluting with a gradient of 10 to 40% EtOAc/hexanes to yield (2K,3 ?)-3-(((ίer butyldimethylsilyl)oxy)me1hyl)hex-5-ene-2-sulfonamide (2.6 g, 8.45 mmol, 82 % yield) as a white solid. ^l H NMR (400 MHz, CDCh) δ 5.76 (dddd, ./ 1 .8. 10.6, 7,4, 6.7 Hz, i l l ). 5 ,06 - 5.14 (m, 2H), 4.88 (broad s, 2H), 3.80 (dd, J=10.9, 7.1 Hz, 1H), 3.65 (dd, J=10.9, 4.4 Hz, 1H), 3.25 (qd, J=7.2, 2.5 Hz, H i ). 2.48 (qdd,■/ 7.3. 4.5, 2.5 Hz, i l l ). 2.27 (dt, ./ 14.0. 6.8 Hz, I I I ). 1.98 - 2,09 (m, 1H), 1.41 i d. ./ 7.2 Hz, 3H), 0,91 (s, 10H), 0,09 (s, 3H), 0,09 (s, 3H). STEP 7: (S)-5-(((lR,2R)-2-i(lS,5R,6R^)-5-(((TERT-

BUTYLDIMETHYLSILYL)OXY)METHYL)-l-HYDROXY-6- SULFAMOYLHEPT-2-EN-.l -YL)CYCLOBUTYL)METHYL)-6'-CHLORO- ;r,4,4^5-TETRAHYDRO-2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPlNE-3,r~ NAPHTHALENE] -7-C ARBOXYLIC ACID

A 3-iieck flask containing a solution of Intermediate AA11 A (1 g, 2.137 mmol) and (27?,37?)-3-(((ter/-butyldimethy]silyl)oxy)rnethyl)hex-5-ene -2- sulfonamide (2,02 g, 6.57 mmol) in 1,2-dichloroethane (20 mL) was evacuated and backfilled with argon three times. Hoveyda-Grubbs 2 ^nd generation catalyst (0.140 g, 0.223 mmol) was then added as a solution in 1, 2-dichloroethane (1.0 mL). The dark green solution was stirred at ambient temperature, during which time it became dark brown. Within 30 minutes, starting materials, olefin homodimers and desired heterodinier product were observed by LC/MS analysis of the reaction mixture. After 4.5 hours, more catalyst (140 mg, 0.223 mmol) was added. An hour later, the reaction mixture was quenched by sparging air through the solution. The reaction solution was then concentrated and the residue was purified by column chromatography eluting with a gradient of 10% to 40% to 70% acetone/DCM, on a 80g Sit column to give a dark brown film (610 mg). MS (ESI): mlz = 746, 8 [M+H] ¹ ,

STEP 8: (1 S,3'R,6' ,7'S,8'EJ l 'R,12'R)-6-CHLORO-l l '-(((TERT- ΒυΤΥΙ.ΟΙΜΕΤΗΥΕ8Π.,ΥΙ. ΟΧΥ)ΜΕΤΕΙΥί)-7'-ΜΕΤΗΟΧΥ-12'-ΜΕΤΗΥΙ.,- 3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]~ 5'-ONE 13", 13 -DIOXIDE

The brown residue from Step 7 (610 mg) in DCM (16 mL) was treated with 4-dimethyiaminopyridine (170 mg, 1.392 mmol) and then l-(3- dirnethylaminopropyl)-3-ethylcarbodiiinideHCl (313 mg, 1 ,632 mmol), which was added in portions over 3 minutes. The brown solution was stirred at ambient temperature for 17 hours. The solution was diluted with DCM then washed successively with 1 M HCI, saturated aqueous NaHCCb and brine. The dark brown solution was dried over MgS0 ₄ , filtered and concentrated. The residue was purified by column chromatography eiuting with a gradient of 30 to 60%

EtOAc/hexanes on a 40g SiO?. column and a tan solid was obtained (250 mg). MS (ESI) miz --- ^: 728.8 | X 1 1 11

STEP 9: (1S,3¾,6'R,7'S,8'E,1 l'R,12'R)-6-CHLORO-l l'-(HYDROXYMETHYL)-

7'-METHOXY- 12'-METH YL-3,4-DIHYDRQ-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[ 13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The tan solid from Step 8 (208 mg) was azeotroped twice with toluene, then dissolved in THF (2.9 mL). Sodium hydride, 60% dispersion in mineral oil (48 mg, 1.200 mmol) was added to the solution, which was stirred for 30 minutes.

The resulting mixture was treated with methyl iodide (0.040 mL, 0.644 mmol) then stirred for 1 hour. The reaction was quenched with saturated aqueous NH ₄ C1, and the solution was diluted with EtOAc: a small amount of water was added to dissolve the precipitated solids. The lay ers were separated, and the organic layer was washed with brine then dried with MgS0 ₄ , filtered and concentrated to yield a light brown film (213 mg). The residue was taken up in 1M TBAF THF solution (3,0 mL) and stirred at 50 °C for 3,5 hours. The reaction was diluted with EtOAc then washed successively with water and brine. The solution was dried with MgSCK filtered and concentrated giving an orange foam residue, which was purified by column chromatography (30 to 70% (0.02% v/v

AcQH/EtOAc)/hexanes, 12g S1O2), to yield the title compound (157 mg, 0.250 mmol) as a white powder, ¾ NMR (400 MHz, CDCb) δ 8,85 (ill. br s), 7.71 {ill. d, ./ 8.6 Hz), 7,19 (IH, dd, ./ 8.4, 2,4 Hz), 7.09 (IH, d, J = 2,4 Hz), 6.97 (IH, dd, J= 8.2, 2.0 Hz), 6.93 (IH, apparent d, J= 8.0 Hz), 6.89 (IH, J = 1.6 Hz), 5.86 (IH, ddd, ./ 15.1, 9.8, 2.5 Hz), 5.59 (IH, dd, ./ 15.1, 9.2 Hz), 4,41 (IH, q, 7,2 Hz), 4.09 (2H, apparent singlet), 3.99 (IH, dd, J= 11.3, 6.0 Hz), 3,82 (ill. d, J = 14.9 Hz), 3.70 (IH, d, J = 14,5 Hz), 3.66 (IH, dd, ,/ 9,4, 3.5 Hz), 3,42 (IH, dd, J= 11.2, 6.2 Hz), 3.23 (3H, s), 3.01 (IH, dd, J= 15.3, 10.2 Hz), 2.82-2.71 (2H, m), 2,50-2.30 (3H, m), 2.16-1.95 (6H, m), 1.87-1.80 (3H, m), 1.70-1,60 (2H, m), 1.56 (3H, d, 8,0 Hz), 1.43-1,37 (IH, m); MS (ESI) !z = 628,9 [M+H] ⁺ . EXAMPLE 2. ! S,,.VR.6 ^' R.7 ^' S.8'I ^; .. I l'R,l 2 ^, R)-6-CHLORO-7'-METHOXY-l 1 ^* - (METHOXYMETHYL) - 12'-METH YL-3 ,4-DIHYDRO-2H, 15 Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8, 16, 18,24]TETRAEN]- '-ONE 13 ',13 '-DIOXIDE

ί !S.3'R,,6'R.7 ^' R.S ^' :. ! i ^' R. ί 2'R)-6-chioro- ! r-{hydrox> nHHhvj}-7'-melhox> - 12'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20ioxa|13jthia[l,14jdiazatetracyclo[14.7.2.0 ³ ^0 ^!9 ' ²⁴ |pentacosa[8,16,^

n]-15'-one 13',13'-dioxide (7.1 mg, 0.011 mmol. Example 1) was dissolved in THF (0.5 mL). Sodium hydride, 60% dispersion in mineral oil (2.6 mg, 0.063 mmol) was added and the mixture was stirred for 30 minutes, then it was treated with iodomethane (2.1 μί, 0.034 mmol). As little reaction was initially observed, excess sodium hydride and iodomethane were added, resulting in complete conversion to the desired product by LC/MS analysis of the reaction mixture. The reaction was quenched with MeOH, and concentrated under reduced pressure. The residue was absorbed onto a plug of SiCte, and then purified by column chromatography eiuting with 40% (0.2% AcOH/EtOAc)/'hexanes, to yield the bismethyieter product. Ή NMR analysis revealed the compound was

contaminated with "grease." The solution was concentrated, and the residue was partitioned between MeCN and hexanes. The layers were separated, and the hexane layer extracted twice with MeCN. The combined MeCN layers were washed again with hexanes. The MeCN layer was concentrated to yield a white film, (4.8 mg, 7.46 μιηοΐ). ¾ NMR (400 MHz, CDCh) δ 8.11 (1H, br s), 7.73 { i l l. d, ./ 8.4 Hz), 7,21 (1H, dd, ./ 8.4, 2.0 Hz), 7.10 (IH, d, J = 2,2 Hz), 6.91 (2H, m), 6.84 (IH, s), 5.84 (IH, ddd, J = 15.0, 10.0, 2.9 Hz), 5.60 (IH, dd, J = 15.0, 9.7 Hz), 4.37 (IH, q, J ------ 4.1 Hz), 4.08 (2H, s), 3.82 (IH, dd, ./ 8.8, 2.9

Hz), 3.81 (IH, d, J --- 15.3 Hz), 3.69 (I H, d, ./ 14.3 Hz), 3,64 (IH, dd, ./ 9.0, 3.1 Hz), 3.33 (3H, s), 3.24 (IH, d, J = 13.7 Hz), 3.23 (3H, s), 3.17 (IH, t, ./ = 9.0 Hz), 2.99 (IH, dd, ./ 15.5, 10.0 Hz), 2.83-2.71 (2H, m), 2.61 (IH, dd, J = 14.0, 10.0 Hz), 2.44 (IH, dq, ./ 9.5 (x3), 3.0 Hz), 2.36-2.27 (IH, m), 2.19-2, 12 (IH, m), 2.05-1.94 (3H, m), 1.86-1.78 (3H, m), 1 ,68-1.6 ! (3H, m), 1.51 (3H, d. ./ 7.4 Hz), 1.43-1.36 (IH, m); MS (ESI) m/z = 642.8 [M+H]

EXAMPLE 3. (1 S,3'R,6'R,7'S,8'E, 1 l ^* R,12'R)-6-CHLORO-l 1 '-((1R)-1- HYDROXYETHYL)-7'-METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1.T. 13'-DIOXIDE or

(IS^'R^l^T'S^T ll^ ' i^-CHLO O-ir-^lS l-HYD OXYETHYL)-?'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- [20]OXA[ 13]TH1A[1 4]DL ZATET1 ACYCLO[14;7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

A mixture of (1 S,3 ^! R,6'R,7'R,8'E,1 l 'R,12'R)-6-chloro-l Γ- (hydroxymethyl)-7'-methoxy- 12'-methyl-3,4-dihydro-2H, 15'H-spiro[naphthalene- l . -

[20]oxa[13]tMa[l,14]diazatetracy^

n]-15'-one 13',13'-dioxide (9.3 mg, 0.015 mmol, Example 1) and triethylamine (10 μΐ,, 0.072 mmol) in DMSO (500 μΕ) was treated with pyridine sulfur tnoxide (7.4 mg, 0.046 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, and then was diluted with EtOAc. The resulting solution was washed with water and then brine (2x), dried over MgSOi, filtered and concentrated to give a white film (10 mg). The residue was taken up in THF (0.5 mL), cooled in an ice bath and treated with MeMgBr (1.4 M in THF/PhMe, 1 :3, 50 uL, 0.07 mmol). After 30 minutes, the reaction mixture was quenched by addition of saturated aqueous NH4CI. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was further extracted with EtOAc (3x). The combined extracts were dried over MgS04, filtered and concentrated to yield a white film. The film was purified by column chromatography eluting with 8: 1 DCM: acetone on a 4g S1Q2 column to provide one of the title compounds as the first eluting diastereomer (1.16 mg). ¾ NMR (400 MHz, CD2CI2) δ 8.31 (broad s, IH), 7,75 id.. ./ H 1 1 Hz, IH), 7.21 (dd, «7=8.5, 2,5 Hz, 1H), 7.13 (s, IH), 6.90-7.04 (m, 3H), 5.80-5.91 (m, IH), 5.59 (dd, ./ 16.7. 8.1Hz, IH), 4.33 (q,

./ 7.30 Hz, IH), 4.17-4.09 (m, 2H), 4.09-4.00 (m, IH), 3.85 (d,■/ 1 .85 Hz, IH), 3,73 (d../ ! 3.9 Hz, III).3.67 (dd, ./ 8.7.3,2 Hz, 1H), 3.29 (d, J=14.5 Hz, H), 3.22 (s, 3H), 3.08 (dd, J=10.07, 15.36 Hz, lH), 2.88-2.72 (m, 2H), 2.52-2.32 (m, 2H), 2.15-1.79 (m, 4H), 1.76-1.66 (m, 1H), 1.62 id../ 7.4 H .3H), 1.57 (br. s., 6H), 1.50-1.39 ( in. ill).1.20 (d, ,/ 6.1 Hz, 311): MS (ESI) m/z = 642,8 | Yl ί ! |

EXAMPLE 4. (lS,3'R,6 ^, R,7'S,8 ^, E,ll ^, R,12'R)-6-CHLORO-l l'-((lR)-l- HYDROXYETHYL)-7'-METH()XY-12'-METHYL-3,4-DIHYDR()-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE or

(lS^'^e'R 'S.S^ll'R^^R^e-CHLORO-ir-iilS^l-HYDROXYETHYL)-?-

METHOXY- 12'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTHALENE-

1 ">"> ^< -

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14.7.2.0 ^3>, 0 ^!9 - ²⁴ ]PENTACOSA [8,16, 18 , 24] TETRAEN] - 15 ^! -ONE 13', 13 ^! -DIOXIDE

The title compound was synthesized as described for Example 3 and was isolated as the second eluting (slower) diastereomer (1.46 mg) in Example 3. ^! H NMR (400 MHz, Π)>Π.·) δ 8,07 (br. s .1H), 7.71 (d, J=8,6 Hz, 1H), 7.17 (dd,

,/ H4.2.3 Hz, lH), 7,09 (d, ./ 2.3 Hz, IH), 6.94 - 6.87 (m, 2H), 6.84 (s, 1H), 5.90

- 5.79 (m, H), 5.62 - 5,52 (m, IH), 4.50 - 4.42 (m, H), 4.34 - 4,27 (m, IH), 4.13

- 4.04 Cm.2H), 3.82 (d, J=15.1 Hz, ill).3.70 (d, ./ 14. j Hz, IH), 3.62 (dd, ./ 9.2. 3.1 Hz, IH), 3.25 { ,! 14.3 Hz, IH), 3.18 (s, Ml).3.03 (dd,J=15.4, 9.9 Hz, IH), 2.84 - 2.69 (ra, 2H), 2,49 - 2.23 (m, 4H), 2.09 - 2.01 (ra, IH), 2,00 - 1.90 (m, 2H), 1,88 - 1.68 (m, 2H), 1.64 id.,/ 7.4!!/.3H), 1.30- 1,24 (m, 5H), 1.19 (d, J=6.7 Hz, 311): MS (ESI) m!z = 642.8 [M+H] ¹ .

EXAMPLE 5.(1S,3¾,6'R,7'S,8'E,1 l'R,12'R)-6-CHLORO-l 1'- (FLUOROMETHYL)-7 ^! -METHOXY-12 ^! -METHYL-3,4-DIHYDRO-2HV15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14.7.2.0 ^3>, 0 ^!9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]~ '-ONE 13", 13-DIOXIDE

A solution of (18,3¾,6Έ,7¾,8Έ,11¾,12¾)-6^ΙοΐΌ-11'

(h}'droxymethyl)-7'-methoxy-12'-meihyS-3,4-di

1 ">"> ^< -

[20joxa[13]thia[l,14]diazatetracycfo[14J _^

n]-15'-one 13',13'-dioxide (9.7 mg, 0.015 mmol. Example 1) in 1 ,2-dichloroethane (500 _, uL) was treated with (diethylamino)sulfur trifluoride (5,09 μΐ,, 0.039 mmol) at 0 °C, which caused the colorless solution to become yellow. The solution was stirred for 15 minutes. The reaction solution was absorbed onto a plug of S1O2 and purified by column chromaotgraphy (10 to 100% EtOAc/hexanes with 0.02% AcOH, 4g Si 0.0 to give the title product (3.7 mg). ¾ NMR (400 MHz, CDCb) δ 8.18 (s, III).7.70 id. j 8.6 Hz, 111).7.19 (dd, .! 2.2.8.5 Hz, III).7.10 id..! 2.3 Hz, 1H), 6.96 - 6.89 (m, 2H), 6,86 (s, 111).5,85 (ddd, j 3 !.10.1, 15.1 Hz, IH), 5.62 (ddd, j 1.2.9.4, 15.3 Hz, IH), 4.73 (ddd, ..! 4,5.9.4, 46.4 Hz, IH), 4.53 (ddd, j 6.H.9.4, 47.0 Hz, IH), 4.44 - 4.38 (m, IH), 4.15 - 4.06 (m, 211 ).3.82 id. j 15, 1 Hz, IH), 3,70 id. j 145 Hz, IH), 3,65 (dd, j 3 1.9.2 Hz, IH), 3.23 (s, Ml).3.01 (dd, j ! 0.3, 15.2 Hz, IH), 2.86 - 2.70 (m, 2H), 2.60 - 2,41 (m, 2H), 2.39 - 2.26

(m, 2H), 2.25 - 2.20 (m, IH), 2.21 - 2.08 (m, IH), 2.07 - 1.91 (m, 2H), 1.90 - 1.77 (m, 2H), 1 .72 - 1.52 (m, 7H), 1 ,40 (t, J=12.9 Hz, i l l ): MS (ESI) rn!z ------ 631.2

[M+H] ⁺ .

EXAMPLE 8. (18,3¾,6'Κ,7'8,8Έ,12Έ)-6-€ΗΙ.,ΟΚΟ-4,4-ΟΐΡΙ.υ θΚΟ-7'- HYDROXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI l^T^.O'^.O'^lPENTACOSA

[8, 16, 18,24]TETRAEN]~15'-ONE 13", 13 -DIOXIDE

STEP 1 : (S)-6'-CHLORO-4;4 ^, -DIFLUORO-N-((R)-HEX-5-EN-2- YLSULFONYL)-5-(((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l- Y ! .)i VC i OBL TYUYl h ! 1 1 Υ ! .)-3'.4. ·Γ.5- Π·. 1 R A! !Y I>RO-2l i.2'1 !- SPIR()[BENZO Bj[ L4]()XAZEPINE-3,r-NAPHTHALENEl-7- CARBOXAMTDE

The title compound was prepared from Intermediate AA18 and

Intermediate EE 17 using a procedure similar to that of Example 6 Step 1.

STEP 2: (lS,3'R,6'R,7'S,8'E,I2'R.)-6-CHLORO-4,4-DIFLUORO-7'-HYDROXY- '-METHYL-S^-DIHYDRO^H S^SPIROINAPHTHALENE-l^^- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 4.7 , 2, 0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] PENT ACO S A [8, 16, 18,24]TETRAEN]-15'-ONE 13', '-DIOXIDE

To a stirred solution of (S)-6'-chloro-4 ^, ,4'-difluoro-N-((R)-hex-5-en-2-ylsulfonyl)- 5-((( 1 R,2R)-2-((S,E)- 1 -hy droxyhex-2-en- 1 -yl)cy clobut l)niethy i)-3',4,4 ^! ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide (150 mg, 0.217 mmol, Step 1 ) in AcOH (5 mL) sealed and sparged with argon was added (l,3-dimesitylimidazolidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium(VI) chloride (13.60 mg, 0.022 mmol). The reaction was pulled under vacuum and then again sparged with argon and set to stir for 3 h, after which the reaction was stripped of solvent and purified over silica with 20% acetone in hexanes to yield the title compound as a white solid (60 mg, 0.088 mmol, 40%). Ή NMR (400 Ml 1/. CD2CI2) δ 7.80 id. ,/ 8 61 Hz, 1H), 7.62 -7.72 (m, IH), 7.47 (s, 1H), 6.91-7.05 (m, 3H), 5.77-5.94 (m, 1H), 5.61- 5.77 (m, IH), 4.23 (dd,J=4.1 1, 7.43 Hz, 1H), 4.12-4.19 (m,2H), 4.02-4.10 (m, IH), 3,87 (d, ,/ 1 .89 Hz, IH), 3.73 (d, 14.48 Hz, IH), 3.2 ! (d, 14 28 Hz,

IH), 2,98 (dd, ./ 9.39. 15.45 Hz, IH), 2.27-2.54 (ra, 5H), 2, 1 1 -2.23 (m, 2H), 2.10 (s, 2H), 2.00 (q, J=8.09 Hz, 1H),1.72-1.92 (m, 5H), 1.66 (q, ./ 9.32 Hz, IH), 1.55 (d, ./ 7.04 Hz, 3H).

EXAMPLE 9. (1S,3'R,6'R,7 ^! S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2-(3,3-DIFLUORO- 1 -AZETIDINYL)ETHOXY)- 11 ', 12 ^, -DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N ΆΡΗΤΗ ALENE- 1.22 ^' -

| 2 ϊ !()ΧΑ| ! 3 ΓΓί ! ΙΛ| Ι . Ι 4 | ί)! ΛΖΛΊ ·:ΓΡνΛί YC ^' I.OI i 4.7.2.0 'Mi'^ ^kNTAi <)SA| 8,16,18,24]TETRAEN]-15'-ONE 13", 13 -DIOXIDE

To a stirred solution of (1 8,3¾,6'Κ,7'8,8Έ, Γί'8,

6-ehloro-l 1 ', 12'-dimethyl~3,4-dihydro-2h, 15'h-spiroj naphtha! ene-1 ,22'- [20joxa 13]thia[ l, 14]diazatetracycfo[14 _^

n]-15'-one 13', 13'-dioxide (17 mg, 0.024 mmol. Example 14) and 4,4- difluoroazetidine hydrochloride (37.9 mg, 0.241 mmol) in 250 μΕ DMSO was added triethylamine (50.3 μΕ, 0.361 mmol) and the reaction stirred at 50 °C overnight. The reaction was then cooled to rt, filtered and purified by prep HPLC to provide the title compound (1.5 mg, 2.01 μηιοΐ, 8.35 % yield) as a white solid. ^] H NMR (400 MHz, CD2CI2) δ 8.07-8.37 (m, 1 H), 7.70 (d, 8. 1 Hz, i l l ). 7, 1 7 (dd, «/=2.35, 8,41 Hz, i l l ). 7.09 (d, ,7=2, 15 Hz, H), 6.92 (s, 2H), 6.81 (s, IH), 5.76-5.95 (m, IH), 5.51 (dd, J=9.59, 15.45 Hz, IH), 4.25 (d, J=7.04 Hz, IH), 4.08 (s, 2H), 3.78 (s, 3H), 3.69 (d, ./ 14.28 Hz, IH), 3.51-3.61 (m, I H), 3.42 (d, ./ 3. 1 Hz, 2H), 3.24 (d, ,/ 14 28 Hz, I H), 2,97-3.08 (m, IH), 2.72-2.85 (m, 2H), 2.70 (s, IH), 2.38-2.50 (m, IH), 2.28-2.38 (m, H), 1.92-2,23 (m, 6H), 1.64-1.88 (m, 4H), 1.44 (d, J=7.24 Hz, 3H), 1.34-1.41 (m, IH), 1.02 (d, J=6.85 Hz, 3H).

EXAMPLE 10. (1S,3'R,6 ^! R,7'S,8'E, 1 l'S,12'R)-6-CHL()RO-7'-(2-(4,4- DIFLUORO - 1 -PIPERIDINYL)ETHOXY)- Γ , 12'-DIMETHYL-3 ,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THlA[l,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ '() ^!9 - ²⁴ ipENTACOSA[ 8,16, 18,24]TETRAEN]-15'-ONE -13,13'-DIOXIDE

The title compound was prepared from (lS^^e^ ^^UlTS TR)-?"^- bromoethoxy)-6-chloro-11^12'-dimethyl-3,4-dihydro-2h,15'h-sp iro[naphthalene-

122'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[14.7.2.0 ³ ' ^{6 l9} - ^24J pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (17 mg, 0.024 rnrnol, Example 14) using a procedure similar to that of Example 9. ^! H NMR (400 MHz, CDCh) δ 7.69 (d, J=8.41 Hz, 1H), 7.19 (dd, ,7=2.25, 8.31 Hz, III .7.10 (d, J=2.35 Hz, III).6.88-6.97 (m, 2H), 6.82 (d, ,7=1,37 Hz, 1H), 5.82-5,96 (m, IH), 5.82-5.95 (m, IH), 5.52 (dd, J=9.39, 14.87 Hz, ill).4,30 (q.J 7.17 Hz, IH), 4.09 (s, 2H), 3.74-3.87 (m, 3H), 3.70 (d, ,7=13.89 Hz, IH), 3.52-3.63 (m, IH), 3.17-3.29 (m, 3H), 3.01 (dd, ,7=10.07, 14.97 Hz, IH), 2,72-2,84 (m, 2H), 2.28-2.50 (ra, IH), 2,09-2.24 (m, IH), 1.93-2.06 (m, 2H), 1,74-1.88 (m, IH), 1.67 (t, ,7=9.00 Hz, IH), 1.50 (d, ,7=7,24 Hz, 3H), 1.32- 1.46 (m, IH), 1.06 (d, J=6.85 Hz, 3H). EXAMPLE 11. (IS^' ^'R 'S^'EjrS/^'Ri^-CHLO O-H^^'-DlMETHYL- 7'-(2-(PHENYLAMINO)ETHOXY)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- ! ,22'-

[20]OXA[13]TH1A[1,14]DL\ZATETRACYCLO[14.7.2.0^ ⁶ O ¹⁹ - ²⁴ ¥ENTACOSA| 8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (lS,3'R,6'R,7'S,8'E, i S,12 ^! R)-7 ^! - (2-bromoethoxy)-6-chloro-i ,12'-dimethyl-3,4-dihydro-2h,15'h- spiro [naph thalene- 1 ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ i 4, 7.2, 0 ³ · ⁶ 0 ^!9 - ²⁴ ipentacosa[8, 16, 18,24]tetrae n]-15'-one 13',13'-dioxide (Example 14) and aniline using a procedure similar to that of Example 9. ^! H NMR (500 MHz, CDCb) δ 7.70 (d, J=8.56 Hz, IH), 7.16- 7,23 (m, 3H), 7.10 (d, ,/ 220 Hz, IH), 6.89-6.98 (m, 2H), 6,86 (d, ./ !.7i Hz, IH), 6,72 (t, .7=7.34 Hz, IH), 6.64 (d, J=7.58 Hz, 2H), 5.71-5.88 (m, H), 5.53 (dd, J=9.29, 15.16 Hz, IH), 4.30 (d, ./ 7.34 Hz, IH), 4.11-4.18 (m, 4H), 4.09 (s, 2H), 3.79 (s, IH), 3.76-3.79 (m, IH), 3.70 (d, ./ 14.43 Hz, 111).3.62 {id. J=5.20, 10.15 Hz, IH), 3,45-3.52 (m, IH), 3.20-3,29 (m, Ml).2.99 (dd, J=10.15, 15.28 Hz, IH), 2.71-2.80 (m, 2H), 2.40-2.51 (m, IH), 2.31-2.36 (ni, IH), 1.86-1.90 (m, 2H), 1.80-1.86 (m, 3H), 1.69-1.78 (m, 6H), 1.54-1.54 (m, 111}.1.48 id. 7.09 H/. 3H), 1.05 (s, 3H).

EXAMPLE 12. (IS^' ^'R 'S^'EJl'S/^'Ri^-CHLO O-H^^'-DlMETHYL- 7'-(2-(2-PYRlDINYLAMINO)ETHOXY)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- ! ,22'- [20]OXA[13]TH1A[1,14]DL ZATETRACYCLO[14.7.2.0-^,6~.0~19,24~]PENT ACOS A[ 8, 16, 18 ,24] TETRAEN | - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (l S,3'R,6'R,7'S,8'E, i S,12 ^! R)-7 ^! - (2-bromoe1hoxy)-6-cMoro-i ,12 ^, -dimethyl-3,4-dihydro-2h,15'h- spiro [naph thalene- 1 ,22'- [20]oxa[ 1 3]thia[ 1 , 14] diazatetracy clo[ I 4, 7.2, 0 ³ · ⁶ 0 ^{! 9} - ²⁴ ipentacosa[8, 16, 18,24]tetrae n]-15'-one 13',13'-dioxide (Example 14) and pyridin-2 -amine using a procedure similar to that of Example 9. H NMR (500 MHz, CDCh) δ 8.36-8.39 (m, 1H), 8,05 (br. s . l i s ). 7.77 (d, .7=7.09 Hz, 2H), 7.69 id. J=8,56 Hz, H), 7.26 (br. s„ IH), 7, 14-7.20 (m, I H i. 7.09 (d, .7=1.47 Hz, IH), 6,86-6,95 (m, 3H), 6.85 (s, IH), 6.72 (t, ./ 6.24 Hz, IH), 5.73-5.92 (m, IH), 5.50 (dd, ./ 8,80. 14.92 Hz, IH), 4.29 (d, ./ 7.09 Hz, IH), 4.08 (s, 2H), 3.76-3.91 (m, 3H), 3.61-3.74 (m, 2H), 3.48 (d, ./ 1 8.34 Hz, 4H), 3,22 (d, ./ 14.43 Hz, IH), 3.00 (dd, ,/ 10 03. 15. 16 Hz, IH), 2.78 (br. s., 3H), 2.43-2.56 (m, 2H), 2.23-2.34 (m, 3H), 1.77-1.86 (m, 2H), 1.73 (d,■/ 6.85 Hz, 2H), 1.56-1.69 (m, 2H), 1.49 (d, .7=7.09 Hz, 4H), 1.27-1.42 (m, 2H), 1 , 05 (d, ,/ 6.85 Hz, 3H).

EXAMPLE 13. (1 S,3'R,6'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO-l 1 ', 12'-DIMETHYL- 7 ^, -(2-(MEraYL(2-PYRi:DrNYL)AMINO)ETHOXY)-3,4-DIHYDRO-2H, 15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]TmA[l,14]DL\ZATETRACYCLO[14.7.2.0-^,6~.0~19,24 ~]PENT ACOS A[ 8, 16, 18 ,24] TETRAEN | - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (1S,3'R,6'R,7'S,8'E,11 ^f S,12'R)-7'- (2-bromoethoxy)-6-chloro- 11 ', 12'-dimethyl-3,4-dihy dro-2H, 15Ή- spiro [naphthalene- 1 ,22'- [2C)joxa[13]thia[l,14]diazatetracy ^

n]-15'-one 13',13'-dioxide (Example 14) and N-methylpyridin-2-amine using a procedure similar to that of Example 9. R NMR (500 MHz, CDCb) δ 8.12 (d, ./ 4.65 Hz, III).7.55-7.76 (m, 2H), 7.10 (dd, ./ 2.20.8.56 Hz, ill).7.02 (s, ill). 6.89 (d, J=9.29 Hz, IH), 6.79-6,85 (m, 2H), 6.67-6.79 (m, 2H), 5.71-5,87 (m, Hi). 5.33-5.48 (m, ill).4,17-4.27 (m, I Hi,.3.98-4,05 (m, 2H), 3.53-3.79 (m, 6H), 3,48- 3.48 (m, IH), 3.37-3.47 (m, IH), 3.20-3.34 (m, 3H), 3.09-3.19 (m, 2H), 2.86-2.87 (m, IH), 2.86-3.00 (m, 2H), 2.15-2.41 (m, 4H), 1.86-2.12 (m, 7H), 1.72 (dd, ,/ 220.6,11 Hz, 2H), 1,48-1,68 (m, 3H), 1.37-1.45 (ra, 311).0,92-1.04 (m, 311). EXAMPLE 14. (1S,3'R,6'R,7'S,8'E,11'8,12¾)-7'-(2-Β10ΜΟΕ1ΉΟΧΥ)-6- CHLORO-11 ', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOI^.y^.O'^O^^PE TACOSAt 8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

STEP 1 : 2-BROMOETHYL TRTFLUOROMETHANESULFONATE

To a stirred solution of pyridine (0.712 mL, 8.80 rnnioi) in 80 mL at -20 °C in an ethylene giy col-dry ice bath was added trifluoromethanesulfonic anhydride (1.344 mL, 8.00 mmol) dropwise. The reaction was stirred for 10 min, followed by slow addition 2-bromoethanol (0.567 ml, 8.00 mmol), and the reaction was again left to stir, warming to RT for 10 minutes. The resulting suspension was filtered, concentrated (using a rotary evaporator, keeping the water bath temp below 20 °C) and petroleum ether (3 mL) was added. The mixture was filtered and concentrated again under reduced pressure to give the title product 2-bromoethyl trifluoromethanesulfonate (1.6 g, 6.23 mmol, 78%) as a clear colorless oil, which was stored cold in a freezer to prevent decomposition.

STEP 2: . (lS,3'R,6'R,7 ^, S,8'E,i rS,12'R)-7'-(2-BROMOETHOXY)-6-CHLORO- 1 1 ', 12'-DIMETHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'~

| 2( >X A | i ? I U Π Λ | ί i J l i^f AZ.Vf l: E R AC YCE C)l i J 7.2 O ^ ^' O ¹ " ^' 'iprNTAC \ | 8/16,18,24]TETRAEN j - 15'-ONE 13', 13'-DIOXIDE

To a stirred solution 2-bromoethyl trifluoromethanesulfonate (844 mg, 3.28 mmol) and il S^'R^'^TS^^i rS. 'R^e-chloro-T-hydro -i r,! ^- dimethyl-3,4-dihydro-2h,15'h-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetn^

n]-15'-one 13',13'-dioxide (246 mg, 0.411 mmol; Example 719, Step 2) in DCM was added 2,6-di-tert-butylpyridine (1386 μΤ, 6.16 mmol), sealed with a pressure release fitted cap and heated to 40 °C. Over three hours, an additional five equivalents of 2-bromoethyl trifluoromethanesulfonate was added portionwise and was again heated to 60 °C. After an additional hour of heating, the reaction was allowed to cool to RT, stripped of solvent and purified over silica using 20% acetone in hexanes to yield the title compound as a brown solid (210 mg, 0.297 mmol, 72.4%), l \Y1R (400 MHz, CDCb) δ 8.19 (br. s . !!!).7.70 (d, J 86! Hz, 1H), 7.18 (dd,J=2.35, 8.41 Hz, lH), 7.08-7.13 (m, 1H), 7.07 (s, 1H), 7.06- 7.11 (m, 1H), 6.94 id../ 0.78 Hz, 2H), 6.85-6.90 {in. III).5.85 (ddd, ./ 3.33.9.49, 15.16Hz, IH), 5.56 (dd, J=9.10, 15.16 Hz, 111).4.33 (q, J=7.11 Hz, III).4.13 (q, J=7.24 Hz, ill).4,09 (s, 2H), 3,66-3.88 (m, 4H), 3.54-3,65 (m, 1H), 3.49 (q,

J=6.91 Hz, IH), 3.38-3.44 (m, 2H), 3.38-3.44 (m, 2H), 3.23 (d, J=14.28 Hz, IH), 3.01 (dd../ 10.17.15.26 Hz, IH), 2.69-2.85 (m, 2H), 2.43-2.54 (m, !!!).2.41- 2,57 (m, IH), 2.25-2.39 (m, H), 2.1 I id. J-9.39 Hz, IH), 2,01 (s, 2H), 1,94-2.00 (m, 2H), 1.79-1.91 (m, 3H), 1,59-1.69 (rn, 3H), 1.50 (d, .7=7.24 Hz, Ml).1.05 (d, J-6.85 Hz, 3H).

EXAMPLE 15. 2-(((lS,3 ^, R,6'R,7'S,8'E,irS,12'R)-6-CHLOR()-ll',12'- DIMETHYL-13',13-DIOXIDO-l 5-0X0-3 ,4-DIHYDRO-2H- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 ''(! ^l " ⁿ H ^> !iN ^' !V\( ^' <)SA| 8, 16, 8,24]TETRAENj-7'-YL)OXY)ETHANESULFONAMIDE

The title compound (5 mg, 7.08 μηιοΐ, 13%) was prepared from

(lS,3Έ,6 ^! R,7Έ,8Έ,ll'S,12'R)-7'-(2-bromoethoxy)-6-chIoro-lΓ,1 2'-dlίnethyl-3,4- dihy dro-2H, 15 Ή-spiro [naphtha] ene- 1 , 22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7,2.0 ³ - ⁶ '0 ¹⁹ - ²⁴ ^

n]-15'-one 13', 13'-di oxide (Example 14) using procedures Similar to those described for Example 18, Steps 6-8 with the exception that the leaving group in Example 14 was the bromide rather than the mesylate. ^! H NMR (500 MHz,

CDCb) δ 7.88-7.98 (m, IH), 7.69 (d, J=8.56 Hz, IH), 7.16-7.21 (m, IH), 7.19 (dd, ,/ 220.8,56 Hz, 1H), 7.10 (d, ./ 2.20 Hz, 1H), 6,89-6.96 (m, 2H), 6.84 (d, ./ !,7i Hz, 1H), 5.91 (ddd, J=3.18, 9.84, 15.10 Hz, IH), 5.55 (dd, J=9.29, 15.16 Hz, 1H), 4.32 (q, ,/ 7.25 Hz, 1H), 4.08-4.13 (in, 2H), 3.82-3.96 (m, 3H), 3.65-3.78 (m, 2H), 3.34 idi. ,/ 4.40.7,09 Hz, 2H), 3.23 (d, J=14.18 Hz, ill).3.02 (dd,J=10.15, 15.28 Hz, IH), 2.72-2.86 (m, 2H), 2,41-2.51 (m, IH), 2.35 (quin, J=9.17 Hz, IH), 2.03- 2.24 (m, 4H), 1.88 (d,J=7.34Hz, 3H), 1.72-1.76 (m, 3H), 1.61-1.63 (ni, 3H), 1.50-1.51 (m, 3H), 1.07 (s, 3H).

EXAMPLE 16. (1 S,3'R,6'R,7'S,9'E, 11 'S, 12 ^* R)-6-CHLORO-l 1 ', 12'-DIMETHYL- 7 ^, -(2-(4-MORPHOLlNYL)ETHOXY)-3,4-DIHYD.RO-2H,15 ^! H- SP1R0 [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [9, 16, 18 ,24]TETRAEN] - 15"-ONE 13 ', 13 '-DIOXIDE

STEP 1: (1S,3'R,6'R,7'S,9'E,1 l'S12 ^, R)-6-CHLORO-7'-HYDROXY-l l',12'- 1)1 MET! !YL-3.4~DI! IYDRO-211.1 Ί I-SFi O|NAP! Π I ΙΛΙ.ΕΝί:· 1.22 ¹ ·· pOlOXAtlSJTO Atl ^DIAZATETRACYCLOtMJ^.O'^.O'^lPE TACOSA

[9, 16, 18 , 24] TETRAEN] - 15 ^! -ONE 13', 13 ^! -DIOXIDE

The title compound was prepared from Intermediate AA13A and (2S, 3R)- N,N-bis(4-methoxybenzyl)-3-methylhex-5-ene-2-sulfonamide using procedures similar to those described for Example 556, Steps 1-4. STEP 2: (1S,3'R,6'R,7'S,9'E,1 rS,12'R)-6-CHLORO-l l ',12'~DIMETHYL-7'-(2-(4- MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[I ,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 O ¹⁹ ' ^24I PENTACOSA[

9, 16, 18,24] TETRAEN] - 15 '-ONE 13', 13'-D10XlDE

To a stirred solution (1 S,3'R,6'R,7'S,9'E, 1 1 'S 12'R)-6-chloro-7'-hydroxy-

1 1 ', 12'-dimethyl-3,4-dihy dro-2H, 15'H-spiro [naphtha] ene- 1 ,22'-

n]-15'-one 13',13'-dioxide (15 nig, 0.025 mmol, Example 16, Step 1) in 350 DMF was added 4-(2-bromoethyl)morpholine hydrobromide (34.4 mg, 0.125 mmol), followed by sodium hydride (10.01 mg, 0.250 mmol). The reaction was stirred overnight at rt. The reaction mixture was then diluted with a few drops of water, followed by 1.5 mL DMSO, and purified directly by preparative HPLC using a 75% isocratic method over 25 rain. Ή NMR (400 MHz, CDCb) δ 7.69 (d, ./ S 4 i Hz, 1H), 7.19 (dd, ./ 2.25. 8.31 Hz, i l l ). 7.10 (d, J=2.35 Hz, IH), 6.88- 6.97 (m, 2H), 6.82 id. ./ 1.37 Hz, i l l ). 5.82-5.96 (m, I I I ). 5.82-5.95 (m, IH), 5.52 (dd, J=9.39, 14.87 Hz, IH), 4,30 (q. ./ 7. 1 7 Hz, IH), 4.09 (s, 2H), 3.74-3.87 (rn, 3H), 3.70 (d, ,7=13,89 Hz, IH), 3.52-3,63 (m, IH), 3.17-3.29 (m, 3H), 3.01 (dd, ./ 10.07. 14.97 Hz, IH), 2.72-2.84 (m, 2H), 2.28-2,50 (m, IH), 2.09-2.24 (m, I H), 1 ,93-2.06 (m, 2H), 1.74-1.88 (m, IH), 1.67 it, .7=9.00 Hz, IH), 1 ,50 (d. ./ 7.24 I I/. 3H), 1 ,32-1.46 (rn, IH), 1.06 (d, .7=6.85 Hz, 3H),

EXAMPLE 17. (1 S,3'R,6'R,7'S,9'E, 1 rS,12'R)-6-CHL()R()-7'-METH()XY- 1 1 ',12'-DTMETHYL-3,4-DTHYDRO-2H,15'H-SPIRO| APHTHALENE-l ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O'^O^^lPE TACOSAt 9,16,18,24]TETRAEN]-15'- ONE 13',13'-DIOXIDE

To a small vial equipped with a stirbar containing a solution of

(lS,3'R,6 ^f R,7 ^, S,9^,irS12 ^, R)-6-chloro-7 ^, -hydroxy-ll\12'-dimethyl-3

2H.15'H-SPIRO[naphthaS ene- 1 ,22 ^! -

nj-15'-one 13',13'-dioxide (15 mg, 0.025 mmol. Example 16, Step 1) in 200 μί, DCE was added methyl trifluoromethanesulfonate (4.11 iL, 0.038 mmol) and 2,6- di-tert-butylpyridine (11.97 mg, 0.063 mmol). The vial was sealed and the mixture stirred at rt overnight, after which the mixture was diluted with 1.5 ml. of DMSO and purified by preparative HPLC to yield the title compound as a white solid (3 mg, 4.89 mmol, 19% yield). ¾ NMR (400 MHz, CDCh) δ 9.92-10.29 (m. 111).7,71 id../ 8.6! Hz, !!!).7.46 !dd. ,/ 1,96.8,22 Hz, III).7.18 (dd, J=2.35, 8.61 Hz, 1H), 7.10 (d, .7=2,35 Hz, III).6.96-7.03 (m, 2H), 5,47-5.67 (m, 1H), 5.31-5.38 (m, IH), 4.13-4.15 (m, 2H), 4.14 (s, 2H), 3.64-3.71 (m, 2H), 3.63 (s, 3H), 3.53-3.60 (m, 1H), 3.44-3.51 (m, IH), 3.28-3.37 (m, 1H), 2.73-2.82 (m, 2H), 2,55 Id. ,/ 6.85 Hz, IH), 2.39 (br, s., IH), 2.06-2.15 (m, 2H), 1,80-1.98 (m, 4H), 1.65-1.72 (m, IH), 1.59 (d, .7=7.04 Hz, 3H), 1.08 (d, .7=6.65 Hz, 3H).

EXAMPLE 18. (1S,3'R,6'R,7'R,I l ^, S)-6-CHLORO-7*-METHOXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

[20]OXA[13]TfflA[l,14]DIAZAPENTACYCLO[14.7.2.2 ^8>ll -0 ³ - ⁶ -0 ⁱ⁹ - ²⁴ ]HEPTAC

OSA[8,16,18,241TETRAEN]-15'-ONE 13,13' DIOXIDE or

(lS,3'R,6'R,7 ^f R,irR)-6-CHLORO-7'-METHOXY-3,4-DIHYDRO-2H,I5'H-

SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZAPENTACYCLO 14.7.2.2 ⁸ ' ^{11 3} ' ^{6 19} ' ²⁴¹ HEPTAC

OSA[8,16 ₅ 18,24]TETRAE ]-15'-ONE 13,13' DIOXIDE or (lS ¾ )'R ^ l'S)-6^iLORO-7'-MFmTOXY-3,4-DiHYDRO-2H,!5'H- SP1RO [NAPHTHALENE- 1 ,22'- pOlOXAI lSlTHIAIl.MlDIAZAPENTACYCLOiM.T^^^^O^^O^^lHEPTAC OSA[8,16,18,24]TETRAE ]-15'-ONE 13,13' DIOXIDE or

(lS,3'R,6 ^F R,7'S,ll¾)-6-CHLORO-7 ^F -METHOXY-3,4-DIHYDRO-2H,15 ^, H- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZAPENTACYCLOIMJ^^s^^O^^O^^lHEPTAC OSA[8,16,18 ₅ 24]TETRAEN]-15'-ONE 13,13' DIOXIDE

or or

-o ~0

STEP 1: (S)-ETHYL 4-

(((TRIFLUOROMETHYL)SULFONYL)OXY)CYCLOHEX-3-

ENECARBOXYLATE and (R)-ETHYL 4-

(((TRIFL;UOROMF;THYL)SULFONYL)OXY)CYCLOHEX-3- ENECARBOXYLATE A stirred solution of ethyl 4-oxocyclohexanecarboxylate (10.6 g, 62,3 mniol) and 2,6-di-tert-bu†yl-4-methylpyridine (15.35 g, 74.7 mmol) under argon was cooled to -78 °C in a dry ice bath, followed by addition of

trifluoromethanesulfonic anhydride (11.87 niL, 62.3 mmol). The reaction was stirred, warming to rt, for 40 hours. The mixture was then poured into ice water, diluted with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 X), washed with water and brine, dried with sodium sulfate, filtered and then concentrated. The residue was purified via column chromatography over a 220g isco column eluting with 10% ethyl acetate/hexanes to yield a mixture of (S)-ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and (R)-ethyl 4- (((trifluoromethyl)sulfonyl)oxy)cyciohex-3-enecarboxylate (9 g, 29.8 mmol, 47.8 % yield) as a brown oil.

STEP 2: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-((S)-4- (ETHOXYCARBONYL)C YCLOHEX- 1 -EN - 1 -

YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE and (S)-METHYL 6'-CHLORO-5- (((1 R,2R)-2-((R)-((R)-4-(ETHOXYCARBONYL)CYCLOHEX- 1 -EN- 1 - YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL)-3 ^f ,4,4',5- TETRAHYDRO-2H,2 ^! H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE and(S)-METHYL 6'-CHLORO-5- (((1 R,2R)-2-((S)-((S)-4-(ETHOXYCARBONYL)C YCLOHEX- 1 -EN- 1 - YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H _s 2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALENE j -7-CARBOXYLATE and(S)-METHYL 6'-CHLORO-5- (((1 R,2R)-2-((S )-((R)-4-(ETHOXYCARBONYL)C YCLOHEX- 1 -EN- 1 - YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

Nickel (II) chloride (0.285 g, 2.203 mmol) and chromium(II) chloride (16.24 g, 132 mmol) were added to a heat-gtm dried 250 ml round bottom flask with heat dried stirbar, and the flask was immediated sealed and flushed with argon. The flask containing the dry reagents was place in an ice bath, and 45 mL fresh dry DMF was added, with stirring. The solvent was sparged with argon, and the flask removed from the bath. The solids were stirred, and then sonicated, until completely dissolved.

A mixture of (S)-ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- enecarboxyiate and (R)-ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- enecarboxylate (from Step 1) and (S)-methyl 6 ^! -chioro-5-(((lR,2R)-2- formylc ' ^, clobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (2 g, 4.41 mmol, Intermediate AA11A, Step 20 A) were added to a separate heat dried 250 mL flask with stir bar, and sealed, and again flushed with argon. Once the solids in the chromium nickel solution were completely dissolved, the solution was transferred to the second flask by cannula, and the reaction was stirred with an argon sparge for 1 hour. The mixture was poured into 500 mL 0.1 N aqueous EDTA solution, and the resulting purple mixture was stirred 0.5 hour, and then extracted with Εΐ2θ (3 X). The ethereal layers were washed with water (2X) and brine (2X), dried over sodium sulfate, filtered and concentrated. The residue was purified via ccolumn chromatography eluting with 10% EA:Hex (containing 0.5% AcOH), to recover (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)-((S)-4-

(ethoxycarbonyl)cyclohex-l-en-l-yl)(hydroxy)methyl)cyclob utyl)methyl)- 3',4,4',5-tetrahydfo-2h,2'h-spifo| ^" benzo| ^" b] |T,4]oxazepine-3, -naphthalene]-7- carboxylate and

(S)-methyl 6 ^! -chk)ro-5-(((lR,2R)-2-((R)-((R)-4~(ethoxycarbonyl)cycl oh 1 -yl)(hydrox )methy l)cyxlobutyl)methyl)-3',4,4',5-tetrahy dro-2h,2'h- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox>'late and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-((S)-4-(ethoxycarbonyl)cyclohex-l- en-l- yl)(hydroxy)methyl)cyclobutyl)me1iiyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2h,2 ^, h- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate and (S)-methyl 6'- (*loro-5-(((lR,2R)-2-((S)-((R)-4-(ethoxycarbon ])cyclohex-l -en-l - yi)(hydroxy)methyl)cycIobutyI)methyl)-3^4,4^5 etrahydro-2h,2¾- spiroj benzoj bj [ T,4]oxazepine-3,r-naphthalene]-7-carboxylate as yellow oil (2.68 g, 4.41 mmol). STEP 3: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-((S)-4- (ETHOXYC ARBONYL)C YCLOHEX- 1 -EN- 1 - YL)(METHOXY)METHYL)CYCLOBUTYL)METHYL)-3 ^, ,4 ₅ 4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPlNE-3, 1 '- NAPHTHALENE] -7-CARBOXYL ATE and (S)-METHYL 6'-CHLORO-5- (((1 R,2R)-2-((R)-((R)-4-(ETHOXYC ARBONYL)CYCLOHEX- 1 -EN- 1 - YL)(METHOXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE and : (S)-METHYL 6 ^* -CHLORO-5- (((] R,2R)-2-((S)-((S)-4-(ETHOXYCARBONYL)C YCLOHEX- 1 -EN- 1 - ΥΕ)(ΜΕΊΉΟΧΥ)ΜΕΊΉΥΤ)εΥ€ΧΟΒυΊΥΧ)ΜΕ ΊΉΥΤ)-3',4,4',5- TETRAHYDRO-2H,2 ^f H-SPIRO[BENZO[B][!,4]OXAZEPiNE-3, l '- APHTH ALENE] - 7 -C ARB OXYL ATE and : (S)-METHYL 6 ^! -CHLORO-5~ (((1 R,2R)-2-((S)-((R)-4-(ETHOXYC ARBONYL)CYCLOHEX-l -EN- 1 - YL)(METHOXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

To a stirred solution mixture (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)-

((S)~4-(ethoxyearbonyj)cyclohex-i^^

3',4,4',5-tetr ally dro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene j -7- carboxylate and

(S)-methyl 6 ^! -chloro-5-(((iR,2R)-2-((R)-((R)-4~(ethoxycarbonyl)cy

1 -yl)(hydroxy)methyl)cyclobut 'l)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiroj benzoj bj [ L4 |oxazepine-3, -naphthaIene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S) (S)-4-(ethoxycarbonyl)cyclohex-l-en-l - yl)(hydroxy)methyl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-((R)-4-(ethoxycarbonyl)cyclohex-l -en-l - yl)(hydroxy)methyl)cyclobuTy'l)methyl)-3',4,4 ^, ,5-tetrahydro-2h,2'h- spiroj benzoj b][ L4 |oxazepine-3, -naphthalene]-7-carboxylate (2.68 g, 4.41 mmol) and 2,6-di-tert-butylpyridine (0.706 mL, 5.29 mmol) in DCM was added methyl trifluoromethanesulfonate (0.579 mL, 5.29 mmol) and the reaction was heated to 40 °C. Over the course of 3 hours an additional two equi valents of methyl trifluoromethanesulfonate and two equivalents of 2,6-di-tert-butylpyridine were added to drive the reaction to completion. The reaction was allowed to cool to RT, and two equivalents of trietliylamine was added to quench any residual methyl trifluoromethanesulfonate. The mixture was loaded onto silica and purified over a 40 g isco column eluting with a gradient of 5-50% ethyl acetate/hexane (containing 0.5 %AcOH) to yield (S)-methyl 6'-chloro-5-(((lR,2R)- 2-((R)-((S)-4-(ethoxy carbony l)cy clohex- 1 -en- 1 - yl)(methoxy)methyl)cyclobutyl)methy])-3 4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-methyl 6'- cWoro-5-(((lR,2R)-2-((R)-((R)-4-(emoxycarbony

yl)(methoxy)methyi)cyclobutyl)methyl)-3',4,4 5-tetiiihydro

spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-((S)-4-(ethoxycarbonyl)cyclohex-l- en-l- yl)(methoxy)methyl)cyclobutyl)methyl)-3',4,4',5-tetraliydro- 2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lr,2r)-2-((s)-((r)-4-(ethoxycarbonyl)cyclohex-l- en-l- yl)(memoxy)me l)cyclobu1yl)me l)-3^4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate

(2.2 g, 3.54 mmol).

STEP 4: (S)-METHYL 6'-CKLORO-5-(((lR,2R)-2-((R)-((S)-4- (HYDROXYME ^' fflYL)C YCLOHEX- 1 -EN- 1 - YL)(METHOXY)METHYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYL ATE and (S)-METHYL 6'-CHLORO-5- ((( 1 R,2R)-2-((R)-((R)-4-(HYDROXYMETHYL)CYCLOHEX- 1 -EN- 1 - YL)(MEra:OXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE and (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S) (S)^-(HYDROXYMETHYL)CYCLOHEX-l-EN-l- YL)(METHOXY) ETHYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPiNE-3, l '- NAPHTHALENE] -7-CARBOXYLATE and (S)-METHYL 6 ^* -CHLORO-5- (((1 R,2R)-2-((S) (R)-4-(HYDROXYMETHYL)C YCLOHEX- 1 -EN- 1 - YL)(METHOXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- N -7-CARBOXYLATE

To a stirred solution (S)-methyl 6"-chloro-5-(((lR,2R)-2-((R)-((S)-4-

(ethoxycarbonyl)cy clohex- 1 -en-1 -yl)(methoxy)methyl)cyclobut 'l)methyl)- 3',4,4',5-tetraliydro-2H,2H-spiro[benzo[b] [l,4]oxazepme-3, -naphthalene|-7- carboxylate and (S)-methyl 6 ^, -chloro-5-(((lR,2R)-2-((R)-((R)-4- (ethoxycarbonyl)cy clohex- 1 -en- 1 -yl)(methoxy)methyl)cy clobuty Drneth yl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-((S)-4- (ethoxycarbonyl)cyclohex-l-en-l-yl)(methoxy)methyl)cyclobuty l)methyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carbox late and (S)-methyl 6'-chloro-5-(((l R,2R)-2-((S)-((R)-4- (ethoxycarbonyl)c>'clohex-l-en-l-yl)(methoxy)methyl)cyclo butyl)methyl)- 3',4,4',5 etraliydro-2H,2H~spiro[benzo[b] [l,4]oxazepme-3, -naphthalenel-7- carboxylate

(2,2 g, 3,54 mmol) in THF at 0 °C with one equivalent MeOH was added a freshly made aqueous solution of lithium borohvdride (0.039 g, 1.768 mmol) (0. Ig/iiiL such that LiBH ₄ solids fully dissolved in THF), and the reaction was stirred, warming to RT for 15 minutes, and then heating to 50 °C for 15 minutes.

This procedure was repeated for several iterations, eventually adding a total of 10 equivalents of lithium borohvdride. After stirring for 1 additional hour at 50 °C, the reaction was cooled to 0 °C in an ice bath, and carefully quenched with 10 ml 10% acetic acid in THF, followed by water. The mixture was stirred for 0.5 hr, warming to RT, and was then extracted with EtOAc (3X), washed with water and brine, dried over sodium sulfate and purified over a 40g isco column eluting with 25% ethyl acetate/hexane to yield (S)-methyl 6'-chloro-5-((( 1 R,2R)- 2-((R)-((S)-4-(hy droxymethy l)cy clohex- 1 -en- 1 - yl)(methoxy)me l)cyclobu1yl)me l)-3^4,4^5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate and (S)-methyl 6'-

(*loro-5-(((lR,2R)-2-((R)-((R)^-(hydroxyme l)cyclohex-l -en-l- yi)(methoxy)methyl)cyclobutyl)me&^

spiroj benzoj bj [ 1,4 ]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-((( 1 R,2R)-2-((S)-((S)-4-(hy droxymethy! )cy cl obex- 1 -en- 1 - yl)(methoxy)methyl)cyc!oh

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-((R)-4-(hydroxymethyl)cyclohex-l-e n-l- yl)(methoxy)methyl)c ]obutyl)me1hyl)-3^4,4 5-tetTahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, l '-naphthalene]-7-carboxylate (635 mg, 1,095 mniol).

STEP 5: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-METHOXY((S)-4- (((METHYLSULFONYL)OXY)METHYL)CY CLOHEX- 1 -EN- 1 -

YL)METHYL)CYCLOBUTYL)METHYL)-3'.4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B] [1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE and (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)- METHOXY((R)-4-(((METHYLSULFONYL)OXY)METHYL)CYCLOHEX-l- EN-l-YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAIiYDRO- 2H,2H-SPlRO[BENZO[B] [l,4]OXAZEPlNE-3J ^! -NAPHTHALENE]-7- CARBOXYLATE and (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)- METOOXY((S)-4-(((MEraYLSULFONYL)OXY)METHYL)CYCLOHEX-l- EN-l -YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAFIYDRO- 2H,2H-SPIRO[BE ZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE and (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)- METHOXY((R)-4-(((METHYLSULFONYL)OXY)METHYL)CYCLOHEX-.l - EN-l-YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SP1R0 [BENZO [B] [ 1 ,4] OXAZEP1NE-3, Γ -NAPHTHALENE] -7- CARBOXYLATE

To a stirring solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)-((S)-4-

(hydroxymethyl)cyclohex^

3 4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate and (S)-methyl 6'-chl oro- (( 1 .2R }-2-{ { )-( ( R )-! -

(hydroxyme1h}d)cyclohex-l-en-l-yl)(methoxy)methyl)cj ⁷ clobutyl)me1h}d)-

3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphtha]ene]-7- carbox late and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-((S)-4-

(hy droxymethyl)cy clohex- 1 -en- 1 -yl)(methoxy)methyl)cy clobutyl)methyl)- 3;4,4',5 etraliydro-2H,2TI-spiro[benzo[bi [ l,4joxazepine-3, -naphihalene|-7- carboxylate and (S)-methyl 6'-ch]oro-5-(((l R,2R)-2-((S)-((R)-4- (hy droxymethyl)cy clohex- 1 -en- 1 -y l)(methoxy )methyl)cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carbox late (635 mg, 1 ,095 mmol) in 5 mL DCM cooled to 0 °C in an ice bath was added triethylamine (305 μ3_, 2.189 mmol), followed by dropwise addition methanes uifony I chloride (128 μΐ _^ , 1.642 mmol). The reaction was warmed to rt for 1 hr, diluted with saturated aqueous sodium bicarbonate solution, extracted into DCM, washed with water and brine, dried over sodium sulfate, filtered and then concentrated to yield (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)-methoxy((S)- 4-(((methylsu]fonyl)oxyjrnethy

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carbox late and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)-methoxy((R)-4- (((methylsulfonyl)oxy)methy l)cyclohex- 1 -en- ! -y l)me1hyl)cyclobutyl)methyl)- 3 ',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [1 ,4]oxazepine-3, l'-naphthalene]-7- carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-methoxy((S)-4- (((methyisdfonyl)oxy)m^^

3\4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate and (S)-methyl

(((methy lsulibnyl)oxy)meihy l)cy clohex- 1 -en-1 -y l)methyl)cyclobut}'i)methyi)- 3',4,4',5-tetrahydro-2H,2H-spiro[bem!;o[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylate (720 mg, 1.094 mmol).

STEP 6: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-METHOXY((S)-4-

((PYRJMIDIN-2-YLTHIO)METHYL)CYCLOHEX~l -EN- 1 - YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B ] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7- C ARBOXYLATE AND (S)-METHYL 6 ^! -CHLORO-5-(((l R,2R)-2-((R)- METHGXY ((R)-4-((PYRlMlDIN-2-YLTH10)METHYL)CY CLOHEX- 1 -EN- 1 YL)METHYL)CYCLOBUTYL)METHYL)-3 ^, .4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND

(S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)-METHOXY((S)-4-

((PYRIMIDIN-2-YLTOIO)METHYL)CYCLOHEX- 1 -EN- 1 - YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)- METHOXY((R)-4-((PYRTMIDIN-2-YLTHTO)METHYL)CYCLOHEX- 1 -EN- 1 YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

To a stirred solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)- methoxy((S)-4-(((methylsulfonyl)oxy)methyl)cy clohex- 1 -en- 1 - yl)methyl)cyclobut 'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((R)-methoxy((R)-4-

(((methylsulfonyl)oxy)methyl)cy clohex- 1 -en- 1 -yl)methyl)cy clobuty l)methyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-methoxy((S)-4- (((methylsulfonyl)oxy)methyl)cy clohex- 1 -en- 1 -yl)methyl)cy clobuty l)methyl)- 3',4,4',5-tetrahydr o-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene |-7- carboxylate and (S)-methyl 6'-chloro-5-(((l R,2R)-2-((S)-methoxy((R)-4- (((methylsulfonyl)oxy)me1hyl)cyclohex-l-en-l-yl)methyl)cyclo butyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spifo[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carbox late (720 mg, 1 ,094 mmol) in 2 mL dry DMF was added potassium carbonate (227 mg, 1.6 1 mmol), followed by pyrimidine-2 -thiol (129 mg, 1.149 mmol) and the reaction was stirred at rt for 40 hrs. The reaction was then diluted with water, extracted with Et?,0 (2X), washed with water (2X) and brine (2X), dried over sodium sulfate and filtered to yield (S)-methyl 6'-chloro-5-(((lR,2R)-2- ((R)-methoxy((S)-4-((pyrimidin-2-ylthio)methyl)cyclohex-l-en -l- yl)methyl)cyclobut l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((R)-rnethoxy((R)-4-((pyriiTiidin-2-ylt hi

1 -en- 1 -yl)me l)cy clobutyl)methyl)-3' ,4,4', 5-tetrahy dro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-methoxy((S)-4-((pyrimidin-2-ylthio )me1hyl)cyclohex- l-en-l -y methy tyclobut rnethy -S'^^'^-tetrahydro^H^'H- spiroj benzoj bj [ L4 |oxazepine-3, -naphthaIene]-7-carboxyiate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-methoxy((R)-4-((pyrimidin-2-ylthio )methyl)cyclohex- l-en-l-y me^ cyclobul methy -S'^^'^-tetrahydro^H^H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate (675 mg, 1.001 mmol, 92 % yield) as a yellow solid. STEP 7: (S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-((R)-METHOXY((S)-4-

((PYRIMIDIN-2-YLSULFONYL)METOYL)CYCLOHEX- 1 -EN- 1 - YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR-AHYDRO-2H,2'H- SPIRO| BENZO[B]|;L4iOXAZEPINE-3, l'-NAPHTHALENE]-7- CARBOXYLATE AND (S)-METHYL 6"-CHLORO-5-(((lR,2R)-2-((R)- METH0XY((R)-4-((PYRJMIDIN-2-YLSUL;F0NYL)METHYL

EN"1-YL)METHYL)CYCL0BU1YL)METHYL)"3',4,4',5-TETRAHYDR0- 2Ι-ϊ,2Ή-8ΡΚ()|;ΒΕΝΖΟ[Β| [ 1,4]ΟΧΑΖΕΡΙΝΕ-3,1·-ΝΑΡΗΤΗΑΕΕΝΕ]-7- CARBOXYLATE AND (S)-METHYL 6'-CHL0R0-5-(((1 ,2R)-2-((S)- MEmOXY((S)-4-((PYmMIDlN"2-YLSULFONYL)METHYL)CYCLOHEX-l- EN-l -YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3 ₅ l ^* -NAPHTHALE E]-7- CARBOXYLATE AND (S)-METHYL 6 ^, -CHL0R0-5-(((1R,2R)-2-((S)- METHOXY((R)-4-((i ¾MlDlN-2"YLSULFONYL)MEraYL)CYCLOHEX-l- EN-l-YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

C ARB OXYL ATE

To a stirred solution of ((S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)- methoxy((S)-4-((pyrimidin-2-y lthio)methyl)cyclohex- 1 -en- 1 - yl)methyl)cyclobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate and (S)-methyl 6'- cMoro-5-(((l R,2R)-2-((R)-me1hoxy((R)-4-((pyrimidin-2-ylthio)methyl)c} ⁷ clohex- l -en-l-y^methy iyclobuty methy -S^^^-tetrahydro^H^'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-methyl 6 - cMoro-5-(((lR,2R)-2-((S)-methox>'((S)-4-((pyrirnidin-2-yl tbio)me1hyl)cyclohex l-en-l -y^meth lJ lobutyl^elhyli-S'^^'^-tetrahydro^H^'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylate and (S)-methyi 6'- cMoro-5-(((lR,2R)-2-((S)-methoxy((R)-4-((pyrirrddin-2-yllhio )methyl)cyclohex- l-en-l-yl)methyl)c^xlobutyl)methyl)-3',4,4',5-tetrahydro-2H, 2'H- spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxylate (375 mg, 0.556 mmol) in 2.25 niL dry DCM at 0 °C in an ice bath was added mCPBA (249 mg, 1.1 12 mrnol), and the reaction was stirred for 0.5 h. The reaction was thrn removed from the bath and warmed to RT over 0.5 h. The reaction was again cooled to 0 °C, one additional equivalent of mCPBA was added, and the reaction was stirred, warming to RT over 1 hour. The reaction was then concentrated and purified over silica eluting with 20% acetone in hexane to yield (S)-methyl 6'- cMoro-5-(((l R,2R)-2-((R)-methoxy((S)-4-((pyrimidin-2- ylsulfonyl)methyl)cyclohex-l-en-l-yl)methy])cyclobutyl)methy l )-3

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, Γ -naphthalene] -7-carboxylate and (S)-methyl 6 ^, -cWoro-5-(((lR,2R)-2-((R)-methox '((R)-4-((pyrimidin-2- ylsidfonyl)meihyl)cycIohex-l-en-l-yl)methyl)cyciobut}4)methy

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, -naphthalene] -7-carboxylate and (S)-methyl 6 ^, -chloro-5-(((lR,2R)-2-((S)-methoxy((S)-4-((pyrimidin-2 - ylsulfonyi)methyl)cyciohex-l-en-l-yl)methyl)cycIobutyl)meihy l)-3',4,4',5- tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthale ne]-7-carboxylate and(S)-methy 1 6'-chloro-5 -((( 1 R,2R)-2-((S)-methoxy {{ R)-i -i i py Hn¾idin-2- ylsulfonyl)methyl)cyclohex-l-en-l-yl)methyl)cy'clobutyl)meth yl)-3',4,4',5- tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7-carboxylate (160 rag, 0.227 mmol),

STEP 8: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-METHOXY((S)-4- (SULF AMOYLMETHYL)C YCLOHEX- 1 -EN- 1 -

YL)METHYL)CYCLOBUTYL)METHYL)-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, i '-NAPHTHALENE]-7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)- METHOXY((R)-4-(SULFAMOYLMETHYL)CYCLOHEX-l -EN-l-

YL)METT-ftT,)CYCIX)BUWI METHY ^' L)-3',4,4',5-TETRAHYDRO-2H,2'I-i SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND

(S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-((S)-METHOXY((S)-4-

(SULFAMOYLMETHYL)C YCLOHEX- 1 -EN- 1 -

YL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARB OXYL ATE AND

(S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-((S)-METHOXY((R)-4- (SULF AMOYLMETHYL)C YCLOHEX- 1 -EN- 1 -

YL METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,

SPIRO [BENZO [B ] 1 1 ,4] OXAZEPINE-3, 1 '- APHTHALENE] -7- CARBOXYLATE

To a stirred solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)- methoxy((S)-4-((pyrimidin-2-ylsulfonyl)methyl)cy clohex- 1 -en- 1 - yl)methyl)cyclobut l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro|benzo|b] [L4]oxazepine-3, i ⁱ -naphihalene]-7-carboxylate and (S)-methyl 6'- chloro-5-((( 1 R,2R)-2-((R)-methoxy((R)-4-((pyriniidin-2- ylsulfony^methy^cyclohex-l-en-l-y^methy^cj lobuty methy^-S'^^'^- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy late and (S)-rnethyi 6'-chloro-5-(((lR,2R)-2-((S)-meilK)xy((S)-4-((pyrimidin-2- ylsulfoiiyl)methyl)cy clohex- 1 -en- 1 -yl)methyl)cy clobur>'i)methyl)-3',4,4',5- tetrahydro-2H,2^spiro[benzo[b][l ,4]oxazepine-3, l'-naphthalene]-7-carboxylate and(S)-methyl 0 ^! -ehloro-5-(((lR,2R)-2-((S)-methoxy((RM^

ylsulfonjd)me1hyl)c\xlohex-l-en-l-yl)methyl)c clobuty'l)methyl)-3',4,4 ^, ,5- tetTahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalen e]-7-carboxylate (157 mg, 1.133 mmol) in MeOH with K2CO3, (Aminooxy)sulfonic acid (128 mg, 1.133 mmol) was added and the reaction was stirred overnight. The reaction was stripped of solvent, diluted with EtOAc and water, extracted into EtOAc, washed with water and brine, dried over sodium sulfate and then concentrated to yield (S)- methyl 6'-chloro-5~(((lR,2R)-2~((R)-methoxy((S)-4-(sulfamoylmethy1) cyc l-en -yi)methyl)cyc3obutyl)methyl)-3^4,4^5-ietrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late and (S)-methyl 6'~ chloro-5-((( 1 R,2R)-2-((R)-methoxy((R)-4-(sulfamoylmethy l)cy clohex- 1 -en~ 1 - yl)methyl)cyxlobut 'l)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-((( TR,2R)-2-(( S)-meihoxy((S)-4-(sulfamoylme†hyl)cy clohex- 1 -en-l- yl)methyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiroj benzoj bj [ 1,4 |oxazepine-3, -naphthalene]-7-carboxyiate and(S)-methyl 6'- chloro-5-((( 1 R,2R)-2-((S)-methoxy ((R)-4-(sulfamoy 1 methyljcy clohex- 1 -en- 1 - yl)me l)c lobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate (146 mg, 0.227 mmol, 100%) as a yellow solid.

STEP 9: (S)-6'-CHLORO-5-((( 1 R,2R)-2-((R)-METHOXY((S)-4- (SULF AMOYLMETHYL)C YCLOHEX- 1 -EN- 1 - YL)METI-^L)CYCLOBUTYL)MF^YI -3^4,4^5-TETRAHYDRO-2Il,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6 ^, -CHLORO-5-(((lR,2R)-2-((R)-METHOXY((R)-4- (SULFA OYLMETHYL)C YCLOHEX- 1 -EN- 1 -

YL)METT-ft3,)CYCIX)BUWL)MF^iYX)-3',4,4',5-TETRAHYDRO-2H,2 Ti- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND

(S)-6'-CHLORO-5-(((lR,2R)-2-(S)-METHOXY((S)-4- (SULF AMOYLMETHYL)C YCLOHEX- 1 -EN- 1 - Y^METHY^CYCLOBUTY^METHY^-S'^^'^-TETRAHYDRO^H^H-

SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3, 1 '- APHTHALENE] -7-C ARBOXYLIC ACID AND

(S)-6'-CHLORO-5-(((l R,2R)-2-((S)-METHOXY((R.)-4- (SULFAMOYLMETHYL)C YCLOHEX- 1 -EN- 1 - YL)METHYL)CYCLOBUTYL)METHYL)-3'.4,4 ^, ,5-TET AHYDRO-2H,2 ^, H-

SPIRO [BENZO [B j [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

(S)-methyl 6 ^, -chloro-5-(((lR,2R)-2-((R)-methoxy((S)-4- (sulfamoyimethyl)cyclohex-l-e^^

tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine-3, l'-naphthalene]-7-carboxylate and (S)-methyl 6'-ch]oro-5-((( ! R,2R)-2-((R)-raethoxy((R)-4- (sulfamoylmetliyl)cy clohex- 1 -en- 1 -yl)methyl)cy elobutyl)methyi)-3',4,4',5- tetrahy dro-2H,2'H-spiro| benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-methoxy((S)-4- (sidfamoylmethyl)cyejohex-l -en^

tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-methoxy((R)-4- (sulfamoylmethyl)cyclohex-l-en-l -yl)m

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (146 mg, 0.227 mmol) was hydrolyzed in 5 rriL 4: 1 THF: MeOH with IN aqueous Li OH (2270 μΐ,, 2.270 mmol) solution at 60 °C overnight. The mixture was then neutralized with IN HC1, extracted into EtOAc, washed with water and brine, dried over sodium sulfate, filtered and concentrated to yield (S)-6'-chloro-5- (((l R,2R)-2-((R)-methoxy((S)-4-(sulfamoylmethyl)cyclohex-l-en-l - yl)me1hyl)cy'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (S)-6'~ chloro-5-(((lR,2R)-2-((R)-methoxy((R)-4-(sulfamoylmethyl)cyc lohex-l-en-l- yl)methyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (S)-6'- cMoro-5-(((l R,2R)-2-((S)-memoxy((S)-4-(sulfamoylmethyl)cyclohex-l-en-l - yl)methyl)cyclobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)~6 ^! - chloro-5-(((lR,2R)-2-((S)-methoxy((R)-4-(sulfamoylmethyl)cyc lohex-l-en-l- yl)methyl)cyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (110 mg, 0.175 mmol, 77 % yield) as a yellow solid.

STEP 10: (1 S,3'R,6'R,7'R,1 rS)-6-CHLORO-7'-METHOXY-3,4-DIHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'- [20]OXA[13]ra ^j :A[l _s 14]DIAZAPE rrACYCLO[14.7.2.2 ⁸ - ¹¹ -0 ³ - ⁶ O ¹⁹ - ²⁴ ]HEPTAC OSA[8, 16, 1 8,24]TETRAEN]~1 5'-ONE 13, 13 ' DIOXIDE OR

( 1 S,3'R,6'R,7'R, 1 rR)-6-CHLORO-7'-METHOXY-3,4-DIHYDRO-2H,l 5Ή-

SPIRO INAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THI A[ 1 , 14]DI AZ APENT AC YCLO[ 14, 7.2, 2 ^{8J f} 0 ³ · ⁶ 0 ¹⁹ - ²⁴ HEPTAC OSA[8,16, 18,24]TETRAEN]-15'-ONE 13, 13 ' DIOXIDE OR

(l S,3'R,6 ^! R,7'S,i rS)-6-CHLORO-7'-METHOXY-3,4~DIHYDRO-2H, 15'H" SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[l , 14]DIAZAPEOTACYCLO[ 147.2.2 ⁸ - ^{11 3} - ^{6 19} ' ²⁴ lHEPTAC

OSA[8,16, 18,24]TETRAEN]-15'-ONE 13, 13 ^" DIOXIDE OR

(l S,3'R,6'R,7'S,i rR)-6-CHLOR()-7'-METHOXY-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

OSA[8,16, 18,24]TETRAEN]-15'-ONE 13,13' DIOXIDE

To a stirred solution (S)-6'-chloro-5-(((lR,2R)-2-((R)-methoxy((S)-4- (sul.famoylmethyl)cyclohex-l -en- l -yl)m

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((R)-methoxy((R)-4- (sulfamoylmethyi)cy d ohex- 1 -en- 1 -yl)methyl)cy clobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S)-methoxy((S)-4-

(sulfamoylmethyl)cyclohex-l -en-l -yl)methyl)cyclobutyl)methyl)-3',4,4',5- tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, r-naphthalene]-7-carboxylic aci d and

(sulfamoylmethyl)cj ⁷ clohex-l -en-l-yl)methyl)c^xlobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyli c acid (85 mg, 0.135 mmol) in. 1 .5 ml, DCM was added 4-(pyrrolidin- l -yl)pyridine (40.0 mg, 0.270 mmol). The mixture was cooled to 0 °C in an ice bath, followed by addition of 3-(((ethylirrur j)methylene)arruno)-N,N,N-trirnethylpropan-l- aminium iodide (92 mg, 0.31 1 mmol) in 3 portions. The reaction mixture was allowed to warm to RT and then heated to 40 °C overnight. The reaction was allowed to cool to RT, and then stripped of solvent and pimfied by preparative HPLC to yield one of the title compounds as a single diastereomer. ¾ NMR (500 MHz, ACETONITRILE-ds) δ 8.96-9.39 (m, 1H), 7.74 (d, J=8.31 Hz, 1H), 7.54 (d, ./ 1 .96 Hz, IH), 7,22 (dd, ./ 2.32. 8.44 Hz, 1H), 7.14 (d, 2 45 Hz, 1H), 7.04 (dd, .7=2.08, 8.19 Hz, IH), 6,89 (d, J=8.07 Hz, IH), 4.62 (d, .7=4,65 Hz, 1H), 4.02- 4.11 C m. 3H), 3.96 (dd, .7=11.86, 15.77 Hz, IH), 3.79-3.90 (m, IH), 3.60 (d, ./ 14.43 Hz, I H), 3.33 (d, ,7=14.43 Hz, IH), 3.11 (dd, ./ 5. 14. 15.89 Hz, IH), 2,96-3.02 (m, IH), 2.94 (s, 3H), 2.69-2.83 (m, 2H), 2.36-2.55 (rn, 4H), 1.76-1.89 (m, 4H), 1.61-1,70 (m, 5H).

EXAMPLE 19. (1 S,3'R,6'R,7'S,8'E)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THlA[ l,12,14]I¾lAZATETiL CYCLO[ 14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ ]l TAC OSA[8,16 ₅ 18,24]TETRAE ]-15'- ONE 13,13' DIOXIDE

STEP 1 : TERT-BUTYL N-(BUT-3-EN-l-YL)SULFAMOYLCARBAMATE

To a solution of chloro-sulfonyl isocyanate (1.062 g, 653 μί, 7.5 rnmol, Sigma- Aldrich Co. St. Louis, MO) in dichloromethane (30 mL) was added t- BuOH (717 \L, 7,6 mmol) dropwise. The solution was then stirred for 30 rain to allow for complete formation of tert-butoxycarbonylsulfamoyl chloride intermediate. The solution was then added via cannula to a solution of 3-buten-I - amine (367 mg, 5.0 mmol) and NjV-diisopropylethylarnine (2.61 mL, 15.0 mmol) in dichlorome thane (15 ml.) at 0 °C. The reaction mixture was allowed to stir at ambient temperature ovemight. The solvent was then removed under vacuum and the crude product was purified by flash chromatography on silica gel (120 gram HP silica column, Teledvne Isco) eluting with 0% to 50% ethyl acetate in hexanes to provide tert-butyl N-(but-3-en-l-yl)sulfamoylcarbamate as a white solid (1 .05 g, 84% yield).

STEP 2: Ν-3-BUTEN-l-YLSULF AMIDE

H

^/\^N , „NH ₂

O O

Tert-Butyl N-(but-3-en-l-yl)sulfamoylcarbaraate (1.05 g, 4. 19 mmol) was treated with 4 Ν HC1 solution in 1 ,4-dioxane (10.5 mL) at room temperature overnight. The reaction was monitored by TLC using iodine stain. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (80 gram flash column, Teledvne Isco) eluting with 25% to 100% ethyl acetate in hexane to provide N-3-buten-l -ylsulfamide as a colorless ceramic (630 mg, 100% yield).

STEP 3: (S)-N-(N-(BUT-3-EN-l -YL)SULFA OYL)-6'-CHLORO-5-(((lR,2R)-

2-((S)- l-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3 ^f ,4,4',5- TETRAH DRO-2H,2 ^! H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- ΑΡΗΊΉ ALENE] -7 -C ARB OXAMIDE

To a solution of (rS)-6'-chloro-5-(((lR,2R)-2-(l- hydrox>'ally])cyclobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[^] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (1.3.1 g, 2,8 mmol, Intermediate AAl 1A), N-3-buten-l-sulfamide (630 mg, 4.19 mmol), NJV- dimethyipy idin-4-amine (513 mg, 4.2 mmol), and N,N-diisopropylethylamine (1.46 mL, 8.40 mmol) in dichloromethane (28 mL) was added Nl - ((ethylimino)methylene)-N3,N3-dimethylpropane-l ,3-dian ^" iine hydrochloride (1074 mg, 5.46 mmol, Chem-lmpex International, Wood Dale, IL) slowly in portions at 0 °C. The reaction mixture thus obtained was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (120 gram HP silica column, Teledyne Isco) eiuting with 5% to 25% ethyl acetate (containing 1% acetic acid) in hexanes to provide (S ^r )-N-(N~(hut-3-en~l~ yl)sulfamoyl)-6'-chloro-5-(((li?,2i?)-2-((S)-l -hydroxy allyl)cyclobutyl)methyl)- 3',4,4',5-tetr ally dro-2H,2'H-spiro[benzo[¾][l,4]oxazepine-3,l '-naphthalene j-7- carboxamide as a white solid (1.15 g, 68% yield). STEP 4: (LS 37^67?,7'.S 8 ^! £:)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[ 13]THL [ l,12,14]TRlAZATETiL CYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OSA 8,16,18,24]TETRAEN]-15'- ONE 13, 13'-DIGXIDE

A a solution of (^-N^N-Cbut-S-en-l-y sulfamo -e'-chloro-S-iiil i^ ?)- 2-((S)-l½droxyallyl)cyclobu1yl)me l)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2H- spiro[benzo[0] [l,4]oxazepine-3,r-naphthalene]-7-carboxamide (1.15 g, 1.92 mmol) in 1,1-dichloroethane (1280 mL) was evacuated and purged with argon (3 cycles), then Hoveyda-Grubbs catalyst 2 ^nd generation (132 mg, 0.21 1 mmol, Sigma-Aldrich Co. St. Louis, MO) was added to the solution under argon atmosphere. The reaction mixture thus obtained was stirred at 50 °C for 24 h and the reaction was monitored by HPLC-MS. At 24 h reaction time point, ethyl- vinylether (210 μΐ,, 2.1 mmol) was added and the reaction mixture was stirred for an additional 10 min. The reaction mixture was concentrated under reduced pressure and the the residue was purified by flash chromatography on silica gel (120 gram HP silica column, Teledyne Isco) eiuting with 25% to 100% ethyl acetate (containing 1% acetic acid) in hexanes to provide ( Ι^,Β'Α',βΆ^'^,δ'ίϊ-β- chloro-7'-hydroxy-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22 '-

[20]oxa[13]thia[l,12 4]triazatetr^

raenj~15 ^f - one 13,.13 '-dioxide as an off-white solid (670 mg, 61% yield). 'HNMR (500 MHz, DMSO-de) δ ppm 11.72 (s, 1 H), 8.06 (m, 1 H), 7,65 (d, J ------ 8.6 Hz, 1

III 7.25 (dd, ,/ 8,6, 2.0 Hz, 1 H), 7.17 (s, 1 H), 6,93 (dd, J ------ 9.0, 2.0 Hz, 1 H),

6.87 (d, J= 9,0 Hz, 1 H), 6.75 (s, 1 H), 5.89 (m, 1 H), 5.50 (dd, ./= 15.4, 8,6 Hz, 1 H), 4.57 (d, ./ 4.2 Hz, 1 H), 4.01 - 4.05 (m, 1 H), 3.94 - 3.98 (m, 2 H), 3.71 (m, 1 H), 3.57 (d, ,/ 14.2 Hz, 1 H), 3.06 - 3.26 {in.2 H), 2.88 - 3.02 {in.2 H), 2.62 - 2,86 (m, 2 H), 2.21 - 2,40 (m, 2 H), 2.03 - 2.21 (m, 2 H), 1.96 (m, 1 H), 1.75 - 1,87 (m, 3 H), 1.61 - 1,67 (m, 3 H), 1.38 (m, 1 H); MS mi ^' z (ESI, +ve ion) 572.2 ⁽ M R)

EXAMPLE 20. (lS,3'R,6'R,7'S,8'E)-6-CHLORO-12'- (CYCLOPROPYLMETHYL)-7'-HYDROXY-3,4-DiHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1.22-

[20]ΟΧΑ[13]ΊΉΙΑ[1,12,14]ΤΚΙΑΖΑΤΕΤΚΑΟΥ ΟίΟ[14.7.2.0- ⁶ .0 ¹⁹ · ²⁴ ]ΡΕΝΤΑΟ

OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13, 13'-DTOXIDE

STEP 1 : ( 1 S,3 ^, R,6'R,7'S,8'E)-6-CHLOR()-7 ^, -((DIMETHYL(2-METHYL-2- PROPANYL)SiLYL)OXY)-3,4-DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE- 1 ">"><-

|2 ⁽ ϊ!()ΧΑ| ΟΓΙ ^' ίΙΙΛΙ 1.12. !4|TRL\ZA ΓΙί ^' Π Λ(Ύ( ^' !.()| I4.7.2.ii ^; ".0 ^! " ^I! !N ! AC OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13, 13'-DIOXIDE

To a solution oi 103'i?,6'/?;7¾8'iil-6-ch3oro-7'-hydroxy-3,4-dihydro- 2H, 15'H-spirofnaphthalene- 1 ,22'-

[20]oxa[ 13]thia[ 1 , 12, 14]triazatetracy clo[ 14.7.2, 0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, 16, 18,24]tet raen]-15'- one 13,13 ^" -dioxide (485 nig, 0.848 mmol, Example 19) in DMF (2.4 mL) were added imidazole (115 mg, 1.7 mmol) and t-but lchlorodimethylsilane (192 mg, 1.27 mmol). The solution thus obtained was stirred at room temperature for 8 h and HPLC-MS analysis indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate and washed with 10% citric acid, water and brine, then dried. The solvent was evaporated and the residue was purified by chromatography on silica gel (80 g flash column, Teledyne Isco) eluting with 0% to 45% ethyl acetate in hexane to provide (18,3'Κ,6'Κ,Τ8β'Ε)~6~άύθΐθ~Τ~ ((dimethy I (2-methy 1-2-propany l)siiy 1 )oxy )-3 ,4-dihy dro-2H, 15 Ή- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l,12,14]triazatetra<^

raen]-15'-one 13, 13" -dioxide as a white solid (495 mg, 85% yield).

STEP 2: (lS,3'R,6'R,7'S,8'E)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)-7 ^! - ((DIMETHYI 2-METOYL-2-PROPA^L)SILYL)OXY)-3,4-DTHYDRO- 2H, 15 Ή-S PIRO [N ΑΡΗΤΉ ALENE- 1 ,22'- |2ίί )ΧΛ| 13ΓΠ!!Λ| ί.Ι2.!4| |-R!AZA ^' S ^' 1 ^: TRA('YC!.()| 14.7.2.ίί ^; " -|Ρ!;ΝΤΛ( ^' OSA[8,16,18,241TETRAEN]-15'- ONE 13,13'-DIOXIDE

To a solution of (15 ^, ,3'R,6 ^, /^7 ₅ 8'^-6-chloro-7 ^, -((dimethy](2-methyl-2- propanyl)silyl)oxy)-3,4-dihydro-2H,15'H-spiro[naphthalene-l, 22'- [20]oxa[13]thia[U2,14]triazatetra^

raen]-15'- one .13, 13 '-dioxide (30 nig, 0.044 mmol) in THF (0.5 mL) wad added 1 .0 M solution of lithium bis(trimethylsilyl)amide in THF (219 μΐ,, 0.219 mmol) and the mixture was stirred at room temperature for 30 min, then

(bromomethyl)cyclopropane (212 μ ,, 2.185 mmol) was added. The mixture thus obtained was heated at 140 °C for 3 h under microwave irradiation. HPLC-MS analysis indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (12 g HP silica, Teiedyne Isco) eiuting 0% to 25% ethyl acetate in hexanes to provide {}S, R,6'R,TS,^E)~6-chlow~l2''

(cyclopropylmethyl)-7^(dimethyl(2-methy

2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[U2,14]triazatetra^

raen]-15'- one .13, 13 '-dioxide as a white solid (1 1 mg, 34% yield).

STEP 3: (l S,:rR,6'R,7'S,8T;)-6-CHLORO-12'-(CYCLOPROPYL;METHYL)-7 ^! - HYDROXY - 3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^, - [20]OXA[ 13;|^ΉIA[U2,14]ΉUAZATETOACT^

OSA[8,16 ₅ 18,24]TETRAE ]-15'- ONE 13, 13'-DIOXIDE

To a solution ol ^' i i .V.37 . 7 7 .87-:)- -chio! - ! 2'-ic> cloprop> lme!h> ! )-7'- ((dimethyl(2-methyl-2-propanyl)silyl)oxy)-3,4-dihydro-2H,15' H- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l,12,14]triazatetra^^^

raenj-15'- one 13,13'-dioxide (10 mg, 0.014 mmol) in THF (0.5 mL) was added 1M tetrabutylarnrnoniurn fluoride in THF (27 uL, 0.027 mmol) and the mixture was heated at 50 °C overnight and HPLC-MS analysis indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried, then concentrated under vacuum. The residure was purified by flash chromatography on silica gel (12 gram HP silica, Teledyne Isco) eluting with 15% to 75% ethyl acetate in hexane to provide (lS,3'R,6'R,TS,8'E)-6-C \oTO- 12'-(cydopropylmethyl)-7'-hydroxy-3,4-dihydro-2H,15'H-spiro| naphthalene- 1,22'- 6J8.24|iei raen]-15'- one 13, 13' -dioxide as a white solid (8 mg, 95%). ¾ NMR (500 MHz, CDC! ^: .) ppm 8.64 (s, 1 H), 7.70 (d, ./ 8.6 Hz, 1 H), 7.17 (dd, ./ 8.6, 2.4 Hz, 1 H), 7.09 (d, ./ 2.0 Hz, 1 H), 6.95 (dd, J= 9.0, 2.0 Hz, 1 H), 6.91 id../ 9.0 Hz, 1 H), 6.87 (br. s., 1 H), 5.90 (m, 1 H), 5.70 idd../ 15.0, 9.0 Hz, 1 !!}.4.19 (m, 1 H), 4.05 - 4.12 (m, 2 H), 3,77 - 3.83 (m, 2 H), 3,65 - 3.70 (m, 2 H), 3,42 - 3.47 (m, 1 H), 3,25 - 3.34 (m, 2 H), 3,08 - 3.15 (m, 1 H), 2,70 - 2,83 (m, 2 H), 2,42 2. 2 (m, 1 H), 2.33 - 2.42 (m, 2 H), 2.27 - 2.31 (m, 1 H), 1.90 - 2.02 (m, 3 H), 1.76 - 1.84 (m, 2 H), 1.62 - 1.74 (m, 3 H), 1.45 (m, 1 H), 1.08 (m, 1 H), 0.53 - 0.63 (rn, 2 H), 0.30 - 0.39 (rn, 2 H); MS m/z (ESI, +ve ion) 626.2 i.VCH) .

EXAMPLE 21. (1 S,3'R,6 ^! R,7'S,8'E)-6-CHLORO-7'-HYDROXY-12 ^! -((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,12 4]TRIAZATCTTIACYCLO[14 .2 ³ '*0 ¹⁹ - ²⁴ ]PENTAC OSA[8,16,18,24]TETRAEN]-15'- ONE 13,13'-DIOXIDE AND

(lS.3 ^, R,6 ^, R,7 ^, S,8'E)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2S)-TETRAHYDRO-2- FURANYLMETHYL)-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22*- [20]OXA[13]THIA[1,12,14]TRJAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTAC OSA[8,16,18,24]TETRAEN]-15'- ONE 13, 13' -DIOXIDE

STEP 1 : (1 S 3¾,6'R J'S,8T,)-6-CHLORO-7 ^! -((DIME ^' mYL(2-METHYL-2- PROPANYL)SILYL)OXY)-12'-((2R)-TETR/I-IYDRO-2-FURANYLMEraYL)- 3,4-ΟΙΗΥΌΚΟ-2Η,15Ή-8ΡΙΚΟ[ΝΑΡΗΤΗΑ1ΕΝΕ- 1,22'-

[20]OXA[13]THIA[1,12,14]T1UAZATETOACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8,16,18,24]TCTRAEN]-15'- ONE 13,13'-DIGX1DE AND

(lS,3'R,6'R,7'S,8'E)-6-CHLORO-7'-((DIMETHYL(2-METOYL-2- PRO ANYL)SILYL)OXY)-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)- 3.4-OIHYDRO-2J !.Ι

|2ujOXA| 13ΓΗ!!Α| U2J4|TR!AXATiTRAi ^' Yi ^' !.(}| 14 .2.ί, ^; ".ί! ^! "-|!>[;^ ^· ! ^· A(· ()SΛ!8.16.18,24]TETR AEN] -15'- ONE 13 ,13' -DIOXIDE

To a solution of (15 ₅ 3 ^, R ₅ 6 ^, R ₅ 7VS ^, ,8 ^, Q-6-chloro-7 ^, -((dimethyl(2-methyl-2- propanyl)silyl)ox\ -3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l ₅ 12,14]triazatetr^

raen|-15 ^f - one 13,.13'-dioxide (60 mg, 0.097 mmol, Example 20, Step 1) in THF (2.0 ml.) wad added 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (437 μΕ, 0.437 mmol) and the mixture was stirred at room temperature for 30 min, then 2-(bromomethyl)tetrahydrofuran (207 μί.., 1.75 mmol) was added. The mixture thus obtained was heated at 140 °C for 3 h under microwave irradiation, HPLC-MS anaysis indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (12 g HP silica, Teledyne Isco) eluting 0% to 30% ethyl acetate in hexanes to provide

(lS,3 ^, R,61 7 ^, S,8T)-6-chioro-7'-((dimetliyl(2-methyl-2-propaiiyl)s

((2R)-tetrahyclro-2-furanylmethyl^

raenj-15'- one 13,13'-dioxide and (l S,3'R,6 ^, R,7 ^, S,8'E)-6-cliloro-7 ^, -((dimethyl(2" methyl -2-propany l)sily l)oxy )- 12'-((2S)-tetrah} ⁷ dro-2-furany lmethy l)-3 ,4-dihy dro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[ 1 3]thia[ 1 , 12, 14]triazatetracy clo[ 14, 7.2, 0 ³ 0 ¹⁹ ' ²⁴ ]pentacosa[8, 16, 18,24]tet raen]-15'- one 13, 13 '-dioxide as a white solid (30 mg, 45% yield). STEP 2: (l S,3'R,6'R,7'S,8'E)-6-CHLORO-7'-HYDROXY-12'-((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- i .22'-

[20]OXA[13]TOIA[ 1 2,14]TT TAZATETRACYCLO[ 147.2.0 ³ '^0 ¹⁹ - ²⁴ ]PE TAC

OSA[8,16,18,24]TETRAEN]-15'- ONE 13,13'-DIOXIDE and

(lS,3'R,6 ^, R,7 ^, S,8 ^, E)-6-CHLORO-7'-HYDROXY-12 ^! "((2S)-TETRAHYDRO-2-

FURA^Γ¥ ^Γ LME^ΉYL)-3,4-DIHYDRO-2H 5Ή-SPIRO[NAPHTHALENE-l,22 ^, - [20]OXA[13]THIA[1 ^2, 14]TRIAZATETOACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC

OSA[8,16,18,24]TETRAEN]"15'- ONE 13,13'~DI0X1DE

To a solution of (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E)-6-chloro-7 ^, -((dimetliyl(2-methyl-2- propanyl)silyl)oxy)-12'-((2R)-tetrahydro-2-furanylrnethyl)-3 ,4-dihydro-2H, 15'H- spiro [naph thalene- 1 ,22'-

[20]oxa[ 1 3]thia[ 1 , 12, 14]triazatetracy clo[ 14, 7.2, 0 - ⁶ .0 ¹ ' ²⁴ ]pentacosa[8, 16, 18,24]tet raen]-15 ^! - one 13, 13' -dioxide and (l S,3'R,6 ^* R,7'S,8'E)-6-chioiO-7'-((dimethyl(2- methy 1-2-propany l)si ly 1 )oxy )- 12'-((2S)-tetrahy dro-2-furany 1 methy l)-3 ,4-dihy dro- 2H, 15 ^! H-spiro[naphthalene- 1,22'-

raenj-15'- one 13,13'-dioxide (30 mg, 0.039 mmol) in THF (1 mL) was added 1 M tetrabutylammonium fluoride in THF (78 uL, 0.078 mmol) and the resutmg mixture was heaied at 50 °C for 7 h and HPLC-MS analysis indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried, then concentrated under vacuum. The residure was purified by flash chromatography on silica gel (12 gram HP silica, Teledyne Isco) eluting with 50% to 100% ethyl acetate in hexane to provide a mixture of (L ,3'«,6 ^! ?,7 ^! S 8' ^

3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[ 13]thia|;i , 12, 14]taazatetracycio[14,7.2,0 -^0 ^l9 - ²⁴ ]pentaco

raen]-15'- one 1 . ! -dioxide and

((2<S)-tetrahydro-2-furanyim^^

[ 20 joxaj 13 ]thia[ 1 , 12, 14]triazateto^^

raen]-15'- one 13, 13 '-dioxide as a white solid (25 mg, 95% yield). ¾ NMR (500 MHz, CDCb) δ ppm 7,69 (m, 1 H), 7. 16 (m, 1 H), 7.08 (m, I H), 7.00 (m, 1 H), 6,83 - 6.90 (m, 2 H), 5,99 - 6.05 (m, 1 H), 5,68 (dd, J = 15.4, 7.6 Hz, I ! ! }. 4,21 (m, 1 H), 4,01 - 4.15 (m, 3 H), 3,83 - 3.89 (m, 2 H), 3.61 - 3,78 (m, 4 H), 3,22 3. 2 (m, 2 H), 2.97 - 3.15 (m, 1 H), 2.70 - 2.82 (m, 2 H), 2.23 - 2.53 (m, 4 H), 1.85 - 2.02 (m, 5 I I ). 1.75 - 1.85 (m, 2 H), 1.55 - 1.73 (m, 5 H), 1.37 - 1.45 (m, 2 H); MS Mi / (ESI, +ve ion) 656,2 (M+H) ⁺ .

EXAMPLE 22. (1 S,3'R,6 ^! R,7'S,8'E)-6-CHLORO-7'-HYDROXY-12 ^! -(2-(2- METHOXYETHOXY)ETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[l ,12, 14]TRIAZATCTTlACYCLO[14.7.2.0 ³ '* 0 ¹⁹ - ²⁴ ]PE3SrrAC

OSA[8,16,18,24]TETRAEN]-15'- ONE 13,13'-DIOXIDE

STEP 1 : ( 1 S,3U R,7'S,8'E)-6-CHLO O-7'-((DIMETHYL(2-METHYL-2- PROPANYL)SILYL)OXY)-12 ^, -(2-(2-METHOXYETHOXY)ETHYL)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'- [20]OXA[13]THIA[l ,12 4]TRIAZATCTTlACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PE3SnrAC OS A[8, 16, 18,24]TETRAEN]-15'- ONE 13,13' -DIOXIDE

To a solution of ^' i i . J7 /»7 7 .87 - hior< 7'-{ { dinHn!u !{ 2-nieih> i-2- propanyl)silyl)oxy)-3,4-dihydro-2H,15'H-spiro[naphtrialene-l ,22'-

raen]-15'- one 13,13'-dioxide (30 mg, 0.044 mmol, Example 20, Step I) in THF (0.5 mL) wad added 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (219 ih, 0.219 mmol) and the mixture was stirred at room temperature for 30 min, then l -bromo-2-(2-methoxyethoxy)ethane (327 ,uL, 2. 185 mmol, Sigma- Aldnch Co. St. Louis, MO) was added. The mixture thus obtained was heated at 140 °C for 3 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (12 g HP silica, Teledyne Isco) eluting with 0% to 25% ethyl acetate in hexanes to provide (\S,3'R,6'R,TS,S'E)-6-Chloro-T- ((dimethyl(2-methyl-2-propanyl)silyl)oxy)-12'-(2-(2-memoxyet hoxy)ethyl)-3,4- dihy dro-2H l 5 Ή-spiro [naphtM

[20]oxa[13]tMa[l,12,14]triazatetr^

raen j-15'- one 13, 13 '-dioxide as a white solid (21 mg, 61% yield).

STEP 2: (lS,3 ^, R,6'R,7 ^, S ₅ 8 ^, E)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-(2- ΜΕΤΗΟΧΎΕΉ-ΪΟΧΥ)ΕΤΗΥΙ,)-3,4-ΟΙΗΥΓ)ΚΟ -2Η, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

| 2u jOXA| 1 3 ΓΗ ! !Α| U 2J 4 |TR ! AXATiTRAi ^' Yi ^' ! .(}| Ι 4.7.2.0 ⁵ ·'·.0 ^, "·· |Ι>ΐ :ΝΐΛ( ^' OS A [ 8, 16, 18,24]TETR AEN] -15'- ONE 13 ,13' -DIOXIDE

To a solution of (15 ₅ 3 ^, R ₅ 6'R ₅ 7VS',8 ^, Q-6-chloro-7 ^, -((dime1hyl(2-methyl-2- propanyl)silyl)oxy)-l2'-(2-(2-methoxye1hoxy)e1hyl)-3,4-dihyd ro-2H,l5'H- spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[l ₅ 12, 14]triazatetra^

raen]-15'- one 13, 13'-dioxide (20 mg, 0.027 mmol) in THF (1 mL) was added 1M tetrabutylammonium fluoride in T ^' HF ( 53.3 μΕ, 0.053 mmol) and the resulting mixture was stirred at 50 °C 24 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried, then concentrated under vacuum.

The residure was purified by flash chromatography on silica gel (12 g HP silica,

Teledyne Isco) eluting with 25% to 100% ethyl acetate in hexane to provide

(15,3'i?,6'i?,7'S 8'£)-6-chloro-7'-hydroxy-12'-(2-(2-metho

dihydro-2H,I5'H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[l ₅ 12, 14]triazatetra^

raen j-15'- one 13, 13 '-dioxide as a white solid (13 rag, 72%). ¾ NMR (500 MHz, CDCb) δ ppra 8.70 (s, 1 H), 7,70 id. ./ 8.6 Hz, 1 H), 7.17 (dd, ,/ 8,6, 2.4 Hz, I H), 7.09 (d, 2.4 Hz, 1 H), 6.93 (dd, J= 9.0, 2,0 Hz, 1 H), 6.90 (d, ,/ 9.0 Hz, 1 H), 6.85 (br. s., 1 H), 5.92 (m, 1 H), 5.69 (dd, «/= 15.4, 8.6 Hz, 1 H), 4,04 - 4.21 (m, 4 H), 3.80 - 3.85 (m, I H), 3.69 - 3.75 (m, 3 H), 3.63 - 3.66 (m, 3 H), 3.56 - 3.61 (m, 1 H), 3.53 ^■ - 3.55 (m, 2 H), 3.46 ^■ - 3.52 (m, 1 H), 3.37 (s, 3 H), 3.25 (d, J ------ 13.9 Hz, 1 H), 3.10 (br. s. 1 I s ). 2.75 - 2.85 (m, 2 H), 2.40 - 2.50 (m, 2 H), 2.31 - 2.40 (m, 1 H), 2.22 - 2.29 (m, 1 H), 1.89 - 2.02 (m, 4 H), 1 ,79 - 1.85 (m, 2 H), 1.61 - 1.73 (m, 2 I I ). 1.39 - 1.46 (m, 1 I I ): MS m/z (ESI, +ve ion) 674.2 ί M H ) .

EXAMPLE 23. 2-((lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-13 ^, ,13 ^, - DIOXIDO-lS'-OXO-S^-DIHYDRO^Iin'H-SPIROINAPHTOALENE-l^^'- [20]OXA[13]TOIA[ 1, 12,14]TT TAZATETRACYCLO[ 14.7.2.0 ³ "« 0 ¹⁹ ' ²⁴ ]PE TAC OS A[8, 16, 18,24]TETRAEN]-12'-YL)-N-METHYLACETAMIDE

STEP 1 : 2-((l S,3'R,6'R,7 ^, S,8'E)-6-CHLORO-7'-((DIMETHYL(2-METHYL-2- PROPANYL)SILYL)OXY)-13 ^, .13 ^, -DIOXIDO-15 ^, -OXO-3.4-DIHYDRO- 2H, 12'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTAC OS A[8, 16, 18,24]TETRAEN]-12'-YL)-N-METHYLACETATE

To a solution of (15 ₅ 3 ^, R ₅ 6 ^, R ₅ 7VS ^, ,8 ^, Q-6-Chloro-7 ^, (dimethyl(2-meth l-2- propany l)sily l)oxy )-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[l ,12 4]triazatetra^

raen |-15 ^f - one 13, .13'-dioxide (45 mg, 0.066 mmol, Example 20, Step 1 ) in THF (1 mL) wad added 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (328 μΕ, 0.328 mmol) and the mixture was stirred at room temperature for 30 min, then methyl 2-bromoacetate (124 μΕ, 1 .311 mmol) was added. The mixture thus obtained was heated at 70 °C overnight and HPLC-MS analysis indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (12 g HP silica, Teledyne Isco) eluting with 0% to 25% ethyl acetate in hexanes to provide 2-((l _J S 3' ?,6 ^, i?,7 ^, 5 ^' ,8'E)-6-chloro-7'-((dirnethyl(2-methyl-2- propanyl)silyl)oxy)-13',13'-dioxido-15'-oxo-3,4-dihydro-2H,1 2'H- spiro [naphthalene- 1 ,22'-

raen]-12'-yl)-N-methylacetate as a white solid (58 mg, 82% yield).

STEP 2: ((1 S,3'R 3' J'S,8Ti)-6-CIfl..ORO-7'-((DIMETHYL(2-METHYL-2- PROP AN YL)SIL YL)OXY) - 13 ', 13 '-DIOXIDO - 15'-OXO-3 ,4-DIHYDRO- 2H, 12H-SPIRO[N APHTH ALENE- 1 ,22'-

[20]OXA[ ;i3]THIA[ 1, 12,14]TRTAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ ,0 ^{i 9} - ²⁴ ]PENTAC OS A[8, 16, 18,24] TETRAEN] - 12'~YL)ACETIC ACID

To a solution of 2-((l 5,3 ^, R,6 ^, R,7 ^, S',8 ^, E)-6-chloro-7 ^, -((dimerthyl(2-methyl-2- propanyl)silyl)oxy)-13',13'-dioxido-15'-oxo-3,4-dihydro-2H,1 2'H- spiro I naphthalene- 1 ,22'-

[20]oxa[13]thia[l ,12, 14]iriazaietracycio[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pen^

raen]-12'-yl)-N-methylacetate (58 mg, 0.076 mmol) in THF/TVIeQH/T bO (3/1/1,

460 μΕ/Ί53 μΕ/153 μΕ) was added lithium hydroxide monohydrate (6.4 mg, 0.153 mmol) and the reaction mixture was stirred at 50 °C overnight. HPLC-MS analysis indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure and acidified with 2 N HC1, then extracted with ehtyl acetate. The organic layers were washed with brine, dried over MgSCh and concentrated in vacuo to provide ((lS,yR,6'R,7S,8'E)-6-chloTo-T- ((dimethyi(2-methyl~2-propaiiyi^

21 i. ! 2Ί i-spiroj naphthalene- i .22'- .iH.24|ιet raen]-12'-yi)acetic acid as a white solid (57 mg, 100% yield).

STEP 3: 2-((lS,3'R,6 ^, R,7^,8¾-6-CHLORO-7 ^, -((DIMETHYL(2-METHYL-2- I'ROPAN VI. )SII.YI.)OXY)- i 3'.1.T-DIOXiDO- 1 -OXO-3.4-OU lYDRO- 2H, 12'H-SPIRO[NAPHTHALENE- 1 ,22'- [2 ]ΟΧΑ[13]ΤΗΙΑ[1,12,14]ΤΚί^^

OSA[8,16,18,24]TETRAEN]-12'-YL)-N-METHYLACETAMTDE

To a solution of ((15 ₅ 3'R ₅ 6 ^, R ₅ 7VS',8 ^, Q-6-chloro-7 ^, -((dime l(2-methyl-2- propanyl)silyl)oxy)-13 ^, ,13'-dioxido-15 ^, -oxo-3,4-dihydro-2H,12 ^, H- spiro I naphthalene- 1,22'- [2Q]oxa[13]thia[l,12,34]ir^^^

raen]-12'-yl)acetic acid (0.076 mmol) in dichloromethane (1 mL) were added 2 M solution of methylamine in THF (76 ul..0.152 mmol), Nl- ((ethylirnino)rnethylene)-N3,N3-dirnethylpropane-.l ,3-diamine hydrochloride (29 mg, 0.152 mmol, Chem-Impex International, Wood Dale, IL), 1H- benzo[<i][l,2,3 jtriazol-l-ol (15 mg, 0.114 mmol), and NJV-diisopropylethylamine (39 μΕ, 0.228 mmol). The mixture thus obtained was stirred at room temperatui ^' e overnight. The reaction mixture was diluted with ethyl acetate and washed with 1Ν HC3, water, and brine respectively. The organic layer was dried over MgS0 ₄ and concentrated to provide crude 2-((15',3'i?,6'i?,7'5',8'E)-6-chloro-7'- ((dimethyl(2-methyl-2-propanyl)silyl)ox\ -13',13'-dioxido-15'-oxo-3,4-dihydro- 2H, 12'H-spiro|naphthalene-l ,22'-

[20]oxa[13]thia[l ,12, 14]triazatetrac> lo[14.7.2.0 ³ ' .0 ^l9 - ²⁴ ]pentacosa[8,16, 18,24]tet raen]-12 ^! -yl)-N-methylacetamide (42 mg) which was used in next de-protection step without further purification.

STEP 4: 2-((lS,3'R,6 ^, R;7'S,8 ^, E)-6-CHLORO-7'-HYDROXY-13V13 ^, -D10XlDO- 15 ^* -OXO-3,4-DIHYDRO-2H, 12'H-SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,12, 14]T1UAZATETOACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16, 18,24]TETRAEN]"12'-YL)- -METHYLACET AMIDE

To a solution of 2 (1^3'ii,6 ^, ii,7 ,8'ii>6~chloro-7 ^, ~((dimethyl(2-methyl~2-- propan}d)silyl)oxy)-13 ^! ,13'-dioxido-15'-oxo-3,4-dihydro-2I-L12'H- spiro [naphthalene- 1 ,22'- i H.24 |iet raen]-12'-yl)-N-methylacetamide (42 mg, 0.056 mmol) in THF (1 mL) was added 1M tetrabuty I ammonium fluoride in TOP (112 iiL, 0.1 12 mmol) and the resutmg mixture was heated at 50 °C for 7 h and HPLC-MS analysis indicated completion of the reaction . The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried, then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (12 g HP silica, Teledyne Isco) eluting with 50% to 100% ethyl acetate (containing 1% AcOH) in hexane to provide 2-((1^3'i?,6'i?,7'^8'i^

dihyclro-2H,12H-spiro[naphthalene-l,22'- i H.24 |iet raenj-12'-yl)-N-methyiacetamide as an off-white solid (32 mg, 89% yield). ^y ll

NMR (500 MHz, CDCb) δ ppm 9,23 (br. s . 1 H), 7.69 i d. J = 8.6 Hz, 1 ! ! }. 7.40 (br. s., 1 H), 7.17 (dd, J 8.6, 2.4 Hz), 7.09 (d,■/ 2.0 Hz, 1 I I ). 7.01 (dd. ./ 8.3, 2,0 Hz, ! H), 6.94 (d, ,/ 8.3 Hz, I ! ! }. 5.80 (m, 1 H), 5.69 (dd, ,/ 15,4, 6.8 Hz, 1 H), 4.24 id . «/ = 19.8 Hz, I H), 4.08 - 4.16 (m, 4 H), 3.56 - 3,72 (m, 3 H), 2.76 - 2,85 (m, 2 H), 2.37 - 2,46 (m, 3 H), 2,28 - 2,35 (m, 1 H), 1.90 - 2.01 (m, 3 H), 1.76 - 1.86 (m, 2 II).1.65 - 1.72 (m, 2 II).1.45 - 1.50 (m, 1 II): MS m/z (ESI, +ve ion) 643.2 (VI H) .

EXAMPLE 24.2-((lS,3 ^! R,6 ^, R,7'S,8'E)-6-CHLORO-7 ^! -HYDROXY-13',13'- DIOXIDO-15'-OXO-3,4-DIHYDRO-2H,12'H-SPIRO[NAPHTHALENE-l,22'- |2ujOXA| 13ΓΗ!!Α| U2J4|TR!AXATiTRAi ^' Yi ^' !.0| i .7.2.{Γ '.O ⁾ [ Pi Ν ^' ΓΛί ^' OS A[ 8, 16, 18,24]TETRAEN] - 12'- YL )-N,N-D ΙΜΕΤΉ Y LAC ET AMIDE

STEP 1: 2-((lS,3'R,6'R,7 ^! S,8'E 6-CHLORO-7'-((DIMETI-IYL(2-METHYL-2- PROP ANYL)STI,YL)OXY)~13', 13"-DIOXIDO- 15"-OXO-3,4-DIHYDRO- 2H, 12'H-S PIRO [N ΑΡΗΤΉ ALENE- 1.22'-

|2ujOXA| 13ΓΗ!!Α| U2J4|TR!AXATiTRAi ^' Yi ^' !.0| 14,7.2.ίί ^; " 0 ^! " -|FI;NTAC OS A[ 8, 16, 18,24jTETRAENj- 12'- YL )-N,N-D IMETH Y LAC ET AMIDE

To a solution of ((15',3 ^, R,6 ^, R,7W _s 8 ^, E)-6-cWoro-7 ^, -((dime1hyl(2-methyl-2- pfopany3)silyl)oxy)-13 13'-dioxido-15'-oxo-3,4-dihydro-2I-L12'H- spiro [naph thalene- 1 ,22'- 6,,i8.24|iei

22,1 raen]-12'-yl)acetic acid (112 rng, 0. 15 mmol, Example 23, Step 2) in DMF (2 ml.) were added dimethylamine hydrochloride (24 mg, 0.30 mmol), Nl- ((ethylimino)methylene)-N3,N3-dimethylpropane- 1 ,3-diamine hydrochloride (58 mg, 0,30 mmol), lH~benzo[a] j l ,2,3]triazol-l-ol (30 mg, 0.225 mmol), and N.N- diisopropylethylamine (156 μΕ, 0.90 mmol). The mixture thus obtained was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% citric acid, 5% NaHCC>3, water, and brine respectively. The organic layer was dried over MgSO |. and concentrated. The residue was purified by flash chromatography on silica gel (24 g HP silica, Teledyne Isco) eiuting with 25% to 75% ethyl acetate in hexanes to provide 2- ((1^3 ^, R,6 ^, R,7 ,8¾-6-chloro-7 ^, -(((iimethyl(2-me l-2-pro^

13',13 ^, -dioxido-15 ^, -oxo-3,4-dihydro-2H,12'H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[l ,12 4]triazatetr^

raen]-12'-yl)-N,N-dimethylac-etamide as a white solid (83 mg, 72%). STEP 2: 2-((lS,3 ^, R,6'R ₅ 7 ^, S,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-13 ^, ₅ 13 ^, -DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H, 12'H-SPIRO[NAPHTHALENE- 1 ,22'- [20iOXA|;i3]TOIA|;i ,12, 14]TRIAZATETRACYCLO|;i4.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PE TAC OSA[8, 16, 18,24 jTETRAEN]- 12'-YL)-N,N-DIMETHYLACET AMIDE

To a solution of 2-((l 5 ^, ,3 ^, R,6 ^, R,7 ,8'£)-6-chloro-7 ^, -((dime1hyl(2-methyl-2- propanyl)silyl)oxy)-13 3'-dioxido-15 ^, -oxo-3,4-dihydro-2H,12 ^, H- spiro I naphthalene- 1 ,22'- [2Q]oxa[ 13]thia[l , 12, 14]tria^^^^

raen]-12'-yl)-N,N-dimethylacetarnide (82 mg, 0.106 mmol) in THF (2.0 mL) was added IM tetrabutylammonium fluoride in THF ( 319 μΐ,, 0.319 mmol) and the resuting mixture was heated at 50 °C for 4 h and HPLC-MS analysis indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried, then concentrated under vacuum. The residue was purified by reversed phase HPLC (Eclipse Plus C18, 5μτη, 30 x 150 mm, Agilent) eiuting with 45% to 100% acetonitrile (containing 0.1% TFA) in water (coniaimng 0. 1 % TFA)] to provide 2-((\S 'R,&R,TS,S'E)~6~Ch]oro~T~ hydroxy-13', 13'-dioxido-l 5'~oxo-3,4~dihydro-2H, 12'H~spiro[naphthalene- 1 ,22'- [20]oxa[ 13]thia[l ₅ 12 4]triazatetr^

raen |-12 ^f -} _' -])-AvV-dimethyla,cetarr!ide as a white solid (57 mg, 82% yield), ^] H N .MR (500 MHz, CDCb) δ ppm 9.59 (br. s., 1 H), 7.7 (d, ,/ 8.3 Hz, 1 H), 7, 1 8 (dd, J --- 8.3, 2.3 Hz, 1 H), 7.07 - 7.90 (m, 2 ! ! }. 6.92 id. ,/ 8,3 Hz, 1 H), 6.88 (br. :s . 1 H), 5,83 - 5,98 (m, 1 H), .5.77 {dd. ./ 15,4, 7.6 Hz, 1 H), 4.73 (d, J = 17,6 Hz, 1 H), 4.04 - 4, 18 (m, 4 H), 3,65 - 3,82 (m, 3 H), 3,52 (br. s., 1 H), 3.30 (d, J = 14.2 Hz, 1 H), 3.15 (dd, ./ 15.2, 9.3 Hz, 1 H), 3.04 is. 3 H), 2.98 (s, 3 H), 2.65 2,83 (m, 2 H), 2.54 - 2,62 (m, 2 H), 2,43 - 2,53 (m, 2 H), 2,36 - 2.41 (m, 2 H), 1 ,90 - 2.05 (m, 3 H), 1,75 - 1.85 (m, 3 H), 1 ,70 (q, ./ 12.0 Hz, 1 H), 1.44 (t, «/ = 12.0 Hz, 1 H); MS z (ESI, +ve ion) 657.2 ( M i l ) .

EXAMPLE 25. (l S,3'R,6'R,7'S,8'E,irS)-6-CHLORO-7'-HYDROXY-12 ^! -(2-(2- METHOXYETHOXY)ETHYL)-.l r-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1 ,22 ^! ~

[20]OXA[13]THIA[1,12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16,18,241TETRAEN]-15'- ONE 13,13'-DIOXIDE

STEP 1 : (1S,3'R,6'R,7'S,8 ^! E,1 l'S)-6-CHLORO-7'-((DIMETHYL(2- ETHYL-2- PROPANYL)SILYL)OXY)-ir-METHYL-3,4-DIHYDRO-2H, 15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]TOIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ² ]PENTAC 08Α[8,16,18,24]ΊΈΊ^ ΕΝ]-15'- ONE 13, 13' -DIOXIDE

To a solution o£ (lS, R,GR,7S,WE,l l'5)-6-chloro-7'-]tydroxy-l I'-methyl- 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20joxaj l 3]thia[ U 2,14]triazatetra^^

raen]-15'~ one 13,13'-dioxide (470 mg, 0.802 mmol, Example 61) in DMF (5.4 mL) were added imidazole (109 mg, 1.6 mmol) and t-butylchlorodimethylsilane (181 mg, 1.2 mmol). The solution thus obtained was stirred at room temperature for 8 h and HPLC-MS analysis indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate and washed with 10% citric acid, water and brine, then dried. The solvent was evaporated and the residue was purified by chromatography on silica gel (80 g flash column, Teledyne Isco) eluting with 0% to 30% ethyl acetate in hexanes to give . (lS,yR,eR,TS,S'E,l l '5)-6-chloro-7 ^* - ((dimethyl(2-methyl-2-propanyl)silyl)ox> -l l'-niethyl-3,4-dihydro-2H,15'H- spiro [naphthalene- 1 ,22'- [2Q]oxa[ 13]thiaj;i ,12, 14]tiiaza^^

raen j~l 5'- one 13, 13 '-dioxide as a white solid (375 mg, 67% yield).

STEP 2: (lS,3'R,6 ^, R,7 ^, S ₅ 8¾i rS)-6-CHLORO-7 ^, -((DIMETHYL(2-METHYL-2- PROPANYL)SILYL)OXY)-12 ^, -(2-(2-METHOXYETHOXY)ETHYL)-l l'-

METHYL-3,4-DIHYDRO-2Il,15 ^SPIRO|NAPHTHALENE-l ,22'- [20]ΟΧΑ[13]ΤΉΙΑ[Μ2^4]ΤΚΙΑΖΑΤΈΤΤ ^

OS A[8, 16, 18,24]TETRAEN]-15'- ONE 13, 3' -DIOXIDE

To a solution o£ (lS, R,GR,7S,WE,l rS)-6-chloro-7'-((dimethyl(2-methyl-

2-propanyl)silyl)oxy)-l r-methyl-3,4~dihydro-2H,l 5'H~

[20joxaj l 3]thia[ U 2,14]triazateto^^

raen]-15'- one .13, 13 '-dioxide (70 nig, 0.10 mmol) in THF (1 mL) wad added 1 .0 M solution of lithium bis(trimethylsilyl)amide in THF (500 μΐ,, 0.50 mmol) and the mixture was stirred at room temperature for 30 min, then l-bromo-2-(2- methoxyethoxy)ethane (538 μΕ, 4.0 mmol, Sigma- Aldrich Co. St. Louis, MO) was added. The mixture thus obtained was heated at 140 °C for 5 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (24 g HP silica, Teledyne Isco) eluting 0% to 35% ethyl acetate in hexanes to provide ( 1S,3'R,6'R,7S,WE,1 l ^, 5)-6-Chloro-7 ^, -((dimethyl(2-mefliyl-2- propanyl)silyl)oxy)-12'-(2-(2-met oxyethoxy)ethyl)-i -methyl-3,4-dihydro- 2H,15'H-spiro[naphthalene-l,22'-

[20ioxa| 13jthia[ l,12,14]triazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[ 8

raen]-15'- one .13, 13 '-dioxide as a white solid (25 mg, 31 % yield).

STEP 3: (! S,3'R,6'R,7'S,8'Fi,l l ^, S)-6-CHLORO-7'-HYDROXY-12'-(2-(2- ΜΕΤΉΌΧΥΕΙΉΟΧΥ)ΕΤΗΥΕ)-1 Γ-ΜΡ;ΐΉΥΕ-3,4-ΟΙΗΥϋΚΟ-2Η, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1 2,14]TTOAZATETOACYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PE TAC OS A[8, 16, 18,24]TETRAEN]-15'- ONE 13,13' -DIOXIDE

To a solution o£ (lS3%6 ⁱ R,TS',8'E,l i ' i-A-(-hl ! -7'-iidi !ncihy!(2-n¾eihv!- 2-propanyl)silyl)oxy)-12'-(2-(2-methoxyethoxy)ethyl)-i -methyl-3,4-dihydro- 2H, 15 Ή-spiro [naphthal ene- 1,22'-

raenj-15'- one 13,13'-dioxide (25 mg, 0.031 mniol) in THF (1.0 mL) was added 1M tetrabutylammonium fluoride in THF (93 μί, 0.093 nimoi) and the resuting mixture was heated for 4 h at 50 °C and HPLC-MS analysis indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried, then concentrated under vacuum. The residue was purified by reversed phase HPLC [(Eclipse Plus C I 8, 5μηι, 30 x 150 mm, Agilent) eluting with 45% to 1QQ% acetonitrile (containing 0.1 % TFA) in water (containing 0.1 % TFA)] to provide (} S,3'R,6'R,7$,8'EA 1 ¾ 6-diloro-7'-hydroxy~ 12'-(2-(2-methoxyethox ethyl)-n'-me l-3,4-dihydro-2H,15'H- spiro [naphthalene- 1 ,22'- [ 20 joxaj 13 ]thia[ 1 , 12, 14]triazateto^^

raen]-15'~ one 13,13'-dioxide as a white solid (13 mg, 61%), Ή NMR (500 MHz, CDCb) δ ppm 8.57 (br. s., 1 H), 7.69 (d, ./ 8.6 Hz, I H), 7.17 (dd, ./ = 8.6, 2,2 Hz, I H), 7.09 (m, 2 H), 6,90 (s, 2 H), 5.72 - 5.78 (m, 1 H), 5.63 (dd, ,/ 15,4, 7.6 Hz, I H), 4.08 - 4.14 (m, 2 H), 4.07 (m, 1 H), 3,81 ~- 3.93 (m, 2 H), 3,67 - 3.79 (m, 4 H), 3.54 - 3.65 (m, 3 H), 3.46 - 3.52 (m, 1 H), 3.39 (s, 3 H), 3.30 (d, J = 14.2 Hz, 1 H), 3.10 - 3.22 (m, 1 H), 2,71 - 2.82 (m, 2 H), 2,35 - 2.48 (m, 3 H), 2.27 (dt, «/= 16.1, 4.8 Hz, 1 H), 1 ,78 - 2.02 (m, 7 H), 1,61 - 1.74 (m, 2 H), 1 ,47 (t, ./ 12.0 Hz, 1 H), 1.33 (d, J = 6.6 Hz, 3 H); MS m/z (ESI, +ve ion) 688.2

{ M · Π } .

EXAMPLE 26. (1 S,3'R,6'R,7'S,8'E, 1 l ^* S)-6-CHLORO-7 ^, -HYDROXY-12'-(2- METHOXYETHYL)-ir-METHYL-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- i . 2 -

[20]OXA[ 13]THIA[ 1 2,14]TTOAZATETOACYCLO[ 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PEOT OSA[8,16 ₅ 18,24]TETRAE ]-15'- ONE 13, 13'-DIOXIDE

STEP 1 : (S)-TERT-BUTYL N-(2-METHOXYETHYL)-N-(PENT-4-EN-

SULFAMOYLCARBAMATE

Pari one: To a solution of (R)-pent-4-en-2-yl 4-methylbenzenesulfonate

(Example 61, Step 1) in dioxane (3 mL) was added 2-methoxyethanamine (0.423 mL, 4.79 mmol) and triethylamine (1.00 mL, 7.18 mmol) in a pressure vessel equipped with a gauge. The reaction was heated at 80 °C for 18 hours and 100 °C for 5 hours to afford a product solution, which was used in the following step without workup and purification. This solution is labeled as A.

Part two: To a solution of isocyanatosulfuryl chloride (0.583 mL, 6.70 mmol) in DCM (4 mL) was added tert-butyl alcohol, anhydrous (0.732 mL, 7.65 mmol) dropwise at 0 °C under an atmosphere of N ₂ and the reaction was stirred at this temperature for 15 minutes. To this reaction was added a solution of A and triethylamine, anhydrous (1.33 mL, 9.57 mmol) in DCM (12 mL) and the resulting mixture was stirred at room temperature for 5 days. This reaction was concentrated and purified by chromatography to afford the title compound (0.414 g, 1.28 mmol, 26.8%).

STEP 2: N~(2"METHOXYETHYL)-N-((2S)-4-PENTEN~2"YL) SULFURIC DIAMIDE

The title compound was prepared from (S)-tert-butyl-N-(2-methoxyethyl)- N-(pent-4-en-2-yl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 ; (0.276 g, 1.24 mmol, 97%). STEP 3: (3S)-6'-CHLORO-5-(((lR,2R)-2-((l S)-l -HYDROXY-2-PROPEN-l- YL)CYCLOBUTYL)METHYL)-N-((2-METHOXYETHYL-)((2S)-4-PENTEN-2-

ΥΕ)8υΕΡΑΜΟΥΕ)-3',4,4\5-ΤΕΤ1^ ΗΥϋ1 0-2Ή-8Ρ11 0[1,5- BENZOXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- C ARBOXAMIDE

To a solution of (l \S)-6'-chloro-5-(((lR,2R)-2-(l - hydroxyaltyl)cyclobutyl)meihyl)-;r,4 4^54etrahydro-2H,2'H- spiro[benzo[&] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (1.615g, 3.45 mmol. Intermediate AA11 A), N-(2-Methoxyethyl)-N-((25)-4-penten-2-yl)sulfuric diamide (1. 15 g, 5.17 mmol), N,N-dimethylpyridin-4-amine (632 mg, 5.18 mmol), and NN-diisopropylethylamine (1.8 mL, 10.35 mmol) in dichloromethane (23 mL) was added -((emylirrdno)methylene)-N3^-dimemy propane-l,3-diamine hydrochloride (1.32 g, 6.90 mmol, Chem-Impex International, Wood Dale, IL ) slowly in portions at 0 °C. The reaction mixture thus obtained was stirred at room temperature overnight then it was concentrated under reduced pressure. The residue was disolved in ethyl acetate, washed with IN HC1, water and brine then it was dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (120 g HP silica column, Teledyne Isco) eluting with 5% to 25% ethyl acetate in hexanes to provide (3S)-6'-chloro-5-(((li?,2i?)-2- ((15)-l-hydroxy-2-propen-l -yl)cyclobutyl)me l)-N-((2-meTJioxyethyl)((25')-4- penten-2-yl)sulfarnoyl)-3',4,4',5-tetrahydro-2'H-spiro| ^" l ,5-benzoxazepine-3, - naphthalene]-7-carboxamide as a white solid (1 .60 g, 69%). STEP 4: fl S,3 ^f R,6'R,7'S,8'E, l rS)-6-CHLORO-7"-HYDROXY- l 2'-(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[1 3]TOIA[ i ;i2 4]TRIAZATETRACYCLO[14.7.2,0~3,6~.0~ 19,24~]P ENTACOSA[8, 16, 18 ₅ 24]TETRAEN]-15'- ONE 13, 13'-DIOXIDE A a solution of (S -6'-chloro-5-(((lR ₅ 2R)-2-((5)-l- hydroxyallyl)cydobutyl)methyl)^

y l)sulfamoyl)-3',4,4',5-tetrahydro-2H,2'H-spiro| benzoj h] [ 1 ,4 joxazepine-3, Γ- naphthalene]-7-carboxamide (1 .60 g, 2.38 mmol ) in 1 ,2-dichloroethane (.1 190 niL) was evacuated and purged with argon (3 cycles), then Hoveyda-Grubbs catalyst 2 ^nd generation (224 mg, 0.357 mmol, Sigma-Aldrich Co. St. Louis, MO) was added to the solution under argon atmosphere. The reaction mixture thus obtained was stirred at 60 °C for 18 h and HPLC-MS analysis indicated completion of the reaction with formation of desired product as major along with other by products. Ethyl-vinylether (341 μΕ, 3.57 mmol) was added and the reaction mixture was stirred for an additional 10 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 10% to 75% ethyl acetate (containing 0.5% acetic acid) in hexanes to provide (lS,3'R,6'R,TS,S'EA VS)-6-Chioro- - hy droxy-12'-(2-methoxy ethyl)- 11 '-methyl-3,4-dihy dro-2H, 15Ή- spiro[naphthalene- l,22'-

[20]oxa[ 13]thia[ 1 , 12, ! 4]triazatetracy clo[ 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16, 18,24]tet raen]-15'- one 13, 13 '-dioxide as a white solid (600 mg, 37%). 'H NMR (500 MHz, CDCh) δ ppm 8.44 (s, 1 H), 7.69 (d, J = 8.6 Hz, 1 H), 7.18 (dd, J = 8.3, 2.4 Hz, I H), 7. 14 (br, s., 1 H), 7,09 (d, «/ = 2.4 Hz, 1 H), 6.88 - 6,92 (m, 2 H), 5,69 - 5,74 (m, I H), 5.63 (dd, J= 15.4, 7.8 Hz, 1 I I I 4.09 - 4. 14 (m, 2 IT), 4.03 ( t, J -------

4.8 Hz, 1 H), 3.88 - 3.97 (m, 2 H), 3.68 - 3.74 (m, 1 H), 3.55 - 3.65 (m, 2 H), 3.40 - 3.45 (m, 1 H), 3.33 (s, 3 H), 3.15 - 3.23 (m, 1 H), 2.71 - 2.83 (m, 2 H), 2,38 - 2.48 (ra, 3 H), 2,26 - 2.33 (ra, I H), 1 .96 - 2.00 (ra, 2 H), 1 .79 - 1.93 (ra, 3 H), 1.62 - 1.68 (m, 2 H), 1.50 - 1.61 (m, 3 H), 1.48 (t «/ = 12.0 Hz, 1 H), 1.34 (d, ./ 6.6 Hz, 3 H): MS m/z (ESI, +ve ion) 644.2 (M+H) ⁺ .

EXAMPLE 27. (1 S,3'R,6'R,7 ^* S,8'E, 1 l'S)-6-CHLORO-7 ^, -METHOXY-12'-(2- METHOXYETHYL)-ir-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THlA[ l,12,14]TRlAZATETiL CYCLO[ 14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ ]l TAC OSA 8,16,18,24]TETRAEN]-15'- ONE 13, 13'-DIOXIDE

To a solution of (1 S,3'R,6'R,TS 'EA l '5)-6-chloro-7 ^, -hydroxy-12 ^, -(2- methoxy ethyl)- 1 1 -methyl-3,4-dihydro-2H, 15 Ή-spiro [naphthalene-! ,22'- [20]oxa[ 13]thia[ 1 , 12, 14]triazateto

raen j-15'- one 13, 13'-dioxide (64 mg, 0.10 mmol, Example 26) in THF (2 mL) was added 60% NaH in mineral oil (20 mg, 0.50 mmol) at 0 °C and the mixture was stirred for 20 min, then iodomethane (31 xL, 0.50 mmol) was added. The reaction mixture thus obtained was stirred at room temperature overnight. The reaction was quenched with sat'd MHUCl and extracted with ethyl acetate, dried and concentrated. The residue was purified by flash column chromatography on silica gel (12 g, HP silica, Teledyne Isco) eluting with 15% to 50% ethyl acetate in hexanes to provide (\S, R,GR,TS,«E,\ r5)-6-chloro-7'-methoxy-12'-(2- methoxy ethyl)- U '-me1hyl-3,4-dity

[20]oxa[13]tMa[l,12,14]triazatetr^

raen j-15'- one 13, 13 '-dioxide as a white solid (29 mg, 44% yield). ¾ NMR (500 MHz, CDCh) δ ppm 8.49 (br. s., 1 H), 7.70 (d,■/ 8.6 Hz, 1 H), 7.18 (dd. ./ 8.3, 2.4 Hz, 1 H), 7.09 id. ./ 2.4 Hz, 1 H), 6.85 - 7.00 (m, 2 H), 6.81 (br. s., 1 H),

5.75 - 5.91 (m, 1 I I ). 5.51 (dd, ./ 15.7, 8.8 Hz, 1 H), 4.05 - 4.15 (m, 2 H), 3.74 - 3.84 (m, 2 H), 3.60 - 3.68 (m, 4 H), 3.40 - 3.45 (m, 1 H), 3.38 (s, 3 H), 3.24 (s, 3 H), 3.03 (dd, J = 15.4, 9.5 Hz, 1 H), 2.68 - 2.91 (m, 2 H), 2.37 - 2.61 (m, 3 H), 2.25 - 2.35 Or, 1 H), 1.90 - 2.05 (m, 3 H), 1.73 - 1.86 (m, 3 H), 1.58 - 1.70 (m, 2 H), 1.41 { {. J 12.0 Hz, 1 1 1 ). 1 .36 (d, ,/ 6.8 Hz, 3 H); MS m/z (ESI, +ve ion) 658,3 (M+H) ⁺ .

EXAMPLE 28. (1S,3'R,6'R,7 ^! S,8'E,1 l'S)-6-CHLORO-12'- (CYCLOPROPYLMETHYL)-7'-HYDROXY- 11 '-METHYL-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1, 12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OS A[ 8, 16, 18,24]TETRAEN]-15'-ONE 13, 13' -DIOXIDE

STEP 1 : (R)-PENT-4-EN-2-YL 4-METHYLBENZENESULFONATE

OTs

To a solution of (i?)-4-penten-2-ol (10 g, 116 mmol, Sigma- Aldrich Co, St, Louis, MO), p-toiuenesuifonyl chloride (26.6 g, 139 mmol), N^V-dimethypyridin- 4-amine ( 1 .42 g, 1 1 .6 ! mmol) in dichloromethane (230 mL) was added triethylamme (32.4 mL, 232 mmol) via syringe at 0 °C. The reaction mixture thus obtained was stirred at room temperature for 48 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with IN HC1, water, and brine, then dried over MgS04. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (330 g flash column, Teledyne Isco) eluting with 0% to 25% ethyl acetate in hexanes to provide (i?)-pent-4-en~2~yl 4- methylbenzenesulfonate as a colorless oil (24.82 g, 89%).

STEP 2: N-(CYCLOPROPYLMETHYL)-N-((l S)-l-METHYL-3-BUTEN- 1YL)SULF AMIDE

To a solution of (i?)-pent-4-en-2-yl 4-methylbenzenesulfonate (2.4 g, 10 mmol) in 1 ,4-dioxane (20 mL) were added c clopropylmethanamine

hydrochloride (1 .08 g, 10.0 mmol) and NN-diisopropylethylamine (5.23 ml,, 30.0 mmol). The mixture thus obtained was heated at 100 °C for 2 days. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and whashed with 5% NaOH, then dried. The solvent was evaporated under reduced pressure to provide crude (iS)-N-(cyclopropylmethyl)pent-4-en-2-amine (400 mg). The crude product was disolved in 1 ,4-dioxane (5 mL) and sulfamine (1.92 g) was added. The mixture thus obtained was heated at 100 °C overnight. The solvent was evaporated under reduced pressure and the residue was subjected to flash chromatography on silica gel (120 g flash column, Teledyne Isco) eluting with 10% to 50% ethyl acetate in hexanes to provide N-(cyclopropylmethyl)-N-((15)-l- methyl-3-buten-lyl)sulfamide as a light yellow solid (37 rng, 2% yield in two steps). STEP 3: (3S)-6'-CHLORO-N-((CYCLOPROPYLMETHYL)((2S)-4-PENTEN-2- YL)SULFAMOYL)-5-(((l R,2R)-2-((l S)- 1 -HYDROXY-2-PROPEN - 1 - YL)CYCLOBUTYL)METHYL)-3',4.4',5-TETRAHYDRO-2H-SPIRO[ l,5- BENZOXAZEPTNE-3,l '-NAPHTHALENE]-7-CARBOXAMTDE

To a solution of (l \S)-6'-chloro-5-(((lR,2R)-2-(l -

spiro[benzo[&] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (70.2 nig, 0.15 mmol, Intermediate AA11A), N-(cyclopropylmethyl)-N-((ljS)-l-methyl-3-buten- ly])sulfarnide (37 mg, 0.169 mmol), NN-dimethylpyridin-4-amine (27.5 mg, 0.225 mmol), and N,N-diisopropylethylamine (78 _, uL, 0.45 mmol) in

dichloromethane (1.5 ml.) was added Nl -((ethylimino)methylene)-N3 ,N3~ dimethylpropane-l ,3-diamine hydrochloride (57.5 mg, 0.30 mmol, Chem-Impex International, Wood Dale, IL) slowly in portions at 0 °C. The reaction mixture thus obtained was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purufied by flash chromatography on silica gel (120 g HP silica column, Teledyne Isco) eluting with 5%» to 25% ethyl acetate (containing 1 % acetic acid) in hexanes to provide (35)-6'-chloro-N-((cyclopropylme1hyl)((2)S -4-penten-2-yl)sulfamoyl)-5- (((li?,2¾~2~((LS l-hydroxy^^

tetrahy dro-2'H-spiro[ 1 ,5-benzoxazepine-3, 1 '-naphthalene] -7-carboxamide as a w hile solid (56 mg, 56%).

STEP 4: (I S,3'R,6'R,7'S,8'EJ l ^, S)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)- 7'-HYDROXY- 1 1 '-METHYL-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,12 4]TRIAZATCTTIACYCLO[14 .2 ³ '*0 ¹⁹ - ²⁴ ]PENTAC

08Α[8,16,18,24]ΊΈΤί ΑΕΝ]-15'- ONE 13,13'-DIOXIDE

A a solution of (¾-6'-chloro-iV-(N~(cyclopropylmethyl)-iV-((,S')-pent-4-eii - 2-yl)sulfamoyl)-5-(((lR,2R)-2-((.^

tetTahydro-2H,2H-spiro[benzo[ft][l,4]oxazepine-3,r-naphth alene]-7-carboxaraide (58 mg, 0.087 mmol ) in 1,2-dichloroethane (58 niL) was evacuated and purged with argon (3 cycles), then Hoveyda-Grubbs catalyst 2 ^nd generation (8.2 mg, 0.013 mrnol, Sigma- Aldrich Co. St. Louis, MO) was added to the solution under argon atmosphere. The reaction mixture thus obtained was stirred at 50 °C for 24 h. Ethyl-vinylether (12 μΕ, 0.13 mmol) was added and the reaction mixture was stirred for an additional 10 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (40 g HP silica column, Teledyne Isco) eluting with 10% to 75% ethyl acetate (containing 0.5% acetic acid) in hexanes to provide (1S,3'R,6'R,TS,S'E,1 VS)-6- chioro-12 ^! -(cy ciopropylmethyl)-7'-hydroxy- 11 -methyl-3,4-dihydro-2H, 15Ή- spiro [naphthalene- 1 ,22'- [20;|oxa|;l3]thia[l,12,

raen]-15*- one 13, 13 '-dioxide as a white solid (25 mg, 45% yield). ^! H NMR (500 MHz, CDCb) δ ppm 8,50 (br. :s .1 H), 7.69 (d, ./ 8.3 Hz, 1 H), 7.17 - 7.18 (m, 2 H), 7.08 (d, ./ 2.4 Hz, I H), 6.86 - 6,92 (m, 2 H), 5.62 - 5,72 (m, 2 III 4.08 -

4.14 (m, 2 H), 4,01 (m, 1 H), 3.89 - 3.95 (m, 1 H), 3.62 - 3.76 (m, 3 H), 3.30 (d, J = 15.0 Hz, 1 H), 3.16 (dd, J= 15.8, 6.5 Hz, 1 H), 2.70 - 2,85 (m, 2 H), 2.28 - 2.51 ins.4 !!}.1.76 - 2.00 (m, 611).1.61 - 1.70 (m, 2 H), 1.44 - 1.48 (m, 111).1.43 (d, J --- 10.0 Hz, 3 H), 1.06-1.11 (m, 1 H), 0.54 - 0.62 (m, 2 H), 0.42 - 0.46 (ra, 1 H), 0.29 - 0.33 (m, 1 H); MS m/z (ESI, +ve ion) 640.3 (M+H) ⁺ .

EXAMPLE 29. (lS,3'R,6 ^, R,7'S,8 ^, E)-6-CHLORO-12'-ETHYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,12,14]TRIAZATCTTlACYCLO[14.7.2.0 ³ '*0 ¹⁹ - ²⁴ ]PE3SnrAC

OSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DiQX!DE

STEP 1 : TERT-BUTYL N-(BUT-3-EN- 1 -YL)-N-

ETHYLSULFAMOYLCARBAMATE

To a solution of isocyanatosulfuryl chloride (2.63 mL, 30.2 mmol) in

DCM (5 mL) was added anhydrous tert-butyl alcohol (3.13 mL, 32.8 mmol) dropwise at 0 °C under N2 atmosphere and the reaction was stirred at 0 °C for 15 minutes followed by an addition of a solution of N-ethylbut-3-en-l -amine (2.50 g, 25.2 mmol) and anhydrous triethylamine (10.5 mL, 76 mmol) in DCM (40 mL), The resulting mixture was stirred at ambient temperature overnight. The reaction was then concentrated and the residue was purified by column chromatography to afford the title compound (1.10 g, 3.95 mmol, 15.7 % yield).

STEP 2: N-(BUT-3-EN-l-YL)-N-ETHYL SULFURIC Di AMIDE

To a solution of tert-butyl N-(but-3-en-l -yl)-N-ethylsulfamoylcarbamate (1.10 g, 3.95 mmol) in dioxane (4 mL) was added 4 M hydrochloric acid solution in 1,4-dioxane (6 mL, 23.6 mmol) and the reaction was stirred at ambient temperature for 28 hours. The reaction was concentrated and the residue was dried on vacuum to afford the title compound (0.745 g, 4.18 mmol, 106% crude yield). STEP 3 : (S)-N-(N-(BUT-3-EN- 1 -YL)-N-ETHYLSULFAMOYL)-6'-CHLORO-5- (((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL) -

3^4,4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B]|;L410XAZEPINE-3, r- N APHTH ALENE1 -7 -C ARB OXAMIDE

To a solution of N,N-dimethylpyridin-4-amine (329 mg, 2.70 mmol), Intermediate AA12A (550 mg, 1.08 mmol), triethylamine (0.600 mL, 4.31 mmol) and N-(but-3-en-l -yl)-N-ethyl sulfuric diamide (692 mg, 3.88 mmol) in DCM (25 mL) at 0 °C was added N-(3-dimethylaminopropyl)-N'-ethyicarbodiimide hydrochloride (517 mg, 2.70 mmol) in portions over 40 minutes. The reaction was stirred at ambient temperature overnight under N ₂ atmosphere. The reaction was concentrated and the residue was dissolved in DCM and purified by silica gel chromatography using Redi-Sep pre-packed Gold silica gel column eiuting with 0- 20%» of ethyl acetate (containing 0.3% acetic acid) in hexane to afford the title compound as a solid (373 mg, 0.556 mmol, 51.6% yield).

STEP 4: (lS,3 ^! R,6'R,7'S,8'E)"6-CHLORO-12'-ETHYL~7'~HYDROXY-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTAC OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

A 500 mL round-bottom flask was charged with (S)-N-(N-(but-3-en-l -yl)- N-ethylsulfamoy])-6'-ch]oro-5-(((lR,2R)-2-((S,E)-l-hydroxyhe x-2-en-l- yl)c 'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine- 3,r-naphthalene]-7-carboxamide (0.373 g, 0.556 mmol), Hoveyda-Grubbs II catalyst (0.070 g, 0.1 1 1 mmol) and acetic acid (192 mL). The solution was purged with N ₂ for 15 minutes and then stirred at ambient temperature under slightly reduced pressure for 17 hours. The reaction was concentrated and the residue was dissolved in methanol and purified by reversed phase preparatory HPLC

(Gemini™ Prep Cis 5 ίη column; Phenomenex, Torrance, CA) to afford the title compound as the first eluting isomer (0,074 g, 0.123 mmol, 22.2% yield). ¾ NMR (400 MHz, (1X1;) δ 8,50 (br. :s.11!}.7,72 (d, J=8.41 Hz, 111).7,20 (dd, J=2.25, 8.51 Hz, 1H), 7.11 (d, J=2.15 Hz, 1H), 6.99 - 6.89 (m, 3H), 5.91 (ddd, ./ 4.89.9.49, 14.8 Hz, ill).5.72 (dd, ./ 7.K3.15.1 Hz, 111).4.2 - 4.19 (m, 111. 4,14 - 4.07 (m, 3H), 3.81 - 3.59 (m, 3H), 3,43 - 3.34 (m, 1H), 3.30 - 3.323 (ra, 2H), 3,17 (m, 1H), 2.80 - 2.74 (m, 2H), 2,48 - 2,25 (m, 5H), 2.03 - 1.93 (m, 3H), 1.86 - 1.82 (m, 2H), 1.75 - 1.66 (m, 2H), 1.48 (t,■/ 12.7 Hz, 1H), 1.27 (t, ,/ 7.Π4 Hz, 311). m/z (ESI, +ve ion) 601.2 {.VI II)

EXAMPLE 30. (lS,3'R,6 ^, R,7'S,8 ^, Z)-6-CHLORO-12'-ETHYL"7'"HYDROXY-3,4- DIHYDRO-2H, 15'H-SPIR0[NAPHTHALENE-1 ,22'- [20]OXA[13]THIA[l,12,14]Ti AZATETOACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16, 18,24]TETR - 15 '-ONE 13', 13'-DIOXIDE

The title compound was isolated as the second eluting isomer (0.025 g, 0.042 mmol, 7.49% yield) from the reversed phase preparatory HPLC separation in Example 29, Step 4. ¾ NMR (400 MHz, CDCb) δ 9.66 (br. s, 1 H), 7.74 (d, ./ K. I Hz, 1 H), 7.39 (dd, ./ I.K6.8.31 Hz, 1 H), 7.20 (dd, ./ 2.3.8.4 Hz, 111}. 7,11 (d, ./ 3.2H Hz, 2 H), 6.99 (d, 7.89 Hz, 1 H), 5.76 - 5.63 (m, 2 H), 4.52 (t, ,/ 636 Hz, 1 H), 4.17 - 4.06 (m, 2 H), 3,95 - 3.81 (m, 2 H), 3,67 (d, ./ 14.28 Hz, 1 H), 3.61 - 3.39 (m, 3 H), 3.32 - 3.10 (m, 2 H), 2.84 - 2.58 (m, 3 H), 2.44 -2.28 (m, 4 H), 2.13 - 1.94 (m, 3 H), 1.87 - 1.84 (m, 2 H), 1.78 - 1.64 (ra, 1 H), 1.62 - 1.38 ίη·.2 H), 1.28 (t, ./ 7.! 4 Hz, 3 H). m/z (ESI, +ve ion) 601.2 (M+H) ^H" .

EXAMPLE 31. (1 S,3'R,6¾,7'S,8^)-6-CHLORO-7'-HYDROXY~12'~(2- YU . H !OXY!. Π I YU-3.4-DU IYORO-21 I. ! Ί f-SP!RO|\ ^' .\PI Π ΉΛ1 J ^: Ni - 1.22'- |2ujOXA| 13ΓΗ!!Λ| U2J4| T!UAXATiTRAi ^' Yi ^' !.(}| 14.7.2.0* '\0 ^{)Μ M} |PLNTAi ^' OSA[8.16,18 ₅ 24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

STEP 1: (lS,3 ^f R,6'R,7'S,8'E)-6-CHLO O-7'-[(TERT- BUTYLDIPHENYLSILYL)OXY-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,12 4]TRIAZATCTTlACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PE3SrrAC

OSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

To a solution of Example 19 (31 mg, 0.054 mmol) in DMF (0.5 mL) was added IH-imidazole (9.59 mg, 0.141 mmol) and tert-butylchlorodiphenylsilane (0.018 mL, 0.070 mmol) under N ₂ aimoshpere and the reaction was stirred at ambient temperature for 36 hours. LCMS showed that the reaction was not completed. More tert-butylchlorodiphenylsilane (0.009 mL, 0.035 mmol) and 1H- imidazole (4.80 mg, 0.071 mmol) were added and the reaction was stirred at ambient temperature for another 6 hours. The reaction was quenched with saturated NH ₄ C1 and extracted with EtOAc. The organic extract was dried with MgSCK filtered and concentrated to give a residue which was purified by silica gel chromatography using Redi-Sep pre-packed Gold silica gel column eluting with 0-20% of ethyl acetate in hexane to afford the title compound (26 mg, 0.032 mmol, 59.2 % yield).

STEP 2: (lS,3 ^! R,6'R,7'S,8'E)"6-CHLORO-7 ^! "HYDROXY-12 ^, -(2~

METOOXYETHYI 3,4-DTHYDRO-2H,15 ~^

[20]OXA[13]THIA[l,12,14]Ti AZATETOACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC QSA[8,16,18,24]TETRAEN ]-15'-QNE 13', '-D10XIDE

To a solution of (lS,3 ^, R,6 ^, R,7 ^! S,8 ^, E)-6-chloro-7'~[(tert- butyldiphenylsilyl)oxy-3,4-dihydro-2H, 15 Ή-spiroj naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1 , 12, 14]triazatetracy clo[ 14.7.2, 0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, 16, 18,24]tet raen]-15'-one 13 ',13 '-dioxide (10 mg, 0.012 mmol) in DMF (0.25 rnL) at 0 °C was added sodium hydride, 60% dispersion in mineral oil (1.48 mg, 0.037 mmol). After the reaction was stirred at room temperature for 30 minutes, l -bromo-2- methoxy ethane (1.49 μΕ, 0,015 mmol) was added. The reaction was stirred at ambient temperature for about 2 hours. Additional l-bromo-2-methoxy ethane (4.47 μί, 0.045 mmol) and sodium hydride, 60% dispersion in mineral oil (1.48 mg, 0,037 mmol) were added to facilitate the reaction and the resulting mixture was stirred at ambient temperature for another 35 hours. The reaction was quenched with saturated NH4CI and extracted with EtOAc. The organic phase was washed with brine and dried using MgS0 ₄ . After filtration and concentration the crude material was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 60% to 75% MeCN in water, w here both solvents contain 0.1% TFA, 30 min method) to afford the title compound as a solid (1.14 mg, 1.81 μηιοΐ, 14,7% yield). ^! H NMR (400 MHz, CDCh) δ 8.55 (br. s, 1H), 7.72 (d, J=8.41 Hz, 1H), 7.20 (dd, J=2.25, 8.51 Hz, i l l . 7.1 1 id. ./ 2. 1 5 Hz, 1H), 6.98 - 6.89 (m, 3H), 5.97 - 5.87 (m, i l l ). 5.72 hid . ,/ 7. 73. 15.5 Hz, I I I ). 4.26 - 4.06 (m, 4H), 3,89 - 3.83 (dt, ./ 4.57. 14.9 Hz, IH), 3.75 - 3.60 (m, 4H), 3.58 - 3.40 (ni, 2H), 3.39 (s, 3H), 3.28 (d, J=14.28 Hz, 1H), 3.15 (dd, ,/ 7.63. 14.1 Hz, IH), 2.85 - 2.72 (m, 2H), 2.53 - 2.35 (m, 3H), 2.34 - 2.20 (m, IH), 2.05 - 1 .89 (m, 3H), 1.85 (br. S, 2H), 1.80 - 1.61 (m, 3H), 1 ,47 (t, J=\ 1.8 Hz, IH). m/z (ESI, +ve ion) 631.2 (M+H) ⁺ .

EXAMPLE 32. METHYL ((l S,3 ^, R,6 ^, R,7 ^, S,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-

13', 13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H,12'H-SPIRO[NAPHTHALENE- l. - [20]ΟΧΑ[ 13]ΤΉΙΑ[ 1, 12,14]ΉΟΑΖΑΤΕΤ^

OS A[8, 16, 18,24]TETRAEN]- 12'-YL)ACETATE

STEP 1 : (l S,3'R,6'R,7'S,8'E)-6-CHLORO-7'-[(TERT- BUTYLDIMETHYLSILY OXY] - 3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THlA[ l,12,14]I¾lAZATETiL CYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTAC OS A| 8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DI OXIDE

To a solution of Example 19 (141 mg, 0.246 mmol) in DCM (6 mL) at 0 °C was added N, N-diisopropylethylamine (0.107 mL, 0.616 mmol) followed by addition of tert-butyldimethylsilyl trifluoromethanesulfonate (0,074 mL, 0.320 mmol). The reaction was stirred at 0 °C for 1 hour and at ambient temperature for 3.5 hours. Trace amount of desired product was detected by LCMS from the reaction. More N,N-diisopropylethylamine (0.107 mL, 0.616 mmol) and tert- butyldimethylsilyl trifluoromethanesulfonate (0.148 mL, 0.640 mmol) were added and the reaction was stirred at ambient temperature for 40 minutes. The reaction was quenched with saturated aqueous NaHCCb and extracted with EtOAc. The organic extract was washed with brine, dried with MgSC>4, filtered and concentrated to give a residue which was purified by silica gel chromatography using Redi-Sep pre-packed Gold silica gel column (40 gj eluting with 0-30% of ethyl acetate in hexane to afford the title compound as a solid (114 mg, 0. 166 mmol, 67.4% yield).

STEP 2: METHYL ((lS,3'R,6 ^, R,7 ^, S,8'E)-6-CHLORO-7 ^, -[(TERT- BUTYLDIMETHYLSILYOOXY j- ^ '-DIOXIDO-lS'-OXO-S^-DIHYDRO- 2H, 12 ^* H-SPIRO[N APHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OS A[ 8, 16, 18,24]TETRAEN] - 12'-YL) ACETATE

To a solution of (lS,3'R,6 ^, R,7 ^! S,8 ^, E)-6-chloro-7 ^! -[(tert- buty ldimethy lsily )oxy ] -3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1,22'- [20ioxa| 13jthia[ l,12,14]triazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[ 8, i raen]-15'-one 13', 13'-dioxide (61rng, 0.089 mmol) in THF (1 mL) was added lithium bis(trinietliylsilyl) amide, 1.0 M solution in tetrahydrofuran (0.355 mL, 0.355 mmol) and the reaction was stirred at ambient temperature for 10 minutes followed by addition of methyl 2-bromoacetate (0.033 ml., 0.355 rnmol). The reaction was transfered to a microwave tube and irradiated at 80 °C for 11 hours and then at 100 °C for another 1.5 hours. The reaction was quenched with saturated NH ₄ C1 and extracted with EtOAc. The organic extract was washed with H2O, brine and dried with MgS0 ₄ and filtered. After concentration the crude material was purified by silica gel chromatography using Redi-Sep pre-packed Gold silica gel column (40 g) eluting with 0-30% ethyl acetate in hexane to afford the title compound (32mg, 0.042 rnmol, 47.5 % yield).

STEP 3: METHYL ((1 S,3'R,6'R,7 ^! S,8'E)-6-CHLORO-7'-HYDROXY- 13', 13 ^f - DIOXIDO-15 ^, -OXO-3,4-DmYDRO-2H 2Ή-SPlRO[NAPHTHALENE-l _s 22 ^, - [20]OXA[ 13]THIA[ 1 2,14]TTOAZATETOACYCLO[ 14 .2.0 ³ ' ^{6 19} - ²⁴ ]PENTAC

OSA[8,16, 18,24]TETRAEN]-12'-YL)ACETATE

Methyl ((lS,3'R,6¾,7'S,8¾-6-chioro-74(tei^

13', 13'-dioxido-l 5'-oxo-3,4-dihydro-2H, 12'H-spiro[naphthalene- 1,22'-

raen]-12'-yl) acetate (32 mg, 0.042 rnmol) was treated with 1 M TBAF solution in THF (0.5 ml.) and a small amout of molecular sieves at 50 °C for 2 hours. The reaction was concentrated to give a crude material which was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound (10 nig, 0.016 mmol, 36.8% yield). ¾ NMR (400 MHz, CDCb) δ 8.92 (br. s., lH), 7.72 (d, 8 4 ! Hz, 1 1 1 ). 7.20 (dd, ,/ 2 35. 8,41 Hz, ! ! ! }. 7.1 1 (d, ./ 1 .96 Hz, i l l ). 7,00 - 6.91 (m, M i l .5.90 - 5,71 (m, 2H), 4.77 id . .7=18.78 Hz, 1H), 4.24 - 4.06 (m, 4H), 4.00 - 3.87 (m, 1H), 3.81 (s, 3H), 3.77 - 3.62 (m, 2H), 3.36 - 3.23 (m, 2H), 3.18 (br. s, I I I ). 2.85 - 2.72 i ns. 2H), 2.51 - 2.37 (m, 3H), 2.31 (dd, ,/ 6.06. 9.00 Hz, 1 H), 2.14 (br. s, 1 H), 2.02 - 1.96 (ra, 3H), 1 ,99 (m, 2H), 1.70 (m, 2H), 1 .48 (t, ./ 12.23 Hz, M l ), m/z (ESI, +ve ion) 645.2 ( M R ) EXAMPLE 33. 3-((l S,3' ,6 ^f R,7'S,8'E)-6-CHLORO-7'-HYDROXY-l 3', ] 3 ^! -

DIOXIDO-15'-OXO-3,4-DIHYDRO-2H,12H-SPIROP^APHTHALENE-l,22 '- j 2 ]OXA[ 13 jTHIA[ l, 12,14]TRiA^^

OS A[8, 16, 18,24]TETRAEN] - 12'-YL)PROP ANOIC ACID

STEP 1 : METHYL 3-((l S,3'R,6'R,7'S,8'E)-6-CHLORO-7'-[(TERT- BUTYLDIMETHYLSILY)OXY]-l 3', 13'-DIOXIDO- 15'-QXO-3,4-DiHYDRQ- 2H, 12'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1 2,14]TTOAZATETOACYCLO[ 14 .2.0 ³ - ^{6 19} - ²⁴ ]PENTAC OS A[8, 16, 18,24]TETRAEN] - 12'- YL) PROPANOATE

To a solution of (lS,3'R,6'R,7'S,8'E)-6-chloro-7 (tert- buty ldimethy lsily )oxy ] -3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[ l,12,14]triazatetracyclo[l .4.7.2.0 ³ " ⁶ .0 ^{] 9} ' ²⁴ ]pentacosa[8,16,18,24]tet raen]-15'-one 13', 13'-dioxide (14 nig, 0.020 rnmol, Example 32, Step 1) in DMF (0.3 mL) was added sodium hydride (8.16 mg, 0.204 rnmol) and the reaction was stirred at ambient temperatui'e for 25 minutes followed by an addition of methyl acryiate (0.012 mL, 0.122 rnmol). The resulting mixture was stirred at ambient temperature for 18 hours and 60 °C for another 4 hours. Since no improvement was obtained by LCMS, more methyl aery late (0,0092 mL, 0.092 mmol) was added and the resulting mixture was stirred at 60 °C for 19 hours. The reaction was quenched with saturated NHsCI and extracted with EtOAc. The organic extract was dried using MgSi filtered and concentrated to give a residue which was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 85% MeCN in w ler. where both solvents contain 0.1% TFA, 30 min method) to afford the title compound.

STEP 2: 3-((lS,3'R,6 ^, R,7'S,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-13 ^, ,13 ^f -DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H, 12'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOIA[ 1 2,14]TT TAZATET11ACYCLO[ 147.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTAC OSAI 8.16, 18,24]TETRAEN]-12'-YL) PROPANOIC ACID

Methyl 3-((l S,3'R,6 ^, R,7 ^, S,8i)-6-chloro-7 ^, -[(tert-bu1yldimethylsily)oxy]- 13',13'-dioxido-15 ^, -oxo-3,4-dihydro-2H, 12'H-spiro[naphthalene-l ,22'-

raen]-12'-yl) propanoate (1.4 mg , 1.81 μπιοΐ) was treated with 1M TBAF solution in THF (0.5 mL) and a small smount of molecular sieves at 60 °C for 1.5 hours. The reaction was concentrated to give a residue, which was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA) to afford the title compound as a solid. ¾ NMR (400 MHz,

CDCh) δ 8.83 (br. s, 1H), 7.70 (d, J=8.41 Hz, 1H), 7.19 (dd, J=6.24 Hz, IH), 7.10 (d, 4 04 Hz, 1 1 1 ). 6.97 - 6.83 (ra, 3H), 5,92 i d. ./ 4.69 Hz, IH), 5.77 - 5.67 (m, IH), 4,36 - 4.21 (m, 2H), 4.15 - 4.02 (m, 2H), 3,76 - 3.62 (m, 3H), 3.42 - 3.31 (m, IH), 3.26 (d, ./ ! 4. i Hz, IH), 3.11 (br. s, IH), 2.80 (br. s, 2H), 2.45 - 2.39 (m, 3H), 2.32 (m, IH), 2.15 (br. s, 5H), 2.03 - 1.93 (m, 3H), 1.84 - 1.82 (m, 2H), 1.74 - 1 ,64 (m, 2H), 1.44 (t, ./ 12.2 Hz, IH). m/z (ESI, +ve ion) 643.0 (M-H ^~ I) ⁺ ,

EXAMPLE 34. (1 S,3'R,6 ^! R,7'S,8'E)-6-CHLORO-7'-HYDROXY-12 ^! ~(2- (METHYLSULFONYL)ETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOlA[ l, 12, 14]I¾lAZATCm CYCLO[ 14 .2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A[8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

To a solution of (l S,3'R,6'R,7'S,8'E)-6-chloro-7'-[(tert- butyldimethylsily)oxy]-12'-(2-(methylsulfonyl)e1hyl)-3,4-dih ydro-2H _^ spiro[naphthalene- l,22'-

[20]oxa[ 13]thia[l ,12, 14]triazatetra^^^

raen]-15'-one 13 ', 13 '-dioxide (7.2 mg, 10.49 μηιοΐ, Example 32, Step 1 ) in DMF (0.2 mL) was added sodium hydride (60% dispersion in mineral oil, 4.20 mg, 0.105 mmol) and the reaction was stirred at ambient temperature for 20 minutes followed by addition of (methylsulfonyl)ethene (5.52 ,uL, 0.063 mmol) and the resulting mixture was stirred at ambient temperature for 80 minutes. The reaction was quenched with saturated aqueous NH4CI and extracted with EtOAc. The organic extract was washed with brine, dried with MgS0 ₄ , filtered and concentrated to give a crude Michael addition product. Tins crude product was treated with tetrabutylammonium fluoride, 1.0 M in tetrahydrofuran (0.505 mL, 0.505 mmol) and moleculer sieves at 60 °C for 1.5 hours. The reaction was concentrated and re-dissolved in MeOH and filtered. The crude material was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μχ column; Phenomenex, Torrance, CA; gradient elution of 30% to 70% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to afford the title compound as a white solid (3.9 mg, 5.75 μηιοΐ, 56% yield). ^] H NMR (400 MHz, CDCI3) 6 8,86 (br. s, 1 H), 7.71 (d, ./ 8. 1 Hz, i l l ). 7,20 (dd, ./ 2.25. 8.51 Hz, 1H), 7.11 (d, .7=2, 15 Hz, 1H), 7.02 - 6, 87 (m, 3H), 5.93 - 5.82 (m, 1H), 5.71 - 5, 81 (m, l H), 4.60 - 4.49 (m, 1H), 4,26 - 4.23 (m, 1 H), 4.19 - 4.04 (m, 2H), 3,93 - 3.77 (m, 2H), 3.77 - 3.63 (m, 2H), 3.58 - 3.33 (m, 3H), 3.33 - 3.20 (m, IH), 3.17 (m, 1H), 3.06 (s, 3H), 2.87 - 2.72 (m, 2H), 2.54 - 2.26 (m, 4H), 2.11 - 1.93 (m, 4H), 1 .86 - 1.77 (ra, 2H), 1 ,75 - 1.64 (m, 2H), 1 .48 (t, 1 2.0 Hz, 1 1 1 ), ns (ESI, +ve ion) 679.2 (M+H) ⁺ .

EXAMPLE 35. 2~((lS,3'R,6 ^! R,7'S,8 ^, E)-6-CHLORO-7'-HYDROXY-13',13'- DIOXIDO-15'-OXO-3,4-DIHYDRO-2H,12'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[l ,12 4]TRIAZATCTTlACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENnrAC OS A[8, 16, 18,24]TETRAEN]-12'-YL)-N,N- DIETHYLETHANESULFONAMIDE

The title compound was prepared from (l S,3'R,6'R,7 ^, S,8'E)-6-chloro-7'- [(tert-butyldimethylsily)oxy]-3,4-d^

[20]oxa[ 13]thia[ 1,12,14] triazatetracy clo[ 14.7 ,2.0 ³ - ⁶ .0 ^{! 9} - ²⁴ ]pentacosa[8, 16, 18,24]tet raenj-15'-one 13',13'-dioxide (Example 32, Step 1) by a procedure similar to the one described in Example 34, and it was obtained as a white solid (1.5 mg, 2.04 μηιοΙ . 12.7 % yield). M l NMR (400 MHz, CDCb) δ 8.62 (s, 11 1 ). 7.69 (d, ,/ K 1 Hz, 1H), 7.18 (dd, .7=2.25, 8,51 Hz, 1H), 7.09 (d, .7=2.15 Hz, 1 1 1 ). 6,96 - 6,87 (m, 3H), 5.90 - 5.80 (m, 1H), 5.78 - 5.69 (m, 1H), 4.52 - 4.42 (m, 1H), 4.20 (dd, J=4.79, 7, 14 Hz, IH), 4.16 - 4,03 (m, 2H), 3.86 - 3.62 (rn, 4H), 3.40 - 3,24 (m, 8H), 3,21 - 3.05 (m, IH), 2.83 - 2.70 (m, 2H), 2,52 - 2.24 (m, 4H), 2.03 - 1.87 (m, 3H), 1.83 (br. s, 2H), 1.79 - 1.58 (m, 3H), 1.53 - 1.34 (m, IH), 1.30 - 1.19 (m, 6H). 'z (ESI, +ve ion ) 736.2 (M+H) ⁺ . EXAMPLE 36. (lS,3'R,6'R,7'S,8'Z)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 15'H-SP1R0[NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ U2,14]TTUAZATETOACT^

OSA[8,16, 18,24]TETRAEN]-15'-ONE 13',!3'-DIOXIDE

STEP 1 : TERT-BUTYL N-(BUT-3-EN-l-YL) SULFAMOYLC ARBAMATE

The title compound was prepared from but-3 -en- 1 -amine by a procedure similar to the one described in Example 29, Step 1. STEP 2: N-(BUT-3-EN-l -YL) SULFURIC D I AMIDE

The title compound was prepared from tert-butyl N-(but-3-en-l-yl) sulfamoylcarbamate by a procedure similar ^" to the one described in Example 29, Step 2. STEP 3: (S)-N-(N-(BUT-3-EN-l-YL)SULFAMOYL)-6'-CHLORO-5-(((lR,2R)- 2-((S,E)-l-HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4 ]OXAZEPINE-3, 1 '-

NAPHTHALEN

CARBOXAMTDE

The title compound was prepared from Intermediate AA12A and N-(but-3- en-l-yl) sulfuric diamide by a procedure similar to the one described in Example 29, Step 3. STEP 4: (lS,3 ^, R,6'R,7 ^! S,8'Z)-6-CHLOR()-7 ^, -HYDROXY-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOIA[1,12,14]T IAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTAC OSA[8,16,18,24jTETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from (s)-N-(N-(but-3-en-l- yl)sulfamoy l)-6*-chl oro-5-((( 1 R,2R)-2~((S,E)~ 1 ~hy droxyhex-2-en- 1 - yl)cyclobu1\d)memyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo [b][l,4]oxazepine- 3,r-naphthalene]-7-carboxamide by a procedure similar to the one described in Example 29, Step 4. ^l H NMR (400 MHz, CDCh) δ 11.12 (br. s, 1H), 7.66 (d, J=8.61 Hz, IH), 7,37 id.../ 7.63 Hz, IH), 7.15 (m, 2 H), 7,08 (s, IH), 6,82 (d, ./ 8.41 Hz, IH), 6.02 (br. s, ill).5.79 - 5.59 (m, 2H), 4.29 (t, ./ 8.41 Hz, IH), 4.05 - 3.93 (m, 2H), 3.80 (d, ./ 5.48 Hz, IH), 3.69 (d, ./ 1 .6 Hz, IH), 3.52 (d, ,/ 143 Hz, IH), 3.19 (br. s, IH), 3.15 - 2.96 (ra, 211).2,82 - 2,63 (m, 311).2.35 - 2.18 (m, IH), 2.17 - 1.91 (m, 5H), 1.90 - 1,75 (m, 3H), 1.66 (dt, J=9.39, 18.4 Hz, IH), 1.52 - 1.34 (m, 2! I ). m/z (ESI, +ve ion) 573.2 {W W) . EXAMPLE 37. (lS,3'R,6'R,7'S,8'Z)-6-CHLORO-7'-HYDROXY-12 ^, -(2- (METHYLSULFONYL)ETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ujOXA| ΠΓΗΙΙΑΙ U2J4|TR!AXA4 ^' lTRAi ^' Yi ^' !.(}| 14,7.2.ίί ^; " 0 ^! " -|F!;NTAC OSA[8,16,18,241TETRAEN]-15'-ONE 13'.13'-DIOXIDE

STEP 1 : (1 S,3'R,6'R,7'S ₅ 8'Z)-6-CHLORO-7'-[(TERT~

BUTYLDIMETHYLSILY)OXY]-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'- [20]OXA[13]TOIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTAC OS A[ 8, 16, 18,24jTETRAEN] - 15 '-ONE 13 13 '-DIOXIDE

The title compound was prepared from Example 36 by a procedure similar to the one described in Example 32, Step 1. STEP 2: (l S,3'R,6'R,7'S,8'Z)-6-CHLORO-7'-HYDROXY-12'-(2- (METHYLSULFONYL)ETHYL)-3,4-DIHYDRO-2H, 15'H- SPIRO[NAPHTHALENE-l,22 ^, -

[20]OXA[ 13]TH1A[ 1,12,14]TR1AZATETRACYCLO[ 14 .2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTAC OS A 8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE The title compound was prepared from (1 S,3'R,6'R,7'S,8'Z)-6-chioro-7'-[ (tert- butyldimethylsily)oxy] -3,4-dihy dro-2h, 15'h-spiro[naphthalene- 1 ,22'- i 8.24 |ιet raenj-15'-one 13', 13'-dioxide by a procedure similar to the one described in example 34. 'Ή NMR (400MHz, CDCb) δ 10.1 (br. s. IH), 7.74 - 7,67 (m,J=8.4 Hz, 111).7.36 (br. s. ills.7.17 (dd, ./ 2.0.8.6 Hz, 1H), 7.09 (s, 2H), 7.03 - 6.92 (m, 1H), 5.68 (br. s, 2H), 4.50 (br. s, 1H), 4.24 (br. s, 1H), 4.19 - 3.99 (m, 2H), 3.84 (br. s, IH), 3.70 - 3.53 (m, 3H), 3.53 - 3,35 (m, IH), 3.21 (d, ,/ 143 Hz, 2H), 3.05 (s, 3H), 2.84 - 2.61 (m, 3H), 2,34 (br. s, 4H), 2,07 - 1,88 (m, 4H), 1.83 (br, s, 2H), 1.79 ·· 1.62 (m, 2H), 1.56 (br. s, Ml).1.46 (br. s, IH). m/z (ESI, +ve ion) 679.2 (VI II) .

EXAMPLE 38. (1 S,3'R,6 ⁱ R,7'S,8'E)-6-CHLORO-7'-HYDRO.XY-l 2'-((2S)-2- OXETANYLMETHYL)-3,4-DIHYDRO-2H,15'H~SPIRO[NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[l 2,14]TTOAZATETOACYCLO[14 .2.0 ³ ' ^{6 19} - ²⁴ ]PEI>rrAC OS A[8, 16, 18,24]TETRAEN]-15'-ONE ! 3', 13'~DIO.XTDE OR

(lS,3'R,6 ^, R,7'S,8 ^, E)-6-CHLORO-7'-HYDROXY-12 ^! "((2R)-2- OXETANYLMETHYL)-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE~ 1,22'-

[20]OXA[13]THIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ² ]PENTAC OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

STEP 1: (S)-OXETAN-2-YLMETHYL 4-METHYLBENZENESULFONATE AND (R)-OXETAN-2-YLMETHYL 4-METHYLBENZENESULFONATE To a solution of 4-methylbenzene-l-sulfonyl chloride (3.28 g, 17,2 mmol) and 4-(dimethylamino) pyridine (0, 191 g, 1.57 mmol) in DCM (40 mL) was added triethylamine, (reagentplus 99.5%, 4.36 mL, 31.3 mmol) followed by an addition of a solution of 2-hydroxymethyloxetane (1.28 mL, 15,7 mmol) in DCM (12 mL) over 10 minutes. The resulting mixture was stirred at ambient temperature for 60 hours. The reaction mixture was filtered to remove thr precipitate produced in the reaction, concentrated and purified by column chromatography to afford the title compound (3.5 g, 14.4 mmol, 92 % yield).

STEP 2: (1 S,3'R,6'R,7'S,8'E)-6-CHLORO-7'-[(TERT~

BUTYLDIMEraYLSILY)OXY]-12'-((2S)-2-OXETANYLMETHYL)-3,4- DIHYDRO-2H, 15TLSPIRO[NAPHTHALENE-l ,22'-

[20]OXA[13]TOIA[ 1 2,14]TT TAZATETRACYCLO[ 147.2.0 ³ "« 0 ¹⁹ ' ²⁴ ]PE TAC OS A[8, 16, 18,24]TETRAEN]-15'-O E 13', 13'-DIOXIDE AND

(lS,3'R,6 ^! R,7 ^, S,8'E)-6-CHL()RO-7'-[(TERT-BUTYLDIMETHYLSILY)OXY]- 12'-((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H,i5'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THlA[ l,12,14]I¾lAZATETiLACYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A[8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

To a solution of (18,3¾,6Έ,7'8,8Έ)-6-Λ1θΓθ-7'-[ 6Γ^

butyldime lsily)oxy]-l 2'-((2S)-2-oxetanylme i)-3,4-dihy dro- 15Ή- spiro [naphthalene- 1 ,22'- [ 20] oxa[ 13 ] thi a[ 1 , 12,14] tri azatetracy cl o [ 14.7 , 2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16,18,24]tet raenj-15'-one 13 ',13 '-dioxide (60 nig, 0.087 mmol, Example 32, Step 1) in THF (1 mL) was added lithium bis(trimethylsilyl)amide, 1.0 M solution in THF (0.350 mL, 0.350 mmol) and the reaction was stirred at ice-bath for 10 minutes followed by an addition of (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate and (R)~ oxetan-2-ylmethyl 4-methylbenzenesulfonate (74.1 mg, 0.306 mmol) in THF (0.4 mL). The reaction mixture was then transferred to a microwave tube under N ₂ and heated at 100 °C for 3 hours. LCMS showed -50% of conversion to product. The reaction was quenched with saturated H ₄ C1 and extracted with EtOAc. The organic extract was washed with water and brine, dried using MgS04, filtered and concentrated. The crude material was purified by chromatography using Redi-Sep pre-packed Gold silica gel column (40g) eluting with ethyl acetate in hexane to afford the title compound (16 mg, 0.021 mmol, 24.2% yield, with impurities).

STEP 3: (lS,3'R,6'R,7'S,8'E)-6-CHLORO-7'-HYDROXY-12'-((2S)-2- OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE-

[20]OXA[ 13]TO1A[ 1,12,14]TR1AZATETRACYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTAC OSA| 8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Ej-6-CHLORO-7'-HYDROXY-l 2'-((2R)-2- OXETANYLMETHYL)-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ">"><-

[20iOXA|;i3]TOLA|;i ,12, 14]TRIAZATETRACYCLO|;i4.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16,18,24]TETRAEN]-15'-ONE J 3', li -DIOXIDE

(lS,3'R,6'R,7'S,8'E)-6-chloro-7'-[(tert-butyldimethylsily )

oxetanyimethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,2 2'- [20]oxa[ 13]thia[l ₅ 12 ₅ 14]triazatefr^

raen]-15'-one 13', 13'-dioxide and (Ιβ^'Κ,ό'Κ,Τ'β,δ'Ε^ό-οΙιΙθΓθ-Τ'-Ιίίβι ΐ- butyldimethylsily)oxy]-12 ^, -((2R)-2-oxetanylmethyl)-3,4-dihydro-2H,15'H- spiro[naphthalene-l,22'- [ 20] oxa[ 13 ] thi a[ 1 , 12,14] tri azatetracy cl o [ 14.7 , 2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tet raenj-15'-one 13 ',13 '-dioxide (16 mg, 0.021 mmol) was treated with

tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.952 mL, 0.952 mmol) and a small amount of molecular sieves at 55 °C for 4 hours. The reaction was concentrated and the crude material was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient eiution of 45% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to give a mixture of two isomers with a ratio of 14/86. (6.6 mg, 5.14 μιηοΐ, 24.3% yield). The mixture was separated by SFC using a chiral column of Chromega Chiral CC4, 3.0 x 25 cm with the following conditions: mobile phase, 55% methanol (20 mM ΝΗ:·ι)/45%) CCte; flow rate, 80 mL/min; SFC outlet pressure, 100 bar; mobile phase temperature, 33 °C; wavelength, 242 nm to afford the title compound as the second eluting isomer. ¾ MR (400 MHz, CDCls) δ 8.72 (s, ill).7.72 {a.J N.4I Hz, III).7.20 (dd,J=2.25, 8.51 Hz, ill . 7.11 (d, J=2.15 Hz, IH), 7.02 - 6.92 (m, 2H), 6.88 (br. s, III).6.00 - 5.90 (m, ill). 5.73 (dd, J=7.63, 15.3 Hz, IH), 5.13 - 5.07 (m, 1H), 4.73 - 4.66 (m, IH), 4.56 (dt, ./ 6.21.8.71 Hz, IH), 4.24 - 4.06 (m, 41!}.3.93 - 3.83 (m, IH), 3.81 - 3.66 (m, ^■ ill).3.29 (d, ./ 14.5 FIz, IH), 3.15 (d, ./ 7.63 FIz, ill).2,85 - 2.67 (m, 411).2,57 - 2.47 (m, H), 2.47 - 2,29 (m, 3H), 2.08 - 1.98 (m, 4H), 1.85 (br. s, H), 1.79 - 1.61 (m, 3H), 1.47 (t, ./ 12.1 Hz, IH). m/z (ESI, +ve ion) 643.2 {M il)

EXAMPLE 39. (lS,3'R,6'R,7'S,8'E)-6-CHLORO-7'-HYDROXY-12 ^! "((2R)-2- OXETANYLMETHYL)-3,4-DIFIYDRO-2FI, 15'H-SPIRO[NAPFITFTALENE- l. "

[20]OXA[13]TOlA[l,12,14]TRlAZATETiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OSA 8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Ej-6-CFiLORO-7'-HYDROXY-l 2'-((2S)-2- OXETANYL,METHYL)-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHA.LENE- 1 ">"> ^< -

[20iOXA|;i3]TOLA|;i,12,14]TRIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTAC OS A[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13*-DIOXIDE

The title compound was isolated as the first eiuting isomer from the SFC separation in the reaction described in Example 38, Step 3. ¾ NMR (400 MHz, CDCb) δ 8,63 (s, H), 7.73 (d, J=8.61 Hz, i l l ). 7,20 (dd, J=2.35, 8.61 Hz, 1H), 7.11 (d, =2.35 Hz, 1H), 7.00 - 6.93 (m, 2H), 6.89 (br. s, IH), 5.99 - 5.91 (m, 1H), 5,75 (dd, J=7.53, 15.4 Hz, IH), 5.12 (qd, 2 84. 7,60 Hz, IH), 4.71 (td, 6 06. 8,02 Hz, IH), 4,56 (dt, .7=5.97, 9.19 Hz, IH), 4.27 - 4.20 (m, 2H), 4.16 - 4.07 (m, 2H), 3.93 - 3.86 (m, IH), 3.77 - 3.64 (m, 3H), 3.54 - 3.46 (m, IH), 3.29 (d, J=14.1 Hz, I H), 3.15 (d, ./ 6,65 Hz, IH), 2.83 - 2.70 (m, 3H), 2.56 - 2.40 (m, 4H), 2.35 - 2.27 (rn, IH), 2.07 - 1 ,91 (m, 3H), 1.89 - 1.64 (rn,2 H), 1.60 (s, 2H), 1.55 - 1,39 (m, 2H). m/z (ESI, +ve ion) 643.2 ( M f i

EXAMPLE 40. (l S _s 3 ^, R,6 ^, R,7 ^, S,8 ^, E)-6-CHLORO-7'-HYDROXY-12 ^, -(3- OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE-

[20]OXA[13]THIA[1 ^2, 14]TRIAZATETOACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

STEP 1 : OXETAN-3-YLMETHYL 4-METHYLBENZENESULFONATE

The title compound was prepared from oxetan-3-ylmethanol by a procedure similar to the one describled in Example 38, Step 1 (1.80 g, 7.43 mmol, 65.5% yield). STEP 2: (lS,3 ^f R,6'R,7'S,8'E)-6-CHLO O-7'-HYD OXY-12'-(3-

OXETANYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTOALENE- 1 ">"><-

| 20 j()XA| i 3 jTI I I.-\| 1. 1 2. ! 4 |TR! AXATHTRAC ^' Yi L()| I 4.7.2.0 ^; ".0 ^! " ^I! !N ! AC OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13', 13'-DIOXIDE To a solution of (1 S,3'R,6'R,7'S,8¾-6-chk)ro-7 (tert~

butyldimethy lsily)oxy] -3 ,4-dihy dro-2H, 15H~spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[l ,12 4]triazatetr^

raen j~15'-one 13',13'-dioxide (58 mg, 0.085 mmol. Example 32, step 1) in THF (1 mL) in an oven-dried microwave tube was added lithium bis(trimethylsilyl) amide, 1.0 M solution in THF (0.338 mL, 0.338 mmol) and the reaction was stirred at 0 °C for 10 minutes followed by the addition of a solution of oxetan-3- ylmethyl 4-methylbenzenesulfonate (71.7 mg, 0.296 mmol) in THF (0.4 mL). The resulting mixture was stirred at 100 °C in a microwave oven for 3.5 hours. The reaction was quenched with saturated NH4CI and extracted with EtOAc. The organic extract was washed with brine, dried with MgS0 ₄ , filtered and concentrated to give a crude alkylation product. The crude was treated with tetrabutylammonium fluoride solution, (1.0 M in THF, 0.994 mL, 3.80 mmol) and a small amout of molecular sieve at 55 °C for 1 hour. After concentration the residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as a solid (42 mg, 0.065 μηιοΐ, 77% yield). ^l H NMR (400 MHz, CDCb) δ 9.16 (br, s, IH), 7.69 Ui.,/ 8.4! Hz, 111).7.19 (dd,J=2.25, 8,51 Hz, IH), 7.11 (d, J=2.15 Hz, IH), 6.97 - 6.81 (m, 2H), 6.76 (br. s, IH), 6.11 - 5.97 (m, IH), 5.72 (dd, ,/ 7.73.15.2 Hz, IH), 4.92 - 4.82 (m, 2H), 4.66 (t, =6.06 Hz, IH), 4.54 (t, ,/ 6.06 Hz, IH), 4.45 - 4.28 (rn, 211).4 17- 3,95 (m, 2H), 3.85 (dd, J=6.55, 15.2 Hz, IH), 3.69 (t, ./ 14.0 Hz, 3H), 3.37 (di, .7=6.82, 13.6 Hz, IH), 3.30 - 3.17 (m, 2H), 3.16 - 2.96 (m, 2H), 2.95 - 2.972 (m, 2H), 2.60 - 2.37 (m, 2H), 2.37 - 2.23 (m, 2H), 2.07 - 1.92 (m, 3H), 1.89 - 1.79 (m, 2H), 1.79 - 1.59 (m, 2H), 1,44 (i, ./ 12. Hz, ill), m/z (EST, +ve ion) 643,2 !\! H)

EXAMPLE 41. (lS,3'R,6 ^, R,7'S,8 ^, E)-6-CHLORO-7'-HYDROXY-12 ^! "(2-(R)- OXIRANYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

[20]OXA[13]THIA[1,12,14]T1UAZATETOACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PEOTAC

OSA 8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE AND

(1 S,3'R,6'R,7'S,8'E)-6-CHLORO-7'-HYDROXY-l 2'-(2-(S)-

OXIRANYLMETHYL)~3,4-DIHYDRO-2H,15 ^! H-SPrRO[NAPHTHALENE- 1 ">"> ^< -

|2 ⁽ i )XAj 13ΓΠ Ι.Ι2.!4ΓΓΚ1ΛΖΑ ΓΗ·Π Λ(·Υ( ^' !.0| I4.7.2.0 ^; ".0 ^! " ^¾! |1 :N TAC OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13', 13'-DIOXIDE

To a solution of diisopropylamine (redistilled, 99.95% , 0.069 mL, 0.490 mmol) in THF (1 mL) in an oven-dried 100 mL round-bottom flask was added butyllithium solution (1.6M in hexanes, 0.331 mL, 0.530 mmol) at 0 °C and the reaction was stirred at 0 °C for 20 minutes. To a solution of (1S,3'R,6'R,7'S,8'E)~ 6-chloro-7'-[(tert-butyldimeto

1,22'-

[20]oxa[ 13]thia[l ,12 4]triazatetr^

raen j~15'-one 13',13'-dioxide (14 mg, 0.020 ramol; Example 32, Step 1 ) in THF (0.3 mL) at -78 °C was added 140 μί, of the LDA solution prepared above and this mixture was stirred for 30 minutes allowing the temperature to rise from -78 degree to 0 °C followed by addition of 2-(bromomethyl) oxirane (4.22 μΐ, 0.051 mmol). The resulting mixture was stirred at ambient temperature for 17 hours and at 60 °C for 24 hours. No desired product was detected by LCMS. The dried reaction mixture was dissolved in 0.5 ml. of 2-(bromomethyl) oxirane, transferred to an oven-dried microwave tube and stirred at 100 °C for 4 hours. The reaction was quenched with saturated NH Cl and extracted with EtOAc. The organic extract was washed with brine, dried with MgSCu, filtered and concentrated. The residue was treated with tetrabutylammonium fluoride, (1.0M in THF, 1.04 mi,, 1.04 mmol) and a amall amount of molecular sieve at 50 °C for 1.5 hours. The reaction was concentrated to give a residue which was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, C A; gradient elution of 30% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as a mixture of two diastereoisomers with a ratio of 4/3 determined by Ή NMR analy sis. ^" Ή NMR (400MHz, CDCh) δ 8.66 (s, 0.4H), 8,61 (s, 0.6H), 7.72 (d, ,7=8,4 Hz, 1H), 7.20 (dd, J=2.1, 8.5 Hz, 1H), 7.11 id. ./ 2.0 R/. 1H), 7.03 - 6.88 (m, 3H), 5.95 - 5.84 (m, 1H), 5.79 - 5.69 (m, 1H), 4.25 - 4.04 (m, 4H), 4.01 - 3.81 (m, 1H), 3.78 - 3.63 (m, 2H), 3.60 - 3.47 (m, 1H), 3,44 - 3.20 (m, 3H), 2.89 - 2.76 (m, 3H), 2,54 - 2.27 (m, 4H), 2.05 - 1.96 (m, 2H), 1 ,95 - 1.76 (m, 4H), 1.69 (br. s, 2H), 1.59 - 1.39 (m, 3H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 42. (1 8,3¾,6'Κ,7'8,8Έ)-6- ;ΗΙ.Ο Ο-7'-ΗΥΟ ΟΧΥ-12'-(2- PROPEN-l-YL)-3,4-DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[l,12 4]TRIAZATCTTlACYCLO[14 .2 ³ '*0 ¹⁹ - ²⁴ ]PE3SnrAC OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

The title compound was prepared from (lS,3'R,6'R,7'S,8'E)-6-chloro-7'- [(tert-butyldimethylsiiy)oxy]-3,4-^^

[ 20] oxa[ 13 ] thi a[ 1 , 12,14] tri azatetracy cl o [ 14.7 , 2.0 ³ ^ 0 ^]9 ' ² ¾eOTtacosa[8,16,18,24]tet raen]-15'-one 13',!3'-dioxide (Example 32, Step 1) by a procedure similar to the one described in Example 34 and it was obtained as a solid (8.0 nig, 0.013 nimoi, 63.3% yield). ^" Ή NMR (500 MHz, CDCh) δ 8,53 (br. s, ill), 7,72 id. J=8.56 Hz, 1H), 7.20 (dd, ,7=2,20, 8.56 Hz, IH), 7,10 (s, ill).6,99 - 6.90 (m, 3H), 5.94 - 5.84 (ni, 2H), 5.73 (dd, ./ 15,41.7.82, 15.4 Hz, IH), 5.32 - 5.24 (ni, 2H), 4.65 (d, ./ 1 .9 Hz, IH), 4.22 (dd, ,/ 4.52.7.46 Hz, IH), 4.26 - 4.07 (m, 2H), 3.91 (dd, ,/ 648.16,8 Hz, IH), 3.80 - 3,64 (m, 3H), 3.37 - 3.19 (m, 2H), 3,17 (br. s, IH), 2,84 - 2.73 (m, 2H), 2.51 - 2.36 (m, 3H), 2,33 - 2.18 (m, IH), 2.04 - 1.88 (m, 3H), 1.88 - 1.79 (m, 2H), 1.79 - 1.61 (ni, 3H), 1.48 (t, ./ 12.2 Hz, IH). m/z (ESI, +ve i on) 613.2 ( +H) ⁺ .

EXAMPLE 43. METHYL (((1 S,3'R,6'R,7'S,8'Ej-6-CHLORO-r2'-ETHYL-

13 ^, ₅ 13 ^, -DIOXIDO-15 ^, -OXO-3 ₅ -DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^, -

[20]OXA[13]THIA[1,12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OS A[ 8, 16, 18,24]TETRAEN|-7'-YL)OXY)ACETATE

To a solution of Example 29 (16 mg, 0,027 mmol) in THF (0.53 ml.) was added sodium hydride, 60% dispersion in mineral oil (5.33 mg, 0.133 mmol) and the reaction was stirred at 0 °C for 30 minutes followed by addition of methyl 2- bromoacetate (4.88 μΕ, 0.053 mmol). The resulting mixture was stirred at ambient temperature for 17 hours whereupon 17 % of the desiresd product was detected by LCMS. Methyl 2-bromoacetate (4.88 μί.., 0.053 mmol) and sodium hydride, 60% dispersion in mineral oil (5.33 mg, 0.133 mmol) were then added and the reaction was stirred at ambient temperature for 25 hours. The reaction was quenched with saturated NEUCl and extracted with EtOAc. The organic extract was washed with brine, dried with MgS€>4, filtered and concentrated to give a residue which was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as a solid (10.2 mg, 0,015 mmol, 56.9 % yield). ^f H NMR (400 MHz, CDCh) δ 8.46 (s, 1H), 7.72 (d, J=8,61 Hz, 1H), 7.20 (dd, ,7=2,25, 8.51 Hz, III).7.11 ( ^■ ± J .2.15 !!/.1H), 6.95 - 6.88 (m, 2H), 6.75 (s, 1H), 6.06 ·· 5.97 (m, ill).5.59 (dd, ./ 9.10.15.6 Hz, ill).4.22 - 4,15 (m, 111).4.13 - 4.01 (ra, 311).3,90 (dd, .7=3.91, 9.00 Hz, 111).3,85 - 3.70 (m, 511).3.38 - 3.18 (m, 311).3,06 (dd, J=9.88, 14.8 Hz, 1H), 2.87 - 2.72 (m, 2H), 2.64 - 2.46 (m, 2H), 2.42 (br. s, 2H), 2.37 - 2.22 (m, 2H), 2.08 - 1.92 (m, 3H), 1.90 - 1.76 (m, 3H), 1.71 - 1.61 (m, 1H), 1.42 (t, .7=12.2 Hz, 1H), 1.29 (t, .7=7,14 Hz, 3H). m/z (ESI, +ve ion) 673.2 (M+H) ⁺ . EXAMPLE 44. (((l S,3'R,6' ,7 ^f S,8'E)-6-CHLORO-12'-ETOYL-13', 13'-

DIOXIDO-15'-OXO-3,4-DmYDRO-2H-SPI^^

j;2Q]OXA[ 13 jTHL4[ l, 12,14]TRIA^^

OS A[8, 16, 18,24]TETRAEN]-7'-YL)OXY)ACETIC ACID

A mixture of Example 43 (8 mg, 0.012 mmol) and lithium hydroxide nionohvdrate (1.50 mg, 0.036 mmol) in THF (0.3 mL), water (0.10 mL) and MeOH (0.100 mL) was stirred at ambient temperature for 1 hour. The reaction was acidified with aqueous ΓΜ HCl and concentrated to give a residue which was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA) to afford the title compound as a solid (4 mg, 6.08 μηιοΙ . 51.1 % yield). ^! ! l NMR (400 MHz, CDCb) 6 8,56 is. i l l ). 7,71 id. ./ 8.6 ! Hz, 1H), 7.20 (dd, .7=2.25, 8,51 Hz, 1H), 7. 1 1 (d, .7=2.35 Hz, IH), 6,95 - 6,88 (m, 2H), 6.77 (br. s, 1H), 6.13 - 6.04 (m, IH), 5.58 (dd, J=9.88, 15.4 Hz, 1H), 4.18 - 3.98 (m, 6H), 3.84 - 3.60 (m, 2H), 3.39 (dd, ./ 7.24. 14.9 Hz, 1H), 3.32 - 3.12 (m, 2H), 3, 10 (br. s, i l l ), 2,86 - 2.69 (m, 2H), 2.65 - 2.44 (ra, 2H), 2,43 - 2.23 (m, 3H), 2,20 (br. s, IH), 2, 14 - 1.93 (m, 3H), 1.90 - 1.69 (m, 4H), 1,45 (t, .7=12.4 Hz, IH), 1.30 (t, ./ 7.D4 Hz, 3H). m/z (ESI, +ve ion) 659.2 { M i l ) .

EXAMPLE 45. (lS,3'R,6'R,7'S,8'E)-6-CHLQRO-12'-ETHYL-7'-HYDRQXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1, 12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OS A[ 8, 16, 18,24]TETRAEN] - 15 '-ONE 13 13 '-DIOXIDE

To a solution of Example 29 (2 mg, 0.035 mmol) in THF (0.5 mL) in a vial (4 mL size) at 0 °C was added sodium hydride, 60% dispersion in mineral oil (8.40 mg, 0.210 mmol) and the reaction was stirred at 0 °C for 30 minutes followed by an addition of iodomethane (6.53 μί, 0.105 mmol). The resulting mixture was stirred at ambient temperature for an additional I hour. LCMS showed completion of the reaction. The reaction was quenched by the dropwise addition of 1 M HQ and extracted with EtOAc, The extract was washed with water and brine, dried with MgSC¼, filtered and concentrated. The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 80%) MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as a solid (6 mg, 9.77 .umol, 27.9% yield). ¾ NMR (400 MHz, CDCb) 5 8.41 (s, 1H), 7.72 (d, ./ 8.41 Hz, 1H), 7.20 (dd, ./ 2.25. 8.51 Hz, IH), 7.11 (d, J-2.35 Hz, ! 1 1 ). 6,95 - 6.86 (m, 2H), 6.75 (d, J=1.56 Hz, IH), 6.06 - 5,97 (m, i l l ). 5.61 - 5.53 (m, i l l ). 4,24 (dd, ./ 7.3-1.. 14.8 Hz, IH), 4.14 - 4.04 (m, 2H), 3.88 - 3.68 (m, 4H), 3.38 - 3.18 (m, 6H), 3.01 (dd, ./ 98. 15.3 Hz, IH), 2.86 - 2.72 (m, 2H), 2.61 - 2.39 (m, 2H), 2.35 - 2.19 (m, 2H), 2.19 - 1.93 (m, 3H), 1.89 - 1.63 (m, 4H), 1 ,42 (t, ./ 12.4 Hz, IH), 1.29 (l, J=7.04 Hz, 3H). m/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 46. (1 S,3 ^, R,6'R,7 ^! S,8'E)-6~CHLORO-7 ^, -METHOXY-3,4"DlHYDRO- 2H, 15H-SPIRO[N APHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[ 1, I 2,14]TRIAZATETRACYCLO[ 14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTAC OSAI 8.16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

To a solution of Example 19 (11 mg, 0.019 mmol) in THF (0.25 mL) in a vial (4 mL size vial) at 0 °C was added sodium hydride, 60% dispersion in mineral oil (4.61 mg, 0. 1 15 mmol) and the reaction was stirred at 0 °C for 20 minutes followed by the addition of iodomethane (3.59 μί, 0.058 mmol) and the reaction was stirred at ambient temperature for 4.5 hours. LCMS showed the completion of the reaction. The reaction was quenched by the dropwise additon of I M HC1 at 0 °C and then extracted with EtOAc. The EtOAc extract was washed with water and brine, dried with anhydrious MgS0 ₄ , filtered and concentrated. The residue was purified by HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, C A; gradient elution of 45% to 80% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to afford the title compound as the first eluting compound. ¾ NMR (400 MHz, CDCb) δ 8.29 (s, 1 H), 7.72 (d, ./ H.4 I Hz, 1H), 7.21 (dd =2.35, 8.61 Hz, 1H), 7. 12 i d. ./ 2. 1 5 Hz, IH), 6,97 - 6.85 (m, 3H), 6.02 - 5,94 (m, IH), 5.78 (t, J=5.97 Hz, IH), 5.59 (dd, J=8.80, 15.3 Hz, 4.16 - 4.05 (m, 2H), 3.83 (d, ./ 14.9 Hz, IH), 3.78 - 3.68 (m, 2H), 3.36 - 3.21 (m, 6H), 3.03 (dd, ./ 10.2. 15.3 Hz, IH), 2.86 - 2,73 (m, 2H), 2.55 - 2.44 (m, 2H), 2.40 - 2.21 (m, 2H), 2.15 - 1.64 (m, 7H), 1.42 (t, .7=12,5 Hz, H). m/z (ESI, +ve ion) 587.2 ( Vl - i l ) . EXAMPLE 47. (1 S,3 ^, R,6 ^, R,7'S,8¾-6-CHLORO-7 ^, -METHOXY-12 ^, -METHYL-

3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l ,22'-

[20]OXA[ 13]TOIA[ 1, 12, 14]TT TAZATETRACYCLO[ 14.7.2.0 ³ "« 0 ¹⁹ ' ²⁴ ]PE TAC OS A[ 8, 16, 18,24]TETRAEN] - 15 '-ONE 13 13 '-DIOXIDE

The title compound was isolated as the second eluting fraction from the reaction described in Example 46 (1.7 mg, 2,83 jimol, 14.7% yield). ^] H NMR (400 MHz, CDCh) δ 8.35 (s, IH), 7.73 (d, .7=8.41 Hz, IH), 7.20 (d, .7=8.84 Hz, I H ). 7.11 (d, ./ .2.35 Hz, IH), 7.03 - 6.89 (m, 2H), 6.79 (d, .7=1.57 Hz, M l ). 6.06 - 5.98 (m, IH), 5.58 (dd, ./ 8.90. 15.6 Hz, IH), 4.24 - 4.05 (m, 2H), 3.90 (dt, ./ 4.62. 14.8 Hz, IH), 3.82 - 3.62 (m, 3H), 3.34 (s, 3H), 3.30 (s, 3H), 3.27 - 3,00 (m, il l ). 2,89 - 2.70 (m, 2H), 2.62 - 2.41 (m, 2H), 2.41 - 2.22 (m, 2H), 2.21 - 1.93 (m, 2H), 1.92 - 1.63 (m, 4H), 1.43 (t, ./ 1 2.3 Hz, IH). rn / (ESI, +ve ion) 601.2 { M · Π )

EXAMPLE 48. (1 S,3'R,6'R,7 ^f S,8'E)-6-CHLORO-7'-(2-METOOXYETHOXY)- 12'-(2-METHOXYETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1,22'-

[20]OXA[ 13]THIA[ 1 2,14]TTOAZATETOACYCLO[ 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PE TAC OS A[8, 16, 18,24]TET RAEN]-15'-ONE 13', 13 ^! -DIOXIDE

The title compound was prepared from (l S,3'R,6'R,7'S,8'E)-6-chloro-7'~ (iert-butyldipheny3silyl)oxy]-3,4-dihydro-2H,15 ^, H-spiro|naphthalene-l,22 ^! - 20]oxa[ ! 3]thia[ 1, 12,14]triazatetracy clo[14.7.2.0 ³ " ⁶ .0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tet raen]-15'-one 13', 13'-dioxide (Exaraple 31 , Step 1 ) by a procedure similar to the one described in Example 34 (0.40 nig, 0.581 μηιοΐ, 4.71% yield). ¾ NMR

(400MHz, CDCb) δ 8.41 (s, IH), 7.72 (d, ./ 8.6 Hz, IH), 7.20 (dd, ./ 2.3. 8.4 Hz, I H), 7.11 (d, 2.2 Hz, IH), 6.95 - 6,88 (m, 2H), 6.79 (s, IH), 6.02 - 5.94 (m, IH), 5.59 (dd, ,7=8,5, 15.6 Hz, IH), 4.33 (id, .7=4.3, 15.5 Hz, IH), 4.14 - 4.05 (m, 2H), 3.91 (td, J=4.5, 15.0 Hz, IH), 3.85 - 3.78 (m, IH), 3.74 (br. s, IH), 3.71 - 3.58 (m, 4H), 3.56 - 3.42 (m, 5H), 3.40 (s, 3H), 3.40 (s, 3H), 3.22 (d, ./ 14.3 Hz, IH), 3,03 (dd, ./ .X. 15.3 Hz, I H), 2,85 - 2.72 i ns. 2H), 2,56 - 2.46 (m, 2H), 2.34 - 2.24 (m, 2H), 2.08 - 1 ,92 (m, 3H), 1.89 - 1.69 (m, 3H), 1.65 (s, 2H), 1.42 (t, ./ 12.2 Hz, IH). m!z (ESI, +ve ion) 689.2 { M · Π } .

EXAMPLE 49. (1 S,3'R,6'R,7'S,8'E, 1 l ^, S)-6-CHLORO-7 ^, -HYDROXY-l l'- METHYL-12'-((2S)-TET¾AHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15'H-SPlRO[NAPHTHALENE- 1 ,22'- [20]OXA[13]TOIA[ 1 2,14]TT TAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTAC OSAI 8.16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

STEP 1 : TERT-BUTYL N-((S)-PENT-4-EN-2~ YL)-N~(((S)- TETRAHYDROFURAN-2-YL) METHYL) SULFAMOYLCARBAMATE

The title compound was prepared from (S)-N-(((S)-tetrahydrofuran-2-yl) methyl) pent-4-en-2-amine by a procedure similar to the one described in

Example 29, Step 1 (0.867 g, 2.49 mmol, 56.9% yield).

STEP 2: N-((S)-PE T-4-EN-2-YL)-N-((S)-TETRAHYDROFURAN-2-YL) SULFURIC DIAMIDE

The title compound was prepared from tert-butyl N-((S)-pent-4-en-2-yl)- N-(((S)-tetrahydrofuran-2-yl) methyl) sulfamoylcarbamate by a procedure similar to the one describled in Example 29, Step 2 (0.583 g, 2.35 mmol, 94% yield).

STEP 3: (S)-6'-CHLORO-5-(((lR,2R 2-((S)-i-

FiYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(N-((S)-PENT-4-EN-2-YL )-

N-(((S)-TETRAHYDROFURAN-2^ METHYL)SULFA¾lOYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALENE! -7-CARBOXAMIDE

The title compound was prepared from Intermediate AA11 A and N-((S)- pent-4-en-2-yl)-N-((S)-tetrahydrofuran-2-yl) sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (61 mg, 0.087 mmol, 58.4% yield). STEP 4: (1 S,3'R,6'R,7'S,8'E,1 rS^-CHLORO-T-HYDROXY-i r-METHYL-lT- ((2S)-TETR/ HYDRO-2-FURA^LMETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- i .22'-

[20]OXA[13]TOIA[ 1, 12,14]TT TAZATETRACYCLO[ 147.2.0 ³ '^0 ¹⁹ - ²⁴ ]PE TAC OSAI 8.16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobut\'l)methyl)-N-(N-((S)-pent-4-en-2-yl)-N -(((S)- tetrahydrofuran-2-yl)me1hyl)sulfamoyl)-3',4,4',5-tetrahydro- 2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide by a procedure similar to the one described in Example 29, Step 4 and it was isolated after HPLC purification, as the first eluting isomer (2.7 mg, 4.03 μηιοΐ, 4.69% yield). Ή

NMR (400 MHz, CDCh) δ 8,58 (s. 11 1 ). 7,72 (d, J=8.41 Hz, ! ! ! ). 7.20 (dd, J=2.25, 8.51 Hz, IH), 7.11 id. J=2.15 Hz, 1H), 7.05 - 6.92 (m, 3H), 5.87 - 5.78 (m, IH), 5.76 - 5.67 (m, IH), 4.19 - 4.06 (m, 4H), 3.94 - 3.69 (m, 6H), 3.48 (dd, ,/ 2 84. 15,9 Hz, IH), 3.30 (d, ./ 14.3 Hz, IH), 3, 14 (dd, J-6.65, 15.1 Hz, IH), 2,85 - 2.74 (m, 2H), 2.65 (ddd, ,/ 5 58. 1 1 ,0, 16.3 Hz, IH), 2,53 - 2.41 (m, 2H), 2.30 - 2.22 (m, IH), 2.10 - 1.84 (m, 7H), 1.84 - 1.61 (m, 5H), 1.51 - 1.34 (m, 4H). ns (ESI, +ve ion) 671.2 I 1 1 > ^" .

EXAMPLE 50. (l S,3'R,6'R,7'S,8'Z,i S)-6-CHLORO-7'-HYDROXY-l Γ- METHYL-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [N APHTH ALEN E- 1 ,22' -

[20iOXA|;i3]TOIA|;i ,12, 14]TRIAZATETRACYCLO|;i4.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTAC OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13', 13'-DTOXIDE

The title compound was prepared in the reaction described in Exampe 49, Step 4 and it was isolated after HPLC purification, as the second elutmg isomer (0.8 mg, 1.19 μηιοΐ, 1.4% yield). Ή NMR (400 MHz, CDCh) δ 9.13 (br. s, 1H), 7.71 (d, ,/ X.4i Hz, !H), 7.24 (s, IH), 7.20-7, 18 (dd, ./ 2.2.8.5 Hz, 111).7. 1 (d, J=2.15 Hz, IH), 6,98 - 6.91 (m, 2H), 5.79 - 5.67 (m, 2H), 4,27 (br. s, IH), 4,20 - 4.02 Cm.4H), 3.92 - 3.85 (m, IH), 3.74 - 3.59 (m, 3H), 3.56 (d, J=9.19 Hz, IH), 3.52 - 3.28 (m, 3H), 2.85 - 2.74 (m, 2H), 2.57 - 2.39 (m, 3H), 2.26 (dt, J=5.50, 15,4 Hz, IH), 2.06 - 1.79 (m, 8H), 1,70 -1.51 (m, 4H), 1.44 - 1.28 (m, -ill) m/z (ESI, +ve ion) 671,3 (VI H ) . EXAMPLE 51. (IS^' ^'R^'S^'EJl'Ri-e-CHLORO-T'-HYD OXY-ir-

ME^WL-12'-((2S)-TETRAl-r ^;" DRO-2-FURANYLME™YL)-3,4-DIHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'-

|2ίί )ΧΛ| 13ΓΠ!!Λ| ί.Ι2.!4| |-R!AZA ^' S ^' 1 ^: TRA( ^' YC!.()| ί ,7.2.( '',0 ^{)Μ ' !} |PI:N ! Λ( ^' OSA[8, 16, 18,24]TETRAEN]-15'-()NE 13', 13'-DI()XIDE

STEP 1: TERT-BUTYL N-((R)-PENT-4-EN-2-YL)-N-(((S)- TETRAHYDROFURAN-2-YL)METHYL)SULFAMOYLCARBAMATE

The title compound was prepared from (R)-N-(((S)-tetrahydrofuran- methyl) pent-4-en-2-amine by a procedure similar to the one described in Example 29, Step 1 (0.88 g, 2.53 mniol, 43.9% yield). STEP 2: N-(R)-PENT-4-EN-2-YL, N-(S)-TETRAHYDROFURAN-2-YL

SULFURIC DIAM1DE

The title compound was prepared from tert-butyl N-((R)-pent-4-en-2-yl)- N-(((S)-tetrahydrofuran-2-yl) methyl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 (0.622 g, 2.50 mmol, 99% yield).

STEP 3: (S)-6'-CHLORO-5-((( lR,2R)-2-((S)-I-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(N-((R)-PENT-4-EN-2-YL) - N-(((S)-TOTRAHYDROFURAN-2-YL)METHYL)SULFAMOYL)-3 ^, ,4,4 ^, ,5- TETRAHYDR0-2H,2'H-SPIR0|;BENZ0[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMIDE

The title compound was prepared from Intermediate AAl 1 A and N-(R)- pent-4-en-2-yl, N-(S)-tetrahydrofuran-2-yl sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (65 mg, 0.093 mmol, 62.2% yield).

STEP 4: (1S,3'R,6'R,7'S,8'E,1 l'R)-6-CHLORO-7'-HYDROXY-l Γ -METHYL- 12 ^, -((2S)-TCTOAHYDRO-2-FURA TYLMETHYL)-3.4-DIIiYDRO-2H ₅ 15 ^, H-

SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1 ,12, 14]TRIAZATETOACYCLO[14 .2 ³ ' ^{6 19} - ²⁴ ]PENTAC

OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE The title compound was prepared from (S)-6'-chloro-5-(((l.R,2R)-2-((S)-l- hydroxyallyl)cyclobur l)methy ^

tetrahydrofuran-2-yl)methyl)sulfamoyl^^

spirojbenzojb] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxamide by a procedure similar to the one described in Example 29, Step 4 and was isolated via preparative HPLC as the first eluting isomer (20 nig, 0.030 mmol, 32.1% yield). ^] H NMR (400MHz, CDCh) δ 9.15 (br. s, 1H), 7.69 (d, ,/ H.4 Hz, 1H), 7.22 (br. s, ill).7,17 !dd../ 2.1.8.5 Hz, III).7.09 id.,/ 22!!/ H), 6.97 - 6,87 (m, 2H), 5.70 (d, J=5.9 Hz, 2H), 4.25 (br. s, IH), 4.18 - 4.06 (m, 4H), 4.03 (br. s, IH), 3.86 (d, ./ 7.8 Hz, IH), 3.72 - 3.57 (m, 3H), 3.57 - 3.44 (m, 2H), 3.40 (d, ./ 14.3 Hz, 2H), 2.82 - 2.70 (m, 2H), 2,51 (d, ,/ 7.8 Hz, IH), 2.42 (d, J=10.6 Hz, 2H), 2.26 (br. s, I Hi.2.06 - 1.78 (m, 5H), 1,75 - 1.47 (m, 5H), 1.41 - 1.21 (m, 5H). m/z (ESI, +ve ion) 671.3 (M il) .

EXAMPLE 52. (1S,3'R,6'R,7'S,8'Z,1 l'R)-6-CHLORO-7'-HYDROXY-l 1'- METHYL- 12'-((2S)-TETRAHYDRO-2-FURANYLMETOYL)-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOlA[l,12,14]I¾lAZATETiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Exampe 51, Step 4 and was isolated via preparative HPLC as the second eluting isomer (4.9 mg, 7.31 μηιοΙ.7.85% yield). ^! il NM (400 MHz, CDCb) δ 10.2 (br. s, IH), 7,74 (d../ 8.4! Hz, IH), 7.44 (dd, ,/ 1.86.8.31 Hz, IH), 7.31 (m, H), 7.19 (dd, J=2,35, 8.41 Hz, IH), 7.11 (d, .7=2.15 Hz, IH), 6,98 (d, J=8.22 Hz, IH), 5,85 (id, J=4.89, 11,0 Hz, IH), 5.67 id± 7.63.10.6 Hz, ill).4.41 {{.J 7.73 Hz, ill). 4.25 - 4.04 (m, 4H), 3.96 - 3.86 (m, 3H), 3.79 (td, J=6.06, 7.83 Hz, ill).3.63 (d, ./ 14.1 Hz, IH), 3.22 - 3.02 {in.3H), 2,90 (br. s, ill).2.84 - 2.72 (m, 2H), 2.31 - 2,18 (m, 2H), 2.13 - 1,87 (m, 7H), 1.86 - 1.79 (m, 2H), 1.72-1,61 (m, 2H), 1.50 - 1.22 (m, 6H), m/z (ESI, +ve ion) 671.4 (M+H) ⁺ .

EXAMPLE 53. (lS,3'R,6'R,7'S,8'E,i S)-6-CHLORO-7'-HYDROXY-l Γ-

METHYL-12'-((2R)-TETR _^ 4IWDRO-2-FURANYLMETi-IYL)-3,4-DIHYDRO- 2H, 1 S'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[l,12,14]Ti AZATETOACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC QSA[8,16,18,24]TETRAEN]-15'-QNE 13',13'-D10XIDE

STEP 1: TERT-BUTYL N-((SyPENT-4-EN-2-YL)-N-(((R)- TETRAHYDROFURAN-2-YL)METHYL)SULFAMOYLCARBAMATE

The title compound was prepared from (S)-N-(((R)-tetraliydrofuran-2-yl) methyl) pent-4-en-2-amine by a procedure similar to the one described in Example 29, Step 1 (0.572 g, 1.64 mmol, 37.5% yield).

STEP 2: N-(S)-PE T-4-EM~2"YL, N-(R)-TETRAHYDROFURAN-2-YL SULFURIC D I AMIDE

The title compound was prepared from tert-butyl N-((S)-pent-4-en-2-yl)- N-(((R)-tetrahydrofuran-2-yl) methyl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 (0.416 g, 1.68 mmol, 102% crude yield).

STEP 3: (S)-6 ^! -CHLORO-5-(((lR,2R)-2-((S)-l -

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(N-((S)-PENT-4-EN-2-YL) - N-(((R)-TETRAHYDROFURAN-2-YL)METHYL)SULFAMOYL)-3',4,4',5- TETRAHYDRO-2H,2 ^* H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7 -C ARB OXAMIDE

The title compound was prepared from Intermediate AAl 1 A and N-(S)- pent-4-en-2-yl, N-(R)-tetrahydrofuran-2-yl sulfunc diamide by a procedure similar to the one described in Example 29, Step 3 (75 mg, 0.107 mmol, 71.8% yield).

STEP 4: ( lS,3 ^f R,6'R,7'S,8'E,i rS)-6-CHLORO-7'-HYDROXY-l l '-METHYL-l^- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

| 2 ⁽ ϊ !( )ΧΑ| Ο ΓΙ ^' ί Ι ΙΛΙ I . i 2. ! 4 |TRL\ZA ri i ! ,\CY( ^' !.0| I 4.7.2.0 ^: ".(! ^! " |! :N ! AC OSA[8, 16,18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE The title compound was prepared from (S)-6'-chloro-5-(((l.R,2R)-2-((S)-l- hydrox\'allyl)c lobutyl)methyl)-N-( -((S)-pent-4-en-2-yl)-N-(((R)- tetrahydrofuran-2-yl)methyl)sulfamoyl)-3',4,4 5-tetrahydro-2H,2'H- spirojbenzojb] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxamide by a procedure similar to the one described in Example 29, Step 4 and was loslated via preparative HPLC as the first eluting isomer (27 mg, 0.040 mmol, 37.5% yield). ^] H NMR (400MHz, CDCh) δ 8.87 (br. s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.11 (d, ,/ 2.2 Hz, IH), 7.02 - 6,88 (m, 2H), 5.85 - 5.72 (m, IH), 5.70 - 5.58 (m, IH), 4.20 - 4.08 (m, 2H), 4.06 (br. s, 2H), 3.94 ·· 3.71 (m, 2H), 3.71 - 3.53 (m, 3H), 3.50 - 3.24 (m, 3H), 2,86 - 2.74 (m, 3H), 2.71 (br. s, 3H), 2.59 - 2.40 (m, 3H), 2.38 - 2.23 (m, IH), 2,08 - 1.80 (m, 6H), 1.74 - 1.48 (m, 4H), 1 ,47 - 1.30 (m, 3H). m/z (ESI, +ve ion) 671.2 ( +H) ⁺ .

EXAMPLE 54. (l S,3'R,6 ^, R,7 ^, S,8 ^, Z,l l ^, S)-6-CHLORO-7 ^, -HYDROXY-l l'- METHYL-12'-((2R)-TCTRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15'H-SPIROjNAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,12, 14]Ti AZATETOACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 53, Step 4 and was ioslated via preparative HPLC as the second eluting isomer (2.5 mg, 3.73 μηιοΐ, 3,47% yield). ¾ NMR (400MHz, CDCb) δ 9,63 (br. s, IH), 7.70 (d, ./ 8.4 Hz, IH), 7.27 ·· 7.23 (m, IH), 7.18 (dd, ./ .2.2. 8.5 Hz, IH), 7.09 (d, ,/ 2 2 Hz, I H), 6.93 (d, J=8.2 Hz, IH), 6.79 i s. i l l ). 5,76 - 5,64 (m, 21 1 ). 4.60 - 4,52 (m, IH), 4.27 - 4.15 (m, 2H), 4.15 - 3,99 (m, 2H), 3.88 - 3.61 (m, 6H), 3.31 (d, 1 4 3 Hz, I H), 3.15 (dd, ./ ' ⁾ 4. 15.1 Hz, 1H), 2.85 - 2,70 (m, 3H), 2.70 - 2.54 (m, IH), 2.47 - 2.25 (m, 2H), 2.20 - 2.06 (m, 3H), 2.04 - 1.60 (m, 9H), 1.48 - 1.33 i ns. 4H). m/z (ESI, +ve ion) 671.3 { M · Π } .

EXAMPLE 55. (l S,3'R,6'R,7'S,8'E,irR)-6-CHLOR()-7'-HYDROXY-ir- METHYL-12'-((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DlHYDRO- 2H, 15 Ή-S PIRO [N ΑΡΗΤΉ ALENE- 1..?..?.'-

[20]ΟΧΑ[13]ΊΉΙΑ[1, 12, 14]ΤΚΙΑΖΑΤΕΤΚΑΟΥΟΧΟ[14.7.2.0 - ⁶ .0 ¹⁹ · ²⁴ ]ΡΕΝΤΑΟ

OSA[8, 16, 1 8,24 jTETRAEN]- 15'-ONE 13', 13'-DIOXIDE

STEP : TERT-BUTYL N-((R)-PENT-4-EN-2-YL)-N-(((R)-

TETRAHYDROFURAN-2-YL) METHYL) SULFAMOYLCARBAMATE

The title compound was prepared from (R)-N-(((R)-tetrahydrofuran-2-yl) methyl) pent-4-en-2-amine by a procedure similar to the one described in Example 29, Step 1 (0.73 g, 2.10 mmol, 36.4% yield).

STEP 2: N-(R)-PENT-4-EN-2-YL, N-(R)-TETRAHYDROFURAN-2-YL SULFURIC DIAMIDE

The title compound was prepared from tert-butyl N-((R)-pent-4-en-2-yl)- N-(((R)-tetrahydrofuran-2-yl) methyl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 (0.513 g, 2.06 mmol, 99% crude yield). STEP 3: (S)-6'-CHLORO-5-((( lR,2R)-2-((S)-i-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(N-((R)-PENT-4-EN-2-YL) - N-(((R)"TCTRAHYDROFUR/ N-2-YL)MEraYL)SULFAMOYL)-3',4,4',5" TETRAHYDRO-2H,2'H-SPIRO j BENZO [B] [ 1 ,4 ] OXAZEPINE-3 , 1 '-

NAPHTHALENE] -7-C ARBOXAMIDE

The title compound was prepared from intermediate AA11 A and N~(R)~ pent-4-en-2-yl, N-(R)-tetrahydrofuran-2-yl sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (65 mg, 0.093 mmol, 62.2% yield). STEP 4: (1 S,3'R,6'R,7'S,8'E, 1 1 'R)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL- i 2 -C i 2R }~ 1 1 : 1 RAi IY DR O-2-R R AW 5 M i l l IY I . )-3. l-i)H i V ORO-2! 1. 1 1 l- SP1RO [NAPHTHALENE- i . - [20]OXA[ 13]raiA[U2, 14]TTOAZATE^

OSA[8, 16 ₅ 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)- l - hydroxyallyl)cyclobut\'l)methyl)-N-(N-((R)-pent-4-en-2-yl)-N -(((R)- tetraliydrofuraii-2-yl)methyi)suifamoyl)-3',4,4',5-tetrahydr o-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide by a procedure similar to the one described in Example 29, Step 4 and was isoalted via preparative HPLC as the first elutmg isomer (14 mg, 0.021 mmol, 22.4% yield). ¾ NMR (400MHz, CDCb) δ 8.82 (hr. s, IH), 7.71 (d, ./ 8.6 Hz, !!!).7.19 (d, ./ 7.9 Hz, IH), 7.11 (d, ,/ 2.3 Hz, 2H), 7.02 (d, ,/ H4 Hz, IH), 6.93 (d, J=8.0 Hz, IH), 5.84 (br. s, IH), 5.73 (br. s, IH), 4.27 - 4.05 (m, 4H), 3.91 (q, ./ 7.0 Hz, IH), 3.84 - 3.69 (m, 3H), 3.66 - 3.50 (m, 3H), 3.44 (d, ./ 1.17 Hz, 2H), 2.84 ·· 2.73 (m, 2H), 2.66 (t, ./ 10.9 Hz, IH), 2.42 (br. s, 3H), 2.31 (br. s, 3H), 2.26 - 2.14 (m, 2H), 2,07 (br. s, ill).2,01 - 1,77 (m, 3H), 1.76 - 1.51 (m, 4H), 1,47 id../ 6.8 Hz, l). m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 56. (lS,3 ^, R,6'R,7 ^! S,8'Z,ll'R)-6-CHLORO-7'-HYDROXY-ll'- METHYL-12'-((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [N APHTH ALENE- 1.22'-

[20]OXA[13]THIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16,18,24jTETRAEN]-l 5'-ONE 13', 13'-DIOXIDE

The title compound was prepared as the from the reaction described in Example 55, Step 4 and it was isolated via preparative HPLC as the second eiuting isomer (4.2 mg, 6.27 μηιοΐ, 6.73% yield). ¾ NMR (400MHz, CDCb) δ 10.55 (br. s, IH), 7.76 (d,■/ K.6 Hz, IH), 7.53 (d, ,/ 8.6 Hz, IH), 7.30 (s, IH), 7.20 (dd, J=2,3, 8.4 Hz, IH), 7.11 (d, J=2.2 Hz, IH), 6.98 (d, «/=8.4 Hz, IH), 5.84 {di. 4.9.11.1 Hz, IH), 5.68 (dd,J=7.4, 10.8 Hz, IH), 4.43 (t, J=7.3 Hz, IH), 4.26 (d, ./ 7, ϊ Hz, !!!).4.20 - 4.04 (m, 2H), 3.98 - 3.84 (m, 3H), 3.77 (dt, ./ 6.3. 7,9 Hz, IH), 3,66 (d, 14.3 Hz, ill).3.51 (dd, ./ 8.7.15.0 Hz, IH), 3.40 (d, ,/ 147 Hz, III).3.21 (d, ,/ i-U Hz, !!!}.3.11 (dd, J=9.0, 15.3 Hz, 2H), 2.86 - 2.72 (m, 2H), 2.63 - 2.36 (m, 1H), 2.33 - 2.15 (m, 3H), 2.13 - 1.90 (m, 6H), 1.88 - 1.79 (m, 2H), 1.71 - 1.44 (m, 7H). m /. (ESI, +ve son) 671.3 (M ·!!:· .

EXAMPLE 57. (1S,3'R,6'R,7'S,8'E,1 rS)-6-CHLORO-12'-ETHYL-7 ^! - HYDROXY- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTHALENE- 1,22'~

|2()jOXA| !3jTIUA| ί.Ι2.!4| |-R!AZA ^' S ^' 1 ^: TRA( ^' YC!.()| 14.7.2.ίί ^; ".ί! ^! " ^¾! |! :N ! AC OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13', 13'-DIOXTDE

STEP 1 : (S)-TERT-BUTYL N-ETHYL-N ^■ T-4-EN-2~YL)

SULFAMOYLCARBAMATE

The title compound was prepared from (S)-N-ethylpent-4-en-2-amine by procedure simialr to the one described in Example 29, Step 1 (2.6 g, 8.89 mmol, 46.0% yield).

STEP 2: N-(S)-PENT-4-EN-2-YL, N-ETHYL SULFURIC DIAMIDE The title compound was prepared from (S)-tert-butyl N-ethyl-N-(pent-4- en-2-yl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 (1.8 g, 9.36 mmol).

STEP 3: (S)-6'-CHLORO-N-(N-ETHYL-N-((S)-PE T-4-EN-2- YL)SULFAMOYL)-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-

2H,2'H-SPIRO[BENZO[B] [ l,4]OXAZEPINE-3, -NAPHTHALENE]-7-

CARBOXAMTDE

The title compound was prepared from Intermediate AA11 A and N~(S)~ pent~4-en-2~yl, N~ethyl sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (117 nig, 0.182 mmol, 83% yield).

STEP 4: (1 S,3'R,6'R,7'S,8'E,1 l ^, S)-6-CHLORO-12 ^, -ETHYL-7 ^, -HYDROXY-l l'- METOYL-3,4-DIHYDRO-2Il,15'H-SPTRO| JAPHTHALENE-! ,22'- [20]OXA[13]THIA[1 ^2, 14]TRIAZATETOACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-N-(N-ethyl-N-((S)- pent-4-en-2-yl)sdfamoyl)-5-(((lR,2R)-2-((S)-l-hydroxyallyl)c ^xlobutyl)memyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxamide by a procedure similar to the one described in Example 29, Step 4 and it was isolated via preparative HPLC as the first eluting isomer (48 mg, 0.078 mmol, 42,9% yield), ^] H NMR (400MHz, ( f)Ch ) δ 8.66 (br. s, I I I ). 7.69 id. J=8.6 Hz, 1H), 7, 17 (dd, .7=2.2, 8.5 Hz, 1H), 7.12 - 7.04 (m, 2H), 7.00 - 6,82 (m, 2H), 5.79 - 5.59 (m, 2H), 4.16 - 4.03 (m, 3H), 3.98 - 3.79 (m, 2H), 3.76 - 3.58 (m, 2H), 3,58 - 3.41 (m, 2H), 3.39 - 3.23 (m, 2H), 3,16 (dd,J=6.1, 14.7 Hz, 111).2,83 - 2.69 (m, 2H), 2.51 - 2.26 (m, 4H), 2.01 ·· 1.75 (m, 4H), 1.73 - 1.62 (m, 2H), 1.49 - 1.24 (m, 7H). n z (ESI, +ve ion) 615.2 (M il) ^' .

EXAMPLE 58. (1S,3'R,6'R,7'S,8'Z,1 rS)-6-CHLORO-12'-ETHYL-7'- HYDROXY- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTHALENE-

1,22'~

|2ujOXA| 13ΓΗ!!Λ| U2.14| Πί!ΛΧΛΤ1ΤΚΛίΎΠ.()| Ι4.7.2.0 ⁵ ·'·.0 ^, "·· |Ρΐ:ΝΊ ^' Λ( ^' OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared as from the reaction described in

Example 57, Step 4 and it was isolated via preparative HPLC as the second efuting isomer (5 mg, 8.14 μηιοΐ, 4.47% yield). ^! H NMR (400MHz, CDCh) δ 8.93 (br. s, 1H), 7.69 (d, J=8.4 Hz, H), 7.22 - 7,07 (m, 3H), 6.99 - 6.89 (m, H), 6.82 (br. s, IH), 5.78 - 5.63 (m, IH), 5.58 - 5.50 (m, IH), 4.58 (dd, ./ 4.6.8.1 Hz, IH), 4.23 - 3.96 (m, 2H), 3.93 - 3.77 (m, 2H), 3.76 - 3.50 (m, 3H), 3.40 - 3.14 (m, 2H), 2,86 - 2.72 (m, 2H), 2.63 (br. s, 2H), 2.51 - 2.34 (ra, H), 2,32 - 2,17 (m, IH), 2.06 - 1.97 (m, 2H), 1.94 (br. s, 2H), 1.90 - 1.66 (m, ill).1,52 - 1.29 (m, 111) m/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 59. (1S,3'R,6'R,7 ^! S,8'E,1 l'R^e-CHLORO- '-ETHYL^'- HYDROXY-ll'-METHYL-3,4-DIHYDRO-2H.15H-SPIRO[NAPHTHALE E- 1,22'-

|2ίί )ΧΛ| 13ΓΠ!!Λ| ί.Ι2.!4| |-R!AZA ^' S ^' 1 ^: TRA( ^' YC!.()| 14,7.2.is ⁱ '·.0 ^{)Μ Μ} |ΡΙ;ΝΤΛ( ^' OSA[8.16,18 ₅ 24]TETRAEN]-15'-ONE 13'.13'-DIOXIDE

STEP 1 : (R)-TERT-BUTYL N-ETHYL-N-(PENT-4-EN-

SULFAMOYLCARBAMATE

The title compound was prepared from (R)-N-ethylpent-4-en-2-amine by a procedure similar to the one described in Example 29, Step 1 (1.25 g, 4.28 mmol, 38,4% yield).

STEP 2: N-(R)-PENT-4-EN-2-YL, N-ETHYL SULFURIC DIAMIDE

The title compound was prepared from (R)-tert-butyl N-ethyl-N-(pent-4- en-2-yl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 (0.816 g, 4.24 mmol, 99% yield).

STEP 3. (S)-6'-CHLORO-N-(N-ETHYL-N-((R)-PE T-4-E -2- YL)SULFAMOYL)-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)]V-ETHYL)-3 ^, ,4 ₅ 4 ^, ,5-TETRAHYDRO-

2H,2'H-SPIR()|;BENZO[B| [ l,4]OXAZEPINE-3,l ^, -NAPHTHALENE]-7- CARBOXAMTDE

The title compound was prepared from Intermediate AA11A and N~(R)~ pent~4-en-2~yl, N~ethyl sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (147 mg, 0.229 mmol, 71.4% yield). STEP 4: (1 S,3'R,6'R,7'S,8'E,1 l 'R)-6-CHLORO-12'-ETHYL-7' iYDROXY-ir- METHYL-3,4-DlHYDRO-2H,15^SPIRO|NAPHTHALENE-.l ,22'- [20]OXA[13]THIA[l ,12, 14]Ti AZATETOACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-N-(N-ethyl-N-((R)- pent-4-en-2-yl)sulfamoyl)-5-(((lR,2R)-2-((S)-l-hyd

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxamide by a procedure similar to the one described in Example 29, Step 4 and it was isolated via preparative HPLC as the first eluting isomer (37 mg, 0.060 mmol, 25.8% yield), ^] H NMR (400MHz, CDCh) δ 8.39 (s, I H ). 7.69 (d, ./ 8.4 Hz, IH), 7.30 (s, IH), 7.19 (t, J=6.7 Hz, IH), 7.1 1 (d, J=2.2 Hz, IH), 6,99 - 6.86 (m, 2H), 5.78 - 5.59 (m, 2H), 4.26 - 4.02 (m, 3H), 3.90 C or. s, IH), 3.81 - 3.61 (m, i l l ). 3.53 (br. s, 2H), 3.50 - 3.27 (m, 2H), 2.79 (d, ./ 5.3 Hz, 2H), 2.63 - 2.35 (m, 6H), 2.26 (td, ,/ 5.6. 15,3 Hz, ! H), 1.96 - 1.70 (m, 5H), 1.63 (br. s, IH), 1.56 (d, J=7.0 Hz, IH), 1.47 - 1.27 (m, 6H). m'z (ESI, +ve ion) 615.2 (M+H) ⁺ . EXAMPLE 60. (IS^' ^'R^'S^'ZJ l'Ri-e-CHLO O- '-ETHYL^'-

HYDROXY-1 1 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- l. -

[20]OXA[ 13]TOIA[ l,12,14]TRlAZATETiL CYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A[8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 59, Step 4 and it was isolated via preparative HPLC as the second eluting isomer (11 mg, 0.018 mmol, 7.67%yield). H NMR (400MHz, CDCb) δ 10.46 (s, 1H), 7.68 (d, ,7=8,6 Hz, H), 7.54 (dd, .7=2.0, 8.4 Hz, 1H), 7.24 (d, «/=1.8 Hz, 1H), 7.15 (t, ./ 7 ! Hz, 1H), 7.08 (d, J=5.5 Hz, ill).6.94 (d, J=8.2 Hz, 1H), 5.82 (d, ./ 5.3 Hz, ill .5.66 (dd../ 7.1.10.3 Hz, 1H), 4.34 { L ./ 8.! Hz, IH), 4.16 - 3.96 (m, Ml).3,90 (d, ./ ! 1.7 Hz, ill).3.78 (d, 14.9 Hz, 111).3.50 (d, ./ 1 I Hz, IH), 3.12 (dd, J=7.2, 15.1 Hz, IH), 3.03 - 2.90 (m, 2H), 2,82 - 2.67 (m, 3H), 2.37 (br, s, 3H), 2.32 - 2.19 (m, IH), 2.16 - 1.96 (ni, 3H), 1.94 - 1.70 (m, 4H), 1.64 (dd, ./ 8.3.10.1 Hz, IH), 1.44 - 1.26 (m, 611 ·. m/z (ESI, +ve ion) 615.2 (M+H)+.

EXAMPLE 61. (1 S,3 ^, R,6 ^, R ₅ 7 ^, S,8'E,ll ^, S)-6-CHLORO-7 ^, -HYDROXY-l 1"- METHYL-3,4-DIHYDRO-2H,15^SPIRO|NAPHTHAL-ENE-l,22'- [20]OXA[13] ^r rHIA[l,12,14]TRJAZATETRACYCLO[14.7.2.0 - ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16,18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

STEP 1: (R)-PENT-4-EN-2-Y NESULFONATE To a solution of 4-methylbenzene-l-sulfonyl chloride (24.3 g, 128 mmol) and 4-(dimethylamino)pyridine (1.42 g, 11.6 mmol) in DCM (300 mL) was added triethylamine (reageniplus 99.5%, 32.3 mL, 232 mmol) at 0 °C followed by the addition of a solution of (R)-(-)-4-penten-2-ol (1 1.9 mL, 1 16 mmol) in DCM (60 mL) dropwise over 15 minutes using an addition funnel. The reaction was stirred at ambient temperature for 45 hours. The reaction was diluted with DCM and washed with saturated NaHCC , water and brine. The DCM solution was dried with MgS04, filtered and then concentrated to give a residue which was purified by silica gel chromatography using Redi-Sep pre-packed Gold silica gel column (300 g) to afford the title compound (23 g, 96 mmol, 82 % yield) as a liquid.

STEP 2: (S)-N-(4-METHOXYBENZYL) PENT-4-EN-2- AMINE

To a solution of (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (5.42 g, 22.6 mmol) in dioxane (17 mL) was added 4-methoxybenzyiamine (5.85 mL, 45.1 mmol) and triethylamine (3.78 mL, 27.1 mmol) in a pressure vessel equipped with a pressure gauge and the resulting mixture was purged with N ₂ for about 20 minutes. The reaction was heated at 90 °C for 41 hours. The reaction was filtered to remove precipitate produced in the reaction and concentrated to give a residue, which was purified by silica gel chromatography using Redi-Sep pre-packed Gold silica gel column (220 g) eluting with 0-100% of EtOAc in hexane to afford the title compound (3.23 g, 15.73 mmol, 69.8 % yield).

STEP 3: (S)-TERT-BUTYL N-(4-METHOXYBENZYL)-N-(PENT-4-EN-2-YL)

SULFAMOYLCARBAMATE

The title compound was prepared from (s)-N-(4-methoxybenzyl) pent-4- en-2-amine by a procedure similar to the one described in Example 29, Step 1 (4.65 g, 12,0 mmol, 77% yield).

STEP 4: N-iS)~PENT-4-EN-2-YL SULFURIC DIAMIDE

0= =sS==.0

H ₂

The title compound was prepared from (5)~tert-butyl N-(4- methoxybenzyl)-N~(pent~4-en~2~yl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 (1.76 g, 10.7 mmol, 92% yield).

STEP 5: (5)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(N-((S)-PENT-4-EN-2-

YL)SULFAMOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OX, ZEPI E-3, 1 '-NAPHTHALENE] - 7- CARBOXAMIDE

The title compound was prepared from Intermediate AA1 1 A and N-(5)- pent-4-en-2-yl sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (1.25 g, 2.04 mmol, 87% yield).

STEP 6: (lS,3 ^* R,6'R,7'S,8'E,i rS)-6-CHLQRQ-7 ^! -HYDROXY-l l '-METHYL-3,4- DIHYDRO~2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1, 12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[8, 16,18,24jTETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox 'ally])cyclobutyl)methyl)-N-(N-((S)-pent-4-en-2-yl)sulfamoyl )-3' _^ tetrahy dro-2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxamide by a procedure similar to the one described in Example 29, Step 4 (641 nig, 1.09 mmol, 50.1% yield). ¾ NMR (4()0MHz, CD3OD) δ 7.65 (d, ,/ 8.6 Hz, 1 H), 7.11 (dd, .7=2.2, 8.5 Hz, IH), 7.04 id . «/=2.2 Hz, 1H), 6.92 - 6.83 (m, 2H), 6,76 (d, J=1.8 Hz, IH), 5.86 - 5.78 (m, IH), 5.61 (dd, J=8.7, 15.2 Hz, IH), 4.16 (dd, ./ 3.9. 8.8 Hz, 21 1 ). 3.76 id. ./ I 5. 1 Hz, IH), 3.67 - 3.53 (m, 2H), 3.15 (d, ./ 14.3 Hz, IH), 2,94 (dd. ./ 10.0. 15.3 Hz, IH), 2.80 - 2.65 (m, 2H), 2.50 - 2,40 (m, IH), 2,40 - 2.30 (m, IH), 2.25 - 2. 12 (m, IH), 2,06 - 1.86 (m, 5H), 1.76 (qd, J=9,6, 19.0 Hz, 3H), 1.67 - 1.53 (m, IH), 1.43 - 1.26 (m, IH), 1 ,23 - 1.15 (m, 3H). m/z (ESI, +ve ion) 587.2 ( \\ · ! ! ) ^' . EXAMPLE 62. (1 S,3'R,6'R,7'S,8'Z, 11 ^* S)-6-CHLORO-7 ^* -HYDROXY- 1 1 "- METHYL-3,4-DIHYDRO-2H,15^SPIRO|NAPHTHAL-ENE-l,22'- | 2u jOXA| 1 3 ΓΗ ! !Λ| U 2J 4 | T!U AXATiTRACYCLOI 14.7.2.0 * '\0 ^{) Μ} ^ΡίίΝΤΑί ^' OSA[8, 16,18,24]TETRAEN]-15'-ONE 13', 13 ^! -DI()XIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cydobutyl)methy

tetrahydro-2H,2H-spiro benzo b]| ,4]oxazepine-3,r-naphmalene]-7-carboxamide

(Example 61, step 5) by a procedure similar to the one described in Example 29, Step 4 and it was isolated via preparative HPLC as the second eluting isomer (25 nig, 0.043 mmol, 2.10% yield). *H NMR (4GGMHz, CD3OD) δ 7.72 (d, J=8.4 Hz, HI).7.15 (dd, ./ 2.2.8.5 Hz, III).7.08 (d, ,/ 2.2 Hz, 1H), 7.03 - 6.98 (m, Hi). 6,96 - 6.87 {Ml.2H), 5.69 - 5.59 (m, ill).5,57-5.5! (m, III).4.47 (dd, J=4.1, 9.0 Hz, IH), 4,15 - 3,98 (m, 2H), 3.93 (d, J=15.3 Hz, IH), 3.70 (d, .7=14.1 Hz, H), 3.58 - 3.40 (m, 2H), 3.18 (dd, ./ 9.K.15.3 Hz, IH), 2.86 - 2.70 (m, 211:·.2.58 -

2,35 (m, 31!}.2.21 (t, J=8.2 Hz, H), 2.10 (d, ./ 13.7 Hz, ill).2.03 - 1,82 (m, 5H), 1.80 - 1.70 (m, ill).1,45 (br. s, ill).1.31 - 1,22 (m, 3H). m (ESI, +ve ion) 587.2 (M+H) ⁺ .

EXAMPLE 63. (1S,3'R,6'R,7 ^* S,8'Z,1 l'S)-6-CHLORO-7'-HYDROXY-12 ^, -(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TOlA[l,12,14]I¾lAZATCTiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

To a solution of Example 62 (24 mg, 0.043 mmol) in DMF (0.5 mL) was added sodium hydride (11.7 mg, 0.341 mmol) and the reaction was stirred at 0 °C for 15 minutes followed by the addition of l-bromo-2-methox ethane (0.020 mL, 0.213 mmol). The resulting mixture was stirred at ambient temperature for 2,5 days. The reaction was quenched with saturated NH4CI and extracted with EtOAc. The organic extract was washed with brine, dried with MgS0 ₄ , filtered and concentrated to give a residue, which was purified by reversed phase preparative HPLC (Gemini™ Prep Cie 5 μιη column; Phenomenex, Torrance, CA; gradient eluiion of 60% to 85% MeCN in water, where both solvents contain 0, 1 % TFA, 30 min method) to afford the title compound as the first elutmg isomer (1.3 mg, 2.02 μηιοΐ, 4.73% yield). ¾ NMR (400MHz, CDCh) δ 9.15 (s, lH), 7.68 (d, ./ K.6 Hz, 1H), 7.22 - 7.12 i ns. 2H), 7.11 - 7.04 (m, I I I ). 6.92 (d, ./ 8.2 Hz, i l l . 6,84 (s, 1H), 5,76 - 5.62 (m, 1 H), 5.62 - 5.47 (m, IH), 4,61 - 4.47 (m, 1 H), 4.14 - 4,00 (m, 2H), 3.98 - 3.88 (m, H), 3.82 - 3,56 (m, 6H), 3.38 (s, 3H), 3.34 - 3.17 (m, IH), 2.88 - 2.71 (m, 2H), 2,71 - 2.55 (m, 2H), 2.48 - 2.35 (m, IH), 2,25 (quin, ./ 8. 1 Hz, IH), 2.1 1 - 1.81 (rn, 6H), 1.79 - 1.63 (m, 2H), 1.52 - 1.33 (rn, 5H). m/z (ESI, +ve ion) 645.2 (M+H) ⁺ .

EXAMPLE 64. (1S,3'R,6 ^! R,7 ^* S,8'Z, 1 l'S)-6-CHLORO-7'-(2- METHOXYETHOXY)- 1 1 '-METHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO[NAPHTHALENE-l,22 ^, -

[20]OXA[13]TOlA[ l,12,14]I¾lAZATCTiLACYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A 8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 63 and was isolated via preparative HPLC as the second eluting isomer (3.3 mg, 5.12 μηιοΐ, 12.0% yield). ¾ NMR (400MHz, CDCh) δ 9.58 (br. s, IH), 7.79 - 7,63 (m, IH), 7.26 - 7.14 (m, 2H), 7.13 - 7,01 (m, 2H), 6.98 - 6.91 (m, IH), 6.03 (br, s, IH), 5,79 - 5.52 (m, 2H), 4.32 - 3.98 (m, 3H), 3,93 - 3.75 (m, 2H), 3.67 (d, J=4.9 Hz, 2Π ). 3.53 (br. s, 2H), 3.42 - 3.28 (ra, 4H), 3,28 - 3. 15 (m, I I I ). 3.07 (br. s, 1H), 2.86 - 2.67 (m, 2H), 2.62 - 2.37 (m, 2H), 2.34 - 2.20 (m, i l l s. 2.11 is. I l l s. 2, 11 - 1.88 (m, 3H), 1.82 (br. s, 1H), 1.72 - 1.39 (m, 3H), 1.32 - 1.18 (m, 5H). m/z (ESI, +ve ion) 645.2 (M+H) ⁺ .

EXAMPLE 65. (1S,3'R,6 ^! R,7'S,8'Z,1 l'S)~6~CHLORO-7'~(2~

METHOX YETHOXY)- 12'-(2-METHOXYETHYL) - 11 '-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[l,12, 14]Ti AZATETOACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OS A[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 63 and it was isolated via preparative HPLC as the third eluting component (9.2 nig, 0.013 mmol, 30.7% yield). ¾ NMR (4GGMHz, CDCb) δ 8.95 (br. s, 1H), 7.70 (d, ./ 8.4 Hz, ! ! ! ). 7.18 (dd, ,/ 2.3. 8.4 Hz, 1H), 7.13 - 7.01 (m, 2H), 6.98 - 6,86 (m, IH), 6.74 (br, s, 1H), 5.67 - 5.42 (m, 2H), 4. 19 - 3,98 (m, 3H), 3.97 - 3.71 (m, 4H), 3.70 - 3.56 (m, il l ). 3,49 (d, ./ 3.7 Hz, IH), 3.43 - 3.28 (m, 9H), 3.24 - 3.23 (m, IH), 2.88 - 2.64 (m, 3H), 2.63 - 2.47 (m, 2H), 2.24 (dt, J=3.0, 8.4 Hz, IH), 2.11 - 1.74 (m, 6H), 1.73 - 1.59 (m, IH), 1.51 - 1.32 (m, 4H). m/z (ESI, +ve ion) 703.2 (M+H) ⁺ .

EXAMPLE 66. (I S^'R^'l^T'S^'E l'S^e-CHLORO^'-HYDROXY-l l'- METHYL-12'-(2-(4-MORPHOLINYL)ETHYL)-3,4-DIHYDRO-2H,15TI- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1 ,12 4]TRIAZATCTTIACYCLO[14 .2 ³ '* 0 ¹⁹ - ²⁴ ]PEOTAC OSA[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13', 13'-DIOXIDE

STEP 1 : 2-MORPHOLINOETHYL 4-METHYLBENZENESLlLFONATE

The title compound was prepared from 4-(2-hydroxy ethyl) morpholine by a procedure similar to the one described in Example 61, Step 1 (0.77 g, 2.7 mmoi, 35,4% yield).

STEP 2: (1 S,3'R,6'R,7'S,8'E,1 l 'S)-6-CHLORO-7'-[(TERT- BUTYLDIMETHYLSILY)OXY]-i -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1,22'-

[20]OXA[13]TOIA[ 1 2,14]TT TAZATETRACYCLO[ 147.2.0 ³ "« 0 ¹⁹ ' ²⁴ ]PE TAC OS A[ 8, 16, 18,24]TETRAEN] - 15 '-ONE 13 13 '-DIOXIDE

The title compound was prepared from Example 61 by a procedure similar to the one described in Example 31, Step 1 (570 mg, 0.814 mmoi, 74.4% yield). STEP 3: (1 S,3'R,6'R,7'S,8'E,1 rS^-CHLORO-T-HYDROXY-ir-METHYL-l T- (2-(4-MORPHOLlNYL)ETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1,12,14]TRTAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTAC OSAI 8.16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

To a solution

butyldimethylsily)oxy]-l r-memyl-3,4-dihydro-2H,15H-spiro[naphmalene-l,22'- [20]oxa[ 13]thia[ 1, 12, 14]triazatetracy clo[ 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tet raenj-15'-one 13 ',13 '-dioxide (30 mg, 0.043 mmol) in THF (0.8 mL) was added lithium bis(trimethylsilyl) amide, 1.0 M solution in THF (0.171 mL, 0.171 mmol) and the reaction was stirred at 0 °C for 10 minutes followed by addition of a solution of 2-morpholinoethyl 4-methylbenzenesulfonate (36.7 mg, 0.128 mmol) in THF (0.32 mL). The resulting mixture was then transferred to an oven-dried microwave tube under N2 atmosphere. The reaction was stirred at 120 °C for 4 hours in a microwave. The reaction was diluted with THF (0.8 mL) and treated with tetrabutylammonium fluoride solution, 1.0 M in THF (0.857 mL, 0.857 mmol) and a small amout of molecular sieves at 55 °C for 1 hour in microwave. Without workup the reaction was concentrated to give a residue, which was purified by reversed phase preparative HPLC (Gemini™ Prep Cis 5 urn column; Phenomenex, Torrance, CA) to afford the title compound (1.4 mg, 2.00 μηιοΐ,

4.67% yield). Ή NMR (400MHz, CD3OD) δ 7.79 - 7.65 (m, I I I ). 7.23 - 7.06 (m, 3H), 7,01 - 6.86 (m, 2H), 5.76 - 5.48 (m, 2H), 4,30 - 3.87 (m, 9H), 3.83 - 3.70 (m, 3H), 3.68 - 3.55 (m, 3H), 3.24 - 3.05 (m, 3H), 2.93 - 2.66 (m, 2H), 2.55 - 2.21 (m, 4H), 2.15 - 1.79 (m, 8H), 1.79 - 1.59 (m, 1H), 1.38 - 1.24 (m, 4H). m!z (ESI, +ve ion) 700.0 (M+H) ⁺ .

EXAMPLE 67. (1 S,3'R,6'R,7'S,8'E,1 l ^* S)-6-CHLORO-l l'-METHYL-7'-(2-(4- MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l ,12 4]TRIAZATCTTlACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PE3SnrAC OSA[8, 16,18,24]TETRAEN]-15'-ONE 13', 13'-DIOXJDE

The title compound was prepared from Example 61 and 4-(2-chloroethyl) morpholine hydrochloride by a procedure similar to the one described in Example 46. ^; l l NMR (400MHz, CD3OD) δ 7.73 - 7.71 (d, ./ 8.4 Hz, 1H), 7.27 - 7.07 (m, 3H), 7.03 - 6.88 (m, 2H), 5.72 - 5.49 (m, 2H), 4.29 - 3.95 (m, 8H), 3.86 - 3.69 (m, 3H), 3.67 - 3.53 (m, 3H), 3,49 - 3.47 (m, 2H), 3.19 - 3.12 (m, 2H), 2.88 - 2.65 (m, 2H), 2.53 ·· 2.19 (ni, 4H), 2.14 - 2.00 (m, 2H), 1.97 - 1.78 (ni, 4H), 1.76 - 1.62 (m, 2H), 1.55 - 1.17 { in. 2H), 1.05 - 0.78 i ns. 4H). m!z (ESI, +ve ion) 700.2 (M+H) ⁺ .

EXAMPLE 68. (1S,3'R,6'R,7'S,8'E,1 l'S)-6-CHLORO-7'-(2- METHOXYETHOXY)- 1 1 ^f -METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THlA[ l,12,14]TRlAZATEmACYCLO[ 14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ ]l TAC OS A 8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from Example 61 by a procedure similar to the one described in Example 63 and it was isolated via preparative HPLC as the second eluting isomer (5.2 mg, 8.07 μηιοΐ, 1 1.5% yield). ¾ NMR (4()0MHz, CD3OD) δ 7.72 (d, 8 6 Hz, 1H), 7.16 (dd, ./ 2 2. 8.5 Hz, 1H), 7,09 (d, ./ 2.2 Hz, ill).6,95 - 6.87 (m, 2H), 6.82 (d, 1.6 Hz, ill).6.02 - 5,94 (m, Hi).5.55 (dd, J=9.5, 15.4 Hz, 111).4.09 - 4.00 (m, 2H), 3.92 - 3.77 (m, 2H), 3.71 - 3.43 (m, 6H), 3.36 (s, 3H), 3.23 (d. ,/ 14.3 Hz, 1H), 3.04 (dd, J=10.3, 15.2 Hz, ill).2.85 - 2.70 (m, 2H), 2,61 id../ 13.7 Hz, 1H), 2.54 - 2.45 (m, !!!}.2.25 !!.,/ 9011/.1H), 2.16 - 2,03 (m, 2H), 1.96 - 1.76 (m, 5H), 1.74 - 1,67 (m, Ui).1.47 - 1.31 (m, IH), 1.20 (d,■/ 6.8 Hz, 3H). m/z (ESI, +ve ion) 645.2 (M il

EXAMPLE 69. (1S,3'R,6'R,7 ^* S,8'E,1 l'S)-6-CHLORO-7'-(2- METHOXYETHOXY)- 12'-(2-METHOXYETHYL)- 11 *-METHYL-3 ,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THlA[l,12,14]I¾lAZATETiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A 8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 68 and it was isolated via preparative HPLC as the third eluting component (9,2 nig, 0.013 mmol, 18.7% yield). *H NMR (400MHz, CD3OD) δ 7.71 (d, J=8.6 Hz, IH).7.14 (d, ,/ 8.1 Hz, 111).7.08 (s, 111).6.97 (m, 1H), 6.91 - 6.85 (m, 2H), 5.79 (id, ./ 6.4.15.5 Hz, IH), 5.54 (dd, 85.15,6 Hz, IH), 4.10 (br. s., 2H), 4,02 - 3,95 (m, IH), 3.89 - 3.70 (m, 3H), 3.66 - 3,54 (m, 4H), 3.51-3.38 (m, 4H), 3,37 (s, 3H), 3.35 (s, 311).3.27-3.24 id../ 14.3 Hz, III).3.10 (dd, ./ 9.4.15.5 Hz, IH), 2,84 - 2.70 ins.211).2,51 - 2.29 (m, 4H), 2,07 id. ,/ 1 7 Hz, IH), 1.98 - 1,76 (m, 5H), 1.67 (q, .7=9,4 Hz, IH), 1.50 - 1,38 (m, IH), 1.33 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 703.2 (M il) .

EXAMPLE 70. METHYL 3-(((lS,3'R,6'R,7'S,8'E,l l'S)-6-CHLORO-l 1'- METOYL-13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THlA[l,12J4]TRlAZATETiLACYCLO[14 .2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTAC OS A[8, 16, 18,24]TETRAEN]-7'-YL)OXY) PROPANOATE

The title compound was prepared from Example 61 and methyl 3- bromopropanoate by a procedure similar to the one described in Example 63. ¾ NMR (400MHz, CDCb) δ 8.42 (s, III).7.70 (d, J=8.4 Hz, IH), 7.18 (dd, ./ 2.2. 8.5 Hz, IH), 7.09 (d, «7=2.2 Hz, 1H), 6.97 - 6.89 (m, IH), 6,87 - 6,79 (m, 2H), 5.96

- 5,84 (m, IH), 5.66 (d, J=7,6 Hz, IH), 5.56 (dd, J=9.2, 15.3 Hz, IH), 4,15 - 4.00 {in.2H), 3.88 - 3.65 (m, 7H), 3.58 (id, ./ 6.3.9.7 Hz, IH), 3.19 (d, ,/ 14.3 Hz,

IH), 2,98 (dd, ./ iO.i.15.2 Hz, IH), 2.86 - 2.67 (ra, 2H), 2,62 - 2,49 (m, 3H), 2,49

- 2.33 (m, H), 2.24 (quin, .7=9,2 Hz, IH), 2.18 - 2.09 (m, IH), 2,07 - 2.00 (m, IH), 2.00 - 1.90 (m, 2H), 1.87 - 1.67 (m, 3H), 1.66 - 1.54 (m, 2H), 1.39 (t, ./ 13,3 Hz, IH), 1.32 - 1.20 (m, 3H). m/z (ESI, +ve ion) 673.2 ! M l!) ^' EXAMPLE 71. (1 S,3'R,6 ⁱ R,7'S,8'E,ri'R)-6-CHLORO-7 ⁱ -HYDROXY-l l'- METHYL-3,4-DIHYDRO-2H,15^SPIRO|NAPHTHAL-ENE-l,22'- |2ujOXA| 13ΓΗ!!Λ| U2J4|TR!AXATiTRAi ^' Yi ^' !.(}| i 4,7.2.0* ' ^' ,0 ^{)Μ ' !} |Ρί:Ν ! Αί ^' OSA[8.16,18 ₅ 24]TETRAEN]-15'-ONE 13',13 ^! -DI()XIDE

The title compound was prepared from the reaction described in Example 62 and it was isolated via preparative HPLC as the first elutmg isomer (58 mg, 0.099 mmol, 4.86% ield). ^! H NMR (400MHz, CDsOD) δ 7.71 (d, ./ 8.4 Hz, ill) 7.15 (dd, ,/ 23.8.4 Hz, ill).7,08 (d, ./ 2.2 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.91 - 6.87 (m, IH), 6.06 - 5,97 (m, IH), 5.61 (dd, .7=6.2, 15,4 Hz, 1H), 4.13 - 4,01 (m, 3H), 3.71 - 3.54 (ni, 3H), 3.26 - 3.12 (m, IH), 2.86 - 2.70 (ni, 2H), 2.53 (t, J=9A Hz, IH), 2.41 - 2.19 (m, Ml).2.04 (d, ./ 13.7 Hz, IH), 1.98 - 1.77 (m, 6H), 1.72 - 1,67 (m, IH), 1.57 - 1.37 (rn, IH), 1.30 - 1.20 (m, 3H). m/z (ESI, +ve ion) 587.2 (M+H) ⁺ . EXAMPLE 72. (18,3¾,6'Κ,7 ^! 8,8Έ,1Γ8)-6"€ΉίΟίΙΟ-7 ^! "ΗΥΟΚΟΧΥ-12'-(3~ METHOXYPROPYL)-! 1 '-ΜΕΉΙ YL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2ujOXA| 13ΓΗ!!Λ| U2.14| T!UAXATiTRACYCLOI i 4,7.2.0* ' ^' ,0 ^{)Μ ' !} |Ρί:Ν ! Αί ^' OSA[8,16,18,24jTETRAEN]-15'-ONE 13'.13'-DIOXIDE

STEP 1: (S)-TERT-BUTYL N-(3-METHOXYPROPYL)-N-(PE T-4-EN-2-YL)

SULFAMOYLCARBAMATE

The title compound was prepared from (S)-N-(3-methoxypropyl) pent-4- en-2-amine by a procedure similar to the one described in Example 29, Step 1 (2.34 g, 6,96 mmol, 56.7% yield). STEP 2: N-(S)-PENT-4-E -2-YL, N-(3-METHOXYPROPYL) SULFURIC

DIAMIDE

The title compound was prepared from (S)-tert-butyl N-(3

methoxypropyl)-N-(pent-4-en-2-yl) sulfamoylcarbamate by a procedure similar to the one described in Example 29, Step 2 (2.07 g, 8.76 mmol).

STEP 3: (S)-6'-CHLORO-5-((( lR,2R)-2-((S)-I- HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-( -(3- METHOXYPROPYL)-N-((S)-PENT-4-EN-2-YL)SULFAMOYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][!,4]OXAZEPiNE-3, I '- N APHTH ALENE] -7 -C ARB OXAMIDE

The title compound was prepared from Intermediate AA1 1 A and N-(S)- pent-4-en-2-yl, N-(3-methoxypropyl) sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (127 mg, 0.185 mmol, 41.8% yield).

STEP 4: (lS,3 ^, R,6 ^, R,rS,8 ^, E,l l ^, S)-6-CHLORO-r-HYDROXY-12 ^, -(3- METHOXYPROPYL)-! Γ-ΜΕΊΉΥΕ-3,4-ΒΙΗΥΒί Ο-2Η,15Ή- SPIRO INAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1, 12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-BIOXiBE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox allyl)cyclobu1yl)methyl)-N-(N-(3-methoxypropyl)-N-((S)-pent- 4-en-2- yl)sdfamoy])-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, . - naphthalene] -7-carboxamide by a procedure similar to the one described in Example 29, Step 4 and was isolated via preparative HPLC as the first eluting isomer (15 nig. 0.023 mmol, 12,0% yield), ^" Ή NMR (400MHz, CDCI3) δ = 8.40 (s, IH), 7.69 (d, J=8.6 Hz, IH), 7.18 (dd, J=2.3, 8.4 Hz, 1H), 7.08 (d, J=6.0 Hz, 2H), 6.93 ·· 6.86 (m, 2H), 5.77 - 5.62 (m, 2H), 4.14 - 4.04 (m, 3H), 3.92 - 3.64 (m, 4H), 3.54 - 3.42 (m, 2H), 3.34 (s, 5H), 3.21 - 3.08 (m, IH), 2.82 - 2.70 (m, 2H), 2,50 - 2.27 (m, 4H), 2,04 - 1.85 (m, 6H), 1 ,83 - 1.65 (m, 4H), 1 .51 - 1.40 (ra, 1H), 1.35 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 659.2 (M+H) ⁺ . EXAMPLE 73. (l S,3 ^, ,6'R,7 ^! S,8'Z,l l'S)-6"CHLORO-7 ^! "HYDROXY-12 ^, -(3~ METHOXYPROPYL)-! 1 '-ΜΕΉ-Ι YL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2u jOXA| 1 3 ΓΗ ! !Λ| U 2J 4 | T!U AXATiTRACYCLOI ί 4.7.2.0 ^; ' ^' .0 ^{) Μ ' !} |Ρί:Ν ! Αί ^' OSA[8.16,18 ₅ 24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 72, Step 4 and was isolated via preparative HPLC as the second eluting isomer (4.6 mg, 6.99 μηιοΐ, 3.69% yield). ^! l l NM (400MHz, CDCb) δ 9.25 C or. s, IH), 7.66 (d, ./ H.4 Hz, IH), 7.18 (d, ./ 8.7 Hz, IH), 7.12 - 7.06 (m, 2H), 6.89 (d, ./ H.3 Hz, IH), 6.74 (br, s, IH), 5.74 - 5.63 (m, I H), 5.55 - 5.47 (m, IH), 4.61 (dd, J=4.0, 8.3 Hz, IH), 4.06 (d, J=11.9 Hz, i l l ). 3.96 (d, .7=12, 1 Hz, H), 3.83 - 3,59 (m, 5H), 3.49 (t, J=5.9 Hz, 2H), 3.35 (s, 3H), 3.33 - 3.11 (m, 2H), 2.85 - 2.68 (m, 3H), 2.67 - 2.55 (m, IH), 2.51 - 2.32 (m, IH), 2.18 (t, ./ 8.3 Hz, IH), 2.13 - 1.91 (m, Ml).1.91 - 1.69 (m, 4H), 1,48 - 1.43(m, 111).1,41 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 659.3 (M+H) ⁺ .

EXAMPLE 74. (1S,3'R,6'R,7 ^! S,8'E,1 l'S)-6-CHLORO-7'-(3- METHOXYPROPOXY)- 11 '-METH YL-3 ,4-D IHYDRO-2H, 15Ή- SPIRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ^J - ⁶ .0 ¹⁹ - ²⁴ ]PENTAC OSA[8 ₅ 16,18,24]TETRAEN]-15'-ONE 13' ₅ 13'-DIOXIDE

The title compound was prepared from Example 61 by a procedure similar to the one described in Example 63 and was isolated via preparative HPLC as the first eluting isomer (4.54 mg, 6.90 μηιοΐ, 11.2% yield). ¾N R (400MHz, CDCb) δ 8.44 is. ill .7.70 id../ 8.6 Hz, IH), 7.18 (dd, ./ 2.2.8.5 Hz, III).7.09 (d, ./ 2.3 Hz, ill).6,94 - 6.89 (m, 111).6.88 - 6.80 (ra, 2H), 5,92 - 5.83 (m, III). 5.65 (d, ,7=7,8 Hz, H), 5.56 (dd, .7=9.1, 15.4 Hz, IH), 4.12 - 4.03 (m, 2H), 3.85 - 3.68 (m, 4H), 3.53 - 3.36 (m, 3H), 3.34 (s, 3H), 3.19 (d, J=14.3 Hz, IH), 2.98 (dd, ,7=10.2, 15.3 Hz, IH), 2.84 - 2.70 (m, 2H), 2.58 - 2.38 (m, 2H), 2.25 (t, ,7=9.0 Hz, IH), 2,18 - 1.90 (m, 5H), 1.87 - 1,59 (m, 6H), 1,43 - 1.36 (m, IH), 1.26 - 1,24 (d, ./ 6,8 Hz, 3H). m/z (ESI, +ve ion) 659.2 (M+H) ⁺ .

EXAMPLE 75. (1S,3¾,6'R,7 ^! S,8'E,1 l'S)-6-CHLORO-7'-(3- METHOXYPROPOXY)-12'-(3-METHOXYPROPYL)-ir-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

[20]ΟΧΑ[13]ΊΉΙΑ[1,12,14]ΤΚΙΑΖΑΤΕΤΚΑΟΥ ΟίΟ[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]ΡΕΝΤΑΟ OSA[8 ₅ 16,18,24]TETRAEN]-15'-ONE 13' ₅ 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 74 and was isolated via preparative HPLC as the third elutmg isomer (10.6 nig, 0.015 mmol, 23.6% ield). ^! H NMR (400 Mi!/. CDCb) δ 8,37 is. ill).7,70 id. J=8.6 Hz, IH), 7.18 (dd, ./ 2.2.8.5 Hz, I Hi.7.09 (d, .7=2,2 Hz, IH), 6.93 - 6,82 (ni, 3H), 5.78 (td, J=6A, 15.4 Hz, IH), 5.52 (dd, J=8.4, 15.5 Hz, IH), 4.09 (s, 2H) _; 3.99 - 3.82 (m, 2H), 3.79 - 3.63 (m, 3H), 3.53 - 3.36 (m, 6H), 3.34(s, 3H), 3.33 (s. Ml).3.21 (d, ,/ 14.3 Hz, !!!).3.04 (dd, 9,0.15,3 Hz, !H), 2,83 - 2,70 (m, 2H), 2,47 - 2.26 (m, 41! ).2.09 - 1.89 (m, 5H), 1,87 - 1.71 (m, 6H), 1.69 - 1.54 (m, IH), 1.44 - 1.42 (m, IH), 1.37-1.35 (d, .7=6.7 Hz, 3H). m/z (ESI, +ve ion) 731.2 iM H) .

EXAMPLE 76. (1 S,3'R,6'R,7'S,8'E, 1 rS)-6-CHLORO-12'-(2- (DLMETHYLAMINO)ETHYL)-7'-HYDR.OXY~ir-METHYL-3,4-DrHYDRO- 2H,15H-SPIROj NAPHTHALENE-!, 22'- |2 ⁽ ϊ!()ΧΑ| ΟΓΙ ^' ίΙΙΛΙ 1.12. !4|TR! AXATLTRAC ^' Yi L()| I4.7.2.0 ^: ".0 ^! " |! :N ! AC OSA[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13*-DIOXIDE

The title compound was prepared from Example 61 by a procedure similar to the one described in Example 63 (4,5 mg, 5.83 μηιοΐ, 8.34% yield). ^! H NMR (400MHz, CDCb) δ 7.69 (d, ./ 8. Hz, IH), 7.27 (s, 2H), 7.17 (dd, ./ 2.2.8.5 Hz, 1H), 7,09 (d, ./ 2.3 Hz, IH), 6.97 - 6.85 (m, 3H), 5.75 - 5,64 (m, IH), 5.64 - 5.51 (m, IH), 4.33 - 4.15 (m, 2H), 4.10 (s, 2H), 4.02 - 3.88 (m, 2H), 3.80 (d, J=15.1 Hz, I H), 3.69 (d, ./ 14. 1 Hz, IH), 3.43 (br. s, 2H), 3.20 (d, ./ 14.3 Hz, IH), 3.09 - 2,93 (m, 5H), 2.90 (br. s, 3H), 2.86 - 2.59 (m, 4H), 2.57 - 2.37 (m, 4H), 2.32 (br. s, IH), 2.23 (d, .7=9,2 Hz, 3H), 2.07 - 1 ,78 (m, 6H), 1.73 - 1.60 (m, 2H), 1.45 - 1.29 (m, 4H), 1.26 (s, IH). m/z (ESI, +ve ion) 658.2 ί M H ) .

EXAMPLE 77. (1 S,3'R,6'R,7 ^* S,8'E, 1 l'S)-6-CHLORO-7 ^, -HYDROXY-12'-(CIS-3- METHOXYC YCLOBUTYL)- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THlA[ l,12,14]TRlAZATETiL CYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A 8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

STEP 1 : TERT-BUTYL N-((lS,3R)-3-METHOXYCYCLOBUTYL)-N-((S)- PENT-4-EN-2-YL)SULFAMOYLCARBAMATE

The title compound was prepared from (I S, 3R)-3-methoxy-N-((S)-pent-4- en-2-yl) c clobutanamine by a procedure similar to the one described in Example 29, Step 1 (120 mg, 0.344 mmol, 8.12% yield).

STEP 2: N-(S)-PENT-4-EN-2-YL, N-(CIS-3-METHOXYCYCLOBUTYL) SULFURIC DIAMIDE

The title compound was prepared from tert-butyl N-((1 S, 3R)-3- methoxycyclobutyl)-N-((S)-pent-4-en-2-yl) sulfamoylcaxbamate by a procedure similar to the one described in Example 29, Step 2 (120 mg, 140% crude yield). STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)]VIETHYL)-N-(N-((l S,3R)-3-

METHOXYCYCLOBUTYL)-N-((S)-PENT-4-EN-2-YL)SULFAMOYL)- 3Vlv4^5-TETUAHYDRO-2H,2'H~SPIRO[BENZO[B][l ,4]OXAZEPINE-3,r- N ΑΡΗΊΉ ALENE] -7 -C ARB OXAMIDE

The title compound was prepared from intermediate AAI 1 A and N-(S)- pent-4-en-2-yl, N-(cis-3-methoxycyclobutyl) sulfuric diamide by a procedure similar to the one described in Example 29, Step 3 (53 mg, 0.076 mmol, 59.2% yield). STEP 4: ( S,3 ^f R,6'R,7'S,8'E,l l'S)-6-CHLORO-7'-HYDROXY-l 2'-(CIS-3- METHOXYC YCLOBUTYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l ,12 4]TRIAZATCTTlACYCLO[14 .2 ³ '^0 ¹⁹ ' ²⁴ ]PE3SnrAC

OSA[8, 16,18,24]TETRAEN]-15'-ONE 13', i3'-DIOXJDE The title compound was prepared from (S)-6'-chloro-5-(((l.R,2R)-2-((S)-l- hydrox\'allyl)c lobutyl)methyl)-N-(^-((lS,3R)-3-me1hoxycyclobut'l)-N-((S)- pent-4-en-2-yl)sulfamoyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spirojbenzojb] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxamide by a procedure similar to the one described in Example 29, Step 4 and was isolated via preparative HPLC as the second eluting isomer (5.1 mg, 7.61 μηιοΐ, 10.0% yield). ¾NMR (400MHz, CD ₃ OD) 67.69 (s, 1H), 7.13 (dd, ./ 2.2.8.5 Hz, 1H), 7.06 (d, ,/ 22 Hz, 1H), 6.99 (dd, J=1.9, 8.1 Hz, ill).6.88 (d, ,/ 8.2 Hz, Hi).6.82 (d, J=1.6 Hz, 1H), 5.92 - 5.84 (m, III).5.64 (dd, ./ 7.5.15.4 Hz, 1H), 4.14 - 4.01 (m, 3H), 3.92 - 3.69 (m, 3H), 3.67 - 3.57 (m, 2H), 3.24 (s, 3H), 3.07 (dd, J=9.2, 15.3 Hz, IH), 2.79 - 2.73 (m, 2H), 2,70 - 2,50 (m, 4H), 2.47 - 2.30 (m, 4H), 2.07 - 1,89 (111, ill).1,89 - 1.76 (m, 3H), 1.64 (t, .7=9.3 Hz, IH), 1.45 - 1.39 (m, IH), 1,33 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 78. (1S,3'R,6'R,7 ^* S,8'Z,1 l'S)-6-CHLORO-7 ^, -HYDROXY-12'-(CIS-3- METHOXYC YCLOBUTYL)- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TOlA[l,12,14]I¾lAZATCTiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TAC OS A 8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from the reaction described in Example 77, Step 4 and was isolated via preparative HPLC as the third eluting isomer (3,96 mg, 5.91 μηοΐ, 7.78% yield). ¾ NMR (400MHz, CD3OD) δ 7.70 (d, J=8.4 Hz, IH), 7,14 !dd../ 2.3.8.4 Hz, IH), 7.10 - 7.04 (m, 2H), 6,90 (d, J=8.2Hz, IH), 6,83 (d, J=2.0 Hz, IH), 5.64 - 5.50 (m, 2H), 4.65 - 4,50 (m, 2H), 4.09 - 3.98 (m, Ml).3,76 - 3.67 (m, 2H), 3.61 (t, 66 Hz, III).3.38 id. J=14.5 Hz, IH), 3,24 (s, 3H), 3.21 - 3.09 (m, 2H), 2.87 - 2.74 (m, 2H), 2.73 - 2.59 (m, 2H), 2.44 - 2.36 (m, 1H), 2.29 - 2.18 (m, 2H), 2.12 - 1.84 (m, 8H), 1.81 - 1.71 (m, 1H), 1.46 - 1.34 (m, 4H). in /, (ESI, +ve ion) 67 ,2 (M+H) ⁺ . EXAMPLE 79, (1 S,3'R,6'R,7'S,8Ti,l rR)-6-CHLORO-7 ⁱ -HYDROXY-12'-(CIS-3- METHOXYCYCLOBUTYL)-ll'-METHYL-3,4-DIHYDRO-2H,15 ^! H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,12 4]TRIAZATCTTlACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PE3SnrAC

OSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from the reaction described in Example 77, Step 4 and was isolated via preparative HPLC as the first eiuting isomer (4.12 nig, 6.15 μιηοΐ, 8.10% yield). ^] H NMR (400MHz, CD3OD) δ 7.74 (d, ./ 8.6 Hz, ill).7, 19 (dd, ./ 2.3.8.4 Hz, III).7.12 id. ,/ 2.2 Hz, H), 6.95 - 6,90 (m, 2H), 6,78 (br. s, IH), 5.84 - 5,76 (m, IH), 5.68 - 5.60 (m, H), 4.33 (br. s, H), 4.20 - 3.99 (m, 4H), 3.94 (br. s, IH), 3.80 (d, J=15.3 Hz, IH), 3.71 - 3.60 (m, 2H), 3.25 (m, 3H), 3.17 - 3.06 (m, IH), 2.86 - 2.59 (m, 5H), 2.42 - 2.17 (m, 4H), 2.11 (d, ./ 13.3 Hz, 2! I ).1,94 - 1.85 (m, 3H), 1.81 - 1.64 (m, 3H), 1.52 - 1.38 (m, 4H). m/z (ESI, +ve ion) 671.2 (M il) . EXAMPLE 80. (lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, S)-6-CHLORO-7'-HYDROXY-12'-(4- METHOXYBENZYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,12,14]TR1AZATETOACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC OS A[8, 16, 18,24]TETRAEN ] - 15'-ONE 13', 13'-DIOXIDE

STEP 1 : N-(S)-PENT-4-EN-2-YL, N-(4-METHOXYBENZYL) SULFURIC DIAMIDE

To a solution of (S)-N-(4-methoxy benzyl) pent-4-en-2-amine (1 ,78 g, 8.67 mmol) in dioxane (20 mL) was added sulfamide (2.92 g, 30.3 mmol) in dioxane (20 mL) and the resulting inixture was heated at 100 °C for 21 hours and at 120 °C for 1 hour. The reaction was concentrated to give a residue which was purified by silica gel chromatography using Redi-Sep pre-packed Gold silica gel column eluting with 0-70% of EtOAc in hexane to afford the title compound (2.31 g, 8.12 mmol, 94 % yield).

STEP 2: (S)-6'-CHLORO-5-(((lR ₅ 2R)-2-((S)-l- HYDROXYALLYL)CYCLOBU L)METHYL)-N-(N-(4- METHOXYBENZYL)-N-((S)-PEOT-4-EN-2-YL)SULFAMOYL)-3 ^* ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMIDE

The title compound was prepared from Intermediate AA11 A and N-(S)- pent-4-en-2-yl, N-(4-methoxybenzyi) sulfuric diamide by a procedure Similar to the one described in Example 29, Step 3 (1.1 g, 1.50 mmol, 70.1% yield).

STEP 3: ί18,3·Κ,6'Κ,7'8,8Έ,1 rS)-6-CHLORO-7 ^! -HYDROXY-12'-(4- METHOXYBENZ YL )- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ίί )ΧΛ| ΠΓΠΙΙΛΙ U2J4|TR!AXATiTRAi ^' Yi ^' !.(}| Ι4.7.2.0 ⁵ ·'·.0 ^, "·· |Ρΐ:ΝΐΛ( ^' OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13', 13'-DTOXiDE

The title compound was prepared from (S)-6'-chloro-5-(((l.R,2R)-2-((S)-l- hydroxy allyl)cyclobutyl)me D

yl)sulfanioyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene|-7-carboxamide by a procedure similar to the one described in Example 29, Step 4 and was isolated via preparative HPLC as the first eluting isomer (0.48 g, 0.680 mmol, 45.4% yield). ¾ NMR (400MHz, CDCh) δ 8.04 (br. s, IH), 7.68 (d, J=8.6 Hz, III).7.31 (d, ,/ H.4 Hz, 3H), 7.17 (dd, ./ 2.2.8.5 Hz, ill).7,09 (d, ./ 2.2 Hz, Hi).6.92 - 6.79 (m, IH), 6,74 id. J=8.Q Hz, 2H), 6,66 (br, s, 1H), 5.89 - 5.76 (m, IH), 5,66 (dd, .7=5.0, 15.6 Hz, IH), 4.88 (br, s, ill).4,26 - 4.04 (m, 5H), 3.80 - 3.75 (m, 3H), 3.58 (d, J=13.3 Hz, 2H), 3.41 (d, J=13.7 Hz, 2H), 2.83 - 2.70 (m, 2H), 2.59 - 2.39 (m, 4H), 2.39 - 2.24 (m, IH), 2.02 - 1.52 (m, 8H), 1.11 (d, ./ 6,7 Hz, 3H), m/z (EST, +ve ion) 707,2 (M+H) ⁺ ,

EXAMPLE 81. (1 S,3'R,6 ^! R,7'S,8'Z, 11 *S)-6-CHLORO-7'-HYDROXY- 12'-(4- METHOXYBENZ YL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,12,14]TRIAZATCTTLACYCLO[14.7.2.0 ³ '*0 ¹⁹ - ²⁴ ]PENTAC OSA[8,16,18,24]TETRAEN]-15'-ONE 13', '-DIOXIDE

The title compound was prepared from the reaction described in Example 80, Step 3 and was isolated via preparative HPLC as the second eluting isomer (0,041 g.0.058 mmol, 3,88% yield). ¾ NMR (400MHz, CDCb) δ 10,36 (br. s, IH), 7.70 (d, J=8.6 Hz, IH), 7.51 (dd, J=l .7, 8.3 Hz, IH), 7.41 - 7.32 (m, J=8.6 Hz, 211).7.26 (m, IH), 7.16 (dd, ./ 2.2.8.5 Hz, IH), 7.08 (d, ,/ 2.2 Hz, IH), 6.96 (d, ./ 8.4 Hz, IH), 6,89 - 6.84 (m, ./ 8.8 Hz, 2H), 5,78 (dt, 5.6.10.8 Hz, IH), 5.67 (dd, J=7,2, 10.4 Hz, IH), 5,33 (d, J=16.0 Hz, IH), 4.41 (t, J=7.2 Hz, IH), 4.21 - 4.05 (m, 3H), 3.97 (d, ./ ! 1.9 Hz, IH), 3.86 (m, IH), 3.81 (s, 3H), 3.55 (d, ./ 14.1 Hz, IH), 3.07 - 2.96 ins.2H), 2.88 (t, ./ I 1.2 Hz, IH), 2.81 - 2.60 (m, 2H), 2,32 - 2.18 (m, 2H), 2.18 - 1.98 (m, 3H), 1,93 - 1.72 (m, 4H), 1.68 - 1.62 (ra, IH), 1.48 - 1.34 (m, 2H), 1.03 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 707.2 (M+H) ⁺ .

EXAMPLE 82. (lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, S)-6-CHLORO-12'-(4- METHOXYBENZYL)-7'-(2-METHOXYETHOXY)- 11 '-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

|2ujOXA| 13ΓΗ!!Λ| U2.14| T!UAXATiTRAi ^' Yi ^' !.(}| 14,7.2.is ⁱ '·.0 ^{)Μ Μ} |ΡΙ;ΝΤΛ( ^' OSA[8.16,18 ₅ 24;|TETRAEN]-15'-ONE 13'.13'-DIOXIDE

The title compound was prepared from Example 80 by a procedure similar to the one described in Example 43 (11 mg, 0.014 mniol, 24.8% yield). ¾ NMR (400MHz, CDCb) δ 8.42 (s, 1H), 7.71 (d, ./ 8.4 Hz, i l l . 7.37 id. ./ 7.9 Hz, 2H), 7.18 (dd, ,/ 2 2. 8.4 Hz, i l l ). 7,09 (d, ./ 2.2 Hz, 1H), 6.93 - 6.86 (m, 5H), 5.86 (td, J=6.3, 15.4 Hz, 1H), 5.56 (dd, .7=8.3, 15,6 Hz, H), .5,24 (d, .7=16.6 Hz, IH), 4,36 (d,■/ 1 .8 Hz, IH), 4.10 (s, 2H), 3.95 (q, ./ 6.7 Hz, IH), 3.81 (s, 3H), 3.80 - 3.74 (m, 2H), 3.68 (d, ,7=14.3 Hz, IH), 3.59 - 3.50 (m, IH), 3.49 - 3.44 (m, 2H), 3.43 - 3,35 (m, 4H), 3.22 (d, J=14.3 Hz, I H), 3.03 (dd, J=9,0, 15.5 Hz, IH), 2,83 - 2,71 (m, 2H), 2.53 - 2.39 (m, 3H), 2,30 (t, .7=8.5 Hz, IH), 2,07 - 1.90 (m, 3H), 1.88 - 1.70 (m, 3H), 1.66 - 1.56 (m, ! ! ! ). 1.50 - 1.33 (m, IH), 1.06 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 765,2 (M+H) ⁺ .

EXAMPLE 83. (1 S,3'R,6'R,7 ^, S,8 ^, E,irS)-6-CHLORO-7 ^, -HYDROXY-l 1\12'- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N ΑΡΗΊΉ ALEN E- 1 ,22'- | 2 ⁽ ϊ !()ΧΑ| Ο ΓΙ ^' ί Ι ΙΛΙ 1. 1 2. ! 4 |TR! AXATLTRAC ^' Yi L()| Ι 4.7.2.0 ⁵ ·'·.0 ^, "·· |Ι>ΐ :ΝΐΛ( ^' OSA[8, 16,18 ₅ 24]TETRAEN]-15'-ONE 13', 13'-DTOXIDE

To a solution of (1S,3'R,6'R,7'S,8'E, 1 l'S)-6-chloro-7'-[(tert- buty ldimethy lsily )oxy ] - 11 '-methyl -3 ,4-dihy dro~2H, 15 Ή-spiro [naphthalene- 1,22 - i 8.24 |ιet raen]-15'-one 13', 13'-dioxide (47 mg, 0.067 mmol, Example 66, Step 2) in THF (1 mL) was added sodium hydride, 60% dispersion in mineral oil (5.65 fiL, 0.268 mmol) and the reaction was stirred at ambient temperature for 10 minutes followed by the addition of iodomethane (0.013 mL, 0.201 mmol). The resulting mixture was stirred at ambient temperature for 21 hours. The reaction was quenched with saturated NH4CI and extracted with EtOAc. The organic extract was washed with watere and brine, dried with MgSt>4, filtered and concentrated to give a residue which was treated with tetrabutylammonium fluoride solution, 1.0 M in THF (1.34 mL, 1.34 mmol) and a small amount of molecule sieves at 55 °C for 1 hour. The reaction was concentrated to give a residue, which was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μπι column;

Phenomenex, Torrance, CA) to afford the title compound (2.4 mg, 4.0 μηιοΐ, 5.96% yield). Ή NMR (400MHz, CDCb) δ 8.50 (s, IH), 7.71 (d, ./ H.6 Hz, ! ! ! ). 7,26 (s. 11 1 ). 7,20 (dd, ./ 2.2. 8.5 Hz, I I I ). 7.11 id. ,/ 2 2 Hz, ! ! ! }. 6.93 (s, 2H), 5.72 - 5.60 (m, 2H), 4.19 - 3.97 (m, 4H), 3.78 - 3.63 (m, 2H), 3.35 (d, J=14.3 Hz, i l l). 3.26 (d, ,/ 14.3 Hz, IH), 3.01 (s, 3H), 2.84 - 2.72 (m, 2H), 2.56 - 2,41 (m, 2H), 2.34 - 2.23 (m, 2H), 2,02 - 1.80 (m, 4H), 1.71 (ra, 2H), 1.71 - 1.62 (m, 2H), 1.52 (t, J=l l ,7 Hz, IH), 1.30 (d, J=6.7 Hz, 3H). ro/z (ESI, +ve ion) 601.0 (M+H) ⁺ .

EXAMPLE 84. (1S,3'R,6'R,7'S,1 rR)-6~CHLORO-12'"ETHYL-7'-HYDROXY- l Γ-ME^ΉYL-3,4-DIHYDRO-2H 5Ή-SPIRO| APH HALENE-l,22 ^, - | 20 jOXA| ! 3 j Π ΠΑ| i . i 2. ! 4|TRf A/A Π ^■ .TRACY ( L()| I 4. ?.2.0 ^: '\0 ^! ' ^{, ;} ^PKYi AC OS A[ 16, 18,24] TRIEN] - 15'-ONE 13 ', 13 '-DIOXIDE

A mixture of Example 59 (13 mg, 0.021 mmol) and platinum (iv) oxide (0.961 mg, 4.23 μηιοΐ) in EtOAc (6 mL) was stirred under a H ₂ balloon at ambient temperature for 1 hour. The reaction was filtered and concentrated to give a residue which was purified by reversed phase preparative HPLC (Gemini™ Prep Ci8 5 μπι column; Phenomenex, Torrance, CA; gradient elution of 40% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound (6.0 mg, 9.74 μη ·οΙ. 46.0% yield). ¾ NMR (400MHz, CDCb) 5 8.67 (s, IH), 7.72 (d, ./ 8.4 Hz, IH), 7.49 (d, ./ ! .H Hz, ! ! ! ). 7.19 (dd,■/ 2.3. 8.6 Hz, ill).7,1 I id../ 2.3 Hz, 1H), 7,03 - 6.93 (m, 2H), 4.28 (br. s, 111).4.16 (s, 2H), 3.89 id../ !4.7 Hz, lH), 3.71 (t, ./ 7.0 Hz, 1H), 3.61 id../ 14.1 Hz, 1H), 3.48 (dd, ./ 7.2.14.9 Hz, 1H), 3.35 - 3.16 (m, 3H), 2.83 - 2.72 (m, 2H), 2.22 (br. s, 2H), 2.11 (s, 1H), 2.05 - 1.87 (m, 3H), 1,87 - 1.76 (m, 2H), 1.72 - 1.59 (m, 1H), 1.59 - 1.39 (m, 7H), 1.36 - 1.29 (m, 7H). rrv'z (ESI, +ve ion) 617.2 .

EXAMPLE 85. (lS,3 ^, R,6'R,7 ^, S,ll'S)-6-CHLORO-12 ^, -ETHYL-7 ^, -HYDROXY- ll'-METHYL-3,4-DIHYDRO-2H,15^SPIRQ[NAPH^

|20j XA| !3j ΠΠΑ| i . i 2. ! 4 |TRf AZ A Π ^■ .TRACY ( L()| I4.?,2,0 ^: ''.ϋ ^! ''· ΑΓ OS A [ 16, 18,24] TRIEN] - 15'-ONE 13 13 '-DIOXIDE

The title compound was prepared from Example 57 by a procedure similar to the one described in Example 84 (11 mg, 0.018 mmol, 68.5% yield), ^" Ή NMR (400MHz, CDCb) δ 8.87 (br. s, ill).7.70 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.19 (d, ./ 8,6 Hz, Hi).7.09 (d, ./ 2.2 Hz, 1H), 7.00 - 6.86 (m, 2H), 4.15 - 4.03 (m, 3H), 3.88 - 3.68 (m, 3H), 3.65 - 3.56 (m, III).3.33 - 3.21 (m, 211).3.12 (d, ./ 15.7 Hz, ill).2.83 - 2.71 (m, 2! I ).2.64 it, ./ 8.6 Hz, ill).2,48 - 2.38 (m, III).2.12 - 1.79 (m, 6H), 1,71 ~- 1.57 (m, 2H), 1.50 - 1.25 (m, 12H), 1,16 - 0.93 (m, III), l -'z (ESI, +ve ion) 617.2 (M+H) ⁺ EXAMPLE 86. (lS,3 ^, R,6 ^, R,7 ^, S)-6-CHLORO-12'-ETHYL-7 ^, -HYDROXY-3,4-

DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13;|THIA[1 ₅ 12,14]TTOAZATETOACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[16,l 8,24]TRIEN]-15 ^* -ONE 13' ₅ 13'-DTOXIDE

The title compound was prepared from Example 30 by a procedure similar to the one described in Example 84 (5.6 mg, 9.30 μηιοΐ, 55.8% yield). ¾ NMR (400MHz, CDCb) δ 9.22 (br. s. 11 1 ). 7,69 (d, ./ 8.4 Hz, ! ! ! ). 7.21 - 7.09 (m, 4H), 6,94 (d, J=8.0 Hz, IH), 4.16 - 4.05 (m, 2H), 3.88 (dd, .7=7.2, 14.7 Hz, IH), 3,82 - 3.74 (m, IH), 3.72 - 3.46 (m, 4H), 3.42 - 3.17 (m, 3H), 2.84 - 2.72 (m, 2H), 2.45 - 2.32 (m, IH), 2.26 (br. s, 2H), 2.02 - 1.78 (m, 5H), 1.75 - 1.63 (m, 3H), 1.62 - 1.41 (m, 6H), 1 ,27 (t, ./ 7.0 Hz, 3H). m/z (EST, +ve ion) 603,2 ! V! I ! ) EXAMPLE 87. (1 S,3'R,6'R,7 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-PROPEN-l- YL)-3,4-DIHYDRO-2H, 15'H-SPIRO|NAPHTHALENE-l ,22'- [20]OXA[13]THIA[l ,12, 14]TRIAZATETOACYCLO[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PIiOTAC OSA! 16.1 8,24] TRIEN ] - 15'-QNE 13 ', 13 '-DIOXIDE

STEP 1 : (1 S,3'R,6'R,7'S)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[ 1,12,14]TRIAZATET1RACYCLO[ 14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[16,18 ₅ 24]TRIEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from Example 36 by a procedure similar to the one described in Example 84 (98 mg, 0.171 mmol, 80% yield). STEP 2: (I S,3'R,6'R,7'S)-6-CHLORO-7'-[(TERT-

BUT YLDIMETHYLSILY)OXY] -3 ,4-DIH YDRO-2H, 15 Ή- SPIRO INAPHTHALENE- 1,22'-

[20]OXA[13]THIA[ 1, 12,14]TRTAZATETRACYCLO[ 14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTAC OSA[16,18,24]TTUEN]-1 '-ONE 13',i3'~DIOXiDE

The title compound was prepared from (l S,3'R,6'R,7'S)-6-chloro-7'- hydrox '-3,4-dihydro-2h,15'h-spiro[naphthalene-l ,22'-

[20]oxa[13]tMa[L12,14]triazate1rac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]trien ]-15'-one ! 3',13'-dioxide by a procedure similar to the one described in Example 32, Step 1 (20 mg, 0.029 mmol, 17.0% yield).

STEP 3: (l S ₅ 3'R,6 ^, R,7 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-PROPEN-l -YL)- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1 ^2, 14]TRIAZATETOACYCLO[14 .2 ³ ' ^{6 19} - ²⁴ ]PENTAC

OS AIT 6, 18.24] TRIEN ^' l- 15'-ONE 13M 3 '-DIOXIDE The title compound was prepared from (lS,3'R,6'R,7'S)-6-chloro-7'-[(tert- buty ldimethy Isily )oxy ] -3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,12,14]triazatetr^

]-15'-one 13',13'~dioxide by a procedure similar to the one describled in Example 34 (11 mg, 0.018 rnmol, 87% yield), ^" Ή NMR (500MHz, CDCh) δ 9.18 (br. s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.25 (br. s, 1H), 7.21 - 7.13 (m, 2H), 7.12 - 7.05 (m, HI).6.96 (d, ./ 8.! Hz, IH), 5.93 - 5.85 (m, 1H), 5.32 - 5.25 (m, 2H), 4.49 (d, ,/ 14 7 Hz, !!!}.4.19 - 4.11 (m, 2H), 3,97 (dd, ./ 6.2.16.0 Hz, III).3.78 (br. s, IH), 3,67 - 3.60 (m, Ml).3.38 (d, .7=12,0 Hz, IH), 3.34 - 3,25 (m, 2H), 2.83 - 2.73 (m, 2H), 2.45 - 2.26 (m, 2H), 2.04 - 1.87 (m, 4H), 1.86 - 1.65 (m, 5H), 1.60 - 1.39 (m, 7H). m/z (EST, +ve ion) 615.2 {\i · H)

EXAMPLE 88. (lS,3'R,6'R,7 ^! S,8'E)-6-CHLORO-12'-ETHYL-7'-(l,3-THIAZOL- 4-YLMETLIOXY)-3,4-DTHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TOIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ² ]PENTAC OSA[8,16,18,24jTETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from Example 29 by a procedure similar to the one described in Example 43. ¾ NMR (400MHz, CDCh) δ 8.89 (d, J=ll.l Hz, IH), 8.32 (br. s, !!!).7.70 (d,■/ 8.5 Hz, IH), 7.32 (s, IH), 7.19 - 7.17 (dd, ./ 2.2.8.5 Hz, IH), 7.09 {O.J 23 Hz, IH), 6.94 - 6.85 (m, 2H), 6.75 (s, IH), 6.06 - 5,98 (m, IH), 5.63 (dd, «/=8.1, 15,6 Hz, IH), 4.73 (d, .7=12,5 Hz, IH), 4.57 (d, ./ 12.9 Hz, IH), 4.18 - 4.02 (m, 3H), 3.96 (dd, J=3.9, 8.8 Hz, IH), 3.82 - 3.66 (m, 3H), 3.39 - 3.17 (m, 3H), 3.01 (dd, ,7=9.5, 15.6 Hz, IH), 2.83 - 2.70 (m, 2H), 2,56 - 2.47 (m, IH), 2.37 - 2,24 (m, 2H), 2.12 - 1 .87 (m, 4H), 1.80 (br. s, 3H), 1.64 (dd, J=9.4, 19.2 Hz, IH), 1.40 (t, J=12.1 Hz, 1H), 1.33 - 1.21 (m, 3H). m/z (ESI, +ve ion ) 698.2 ( +H) ⁺ . EXAMPLE 89. (l S,3 ^, R,6'R,7 ^! S,8'E)-6-CHLORO-12 ^, -ETHYL-7'-(2-OXO-2-(l- PYRROLIDINYL)ETHOXY)-3,4-DIHYDRO-2H,15H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1, 12,14]TRJAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OS A[ 8, 16, 18,24]TETR '-ONE 13', 13'-DIOXIDE

A mixture of Example 44 (4 mg, 6.08 μηιοΐ), hydroxy] amine

hydrochloride (2.11 mg, 0.030 mmol), N-ethyl-N-isopropylpropan-2-amine (3.49 μΕ, 0.020 mmol) and (i H ienzo[d] [l,2,3 |triazo3-l -yl)oxy)tri(pyriOlidin-l- yl)phosphonium hexafluorophosphate(V) (6.32 mg, 0.012 mmol) in THF (0.25 mL) and DCM (0.2.5 mL) was stirred at ambient temperature for 1 hour. The reaction was quenched with H?Q and extracted with EtOAc. The organic extract was washed with H?.0, brine, dried with MgS04 and filtered. After concentration the residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cm 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 85%

MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound (0.66 mg, 0.928 mmol, 15,3% yield). ¾ NMR (400MHz, CDCh) δ 8.67 (br, s, 1H), 7.72 (d, .7=8.6 Hz, 1H), 7.20 (dd, J=2,3, 8.4 Hz, IH), 7.11 (d, J=2.3 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.84 (br. s, IH), 6.11 - 6.03 (m, i l l ). 5,61 (dd. J=8.6, 15.7 Hz, 1 1 1 ). 4.21 - 3.99 (ra, 5H), 3,89 (dd, J=4.Q, 8.5 Hz, 1 1 1 ). 3.81 - 3.64 (m, 3H), 3.60 - 3.50 (m, 2H), 3.48 - 3.23 (m, 5H), 3.12 (br. s, IH), 2.84

- 2.72 (m, 2H), 2.61 - 2.44 (m, 2H), 2.39 - 2.24 <m. 3H), 2.09 - 1.81 (m, 6H), 1.78

- 1 ,58 (m, 4H), 1.49 - 1 .42 { ra IH), 1.28 (t, ,/ 7 0 Hz, 3H). m/z (ESI, +ve ion) 712.3 (M+H) ⁺ .

EXAMPLE 90. (1 S,3'R,6'R,7'S,8'E, 1 l'R,14^)-6-CHL()RO-7'-HYDR()XY-3,4- DIHYDRO-2H,17'H-SPIRO[NAPHTHALENE-l ,24'-

^lOXAtlSlTHIAt^ieiDIAZAPE TACYCLOIl&T^-O^^O ^! ^^^^lHEPTA COS A[8, 18,20,26]TETRAEN] - 17'-ONE 15', 15'-DIOXIDE

STEP 1 : 2-CYCLOBUTYLIDENE-l ,l-DIMETHYLHYDRAZrNE

To a stirred solution of cyciobutanone (25 g, 36 mmol) in benzene (149 mL) was added 1 ,1-dimethylhydrazine (21.44 g, 357 mmol) and 2,2,2- trifluoroacetic acid (0.407 g, 3,57 mmol). The stirred reaction mixture was heated at reflux for five hours using a Dean-Stark trap, after which time ca. 8 mL water had condensed. The reaction mixture was then cooled to rt and partitioned between diethyl ether and water, back-extracting the aqueous phase with ether, The combined organic extracts were dried over MgSOs, filtered and concentrated in vacuo. Distillation was carried out using a short-path apparatus, and the fraction boiling at 75-95 °C at ca. 20 mm of Hg was collected to provide 2- cyclobutylidene-l,l-dimethylhydrazine (18.0 g, 160 mmol, 45.0 % yield).

STEP 2: (S)-2-ALLYLCYCLOBUTANONE AND (R)-2- ALLYLCYCLOBUTANONE

To a stirred, ca. -10 °C solution of 2-cyclobutylidene-l, l- dimethylhydrazine (12,0 g, 107 mmol) in diethyl ether (206 mL) under a nitrogen atmosphere was added ra-butyllithium (nominally 2.5 M solution in hexanes; 42.8 mL, 107 mmol) dropwise via syringe over 20 minutes. The reaction mixture was stirred at -10 °C for one hour. After this time, allyl bromide (9.26 mL, 107 mmol) was added, and the mixture was allowed to warm to room temperature overnight. After this time, the mixture was acidified with aqueous HCI (1 M, 215 mL) and stirred at rt for 40 minutes. The separated aqueous layer was then extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo (pressure: 100 mm of Hg) to give 2-allylcyclobutanone (10.55 g, 96.0 mmol, 90 % yield).

STEP 3: ( 1 ,2R)-2- ALLYLC YCLOBUT ANOL AND (l S,2S)-2~

ALLYLCYCLOBUT ANOL

To a stirred solution of 2-allylcyclobutanone (10.5 g, 95.0 mmol) in TOP (191 mL) at -78 °C under a nitrogen atmosphere was added dropwise via an addition funnel l-selectride (1 M in THF; 105 ml, 105 mmol). The reaction mixture was stirred at -78 °C for two hours and then it was allowed to warm to rt over 20 minutes. After this time, the reaction was quenched by addition of NH4CI (saturated aqueous solution) and diluted with EtOAc. The separated aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over MgSCH, filtered and concentrated in vacuo. Column chromatography (120 g silica gel ; Hexanes:EiOAc, 1 :0 to 4: 1 solvent gradient) gave the title compound (5.60 g, 49.9 mmol, 52 % yield) as a colorless liquid.

STEP 4: (lR,2R)-2-ALLYLCYCLOBUTANOL METHANESULFONATE AND (lS,2S)-2-ALLYLCYCLOBUTANOL METHANESULFONATE

To a stirred solution of racemic c i-2-allylc clobutanol (5.60 g, 49.9 mmol) in DCM (250 ml) at 0 °C was added triethylamine (13.9 mL, 100 mmol) followed by methanesulfonyl chloride (5.84 mL, 74.9 mmol). The reaction mixture was allowed to warm to rt overnight. After this time, the mixture was partitioned between DCM and I M HCl (aq.). The separated aqueous layer was extracted with DCM and the combined organic extracts were washed with brine, dried over MgSC¼, filtered and concentrated in vacuo. Column chromatography (120 g silica gel; isocratic DCM) gave racemic c s-2-allylcyclobutanol methanesulfonate (6.63 g, 34.8 mmol, 70 % yield). STEP 5: 2-(((l S,2R)-2-ALLYLCYCLOBUTYL)THIO)PYRIMIDINE AND 2-

(((lR,2S)-2-ALLYLCYCLOBUTYL)THIO)PYRlMlDINE

To a stirred solution of racemic 675-2-alrylcyclobutanol methanesulfonate (6.60 g, 34.7 mmol) in DMF (69.4 mL) was added 2-mercaptopyrimidine (3.89 g. 34.7 mmol) and potassium carbonate (4.79 g, 34.7 mmol). The reaction mixture was heated at 70 °C for 90 minutes. After this time, the mixture had solidified. More DMF (30 mL) was added, and heating at 100 °C was continued for 90 minutes. Additional portions of 2-mercaptopyrimidine (1.9 g) and potassium carbonate (2.4 g) were then added, and the mixture was heated at 100 °C for two hours. Upon cooling to room temperature, the mixture was partitioned between EtOAc and water. The separated aqueous layer was extracted with EtOAc and the combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Column chromatography (120g silica gel; hexanes:EtOAc, 1 :0 to 4: 1 solvent gradient) gave racemic ra.¾'-2-((2-ally]cyclobutyl)thio)pyriiradine (4.60 g, 22.3 mmol, 64 % yield). STEP 6: 2 ((l S,2R)~2"ALLYLCYCLOBUTYL)SULFONYL)PYi IMlDlNE AND 2-(((lR,2S)-2-ALLYLCYCLOBUTYL)SULFONYL)PYRIMIDINE

To a vigorously stirred mixture of sodium tungstate dihydrate (0.320 g, 0.969 mmol), phenylphosphonic acid (0.153 g, 0.969 mmol) and

tetrabutylammonium sulfate (50 weight % solution in water; 1.126 mL, 0.969 mmol) in water (8.81 mL) was added hydrogen peroxide (30 weight % solution in water; 4.95 mL, 48.5 mmol). After two minutes, a solution of racemic trans-2- ((2-allylcyclobutyl)thio)pyrimidine (4.00 g, 19.4 mmol) in toluene (88 mL) was added dropwise and the reaction mixture was stirred at 54 °C overnight. Upon cooling to rt, the mixture was between EtOAc and water. The organic layer was washed with saturated aqueous sodium sulfite, dried over MgSC¼, filtered and concentrated in vacuo. Column chromatography (40 g silica gel; hexanes:EtOAc, 1 :0 to 3: 1 solvent gradient) gave racemic trans-2-((-2- allylcyclobutyl)sulfonyl)pyrimidine (3.80 g, 15.9 mmol, 82 % yield) as a colorless oil. STEP 7: (1 S,2R)-2-ALLYLCYCLOBUTANE-l -SULFONAMIDE AND (1R,2S)~ 2- ALL YLC Y C LOBU TAN E- 1 -SULFONAMIDE

To a stirred solution of racemic tran -2-((-2- allylcyclobutyl)sulfony])pyrimidine (2 g, 8.39 mmol) in MeOH (84 mL) was added solid potassium carbonate (3.48 g, 25.2 mmol). The reaction mixture was stirred at rt for 30 minutes. Amidoperoxymonosulfunc acid (4.75 g, 42.0 mmol) was then added in one portion followed by 100 mL of water, causing a mild exotherm. The reaction was stirred at rt for 10 minutes, heated at 90 °C for five minutes, and finally allowed to cool to rt over one hour. The mixture was then concentrated in vacuo to ca. 1/3 of its initial volume and then it was basified by- addition of IN NaOH (aq.). The aqueous layer was back-extracted with EtOAc (2 X) and the combined organics were washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (120 g silica gel; hexanes: EtOAc, 1 :0 to 3: 1 solvent gradient) to give ra«5-2-ally]cyclobutane-l -sulfonamide (0.95 g, 5.4 mmol, 65 % yield).

STEP 8: (S)-6'-CHL0R0-5-(((IR,2R)-2-((S,E)-l -HYDROXY-4-((l S,2R)-2- SULFAMOYLCYCLOBUTYL)BUT-2-EN-l-YL)CYCLOBUTYL)METHYL)- S'^^' -TETRAHYDRO^H^TI-SPIROIBENZOtBJj l ^lOXAZEPINE-S,!'- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((IR,2R)- 2-((S,E)~ 1 -HYDROXY-4-((l R,2S)-2-SULF AMOYLCY CLOBUTYL)BUT-2- EN-l-YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SPIR()[BENZO I B ] [ 1 ,4]OXAZEPEME-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

A stirred solution of Intermediate AA12A (234 mg, 0.459 mrnol) in 1,2- dichloroethane (6.55 mL) was sparged with argon for five minutes. After this time, a solution of (l,3-dimesitylimidazolidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium(VI) chloride (28.7 mg, 0.046 mrnol) was added dropwise via syringe while sparging argon through the mixture. The reaction was stirred at rt under argon for 90 minutes. The catalyst was then deactivated by sparging air through the reaction mixture. The mixture was concentrated in vacuo, and the remaining solids were triturated with DCE (ca 2 ml.) and filtered, washing the filter cake with DCE (ca 2 mL). The combined organics were concentrated in vacuo and purified by column chromatography (12g silica gel; hexanes:(99: 1 EtOAc: AcOH), 1 :0 to 3: 1 solvent gradient) to give a mixture of (S)- 6 ^! -chloro-5-(((L#,2#)~2~((^^

2-en- 1 -yl)cyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[6] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)-&- chloro-5-((fli?,2i?)-2-((^^

en-l-yl)c 'clobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro I benzoj l,4 |oxazepine-3, -naphthalene]-7-carboxylic acid (140 mg, 0.228 mrnol, 50 % combined yield). STEP 9: ( lS,3 ^f R,6'R,7'S,8'E,I l'R, I4'S)-6-CHLO O-7'-HYD OXY-3,4- DIHYDRO-2H, 17 Ή- SPIRO [N APHTH ALENE- 1 ,24'-

| 22 |()XA| 1 ΓΠ I IA| I . i 6 | Ι)! Λ/ΛΡΗΝΤΛ( ΎΠ.ϋΙ 16.7.2. ( ϊ ". Ο ^{η !} '.ϋ" '"|! !HPTA COSA[8,18,20,26]TETRAEN]-17 ^* -ONE 15', 15"-DIOXIDE

To a stirred, rt solution of (5)-6'-chloro-5-(((li?,2i?)-2-((S^E)-l -hydroxy-4- ((LV,2«)~2~sulfamoylcyclob^ tetrahydro-2H,2'H-spiro[benzo[A][l ,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (5)-6'-cMoro-5 ((lR,2R)-2 (^-l-^droxy-4-((1^25)-2- sulfamoylcyclobu1yl)but-2-en-l-yl)c} ⁷ clobutyl)me1hyl)-3',4,4 ^, ,5-tetrahydro- 2H,2'H-spiro [benzo [b] [ I A] oxazepine-3, 1 '-naphthalene ] -7-carboxy li c aci d (i . e. , the diastereomer mixture prepared in Step 8; 140 mg, 0.228 mmol total) in DCM (1.14E+05 μΕ) was added DMAP (47.3 mg, 0.387 mmol). The resulting reaction mixture was cooled to 0 °C and treated with EDC (87 mg, 0.45 mmol) portionwise over five minutes. The mixture was stirred at rt overnight, and then partitioned between DCM and 1M HC1 (aq.). The aqueous layer was extracted with DCM and the combined organics were washed with brine, dried over MgSCu, filtered and concentrated in vacuo. Column chromatography (24 g silica gel,

hexanes:(99: l EtOAc:AcOH), 1 :0 to 3: 1 solvent gradient) gave an early-eluting diastereomer identified as (IS,3'R,&R,TS,S'E,11 il4'5)-6-chloro-7'-hydroxy-3,4- dihy dro-2H, 17'H-spiro[naphthalene- 1 ,24'- [22]oxa[15]thia[l,16]diazapent^

]tetraen]-17'-one 15',15'-dioxide (i.e., the title compound; 24 mg, 18 % yield) as a white film. ^j I I NMR (400 MHz, CD3OD) δ ppm 7.72 (d, J=8.6 Hz, 1 i ! ). 7.17 (dd, 8.4. 2,3 Hz, 1 H), 7. 10 (d, 2.2 Hz, 1 H), 7.05 (dd, 8 2. 2.2 Hz, 1 I s ). 6.95 (d, ,7=2,0 Hz, 1 H), 6.91 id . «/=8.2 Hz, 1 H), 5.84 - 5,95 (m, 1 H), 5.58 (dd, J=15.5, 6.3 Hz, 1 H i. 4.28 (q, J=9.1 Hz, 1 H), 4.07 - 4.12 (m, 1 H), 4.06 (s, 2 H), 3.63 - 3.74 (m, 2 H), 3.39 (d, ./ 14.5 Hz, 1 ! ! }. 3.17 (dd, ,/ 15.3. 10.4 Hz, 1 H), 2,83 - 2.92 { Ml. 1 I I ). 2,71 - 2.82 (m, 2 I I ). 2,48 - 2.61 (m, 1 H), 2,22 - 2.44 (m, 6 H), 2.00 - 2.11 (m, 2 H), 1.85 - 1.99 (m, 2 H), 1.67 - 1.84 (m, 4 H), 1.55 - 1.65 (m, 1 H), 1.43 - 1.53 (m, 1 H). m (ESI, +ve ion) 597.1 ( \\ The absolute stereochemistr ' of the title compound (and hence also the absolute

stereochemistries of all compounds stereospecifically derived from it) was established by X-ray ciystailography of a co-crystal obtained upon coniplexation with Mcl-1. A late-elutmg diastereomer having opposite chiral sense at both sulfamoylcyclobutyl stereocenters, (} S,3'R,6'R,7$,8'EA l 'SU4'i?)-6-chloro-7'- hydrox>'-3,4-dihydro-2H,17'H-spiro[naphthalene-l,24'- [22]oxa[15]thia[l,16]diazapentacy^^

]tetraen]-17'-one 15',15'-dioxide (25 nig, 18 % yield), was also obtained from the chromatography experiment.

EXAMPLE 91. (1S,3'R,6'R,7'S,1 Γ ,14·Κ)-6-(:ΗΕΟ Ο-7'-ΗΥΟΚΟΧΥ-3,4- DIHYDRO-2H,17Ή-SPIRO| APHTHALENE-l,24 ^, -

|22!ΟΧΛ| i^lUUAl l..i6|i)!.\/.\Pi-::\ ΓΛίΎΠ.ΟΙ 16.7.2 (;· ".O ^{11 1} '.· ) ^,; ' ^!, |» IhP 1 Λ COS A[ 18,20,26 jTRlENj- 17'-ONE 15', 1 S'-DIOXIDE

To a stirred solution of (15',3'ii,6 ^, ii,7 ,8'£,ll'5',14 ^, ii)-6-chioro-7'-hydroxy- 3,4-dihydro-2H, 17'H-spiro|naphthalene-l ,24'-

[22]oxa[!5]thia[l,16]diazapeniacyclo[ 16,7.2.0 ³ ' ⁶ ,0 ^iiJ4 .0 ^2l - ²⁶ ]heptacosa[8,18,20,26 ]tetraen]-17'-one 15',15'-dioxide (i.e., the late diastereomer from Step 9 of Example 90; 10 mg, 0.017 mmol) in EtOAc (3349 μΕ) was added platinum(IV) oxide (3.8 mg, 0.017 mmol), and the reaction mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 30 minutes. After this time, the reaction mixture was filtered through celite, washing the filter cake with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (4 g silica gel; hexanes: (99:1 EtOAc:AcOH), 1:0 to 4:1 solvent gradient) to give the title compound (5.2 mg, 8.7 μπιοΐ, 52 % yield) as a white solid. ^l H NMR (400 MHz, CD2CI2) δ ppm 10.38 (br. s, 1 H), 7.66 (d, J=8.4 Hz, 1 H), 7.49 (br. s., 1 H), 7.41 (d, ,/ H.2 Hz, 1 H), 7.15 (dd, ,/ 8.4.2.3 Hz, 1 H), 7.09 (d, J=2.3 Hz, 1 H), 6.96 (d, ,/ 82 Hz, 1 H), 4.18 - 4.25 (m, 1 H), 4.12 - 4.17 (m, 1 H), 4.05 (q, J=9.0 Hz, 1 H), 3.81 (br. s., 1 H), 3.44 (q, ./ 7.0 Hz, 1 H), 3.48 (br. s., 3 H), 2.92 - 3.07 (m, 1 H), 2.71 - 2.80 (m, 2 H), 2.41 - 2.57 (m, 1 H), 2.23 - 2.35 (m, 3 H), 2,01 - 2.10 (m, 2 II).1,89 (d, ./ 6.5 Hz, 2 III 1.68 - 1.85 (m, 4 H), 1.61 {til J=\ 9.5, 9.8 Hz, 4 H), 1.48 (br. s. , 2 ! ! }. 1.32 - 1.44 (m, 3 H). m/z (EST, +ve ion) 599.2 (M+H) ⁺ .

EXAMPLE 92. (1 S,3'R,6'R,7 ^! S,1 rS,14'S)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 17'H-SPIRO[NAPHTHALENE-l,24'- [22]OXA[15]TfflA[l,16]DIAZAPENTACYCLO[16.7.2.0 ³ ' ⁶ .0 ¹¹ ' ¹⁴ .0 ^2! ' ²⁶ ]HEPTA COSA[18,20,26]TRIEN]-17'-ONE 15',15'-ϋΙΟΧΓΟΕ

To a stirred solution of (\S, R,6'R,TS,S'E,\ l 'i?,14'5)-6-chioro-7'-hydroxy- 3,4-dihydro-2H,17^-spiro[naphthalene-L24'- [22]oxa[15j1hia( U6j&azapentacy^

]tetraen]-17'-one lS', 15'-dioxide (i.e., the early-eluting diastereomer from Step 9 of Example 90; 17 mg, 0.028 mmol) in EtOAc (5.69 mL) was added platinum(iV) oxide (6.46 mg, 0.028 mmol), and the reaction mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 30 minutes. After this time, the reaction mixture was filtered through celite, washing the filter cake with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (4 g silica gel; hexanes: (99: 1 EtOAc: AcOH), 1 :0 to 4: 1 solvent gradient) to give the title compound (6.6 mg, 0.01 1 mmol, 39 % yield) as a white solid. ^" Ή NMR (400 MHz, CD2CI2) δ ppm 9.48 (br. s., 1 H), 7.71 (d, .7=8.4 Hz, 1 H), 7.29 (dd, J=8.2, 2.0 Hz, 1 H), 7.18 (d, J=2.3 Hz, 1 H), 7.16 (d, J=2.2 Hz, 1 H), 7.09 (d, ,/ 2.3 Hz, 1 H), 6.97 (d, ,/ 8.4 Hz, 1 H), 4.14 (s, 2 H), 3.74 (q, ./ 9. 1 Hz, 1 H), 3,48 - 3.67 (m, 3 H), 3.22 - 3.45 (m, 2 H), 2,95 (quind, ./ 9 3. 9.3, 9.3, 9.3, 3.7 Hz, 1 H), 2.68 ·· 2.85 (m, 4 H), 2.22 - 2.34 (m, 1 H), 2.09 - 2.20 (m, 1 H), 2.00 { in. 3 H), 1.50 (m, 14 H). m/z (ESI, +ve ion) 599.2 ( +H) ⁺ . EXAMPLE 93. (1 S,3'R,6'R,7'S,8'E,1 l'S,14'R)-6-CHLORO-7'-(2- ETHOXYETHOXY)-3,4-DIHYDRO-2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'- | 22 i()XA| ! 5 ΓΠ ! ΙΛ| i J 0 | D! AZ,\PLN rACYCi.()i 1 .7.2.0^ 0 ^{1 l u} o ^{' ;} -'|i ΙΗΡΤΛ COSA[8,1 8,20,26]TETRAEN]-17'~ONE 15',15'-DIOXTDE

To a stirred solution of (\S,3 6 7'S,S'E,n'S,14'R)-6-(MoTO-7- ydioxy- 3 ,4-dihy dro-2H, 17'H-spiro [naphthal ene- 1 ,24'-

]tetraen]-17'-one 15', 15'-dioxide (i.e., the late diastereomer from Step 9 of Example 90; 10 mg, 0.017 mmol) in DMF (335 μΐ.) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 6.7 mg, 0.17 mmol). The reaction mixture was stirred at this temperature for 15 minutes. After this time, 2-bromoethyl methyl ether (7.9 μΐ,, 0.084 mmol) was added, and the reaction mixture was stirred at rt over the weekend. The reaction mixture was then partitioned between EtOAc and water. The separated organic layer was dried over MgS04, filtered and concentrated in vacuo. Column chromatography (4 g silica gel;

DCM:acetone, 1 :0 to 9: 1 eluent gradient) gave the title compound (4.0 mg, 6.1 μπιο!, 36 % yield) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ ppm 8.56 (br, s, 1 H), 7.70 (d, J=8.4 Hz, 1 H), 7.16 (dd, J=8.6, 2.3 Hz, 1 H), 7.09 (d, J=2.2 Hz, 1 H), 6.94-7.04 (br. s., 2 H), 6.88 - 6.93 (m, 1 H), 5.71 - 5.84 (m, 1 H), 5.60 (dd, ./ 15.6, 7.6 Hz, I 1 1). 4.56 (d, ./ 8.4 Hz, 1 ! ! }. 4.10 (s, 2 H), 3,83 (dd, ./ 7.4. 5.5 Hz, 1 H), 3.59 - 3,74 (m, 3 H), 3.44 - 3,53 (m, 3 H), 3.33 (s, 3 H), 3.12 - 3.32 (m, 2 H), 2.86 - 2.98 (m, 1 H), 2.69 - 2.81 (m, 2 H), 2.52 (dd, J=9.1, 5.6 Hz, 1 H), 2.43 (dt, ./ 20.( 9.8 Hz, I H), 2.13 - 2,35 (m, 4 H), 2.00 (s, 2 I s ). 1.60 - 1.94 (m, 7 I s ). 1 ,40 - 1.52 (m, 1 H), m/z (ESI, +ve ion) 655.3 (M+H) ⁺ . EXAMPLE 94. (IS,3%6'R,TS,VE, 11 % 14 S)-6-CHLORO-7'-(( 1 -METHYL- \H- 1 ,2,4-TRl AZGL-3- YL)METHOXY)-3,4-DlHYDRO-2H, 1 TH- SPIRO INAPHTHALENE- i .24'-

[22]OXA[15]TOIA[l, 16]DIAZAPE TACYCLO[16.7.2.0 ³ ' ⁶ .0 ^{l l} ' ¹⁴ .0 ²¹ " ²⁶ ]HEPTA COSA[8,18,20,26]TETRAEN]-17'-ONE 15',15 ^! ~DIOXIDE

To a stirred solution of (ΙΞ 'Κ&ΙΙΤΞβ'ΕΛ l 'i?,14 )-6-chIoro-7 ^! -hydroxy- 3,4-dihydro-2H,17'H-spiro[naphthalene-l,24'- [22]oxa[15]ihia[ U6]diazapentacyd^

]tetraen]-17'-one 15', 15'-dioxide (i.e., the early diastereomer from Step 9 of Example 90; 7.0 rng, 0.012 mmol) in THF (234 μί) under an atmosphere of nitrogen was added sodium hydride (60 % dispersion in mineral oil; 4.7 mg, 0.12 mmol). The reaction was stirred at rt for 15 minutes and then it was treated with a solution of 3-(chloromethyl)-l -methyl-lH-l,2,4-triazole h drochloride (9.8 mg, 0.059 mmol) in DMF (234 μΕ) dropwise over one minute. The resulting mixture was stirred at rt for three hours. After this time, additional portions of sodium hydride (4.7 mg, 0.12 mmol) and 3-(chloromethyl)-l-methyl-lH-l,2,4-triazole hydrochloride (9.9 mg, 0.059 mmol) were added and the reaction was stirred at rt over the weekend. The reaction mixture was then partitioned between EtOAc and brine. The separated organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. Column chromatography (Ig silica gel; hexanes: (99: 1 EtOAc:AcOH), 1 :0 to 1 :2 eluent gradient) gave the title compound (3.5 mg, 5. 1 μιηοΐ, 43 % yield) as a white solid. ^l H NMR (500 MHz, CD2CI2) δ ppm 8.01 (s, 1 H), 7.69 (d, ,/ 8.6 Hz, I H), 7.16 (dd, ./ 8.4.2.3 Hz, I H), 7.08 (d, ./ 2.2 Hz, 1 H), 6.89 - 6.99 (m, 2 H), 6.87 (d, J=8.1 Hz, 1 H), 5.79 - 5.88 (m, 1 H), 5.61 (dd, ./ 15.5.7.9 Hz, 1 H), 4.60 - 4.67 (m, 1 H), 4.57 (d, ./ Π.7 Hz, 1 II).4.41 (d, ./ 12.0 Hz, 1 H), 4.04 - 4.11 (m, 2 H), 3.91 (s, 3 H), 3,88 (s, 1 H), 3.60 - 3.71 (m, 2 H), 3.25 (d, ./ 14.2 Hz, 1 Hi 3.12 (br. s, 1 H), 2,85 - 2.94 (m, 1 H), 2,69 - 2.81 (ni, 2 H), 2.47 - 2.55 (ni, 1 H), 2.39 - 2.46 (ni, 1 H), 2.27 - 2.34 (ni, 1 H), 2.16 - 2.27 (ni.3 H), 1.95 - 2.03 (ni.2 H), 1.86 - 1.95 (ni.2 H), 1.61 - 1.86 (ni.6 H), 1,39 - 1.48 (m, 1 H). m/z (ESI, + ve ion) 692.2 ( VI II) .

EXAMPLE 95. (1S,3 6'R,7S,WE,1 l'i 4VV)~6~CHLQRO~7'~METHQXY-3,4- DIHYDRO-2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'-

|22i()XA| 15jTIIIA| Μ6|Ι)ΙΛ/ΛΙ ΎΛ(ΎΠ.<>! 16.7.2.0^ O ^{1 l u} o ^'; -'|i !HPTA COS A[8, 18,20,26]TETRAEN] - 17'-ONE 15', 1 S'-DIOXIDE

To a stirred solution oi(lS,3 6 TS,^^VR,l4'S)-6-di\oTO-T-hy roxy- 3,4-dihydro-2H, 17'H-spiro[naphthalene-l ,24'- [22]oxa[15]thia[U6]diazapentacyclo[16.7 _^ ^ _^

]tetraen]-17'-one !5', ! 5'-dioxide (i.e., the early diastereomer from Step 9 of Example 90; 4.0 mg, 6.7 μπιοΐ) in THF (0.67 ml.) under a nitrogen atmosphere was added sodium hydride (60 % dispersion in mineral oil: 1.3 mg, 0.033 mniol) in one portion. After 10 minutes, iodomethane (1.3 ,uL, 0.020 mmol) was added and the resulting mixture was stirred at rt. for four hours. Additional portions of sodium hydride (4.0 mg, 0.099 mmol) and Mel (5 uL, 0.077 mmol) were than added, and the reaction mixture was stirred at rt overnight. On the following day, the reaction mixture was partitioned between EtOAc and water. The separated organic layer was dried over MgSC , filtered and concentrated in vacuo. Column chromatography (ca. 1 g silica gel ; hexanes: (99: 1 EtOAc:AcOH), 1 :0 to 4: 1 eluent gradient) gave the title compound (1.4 mg, 2.3 μιηοΐ, 34 % yield) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ ppm 8.40 (br. s., 1 H), 7.70 (d. ./ K.4 Hz, 1 H), 7.16 (dd. ,/ X f,. 2.3 Hz, 1 1 1 ). 7.09 (d, ,/ 2 2 Hz, ! H), 6.86 - 7.01 (m, 3 H), 5.73 - 5.84 (m, I H), 5.52 - 5.62 (m, 1 H), 4.57 - 4.68 (m, 1 H), 4.04 - 4.14 (m, 2 H), 3.71 (dd, ./ 8.2. 4.9 Hz, 1 H), 3.66 (d, ./ 4 7 Hz, 1 H), 3.31 (s, 2 H), 3.27 (d, ./ 14.7 Hz, 1 H), 3.15 (br. s., 1 H), 2.87 - 2.99 (m, 1 H), 2.69 - 2.83 (m, 2 H), 2.38 - 2.56 (m, 2 H), 2.12 - 2.33 (m, 4 H), 2.04 (br, s., 1 H), 1 ,77 - 2.00 (m, 4 H), 1.61 - 1 ,76 (m, 4 H), 1 ,39 - 1 ,50 (m, 2 H), 1 ,31 (br. s. , 1 H). m/z (ESI, +ve ion) 61 1.2 I 1 1 > ^" .

EXAMPLE 96. (1 S.3 ^, R,6 ^, R)-6-CHLORO-8 ^, -(4-METHOXYBENZYL)-3 ₅ 4- DffiYDRO~2H,7'H, 15'H-SPIRO[NAPHTHALENE-l ,22"-

[20]OXA[13]THIA[1,8,14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACO

SA[16,18,24]TRIEN]-7',15'-DIONE 13',13'-DIOXIDE

STEP 1 : PROP-2-ENE-1 -SULFONAMIDE

_¾J ^ _x/ S0 ₂ NH ₂

To a 250-mL round-bottom flask was added prop-2-ene-l-sulfonyl chloride (Matrix Scientific; 2.00 g, 14,2 mmol) in 10 mL of 1 ,4-dioxane.

Ammonia (0.5 M solution in methanol; 71.1 mL, 35.6 mmol) was added to the solution at rt over one hour, causing formation of a white precipitate. The reaction mixture was stirred at it overnight and then diluted with water (20 mL). The resulting mixture was extracted with 3: 1 chloroform.: isopropanol (4x30 mL). The organics were concenirated in vacuo and the resulting crude material qwas further purified by columnn chromatography (40 g silica gel : 40 to 100% eluent gradient of EtOAc m hexanes) to provide prop-2-ene-l -sulfonamide (0.72 g, 5.9 mmol, 42 % yield). STEP 2: ( lR,2R)-2-(((S)-7-(TERT-BUTYOXYCARBONYL)-6'-CHLORO-3',4'- DIHYDRO-2H,2H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALEN]- 5(4H)-YL)METHYL)CYCLOBUTANECARBOXYLIC ACID

To a stirred solution of (5)-fcrf-butyl 6'-chloro-5-(((li?,2i?)-2'

formylcvxlobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo \b] [1,4] oxazepine-3 , Γ -naphtha! ene] -7-carboxy late (440 mg, 0.887 mmol, intermediate ΛΛ Ι I Λ . step 20B) in r-BuOH (1.8 ml.) and 2-methyl-2- butene (1.8 mL) was added a solution of sodium chlorite (168 nig, 1.86 mmol) and dihydrogen sodium phosphate (1 12 μΐ,, 1.86 mmol) in water (1.5 mL). The reaction mixture was stirred at rt for five hours. After this time, the reaction mixture was partitioned between EtOAc and 1 M HC1. The separated organic layer was dried over MgSC , filtered and concentrated in vacuo. Column chromatography (12g silica gel; hexanes;(99: l EtOAc: AcOH), 1 :0 to 2: 1 eluent gradient) gave (li?,2i¾)-2-(((5)-7-(ter^utoxycarbonyl)-6 ^, -chloro-3',4'-dih

2H,2 ^, H-spiro[benzo[¾][L4]oxazepine-3,r-naphthalen]-5(4H)- yl)methyl)cyclobutanecarboxylic acid (300 mg, 0.586 mmol, 66 % yield).

STEP 3: (S)-TERT-BUTYL 5-(((lR,2R)-2-(ALLYL(4- METHOXYBENZYL)CARBAMOYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4',5"TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

To a stirred solution of (lit2ii)-2-(((5)-7-(teri-butoxycarbonyl)-6'-chloro- 3',4'-dihydro-2H,2^-spiro[benzo[6] [l,4]oxazepine-3,r-naphthalen|-5(4H)- yl)methyl)cyclobutanecarboxylic acid (300 mg, 0,586 mraol) and N-(4- methoxybenzyl)prop-2-en-l -amine (208 mg, 1.17 mmol) in DCM (2929 ,uL) was added EDC (146 mg, 0.762 mmol) and ΗΟΒΤ (117 mg, 0.762 mmol). The reaction mixture was stirred at rt overnight and then partitioned between DCM and saturated sodium bicarbonate (aqj. The separated organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. Column chromatography (12 g silica gel; hexanes:(99: l EtOAc:AcOH), 1 :() to 4: 1 eluent gradient) gave (S)-tert- butyl 5-(((li?,2i?)-2-(allyl(4-methoxybenzyl)carbamoyl)c lobut 'l)methyl)-6'- chloro-3',4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[0] [l ,4]oxazepine-3, - naphthalene] -7-carboxylate (300 mg, 0.447 mmol, 76 % yield).

STEP 4: (S)-5-(((l R,2R)-2-(ALLYL(4-

METHOXYBENZYL)CARBAMOY ^T L)CYCLOBUTYL)METHYL)-6'- CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SPlRO[BENZO[B][l,4]OXAZEPlNE-3,l'-NAPHTHALENE]-7-CARBOXYL IC ACID

A solution of (S)-reri-buty 1 I /-?.2A?}-2-iaIh ii -l-

2H,2'H-spiro benzo ¾][ l,4]oxazepine-3,l '-naphthalene|-7-carbox late (300 mg, 0.447 mmol) in CH2CI2 (3352 μ,Ε) and TFA ( ! 1 17 μ,Ε) was stirred at ri ovemighi. After this time, the reaction mixture was concentrated in vacuo and partitioned between DCM and saturated sodium bicarbonate. The separated organic layer was dried over MgSC , filtered and concentrated in vacuo to give crude (S'J-S- (((li?,2i?)-2-(allyl(4-methoxybenzyl)carbamoyl)cyclobu1\d)me thyl)-6'-cMoro^ 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r -naphthalene]-7- carboxylic acid (230 mg, 0.374 mmol, 84 % yield), which was used in the subsequent step without further purification.

STEP 5: (S)-5-(((!R,2R)-2-(ALLYL(4-

METHOXYBENZYL)CARBAMOYL)CYCLOBUTYL)METHYL)-N- (ΑΕΕΥΕ8υΕΡΟΝΥΕ)"6'-€ΉΕΟίΙΟ-3 ^! ,4,4',5-ΊΈΤί , ΗΥΒί Ο-2Η,2Ή"

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

To a stirred solution of (5)-5-(((lR,2iR)-2-(allyl(4- methoxybenz 'l)carbamoyl)cyclobulyl)methyl)-6'-chloro-3',4,4',5-tetrahyd ro- 2H,2'H-spiro benzo £> ] [ l ,4]oxazepine-3, l '-naphthalene |-7-carbox lic acid (50 mg, 0.081 mmol) in DCM (1626 μΐ.) was added prop-2-ene-l -sulfonamide (29.5 mg, 0.244 mmol Example 96, step 1), EDC (46,7 mg, 0.244 mmol) and DMAP (29.8 mg, 0.244 mmol). The reaction was stirred at rt for three hours and was then partitioned between DCM and saturated sodium bicarbonate (aq.). The separated organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. Column chromatography (12 g silica gel, hexanes:(99: l EtOAc:AcOH), 1 :0 to 3 : 1 eluent gradient) gave (5)-5-(((lR,2R)-2-(aIly 1(4- methoxybenzyl)carbamoyl)c lobut>d)methyl)-N-(allylsulfonyl)-6 ^, -chloro- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[0] [ l ,4]oxazepine-3, -naphthalene]-7- carboxamide (42 mg, 0.058 mmol, 72 % yield).

STEP 6: (l S,3'R,6'R, 10'E)-6-CHLORO-8 ^! -(4-METHOXYBENZYL)-3,4- DII^YDRO-2H,7 ^, H, 15Ή-SPIRO| APHTHALENE-l ,22 ^, -

[20]OXA[13]TfflA[l ,8, 14jTRIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^!9 ' ²⁴ ]PENTACO S A[ 10, 16, 18,24]TETRAEN] - T.15'-DIONE 13', 13 ^! -DlGXlDE OR

(l S ₅ 3 ^, R,6 ^, R,10 ^, Z)-6-CHLORO-8 ^, -(4-METHOXYBENZYL)-3.4-DIHYDRO- 2H,7'H, 15'H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]THIA[1 ,8, 14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACO S A[ 10, 16, 18,24] TETRAEN] -7', 15'-DIONE 13', 13'-DIOXIDE

A stirred solution of (S)-5-(((lR,2R)-2-(allyl(4- emoxybenz 'l)carbamoyl)cyclobutyl)methyl)-N-(allylsulfonyl)-6'-chloro- 3 4,4 5-tetrahydro-2H,2'H-spiro[benzo[i?j][l,4]oxazepine-3, -naphthalene]-7- carboxamide (41 mg, 0.057 mmol) in toluene (57 mL) was sparged with argon for 20 minutes. After this time, Hoveyda-Grubbs, 2 ^nd generation catalyst (7.1 mg, 0.011 mmol) was added and the reaction mixture was heated at 1 10 °C for 90 minutes. Upon cooling to rt, air was sparged through the mixture for five minutes to deactivate the catalyst. The solvent was then evaporated in vacuo and the resulting residue was purified by column chromatography (4g silica gel; hexanes: (99; 1 EtOAc: AcOH), 1 :0 to 4: 1 eluent gradient) to give the title compound (20 mg, 0.029 mmol, 51 % yield). Stereochemical configuration of the ol efin at the 10' position was not rigorously determined.

STEP 7: ( 1 S,3 ^, R,6'R)-6-CHLORO-8 ^, -(4-METHOXYBE ZYL)-3,4-DIHYDRO- 2H, 7Ή, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,8,14]TWAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACO SA[16,18,24]TRIEN]-7',15'-DIONE 13',13'-DIGXIDE To a stirred solution of either ( IS,3'R,6'R, 10'£)-6-chforo-8'-(4- methoxybenzyl)-3,4-dihydro-2H,7'H, 5'H-spiro[naphthalene- 1 ,22'- 1 20 jo\aj i 3 |thia| 1 A ! 4 |ma/auMrae> do! 1 .7.2.0 ^; " 0 ¹ " ⁿ |pen!acosni 1 0. 16. 1 8.2-i |lcl raenj-7',15 ^! -dione 13', 13 '-dioxide or (LS 3'i?,6'i?,10'Z)-6-chioiO-8'-(4- methoxybenzyl)-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-l,2 2'- [20]oxa[ 3] thia[ 1 ,8, 14]triazatetracyclo[ 14.7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[l 0, 16, 18,24]tet raen]-7',15'-dione 13',13'-dioxide (85 mg, 0.123 mmol) in ethyl acetate (15 mL) was added platinum(IV) oxide (28.0 mg, 0.123 mmol). The flask was evacuated and filled with hydrogen gas (three times) and the reaction mixture stirred at rt for one hour under a hydrogen atmosphere. After this time, an additional portion of platinum (IV) oxide (15 mg, 0.066 mmol) was added and the flask was charged with hydrogen again as described above. The reaction mxture was stirred at rt for five more hours, and was then filtered through celite, washing the filter cake with ethyl acetate. The filtrate was concentrated in vacuo and the resulting crude material was purified by column chromatography (4 g silica gel; hexanes:(99: l EtOAc:AcOH), 1 :0 to 3: 1 eluent gradient) to give (16',3'/?,6'/?)-6-Ο1Ί1ΟΓΟ-8'-(4- methoxybenzyl)-3,4-dihydro-2H,7 ^, H,15'H-spiro[naphthalene-l,22'- i;20]oxa[ 13]thia|;i ,8,14jtriazatetracyc3o| 14.7.2.0 ³ - ⁶ .() ¹⁹ - ²⁴ ;|peniacosa[16,18,24jtrien| ~7',I5'-dione 13',13'~dioxide (20 mg, 0.029 ramol 23 % yield) as a white solid. ^l H NMR (400 MHz, CDCb δ ppm 10.17 is. 1 H), 9.89 (br, s., 1 H), 7.73 id . «/=8.6 Hz, 1 H), 7.51 (dd, J=8.3, 2.1 Hz, 1 H), 7.43 (d, J=2.0 Hz, 1 H), 7.18 (dd, J=8.5, 2.2 Hz, 1 H), 7.09 (d, ./ 2.3 Hz, 1 H), 7.01 - 7.05 (m, 2 H), 6.99 id. ./ 8.4 Hz, 1 H), 6.85 - 6.93 (m, 2 H), 4,33 - 4.54 (m, 2 H), 4,07 - 4.19 (m, 2 H), 3,82 (s, 3 H), 3,63 - 3.75 (m, 3 H), 3,52 - 3.63 (m, 1 H), 3,39 - 3.51 (m, 1 H), 3,29 - 3.38 (m, 1 H), 3.10 - 3.28 (in, 3 H), 2.87 - 2.99 (m, 1 H), 2.71 - 2.83 (in, 2 H), 2.08 (d, ./ 3.9 Hz, I H), 1.85 - 2,04 (m, 5 H), 1.66 - 1.85 (m, 2 H), 1.45 - 1,62 (m, 3 H), ni (ESI, +ve ion) 692.2 (M+H) ⁺ .

EXAMPLE 97. (l S,3'R,6'R,I0'E)"6-CHLORO-3,4-DIHYDRO-2H,7 ^! H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TraA[l ₅ 8, 14]raAZATCTRACYCLO[14.7.2.0 ³ f0 ¹⁹ " ²⁴ ]PENTACO S A[ 10, 16, 18,24] TETRAEN] -T.15 ^! -DIONE 13', 13 ^! -DIOXIDE OR

(1 S,3'R,6'R, 10'Z)-6-CHLORO-3,4-DIHYDRO-2H,7'H, 15Ή- SPIRO I NAPHTHALENE- 1 ,22' -

[20]OXA[ 13]THIA[ 1 ,8, 14] TRI AZ ATETR AC YCL O [ 14.7.2.0 ³ ' ⁶ ,0 ⁱ⁹ - ²⁴ ]PENTACO S A[ 10, 16, 18,24]TETRAEN] ~T, 15'-DIONE 13 ^! , 13'-DIOXIDE

A stirred solution of either (15,3'/?,6'Λ,Ι0'£)-6-Λ1ΟΓΟ-8'-(4- methoxybenz}4)-3,4~dihydro-2H,7H, 15H-spiro[naphthalene-l ,22'~

[20]oxa[13]thia[l,8,14]triazatetracyclo[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]pentacosa[10,16,18,24]te^ raen |-7',15'-dione 13', 13 '-dioxide or (lS',3 ^, R,6 ^, R,10 ^, Z)-6-chloro-8 ^, -(4- methoxybenz}d)-3,4-dihydro-2H,7'H, 15'H-spirofnaphthalene- 1 ,22'-

[20]oxa[13]thia[I,8,14]triazatetracyeM

raen]-7',15'-dione 13 ',13 '-dioxide (20 mg, 0.029 mmol; Example 96, Step 7) in trifluoroacetic acid (2232 μ,Ε, 29.0 mmol) was heated at 65 °C for five hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was partitioned between DCM and saturated sodium bicarbonate (aq.). The organic layer was dried over MgS0 ₄ , filtered and concentraetd m vacuo. Column chromatography (4 g silica gel; hexanes: (99: 1 EtOAc:AcOH), 1 :0 to 3: 1 eluent gradient) gave the title compound (2.8 mg, 4.91 μιηοΐ, 16.95 % yield) as a white solid. Ή NMR (400 MHz, CDCh) δ ppm 9.68 (s, 1 H), 7.67 id. ./ 8.4 Hz, 1 H), 7.26 - 7.30 ( ns. 1 H), 7.18 (dd, ,/ H 5. 2.2 Hz, 1 H), 7.09 (d, ,/ 2 2 Hz, 1 H), 6,97 (d, J=8.2 Hz, 1 H), 6.89 (d, J=2,0 Hz, 1 H), 5,94 (t, .7=5.4 Hz, 1 H), 5.87 (dt, J=15.6, 7.5 Hz, 1 H), 5.67 - 5.77 (m, 1 H), 4.22 (dd, J=14.3, 8.0 Hz, 1 H), 4.09 (s, 2 ! ! }. 4.03 (dd, ,7=14.1 , 7.0 Hz, 1 H), 3.74 - 3.91 (m, 3 H), 3.67 (d, J=13.9 Hz, 1 H), 3.23 - 3.36 (m, 2 H), 2,71 - 2.82 (m, 4 H), 1 ,99 - 2.08 (m, 2 H), 1 ,88 - 1.97 (m, 2 H), 1.74 - 1.88 (m, 2 H), 1.52 (t, .7=1 1.5 Hz, 1 H). m/z (ESI, +ve ion) 570.2

EXAMPLE 98. (lS,3'R,6'R)-6-CHLORO-3,4-DIHYDRO-2H,7'H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,8^4]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACO S A[ 16, 18,24]TRIENE]-7', 1 S'-DIONE 13', 13'-DIOXIDE

A stirred solution of (l^,3 ^, i?,6'i?)-6-chloro-8'-(4-methoxybenzyl)-3,4- dihy dro-2H ₅ 7 ^* H, 15 'H-spiro [naph thai ene- 1 ,22'- 3 |shia| f 8. ! 4 |ina/aieirac> cloi Ι 4, 7.2.0 ^{; ί} ' 0 ¹ " ⁿ |pcn!ac<«ai 1 . ! 8.24 |incn -7',15'-dione 13',.13'-dioxide (15 mg, 0.022 mmol, Example 96, step 7) in

trifluoroacetic acid (835 μΕ, 10.8 mmol) was heated at 65 °C for three hours. After this time, the reaction mixture was cooled to rt and concentrated in vacuo. The resulting residue was partitioned between DCM and saturated sodium bicarbonate (aq.). The aqueous layer was extracted with DCM (2X) and the combined organics were dried over MgSC¼, filtered and concentrated in vacuo. Column chromatography (4 g silica gel; hexanes:(99: l EtOAc:AcOH), 1 :0 to 2: 1 eluent gradient) gave (15,3 ^f ?,6 ^f ?)-6-ch]oro-3,4-dihydro-2H,7'H, 15'H- spiro[naphthalene-l,22'- [20]oxa[ 13]thia[l ,8 4]triazatetr^

]-7',15'-dione 13',13'-dioxide (4.9 mg, 8,6 μτηοί, 39 % yield) as a white solid. ^" Ή NMR (400 MHz, (1X 1 ;) δ ppm 9.86 - 10,23 (m, 1 H), 7.71 (d, ./ 8.6 Hz, 1 H), 7.39 (dd, J=8.2, 2.0 Hz, 1 H), 7.23 (d, J=2.0 Hz, 1 H), 7.18 (dd, J=8.6, 2.3 Hz, 1 H), 7.09 (d, ,/ 2.2 Hz, 1 H), 6.96 id. ./ 8.4 Hz, 1 H), 5.95 (t,■/ 6.3 Hz, 1 H), 4.03 - 4.12 (m, 2 H), 3.96 i d. ./ 15. ! Hz, 1 1 1 ). 3.70 - 3.82 (ra, 1 1 1 ). 3.63 - 3.70 (ra, 2 H), 3.41 - 3.50 (m, 1 H), 3.07 - 3.24 (m, 3 H), 2.74 - 2.84 (m, 4 H), 2,04 - 2.15 (m, 1 H), 1.86 - 2.03 (m, 6 H), 1.69 - 1.83 (m, 4 H), 1.44 (t, J=l 1.9 Hz, 1 H). m / (ESI, +ve ion) 572.2 (M+H) ⁺ .

EXAMPLE 99. (lS,3'R,6'R)-6-CHLORO-8'-METHYL-3,4-DIHYDRO- 2Η,7Ή, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,8 4]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACO S A [ 16, 18,24] TRIEN] -7', 15 '-DIONE 13 ', 13 '-DIOXIDE

STEP 1 : (S)-TERT-BUTYL 5-(((lR,2R)-2-

(ALLYL(METHYL)CARBAMOYL)CYCLOBUTYL)METHYL)-6'-CHLORO- ;r,4,4 5-TETRAHYDRO-2H,2Ή-SPIRO[BENZO[B][l,410XAZEPINE-3,l '- ΑΡΗΊΉ ALENE] - 7 -C ARB OXYL ATE

To a stirred solution of (l /?,2/?)-2-(((<S)-7-(/eri-butoxycarbonyl)-6'-chloro- 3^1'-dihydro-2H,2^-spiro[benzo[ >] ^^^

yl)methyl)eyclobutaiiecarboxylic acid (125 nig, 0.244 mmol; Example 96, step 2) in DCM (1221 μΕ) was added EDC (56.2 mg, 0.293 mmol), HOBT (44.9 mg, 0.293 mmol) and N-methylallylamine (34.7 μΕ, 0.488 mmol). The resulting reaction mixture was stirred at rt for four hours and then partitioned between DCM and saturated sodium bicarbonate (aq.). The organics were dried over MgS€>4, filtered and concentrated in vacuo. The resulting residue by column chromatography (12 g silica gel; hexanes:(99: l EtOAc:AcOH), 1 :0 to 85:5 eluent gradient) to give (S)-tert-butyl 5-(((l ?,2 ?)-2- (allyl(methyl)carbamoyl)cyclobutyl)m

spiro[benzo[^] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (120 mg, 0.212 mmol, 87 % yield).

STEP 2: (S)-5-(((lR,2R)-2-

(ALLYL(METHYL)CARBAMOYL)CYCLOBUTYL)METHYL)-6'-CHLORO-

3 ^f ,4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7 -C ARB OXYLIC ACID

A solution of (S)-ter(-huiyl 5-(((lR,2R)-2- (allyl(methyl)carbamoyl)cydobutyi)m

spiro [benzo [b] [ 1 ,4] oxazepine~3 , Γ -naphthalene] -7-carboxy 1 ate ( 120 mg, 0.212 mmol) in DCM (1593 μΕ) and TFA (531 μΕ) was stirred at rt for six hours and then concentrated in vacuo. The residue was partitioned between DCM and saturated sodium bicarbonate (aq.). The organics were dried over MgS0 ₄ , filtered and concentrated in vacuo to give crude (S)~5~(((lR,2R)-2~

(aliy3(methyl)carbamoyl)cyciobutyi^^

spiro[benzo[¾[l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid (90 mg, 0. 18 mmol, 83 % yield) as a white solid.

STEP 3: (S)-5-(((lR,2R)-2-

(ALLYL(METHYL)CARBAMOYL)CYCLOBUTYL)METHYL)-N- (ALLYLSULFONYL)-6'-CHLORO-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO[BENZO[B][l,4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXAMIDE

To a stirred solution of (5)-5-(((li?,2i?)-2- (allyl(methyl)carbamoyl)c 'clobutyl)methyl)-6'-chloro-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[6 | [l,4]oxazepine-3,r-naphtha3ene|-7-carboxylic acid (70 mg, 0.138 mmol) in DCM (1375 μί) under a nitrogen atmosphere was added prop-2-ene-l- sulfonamide (33.3 mg, 0.275 mmol; Example 96, step 1) and DMAP (33.6 mg, 0.275 mmol). The reaction mixture was cooled at 0 °C and treated with EDC (52,7 mg, 0.275 mmol) portionwise over one minute. The reaction was allowed to warm to rt overnight. After this time, the reaction mixture was partitioned bewteen DCM and saturated sodium bicarbonate (aq.). The organic layer was dried over MgSC¼, filtered and concentrated in vacuo. The residue was purified by column chromatography (12 g silica gel; hexanes:(99: l EtOAc:AcOH), 1 :0 to 4: 1 eluent gradient) to give (5)-5-(((li?,2i?)-2- (diyl(methyl)carbamoyl)cycIobutyl)meihyl)-N-(allyisdfony

tetTahydro-2H,2'H-spiro[benzo[ft][l,4]oxazepine-3,r-napht halene]-7-carboxamid^ (65 mg, 0.106 mmol, 77 % yield).

STEP 4: (1S,3 ^! R,6'R, 10T;)-6~CHLORO-8 ^! -METHYL-3,4-DIHYDRO~

2Η,7Ή,15Ή-8Ρ11 0[ΝΑΡΗΊΉΑΕΕΝΕ-1,22'- [20]OXA[13]THIA[l ₅ 8 4]mAZATET¾ACYCLO[14 .2 ³ f0 ¹⁹ " ²⁴ ]PENTACO S A[ 10, 16, 18,24] TETRAEN] -7', 15'-DIONE 13', 13'-DIOXIDE OR

(1S,31 ,6'R,10'Z)-6-CHLORO-8'-METHYL"3,4-DIHYDRO-2H,7'H,15 ^, H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1 ,8, 14] TRI AZ ATETR AC YCL O [ 14.7.2.0 ³ ' ⁶ ,0 ⁱ⁹ - ²⁴ ]PENTACO S A[ 10, 16, 18,24]TETRAEN] ~T, 15'-DIONE 13', 13'-DIOXIDE

A stirred solution of (5)-5-(((li?,2i?)-2- (dlyl(memyl)carbamoyl)cyclobutv'l)methyl)-N-(allylsulfonyl)- 6'-chloro-3',4,4 ^, ,5- tetrahydro-2H,2'H-spiro[benzo[6] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxamide (0.065 g, 0.106 mmol) in toluene (106 niL) was sparged with argon for 20 minutes. Hoveyda-grubbs 2" ^d generation catalyst (0.013 g, 0.02 ! mmol) was added and the reaction mixture was heated at reflux for 90 minutes. After this time, the reaction mixture was cooled to rt and air was bubbled through it for 10 minutes to deactivate the catalyst. Solvents were evaporated in vacuo and the product was purified by column chromatography (12 g silica gel, hexanes: (99: 1 EtOAc:AcOH), 1 :0 to 85: 15 eluent gradient) to give the title compound (0.030 g, 0.051 mmol, 48 % yield). The stereochemical configuration of the olefin at the 10' position was not rigorously determined.

STEP 5: (18,: Κ,6'Κ)-6-εΗΕΟΚΟ-8'-ΜΕ1ΉΎΕ~3,4-ΟΙΗΥΟΚΟ-2� �,7Ή, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ l,8,14]TRIAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ jPENTACO SA[ 16, 18,24]TRIEN]-7', 15'-DIONE 13', 13'-DIOXIDE

To a solution of either (kV,3'^,6'^, 10'Q-6~chloro~8 ^! ~methyl-3,4-dihydro- 2H,7'H, 15'H-spiro[naphthalene- 1 ,22'- 3 |ihuij ! .8. l 4 |iria/aieirac> cloi i 4.7.2. o ^; ".0 ^{| u} |peniaco:>aj ! 0. 1 . 1 8.24 |iei raen]-7", 15 -dione 13', 13'-dioxide or ( IS,3'R,6'R, 10'Z)-6-chioro-8'-methyl-3,4- dihydro-2H,7'H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,8,14]triazatetracyclo[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]pentacosa[10,16,18,24]tet raen |-7',15'-dione 13',13'-dioxide (15 mg, 0.026 mmol) in ethyl acetate (2568 μΙ_) was added platinum (IV) oxide (5.83 mg, 0.026 mmol), and the reaction mixture was placed under a hydrogen atmosphere and stirred at rt for two hours. After this time, an additional portion of Pt (IV) oxide (5.0 mg, 0.022 mmol) was added and stirring under hydrogen was continued for two more hours. The reaction mixture was then filtered through celite, washing the filter cake with EtOAc. The solvent was evaporated in vacuo and the product was purified by column chromatography (4 g silica gel; hexanes:(99: l EtOAc:AcOH), 1 :0 to 85: 15) to give (1Δ 3'Λ,6'Λ 6- chloro-8'-methyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-l ,22'- 14.7.2. ^{! |} |pentaco a! ! 6. i 8.24|irien l -7',15'-dione 13',13'-dioxide (6.0 mg, ΙΟμηιοΙ, 40 % yield) as a white solid. ¾ NMR (400 MHz, CDCh) δ ppm 10.17 (s, 1 H), 7.74 (d, ./ 8.4 Hz, 1 H), 7.50 (dd, J=8.3, 2.1 Hz, 1 H), 7.37 (d, J=2.0 Hz, 1 H), 7.19 (dd, J=8.6, 2.3 Hz, 1 H), 7.09 (d, ./ 2.2 Hz, 1 1 1 ). 6.97 (d, ./ K.4 Hz, 1 H), 4.06 - 4.20 { in. 2 H), 3.60 - 3.78 { in. 3 H), 3.34 - 3.45 (m, 1 H), 3.23 - 3.32 (m, 2 H), 3.05 - 3.22 (m, 2 H), 2.97 (s, 2 H), 2.91 (q, ,7=9,4 Hz, 1 H), 2.74 - 2.81 (m, 2 H), 2.23 - 2.32 (m, 1 H), 2.09 - 2.17 (m, 4 H), 1.40 - 2.03 (m, 12 H). m/z (ESI, +ve ion) 586.2 { M l ! )

EXAMPLE 100. (l S,3'R,6'R,7'S,8 ^! E, l() ^! S,12'R)-6-CHL()RO-7'-HYDR()XY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[1,14]DIAZAPENTACYCLO[14.7.2.1 ¹⁰ ' ¹² .0 ⁵ - ⁶ .0 ¹⁹ ' ² ]HEXAC QSA[8,16,18,24]TETRAEN ]-15'-QNE 13', '-DIOXIDE

STEP 1 : METHYL 3,3-DIMETHOXYCYCLOBUTANECARBOXYLATE

A solution of 3-oxocyclobutaaecarboxylic acid (10.5 g, 92.0 mmol) mdp- toluenesulfonic acid monohydrate (0.700 g, 3.68 mmol) in MeOH (300 niL) was heated at reflux overnight. After this time, the reaction mixture was cooled to rt, concentrated to a small volume in vacuo, and diluted with water. The resulting mixture was extracted with DCM (2X). The organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo to give methyl 3,3- dimethoxycyclobutanecarboxylate (14 g, 80 mmol, 87 % yield).

STEP 2: (3,3 -DIMETHOXYC YCLOBUTYL )METH ANOL

To a stirred solution of methyl 3,3-dimethoxycyclobutanecarboxylate (14 g, 80 mmol) in THF (161 ml) at 0 °C under a nitrogen atmosphere was added lithium aluminum hydride (2M in THF, 44.2 ml, 88 mmol) dropwise over five minutes. When the addition was complete, the ice bath was removed and the reation was stirred at rt for one hour. The reaction was then carefully quenched by addition of water (6 mL), 20 g of celite were added, and the mixture was stirred vigorously. The resulting slurry was filtered, washing the filter cake with ethyl acetate. Concentration of the filtrate in vacuo gave (3,3- dimethoxycyclobutyl)methanol (9.0 g, 62 mmol, 77 % yield).

STEP 3: TERT-B UTYL((3 , 3 -

DIMETH()XYCYCLOBUTYL)METH()XY)DIPFIENYLSILANE

To a stirred solution of (3,3-dimethoxyc clobutyl)methanol (8.0 g, 55 mmol) in DCM (219 mL) was added triethylamine (1 1.4 mL, 82.0 mmol), DMAP (0.669 g, 5.47 mmol) and fe/ -butyldiphenylsilyl chloride (15.5 mL, 60.2 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was then partitioned between DCM and NaFICC (sat. aq. solution). The organic layer was washed with brine, dried over MgSCn, filtered and concentrated in vacuo. The resulting oil was adsorbed onto a 40g silica gel cartridge, and purified by column chromatography (220 g silica gel; hexanes:EtOAc, 1 :0 to 20:80 eiuent gradient) to give ifer^but>d((3,3-dimethoxycyclobutyl)methoxy)diphenylsilan e (14 g, 36 mmol, 66 % yield) as a colorless oil. STEP 4: 3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTANONE

To a stirred solution of i¾fi-butyi((3,3- dimethoxycyclobutyl)methoxy)diphenylsilane (13 g, 39 mmol) in acetone (75 mL) and water (37,6 mL) was added /?-toluenesulfonic acid monohydrate (0,643 g, 3,38 mmol). The reaction mixture was heated at 55 °C for four hours, and was then cooled to rt and partitioned between EtOAc and saturated NaHCC (aq.). The organic layer was dried over MgS€>4, filtered and concentraetd in vacuo to give 3-(((ter/-butyldiphenylsilyl)oxy)methy )cyclobutanone (9.06 g, 26.8 mmol, 79 % yield) as a white solid,

STEP 5: (lS,3S)-3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTANOL AND (1 R,3S)- 3-(((TCRT-BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTANOL

To a stirred solution of 3-(((fer?- but diphenyisiiyl)oxy)niethyl)cyclobutanone (5.00 g, 14.8 mmol) in THF (46.9 mL) was added sodium borohydride (0.559 g, 14,8 mmol) followed by MeOH (2,345 mL). The resulting reaction mixture was stirred at rt for two hours. After this time, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo to give 3-(((fer -butyldiphenylsily])oxy)methy])cyclobutanol (mixture of c and trans isomers, predominantly cis; 5.00 g, 14.7 mmol, 99 % yield). STEP 6: TRANS-3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTANOL

To a stirred solution of 3-{{{tert- butyldiphenylsiiyl)oxy)methyl)c} _' Xlobutanol (diastereomer mixture favoring the cis isomer prepared in Step 5 above; 3,80 g, 11.2 mmol) in THF (1 12 mL) was added benzoic acid (2.044 g, 16.74 mmol) and triphenylphosphme (4.39 g, 16.7 mmol). The reaction was cooled to 0 °C for 10 minutes and then (£)-diisopropyl diazene-1 ,2-dicarboxylate (3.25 mL, 16.7 mmol) was added dropwise via syringe over 10 minutes. After this time, the reaction was stirred at 0 °C for 30 minutes and was then stirred overnight at room temperature. The reaction mixture was then partitioned between EtOAc and brine. The organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. The crude product was adsorbed onto a 40 g silica gel cartridge and purified by column chromatography (80 g silica column; hexanes:EtOAc, 1 :0 to 95:5 eluent gradient) to give the intermediate /ram"-3-(((/eri-butyldiphenylsilyl)oxy)methyl)cyclobutyl benzoate (3.7 g) containing minor impurities.

To a stirred solution of fra¾v-3-(((fe -buty diphenylsilyl)oxy)methy1)cyxlobuty benzoate (3.7 g, 8.3 mmol) in THF (41.6 mL) was added a solution of sodium hydroxide (0.333 g, 8,32 mmol) in water (6 mL) followed by MeOH (6 mL). The reaction mixture was stirred at rt for one hour and then partitioned between EtOAc and water. The organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (80 g silica gel, hexanes: EtOAc, 1 :0 to 4: 1 solvent gradient) to give trans-3-(((tert- butyldiphenyisilyl)oxy)methyl)cyclobutanol (2.3 g, 6.7 mmol, 61 % overall yield from the diastereomer mixture prepared in Step 5). STEP 7: TRANS-3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTYL

METHANESULFONATE

To a stirred solution of trans -3-(((tert- butyldiphenylsilyl)oxy)methyl)cyclobutanol (2.3 g, 6.7 mmol) in DCM (33.8 ml) was added triethylamine (1.883 mL, 13.51 mmol) followed by methanesulfonyl chloride (0.892 mL, 11.4 mmol). The reaction mixture was stirred at rt for two hours and then partitioned between DCM and 1M HCl (aq.). The organic layer was dried over MgSC¼, filtered and concentrated in vacuo to give crude · «5-3- (((/ert-butyidiphenylsilyl)oxy)methyl)cyclobutyl methanesulfonate (2.43 g, 5.80 mmol, 86 % yield), which was used in the subsequent step without further purification.

STEP 8: CIS-3-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)CYCXOBUTYL)THIO)PYRIMIDT

NE

To a stirred solution of trans~3-(((tert- butyidiphenylsilyl)oxy)methyl)cyclobutyl methanesulfonate (2.43 g, 5.80 mmol) in DMF (23.22 mL) was added potassium carbonate (1.203 g, 8.71 mmol) and 2- mercaptopyrimidine (0.781 g, 6.97 mmol). The resulting reaction mixture was heated at 70 °C for two hours. After this time, additional portions of 2- mercaptopyrimidine (0.3g, 2.7 mmol) and K2CO3 (0.5g, 3.6 mmol) were added and the reaction mixture was stirred at 70°C for four more hours. Upon cooling the rt, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with brine (2X), dried over MgS€>4, filtered and concentrated in vacuo. The crude product was adsorbed onto a 24 g silica cartridge and purified by flash chromatography (80 g silica: hexanes: EtOAc, 1 :0 to 4: 1 solvent gradient) to provide c s-2-((3-(((rerf- butyldiphenylsilyl)ox niethyl)cyclobutyl)thio)pyrimidine (2.1 g, 4.8 mmol, 83 % yield). STEP 9: ClS-3-(PY lMIDI -2-YLTHIO)CYCLOBUTYL)METHANOL

To a stirred solution of6v~2-((-3-(((teri- but diphenylsiiyl)oxy)niethyl)cyclobuty )thio)pyriiiiidine (2.1 g, 4.8 mmol) in THF (48,3 mL) was added tetrabutylamrnoniurn fluoride (1 M in THF; 5.31 mL, 5.31 mmol). The resulting reaction mixture was stirred at rt for two hours and then partitioned between EtOAc and brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo. Column chromatography (24 g silica gel; hexanes: EtOAc, 1 :0 to 3: 1 solvent gradient) gave c«-(3-(pyrimidin-2- ylthio)cyclobutyl)methanol (0.70 g, 3.6 mmol, 74 % yield).

STEP 10: CIS-3-(PYRI IDIN-2- YLTHIO)CYCLOBUTANECARBALDEHDYE

To a stirred solution of c s ^, -(3-(pyrimidin-2-ylthio)cyclobutyl)methanol (0.70 g, 3.6 mmol) in DCM (17.83 mL) was added Dess-Martin periodinane (1.513 g, 3.57 mmol), and the resulting reaction mixture was stirred at rt for 30 minutes. After this time, the reaction mixture was diluted with diethyl ether, saturated aqueous sodium thiosuifate (sat aq. solution) was added, and the resulting mixture was stirred at rt for 20 minutes. The organic layer was separated, washed with sodium thiosuifate (sat. aq. solution), NaHCCb (sat. aq. solution), dried over MgS0 ₄ , filtered and concentrated in vacuo to give cis-3- (pyrimidin-2-ylthio)cyclobutanecarbaldehyde (0.57 g, 2.9 mmol, 82 % yield).

STEP 1 1 : 2-((CIS-3-VI TYLCYCLOBUTYL)THIO)PYRI IDINE

To a stirred solution of methyltriphenylphosphonium bromide (5.24 g, 14.7 mmol) in THF (29.3 mL) was added potassium ?e/ -butoxide (0.988 g, 8.80 mmol), and the resulting reaction mixture was stirred at rt for 30 minutes. After this time, the reaction mixture was cooled to 0 °C and treated with a solution of c s~3"(pynmidin~2"ylthio)cyclobutanecarbaldehyde (0.57 g, 2.93 mmol) in THF (3 mL) dropwise over five minutes. The resulting mixture was stirred at 0 °C for 30 minutes and at rt. overnight. On the following day, the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12 g silica gel; hexanes:EtOAc, 1 :0 to 2: 1 solvent gradient) gave 6 v~2-((3-vinylcyclobutyl)thio)pyrimidine (0.28 g, 1.456 mmol, 49.6 % yield). STEP 12: 2-((CIS-3-VINYLCYCLOBUTYL)SULFONYL)PYRIMIDINE

To a stirred solution of c 5"-2-((-3-vinylcyclobutyl)thio)pyrimidine (280 mg, 1.46 mmol) in DCM (7281 μΐ.,) was added jweto-chloroperoxybenzoic acid (ca. 77 %, balance /weto-chlorobenzoic acid and water; 718 nig, 3.20 mmol). The reaction mixture was stirred at rt for two hours and partitioned between DCM and NaHCCb. The organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. Column chromatography (12 g silica gel; hexanes:EtOAc, 1 :0 to 2: 1 solvent gradient) gave a v-2-((3-vinylcyciobut>'l)sulfonyl)pyrimidine (140 mg, 0.624 mmol, 43 % yield).

STEP 13 : CIS-3- VINYLCYCLOBUTANE- 1 -SULFONAMIDE

To a stirred solution of c s-2-((-3-vinylcyclobut 'l)sulfonyl)pyrirnidine (0.14 g, 0.624 rnmol) in MeOH (6.24 mL) was added sodium methoxide (0.143 mL, 0.624 rnmol), and the resulting reaction mixture was stirred at rt for 45 minutes. After this time, the solvent was evaporated in vacuo. Diethyl ether was added to the mixture, and the solid was filtered, washed with diethyl ether and dried under vacuum to give crude sodium c/.v-3-vinylcyclobutane-l -sulfmate (0.1 g, 0.595 rnmol, 95 % yield). To a stirred solution of sodium cz ^' s-3-viny lc clobutane- 1 -sulfmate (0.1 g,

0.595 rnmol) in water (5.95 mL) was added sodium aceiate (0.098 g, 1 .189 mmol) and hydroxylamine-O-sulfonic acid (0.101 g, 0.892 mmol), and the reaction mixture was heated at 50 °C for one hour. After this time, the reaction was cooled to rt and basified with IM aqueous NaOH. The aqueous layer was extracted with EtOAc (2X), DCM (2X), and the combined organics were dried over MgSOi, filtered and concentrated in vacuo to give 35 mg of czs-3-vinylcyclobutane-l- sulfonamide. The aqueous layer was concentrated in vacuo and dried under high vacuum overnight. The resulting white solid was triturated with DCM, filtered and dried under high vacuum and additional 30 mg of desired product. Both product fractions were combined to give cz ^' s-3-vinylcyclobutane-l -sulfonamide (0.062 g, 0.39 mmol, 65 % yield). STEP 14: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -HYDROXY-3-((l S,3R)-3- SULFAMOYLCYCLOBUTYL)ALLYL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALENE] -7-C ARBOXYLIC ACID

A solution of Intermediate AA12A (62 mg, 0.12 mmol) and cis-3- vinylcyclobutane-l-suifonamide (58.8 mg, 0.365 mmol) in 1,2-dichloroethane (1736 μΕ) was sparged with argon for 10 minutes. The reaction mixture was then charged with (l,3-dimesitylimidazolidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium(VI) chloride (7.6 mg, 0.012 mmol) and stirred at rt for three hours, after which time the catalyst was then deactivated by sparging air through the mixture for five minutes. Solvents were removed in vacuo and the residue was purified by column chromatography (4 g silica gel; hexanes:(99:l Et()Ac:AcOH), 1:0 to 6:4 solvent gradient) to give (S)-6'-chloro-5-(((lR,2R)-2- ((5, )-I-hydroxy-3-((LS',3 ?)-3-sulfamoylcyckjbutyi)al]yl)cyclobufy

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[¾][l,4]oxazepine-3, r-naphthalene]-7- carboxylic acid (40 mg, 0.067 mmol, 54.7 % yield).

STEP 15: (lS,3'R,6¾,7 ^! S,8'E,l()'S,12 ^, R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |20i()XA| i ^• .|UUA| l..i-l|i)!.\/.\Pi-::\ i,\C VCi. Ol i -1.7.2 ! ^{)() 1} ".0 ^: ".0 ^; '·" ^; IHL.XAC OS A[ 8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

To a stirred, 0 °C solution of (6>6'-cWoro-5-(((lR,2R)-2-((^

hydroxy-3-((LS3i?)-3-sulfamoylcyclobu 4)aliyl)cyclobutyl)me ^ ^{^}

tetrahydro-2H,2'H-spiro[benzo[i][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (40 mg, 0,067 mraol) in DCM (3.33E+04 μΐ,) was added DMAP (13.8 mg, 0.113 mmol) followed by EDC (25.5 mg, 0.133 mmol). The resulting reaction mixture was stirred at rt over the weekend and then washed with IM aqueous citric acid. The organic layer was dried over MgSi filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (4 g silica gel, DCM:acetone, 1:0 to 9:1 solvent gradient) to give

(1Δ37?,6 ζ 7¾8 ζ 1 OS 12 ^

spiro [naphtha] ene- 1 ,22'-

[20]oxa[l 3]thia[l, 14]diazapentacyclo[14,7.2.1 ¹⁰ · ¹² .0 ³ ^ 0 ¹⁹ - ²⁴ ]hexacosa[8,16,l 8,24] tetraen]-15'-one 13',13'-dioxide (8.5 mg, 22 % yield) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ ppm 8,05 (br. s,, 1 H), 7.71 (d, ./ 8.6 Hz, 1 H), 7.17 (dd, J=8.4, 2.3 Hz, 1 H), 7.10 (d, ./ 2.2 Hz, 1 H), 6.91 - 7.01 (m, 3 H), 5.97 (dd, J=15.7, 6.6 Hz, 1 H), 5.52 (dd, J=15.3, 7.0 Hz, 1 H), 4.02 - 4.17 (m, 4 H), 3.71 - 3.85 (m, 2 H), 3.34 id../ 14.3 Hz, 1 H), 3.14 (dd, .7=15.2, 10.1 Hz, 1 H), 2.93 - 3,08 (m, 2 H), 2.82 - 2,93 (m, 1 H), 2.68 - 2.81 (m, 3 H), 2.51 (br. s„ 1 H), 2.29 - 2,41 (m, 1 H), 2.15 - 2,25 (m, 1 H), 2.04 (d, .7=10.8 Hz, I H), 1.78 - 1.99 (m, 4 H), 1.58 - 1.72 (m, 2 H), 1.40 - 1.51 (in, 2 H). m/z (ESI, +ve ion) 585.2 ( +H) ⁺ .

EXAMPLE 101. (lS,3'R,6'R,7'S,l() ^! S,12'S)-6-CHLORO-7'-HYDROX ^;" -3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |20i()XA| i ^• .|UUA| IJ-l|i)!.\/.\Pi-::\ ΓΑίΎΠ.ΟΙ i -1.7.2 ! ^{)() 1 "} .0 ^: ".0 ^;' ·" ^; |H!-.XAC OS A[ 16, 18,24] TRlENj - 15'-ONE 13 13 '-DIOXIDE

To a stirred solution of (15 ^, ,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E ₅ 10 ^, 5 ^, ,12 ^, R)-6-c-iloro-7 ^, -hydroxy- 3 ,4-dihy dro-2H, 15 'H-spiro [naphthalene- 1 ,22'- [20]oxa[l 3]thia[ 1,14]diazapentacyclo[14.7.2.1 ^{i0 2} ,0- ⁶ .0 ^l9 - ²⁴ ]hexacosa[8, 16, 8,24] tetraen]-15'-one 13', 13'-dioxide (5.0 mg, 8.6 μηιοΐ, Example 100, step 15) in EtOAc (1715 μΐ) was added platinum(lV) oxide (1.95 mg, 8.6 μη οΐ). The flask was evacuated and placed under a hydrogen atmosphere and the reaction mixture was stirred at rt for 90 minutes. The reaction mixture was then filtered through celite, washing the filter cake with EtOAc. Evaporation of solvents gave

(15 3'ii,6 ^7 ,10'^12 ^, 5)~6"cWoro-7 ^! iydroxy-3,4-dihydro-2H,15'H- spiro[naphthalene-l,22'- [20]oxa[13]mia[U4]diazapenta^

en]-15'-one 13',13'-dioxide (2.1 mg, 3.6 μιηοΐ, 42 % yield) as an off-white solid. ¾ NMR (500 MHz, CD2CI2) δ ppm 8.15 (br. s., 1 H), 7.72 (d, ./ K.6 Hz, 1 H),

7.17 (dd, ,/ X 4. 2.3 Hz, 1 1 1 ). 7.09 (d, ,/ 2 4 Hz, 1 H), 6.91 - 7.04 (m, 3 H), 4.06 - 4.17 (m, 2 H), 4.01 (quin, .7=8.7 Hz, 1 H), 3.76 (d, .7=14,7 Hz, 1 H), 3.71 (d, ./ 14.4 Hz, 1 H), 3.52 - 3.61 (m, 1 H), 3.36 (d, ./ 1 -1.2 Hz, 1 H), 3.30 (dd, J=15.3, 8.4 Hz, 1 H), 2.70 - 2.84 (m, 2 H), 2.61 - 2.69 (m, 1 H), 2.48 - 2.59 (m, 2 H), 2.38 - 2.48 (m, 2 H), 2.18 - 2.30 (m, 2 H), 2.04 (d, J=9.8 Hz, 2 I I ). 1.80 - 1 ,96 (m, 3 H), 1.64 - 1.79 (m, 3 H), 1,42 - 1.63 (m, 5 H). m/z (ESI, +ve ion) 585.3 ( M · f i

EXAMPLE 102. (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THIA[ 1 , 14]DI AZ APENTACYCLO[ 14,7.2, 1 ^{i 0J 2} .0 ³ - ⁶ .0 ¹⁹ " ²⁴ ]HEXAC OSAI 8.16, 18,24]TETRAEN]-i.5'-ONE 13', 13 ^! -DIOXIDE

STEP 1 : (lS,3S)-3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTYL

METHANESULFONATE AND (lR,3S)-3-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTYL

METHANESL1LFONATE

To a stirred solution of 3-(((tert- butyldiphenylsilyl)oxy)methyl)cyclobutanol (cis and trans mixture; 5,00 g, 14.7 mmol; Example 100, Step 5) in DCM (73.4 mL) was added triethylamine (4.09 ml, 29.4 mmol) followed by methanesulfonyl chloride (1.72 mL, 22.0 mmol). The reaction mixture was stirred at rt overnight and then partitioned between DCM and 1M HC1 (aq.). The organic layer was washed with brine, dried over MgSCu, filtered and concentrated in vacuo to give crude 3-(((tert- butyldiphenylsilyl)oxy)methyl)cyclobutyl methanes ulfonate (cis and trans mixture; 6.00 g, 14.3 mmol, 98 % yield), which was used in the subsequent step without further purification.

STEP 2: 2-(((lR,3R)-3-(((TERT- BUTYLDIPHENYLSlLYL)0XY)METI-n L)CYX L0BUTYL)THI0)PYRlMIDI NE AND 2-(((l S,3R)-3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTYL)TFiIO)PYRIMIDI

NE

To a stirred solution of 3-(((,¾/ -but}4diphenylsilyl)oxy)methyl)cyclobuty'l methanes ulfonate (cis and trans mixture; 6.00 g, 14.3 mmol; Example 102, Step 1) in DMF (57.3 mL) were added 2-mercaptopyrimidine (1.929 g, 17.20 mmol) and potassium carbonate (2.97 g, 21.50 mmol). The reaction mixture was stirred at rt over the weekend and then partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (80 g silica gel; hexanes:EtOAc, 1 :0 to 4: 1 solvent gradient) to give 2-((3~(((ferf~ butyldiphenylsilyl)oxy)methyl)cyclobutyl)thio)pyrimidine (mixture of cis and trans isomers; 5.00 g, 11.50 mmol, 80 % yield)

STEP 3: ((lR,3R)-3-(PYRlMlDlN-2^LTH10)CYCLOBUTYL)MEraANOL AND (( 1 S,3R)-3-(PYRTMIDIN-2-YLTHTO)CYCLOBUTYL)METHANOL

To a stirred solution of 2-((3-((( err- but diphenylsilyl)oxy)methyl)cyclobut )thio)pyriiriidine (cis and trans mixture: 5.00 g, 1 1.5 mmol; Example 102, Step 2) in THF (115 mL) was added TBAF (I M in THF; 12.65 ml,, 12.65 mmol), and the resulting reaction mixture was stirred at rt overnight. On the following day, the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo to give a crude residue that was further purified by column chromatography (40 g silica gel: hexanes: EtOAc, 1 :0 to 1 :4 solvent gradient) to provide (3-(pyrirnidin-2-ylthio)c 'clobutyl)methanol (cis and trans mixture; 1.86 g, 9.48 mmol total, 82 % yield). STEP 4: ( lR,3R)-3-(PYRTMIDIN-2-

YLTHIO)CYCLOBUTANECARB ALDEHYDE AND (l S,3R)-3-(PYRIMIDlN~ 2-YLTHIO)CYCLOBUTANECARB ALDEHYDE

To a stirred solution of (3-(pyrimidin-2-ylthio)cyclobut d)methanol

(mixture of cis and trans isomers; 1,75 g, 8.92 mmol; Example 102, Step 3) ^' DCM (44.6 ml) was added Dess-Martin periodinane (4.54 g, 10.7 mmol), and the resulting reaction mixture was stirred at rt for 20 minutes. An additional portion of Dess-Martin periodinane (1.5 g, 7.6 mmol) was added, and stirring was continued for 30 minutes, after which time a third portion of Dess-Martin periodinane was added (1.5 g, 7.6 mmol). The reaction mixture was stirred at rt for 40 mintutes, diluted in diethyl ether, and treated with saturated aqeuous sodium thiosulfate, giving a biphasic mixture that was vigorously stirred for 20 minutes. The organic layer was separated, washed sequentially with saturated aqueous sodium thiosulfate and saturated sodium bicarbonate, and dried over MgSCk Filtration and evaporated of solvents m vacuo gave a crude residue that was further purified by column chromatography (24 g silica gel; hexanes: diethyl ether, 1 :0 to 3: 1 solvent gradient) to provide 3-(pyrimidin-2- ylthio)cyclobutanecarbaldehyde (mixture of cis and trans isomers; 0.76 g, 3.9 mmol total, 44 % yield). STEP 5: 2-(((lR,3R)-3-VINYLCYCLOBUTYL)THIO)PYRIMIDINE AND 2-

(((1S,3R)-3 'INYLCYCL0BUT X)TOI0)PYRIMIDINE

To a stirred suspension of methyltriphenylphosphonium bromide (6.90 g, 19.30 mmol) in THF (38.6 mL) was added potassium /eri-hutoxide (1.300 g, 11.58 mmol). The reaction was stirred at rt for 30 minutes, cooled to 0 °C, and treated with a solution of 3-(pyrimidin-2-ylthio)cyclobutanecarbaldehyde (cis and trans mixture; 0.75 g, 3.9 mmol; Example 102, Step 4) in THF (4 mL) dropwise over one minute. Five minutes later, the cooling bath was removed, and the reaction mixture was stirred at ambient temperature for four hours, after which it was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over MgSi filtered and concentrated in vacuo. Flash chromatographic purification (12 g silica gel ; hexanes: diethyl ether, 1 :0 to 4: 1 solvent gradient) of the crude residue gave 2-((3-vinylcyclobutyl)thio)pyrimidine ( s and trans isomer mixture; 0.51 g, 2,6 mmol, 69 % yield) as a colorless liquid.

STEP 6: 2-(((lR,3R)-3-VI TYLCYCLOBUTYL)SULFONYL)PYRIMIDINE AND 2~(((1 S,3R)-3A' ⁷ ]NYIX^ .LOBUWL)SULFONYL)PYRIMIDTNE

To a vigorously stirred mixture of sodium tungstate dihydrate (0.044 g, 0.133 mmol), phenylphosphonic acid (0.021 g, 0. 133 mmol) and

tetrabutylammomum sulfate (50 weight % solution in water: 0.154 niL, 0.133 mmol) in water (2.411 mL) was added hydrogen peroxide (30 weight % solution in water; 0.677 mL, 6.63 mmol). After two minutes, a solution of 2-((3- vmykyc!obuty!)thio)pyrimidine (as and trans mixture; 0.51g, 2.6 mmol;

Example 102, Step 5) in toluene (24.11 mL) was added, and the resulting reaction mixture was stirred at 50 °C overnight. On the following day, the reaction mixture was cooled to rt and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed w th brine, dried over MgS(>4, filtered and concentrated in vacuo to give crude 2- ((3-vinylcyclobutyl)sulfonyl)pyrimidine (distereomer mixture, cis rans ------ ca. 1 :5;

0.43 g, 1.9 mmol total, 72 % yield), which was used in the subsequent step without further purification.

STEP 7: ( 1 R,3R)-3-VINYLCYCLOBUTANE- 1 -SULFONAMIDE AND (1 S,3R)-3-VINYLCYCLOBUTANE- 1 -SULFONAMIDE

To a solution of 2-((3-vinylcyclobutyl)sulfonyl)pyrimidine (civ and trans mixture; 0.43 g, 1.9 mmol; Example 102, Step 6) in MeOH (19.17 mL) was added sodium methoxide (25 % solution in methanol; 0.438 mL, 1.92 mmol) and the resulting reaction mixture was stirred at rt for 90 minutes. Solvents were evaporated in vacuo and the resulting solid was triturated with Et ₂ 0 and dned under high vacuum for 10 minutes to give crude sodium 3-vinylcyclobutane-l- sulfmate (0.30 g, 1.7 mmol, 93 % yield).

To a stirred solution of predominantly trans sodium 3-vinylcyclobutane-l- sulfmate (0.30 g, 1.7 mmol) in water ( 7.84 mL) were added sodium acetate (0.293 g, 3.57 mmol) and hydroxylamine-0-sulfonic acid (0.242 g, 2.140 mmol), and the resulting reaction mixture was heated at 55 °C for two hours. Upon cooling, the mixture was basified with IM aqueous NaOH. The aqueous layer was extracted with EtOAc (2X) and DCM (IX), and the combined organic extracts were dried over MgSiX filtered and concentrated in vacuo to give 3- vin Icy clobutane-1 -sulfonamide (cis:tram = ca. 1 :7 by NMR; 0.18 g, 1.1 mmol;

37 % yield) as a white solid.

STEP 8: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -HYDROXY-3-((lR,3S)-3-

SULFAMOYLCYCLOBUIYL)ALLYL)CYCLOBUTYL)METHYL)-3',4,4' TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE! -7-C ARBOXYLIC ACID

A stirred solution of Intermediate AA12A (80.0 nig, 0.157 mmol) and predominantly trans-3-vinylcy clobutane- 1 -sulfonamide (cis rans -------- ca. 1 :7; 25.3 mg, 0.157 mmol) in 1 ,2-dichloroethane (3137 _, uL) was sparged with argon for 10 minutes and then charged with a solution of (l,3-dimesitylimidazolidin-2- ylidene)(2-isopropoxybenzylidene)mtheruum(VI) chloride (9.83 mg, 0.016 mmol) in DCM (1 mL). The resulting reaction mixture was stirred at rt for three hours, after which the catalyst was deactivated by bubbling air through the reaction mixture. Silica gel (ca, 2 g) was added to the mixture and solvents were removed in vacuo. The silica-adsorbed product was tranferred to a solid loading cartridge and pun i led by column chromatography (12 g silica column; hexanes:(99: l

EtOAciAcOH), 1 :0 to 6:4 solvent gradient) to give (,S -6'-chloro-5-((( ].R,2R)-2- ((S,E)- 1 -hydroxy -3 -(( IR, 3S)-3 -sulfamoy Icy clobuty l)ally l)cy clobuty l)methy 1)~ 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[0] l ,4]oxazepine-3, -naphthalene]-7- carbox lic acid (82 mg, 0.14 mmoi, 87 % yield).

STEP 9: ( 1 S,3'R,6'R,7'S,8'E, 1 O'R, 12'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s -

[20]OXA[13]ra ^j :A[l _s 14]DIAZAPEOTACYCLO[14J.2.1 ¹⁰ - ¹² .0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]HEXAC OSA[8, 16, 18,24 jTETRAEN]- 15'-ONE 13', 13'-DTOXTDE

To a stirred solution of (S)-6'~chloro~5~(((l /?,27?W

((li?,3S)-3-sulfamoylcyclobutyl) lyl)cyclobu^

2H,2'H-spiro [benzo \b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (0.041 g, 0.068 mmol) in DCM (34.1 mL) was added DMAP (0.014 g, 0.12 mmol), and the resulting solution was cooled to 0 °C and charged with EDC (0.026 g, 0.14 mmol) portionwise over five minutes. After five minutes at 0 °C, the cooling bath was removed and the reaction mixture was stirred at rt over the weekend. After this time, the reaction mixture was partitioned between DCM and I M HCl (aq.). The organic layer was dried over MgS04, filtered and concentrated in vacuo. Flash chromatographic purification (4 g silica gel; hexanes:(99: 1 EtOAc: AcOH), 1 :0 to 3: 1 solvent gradiednt) gave the desired product (8 mg), albeit in impure form. This material was further purified by a second round of column

chromatography (ca. 1 g silica gel; DCM: acetone, 1 :0 to 9: 1 solvent gradient) to give (lX3' ?,6' ?,7 ^! 5 8'/!a^ spiro [naphtha! ene- 1 ,22'-

| 2i! loxa| I 3 |thia| i . i 4|dia/apentacyclo| 1 .7.2. 16.1 S.24 j tetraen]-15'-one 13',13'-dioxide (1.3 mg, 2.2 μηιοί, 3.3 % yield) as an off-white solid, Ή NMR (400 MHz, CD2CI2) δ ppra 7.64 - 7.83 (rn, 2 1 1 ). 7.19 (dd, ,/ 8 6. 2.3 Hz, 1 H), 7. 12 (d, .7=2.2 Hz, 1 H), 6.91 - 7.02 (m, 2 H), 6.86 (d, J=1.8 Hz, 1 H), 5.83 ·· 5.92 (m, 1 H), 5.69 - 5.80 (m, 1 H), 4.24 - 4.41 (m, 3 H), 4.05 (d, J=l 1.9 Hz, 1 H), 3.50 - 3.62 { in. 2 H), 3.30 (d, ./ 14.3 Hz, 1 H), 3.16 (dd, ./ 14.3. 8,8 Hz, 1 H), 2.90 (d, ,/ 4. 7 Hz, I H), 2.75 - 2,84 (m, 2 H), 2.60 - 2,73 (m, 2 H), 2.54 (td, .7=8.3, 4.4 Hz, 1 H), 2.35 - 2.46 (m, 1 H), 2.01-2.06 (m, 1 H), 1.93 - 2.00 (m, 1 H), 1.69 - 1.92 (m, 5 H), 1.46 - 1.69 (m, 4 H). m/z (ESI, +ve ion) 583.2 ( W W ) .

EXAMPLE 103. (1 S,3'R,6'R,TSA 'RA 2'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 'H- SPIRO [N ΑΡΗΤΗ ALENE- 1 ,22'-

[20]OXA[13]TOIA[l,14]DIAZAPENTACYCLO(14.7.2.1 ^l0>12 .0 ³ ' ⁶ .0 ⁱ⁹ ' ²⁴ jHEXAC OSA[16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE

To a stirred solution of ( S^ 6 TS,S ^ 0 2 )-6-d\loTO-T -hydroxy - 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

tetraen]-15'-one 13', 13'-dioxide (7.0 nig, 0.012 mmol; Example 102) in EtOAc (2401 μΕ) was added platinum(IV) oxide (3.00 mg, 0.0.13 mmol). The flask was evacuated and placed under a hydrogen atmosphere, and the reaction mixture was stirred for one hour, filtered through celite and concentrated in vacuo. Flash chromatographic purification (1 g silica gel; hexanes:(99: 1 EtOAc: AcOH), 1 :() to 1 :2 solvent gradient) gave (I5',3 ^! i?,6 ^! i?,7W, 10'i?, 12'i?)-6-ch!oro-7'-hydroxy-3,4- dihy dro-2H, 15 'H-spiro [naphtha] ene- 1 ,22'-

1 20 joxaj i 3 |thia| i . i 4|dia/apentacyclo| 1 .7.2. 1 ^{i : i} \o ^•• ".o ¹ " ' ¹ |he\acosa| i 6. i 8.24 |tn en]-15'-one 13', 13'-dioxide (1.3 nig, 2,2 μηιοΐ, 19 % yield) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ ppm 8.18 (br. s„ 1 H), 7.72 id. ./ 8.4 Hz, 1 1 1 ). 7.18 (d, J=8.4 Hz, 1 H), 7.09 (s, 1 H), 6,95 (br. s., 2 H), 6.88 (br. s„ 1 H), 4.02 - 4.17 (m, 2 H), 3.94 (br. s., 1 H), 3.80 (d, J=15.5 Hz, 1 H), 3.73 (d, J=14.1 Hz, 1 H), 3.54-3.60 { in. 1 H), 3.28 (d, ./ 14. ! Hz, 1 H), 3.11 - 3.20 (m, 1 H), 2.91 (br. s., 1 H), 2.72 - 2.82 (m, 2 H), 2,57 - 2.70 (m, 2 H), 2.13 - 2.44 (m, 4 H), 1 ,97 - 2.04 (m, 1 H), 1.74 - 1.96 (m, 4 H), 1.37 - 1.74 (m, 8 H). l -'z (ESI, +ve ion) 585.1 (M+H) ⁺ .

EXAMPLE 104. (1 S,3'R,6'R,7'S,8'E,10'S,14'S>6-CHLOR()-7'-HYDROXY-3,4- DIHYDRO-2H, .17'H-SPIRO[NAPHTHALENE-l,24'-

[22]OXA[15]THL\[l,16]DL\ZAl TACYCLO[16.7.2.1 ¹⁰ l0 ³ -^0 ^{2 i} - ²⁶ ]OCTAC OS A[ 8, 18,20,26]TETRAEN] - 17'-ONE 15', 1 S'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 14'R)-6-CHLORO-7'-HYDROXY-3,4-DTHYDRO- 2H, 17'H-SPIRO[NAPHTHALENE- 1 ,24'-

[22]OXA[15]TfflA[l,16]DIAZAPENTACYCLO[16.7.2.1 ¹⁰ ' ¹⁴ .0 ³ - ⁶ .0 ²¹ ' ²⁶ ]OCTAC OSA[8,18,2(),26]TETRAEN]-17'-ONE 15',15'-DIOXIDE

STEP 1 : (S)-3-VI YLCYCLOHEXANONE AMD (R)-3

VINYLCYCLOHEXANONE The title compound was prepared according to the procedure described by Kerdesky, et al., Journal of Medicinal Chemistry, 1987, 30, 1177-1186.

STEP 2: (lR,3S)-3-VINYLCYCLOHEXANOL AND (lS,3R)-3- VINYLCYCLOHEXANOL

To a stirred, 0 °C solution of 3-vinylcyclohexanone (3.30 g, 26.6 mrnol) in THF (100 mL) under a nitrogen atmosphere was added sodium borohydride (1.11 g, 29.2 mmol) portionwise over three minutes. After five minutes the cooling bath was removed and the reaction was warmed to rt for one hour. The reaction was then quenched by addition of water (5 mL) and the resulting mixture was stirred at rt for 20 minutes and subsequently partitioned between EtOAc and water. The organic layer was dried over MgSC filtered and concentrated in vacuo. Column chromatography (80 g silica gel; hexanes:EtOAc, 1 :0 to 3: 1 solvent gradient) gave race mi e e v~3~vinylcyxlohexanol (2.00 g, 15.9 mmol, 60 % yield). STEP 3: (lR,3S)-3-VINYLCYCLOHEXYL METHANESULFONATE AND (1 S,3R)-3-VlNYLCYCLOHEXYL METHANESULFONATE

To a stirred, 0 °C solution of racemic czs-3-vinylcyclohexanol (2.00 g, 15.9 mmol) in DCM (79 mL) under a nitrogen atmosphere was added

triethylamine (4.42 mL, 31.7 mmol) followed by methanesulfonyl chloride (1.85 mL, 23.8 mmol). After five minutes, the cooling bath was removed and the reaction was stirred at rt overnight. On the following day, the reaction mixture was partitioned between DCM and 1M HC1 (aq.). The organic layer was washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo. Column chromatography (80 g silica gel: isocratic DCM eluent) gave racemic cis-3- vinylcyciohexyi methanesulfonate (2.40 g, 1 1.7 mmol, 74 % yield) as a light yellow liquid. STEP 4: 2-(((lS,3S)-3-VINYLCYCLOiiEXYL)raiO)PYRIMIDINE AND 2-

(((1 R,3R)~3-VINYLCYCL0HEXYL)THI0)PYRJMIDINE

To a stirred solution of racemic c7s~3~vinylcyclohexyl methanesulfonate (2.30 g, 11.3 mmol) in DMF (37.5 mL) were added 2-mercaptopyrimidine (1.263 g, 1 1.26 mmol) and potassium carbonate (1.556 g, 1 1.26 mmol). The reaction mixture was stirred at 80 °C for three hours. Upon cooling to room temperature, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo. Column chromatography (40 g silica gel: hexanes: EtO Ac, 1:0 to 4: 1 solvent gradient) gave racemic trans-2- ((3-vinylcyclohexyl)thio)pyrirrddine (1.32 g, 5.99 mmol, 53 % yield).

STEP 5: 2-(((lS,3S)-3-VlNYLCYCLOHEXYL)SULFONYL)PYRlMlDINE

AND 2-(((1R,3R)-3^INYLCYX L()H:EXYL)SULF0NYL)PYR1M1DINE

To a vigorously stirred mixture of sodium tungstate dihydrate (0.099 .300 mmol), phenylphosphonic acid (0.047 g, 0.300 mmol) and tetrabutylammonium sulfate (50 weight % solution in water; 0.348 mL, 0.300 mniol) in water (5.45 mL) was added hydrogen peroxide (30 weight % solution in water; 1.530 mL, 14.98 mmol). After two minutes, a solution of racemic trans -2- ((3-vinylcyclohexyl)thio)pyrimidine (1.32 g, 5.99 mmol) in toluene (54.5 mL) was added, and the reaction mixture was heated at 50 °C overnight. Upon cooling to rt, the mixture was partitioned between EtOAc and water. The organic layer was dried over MgSC , filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (24 g silica gel; hexanes:EtOAc, 1 :0 to 3: 1 solvent gradient) gave racemic tratts-2-((3- vinylcyc3ohexy3)suifonyl)pyrimidine (1.00 g, 3.96 mmol, 66 % yield).

STEP 6: (1 S,3S)-3A^NYLCYCLQHEXANE -SULFONAMIDE AND (1 R,3R)-3-VINYLCYCLOHEXANE-l -SULFONAMIDE

To a stirred solution of racemic lrans~2~((3- vinylcyclohexyl)sulfonyl)pyrimidine (LOO g, 3.96 mmol) in MeOH (39.6 mL) was added sodium methoxide (25 weight % solution in MeOH; 0.906 ml, 3.96 mmol), and the resulting reaction mixture was stirred at rt for 45 minutes. After this time, solvents were removed in vacuo and the residue was triturated with diethyl ether. The resulting solids were filtered, washed with diethyl ether and dried under high vacuum to give crude racemic sodium ira¾?-3-vinylcyclohexane 1 -sulfinate (0.778 g, 3.96 mmol, 100 % crude yield for the pyrimidine cleavage step), which was used without further purification.

To a solution of crude racemic sodium ira«,s-3-vinylcyclohexane-l- sulfinate (0.78 g, 4.0 mmol) in water (39.7 mL) were added sodium acetate (0.65:1 g, 7.95 mmol) and hydroxylamine-O-sulfonic acid (0.450 g, 3.97 mmol), and the resulting reaction mixture was heated at 50 °C for 30 minutes. After this time, th< reaction was cooled to 0°C for 10 minutes and basified to pH ^:: = ca. 12 with NaOH (up to pH -12). The resulting mixture was extracted with EtOAc, and the combined organic extracts were dried over MgS04, filtered and concentrated in vacuo to give racemic tram'-3-vinylcyclohexane-l -sulfonamide (0.64 g, 3.4 mmol, 85 % yield for the nucleophilic sulonamidation; 85 % overall yield from the sulfonyl pynmidine).

STEP 7: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-3-((lR,3R)-3- SULFAMOYLCYCLOiiEXYX)ALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5-

TETRAH DRO-2H,2 ^! H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLlC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S ₅ E)-l-HYDROXY-3-((lS,3S)-3-

SULFAMOYLCYCLOHEXYL)ALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-C ARBOXYLIC ACID

A solution of intermediate AA 12A (130 mg, 0.255 mmol) in 1,2- dichloroethane (3641 μΐ,) was sparged with argon for 10 minutes and charged with (l,3-dimesitylimidazolidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium(VI) chloride (16.0 mg, 0.0250 mmol), and the resulting mixture was stirred at rt overnight. On the following day, the catalyst was deactivated by sparging air through the mixture for five minutes. Solvents were removed in vacuo, and the crude residue obtained was purified by column chromatography (4 g silica gel; hexanes;(99: i EtOAc:AcOH), 1 :0 to 6:4 solvent gradient) to give a mixture of ( ₍ S)-6'-chloro-5-(((li?,2i?)-2-(( ₁ S',E)-l-hydrox\'-3- (( l¾:iR)-3-s u] famoy 1 cy ckte

2H,2'H-spiro[benzo[^][ l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (5)- e'-dUoro-S-^lR.^^-ii^-l -hydroxy-S-tilS ^' ^S)^- sdfamoylc lohexyl)a]lyl)c ]obuty])me1hyl)-3 4,4 5-tetTahydro-2H,2'H- spiro[benzo[6] [l,4]oxazepine-3, -naphthalene]-7-carbox\'lic acid (95 mg, 0.15 mmol total, 59 % combined yield).

STEP 8: (lS,3'R,6'R,7'S,8'E,10'S,14'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H,17'H-SPIRO[NAPHTHALENE-l ,24'-

[22]OXA[15]THIA[1,16]DIAZAPENTACYCLO[16.7.2.1 ¹⁰ ' ¹ .0 ⁵ - ⁶ .0 ²¹ ' ²⁶ ]OCTAC QSA[8,18,20,26]TETRAEN]-17'-QNE 15',15'-D10XIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,14'R)-6-CHLORO-7'-HYDROXY-3,4-DIHYD RO- 2H, 17'H-SPIRO[NAPHTHALENE- 1 ,24'-

| 22 !ΟΧ Λ| i ^ l U U Al l .. i 6 | i)!,\/.\Pi-::\ ΓΛίΎΠ .ΟΙ 16.7.2 ! ^{) () 1 !} .ί ) ^: ".· ! ^{, ;} ' ^! '|0( ^' TAC OSA[8, 18,20,26]TETRAEN]-17'-ONE 15', 15'-DIOXIDE To a stirred solution containing a mixture of S)-6'-criloro-5-(((li?,2i?)-2-

((S,E)~ 1 ~hy droxy -3 -(( 1 i?, 3A*)~3 ~s ulf ^

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[ )][l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid and (^-e'-cWoro-S^lR^^-ttS'^-l^drox -S-^lS'^^-S- sulfamoylcyclohexyl)allyl)c} ⁷ clobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[6] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox dic acid (95 mg, 0.15 mmol total) in DCM (7.55E+04 μΕ) at 0°C under a nitrogen atmosphere was added DMAP (31.4 mg, 0.257 mmol). After five minutes, the reaction mixture was charged with EDC (57.9 mg, 0.302 mmol) portion wise over five minutes and stirred at rt over the weekend. After this time, the reaction mixture was partitioned between DCM and 1 M HCi (aq.). The organic layer was dried over MgSCu, filtered and concentrated in vacuo. Purification of the resulting crude residue by column chromatography (12 g silica gel; hexanes:(99: l EtOAc:AcOH), 1 :0 to 4: 1 solvent gradient) gave one of the title compounds as the first eluting isomer (18 mg, 0.029 mmol, 20 % yield) as a white solid. ^l ll NMR (400 MHz, CD3OD) δ ppm 7.72 (d, ,/ 8.4 Hz, 1 H), 7, 17 (dd, ./ 8Λ 2.2 Hz, I H), 7, 10 id. J=2.2 Hz, 1 H), 6.83 - 6.98 (m, 3 H), 5.91 (dd, J=15.6, 6.6 Hz, 1 H), 5.62 (dd, ./ 15.2.4.8 Hz, 1 H), 4.06 - 4.14 (m, 2 H), 3.96 - 4.05 (m, 3 H), 3.68 (d, ./ 14.7 Hz, I H), 3.43 - 3,57 (m, 2 H), 2.69 - 2,92 (m, 4 H), 2.17 - 2,30 (m, 2 H), 1.97 - 2.08 (m, 3 H), 1.73 - 1.96 (m, 6 H), 1.64 (br, s., 4 H), 1.45 - 1.56 (m, 1 H), 1,24 (t, ./ 7.1 Hz, 1 H). m/z (ESI, +ve ion) 611.2 (M R)

EXAMPLE 105. (lS,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E.10 ^, R,14 ^, R)-6-CHLORO-7 ^, -HYDROXY-3.4- DIHYDRO-2H,17H-SPIRO[NAPHTHALENE-l ₅ 24*-

[22]OXA[15]THIA[1,16]DIAZAPENTACYCLO[16.7.2.1 ¹⁰ ' ¹ .0 ⁵ - ⁶ .0 ²¹ ' ²⁶ ]OCTAC OSA[8,18,20,26]TETRAEN]"17'-ONE 15',15'-D10XIDE OR

(lS,3'R,6'R,7'S,8'E,10'S,14'S)-6-CHLOR()-7'-HYDROXY-3,4-DIHY DRO- 2H, 17'H-SPIRO[NAPHTHALENE- 1 ,24'-

|22!ΟΧΛ| i^lUUAl IJ6|i)!A/.\Pl-::\ ΓΛίΎΠ.ΟΙ 16.7.2 ! ^{)() 1 !} .ί) ^: ".·! ^,; ' ^! '|0( ^' TAC OSA[8, 18,20,26]TETRAEN]-17'-ONE 15', 15'-DIOXIDE

The title compound was prepared as described in Exampie 104, step 8 and was isolated as the second eluting isomer (16 mg, 0.026 mmol, 17 % yield) as an off-white solid. *H NMR (400 MHz, CD2CI2) δ ppm 7.71 (d, J=8.4 Hz, 1 H), 7.17 (dd, ,/ 8.6.2.3 Hz, 1 H), 7.09 (d, ,/ 2.2 Hz, 1 H), 6.93 id../ 0.8 Hz, 2 H), 6.88 (s, 1 H), 5.76 - 5.85 (m, 1 H), 5.61 - 5.71 (m, 1 H), 4.46 (I.,/ 4.8 Hz, 1 H), 4.12 - 4,22 (m, 1 H), 4.07 - 4.11 (m, 2 H), 3.87 (d, .7=14.9 Hz, I H), 3.69 (d, J=14.3 Hz, 1 H), 3.22 (d, ./ 1-1.3 Hz, 1 H), 3.01 (dd, ./ 15.-1.9.9 Hz, 1 H), 2.69 - 2.84 (m, 3 III 2.40 - 2.50 (m, 1 H), 2.27 - 2.40 (m, 2 H), 2.03 (br. s„ 111).1.92 id. ,/ 74 Hz, 5 H), 1,68 - 1.76 (m, 3 H), 1,60 - 1.68 (m, 2 H), 1,49 - 1.60 (m, 3 H), 1,36 - 1.47 (m, 1 H). m/z (ESI, +ve ion) 611.2 (M R) EXAMPLE 106. (1 S,3'R,6'R,7'S, 10'R, 14'S)~6~CHLORO~7'~HYDROXY-3,4- DIHYDRO-2H,17'H-SPIRO[NAPHTHALENE-l,24'-

[22]OXA[ 15]THIA[ l 6]DIAZAPENTACYCLO|;i6.7.2.1 ¹⁰ ' ¹⁴ .0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTAC OSA[18,20,26]TRIEN]-17 ^* -ONE 15 ',15 '-DIOXIDE OR

(1 S,3'R,6'R,7'S, 1 O'S.l 4'R)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[22]OXA[15]THIA[l ,16]DIAZAPE TACYCLO[ 16.7.2.1 ¹⁰ ' ^l4 .0 ³ ' .0 ²¹ ' ²⁶ ]OCTAC OSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE

To a stirred solution of either (lS,3'R,6'R,rS,VE, 10'S, 14'¾-6-chloi -7'- hydroxy-3,4-dihydro-2H,17'H-spiro[naphthalene-l,24'-

[22]oxa[l 5jthia[ 1,16]diazapentacyclo[ 16,7.2. 1 ^{i 0 i4} ,0 - ⁶ .0 ^2l - ²⁶ ]octacosa[8, 18,20,26]t etraen] - 1 /'-one 15', 15'-dioxide or (1S,3'R,&R,7S,VE, 1 07c. 14'i?)-6-chloro-7'- hy droxy-3,4-dihy dro-2H, 17'H-spiro[naphthalene- 1 ,24'- 12 lox l i 5 |ihia| I . i 6|dia/apeniac> clo| 1 (> 2. 1 ^! " ^{! s} . ⁽ r ^f \ ^{) l!} ' |ociaco^a! H. ! 8.2ϋ.26|ί etraen] -17'-one 15', 15'-dioxide (Example 104; 10 mg, 0.016 mmol) in EtOAc (3272 ί) was added platinum(IV) oxide (3.7 mg, 0.016 mmol), and the reaction vessel was evacuated and filled with hydrogen (3X). The reaction mixture was stirred at rt for 45 minutes and filtered through ceiite, washing the filter cake with EtOAc. Removal of solvents in vacuo and purification of the resulting residue by column chromatography (4 g silica gel; hexanes:(99: l EtOAc: AcOH), 1 :0 to 80:20 solvent gradient) gave the title compound (4.7 mg, 7.7 μηιοΐ, 47 % yield) as a white solid. ³ H NMR (500 MHz, CD3OD) δ ppm 7,73 (d, J=8.6 Hz, 1 H), 7. 17 (dd, J=8.6, 2.2 Hz, 1 H), 7.10 (d, J=2.2 Hz, 1 H), 7.07 (br. s., 1 H), 7.03 (dd, ./ K.1 , 2.0 Hz, 1 H), 6.93 (d, ./ K.1 Hz, 1 H), 4.01 - 4.10 (m, 2 H), 3.77 - 3.90 (m, 2 ! ! }. 3.70 (d, J=14.4 Hz, ! H), 3.55 (dd, ,/ ! 1.0, 2,7 Hz, 1 H), 3,40 (d, ./ 14.2 Hz, 1 H), 3.19 ·· 3.28 (ni, 1 H), 2.70 - 2.87 (ni, 2 H), 2.58 (qum, J=8.3 Hz, I l i s. 2. 1 8 ·· 2,26 (m, 1 H), 2.02 - 2, 12 (m, 6 H), 1.85 - 1.98 (m, 4 H), 1.72 - 1.84 (m, 2 H), 1 .61 - 1.72 (ra, 3 H), 1.39 - 1.60 (m, 5 H), 1.27 - 1.34 (ra, 1 H). m/z (ESI, +ve ion) 613.3 (M+H) ⁺ .

EXAMPLE 107. (1 S,3 ^, R,6 ^! R,7^,10 ^! S,14'R)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H,17H-SPIRO[NAPHTHALE E-l,24'-

[22]OXA[15]THIA[l ,16]DIAZAPE TACYCLO[16.7.2.1 ¹⁰ " ^l4 .0 ³ ' .0 ²¹ ' ²⁶ ]OCTAC OSA[18,20,26]TR1E ]-17'-QNE 15 ',15 '-DIOXIDE OR

(1 S,3'R,6'R,7'S, 10'R, 14 ^, S)-6-CHLORO-7 ^, -HYDROXY-3,4-DIHYDRO-2H, 17Ή- SPIRO INAPHTHALENE- i .24'-

[22]OXA[15]TfflA[l, 16]DIAZAPENTACYCLO[16.7.2.1 ¹⁰ - ¹⁴ .0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTAC OS A[ 18,20,26]TRIEN]-17'-QNE 15', 15'-DIOXIDE

To a stirred solution of either (lS,3'R,6'R,TS,8'E, l O'R, U'R 6~c low~T- hydroxy -3,4-dihydro-2H, ! 7'H-spiro[naphthalene-l ,24'-

| 22 !<^ai I |ih:a| 1. 1 |dia/apenuic> c!o| 16.7 2. 1 ^ ^ '.Ο ¹ " α ^' ' |oc!ac<«ai 8. 1 S.20.2 11 etraen]-17 ^* -one 15',15'-dioxide or (1^3 ^* ii,6'ii,7'^8'ii,10'5',14 ^, ¾-6-chloi -7'- hydroxy-3,4-dihydro-2H,17'H-spiro[naphthalene-l,24'- [22]oxa[l 5jthia[ 1, 16]diazapentacyclo[ 16,7.2. 1 ³⁰ - ³⁴ ,0 ³ ' ⁶ .0 ²¹ - ²⁶ ]octacosa[8, 18,20,26]t etraen]-17'-one 15',15'-dioxide (Example 105: 8.0 mg, 0.013 mmol) in EtOAc (2618 ,uL) was added platinum(IV) oxide (3.0 mg, 0.013 mmol), and the reaction vessel was evacuated and filled with hydrogen (3X). The reaction mixture was stirred for 45 minutes at ambient temperature and then filtered through celite, washing the filter cake with EtOAc. Removal of solvent in vacuo and purification of the resulting crude residue by column chromatography (4 g silica gel;

hexanes:(99:l EtOAc:AcOH), 1:0 to 75:25 solvent gradient) gave the title compound (2.1 mg, 3.4 μτηοΐ, 26 % yield) as a white solid. ¾ NMR (400 MHz, CD2CI2) 6 ppm 7.76 (d, ./ 8.6 Hz, 111).7.22 (dd, ,/ H 4.2.3 Hz, 111).7.14 (d, J=2.3 Hz, 1 H), 7.01 - 7.06 (m, 1 H), 6.93 - 7.00 (m, 2 H), 4.08 - 4.25 (m, 3 H), 3.78 - 3.91 (m, 2 H), 3.74 (d, J=14.1 Hz, 1 H), 3.25 (d, J=14.3 Hz, 1 H), 3.07 (dd, ./ 15.4.9.3 Hz, 1 H), 2.73 - 2,90 (m, 2 H), 2.23 - 2,54 (m, 3 H), 2.05-2,10 (br. s., 1 H), 1.93 - 2.03 (m, 3 H), 1,39 - 1.9! (m, 17 H). m/z (ESI, + ve ion) 613.2 i.V! H) .

EXAMPLE 108, (1 S,3'R,6'R,7'S,8'E, 10'R, 14 ^f R)-6-CHLORO-7'-METHOXY-3,4- DIHYDRO-2H,17'H-SPIRO[NAPHTHALENE-l,24'-

|22j()XA| 15jTIIIA| Μ6|Ι)ΙΛΖΛΙ ΎΛ(ΎΠ.<>! 16.7.2, 1 " ^u \0 ^; ",0 ^{'; '} "|0< ^" ΓΑί ^' OS A[8, ! 8,20,26]TETRAE ] - 17'-ONE 15', 15'-DIOXIDE OR

(lS,3'R,6'R,7 ^, S,8 ^, E,10 ^, S,14'S)-6"CHLORO-7 ^! ~METHOXY-3,4-DlHYDRO- 2H, 17'H"SPIRO| NAPHTHALENE- 1 ,24'- [22iOXA|;i5]THIA|l,16]DIAZAPENTACYCLO[16.7.2.1 ^10>l ^0 ³ ^0 ²ⁱ - ²⁶ ]OCTAC OSA[8, 18,20,26]TETRAEN]-17'-ONE 15', 15'-DIOXJDE

To a stirred solution of either (LS',3'i?,67i7'5',8 ^* £ ^, ,10 ^* ii,14 ^* ii)-6-chioro-7'- hydroxy-3,4-dihydro-2H,r7'H-spiro[naphthaiene-l,24'- |22|ox;i| i |lhia| I. i 6|di;!/apc!ii;!C> clo| 16.72. ! ^ ¹ '.ί! ^; " U ^"1 '| c! coha|H. ! 8.2(!.26|i etraen]-17 ^* -one 15',15'-dioxide or (1^3 ^* ii,6'ii,7'^8'ii,10'5',14'¾-6-chloi -7'- hydroxy-3,4-dihydro-2H,17'H-spiro[naphthalene-l,24'-

[22]oxa[l 5jthia[ 1,16]diazapentacyclo[ 16,7.2.1 ⁱ⁰ⁱ⁴ ,0- ⁶ .0 ^2l - ²⁶ ]octacosa[8, 18,20,26]t etraen]-17'-one 15',15'-dioxide (Example 105; 4.0 mg, 6.5 μηιοΐ) in THF (654 μΐ,) under a nitrogen atmosphere was added sodium hydride (60 % dispersion in mineral oil; 1.3 mg, 0.033 mmol). The resulting mixture was stirred at rt for 20 minutes, charged with iodomethane (2.05 μL·, 0.033 mmol and stirred at rt over the weekend. Subsequently, the reaction mixture was partitioned between EtOAc and 1 M HC1 (aq.). The organic layer was dried over MgS0 ₄ , filtered and concentrated in vacuo. Purification of the crude residue by column

chromatography (1 g silica gel; hexanes:(99:l EtOAc :AcOH), 1:0 to 4:1 solvent gradient) gave the title compound (1.5 mg, 2.4 μτηοΐ, 37 % yield) as a white solid. ³ H NMR (400 MHz, CD2CI2) δ ppm 8,03 (br. s . I H), 7.71 id../ 8.4 Hz, 1 !!}. 7.17 (dd, J=8.4, 2.3 Hz, 1 H), 7.09 (d, J=2.3 Hz, 1 H), 6.90 - 6.94 (m, 1 H), 6.86 - 6.89 (m, 1 H), 6.84 (d, J=1.8 Hz, 1 H), 5.81 (dd, ./ 15.7.6.7 Hz, 1 H), 5.47 (ddd, ./ 1 .6.6.7, 1.4 Hz, 1 H), 4.25 {{. 12.0 Hz, 1 H), 4.04 - 4.12 (ra, 2 H), 3.85 (d, J=15.5 Hz, 1 H), 3.79 - 3.83 (m, 1 H), 3.71 (d, .7=13.7 Hz, 1 H), 3.25 (s, 2 H), 3.24 (d, J=14.1 Hz, 1 H), 3.01 (dd, J=15.3, 10.4 Hz, 1 H), 2.75 - 2.81 (m, 2 H), 2.44 - 2.55 (m, 1 H), 2.29 - 2.39 (m, 2 H), 2.02-2.08 (m, 1 H), 1.78 - 1.98 (m, 6 H), 1.46 - 1.76 {m.10 H), 1.35 - 1.45 (m, 2 H). m/z (ESI, +ve ion) 625.2 (M+H) ⁺ .

EXAMPLE 109. (1 S,3 ^! R,6'R,7'S,8'E, 10'S, 1 i'RK-C! U.ORO-7'-l h ^' i)ROX -3.4- DIHYDRO^H T'H-SPlROtNAPHTHALENE-l^'- i 22 jOXAj !5! !!ΙΛ| iJolDIAZAPIiNrAC' Ci.Oi 16.7.2.1 ^{ii! 1} '.0 ^; ". ϊ ^{'; '} "|<)( ^" ΓΛ( ^' OS A[8, 18,20,26]TETRAE ] - 17'-ONE 15', 1.5'-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^, S,8 ^, E,10 ^, R,14 ^, S)-6-CHLORO-7 ^, -HYDROXY-3,4-DfflYDRO- 2H, 17'H"SPIRO| NAPHTHALENE- 1 ,24'-

[22iOXA|;i5]THIA|l,16]DIAZAPENTACYCLO[16.7.2.1 ^10>l4 .0 ³ ' ⁶ ,0 ²ⁱ - ²⁶ ]OCTAC OSA[8, 18,20,26]TETRAEN]-17'-ONE 15', 15'-DIOXIDE

STEP 1 : (1 S,3S)-3-VINYLCYCLOHEXANOL AND (1R,3R)~3~

VINYLCYCLOHEXANOL

To a solution of 3-vinylcyclohexanone (Example 104, Step 1; 1.70 g, 13.7 mmol) in THF (68.4 mL) at -78 °C under a nitrogen atmosphere was added dropwise via syringe a solution of 1-Selectride (1 M in THF; 16.43 ml, 16.43 mmol). The reaction mixture was stirred at this temperature for one hour and was then allowed to warm to rt over 20 minutes, after which time the reaction was quenched by addition of water (4.5 mL) and the mixture was treated with MeOH (2 mL) and 15% aqueous NaOH (18.3 mL). The resulting mixture was cooled to 0 °C in an ice/water bath, and hydrogen peroxide (30 weight % solution in water, 7.0 mL) was added dropwise via syringe over 5 minutes. Stirring at rt was continued for an additional five minutes and then the mixture was extracted twice with diethyl ether. The combined organic extracts were washed with sodium sulfite (saturated aq. solution) until it tested negative for peroxides using

Quantofix indicator paper. The organic layer was dried over MgSOi, filtered and concentrated in vacuo. Column chromatography (40 g silica gel; hexanes:EtOAc, 1 :0 to 7:3 eluent gradient) gave racemic irans-3-vinylcyclohexanol (1.00 g, 7.92 mmol, 58 % yield).

STEP 2: (lS,3S)-3-VINYLCYCLOHEXYL METHANESULFONATE AND (lR,3R)-3-VINYLCYCLOHEXYL METHA ESULFONATE

To a stirred solution of racemic iraras-3-vinylcyclohexanol (1.00 g, 7.92 mmol) in DCM (39.6 mL) at 0 °C under a nitrogen atmosphere was added dropwise via syringe methanesulfonyl chloride (0.926 mL, 11.9 mmol). The reaction mixture was allowed to warm to it overnight and was subsequently partitioned between DCM and 1 M HCl (aq.). The organic layer was dried over MgS€>4, filtered and concentrated in vacuo. Column chromatography (40 g silica gel, isocratic DCM eluent) gave racemic ?ra¾s-3-viny!eyclohexyl

methanesulfonate (1.35 g, 6.61 mmol, 83 % yield).

STEP 3: 2-(((lR,3S)-3^TNYLCYCLOHEXYL)TH10)PYRIMlDlNE AND 2- (((lS,3R)-3-VINYLCYCLOHEXYL)THIO)PYRIMIDINE

To a stirred solution of racemic ira/3s-3-vinyleyclohexyl methanesulfonate

(1.35 g, 6.61 mmol) in DMF (13.22 mL) were added 2-mercaptopyrimidine (0.815 g, 7.27 mmol) and potassium carbonate (1.00 g, 7.27 mmol). The reaction mixture was stirred at 60 °C for three hours, after which time additional portions of 2-mercaptopyrimidine (0.40 g, 3.6 mmol) and potassium carbonate (0.50 g, 3.6 mmol) were added to it. The reaction mixture was then heated at 95 °C for two hours. Upon cooling to rt, the mixture was partitioned between EtOAc and water, and the organic layer was washed with brine (2X), dried over MgSCu, filtered and concentrated in vacuo. Purification of the crude residue by column

chromatography (40 g silica gel; hexanes:EtOAc, 1 :0 to 3: 1 solvent gradient) gave racemic 675~2~((3-vinylcyclohexyl)thio)pyrimidine (0.64 g, 2.9 mmol, 44 % yield).

STEP 4: 2-(((lR,3S)-3A NYLCYCLOHEXYL)SULFONYL)PYRIMrDlNE AND 2-(((lS,3R)~3"VlNYLCYCLOHEXYL)SULFONYL)PYRlMIDINE

To a vigorously stirred mixture of sodium lungstate dihydrate (0,048 g, 0, 145 mmol), phenylphosphonic acid (0.023 g, 0. 145 mmol) and

tetrabutylammonium sulfate (50 weight % solution in water (0.169 mL, 0, 145 mmol) in water (2.64 mL) was added hydrogen peroxide (30 weight % solution in water; 0.742 mL, 7.26 mmol). After two minutes, a solution of cis-2-((3- vmykyc!ohexy!)tmo)pyrimidine (0.64 g, 2.90 mmol) in toluene (26,4 mL) was added dropwise via syringe and the reaction was stirred at 54 °C overnight. On the following day, the mixture was treated with additional portions of sodium tungstate dihydrate (0.048 g, 0, 145 mmol), tetrabutylammonium sulfate (50 % in water; 0.169 mL, 0, 145 mmol), phenylphosphonic acid (0.023 g, 0.145 mmol) and hydrogen peroxide (30 % in water; 0.742 mL, 7.26 mmol) and the reaction was heated at 75 °C for three more hours. After this time, the mixture was cooled to rt and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over MgS(>4, filtered and concentrated in vacuo. Purification of the crude residue by column

chromatography (12 g silica gel; hexanes: EtOAc, 1 :0 to 6:4 solvent gradient) gave racemic c 5-2-((3-vmycyclohexyl)sulfonyl)pyrimidine (0,320 g, 1.27 mmol, 44 % yield).

STEP 5: (l R,3S)-3-VINYLCYCLOHEXANE-l-SULFONAMIDE AND

(1 S,3R)-3-VlNYLCYCLOHEXANE- 1 -SULFONAMIDE

To a stirred solution of racemic cis-2-((3- vinycyclohexyl)sulfonyl)pyrimidine (0.320 g, 1.27 mmol) in MeOH (12.68 mL) was added sodium methoxide (25 weight % solution in methanol; 0.290 ml, 1.268 mmol), and the resulting reaction mixture was stirred at rt for 75 minutes, after which time solvents were removed in vacuo to give a white solid that was triturated with diethyl ether and dried under high vacuum to provide the intermediate, crude sodium ira«s-3-vinylcyclohexane-l-sulimate (0.24 g, 1.223 mmol, 96 % crude yield for the pyrimidine cleavage step).

A stirred solution of crude sodium iraw-3-vinylcy clohexane-1 -suifinate (0.24 g, 1.223 mmol) in water (12.23 mL) was charged with sodium acetate (0.201 g,

2.446 mmol) and hydroxylamine-O -sulfonic acid (0.277 g, 2.446 mmol), and the resulting reaction mixture was heated at 50 °C for 30 minutes. Subsequently, the mixture was cooled to 0 °C for 10 minutes and basified to pH = ca. 12 by addition of sodium hydroxide. The crude product was extracted into EtOAc, and the organics were dried over MgSCn, filtered and concentrated in vacuo to give racemic c v~3~vinylcyclohexane-l -sulfonamide (0.17 g, 0.90 mmol, 73 % yield for the sulinate amidation step, 70 % overall yield from the sulfonyl pyrimidine).

STEP 6: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-3-((lS,3R)-3- SULFAMOYLCYCLOHEXYL)ALLYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2 ^* H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 ^* -

NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S,E)-l-HYDROXY-3-((lR,3S)-3-

SULFAMOYLCYCLOiiEXYX)ALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5-

ΤΕΤ ΑΗΥΟ Ο-2Η,2Ή-8Ρ¾0[ΒΕΝΖΟ[Β][1,4]ΟΧΑΖΕΡΙΝΈ-3, 1 '- NAPHTHALENE! -7-CARBOXYLIC ACID

To a stirred solution of Intermediate AA12A (143 mg, 0.280 mmol) in 1 ,2- dichioroethene (4005 μL) was added racemic «s-3-vinyicyclohexane-l- sulfonamide (159 mg, 0.841 mmol). The reaction mixtui'e was sparged with argon for five minutes and charged with a solution of (l,3-dimesitylimidazolidin-2- ylidene)(2-isopropoxybenz\'lidene)ruthenium(VI) chloride (17.6 mg, 0.028 mmol) in DCE (1 mL). The resulting mixture was stirred at ambient temperature for two hours, after which time the catalyst was deactivated by bubbling air through the reaction mixture for 10 minutes. The mixture was partially concentrated in vacuo and purified as such by column chromatography (12 g silica gel; hexanes:(99: 1 EtOAc:AcOH), 1 :0 to 70:30 solvent gradient) to give (S)-6'-cnloro-5-(((lii,2ii)-2- ((S,E ~ 1 -hydroxy -3 -(( 1 S',3/?)-3 -su^^

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[ )][l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid and (^^'-cWoro-S^lR^^-^^-l-hydroxy-S-^l^SS)^- sulfamoylcyclohexy allylJcj'clobuty memy -S'^^' -tetrahydro-^^'H- spiro[benzo|7,'] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (1 10 mg, 0.175 mmol total, 62 % combined yield) as an inseparable mixture of diastereomers.

STEP 7: (lS,3'R,6'R,7 ^, S,8'E,10'S,14 ^, R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H,17TI-SPIRO[NAPHTHALENE-l,24'- [22]OXA[15]TO A[l ,16]DIAZAPE TACYCLO[16.7.2.1 ¹⁰ " ^l4 .0 ³ ' .0 ²¹ ' ²⁶ ]OCTAC OS A[8, 18,20,26]TETRAEN]-17'-ONE 15', 15'-D10XIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,14'S)-6-CHLORO-7'-HYDROXY-3,4-DI HYDRO- 2H, 17'H-SPIRO[NAPHTHALENE- 1 ,24'-

| 22 !ΟΧ Λ| i ^ l U U Al I J 6 | i)l,\/.\Pi-::\ i AC VCi .Ol 16.7.2 ! ^{i !} ' ^{l l} .O ^: ".0 ^{, )} ' ^! '|0(Ί AC OSA[8,18,20,26]TETRAEN]-17'-O E 15',15'-DI0X1DE To a stirred solution containing a mixture of (5)-6'-ch]oro-5-((( ! i?,2i?)-2- (( Ji)- 1 -hy droxy -3 -(( 1.

3',4,4',5-tetrahydro-2H,2'H-spiiO| benzo|Z)]| l,4]oxazepine-3, -naphthalene]-7- carbox lic acid and (S)-6'-chloro-5-(((l R )-2 (S,E)~ l~ ydroxy-3-((lR,3S)~3~ sulfamoylcyclohexyl)allyl)cyclobutyl)m

spiro[benzo[6] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (110 mg, 0.175 mmol total) in DCM (8.74E+04 μΕ) was added DMAP (36.3 mg, 0.297 mmol) under a nitrogen atmosphere. This solution was cooled at 0 °C and charged with EDC (67.0 mg, 0.350 mmol) portionwise over four minutes, and the resulting reaction mixture was allowed to warm to rt overnight. On the following day, the reaction mixture was partitioned between 1M HC1 (aq. ) and DCM, and the aqueous layer was back-extracted with DCM. The combined organic extracts were dried over MgS0 ₄ , filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (24 g silica gel; hexanes:(99: l

EtOAc: AcOH), 1 :0 to 7:3 solvent gradient) gave on of the title compounds (10 mg) as the first eluting isomer. This material was further purified by reverse-phase preparative I ! PLC (15 to 70 % (99.9:0.1 ACN:TFA) in (99.9:0.1 water: TF A) eluent gradient, 30 minutes) to provide the title compound as a white film (1.6 mg, 4.7 % yield based on the mixture of acyclic precursors used i Step 6 of Example 109). ¾ NMR (400 MHz, CD2CI2) δ ppm 8.00 (br. s., 1 H), 7.73 (d, J=8.4 Hz, 1 H), 7.18 (dd, ,/ 8.6. 2.3 Hz, 1 H), 7.10 (d, ,/ 2.2 Hz, 1 H), 6.98 - 7.02 (m, 2 H), 6,93 - 6.97 (m, 1 H), 6,87 (s, 1 H), 5.66 - 5.75 (m, 1 H), 5.52 - 5.61 (m, 1 H), 4.19 - 4.26 (m, 2 H), 3.97 (d, J=12.1 Hz, 1 H), 3.70 (dd, J=14.2, 3.4 Hz, 1 H), 3.63 (d, ./ 14.7 Hz, 1 H), 3.43 (tt, ./ I 2. I . 3.4 Hz, 1 H), 3.31 (d, ./ 14.3 Hz, 1 H), 2.97 (dd, ./ 1 .2. 11 .1 Hz, I H), 2.76-2,81 (m, I H), 2.52 i d. ./ 7.8 Hz, 1 ! ! }. 2,21 - 2.34 (m, 2 H), 2,08 - 2.17 (m, 2 H), 1 ,95 - 2.03 (m, 1 H), 1,79 - 1.94 (m, 3 H), 1,59 - 1.72 (m, 5 H), 1.46 - 1.57 (m, 4 H), 1.35 - 1.42 (m, 1 H), 0.99 - 1.12 (m, 1 H). m/z (ESI, +ve ion) 611 ,2 ( VI I D ^' .

EXAMPLE 1 10. (lS,3 ⁱ R,6'R,7'S,8'E, 10'RJ 4 ^f S)-6-CHLORO-7'-I-IYDROXY-3,4- DIHYDRO-2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'- [22]OXA[15]TfflA[l ,16]DIAZAPE TACYCLO[16.7.2.1 ¹⁰ - ¹⁴ .0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTAC QSA[8,18,20,26]TETRAEN]-17'-QNE 15',15'-D10XIDE OR

(lS ₅ 3 ^, R,6 ^, R,7 ^, S,8 ^, E,10 ^, S,14 ^, R)-6-CHLORO-7 ^, -HYDROXY-3 ₅ 4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALENE- 1 ,24'- | 22 !ΟΧ Λ| i ^ l U U Al I J 6 | i)!A/.\Pi-::\ ΓΑίΎΠ .ΟΙ 16.7.2 I ^{i !i 1 ι} .ϋ ^: ".θ' ¹ ' ^! '|()C 1 AC OSA[8,18,20,26]TETRAEN]-17'-O E 15',15'-DIOXiDE

The title compound was prepared as descibed in Example 109, Step 7 and was isolated as the second eluting isomer (10 mg). This material was further purified by reverse-phase preparative HPLC (15 to 70% (99.9:0.1 ACN:TFA) in (99.9:0.1 watenTFA) eluent gradient, 30 minutes) to give the title compound as an off-white solid (5.0 mg, 1.5 % yield based on the mixture of acyclic precursors used in Step 6 of Example 109). ¾ NMR (400 MHz, CD2CI2) δ ppm 8.32 (br. s„ 1 H), 7.72 (d, ,7=8,6 Hz, 1 H), 7.17 (dd, .7=8.5, 2.2 Hz, 1 H), 7.10 (d, .7=2.3 Hz, 1 H), 6.90 - 7.00 (m, 2 H), 6.84 (s, 1 H), 5.92 (dd, J=15.6, 5.2 Hz, 1 H), 5.62 (dd, J=15.8, 4.7 Hz, 1 H), 4.26 (t, ,7=4.1 Hz, 1 H), 4.16 (d, J=11.9 Hz, 1 H), 4.01 id. J=12.1 Hz, 1 H), 3.70 - 3.79 (m, 2 H), 3.62 - 3.70 (m, 1 H), 3.23 - 3.59 (m, 3 H), 3.16 (dd, J=14.6, 10.9 Hz, 1 H), 2.73 - 2.83 (m, 2 H), 2.65 (t, J=7.8 Hz, 1 H), 2.18 - 2.35 (m, 3 H), 2.14 (d,■/ i 1 .3 Hz, 1 H), 2.03 id. ./ 3.5 Hz, 1 H), 1.73 - 1.96 (m, 7 H), 1 .62 - 1.70 (m, 1 H), 1 .41 - 1.60 (ra, 3 H). m/z (EST, +ve ion) 61 1.2

{ M ί i )

EXAMPLE 111. (l S,3'R,6 ^! R,7'S,8 ^, E,10 ^, R,14 ^, S,28 ^, S)-6-CHLORO-7'- ilYDROXY-28'-METHYL-3,4-DIHYDR()-2I-I,17'H-SPIRO[NAPHTHALENE -

1 ,24'- [22]OXA[15]THIA[1 ,16]DIAZAPE TACYCLO[16.7.2.1 ¹⁰ - ¹⁴ .0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTAC

QSA[8,18,20,26]TETRAEN ]-17'-QNE 15',15'-D10XIDE

STEP 1 : (S)-2-BROMO-2-METHYLCYCLOHEXANONE AND (R)-2- BROMO-2-METHYLCYCLOHEXANONE

A suspension of 2-methylcyclohexanone (14.1 mL, 116 mmol) and N- bromosuccinimide (20.63 g, 116 rnmol) in CC (290 mL) was heated at reflux for 90 minutes. The reaction mixture was subseqeuently cooled to 0 °C, and the white solids were removed by filtration. The filtrate was concentrated in vacuo to give crude 2-bromo-2-methylcyclohexanone (21 g, 110 rnmol, 95 % yield) as a brown liquid.

STEP 2: 2-METHYLCYCLOHEX-2-ENONE

To a stirred solution of 2-bromo-2-methylcyclohexanone (21 g, 110 rnmol) in DMF (220 mL) was added portionwise lithium carbonate (17.87 g, 242 rnmol). The resulting mixture was heated at 145 °C overnight, cooled to rt and partitioned bewteen Et ₂ 0 and brine. The aqueous layer was extracted with EfeO (2X), and the combined organic extracts were washed with brine (2X), dried over MgS€>4, filtered and concentrated in vacuo. The resulting crude residue was purified by distillation through a short-path apparatus at a pressure of ca. 20 mm Hg, collecting the fraction boiling at 90-1 15 °C to provide 2-meth lc clohex-2-enone (8.7 g, 79 mmol, 71.9 % yield) as a colorless liquid. STEP 3: (2S,3S)-2-METHYL-3-VINYLCYCLOHEXANONE AND (2R,3R)-2- METHYL-3-VINYLCYCLOHEXANONE AND (2S,3R)-2-METHYL-3- VIN YLC YCLOHEXA ONE AND (2R,3S)-2-METHYL-3- VINYLCYCLOHEXANONE

Copper(I) iodide (2.204 g, 11.57 mmol) was added to a stirred, 0 °C solution of vinylmagnesium bromide (1 M in THF; 136 rnL, 136 mmol) under a nitrogen atmosphere and the resulting solution was stirred for 15 mm at this temperature. A solution of 2-methylcyclohex-2-enone (7.5 g, 68.1 mmol) in THF (76 mL) was then added dropwise via addition funnel over five minutes. Five minutes later, the cooling bath was removed and stirring was continued at ambient temperature for one hour, after which time the reaction was quenched by careful addition of saturated ammonium chloride (aq) and the resulting mixture was partitioned between Et ₂ 0 and water. The organic layer was washed with brine, dried over MgSC , filtered and concentrated in vacuo. Column chromatography (120 g silica gel: hexanes:EtOAc, 1 :0 to 4: 1 solvent) gave the title compounds (3.0 g, 32% combined yield) as a mixture of diastereomers.

STEP 4: (lR,2R,3R)-2-METHYL-3-VINYLCYCLOHEXANOL AND

(lR,2S,3R)-2-METHYL-3-VINYLCYCLOHEXANOL AND (lR,2R,3S)-2- METHYL-3-VINYLCYCLOHEXANOL AND (lR,2S,3S)-2-METHYL-3- VINYLC YCLOHEXANO L AND (l S,2S,3S)-2-METHYL-3- VINYLCYCLOHEXANOL AND (1 S,2R,3S)-2-METHYL-3- VINYLCYCLOHEXANOL AND (1 S,2S,3R)~2-METHYL~3~

VINYLCYCLOHEXANOL AND (lS,2R,3R)-2-METHYL-3- VI YLCYCLOHEXANOL

To a stirred solution of 2-methyl-3-vinylcyclohexanone (diastereomer mixture obtained in Step 3; 3.0 g, 21.71 mmol) in THF (109 mL) was added sodium borohydride (0.821 g, 21.7 mmol). The reaction mixture was stirred at rt for one hour and subsequently quenched by addition of MeOH (5 mL). This mixture was stirred at rt for one more hour and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo to give the desired product (3.0 g, 99% combined yield) as a 1 : 1 : 1 : 1 mixture of four diastereomers, each of which was present as the racemate (8 total stereoisomers).

STEP 5: (1 R,2R,3R)-2-METHYL-3-VINYLCY CLOHEXYL

METHANESULFONATE AND (lR,2S,3R)-2-METHYL-3- VINYLCYCLOHEXYL METHANESULFONATE AND (lR,2R,3S)-2- METHYL-3-VINYLCYCLOHEXYL METHANESULFONATE AND

(lR,2S,3S)-2-METHYL-3-VINYLCYCLOHEXYL METHANESULFONATE AND (l S,2S,3S)-2-METHYL-3-VINYLCYCLOHEXYL

METHANESULFONATE AND (lS,2R,3S)-2-METHYL-3- MNY S .C YCI.OI l XYI. METHANESULFONATE AND (l S,2S,3R)-2- METHYL-3-VINYLCYCLOHEXYL METHANESULFONATE AND

(1 S,2R,3R)-2-METHYL-3- VLNYLCYCLOHEXYL METHANESULFONATE

A stirred solution of 2-methyl-3-vinylcyclohexanol (racemic diastereomer mixture prepared in Step 4; 3.0 g, 5.3 rnmol) in DCM (26.7 mL) was cooled to 0 °C and charged with triethylamine (1.491 mL, 10.70 mmol) and methanesulfonyl chloride (0.625 mL, 8.02 mmol). The reaction mixture was stirred at 0 °C for 10 minutes and then allowed to warm to rt for one hour. After this time, the reaction mixture was partitioned between DCM and I M HCl (aq). The organic layer was washed with saturated NaHCOs (aq.), dried over MgSCn, filtered and

concentrated in vacuo. The crude residue was purified by column

chromatography (120g silica gel, isocratic DCM eluent) to give 2-methyl-3- vinylcyclohexyl methanesulfonate compound as a 1 : 1 : 1 : 1 mixture of

diastereomers, each of which was present as the racemate (3.2 g, 3.7 mmol total, 69% combined yield). STEP 6: 2-(((lR,2S,3S)-2-METHYL-3-

VINYLCYCLOHEXYL)SULFONYL)PYRIMIDINE AND 2-(((l S,2R,3R)-2- METHYL-3-VINYLCYCLOHEXYL)SULFONYL)PYRIMIDINE

To a stirred solution of 2-methyl-3-vinylcyclohexyl methanesulfonate (racemic diastereomer mixture obtained in Step 5; 3.2 g, 3.7 mmol) in DMF (12.21 mL) were added potassium carbonate (0.760 g, 5.50 mmol) and 2~ mercaptopyrimidine (0.493 g, 4.40 mmol), and the resulting reaction mixture was stirred at 70 °C overnight. After this time, additional portions of 2CO3 (1.5 g, 11 mmol) and 2-mercaptopyrimidine (1.0 g, 8.9 mrnol) were added, and the reaction mixture was stirred at 100 °C for three hours, after which time it was cooled to rt and partitioned between EtOAc and brine. The organic layer was washed with brine, dried over MgSiX filtered and concentrated in vacuo. The crude residue was purified by column chromatography (80 g silica gel; hexanes: EtOAc, 1 :0 to 3: 1 solvent gradient) to give a racemic mixture of 2-(((li?,25',35)-2-methyl-3- vin lcyclohexyl)thio)pyriinidine and 2-(((15',2i?,3i?)-2-methyl-3- vin lcyclohexyl)thio)pyrimidine (1.2 g, 35 % material recovery) as the only isolated product. This material was redissolved in DCM (25.6 mL) and the resulting solution was charged with /weto-chloroperoxy benzoic acid (ca. 77 %, balance = meta- chlorobenzoic acid and water; 2.98 g, 13.3 ! mmol) and stirred at rt for three hours. After this time, the reaction mixture was partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was dried over MgS€>4, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (24 g silica gel; hexanes: EtO Ac, 1 :0 to 2: 1 solvent gradient) gave a racemic mixture of 2-(((li?,2^,35)-2-methyl-3- vinylcyc3ohexy3)suifonyl)pyrimidine and 2-(((l ,2i?,3i?)-2-methyl-3- vmylcyclohexyl)sulfonyl)pyrimidine (0.40 g, 1 .5 mmol, 10 % overall yield). STEP 7 : ( 1 R,2S ,3 S)-2~METHYL-3 -VINYLCYCLOHEXANE- 1 -

SULFONAMIDE AND (l S,2R,3R)-2-METTTYL-3-VINYLCYCLOHEXANE-l- SULFONAMIDE

NH

To a stirred solution containing a racemic mixture of 2-(((ϋ?,25,35 -2- methyl-3-vinylcyclohexyl)sulfonyl)pyrimidine and 2-(((LS',2i?,3i?)-2-methyl-3- vinylcyclohexyl)sulfonyl)pyrimidine (400 mg, 1.50 mmol) in MeOH (15 mL) was added sodium methoxide (25 weight % solution in methanol; 343 iL, 1.50 mmol), and the resulting reaction mixture was stirred at rt for one hour. The solvent was evaporated in vacuo and diethyl ether was added to the mixture. The solids were filtered under vacuum, washed with diethyl ether and dried under high vacuum to give a racemic mixture of sodium (lAV2A ^, ,35)-2-methyl-3-vinylcyclohexane-l - sulfmate and sodium (15,25,3i?)-2-methyl-3-vinylcyclohexane-l-sulfinate (0.310 g, 1.47 mmol, 98 % yield).

A solution of a racemic mixture of sodium (L i,2i?,3,S)-2-methyl-3- vinylcyclohexane-1 -sulfmate and sodium CiS,2S,3/?)-2-methyl-3- vmylcyclohexane-1 -sulfmate (0.31 g, 1.474 mmol) in water (14.74 mL) was charged with sodium acetate (0.242 g, 2.95 mmol) and hydroxylamine-O-sulfonic acid (0.250 g, 2.211 mmol), and the reaction mixture was heated at 50 °C for one hour. After this time, the reaction mixture was cooled to rt, basified with NaOH to pH = ca.12 and extracted with EtOAc, The aqueous layer was extracted with EtOAc followed by DCM, and the combined organic extracts were dried over MgS04, filtered and concentrated in vacuo to give a racemic mixture of

(li?,2^,35)-2-memyl-3-vinylc\'clohexane-l-sulfonamide and { I S2!<3!<)~2~ methyl-3-vinylcyclohexane-l-sulfonamide (0.20 g, 0.98 mmol, 67 % yield for the sulfmate amidation, 66 % overall yield).

STEP 8: (S)-6'-CHLORO-5-(((l R,2R)-2-((S,E)-l -HYDROXY-3-((l R,2R,3S)-2- METHYL-3-

8υΕΡΑΜΟΥΕ€Υ€ΕΟΗΕΧΥΕ)ΑΕΕΥΕ)€Υ� ��ΕΟΒυΤΥΕ)ΜΕΤ1ίΥΕ)"3',4,4',5~ TETRAHYDR0-2H,2'H-SPIR0|;BENZ0[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S,E)-l-HYDROXY-3-((l S,2S,3R)-2-METHYL-3- SULFAMOYLCYCLOHEXYL)ALLYL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4 ]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID

A solution of Intermediate AA12A (80.0 mg, 0.157 mmol) and a racemic mixture of (li?,2<S,35 -2-me1hyl-3-vinylcyclohexane-l-sulfonarnide and

(l^,2i?,3i?)-2-methyl-3-vinylcyclohexane-l -sulfonarnide (96.0 mg, 0.471 mmol) in 1,2-dichloroethane (1568 μΕ) was sparged with argon for 10 minutes and then charged with (l,3-dimesitylimidazolidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium(VI) chloride (9.83 mg, 0.016 mmol). The resulting mixture was stirred at rt for two hours. After this time, titanium tetra(isopropoxide) (3 drops) and an additional portion of (1,3- dimesitylimidazolidin-2-) _' 1idene)(2-isopropoxybenzylidene)mthenium(VI) chloride (9.83 mg, 0.016 mmol) were added. Stirring at room temperature was continued overnight. On the following day, the catalyst was deactivated by sparging air through the mixture for five minutes. Solvents were removed in vacuo, and the residue was purified by column chromatography (4 g silica gel; hexanes:(99: 1 EtOAc:AcOH), 1 :0 to 6:4 solvent gradient) to give a mixture (5)-6 - cMoro-5-(((l-¾2R)-2-((S,^

sulfamoylcyclohexyl)allyl)cyclobutyl)methyl)-3 4,4^5-tetrahydro-2H,2'H- spiro[benzo[£] [l,4]oxazepine-3, 1 '-naphthalene] -7-carboxylic acid and (<S)-6'- chloro-5-(((lii,2ii)-2-((^-l-hydroxy-3-((1.5 2 _; S 3i -2-methyl-3- su3famoylcyclohexyl)allyi)cyclobulyl)methyi)-3',4,4',5-teira hydro-2H

spiro|benzo|7,'] [},4]oxazepine-3,r-naphthalene]-7-carboxylic acid (40 mg, 0.062 mmol total, 40 % combined yield).

STEP 9: (lS^' ^'R 'S 'EJO'i^M'S^g'R^e-CHLORO^'-HYDROXY- METHYL-3,4-DIHYDRO-2H,17 ^, H-SPIRO NAPI-m-IALENE-l,24'- [22]OXA[15]TO A[1,16]DIAZAPE TACYCLO[16.7.2.1 ¹⁰ - ¹⁴ .0 ³ - ⁶ .0 ²¹ ' ²⁶ ]OCTAC

QSA[8,18,20,26]TETRAEN]-17'-QNE 15',15'-D10XIDE

To a stirred solution of (-¾-6'-cWoro-5-(((lR,2R)-2-((^

((U?,2/ -S 2-me1hyl-3-sulfam^^

tetrahy dro-2H,2'H-spiro [benzo [b ] [ 1 ,4] oxazepine-3, 1 '-naphthal ene] -7-carboxy li c acid and ( _; S 6 ^! -chloro-5-(((L«,2«)~2^^

sulfamoylcyclohexyl)allyi)cyclobut4)methyl)"3',4,4',5-tet rahy

spiro[benzo[¾[l,4]oxazeprae-3,l'-naphthalene]-7-carboxyl ic acid (40 rng, 0.062 mmo!) in DCM (3.11E+04 μΕ) at 0 °C was added DMAP (12.9 rng, 0.106 mmol) followed by EDC (23.84 nig, 0.124 mmol). The reaction mixture was stirred at rt for two day s and then partitioned between DCM and aqueous citric acid. The organic layer was dried over MgSCH, filtered and concentrated in vacuo.

Purification of the crude residue by column chromatography (4 g silica gel;

DCM:acetone, 1:0 to 9:1 solvent gradient) gave the title compound,

(15 ^, ,3 ^, R,6 ^, /^7 ₅ 8'E ₅ 10 ^, R ₅ 14 ,28 ^, R)-6-chloro-7 ^, ½droxy-28 ^, -methyl-3,^

2H, 17'H-spiro[naphthalene- 1 ,24'-

122!oxa! 1 |ihia| U |dia/upeniacycIo| 16.7.2.1 ^i:i ' '.ίί' ^J '.o ^M '"lociacosajS.18.20..26|t etraen|-17'-one 15',15'-dioxide (4.5 mg, 11.6% yield) as the second eluting isomer. ¾ NMR (400 MHz, CD3OD) δ ppm 7.72 id../ 8.4 Hz, ! H), 7.68 (d, 8.6 Hz, 0.2 H), 7.51-7.53 (m, 0,2 H), 7.36-7.41 (m, 0.3 H), 7.17 (dd, .7=8.4, 2,3 Hz, 1 H), 7.10 (s, 1 H), 6,85 - 6.97 (m, 2 H), 6.06 - 6.18 (m, 1 H), 5.67 (d, J=12.1 Hz, 1 H), 5.59-5.63 (m, 0.4 H), 4.15 - 4.27 (m, 1 H), 3.98 - 4.07 (m, 2 H), 3.66 (d, ./ 14.5 Hz, 1 H), 3.42 - 3.52 (m, 2 H), 2.70 - 2.97 (m, 3 H), 2.63 (s, 1 H), 2.38 (br. s., 1 H), 2.22 - 2.31 (m, 1 H), 2.17 - 2.19 (m, 1 H), 2.16 (s, 3 H), 2.02 - 2.13 (m, 3 H), 1.60 - 1.97 (m, 10 H), 1.39 - 1.56 (m, 3 H), 1.14 - 1.36 (m, 9 H). m/z (ESI, +ve ion) 624.8 (M+H) ⁺ .

EXAMPLE 112. (lS,3'R,6 ^! R,7'S,8 ^! E,10 ^! S,14'R,28'S)-6-CHLORO-7'-HYDROXY- 28'-METHYL-3 ,4-DlHYDRO-2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'- [22]OXA[15]TfflA[l ,16]DIAZAPE TACYCLO[16.7.2.1 ¹⁰ - ¹⁴ .0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTAC

OSA[8,18,20,26]TETRAEN]"17'-ONE 15',15'-D10XIDE

STEP 1: (S)-METHYL 5-(((lR,2R)-2-ACRYLOYLCYCLOBUTYL)METHYL)- e'-CHLORO-S'^^' -TETRAHYDRO^H^'H-

SPTRO[BENZO[B][l ₅ 4]OXAZEPTNE-3,l'-NAPHTHALENE]-7- CARBOXYLATE

stirred solution of Intermediate AA11A (1.78 g, 3.69 mmol) in DCM (36.9 mL) was added Dess-Martin periodinane (1.88 g, 4.43 mmol), and the resulting reaction mixture was stirred at rt for 45 minutes. After this time, the mixture was diluted with diethyl ether and saturated sodium thiosulfate (aq.) was added to it. This mixture was stirred at rt. for 10 minutes, and then the layers were separated. The organic layer was washed with saturated sodium thiosulfate (aq.), saturated sodium bicarbonate (aq.), dried over MgsC , filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (40 g silica gel; liexanes:EtOAc, 1:0 to 3:1 solvent gradient) gave (5)-methyl 5-(((li?,2i?)-2- aciyloylcyclobut ⁷ l)methyl)"6'"Chloi -3',4,4',5~tetrahydro-2H,2'H~

spiro I benzoj T,4]oxazepine-3,r-naphthalene]-7-carboxylate (1.2 g, 2.5 mmol

68 % yield). STEP 2: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((E)-3-((l S,2S,3R)-2- METHYL-3-(PYRIMIDIN-2-

YLTHIO)CYCLOHEXYL)ACRYLOYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7 -C ARB OXYL ATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((E)-3-((lR,2R,3S)-2-METHYL-3-(PYM lDlN-2-

YLTHIO)CYCL{)HEXYL)ACRYLOYL)CYCL()BUT iX)METHYL)-3',4,4',5- TETRAHYDRO-2H,2 ^f H-SPIRO[BENZO[B] [! ,4]OXAZEPiNE-3, l '- NAPHTHALENE] -7-CARBOXYLATE

A solution of (<S niethyi 5-(((li^2i?)-2-acryloylcyclobutyl)n-iethyi)-6'- chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[i? ^j ] [ 1 ,4]oxazepine-3, 1 '- naphthalene] -7-carboxylate (0,430 g, 0.896 mmol) and a racmic mixture of a racemic mixture of 2-(((lii,25,35)-2-methyl-3-vinylcyclohex 'l)tMo)pyrimidine and 2-(((16 ¹ ,2 ?,3 ?)-2-methyl-3-vinylcj ⁷ clohexyl)thio)pyrimidine (prepared as in the first part of Step 6 in Example 1 11 ; 0.231 g, 0.985 mmol) in 4.6 mL DCE was sparged with argon for 10 minutes and then charged with a solution of (1 ,3- dimesit dimidazolidin-2-ylidene)(2-isopropoxybenz didene)mtheniuni(Vl) chloride (0.070 g, 0.11 mmol) in DCE (2 mL) by drop wise addition over one minute. The resulting reaction mixture was heated at reflux overnight. On the following day, the catalyst was deactivated by sparging air through the reaction mixture for five minutes. Purification of the crude products by column chromatography (24 g silica gel; hexanes:EtOAc, 1 :0 to 3 : 1) gave a mixture of (.S)-methyl 6'-chloro-5-(((li?,2i?)-2-((£)-3-((LS',25',3i?)-2-methyl-3- (pyrirnidin-2- ylthio)cyclohexyl)aciyloyl)cyclobut )methyl)"3',4,4',5^efrahydro-2H,2'H~ spiro [benzo [b j [ 1 ,4] oxazepine-3 , 1 '-naphthaien e] -7-carboxyl ate and (5 -methyl 6'- cWoro-5-(((lR,2R)-2^(E)-3-((lR ₅ 2 ? ₅ 35)-2-me 1 -(pyrimi

yllhioJcj'clohexy acrv'loy cyclobutylJmelhy -S'^^' -tetrahydro^H^'H- spirojbenzo [6] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7-carboxylate (0.400 g, 0.583 mmol total, 65 % combined yield).

STEP 3: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((E)-3-((l S,2S ₅ 3R)-2- METHY L - 3 - (P Y RIMlDIN-2-

YLSULFONYL)CYC OHEXYL)ACRYLOYL)CYCLOBUTYL)METHYL)-

;r,4 4^5-TETRAHYDRO-2H,2H-SPIRO[BENZO[B] [L4]OXAZEPlNE-3,r~ N APHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((l R,2R)-2-((E)-3-((lR,2R,3S)-2-MEraYL-3-(PYRiMIDIN-2- YLSULFONYL)CYCLOHEXYL)ACRYLOYL)CYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H,2'Fi-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3, - NAPHTHALENE] -7-CARBOXYLATE

To a stirred solution of (5)-methyl 6'-chloro-5-(((li?,2i?)-2-((E)-3- (( 15',25',3i?)-2-methy 1 -3 -(py rimidin-2- ylmio)cy lohexyl)acryloyl)cy lobutyl)memyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[6] [l,4]oxazepine-3, l'-naphmalene]-7-carboxylate and (>S)-methyl 6'- diloro-5-iiil^2i?)-2-((ii)~3~((l^ _^

ylthio)cyclohexyl)acryloyl)cyclobutyl)metty

spiro [benzo [b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxylate (diastereomer mixture obtained in Step 2; 0.900 g, 1.31 mmol) in toluene (2.384 mL) and water (0.238 mL) were added sodium tungstate dihydrate (0.043 g, 0.13 mmol), phenvlphosphonic acid (0.015 mL, 0.13 mmol) and tetrabutylammomum sulfate (50 weight % solution in water; 0.152 mL, 0.131 mrnol). After two minutes, hydrogen peroxide (30 weight % solution in water; 0.335 mL, 3.28 mrnol) was added in one portion, and the reaction mixture was heated at 55 °C. After one hour, additional portions of phenylphosphonic acid (0.015 mL, 0.13.1 mrnol), tetrabutyl ammonium sulfate (50 % solution; 0.152 mL, 0.131 mmol), sodium tungstate dihydrate (0.043 g, 0.131 mmol) and hydrogen peroxide (30 % solution; 0.30 mL, 2.9 mmol) were added, and the reaction was subsequently heated at 95°C for one hour. Further additions of sodium tungstate dihydrate (0.043 g, 0.131 mmol) and hydrogen peroxide (30 % solution; 0.50 mL, 4.8 mmol) were performed at this time, and heating at 95 °C was continued for two more hours. The reaction mixture was then cooled to rt and partitioned between EtOAc and saturated aqueous sodium sulfite. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed sequentially with saturated aqueous sodium thiosulfate and brine, dried over MgS( filtered and

concentrated in vacuo. Purification of the crude residue by column

chromatography (24 g silica gel; hexanes: EtOAc, 1 :0 to 3: 1 solvent gradient) gave a mixture of (5 rnethyl 6'-chloro-5-(((li?,2i?)-2-((E)-3-((15 ^' ,2 ₎ S',3i?)-2-methyl-3- (pyrimidin-2-ylsulfonyl)cyclohexyl)ac-ryloyl)cyclobutyl)memy l)-3',4,4',5- tetrahydro-2H,2'H-spiro[benzo[6] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylate and ©-methyl 6'-chloro-5-(((lR,2R)-2-((E)-3-((lR ₅ 2 ? ₅ 3S)-2-methyl-3- (pyriiriidin-2-ylsidfonyl)cyxlohexy

tetrahydro-2H,2'H-spiro[benzo[A][l ,4]oxazepine-3,r-naphthalene]-7-carboxylate

(0,36 g, 0.50 mmol total, 38 % combined yield).

STEP 4: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-3- ((1 S ₅ 2S ₅ 3R)-2-METHYL-3-(PYRI IDIN-2-

YLSULF0NYL)CYCL0HEXYL)ALLYT )CYCL0BUWL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S,E)-l-HYDROXY-3-((lR,2R,3S)-2-METHYL-3-(PYRIM IDIN-2- YLSULFONYL)CYCLOHEXYL)ALLYL)CYCLOBUTYL)METHYL)-3 ^f ,4,4',5- TETRAHYDRO-2H,2'H-SPI O[BENZO[B][l,4]OXAZEPiNE-3, I '- ΑΡΗΊΉ ALENE] -7 - C ARB OXYL ATE

To a stirred, 0 °C solution of (S)-methyl 6'-chloro-5-(((lR,2 ?)-2-((E)-3- ((15,2 ₎ S,3i?)-2-methyl-3-(pyrimidin-2- ylsulfonyl)cyclQhexyl)acryloy

spiro[benzo[6] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((li?,2i?)-2H(£)-3-((li?,2i?,3S)-2-niethy

ylsulfonyl)cyclohexyl)acryloyl)cyclobutyl)methy^

spiro [benzo [b ] [ 1 ,4] oxazepine-3 , l '-naphtha! en e] -7-carboxy I ate (di as tereomer mixture obtained in Step 3; 0.35 g, 0.487 mmol) in THF (8.66 mL) and MeOH (1.083 mL) were added cerium(III) chloride (0.132 g, 0.536 mmol) and sodium borohydride (0.041 g, 1.072 mmol), and the reaction mixture was stirred at 0 °C for one hour. After this time, 1M aqueous citric acid was added, and the mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography gave in order of elution: (5)-methyl 6 -ch ! orc-5-i { ί ! R.2 R )~2~{{ .S7-> i An d ro\y -3 -( ( 1 S.2.V. i< }- 2- methyl"3-(py iniidiii-2-yisulfonyl)cyclohexyi)allyi)cyclobut}d)methy

tetrahydro-2H,2'H-spiro benzo ¾][ l,4]oxazepine-3,r-naphthalene|-7-carboxj ⁷ late (0.130 g, 37 % yield), and (S)-methyl e^chloro-S-iiil^ZRJ^-^ -l-hydro y-S- {{ l /^2/^3^ 2-roe!hy!-3-{])> nnisdin-2- ylsulfony^c^ lohexy' ally^cyclobuty^methy^-S'^^'^-tetrahydro^H^'H- spiro[benzo[¾[l,4]oxazeprae-3,r-naphthalene]-7-carboxylate (135 mg, 38 % yield). Comparison of the final product (Step 7 of this example) to the early - eluting disatereorner obtained in Step 9 of Example 1 1 1 ) established the absolute stereochemistries of these compounds.

STEP 5: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((E)-3-((l S,2S ₅ 3R)-2- METHYL-3- SULFAMOYLCYC OHEXYL)ACRYLOYL)CYCLOBUTYL)METHYL)-

3Vlv4^5-TETUAHYDRO-2H,2'H~SPIRO[BENZO[B][l ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-C ARBOXYLATE

To a stirred solution of (S)-metbyl 6 ^, -cMoro-5-(((lR,2R)-2-((£ ^, )-l- hydroxy-3-((l ,2S,3Z?)-2-nieAyl^

ylsulfonyl)cyclohexyl)allyl)cyclobutyl)m^

spiro[benzo[6][l,4]oxazepine-3, -naphthaIene]-7-carboxylate (the earS -eluting diastereomer obtained in Step 4; 136 mg, 0.189 mmol) in MeOH (3776 μΕ) was added potassium carbonate (130 mg, 0.944 mmol), and the resulting mixture was sirred at rt for one hour and subsequently charged with a solution of

hydroxylamine-O-sulfonic acid (27.8 mg, 0.245 mmol) in water (3 mL). The resulting mixture was heated at 50 °C for 90 minutes, cooled to room tempeature, and partitioned between EtOAc and IM HC1 (aq. ). The aqueous layer was extracted with DCM, and the combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (24 g silica gel; hexanes;EtOAc, 1 :0 to 3: 1 solvent gradient) gave (S)-methyl 6 ^! ~chloro~5-(((li?,2i?)~2 (^^

sulfamoylcyxiohexyl)acryloyl)cyxiobuty ^ spiro [benzo [b j [ 1 ,4] oxazepine-3 , 1 '-naphtha! en e] -7-carboxy 1 ate (62 mg, 0, 094 mniol, 50.0 % yield).

STEP 6: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-3-((l S,2S,3R)-2- METHYL-3- SULFAMOYLCYCLOHEXYL)ALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]QXAZEPINE-3, 1 '- NAPHTHALENE] -7-C ARBOXYLIC ACID

To a stirred solution of (S)-methyl 6'-chloro-5-(((lii,2ii)-2-((E)-3-

((l ,2S,3i?)-2-niethyl-3-sulfamoy^^

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[i?j][l,4]oxazepine-3 , -naphthalene]-7- carboxylate (62 mg, 0.094 mmol) in THF (629 μΐ,) and MeOH (629 μ!.} was added a solution of sodium hy droxide (18.9 mg, 0.472 mmol) in water (629 ,uL). The reaction mixture was stirred at 60 °C for three hours, cooled to rt and partitioned between DCM and ΓΜ HC1 (aqj. The aqueous layer was extracted with DCM, and the combined organic extracts were washed with brine, dried ove MgS{)4, filtered and concentrated in vacuo to give (5)-6'-chloro-5-(((li?,2i?)-2- ((S,E)- i -hydroxy -3 -(( 15',2S',3^)-2-methy 1-3 - sulfamoylcyxlohexyl)allyl)cyxlobutyl)methyl)-3',4,4',5-tetra ]^

spiro I benzoj l,4 |oxazepine-3, -naphthalene]-7-carboxyiic acid (40 mg, 0.062 mmol, 66 % yield).

STEP 7: (I S,3'R,6'R,7'S,8 ^f EJ 0 ^f S, 14'R,28 ^f S)-6-CHLORO-7'-HYDROXY-28'- METHYL-3,4-DmYDRO-2H,i7'H-SPIRO[NAPHTHAI.ENE-l,24'- [22]OXA[15]TfflA[l ,16]DIAZAPE TACYCLO[16.7.2.1 ¹⁰ - ¹⁴ .0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTAC

QSA[8,18,20,26]TETRAEN ]-17'-QNE 15',15'-D10XIDE

To a stirred solution of (S)-6'- Mor 5^((lR,2R 2 ((S^l-l^iboxy-3^ ((l,S 2S,3. ?)-2-methyl-3-sulfamoylcyclohexy

tetrahy dro-2H,2'H-spiro [benzo [b ] [ 1 ,4] oxazepine-3, 1 '-naphtha! ene] -7-carboxy li c acid (40 nig, 0.062 mmol) in DCM (3.11E+04 μΕ) under a nitrogen atmosphere was added DMAP (12.9 mg, 0.106 mmol). The resulting solution was cooled to 0 °C and treated with EDC (23.84 mg, 0.124 mmol) portionwise over one minute. When the addition was complete, the cooling bath was removed and the reaction was stirred at rt overnight. On the following day, the reaction mixture was partitioned between DCM and 1 M HCI (aq.), and the organic layer was washed with brine, dried over MgSC¼, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (4 g silica gel; DCM: Acetone, 1 :0 to 9: 1 solvent gradient) gave the desired compound (14 mg) along with ca. 5% of the (\0'RA 4'S,28'R) diasteromer. A second round of chromatography (4 g silica gel; DCM: Acetone, 1 :0 to 9: 1 gradient) furnished diasiereopure

(l&3'^6 i7'5 8'£yi0' ^

2H, 17'H-spiro[naphthalene-l ,24'-

12 !o ii! i (ihial i . i 1 '" ".O' " 0 ^l! ' |oc!acohaj K. ! 8.2ϋ.26| ί etraenj~17'~one 15', !5'-dioxide (8.2 mg, 0.013 mmol, 21 % yield) as a white solid. Ή MR (500 MHz, CD2CI2) 6 ppm 8.14 (s, 1 H), 7.71 (d, ./ 8.6 Hz, 1 H), 7.17 (dd, ,/ 8.4. 2,3 Hz, 1 H), 7.09 (d, ,/ 2.4 Hz, I I I ). 6.88 - 6,96 (m, 3 H), 5.94 - 6,02 (m, 1 H), 5,77 (ddd, J=15.4, 6.8, 1,0 Hz, 1 H), 4.38 (br. s,, 1 H), 4,30 (dt, ,7=12,9, 2.8 Hz, 1 H), 4.09 (s, 2 H), 3.85 (d, ./ 1 .2 Hz, 1 H), 3.70 (d, ./ 4 2 Hz, 1 H), 3.25 (d, ,/ 14.2 Hz, 1 H), 3.04 (dd, ./ 1 .4. 10.0 Hz, 1 H), 2.70 - 2.84 (m, 2 H), 2.41 - 2.50 (ra, 1 H), 2.29 - 2.40 (m, 2 H), 2.10 - 2. 19 (ra, 1 H), 1.90 - 2.07 (ra, 5 H), 1.65 - 1.90 (m, 8 H), 1.54-1.63 (m, 1 H), 1.37 - 1.52 (m, 3 H), 1.20 (d, .7=7.1 Hz, 3 H). m/z (ESI, +ve ion) 624.8 (M+H) ⁺ . EXAMPLE 1 13. iI S,3'R,6'S,7'E,9'R, l l ^, S ₅ 12'R)-6-CHLORO-9'-(2- HYDROXYETHYL)-l 1 ', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [7,16, 18,24]TETRAEN] - 15'-ONE l .T. 13 '-DIOXIDE

NN-diisopropylethylamine (21.2 μΕ, 0.122 mmol) was added to a stirred suspension of the macrocycle starting material (Example 192; 78.0 mg, 0.122 mmol) and BOP (53.8 mg, 0.122 mmol) in THF (2433 μΐ,). The mixture was stirred at rt for 10 minutes, and then sodium borohydride (4.60 mg, 0.122 mmol) was added in one portion at rt. After 30 min, an additional portion of sodium borohydride (15 mg, 0.40 rnmol) was added, and stirring at rt was continued for 30 minutes. A third portion of sodium borohydride (10 mg, 0.27 mmol) was then added, and, after a final 30 minutes of stirring, the mixture was partitioned between EtOAc and 1M HCi (aq.). The organic layer was sequentially washed with saturated sodium bicarbonate (aq.) and brine, dried over MgS0 ₄ , filtered and concentrated in vacuo. Purification of the crude residue by column

chromatography (4 g silica gel; DCM: Acetone, 1 :0 to 4: 1 solvent gradient) gave (1 S,3'R,6'S,TE,9'R, 1 1 'S, 127?)-6-chioro-9'-(2-hydroxy ethyl)- 1 1 ', 12'-dime†hyl-3,4- dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[7,16,18,24]tetrae n]-15'-one 13', 13'-dioxide (76 mg, 0.12.1 mmol, 100 % yield) as a white solid. ^" Ή NMR (400 MHz, CD2CI2) δ ppm 8.35 (br, s., 1 H), 7.71 (d, «/=8.6 Hz, 1 H), 7, 16 (dd, J=8.5, 2.2 Hz, 1 H), 7.10 (d, J=2.2 Hz, 1 H), 6.82 - 7.03 (m, 3 H), 5.79 (d, ./ 12.5 Hz, 1 ! ! }. 5.13 (dd, ./ 15.5. 7.8 Hz, 1 H), 4.10 - 4.20 (m, 2 H), 3.52 - 3.83 (m, 4 H), 3,03 - 3.29 (m, 2 H), 2,71 - 2.84 (m, 2 H), 2,55 (br. s . I H), 2, 14 - 2,27 (m, 2 H), 1.95 - 2.09 (m, 1 H), 1.74 - 1.94 (m, 4 H), 1.36 - 1.71 ί η ·. 11 I I ). 1.22 - 1.34 (m, 1 H), 0.97 (it J=6.8 Hz, 3 H). m (ESI, +ve ion) 626.8 (M+H) ⁺ .

EXAMPLE 114. (1 S,3 ^! R,6 ^* S,7'E,9'R,1 l'S,12 ^, R)-6-CHLORO-9 ^, -(2- METHOXYETHYL)- 1 1 12 -DIMETHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ⁱ⁴ ]PE TACOSA [7, 16, 18,24]TETRAEN]~15'-ONE 13", 13 -DIOXIDE

To a stirred solution of (lS, R,6'S,TE,9'R, 11 'S, 12 ^, R)-6-chloro-9 ^, -(2- hydroxy ethyl)- 11 12'-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20ioxa| 13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ³ ^0 ^!9 ' ²⁴ |pentacosa[7,16,l^ n]-15'-one 13', 13'-dioxide (Example 113; 16 nig, 0.026 mmol) in THF (1020 μΕ) under a nitrogen atmosphere was added sodium hydride (60 % dipsersion in mineral oil; 5.10 nig, 0.128 mmol). The reaction mixture was stirred at rt for 10 minutes, charged with iodomethane (7,98 μΐ,, 0.128 mmol) and stirred at rt over the weekend. The reaction mixture was then partitioned between EtOAc and water, and the organic layer was dried over MgSO-j, filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (4 g silica gel; DCM: Acetone, 1 :0 to 3: 1 solvent gradient) gave

(1^3 ^, R,6 ,7 ^, E ₅ 9 ^, R ₅ ir_?, 12 ^, R)-6-chloro-9 ^, -(2-methoxye l)-i r

dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'-

nj-15'-one 13',13 ^! ~dioxide (5.7 mg, 8,9 μιηοΐ, 35 % yield) as a white solid. ^" Ή NMR (400 MHz, CD ₂ C1 ₂ ) δ ppm 8.07 (br. s., 1 H), 7.72 (d, ./ H.6 Hz, 1 H), 7.17 (dd, ,/ 8.5.2,2 Hz, ! H), 7.09 (d, ,/ 2.2 Hz, I H), 6.95 - 7,04 (m, 2 H), 6.89 - 6,94 (m, 1 H), 5,81 (dd, J=15.4, 4.8 Hz, 1 H), 5.16 (dd, J=15.7, 7.3 Hz, 1 H), 4.09 - 4.17 (m, 2H), 3.83 (d,J=15.1 Hz, 1 H), 3.63 (d../ 14. \ Hz, 1 H), 3.32 (id.-/ 6.7. 1.6 Hz, 2H), 3.28 (s, 3 H), 3.20 id 14.1 Hz, I !!}.3.07 (dd../ 15.5.8.2 Hz, 1 H), 2.69 - 2.83 (m, 2 H), 2.51 - 2.62 (m, 1 H), 2.13 - 2.24 (m, 2 H), 1.94 - 2.07 (m, 1 H), 1.72 - 1.94 (m, 4 H), 1.37 - 1.70 (m, 11 H), 1.30 (br. s., 1 H), 0.96 (d, ./ 6.8 Hz, 3 II). m /. (ESI, +ve ion) 640.8 (XI II)

EXAMPLE 115. (1S,3'R,6'S,7'E,9'R,1 l'S,12'R)-6-CHLORO- ',12'-DIMETOYL- 9 ^, 2-(4-MORPHOLINYL)ETHYL)-3,4-DIHYDRO-2H,15 ^! H- SP1RO [NAPHTHALENE- 1 ,22'- pOlOXAIlSlTHIAIl.MlDIAZATETRACYCLOiM.T^.O'^.O^^lPENTACOSA

[7,16, 18 ,24]TETRAEN] - 15"-ONE 13 ', 13 '-DIOXIDE

STEP 1: (1S,3'R,6'S,7 ^! E,9'R,1 rS,12'R)-6-CHLORO-9 ^! -FORMYLMETHYL- 11^12'-DIMETHYL-3,4-DIHYDRO-2H,151I-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [7,16,18,24]TETRAEN] - 15'-ONE !.T.13 '-DIOXIDE

To a stirred solution of (lS^'R^'^T'E^'i^ll'^^'R e-chloro-^^- hydroxyethyl)-i ,12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'' ⁿ jpeniacosn| 7. ! 6J S.2-l ju,Hrae n]-15'-one 13',13'-dioxide (20 nig, 0.032 mmol; Example 113) in DCM (1275 μΕ) was added Dess-Martin periodinane (17.6 mg, 0.041 mmol) in one portion, and the reaction mixture was stirred at rt for 40 minutes. After this time, ether and saturated sodium thiosulfate (aq.) were added and the resulting mixture was stirred at rt for 10 minutes. The layers were separated and the organic layer was washed sequentially with saturated sodium thiosulfate (aq.) and saturated sodium bicarbonate (aq.), dried over MgS04, filtered and concentrated in vacuo to give Π .Υ..ΪΛ\ \\ 77^ 'Λ\ 11 'S, 12 ^* R)-6-chloro-9 ^, -formylmethyl - 11 12 ^* -dimethyl-3,4- dihydro-2H,l 57/-spiroj naphthalene- 1, 22'- [2Q]oxa[13]ihia[l ,14]diaza ^^

n]-15'-one 13',13'~dioxMe (9.0 mg, 0,014 mmol, 45.1 % yield).

STEP 2: (1S,3'R,6'S,7'E,9'R,1 l'S,12'R)-6-CHLORO-l l',12'-DlMETHYL-9'-(2- (4-MORPHOLINYL)ETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [7, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

To a stirred solution of (lS, R,&S,7E,9R,l VS,12'R)-6-ddoro-9'- formylmethy 1- 11 ', 12'-dimethy 1-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20] oxa[ 13] thi a[ 1 , 14] diazatetracy clo [ 14, 7.2, 0 ³ * ⁶ .0 ¹⁹ · ²⁴ ] pentacosa[7, 16, 18 ,24] tetrae n]-15'-one 13',13'-dioxide (9.0 nig, 0.014 mmol) in 1,2-dichloroethane (720 μΕ) was added morpholine (3.8 μΕ, 0.043 mmol), and the resulting solution was stirred at rt for one hour. Sodium triacetoxyborohydride (9.1 mg, 0.043 mmol) was then added in one portion, and the reaction mixture was stirred at rt for two hours and subsequently partitioned between DCM and water. The organic layer was dried over MgSC , filtered and concentrated in vacuo. Purification of the crude residue by column chromatography (4 g silica gel: DCM: acetone, 1:0 to 1 : 1 solvent gradient) gave ( I Λ ^' .3'Λ'.6'Λ.77-. ^' .97^. 1 1 '.V. 127<')-6-ch!oro- 1 ! '. 1 '-duneihyl -9'- (2-(4-morpholinyi)ethyl)-3,4-dihydro-2H,157/-spiiO|naphihaie ne-l,22'- [20]oxa[13]1hia[l,14]diazatetTac lo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[7,16,18,24]tetrae n]-15'-one 13',13'-dioxide (1.45 mg, 2.08 μηιοΐ, 14 % yield) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ ppm 7.72 id../ 8.4 Hz, 1 H), 7.16 (dd, ,/ H.5.2.4 Hz, 1 H), 7,01 - 7. (m, 3 H), 6,90 (d, J=8.0Hz, I !!}.5.78 (dd,J=15.6, 5.2 Hz, 1 H), 5.18 (dd, J=15,9, 8.3 Hz, 1 H), 4.07 - 4.15 (m, 2 H), 4.00 (br, s., 1 H), 3.81 (d,

J=15.5 Hz, 1 H), 3.73 (t, ./ 4.6 Hz, 4 H), 3.63 (d, J=14.5 Hz, 1 H), 3.22 (d, ./ 1-1.3 Hz, 1 H), 3.06 (dd,■/ 15.3.8.4 Hz, 1 H), 2.73 - 2.79 (m, 2 H), 2.33 - 2.58 (m, 8 H), 2.09 - 2.29 (m, 3 H), 1,95 - 2.03 (m, 2 H), 1,75 - 1.94 (m, 5 H), 1.60 - 1.68 (m, 1 H), 1.41 - 1.50 (m, 4 H), 1.37 (d, ,7=7,0 Hz, 3 H), 0.97 (d, .7=6.8 Hz, 3 H). m/z (ESI, +ve ion) 696.3 < M 11 > .

EXAMPLE 116. (1 S,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-7'-HYDROXY-6',12'- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETR _J! 4EN1-15'-0NE 13',13'-DIOXIDE OR

(lS,3¾,6'R,7¾,8T,12¾)-6-CHLORO-7'-I-IYDROXY-6',12'-DIM ETOYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATEIIACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'S,6'S,7'S,8'E,12'R)- 6-CHLORO-7'-HYDROXY-6', 12'-DIMETOYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]TH1A[1,14]DL ZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]1^ ^{^}

[8,16,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'S,6'S,7'R,8'E,12'R)-6-CHLORO-7'-HYDROXY-6',12'-DrME THYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13 ^* -DIOXIDE

STEP 1 : ( 1 R,2R)-METHYL 2-((TERT-BUTYLDIPHENYLSILYL)METHYL)-l- METHYLCYCLOBUTANECARBOXYLATE AND (1S,2S)- METHYL 2- ((TERT-BUTYLDIPHENYLSILYL)METHYL)- 1 - METHYLCYCLOBUTANECARBOXYLATE

A solution of methyl methacrylate (17.66 mL, 166 mrnol) in DCM (80 mL) was added to a stirred solution of titanium (IV) chloride (19.20 mL, 174 mrnol) in DCM (160 mL). A solution of allyl (tert-butyl) diphenvlsilane (67.4 g, 240 mrnol) in DCM (80 mL) was then added and the reaction was heated at reflux for 2 days. After this time the reaction was cooled to ambient temperature and poured into NaHCCb (saturated aqueous solution) and ice. NH4CI (saturated aqueous solution) was then added, the organic layer was separated, and the aqueous layer was extracted with DCM (x2). The combined organic extracts were filtered over celite. The filtrate was dried over MgSC , filtered and evaporated in vacuo. The residue was adsorbed in a plug of S1O2 (65 g) and purified by column chromatography (330 g S1O2, hexanes:EtOAc, 1 :0 to 20: 1 ) to provide (1R,2R)- methyl 2-((tert-butyldiphenylsilyl)me†jiyl)- 1 -methylcy clobutanecarboxylate and (1S,2S)~ methyl 2-((tert-butyldiphenylsilyl)methyl)-l- methylcyclobutanecarboxylate (46.9 g, 123 mmol, 74%). m/z (ESI, +ve ion) 627.1

STEP 2: ( 1 R,2R)-METHYL 2-((TERT-BUTYLDIFLUOROSILYL)METHYL)- 1 -METHYLC YCLOBUTANECARBOXYL ATE AND ( 1 S,2S)-METHYL 2- ((TERT-BUTYLDIFLUOROSILYL)METHYL)-l - METHYLCYCLOBUTANECARBOXYLATE

To a stirred solution of (l R,2R)-methyl 2-((tert

butyldiphenylsilyl)methyl)-l-methylcyclobutanecarboxylate and (lS,2S)-methyl 2-((tert-butyldiphenylsilyl)methyl)- 1 -methy Icy clobutaoecarboxy late (46.9 g, 123 mmol) in DCM (616 mL) was added boron trifluonde acetic acid complex (86 mL, 616 mmol). The reaction was heated at reflux overnight. After this time the reaction was cooled to ambient temperature and poured into ice/NaHCC . The separated organic layer was dried over MgSi filtered and evaporated in vacuo to give ( 1 R,2R)-methy 1 2-((tert-butyldifluorosily l)methy 1)- 1 - methylcyclobutanecarboxylate and (l S,2S)-methyi 2-((tert- butyldifluorosilyl)methyl)-l-methylcyclobutanecarboxylate (29.6 g, 112 mmol, 91 % yield).

STEP 3: ( 1 R,2R)-METHYL 2-(H YDROXYMETHYL)- 1 - METHYLCYCLOBUTANECARBOXYLATE AND (1S,2S)- METHYL 2- (HYDROXYMETHYL)- 1 -METHYLCYCLOBUTANEC ARBOXYL ATE

To a stirred solution of (lR,2R)-methyl 2-((tert-but 'ldifluorosilyl)methyl)' 1- methylcyclobutanecarboxylate and (1 S,2S)-methyl 2-((tert- but 'lclifluorosilyl)methyl)-l-methylcyclobutanecarboxylate (29.6 g, 112 mmol) in THF/MeOH (300 mL/300 mL) was added potassium fluoride (19.51 g, 336 mmol) and sodium bicarbonate (9.41 g, 112 mmol) and the reaction was cooled to 0 °C. A 30% aqueous solution of hydrogen peroxide (57.2 mL, 560 mmol) was then added dropwise via addition funnel over 15 minutes. After this time the reaction was allowed to warm to ambient temperature and stirred overnight. After this time the reaction was treated with Et ₂ 0, cooled to 0 °C and treated with a saturated aqueous solution of Na ₂ SCb. The separated organic layer was washed with Na ₂ SCb (sat aq solution; until organic layer tested negative with starch paper), dried over MgSCH, filtered and evaporated in vacuo. The resulting residue was adsorbed in a 80g pre-pack silica cartridge and then purified by column chromatography (330 g SiCte, hexanes: EtOAc, 1 :0 to 4: 1) to give (lR,2R)-methyl

2- (hydroxymethyl)-l-methylc clobutanecarboxylate and (1 S,2S)- methyl 2- (hydroxymethyl)-l-meihylcyclobutanecarboxylate (7.3 g, 46.18 mmol, 41.2 % yield).

STEP 4: ( 1 R,2R)-METHYL 2-FORMYL-l-

METHYLCYCLOBUTANECARBOXYLATE AND (1 S,2S)-METHYL 2- FORMYL-1-METHYLCYCLOBUTANECARBOXYLATE

To a stirred solution of (l R,2R)-methyl 2-(hydroxymethyl)-l- methylcyclobutanecarboxylate (2.5 g, 15.80 mmol) and (l S,2S)-methyl 2-formyl- 1-methylcyclobutanecarboxylate in DCM (79 mL) was added Dess-Martin periodinane (8.04 g, 18.96 mmol) in one portion. The reaction was stirred at ambient temperature for 30 minutes. After this time the reaction was diluted with Et ₂ 0 (100 mL) and treated with Na ₂ S ₂ 03 (saturated aqueous solution). The separated organic layer was dried over MgSiX filtered and carefully evaporated in vacuo. Column chromatography (24 g SiO?., Pentane: Et?,0 (1:0 to 5: 1) gave (lR,2R)-methyl 2-formyl-l-methylc clobutanecarboxylate and (lS,2S)-methyi 2- foimyl-l-methylcyclobutanecarboxylate (1.3 g, 8.333 mniol, 53 % yield) as a colorless liquid.

STEP 5: (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2- (METHOXYCARBONYL)-2-METHYLCYC OBU L)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-B UTYL 6'-CHLORO- 5-i(ilS,2S)-2-(METHOXYCARBONYL)-2-

METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEP1NE-3, 1 '-NAPHTHALENE] -7-

CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((lS,2R)-2- (METHOXYCARBONYL)-2-METHYLCYC OBU L)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]ΟΧΑΖΕΡΓΝΕ-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-B UTYL 6'-CHLORO- 5-(((lR,2S)-2-(METOOXYCARBONYL)-2-

METHYIXYCLOBUT ^r L)METHYL)-3',4,4',5-TETRAI-IYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPlNE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE

A solution of (S)-tert-butyl 6'-chioro-3',4,4\54etrahydro-2H,2Tf spiro|benzo|b][l,4]oxazepine-3, i'-naphihalene]-7-carboxylaie (Intermediate ΑΑΓ1Α, Step 12B; 2 g, 5.00 mmol) and (lR,2R)-methyl 2-formyl-l- methylcyclobutanecarboxylate and (l.S,2S)-methyl 2-formyl-l- methylcyclobutanecarboxylate (1.172 g, 7.50 mmol) in CH2CI2 (33.3 mL) and AcOH (16.67 mL) was stirred at ambient temperature for 20 minutes. After this time the reaction was cooled to 0 °C and treated with a solution of sodium cyanoborohydride (0. 126 g, 2.00 mmol) in THF (3 mL) dropwise via syringe pump for 2 hours. The reaction was stirred at ambient temperature overnight. After this time the reaction was partitioned between EtOAc and aq NaOH. The separated aqueous layer was extracted with DCM and the combined organic extracts were dried over MgS0 ₄ , filtered and evaporated in vacuo. Column chromatography (40 g SiO?., hexanes:EtOAc (containing 1% AcOH), 1 :0 to 9: 1) gave (S)-tert-butyl 6'-chloro-5-(((! R,2R)-2-(methoxycarbonyl)-2- methylc}'clobutyl)meth}'l)-: ,4 4V -tetrahydi 2H,2^H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((lS,2S)-2-(methoxycarbonyl)-2-methylc\xlobutyl )methyl)-3',4,4',5- tetrahydro-2H,2H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((l S,2R)-2-(methoxycarbonyl)-2- methylcyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox>'late and (S)-tert-butyl 6'-chloro-5-(((lR,2S)-2-(methoxycarbonyl)-2-m

tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (2.15 g, 3.98 mmol, 80 % yield) as a white solid.

STEP 6: (S)-TERT-BUTYL e'-CHLO O-S-^ilR^Rl^- -iYDROXA^MEraYL)- 2-METOYIXYCIX)BU L)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO[B] [ 1 ,4] OXAZEPlNE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-((( 1 S,2S)-2-

(HYDROXYMETHYL)-2-METOYLCYCLOBUTYL)METOYL)-3',4,4 ^f ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-B UTYL 6'-CHLORO- 5-(((l S,2R)-2-(HYDROXYMElHYL)-2-METHYLCYCLOBUTYL)ME ^r THYL)- ;r,4 4' ₅ 5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][L4]OXAZEPlNE-3,l'- NAPHTHALENE] -7-CARBOXYL ATE AND (S)-TERT-BUTYL 6'-CHLORO- 5-(((lR,2S)-2-(HYDROXYMETOYL)-2-METOYLCYCLOBLITYL)METHYL)- 3 ^, ,4,4',5-TETRAHYDR()-2H,2'H-SPIRO[BENZ()[B;||;i ,4]OXAZEPINE-3,r- N APHTH ALENE1 -7 -C ARB OXYL ATE

To a stirred solution of (S)-teri-butyl 6'-chloro-5-(((lR _: ,2R)-2- (niethoxycai¾onyl)-2-niethylcyelobuty^

spiro[benzo[b] [ 1 ,4 ]oxazepme-3, 1 '-naphthalene] -7-carboxylate and (S)-tert-buty 1 6'-chloro-5-((( lS,2S)-2-(raethoxycarbonyl)-2-rnethylcyclobutyl)m

tetrahy diO-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((l S,2R)-2-(methoxycarbonyl)-2- methylcyclobutyl)methy])-3',4,4',5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxy late and (S)-tert-buty 1 6'-chloro-5-(((lR,2S)-2-(methoxycarbonyl)-2-methylcyclobutyl )methyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (2, 15 g, 3.98 rnmol) in Et20 (80 mL) was added lithium borohydride (0.087 g, 3.98 rnmol). The reaction was stirred at ambient temperature for 4 hours. After this time the reaction was diluted with EtOAc and quenched by the careful addition of NH4CI (sat aq solution). The separated aqueous layer was extracted with EtOAc and the combined organic extracts were dried over MgS0 ₄ , filtered and evaporated in vacuo. Column chromatography (80g S1O2, hexanes:EtOAc (containing 1 % AcOH), 1 :0 to 9: 1 ) gave a 1 : 1 mixture of (S)-tert-butyl ό'-chloro- 5-(((lR,2R)-2-(hydroxymethyl)-2-methylcyclobutyl)methy])-3 ^, ,4,4 ^, ,5-tetrahydro- 2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)- tert-butyl 6'-chloro-5-(((lS,2S)-2-(hydroxymethyl)-2-methylcyclobutyl)m ethyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphtha]ene]-7- carboxylate as the first eluting major component (0,95 g).

Further elution provided a 1 : 1 mixture of (S)-tert-butyl 6'-chloro-5-(((lS,2R)-2- (hydroxymethyl)-2-meth lcyclobutyl)meth^

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyla te and (S)-tert-butyl 6'-chloro-5-(((lR,2S)-2-(hy(koxymethyl)-2-me lcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro| benzoj b] [ 1 ,4] oxazepine-3, Γ -naphthalene ] -7-carboxylate as the second eluting minor component (0.42 g),

STEP 7: (S)-TERT-BUTYL 6'-CHLORO-5-(((l R,2R)-2-FORMYL-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYI)RO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((l S,2S)-2-

F0RMYL-2-METHYIX:YCI BUTYL)METHYL)-3',4,4',5-TETRAI-IYDR0- 2H,2'H-SP1R0 [BENZO [B] [ 1 ,4] OXAZEPINE-3, Γ -NAPHTHALENE] -7- CARBOXYLATE

To a stirred solution of (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-

(hydroxyme†hyl)-2-methylcydobu1yl^

spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-tert-butyl 6 ^, -chloro-5-(((lS,2S)-2-(hydroxy'me l)-2-me1hylcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (Step 6, first eluting major component; 0,98 g, 1 .914 mmoi) in CH2CI2 (19.14 raL) at rt was added Dess-Martin penodinane (0.893 g, 2.105 mmoi) in one portion. The reaction was stirred at ambient temperature for 30 minutes. After this time the reaction was partitioned between Et ₂ 0 and Na ₂ S ₂ 03 (sat aq solution). The separated organic layer was dried over MgS04, filtered and evaporated in vacuo. Column chromatography (24g S1O2, hexanes:EtOAc, 1 :0 to 5: 1) gave (S)-tert- butyl 6'-chloro-5-(((l R,2R)-2-formyl-2-me1 ylc\'clobutyl)methyl)-3',4,4',5- tetrahydro-2H,2H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-cMoro-5-(((lS,2S)-2-formyl-2-methylc 'clobu1yl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spifo[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carbox late (0.85 g, 1.666 mmoi, 87 % yield) as a white solid.

STEP 8: (S)-TERT-BUTYL 6'-CHLORO-5-(((l R,2R)-2-((S)-l- HYDROXYALLYL)-2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPrNE-3, 1 '- NAPHTHALENE j -7-C ARBOXYLATE AND (S)-TERT-B UTYL 6'-CHLORO- 5 -(((1 S,2S)-2-((S)- 1 -HYDROXY ALLYL)-2-

METHYLCYCLOBmTL)METHYL)"3 ^! ,4,4',5-TEm HYDRO-2H,2'H" SPIRO| BENZO[B]|;L4iOXAZEPINE-3, l'-NAPHTHALENE]-7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2-((R)-l - HYDROXY ALLYL)-2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPrNE-3, 1 '- NAPHTHALENE] -7-C ARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO- 5-(((l S,2S)-2-((R)- 1 -T-rY ^T DROXYAT,LYL)-2-

METHYLCYCLOBUlTL)METHYL)-3 ^! ,4,4',5-TEm HYDRO-2H,2'H- SPIRO BENZO[B] [1 ,4 jOXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE

To a stirred solution of (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-fornTyl-2- methylcyclobut>d)methyl)-3 ^! ,4,4',5-tetrahydro-2H,2H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((l S,2S)-2-formyl-2-meth lcyclobuty^

2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carbox late (570 mg, 1.118 mmol) in THF (11.2 mL) at 0 °C under a N ₂ atmosphere was added a 1M solution of vinylmagnesium bromide (838 μΙ_, 1.341 mmol) in THF. The reaction was stirred at this temperature for 30 minutes and at ambient temperature for 2 hours. After this time the reaction was partitioned between EtOAc and NH ₄ C1. The separated organic layer was dried over MgS04, filtered and evaporated in vacuo. Column chromatography (12g SiO?., hexanes:EtOAc (containing 1% AcOH), 1 :0 to 85: 15) gave (S)-tert-butyl A'-ch!oro- -{{{ ! R.2R )-2-{{S )- l - hydroxyallyl)-2-methylcyclobuty'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((lS,2S)-2-((S)-l -hydroxy allyl)-2-me lcyclobutyd)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate or (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((R)-l-hydroxyallyl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetraliydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carbox 'late and (S)-tert-butyl 6'-chloro-5-(((l S,2S)-2-((R)-l-hydroxydlyl)-2-methylcyclobuty'l)methyl)- 3 4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate as the first eiutiiig major component (200 mg).

Further elution provided (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)-2-methylcyclobutyl)methyl)-3^4,4 5-tetrahydro-2H,2'H- spiro[benzo[b] [ l,4]oxazepine-3, 1 -naphtha! ene]-7-carboxylate and (S)-tert-buty! 6'-chloro-5-(((lS,2S)-2-((S)-l-hyckoxyallyl)-2-rnethylcyclob utyl)rnethyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1,4 joxazepme-3,1 '-naphthalene j-7- carboxylate or (S)-tert-butyl 6'-chloro-5-(((l R,2R)-2-((R)-.l -hydroxyallyl)-2- methylcyclobut}4)m.ethyl)-3V ,4',5~tetrahydro-2H,2 ^! H~

spiro I benzo | b j [ 1 ,4] oxazepine-3 , Γ-naphthal ene ] -7-carboxy late and (S)-tert-buty 1 6'-chloro-5-(((l S ₅ 2S)-2-((R)-l½droxyallyl)-2-methylcyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylate as the second eluting minor component (80 nig).

STEP 9: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l -HYDROXY ALLYL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lS,2S)-2-((S)-l -HYDROXY ALLYL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lR ₅ 2R)-2-((R)-l-HYDROXYALLYL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETR.AHYDRO-2H,2'H- SPIRO [BENZO | B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLI C ACID AND (S)-6'-CHLORO-5-(((l S,2S)-2-((R)-l -HYDROXY ALL YL)-2- METHYLCYCLOBUlYL)METHYL)-3 ^! ,4,4',5-TEmAHYDRO-2H,2'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID

A solution of (S)-tert-butyl 6'-chloro-5-(((l R,2R)-2-((S)-l-hydro^allyl)- 2-methylcyc]obutyl)methyl)-3',4,4',5-tetTahydro-2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy 1 ate and (S)-tert-but>'l 6'-chloro-5-(((lS,2S)-2-((S)-l-hydrox 'allyl)-2-methylcyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spifo[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carbox late or (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((R)-l-hydroxyallyl)-2-

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-((( 1 S,2S)-2-((R)- 1 -hydroxyallyl)-2-methylcyc]obuty l)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate (Example 116, Step 8, first eluting major isomer: 200 mg, 0.372 mmol) in CH2CI2 (2.5 mL) and TFA (1.2 mL) was stirred at ambient temperature for 4 hours. After this time the reaction was evaporated in vacuo. The resulting residue was partitioned between DCM and NaHCQi. The separated organic layer was dried over MgS04, filtered and evaporated in vacuo to give (S)-6'-chloro-5- (((iR,2R)-2-((S)-l-hydiX)xyaliyl)-2-methylcyclobuiyl)meihyi) -:r^

2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy lie acid and (S)-6 ^, -cWoro-5-(((lS,2S)-2-((S)-l-hydroxyallyl)-2-methylcycl obu1yl)methyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b][l ,4]oxazepine-3, -naphthalene]-7- carboxylic acid or (S)-6'-chloro-5-(((lR,2R)-2-((R)-l-hydroxyallyl)-2- methylcyciobut 4)methyl)--3 ^! ,4,4',5~tetrahydro-2H,2 ^! H~

spiro benzo b] l,4]oxazepine-3, -naphthalene|-7-carboxylic acid and (S)-6'- chloro-5-(((I S,2S)-2 (R.)- 1 iydroxyallyl)-2-methylcyclobutyl)m

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylic acid (180 mg, 0.373 mmoL 100 % yield).

STEP 10: (S)-6'-CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)-5-(((lR,2R)-2-

((S)-l-IT DROXYALLYL)-2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5-

TETRAHYDRO-2H,2 ^! H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- APHTHALENE] -7 -C ARB OXAMIDE AND (S)-6'-CHLORO-N-((R)-HEX-5- EN-2-YLSULFONYL)-5-(((l S,2S)-2-((S)- 1 -HYDROXY ALLYL)-2- METHYIX;YCLOBUTTL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'I-I- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXAM1DE OR (S)-6'-CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)- 5-(((lR,2R)-2-((R)-l-HYDROXYALLYL)-2-

METHYLCYCIX)BUTYT.)METHYL)-3 ^f ,4,4',5-TETRAI-IYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] 0¾ ZEPlNE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6'-CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)- 5 -((( 1 S,2S )-2-((R) - 1 -HYDROXY ALL YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '- APHTHALENE] -7- CARBOXAMIDE

To a stirred solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxyallyl)-2- methylcyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepme-3, ~naphthalene]-7-carboxylic acid and (S)-6'- chloro-5-(((l S,2S)-2-((S)-l-hydroxyailyl)-2-m^

tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid or (S)-6'-chloro-5-(((l R,2R)-2-((R)-l -hydroxy a]lyi)-2- rnethylcyclobut 4)m.ethyl)-3V ,4',5~tetrahydro-2H,2 ^! H~

spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid and (S)-6'- chloiO-5-(((l S,2S)-2-((R)-1 iydroxyallyl)-2-methylcyxlobutyI)inethy )-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy li c acid (105 mg, 0.218 mmo!), (R)-hex-5-ene-2-sulfonamide (Intermediate EE20: 107 mg, 0.654 mrnol), DMAP (39.9 mg, 0.327 mrnol) and triethylamine (60.7 μΕ, 0.436 mrnol) at 0 °C under a N2 atmosphere was added EDC (84 mg, 0.436 mrnol) portionwise over 1 minute. The reaction was stirred at ambient temperature overnight. After this time the reaction was treated with more EDC (42 nig), DMAP (20 mg), EtsN (0.03 mL) and chirai sulfonamide (50 mg) and the reaction was stirred at ambient temperature for 24 hours. After this time the reaction was partitioned between EtOAc and NaHCC . The separated organic layer was dried over MgS()4, filtered and evaporated in vacuo. Column chromatography (12g SiC , hexanes:EtOAc (containing l%AcOH, 1 :0 to 4: 1 ) gave (S)-6'-chloro-N- ((R)-hex-5-en-2-ylsulfonyl)-5-(((lR,2R)-2-((S)-l -hydroxyallyl)-2- methylcyclobut 'l)methyl)--3 ^! ,4,4',5~tetrahydro-2H,2 ^! H~

spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfon l)-5-(((lS,2S)-2-((S)-l-h droxyallyl)-2- methy!cvclobut> ! )n Hhvl )-:VA4^5-ielnihvdi -2l Ι.2Ί I- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxamide or (S)-6'-chloro-

N-((R)-hex-5-en-2-ylsdfonyl)-5-(((l R,2R)-2-((R)-l-hydroxyallyl)-2- methylcyclobuiyi)methyl)-3',4,4',5-teirahydro-2I-I,2 ^f H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfony l)-5-(((l S,2S)-2-((R)- 1 -hydroxyallyI)-2- methylcyclobutyl)methy])-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxamide as the first e!uiing major component (29 nig).

Further elution provided (S)-6'-chloro-N-((R)-hex-5-en-2-ylsulfonyl)-5-(((lR,2R)- 2-((S)-l-hydroxyallyl)-2-me lcyclobutyl)me l)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)-6'-chloro- -((R)-hex-5-en-2-ylsuifony )-5-(((lS,2S)-2-((S)-l-hydroxyallyl)-2- methylcyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spirojbenzojb] [ 1 ,4] oxazepine-3, 1 '-naphthaleneJ-7-carboxamide or (S)-6'-chloro- N~((R)4iex-5~en-2-y!sulfo^

methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfonyl)-5-(((l S ₅ 2S)-2 (R)-l-h droxyallyl)-2- methylcyclobut 'i)methyl)-3 ^! ,4,4',5-tetrahydro-2H,2'H- spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxarnide as the first eluting major component (27 mg).

DIMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS ₅ 3 ^, R,6 ^, R,7 ^, R,8i 2 ^, R)-6-CHLORO-7 ^, -HYDROXY-6 ^, ,12 ^, -DlMETHYL-3 ₅ 4- DIHYDRO-2H, 15TI-SPIRO[NAPHTHALENE-L22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'S,6'S,7'S ₅ 8'E ₅ 12'R)- 6~CHLORO-7 ^, ~HYDROXY-6',12'-DIMETHYL-3,4-DIHYDRO-2H,I5'H- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'S,6'S,7'R,8'E,12'R)-6-CIlLORO-7'-HYDROXY-6',12'-DIM ETHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.20 ^;ί '.ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN] -15'-ONE i.T.i 3'-DIOXIDE

A stirred solution of (S)-6'-chloro-N-((R)-hex-5-en-2-ylsulfonyl)-5- (((IR,2R)-2-((S)-l-hydroxyaliyl ^

2H,2H-spiro[benzo[b][l,4]oxazepine-3, -naph†Jialene]-7-carboxarnide and (S)-

6'-chloro-N-((R)-hex-5-en-2-ylstdfonyl)-5-(((lS,2S)-2-((S )-l-hydroxyallyl)-2- methylcyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4]oxazepine-3, l.'-naphthalene]-7-carboxamide or (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfonyl)-5-(((lR,2R)-2-((R)-l-hy

methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfonyl)-5-(((lS ₅ 2S)-2 (R)-l-h droxyallyl)-2- methylcyclobutd)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro benzo b]|T,4]oxazepine-3, -naphthalene]-7-carboxamide (Example 116, Step 10, second eluting isomer; 27 rng, 0.043 mmol) in CH2C2 (21.5 mL) was degassed with Ar(g) for 10 minutes. After this time the reaction was heated at reflux for 3 hours. LC/MS after this time shows starting material and only a few traces of desired product. The reaction was then treated with 0.15 eq of a different bottle of Hoveyda Grubbs 2nd generation and stirring continued at reflux for 6 hours and at 40 °C (oil hath) overnight. After this time the reaction was cooled to ambient temperature and the catalyst was deactivated by sparging air through the mixture for 5 minutes. The reaction was evaporated in vacuo and the product was purified by column chromatography (4g SiC , hexanes:EtOAc (containing 1%ACOH), 1:0 to 3:1) to give (lS,3'R,6'R,7 ^! S ₅ 8T;]2'R)-6-chloro-7'-hydroxy- 6', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'~

[20joxa 13]thia[l,14]diazatetracycfo[M _^

n]-15'-one 13',13"-dioxide or (1 S,3'R,6'R,7'R,8'E,12 ^f R)-6-chioro-7'-hydroxy~6',12'- dimethyl-3,4-dihydro-2H,15 -SPIRQjnaphthalene-l,22 ^* - [20]oxa[13]thia[l,14]cUazatetracyclo|^^

n]-15'-one 13',! .3'-dioxide or (lS,3'S,6 ^f S,7'S,8'E,12'R.)-6-chloro-7'-hydroxy-6',12 ⁱ - dimethyl-3,4-dihydro-2H,15'H-spiro[naphtiialene-l,22'- IKJ4jtctrao n|-15'-one 13',13'-dioxide orilS.S'S^'S 'R^'E.n'R^e-chloro-T-hydro -e',!^- dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracy^

n]-15'-one 13',13'-dioxide (3.2 mg, 5.34 μηιοΐ, 12.41 % yield). ^! H NMR

(400MHz, YleOI \~J ) δ 7.72 (d, 8.6 Hz, 111).7. 7 (dd, 23.8.6 Hz, ill).7.10 (d, J=2.2 Hz, IH), 6,98 (dd, J=2.0, 8.4 Hz, 1H), 6.91 (d, ,/ 82 Hz, 1H), 6.80 (d, J=2.0 Hz, IH), 5.86 (td, .7=6.7, 15.1 Hz, I!!}.5.76 (dd, ./ 7.4.15.7 Hz, III).4.21 - 4.12 (m, IH), 4.10 - 4.02 (m, 2H), 3.91 (d, ./ 7.4 Hz, IH), 3.78 (d, ./ 15.3 Hz, IH), 3,66 (d, ./ 14.7 Hz, !!!).3.24 (d, ,/ i 43 Hz, 111).3.1 (dd, ,/ i08.15,1 Hz, IH), 2,87 - 2.70 (m, 2H), 2.50 - 2.41 (m, IH), 2,41 - 2.32 (m, IH), 2.22 (dd, J=6.3, 9.8 Hz, IH), 2.09 (d,J=13.5 Hz, IH), 1.98 - 1.85 (in, 5H), 1.77 - 1.65 (m, IH), 1.47 (d,J=7,0Hz, 3H), 1.46 - 1,42 (m, IH), 1.41 - 1.32 (m, 2H), 1.31 is. 3H). MS (ESI, +ve ion) m/z 599,2 (M+H) ⁺ ,

EXAMPLE 117. (1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7'-HYDROXY-6', 12'- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N ΑΡΗΊΉ ALEN E- 1 ,22'- [20]OXA[13]TO A[l,14]DIAZATEmACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR (lS,3'R ₅ 6 ^, R,7 ^, R ₅ 8¾12¾)-6-CHLORO-7 ^, -HYDROXY-6\12 ^, -DIMETHYL-3,4-

D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l 4jDIAZATETRACYCLO|14 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DiOXlDE OR (1S,3'S,6'SJ'S,8'EJ2'R)- 0-CHLQRQ-7'-HYDRQXY~6', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THIA[l 4]DIAZATETRACYCL)[14J.2X) ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAENi-!5'-ONE 13', 13 '-DIOXIDE OR

(lS,3'S,6'S,7'R,8X 2 ^! R)-6-CHLORO-7'-HYDROXY-6',12'-DIMETHYL-3,4- DIHYDRO-2H, 15TI-SPIRO[NAPHTHALENE-L22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

STEP 1: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((S)-l -HYDROXY ALLYL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ][ 1,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHL()RO-5-(((lS,2S)-2-((S)-l-HYDROXYALLYL)-2- MF^mXYTLOBUT^X)METHYL)-3',4,4',5-TETRAI-IYDRO-2H,2'H- SPs ROi 5· /ΟΙ P || i .4 !i >X ΛΖ! · P i \ !· -3.1 Λ Fi! Π !Λ1 J N !: !-?~(\\! ! )Χ Y I ACID OR (S)-6'-CHLORO-5-(((lR,2R)-2-((R)-l-HYDROXYALLYL)-2- METOYLCYCIi3BUTYL)METHYL)-3',4,4',5-TETRAHY ^' DRO-2H,2'I-I- SPIRO[BENZO[B][l 4]OXAZEPINE-: l'-NAlWHALENE]-7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lS,2S)-2-((R)-l -HYDROXY ALLYL)-2-

METHYLCYCLOBmYL)METHYL)"3 ^! ,4,4',5-TEm HYDRO-2H,2'H"

SPIRO| BENZO[B;||;i,4|OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC

ACID

The title compounds were synthesized from (S)-tert-butyl 6'-chloro-5-

(((l R,2R)~2-((S)~1 iydroxyallyl)-2-T^^

2H,2'H-spiro[benzo[b][l,4]oxazepme-3,r~naphthalene]-7-carbox yiaie and (S)~

6 ^, -chloro-5-(((lS,2S)-2"((S)-l-liydroxyallyl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-tert-butyl 6'- chloro-5~(((lR,2R 2~((R)-1 wdroxy

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((lS,2S)-2-((R)-l-hydroxyallyl)-2- methylcyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (Example 116, Step 8, second eluting minor isomer; 80 mg, 0.149 mmol) following the procedure described for Example 1 16, Step 9. After aqueous workup, the isolated crude mixture of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxyallyl)-2- methylcyclobuiyi)rnethyl)-3 ^f ,4,4',5-teirahydro-2I-I,2'H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid and iS }--<Y~ cWoro-5-(((l S,2S)-2 (S)-l½droxyallyl)-2-me l<yclobutyl)methyl)-3 ^, ,4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyli c acid or (S)-6'-chloiO-5-(((lR,2R)-2-((R)-l -hydroxyallyl)-2- methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid and (S)-6 ^! - chloro-5-((( 1 S,2S)-2-((R)- 1 -hydroxy ally l)-2-methylcyclobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (55 mg, 0.114 mmol, 77 % yield) was taken on withouth further purification.

STEP 2: (S)-6'-CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)-5-(((lR,2R)-2- ((S)-l-HYDROXYALLYL)-2-METHYLCYC OBU L)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]QXAZEPiNE-3, 1 '- NAPHTHALENE] -7-CARBOXAM1DE AND (S)-6'-CHLORO-N-((R)-HEX-5- EN-2-YLSULFONYL)-5-(((l S,2S)-2-((S)-l-HYDR()XYALLYL)-2-

MFXHYLCYCLOBU L)METHYL)-3',4,4',5-TETRAI-IYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE OR (S)-6'-CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)- 5-(((l R,2R)-2-((R) - 1 -HYDROXY ALL YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OX, ZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXAMIDE AND (S)-6'-CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)- 5-(((l S,2S)-2-((R)- 1 -T-rY ^T DROXYALLYL)-2-

METHYLCYCLOBUlYL)METHYL)-3 ^! ,4,4',5-TEm HYDRO-2H,2'H- SPIROj BENZO [B] [1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE]-7- CARBOXAMIDE

The title compounds were synthesized from (S)-6'-chloro-5-(((lR,2R)-2-

((S)-1 iydroxyailyl)-2-methylcyclobutyl)methyl)-3^4,4^54etrahydro-2 H,2'H- spiro|benzo|b] [l,4]oxazepine-3, i'-naphihalene]-7-carboxylic acid and (S)-6'- cMoro-5-(((l S,2S)-2-((S)-l-hydroxyallyl)-2-methylc>'clobulyl)methyl)- 3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid or (S)-6'-chloro-5-(((lR,2R)-2-((R)-l -hydroxyallyi)-2- methylcyclobutyl)methyl)-3 ^f ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [1,4] oxazepine-3, Γ-naphthalene] -7-carboxylic acid and (S)-6'- chloro-5-(((lS,2S)-2-((R)-l-hydroxyallyl)-2-methylcyclobut 4)methyl)-3 4,4^5- tetrahy dro-2H,2'H-spiro| benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (55 mg, 0.114 mmol) and (R)-hex-5-ene-2-sulfonaxnide (Intermediate EE20;

56 mg, 0.342 mmol) following the procedure described for Example 116, Step 10.

Column chromatography (12g S1O2, hexanes:EtOAc (containing l %AcOH)) gave (S)-6'-chloro-N-((R)-hex-5-en-2-ylsulfonyl)-5-(((l R,2R)-2-((S)-l -hydroxyallyl)-

2-niethylcyclobutyl)methyl)-3V4,4 5-tetrahydro-2H,2'H- spiro| beiizo[b][l,4]oxazepiiie-3,r-naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfonyl)-5-(((lS,2S)-2-((S)-l-hydroxv'a llyl)-2- methylcyclobutyl)methyl)-: ,4,4V5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-6'-chloro-

N-((R)-hex-5-en-2-y3suifonyl)-5-(((l R,2R)-2-((R)-l-hydi xyaI3yl)-2- methylcyclobutyl)methyl)-3 ^f ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [1,4] oxazepine-3, i'-naphthalene]-7-carboxamide and (S)-6'-chioro- N-((R)-hex-5-en-2-ylsulfonyl)-5-(((l S ₅ 2S)-2-((R)-l-h droxyallyl)-2- methylcyclobut 'l)methyl)--3 ^! ,4,4',5~tetrahydro-2H,2 ^! H~

spiro benzo b] l,4]oxazepine-3,l'-naphthalene]-7-carboxamide as the first eluting major component (40 mg, 0,064 mmol, 56% yield). STEP 3: (!S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-HYDROXY-6'J 2 ^f - DIMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14J.2 ³ ' ^{6 19i4} ]PE TACOSA

[8J 6, 18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 12'R)~6-Cffl,QRQ~7'~HYDRQXY-6', 12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[l 4]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, 18 ,24] TETRAEN] - 15'-ONE 13', 13 ^* -DIOXIDE OR (1 S,3'S,6'S,7'S,8'E, 12'R)- 6-CHLORO-7 ^, -HYDROXY-6',12'-DIMETHYL-3,4-DIHYDRO-2H,I5'H- SPIRO [NAPHTHALENE- 1 ,22'- [20iOXA|;i3]THIA[l,14]DIAZATETRACYCL )[14J.2X) ³ >^0 ^{! 9} - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'S,6'S,7'R,8'E,12'R)-6-CHLORO-7'-HYDROXY-6',12'-DIME THYL-3,4- DIHYDRO-2H, 15TI-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

The title compound was synthesized from (S)-6'-chioro-N-((R)-hex-5-en- 2-y lsulfonyl)-5-(((lR,2R)-2-((S)-l -hydroxy ally l)-2-methy Icy ciobutyl)methy 1)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,l '-naphthalene |-7- carboxamide and (S)-6'-chloro-N-((R)-hex-5-en-2-ylsulfonyl)-5-(((lS,2S)-2-(( S)- l-hydroxyailyl)-2-methylcyclobut}4)methyi)-3',4,4',5-tetrahy dro-2H,2'H- spiroj benzoj b][ 1,4 ]oxazepine-3, -naphthalene]-7-carboxamide or (S)-6'-chloro-

N~((R)-hex-5~en-2-ylsulfonyl)^^

methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfonyl)-5-(((l S ₅ 2S)-2-((R)-l-h droxyallyl)-2- methylcyclobut d)methyl) ^» 3 ^! ,4,4',5~tetrahydro-2H,2 ^! H~

spiro| ^" benzo| ^" b] |T,4]oxazepine-3, -naphthalene]-7-carboxarnide (40 mg, 0.064 mmol) following ihe procedure described for Example 1 16, Step 11. The reaction was evaporated in vacuo and the product was purified by column chromatography (4g S1O2, hexanes:EtOAc (containing 1%ACOH), 1 :0 to 5: 1) to give

(lS,3¾,6 ^, R,7'S,8¾,12'R)-6-cWoro-7'-hydrox -6 2 ^, -dime l-3,4-dihydro- 2H, 1 5'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l, 14]diazatetracyclo^

n]-15'-one 13',13'-diQxide or (18,3'Κ,6'^7'Κ,8Έ,12'Κ)-6-ΰΜοΐΌ-7'-1ι ^Γθχν-6;12·- dimethyl-3,4-dihydro-2H,15'H-spirofnaphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracy^

n]-15'-one 13',13'-dioxide or (lS,3 ^* S,6 ^! S,7'S,8 ^, E;i2 ^, R)-6-chloro-7'-hydi xy-6',12 ^, ~ dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l, 14]diazatetracyclo[14^^^

n]-15'-one 13 ^* ,13'-dioxide or (lS,3'S,6 ^, S,7'R,8 ^, E,12'R)-6-chloro-7 ^* -hydroxy-6',12 ^* - dimethy3-3,4-dihydro-2H,15'i-I-spiro|naphthalene-l,22 ^! -

[20]oxa[13]thia[l ,14]diazatefra<y^

n]-15'-one 13',13'-dioxide as the first eluting major isomer (5.0 mg, 8.34 μπιοΐ, 13.09 % yield). ¾ NMR (400MHz, MeQH-oV) δ 7.73 (d, J=8.4 Hz, 1H), 7.34 (d, ./ 2,0 Hz, 1H), 7.15 (dd, ,/ 2.3. 8.4 Hz, IH), 7.09 (d, ,/ 2.2 Hz, IH), 6.99 (dd, J=2,2, 8.2 Hz, IH), 6.91 (d, J=7.8 Hz, IH), 5.87 (id, .7=5.1, 15.6 Hz, IH), 5.73 (dd, ./ 6.3. 15.7 Hz, IH), 4.19 - 4.10 (m, IH), 4.09 - 4.03 (m, 2H), 3.94 (d, ./ 1 . 1 Hz, I H), 3.75 (d, ./ 6. 1 Hz, IH), 3.62 (d, ./ 14.3 Hz, IH), 3.20 (d, ./ 14. 1 Hz, I H), 3.02 (dd, ./ I <> 7. 15.0 Hz, IH), 2,85 - 2,71 (m, 2H), 2.70 - 2.61 (ra, IH), 2,44 - 2,32 (m, IH), 2.25 - 2.15 (m, H), 2. 13 - 2,02 (m, 2H), 1.97 - 1.84 (m, 3H), 1 ,84 ·· 1.78 (m, IH), 1.77 - 1.65 (m, 3H), 1.44 (d, J=7.0 Hz, 3H), 1.47 - 1.38 (m, IH), 1.30 (s, 3H). MS (ESI, +ve ion) m/z 599.2 (M+H) ⁺ .

EXAMPLE 1 18. (I S,3'R,6'R,7 ^f S,8'E, 12'R)-6-CHLORO-7'-HYDROXY-6', 12'- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [N ΑΡΗΊΉ ALENE- 1 ,22'- [20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA 13',13'-DIOXIDE OR

(lS.3 ^, R,6 ^, R,7 ^, R,8Έ 2 ^, R)-6-CHLORO-7 ^, -HYDROXY-6^12 ^, -DIMETHYL-3 ₅ 4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |20i() A| 1311 HI Λ| I . ! -i |OI A/A Π·. ΓΗ. Αί ^' ΥΌ.01 i -i.7.2 (Γ ".O ¹ " ^M |PH\ i ACOS A [8,16,18,24]TETiL E ]-15'-ONE 13', W -DIOXIDE OR (1S,3'S,6'S,7'S,8'E,12'R)- 6-CHLORO-7 ^! -HYDROXY-6',12'-DlMETHYL-3,4-DlHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'S ₅ 6 ^, S,7 ^, R ₅ 8¾12 ^, R)-6-CHLORO-7 ^, -HYDROXY-6\12 ^, -DIMETHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s -

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PLNTAi SA

[8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE

The title compound was synthesized from (S)-6'-chloro-N-((R)-hex-5-en- 2-ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hydroxydlyl)-2-me lcyclobut\'l)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spifo[benzo[b][l,4]oxazepine-3, -naphthalene]-7- carboxamide and (S)-6'-chloro-N-((R)-hex-5-en-2-ylsulfonyl)-5-(((l .S,2S)-2-((S)- 1 -hydroxy dlyl)-2-methylcyclobut\'l)methyl)-3',4,4',5-tetrahydro-2H,2' H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulf(myl)-5-(((lR,2R)-2-((R)-l½droxyall y])-2- methylcyclobut'l)methyl)--3 ^! ,4,4',5~tetrahydro-2H,2 ^! H~

spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hex-5-en-2-ylsulfon l)-5-(((l S,2S)-2-((R)- 1 -hydroxy allyl)-2- methylcyclobutyl)meihyl)-: ,44V-tetrahydro-2H,2^H- spiro [benzo [b j [1,4] oxazepme-3 , -naphthalene] - 7-carboxamide (Example 117, Step 2; 40 mg, 0.064 mmol) following the procedure described for Example 116, Step 11. The reaction was evaporated in vacuo and the product was purified by column chromatography (4g SiC , hexanes:EtOAc (containing 1% AcOH), 1:0 to 5:1) to give (lS,3'R,6 ^, R,7¾,8¾,12 ^, R)-6-cWoro-7 ^, -hydroxy-6',12*-dimethyI-3,4- dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracyclo[ ^

n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6 ^, R,71 ,8¾,12 ^, R)-6-chioro-7 ^, -hydiOxy-6',12 ^! ~ dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[i,14]diazatetra^

n]-15'-one 13',13'-dioxide or (lS^'S^'S 'S^'^^'R^e-chloro-T-hydrox -e',!^- dimethy3-3,4-dihydro-2H,15'H-spiro|naphihalene-l,22 ^! - [2Q]oxa[13]thia[l,14]diaza ^^

n]-15'-one 13*, 13 ^! ~dioxide or (1 S,3'S,6 ^! S,7'R,8 ^! E, 12 ^! R)-6-chk>ro-7'-hydroxy~6', 12'- dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20ioxa|13jthia[l,14jdiazatetracyclo[14.7.2.0 ^3>6 .0 ^!9 ' ²⁴ ]pentacosa[ 8,16,18,24jtetrae n]-15'-one 13',13'-dioxide as the second eluting minor isomer (3.2 mg, 5.34 μπιοΐ, 8.37 % yield). R NMR (400MHz, MeOH-d¾ δ 7.59 (d, J=8.2 Hz, 1H), 7.16- 7.09 (m, 2H), 7.02 (dd, ./ 3.1.8.8 Hz, IH), 6.95 (d, J=8.2 Hz, III).6.91 (s, III). 5.89(td,J==6.8, 15,5 Hz, IH), 5.69 (dd, .7=7.8, 15.3 Hz, IH), 4, 15 (d, J= 1.9 Hz, IH), 4.01 (d, .7=11,9 Hz, H), 3.94 (d, 7=7.8 Hz, IH), 3,92 - 3.86 (m, IH), 3.69 (dd, J=2.6, 14.0 Hz, IH), 3.47 (d, J=14.5 Hz, IH), 3.35 (d, J=14.5 Hz, IH), 2.94 (dd, ./ 12.0.14.2 Hz, IH), 2.83 - 2.74 ins.2H), 2.57 - 2.46 (m, IH), 2.44 - 2.32 (m, IH), 2.27 - 2,16 (m, IH), 2.12 - 2.01 (m, 3H), 1.91 - 1.81 (m, 3H), 1,80 - 1.69 (m, 3H), 1.66 - 1.60 (m, 1H), 1,47 (d, J=7.0Hz, 3H), 1.11 (s, 3H). MS (EST, +ve ion) m/z 599.2 (M+H) ^H" .

EXAMPLE 119. (IS^'R^'R 'S^U^'R^e-CHLORO- '-ETHYL^'- HYDROXY-6'-METHYL-3,4-DIHYDRO-2H.15H-SPIRO[NAPHTHALENE- 1,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ' ".U ¹ "' ¹ |PH\ i ACOSA

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS ¾ )'R ¾,8T;/12¾.)-6-CHLORO-12'-ETOYL-7' 4YDROXY-6'-METHYL- .4-DIHYDRO-211. i Ί f-SP!RO|\ ^' .\PI Π I !,\U ^: NI:-i.22'- [20]OXA[13]THLA[1 4]DL ZATET1ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DK)XIDE OR (1S,3'S,6'S,7'S,8'E,12'R)- 6-CHLORO-l 2'-ETHYL-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE-1 ,22'-

[20iOXA|;i3]THLA|;i 4]DlAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS,3'S,6'S,7'R,8'E,12'R)-6-CHLORQ-12'-ETH^^

3 ,4-DlH YDRQ-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13 ^* -DIOXIDE

STEP 1 : (S)-6'-CHLORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)-5-(((lR,2R)-2- ((S)-l-HYDROXYALLYL)-2-METHYLCYCLOBUTYL)METHYL)-3 ^, .4,4'.5-

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l ,4]OXAZEPINE-3,l '- NAPHTHALENE] -7-C ARBOXAMIDE AND (S)-6'-CHLORO-N-((R)-HEPT-6- EN-3-YLSULFONYL)-5-(((l S,2S)-2-((S)-l -HYDROXY ALLYL)-2-

METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'I-I- SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l '-NAPHTHALENE]-7- CARBOXAMIDE OR (S)-6'-CHLORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)- 5-(((l R,2R)-2-((R)- 1 -HYDROXY ALL YL)-2-

METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6'-CHLORO-N-((R)-HEPT-6-EN-3- YLSULFONYL)-5-((( 1 S,2S)-2-((R)- 1 -HYDROXY ALLYL)-2-

METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHY ^' DRO-2H,2 ⁱ I-I-

SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7-

CARBOXAMIDE

The title compounds were synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l-hydroxyallyl)-2-methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (S)~6'~ chloro-5-((( 1 S,2S)~2~((S)~ l½droxyallyl)-2-niethylcyclobu1yl)methyl)-3 ^, ,4,4 ^, ₅ 5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid or (S)-6'-ch3oro-5-(((l R,2R)-2-((R)-l-hydroxyallyI)-2- methylc clobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , -naphthalene] -7-carboxylic acid and (S)~6'~ chloro-5-((( 1 S,2S)-2-((R)- 1 -hydroxy ally l)-2-methylcyclobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (107 mg, 0.222 mmol) and (R)-hept-6-ene-3-sulfonamide (Intermediate EE21; 118 mg, 0.666 mmol) following the procedure described for Example 116, Step 10. Column chromatography (12g S1O2, hexanes:EtOAc (containing 1% AcOH, 1 :0 to 4: 1)) gave (S)-6'-chloro-N-((R)-hept-6-en-3-ylsulfonyl)-5- (((lR,2R)-2-((S)-l-hydroxyallyl)-2-me ^

2H,2H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7-carboxamide and (S)- 6 ^, -chloro-N-((R -hept-6-en-3-y sulfonyl)-5-(((lS,2S)-2H

methylcyclobutv'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3, r-naphthalene]-7-carboxamide or (S)-6'-chloro- N-((R)-hept-6-en-3-ylsulf«Miyl)-5-(((lR,2R)-2-((R)- 1 -hydroxy allyS 2- methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hept-6-en-3-ylsulfonyl)-5-(((lS,2S)-2-((R)-l -hydroxyallyl)-2- methylcyclobut>d)methyl)-3 ^! ,4,4',5-tetrahydro-2H,2H- spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxamide as the first eluting major component (45 mg, 0.070 mmol, 31.7% yield).

Further elution provided (S)-6'-chloro-N-((R)-hept-6-en-3-ylsulfonyl)-5- (((l R,2R)-2-((S)-l-hydroxydlyl)-2-me lcyclobu1\d)me l)-3^4,4V^-tetrahydro- 2H,2H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxarnide and (S)- 6'-cMoro-N-((R)-hept-6-en -ylsulfoJiyl)-5 ((lS,2S)-2-((S)-l½<ko^allyl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 ^f H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxarnide or (S)-6'-chloro- N-((R)-hept-6-en-3-ylsulfony l)-5-(((lR,2R)-2-((R)- 1 -hydroxyally l)-2- methylcyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxamide and (S)-6'-chl oro-

N-((R)-hept-6-en-3-ylsulfonyl)-5-(((lS,2S)-2-((R)-l-hydro xyallyl)-2- rnethylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxamide as the second eluting minor component (29 mg, 0.045 mmol, 20.4% yield).

STEP 2: (ΙΒ _^ ΤΚ,όΊΙ^^,ΒΈ,^'ί^-ό-εΗΕΟΚΟ-^'-ΕΙΉΥΕ ^'-ΗΥΟΚΟΧΥ-β'- METl-iYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[ 13]THIA[ 1, 14]DIAZATETRACYCLO[14.7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - i 5'-ONE 13', 13'-DIOXIDE OR

(lS,3¾,6 ^! R;7 ^, R,8Ta2'R)-6-CHL()RO-12'-E™YL-7'-HYDR()XY-6'-METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ' ²⁴ ]PENTACOSA [8 ₅ 16,18,24]TETRAEN]-15'-ONE 13', 13'~D10X1DE OR (lS,3 ^, S,6 ^! S,7'S,8'E,i2'R)- 6 HL0R()-12 ^, -ETI1YL-7' -IYDR0XY-6'-METHYL-3,4-DIHYDR0-2I-L 15'H- SPTRO[NAPHTHALENE-l ,22'-

| 2 ⁽ !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 0 ' ".O ¹ '' ' ¹ |Pi-NT.\( SA [ 8, 1 6, 18,24]TETRAEN1-15'-0NE 13 ^! J 3 ^* -DIOXIDE OR

(I S,3'S,6'S,7'R,8'E, 12'R)-6-CHLORO- 12'-ETHYL-7'-HYDROXY-6'-METHYL- .4-DI HY DRO-2J 1. i Ί i-SP!RO| \ ,\Pi Π H \i J-NI - ! 22'-

[20]OXA[ 13]TH1A[ 1 4]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was synthesized from (S)-6'-chloro-N-((R)-hept-6-en-3- ylsulfonyl)-5-(((l R,2R)-2-((S)- 1 -by droxy ally 1 )-2-methylcy cl obuty l)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine-3, -naphthalene]-7- carboxamide and (S)-6'-chloro-N-((R)-hept-6-en-3-ylsulfonyl)-5-(((l S,2S)-2-((S)- l-hydroxyally])-2-meihylcyclobuly])methyi)-3',4,4V5 etrahydro-2i-I,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthdene]-7-carboxamide or (S)-6'-chloro- -((R)-hept-6-en-3-ylsulfonyi)-5-(((lR,2R)-2-((R)-l-hydroxyal lyl)-2^ methylcycloburyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxamide and (S)-6'-chloro-

N-((R)-hept-6-en-3-ylsulfonyl)-5-(((lS,2S)-2-((R)-l-hydro xyallyl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-

42,1 spiro[benzo[b][l,4]oxazepine-3, l '-naphthalene]-7-carboxamide (Example 1 19, Step 1, first eluting major component; 17 mg, 0.027 mmol) following the procedure described for Example 116, Step 11. The reaction was evaporated in vacuo and the product was purified by column chromatography (4g S1O2, hexanes : EtO Ac (containing 1 % AcQH), 1 : 0 to 3: 1) to give

(lS,3'R,6 ,7 ^, S,8T,121 )~6~cWoro-12'-e l-7 ^, ½droxy-6 ^, ~methyl.3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[ l, 14]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13', '-dioxide or (lS,3'R,6 ^, R,7 ^, R,8'E,12'R)-6-chioro-12 ^, -ethyl-7'- h droxy -6'-methyl-3,4-dihydro-2H, 15'H-spiro| naphthalene- 1 , 22'- [20]oxa[13]thia[l ,14]diazatefra<^

n]-15'-one 13',13'-dioxide or (lS,3 ^! S VS,7 ^, S,8'E,12'R)-6-chloro-12 ^! ~ethyS-7'- hydroxy-6'-methyl-3,4-dihydro-2H,15 ^, H-spiro[naphthalene-l,22'-

[20ioxa| 13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ^3>6 .0 ^{! 9} ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]~15'~one 13', 13'-dioxide or (lS,3 ^, S,6'S,7 ^! R,8'E, 12'R)-6-chloro-12 ^! -ethyl-7'- hydroxy-6'~niethyl-3,4-dihydro-2H,15'H-spiro|naphthalene-l,2 2'- [20]oxa[ 13]thia[l ,14]cUazatetracyc^

n]-15'-one 13', ! 3'~dioxide (2.5 mg, 0,005 mmol, 15.4% yield). ^l H NMR

(400MHz, MeO! \~ ) δ 7.63 id . «/=8.2 Hz, 1H), 7.18 - 7.11 (m, 3H), 7.08 (br. s., 1H), 6.94 (d, J=8.2 Hz, 1H), 5.88 (td, J=5.8, 15.6 Hz, IH), 5.68 (dd, J=7.2, 15.5 Hz, i l l . 4.18 id. ./ I 1.7 Hz, IH), 4.02 (d, ./ ! 1.9 Hz, 1H), 3.82 (dd, ,/ 2.5. 13.9 Hz, i l l ). 3,69 i d. ./ 7.(! Hz, IH), 3,57 - 3.49 (m, I H), 3.44 (d, ,/ 14. i Hz, H), 3.36 (d, ./ 14.3 Hz, IH), 2.95 (dd, ./ 1 1 .6. 14.4 Hz, IH), 2.84 - 2.74 (m, 2H), 2,66 (q, ./ 9.3 Hz, IH), 2,53 - 2.38 (m, 2H), 2,25 - 1.70 (m, 10H), 1 ,42 - 1.34 (m, 2H), 1 .14 (s, 3H), 1.13 (t, ,/ 7,4 Hz, 3H). MS (ESI, +ve i on) m/z 613,2 (M+H) ⁺ .

EXAMPLE 120. (1 S,3'R,6 ^f R,7'S,8'E,12'R)-6-CHLORO-12 ^f -ETHYL-7'- HYDROXY-6'-METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

1 22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA [8,16, 18,24]TETRAEN]-15 ^! -ONE 13 ',13 '-DIOXIDE OR (18 Έ )' ^¾,8Τ;/12¾.)-6-εΗΙ,ΟΚΟ-12'-ΕΉ^Ε-7' ^Γ)ΚΟΧΥ-6'-ΜΕΤΗΥΙ,- 3,4-DlHYDRQ-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l 4jDIAZATETRACYCLO| 14 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18 ,24] TETRAEN] - 15'-ONE 13', 13 ^* -DIOXIDE OR (1 S,3'S,6'S,7'S,8'E, 12'R)- 6~CHLORO-12 ^! ~ETHYL-7 ^! -HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H~ SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THIA|;i ,14]DlAZATETRACYCLO[ 14J.2X) ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~13'~ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, S,6'S,7'R,8'E,12'R)-6-CHLORO-12'-E ^r fflYL-7'-HYDROXY-6 ^, -METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

The title compound was synthesized from (S)-6'-chioro-N-((R)-hept-6-en-

3-ylsdfonyl)-5-(((l R,2R)-2-(^

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxamide and (S)-6'-chloro-N-((R)-hept-6-en-3-ylsulfonyl)-5-(((l S,2S)-2-((S)-

1 -hydroxy ailyl)-2-methylcyc3obutyl)methyl)-3',4,4',5-tetrahydro-2H,2' H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carboxamid e or (S)-6'-chloro- N~((R)-hept~0-en-3~ylsidfonyl^^ methylcyclobuiyi)rnethyl)-3',4,4',5-teirahydro-2I-I,2 ^f H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxamide and (S)-6'-chloro- N-((R)-hept-6-en-3-ylsidfonyl)-5-(((lS.2S)-2-((R)-l-hydroxya llyl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxamide (Exampl e 119,

Step 1, second eluting minor component; 29 mg, 0.045 mmol) following the procedure described for Example 116, Step 11. The reaction was evaporated in vacuo and the product was purified by column chromatography (4g SiCte, hexanes:EtOAc (containing 1% AcOH), 1:0 to 4:1) to give

(lS,3 ^, R,6'R,7'S,8U12¾)-6-cMoro 2 ^, -e l-7 ^, -hydroxy-6 ^, -methyI-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracy'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, ^' 16,18,24]tetrae n]-15'-one 13',13'-dioxide or (Ιβ^'Κ,ό'Κ^'ί ,δ'Ε,Ι^-ό-ΰΜθΓθ-Π'-βΛνΙ^'- hydroxy-6'-methyl-3,4-dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra<yd^^

n]-15'-one 13*,13'-dioxide or (IS^'S^'S 'S^'En'i^-b-chioro-l^-ethyl-?*- hydroxy'-6'-methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,2 2'-

[20]oxa[13]thia[l,14]diazatefra<yc^

n]-15'-one 13',13 ^! -dioxide or (lS 3 ^! S VS 7'R,8 ^! E,12 ^! R)-6-chloro-12'-ethy -7'- hydroxy-6'-methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22 '-

[20joxa 13]thia[l,14]diazatetracycfo[14J _^

n]-15'-one I.V.LV-dioxide (4.2 mg, 0.007 mmol, 15.2% yield). ¾ NMR

(400MHz, CD3OD) δ 7.72 (d, J=8.4 Hz, 1H), 7.16 (dd, J=2.2, 8.5 Hz, lH), 7.10 (d, ./ 2.2 Hz, III .6.96 (dd, ./ 2.5.9.0 Hz, 1H), 6.91 (d, ./ 7.4 Hz, 1H), 6.78 (d, J=2.0 Hz, i l l).5.86 (td, ./ 7.0.15.3 Hz, !!!).5.76 (dd, J=7.8, 15,3 Hz, ill).4.10 - 4.04 (m, 2H), 4.04 - 3,98 (m, 1H), 3.90 (d, .7=7.6 Hz, I I I).3.78 (d, ,7=15,1 Hz, 1H), 3.66 (d, J=14.3 Hz, lH), 3.23 (d, J=14.3 Hz, 1H), 3.09 (dd, J=10.7, 15.2 Hz, 1H), 2.87 - 2.69 (m, 2H), 2.49 - 2.40 (m, 1H), 2.37 (dd, ./ 4.H.10.3 Hz, III).2.30 - 2.19 (m, 1H), 2.12 - 2,05 (m, 2H), 1.98 - 1.77 (m, 8H), 1.48 - 1,33 (m, 2H), 1.30 (s, 3H), 1.15 (t, J=7.5 Hz, 3H). MS (ESI, +ve ion) m/z 613.2 (M+H) ⁺ . EXAMPLE 121. (1 S,3'R,6'S,7'S)-6-CHLORO-7'-HYDROXY-6'-METOYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHL4[ l 4jDIAZATETRACYCLO| 14.7.2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [16,18,24]TRIEN]-15'-ONE 13', 13'-DTOXIDE (1 S 'R,6'S,7'R)~0-CHL0R0~7'~ HYDROXY-6'-METHYL-3,4-DiHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1 ">"><-

[2()iOXA|;i3]THIA|;i 4]DlAZATETRACYCLO[ 14J.2X) ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA

[16, 18,24]TRIEN]-15'-ONE 13\13'-DIOXIDE OR (l S,3'S,6'R,7'S)-6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DlHYDRO-2H,15'H-SPlRO[ APHTHALENE- 1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-QNE 13', 13'-DIOXIDE OR (l S,3'S,6'R,7'R)-6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15 ^, H-SPIRO[NAPHTHALENE-

1 22'- [20]OXA[13]Tffl A[l .MIDIAZATETRACYCLOIMJ^.O^^O'^IPENTACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

STEP 1 : (S)-TERT-BUTYL 6'-CHLORO-5-(((l S,2R)-2-FORMYL-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((l R,2S)-2-

F0RMYL-2-METHYIX:YCL0BUTYL)METHYL)-3',4,4',5-TETRAI-IYDR0 - 2H,2H-SPIRO[BENZO[B] [ l,4]OXAZEPINE-3,T-NAPHTHALENE]-7-

C ARB OXYL ATE

The title compounds were synthesized from (S)-tert-butyl 6'-chloro-5-

(((lS,2R)-2-(hydroxymethyl)-2-me lc^xlobut )methyl)-3',4,4 ^, ,5-tetrahydro- 2H,2'H-spiro| benzoj bj[ l,4]oxazepine-3 J .'-naphthalene|-7-carboxylate and (S)- tert-butyl 6'-chloro-5-(((lR,2S)-2-(hydroxymethyl)-2-methylcyclobutyl)m ethyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylate (Example 1 16, Step 6, second eluting minor component; 430 mg,

0,840 mrnol) following the procedure described for Example 1 16, Step 7. Column chromatography (4g Si0 ₂ , hexanes:EtOAc, 1 :0 to 9:1) gave (S)-tert-butyl 6'- chloro-5-(((l S,2R)-2-formyl-2-methylcyclobut 4)methyl) ^» 3 4,4^5~tetrahydro- 2H,2'H-spiro| benzoj bj[ l,4]oxazepine-3,r-naphthalene|-7-carboxylate and (S)- tert-butyl 6'-chloro-5-(((l R,2S)-2-forrnyl-2-methylc^ lobuty])methyl)-3^4,4 5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (388 mg, 0.761 mrnol, 91 % yield).

STEP 2: (S)-TERT-BUTYL 6'-CHLORO-5-(((l S,2R)-2-((S)-l -HYDROXYBUT- 3-EN-l-YL)-2-MEIHYLCYCLOBUTYL)MEIHYL)-3',4,4\5-TEII AHYDRO- 2H,2'H-SPIRO[BENZ()[B] |;i ,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((l S,2R)-2-((R)-l- HYDROXYBUT-3-EN-l-YL)-2-METHYLCYCLOBUTYL)MEraYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [ 1 ,4]OXAZEPINE-3, 1

NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO- 5-(((lR,2S)-2-((S)-l -HYDROXYBUT-3-EN-l-YL)-2- METHYLCYCLOBUTYL)METHYL)-3' ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2S)-2-((R)-l- HYDROXYBUT-3-EN-l -YL)-2-METHYLCYCLOBU L)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]QXAZEPiNE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

To a stirred solution of allyl iodide (280 uL, 3.04 mrnol) and (S)-tert-butyl 6'-chloro-5-(((lS,2R)-2-forrr^ -2-memylcyclobu1yl)me1iiyl)-3 ^, ,4,4 ^, ,5-tetrahydro- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carbo x\'late and (S)- tert-butyl 6'-chloro-5-(((lR,2S)-2-forrmd-2-me l(yclobutyl)methyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (388 mg, 0.761 mrnol) in DMF (15.2 mL) was added indium (Sigma Aldrich; 262 mg, 2.282 mrnol). The reaction was stirred at ambient temperature for 30 minutes. After this time the reaction was paritioned between EtOAc and 1M LiCl. The separated organic layer was dried over MgS04, filtered and evaporated in vacuo. Column chromatography (40g S1O2, hexanes:EtOAc (containing 1 %ACOH, 1 :() to 85; 15) gave (S)-tert-butyl 6'-chloro-5-(((l S,2R)-2-((S)-l -hydroxybut-3-en-l -yl)-2- methylcyclobur>'i)methyl)--3',4,4',5~tetrahydro-2H,2'H~

spiroj benzoj b] [ 1,4 |oxazepine-3,r-naphthaIene]-7-carboxyiate and (S)-tert-butyl 6'-chloro-5-(((l S ₅ 2R)-2-((R)-l -hydroxybut-3-en-l-yl)-2- meth}dcyclobutyl)methyl)-: ,4,4',5 etrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-tert-butyl 6'- chloro-5-(((lR,2S)-2-((S)-l-hydroxybut-3-en-l-yl)-2-methylcy clobut 'l)methyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carbox late and (S)-tert-buty 1 6'-ch] oro-5-((( 1 R,2S )-2-((R)- 1 -hy droxy but-3 -en- 1 - yl)-2-niethyicyclobutyl)rnethyl)-3V4,4V5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate as the first eluting major component (210 mg, 0.380 mmol, 50% yield).

Further elution provided (S)-tert-butyl 6'-chloro-5-(((l S,2R)-2-((S)-l - hy droxy but-3-en-l-yl)-2-methylcyc3obutyl)methyl)-3',4,4',5-tetrahyd ro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-((( 1 S,2R)-2-((R)- 1 -hydroxy but-3-en- 1 -yl)-2- methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate or (S)-tert-butyl 6'- chloro-5-(((lR,2S)-2-((S)-l -hydroxybut-3-en-l -yl)-2-methylcA ]obutyl)rnethyl)- 3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-na phthalene]-7- carboxylate and (S)-tert-butyl 6'-chloro-5-(((lR,2S)-2-((R)-l-hydroxybut-3-en-l- yl)-2-meihyicyc]obutyl)methyl)-3',4,4 5-tetrahydro-2Il,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate as the second elutmg minor component (114 mg, 0.206 mmol, 27% yield).

STEP 3: (S)-6'-CHLORO-5-(((l S,2R)-2-((S)-l-HYDROXYBUT-3-EN-l-YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6 ^* -CHLORO-5-(((lS,2R)-2-((R)-l-HYDROXYBUT-3-EN-l-

YL)-2-METHYLCYCLOBOTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2' H- SPIRO| BENZO[B]|;i,4iOXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lR,2S)-2-((S)-l -HYDROXYBUT-3-EN-l-YL)- 2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '- APHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2S)-2-((R)-l-HYDROXYBUT-3-EN-l- YL)-2-MEmYIX^ .LOBUWL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPn O[BENZO[B][L4]OXAZEPlNE"3,r-NAPHTHALENE]-7-CARBOXYLIC ACID

The title compounds were synthesized from (S)~tert~butyl 6'-chloro-5- (((lS,2R)-2-((S)-l½droxybut-3-en-l-yl)-2-methyl<yclobu1y l)me l)-3 ^, ₅ 4,4 ^, _s 5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy late and (S)-tert-butyl 6'-chloro-5-(((l S ₅ 2R)-2-((R)-l -hydroxybut-3-en-l-yl)-2- me lcyclobut>'l)methyl)-3 ^f ,4,4',5-tetrahydro-2H,2H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate or (S)-tert-butyl 6'- chloro-5-(((IR,2S)-2-((S)-l-hydroxybut-3-en-l-yl)-2-methylcy clobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylate and (S)-tert-butyl 6'-chloro-5-(((lR,2S)-2-((R)-l-hydroxybut-3-en-l- yl)-2-methylcyclobut 'l)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [ 1 ,4]oxazepine-3, r-naphthalene]-7-carboxylate (Example 121 , Step 2, first eluting major component; 210 mg, 0.380 mmol) following the procedure described for Example 116, Step 9. After aqueous workup, the isolated crude mixture of (S)-6'-chloro-5-(((l S,2R)-2-((S)-l-hydroxybut-3-en-l -yl)-2- methylcyclobutyl)methyl)-: ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (S)-6'~ chloro-5-(((lS,2R)-2-((R)-l-hydroxybut-3-en-l -yl)-2-methylcyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carbox lic acid or (S)-6'-chloro-5-(((l R,2S)-2-((S)-l-hydroxybut-3-en-l-yl)-2- methylc clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid and (S)~6'~ cMoro-5-(((lR,2S)-2-((R)-l-hyclroxybut-3-en-l-yl)-2-methylcy clobut 'l)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1,4 joxazepme-3,1 '-naphthalene j-7- carboxylic acid was taken on to the next step without further purification.

STEP 4: (S)-NHBUT-3-EN-l-YLSULFONYL)-6'-CHLORO-5-(((lS,2R)-2~((S)- 1 -HYDROXYBUT-3-EN-l-YL)-2-METHYLCYCLOBUTYL)METHYL)- 3^4,4^5-TETRAHYDR()-21i2'H-SPIRO[BENZO[B]| L410XAZEPINE-3,r- NAPHTHALENE] -7-CARBOX AMIDE AND (S )-N-(BUT-3-EN- 1 - YLSULFONYL)-6'-CHLORO-5-(((lS,2R)-2-((R)-l-HYDROXYBUT-3-EN-l - YL)-2-METHYLCYCLOBUWL)METHYL)~3\4,4 5-TETl AHYDRO-2H,2'H~ SPIR()[BENZO[Bj[ l,4]()XAZEPINE-3,r-NAPHTHALENEl-7-

CARBOXAMIDE OR (S)-N-(BUT-3-EN-l-YLSULFONYL)-6 ^* -CHLORO-5- (((lR,2S)-2-((S)-l-HYDROXYBUT-3-EN-l-YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l'-NAPHTHALENEl-7- CARBOXAMIDE AND (S)-N-(BUT-3-EN-l -YLSULFONYL)-6'-CHLORO-5- (((1 R,2S)-2-((R)- 1 -HYDROXYB UT-3 -EN - 1 - YL)-2- METHYLCYCLOBUTYL)METHYL)-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H.2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

The title compounds were synthesized from (S)-6'-chloro-5-(((l S.2R )-2~ ((S)~ 1 -hydroxy but-3-en- 1 -yl)-2-methylcyclobut\'l)methyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carbox>'lic acid and (S)-6'-chloro-5-(((lS,2R)-2-((R)-l-liydroxybut-3-en-l -yl)-2- methylcyclobut d)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid or (S)~6 ^! - cMoro-5-(((l R,2S)-2-((S)-l-hydroxybut-3-en-l-yl)-2-methylcyclobut 'l)methyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylic acid and (S)-6'-chloro-5-(((lR,2S)-2-((R)-l-hydroxybut-3-en-l -yl)-2- methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (200 mg, 0.403 mmol) and but-3-ene-l -sulfonamide (Intermediate EE15; 164 mg, 1.21 mmol) following the procedure described for Example 116, Step 10. The crude material was dissolved in DCM and adsorbed in a 5 g silica gel cartridge and purified by column (4 g Si0 ₂ , hexanes:EtOAc(containing 1 % AcOH), gradient 1 :0 to 85: 15 and 85: 15 isocratic) to give (S)-N-(but-3-en-l-ylsulfonyl)-6'-chloro-5-(((lS,2R)-2- ((S)- 1 -hydroxy but-3-en- 1 -yl)-2-methylcy clobutyl)methyl)-3',4,4', 5-tetrahy dro- 2H,2H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxarnide and (S)- N-(but-3-en-l-ylsidfoityl)^

2-methylcyclobut 'l)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-N-(but-3- en-l-ylsulfonyl)-6'-chloro-5-(((l R,2S)-2-((S)-l-hydroxybut-3-en-l -yl)-2- methylcyclobuiyi)rnethyl)-3',4,4',5-teirahydro-2I-I,2 ^f H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxamide and (S)-N-(but-3- en- 1 -y lsulfony l)-6'-chloro-5 -((( 1 R,2S)-2-((R)- 1 -hydroxy but-3 -en- 1 -y l)-2- methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxamide as the first eluiing minor isomer (20 mg, 0.033 mmol, 8.1% yield).

Further elution provided (S)-N-(but-3-en-l-ylsulfonyl)-6'-chloro-5-(((l S,2R)-2-

((S)-l-hydroxybut-3-en-l -y])-2-methylcA ]obuty])me1hyl)-3^4,4\5-tetrahydro-

2H,2'H-spiro[benzo[b][l,4]oxazepine~3,r-naphthalene]-7-ca rboxamide and (S)- N-(but-3-en-l-ylsulfony3)-6'-chioro-5-(((lS,2R)-2-((R)-l-hyd roxybut-3-en-l-yl)-

2-methylcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide or (S)-N-(but-3- en-l-ylsulfonyl)-6 ^, -dUoro-5-(((lR,2S)-2-((S)-l½droxybut-3-en-l-yl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-N-(but-3- en-l-ylsulfonyl)-6'-chloro-5-((( ^' lR,2S)-2-((R)-l-hydroxybut-3-en-l -yl)-2- methylcyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxaraide as the second eluting major isomer (95 mg, 0. 155 mmol, 38.5% yield).

STEP 5: (1 S,3'R,6'S,7'S, 9'Z)-6-CHL()RO-7'-I-r¾' ^r DROXY-6 ^! -METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* - pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[9,16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND (1 S,3'R,6'S,7'R, 9'Z)-6- CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO~2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

| 2u jOXA| 1 3 ΙΊ ! !1Λ| l . l 4 |! !A/.Vr!-;i ^' R A( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |Pl-N i ^' AC<)SA [9,16,18,24]TETRAENj-15'-ONE 13 ',13 '-DIOXIDE AND (1 S,3'R,6'S,7'S, 9'E)-6- CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,I5'H- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA

[9,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND (1S,3'R,6'S,7'R, 9'E)-6- CHL()RO-7'-HYDROXY-0'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- |20i()XA| ΐ: ΐΗ1Λ| Κ4 |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 (Γ ".O ¹ " ^M |PH\ i ACOSA [9,16,18,24]TETiL E ]-15'-QNE 13' _s 13'-DIOXIDE OR (1S,3'S,6'R,7'S, 9'Z)-6- CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA | 9,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE AND (1S,3'S,6 ^* R,7'R, 9'Z)-6- CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί) ^|: " ¹ |P1-M ^' .\C<)SA

[9,16,18,24]TETRAENj-15'-ONE 13 ',13 '-DIOXIDE AND (1S,3'S,6'R,7'S, 9'E)-6- CHTORO-7'-HYDROXY-6'-METHYL-3,4-DlHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [9 ₅ 16,18,24]TETRAEN]-15"-ONE 13',13'-DIOXIDE AND (1S,3'S,6'R,7'R, 9'E)-6- CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H ₅ 15'H- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14.7.2.0 ^3>, 0 ^!9 - ²⁴ ]PENTACOSA [9, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

A stirred solution of (S)-N-(but-3-en-l-ylsulfonyl)-6'-chloro-5-(((l S,2R)- 2-((S)-l-hydrox 'but-3-en-l-yl)-2-me1hylc lobutyl)methyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro| benzoj bj[ l,4]oxazepine-3 J .'-naphthalene|-7-carboxamide and (S)- N-(but-3-en- 1 -y 1 sulfonyl)-6'-chloro-5-((( 1 S,2R)-2-((R)- 1 -hy droxybut-3-en- 1 -y ])- 2-methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [1,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide or (S)-N-(but-3- en-l -ylsidfonyl)-6'-chloro-5 ((lR,2S)-2-((S)-l - droxybut-3-en-l-yl)-2- me lcyclobut>'l)methyl)-3 ^f ,4,4',5-tetrahydro-2H,2H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide and (S)-N-(but-3- en- 1 -y lsulfony f )-6'-chf oro-5 -((( 1 R,2S)-2-((R)- 1 -hydroxy but-3 -en- 1 -y l)-2- methylcyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro [benzo [b j [1,4] oxazepine-3 , -naphthalene] -7-carboxamide (Example 121, Step 4, second eluting major isomer; 95 mg, 0.155 mmol) in Toluene (155 mL) was degassed by sparging Ar(g) through for 20 minutes. After this time Hoveyda- Grubbs catalyst 2 ^nd generation (19.4 mg, 0.031 mmol) was added and the reaction was heated at reflux for 90 minutes. After this time the reaction was cooled to ambient temperature and the catalyst was deaciivated by sparging air through. The reaction was evaporated in vacuo and the residue was adsorbed in a 5g Si0 ₂ plug and purified by column chromatography (4g SiCh, hexanes:EtOAc (containing 1%ACOH), 1 :0 to 85: 15) to give (1 S,3'R,0'S,7 ^* S, 9'Z)-6-chloro-7 ^! -hydi xy-6'- methy 1-3 ,4~dihy dro-2H, 15 Ή-spiro j naphfc

n]-15'-one 13', 13"-dioxide and (1 S,3'R,6'S,7'R, 9'Z)-6-chloro-7'-hydroxy-6'- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

n]- 15'-one 13', ! 3'-dioxide or (1 S.3'R.6'S,7'S, 9'E)-6-chloro-7'-hydroxy-6'-meihyi- 3,4-dihydro-2H, ] 5 ^, H-spiro[naphthalene-L22'- [20]oxa[13]lhia[ U4]diazatetracyclo[l^

n|-15'-one 13', 13'-dioxide and (1 S,3'R,6'S,7'R, 9'E)-6-chloro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetr^

n]-15'-one 13',13'-dioxide or (1 S.3'S,6'R,7'S, 9'Z)-6-chloro-7'-hydroxy-6'-methyl- 3.4-dihy dro-2H, 15TJ-spiro[naphthalene-l ,22'-

n]-15'-one 13',13'-dioxide and (1S,3'S,6'R,7'R, 9'Z)-6-chIoro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2H,15'H-spiro[naphthalene-l,22'-

n]-15'-one 13',13'-dioxide or (1 S,3'S,6'R,7'S, 9'E)-6-chloro-7'-hydroxy-6'-methyl- 3.4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[ 13] thia[ 1 , 14]di azatetracy cloj 14 .2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9, i 6.18,24]t.eirae n]-15'-one 13 ^* ,13'-dioxide and (1 S.3'S,6'R,7'R, 9'E)~6~chioro-7 iydroxy-6'- methyl-3 ,4-dihy dro-2H.15 Ή-spiro [naphthalene- 1 ,22'- [20[oxa[13[thia[ l, 14[diazatetracycfo[^^

n]-i.5'-one 13', 13'-dioxide (75 mg, 0, 128 mmol, 83% yield).

STEP 6: (lS,3 ^, R,6 ^, S ₅ 7 ^, S)-6-CHLORO-7 ^, -HYDROXY-6'-METHYL-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-1.22'-

[20]OXA[ 13]THIA[ i, 14]DlAZATETRACYCLO| 14.7.2.0 ^{3 ,} .0 ^l9 ' ²⁴ ]PENTACOSA [ 16, 18,24]TRIEN] - 15 ^* -ONE 13', 13'-DIOXIDE (1 S^'R^'S ^-e-CHLORO-?'- HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14J.2X ⁾³ - ⁶ 0 ¹⁹ ^ ⁴ ]PENTACOSA [16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (l S,3'S,6'R,7'S)-6-CHLORO-

7'-HYDROXY-6'-METHYL-3,4-DlHYDRO-2H,15'H-SPlRO[ APHTHALENE~

1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13', 13'-DiQX!DE OR (l S,3'S,6'R,7'R)-6-CHLORO- 7'~HYDROXY-6'~METHYL-3,4~DIHYDRO-2H,15'H"SPIRO[NAPHTHALENE- 1 22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE To a stirred solution of (1 S,3'R,6'S,7 ^* S, 9'Z)-6-ehloro-7'-hydroxy-6'- methyl-3,4-dihydr o-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[U4]diazatefra<yc^

n]-15'-one 13',13'-dioxide and (1 S,3'R,6'S,7'R, 9'Z)-6-chloro-7'-hydroxy-6'- methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[U4]diazate1ra^

n]-15'-one 13', 13'-dioxide or (1S,3'R,6'S,7'S, 9'E)-6-chloro-7'-hydroxy-6 ^f -methyi- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [2Q]oxa[ 13]thia[ 1 , 14] di azateto^

n]-15'-one 13',13'-dioxide and (1 S,3'R,6'S,7'R, 9'E)~6~chloro~7'~hydroxy-6'- methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[9,16,18,24]tetrae n]-15'-one 13', 13"-dioxide or (1 S,3'S,6'R,7'S, 9'Z)-6-ch]oro-7'-hydrox} _' -6'-methyl-

3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[l,14]diazatetra^

n]-15'-one 13',13'-dioxide and (1S,3'S,6'R,7 ^* R, 9'Z)-6-chIoro-7'-hydroxy-6'- methyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-I ,22'- 8.24i !cirac n]-15'-one 13',13'-dioxide or (1 S,3 ^* S,6'R,7'S, 9'E)-6-chloro-7'-hydroxy-6'-methyl- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- n]-15'-one 13',13"-dioxide and (1S,3'S,6'R,7'R, 9'E)-6-chioro-7'-hydroxy-6'- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]mia[l,14]cUazatetracyclo^

n]-15'-one 13',13'-dioxide (75 mg, 0.128 mmol) in ethyl acetate (25.6 mL) was added platinum(IV) oxide (Sigma Aldrich; 14.55 mg, 0.064 mmol). The system was evacuated and filled with H ₂ (g) (x3). The reaction was stirred at ambient temperature for 1 hour. After this time an additional portion of PtO?. (6 mg) was added and the system was placed under H ₂ . After 1 hour an additional portion of PtO?. (10 mg) and the reaction was placed under H? for 1 hour. After this time TLC and LC/MS shows desired product. The reaction was filtered over cetite washing the cake with EtOAc (200 mL). The solvent was evaporated in vacuo. The resulting residue was purified by column chromatography (12g SiO?, hexanes:EtOAc(containing 1 %A cOH), 1:0 to 80:20) to obtain partial separation of two single diastereomers. (lS,3'R,6'S,7'S)-6-chloro-7'-hydroxy-6'-methyl-3,4- dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[ 13]thia[ U 4] diazatetnK^

15'-one 13',13'-dioxide or (lS,3'R,6'S,7 ^! R)-6-chloro-7'-hydroxy-6'-methyl-3,4- dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]mia[U4]diazatetra<yclo[14.7 ^

15'-one 13',13*-dkmde or (lS,3'S,6 ^, R7 ^, S)-6-chloro-7 ^, -hydroxy-6 ^, -metliyl-3,4- ctohyclro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[16J8,24]tnen]- 15'-one 13',13'-dioxide or (lS^'S^'R^'l j-e-chloiO^'-hydroxy-e'-methyl-S^- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- |2 ⁽⁾ joxsij I3|t ia| i. i4|dia/aielracveioj 14.7.20 ^{; !} '.0 ^|1! ipemacosa| 16. i 8.24|iricn|- 15'-one 13',13'-dioxide (4 mg, 0.0068 mmol, 10.6% yield) was obtained as the second eluting minor isomer. ¾ NMR (500MHz, CD2CI2) δ 9.62 (br. s., 1H), 7.73 (d,■/ 8.3 Hz, Hi).7.31 (dd, ./ 2.2.8.3 Hz, 1H), 7.22 id../ 2.2 Hz, III).7.17 (dd, ,/ 23.8.4 Hz, IH), 7,09 (d, ./ 2.2 Hz, IH), 6.95 (d, ,/ 8.3 Hz, IH), 4.12 - 4.08 (ra, 2H), 3,87 (d, «7=14.9 Hz, IH), 3.69 (d, .7=14.2 Hz, IH), 3.61 (d, J=9.5 Hz, IH), 3,57 (ddd, ./ 3.7.6.4, 14,9 Hz, ill).3.39 - 3.31 (m, ill).3.13 (d, ,/ 14.4 Hz, Hi). 3.01 (dd, ./ 9.7.15.3 Hz, 1H), 2.83 - 2.70 (m, 2H), 2.34 (q, J=9A Hz, III).2.06 - 1.97 (m, 3H), 1.95 - 1.88 (m, 2H), 1.88 - 1.82 (m, 2H), 1.72 - 1.63 (m, 311).1.59 (id, .7=4.9, 14,2 Hz, 3H), 1.46 - 1,38 (m, 2H), 1.28 - 1.20 (m, 2H), 1.13 is.3H), MS (ESI, +ve ion) m/z 587.2 ( M H )

EXAMPLE 122. (1 S,3'R,6'S,7'S)-6-CHLORO-7'-HYDROXY-6'-METOYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

|2ujOXA| 1ΉΤί!1Λ| Ι.Ι4|ΠίΛ/.ΥΠ:ΤΗΛ(ΎΠ.ΟΙ i 4.7.2. · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[16,18,24]TRIENj-15'-ONE 13',13'-DIOXIDE (1 S^'R^'S^'Rl^-CHLORO-?'- HY ^T DROXY-6'-METOYL-3,4-DIHY ^T DRO-2H,15TI-SPIRO[NAPHTHALENE- l. -

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,I8,24]TRIEN]-15'-ONE 13',13'-DIOXTDE OR (1S,3'S,6'R,7'S)~6~CHL0R0~ 7 ^! ~HYDROXY-6'-METHYL-3,4~DiHYDRO~2H, 15H-SPIRO[N APHTH ALENE- 1 ">"> ^< -

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE !3',13'-DIOXIDE OR (lS^'S^'R 'R^e-CHLORO- 7'-HYDROXY-6 ^, -METHYL-3,4-DlHYDRO¾

L22'"

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTA(X)SA [16, 18,24] TRIEN] - 15 '-ONE 13', 13 '-DIOXIDE

The title compound was synthesized as described for Example 121, step 6. (lS,3'R,6 ^, S,7 ^, S)-6-(Woro-7 ^, -hydroxy-6 ^, -me1hyl-3,4-dihydro-2H,15 ^, H- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetr^

15'-one 13',13'-dioxide or (lS,3'R,6'S,7'R)"6-chloi -7'-hydroxy-6 ^, -methyl-3,4- dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetra<yclo[^^

15'-one 13',13'-dioxide or (lS,3'S,6 ^, R,7 ^, S)-6-chloro-7 ^, -hydroxy-6 ^, ~methyi-3,4- dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatete^^

15'-one 13',13'-dioxide or (lS,3'S,6¾_,7 ^! R)-6-chloro-7'-hydroxy-6'-methyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1,22'- [20]oxa[13]thia[l,14]cUazatefracyclo[^

15'-one 13', 3'-dioxide (10 mg, 0.017 mmol, 26.6% yield) was obtained as the first eluting major isomer. Ή N.V1R (400MHz, CDCh) δ 9.95 (br. s., 1H), 7.73 (d, ./ K.4 Hz, 1H), 7.43 (dd, ,/ 2.!.8.3 Hz, III).7.22 (d, ,/ 2.2 Hz, IH), 7.20 (dd, ./ 23.8.4 Hz, ill).7.10 (d, ./ 2.3 Hz, ill).6.93 (d, ,/ 8.2 Hz, 111).4.20 (d,

J=12.3 Hz, 1H), 4.08 (d, ,7=11,7 Hz, H), 3.87 (d, .7=14.7 Hz, IH), 3,67 - 3,60 (m, IH), 3.60 (d, ./ 9.2 Hz, IH), 3.48 - 3.40 (m, IH), 3.37 (d, J=14.1 Hz, IH), 3.25 (d, ./ 13.9 Hz, IH), 2.87 (dd, ./ 9.9.14.8 Hz, IH), 2.75 (t, J=5.9 Hz, 2H), 2.33 (q, J=9.5 Hz, IH), 2.08 - 1.94 (m, 3H), 1.91 - 1.72 (m, 7H), 1,71 - 1.62 (m, 3H), 1.62 - 1.54 (m, IB), 1.48 - 1.39 (m, 1H), 1.33 - 1.23 (m, 2H), 1.12 (s, 3H). MS (ESI, +ve ion) m/z 587.2 (M+H) ⁺ .

EXAMPLE 123. (1 S,3 ^, R,6 ^, S,7 ^, S)-6-CHLORO-7 ^, -HYDROXY-6 ^, -METHYL-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTIiALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 3', 13 '-DIOXIDE (lS,3'R,6'S,7'R)-0-CHLQRQ~7'~ HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [16,18,24]TRIEN]-15*-QNE 13',13'-DIQXiDE OR (lS,3'S,6'R,7'S)-6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15 ^, H-SPIRO[NAPHTHALENE-

1,22'-

|2 ⁽ >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^' ".O ^1* " ¹ |PLNT.\i SA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'S,6 ^* R,7'R)-6-CHLORO- 7' IYDROXY-6'-MFmm _J -3,4-DIHY ^T DRO-2H,15'Il-SPIRO[NAPHTHALENE- l. -

[20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

STEP 1: (S)-6 ^, -CHLORO-5-(((lS,2R)-2-((S)-l-HYDROXYBUT-3-EN-l-YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-((( 1 S,2R)-2-((R)- 1 -HYDROXYBUT-3-EN- 1 - YL)-2-METHYLCYCLOBOTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO| BENZO[B;||;i,4|OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lR,2S)-2-((S)-l -HYDROXYBUT-3-EN-l-YL)- 2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2S)-2-((R)-l-HYDROXYBUT-3-EN-l- YL)-2-METOYTX^ .IOBUWl METHYT _J )-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

The title compounds were synthesized from (S)-tert-butyl 6'-chloro-5- (((lS,2R)-2-((S)-I -hydrox ^ut-3-en-l-yl)-2-me lcyclobutyl)me1hyl)-3 ^, ,4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-tert-buly 1 6'-chloro-5-(((l S,2R)-2-((R)- 1 -hydroxy but-3-en- 1 -yl)-2- methylcycloburv )methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carbox 'late or (S)-tert-butyl 6'- chloro-5 -((( 1 R,2S)-2-((S)- 1 -by droxybut-3 -en- 1 -y l)-2-methy Icy clobuty l)methy 1)- 3^4,4^5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3,r-naphthalene]-7- carboxylate and (S)-tert-butyl 6'-cMoro-5-(((lR,2S)-2-((R)-I -hydroxybut-3-en-l - yl)-2-methylcyclobur>'l)methyl)-3',4,4',5-tetrahydro-2H,2 'H- spiro[benzo[b][l,4]oxazeprae-3,l'-naphthalene]-7-carboxylate (Exaraple 121, Step 2, second eluting minor component; 150 mg, 0.272 mmol) following the procedure described for Example 116, Step 9. After aqueous workup, the isolated crude mixture of (S)-6'-chloro-5-(((lS,2R)-2-((S)-l -hydroxybut-3-en-l-yl)-2- methy!cvclobut> ! )n Hhvl )-:VA4^5-ielnihvdKv2l Ι.2Ί I- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and {Β}··6'·· chloro-5-(((lS,2R)-2-((R)-l-hydroxybut-3-en-l-yl)-2-methylc^ xlobut )methyl)- 3\4,4 5-tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r-naphthal ene]-7- carboxylic acid or (S)-6'-chloro-5-((( ^' lR,2S)-2-((S)-l-hydroxv'but-3-en-l-yl)-2- methylcyclobutv'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro [benzo [b] [1,4] oxazepine-3 , 1. '-naphthal ene] -7-carboxy li c aci d and (S)-6'- cMoro-5-(((lR,2S)-2-((R)-l-hydroxybut-3-en-l-yl)-2-me1hylcy lobutyl)methyl)- 3',4,4',5 etraliydro-2H,2'i-i~spiro[benzo[b][l,4]oxazepme-3,i'-naphtha lene|-7- carboxylic acid was taken on to the next step without further purification. STEP 2: (S)-N-(BUT-3-EN-l-YLSULFONYL)-6'-CHLORO-5-(((lS,2R)-2-((S)- l-HYDROXYBUT-3-EN-l-YL)-2-METHYLCYCLOBUTYL)METHYL)- 3' ₅ 4 ₅ 4' _j 5-TETR _J < HYDRO-2H,2 ^, H-SPlRO[BE ZO[B][l,4]OXAZEPlNE-3,r~ NAPHTHALENE] -7 -C ARB OXAMIDE AND (S )-N-(BUT-3-EN- 1 - YLSULFONYL)-6 ^* -CiiLORO-5 ((lS,2R)-2-((R)-l-ilYDROXYBUT-3-EN-l- YL)-2-METHYLCYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2H- SPIRO [BENZO [B ] [ 1 ,4] QXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXAMIDE OR (S)-N-(BUT-3-EN-l-YLSULFONYL)-6'-CHLORO-5- (((1 R,2S)-2-((S)- 1 -HYDROXYBUT-3-EN- 1 -YL)-2- METHYLCYCLOBUlTL)METHYL)"3 ^! ,4,4',5-TEm HYDRO-2H,2'H" SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALENE]-7-

C ARBOXAMIDE AND (S)-N-(BUT-3-EN-l -YLSULFONYL)-6"-CHLORO-5- (((1 R,2S)-2-((R)~ 1 -HYDROXYBUT-3-EN- 1 -ΥΠ-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

The title compounds were synthesized from (S)-6'-chloro-5-(((l S,2R)-2- ((S)-l-hydroxybut-3-en-l-yl)-2-m

2H,2'H-spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy lie acid and (S)-6'-chloro-5-(((l S ₅ 2R)-2-((R)-l-hydroxybut-3-en-l-yl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , -naphtha! ene] -7-carboxy lie acid or (S)-6'- chloro-5-(((lR,2S)-2-((S)-l-hydroxybut-3-en-l-yl)-2-methylc} ⁷ clobutyl)methyl)- 3 4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid and (S)-6'-chloro-5-(((lR,2S)-2-((R)-l-hydroxybut-3-en-l-yl)-2- methylcyclobut 'i)methyl)--3 ^! ,4,4',5~tetrahydro-2H,2 ^! H~

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carbox}'lic acid (1 10 mg, 0.222 mmol) and but-3-ene-l -sulfonamide (Intermediate EEI5; 90 mg, 0.665 mmol) following the procedure described for Example 116, Step 10. Purification by column chromatography (12 g S1O2, hexanes:EtOAc( containing 1% AcOH), gradient 1 :0 to 85: 15) to give (S)-N-(but-3-en-l -ylsulfonyl)-6 ^, -chloro-5-(((l S,2R)- 2-((S)-l-hydroxybut-3-en-l -yl)-2-methylcyclobu1yl)methyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)- N-(but-3-en-l-ylsulfony3)-6'-chioro-5 ((lS,2R)-2-((R)-l-hydroxybut-3-en-l-y 2Hnethylcyck)butyl)methyl)-3',4,4',5-ietraliydro-2H,2'H- spiro[benzo[b] [ i,4]oxazepine-3, 1 '-naphtha! ene]-7-carboxamide or (S)-N-(but-3- en-l-ylsulfonyl)-6 ^, -dUoro-5-(((lR,2S)-2-((S)-l½droxybut-3-en-l-yl)-2- methylcyclobuiyi)rnethyl)-3',4,4',5-teirahydro-2I-I,2 ^f H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxamide and (S)-N-(but-3- en- 1 -y lsulfony l)-6'-chloro-5 -((( 1 R,2S)-2-((R)- 1 -hydroxy but-3 -en- 1 -y l)-2- methylcyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide (100 mg, 0.163 mmol, 73.5% yield).

STEP 3: (1S,3'R,6'S,7'S, 9'Z)~6~CHLORO~7'~I TOROXY-6'-METHYL-3,4~ DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |;20]OXA[13iTHIA[l,14jDL4ZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [9,I6,18,24]TETRAEN]-15'-ONE 3', 13 '-DIOXIDE AND (1S,3'R,6'S,7'R, 9'Z)-6- CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14.7.2.0 ^3>, 0 ^!9 - ²⁴ ]PENTACOSA [9,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND (1S,3'R,6'S,7'S, 9Έ)-6- CHLORO-7'-HYDROXY -6'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE AND (1S,3'R,6'S,7'R, 9'E)-6- CHLQRQ-7'-HYDRQXY-6'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [9,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'S,6'R,7'S, 9'Z)-6- CHL()R()-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|20jOXA| I 311 HI Λ| I .. N |PI A/A Π·. ΓΗ. ΑίΎί ^' ί.ΟΙ i -i.7.20 ^{:' i'} .0 ^li ' |Pi-:N iACOSA [9,I6,18,24]TETiL EN]-15'-ONE 13', 13 '-DIOXIDE AND (1S,3'S,6 ^! R,7'R, 9'Z)-6- CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15TI- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA [9J 6, 18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE AND (1 S,3'S,6'R,7'S, 9Έ)-6-

CHLORO-7'-HYDROXY-6'"METHYL-3,4-DIHYDRO-2H,I5'H-

SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9,16, 18,24]TETRAEN]-15'-ONE 13 I 3 '-DIOXIDE AND (1 S,3'S,6'R,7'R, 9Έ)-6- CHLQRQ-7'-HYDRQXY-6'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [9, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compounds were synthesized from (S)-N-(but-3-en-l-ylsulfonyl)- 6'-chloro-5-(((l S ₅ 2R)-2-((S)-l-hydroxybut-3-en-l-yl)-2- meth}dcyclobutyl)methyl)-: ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-N-(but-3- en-l-ylsulfonyl)-6'-chloro-5 ((lS,2R)-2-((R)-l-^droxybut-3-en-l -yl)-2- methylcyckjbutyi)rnethyi)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide or (S)-N-(but-3- en-l-ylsulfonyI)-6'-chIoro-5-(((l R,2S)-2-((S)-l-hydroxybut-3-en-l-yI)-2- methylcyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-N-(but-3- en- 1 -y Isulfony l)-6'-chloro-5 -((( 1 R,2S)-2-((R)- 1 -hydroxy but-3 - en- 1 -y l)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, 1 '-naphthalene]-7-carboxamide (100 mg, 0.163 mniol) following the procedure described for Example 121, Step 5. The reaction was evaporated in vacuo and the residue was purified by column chromatography (12g S1O2, hexanes:EtOAc (containing 1 % AcOH), 1 :0 to 9: 1 ) to give

(1 S,3'R,6'S,7'S, 9 ^f Z)-6-chioro-7'-hydroxy-6 ^, -methyi-3,4-dihydro-2H, 15Ή- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetracycfo[14J _^

n]-15'-one 1 '. 1 ^' -di oxide and (1 S,3'R,6'S,7'R, 9'Z)-6-chioro-7'-hydroxy-6'- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [2Q]oxa[ 13]thia[l ,14]diazatetra^^^

n]-15'-one 13', ! 3'~dioxide or (1S,3'R,6'S,7'S, 9'E)-6-chloro-7'-hydroxy-6'-methyl- 3,4-dihydro-2H,15H-spiro[naphthalene-l,22'- I KJ4j tctrao n|-15'-one 13', 13'-dioxide and (1 S,3'R,6'S,7'R, 9'E)-6-chioro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14;7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9,

n]-15'-one 13',13'-dioxide or (1 S,3'S,6'R,7'S, 9'Z)-6-chloro-7'-hydroxy-6'-methyl-

3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'-

[20]oxa[13]thia[l , 14]diazateto^

n]-15'-one 13',13'-dioxide and (1S,3'S,6'R,7'R, 9'Z)-6-chioro-7'-hydiOxy-6'- methyl-3 ,4-dihy dro-2H,15'H-spiro[naphthalene-l,22'- ⁿ j penlacosa| . ! 6J S.2 jlcirae n]-15'-one 13',13'-dioxide or (1 S,3'S,6'R,7'S, 9'E)-6-chloro-7'-hydroxy-6'-methyl- 3 ,4-dihy dro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l , 14]diazaietracycio[14,7.2,0 -^0 ^l9 - ²⁴ ]pentacosa[9 _^

n]-15'-one 13',13'-dioxide and (1S,3'S,6'R,7'R, 9'E)-6-chloro-7'-hydroxy-6'- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

[20joxa[13]thia[ l, 14]diazatetracycfo[14^

n]-15'-one 13', 13'-dioxide (75 mg, 0, 128 mmol, 79% yield). STEP 4: (1 S,3'R,6'S,7'S)-6-CHLORO-7'-HYDROX ^T -6'-METHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTfflA[ l,14jDIAZATETRACYCLO| 14 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [16,18,24]TRIEN]-15'-ONE 13', i;r-DTOXIDE (18,3Έ,6'8,7Έ)~6-ί:ΗΙ^Ο~7'~ HYDROXY-6'-METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

[2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCL )[ 14J.2X) ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA

[16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (l S,3'S,6'R,7'S)-6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DlHYDRO-2H,15'H-SPlRO[ APHTHALENE~ 1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE OR (1 S,3'S,6'R,7'R)-6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 22'- [20]OXA[13]Tffl A[l J^DIAZATETRACYCLOlMJ^.O^^O'^jPENTACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was synthesized from (1S,3'R,6'S,7'S, 9'Z)-6-chloro- 7'-hydroxy-6'-methy3-3,4-dihydro-2H,15'H-spiro|naphthalene-l ,22'- [20]oxa[13]thia[l ,14]diazatefra^

n]-15'-one 13',13'-dioxide and (1 S,3'R,6'S,7'R, 9'Z)~6~chloro-7'-hydroxy-6'- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetracycfo[^^

n]~15'~one 13', 13'-dioxide or (1S,3'R,6'S,7'S, 9'E)-6-chloro-7'-hydroxy-6'-methyl- 3,4-dihydro-2H, 15 'H-spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[U4]cUazatetracyc^

n]-15'-one I 3',13'~dioxide and (1S,3'R,6'S,7'R, 9'E)-6-chloro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2H,15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[9,16,18,24]tetrae n]-15'-one 13', 13'-dioxide or (1 S,3'S,6'R,7'S, 9'Z)-6-ch]oro-7'-hydroxy-6'-methyl- 3 ,4-dihy dro~2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[ 4]diazate1racyd^^

n]-15'-one 13',13'-dioxide and (1S,3'S,6'R,7'R.9'Z)-6-chloro-7'-hydroxy-6'- methy 1 -3 ,4-dihy dr o-2H. ,15 'H-spi ro [naphtha! ene- 1,22'-

[20] oxa[ 13] thi a[ 1 ,14] diazatetracy ci o 114.7.2.0 ^{3 x} 0 ^|9 · ²⁴ ] pen tacosa[9,16,18,24]tetrae n]-15'-one 13', 1.3'-dioxide or (1S,3'S,6 ^! R,7'S, 9'E)-6-ehloro-7'-hydroxy~6'~methyl- 3,4-dihydro-2H, 15 'H-spiro[ naphthalene- 1 ,22'- [20[oxa[13[thia[U4[diazatetracyclo[^^

n]-15'-one 13',13'-dioxide and (1S,3'S.6'R,7'R„ 9^-6-chloro-7'-hydroxy-6'- methyl-3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1,22'- [20]oxa[13|thia[l,14|diazatetracydo| 14.7.2.0' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9, 16,18,24]tetrae n]-15'-one 13', 13'-dioxide (75 mg, 0.128 rnmol) following the procedure described for Example 121, Step 6. The crude material was purified by column

chromatography (12g SiO?., hexanes:EtOAc (containing 1% AcQH), 1:0 to 85:15) to give a 1:1 mixture of diastereomers. The two diastereomers (total of 38 mg) were separated by reverse-phase HPLC elutmg with a gradient of 40-95% acetonitrile (containing 0.1% TFA) in water (containing 0.1% TFA).

(lS,3'R,6'S,7'S)-6-chloro-7'-hydroxy-6'-methyT-3,4-dihydr o-2H,15'H- spiro [naph thai ene- 1 ,22'-

[20]oxa[13]thia[ 1 ,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[l 6, 8.2-11 in on j- 15'-one 13',13'-dioxide or (lS,3'R,6'S,7'R)-6-chloro-7 ^, -hydroxy-6'-methyl-3,4- dihydro-2H,15'H-spiroinaphthalene-l,22'- [20]oxa[13]thia[l,l4]diazate1racy^

15'-one 13',13'-dioxide or (lS,3'S,6'R,7'S)~6-chloro-7 ^! -hydroxy-6'-methyl-3,4- dihy dro-2H, 15 'H-spiro [naphthalene- 1 ,22'- |2 ⁽⁾ joxsij I3|t!iia| i.i4|dia/aielracveioj 14.7.20 ^{; !} '.0 ^|1! lpeniacosa| i6.j8.24|inenj~ 15 ^! -one 13' ₅ 13'-dioxide or (!S,:rS,6 ^! R,7'R)-6-chloro-7'-hydroxy-6'-methy!-3,4- dihydro-2H.15'H-spiroinaphthalene-1.22'- [20[oxa[13]thia[l,14]diazatetracycta^

15'-one 13', 13'-dioxide was obtained as a 4: 1 mixture of diastereomers as the second eluting major component (20 mg, 0.034 mmol, 26.6% yield). Analytical data are provided for the major isomer. Ή NMR (500MHz, CDCb) δ 9.06 (br. s., IH), 7.72 id../ 8.6 Hz, 1H), 7.24 (d, ./ 2.0 Hz, 1H), 7.19 (d, ./ 1.2 Hz, 1H), 7.18 (d, ./ 2.0 Hz, III .7.09 (d, ./ 2.2 Hz, 1H), 6.94 (d, 8.1 Hz, IH), 4.09 (s, 2H), 3.91 id. ,/ 14 Hz, IH), 3.81 (td, 72.14,6 Hz, IH), 3.68 (d, ./ 14.2 Hz, IH), 3.51 - 3.41 (m, IH), 3,33 (d, J=9.5 Hz, IH), 3.15 (d, .7=14.2 Hz, IH), 3.00 (dd, J=9.8, 15.2 Hz, IH), 2.85 - 2.71 (m, 2H), 2.50 (q, J=9.0 Hz, IH), 2.06 - 1.92 (m, 3H), 1.91 - 1.77 (m, 6H), 1.77 - 1.69 (m, 2H), 1.66 - 1.54 (m, 3H), 1.46 - 1.36 (m. Ml).1,30 (s, 3H). MS (ESI, +ve ion) m/z 587.2 (M il) .

EXAMPLE 124. (1 S,3¾,6¾,7 ^! S)-6~CHLORO-7 ^! ~HYDROXY-6'-METHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA

[16,18,24]TRIEN]-15'-ONE !3',13'-DIOXIDE OR (1 S,3'R,6'R,7'R)- 6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ">"> ^< - [20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ^3> ^0 ^!9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13 ^! -DIOXIDE OR (1S,3 ^! S,6'S,7'S)- 6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE-

1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'S,6'S,7'R)~ 6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 122'-

[20]OXA[13]THTA[1.MlDIAZATETRACYCLOlMJ^.O^^O'^jPENTACOSA

[16,18,24] TRIEN] - 15 '-ONE 13', 13 '-DIOXIDE

STEP 1 : (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT- 3-EN-l-YL)-2-METHYLCYCLOBUTTL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2-((R)-l- HYDROXYBUT-3-EN-l-YL)-2-METHYLCYCLOBUT L)METHYL)-3'.4,4 ^, ,5- TETRAHYDRO-2H,2 ^f H-SPIRO[BENZO[B][!,4]OXAZEPiNE-3, l '- NAPHTHALENE] -7-CARBOXYLATE OR (S)-TERT-BUTYL 6'-CHLORO-5- (((lS,2S)-2-((S)-l-HYDROXYBUT-3-EN-l-YL)-2- METOYLCYCLOBUTYL)METTTYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '- APHTHALENE] -7- CARBOXYLATE AND (S)-TERT-B UTYL 6'-CHLORO-5-(((l S,2S)-2-((R)-l- HYDROXYBUT-3-EN-l-YL)-2-METHYLCYCLOBUTYL)MEraYL)-3',4,4',5- TETRAHYDRO-2H,2 ^f H-SPIRO[BENZO[B][!,4]OXAZEPiNE-3, l '- NAPHTHALENE] -7-CARBOXYLATE

The title compounds were synthesized from (S)-tert-butyl 6'-chioro-5~ (((l R,2R)-2-formyl-2-me l^xlobutyl)methyl)-3^4,4^5-tetrahydro-2H,2'H- spiro|benzo[b] [l,4]oxazepine-3,r-naphihalene]-7-carboxylate or (S)-tert-butyl 6'- cMoro-5-(((l S,2S)-2-formyl-2-methylcyclobu1yl)me l)-3^4,4^5-tetrahydro- 2H,2'H-spiro [benzo[b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxylate (Example 1 16, Step 7; 141 mg, 0.276 mmol) following the procedure described for Example 121, Step 2. Purification of the crude material by column chromatography provided (S)-tert-butyl 6'-chloro-5-(((l R,2R)-2-((S)- 1 -b droxybut-3-en- 1 -yl)-2- methylcyclobutv'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-((( 1 R,2R)-2-((R)- 1 -hydroxy but-3-en- 1 -yl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-tert-butyl 6'- chloro-5-(((lS,2S)-2-((S)-l-hydroxybut-3-en-l-yl)-2-me1hylcy clobury'l)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r -naphthalene]-7- carboxylate and (S)-tert-butyl 6'-chloro-5-(((lS,2S)-2-((R)-l-hydroxybut-3-en-l - yl)-2-meihyicyc]obutyl)methyl)-3',4,4 5-tetrahydro-2I-I,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxylate (130 mg, 0.235 mmol, 85% yield).

STEP 2: (S)-6 ^, -CHLOR()-5-(((l R,2R)-2-((S)-l -HYDROXYBUT-3-EN-l-YL)-2- METHYLCYCLOBU L)METHYL)-3',4,4',5-TETRAI-IYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , ! '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2R)-2-((R)- 1 -HYDROXYBUT-3-EN- 1 - YL)-2-METOYLCYCL()BUT iX)METHYL)-3',4,4 ^, ,5-TETRAI-IYDR()-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lS,2S)-2-((S)-l-HYDROXYBUT-3-EN-l-YL)- 2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLI C ACID AND (S)-6'-CHLORO-5-(((lS,2S)-2-((R)-l -HYDROXYBUT-3-EN-l- YL)-2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

The title compounds were synthesized from (S)-tert-butyl 6'~chloro~5- (((lR,2R)-2-((S)-l-hydroxybut-3-en-l-yl)-2-methylcvxlobutyl) methyl)-3',4,4',5- tetrahydro-2il,2'H-spiro[benzo[b][l,4]oxazepine-3J '-naphthalene]-7-carboxylate and (S)-tert-butyl 6 ^, -chloro-5-(((lR,2R)-2-((R)-l -hydroxybut-3-en-l-yl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate or (S)-tert-butyi 6'- chloro-5-((( lS,2S)-2-((S)-l -h) droxybut-3-en-l-yi)-2-methylcyclobufy

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine- 3,r-naphthalene]-7- carboxylate and (S)-tert-butyl 6'-chloro-5-(((lS,2S)-2-((R)-l-hydroxybut-3-en-l- yl)-2-methylcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate (130 nig, 0.235 mmol) following the procedure described for Example 1 16, Step 9. After aqueous workup, the isolated crude mixture of (S)-6'-chloro-5-(((I R,2R)-2-((S)-l - hydroxybut-3-en-l-yl)-2-me1hylcyclobu1\ )methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and iS }--6 ^' ~ chloro-5-(((lR,2R)-2-((R)-l-hydroxybut-3-en-l-yl)-2-methylcy clobutyl)methyl)- 3\4,4 5-tetrahydro-2H,2H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid or (S)-6'-chloro-5-(((lS,2S)-2~((S)-l-hydroxybut~3~en-l-yl)~2- methylcyclobutv'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro [benzo [b] [1,4] oxazepine-3 , 1. '-naphthal ene] -7-carboxy li c aci d and (S)-6'- cMoro-5-(((l S,2S)-2-((R)-l-hydroxybut-3-en-l-yl)-2-methylcyclobu1\'l)met hyl)- 3',4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7- carboxylic acid was taken on to the next step without further purification. STEP 3: (S)-N-(BUT-3-EN-l-YLSULFONYL)-6'-CHLORO-5-(((l R,2R)-2-((S)- l-HYDROXYBUT-3-EN-l-YL)-2-METHYLCYCLOBUTYL)METHYL)- 3' ₅ 4 ₅ 4' _j 5-TETR _J < HYDRO-2H,2 ^, H-SPlRO[BE ZO[B][L4]OXAZEPlNE-3,r~ NAPHTHALENE] -7 -C ARB OXAMIDE AND (S )-N-(BUT-3-EN- 1 - YLSULFONYL)-6 ^* -CHLORO-5-(((l R,2R)-2-((R)- 1 -HYDROXYBUT-3-EN- 1 - YL -2-METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO [B] 11 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXAMIDE OR (S)-N-(BUT-3-EN-l-YLSULFONYL)-6'-CHLORO-5- ((( 1 S ,2S)~2~((S)~ 1 -HYDROXYBUT-3 -EN- 1 -YL)-2- METHYLCYCLOBLriYL)METHYL)-3 ^! ,4,4',5-TEm HYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE]-7-

C ARBOXAMIDE AND (S)-N-(BUT-3-EN-l -YLSULFONYL)-6'-CHLORO-5- (((l S,2S)-2-((R)-l-HYDROXYBUT-3-EN-l-YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIR()[BENZO[B][ l,4]()XAZEPINE-3,r-NAPHTHALENE]-7- CARBOXAMIDE

The title compounds were synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)- 1 -hydroxy but-3-en- 1 -yl)-2-methylcy clobuty l)methyl)-3',4,4', 5-tetrahy dro- 2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy lie aci d and (S)-6'-chloro-5-(((lR,2R)-2-((R)-l-h droxybut-3-en-l-yl)-2- methylcyclobut 4)m.ethyl)-3V ,4',5~tetrahydro-2H,2 ^! H~

spiroj benzoj b] [ L4 |oxazepine-3, -naphthalene]-7-carboxyiic acid or (S)-6'- chloro-5-(((.l S,2S)-2-((S)-l -hydroxy but-3-en-l -yl)-2-methy]cyclobutyl)meihyl)- 3',4,4',5-tet ahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3,r-naphthalene]-7- carboxylic acid and (S)-6'-chloro-5-(((lS,2S)-2-((R)-l-hydroxybut-3-en-l-yl)-2- rnethylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (100 rng, 0.202 mmol) and but-3-ene-l -sulfonamide (Intermediate EE15; 82 mg, 0.605 mmol) following the procedure described for Example 1 16, Step 10. The crude material was purified by column (12 g Si0 ₂ , hexanes:EtOAc(containing 1% AcOH), gradient 1 :0 to 4: 1) to give (S)-N-(but-3-en-l-ylsulfonyl)-6'-chloro-5-(((lR,2R)-2- ((S)- 1 -hydroxy but-3-en- 1 -yl)-2-methylcy clobuty l)methyl)-3',4,4', 5-tetrahy dro- 2H,2'H-spiro[benzo[b]| T,4]oxazepine-3,r-naphthalene]-7-carboxamide and (S)- N-(but-3-en-l-ylsidfonyl)-6'-chloro-5-(((l R,2R)-2-((R)-l ½droxyb^

2-niethylcyclobutyl)methyl)-3V4,4',5~tetrahydro-2H,2'H~

spiroj benzoj b] 1 1,4 |oxazepine-3, 1 '-naphthalene]-7-carboxamide or (S)-N-(but-3- en- 1 -ylsulfonyl)-6'-chloro-5-(((l S ,2S)-2-((S)- 1 -h droxy but-3-en- 1 -yl)-2- methylcyclobut 'l)methyl)--3 ^! ,4,4',5~tetrahydro-2H,2 ^! H~

spiro benzo b] l,4]oxazepine-3,l'-naphthalene]-7-carboxamide and (S)-N-(but-3- en-l-yisulfonyl)-6'~chloro0^

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxamide as the first eluting major isomer (66 mg, 0.108 mmol, 53.2% yield).

Further elution provided (S)-N-(but-3-en-l-ylsulfonyl)-6'-chloro-5- (((l R,2R)-2-((S)-l-hydroxybut-3-en-l-yl)-2-methylcvxlobutyl)meth yl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)-N-(but-3-en- 1 -ylsulfonyl)-6'-chloro-5-(((l R,2R)-2-((R)- 1 -hydroxybut-3- en-l-yl)-2-methylcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide or (S)-N-(but-3- en- 1 -y ] sulfonyl)-6'-chloro-5-((( 1 S ,2S)-2-((S)- 1 -hy droxy but-3-en- 1 -yl)-2- methylcyclobut 4)m.ethyl)-3V4,4',5~tetrahydro-2H,2'H~

spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-N-(but-3- en-l-yisulfonyl)-6'~chloro0^

methylcyclobutyl)methyl)-: ,4 4',5 etrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxamide as the second eluting minor isomer (16 mg, 0.026 mmol, 12.9% yield).

STEP 4: (1 S,3'R,6'R,7'S, 9'Z)-6-CHLORQ-7'-HYDROXY~6'~METHYL-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9,16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE AND (1 S,3'R,6'R,7'R, 9'Z)- 6-CHLORO-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H"

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [9,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND (1 S,3'R,6'R,7'S, 9'E)-6- CHLORO-7'-HYDROXY-6 ^f -METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [9,16, 18,24]TETRAEN]-15'-ONE 13', 13'-DTOXIDE AND (1 S,3'R,6'R,7'R, 9Έ)- 6~CHLORO-7 ^! ~HYDROXY-6'-METHYL-3,4~DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA[13]THIA[l ,14]DIAZATETRACYCL )[ 14J.2X) ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [9,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXiDE OR (1S,3'S,6'S,7'S, 9'Z)~6~ CHLQRQ-7'-HYDRQXY-0'-METHYL-3,4-DlHYDRQ-2H,15'H- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9,16,18,24]TETRAEN]-15'-ONE 13 ^f ,13'-DIOXIDE AND (1S,3'S,6 ^! S,7'R, 9'Z)-6- CHLQRQ-7'-HYDRQXY-6'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1.MIDIAZATETRACYCLOIMJ^.O^^O'^IPENTACOSA

[9,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND (1 S,3'S,6'S,7'S, 9'E)-6- CHL()R()-7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'- [20]QXA[13]TffiA[U4]DL^

[9,16,18,24]TETiL4EN]-15'-QNE 13', 13 '-DIOXIDE AND (1 S,3'S,6'S,7'R, 9'E)-6- CHLORQ-7'-HYDROXY-6 ^* -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[9, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-D )XIDE

The title compounds were synthesized from (S)-N-(but-3-en-l-ylsulfonyl)- 6'-chlofo-5-(((l R,2R)-2-((S)-l -hydroxj'but-3-en-l-yl)-2- methylcyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxarnid e and (S)-N-(but-3- en-l-ylsulfonyl)-6 ^, -cWoro-5-(((lR,2R)-2-((R)-l½droxybut-3-eii-l-yl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide or (S)-N-(but-3- en- 1 "ylsulfonyi)-6'-chioro-5-(((l S,2S)-2-((S)- 1 -hydroxy but-3-en- 1 -yl)-2- methylcyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carboxamid e and (S)-N-(but-3- en- 1 -ylsulfonyl)-6'-chloro-5-(((l S,2S)-2-((R)- 1 -hydroxy but-3-en- 1 -yi)-2- methylcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxamide (Example 124, Step 3, first eluting major isomer; 66 mg, 0.108 mmol) following the procedure described for Example 121, Step 5. The reaction was evaporated in vacuo and the residue was purified by column chromatography (12g Si0 ₂ , hexanes:EtOAc (containing 1% AcOH), 1 :0 to 85: 15) to give ( S,3'R,6'R,7'S, 9'Z)-6-chloro-7'- hydroxy-6'-me1hyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22 '- [20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[9,16,18,24]tetrae n|-15'-one 13', 13'-dioxide and (1 S,3'R,6'R,7'R, g^-e-chloro^'-hyd oxy-e'- methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracycio[14;7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9,16,18,24] n]-15'-one S 3', 13'-dioxide and (1 S,3'R,6'R,7'S, 9'E)-6-chioro-7'-hydroxy-6'- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [2Q]oxa[ 13]thiaj l ,14]diazatetra^^^

n]-15'-one 13', ! 3'~dioxide and (1 S,3'R,6'R,7'R, 9'E)-6-chloro-7'-hydroxy~6'~ methyl-3 ,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 , 22'- I KJ4j tctrao n|-15'-one 13', 13'-dioxide or (1 S,3'S,6'S,7'S, 9'Z)-6-cWoro-7'-hydroxy-6'-methyl- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[i, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9,16

n]-15'-one 13 ',13 '-dioxide and (1 S,3'S,6'S,7'R, 9'Z)-6-chloro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2H, 15'H-spiro[naphth a] ene- 1 ,22'- [20]oxa[13]thia[l , 14]diazatetracyclo[14,7.2,0 ³ ' ⁶ .0 ¹⁹ ' ² '¾

n]-15'-one 13',13'-dioxide and (1S,3'S,6'S,7'S, 9'E)-6-chloi -7'-hydroxy-6'-methyl- 3,4-dihydro-2H, 15'H-spiro|naphthalene-l ,22'- [20]oxa[13]ftia[l, 14]diazatefra<yclo[

n]-15'-one 13 ^* ,13'-dioxide and (1S,3'S,6'S,7'R, 9'E)-0-chloro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l ,14]diazatetracycio[14,7.2,0 -^0 ^l9 - ²⁴ ]pentacosa[

nj-15'-one 13',13'-dioxide (3 nig. 0.005 mmo!, 4.76% yield). STEP 5: (lS,3 ^! R,6'R,7'S)-6-CHLORO-7'-HYDROXY-6'-MF; ^" fflYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20iOXA[13]THLA|;i ,14]DlAZATETRACYCLO[ 14.7.2.( ^)3> ^0 ^{! 9} - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R)- 6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DlHYDRO-2H,15'H-SPlRO[ APHTHALENE- 1,22'-

[20]OXA[ 13 [THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 3',13'-DIQXTDE OR (1 S,3'S,6'S,7'S)~ 6-CHLORO- 7'-HYDROXY-6'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'S.6'S,7'R)- 6-CHLORO- 7'-HYDROXY-6'-METHYL-3.4-DlHYDRO-2H,15 ^* H-SPlRO[ APHTHALENE~ 1.22'-

[2 ⁽⁾ ]OXA[13]THiA[ L 14]DiAZATETRACY ^T CLO|; i4.7.2,0 ^{3 (,} .0 ¹⁹ - ² ]PENTACOSA [ 16,18,24]TRIEN]- 15'-ONE 13', 13'-DIOXIDE

The title compound was synthesized from (1 S,3'R,6'R,7'S, 9'Z)-6-chloro- 7 ^, -hydroxy-6'-methyl-3,4-dihydro-2H,15'H-spiro[naphthale ne-l,22'-

[ 20] ox a[ 13 ] thi a[ 1 , 14] di aza^^

n]-15'-one 13', 13'-dioxide and (1 S,3'R,6'R,7'R, 9'Z)~6-ch]oro-7'~hydroxy-6'- methyl-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[U4]diazatetracycIo|; ^

n]- 15'-one 13 ^* ,13'-dioxide and (1 S,3'R,6'R,7'S, 9'E)-6-chioro-7'-hydroxy-6'- methy 1-3 ,4-dihy dro-2H.15 Ή-spiro [naphthalene- 1 ,22'- i 8.24j[eirae n]-15'-one 1 '. 1 ^' -di xide and (1 S,3'R,6'R,7'R, 9'E)-6-ch1oro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2HJ 5'H-spiro[naphthalene- 1,22'-

[20]oxa[13]thia[lJ4]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ² ]pentacosa[9.16,18,24] n]- 15'-one 13M 3'-dioxide or ( 1 S,3'S.6'S,7'S, ^ZJ-e-chloro-T-hydroxy-ff-methyl-

3 ,4-dihy dro-2H, 15 Ή-spi ro [naph thai ene- 1,22'-

n]-15'-one 13',13'-dioxide and (1 S,3'S,6'S,7'R, 9'Z)-6-chloro-7'-hydroxy-6'- methyl-3 ,4-dihy dro-2H,15'H-spiro[naphthalene- 1,22'-

[20]oxa[ 13]thia[ 1, 14]diazaletracy clo[ 14.7,2.0 ³ - ⁶ .0 ^{! 9} ' ²⁴ ]pentaeosa[9,] 6, 18,24]ietrae n]-15'-one 13 ^* ,13'-dioxide and ( 1 S,3'S,6'S,7'S, 9'E)-6-chloro-7'-hydroxy-6'-methyl- 3.4-dihydro-2H,15Tl-spiro[naphthaiene-l,22'- [20]oxa[13]thia[ l , 14]diazate1racyc^

n]-15'-one 13',13'-dioxide and (1S,3'S,6'S,7'R, 9'E)-6-chloro-7'-hydroxy-6'~ methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

nj~15'~one 13', 13'-dioxide (3 nig, 0,005 mmol) following the procedure described for Example 121, Step 6. Purification of the crude material by column

chromatography (lg SiC , hexanes:EtOAc (containing 1% AcOH), 1:0 to 85:15) provided (1 S,3'R,6'R,7'S)-6-chloro-7'-hydroxy-6'-rnethyl-3,4-dihydro-2H , 15Ή- spiro [naph thalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra<yd^^

15'-one 13',13*-dioxide or (lS 'R,6 7R)-6-chloTO-7- y<koxy-G-m^l-3,4- dihyclro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[l 3]thia[ 1, 14]diazatetracy clo[ 1.4.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]trien]- 15'-one 13 ',13 '-dioxide or (lS,3'S,6'S,7'S)-6-chloro-7'-hydroxy-6'-methyl-3,4- dihydro-2H, 15 Ή-sptroj naphthalene- 1 , 22'-

|2 ⁽⁾ joxsij I3|t ia| i. i4|dia/aielracveioj 14,7.20 ^{; !} '.0 ^|1! ipemacosa| 16. i H.24|iricn|- 15'-one 13',13'-dioxide or (lS,:rS,6 ^! S,7'R)-6-chloro-7'-hydroxy-6 ^! -methyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracycfo[14^

15'-one 13',13'-dtoxide (1.8 mg, 0.003 mmol, 59.8% yield). ¾ NMR (400MHz, CD2CI2) 58.44 (br. s, 1H), 7.72 (d, ./ 8.6 Hz, 1H), 7.53 (s, 1H), 7.19 (dd, J=2.3, 8.6 Hz, 1H), 7.10 (d, ,/ 2.3 Hz, 1H), 7.07 (dd, ./ 1.9.8.1 Hz, ill .7.01 id../ 7.4 Hz, 111).4.14 - 4.09 (m, 211).3,92 - 3,82 (m, 3H), 3.61 (dd, ,/ 42.11,1 Hz, 1H), 3.53 - 3.45 (m, ill).3,39 - 3.31 (m, III).3.10 (d, ,7=14,1 Hz, 1H), 2.84 - 2,71 (m, 3H), 2.46 - 2.38 (m, IH), 2.35 - 2.29 (m, 1H), 1.99 - 1.85 (m, 4H), 1.54 (br. s., 7H), 1.45 - 1.33 (m, 4H), 1.15 (s, 3H). MS (ESI, +ve ton) m/z 587.2 !\Mi) .

EXAMPLE 125, (1 S,3'R,6'R,7'S,8'E, 11 'R)-6-CHLORO-7'-HYDROXY-6', 11 *- DIMETHYL-3,4-DIHYDRO-2H, 14 ^! H-SPlRO [NAPHTH ALENE- 1,21'- [19]OXA[12]TH1A[1,13]DIAZATET1 ACYCLO[13.7.2.0 ³ - ⁶ .0 ¹⁸ - ²³ ]PENTACOSA [8,15,17,23]TETRAEN]-14'-ONE 12',12'-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 11 'R)-6-CHLORO-7'-HYDROXY-6 ^f , 1 r-DIMETOYL-3,4- DiHYDRO-2H,14'H-SPIRO[NAPHTHALENE-l,21'-

[19]OXA[12]THL\|;i,13]DL ZATETRACYCLO[13.7.2.0 ³ - ⁶ .0 ^!8 - ²³ ]l TACOSA [8J5,17,23]TETRAEN]-14'-ONE 12', 12' -DIOXIDE OR (1S,3'S,6'S,7'S,8'E,I i'R.)~ 6-CI l!.()RO-7 -! iVDR()XY- '. I i'-DIMl 11Y1.-3.4-DU !Y!)RO-2H. !4'! 1- SPIRO [NAPHTHALENE- 1,2Γ-

[19]OXA[ 12]TH1A[1 3]DIAZATEII ACYCLO[13;7.2.0 - ⁶ .0 ¹⁸ - ²³ ]PENTACOSA [8,15,17,23]TETRAEN]-14'-ONE 12',12'-DIOXIDE OR

(1 S,3'S,6'S,7'R,8'E, 11 'R)-6-CHLORO-7'-HYDROXY-6', ! 1 '-DIMETHYL-3 ,4- DiHYDRO-2H,14'H-SPIRO[NAPHTHALENE-l,21 ^! -

[19]OXA[12]THIA[l _s 13]DIAZATETRACYCLO[13.7.2.0^ ⁶ .0 ¹⁸ - ²³ ]PENTACOSA [ 8,15,17,23 ]TETRAEN]-14'-ONE 12',12 ^* -DIOXiDE

STEP 1: (S)-TERT-B UTYL 6'-CHLORO-5-(((lR,2R)-2-((lS,5R,E)-l- HYDROXY-5-SULFAMOYLHEX-2-EN- 1 -YL)-2-

METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2- ((l R,5R,E)-l-HYDROXY-5-SULFAMOYLHEX-2-EN-l -YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-TERT-BUTYL 6'-CHLORO-5-(((lS,2S)-2- ((lS,5R,E)-l -HYDROXY-5-SULFAMOYLHEX-2-EN-l-YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7-

CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((lS,2S)-2- ((1 R,5R,E)- 1 -HYDROXY-5-SULF AMOYLHEX-2-EN- 1 -YL)-2- METHYLCYCLOBUlTL)METHYL)"3',4,4',5-TETiL HYDRO-2H,2'H" SPIRO| BENZO[B] [L4|OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE

To a stirred solution of (S)-tert-but l 6'-chloro-5-(((l R,2R)-2-((S)-l - hydrox 'allyl)-2-methylcA ]obuty])me1hyl)-3 4,4 5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((lS,2S)-2-((S)-l-hydrox>'allyl)-2-methylcyc lobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spifo[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carbox late or (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((R)-l-hydroxyallyl)-2-

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-((( 1 S,2S)-2-((R)- 1 -hydroxyally])-2-methyicyc]obuty l)methyl)- 3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate (Example 116, Step 8, first eluting isomer; 140 mg, 0.260 mmol) and (R)-pent-4-ene-2-sulfonamide (Intermediate EE17; 116 mg, 0.780 mmol) in EbO (2 mL) was degassed with Ar(g) for 10 minutes. After this time the reaction was treated with copper(I) iodide (1.7 mg, 9.11 μηιοΐ) and Grubbs catalyst, 2 ^nd generation (6.63 mg, 7.80 umol). The reaction was heated at reflux for 5 hours. After this time the catalyst was deactivated by sparging air through the reaction. The reaction was then evaporated in vacuo and purified by column

chromatography (12g S1O2, hexanes:EtOAc(containing 1% AcOH), 1:0 to 2:1) to give (S)-tert-buty 16'-chloro-5-(((l R,2R)-2-((l S,5R,E)-1 -hydroxy-5-sulfamoylhex- 2-en-l-yl)-2-methylcyclobut l)methyl)-3',4,4 ^, ,5-te^^

spiro[benzo[b] [ l,4]oxazepine-3, 1 -naphtha! ene]-7-carbox late and (S)-tert-buty! 6'-(^oro-5-(((lR,2R)-2 (lR,5R,E)-l½drox'-5-sulfamoylhex-2-en-l-yl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-tert-butyl 6'- diloro -(((IS S)-2-((!S.5RJ -i-li>^

methylcyclobutv'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carbox>'l ate and (S)-tert-butyl

6'-cUoro-5-(((lS ₅ 2S)-2-((lR,5R,E)-l-hydro

methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylate as the first eluting major component (50 mg, 0.076 mmol, 29.0% yield).

Further elution provided (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((lS ₅ 5R,E)-

1- hydroxy-5-sulfamoylhex-2-en-l-yl)-2-methylcyclobutyl)methyl) -3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-tert-butyl 6'-cMoro-5-(((lR,2R)-2-((lR,5R,E)-l½droxy-5-sidfamo>'lhe x-

2- en-l-yl)-2-methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H, 2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-tert-butyl 6'- chloro-5-(((lS,2S)-2~((lS,5R ₅ E)-l-hydroxy-5-sulfamoy1hex-2-en-l^

methylcyclobutv'l)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carbox>'l ate and (S)-tert-butyl 6 ^! ~chloro-5-(((lS,2S)-2-((lR,5R,E)-l-hydroxy-5-sulfamoy1 hex-2-en^

methylcyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate as the first eluting major component (15 mg, 0.023 mmol, 8,7% yield). STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((l S,5R,E)-l-HYDROXY-5- SULFAMOYLHEX-2-EN-l-YL)-2-METHYLCYCLOBUTYL)METHYL)- 3^4,4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B]|;i ,410XAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((lR,5R,E)-l-HYDROXY-5-SULFAMOYLHEX-2-EN-l-YL)-2-

METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO I B j [ 1 ,4]OXAZEPHME-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)~6'~CHI,ORO~5~(((l S,2S)-2-((lS ₅ 5R,E)-l-HYDROXY-5- SULFAMOYmEX-2-EN-l-YL)-2-METHYLCYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B]|;i ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l S,2S)- 2-(( 1 R,5R,E)- 1 -H YDROXY-5 -SULF AMO YLHEX-2-EN- 1 -YL)-2- METHYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO | B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7 -C ARB OXYLI C ACID

To a stirred solution (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((l S,5R,E)-l- hydroxy-5-sulfamoylhex-2-en-l-yl)-2-me1hylc lobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy late and (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((lR,5R,E)-l -hydroxy-5-sulfamo ]hex- 2-en-l -yl)-2-methylc>'clobu1yl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-tert-butyl 6'- chloro-5-(((lS,2S)-2-((lS,5R,E)-l-hydroxy-5-sulfamoylhex-2-e n-l-yl)-2- methylcyclobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late and (S)-tert-butyl 6'-cUoro-5-(((l S,2S)-2-((lR,5R,E)-l½dro

methylcyclobu1yl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 125, Step 1 first eluting major component; 50 mg, 0.076 mmol) in DCM (1517 uL) was added trifluoroacetic acid (117 uL, 1.517 mmol). The reaction was stirred at ambient temperature for 3 hours. After this time the reaction was evaporated in vacuo. The crude material was dissolved in DCM and washed with aqueous NaHCCb. The crude isolated mixture of (S)-6'-chloro-5-(((lR,2R)-2-((lS,5R,E)- l-hydroxy-5-sulfamoylhex-2-en-l-yl)-2-methylcyclobu1yl)methy l)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid and (S)-6'-chloro-5-(((lR,2R)-2-((lR,5R,E)-l-hydrox '-5-sulfarnoylhex-2-en- l-yl)-2-methylcyclobu1yl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro| benzo| bj [ l,4 |oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-6'- chloro-5-(((.l S,2S)-2-((lS,5R,E)-l -hydroxy-5-sulfamoylhex-2-en-l-yl)-2- methylcyclobutyl)methyl)-: ,4,4V5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (S)-6'~ chloro-5-((( 1 S,2S)-2-((l R,5R,E)-1 -hydroxy-5-sulfamoylhex-2-en- 1 -y l)-2- methylcyckjbutyi)methyl)-3',4,4',5-tetrahydro-2I-I,2 ^f H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (45 mg, 0.075 mmol, 98 % yield) was used without further purification in the next step.

STEP 3: (lS,3 ^f R,6'R,7'S,8'E,l l'R.)-6-CHLORO-7'-HYDROXY-6',l V- DIMETHYL-3,4-DIHYDRO-2H, 14'H-SPIRO[N APHTHALENE- 1 ,21 '- [19]OXA[12]ra ^j :A[l _s 13]DIAZATET ACYCLO[13J.2 ³ '^0 ¹⁸ ^ ³ ]PENTACOSA [8, 15, 17,23 ] TETR AEN 1 - 14'-ONE 12', 12 -DIOXIDE OR

(1 S,3'R,6'R,7 ^! R,8'E, 11 'R)-6~CHLORO-7'-HYDROXY-6', 1 1 '-DIMETHYL-3,4- DIHYDRO-2H, 14TI-SPIRO[NAPHTHALENE-l ,21 ^* -

[19]OXA[ 12]TH1A[1,13]DL ZATET1 ACYCLO[13;7.2.0 ³ -^0 ¹⁸ - ²³ ]PENTACOSA [8 ₅ 15.17,23]TETRAEN]-14'-ONE 12',12'-DIOXIDE OR (1S,3'S,6'S,7'S,8'E,1 I 'R)- 6-CHLORO-7'-HYDROXY-6', l l '-DIMETHYL-3,4-DIHYDRO-2H,14'H- SPIRO [NAPHTHALENE - 1 ,21'-

[19]OXA[12]ra ^j :A[l _s 13]DIAZATETRACYCLO[13J.2 ³ '^0 ¹⁸ⁱ³ ]PENTACOSA [ 8,15,17,23 ]TETRAEN]-14'-ONE 12',12 ^* -DIOXIDE OR

(1S,3'S,6'S,7'R,8'E,1 1 ^f R)-6-CHLORO-7'-HYDROXY-6', l l'-DIMETHYL-3,4- DIHYDRO-2H, 14'H-SP1R0[NAPHTHALENE-1 ,21 ^* - [19]OXA[ 12 |THIA[ 1,13 ]DIAZATETRACYCLO[ 13.7.2.0 ³ - ⁶ .0 ¹⁸ - ² ]PENTACX)SA [8,15, 17,23]TETRAEN]-14"-ONE 12', 12 ^* -DIOXIDE

To an ice cooled solution of (S)-6'-chloro-5-(((l R,2R)-2-((l S,5R,E)-l- hydroxy-5-sulfamoylhex-2-en-l-yl)-2-me1hylc lobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid and (S)-6'-chloro-5-(((lR,2R)-2-((lR,5R,E)-l -hydroxy ~S~sidfamoylhex~2-en- l-yl)-2-methylcyclobu1\'l)methyl)-3',4,4',5-tetrahydro-2H,2' H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid or (S)-6 ^! - chloro-5-(((l S,2S)-2-((lS,5R,E)-l -hydroxy-5-sulfamoylhex-2-en-l-yl)-2- methylcyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)~6'~ chloro-5-(((lS,2S)-2-((lR,5R,E)-l-hydroxy-5-sulfamoylhex-2-e n-l-yl)-2- methylcyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (0.045g, 0,075 mniol) and 4-dimethylaminopyridine (0.015 g, 0.127 mniol) in CH2CI2 (37.3 mL) under a N ₂ atmosphere was added EDC (0.029 g, 0.149 mniol) portionwise over 2 min. The reaction was allowed to warm to ambient temperature overnight. After this time the reaction was partitioned between EtOAc and NaHCOs. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated in vacuo.

Purification by reverse phase HPLC eluting with a gradient of 35-95% acetonitnle (containing 0.1% TFA) in water (containing 0.1% TFA) over 40 minutes provided (lS 'R/ 'R 'S,8Ta ! 'R)-6-cW^^^

2H, 14'H-spiro[naphthalene- 1,21'- [19]oxa[ 12]thia[l ,13]cUazatetra^

n]-14'-one 12', 12'~dsoxide or (l S,3'R,6'R,7 ⁱ R,8'E,i rR.)-6-chloro-7'-hydroxy-6'J V- dimethyl-3,4-dihydro-2H,14H-spiro[naphflialene-l,2r-

[19]oxa[12]thia[ l,13]diazatetracyclo[13.7.2.0 ' ⁶ .0 ¹⁸ ' ²³ ]pentacosa[8,15,17,23]tetrae n|-14*-one 12',12'-dioxide or (1S,3'S,6'S,7'S,8 ^* E,1 rR)-6-chloro-7 ^! -hydroxy-6',H ^! - dimethyl-3,4-dihydro-2H, 14'H-spiro[naphthalene-l ,21.'-

n]-14'-one 12',12'-dioxide or (lS,3'S,6 ^* S,7 ^! R,8 l l'R)-6-chloro-7'-hydroxy-6' 1'- dimethyl-3,4-dihydro-2H, 14'H~spiroj naphthalene- ,21 '-

[19]oxa[12]thia[l , 13]diazatetracydo[13.7.2.0 ³ ' ⁶ .0 ¹⁸ ' ²³ ]pentacosa[8,15, 17,23]tetrae n]-14'-one 12',12' -dioxide as the second eiuting major isomer (3.1 mg, 5.30 umol, 7.10 % yield). ^! I I NMR (50()MHz, CD3OD) δ 7.73 (d. J=8.6 Hz, IH), 7.60 - 7.26 (m, IH), 7.15 (d, ,7=8,3 Hz, H), 7.10 (d, .7=2.2 Hz, IH), 7.12 (br. s,, IH), 6.87 (br, s., IH), 6.07 (td, J=6.6, 15.4 Hz, IH), 5.80 (dd, ./ 7.6. 15.4 Hz, IH), 4.09 - 4.00 (m, 2H), 3.76 (br. s., 2H), 3.68 (d, ./ 14.4 Hz, IH), 2,88 - 2.71 i ns. 3H), 2.70 - 2.50 (rn, 2H), 2.14 - 2,06 (m, 2H), 2.01 - 1.84 (rn, 4H), 1.52 - 1,39 (m, 5H), 1.29 (s, 3H), 1 ,22 (s, 3H), MS (ESI, +ve ion) m/z 585.1 { M H ) EXAMPLE 126. (1 S,3'R,6'R,7'S,8'E,10'R,1 l'R.)-6-CHLORO-iO'-

(HYDROXYMETHYL)-7'-METHOXY-ir-METHYL-3,4-DlHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3 ^! R,6 ^, R,7'S,8'E,10'S,l l 'S)-6-CHLOR()-10 ^, -(HYDROXYMETHYL)-7'-

METHOXY- 11 '-METHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTH ALE E-

1,22'-

[20]OXA[13]THIA|;i,14]DL ZATCTRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]i

[8, 16, 18,24]TETRAENj~l S'-ONE 13", 13'-DIOXTDE

STEP 1 : (3S,4S)-3-METHYL-4-VINYLDIHYDROFURAN-2(3H)-ONE AND

(;«,4R)-3-METHYL-4-VINYLDIHYDROFURAN-2(3H)-ONE

A 50 mL round bottom flask fitted with a short-path distillation apparatus was charged with (E)-but-2-ene-l ,4-diol (TCI; 10 g, 1 14 mmol), triethyl orthopropionate (Sigma Aldrich; 44.0 mL, 221 mmol) and benzohydroquinone (Acros Organics; 1.000 g, 9.08 mmol) and the mixture was heated at 140-150 °C for 12 hours (EtOH was collected in a receiving flask for the first 2 hours of the reaction). After this time the reaction was distilled under reduced presure (ca. 20 mm of Hg) and the fraction boiling between 110-130 °C was collected to give (3S,4S)-3-methyl-4-vinyldihydrofuran-2(3H)-one and (3R,4R)-3-methyl-4- vinyldihydrofuran-2(3H)-one (8.2 g, 65.0 mmol, 57.3 % yield).

STEP 2: (2S,3S)-3-(HYDROXYMETOYL)-N-METOOXY-N,2- DIMETHYLPENT-4-ENAM1DE AND (2R,3R)-3-(HYDROXYMETHYL)-N- METHOXY-N,2-DIMETHYLPENT-4-EN AMIDE

Trimethylaluminum (Sigma Aldrich, 2 M in hexanes; 9.5.1 mL, 19.02 mmol) was added at 0 °C to a suspension of N,0-dimethylhydroxylamine hydrochloride (Sigma Aldrich; 1.856 g, 19.02 mmol) in DCM (15.85 mL) and the resulting mixture was stirred for 2 hours at 0° C. Next a solution of (3S,4S)~3~ methyl-4-vinyldihydrofuran-2(3H)-one and (3R,4R)-3-methyl-4- vinyidihydrofuran~2(3H)~one (1 g, 7.93 mmol) in DCM (15.85 niL) was added dropwise over 5 minutes and the mixture was stirred at 0 °C for 2 hours. After this time the reaction was quenched by the careful addition of HC1 (1 M aqueous solution). The separated aqueous layer was extracted with DCM and the combined organic extracts were washed with brine, dried over MgS0 ₄ , filtered and evaporated in vacuo to give (2S,3S)-3-(hydroxymethyl)-N-methoxy-N,2- dimethylpent-4-enamide and (2R,3R)-3-(hydroxymethyl)-N-rnethoxy-N,2- dimethylpent-4-enamide (1.2 g, 6.41 mmol, 81 % yield). Analytical Data showed desired product and starting material (ca. 3: 1 ratio). This material was used without further purification in the next step.

STEP 3 : (2S,3S)-3-(((TERT-BUTYLDIPHENYLSILYL)OXY)METTTVL)-N- METHOXY-N,2-DIMETHYLPENT-4-ENAMIDE AND (2R,3R)-3~(((TERT- BUTTLDIPHENYLSILYL)OXY)METHYL)-N-METHOXY-N,2- DIMETHYLPENT-4-EN AMIDE

To a stirred solution of (2S,3S)-3-(hydroxymethyl)-N-methoxy-N,2- dimethylpent-4-enamide and (2R, 3R)-3-(hy droxymethyl)-N-methoxy-N,2- dimethylpent-4-enamide (1.2 g, 6.41 mmol) in DMF (32.0 mL) was added imidazole (Sigma Aldrich; 0.873 g, 12.82 mmol) and terf-butyldiphenylsilyl chloride (1.811 mL, 7.05 mmol) and the reaction was stirred at ambient temperature overnight. After this time the reaction was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated in vacuo. Column chromatography (40g SiCte, hexanes: EtOAc, 1 :0 to 4: 1) gave (2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)- N-memoxy-N,2-dimethylpent-4-enamide and (2R,3R)-3-(((tert- butyldiphenylsilyl)ox> niethyl)-N-memoxy-N,2-dimethy]pent-4-enamide (1 .6 g, 3,76 mmol, 58.7 % yield). Analytical Data were consistent with the desired product (contaminated with the corresponding lactone).

STEP 4: (2S,3S)-3-(((TERT-BUTYLDIPHENYLSlLYL)OXY)METHYL)-2- METHYLPENT-4-EN- 1 -OL AND (2R,3R)-3-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)-2-METHYLPENT-4-EN- 1 -OL

To a solution of (2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyi)-N methoxy-N,2-dimethylpent-4-enamide (1.5 g, 3.52 mmol) in THF (17.62 mL) was added lithium borohydride (Sigma Aldrich; 0.230 g, 10.57 mmol) followed by methanol (0.428 mL, 10.57 mmol). The reaction was stirred at ambient temperature for 3 hours. After this time an additional portion of lithium borohydride (0.230 g, 10.57 mmol) and methanol (0.428 mL, 10.57 mmol) was added and the reaction was stirred at ambient temperature over the weekend. After this time the reaction was diluted with EtOAc (70 mL) and 1M HC1. The separated aqueous lay er was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgS0 ₄ , filtered and evaporated in vacuo. Column chromatography (40g Si0 ₂ , hexanes:EtOAc, 1 :0 to 4: 1) gave (2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpen t-4-en-l-ol and (2R,3R)-3-(((tert-butyldipheny sily])oxy)methy])-2-meihyipent-4-en- ! -ol (0.84 g, 2.279 mmol, 64.7 % yield) as a colorless oil.

STEP 5 : (2S,3S)-3-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)-2- METHYLPENT-4-EN-l-YL METHANES ULFON ATE AND (2R,3R)-3- (((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)-2-METHYLPENT-4-EN- 1-YL METHANESULFONATE and

TBDPSQ- OMs TBDPSO" OMs

To a stirred solution of (2S,3S)-3-(((tert-but 'ldiphenylsilyl)oxy)methyl)-2- methylpent-4-en-l-ol (0.83 g, 2.252 mnrol) in DCM (22,52 mL) was added triethylamine (Acros Organics; 0.565 mL, 4.05 mmol) and methanesulfonyl chloride (Sigma Aldrich; 0.228 mL, 2.93 mmol). The reaction was stirred at ambient temperature for 30 minutes. After this time the reaction was partitioned between DCM and NaHCCb. The separated organic layer was washed with brme, dried over MgS04, filtered and evaporated in vacuo to give (2S,3S)-3-(((tert- butyldiphenylsiiyl)oxy)methyl)-2-methy]pent-4-en-l -y] methanesuifonate and (2R,3R)-3-(((iert~butyk1iphenylsiM 1 -y! methanesuifonate (0.91 g, 2.037 mmol, 90 % yield) as a light yellow oil.

STEP 6: 2^((2S,3S)-3-(((TERT-BUTYLDIPHENYLSlLYL)OXY)METHYL)-2- METHYLPENT-4-EN- 1 -YL)THIO)PYRIMIDINE AND 2-(((2R,3R)-3-(((TERT- BUTYLDIPIlENYLSILYL)OXY)METHYL)-2-METilYLPENT-4-EN-l- YL)THIO)PYRJMIDINE

To a solution of (2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2- methylpent-4-en-l-yl methanesuifonate and (2S,3S)-3-(((tert- buty'ldiphenylsilyl)oxy)methyl)-2~methylpent-4-en~l -yl methanesuifonate (0.91 g, 2.037 mmol) in DMT (6.79 mL.) was added 2-mercaptopyrimidine (TCI; 0.274 g, 2,445 mmol) and potassium carbonate (0.422 g, 3.06 mmol). The reaction was stirred at ambient temperature for 20 minutes and at 50 °C for 3 hours. After this time the reaction was cooled to ambient temperature and partitioned between EtOAc and brme. The separated organic layer was washed with brine, dried over MgSCn, filtered and evaporated in vacuo. Column chromatography (24g Si0 ₂ , hexanes: EtOAc, 1 :0 to 4: 1 ) gave 2-(((2S,3S)-3-(((tert- butyldiphenylsilyl)oxy)rnethyl)-2^ and 2-

(((2R^3R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-meth ylpent-4-en-l - yl)thio)pyrimidine (0.63 g, 1.362 mmol, 66.8 % yield).

STEP 7 : 2-(((2S ,3 S)-3 -(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)-2- METHYLPENT-4-EN- 1 - YL ) SULF ONYL)P YRIMIDINE AND 2-(((2R,3R)-3- (((TERT-BUWLDIPHENYLSILYL)OXY)METFfYL)-2-METHYLPENT-4-EN- 1 - YL)S ULF ON YL)P Y RIMIDINE

To a well stirred mixture of tetrabutylammonium sulfate, 50 wt. % solution in water (Sigma Aidrich; 78 μ,Ε, 0.067 mmol), phenylphosphonic acid (Sigma Aldrich; 7.46 xL, 0.067 mmol) and sodium tungstate dihydrate (Sigma Aidrich; 22.10 mg, 0.067 mmol) was added hydrogen peroxide (Sigma Aidrich; 342 μΙ_, 3.35 mmol) and the reaction was stirred at ambient temperature for 5 minutes. After this time a solution of 2-(((2S,3S)-3-(((tert- but ldiphenylsilyl)oxy)methyl)-2-methylpent-4-en- 1 -yl)thio)pyrimidine and (2R,3R)-3-(((tert-butv'ldiphenylsilyl)oxy)me1hyl)-2-metJiylp ent-4-en- l -yl methanesulfonate (620 rng, 1.340 mmol) in toluene (1340 μΐ.) was added and the reaction was stirred at ambient temperature for 30 minutes and at 55 °C for 1 hour. After this time LC/MS shows desired product. The reaction was stored in the freezer overnight. Next morning the reaction was partitioned between EtOAc and water. The separated aqueous layer was extracted with EtOAc and the combined organic extracts were dried over MgS04, filtered and evaporated in vacuo.

Column chromatography (12g SiCfc, hexanes:EtOAc, 1 :0 to 2: 1 ) gave 2-(((2S,3S)- 3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpent-4-en- l - yl)sulfonyl)pyrimidine and 2-(((2R,3R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)- 2-methylpent-4-en-l-yl)sulfonyl)pyrimidine (612 mg, 1.237 mmol, 92 % yield). STEP 8: SODIUM (2S,3S)-3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)-2-METHYLPENT-4-ENE-l- SULFINATE AND SODIUM (2R,3R)-3-(((TERT-

ΒυΤΥΤ.ΟΙΡΗΕΝΥΕ8ΙίΥΕ)ΟΧΎ)ΜΕΤΗΥΙ, )-2-ΜΕΤΗΥΕΡΕΝΤ-4-ΕΝΕ-1 - SULFINATE

To a stirred solution of 2-(((2S,3S)-3-(((tert- hutyldiphenylsilyl)oxy)methyl)-2-m^ and 2-(((2R,3R)-3-(((tert-but 'ldiphenylsilyl)ox\')niethyl)-2-methylpent-4-en-l- yl)sulfonyl)pyrimidine (0.62 g, 1.253 mmol) in MeOH (12.53 mL) was added sodium meihoxide (0.344 mL, 1 ,504 mrnoi). The reaction was stirred at ambient temperature for 45 minutes. After this time the reaction was evaporated in vacuo providing sodium (2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpen t- 4-ene- 1 -suifinate and sodium (2R,3 R)-3-(((tert-butyldiphenylsilyl)ox )methyl)-2- methylpent-4-ene-l -suifinate (0.62 g). Analytical Data were consistent with desired product (contaminated with 2-methoxypyrimidine). This material was used without further purification in the next step.

STEP 9: (2S,3S)-3-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)-2- METOYLPENT-4-ENE-l -SULFONAMIDE AND (2R,3R)-3-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)-2-METHYLPENT-4-ENE-l-

SULFONAMIDE To a stirred solution of sodium (2S,3S)-3-(((tert- but diphenylsilyl)oxy)niethyl)-2~methylpent-4-ene-l-sulfmate and (2R,3R)-3~ (((tert-but} diphenylsilyl)oxy)meih l)-2-meth lpeni-4-ene-l -sdfinate (0.55 g, 1 .254 mmol) in water (12.54 mL) and MeOH (2 mL) was added sodium acetate (0.206 g, 2.508 mmol) followed by amidoperoxymonosulfuric acid (0. 170 g,

1.505 mmol). The reaction was stirred at ambient temperature for 30 minutes and at 50 °C for 1 hour. After this time the reaction was allowed to cool to rt and evaporated in vacuo. The mixture was partitioned between EtOAc and water. The separated aqueous layer was extracted with EtOAc (x2) and the combined organic extracts were dried over MgS04, filtered and evaporated in vacuo.

Column chromatography (12g Si0 ₂ , hexanes: EtOAc, 1 :0 to 2: 1 ) gave (2S,3S)-3- (((tert-but 'ldiphenylsilyl)ox\ memyl)-2-methylpent-4-ene-l -sulfonarnide and (2R,3R)-3-(((tert-but\'ldiphenylsilyl)oxy)methyl)-2-methylpe nt-4-ene-l- sulfonamide (0.35 g, 0.811 mmol, 64.7 % yield). STEP 10: (S)-5-(((l R,2R)-2-((l S,4S,5S,E)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)- 1 -HYDROXY-5-METHYL-6- SULFAMOYLHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'-CHLORO- 3^4,4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B]|;i ,410XAZEPINE-3,r- NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-5-(((lR,2R)-2- ((l S,4R,5R,E)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)-l - HYDROXY-5-METHYL-6-SULF AMOYLHEX-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-6 ^, -CHLORO-3 ^, .4,4 ^, ₅ 5-TETRAHYDRO-2H,2 ^, H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

A solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobut5 _' l)methyl)-3^4,4^54etrahydro-2H,2'H- spiroj benzoj b][ L4 |oxazepine-3, -naphthalene]-7-carboxy lie acid (Intermediate A Al l A; 100 mg, 0.2.14 mmol) and (2S,3S)-3-(((tert- butykliphenylsilyl)oxy)methyl)-2-m.ethylpent~4~ene~ 1 -sulfonamide and (2R,3R)- 3 -(((tert-buty Idipheny isiiy l)oxy )methy l)-2-methy lpent-4-ene- 1 -sulfonamide (Example 126, Step 9; 304 mg, 0.705 mmoi) in 1,2-dichloroethane (3053 μΕ) was degassed for 10 minutes with Ar(g). The reaction was then treated with a solution of (l ,3-dimesitylirmdazolidin-2-ylidene)(2-isopropoxy

chloride (Sigma Aldrich; 13.39 mg, 0.021 mmoi) in 1,2-dichloroethane (3053 μΙ_) and stirred at ambient temperature for 1 hour. After this time Ti(iPrO)4 (3 drops) was added and the reaction was stirred at ambient temperature for 4 hours. After this time the catalyst was deactivated by sparging air through the reaction mixture for 5 minutes. SiO?. (ca 1 g) was added to the reaction mixture and the solvent was evaporated in vacuo. The solid was trasferred into a solid loading cartridge and purified by column chromatography (4g S1O2 , hexane: acetone, 1 :0 to 70: 30) to give (S)-5 ((lR,2R)-2 (lS,4S,5S,E)-4 ((tert-bulyidiphenyIsiiyl)oxy)methyl)-l- hydroxy-5-methyl-6-su]famoylhex-2-en-l -y])cyclobutyl)methyl)-6'-chloro- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxyhc acid and (S)-5-(((lR,2R)-2-((l S,4R,5R,E)-4-(((tert- bulyldiphenylsiiyl)oxy)methyl)-1 iydroxy-5-methyi-6-sdf½noylhex-2-en-l- yl)cyclobut 'l)methyl)-6'-chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (18 mg, 0.021 mmol, 9.66 % yield). STEP 11 : (1S,3'R,6'R,7'S,8'E,10'R,1 l'R)-6-CHLORQ-10'-

(HYDROXYMETHYL)-7'-METHOXY-l l '-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14J.2 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8J 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'S, 1 l ^* S)-6-CHLORO-l 0'-(HYDROXYMETHYL)-7'~ ΜΕΤΉΟΧΥ-l -METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

L22'"

|;20]OXA[ 13 iTHIA[ l 4jDIAZATETRACYCLO| 14 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13 ^* -DIOXIDE To a stirred solution of (S)~3~(((l R,2R)~2~((1 S,4S,5S,E)-4-(((tert- butyidiphenylsilyl)oxy)methyl)- 1 -hy droxy-5-melhyl-6-sulfamoylhex-2-en- 1 - yl)cyclobtm _' l)methyl)-6'-chloro-3',4,4^54etrahydro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3,l'-naphthalene]-7-carboxylic acid and (S)-5- (((1R,2R)-2~((1S,4R,5R,E)~4~((^^

methyl-6-sulfamoylhex-2-en-l -yl)cyclobutyl)methyl)-6'-chloro-3',4,4',5- tetrahydro-2H,2H-spiro benzo b]| ,4]oxazepine-3,r-naphthalene|-7-carboxj'lic acid (0.018g, 0.021 mmol) in DCM (10.33 mL) at 0 °C was added N,N- dimethylpyridin-4-amine (4.29 mg, 0.035 rnniol) followed by Nl- ((ethylimino)methylene)-N3,N3-cUmethylpropane-l,3-diamine hydrochloride (Oakwood; 7.92 mg, 0.041 mmol). The reaction was stirred at ambient iernperaiure overnight. After this time the reaction was partitioned between DCM and NaHCCb. The separated aqueous layer was extracted with DCM and the combined organic extracts were dried over MgSC¼, filtered and evaporated in vacuo. The crude product (15 mg) was dissolved in THF (1.5 mL) and sodium hydride (2.478 mg, 0.103 mmol) was added followed by iodomethane (6.46 μΐ, 0.103 mmol) and the reaction was stirred at ambient temperature for 4 hours. After this time the reaction was partitioned between EtOAc and 1 M HC1. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated in vacuo. The crude material (14 mg) thus obtained was dissolved in THF and treated with TBAF (Sigma Aldrich, 1 M solution in THF; 0.207 mL, 0.207 mmol). The reaction was stirred at ambient temperature for 3 days. After this time the reaction was partitioned between EtOAc and water. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated in vacuo. Column chromatography (4g SiCh , DCM:Acetone, 1 :0 to 3: 1) gave (1S,3'R,6'R,7'S,8'E, 10'R,1 R)-6-chloro-! 0'- (hydroxy methy l)-7'-methoxy - 1 1 '-methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- Y^

[20]oxa[13]thia[U4]diazatetracy^^

n]-15'-one 13',13'-diQxide or (lS,3'R,6 ^! R,7 ^* S,8'E,10'S,irS)-6-chlQro-10'- (hydroxymethyl)-7'-methoxy- 11 '-methy l-3,4-dihydro-2H, 15'H-spiro[naphthalene- 1.22'- IKJ4jtctrao n|-15'-one 13',13'-dioxide (1.4 mg, 2.225 μηιοΐ, 10.77 % yield) as a single diastereorner. Ή NMR (400MHz, CD2CI2) δ 7,71 id../ 8.4 H .1H), 7.17 (dd, ./ 2,2.8.5 Hz, IH), 7.09 (d, J=2.3 Hz, IH), 6.91 (d, ./ 0.8 Hz, 2H), 6.84 (s, IH), 5.84 (dd, ./ H,3.15.4 Hz, IH), 5,54 (dd, ./ 8.9.15.6 Hz, !!!).4.31 (dd, J=3.9, 15,3 Hz, 111).4.08 (s, 211).3.83 (d, ,/ i 57 Hz, IH), 3.76 - 3,64 ins.3H), 3,63 - 3.55 (m, 2H), 3,24 (d, J=14.5 Hz, IH), 3.20 (s, 3H), 3.08 (dd, ./ 9, 1, 15,2 Hz, IH), 3.03 (dd, J=10.3, 15.4 Hz, IH), 2.85 - 2.70 (m, 2H), 2.52 - 2.37 (m, 2H), 2.37 - 2.26 (m, IH), 2.10 - 2,01 (m, IH), 1.98 - 1.89 (m, 2H), 1.87 - 1,73 (m, 3H), 1.72 - 1.63 (m, 2H), 1.41 - 1.36 (m.111).1 ,22 id, ./ ?.o Hz, 3H). MS (EST, +ve ion) m/z 629.2 (M+H) ⁺ .

EXAMPLE 127. (IS^'R^'R 'S^'EJO'S/ 'S^e-CHLORO-lO'- (ilYDROXYMETHYL)-7'-METI-IOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H - SPTRO[NAPHTH ALENE- 1 ,22'- |20jOXA| I 311 HI Λ| I„!-! |P!.\/.\ Th ΓΚΑίΎί ^' ί, Ol i 1,7.20 ' ".U ¹ "' ¹ |PH\ iACOSA [8,16,18,24]TETiL4EN]-15'-QNE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,I0'S,12'R)-6-CHLORO-10'-(HYDROXYMETOY L)-7'- METHOXY-12'-METOYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'- |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2,0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,12'R)-6-CHLORO-10'-(HYDROXYMETHY L)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 122'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN] S'~ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'EJ0'R 2'S)-6~CHLORO-10'-(HYDROXYMETHYL)"7'"

METHOXY-12'-METHYL-3,4-DIHYDRO-2H 5H-SPIRO[NAPHTHALENE-

1,22'- |20i()XA| Γ Η1Α| Ι..Ν|Ρ!Λ/.ΥΠ:ΠίΛίΎ(ΤΟί 117.20 ^;ί '.ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE i.T.i 3'-DK)XIDE

STEP 1 : (Z)-4-((TERT-BUTYLDIPHENYLSILYL)OXY)BUT-2-EN-l -OL

To a stirred solution of cis-2-butene-l,4-diol (10.00 mL, 114 mmol), tnetrr] amine (15.82 mL, 114 mmol) and DMAP (0.693 g, 5,68 mmol) in DCM (100 ml.) was added TBDPS-Cl (14.58 mL, 56,8 mmol) in DCM (50 mL) dropwise via an addition funnel. After the addition was complete the reaction was stirred at ambient temperature ovemight. After this time water was added to the reaction. The separated organic layer was washed with 1M HC1, dried over

MgS04, filtered and evaporated in vacuo. The crude product was loaded into a 40 g S1O2 cartridge and purified by column (120 g redisep gold, hexanes:EtOAc, 1:0 to 4:1) to give (Z)-4-((tert-butyldiphenylsilyl)oxy)but-2-en-l-ol (13 g, 39.8 mmol, 35,1 % yield). STEP 2: (S)-ETHYL 3-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-ENOATE AND ( R) ETHYL 3 -(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-

ENOATE

Triethyl orthoacetate (Sigma Aldrich; 37.4 mL, 203 mmol) and propionic acid (Sigma Aldrich; 0.149 mL, 1.991 mmol) were added to a solution of (Z)-4- ((tert-butyldiphenylsilyl)oxy)but-2-en-l-ol (13 g, 39.8 mmol) in p-xylene (160 mL). The mixture was heated at 140 °C for 3 hours with removal of ethanol using a short pad distillation kit. After this time the reaction was allowed to cool to ambient temperature and water was added to the reaction. The separated organic layer was washed with NaHCCb (sat. aq. solution) and then it was dried over MgSCK filtered and evaporated in vacuo. Column chromatography (120g SiCte, hexanes: EtOAc, 1 :0 to 4: 1 ) gave (S)-ethyl 3-(((tert- butyldiphenylsilyl)oxy)methyl)pent-4-enoate and (R)-ethyl 3-(((tert- butyldiphenylsilyl)oxy)methyl)pent-4-enoate (11.9 g, 30.0 mmol, 75 % yield) as a colorless oil.

STEP 3: (S)-3-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4- ENAL AND (R)-3-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-

To a stirred solution of (S)-ethyl 3-(((tert~

butyldiphenylsilyl)oxy)methyl)pent-4-enoate and (R)-ethyl 3-(((tert- butyldiphenylsilyl)oxy)methyl)pent-4-enoate (11.9 g, 30.0 mmol) in toluene (1 mL) at -78°C was added dropwise via syringe a solution of DIBA1-H (Sigma Aldrich, 1M in hexanes; 33.0 mL, 33.0 mrnol). The reaction was stirred at -78 °C for 1 hour. After this time the reaction was cooled to 0 °C and treated with 1.32 mL of water, 1.32 mL. of 15% aq. NaOH and 3 mL of water. The reaction was stirred for 30 minutes at ambient temperature. After this time EtOAc (200 mL) was added to the reaction followed by water (50 mL) and IM NaOH (50 mL) and the mixture was stirred for 10 minutes. The separated organic layer was dried over MgS04, filtered and evaporated in vacuo to give crude (S)-3-(((tert- butyldiphenylsilyl)oxy)methyl)pent-4-enal and (R)-3-(((tert- butylctophenylsilyl)oxy)methyl)pent-4-enal (10 g, 28.4 mrnol, 95 % yield). This material was used without further purification in the next step.

STEP 4: (2R,4S)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)HEX- 5-EN-2-OL OR (2S,4S)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-OL OR (2S,4R)-4- (((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-OL OR (2R,4R)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- OL AND (2R,4S)-4-(((TERT-BU LDIPHENYLSILYL)OXY METHYL)HEX- 5-EN-2-OL OR (2S,4S)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-OL OR (2S,4R)-4- (((TERT-BUWLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-OL OR (2R,4R)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- OL

To a stirred solution of (S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4- enai and (R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-enal (6.1 g, 17.30 mmol) in THF (87 mL) at 0 °C under a N ₂ atmosphere was added dropwise via syringe a solution of methylmagnesium bromide (Sigma Aldrich, 1.4 M in THF/toluene; 13.60 mL, 19.03 mmol). The reaction was stirred while allowing to warm to ambient temperature for 1 hour. After this time the reaction was cooled to 0 °C and carefully treated with 1 M HC1 (sat. aq. solution) and EtOAc. The mixture was stirred at ambient temperature for 10 minutes. A fter this time the reaction was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated in vacuo to give a 1 : 1 mixture of (2R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en- 2-ol or (2S,4S)-4-(((tert-butyidiphenylsiiyl)oxy)methyl)hex-5-en-2-o i or (2S,4R)- 4-(((tert-butyldiphenylsilyl)ox ')methyl)hex-5-en-2-ol or (2R,4R)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol and (2R,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2S,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2S,4R)-4-(((tert- butyldiphenylsiiyl)oxy)methyl)hex-5-en-2-ol or (2R,4R)-4-(((tert- butylctophenylsilyl)oxy)methyl)hex-5-en-2-ol as the first eluting major component (3.5 g, 9.496 mmol, 54.9%).

Further elution provided a 4: 1 mixture of (2R,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2S,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2S,4R)-4-(((tert- buty ldipheny isiiy l)oxy )methy l)hex-5 -en-2-ol or (2R,4R)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol and (2R,4S)-4-(((tert- butyldiphenylsiiyl)oxy)methyl)hex-5-en-2-ol or (2S,4S)-4-(((tert- butyldipheny Isiiy l)oxy)methyl)hex-5-en-2-ol ₀ r (2S,4R)-4-(((tert- butyldiphenyisiiy3)oxy)methyi)hex-5-en-2-ol or (2R,4R)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol as the second eluting minor component (2.0 g, 5.426 mmol, 31.3%).

STEP 5 : (2R4S)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)HEX- 5-EN-2-YL METHANESULFONATE OR (2S,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-YL METHANESULFONATE OR (2S,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-YL

METHANESULFONATE OR (2R,4R)-4-(((TERT- BUTTLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-YL

METHANESULFONATE AND (2R,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-YL

METHANESULFONATE OR (2S,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METFfYL)HEX-5-EN-2-YL

METHANESULFONATE OR (2S,4R)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-YL

METHANESULFONATE OR (2R,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-YL

METHANESULFONATE

To a stirred solution of a mixture of (2R,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2S,4S)-4-(((tert- buty'ldiphenylsiiyl)oxy)meihyl)hex-5-en-2~ol or (2S,4R)-4-(((tert- but 4diphenylsilyl)oxy)methyl)hex-5-en-2~ol or (2R,4R)-4-(((tert- but 'ldiphenylsilyl)oxy)methyl)hex-5-en-2-ol and (2R,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2S,4S)-4-(((tert- bu1yldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2S,4R)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol or (2R,4R)-4-(((iert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-ol (Example 12, siep 4, second eluting minor component; 2.0 g, 5.426 mmol) in DCM (27.1 mL) at 0 °C under a N ₂ atmosphere was added triethylamine (1.134 mL, 8.14 mmol) followed by methanes ulfonyl chloride (Sigma Aldrich; 0.465 mL, 5.97 mmol). The reaction was stirred at 0 °C for 5 minutes and then the cooling bath was removed and the reaction was stirred at ambient temperature for 30 minutes. After this time the reaction was partitioned between DCM and 1M HCi. The separated organic layer was washed with NaHCC (sat. aq. solution), brine (sat. aq. solution) and then it was dried over MgS0 ₄ , filtered and evaporated in vacuo to give (2R,4S)-4-(((tert- butylctophenylsilyl)oxy)methyl)hex-5-en-2-yl methanesulfonate or (2S,4S)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2-yl methanesulfonate or (2S,4R)- 4-(((tert-butyldiphenylsiiyl)oxy)methyl)hex-5-en-2-yi methanesulfonate or (2R,4R)~4~(((tert-but 4dipheny silyl)oxy)meihyl)hex~5-en-2-yl methanesulfonate and (2R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2-y l

methanesulfonate or (2S,4S)-4-(((iert-butyldipheny3silyl)oxy;)methyl)hex-5-en-2- yl methanesulfonate or (2S,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en- 2-yl methanesulfonate or (2R,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5- en-2-yl methanesulfonate (2.4 g, 5.37 mmol 99% yield).

STEP 6: 2-(((2S ₅ 4S)-4-(((TERT-

BUTYLDIPI-IENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)THIO)PYRIMIDINE OR 2-(((2R,4S)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)THIO)PYRIMIDINE OR 2-(((2R,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)TH10)PYR1M1D1NE OR 2-(((2S,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)THIO)PYRIMIDINE AND 2-(((2S,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)THIO)PYRIMIDINE OR 2-(((2R,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)THIO)PYRIMlDINE OR 2-(((2R,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)TH10)PYR1M1D1NE OR 2-(((2S,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)THIO)PYRIMIDINE

To a stirred solution of (2R,4S)-4-(((tert- butylctophenylsilyl)oxy)methyl)hex-5-en-2-yl methanesulfonate or (2S,4S)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2-yl methanesulfonate or (2S,4R)- 4-(((tert-buty ldiphenylsilyl)oxy)methyl)hex-5-en-2-yl methanesulfonate or

(2R 4R)~4~(((tert-but 4diphenylsilyl)oxy)meihyl)hex~5-en-2-yl methanesulfonate and (2R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2-y l

methanesulfonate or (2S,4S)-4-(((iert-butyldipheny3silyl)oxy)methyl)hex-5-en-2- yl methanesulfonate or (2S,4R)-4-(((tert-butyldiphenylsiiyl)oxy)me{hyl)hex-5-en- 2-yl methanesulfonate or (2R,4R)-4-(((tert-butyldiphenylsilyl)ox ')methyl)hex-5- en-2-yl methanesulfonate (2.4 g, 5.37 mmol) in DMF (10.75 inL) was added potassium carbonate (0.965 g, 6.98 mmol) and 2-mercaptopyrimidine (0.723 g, 6.45 mmol) and the mixture was stirred at ambient temperature for 1 hour. After this time the reaction was heated at 60 °C for 90 minutes and then it was treated with more DMF (8 mL) and stirred at 45 °C overnight. After this time an additional portion of 2-mercaptopyrimidine (0.3g) and potassium carbonate (0.4g) was added and the reaction was stirred at 60 °C for 40 minutes and at 100 °C for 3 hours. After this time the reaction was allowed to cool to ambient temperature and partitioned between EtOAc and brine. The separated organic layer was washed with brine, dried over MgS€>4, filtered and evaporated in vacuo. Column chromatography (40 g S1O2 , hexanes:EtOAc, 1 :0 to 3: 1) gave 2-(((2S,4S)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2-jd)lWo)pyri midine or 2- (((2R,4S)-4-(((tert-butyldiphenylsilyl)oxy)me1hyl)hex-5-en-2 -yl)thio)pyrimidine

yl)thio)pyrimidine or 2-(((2S,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5- en-2-yl)thio)pyrimidine and 2-(((2S,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-yl)thio)pyrimidine or 2-(((2R,4S)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2-yl)thio)pyr irrddm or 2- (((2R,4R)-4-(((tert-butyidiphenylsiiyl)oxy)m

or 2-(((2S,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en -2- yl)thio)pyrimidine (1.6 g, 3.46 mmol, 64.4 % yield).

STEP 7: 2-(((2S,4S)-4-(((TERT-

BUTYLDlPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)S ULFONYL)PYRIMIDINE OR 2-(((2R,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)SULFONYL)PYRIMIDINE OR 2-(((2R,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)SULFONYL)PYRIMIDINE OR 2-(((2S,4R)-4-(((TERT- BUTTLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2-

YL)S ULFONYL)PYRlMIDINE AND 2-(((2S,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METFTYL)HEX-5-EN-2- YL)SULFONYL)PYRTMIDINE OR 2-(((2R,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)SULFONYL)PYRIMIDINE OR 2-(((2R,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)S ULFONYL)PYRlMIDINE OR 2~(((2S,4R)-4-(((TERT- BUTYLDlPHENYLSILYL)OXY)METHYL)HEX-5-EN-2- YL)SULFONYL)PYRIMIDINE

To a well stirred mixture of tetrabutylammonium sulfate, 50 wt. % solution in water (Sigma Aldrich; 0.201 mL, 0.173 mmol), phenylphosphonic acid (Sigma Aldrich; 0.027 g, 0.173 mmol) and sodium tungstate dihydrate (Sigma Aldrich; 0.057 g, 0.173 mmol) was added hydrogen peroxide (0.883 mL, 8.64 mmol) and the reaction was stirred at ambient temperature for 5 minutes. After this time a solution of 2-(((2S,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5- en-2-yl)thio)pyrimidme or 2-(((2R,4S)-4-(((tert- butyldiphenylsilyl)oxy)memyl)hex-5-en-2-yl)mio)pyrimidine or 2-(((2R,4R)~4- (((iert-butyldipheny3silyl)oxy)methyl)hex-5-en-2-yl)thio)pyn iriidine or 2- (((2S,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2 -yl)thio)pyrinTidine and 2-(((2S,4S)-4-(((tert-bu1yldiphenylsilyl)oxy)methyl)hex-5-en -2- yl)thio)pyrimidine or 2-(((2R,4S)-4-(((teri-butyldiphenyisiIy3)oxy)methy3)hex-5- en-2-yl)thio)pyrimidine or 2-(((2R,4R)-4-(((tert- butykliphenylsilyl)oxy methyl)hex-5~en-2-yl)thio)pyrimidine or 2-(((2S,4R)-4- (((tert-but\'ldiphenylsilyl)oxy)methyl)hex-5-en-2-yl)mio)pyr imidine (1.6 g, 3.46 mmol) in toluene (3.46 mL) was added and the reaction was stirred at ambient temperature overnight. After this time the reaction was partitioned between EtOAc and water. The separated organic layer was washed with Na2S?. ⁾ 3,

NaHSC and brine (at this stage organic lay er tested negative for peroxides using Quantofix strips), dried over MgSCH, filtered and evaporated in vacuo.

Purification by column chromatography (24 g S1O2, hexanes:EtOAc, 1 :0 to 2: 1 ) gave 2-(((2S,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en -2- yl)sulfoiiyl)pyrimidme or 2-(((2R,4S)-4-(((tert- but cUphenylsilyl)ox\ me1hyl)hex-5-en-2-yl)sulfonyl)pyrimidine or 2-(((2R,4R)- 4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2-yl)sulfon yl)pyrimidine or 2-

yl)sulfonyl)pyrimidine and 2-(((2S,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-en-2-yl)sulfon}d)pyrimid ine or 2-(((2R,4S)-

4- (((tert-butyldiphenylsilyl)oxy)me1hyl)hex-5-en-2-yl)sulfonyl )pyrirrudm^ or 2- (((2R,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2 - l)sulfonyl)pyrimidine or 2-(((2S,4R)-4-(((tert- butyldiphenylsilyl)oxy)me1hyl)hex-5-en-2-yl)sulfonyl)pyrirri idine (1 ,33 g, 2.69 mmol, 78 % yield).

STEP 8: SODIUM (2S,4S)-4-((CTERT-

BUTYLDlPHENYLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFINATE OR SODIUM (2R,4S)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFINATE OR SODIUM (2R,4R)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFINATE OR SODIUM (2S,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METFiYL)HEX-5-ENE-2-SULFINATE AND SODIUM (2S,4S)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-

5- ENE-2-SULFINATE OR SODIUM (2R,4S)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFINATE OR SODIUM (2R,4R)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFINATE OR SODIUM (2S,4R)-4-(((TERT-

ΒυΤΥΙ^3ΓΡΗΕΝΥΕ8Π Ί.)ΟΧΥ)ΜΕΤΗΥί ΗΕΧ-5-ΕΝΕ-2~8υΕΡΙΝΑΊΈ

To a stirred solution of 2-(((2S,4S)-4-(((tert- butyldiphenylsilyl)ox n ethyl)hex-5-en-2-yl)su]fonyl)pyrimidine or 2-(((2R,4S)- 4-(((tert-butyldiphenylsilyl)oxy)methyl)h^ or 2-

(((2R,4R)-4-(((tert-bu1yldiphenylsilyl)oxy)methyl)hex-5-e n-2- yl)sulfonyl)pyrimidine or 2-(((2S,4R)-4-(((tert- butyldiphenylsilyl)oxy)me1hyl)hex-5-en-2-yl)sulfonyl)pyrirri idine and 2- (((2S,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-en-2 - yi)sulfony l)pyrimidine or 2-(((2R,4S)-4-(((tert- butyldiphenylsilyl)ox> n ethyl)hex-5-en-2-yl)su]fonyl)pyrirnidine or 2-(((2R,4R)- 4-(((tert-butyldiphenylsilyl)oxy)methyl)h^ or 2-

(((2S,4R)-4-(((tert-bu1yldiphenylsilyl)oxy)methyl)hex-5-e n-2- yl)sulfonyl)pyrimidine (1.33 g, 2.69 mmol) in MeOH (26.9 mL) was added sodium methoxide (0.676 mL, 2,96 mmol) and the reaction was stirred at ambient temperature for 30 minutes. After this time the reaction was evaporated in vacuo to give sodium (2S,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfmate or sodium (2R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfinate or sodium (2R,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfinate or sodium (2S,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfinate and sodium (2S,4S)-4-(((tert-but 'ldiphenylsilyl)oxy)methyl)hex-5-ene- 2-sulfinate or sodium (2R,4S)-4-(((tert-butyidipheny sily])oxy)methy])hex-5-ene- 2-sulfinate or sodium (2R,4R)-4-(((tert-but\'ldiphenylsilyl)oxy)methyl)hex-5-ene- 2-sulfinate or sodium (2S,4R)-4-(((tert-but 'ldiphenylsilyl)oxy)methyl)hex-5-ene- 2-sulfmate (contaminated with 2-methoxypyrimidine; 1.17 g, 2.67 mmol, 99 % yield).

STEP 9: (2S,4S)-4-(((TERT-BUTYLDlPHE slYLSlLYL)OXY)METHYL)HEX- 5-ENE-2-SULFONAMIDE OR (2R,4S)-4-(((TERT-

ΒυΤΥΊ.ΟΙΡΙ4ΕΝΥΕ8ΙΙΛ .)ΟΧΥ)ΜΕΤΗΥΙ,)ΗΕΧ-5-ΕΝΓ 2-8υΕΡΟΝΑΜΙΒΕ OR (2R,4R)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5- ENE-2-SLlLFONAMIDE OR (2S,4R)"4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFONAMIDE AND (2S 4S)-4-(((TE;R:r~BUTYIJ3rPHENYLSiLYl _J )OXY)MF;THYL HEX-5- ENE-2-S ULFON AMIDE OR (2R,4S)-4-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFONAMIDE

OR (2R,4R)-4-(((TERT-BUTYT.DIPI1ENYLSILYL)OXY)METHYL)HEX-5- ENE-2-SULFONAMIDE OR (2S,4R)-4-(((TERT-

BUTYLDIPHF_ YLSILYL)OXY)METHYL)HEX-5-ENE-2-SULFON AMIDE

To a stirred solution of sodium (2S,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfinate or sodium (2R,4S)-4-(((tert- butykliphenylsilyl)oxy)methyl)hex-5-ene-2-sulfinate or sodium (2R,4R)-4-(((tert- butyldiphenyisiiyl)oxy)methyl)hex-5~eiie-2~sulfinate or sodium (2S,4R)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfinate and sodium (2S,4S)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfinate or sodium (2R,4S)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfinate or sodium (2R,4R)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfinate or sodium (2S,4R)-4- (((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfinate (1 .17 g, 2.67 mmol) in water (26.7 mL) was added sodium acetate (0.438 g, 5.33 mmol) and

amidoperoxymonosulfuric acid (0.362 g, 3.20 mmol). The reaction was stirred at 50 °C for 90 minutes. After this time the reaction was cooled to ambient temperature, treated with MeOH (2 mL) and it was sonicated for 2 minutes. The reaction was placed back in the heating bath at 50 °C for 2 hours. After this time the reaction was cooled to ambient temperature and partitioned between 1M NaOH and Ethyl Acetate. The separated aqueous layer was extracted with EtOAc (x2) and the combined organic extracts were washed with brine, dried over MgSCK filtered and evaporated in vacuo. Column chromatography (40 g SiC , hexanes:EtOAc, 1 :0 to 3: 1) gave (2S,4S)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfonamide or (2R,4S)-4-(((tert~ butyl dipheny lsily l)oxy )methy l)hex-5 -ene-2-sulfonamide or (2R,4R)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfonamide or (2S,4R)-4-(((tert- butyldiphenylsilyl)ox ')rnethyl)hex-5-ene-2-su]fonamide and (2S,4S)-4-(((tert- butyldiphenylsilyl)ox niethyl)hex-5-ene-2 -sulfonamide or (2R,4S)~4~(((tert- butyldiphenyisiIy3)oxy)methyl)hex-5-ene-2-sulfonamide or (2R,4R)-4-(((tert- butyldiphenylsilyl)oxy)methyl)hex-5-ene-2-sulfonamide or (2S,4R)-4-(((tert- butyldiphenyisily3)oxy methyl)hex-5-ene-2-sulfonamide (0.65 g, 1.506 mmol, 56.5 % yield).

STEP 10: (S)-5-(((lR,2R)-2-((l S,4S,6S,E)-4-(((TERT-

BUTTLDIPHENYLSILYL)OXY)METHYL)-l-HYDROXY-6-

SULFAMOYLHEPT-2-EN-l -YL)CYCLOBU L)METHYL)-6'-CHLORO-

S'^^'j.TETRi^HYD O^H^'H-SPl OtBE ZOtBJI l^iOXAZEPlNE-S,!'- NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)-5-(((lR,2R)-2-

((1 S,4S,6R,E)-4-(((TERT-BUTYLDIPHENYLSILYl OXY)METHYL)- 1- HYDROXY-6-SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B][ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7 - C ARB OXYLI C ACID OR (S)-5-(((l R,2R)~2~((1 S,4R,6R,E)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)-l-HYDROXY-6- SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'-CHLORO-

3^4,4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B]|;i ,410XAZEPINE-3,r- NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-5~(((1 R,2R)~2~

((1 S,4R,6S,E)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)- 1 -

HYDROXY-6-SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , ! '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-5-(((lR,2R)-2-((l S,4S,6S,E)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)- 1 -HYDROXY-6-

SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'-CHLORO-

3Vlv4',5-TCTRAHYDRO-2H,2'H-SPIRO[BENZO[B][] ,4]OXAZEPINE-3,r-

NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-5-(((lR,2R)-2-

((1 S,4S,6R,E)-4-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)- 1 - HYDROXY-6-SULF AMOYLHEPT-2-EN- 1 -YL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO| BENZO[B]|;i,4iOXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID OR (S)-5-(((lR,2R)-2-((lS,4R,6R,E)-4-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)-l-HYDROXY-6- SULFAMOYLHEPT-2-EN-l-YL)CYCLOBLriTL)METHYL)-6 ^! -CHLORO- 3 4,4',5-TETP^HYDRO-2H,2 -SPIR()|;BENZO| B][ l,4]OXAZEPINE-3,r- NAPHTHALE EJ-7-CARBOXYLIC ACID OR (S)-5-(((lR,2R)-2- ((lS,4R,6S,E)-4-(((TERT-BUTTLDIPHENYLSILYL)OXY)METHYL)-l- HYDROXY-6-SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'- CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

A solution of (2S,4S)- -(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfonamide or (2R,4S)-4-(((tert-butyldiphenylsilyl)ox>')methyl)hex-5-en e-2- sulfonamide or (2R,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfonamide or (2S,4R)-4-(((tert-bu1\'ldiphenylsilyl)oxy)methyl)hex-5-ene-2 - sulfonamide and (2S,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfonamide or (2R,4S)-4-(((tert-but ldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfonamide or (2R,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfonamide or (2S,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hex-5-ene-2- sulfonamide (498 mg, 1.154 mniol) in 1,2-dichloroethane (3846 μΕ) was degassed for 10 minutes by sparging Ar(g). The reaction was then treated with a solution of Hoveyda-Grubbs catalyst 2 ^nd generation (24.10 mg, 0.038 mmol) in DCE (0.8 mL) and Ti(iPrQ) ₄ (3 drops) and a solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3, r-naphthalene]-7-carboxylic acid (Intermediate AA11A; 180 mg, 0.385 mmol) in DCE (2 mL) was added dropwise via syringe pump over 3 hours while sparging Ar(g) through the reaction (30 minutes after the addition had started, Ti(iPrO)4 (3 drops was added); 1 hour after the addition had started an additional portion of Hoveyda-Grubbs catalyst 2 ^nd generation (24 mg) and Ti(iPrO)4 (3 drops) was added). Once that the addition was completed the reaction was stirred at ambient temperature overnight. After this time the catalyst was deactivated by sparging air (g) through the reaction mixture for 5 minutes. SiC (ca. 3 g) was added to the mixture and the solvent was evaporated in vacuo. The product was transferred to a solid loading cartridge and purified by column chromatography (12 g SKh , DCM:acetone, 1 :0 to 4: 1 ) to give (S)-5-(((l R,2R)-2- ((1 S,4S,6S,E)-4-(((tert-butyldiphenylsilyl)oxy )methyl)- 1 -hydroxy-6- sulfamoylhept-2-en-l-yl)cyclobutyl)methyl)-6'-chloro-3',4,4' ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4S,6R )-4-(((tert-butyldiphenylsiIyl)oxy)met

sulfamoylhept-2-en-l-yl)c lobut>d)methyl)-6'-chloro-3\4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid or (S)-5- (((l R,2R)-2-((l S,4R,6R,E)-4-(((tert-bu1yldiphenylsilyl)oxy)me1hyl)-l-hydrox y-6- sdfamoylhept-2-en-l -yl)cyclobutyl)methyl)-6 ^, -chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4]oxazepine-3 , -naphthalene] -7-carboxylic acid or (S)-5- (((lR,2R)-2-((l S,4R,6S,E)-4-(((tert-but 'ldiphenylsilyl)oxy)methyl)-l-hydroxy-6- sulfamoylhept-2-en-l-yl)c^ lobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3,r-naphthalene]-7-carboxylic acid and (S)-5-

{{{ 1 I S. S _^ 6S.I- )- -({ ( iC!l-bul> Idiphcm isiK = >ox> )n¾eih j- l -h> droxv-6- sulfamoylhept-2-en-l-yl)cyclobutv'l)methyl)-6'-chloro-3^4,4' ,5-tetrahydro-2H,2H^ spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid or (S)-5- (((1 R,2R)~2-((1 S,4S,6R,E)-4-(((tert-bulyldipheiiylsilyl)oxy)methyl)-l-ltydr oxy-6- sulfamoylhept-2-en-l-yl)cy lobutyl)methyl)-6'-cMoro-3^4,4^5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4R,6R,E)-4-(((tert-butyddipheny1silyl)oxy)m ethyl)-l-hydroxy-6- sulfamoylhept-2-en-l-yl)cy lobutyl)methyl)-6'-cMoro-3^4,4 ^, ,5-tetrahydro-2H,2'H- spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((l R,2R)-2-((l S,4R,6S ₅ E)-4-(((tert-butyldiphenylsilyl)oxy)me l)-^

sulfamoylhept-2-en-l-yl)cyclobutyl)methyl)-6'-chloro-3',4 ,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid as the first eluting minor component (38 mg, 0.044 mmol, 11.3% yield).

Further elution provided (S)-5-(((lR,2R)-2-((lS,4S,6S,E)-4-(((tert- butyldiphenylsilyl)oxy)methyl)-l-hydroxy-6-sulfanioylhept-2- en-l- yl)cyclobut'l)methyl)-6'-chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4S,6R,E)-4-(((tert-bu1yldiphenylsilyl)oxy)m ethyl)-l-n^ sdfamoylhept-2-en-l-yl)cyclobutyl)methyl)-6'-chloro-3 4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4R,6R,E)^^((tert-bu1yldiphenylsilyl)oxy)met hyl)-^

sulfamoylhept-2-en-l-yl)c^ lobu1yl)methyl)-6'-cMoro-3',4,4',5-tetfahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- {{( i R.2 )-2-{{ i S. R.6S.i ^; )- -{{(ierl~biH> idiphc:-> Isi !> i )ON> )me!h> ! )- 1 -I d >x> ~6- sulfamoylhept-2-en-l-yl)cyclobu1y'l)methyl)-6'-chloro-3 4,4 ^, ,5-tetrahydfo-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carbox> 'lic acid and (S)-5-

sulfamoylhept-2-en-l-yl)cycIobutyI)m

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid or (S)-5- (((lR,2R)-2-((lS,4S,6R,E)-4 ((tert-bui>1diphenylsilyl)oxy)me1hyl)-l-hydroxy sulfamoylhept-2-en-l-yl)cyclobutyl)me1

spiro benzo b] l,4]oxazepine-3, -naphthalene|-7-carboxylic acid or (S)-5- (((1 R,2R)-2-((l S ₅ 4R,6R,E)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-l -hydroxy-6- sulfamoylhept-2-en-l-yl)cyclobu1yl)methyl)-6'-chloro-3^4,4', 5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4R,6S,E)-4-(((tert4>utylcUp^

sulfamoylhept~2~en-l-yl)cydob^

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid as the second eluting major component (58 mg, 0.067 mmoi, 17.3% yield). STEP 11: (lS,3'R,6¾J^,8'E,l()'SJ2'S)-6-CHL()RO-10'-(((TERT-

BUTYLDIPHEr^LSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

[20]OXA[13]raj:A[l _s 14]DIAZATETRACYCLO[14J.2 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS 3'R >'R ₅ 7'S,8'E,10'S;i2'R)-6-CHLORO-U)'-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4-

D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l 4jDL4ZATETRACYCLO|14 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8 ₅ 16,18,24]TETRAEN]-15"-ONE 13' ₅ 13 ^* -DIOXIDE OR

( 1 S, 3 'R,6 ^! R,7'S , 8Έ, 10'R, 12'R)-6-CHLORO- 10'-(((TERT-

BUTYLDlPHENYLSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,l()'R,12 ^! S)-6-CHLORO-l()'-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

|2ujOXA| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί·ΗΛ(·Υ(·ί.ΟΙ 14.7.2.0'^ 0 ^{|:, !|} |PL\,T.\i SA [8^6,18,24]ΤΈΤ¾ΑΕΝ]-15'-ΟΝΕ 13 ^! J3 ^* -DIOXIDE

To a stirred solution of (S)-5-(((lR,2R)-2-((lS.4S,6S,E)-4-(((tert- butyldiphenylsilyl)oxy)methyl)-l-hydrox'-6-sulfamoylhept-2-e n-l- yl)c>'clobu1yl)methyl)-6 ^, -chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4S,6R,E)-4-(((tert4>uty ^

sulfamoylhept-2-en-l-yl)c lobu1>d)methyl)-6'-chloro-3\4,45-tetTahydro-2H,2H^ spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4R,6R,E)-4-(((tert-b^

sulfamoylhept-2-en-l-yl)c clobutyl)methyl)-6'-chloro-3 4,4',5-tetrahydro-2H _^ spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid or (S)-5- (((l R,2R)-2-((! S,4R ₅ 6S,E)-4-(((tert-bu^

sulfamoylhept-2-en-l-yl)c lobulyl)methyl)-6'-cMoro-3^4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)-5- (((lR,2R)-2-((lS,4S,6S ₅ EM-(((tert-^

sulfamoymept-2-en-l-yl)cyclobutyl)methy^^

spiro benzo b] l,4]oxazepine-3, -naphthalene|-7-carboxylic acid or (S)-5- (((l R,2R)-2-((l S,4S,6R ₅ E)-4-(((tert-butyldiphCTLylsilyl)oxy)me ]>

sulfamoylhept-2-en-l-yl)cyclobu1yl)methyl)-6'-chloro-3 4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4R,6R,E)-4-(((tert-butyldiphenylsilyl)oxy)m ethyl)-l-hydroxy-6- sulfamoylhept-2-en- 1 -yl)c lobutyl)methyl)-6'-chloro-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid or (S)-5- (((l R,2R)-2-((l S,4R,6S,E)-4-(((tert-bu1yldiphenylsilyl)oxy)me l)-l-l^ sdfamoylhept-2-en-l -yl)cyclobutyl)meth^

spiro [benzo [b] [ 1 ,4] oxazepine-3 , -naphtha! ene] -7-carboxy lie acid (Example 127, Step 10, first eluting minor component: 38 mg, 0.044 mmol) in DCM (14.5 mL) at 0 °C under a N?. atmosphere was added N,N-dimethylpyridin-4-amine (9.05 mg, 0.074 mmol). After 3 minutes Nl-((ethylimino)methylene)-N3,N3- dimethylpropane-l,3-diamine hydrochloride (16.72 mg, 0.087 mmol) was added portionwise over 3 minutes and the reaction was allowed to stirred at ambient temperature overnight. After this time the reaction was partitioned between DCM and IM HC1. The separated aqueous layer was back-extracted with DCM and the combined organic extracts were washed with brine, dried over MgS0 ₄ , filtere and evaporated in vacuo. The product was adsorbed in ca. lg of S1O2 and purified by column chromatography (4g Si0 ₂ , DCM;acetone, 1 :0 to 4: 1) to provide

(lS 3¾,6¾.J¾,8T; !0'S,12^)-6-chloro-10'-(((teri-butyk!iphenylsily!)oxy 7*-hy droxy- 12'-meihyi-3,4-dihy dro-2H, 15'H-spiro[napht a] ene- 1 ,22'- [20]oxa[13]thiajlJ4]diazatetracy^

n]-15'-one 13'J 3'-dioxide or (lS.3 ^, R.6 ^, R,7 ^, S,8 ^, E ₅ 10 ^, S ₅ 12'R)-6-chloro-10 ^, -(((tert- butyldiphenyisihl)oxy)rnethyl)-7' iydroxy-12 ^, -me

spiro[naphthalene- 1.22'-

n]-15'-one 13',13'-dioxide or ilS,3'R,0'R,7'S,8¾10'R,12'R)-6-ch ro-10M^^^ butyldiphenylsilyl)oxy)methyl)^

spiro[naphthalene-l,22'- !6JH.24iieifae n] - 15'-one 13', 13'-dioxide or ( 1S,3'R,6'R.7'S,8'E, 10'R.12'S)-6-ch1oro- 10'-(((tert- butykliphenyisilyI)oxy)meihyl)-7'4riydroxy-12'-nieihy

spiro [naphthalene- i.22'-

[20joxa[13]thia[l,14]dia¾tetracyc^^

nj~15'~one 13',13'-dioxide as the first eluting major isomer (12 mg, 0.014 mmol,

32.3% yield).

Further elution provided (lS.3'R.6'R,7 ^! S,8'E,10'S,12'S)-6-chloro-i0'-(((tert- butyidiphenylsifyl)oxy)meft

spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracyxlo[i4,7.2,0^ ⁶ .0 ¹⁹ - ² ]pen

n]-15'-one 13',13'-dioxide or (ΙΒ^'Κ,δ'Κ,Τ'Β,δΈ,ΙΟ'Β,^' νό-οηΙθΓθ-ΙΟ'-ίίίίβΓί- butyldiphenylsilyl)ox^ niethyl)-7'-hydroxy-12'-me1hyl-3,4-dihydro-2H,15 ^, H- spiro [naphtha] ene- 1 ,22'-

[20]oxa[13]thia[U4]diazatetracy^

n]-15'-one 13',13'-dioxide or (iS.3'R,6 ^! R,7'S,8'E,10'R.]2'R)-6-ch3oro-l()'-(((tert- butyldiphenyisih 'l)oxy)methyl)-7 ^, -hydroxy-12'-methy]-3,4-dihydro-2H,15'H- spiro[naphthalene- 1.22'-

n]-15*-one i .V. ! -dioxide or (1 S,3'R,6'R,7'S,8'E,10'R,12'S)-6-chloro-10'-(((tert- i 2'-mclliyl-3.4-dihydro-2l i. ! 5Ί l- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[i,14]diazatetra^

n]-15'-one 13',13'-dioxide as the second eluting minor isomer (7 mg, 0.008 mmol, 18.8% yield), STEP 12: (iS,3'R,6'R,7'S,8'E,10'SJ2'S)-6-CHLORO-i0'-

(HY ^" DROXYMETHYL)-7'-METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H - SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ "*0 ^]9 ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'S, I2'R)-6-CHLORO-10'-(HYDROXYME ^r nTYL)-7'-

METHOXY-12'-METHYL-3,4-DIHYDRO-2H 5H-SPIRO[NAPHTHALENE-

1,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ' ".O ^1* " ¹ |PHNT. SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-CHLORO- 10'-(HYDROXYMETHYL)-7 ^* -

\Ι !Ί !ΟΧΥ-!2'-.Υ1Ι· ^" Π !YL~3. l-P!HYDRO-2} ί.1 Ί !-SPiR()|\APi 1 Π ί.\5 Ι Ι·.-

1,22'-

[20]OXA[13iTHIA[l,14jDL4ZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,18,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(lS^'R.e'R.T'S.S'E^O'R^^S^e-CHLORO-lO'-CHYDROXYMETHYL)-?' -

METHOXY- I2'-MEraYL-3,4-DIHYDRO-2H, 15'H-SPIRO[N APHTHALENE-

122'-

[20]OXA[13]Tffl A[l .MIDIAZATETRACYCLOIMJ^.O^^O'^IPENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE To a stirred solution of (lS^'^e'^T'S^'E O'S ^S^-chloro-lO'-^tert- but cUphenylsilyl)ox niethyl)-7'-hydroxy-12'-methyl-3,4-dihydro-2H,15'H- spiro [naph thai ene- 1 ,22'- i 8.2 |ietrae nj-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,10'S,12'R)-6-chioro-10'-(((iert- butyldiphenylsiiyl)oxy)methyl)~7'~hy

spiro [naphthalene- 1 ,22'-

n] - 15'-one 13', 13'~dioxide or (1 S,3'R,6'R,7'S,8'E, 1 O'R, 12'R)-6-chloro- 10'-(((tert- butyldiphenylsilyl)oxy)me l)-7'-hydrox

spiro [naphthalene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetracycfo[l^ _^

n]-15 ^* -one 13', 13'-dioxide or (1 S,3'R,6'R,7'S,8'E, 10'R, 12'S)-6-cM^

butyldiphenylsiiyl)oxy)niethyl)-7'-hy

spiro [naphthalene- 1 ,22'-

n]-15'-one 13', 13'-dioxide (Example 12, Step 11, first eluting major isomer; 12 nig, 0.014 mmol) in THF (703 μΕ) under a N ₂ atmosphere was added sodium hydride (5.62 mg, 0.141 mmol) and the reaction was stirred at ambient temperature for 15 minutes. After this time iodomethane (4.40 \xh, 0.070 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was then treated with EtOAc and water. The separated organic layer was washed with brine, dried over MgSi filtered and evaporated in vacuo to give the desired methyl-ether intermediate.

The crude product was dissolved in THF (0.3 mL) and treated with TBAF (Sigma Aldnch, 1M in THF; 141 μΕ, 0.141 mmol). The reaction was stirred at ambient temperature overnight. After this time the reaction was partitioned between EtOAc and 1M HCi. The separated aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brme, dried over MgSC , filtered and evaporated in vacuo. Column chromatography (ca, 2g Si02 , DCM: acetone, 1 :0 to 9: 1) gave the partially purified title compound. Further purification by- column chromatography (ca. lg S1O2 , hexanes:EtOAc (containing l%AcOH), 1 :0 to 2: 1) gave (18,3¾,6¾,7'8,8Έ,10'8,12Έ)-6-ΰΜο™-10'-^νάΓθχν ηΐ6 1)-7'- methoxy- 12'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthal ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetr^ n]-15'-one 13',13" -dioxide or (1 S,3'R,6'R,7'S,8'E,10'S,^^^^^-^"- (hydroxyme1hyl)-7 ^, -methoxy-12 ^, -methyl-3,4-dihydro-2H,15 ^, H-spiro[naphthalene-

1,22'-

[20]oxa[13]thia[l,14]diazaietracycio[14 .2,0-^0 ^l9 - ²⁴ ]peniacosa[

n]-15'-one 13',13 ^! ~dioxide or { i S.3'R.6 ^' R.7'S,.8'!;,, i O'R.12 ^' RK>-chioro- i (!'-

(hydroxyme1hyl)-7 ^, -methox ^, -12 ^, -methyl-3,4-dihydro-2H,15Ή-spiro[naphthalene-

122'-

|20jo\aj I |ihi«i| i . I4|dia/aieuae> ck>j U. Z^.O^' ^1' ' ⁿ |pen!acosa|H.I .i8.2-!|icirae n]-15'-one 13 ^* ,13'-dioxide or (18,3¾,6Ί ,7'8,8Έ,10 ^* ¾12'8)-6-ο1ι1οΐΌ-10'- (hydroxymethy3)-7'-methoxy-12'-meih l-3,4-dihydro-2I-I,15'H- 1,22'-

[20] oxa[ 13] thia[ 1 , 14] diazatetracy cl o [ 14 ,7.2.0 ³ · ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (1.6 nig, 2.54 μιηοΐ, 18.09 % yield). ¾NMR

(400MHz, CD2CI2) δ 7.71 (d, ,/ 8.6 Hz, IH), 7.17 (dd,■/ 2.3.8.4 Hz, IH), 7.09 (d, .7=2.2 Hz, IH), 6.95 (dd, J=2,0, 8.0 Hz, IH), 6.91 (d, J=8.0 Hz, IH), 6.84 (s, IH), 5.73 (dd, J=6.9, 15.7 Hz, IH), 5.56 (dd, ./ 7.6.15.8 Hz, IH), 4.29 - 4.20 (m, IH), 4.14 - 4.07 ins.2! I ).3.79 (d, ,/ 15.7 Hz, !!!).3.72 - 3.68 (m, IH), 3.66 (d, ./ 14.7!!/. IH), 3,62 (dd, J=6.5, 10.6 Hz, IH), 3.53 (dd.,/ 74.10.2 Hz, ill).3,24 (s, 3H), 3,20 (d, .7=14.7 Hz, IH), 3,06 (dd, J=8.9, 15.4 Hz, IH), 2.84 - 2.68 (m, 2H), 2.60 - 2.44 (m, 2H), 2.35 - 2.25 (m, IH), 2.21 (ddd, J=3.8, 6.9, 14.9 Hz, IH), 2.02 (br. s., IH), 1.98 - 1.88 (m, 2H), 1.86 - 1.79 (m, !!!).1.78 - 1.62 (m, 4H), 1,57 (d, ./ 7.0 Hz, 3H), 1.42 (i, J=l 1.6 Hz, IH). MS (ESI, +ve ion) m/z 629.2 (M+H) ^" * ^' .

EXAMPLE 128. (IS,3'R,6'R,7 ^! S,8'E,10'S,12'S)-6-CHLORO-10'- (IlYDROXYMETHYL)-7'-METi-IOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H - SPTRO[NAPHTH ALENE- 1 ,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ' ".O ¹ '" ¹ |PH\ i ACOSA [8,I6,18,24]TETiL E ]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,I0'S,I2'R)-6-CHLORO-10 ⁱ -(HYDROXYMETOYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- [20]OXA[13]TH1A[1 4]DL ZATET1ACYCLO[14;7.2 -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R^'S,8 .;iO¾ 2¾.)-6-CHLORO-10'-(IlYDROXYMETI-IYI.)-7 ^f - METOOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R 'S,8'EJ0'R 2'S)-6-CHLORO-10'-(HYDROXYMETHYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H 5H-SPIRO[NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO^

[8, 16, 18,24]TETRAEN]-15'-ONE 13 I 3'-DIQXlDE AND

(lS,3'R,6'R;7'S,8'E,l()'S,12'S)-6-CHLORO-l()'-(HYDROXYMEr aYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIROP^APHTHALENE- l. -

|;20]OXA[13iTHIA[l 4jDIAZATETRACYCLO|14 ³ -V0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS 'R,6 ^! R7'S,8'E/U ⁾ 'S ₅ 12'R)-6 Hl RO-10' HYDROXYMETHYL)-7'- METHOXY-I2'-METOYL-3,4-DIHYDRO-2HJ5'H-SPIRO[NAPHTHALENE- 122'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCI [147 A ⁾³ -V0 ^!9 - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,10'R,12'R)-6-CHL()RO-1()'-(HYDR()XYME THYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H, 15 'H-SPIRO [N APHTHALENE-

1,22'~

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥΠ:ΤΗΑ(ΎΠ.ϋΙ i 4.7.20 · ^, '.ί ^)|: " ¹ |P1-M ^' AC<)SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(I S,3'R,6'R,7'S,8'E, 1 O'R, 12'S)-6-CHLORO-l 0'-(HYDROXYMETHYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALE E- [20]OXA[13]TH1A[1 4]DL ZATET1 ACYCLO[14;7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

STEP 1: (lS,3'R,6 ^, R,7 ^, S,8 ^, E,10 ^, S,12'S)-6-CHLORO-10 ^, -(((TERT- ΒυΤΥΕΟΙΡΙ-ίΕΝΥΕ8ΙΕΥΕ)ΟΧΥ)ΜΕΤΗΥΕ)- 7'-ΗΥΟΚΟΧΥ-12·-ΜΕΤΗΥΕ-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|2θ!() Λ| I 311 HI Λ| I .. N |ΟΙΛ/Λ Π·. f ^' RACYCf .Oj N.7.2 (Γ ".O ¹ " ^M |PH\ i ACOS A

[8,I6,18,24]TETiL EN]-15'-QNE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^, S,8'E,l()'S,12'R)-6-CHL()RO-10'-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,I6,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

( 1 S, 3 'R,0'R,7'S , 8Έ, 10'R, 12'R)-6-CHLORO- 10'-(((TERT-

BLiTYLDlPHENYLSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4 - DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ "*0 ^]9 ^ ⁴ ]PENTACOSA [8 ₅ ]6,18,24]TETRAEN]-15 ^! -ONE 13', 13 -DIOXIDE OR

(1 S,3*R,6'R,7'S,8'E, 10'R, 12'S)-6-CHLORO-10 ^, -(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'- [20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND

(IS^'R^'R 'S^E O'SJ^'Si-e-CHLORO-lO'-^TERT-

BUTYLDIPHE>nLSILYL)OXY)METHYL)-7'-HYDROXY-12 ^, -METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί) ^|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24]TETRAENj-15'-ONE 13',13'-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E, 10'S, 12 ^* R)-6-CHLORO- 10'-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)-7'-HYDROXY -12'-METHYL-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-L22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0- ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(IS^'R^'l^yS^E O'^^'R^e-CHLO O-lO'-^CrE T"

BUTYLDIPHENYLSILYL)OXY)METI-IYL)-7'-I-r¾' ^r DROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* - pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,0'R,7'S,8'E, 1 O'R, 12"S)-6-CHLORO- 10'-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)-7'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALE E- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.() ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

To a stirred solution of (S)-5-(((l R,2R)-2-((l S,4S,6S,E)-4-(((tert- but 'ldiphenylsilyl)oxy)methyl)-l -hydrox\'-6-sulfamoylhept-2-en-l- yl)cyclobtm4)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4S,6R )-4-(((tert-butyW^^

sulfamoylhept-2-en-l-yl)c^ lobutyl)methyl)-6'-cMoro-3^4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid or (S)-5- (((1 R,2R)-2-((l S ₅ 4R,6R,E)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-l -hydroxy-6- sulfamoylhept-2-en-l-yl)cyclobu1yl)methyl)-6'-chloro-3 4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((l S,4R,6S )-4-(((tert-butyldiphenyIsiIyl)oxy)

sulfamoylhept-2-en-l-yl)cyclobutyl)methyl)-6^

spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid and (S)-5-

(((lR,2R)-2-((lS,4S,6S,E)-4-(((tert-bu1yldiphenylsilyl)ox y)methyl)-l-hydroxy-6- sdfamoylhept-2-en-l -yl)cyclobutyl)methyl)-6 ^, -chloro-3 4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4]oxazepine-3 , -naphthalene] -7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4S,6R,E)-4-(((tert-but 'ldiphenylsilyl)oxy)methyl)-l-hydroxy-6- sulfamoylhept-2-en-l-yl)c^ lobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5- (((lR,2R)-2-((lS,4R )RX;)-4-(((tert-buiy4diphenyls

sulfamoylhept-2-en-l-yl)cyclobut\'l)methyl)-6'-chloro-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-5-

(((lR,2R)-2-((lS,4R,6S,E)-4 ((tert-bi diplienylsilyl)oxy)me

sulfamoylhept-2-en-l-yl)cyclobutyl)methyl)-6'-chloro-3 4,4',5-tetrahydro-2H,2H- spiro|benzo|b] [l,4]oxazepine-3, i'-naphihalene]-7-carboxylic acid (Example 127, Step 10, second eluting major component; 58 mg, 0.067 mmol) in DCM (22.2 niL) at 0 °C under a N ₂ atmosphere was added N,N-dimethylpyridin-4-amine (13.82 mg, 0.113 mmol). After 3 minutes Nl -((ethylimino)methylene)-N3,N3- dimethylpropane-l,3-diamine hydrochloride (25.5 mg, 0.133 mmol) was added portionwise over 3 minutes and the reaction was allowed to warm to ambient temperature overnight. After this time the reaction was partititoned between

DCM and I M HCl. The separated aqueous layer was back-extracted wtih DCM and the combined organic extracts were washed with brine, dried over MgSCn, filtered and evaporated in vacuo. The product was adsorbed in ca. lg of S1O2 and purified by column chromatography (4g S1G2 , DCM: Acetone, 1 :0 to 4: 1) to provide (1 S,3'R,6 ^! R,7'S,8'E,10 ^! S,12'S)-6-chloro-10'-(((tert- butyldiphenyisiiyl)oxy)niethyl)-7'-hy

spiro I naphthalene- 1 ,22'- [20]oxa[13]thia[l ,14]diazate1r^

n]-l 5'-one 13', 13'~dioxide or (1 S,3'R,6'R,7'S,8'E, 10'S, 12'R)~6~chloro~l 0'-(((tert- butyldiphenylsilyl)oxy)memyl)-7'-hycLroxy

spiro[naphthalene-l,22'- [20]oxa[13]thia[U4]diazatetra<yclo^

n]-15'-one 13',13'-dioxide or (l S^'R-e'^TS^'E O'^l^RVe-chloro-lO'-^tert- but cUphenylsilyl)ox niethyl)-7'-hydroxy-12'-methyl-3,4-dihydro-2H,15'H- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracy^

n]-15'-one 13',13'-dioxide or (18,3¾,ό¾,7'8,8Έ,10¾,12'8)-6-ΰωοΓθ-10^^

butyldiphenylsilyl)oxy)methyl)-7'-hydrox

spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[U 4]diazatetra<yclo[ ^ n]-15'-one 13', 13 '-dioxide and (lS^'R^^T'S^UlO'S^^SJ-e-chloro-lO'-iiitert- but cUphenylsilyl)ox^ nle )-7 ^, -hydrox -12 ^, -methyl-3,4-dihydro-2HJ5Ή- spiro I naphthalene- 1,22'- [20]oxa[13]lhia[U4]diazate1ra^

n]-15*-one 13',13'-dioxide or (lS,3 ^, R.6 ^, R,7'S,8 ^, E,10 ^, S ₅ 12 ^, R)-6-chloro-10 ^, -(((tert- butyldiphenyisilyl)oxy)methyl)-7'-hydroxy

spiro[naphthalene-l,22'-

n]-15'-one 13'.13'-dioxide or (IS^'R^'RJ'S^'E O' / 'Ri^-chloro-lO'-C tert- bulyldipher lsi!> i)oxv)rneih> !)-7'4svdrux> -i2'-nieih> i~3.4-dih> dro-2! U ^' li- spirojnaphihalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetrac clo[14 .21J ³ '^0 ^l ' ² ]pentacosa[8,16.18,24]tetrae n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6 ^, R,7'S,8¾,10'R 2 ^, S)-6-chloro-10'-(((tert- butyldiphenylsilyl)ox )methyl)-7'-hydroxy-12'-me1hyl-3,4-dihydro-2H,15'H spiro[naphthalene-l,22'-

[20]oxa[13]thia[U4]diazatetracy^^

n]-15'-one 13',13'-dioxide as the first elutmg isomer (7 mg, 0.008 mmol.12.3% yield).

Further elution provided (lS,3'R,6'R,7'S.8 ^, E,10 ^, S,12'S)-6-chloro-i0'-(((tert- butyldipheny lsi.iyl)oxy)methyl)-7'-hy droxy- 12'-methy 1 -3,4-dihy dro-2H, 15Ή- spiro [naphthalene- 1 ,22'- [20joxajl3]thia[l,14]diazatetracy ^

n]-15'-one 13'J3*-dioxide or (Ιβ^'Κ,ό'Κ^'β,δ'Ε,ΙΟ'β,^'Κ^ό-άιΙθΓθ-ΙΟ' -ίίίίβΓϋ- but'idiphenylsiiyl)oxy)me l)-7'-hydroxy-12'-methyl-3,4-dihydro-2H,15'H- spiroj naphthalene- 1,22'-

[20]oxail3]ihia[l,14]diazatetrac> lo[14.7 .0 ³ ^0 ^l9 - ²⁴ ]pentacosa[8,i6,18,24]tetrae n]-l 5'-one 13', 13'-dioxide or (1 S,3'R,6'R.7'S,8'E, 10'R, 12'R)-6-chloiO- 10'-tiiiers- buty1diphenylsilyl)oxy)methyl)-7'-hydroxy-12'-methyl-3,4-dih ydro

spiro[naphthalene-l,22'- [20]oxa[13]thia[ 4]diazatetra<yclo[K n]-15 ^* -one 13', 13'-dioxide or (1

but 'lcUphenylsilyl)ox\ niethyl)-7'-hydroxy-12 ^, -methyl-3,4-dihydro-2H,15 ^, H- spiro I naphthalene- 1 ,22'- [20]oxa[13]thia[U4]diazatefra^

n]-15'-one 13',13'-dioxide and (l S,3'R,6 ^! R,7 ^, S,8'E,10'S,12 ^! S)-6~chloro-10 ^! -(((tert- butyldiphenylsilyl)oxy)methyl)-7'-hydroxy-12'-me1hyl-3,4-dih ydro-2H spiro[naphthalene-l,22'-

| 20 jo\aj I |ihi«i| i I 4|dia/aicu a > ciol 14.7 2.(! ^; " O ^{1 '} ' ⁿ jpen!acosa| K. i < .24 jieirae n]-15'-one 13 ^* ,13'-dioxide or (18,3¾,6Ί ;7'8,8Έ, 10'8,12 ^! ί )-6-οωοΐΌ-10'-(((ί6Π- but cUphenylsilyl)ox nie1hyl)-7'-hydroxy-12'-methyl-3,4-dihydro-2H,15'H- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'-dioxide or (l S,31 ,6'R,7'S,8'E,10'R,12'R)-6-chloro-10'-(((tert- butylcUphenylsilyl)oxy)methyl)-7'-hydrox

spiro[naphthalene-l,22'-

[20]oxa[13]thia|;i,14]diazatetracyclo[14;7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24] n]-15'-one 13',13'-dioxide

butyldiphenylsilyl)oxy)me1hyl)-7'-hydroxy-12'-methy]-3,4- dihydro-2H, 15'H- spiro [naphthalene- 1 ,22'- 8.24j teirae n|-15'-one 13', 13'-dioxide as the second eluting isomer (7 mg, 0.008 mmol, 12.3% yield).

STEP 2: (l S,3'R,6'R,7'S,8'E,10'S, 12'S)-6-CHLORO-l()'-(HYDROXYMETHYL)- 7'-METHOXY- 12'-METHYL-3,4-DTHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6 ^! R,7'S,8'E,U ⁾ 'S,12'R)-6-CHLORO-10 ^, -(HYDROXYMETHYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALElSIE- [20]OXA[13]TH1A[1 4]DLZATET1ACYCLO[14;7.2 -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R^'S,8 .;iO¾ 2¾.)-6-CHLORO-10'-(IlYDROXYMETI-IYI.)-7 ^f - METOOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-

1 ">"><-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R 'S,8'EJ0'R 2'S)-6-CHLORO-10'-(HYDROXYMETHYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H 5H-SPIRO[NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO^

[8, 16, 18,24]TETRAEN]-15'-ONE 13 I 3'-DIQXlDE AND

(lS,3'R,6'R;7'S,8'E,l()'S,12'S)-6-CHLORO-l()'-(HYDROXYMEr aYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIROP^APHTHALENE- l. -

|;20]OXA[13iTHIA[l 4jDIAZATETRACYCLO|14 ³ -V0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS 'R,6 ^! R7'S,8'E/U)'S ₅ 12'R)-6 Hl RO-10' HYDROXYMETHYL)-7'- METHOXY-I2'-METOYL-3,4-DIHYDRO-2HJ5'H-SPIRO[NAPHTHALENE- 122'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCI [147 A) ³ -V0 ^!9 - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,10'R,12'R)-6-CHL()RO-1()'-(HYDR()XYME THYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H, 15 'H-SPIRO [N APHTHALENE-

1,22'~

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥΠ:ΤΗΑ(ΎΠ.ϋΙ i 4.7.20 · ^, '.ί ^)|: " ¹ |P1-M ^' AC<)SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(I S,3'R,6'R,7'S,8'E, 1 O'R, 12'S)-6-CHLORO-l 0'-(HYDROXYMETHYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALE E- [20]OXA[13]THlA[l,14]DL\ZATETl ACYCLO[14.7 i) -^0 ¹⁹ - ²⁴ ]PENTACOSA [8.16, 18,24]TETRAENj-15'-ONE 13',13'-DIOXIDE

To a stirred solution of (lS^' -e'^T'S^'aiO'S^TSJ-e-chloro-lO'-^tert- butyldiphenylsilyl)oxy)rnethyl)-7'-hydroxy-12'-methy]-3,4-di hydro-2HJ spiro [naphthalene- 1 ,22'-

n]-15*-one i .V. ! -dioxide or (1 S,3'R,6'R,7'S,8'E,10'SJ2'R)-6-chloro-K

spirojnaphthalene-1,22'-

[20]oxa[13]thia[U4]dazatetrac> Io|; ^

n] - 15'-one 13', 13'-dioxide or (1 S,3'R,6'R,7'S,8'E, 10'R.12'R)-6-chloro- 10'-(((tert- but idipbenyisiiyi)ox> )methyi)-7'-rn ciroxy- 12 ^' -methvi .4-dihyd)'o-2l i.15! I- spiro [naphthalene- 1 ,22'- [20joxajl3]thia[l,14]diazatetracycfo[^^

n]-15'-one 13',13'-dioxide or (1 S,3'R,6 ^! R,7'S,8'E,10'R,12 ^, S)-6-chloro-10'-(((iert- butylctophenylsilyl)oxy)methyl)-7'-hydro^

spiro j naphthalene- 1 ,22'-

n]-15'-one 13',13 ^! -dioxuie and (lS,3'R,6 ^! R,7'S,8'E,10'S.12 ^, S)-6-chloro-10 ^! -(((tert- butyldiphenylsilyl)oxy)methyl)-7'-hyclro^

spiro[naphthalene-l,22'-

[20]oxa[I3]thia[l,I4]diazatelracyclo^

n]-15'-one 13',13'-dioxide or (18.3¾,6Ί ,7'8,8Έ,10'8,12 ^' Κ)-6-ςωοΐΌ-10'-(((ί6Λ- bu1yfcUphenylsilyl)oxy)me l)-7'-hyd

spiro [naphthalene- 1 ,22'-

n]-15'-one 13',13'-dioxide or (Ιβ^'Κ,ό'Κ,Τβ,δΈ,ΙΟ'Κ,Ι^^-ό-οωοΓθ-ΙΟ'-� �ίίΐβιΙ- butyldiphenylsilyl)ox> niethyl)-7'-hydroxy-12'-me1hyl-3,4-dihydro-2H,15 ^, H- spiro[naphthalene-l,22'-

n]-15'-one 13*, 13'-dioxide or (Ι β,Β'Κ,ό'Κ,Τ'β,δΈ, ΙΟ'Κ,

but cUphenylsilyl)ox nie1hyl)-7 ^, -hydroxy-12'-methyl-3,4-dihydro-2H, 15'H- spiro [naph thalene- 1 ,22'- [20]oxa[13]thia[l , 14]diazatetra<yc^

n]-15'-one 13', 13'-dioxide (Example 128, Step 1 , first eluting isomer; 7 mg, 0.008 mmol) in THF (410 μΕ) under a N ₂ atmosphere was added sodium h dride (3.28 mg, 0.082 mmol) and the reaction was stirred at ambient temperature for 1 5 minutes. After this time iodomethane (2.56 uL, 0.041 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was then treated with EtOAc and water. The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated in vacuo to give the desired methyl-ether intermediate. The crude product (9 mg) was dissolved in THF (0.3 mL) and treated with TBAF (Sigma Aldnch, 1 M in THF; 123 μΕ, 0.123 mmol). The reaction was stirred at ambient temperature overnight. After this time the reaction was partitioned between EtOAc and 1M HC1. The separated organic layer was dried over MgS(>4, filtered and evaporated in vacuo. Column chromatography (ca. 2g SiC , DCM:acetone, 1 :0 to 4: 1) gave the title compound as a 70:30 mixture of diastereomers (1.9 mg, 3.02 μηιοΐ, 36.8 % yield).

Analytical data are reported for the major isomer. ^] H NMR (400MHz, CD2CI2) δ 7.71 (d, ./ 8.4 Hz, ! ! ! ). 7.17 (dd, ,/ 2.2. 8.4 FIz, 1H), 7.09 (d, ./ 2.3 Hz, i l l . 6.98 - 6.90 (m, 3H), 5.65 (dd, .7=4.9, 16.2 Hz, IH), 5.48 (ddd, J=2.0, 6.5, 16.4 Hz, H), 4.30 - 4.21 (m, IH), 4.14 - 4.08 (m, 2H), 3.84 (d, J=15.5 Hz, 1H), 3.80 - 3.75 (m, i l l ). 3.71 (dd, ./ 4.3. 10.4 Hz, IH), 3.69 (d, ./ 1 3.5 Hz, IH), 3.50 (dd, ./ 6.7. 10.9 Hz, 1 1 1 ). 3.26 (s, 3H), 3.20 (d, ,/ 1 4 7 Hz, I H), 3.04 (dd, J=9.7, 15.6 H/. IH), 2.85 - 2.69 (m, 2H), 2,52 - 2.38 (m, 2H), 2.32 - 2. 17 (m, 2H), 2,02 (br. s,, IH), 1.98 - 1.90 (m, 2H), 1.78 - 1.59 (m, 5H), 1.52 (d, J=7.0 Hz, 3H), 1.47 - 1.36 (m, IH). MS (ESI, +ve ion) m/z 629.2 (M+H) ⁺ .

EXAMPLE 129. (1 S,3'R,6'R,7'S,8'E, 10'S,12'S)-6-CHLORO-10'- (HYDRO.XYMETHYL)-7'-METHOXY-12'-METHYL-3,443IHYDRO-2H, 15'H~ SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S,8Έ,10 ^, S,12 ^, R)-6-C^^LORO-10 ^, -(HYDROXYME^ΉYL)-7 ^, - METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O'^lPE TACOSA

[8J6,18,24]TETRAEN]~13'~ONE 13', 13 '-DIOXIDE OR

(IS^'R^'R 'S^'EJO'^n'Rj-e-CHLORO-lO'-iHYDROXYMETHYL)-?'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H 5H-SPIRO[NAPHTHALENE- 1,22'-

[20]QXA[13]THIA[U4]DL^

[8,I6,18,24]TETiLAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,l()'R,12'S)-6-CHL()RO-10'-(HYDROXYMET HYL)-7'- METHOXY-12'-METOYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- l. -

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14 ³ -^0 ¹⁹ - ²⁴ ;|PENTA(X)SA [8, 16, 18,24]TETRAEN]-15"-ONE 13', 13'-DIOXIDE AND

(1 S,3'R,6'R,7'S,8'E, lO'S, 12'S)-6-CHLORO-l 0'-(HYDROXYMETHYL)-7'- METHOXY-12'-METOYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 122'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[147 A) ³ -^0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-0NE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,10'S,12'R)-6-CHLORO-1()'-(HYDROXYME� �YL)-7'- METHOXY- 12'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTH ALE E- 1,22'-

|2(>j XA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i.()l i 4.7.20 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-CHLORO- 10'-(HYDROXYMETHYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- [20]OXA[13]TH1A[1,14]DL ZATET1ACYCLO[14;7.2 -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R,7'S,8Έ;0Έ,12'S)-6-CHI RO-10'-(HYDROX^ ^r METHYL)-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O'^lPE TACOSA [8, 16, 18,24]TETRAEN]~15'-ONE 13", 13-DIOXIDE

To a stirred solution of (lS,3 ^, R,6 ^, R,7'S.8 ^, E.10 ^, S ₅ 12 ^, S)-6-chloro-10 ^, -(((tert- butyldiphenylsilyl)oxy)methyl)-7'-hy

spiro[naphthalene-l,22'-

[20]oxa[13]thia[U4]diazatetnK^^

n]-15'-one 13'J3'~dioxide or (18,3Έ,6¾,7Έ,8Έ,10'8,12Έ.)-6-ο1ι1θΓθ-10'-(((ί6ί1 - hutyldiphenylsilyl)oxy)methy

spiro [naphthalene- 1 ,22'- [2C)joxa[13]thia[l,14]diazatetracycf^^

n]-15 ^* -one 13 ^* , 13 '-dioxide or (1 S,3'R,6'R,7'S,8'E,10'R,12'R)-6-Ghloro-10'-(((tert- butylctophenylsilyl)oxy)rnethyl)-7'-hydro

spiro [naphthalene- 1,22'- [20]oxa[13]thia[l,14]cUazatetracyclo|^

n]-15'-one 13',13 ^! -dioxide or (lS 3'R,6'RJ ^! S,8'E ₅ 10'RJ.2 ^! S)-6-chloro-10 ^! ~(((tert- buiyldiphenylsiiyl)oxy)methyl)-7'-hydrox}'--12'-rnethyl-3,4- d spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[U4]cUazatetracyc^

n]- 15'-one ! 3', ! 3'-dioxide and (1 8,3¾,6'Κ,7'8,8'Ε, 10'8, 12'8)-6-Λ1οίΌ-10'-(((ΐ.θΐ1- butyldiphenylsilyl)oxy)rnethyl)-7'-hydroxy-12'-methyl^

spiro [naphthalene- 1 ,22'- [20 joxa[ 13]thia[ l, 14]diazatetracycfo[ 14 _^

n]-15*-one 13', 13'-dioxide or (1 S,3 ^, R,6'R ₅ 7 ^, S,8 ^, E ₅ 10 ^, S, 12 ^, R)-6-chloro- 10 ^, -(((tert- butyldiphenylsiiyl)oxy)niethyl)-7'-hyd

spiro [naphthalene- 1 ,22'-

[20]oxa[ 13] thia[ l , 14]diazatefr^

n]-l 5'-one 13', 13'-dioxide or (1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-chloro- 1 U'-ii i iers- butyldiphenylsilyl)oxy)methyl)-7'-hyclroxy-12'-me1iiyl-3,4-d ihydro^

spiro[naphthalene- l,22'-

n]-15'-one 13*, 13'-dioxide or (18,3¾,6Ί ,7'8,8Έ, 10¾, 12'8)-6-οωοΐΌ-10'-((α6Λ- butyldiphenyisiiyl)oxy ^

spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l , 14]diazatetracyclo[14.7.2.0^

n[-15'-one 13', 13'-dioxide (Example 128, Step 1 , second eluting isomer; 7 mg,

0.008 mmol) in THF (410 μΙ_) under a N?. atmosphere was added sodium hydride (1 mg, 0.025 mmol) and the reaction was stirred at ambient temperature for 15 minutes. After this time iodomethane (1 μΕ, 0.008 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was then treated with EtOAc and water. The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated in vacuo to give the desired methyl-ether intermediate. The crude product (9 mg) was dissolved in THF (0.3 mL) and treated with TBAF (Sigma Aldrich, 1 M in THF; 8 μΕ, 0.008 mmol). The reaction was stirred at ambient temperature overnight. After this time the reaction was partitioned between EtOAc and 1M HCS . The separated organic layer was dried over MgSC¼, filtered and evaporated in vacuo. Column chromatography (ca.2g S1Q2, DCM: acetone, 1:0 to 4:1) gave the title compound as a 3:1 mixture of diastereomers (1.4 mg, 2.23 μιηοΐ, 27.1 % yield). Analytical data are reported for the major isomer. ^l H NMR (400MHz, CD2CI2) δ 8.12 (s, 1H), 7.68 (d, 84 Hz, 1H), 7.16 (dd, .7=2.3, 8.4 Hz, IH), 7.10 (d, J=2.2 Hz, IH), 7.07 - 7.04 (m, IH), 7.03 (d, J=8.0 Hz, IH), 6.92 (d, J=8.4 Hz, IH), 5.82 (dd, J=7.0, 15.8 Hz, IH), 5.47 (dd, ./ 7.2.15.8 Hz, IH), 4.11 (s, 2H), 3.98 (dd, J=6.0, 12.8 Hz, IH), 3.65 (dd, ./ 6.4.10.5 Hz, IH), 3.59 - 3.51 (m, 2H), 3.50 - 3.37 (m, 4H), 3.30 (s, 3H), 2,83 - 2.69 (m, 2H), 2.64 - 2.57 (m, IH), 2,56 - 2.47 (m, IH), 2.46 - 2.22 (m, Hi). 2,13 (ddd, ./ .18.6.0, 15.2 Hz, IH), 1.95 - 1.78 (m, 4H), 1.78 - 1.65 (m, 3H), 1.55 (d, ./ 7.0 Hz, 3H). MS (ESI, +ve ion) m/z 629.2 ( M II) .

EXAMPLE 130. ilS,3'R,6'R,7'S,8'E,l l'R,l 5 ^, S)-6-CHLORO-7'-HYDROXY-ll'- METHYL-3 ₅ 4-DIHΎDRO-2H _s 18Ή-SPIRO[ APH^ΉALENE-l _: ,25 ^, -

|23i()XA| Ι !Ί I . i 7 |Di ΛΖΛΡΙΐΝ ΓΛί YCLO! i 7.7.2.( ϊ ^; ",ο ^{1 !} .ii ^> ' ^' |OCT.\C OSA[8,19,21,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR

(lS,3¾,6¾,7¾,8¾ll'S,15¾)-6~CHLORO-7'-HYDROXY-ll'-METHYL -3,4- D1HYDRO-2H, 18'H-SPIRO [NAPHTHALENE- 1 ,25 '- |;23]()XA[16iTHIA[l,17jDIAZAPENTACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹ l0 ²² -^

OS A| 8, 19,21 ,27]TETRAEN]- 18'-ONE 16',16'-DIOXIDE OR

(1S,3'R,6 ^! R,7'S,8'E,1 l'S,l 5'S)-6~CHLORO-7 ^! ~HYDROXY-l Γ-ΜΕΊΉΥ1,-3,4~ DIHYDRO-2H, 18 Ή- SPIRO [N APHTH ALENE - 1 ,25'-

[23iOXA|;i6]THIA|;i,17]DIAZAPENTACYCL)[17.7.2.0 ^3> ^0 ^!! - ⁱ 0 ²² - ²⁷ ]OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16', 16'-D10XJDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S _s 8¾ll ^, R ₅ 15 ^, R)-6-CHLORO-7 ^, -HYDROXY-ll ^, -METHYL-3,4- DIHYDRO-2H, 18 Ή- SPI RO [ NAPHTHALENE- 1,25'-

[23]OXA[16]THIA[l,.17]DIAZAPENTACYCLO[.17.7.2.0 ³ ' .0 ^ll ' ¹⁵ .0 ²²ⁱ²⁷ ]OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16', 16 ^! -DIOXIDE

STEP 1 : (R)-2-ALLYL l-METHYL-2-

OXOCYCLOPENTANECARBOXYLATE AND (R)-2-ALLYL 1 -METHYL-2- OXOCYCLOPENTANECARBOXYLATE

To a stirred solution of THF (110 mL) under a N ₂ atmosphere was added sodmm hydride (0.972 g, 24.31 mmol). Diailyl adipate (Pfaltz & Bauer, Inc.; 5.00 ml, 22.10 mmol) in THF (30 mL) was then added dropwise via syringe (reaction turns blue as starting material is added) and the reaction was stirred at ambient temperature for 1 hour. After this time the reaction was heated at reflux for 90 minutes. The reaction was then cooled to ambient temperature and iodomethane (1.796 mL, 28.7 mmol) was added dropwise via syringe over 1 minute and the reaction was then heated to reflux for 2 hours. The reaction was then cooled to ambient temperature and partitioned between EtOAc and brine. The separated organic layer was dried over MgS04, filtered and evaporated in vacuo. Column chromatography (8Qg S1O2 , hexanes:EtOAc, 1 :0 to 4: 1) gave (R)-2-allyl I - methyl-2-oxocyclopentanecarboxylate and (S)-2-aliyl l-methyl-2- oxocyclopentanecarboxylate (3.35 g, 18.38 mmol, 83 % yield). STEP 2: (S)-2-ALLYL-2-METHYL-2-CYCLOPENTANONE AND (R)-2- ALLYL-2-METHYL-2-CYCLOPENTANONE

To a solution of (R)-2-allyi l-methyl-2-oxocyclopentanecarboxylate and

(S)-2-allyl l-methyi-2-oxocyclopentanecarboxylate (3.35 g, 18.38 mmol) in THF (36.8 mL) was added palladium(II) acetate (Sigma Aldrich; 0.041 g, 0.184 mmol) and triphenylphosphine (Sigma Aldrich; 0.193 g, 0.735 mmol) and the reaction was heated at reflux under a N ₂ atmosphere for 1 hour. After this time the reaction was cooled to ambient temperature and partitioned between EtzO and brine. The separated organic layer was dried over MgSOt, filtered and evaporated in vacuo. The resulting liquid was purified by short path distillation under house vacuum (ca. 20 mm of Hg) and the fraction boiling at 100-125 °C was collected to (S)-2-allyl-2-methyl-2-cyclopentanone and (R)-2-allyl-2-methyl-2- cyclopentanone (1.4 g, 10.13 mmol, 55.1 % yield).

STEP 3: (lR,2R)-2-ALLYL-2-METHYLCYCLOPENTANOL AND (lS,2S)-2- ALLYL-2-METHYLCYCLOPENTANOL AND (1 R,2S)-2-ALLYL-2- METHYLC YCLOPENT ANOL AND ( 1 S ,2R)-2- ALL YL-2- M

To a stirred solution of (S)-2-allyl-2-methyl-2-cyclopentanone and (R)-2- allyl-2-methyl-2-cyclopentanone (1.12 g, 8.10 mmol) in Et20 (40.5 mL) at -78 °C under a N ₂ atmosphere was added dropwise via syringe a solution of 1-selectride (Sigma Aldrich, 1 M in THF; 8.91 mL, 8,91 mmol). The reaction was stirred at - 78 °C for 2 hours and then it was allowed to wann to ambient temperature for 20 minutes. After this time the reaction was quenched with NH4CI (saturaied aqueous solution) and diluted with EtOAc. The separated aqueous layer was extracted with EtOAc and the combined organic extracts were dried over MgS0 ₄ , filtered and evaporated in vacuo. Column chromatography (24 g S1O2 , hexanes: EtOAc, 1 :0 to 4: 1) gave (lR,2R)-2-ailyl-2-mefliylcyclopentanol and (l S,2S)-2-allyl-2- methylcyclopentanol and (lR,2S)-2-allyl-2-methylcyclopentanol and (l S,2R)-2- allyl-2-methylcyclopentanol (1 g, 7.13 mmol, 88 % yield).

STEP 4: ( 1 R,2R)-2- ALLYL-2- ETHYLC YCLOPENTYL

METHANESULFONATE AND (1 S,2S)-2-ALLYL-2-

METHYLCYCLOPENTYL METHANE S ULF ON ATE AND (lR,2S)-2-ALLYL- 2- METHYLCYCLOPENTYL METHANES UL FON ATE AND (lS,2R)-2- A -2- METHYLCYCLOPENTYL METHANESULFONATE

To a stirred solution of (l R,2R)-2-allyl-2-meth lcyclopentanol and (l S,2S)-2-allyl-2-methylcyclopentanol and (lR,2S)-2-allyl-2-meth lcyclopentanol and (l S,2R)-2-aliyl-2-methylcyclopentanol (1.0 g, 7.13 mmol) in DCM (35.7 mL) at 0 °C under a N ₂ atmosphere was added triethylamine (1.99 mL, 14.26 mmol) followed by methanes ulfonyl chloride (0.72 mL, 9.27 mmol). The reaction was allowed to warm to ambient temperature for 2 hours. After this time the reaction was partitioned between DCM and NaHCOs. The separated organic layer was dried over MgS()4, filtered and evaporated in vacuo. Column chromatography (40 g S1O2 redisep gold, DCM) gave (lR,2R)-2-allyl-2-methylcyclopentyl methanesulfonate and (lS,2S)-2-allyl-2- methylcyclopentyl methanesulfonate and (lR,2S)-2-allyl-2- methylcyclopentyl methaxiesulfonate and (l S,2R)-2-allyl-2- methylcyclopenlyl methanesulfonate (1.24 g, 5.68 mmol, 80 % yield).

STEP 5: 2-(((lS,2R)-2-ALLYL-2-

METOYLCYCLOPENTYL)THIO)PYRJMIDINE AND 2-(((l R,2S)-2-ALLYL- 2-METHYLCYCLOPENTYL)THIO)PYRIMIDINE AND 2-(((l S,2S)-2-

ALL YL-2-METHYLC Y CLOPENT YL)THIQ) YRIM1D1NE AND 2-((( 1 R,2R)- -ALLYL-2-METHYLCYCLOPENTYL)THIO)PYRlMIDINE

To a stirred solution of (lR,2R)-2-allyl-2 -methylcyclopentyl

methanesulfonate and (l S,2S)-2-allyl-2- methylcyclopentyl methanesulfonate and (lR,2S)-2-allyl-2-methylcyclopentyl methanesulfonate and (1 S,2R)-2-allyl-2- methylcyclopentyl methanesulfonate (2.7 g, 12.37 mmol) in DMF (49.5 mL) was added 2-mercaptopyrimidine (TCI Co. ltd.; 1.66 g, 14.84 mmol) and cesium carbonate (2.05 g, 14.84 mmol). The reaction was heated at 60 °C overnight. After this time an additional portion of 2-mercaptopyrimidine (0.5 g) was added and the reaction was heated at 80 °C for 3 hours. After this time an additional portion of 2-mercaptopyrimidine (0.5 g) was added and the reaction was heated at 100 °C for 3 hours. After this time the reaction was cooled to ambient temperature and partitioned between EtOAc and brine. The separated organic layer was dried over MgS( filtered and evaporated in vacuo. Column chromatography (40 g S1O2 , hexanes:EtOAc, 1 :0 to 3: 1) gave 2-(((l S,2R)-2-allyl- 2-methylcyclopentyl)thio)pyrimidine and 2-(((lR,2S)-2-allyl-2- methylcyclopentyl)thio)pyrimidine and 2-(((l S,2S)-2-ailyl-2- methylcyclopentyl)thio)pyrimidine and 2-(((l R,2R)-2-allyl-2- methylcyclopent> )thio)pyrimidine (0.59 g, 2.52 mmol, 20.36 % yield). STEP 6: 2-(((lS,2R)-2-ALLYL-2-

METHYLCYCLQPENTYL)SULFQNYL)PYRIMIDiNE AND 2-(((lR,2S)-2- ALLYL-2-METHYLCYCLOPENTYL)SULFQNYL)PYRIMIDI E AND 2- (((18,28)-2-ΑΙΧΥΙ,-2-ΜΓ^^.€ΥεΕΟΡΕΝΤΥΕ)8υ ΕΤΟΝΥΕ)ΡΥΚΙΜΙΒΙΝΕ AND 2~(((1R,2R)~2-ALLYL~2~

To a stirred solution of 2-(((l S,2R)-2-allyl-2- methyleyclopentyl)thio)pyrimidme and 2-(((lR,2S)-2-allyl-2- methylcyclopentyl)1hio)pyrimidine and 2-(((l S,2S)-2-allyl-2- methylcy clopentyl)thio)pyriirridine and 2-(((l R,2R)-2-allyl-2- methylcyclopent 'l)1hio)pyrirnidine (0.59 g, 2.52 mmol) in DCM (16.78 niL) was added MCPBA (Sigma Aldrich, 77% wt; 1.185 g, 5.29 mmol). The reaction was stirred at ambient temperature for 3 hours. After this time the reaction was partitioned between DCM and NaHCCb. The separated organic layer was dried over MgSC filtered and evaporated in vacuo. Column chromatography (24 g S1O2 , hexanes:EtOAc, 1 :0 to 3: 1 ) gave 2-(((lS,2R)-2-ailyl-2- methylcyclopent\d)sulfonyl)pyrirnidine and 2-(((lR,2S)-2-allyl-2- methylcyclopentyl)sulfonyl)pyrimidine and 2-(((lS,2S)-2-allyl-2- methylcyclopentyl)sulfonyl)pyrimidine and 2-(((lR,2R)-2-allyl-2- methylcyclopentyl)sulfony])pyrimidine (0.19 g, 0.713 mmol , 28.3 % yield). STEP 7: SODIUM (IS ,2R)-2- ALLYL-2-METHYLC YCLOPENTANE- 1 - SULF1NATE AND SODIUM (lR,2S)-2-ALLYL-2- METHYLCY CLOPENTANE- 1 -SULFI ATE AND SODIUM (1 S,2S)-2- ALLYL-2-METHYLCYCLOPENTANE- 1 -SULFIN ATE AND SODIUM (lR,2R)-2-ALLYL-2-METHYLCYCLOPENTANE-l-SULFINATE

To a stirred solution of 2-(((l S,2R)-2-allyl-2- methylcyclopentyl)sulfonyl)pyrimidine and 2~(((1 R,2S)-2-al lyl-2- methylc clopentyl)sulfonyl)pyrimidine and 2-(((l S,2S)-2-allyl-2- methylcyclopentyl)sulfonyl)pyrimidine and 2-(((lR,2R)-2-allyl-2- rnethylcyclopentyl)sulfonyl)pyrimidine (0.19 g, 0.713 mmol) in MeOH (7.13 mL) was added sodium methoxide (Sigma Aldrich, 25% wt; 0.179 mL, 0.785 mmol). The reaction was stirred at ambient temperature for 1 hour. After this time the reaction was evaporated in vacuo and treated with Et ₂ 0. The white solid was triturated with Et?.0, filtered and dried under vacuum to give sodium (l S,2R)-2- ally 1 -2-methylc el opentane- 1 -sulfmate and sodium (1 R,2S)-2~allyl-2- methylcyclopentane-l-sulfinate and sodium (l S,2S)-2-allyl-2- methylcyclopentane-l -sulfinate and sodium (lR,2R)-2-all l-2- methylcyclopentane-l -sulfinate (0. 14 g, 0.666 mmol, 93% yield).

STEP 8: (1 S,2R)-2-ALLYL-2-METHYLCY CLOPENTANE- 1 -SULFONAMIDE AND (lR,2S)-2-ALLYL-2-METHYLCYCLOPENTANE-l -SULFONAMIDE AND (l S,2S)-2-ALLYL-2-METHYLCYCL0PENTANE-l -SULFONAMIDE

~2~ ALLYL-2-METHYLCYCLOPENTANE- 1 -SULFONAMIDE

To a solution of sodium (lS,2R)-2-allyl-2-methylcyclopentane-l-sulfinate and sodium (.lR,2S)-2-ally]-2-methylcyclopentane-l -sul.finate and sodium (lS,2S)-2-allyl-2-methylcyclopentane-l -sulfmate and sodium (lR,2R)-2-allyl-2- methylcyclopentane-1 -sulfmate (0.14 g, 0.666 mmol) in water (6.66 mL) was added sodium acetate (0, 109 g, 1.332 rnmol) and (aminooxy)sulfonic acid (Sigma Aldrich; 0.113 g, 0.999 rnmol) and the reaction was heated at 50 °C for 1 hour. After this time the reaction was cooled to ambient temperature and basified with NaOH. The aqueous layer was extracted with EtOAc (x2), DCM (x2), dried over MgS0 ₄ , filtered and evaporated in vacuo to give (lS,2R)-2-allyl-2- methylcyclopentane-1 -sulfonamide and (lR,2S)-2-allyl-2-methylcyclopentane-l- sulfonamide and (l S,2S)-2-allyl-2-methylcyclopentane-l-sulfonamide and (lR,2R)-2-allyl-2-methylcyclopentane-l .-sulfonamide (0.079 g, 0.389 rnmol, 58,4 % yield ).

STEP 9: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-4-((lR,2S)-l - METHYL-2-SULFAMOYLCYCLOPENTYL)BUT-2-EN-l-

YL)CYCLOBUlYL)METHYL)-3',4,4',5~TETiLAHYDRO-2H,2'H- SPIR()[BENZO I B j [ 1 ,4]OXAZEPHME-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-((( 1 R,2R)-2-((S,E)- 1 -HYDROXY-4-((l S,2R)- 1 - METHYL-2-SULFAMOYLCYCLOPENTYL)BUT-2-EN-l- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-4-((l S,2S)-l- METHYL-2-SULF AMOYLCYCLOPENTYL)BUT-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _! 4HYDRO-2H,2 ^, H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-4-((lR,2R)-l - METHYL-2-S ULFAMOYLCYCLOPENTYL)BUT-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5~TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

A solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, Hspiro[

benzo[b] [ l,4]oxazepine-3, -naphthalene|-7-carbox lic acid (Intermediate AA1A; 100 mg, 0.214 mmol) and (1 S,2R)-2-allyl-2-methylcyclopentane-l -sulfonamide and (lR,2S)-2-allyl-2-methylcy clopentane- 1 -sulfonamide and (I S ,2S)-2-ally 1-2- methy 1 cy clopentane- 1 -sulfonamide and ( 1 R2R)-2-ally 1-2-methy 1 cy clopentane- 1 - sulfonamide (109 mg, 0.534 mmol) in 1,2-dichloroethane (3053 μ.Ε) was degassed for 10 minutes with Ar. After this time a solution of (l ,3-dimesitylirnidazolidin-2- ylidene)(2-isopropoxybenz lidene)ruthenium(VI) chlonde (Sigma Aldnch; 13.39 mg, 0.021 mmol) in DCE (1 mL) was added and the reaction was stirred at ambient temperature for 1 hour. After this time 2 drops of Ti(PriO)4 was added and the reaction was stirred at ambient temperature for 2 hours. After this time the catalyst was deactivated by sparging air through the reaction for 5 minutes. Si0 ₂ (ca. Ig) was added and the mixture was evaporated in vacuo. The product was loaded onto a solid loading cartridge and purified by column chromatography (4 g S1O2, DCM:acetone, 1 :0 to 85: 15) to give (S)-6 ^, -chloro-5-(((lR _s 2R)-2-((S,E)- l-hy(koxy-4-((l R,2S)-l-methyl-2-sulfamoylcyclopentv'l)but-2-en-l- yl)cyclobu1\d)methyl)-3',4,4^5-tetrahydro-2H,2'H-spiro[benzo [b][l ,4]oxazepine- 3, -naphthaleiie]-7-earboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxv'-4-((lS,2R)-l -memyl-2-sulfamoylcyclopentj'l)but-2-en-l- yl)c lobutyl)methyl)-3 4,4 5-tetrahydro-2H,2^spiro[benzo[b][ l,4]oxazepine- 3,1 '-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxy-4-((l S,2S)-1 -methyl-2-sulfamoylcyclopentyl)but-2-en-l - yl)cyclobu1yl)methyl)-34,45-tetrahydro-2H,2'H-spiro[benzob][ l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxy -4-((lR,2R)-l-methyl-2-sulfamoylcyclopen^

yl)cyclobulyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[b enzo[b][l,4]oxazepine- 3, -naphthalene|-7-carboxylic acid (50 mg, 0.078 mmol, 36.4 % yield). The product was azeotroped from toluene (x2) before it was used in the next step. STEP 10: (1S,3'R,6'RJ'S,8'E,1 l'R,15'S)-6-CHLORO-7'-HYDROXY-l 1'- METHYL-3,4-DlHYDRO-2H,l 8'H-SPIRO[NAPHTHALENE-l ,25'- pSlOXAtieiTHIAt^iyiDIAZAPE TACYCLOin-T^-O^^O ^!! -^^^OCTAC QSA[8,19,21,27]TETRAEN]-18'-QNE 16',16'-D10XIDE OR

(1 S,3'R,6'R,7'S,8'E,I l'S,15'R)-6-CHLORO-7'-HYDROXY-l l'-METHYL-3,4- DIHYDRO-2H, 18 Ή- SPIRO [N APHTH ALENE- 1 ,25'-

|2 jOXA| 1 ΙΊ I Ι1Λ| I . i 7|ΠίΛ/.\Ρ1· ΓΛ(ΎΟ.ΟΙ i 7.7.2.ϋ'· ^, '.0 ^{ι ι} · ^ι ·\0 ^,, ·· ^," |Ο(ΎΑ( ^' OS A[ 8, 19,21 ,27]TETRAEN|-18'-ONE 16', 16'-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8^11'S,15'S)-6 ;HI RO-7' iYDROXY-ll'-METI-IYL-3,4- DIHYDRO-2H, 18 Ή- SPIRO [NAPHTHALENE- 1 ,25'- 12 !C)XA| 1 jTl i. i 71 DI ΛΖΛ P!: TAC YC! X>| I 7.7.2.U ^; ''.0 ^{1 u} \o ^{" '"} |ϋί ^* ΎΛί ^' OS A[8, 19,21 ,27]TETRAEN] - 18'-ONE 16',16'-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E, jAR,15 ^, R)-6-CHLORO-7'-HYDROXY-ir-METHYL-3,4- DIHYDRO-2H, 18 Ή- SPIRO [N APHTH ALENE - 1 ,25'-

[23]OXA[16]THIA[1,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]OCTAC OSA[8,19,21 ,27]TETRAEN]-18'-ONE 6',16'-DTOXTDE

To a stirred solution of (S)-6'-chioro-5-(((IR,2R)-2-((S,E)-l-hydroxy-4- ((1 R,2S)- 1 -methyl-2-sulfamoylcyclopentyl)but-2-en- 1 -yl)cy clobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spifo[benzo[b][l,4]oxazepine-3, -naphthalene]-7- carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxy-4-((l S,2R)-I~ methyl-2-sulfamoylcv'clopentyl)but-2-en-l-yl)cyclobutyl)meth yl)-3',4,4',5- tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalen e]-7-carboxylic acid and (S)-6'-ehloro-5-(((lR,2R)-2 (S,E)-l iydroxy

sulfamoylcyclopentyl)but-2-en-l-yl)cyclobutyl)methy

2H,2'H-spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naph thalene] -7-carbox li c aci d and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxy-4-((lR,2R)-l-me thyl-2- sulfamoylcyclopen1y )but-2-en-l-yl)cyclobu1yl)me1hy )-3 ^, ,4,4 ^, ,5-tetrahydro- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (42 mg, 0,065 mrnol) in DCM (32,6 mL) at 0 °C was added DMAP (Sigraa Aldrich; 13,56 mg, 0.111 mrnol), followed by EDC (Oakwood; 25.03 mg, 0.131 mrnol; added portionwise over 2 minutes). The reaction was allowed to warm to ambient temperature overnight. After this time the reaciton was washed with 1M HCl, The separated organic layer was dried over MgS0 ₄ , filtered and evaporated in vacuo. The crude product was combined with the crude product of a previous run (ca.50 mg) and purified by column chromatography (12 g SiO?. redisep gold,

DCM: Acetone, 1:0 to 85: 15) to give the partially purifed title compound as the first eluting isomer (7 mg). This material was further purified by column chromatography (1 g, hexanes:EtOAc (containing 1%ACOH), 1:0 to 1:1) to give (lS,3'R,6¾,7'S,8 ,ll¾,15'S)-6-chioro-7'½droxy-ir-methyl-3,4-dihydro- 211.18'H-spiro[naphthalene- 1 ,25'- [23]oxa[16]tliia[l,17]diazapentacyclo[17.7.2.0 ³ -^0 ⁱⁱ - ^l5 .0 ²² - ² ^octacosa[8,19,21,27]t etraen]-18'-one 16',16'-dioxide or (lS,3'R,6'R,7'S,8 ^! E,irS,15'R)-6-chloiO-7'- hydroxy-l r~methy1~3,4-d^

12 !οχα| I6|thia| i.i7|dia/apentacyclo| 17.7.2.(ί ^;, ·.ίί ^{:: );} .s ⁾ " ' ^" lociacosajH. i ^! >.2i.27|t etraenj-18'-one 16',16'-dioxide or (IS^R^'RJ'S^'EjrSJS'Si-e-chloo-?'- hydroxy -1 l'-methyl-3,4-dihydro-2H,l 8 ^f H-spiro| naphthalene- 1 ,25'- [23]oxa[16]mia[U7]diazapentacyclo[l^^

etraen]-18 ^* -one 16',16'-dioxide or (lS,3'R,6 ^! R,7'S,8'E,irR,15'R)-6-cliloro-7'- hydroxy-ir-methyl-3,4-dihydro-2H,18'H-spiro[naphthalene-l,25 '- [23]oxa[16]thia[ 1, 17]diazapentacydc^^

etraen]-18 ^* -one 16',16'-dioxide (1.8 mg, 0.003 mmol). ^> \\ NMR (400MHz, CD2CI2) δ 7.7 ! (d, Κί, Hz, IH), 7.17 (dd, ./ 23.8.4 Hz, 1H), 7,09 (d, ./ 2.3 Hz, IH), 6.91 id. J=0.8 Hz, 2H), 6.81 (s, IH), 5.86 (ddd, J=6.1, 8.2, 15.1 Hz, Ml). 5.67 (dd, ./ v.I.15.2 Hz, IH), 4.31 (t, J=9.2 Hz, IH), 4.24 (dd, ./ 4.2.9.1 Hz, 1 IT), 4.07 (s, 2H), 3.82 (d, ,/ 15.3 Hz, IH), 3.71 (d, ./ 14.! Hz, IH), 3,20 id. J=14.3 Hz, IH), 3,01 (dd, ./ I0.il 15.5 Hz, IH), 2.85 - 2.67 (m, 2H), 2,48 - 2,29 (m, 3H), 2.28 - 2.14 (m, 3H), 1.99 - 1.89 (m, 3H), 1.88 - 1.76 (m, 3H), 1.74 - 1.68 (m, 2H), 1.67 - 1.61 (m, 2H), 1.55 - 1.45 (m, IH), 1.39 (t,■/ 12.3 Hz, IH), 1.12 (s, Ml). MS (ESI, +ve ion) m/z 625.3 (M il) .

EXAMPLE 131, (1 S,3'R,6'R,7'S,8 ^! E, 11 .15'S)-6-CHLORO-7 ^, -HYDROXY-l 1 '- MEmYL-3,4-DIHYDRQ-2H,18^SPIRQ[NAPHTHALENE-l,25'- pSlOXAIl&ITHIAIl TlDIAZAPENTACYCLOin-T^-O^^O ^!! -^^^OCTAC OS A| 8, 19,21 ,27]TETRAEN]- 18'-ONE ! 6',16'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, S,15'R)-6-CHLORO-7'-HYDROXY-ir-METHYL-3,4- DIHYDRO-2H, 18 Ή- SPIRO [N APHTH ALENE - 1 ,25'- [23iOXA|;i6]THIA|;i,17]DIAZAPENTACYCLO[17.7.2.0 ^3> ^0 ^!! - ⁱ 0 ²² - ²⁷ ]OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16', 16'-D10XJDE OR

(lS,3 ^, R,6'R,7'S,8'E,irS,15'S)-6-CHLORO-7'-HYDROXY-ir-METHYL~ 3,4- DIHYDRO-2H, 18 Ή- SPI RO [ NAPHTHALENE- 1,25'-

[23]OXA[16]TfflA[l,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ^ll ' ^ls .0 ²² " ²⁷ ]OCTAC OS A[8,19,2L27]TETRAEN]-18'-ONE 16', 6'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8¾irR ₅ 15 ^, R)-6-CHLORO-7 ^, -HYDROXY-ir- ETHYL-3,4- DIHYDRO-2H, 18'H-SPIR()[NAPHTHALENE-1 ,25'- pSJOXAtieiTO At^niDIAZAPENTACYCLOtn ^j ^-O^^O ^! ^^^^OCTAC OS A[8, 19,21,27]TETRAEN]-18'-ONE 16', 16'-D10XIDE

The title compound was synthesized as described in Example 120, Step 10 and was isolated as the second eiuting isomer (10 mg). This material was further purified by column chromatography (1 g, hexanes:EtOAc (containing 1% AcOH), 1:0 to 1:1) to give (Ιβ,Β'Κ,ό'Κ,Τβ,δΈ,ΙΓΚ,^'β^ό-ίΛΙθΓθ-Τ^ Γθχγ-ΙΓ-ι ^η βΙ-ΊγΙ- 3,4-dihydro-2H, 18'H-spiro[naphthalene-l ,25'-

12 ! xii! i (>|ihial I. i 7|dia/apemac> cloj 17.7.2.0 ^; ".0 ^{; ; !} " o" Π ο!η α|Κ.19.21.27|i etraen] -18'-one 1 (· ^' .16'-dioxide or (1 S,3'R,6 ^! R,7'S,8 ^! E, 1 l'S.l 5'R)-6-chloro-7'- hydroxy-i -methyl-S^-dihydro^H _j lS'H-spiroInaphthalene-l^S'- [23]oxajl6]thia[l,17]diazapentacydo[17.7.2^

etraen]-! 8 ^* -one 16\16-dioxide or (1S3'R,6'R,7'S,8'E,1 rS,15'S)-6-ch]oro-7'~ hydrox>'-l l ^! -methyl-3,4-dihydro-2H, 18'H-spiro[naph1halene- 1 ,25'- 12 !οχα| I6|thia| i .17|dia/apenlacyclo| 17.7.2.( ·'\0· ^! · ^! ·'·\0· ^{' : '} lociacosajH.19.2i.27|t etraen] -18'-one 6',16'-dioxide or (!S,:m,6¾,7'S,8T l¾,15¾)~6~chloro~7'~ hydroxy-i -methyl-3,4-dihydro-2H,18'H-spiro[naphthalene-l,25'- [23]oxa[16]thia[l,17]diazapentacyclo[17.7.2.0^

etraen]-! 8'-one 16',16'-dioxide (4.0 mg, 0.006 mmol). ^] H NMR (400MHz, CD2CI2) δ 7.69 (d, H4 Hz, III).7.22 - 7.12 (m, 2H), 7,09 (d../ 2.2 Hz, ill). 6,95 (br. s . !H), 6.93 (d, .7=8.2 Hz, 1H), 6.17 (td,«/=7.2, 15.0 Hz, 1H), 5.67 (dd, J=5.1, 15.5 Hz, 1H), 4.18 (t, J=4.7 Hz, lH), 4.12 (s, 2H), 3.89 - 3.81 (m, 1H), 3.61 (d, ./ 14.5 Hz, 1H), 3.52 - 3.32 (m, 3H), 2.85 - 2.71 (m, 2H), 2.62 - 2.53 (m, 2H), 2,51 - 2.46 ins. ill).2,44 - 2.34 (m, 2H), 2,22 (dd, ./ 74.1 .5 Hz, ill).2,00 - 1,93 (m, 2H), 1.9! - 1.82 (m, 4H), 1.80 - 1.72 (m, 4H), 1.56 - 1.46 (m, 2H), 1.04 (s, 311). MS (ESI, +ve ion) m/z 625.3 (M+H) ⁺ .

EXAMPLE 132. (1S,3'R,6'R,7'S,8'E,1 rR,15'S)-6-CHLORO-7'-HYDROXY-l Γ- METHYL-3,4-DIHYDRO-2H,18'H-SPIRO[NAPHTHALENE-l,25'- pSlOXAtieiTHIAIl TJDIAZAPENTACYCLOin ^-O^eo ^!! -^^^OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'~ONE 16', 16'~DiOXiDE OR

(lS,3 ^, R,6 ^, R,7 ^, S.8 ^, E.ll ^, S ₅ 15 ^, R)-6-CHLORO-7 ^, -HYDROXY-ir-METHYL-3,4- DIHYDRO-2H, 18'H-SPIRO[NAPHTHALENE-l ,25*-

[23]OXA[16]THIA[1,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ ' ³⁵ .0 ²² ' ²⁷ ]OCTAC OSA[8,19,21,27]TETRAEN]"18'-ONE 16',16'-D10XIDE OR

(lS,3'R,6'R,7^,8¾irS,15'S)-6-CHLOR()-7'-HYDROXY-ir-METHYL-3 ,4- DIHYDRO-2H,I8'H-SPIRO[NAPHTHALENE-l,25'-

|23!ΟΧΛ| Ι6| Η1Λ| I J7|i ⁾ |,\/.\Pi-::\ ΓΛίΎΠ.ΟΙ i .7.20'·".θ' ^ι · ^ι ·\υ ^,, ·· ^," |0( ^' ΤΛ( ^' OS A[ 8, 19,21 ,27TETRAEN|-18'-ONE 16', 16'-DIOXIDE OR

(lS,3'R ₅ 6 ^, R,7 ^, S,8¾ll ^, R,15 ^, R)-6-CHLORO-7 ^, -HYDROXY-ll ^, -METHYL-3,4- DIHYDRO-2H, 18 Ή- SPIRO [NAPHTHALENE- 1 ,25'-

[23]OXA[16]TH1A[1,17]DIAZAPENIACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹ 0 ²² ^OCTAC OS A8, 19,21 ,27]TETRAEN ]- 18'-ONE 16', 16'-DIOXIDE

The title compound was synthesized as described in Example 120, Step 10 and was isolated as the third eluting isomer (5 mg). This material was further purified by column chromatography (1 g, hexanes:EtOAc (containing l%AcOH), 1:0 to 1:1) to give (18,3ΊΙ,61,7 ^, 8,8Έ,11¾,15'8)-6-ΰωοΐΌ-7'¾^Γθχν-11'-ηΐ6 1- 3,4-dihydro-2H, 18'H-spiro[naphthalene- 1 ,25'-

12 !οχα| I6|thia| i.i7|dia/apentacyclo| 177.2.(ί ^;, ·.ίί ^{:: );} .s ⁾ " ^!" |octaco a!S.19.21.27|t etraen]-18'-one 16',16'-dioxide or (lS,3 ^! R,6'R,7'S,8'E,ll'S,15'R)-6-chlQro-7'- hydroxy-1 r-methyl-3,4-dihydro-2H,18'H-spirofnaphlhalene-l,25'- [23]oxa[16]thia[l,17]diazapentacyclo^^

etraen]-18'-one 16',16'-dioxide or (lS,3'R,6 ^! R,7'S,8'E,irS,15'S)-6"Chloro-7'- hydroxy-ir-methyl-3,4-dihydfo-2H,18'H-spiro[naphthalene-l,25 '-

[23]oxa[16]thia[l,17]diazapentacycto^^

etraen]-18'-one 16',16'-dioxide or (IS,3'R,6'R,7'S,8'E,ll'R,15 ^! R)-6-chloro-7^ hydrox\'-i -methyl-3,4-dihydro-2H,18'H-spiro|naphthalene-l,25'-

etraen]~18'~one 16',16'-dioxide (1.5 mg, 0.002 mmol). ¾ NMR (400MHz, CD2CI2) δ 7.65 (d, J=8.6 Hz, IH), 7.15 (dd, J=2.3, 8.4 Hz, 1H), 7.10 (d, J=2.3 Hz, IH), 6.99 - 6.90 (m, III).6.89 (s, 2H), 5.70 - 5.56 (m, 2H), 4.27 (i, ./ 8.1 Hz, III). 4.16 (br. s .2H), 4.02 (br, s., I Hi.3.61 (d, .7=14.1 Hz, IH), 3.50 - 3,37 (m, 2H), 3.22 (br. :s . IH), 2.82 - 2.70 (m, 3H), 2.62 - 2,52 (m, IH), 2.48 - 2.31 (m, 4H), 1.88 - 1.46 (m, 12H), 1.15 (s, 3H). MS (ESI, +ve ion) m/z 624.8 (M ·!!:· .

EXAMPLE 133. (1 S,3'R,6'R,7'S,8'E,1 rR,15'S)-6-CHLORO-7'-HYDROXY-l 1 '- METHYL-3,4-DIHYDRO-2H,18'H-SPIRO[NAPHTHALENE-l,25'- |23!ΟΧΛ| I6j i HiA| U7|pj,\/.\PH\ f AC VC ! (>! S 77.20' ".O ¹¹ ' J' ^" |()C i AC OSA[8,19,21,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR

(lS,3'R,6'R,7'S,8^11'S,I5'R)-6-CHLORO-7'-IWDROXY-ll'-METH YL-3,4- DIHYDRO-2H, 18'H-SPIRO[NAPHTHALENE-l ,25'-

[23]OXA[16]THLA[l,17]DIAZAPENTACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹ 0 ²² ^OCTAC OSA| 8,19,21,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR

(lS,3'R,6 ⁱ R,7'S,8'E,irSJ5'S)-6-CHLORO-7'-HYDROXY-l '-METHYX-3,4- DIHYDRO-2H, 18 Ή- SPIRO [N APHTH ALENE- 1 ,25 ^s -

|2 jOXA| 16ΙΊ !!1Λ| Ι.Ι7|! !Λ/ΛΡ1 ^: Ν ί \( ^' Υ( ..()Ι Ι7.7.2.0 ·'.ί) ^{η !} \0 ^Λ |Οί Λ( ^' OSA[8,19,21 ,27]TETRAEN]-18'-ΟΝΕ 16',16'-DIOXIDE OR

(lS^'R^'R^'S^'E,! l'R,15'R)-6-CHLORO-7 ^f -HYDROXY-l l'-METHYL-3,4- DIHYDRO-2H, 18'H-SPIRO[NAPHTHALENE-l ,25'-

[23]OXA[16]TH1A[1,17]DIAZAPENTACYCLO[17.7.2 ³ -^0 ¹¹ - ¹ 0 ^2Z27 ]OCTAC OS A 8, 19,21 ,27]TETRAEN ] - 18'-ONE 16', 16'-DIOXIDE

The title compound was synthesized as described in Example 120, Step 10 and was isolated as the third eluting isomer (6 mg). This material was further purified by column chromatography (1 g, hexanes:EtOAc (containing l%AcOH), 1:0 to 1:1) to give (lS,3 ^, R,6'R,7 ^! S,8¾,ll¾,15 ^, S)-6-cliloro-7 ^, -hydi xy-ll'-methyl" 3,4-dihydro-2H, 18'H-spiro|naphthalene-l ,25'- [23]oxa[16]thia[l,17]diazapen^

etraen]-18'-one 16',16'-dioxide or (18,3Ί ,6¾,7'8,8Έ,1Γ8,15¾)-6~ΰΜθΓθ-7 ^! " hydroxy-i -methyi-3,4-dihydro-2H,18'H-spiro|naphthalene-l,25 ^! - ^{; !} · ^: o" ' eiacohiiiS.i ^l >.2l.27|i etraen]- 8'-one 6 ^! ,16'-dioxide or (lS,3'R,6 ^! R,7'S,8 ^! E,ll ^! SJ5'S)-6-chloro-7'- hydiOxy-ir-methyi-3,4-dihydro-^

12 joxaj 16|ihi«i| i . I 7|dia/apcniacvck)| ! 77.2.0 ^; '·. ⁽⁾ " ^j ". - ^" |« iacosai 8. ! 9. 1.2? |i etraen]-18'-one

hydrox\'-ir-methyl-3,4-dihydro-2H,18'H-spiro[naphthalene- l,25'- [23]oxa[16]thia[l,17]diazapenta(yc^

etraen]-18'-one 6',16'-dioxide (2,5 mg, 0.004 mmol). TINMR (400MHz,

CD2CI2) δ 7.72 (d, J=8.6 Hz, IH), 7,28 (dd, J=2.0, 8.2 Hz, IH), 7.17 (dd, J=2,3, 8.4 Hz, IH), 7.09 id../ 2.2 Hz, IH), 6.96 id../ 8,2 Hz, IH), 6.74 (br. s., Ml).6.20

52,9 (br, s.. III).5.67 (dd, J=7.9, 15.2 Hz, ill).4, 18 (dd, ./ 3.18.0 Hz, 111).4.09 (s, 2H), 3.85 (br. s., IH), 3.77 (dd, J=2.2, 14.8 Hz, 1H), 3.74 (d, J=14.5 Hz, IH), 3.37 (d, ./ 14.5 Hz, ill .3.11 (dd, ./ 10.9.15.4 Hz, 1H), 2.86 - 2,70 (m, 3H), 2.58 - 2,46 (m, IH), 2.46 - 2.24 (m, 4H), 1.97 - 1.90 (m, 2H), 1.86 - 1,74 (m, 5H), 1.74 - 1.68 (m, 2H), 1.67 - 1.62 (m, 2H), 1.46 - 1.38 (m, IH), 1.11 (s, 3H), MS (ESI, +ve ion) m/∑ 624.8 (M+H) ⁺ .

EXAMPLE 134. (lS,3'R,6'R,7'S,8 ^! E,10 ^! S,13'R)-6-CHL()RO-7'-HYDR()XY-3,4- DIHYDRO-2H,17'H-SPIRO[NAPHTHALENE-l,24'-

[22]OXA[15]THIA[1,16]DIAZAPENTACYCLO[16.7.2.0 ³ ' ⁶ .0 ¹⁰ ' ³⁵ .0 ²¹ ' ²⁶ ]HEPTA CQSA[8,18,20,26]TETiAEN]--17'-QNE 15',15'-D10XIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,13'S)-6-CHLORO-7'-HYDROXY-3,4-DIHYD RO- 2H, 17'H-SPIRO[NAPHTHALENE- 1 ,24'-

|22!ΟΧΛ| i^l lHl Al I J6|i)l.\/.\Pi-::\ i ACVCi.Ol 16.7.20' ".i) ^{ln 1 :} .ί ^; ' ^! '|! !S:PTA COS A[8 ₅ l 8,20,26] TETRAEN]-! 7'-ONE 15', 15'-DIOXIDE

STEP 1: ( 1 R,2R)-CYCLOB UTANE- 1 ,2-DIYLDIMETHANOL AND (1S,2S)~ C YCLOBUTANE - 1 ,2-DIYLDIMETHANOL

Trans- 1,2-cyclobutanedicarboxy lie acid (Synthon; 5 g, 34.7 mmol) in THF (34.7 mL) was transferred into a 3 neck round bottom flask fitted with an addition funnel, nitrogen inlet and thermometer and the flask was cooled to 0 °C. Borane tetrahydrofuran complex (Sigma Aldrich, 1M in THF; 83 mL, 83 mmol) was then cannulated into the addition funnel. The borane tetrahydrofuran complex was then added into the stirred cooled mixture dropwise over 15 minutes (hydrogen gas evolved rapidly). After the addition was completed the reaction was allowed to warm to ambient temperature overnight under a N ₂ atmosphere. After this time the reaction was treaied with MeOH (50 mL) and then the mixture was trasferred to a 500 mL flask and evaporated in vacuo. The solution was taken back up in MeOH and concentrated again. This process was repeated 3 times. The final clear grey oil was kept under vacuum for 3 hours to give (lR,2R)-cyclobutane- 1,2-diyldi methanol and (l S,2S)-cyclobutane-l ,2-diy]dimethanol (3.5 g, 30.1 mmol, 87 % yield).

STEP 2: ((lR,2R)-2-(((TERT-

BUTYLDIMETHYLSILYL)OXY)METHYL)CYCLOBUTYL)METHANOL AND (( 1 S ,2 S)-2-(((TERT-

BUTYLDIMETHYLSILYL)OXY)METHYL)CYCLOBUTYL)METHANOL

To a suspension of sodium hydride (0.861 g, 21.52 mmol) in THF (86 mL) at 0 °C under a N ₂ atmosphere was added a solution of (lR,2R)-cyelobutane-l,2- diyldimethanol and (lS,2S)-cyclobutane-l,2-diyldimethanol (2.5 g, 21.52 mmol) in THF (20 mL) dropwise over 20 minutes. After this time the reaction was heated at 55 °C for 45 minutes and then it was cooled down to 0 °C and treated with a solution of TBS-C1 (Sigma Aldnch; 3.24 g, 21.52 mmol) in THF (15 mL). The reaction was stirred at ambient temperature overnight. After this time the reaction was quenched with NH ₄ C1 (sat. aq. solution) and diluted with EtOAc. The separated aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over MgSO*, filtered and evaporated in vacuo. Column chromatography (80 g Si0 ₂ , hexanes: EtOAc, 1 :0 to 4: 1) gave ((l R,2R)-2-(((tert-butyldimemylsilyl)oxy)methyl)cv'clobutyl)rne thanol and ((l S,2S)-2-(((tert-bu ddimethylsilyl)oxy)me1hyl)cyclobut ' ^, l)methano] (3.45 14.97 mmol, 69.6 % yield).

STEP 3: ((lR,2R)-2-(((TERT-

ΒυΤΥΕΟΙΜΓ^1ΥΕ8Π.,ΥΙ,)ΟΧΥ)ΜΕΤΗΥΕ)� �Υ€ΕΟΒυΤΥΐ )ΜΕΤΪ-ΙΥΕ METHANE SULFONATE AND ((lS,2S)-2-(((TERT- BLiTYLDlMETHYLSILYL)OXY)METHYL)CYCLOBLiTYL)METHYL METHANESULFONATE To a stirred solution of ((1 R,2R)-2-(((iert- but 'ldimethylsilyl)oxy)methyl)c\'clobutyl)rnethanol and ((1 S,2S)-2-(((tert- butyldimethylsilyl)oxy)methyl)cyclobutyl)inethano3 (3.45 g, 14.97 mmol) in DCM (74.9 mL) at 0 °C was added iriethylarame (3.13 ml,, 22.46 mmol) followed by methanesulfonyl chloride (1.283 mL, 16.47 mmol). The reaction was stirred at ambient temperature for 2 hours. After this time the reaction was transferred to a separating funnel and succesivelv washed with 1M HCI, NaHCCb and brine. The separated organic layer was dried over MgSi filtered and evaporated in vacuo to give ((lR,2R)-2-(((tert-butyldimethylsilyl)oxy)memyl)c^xlobut\'l) methyl methane sulfonate and ((lS,2S)-2-(((tert-buty dimethylsiiyl)oxy)meihyl)cycIobutyl)meihyl methanesuifonate (4.15 g, 13.45 mmol, 90% yield).

STEP 4: ((l R,2R)-2-(((l-PHENYL-lH-TETRAZOL-5- YL)THIO)METHYL)CYCLOBUTYL)METHANOL AND ((1 S,2S)-2-(((l- PHENYL-1H-TETRAZOL-5- YL)THIO)METHYL)C Y CLOBU TYL)METH ANOL

EtOH (45 mL) was degassed by sparging Ar(g) through for 30 minutes. 1- phenyl-lh-tetrazole-5-thiol (Sigma Aldrich; 4,79 g, 26.9 mmol) in the previously degassed EtOH (25 mL) under a N ₂ atmosphere was treated with sodium ethoxide (Sigma Aldrich, 21% in EtOH; 7.53 mL, 20.18 mmol) and the mixture was stirred at ambient temperature for 30 minutes. After this time a solution of ((lR,2R)-2- (((tert-butyldimethylsilyl)oxy)methyl)cyclobut 'l)methyl methane sulfonate and ((l S,2S)-2-(((tert-but\'ldimethylsilyl)oxy)methyl)cyclobutyl)me thyl

methanes ulfonate (4.15 g, 13.45 mmol) in degassed EtOH (20 mL) was added dropwise via syringe and the mixture was stirred at ambient temperature over the weekend. After this time the reaction was heated at 60 °C for 3 hours. After this time the reaction was cooled to ambient temperature and the mixture was concentrated in vacuo. The residual material was partitioned between ethyl acetate and brine. The brine layer was back-extracted with ethyl acetate and the combined organics were then dried over magnesium sulfate, filtered, and evaporated in vacuo. Column chromatography (40 g S1O2, hexanes: EtOAc, 1 :() to 1 : 1) gave ((lR,2R)-2-(((l-phenyl-lH-tetrazol-5- yl)thio)memyl)cyclobutyl)methanol and ((l S,2S)-2-(((l-phenyl-lH-tetrazol-5- yl)thio)methyl)cyciobutyi)methanol (2.0 g, 7.24 mmol, 53.8 % yield).

STEP 5 : (( 1 R,2R)-2-((( 1 -PHENYL- lH-TETRAZOL-5-

YL)SULFONYL)METHYL)CYCLOBUTYL)METHANOL AND ((1 S,2S)-2- (((1 -PHENYL-1 H-TETRAZOL-5-

YL)SULFONYL)METHYL)CYCLOBUTYL)METHANOL

To a stirred solution of ((lR,2R)-2-(((l-phenyl-lH-tetrazol-5- yl)thio)methyl)cyclobutyl)methanol and ((1 S,2S)-2-(((l-phenyl-lH-tetrazol-5- yl)thio)memyl)cyclobutyl)methanol (0.5 g, 1.809 mmol) in toluene (3.29 mL) and water (0.329 mL) was added phenylphosphonic acid (Sigma Aldrich; 0.029 g, 0.181 mmol), tetrabutylammonium sulfate (Sigma Aldrich, 50 wt. % solution in water; 0.210 mL, 0.181 mmol), sodium tungstate dihydrate (Sigma Aldrich; 0.060 g, 0.181 mmol) and hydrogen peroxide (0.462 mL, 4.52 mmol). The reaction was stirred overnight at 40 °C. After this time the reaction was cooled to ambient temperature and partitioned between EtOAc and Na ₂ SC . The separated aqueous layer was extracted with EtOAc and the combined organic extracts was washed with Na ₂ S03, brine, dried over MgSC>4, filtered and evaporated in vacuo. Column chromatography (24 g SiCte, hexanes: EtOAc, 1 :0 to 2: 1) gave ((lR,2R)-2-(((l- phenyl-lH-tetrazol-5-yl)sulfonyl)methyl)cyclobut 'l)methanol and ((lS,2S)-2- (((l-phenyl-lH-tetrazol-5-y])sulfonyl)memyl)cyclobutyl)metha nol (0.42 g, 1.362 mmol, 75 % yield).

STEP 6: 2-((((l R,2R)-2-(((l -PHENYL-1 H-TETRAZOL-5- YL SULFONYL)METTTY ^' L)CYCLOBUTYL)METTTY ^' L)THIO)PYRJMIDINE

AND 2-((((18,28)-2-(((1-ΡΗΕΝΥΤ-1Η-ΊΈΊ^ ΖΟί-5~

YL)SULF L)M IDlNE

A dry- flask containing a stir bar was charged with triphenylphosphine (Sigma Aidnch; 196 mg, 0.746 mmol) and the atmosphere was replaced with Ar and degassed toluene (6486 uL) was added. The solution was cooled to -5 °C in an ice brine bath. Diethyl azodicarboxylate (Sigma Aldrich, 40 wt.% solution in toluene; 294 uL, 0.746 mmol) was then added dropwise over 1 minute and the reaction was stirred for 10 mm. at -5 °C. After this time (( lR,2R)-2-(((l -phenyl- lH-tetrazol-5-yl)sulfonyl)methyl)cyclobu1yl)methanol and ((1 S,2S)-2-(((l - phenyl- lH-tetrazol-5-yl)sulfonyl)methyl)cyclobutyl)methanol (200 mg, 0.649 mmol) in toluene (2.5 mL) was added and the reaction was stirred at -5 °C for 5 minutes. After this time 2-mercaptopyrimidine (Sigma Aldrich; 84 mg, 0.746 mmol) in THF (1.5 mL) was added over 2 minutes in 2 portions. The reaction was stirred at -5 °C for 3 hours. After this time the reaction was then quenched by addition of pH 7 buffer and the mixture was diluted with EtOAc. The separated aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgS€>4, filtered and evaporated in vacuo. Column chromatography (12 g SiO?., hexanes: EtOAc, 1 :0 to 4: 1) gave 2-((((lR,2R)-2-(((l- phenyl-lH-tetrazol-5-yl)sulfonyl)methyl)cyd and 2-((((l S,2S)-2-(((l-phenyl-lH-tetrazol-5- yl)sulfonyl)m.ethyl)cyclobuiv4)methyl)thio)pyrimidine (200 mg, 0.497 mmol, 77 % yield).

STEP 7: (S)-METHYL 5-(((lR,2R)-2-((S)-l -

((TERTBUTYLDIMETHYLSILYL)OXY)ALLYL)CYCLOBUTYL)METHYL)- 6'-CHLORO-3 4,4^5-TCTRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l '-NAPHTHALENEl-7- CARBOXYLATE

To a 250 mL flask which had been charged with an oven-dried stir bar was added (S)-methyl 6 ^! "Chloro-5-(((lR,2R)-2-((S)-l- hydroxya31yl)cyciobutyi)methyl)-3',4,4',5-tetrahydro- 2H,2'Hspiro[benzo[b] [l,4]oxazepine-3,l '-naphthalene]-7-carbox ' ^, late

(Intermediate AA11A, Step 21 ; 8,77 g, 18. 19 mmol). The atmosphere was replaced with nitrogen and the starting material was dissolved in anhydrous DCM (100 mL). 2,6-iutidine (5.4 mL; 46.6 mmol) was added and the solution was cooled to -5 °C. Tert-butyldimethylsilyl trifluoromethanesulfonate (Aldtich; 5.0 mL, 21.77 mmol) was added dropwise over the course of seven minutes via syrmge. After 1 hour the mixture was quenched by the addition of saturated sodium bicarbonate (20 mL) and the mixture was partitioned between DCM and saturated sodium bicarbonate. The aquous layer was back-extracted twice. The combined organics were washed with 10% citric acid, water, brine and dried over magnesium sulfate, filtered, and stripped in vacuo to give the crude product. This material was further purified by flash chromatography on a 330 g isco Gold silica column eluted with 0 to 20% EtOAc (containing l%AcOH) in heptanes providing (S)-methyl 5-(((l R,2R)-2-((S)-l -

((tertbu ddimethylsilyl)oxy)allyl)c lobu d)methyl)-6'-chloro-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (5 g, 8.39 mmol, 46% yield).

STEP 8: (S)-METHYL 5-(((lR,2R)-2-((lR,2R)-l -((TERT- BUT YLDIMETHYL S IL YL)OXY)-2, 3 -

DIHYDROXYPROPYL)CYCLOBUTYL)METHYL)-6'-CHLORO-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4] OXAZEPINE-3, Γ-

NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 5-(((lR,2R.)-2- ((lR,2S)-l ( ERT-BUTYLDIMETHYLSILYL)OXY)-2 ₅ 3-

DIHYDROXYPROPYL)CYCLOBUTYL)METHYL)-6'-CHLORO-3 ^! ,4,4',5- TETRAHYDRO-2H,2 ^f H-SPIRO[BENZO[B][l,4]OXAZEPiNE-3, l '- NAPHTHALENE] -7-CARBOXYLATE

Osmium tetroxide (Sigma Aldrich; 0. 132 ml, 0.419 mmol) was added to a stirred triphasic mixture of (S)-methyl 5-(((lR,2R)-2-((S)-l-((tert- bulyldiinethylsilyl)Qxy)alIyl)cy^

2H,2'Hspiro[benzo[b] [1 ,4]oxazepine-3, l'-naphthalene]-7-carboxylate (5 g, 8.39 mmol) and NMO (Sigma Aldrich; 3.93 g, 33.5 mmol) suspended in acetone (55.9 mL) and water (28.0 mL). The mixture was stirred at ambient temperature overnight. After this time an additional portion of NMO (0.4g) and Os04 (O.Olg) was added followed by THF (50 mL) and tBuOH (15 mL). The mixture was stirred at ambient temperature for 3 hours. After this time the reaction was quenched by addition of solid sodium sulfite in water and the mixture was stirred at ambient temperature for 1 hour. After this time the reaction was partitioned between EtOAc and saturated sodium sulfite. The aqueous layer was back- extracted with EtOAc and the combined organics were washed with citric acid (15%), saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to give the crude product. Column

chromatography (120 g S1O2, hexanes:EtOAc, 1 :0 to 3: 1) gave (S)-methyl 5- (((lR,2R)-2-((lR,2R)-l-((tert-butyldimethylsilyl)oxy)-2,3- dihydroxypropyl)cyclobu d)methyl)-6'-chloro-3\4,4^5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylate and (S)-methyi 5- (((1 R,2R)-2-((l R,2S)- 1 -((tert-buly ldimethylsilyl)oxy)-2,3- dihydroxj^ropyl)cyclobutyl)methyl)-6'-chloro-3 4,4 5-tetrahydro-2H,2H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox>date (4.6 g, 7.30 mmol, 87 % yield) as a white solid. STEP 9: (S)-METHYL 5-(((lR,2R)-2-((R)-l- ((TERTBUTYLDlMETHYLSILYL)OXY)-2- OXOETHYL)CYCLOBUTYL)METHYL)-6'-CIiLORO-3 ^, ₅ 4.4 ^, ,5- TETRAHYDRO-2H,2 ^* HSPIRO [BENZO [B] [1 ,4] OX AZEPINE-3 , 1 '- NAPHTHALENE] -7~C ARBOXYLATE

To a stirred solution of (S)-methyl 5-(((lR,2R)-2-((lR,2R)-l-((tert- butyldimethylsilyl)oxy)-2,3-dihydroxypropyl)cyclobutyl)methy l)-6'-chloro- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate and (S)-methyl 5-(((lR,2R)-2-((lR,2S)-l-((tert- but cUmethylsilyl)oxy)-2,3-dihydroxypropyl)cj ⁷ clobutyl)methyl)-6 ^, -chloro- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphtha]ene]-7- carboxylate (600 mg, 0.952 mmol) in THF (4760 uL) and water (4760 μΕ) was added sodium periodate (Sigma Aldrich; 814 mg, 3.81 mmoi) in one portion. The reaction was stirred at ambient temperature for 90 minutes. After this time the reaction was treated with an additional portion of sodium periodate (270 mg) and the mixture was stirred at ambient temperature for 30 minutes. After this time the reaction was partitioned between EtOAc and water. The separated aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgS0 ₄ , filtered and evaporated in vacuo to give (S)-methyl 5- (((lR,2R)-2-((R)-l-((tert-butyldimemylsilyl)oxy -2-oxoe1hyl)c 'clobutyl)methyl)- 6'-chloro-3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene]-7-carboxylate (400 mg, 0.669 mmol, 70.2 % yield) as a white solid. STEP 10: (S)-METHYL 5-(((lR,2R)-2-((S,E)-l-((TERT-

BUTYLDIMETHYLSILYL)OXY)-3-((l S,2R)-2-((PYRIMIDlN-2- YLTHIO)METHYL)CYCLOBUT L)ALLYL)CYCLOBUTYL)METHYL)-6'- CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S,E)-l- ((TERT-BUTYLDIMETOYLSII^ _J )OXY)-3-((l R,2S)-2-((PYRIMIDIN-2- YLTHIO)METHYL)CYCLOBUTYL)ALLYL)CYCLOBUTYL)METHYL)- 3' _; 4' ₅ 5-TETl AHYDRO-2H,2'H~SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S,Z)- 1 -((TERT-BUTYLDIMETHYLSILYL)OXY)-3 -(( 1 S,2R)-2~ ((PYRIMIDIN-2- YLTOI0)METHYL)CYCL0BUTYL)ALLYL)CYCL0BU1YX)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 "- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S,Z)- l-((TERT~BUTYLDlMETHYLSILYL)OXY)-3-((lR,2S)-2- ((PYRIMID1N-2- YLTHIO)METHYL)CYCLOBU L)ALLYL)CYCLOBU L)METHYL)- 3 ^, ,4 ₅ ^, ,5-TETRAHYDRO-2H,2Ή-SPIRO[BENZO[B][l,4]OXAZEPINE-3,l ^, -

NAPHTHALENE] -7-CARBOXYLATE

To a stirred solution of 2-((((l R,2R)-2-(((l -phenyl- lH-tetrazol-5- yl)sulfonyl)me1hyl)cyclobu1\d)methyl)thio)pyriiTiidine and 2-((((l S,2S)-2-(((l - phenyl-lH-tetrazoi-5-yl)sulfonyl)methyi)cyclobut )methyl)thi

(Example 134, step 6; 50.5 nig, 0.125 mmol) in THF (1.0 mL) was added 18- crown -6 (Sigma Aldrich; 66.3 rag, 0.251 mrnol) and the mixture was cooled to -78 °C under a ^' N ₂ atmosphere. The mixture was then treated with KHMDS (Sigma Aldrich, 1 M in THF; 125 μ.Ε, 0.125 mrnol) dropwise over 2 minutes (rxn turns yellow) and the mixture was stirred at -78 °C for 35 minutes. After this time a solution of (S)-methyl 5-ίίί i R .2R )-2-{{ R }- 1

oxoethyl)cyciobut5 _' l)methyl)-6'-chloro-3',4,4',5-tetrahydro- 2H,2'Hspiro[benzo[b] [ 1 ,4 ] oxazepine-3, 1 '-naphthalene] -7-carboxy late (75 mg, 0.125 mrnol) in THF (1.5 mL) was added dropwise via syringe over 2 min and the mixture was stirred at -78 °C for 90 minutes. After this time the mixture was quenched at -78 °C with NH4CI (sat. aq. solution) and diluted with EtOAc and water and allowed to warm to ambient temperature. The separated organic layer was dried over MgS04, filtered and evaporated in vacuo. Column

chromatography (12 g S1O2, hexanes: EtOAc, 1 :0 to 85: 15) gave a ca. 5: 1 mixture of (S)-methyl 6'-ch3oro-5-(((lR,2R)-2-((S,E)-l-((tertbutyldimethylsiiyl)ox y)-3- ((i S,2R)-2-((pyriniidin-2-ylthio)m

3 4,4',5-tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r-nap hthalene]-7- carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l- ((tertbut ddimethylsilyl)oxy)-3-((lR,2S)-2-((pyrimidin-2- ylmio)me l)c lobund)allyl)cyclobur\ )methyl)-3^4,4^5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-methyl 6'- cWoro-5-(((lR ₅ 2R)-2-((S,Z)-l-((tertbutyldimethylsilyl)oxy)-3-((l S,2R)-2- ((pyriiradin-2-yUhio)methyl)cyclobutyl)allyi)cyclobuty

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,Z)-l -((tertbutyldimethylsilyl)oxy)-3- ((l R,2S)-2-((pyrirrudin-2~ylthio)m

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine-3, -naphthalene]-7- carboxylate (23 mg, 0.030 mrnol, 23.69 % yield).

STEP 1 1 : (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -

((TERTBUTYL;DIMETHYLSILYL)0XY)-3-((1 S,2R)~2-((PYRJMIDIN YLSULFONYL)METHYL)CYCLOBUTYL)ALLYL)CYC OBUTYL)METHY L)~3\4,4^5-TETl AHYDRO-2H,2'H"SPIRO[BENZO[B] [ l,4]OXAZEPINE-3;r- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((l R,2R)-2-((S,E)-l-((TERTBUTYLDIMETFfYLSILYL)OXY)-3-((l R,2S)-2- ((PYRJMIDIN~2-

YLSULFONYL)METHYL)CYCLOBUTYL)ALLYL)CYCLOBUTYL)METHY

NAPHTHALENE] -7-CARBOXYLATE AND (S)-METH X 6'-CHLORO-5- (((lR,2R)-2-((S,Z)-l-((TERTBUTYLDIMETHYLSILYL)OXY)-3-((lS,2R )-2- ((PYRIMIDIN-2-

YLSULFONYL)MEraYL)CYC OBU L)ALLYL)CYCLOBU L)METFTY L)-;r,4 4^5-TEl¾AHYDRO-2H,2H-SPlRO[BENZO[B] [l,4]OXAZEPlNE-3,r- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S,Z)-l-((TCRTBUTYLDIMETHYLSILYL)OXY)-3-((lR,2S )-2- ((PYRIMIDIN-2-

YLSULFONYL)METHYL)CYCLOBL YL)ALLYL)CYCLOBUTYL)METHY L)-3 4,4 5-TETRAHYDRO-2H,2'H-SPIR()[BENZO[Bi [ l,4jOXAZEPINE-3J '- NAPHTHALENE] -7-CARBOXYLATE

To a stirred solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l- ((tertbutyldimethylsilyl)oxy)-3-((lS,2R

ylthio)nieihyl)cyclobuty¾

spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((l R,2R)-2-((S,E)-l-((tertbutyldimethylsilyl)oxy)-3-((lR,2S)-2- ((pyrimidin~2~ylthio)methy

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,Z)-l -((tertbutyldimethylsilyl)oxy)-3- ((l S,2R)-2-((pyrimidin-2-ylthio)methyl)cj ⁷ clobutyl)allyl)cyclobutyl)me1hyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r -naphthalene]-7- carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S _s Z)-l- ((tenbuty3dimethyisiIyl)oxy)-3-((lR,2S)-2-((pyriinidin-2- ylthio)methyl)cyclobutyl)allyl)cyd^

spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carbox\'late (57 nig, 0.074 mmol) in toluene (1338 \L) and water (134 μί,) was added sodium tungstate dihydrate (Sigma Aidrich; 2.427 mg, 7.36 fimol), phenylphosphonic acid (Sigma Aidrich; 0.819 μί_,, 7.36 umol), tetrabutyl ammonium sulfate (Sigma Aidrich, 50 wt. % solution in water; 8.55 \L, 7.36 umol) followed by hydrogen peroxide (18.79 0.184 mmol). The reaction was stirred at ambient temperature for 1 hour. After this time an additional portion of phenylphosphonic acid (0.819 L, 7.36 μηιοΐ), sodium tungstate dihydrate (2.427 mg, 7.36 μηιοΐ) and hydrogen peroxide (18.79 uL, 0.184 mmol) was added and the reaction was heated at 60 °C for 4 hours. After this time the reaction was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NaaSCb, The separated aqueous layer was extracted with EtOAc and the combined organic extracts were washed with Na?.S03, dried over MgSC filtered and evaporated in vacuo. The crude material was combined with that from a previous run and purified by column

chromatography (4 g SiC , hexanes:EtOAc, 1 :0 to 4: 1) to give (S)-methyl 6'~ cMoro-5-(((lR,2R)-2^(S,E)-l-((tertb^

((pyriiradin-2-ylsidfony tetrahydro-2H,2^spiro[benzo[b] [l ,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l -((tertbutyldimethylsilyl)oxy)-3- ((l R,2S)-2-((pyrimidin-2-ylsulfonyl)methyl)cyclob^

3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphtha]ene]-7- carboxylate and (S)-methyl 6'- 1 -5-{ { { I K .2R)-2-ii S./.)- i - ((tertbutyldimethylsilyl)oxy)-3-((l S,2R)-2-((pyrimidin-2- ylsulfonyl)methyl)cyclobutyl)allyl)cyclobuty^^

2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((lR,2R)-2-((S,Z)-l -((tertbu ^' h'ldime1hylsilyl)oxy)-3-((lR,2S)- 2-((pyrimidin-2- ylsulfonyl)methyl)cyclobutv'l)allyl)c} ⁷ clobutyl)niethyl)-3 ^, ,4,4',5- tetTahydro-2H,2^spiro[benzo[b] [ l,4]oxazepine-3,r-naphthalene]-7-carboxylate (50 mg, 0.062 mmol).

STEP 12: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S,E)- l - (( ERTBUTYLDIMETHYLSILYL)OXY)-3-((l S,2R)-2-

(SULFAMOYLMETHYL)CYCLOBUTYL)ALLYL)CYCLOBUTYL)METHYL

N APHTH ALENE] -7 -C ARB OXYL ATE AND (S)-METHYL 6*-CHLORO-5- (((l R,2R)-2-((S,E)-l-((TERTBUTYLDIMET^

(SULFA]V10YLMETHYL)CYCLOBUIY^L)ALLYL)CYCLOBLiTYL)METHYL )-3 ^, ,4,4 ^, .5-^ΈTRAHYDRO-2H,2Ή-SPIRO[BENZO[B;| [ 1.4]OXAZEPINE-3,l ^, - NAPHTHALENE]-7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S,Z)- l-((TERTBUT^LDIMETFTYLSILYL)OXY)-3-((l S,2R)-2- (SULFAM()YLMETHYL)CYCLOBUTY ^" L)ALLYL)CYCL()BUTYL)METHYL )-3 ^f ,4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ I ,4]OXAZEPINE-3,r- NAPHTHALENE] -7 -C ARB OXYL ATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)~2 (S,Z)-l~((TCRraL ⁱ lTLDIMEraYLSlLYL)OXY)-3-((lR,2S)-2- (SULFAMOYLMETHYL)CYCLOBUTYL)ALLYL)CYCLOBUTTL)METHYL )-3 4,4^5-TETRAFTYDRO-2H,2H-SPIRO[BENZO[B] [ l ,4]OXAZEPINE-3, - N APHTH ALENE] -7 - C ARB OXYL ATE

To a stirred solution of (S)-meth l 6'-chloro-5-(((lR,2R)-2-((S,E)-l - ((tertbuiyldimethyisilyl)oxy)^

ylsulfonyl)memyl)cyclobutyl)allyl)cyclobutyl)m

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((l R ₅ 2R)-2-((S,E)-l-((tertbutyldime lsU

2-((pyriirridin-2-ylsulfonyl)methyl)cyd^

tetrahy dro-2H,2'H-spiro| benzoj b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-methyl 6'-cWoro-5-(((lR,2R)-2-((S,Z)-l -((tert^

((l S,2R)~2~((pyrimidin~2~yisulfonyl)m

3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7- carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,Z)-l- ((tertbutyldimethylsilyl)oxy)-3-((l R,2S)-2-((pyrimidin-2- ylsijlfonyl)meihyl)cyclobutyl)allyi)cyclobutyl)m

2H,2'H-spiro| benzoj b] [ l,4]oxazepine-3, -naphthalene|-7-carbox late (50 mg,

0.062 rnniol) in MeOH (1.8 mL) was added potassium carbonate (42.8 mg, 0.310 rnmol). The reaction was stirred at ambient temperature for 1 hour. After this time the reaction was treated with hydroxylaminesulfonic acid (Sigma Aldrich;

10.52 mg, 0.093 rnmol) in water (1.0 mL) and the mixture was heated at 45 °C for 90 minutes. After this time the reaction was cooled to ambient temperature and partitioned between EtOAc and 1M HC1. The separated organic layer was dried over MgSC filtered and evaporated in vacuo. Column chromatography (4 g S1O2, hexanes:EtOAc, 1 :0 to 4: 1) gave (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S,E)- 1 -((tertbutyldimeth lsilyl)oxy )-3-((l S,2R)-2- (sulfamoylme1hyl)cyclobutyl) lyl)cyclobu1yl)m

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 6 ^, -chloro-5-(((lR ₅ 2R)-2^(S.E)-l^(tertbiityl<Ume lsilyl)oxy)-3-((lR,2S)- 2-(sulfamoylmethyl)cyclobutyl)aUyl)cyclobutyl)methyl)-3\4,4 5-tetrahydro- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 6'-ch3oro-5-(((lR,2R)-2-((S,Z)-l-((iertbuty-ldimethyIsilyl)o xy)-3-((lS,2R)- 2-(suifamoylmeihyl)cyclobuiy])allyl)cyclobutyi)methyl)-3 ⁱ ,4,4 ^f ,5- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carbo x>'late and (S)~ methyl 6'-chloro-5-(((lR,2R)-2-((S,Z) (tertbut54dmiethylsily

2-(sulfamoylmemyl)cyclobutyl)allyl)cyclobutyl)m

2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3,l'-naphthalene]-7-carboxylate (23 mg, 0,031 mmol, 49.9 % yield).

STEP 13: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l- ((TERTBUTYLDTMETHYLSILYL)OXY)-3-((l S,2R)-2- (SULFAMOYLMETHYL)CYCLOBUTYL)ALLYL)CYCLOBUTTL)METHYL )-3',4,4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3, - NAPHTHALENEj-7-CARBOXYLlC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S ,E) - 1 -((TERTBUTYLDIME HYLSILYL)OXY)-3 -(( 1 R,2S)-2- (SULFAMOYLMETHYL)CYCLOBUTYL)ALLYL)CYCLOBUTYL)METHYL

N APHTH ALENE J -7 -C ARB OXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S )-l-((T^RTBUWLDIMETHYLSILYL)OXY)-3-((lS,2R)-2- (SULFA 10YLMETHYL)CYCLOBUIY ^r L)ALLYL)CYCLOBLiTYL)METHYL )-3^4,4 ^, .5-TETRAHYDRO-2H,2Ή-SPIRO[BENZO[B;| [ 1.4]OXAZEPI^ΓE-3,l ^, - NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2 (S,Z)-l^(TE TBUTYLDIMETHYLSiLYL)OXY)-3-((lR,2S)-2- (SULFAMOYLMETHYL)CYCLOBUTYL)ALLYL)CYCLOBUTYL)METHYL )-3 ^, ₅ 4.4 ^, ,5-TETRAHYDRO-2H.2H-SPIRO[BENZO[B] [l ,4]OXAZEPI E-3,l'- NAPHTHALENE1 -7-C ARBOXYLIC ACID

To a stirred solution of (S)-methyl 6'-chloro-5-(((l.R,2R)-2-((S,E)-l- ((iertbutyldimethylsiiyl)oxy)-3-((lS,2R)-2- (sulfamoylmethyl)cyclobutyl)allyl)cyclobutyl)m^

2H,2'H-spiro benzo b][ l,4]oxazepine-3,r-naphthalene|-7-carboxylate and (S)- methyl 6'-chloro-5-(((lR,2R)-2 (S,E)-l (iertbutyldimethylsil}1)oxy

2-(sulfamoylmethyl)cyclobutyl)dlyl)cyclobuty^^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carbox\'late and (S)- me 1 6'-chloro-5-(((l R,2R)-2-((S,Z)-l-W

2-(sulfamoylmethyl)cyxk>b^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((lR,2R)-2^(S,Z) -((tertbu

2-(sulfamoylmethyl)cyclobutyl)allyl)cyd^

2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylate (23 mg,

0.031 mmol) in THF (516 uL) and MeOH (516 μΕ) was added lithium hydroxide (22.23 mg, 0.928 mmol) in water (516 μΐ,). The reaction was stirred at 60 °C for 4 hours and at ambient temperature overnight. After this time an additional portion of lithium hydroxide (22.23 mg, 0.928 mmol) in water (516 uL) was added and the reaction was stirred at 60 °C for 24 hours. After this time the reaction was cooled to ambient temperature and partitioned between EtOAc and water. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated in vacuo to give (S)-6'-chloiO-5-(((lR,2R)-2-((S,E)-l-m _^

((l S,2R)-2-(sulfamoylmethyl)cyclobutyl)ally^

tetrahy dro-2H,2H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7-carboxylic aci d an d (S)-6'-chloro-5 -((( 1 R,2R)-2-((S .!· )- 1 -((tertbuty 1 dimethyl sily l)oxy )-3 - ((l R,2S)-2-isuliamoyimethyl)cyc3obuty3)aliyl)cyclobutyl)methyl) -3 4,4

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyli c acid and (S)-6'-chloro-5-(((lR,2R)-2-((S ₅ Z)-l-((tertbu†yldimethyl

((l S,2R)-2-(sulfamoylme l)cyclobutyl)allyl)cyclobu1yl)methyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid and (S)~6'-chloro-5-(((lR,2R)-2-((S,Z)-l -((tertbutyldimethylsilyl)oxy)-3- ((lR,2S)-2-(sulfamoylme l)c lobu1yl)allyl)c\ lobutyl)methyl)-3 ^, ,4,4',5- tetrahy dro-2H,2'H-spiro| benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (22.5 mg, 0.031 mmol, 100 % yield).

((TERTBUTYLDIMETHYLSILYL)OXY)-3,4-DlHYDRO-2H,17'H- SPIRO [NAPHTHALENE- 1 ,24'-

^lOXAtl SlTO Atl eiDIAZAPEOTACYCLOtiej^.O'-^O^^.^^lHEPTA COS A[8, 18,20,26]TETRAEN] - 17'-ONE 15', 15'-DIOXIDE AND

(lS,3'R,6 ^, R,7'S,8'E,10'R, 13'S)-6-CHLORO-7'-

((TCRTOUTYLDlMETOYLSILYL)OXY)-3,4-DmYDRO-2H, 1 7Ή- SPIRO[N ΑΡΗΊΉ ALENE- 1.24 ^' -

| 22 )ΧΛ| i ^ lT! !lAI l . i 6 |! !A/.\Pl ^: N I ^' ACYCLOI I 6.7.2.U ".i ^{) l n !} '"|! Π:ΡΊ Λ COSA[8,18,2Q,26]TETRAEN]-17'-ONE 15', 15"-DIOXIDE AND

(lS,3 ^! R,6'R,7 ^! S,8'Z, 10'S,13'R)-6-CHLORO-7'- ((TERTBUTYLDIMETHYLSIL YL)OXY)-3 ,4-DIHYDRO-2H, 17Ή-

SP1RO [NAPHTHALENE- 1 ,24'-

|22j()XA| 15jTIIIA| Μ6|Ι)ΙΛΖΛΙ ΎΛ(ΎΠ.<>! 1 .7.2.0^ 0 ^{|n i} \o ^' -''|i !HPTA COSA[8,l 8,20,26]TETRAEN]-17'-ONE 15',15'-DIOXIDE AND

(lS,3 ^, R,6 ^! R,7'S,8'Z,10'R,13'S)-6-CHLORO-7'-

(( ERTBUTYLDIMETHYLSILYL)OXY)-3,4-DlHYDRO-2H,17'H- SPIRO [NAPHTHALENE- 1 ,24'-

^lOXAtlSlTO Atl eiDIAZAPEOTACYCLOtie.y^.O'^.O^^.^^lHEPTA COS A[8, 18,20,26]TETRAEN] - 17'-ONE 15', 15'-DIOXIDE

To a stirred solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- ((tertbutyldimethylsilyl)oxy)-3-((lS,2R)-2- (suliknoyimethyl)cyclob^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carb oxylic acid and (S)-6 ^, -cWoro-5-(((lR ₅ 2R)-2^(S ₅ E)-l-((tertbutyldime lsilyl)oxy)-3-((lR ₅ 2 (sulfamoylme1hyl)c> ⁷ clobutyl)allyl)c^ lobul5d)methyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naph thalene] -7-carbox li c aci d and (S)-6'-chloro-5-(((lR,2R)-2 (S,Z)-l~((tertbuU4diniethy

(sulfamoylmethyl)cyclobutyl)allyl)cyclobutyl)m

2H,2'H -spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy he acid and (S)-6'-chioro-5^((IR,2R)-2-((S,Z)-l (ieributyldiraethylsiiy

(sidfamoylmethyl)cyclobutyl)alM^

2H,2'H-spiro| benzoj b] [ l,4]oxazepine-3 ,1 '-naphthalene |-7-carboxylic acid (22 mg, 0.030 mmol) in DCM (15.1 mL) was added EDC (Sigma Aidrich; 1 1.56 mg, 0.060 mmol). The reaction was cooled to 0 °C and treated with DMAP (Sigma Aidrich; 6.26 mg, 0.051 mmol) portionwise over 2 minutes. After this time the cooling bath was removed and the reaction was allowed to warm to ambient temperature overnight. After this time the reaction was partitioned between 1M HC1 and DCM. The separated organic layer was washed with NaHCQs, dried over MgS04, filtered and evaporated in vacuo to give

(l S,3'R,6'R,7'S,8¾ 10'SJ 3'R)-6-chk)ro-7^^^

dihydro-2H,17'H-spiro[naphthalene-l,24'- [22]oxa[15]thia[ U6]diazapentacy^

jtetraenj-17'-one 15', 15'-dioxide and (lS,3'R,6'R,7'S,8'E,10'R,13'S)-6-chloro-7'- ((tertbutylcUmethylsilyl)oxy)-3,4-dihydro-

]tetraen]-17'-one 15',15'-diQxide and O S,3'R,6'R,7'S,8'Z,10'S,13 ^* R)-6-chloro-7'- ((tertbutyldimethylsilyl)oxy)-3,4-d^

[22]oxa[15]thia[l ,16]diazapentacyclo[16.7.^^

]tetraen]-17'-one 15',15'-dioxide and (lS,3'R,6'R,7'S,8'Z,10'R,13'S)-6-chloiO-7'- ((tertbutyldimethylsilyl)oxy)-3,4-dihydro-2H,17'H-spiro[naph thalene-l,24'- [22]oxa[15]thia[ l, 16]diazapentacyclo[ 16,7.2.0 ³ - ⁶ ,0 ^{10J 3} .0 ²¹ - ²⁶ ]heptacosa[8,18 ₅ 20,26 ]tetraen]-17'-one 15',15'-dioxide (14 mg, 0,020 mmol, 65.2 % yield). This material was used without further purification in the next step.

STEP 15: (1 S,3'R,6'R,7 ^! S,8'E, 10'S, 13'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO^H TH-SPlROtNAPHTHALENE-l^'-

| 22 j()XA| ! 5 ΓΠ ! ΙΛ| Ι . 1 ό |Ι}! ΑΖΛΡΗΝ ΓΛ(· ¾ ^' {Ί.Ο! i 6.7.2. U ^{; !} '.0 ^{| :υ ;} .0 '"l! Π ίΡ ^' ΓΛ COSA[8,18,20,26]TETRAEN]-17'-ONE 15', 15'-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,10 ^, R,13'S)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 17'H-SPI OjNAPHTH ALENE- 1 ,24'-

[22]OXA[ 15]THlA[l,16]DL ZAPENTACYCLO[16;7.2 ³ -^0 ¹⁰ - ¹ l0 ^2L26 ]HEPTA COSA 8,18,20,26]TETRAENj-17'-ONE 15',15'-DIOXIDE

in a 25 mL round bottom flask containing (1 S,3'R,6'R,7'S,8'E, 10'S, 13'R)- 6~chk)ro-7'-((tertbutyldimethylsilyl)oxy)-3,4-dihydro~2H, 17

1,24'-

]tetraen]-17'-one 15', 15'-dioxide and (l S^'R.e'RJ'S^U l O'^lS'S^e-chloro-?'- ((tertbutyldimethylsilyl)ox\ -3,4-dihydro-2H,17 ^, H-spiro[naphthalene-L24'- ^loxat lSJthiall J^cUazapentacyclotiej^.O^^O^^ O^^lheptacosal 8,18,20,26 ]tetraen]-17'-one 15',15'-dioxide and (1 S,3'R,6'R,7'S,8'Z,10'SJ 3 ^f R)-6-chloro-7'- ((tertbutyldimethylsilyl)oxy)-3,4-dihydro-2H, 17'H-spiro[naphthalene-l ,24'- [22]oxa[15]thia[ l,16]diazapentacydo[ 16.7.2.0^

|tetraen|-17'-one 15', 15'-dioxide and (lS,3'R,6'R,7'S,8'Z,10'R,13'S)-6-chloro-7'- ((iertbutyldimethylsiiyl)oxy)~3,4-dihydro-2H,17'H- [22]oxa[15]thia[l, 16]diazapentacy^^

]tetraen]-17'-one 15',15'-dioxide was added a 1M THF solution of TBAF (394 μ.Ε, 0.394 rnmol). The reaction was stirred at ambient temperature for 1 hour. The desired product was not observed. An additional portion of 1M THF solution of TBAF (394 uL, 0.394 mmol) was added and the reaction was stirred at ambint temperature for 8 hours. After this time the reaction was stored in the freezer for 14 days. The reaction was treated with an additional portion of TBAF (394 fiL, 0.394 mmol) and then it was stirred at ambient temperature for 3 days. After this time the reaction was partitioned between EtOAc and 1M HC1. The separated organic layer was washed with NaHCCb and the organic layer was dried over MgS04, filtered and evaporated in vacuo. Column chromatography (1 g S1O2, DCM: acetone, 1 :0 to 7:3) gave a mixture of the title compounds (9 mg). This material was purified by reverse phase preparative HPLC (CI 8 column, 10 to 90% acetoniirile:water, 30 minutes) to give (lS,3'R,6'R,7 ^f S,8'E, I 0'S, 13'R)-6-chloro-7'- hydroxy-3,4-dihydro-2H,17'H-spiro[naphthalene-l,24'- [22]oxa[15]thia[l,16]diazapent^^

]tetraen]-17'-one 15',15'-dioxide or (lS,3'R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,B'S)-6-chloiO-7'- hydrox\'-3,4-dihydro-2H,17'H-spiro|naphthalene-l,24'-

[22]oxa[15]thia[l,16]diazapentacy^

]tetraenj-17'-one 15',15'-dioxide as the first eluting minor isomer (1.5 mg, 0.003 mmol, 12.8% yield). ¾ MR (500MHz, CD2CI2) δ 8.79 (br. s., IH), 7.72 (d, ./ K.6 Hz, 1H), 7.17 (dd, ,/ 1.7.8.3 Hz, I I I).7.14 (d, ,/ 8.6 Hz, IH), 7.09 (d, ,/ i 5 Hz, 1H), 6.95 (d, J=8.1 Hz, IH), 6,74 (s, IH), 6.13 (dd, ./ 3.8.15.5 Hz, IH), 5,63 (dd, ./ 6.2.15.3 Hz, I I I).4.22 (br. s., H), 4.11 - 4,04 (m, 2H), 3.74 (d, ./ 14.2 Hz, IH), 3.77 (br. s., IH), 3.68 (d, ./ 14.4 Hz, IH), 3.56 (dd, ,/ 4.8.14.8 Hz, 111).3.37 (d, ,/ 1 7 Hz, IH), 3.12 (dd, ,/ 109.14.8 Hz, ill).2,90 - 2,82 (m, IH), 2.82 - 2.71 (m, 2H), 2,66 - 2.56 (m, ill).2.45 (dd, ,7=8,3, 14.7 Hz, IH), 2,38 - 2.30 (m, 2H), 2.14 - 1.52 (m, 12H). MS (ESI, +ve ion) m/z 624.8 (M il)

EXAMPLE 135. (lS,3'R,6'R,7'S,8 ^! E,10 ^! R,13 ^, S)-6-CHL()RO-7'-HYDR()XY-3,4- DIHYDRO-2H,17'H-SPIRO[NAPHTHALENE-l ,24*-

[22]OXA[15]THIA[l,16]DIAZAPENTACYCLO[16 .2.0 ³ '^0 ¹⁰ ' ³ l0 ²¹ ' ²⁶ ]HEPTA COSA[8,18,20,26]TEm EN]"17'-ONE 15',15'-D10XIDE OR

(lS.S'R.e'I^T'S^'E O'S S'RJ-e-CHLORO-T'-HYDROXY-S^-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALENE- 1 ,24'- |22!ΟΧΛ| i^lllUAl l,,i6|DI,\/.\Pl-::\ iACVCi.Ol 16,7.20' ".O ^{101 :} .0 ^,; Ι!·.Ρ Λ COSA[8,18,20,26]TETR.AEN]-17'-ONE 15',15'~DI0X1DE

The title compound was synthesized as described in Example 134, Step 15. After purification by reverse phase preparative HPLC (CI 8 column, 10 to 90% acetonitnle: water, 30 minutes) (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,13 ^, S)-6-chloro-7'- hydroxy-3,4-dihydro-2H,17TI-spiro[naphihalene-l,24'- [22]oxa[15]thia[l,16]diazapentacy^

]tetraen]-17'-one 15',15'-dioxide or (lS,3'R,6 ^, R,7 ^, S,8 ^, E,10 ^, S,13 ^! R)-6-chloro-7'- hydrox'-3,4-dihydro-2H,17'H-spiro|naphthalene-l,24'- [22]oxa[15]thia[l,16]diazapentacyclo[16.7.^^^^

]tetraen]-17'-one 15',15'-dioxide was isolated as the second eluting major isomer (2.6 mg, 0.004 mmol, 22.1% yield). Ή MR (500MHz, CD2CI2) δ 9.24 (br. s., HI).7.71 (d, ,/ 8.6 Hz, Hi).7.22 (dl.■/ 1.5.8.1 Hz, 1H), 7.17 (dd, ./ 2.2.8.6 Hz,

7,09 (d, ,/ 2.2 Hz, Hi).6.95 (d, ,/ H3 Hz, III).6.74 (br. s., ill).6,16 id. J=15.2 Hz, ill).5.56 (dd, ,7=6,1, 15.6 Hz, ill).4,26 - 4.15 (m, III).4.13 - 4.04 ins.2H), 3.75 (br. s., ill).3.71 (d, ./ 14.2 Hz, III).3.67 - 3.61 ins.1H), 3.58 (dd, ./ 3.2.14.9 Hz, 111).3.40 (d, ,/ 144 Hz, III).3.23 - 3.13 (m.111).2,88 (d, ./ 8.3 Hz, 1H), 2.83 - 2.71 (m, 2H), 2,59 - 2,47 (m, 2H), 2.38 (br, s., 1H), 2.16 - 2.07 (m, 1H), 2.06 ·· 2.01 (ni, 2H), 1.96 - 1.85 (m, 4H), 1.78 - 1.67 (ni, 4H), 1.60 (td, ./ 7.4. 14.7 Hz, 1H), 1.48 - 1.41 (in, III). MS (ESI, +ve ion) m/z 624.8 iVI H) . EXAMPLE 136, (1 S,3'R,6'R,7'S,8'E,1 'S, 12'R)-6-CHLORO-7'-HYDROXY-l 1 '- METHYL-12 (2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13 ] TH1A[ 1,14]

DIAZATETRACYCL()[14.7.2.() ³ - ⁶ .() ⁱ⁹ - ²⁴ i PENTACOSA[8,16,18,24]TETRAEN]- 15-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S.12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL-

12'((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- S PIRO [NAPHTHALENE- 1,22'- [20] OX A [13] THI A[ 1,14]

DIAZATETRACYCLO[14,7.2.0 ^3/1 .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]

TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 l ^, R ₅ 12 ^, R)-6-CHLORO-7 ^, -HYDROXY-l l'-METHYL-

12'((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,.15'H - SPIROfN APHTHALENE- 1 ,22'-[20] OXA[ 13] THIA[ 1 , 14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]

TETR AEN 1 -15' -ONE I3',l 3'-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E, 1 l 'RJ 2'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12 (2S)-TETR/ HYDRO-2-FURANYLMETHYL)-3,4-DlHYDRO-2H,15 ^, H- SPIRO [NAPHTHALENE- 1 ,22'-[20] ()XA[ 13] THIA[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ³⁹ ' ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN] 15'-ONE 13' ₅ 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, Z,i rS,12'R)-6-CHLORO-7'-HYDROXY-ir-METHYL- 12 (2S)-TCTRAHYDRO-2-FURA TYLMETHYL)-3.4-DIIiYDRO-2H ₅ 15 ^, H- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[ 1 , 14]

DL4ZATETRACYCLO[14,7.2.0 ³ '.0 ¹⁹ - ² ] PENTACQSA[8,16,18,24]TETRAEN] 15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z, 11 ^* S, 12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL- ! 2 ^" (( 2S )-Th ΓΗ..\! Γν Ι ⁾ R. ( ) - 2 - 1 I R Λ \ Y I Λ 11 ; ! !Y l .)-3.4-DU iYDRO-21 1. Ι 5 1- SPIRO[ APHTHALENE- 1 ,22'-[20] OXA[l 3] THIA[ 1,14]

D1AZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTAC()SA [8,16, 18,24]

TETRAEN] - 15 ' -ONE 13',13'-DlOXiDE OR

(lS,3 ^, R,6'R,7 ^! S,8'Z,i rR,12 ^! R)-6-CHLORO-7 ^! -HYDROXY-l l'-METHYL- 12'((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[13] THIA[ 1 ,14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ³⁹ ' ²⁴ ]PENTACOSA [8, 16,18,24]

TETRAEN j - 15 ' -ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6 ^! R,7 ^* S,8'Z, 1 1 'R, 12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL- 12Y(2S)-TETRAIIYDRO-2-FURANYLMETIWL)-3,4-DIHYDRO-2H,15'I-i- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3] 1 Η 1Λ! 1 , 14]

DlAZATETRACYCL()[14.7.2.() ³ - ⁶ .() ^{i 9} - ²⁴ iPENTACOSA [8, 16,18,24]TETRAEN] 15 -ONE 13 ^* , 13'-DIOXJDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,l l ^, S, 12 ^, R)-6-CHLORO-7 ^, -HYDROXY-l l ^, -METHYL- 12'((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DlHYDRO-2H,15'H-

SPIRO |ΝΑΡΗΉ-ΐ:ΑίΕΝΕ-1,22·-[20]ΟΧΑ[ 13]ΤΗΙΑ[ 1, 14]

DIAZATETRACYCLO[14,7.2.0 ^3/1 .0 ¹⁹ - ² ]PENTACOSA [8,16, 18,24]TETRAEN] 15'-ONE 13 ',1 '-DIOXIDE OR (IS ,3'R,6'R,7'S,8'E, 1 l 'S,12'S)-6-CHLORO-7'-HYDROXY-l l '-METHYL- 12^(2R)-TET¾AHYDRO-2-FURANYL ETHYL)-3,4-DmYDRO-2H,15H- SPIRO [NAPHTHALENE- 1.22 ^: -| 20i ()XA[ 13] THIA[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ³⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]

TETRAEN] - 15'-QNE J 3 13 '-DIOXIDE OR

(lS^'R-e'R-T'S^^l l'^l^RVe-CHLORO-T'-HYDROXY-i r- ETHYL- 12 (2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-[20] OXA[ 13] THIA [1, 14]

DL ZA^TRACYCLO[14 .2i) ³ '.0 ¹⁹ - ² ]PENTACOSA [8,16,18,24]

TETRAEN] -15'-ONE 13', 13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,1 rR, 12'S)-6-CHL0R0-7'-HYDR0XY~l 1 '- ETHYL- 12'((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[N APHTHALENE- 1 ,22'-[20] QXA[ I 3] THIA[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]- 15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,l l'S,I2'R)-6-CHLORO-7'-HYDROXY-l I'-METHYL- 12'((2R)-TETTlAHYDRO-2-FURANYT _J METHYL)-3,4-DIHYDRO-2H ₅ 15H- SPIRO [NAPHTOALENE-1,22'-[20]OXA[13]THIA[1 ,14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ³⁹ - ²⁴ ] PENTACOSA[8J 6,18,24]TETRAEN]~ 15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'Z, l l'S,12'S)-6-CHLORO-7 ^! -HYDROXY-l l '-METHYL- 12' ((2R)-TETRAHYDRO-2-FUR ANYLMETFIYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3] THIA[ 1 , 14]

DIAZATETRACYCL()[14.7.2.() ³ - ⁶ .() ^{i 9} - ²⁴ ]PENTACOSA [8, 16,18,24]

TETRAEN]- 15'-ONE 13', 13"-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'Z,jJ.'R,12'R)-6-CHL RO-7'-HYDROXY-i r-METHYL- 12'((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- S PIRO [NAPHTHALENE- 1,22'- [20] OX A [13] THI A[ 1, 14]

DIAZATETRACYCLO[14,7.2.0 ^3/1 .0 ¹⁹ - ² ]PENTACOSA [8,16, 18,24]

TETRAEN] - 15 ' -ONE 13 ^* ,13'-DIOXIDE OR (1 S,3'R,6'R,7'S,8'Z, 1 l 'RJ 2'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12^(2R)-TETRAHYDRO-2-FURA YLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-[20] ()XA[ 13] TI I IAj 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ³⁹ ' ²⁴ ]PENTACOSA [8, 16,1 8,24]TETRAEN] 15'-ONE 13', 13'-DIOXIDE

STEP 1 : (2S,3R)-N,N-BIS(4-METOOXYBENZYL)-3-METHYL-l- (TETRAHYDRO-2-FURA YL)-5-HEXENE-2-SULFONAMIDE AND

(2S ₅ 3S)-N,N-BIS(4- ETHOXYBENZYL)-3-METHYL-l-(TETRAHYDRO-2- FURANYL)-5-HEXENE-2-SULF ON AMIDE AND

(2R,3R)-N,N-BIS(4-METHOXYBENZYL)-3-METHYL-l-(TETRAHYDRO-2- FURANYL)-5-HEXENE-2-SULFON AMIDE AND

(2R,3 S)-N,N-BIS(4-METHOXYBENZYL)-3-METFTYL- 1 -(TETR AHYDRO-2- FURANYL)-5-HEXENE-2-SULFONAMIDE AND

(2S,3R)~N,N"BIS(4"METHOXYBENZYL)-3-METHYL-l-((2R)- TETRAHYDRO-2-FURANYL)-5-HEXENE-2-SULFONAMIDE AND

(2S,3S)-N,N-BTS(4-METHOXYBENZYL)-3-METHYL-l-((2R)- TETRAHYDRO-2-FURANYL)-5-HEXENE-2-SULFONAMIDE AND

(2R,3R)-N,N-BIS(4-MEraOXYBENZYL)-3-METHYL-l-((2R)- TETRAHYDRO-2-FURANYL)-5-HEXENE-2-SULFONAMIDE AND

(2R,3 S)-N,N-BIS(4-METHOXYBENZYL)-3-METHYL- 1 -((2R

lETRAHYDRQ^-FURANYLj-S-HEXEN^^-SULFQNAMIDE

The title compounds were prepared from a mixture of (2S)-N,N-bis(4- methyoxybenzyl)-2-methylpent-4-ene-l-sulfonamide and (2R)-N,N-bis(4- methyoxybenzyl)-2-methylpent-4-ene-l-sulfonamide (Example 472, Step 1 ) using a similar procedure described in Example 380, Step 2, replacing

(bromomethyl)cyclopropane with 2-(bromomethyl)tetrahydrofuran. STEP 2: (2S,3R)-3- ETHYL-l-((2R)-TETRAHYDRO-2-FURANYL)-5- HEXENE-2-SULFONAMIDE AND

(2R,3R)-3-METHYL-l -((2R)-TETRAHYDRO-2-FURANYL)-5-HEXENE-2- SULFONAMIDE AND

(2S,3S)-3-I^THYL-l-((2R)-TCTRAHYDRO-2-FURANYL)-5-HEXENE-2- SULFONAMIDE AND

(2R,3S)-3-METHYL-l-((2R)-TEI¾AHYDRO-2-FURANYL)-5-HEXENE-2~ SULFONAMIDE

(2S,3R)-3-METFIYL-l-((2S)-TETRAHYDR()-2-FURANYL)-5-HEXENE-2- SULFONAMIDE AND

(2R,3R)-3-METHYL~l-((2S)-TETRAHYDRO-2-FURANYL)-5-HFXENE-2 - SULFONAMIDE AND

(2S.3S)-3- EraYL-l^(2S)-TET¾AHYDRO-2-FURANYL)-5-HEXENE-2- SULFONAMIDE AND

(2R,3S)-3-METHYL-l-((2S)-TCTR/ HYDRO-2-FUI . NYL)-5~HEXENE-2- SULFONAMIDE

The title compounds were prepared from above mixture of (2S,3R)-N,N- bis(4-methoxybenzyl)-3-meth l-l-(tetrahydro-2-furanyl)-5-hexene-2-sulfonamide and (2S,3S)-N,N-bis(4-methoxybenzyl)-3-methyl-l-(tetrahydro-2-fu ranyl)-5- hexene-2-sulfonamide and (2R,3R)-N,N-bis(4-methoxybenzyl)-3-methyl-l- (tetrahydro-2-furanyl)-5-hexene-2-sulfonamide and (2R,3S)-N,N-bis(4- methoxybenzy'l)-3-meth l-l-(tetrahydro-2-furanyl)-5-hexene-2-sulfonamide and (2S,3R)-N,N-bis(4-methoxybenzyl)-3-methy]-l-((2R)-tetrahydro -2-furanyl)-5- hexene-2-sulfonamide and (2S,3S)-N,N-bis(4-methoxybenz>'l)-3-methyl- 1 -((2R)- tetrahydro-2-furanyl)-5-hexene-2-sulfonamide and (2R,3R)-N,N-bis(4- methoxybenzyl)-3-rnethyl-l -((2r)^

and (2R,3S)-N,N iis(4-methoxybenz}4)-3-m.ethyl~l-((2R) etrahydro

5-hexene-2-sulfonamide usmg a similar procedure described in Example 472, Step 3.

STEP 3 : (3 S)-6'-CHLORO-5 -((( 1 R,2R)-2-(( 1 S,2E)- 1 -HYDROXY-2-HEXEN - 1 - YL)CYCLOBUTYL)METHYL)-N-(((2R,3R)-3-METHYL-l-(((2S)- TETRAHYDRO-2-FURANYL)-5-HEXEN-2-YL)SULFO YL)-3',4 ₅ 4 ^, .5- TETRAHYDRO-2 l-SPiRO[l ,5-BENZOXAZEPINE-3,l '-NAPHTOALENE]-7- CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l- YL)CYCLOBUT L) METHYL)-N-(((2R,3S)-3-METHYL-l-(((2S)- TET AilYDR0-2-FURANYX)-5-HEXEN-2-YL)SULF0NYL) ^4,4 ^, ,5- TETRAHYDRO-^H-SPIROIl^-BENZOXAZEPINE-S '-NAPHTHALENE]-?- CARBOXAMIDE AND (3S)-6"-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXE -l-

YL)CYCLOBUTYL) METHYL)-N-(((2R,3S)-3-I^ETHYL-l-(((2S)-

TETRAHYDRO-2-FURANYL)-5-HEXEN-2-YL)SULFO YL)-3',4 ₅ 4 ^, .5-

TETRAHYDRO-2Tl-SPiRO[l ,5-BENZOXAZEPlNE-3,l '-NAPHTOALENE]-7- CARBOXAMIDE AND

(3S)-6 ^, -CHLORO-5-(((lR,2R)-2~((l S,2E)-l"HYDROXY-2-HEXEN~l~

YL)CYCLOBUT L) METHYL)-N-(((2R,3S)-3-METHYL-l-(((2S)- TETRAilYDRO-2-FURANYL)-5-HEXEN-2-YL)SULFONYL)-3 ^, ₅ 4,4 ^, ,5- TETRAHYDRO-^H-SPIROIl^-BENZOXAZEPINE-S '-NAPHTHALENE]-?- CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((l R,2R)-2-((l S,2E)-1 -HYDROXY-2-HEXEN-l - YL)CYCLOBUTYL)METHYL)-N ((2R m)~3-METHYL-l-(((2R)- TETiL HYDRO-2-FURANYL)-5-HEXEN-2^L)SULFONYL)-3',4,4',5- TETR, 1-iYDRO-2 -i-SPIRO[ l,5-BENZ()XAZEPINE-3,r-NAPHTHALENE|-7- CARBOXAMIDE AND

(3S)-6 ^, -CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXE -l- YL)CYCLOBUT L) METHYL)-N-(((2R.3S)-3- ETHYL-l-(((2R)- TETRAHYDRO-2-FURANYL)-5 1EXEN-2-YL)SULFONYL)-3',4,4',5- TETRAHYDRO-2'H-SPIRO[l ,5~BENZOXAZEPINE-: l'-NAPHTHALENE]-7- CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR.2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l- YL)CYCLOBUTYL) METOYL)-N-(((2R,3S)-3-MEWIYL- 1 -(((2R)- TETRAHYDRO-2-FURANYL)-5-HEXEN-2-YL)SULFONYL)-3' ₅ 4,4 ^, ,5- TETRAHYDRO-2'H-SPIROj 1 ,5-BENZOXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2~((l S,2E)-l-HYDROXY-2-HEXEN~l~

YL)CYCLOBUTYL) METHYL)-N-(((2R,3S)-3-METHYL-l-(((2R)- TETR, I-iYDRO-2-FURANYL)-5-HEXEN-2-YL)SULFONYL)-3',4,4',5- TETRAIIYDRO-2'H-SPIRO[ l,5-BENZOXAZEPINE-3;i'-NAPHTOALENE]-7- CARBOXAMIDE

N,N-dimethylpyridin-4-amine (182 mg, 1.49 mmol) was added to a solution of (S)-6'-chloro-5-((( 1 R,2R)-2-((S,E)- 1 -hydrox hex-2-en- 1 - yl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine- 3,r-naphthalene]-7-carbox 'lic acid (IntermediateAA12A, 380 mg, 0.745 mmol), a mixture of (2S,3R)-3-methyl-l -((2R)-tetrahydro-2-furanyl)-5-hexene-2- sulfonamide and (2R,3R)-3-methyl-l -((2R)-tetrahydro-2-furany])-5-hexene-2- sulfonamide and (2S,3S)-3-methyl-l-((2R) etrahydro-2-furanyi)-5-hexene-2- sulfonamide and (2R,3S)-3-methyl-l-((2R)-tetrahydro-2-furanyl)-5-hexene-2- sulfonamide (2S,3R)-3-methyl-l-((2S)-tetrahydro-2-furanyl)-5-hexene-2- sulfonamide and (2R,3R)-3-methyl-l-((2S)-tetrahydro-2-furanyl)-5-hexene-2- sulfonamide and (2S,3S)-3-methyl-l-((2S)-tetrahydro-2-furanyl)-5-hexene-2- sulfonamide and

(2R,3S)-3-methyl-l-((2S)-tetrahydro-2-furanyl)-5-hexene-2-su lfonaraide (369 mg, 1.49 mmol) and triethylamine (0.326 niL, 2.352 mmol) in DCM (2 mL) at ambient temperature. Then l-((ethylimino)methylene)-N3,N3- dimethylpropane-l,3-diamine hydrochloride (286 rng, 1.49 mmol) was then added slowly. The reaction mixture was stirred at ambient temperature for 18 h and washed with saturated sodium bicarbonate. The mixture was diluted with dichloromethane, and the organic layer was washed with water, brine, dried ( Yi SO i). filtered and concentrated. The crude residue was chromatographed (silica gel, 5 to 100%, EtOAc+l%HOAc/hexane) to afford the title compound (430 mg, 78%). m/z (ESI, +ve ion) 739.3 (M+Na) ⁺ .

STEP 4: (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORQ-7'-HYDROXY~l - METHYL-12 (2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15 Ή - SPIRO [NAPHTHALENE- 1 ,22'- [20 j OXA[ 13] THIA [1,14]

DIAZATETRACYCLO[14,7.2.0 - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]- 15'~ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,l l'S, 12'S)-6-CHLORO-7'-HYDROXY-l l'-METHYL- 12'((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-1 ,22'-[20]OXA[13] THIA[1 ,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]

TETRAEN] - 15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E, l l 'R,12 ^f R)-6-CHLORO-7'-ir¾ ^r DROXY-i r-METHYL- 12^(2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H ₅ 15'H-

SP1RO [NAPHTHALENE- 1 ,22'-[20] OXA[ 13] THIA[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ . ⁶ .0 ³⁹ ' ²⁴ ]PENTACOSA [8, 16,1 8,24]TETRAEN |- 15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,l l'R, 12'S)-6-CHLORO-7'-HYDROXY-l l'-METHYL- 12 (2S)-TCTRAHYDRO-2-FURA TYLMETHYL)-3.4-DIFiYDRO-2H ₅ 15 ^, H-

SPIRO [NAPHTHALENE- 1 ,22'- [20] OX A [13]

THIA[1,14]DIAZATETRACYCLO[14.7.2,0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETR _i \EN]-15 ^, -ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,i rS,12'R)-6-CHLORO-7'-mOROXY-l l '-METI-IYL- 12' ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[ 1 , 14]

DL\ZATETRACYCLO[14.7.2.0 ³ '.0 ¹⁹ - ² ]PENTACOSA [8,10,18,24]TETRAEN j- 15 ^* -ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 ^* S, 12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL- 12X(2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3] THIA[ 1,14]

DIAZATETRACYCLO| 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTAC()SA [8,16,18,24]

TETR AEN] -15' -ONE 13\13'-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,l l'R,12 ^! R)-6-CHLORO-7 ^! -HYDROXY-l l ^, -METHYL- 12 (2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTHALENE-1 ,22'-[20]OXA[13] THIA[1 ,14]

DIAZATE RACYCLO[14.7.2.0 ³ ' ⁶ .0 ³⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]- 15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,0'R,7 ^* S,8'E, 11 'R, 12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12 (2R)-TETRAHYDRO-2-FURA YLMETHYL)-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]

THLA[l,14]DIAZATETRACYCLO[ 14.7.2.() ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DTOXIDE

A round bottom flask was charged with a mixture of (3S)-6'-chloro-5- (((lR,2R)-2-((lS,2E)-l-hydroxy-2-hexen-l-yl)cyclobut}4)methy l)-N-(( methyl-l-(((2S)-tetrahydro-2-furanyl)-5-h^

2'H-spiro[l,5-benzoxazepine-3,r-naphthalene]-7-carboxamide and (3S)-6'-chloro-

5-(((lR,2R)-2-((lS,2E)-l-hydroxy-2-hexen-l-yl)cyc3obuU4)

3-methyl-l-(((2S)-tetrahydro-2-furanyl)-5-hexen-2-yl)sulfony l)-3',4,4',5- tetrahydro-2'H-spiro[l ,5-benzoxazepine-3, 1 '-naphthalene] -7-carboxamide and (3S)-6'-chloro-5-(((lR,2R)-2-((lS,2E)-l -hydroxy-2-hexen-l-yl)cyclobutyl) methyl)-N-(((2R,3S)-3-methyl-l-(((2S)-tetrahydro-2-furanyl)- 5-hexen-2- yl)sulfonyl)-3',4,4',5-tetrahydro-2'H-spiro[ l,5-benzoxazepine-3, -naphthalene]-7- carboxamide and (3 S)-6'-ch] oro-5-((( l.R,2R)-2-((l S,2E)- 1 -h droxy-2-hexen- 1 - yl)cydobutyl) methyl)-N-(^ hexen-2-yl)sdfonyl)-3',4,4',5-tetrahydro-2H-spiro[l,5-benzox azepine-3,r- naphthalene]-7-carboxamide (3S)-6'-chloro-5-(((lR,2R)-2-((lS,2E)-l-hydrox '-2- hexen-l-yl)(^clobutyl)methyl)-N-(((2R,3R)-3-methyl-l -(((2R)-tetrahydro-2- furanyl)-5-hexen-2-yl)sulfonyl)-3 4,4',5-tetrahydro-2'H-spiro[.l ,5-benzoxazepine- 3,1 '-naphthalene] -7-carboxaniide and (3 S)-6'-chloro-5-(((l R,2R)-2-((l S,2E)- 1 - hydroxy-2-hexen-l-yl)cyclobutyl) methyl)-N-(((2R,3S)-3-methyl-l-(((2R)- tetrahydro-2-furanyl)-5-hexen-2-yl)sulfonyl)-3',4,4',5-tetfa hydro-2'H-spiro[ l,5- benzoxazepine-3, 1 '-naphtha! ene]-7-carboxamide and (3S)-6'-chloro-5-(((lR,2R)- 2-(( ^' lS,2E)- ^' l-hydroxy-2-hexen-l-yl)cyclobu1yl) me1hyl)-N-(((2R,3S)-3-methyl-l- (((2R)-tetrahydro-2-furanyl)-5-hexen-2-yl)sd^^

spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxamide and (3S)-6'-chloro-5- (((1 R,2R)-2-((l S.2 ! ·.)- ! -hydroxy-2-hexen-l-yi)cyclobutyl) nu;th> ! )-V{(( 2R.3S)-3- methyl-l-(((2R)-tetrahydro-2-furanyl)-5-hexen-2-yl)sulfonyl) -3',4,4',5-tetrahy 2'H-spiro[ l,5-benzoxazepine-3, -naphthalene]-7-carboxamide (432 mg, 0.584 mmol) in DCE (195.0 mL) . The mixture was stirred at ambient temperature and bubbled argon into the reaction flask for 30 mm. To this homogeneous solution was added Hoveyda-Grubbs II (73.2 mg, 0.117 mmol) at ambient temperature and stirred under reduced pressure for 18. The reaction mixture was concentrated and the crude material was chromatographed (silica gel, 0 to 100%,

EtOAc+0.5%HOAc/hexane) to afford an oil. This oil was further purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column;

Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as the first eluenting isomer. ^] H NMR (400MHz, CD2CI2) δ 8.24 (br s, 1 H), 7,70 (d, J 8.4 Hz, 1 1 1 ). 7.16 (dd, .! 2.3. 8.4 Hz, 1 H), 7,09 id. J 2.3 Hz, 1 H), 7.00 (br s, 1 H), 6.96 - 6.89 (m, 2 H), 5.85 - 5.77 (m, 1 H), 5.73 - 5.65 (m, 1 H), 5.33 ·· 5.30 (m, 6 H), 4.21 - 4.05 (m, 5 H), 3.92 - 3.82 (m, 1 H), 3.82 - 3.61 (m, 3 ! ! }. 3.43 (q, J=7.0 Hz, 1 H), 3.29 (d, J 14.3 Hz, 1 H), 3.14 (br s, 1 H), 2.82 - 2,69 (m, 2 H), 2.44 - 2,27 (m, 3 H), 2.16 (dd, .1 3 7. 1 1.3 Hz, 2 I s ). 2.10 - 2,02 (m, 2 H), 2.00 - 1.88 (m, 5 H), 1.85 - 1.76 (m, 4 H), 1.72 - 1.67 (m, 1 H), 1.62 (d, .! 7.0 Hz, I H), 1.57 - 1,40 (m, 6 H), 1.34 - 1,21 (m, 5 III 1.17- 1,1 I (m, 2 III 1.05 (d, j 6.7 Hz, 3 H), 0.92 - 0.81 (m, 3 H). m/z (ESI, +ve ion) 669.2 (M il) .

EXAMPLE 137. (1S,3'R,6'R,7'S,8 ^! E,1 Γ ,12Έ)-6-{:ΗΕ()Κ0-7'-ΗΥ0Κ()ΧΥ-1Γ- METHYL - 12'-((2R)-2-OXETANYLMETHYL)-3 ,4-DIHYDRO-2H, 15 Ή-

SPIRO[NAPHTHALENE~l,22'-[20]OXA[13]THIA[l,14]DiAZATETRACY CLO [14.7.2.0 - ⁶ .0 ^!9 -24]PE TACOSA[8,16,18,24]TETRAEN]-15'- ONE 13',13'~ DIOXIDE OR

(lS,3'R,6 ^! R,7^,8^E,ll¾,12¾.)-6-CHLORO-7'-HYDROXY-ir-METHYL-12 ^! - ((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 .0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]~15'~ ONE 13 I 3 '-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'E,irS,12'S)-6-CHLORO-7'-HYDROXY-ir-METHYL-12'- ((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2ujOXA| !3jTIUA| U4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2.0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA |8,16,18,24]TETRAENj-15'- ONE 13',13'-DIOXIDE OR

(lS,3¾,6'R,7^,8^11'S,12¾)-6-CHLORO-7'-I-IYDROXY-ll'-MET HYL-I2'- ((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ - ⁶ .0 ^l9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8 ^, Z,ll ^, R,12'S)-6-CHLORO-7'-HYDROXY-ir-METHYL-12'- ((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ '24]PENTACOS A[8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,n'R,12 ^! R)-6-CHLORO-7'-I-r ^;" DROXY-ir-METHYL-12'- ((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R R,7'S,8'Z;ri'SJ2'S)-6-CHLORO-7 ⁱ -HYDROXY-ir-METHYL-12'- ((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THIA|;i,14]DIAZATETRACYCL)[14J.2X) ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAENi-!5'- ONE 13',13'-DTOXIDE OR

(IS^l^e'R 'S^'ZjrS/n^-e-CHLORO^'-HYDROXY-ll'-METHYL-^'- ((2R)-2-OXETANYLMETHYL)-3,4-DiHYDRO-2H, 15Ή- SPIRO[NAPHTH ALENE- 1 ,22'-

|2θ!() Λ| I 311 HI Λ| I .. N |PIA/A Π·. ΓΚΛ(Ύ(Ί .Oj N.7.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R, 7 ^* S,8'E, 11 'R, 12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12'- ((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ -24]PENTACOS

A [8,10,I8,24]TETRAEN]-I5'~ ONE 13',13"-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,rJAR,12'R)-6-CHIORO-7'-HYDROXY-ll'-ME THYL-12'- ((2S)-2-QXETANYLMETHYL)-3,4-DlHYDRQ-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'~ ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 l'S, 12'S)-6-CHLORO-7'-H YDROXY- 11 '-METHYL- 12'- ((2S)-2-OXETANYLMETHYL)-3,4-DIi-IYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.0 · ^, \0 ^{|:, ! 1} |PHNTAi SA

|8,16,18,24]TETRAENj-15'- ONE 13',13'-DIOXIDE OR

(lS 'R,6'R,7 ^f S,8'E,ll'S,12'R)-6-CHLORO-7'-I-IYDROXY-ll'-METHYL-12'- ((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16.18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z,1 !'R,12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL- 12'- ((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H ₅ 15Ή- SPIRO [NAPHTHALENE- 1,22'-

|2 ⁽ ϊ!()ΧΑ| !3ΓΠ!Ι,\| j.l4|l)!AZA ^' ! ^' LTRA( YCI.OI i 4.7.2.0 ^; "O ¹ " 24|ΡΗΝΤΑί OS A[8,16,18,24]TETRAE ]-15'- ONE I3',13'-DIOXIDE OR

(lS,3 ^, R,6'R ^! S,8'Zai'R,12 ^, R)-6-CHLORO-7 ^! -HYDROXY-ir-METHYL-12'- ((2S)-2-()XETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ ! |ί)!Λ/Λ! :ΓΗ.Λ(Α ^' Χ)Ι IL7.20 ^:'i' .0 ^li ' |Pi-:N i ACOSA [8,16,18,24]TETiL EN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,ll'S,12'S)-6-CHLORO-7'-HYDROXY-ll'-ME THYL-12'- ((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO[14.7.2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,18,24]TETRAEN]-15'- ONE 13', 13 '-DIOXIDE OR

(Ιβ,Β'Κ,ό'Κ,Τ'β,δ'Ζ,ΙΙ'β, 'Κνό-ΟΗΕΟΚΟ-Τ'-ΗΥΟΚΟΧΥ-ΙΙ'-ΜΕΤΗΥΕ-� �^- ((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13', 13 '-DIOXIDE

STEP 1 : (BUT-3-EN-l-YLOXY)( -BUTYL)DTPHENYLSILANE

To a solution of 3-buten-l -ol (5 mL, 58.5 mmol) and imidazole (7.71 mL, 117 mmol) in DMF (30 mL) was added tert-butylchiorodiphenylsilane (18.24 mL, 70.1 mmol) at ambient temperature under Ar. The reaction mixture was stirred at this temperature for 18 h. The mixture was quenched with saturated aquoes NH4CI, and extracted with DCM. The combinded organic layers were washed with brine, dried (NaaSC ) and concentrated. The resulting residue was chromatographed (silica gel, 0-5%, EtOAc/hexane) to afford the title compound (17 g, 94%).

STEP 2: TERT-BUTYL(2-(OX -2-YL)ETHOXY)DIPHENYLSILANE

To a solution of (but-3-en-l -yloxy)(tert-butyl)diphenylsilane (17.3 g, 55.8 mmol) in anhydrous dichloromethane (150 mL) at ambient temperature was added 3-chlorobenzoperoxoic acid (18.75 g, 84.0 mmol) portionwise. The reaction mixture was stirred at this temperature for 18 h. A white precipitate was formed. The mixture was quenched with saturated aqueous NaHCC , and extracted with DCM (3x). The organic l yer was washed with saturated aqueous NaHCO., (3x), dried (NaaSCU), concentrated and chromatographed (silica gel, 0-5%,

EtOAc hexane) to afford the title compound (17.2 g, 94%) as a colorless.

STEP 3 : (4R,5 S,7S)-7-HYDROXY-N,N~BlS(4~METHOXYBENZYL)-4- METHYL-9-(((2-METHYL-2-PROPANYL)(DIPHENYL)SILYL)OXY)-l- N ONENE- 5 - SULFON AMI D E AND

(4S,5S,7S)-7 -iYDROXY-N,N-BIS(4-METI-IOXYBENZYL)-4-METOYL-9- (((2-METHYL-2-PROPANYL)(DIPHENYL)SILYL)OXY)-l-NONENE-5- SULFONAMIDE AND

(4R,5R,7S)-7 -^DROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-9- (((2-METFTYL-2-PROPANYL)(DIPHENYL)SILYL)OXY)-l-NONENE-5- SULFONAMIDE AND (4S,5R,7S)-7-IiYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-NlETHYL-9- (((2-METHYL-2-PROPANYL)(DIPHENYL)SILYL)OXY)-l-NONENE-5-

SULFGNAMIDE AND

(4R,5SJR)-7 iYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-9- (((2-METHYL-2-PROPANYL)(DIPHENYL)SIL YL)OXY)- 1 -NONENE-5- SULFON AMIDE AND

(4S,5S,7R)-7-HYDROXY-N ₅ N-BIS(4-METHOXYBENZYL)-4-METHYL-9- (((2-METFIYL-2-PROPANYL)(DIPHENYL)SILYL)OXY)-l-NONENE-5- SULFONAMIDE AND

(4S,5S,7R)-7-HYDROXY-N,N-BIS(4-METH()XYBENZYL)-4-METOYL-9 - (((2-METHYL-2-PROPANYL)(DIPHENYL)SILYL)OXY)-.l-NONENE-5- SULFONAMIDE AND

(4S,5R,7R)-7-HYDROXY-N,N~BlS(4~ME ^' raOXYBENZYL)-4-METHYL-9- (((2-METHYL-2-PR()PAN iX)(DIPi-IENYL)SILYL)OXY)-l-NONENE-5-

To a round bottom flask was added (2S)-N,N-bis(4-methoxybenzyi)-2- methylpent-4-ene- 1 -sulfonamide (1.70 g, 4.21 mmol; Example 380, Step 1) in THF (6 mL) at -78 °C, butyllithium solution, 2.5 M in hexanes (2.022 mL, 5.06 mmol). The mixture was stirred for 5 rain at this temperature, followed by the addition of tert-butyl-(2-(oxiran-2-yl)ethoxy)diphenylsilane (5.50 g, 16.85 mmol). The reaction mixture was then allowed to warm up to ambient temperature and stirred for 2 h. the mixture was quenched with saturated NH4CI, and extracted with diethyl ether (2x). The combined organic layers were washed with brine, dried (MgSQ ), filtered and concentrated. The resulting crude residue was chromatographed (silica gel, 0 to 20%, EtOAc/liexane) to afford the title compound (1.0 g, 32.5%). m/z (ESI, +ve ion) 752.2 (M+Na) ⁺ . STEP 4: (4R,5S.7R)-9-DIHYDROXY-N.N-BIS(4-METHOXYBENZYL)-4- METHYL-1 -NONENE-5-SULFON AMIDE AND

(4R,5R,7R)-9 ^IHYDROXY-N,N-BlS(4-METOOXYBENZYL)-4-METOYL-l- NONENE-5-SULFONAMlDE AND

(4S.5S,7R)-9-DIHYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-l- NONENE-5-SULFON AMIDE AND

(4S,5R,7R)-9-DIHYDROXY-N,N-BIS(4-METHOXYBE ZYL)^-METHYL-l- NO ENE-5 - S ULFON AMIDE AND

(4R,5S,7S)-9-DIHYDROXY ^T -N,N-BIS(4-METOOXYBENZYL)-4-METHYL- 1 - NONENE-5-SULFONAMIDE AND

(4R,5R,7S)-9-DIHYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL- l - N ONENE- 5 - SULFON AMI D E AND

(4S,5S,7S)-9-DIHYDROXY-N^N-BIS(4-METI-IOXYBENZYL)-4-METHYX- 1 - NONENE-5-SULFONAMIDE AND

(4S,5R,7S)-9-DIIiYDROXY-N.N-BIS(4-METHOXYBENZYL)-4-METHYL-l - NONENE-5-SULFONAMIDE

To a solution of (4R,5S,7S)-7-Hydroxy-N,N-bis(4-methoxybenzyl)-4- methyl-9-(((2-methyl-2-propanyl)(diphenyl)silyl)ox -l-nonene-5-sulfonarrud and (4S,5S,7S)-7 iydroxy-N^N-bis(4-niethoxybenzy^^

propanyl)(diphenyl)silyl)oxy)-l-nonene-5-sulfonamide and (4R,5R,7S)~7~ hydroxy -N,N-bis(4-methoxybenzyl)-4-methyl-9-(((2-methyl-2- propanyl)(diphenyl)silyl)oxy)-l-nonene-5-sulfonamide and (4S,5R,7S)-7- hydroxy-N,N-bis(4-methoxybenzyl)-4-methyl-9-(((2-methyl-2- propanyl)(diphenyl)silyl)oxy)-.l -nonene-5-sulfonamide and (4R,5S,7R)-7- hydroxy-N,N-bis(4-memoxybenzyl)-4-memyl-9-(((2-mem^ ^{^}

propanyl)(diphenyl)silyl)oxy)-l-nonene-5-sulfonamide and (4S,5S,7R)-7- hydroxy-N,N-bis(4-methoxybenzy])-4-methyl-9-(((2-meth l-2- propanyl)(diphenyl)silyl)oxy)-l-nonene-5-sulfonamide and (4S,5S,7R)-7- hydroxy-N,N-bis(4-methoxybenzyl)-4-methyl-9-(((2-methyl-2- propanyl)(diphenyl)silyl)oxy)- 1 -nonene-5-sulfonamide and (4S,5R,7R)-7- hydroxy -N,N-bi s(4-memoxybenzyl)-4-methyl-9-(((2-methyl-2- propanyl)(diphenyl)silyl)oxy)-l-nonene-5-sulfonamide (1.80 g, 2.466 rnmol) in THF (15 mL) was added tetrabutvlammonium fluoride solution, 1.0 M in THF (4.93 mL, 4.93 mmol) at 0°C. The reaction was allowed to warm up to ambient temperature and stirred for 18 h. The reaction was quenched with saturated aqueous H ₄ C1, and extracted with EtOAc. The organic layer was washed with brine, dried (Na?.S04), concentrated and chromatographed (silica gel, 20 to 100%, EtGAc/hexane) to afford the title compound (0.95 g, 78%),

STEP 5: (2S,3S.5R)-5,7-DIHYDROXY-3-(2-PROPE -l-YL)- HEPTANESULFON AMIDE AND

(2S,3R,5R)-5,7-DiHYDROXY-3-(2-PROPEN-l -YL)-2- HEPTANES ULFONAMIDE AND

(2R,3S,5R)-5 ₅ 7-DIHYDROXY-3-(2-PROPEN-l-YL)-2- HEPTANESULFONAMIDE AND (2R,3R,5R)-5 ₅ 7-DlHYDROXY-3-(2-PROPEN-l -YL)-2- HEPTANESL1LFONAMIDE AND

(2S,3S,5S)-5,7-DIHYDROXY-3-(2-PROPE -l-YL)-2- HEPTANESULFON AMIDE AND

(2S,3R,5S)-5,7-DIHYDROXY-3-(2-PROPEN-l-YL)-2- HEPTANES ULFONAMIDE AND

(2R,3S,5S)-5,7-DIHYDROXY-3-(2-PROPE -l-YL)-2- HEPTANESULFONAMIDE AND

(2R,3R,5S)-5,7-DIHYDROXY-3-(2-PROPEN-l-YL)-2- HEPTANESULFON AMIDE

To a solution of (4R,5S,7R)-9-dihydroxy-N,N-bis(4-methoxybenz 'l)-4- methyl-l-nonene-5-sulfonamide and (4R,5R,7R)-9-dihydroxy-N,N-bis(4- methoxybenzyl)-4-methyl- 1 -nonene-5-sulfonaraide and (4S,5S,7R)-9-dihydroxy- N,N-bis(4-methoxybenzyl)-4-methy 1- 1 -nonene-5-sulfonamide and (4S,5R,7R)-9- dihy(koxy-N,N-bis(4-methoxybenz 'l)-4-methyl-l-nonene-5-sulfonamide and(4r,5s,7s)-9-dihydfoxy-N,N-bis(4-methoxybenzyl)-4-methyl- l-nonene-5- sulfonamide and (4R,5R,7S)-9-dihydroxy-N,N-bis(4-methoxybenz 'l)-4-methyl-l- nonene~5-sulfonaniide and (4S,5S,7S)-9-dihydroxy-N,N-bis(4-methoxybenz>'l)-4- methyl-1 -nonene-5-sulfonamide and (4S,5R,7S)-9-dihydroxy-N,N-bis(4- methoxybenzyl)-4-methyl-l -nonene-5-sulfonarnide (2.00 g, 4.07 mmol) in anisole (22, 1 1 mL, 203 mmol) was added 2,2,2-trifluoroacetic acid (15.67 mL, 203 mmol) at ambient temperature and stirred for 18 h. The excess TFA was removed under reduced pressure and the reaction mixture was chromatographed (silica gel, 0 to 20 %, MeOH/0.3%AcOH+ DCM) to afford the trifluoroacetate as an oil. The oil was then dissolved in a mixed solvent (THF/MeOH/H ₂ 0: 8 mL/8 mL/8 mL) and was added LiOH (4 eq). The resulting mixture was stirred at ambient temperature for 1 h, concentrated, added water, and extracted with 25% iPrOH in CHCb. The organic layer was concentrated to afford the title compound (610 mg, 60%).

STEP 6: (3R,5S)-3-HYDROXY-5-((lS)-l-SULFAMOYLETHYL)-7-OCTEN-l - Y AND

(3R,5R)-3-HYDROXY-5-(( 1 S)~ i - SULF AMOYLETHYL)-7-OCTE - 1 - Y AND (3R,5R)-3-HYDROXY-5-((lR)-l -SULFAMOYLETHYL)-7-OCTEN-l-Y AND (3R,5S)-3-HYDROXY-5-((lR)-l-SULFAMOYLETHYL)-7-OCTEN-l-Y AND (3S,5S)-3-HYDROXY-5-((lS)-l-SULFA OYLETHYL)-7-OCTEN-l -Y AND (3S,5R)-3-HYDROXY-5-((l S)-i-SULFAMOYLETHYL)-7-OCTEN-l-Y AND (3S,5R)-3-HYDROXY-5-((lR)-l -SULFAMOYLETHYL)-7-OCTEN-l-Y AND (3S.5S)-3-HYDROXY-5-((l R)-l-SULFAMOYLETFTYL)-7-OCTEN-l-Y

To a mixture of (2S,3S,5R)-5,7-dihydroxy-3-(2-propen-l -yl)-2- heptaxiesulfonamide and (2S,3R,5R)-5,7-dihy droxy-3-(2-propen- 1 -yl)-2- heptanesulfonamide and (2R,3 S,5R)-5,7-dih droxy-3-(2-propen- 1 -yl)-2- heptanesulfonamide and (2R,3R,5R)-5,7-dihydroxy-3-(2-propen-l-yl)-2- heptanesulfonamide (2S,3S,5S)-5,7-dihydroxy-3-(2-propen-.l -yl)-2- heptanesulfonamide and (2S,3R,5S)-5,7-dihydroxy-3-(2-propen-l-yl)-2- heptanesulionamide and (2R,3S,5S)-5,7-dihydroxy-3-(2-propen-l -yl)-2- heptanesulfonamide and (2R,3R,5S)-5,7-dihydroxy-3-(2-propen-l-yl)-2- heptanesulfonamide (480 mg, 1.910 mmol) in DCM (10 mL) at 0 °C was added triethylamine (1.06 mL, 7.64 mmol), and a solution of p-toluenesulfonyl chloride (728 mg, 3.82 mmol) in portions. The mixture was stirred from 0 °C to ambient temperature for 2 h and extracted with 10% MeOH in DCM. The organic layer was washed with H2O, dried (MgSCu), filtered and concentrated. The resulting crude orange oil was chromatographed (silica gel, 0 to 20 %, MeOH/0.3% AcOH in DCM) to afford the title compound (500 mg, 64.6%).

STEP 7: (2S,3R)-3-METHYL-l -((2R)-2-OXETA YL)-5-HEXENE-2- SULFONAMIDE AND

(2S,3S)-3-METHYL-l~((2R)-2-OXETANYL)-5-HEXENE"2-SULFONAMlDE AND

(2R,3R)-3-METHYL-l -((2R)-2-OXETA YL)-5-HEXENE-2-SULFONAMIDE

AND

(2R,3S)-3-METIiYL-l -((2R)-2-OXETANYL)-5-HEXENrE-2-SULFONAMIDE

AND

(2S,3R)-3-METHYL-l -((2S)-2-OXETANYL)-5-HEXENE~2-SUL,FONAMID AND

(2S,3S)-3-METHYL-l-((2S)-2-OXETANYL)-5-HEXENE-2-SULFONAMIDE

AND

(2R,3R) -METHYL-l-((2S)-2-0XETANYL)-5-H^

AND

(2R,3S)-3-METHYL- 1 -((2S)-2-OXETANYL)-5-HEXENE-2-SULFON AMIDE

Potassium 2-methylpropan-2-olate (2,50 mL, 2,47 mraol) was added to a solution of 3-hydroxy-6-methyl-5-sulfamoylnon-8-en-l-yl 4- methylbenzenesulfonate (500 nig, 1 ,233 mmol) in THF (12 mL) at ambient temperature. The reaction mixture was stirred at for 2 h. Solvent was evaporated, the residue was extracted with 10%MeOH/DCM. The organic layer was washed with saturated M Cl brine, dried (Na2S0 ₄ ) and concentrated to afford the title compound (154 mg, 53,5 %).

STEP 8: (3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l-

YL)CYCLOBUTYL)METHYL)-N-(((2R,3S)-3-METHYL-l-((2S)-2- OXETANYL)-5-HEXEN-2-YL)SULFONYL)-3',4,4',5-TETRAI-IYDRO-2 ^f H- SPIRO[l,5~BENZOXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXAMIDE AND

(3S)-6 ^! -CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l-

YL)CYCLOBUTYL)METHYL)-N i(2S,3R)-3-METI-IYL-l-((2S)-2-

OXETANYL)-5-HEXEN-2-YL)SULFONYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2 ^, H-

SPIRO| l,5-BENZOXAZEP]NE-3,r-NAPHTHALENE]-7-CARBOXAMIDE AND

(3S)-6 ^! -CHLORO-5-(((lR,2R)-2~((l S,2E)-l-HYDROXY-2-HEXEN~l~

YL)CYCLOBUTYL)MEraYL)-N-(((2R,3R)-3-METHYL-l-((2S)-2-

OXETANYL)-5 iEXEN-2-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2'H- SPIRO[l,5-BENZOXAZEPINE-3,r-NAPHTHALEN i-7-CARBOXAMIDE AND (3S)-6'-CHLORO-5 ((lR,2R)-2-((IS,2E)-l-HYDROXY-2-HEXEN-l- YL)CYCLOBLrrYL) METHYL)-N~(((2S,3S)-3-ME ^r rHYL~l"((2S)-2" OXETANYL)-5 -iEXEN-2-YL)SULF()NYL)-3 ^, ,4,4',5-TETRAHYDR()-2 ^, H- SPTRO[ 1 ,5-BENZOXAZEPINE-3, 1 '-NAPHTHALENEJ-7-CARBOXAMTDE AND

(3S)-6 ^, -CHLORO-5-(((lR,2R)-2~((lS,2E)-l"HYDROXY-2-HEXEN~l~ YL)CYCLOBUTYL)METHYL)-N-(((2R,3S)-3-METOYL-l-((2R)-2- OXETANYL)-5 1EXEN-2-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2'H- SPIRO[l,5-BENZOXAZEPINE-3,r-NAPHTHALEN^^

AND

(3S)-6'-CHLORO-5-(((l R,2R)-2-((l S,2E)-1 -HYDROXY-2-HEXEN- 1 -

YL)CYCL0BUTYL)METHYL)-N~(((2S,3R)-: MF;THYL-1-((2R)-2- OXETANYL)-5-HEXEN-2-YL)SULFONYL)-3 ^! ,4,4',5-TETRAHYDRO-2 ^! H- SPIR()[l,5-BENZ()XAZEPINE-3,r-NAPHTHALENEl-7-CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((lS,2E)-l-HYDROXY-2-HEXEN-l-

YL)CYCLOBUTYL)METHYL)-N-(((2R,3R)-3-METFIYL-l-((2R)-2-

OXETANYL)-5-HEXEN-2-YL)SULFONYL)-3',4,4',5-TETRAFIYDRO-2 ^f FI-

SPIRO[l,5~BENZOXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((lS,2E)-l-HYDROXY-2-HEXEN-l- YL)CYCLOBUTYL) METFfYL)-N-(((2S,3S)-3-METFTYL-l -((2R)-2- 0XETANYL)-5-HEXF;N-2-YL)SULJ NYL)-3V4 4V5-TETRAHYDR0-2'H- SPIRO l,5-BENZOXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXAMIDE

The title compounds were prepared from a mixture of (2S,3R)-3-methyl-l- ((2R)-2-oxetanyl)-5-hexene-2-sulfonamide and(2S,3S)-3-methyl-l-((2R)-2- oxetanyl)-5-hexene-2-sulfonamide and (2R,3R)-3-methyl-l-((2R)-2-oxetanyl)-5- hexene-2-sulfonamide and (2R,3S)-3-methyl-l-((2R)-2-oxetanyl)-5-hexene-2- sulfonamide (2S,3R)-3-methyl-l-((2S)-2-oxetanyl)-5-hexene-2-sulfonamide and (2S,3S)-3-methyl-l-((2S)-2-oxetanyl)-5-hexene-2-sulfonamide and (2R,3R)-3- methyl-1 -((2S)-2-oxetanyl)-5-hexene-2-sulfonamide and (2R,3S)-3-methyl-l- ((2S)-2-oxetanyl)-5-hexene-2-sulfonamide and (S)-6'-chloro-5-(((lR,2R)-2-

((S,E)-l-hydrox 'hex-2-en-l-yl)cyclobutyl)me1hyl)-3^4,4^5-tetfahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carbox dic acid (Intermediate AA12A) by a similar procedure described in Step 3 of Example 136. STEP 9: (I S,3'R,6'R,7'S,8'EJ l ^, R,12'S)-6-CHLORO-7 ^, -HYDROXY-l 1"- METHYL-l 2'-((2R)-2-OXETANYLMETHYL)-3 ,4-DIHYDRO-2H, 15 Ή-

SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ '24]PENTACOS

A [8,16,18,24]ΤΕΤί ΑΕΝ]-15'- ONE 13',13'-DIOXIDE OR

(IS 'R^'R ^^T r^n'R^e-CIiLORO^'-I-riOROXY-ll'-METHYL-^'-

((2R)-2-OXETANYLMETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1 ,22'-

|2ujOXA| !3jTIUA| U4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

|8,16,18,24]TETRAENj-15'- ONE 13',13'-DIOXIDE OR

(IS ,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-CHLORO-7'-HYDROXY-l I'-METHYL-12'-

((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18,24]ΊΈΊΈΑΕΝ]-15'- ONE 13', 13 -DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, S,12'R)-6-CHLORO-7'-HYD OXY-lr-MEΊΉYL-12 ^, -

((2R)-2-OXETANYLMETHYL)-3,4-DfflYDRO-2H,15'H- SPIRO[NAPHTHALE E-l,22"- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13',13'-DIOXIDE OR

(1 S,3'R,0'R,7'S,8'Z,1 rR,12'S)-6-CHLORO-7'-HYDROXY~l 1 '-METHYL- 12'-

((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.() ^3>, 0 ^!9 4iPENTACOS

A[8,10,18,24]TETRAEN]-15'~ ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'ZJl'R 2 ^, R)-6-CHLORO-7 ^! -H' ^r DROXY-ll ^, -METHYL-12'-

((2R)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA

[8,I6,18,24]TETiL EN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'Z,ll'S,12'S)-6-CHLORO-7 ^! -HYDROXY-ll'-METHYL-12'-

((2R)-2-OXETANYLME HYL)-3,4-DIHYDRO-2H,15'H- SPIRO [N APHTHALENE- 1,22'- [20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13', 13 '-DIOXIDE OR

(lS 'R,6'R 'S,8'Z rS,12'R)-6-CHLORO-7'-mOROXY-ll'-METHYL-12'-

((2R)-2-OXETANYLMETHYL)-3,4-DlHYDRO-2H,l 5Ή- SPIRO[NAPHTHALENE- 1 ,22'-

|2 ⁽ >jOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

|8,16,18,24]TETRAENj-15'- ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 l'RJ 2'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12'-

((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H ₅ ]5'H- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 '24]PENTACOS

A [8,16,18,24]TETRAEN]-15'- ONE 13',13'~D!OXIDE OR

(lS^'^e'^T'S^^ir^^'RVe-CHLORO-T'-HYDROXY-ir- ETHYL-l^-

((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H,15 ^, H- SPIRO [NAPHTHALENE- 1,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6¾,7'S,8¾ri'SJ2'S)-6-CHLORO-7 ⁱ -HYDROXY-Il'-METHYX-12'-

((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H,15 ^, H- SPIRO[NAPHTHALENE-l,22'-

^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOIl^T^.O'^.O'^lPE TACOSA

[8,16,18,24]TETRAEN]~15'~ ONE 13 I 3 '-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8¾ll ^, S,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-ir-METHYL-12'-

((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,0'R,7 ^* S,8'Z, 1 l'RJ 2'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12'-

((2S)-2-OXETANYLMETHYL)-3,4-Dn-I TJRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ '24]PENTACOS

A[8,10,18,24]TETRAEN]-I5'- ONE 13 ',13 '-DIOXIDE OR

(lS 'R,6'R,7'S,8'Z,n'R 2 ^! R)-6-CIlLORO-7'-I-r ^;" DROXY-ir-METHYL-12'-

((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

|2( ⁾ jOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/.ΥΠ:ΤΗΛ(ΎΠ.ΟΙ i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' .\C0SA

|8,16,18,24]TETRAENj-15'- ONE 13',13'-DIOXIDE OR

(lS 'R )'RJ ^f S,8'Z,ll'S/12'S)-6 ;HI RO-7' iYDROXY-ll'-METim _J -12 ⁱ -

((2S)-2-OXETANYLMETHYL)~3,4-DIHYDRO-2H ₅ 15'H- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0- ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'Z,ll'S,12'R)-6-CHLORO-7'-HYDROXY-ll'-METHYL-12 '-

((2S)-2-OXETANYLMETHYL)-3,4-DIHYDRO-2H,15 ^, H- SPIRO[NAPHTHALE E-l,22"- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15 ^! - ONE 13 ',13 '-DIOXIDE

A round bottom flask was charged with a mixture of (3S)-6'-chloro-5-

(((lR,2R)-2-((lS,2E)-l-hydroxy-2-hexen-l-yl)cyclobutyl)me thyl)

methyl-l-((2S)-2-oxetanyl)-5-hexen-2-yl)sulfonyl)-3',4,4 ^, ,5-tetrahydro-2 ^, H- spiro[l,5-benzoxazepine-3,l '-naphthalene |-7-carboxamide and (3S)-6'-chloro-5-

(((lR,2R)-2-((lS,2E)-l -hydroxy -2-hexen- 1 -yl)cy clobutyl)methyl)-N-(((2S,3R)-3- methyl-l-((2s)-2-oxetanyl)-5-hexen-2-yl)sulfonyl)-: ,4,4',5 etrah}^

spiroj l,5-benzoxazepine-3,l'-naphthalene]-7-carboxamide and (3s)-6'-chloro-5- (((1 R,2R)~2-((1 S,2E)-1 -hydroxy -2-hexen-l-yl)cy clobutyl)methyl)-N-(((2R,3R)-3- methyl~l~((2S)~2~oxetanyl)~5~hex

spiro[l,5-benzoxazepme-3,l '-naphthalene j-7-carboxamide and (3S)-6'-chloro-5-

(((lR,2R)-2-((ls,2e)-l-hydroxy-2-hexen-l-yl)cyclobu1yl)me 1hyl)-N-(((2S,3S)-3- methyl-I-((2S)-2-oxetanyl)-5-hexen-2-yl)sulfonyl)-3',4,4',5- tetrahydro-2'H- spiro[l,5-benzoxazepine-3J'-naphthalene]~7~carboxamide and (3S)-6'-chloro-5- (((lR,2R)-2-((l S,2E)-l-hydroxy-2-hexen-l -yl)c clobutyl)me l)-N ((2R,3S)-3^ methyl-l-((2R)-2-oxetanyl)-5-hexen-2-yl)sulfonyl)-3 ^, ,4,4',5-tetrahydro-2'H- spiroj l,5-benzoxazepine-3,l'-naphthalene]-7-carboxamide and (3S)-6'-chloro-5- (((1 R,2R)-2-((l S,2E)-1 -hydroxy-2-hexen-l-yl)cyclobutyl)tnethyl)-N-(((2S,3R)-3- methyl-l-((2R)-2-oxetanyl)-5-hexen-2-yl)sulfonyl)-3',4,4',5- tetrahydro-2'H- spiro[l,5-benzoxazepine-3, -naphthalene]-7-carboxamide and (3S)-6'-chloro-5- (((lR,2R)-2-((l S,2E) iydroxy-2-hexen-l^

methyl-I -((2R)-2-oxetanyl)-5-hexen-2-yl)sulfonyl)-3',4,4',5-tetrahyd ro-2'H- spiro[l,5-benzoxazepine-3J '-naphihalene]~7~carboxamide and (3S)-6'-chloro-5- (((l R,2R)-2-((l S,2E)-l ½droxy-2-hexen-l-yl)(yclobutyl) methyl)-N-(((2S,3S)-3- methyl-l-((2R)-2-oxetanyl)-5-hexen-2-yl)sulfony])-3',4,4',5- tetrahydro-2'H- spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxamide(265 mg, 0.365 mmol) in DCE (179.0 mL). The mixture was stirred at ambient temperature and bubbled with argon into the reaction flask for 30 mm. To this homogeneous solution was added Hoveyda-Grubbs II (45.8 mg, 0.073 mmol) at ambient temperature and the mixture was stirred under reduced pressure for 18 h. The reaction mixture was concentrated and the crude residue was chromatographed (silica gel column, 0 to 100%, EtOAc+0.5%HOAc hexane) to afford a mixture of the isomers. The mixture was further purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column: Phenomenex, Torrance, CA; gradient eltition of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as the first eluenting isomer. ^l H NMR (400MHz, CD2CI2) δ 8.12 (br s, 1 I I ). 7.74 - 7.69 (m, 1 l i s. 7.17 (dd, J 2.2. 8.5 Hz, I I I }. 7.13 - 7.06 (m, 1 H), 7.01 - 6.81 { in. 3 H), 5.85 - 5.65 (m, 2 H), 5.20 - 5.06 (m, 1 H), 4.66 (br s, 1 I I I 4.50 (br s, I H), 4.20 - 4.04 (m, 4 H), 3.82 (d, .! 1 .3 Hz, 1 ! ! }. 3.68 (d, .1 1 7 Hz, 1 H), 3.25 (d, J=14.3 Hz, 1 H), 3,04 (dd, J 9.6. 15.3 Hz, 1 H i.. 2.84 - 2.70 (m, 3 H), 2.350 - 2. 10 (m, 6 I I }. 2.10 - 1.50 (m, 8 I I }. 1.45 - 1.35 (m, 1 I I }. 1.11 (br s, 1 ! ! }. 1.04 (d, j 6.5 Hz, 3 H i. m/z (ESI, +ve ion) 677.0 (M+Na) ⁺ . EXAMPLE 138. (18,3Έ )' Έ,8Έ^ 2¾)-6-α-ίΕΟΚΟ-7'-Ι-Γϊ ^Γ Ο ΟΧΥ-12'-((28)-

TETRAHYDRO^-FURANYLMETHYL^S^-DIHYDRO-ZH S'H-

SPIRO|NAPHTHALENE-1,22'-[20]OXA[ 13]THIA[ 1, 14]DIAZATETRACYCLO

[14.7.2.0 ³ - ⁶ .0 ^{i 9} - ²⁴ ]PENTACOS A[8, 16, 18,24]TETRAE ]-15'- ONE 13', 13'- DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-TETRAHYDRO-

2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

1,22'-[20]OXA[13]

HIAEl,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ ' ²⁴ jPENTACOSA[8,16,18,24]T ETRAENJ-15'- ONE 13 ^* ,13'-DIOXIDE OR

(l S,3'R,6 ⁱ R,7'S,8'E,12'S)-6-CFILORO-7'-HYDROXY-r2'-((2R.)-TETRAF IYDRO- 2~FURANYLMETHYL)~3,4-DIHYDRO-2H,15H-SPrRO[NAPHTHALENE- 1 ">"><-

^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOI l^T^.O'^.O'^lPE TACOSA

[8,16,18,24]TETRAEN]-15 ^! - ONE 13 I 3 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12 ^, ~((2S)-TETRAHYDRO- 2-FURANYLMETOYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 ,22'-

| 2 ⁽ >X A| i ? I U Π Λ| ί i J l i^f AZ.Vf l: ί RAC YCi C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8, -15'- ONE 13 ',13 '-DIOXIDE

STEP 1 : (2R)-N.N-BIS(4-METHOXYBENZYL)-l-((2R)-TETRAHYDRO-2- FURANYL)-5-HEXENE-2-SULF ON AMIDE AND (2Κ)-Ν,Ν-ΒΚ(4-ΜΕΤΗΟΧΥΒΕΝΖΥΕ)-μ((28)-ΤΕ� �ΚΑΗΥΟ Ο-2-Ρυ ΑΝΥΙ,)- 5-HEXE E-2-SULFONAMIDE AND

(2S)-N,N-BIS(4-METHOXYBENZYL)-l-((2S)-TETOAHYDRO-2-FURANYL)- 5-HEXENE-2-SULFONAMIDE AND

(2S)-N ₅ N~BlS(4~METHOXYBENZYL)-l-((2R)-TETUAHYDRO-2-FURANY -HEXENE-2-SULFONAMIDE

The title compound was prepared from N,N-bis(4-methoxybenzyl)pent-4- ene-1 -sulfonamide (Intermediate EE 19), using a similar procedure described in Example 373, Step 2, replacing 2-(bromomethyl)thiazole with 2-(bromomethyl) tetrahydrofuran.

STEP 2: (2R)~l-((2R)-TETRAHYDRO-2-FURANYL)~5-HEXENE-2- SULFONAMIDE AND

(2R)-l-((2S)-TET¾AHYDRO-2-FURANYL)-5-HEXE TE-2-SULFONAMIDE

AND

(2S)-l-((2S)-TETRAHYDRO-2-FORANYL)-5-HEXENE-2-SULFONAMIDE

(2 -l -((2R)-TETRAI- -2-FURAN -SULFONAMTDE

The title compound was prepared from (2R)-N,N-bis(4-methoxybenz>'l)-l - ((2R)-tetrahydro-2-fiffanyl)~5~hexene-2-sulfonamide, (2S)-N,N-bis(4~ methoxy benz l)- 1 -((2S )-tetrahy dro-2-furany l)-5 -h exene-2-s ulfonami de, (2S)- N,N-bis(4-methoxybenzyl)-l-((2R)-tetrahydro-2-furanyl)-5-hex ene-2- sulfonamide and (2R)-N,N-bis(4-methoxybenzyl)-l -((2S)-tetrahydro-2-furanyl)- 5-hexene-2-sulfonamide by a similar procedure described in Step 3 of Example 373.

STEP 3: (3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l-

YL)CYCLOBUTYL)METHYL)-N-(((2S)-l -((2S)-TETRAHYDRO-2- FURANYL)-5 iEXEN-2-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2'H- SPIRO[l,5-BENZOXAZEPINE-3, Γ - APHTHALENE] -7-CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l-

YL)CYCLOBUTYL)METHYL)-N ((2R)-l~((2S)-TETRAHYDRO-2- Ρυΐ ΑΝΥΕ)-5-ΗΕΧΕΝ~2"ΥΕ)8υΕΡΟΝΥΕ)-3',4,4',5-Τ� �Τ^ ΗΥϋ1 0-2Ή- SPIROi; l,5-BENZOXAZEPINE-3, Γ -NAPHTHALENE] -7-CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l- YL)CYCLOBUTYL)METHYL)-N-(((2S)-l-((2R)-TETRAHYDRO-2-

FURANYL)-5-HEXEN-2-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2'H- SPIR0[1,5-BENZ0XAZEP1NE-3J. ^! -NAPHTOAL;ENE]-7-CARB0XAM1DE AND

(3S)-6 ^, -CHLORO-5-(((lR,2R)-2-((l S ₅ 2E)-l-HYDROXY-2-HEXEN-l- YL)CYCL0BUTYL)METHYL)-N-(((2R)-1-((2R)-TETRAHYDR0-2-

FUR _J ' NYL)-5-HEXEN-2-YL)SULFONYL)-3',4,4',5-TETiLAHYDRO-2'H- SPIRO[ 1 ,5-BENZOXAZEPINE-3, -NAPHTHALENE] -7-CARBOXAMIDE

The title compounds were prepared from a mixture of (2R)- 1 -((2R)- tetrahydro-2-furanyl)-5-hexene-2-sulfonamide, (2R)-l-((2S)-tetrahydro-2- furanyl)-5-hexene-2-sulfonamide, (2S)-l-((2R)-tetrahydro-2-furanyl)-5-hexene-2- sulfonamide, and (2S)-l-((2S)-tetrahydro-2-furanyl)-5-hexene-2-sulfonamide, reacting with (S)-6'-chloro-5-(((l R,2R)-2-((S,E)- 1 -hy droxyhex-2-en- 1 - yl)cv'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[ben zo[b][l,4] oxazepine- 3,l '-naphthalene]-7-carbox lic acid (intermediate AA12A) by a similar procedure described in Step 3 of Example 136,

STEP 4: (lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-HYDRO,W-12 ^, -((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]TH1A[1,14]DIAZATEII ACYCLO[14;7.2 - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8 ₅ 16.18,24]TETRAEN]-15'- ONE 13 ^! J 3 ^* -DIOXiDE OR

(l S,3'R,6 ⁱ R,7'S,8'E,12 ⁱ R)-6-CHLORO-7 ⁱ -HYDROXY-12'-((2R)-TETRAHYDRO-

2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15H-SPIROpSiAPHTHALENE-

1,22'-[20]OXA[13]

TIflA[lJ 41DIAZATETRACYCLO[147/2 ³ -^0 ⁱ - ²⁴ ]PENTACOSA[8,16,18,24]T ETRAEN]-15'- ONE 13',13 ^! -DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8¾12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-TETRAHYDRO- 2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- [20]OXA[ 13]TH1A[1 4]DL ZATET1 ACYCLO[14;7.2 -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'- ONE 13',13'-DIOXIDE OR

(l S,3'R,6 ^, R ₅ 7 ^, S,8¾12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, (2S)-TETOAPIYDRO- 2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [8J 6, 18,24]TETRAEN]-!5'- ONE !3', 13'-DiOXIDE

A round bottom flask was charged with a mixture of (3S)-6'-chloro-5- (((l R,2R)-2-((l S,2E)-l ½droxy-2-hexen-l-yl)(yclobutyl)methyl)-N-(((2S)-l- ((2S)-tetTahydro-2-furanyl)-5-hexen-2-yl)sulfonyl)-3',4,4',5 -tetrahydro-2'H- spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxaniide, (3S)-6'-chloro-5- (((lR,2R)-2-((l S,2E)-1 ½dro^'-2-hexen-l -yl)(y dobu1yl)me l)-N-(((2S)-l - ((2R)-tetrahydro-2-furanyl)-5-hexen-2-yl)sulfonyl)-3',4,4',5 -tetrahydro-2'H- spiro[l,5-benzoxazepine-3, -naphthalene]-7-carboxamide, (3S)-6'-chloro-5- (((lR,2R)-2-((l S,2E)-l½droxy-2-hexen-l-yl)cyck)bu†l)me

((2S)-tetrahydro-2-furanyl)-5-hexen-2-yl)sulfonyl)-3\4,4 5-tetrahydro-2'H- spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxamide, and (3S)-6'-chloro-5- (((l R,2R)~2-((l S,2E)~l ½-droxy-2-hexen-l-yl)cyclobuty1)methyl)

((2R)-tetrahydro-2-furanyl)-5-hexen-2-yl)sulfonyl)-3^4,4^ 5-tetrahydro-2'H- spiro[ l,5-benzoxazepine-3, l '-naphthalene|-7-carboxamide (180 mg, 0.248 mmol) in toluene (85 ml.). The mixture was stirred and sparged with Ar into the reaction flask for 30 mm at ambient temperature. To this homogeneous solution was added Hoveyda-Grubbs II (31.1 mg, 0.050 mmol). The reaction mixture was stirred at ambient temperature under reduced pressure for 18 h. Solvent was evaporated, and the crude residue was chromatographed (silica gel, 10 to 100%, EtOAc+0.5%HOAc/hexane) to afford an oil. Further purification of this oil by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column;

Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TP A, 30 min method) afforded the title compound as the first eluenting isomer. ³ H NMR (400MHz, CD2CI2) δ 7.71 (d, j 8.6 Hz, 1 l i s. 7.17 (dd, J 2.3. 8.6 Hz, 1 H), 7.09 (d, J 2.2 Hz, 1 H), 6.96 (s, 1 H), 6.93 - 6.88 (m, 3 H), 5.89 - 5.81 (m, 1 H), 5.70 (dd, j 1 5.3. 8.0 Hz, 1 H), 4.28

- 4, 16 (m, 3 H), 4.12 - 4,04 (m, 2 I I I 3.88 - 3,68 (m, 4 H), 3.26 (d, 14.3 Hz, 1 H), 3.04 (dd, j 9 5. 15,4 Hz, 1 H), 2.83 - 2.70 (m, 2 H), 2.45 - 2.20 (m, 5 H), 2.12

- 2.01 (m, 3 H), 1.97 ·· 1.46 (m, 12 H). m/z (ESI, +ve ion) 656.2 (M+ a) ^H \

EXAMPLE 139. (1 S,3 ^, R,6'R ₅ 7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22 ^! ~[20]OXA[13]raiA[l,14]DlAZATETRACYCLO [ 14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSA[8, 16,18,241TETRAEN]-15'- ONE 13',13'- DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7'-HYDROXY- 12'-((2R)-TETRAHYDRO- 2-FURANYLMETHYL)-3,4-DJHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACQSA [8,16,18,24]TETiL E ]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12'-((2R)-TETR AHYDRO- 2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15H-SPIRO[NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,I6, I 8,24]TETRAEN1-15'- ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'S)-6-CHI,ORO-7'-HYDROXY-12'-((2S)-TET RAHYDRO- 2-F URAN YLMETHYL)-3 ,4-DIHY DRO-2H, 15 Ή-SPIRO [NAPHTHALENE - 1 22'- pOlOXAtl SJTO Atl ^DIAZATETRACYCLOtMJ^ ^^ O'^lPE TACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13',13'-DiOXIDE

The title compound was obtained as a white solid as the second eluting isomer from the reversed phase preparative HPLC separation in Example 138. ¹ H N.V1R (400MHz, CD2CI2) δ 7.71 (d, J 8.6 Hz, 1 H), 7.16 (dd, J 2.2. 8.5 Hz, 1 H), 7.09 (d, j 2.3 Hz, 1 H), 6.96 - 6.87 (m, 3 H), 5.86 - 5.77 (m, 1 H), 5.68 (dd, j 7.4. 15.3 Hz, 1 I I I 4.20 - 4.04 (m, 5 ! ! }. 3.92 - 3.67 (m, 4 ! ! }. 3.25 id. j 14. 1 Hz, I H), 3.04 (dd, J 9.0. 15.3 Hz, 1 H), 2,83 - 2.69 (m, 2 H), 2,45 - 2.22 (m, 5 H), 2.1 1 - 1.46 (m, 15 H). m/z (ESI, +ve ion) 656.2 (M+Na) ⁺ . EXAMPLE 140. (1 S,3'R,6'R,7'S,8'E, 12 ^, R)-6-CHLORO-7"-HYDROXY- 12'-((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO

[NAPHTHALENE- 1 ,22'-[20] OXA[ 13 ]THIA[ 1 , 14]DIAZ ATETRAC YCLO

[14.7.2.0 ³ - ⁶ .0 ^{i 9} - ²⁴ ]PENTACOSA[8, 16, 18,24] TETRAENJ-15'- ONE 13',13'- DIOXIDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-TETRAHYDRO- 2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPH ^r rHALENE- 1,22'-[20]OXA[13] THIA

[1,14]DIAZ ATETRAC YCLO[ 14.7.2, 0 ³ · ⁶ .0 ¹⁹ - ²⁴ ]PENTACOS A[8, 16, 18,24]TETR AEN]-15'- ONE 13',13'-DIOXIDE OR

(l S,3'R,6¾,7'S,8¾.,12^)-6-CI-ILORO-7'-FiYDROXY-12'-((2R.)-TE TRAI-IYDRO- 2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15H-SPIROP ^> «iAPHTHALENE- 1,22'-[20]OXA[13] THIA [1,14]DI AZ ATETRAC YCLO[ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]ΡΕΝΤ ACOS A[8, 16, 18,24] TETRAEN]-15'- ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12 ^! -((2S)-TETRAIiYDRO- 2~FURANYLMETOYL)~3,4-DIHYDRO-2H, 15 ~SPIRO[NAPHTHALENE- 1 ,22'- [20] ΟΧΛΙ 13] THIA

TETRAENJ-15'- ONE 13',13'-DIOXIDE

The title compound was obtained as a white solid as the third eluenting isomer from the reversed phase preparative HPLC separation in Example 138. ¾ NMR (400MHz, CD2CI2) δ 8.20 (br s, 1 H), 7.66 (d, j 8.4 Hz, 1 H), 7.52 (br s, i l l). 7.15 (dd, j 2.3. 8,4 Hz, ! H), 7.10 (d, J 2.3 Hz, 1 H), 6.97 - 6.87 (m, 2 H), 5.70 (dd, J=4, l, 15.8 Hz, I H), 5.58 - 5.48 (m, I H), 4.27 - 4.17 (m, 3 H), 4.12 - 4.04 (m, 1 H), 3.97 - 3.66 (m, 5 H), 3.38 (d, ./ 14. 1 Hz, 1 H), 3.19 (d, J=16.8 Hz, 1 H), 2.80 - 2.70 (m, 3 H), 2,55 - 2.41 (m, 2 H), 2.38 - 1.40 (ra, 15 H), 1.58 - 1.40 (m, 1 H). m/z (ESI, +ve ion) 656.2 (M+Na) ⁺ .

EXAMPLE 141. (lS,3'R,6 ^! R,7'S,9 ^, Z,i rS)-6-CHLORO-7'-HYDROXY-l Γ- METHYL-3,4-DIHYDRO-2H,15'H-SPIRO|NAPHTHALENE-l,22'-

[20]OXA[13]THIA[I , ! 4] DIAZATETRACYCLO[14 .2 ^3/ \0 ¹⁹ - ² ]PENTACOSA[9,16,! 8,24]TETRAEN] 15'- ONE I3',13'-DIQXIDE OR

(1S,3'R,6'R,7'S,9'Z,1 l'R)-6-CHLORO-7'-HYDROXY-l l'-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1, 14]DIAZATETRACYCLO [14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[9,16 8,24]TETRAEN]-15'- ONE 13' _s 13'-DIOXIDE OR

(lS,3¾,6 ^! R,7^,9T, l l'S)-6-CHLORO-7 ^, -HYDROXY-i r-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[l , 14]DiAZATETRACYCL,O I M 7.2 0 ' ^, '.i ) ^{| :, ! |} |

PENTAC()SA[9,16,18,24]TETRAEN j-15'- ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,9E,1 l ^* R)-6-CHLORO-7'-HYDROXY-l l'~METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - [20]OXA[13]TH1A[1,14]DIAZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PEN -15'- ONE 13',13'-DIOXIDE

STEP 1 : (2S)-2-METHYL-3-BUTENE-l -SULFONAMIDE AND (2R)-2- METHYL-3-BUTEN - 1 -SULFONAMIDE

The title compound was prepared from 2-methyl-3-buten-l-ol using a similar procedure described in Intermediate E22, Step 3-6, replacing (2S,3S)-3- methylhex-5-en-2-ol in Step 3. STEP 2: (3S)-6'-CHLORO-5-(((lR,2R)-2-((l S)-l-HYDROXY-3-BUTEN~l- YL)CYCXOBUTYL)METHYL)-N-(((2S)-2-METHYL-3-BUTEN-l- YL)SULFONYL)-3 ^, ,4.4 ^, ,5-TETRAHYDRO-2 ^, H-SPIRO|;i,5- BENZOXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXA IDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((lS)-l-HYDROXY-3-BUTEN-l- YL)C YCLOB UTYL)METHYL)-N-(((2R)-2-METHYL- 3 -BUTEN- 1 - YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2'H-SPIRO[ 1 ,5- BEN -3,l'-NAPHTHALENE]-7-CARBOXAMTDE

The title compound was prepared from (2S)-2-methyl-3-butene-l- sulfonamide and (2R)-2-methyl-3-butene-l-sulfonamide and (S)-6'-chloro-5-

(((lR,2R)-2-((SH-hydroxybut-3-en^

2H,2'H-spiro[benzo[b] [1 ,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Intermediate AA13A) using a similar procedure described in Step 4 of Example 136.

STEP 3: (1S,3'R,6'R,7'S,9'ZJ l ^, S)-6-CHLORO-7 ^, -HYDROXY-l l ^, -METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THTA[1 ,14] DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ² ]PENTACOSA[9,16,18,24]TETRAENj- 15'- ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,9'Z,1 l ^* R)-6-CHLORO-7'-HYDROXY-l Γ-ΜΕΉ-ΪΥΧ-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - [20]OXA[13]TH1A[1,14]D1AZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PENTACOSA[9 ₅ 16,18,24]TETRAEN]-15'- ONE 13",13'-DIOXIDE OR (lS ¾,6'RJ^,9^ 1 1 'S)-6-CHIX)RO-7' 1YDROXY-ri'-METHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PENTAC0SA[9J 6,18,24]TETRAEN]~1S'~ ONE 13', 13'-DiOXIDE OR

(lS,3'R,6 ^! R 7^,9EJ. l¾)~6-CHLORO-7 ^! ~HYDROXY-rr-ME ^" fflYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO 114.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PE TACOSA[9, 16,l 8,24]TETRAEN]- 15'- ONE 13", 13'-DIOXIDE A round bottom flask was charged with (1 'S)-6'-chloro-5-(((lR,2R)-2-((S)-

1 -hydroxy but-3-en-l-yl)cyclobut )methyl)-N-((2-methylbut-3-en-l-yl)sulfonyl)- 3\4,4 5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7- carboxamide (0.200 g, 0.326 mniol) in toluene (112 ml,). The mixture was stirred at ambient temperature and sparged with N ₂ into the reaction flask for 30 min. To this homogeneous solution was added Hoveyda-Grubbs Π (0.041 g, 0.065 mmol). The mixture was stirred and heated at 100 °C for 2 h. Solvent was evaporated and the crude residue was chromatographed (silica gel, 10 to 100%,

EtOAc+0.5%HOAc/hexane) to afford a mixture of the title isomers. Further purification by both reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) and then chiral separation (Column: Chiralpak OD-H, 3.0 x 25 cm; Mobile phase: 35%

Methanol (20mM NH3)/ 65% CO2; Flow rate: 120 mL/min: SFC Outlet pressure: 100 bar, Temp. = 23C, Wavelength: 248 iim; Sample dissolved to 6 mg/mL in (3: 1) Methanol: DCM (30 mg in 5 mL); introduced 0.4 mL of sample solution, or 2.4 mg crude sample in each preparative injection) afforded the title compound as the first eluenting isomer, Ή NMR (400MHz, CD2CI2) δ 7.73 (d, j 8,1 Hz, 1 H), 7.48 - 7.38 (m, 2 H), 7.17 (dd, J=2.3, 8.4 Hz, 1 H), 7.09 (d, J=2.3 Hz, 1 H), 6.97 (d, j H.8 Hz, 1 H), 5.15 (s, 1 ! ! }. 5.09 (s, 1 H), 4.32 - 4.17 (m, 2 H), 4.16 - 4.07 (m, 2 H), 3.70 - 3.59 (m, 2 H), 3.23 (d, j 1.19 Hz, 1 H), 3.12 (dd, J=8,7, 15.2 Hz, 1 H), 2.95 - 2.86 (m, 2 H), 2,82 - 2.71 (m, 2 H), 2.55 - 2.44 (m, 1 H), 2.42 - 2.23 (m, 2 H), 2.06 - 1.87 ί η ·. 6 H), 1.85 - 1.72 (m, 2 I I ). 1.07 (t, j 7.2 Hz, 4 H). m/z (ESI, +ve ion ) 685.2 ( +Na) ⁺ . EXAMPLE 142, METHYL l-(((lS,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7'- HYDROXY - 1 '. 13 '-DIOXIDO- 15 '-OXO-3,4-DIHYDRO-2H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 |THIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ - ⁶ .0 ^l9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TETRAEN] - 12'-YL)C ARBON YL)-4- PIPERIDINECARBOXYLATE OR

METHYL !-((( 1 S,3 ^* R,6'R,7'S,8'E, 12'S)-6-CHLORO-7'-HYDROXY-l 3', 13'- DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20] OX A [13] ΊΉΪ A [ 1 , 14]DI AZ ATETRACYCLO

[M.T.ZO^^O^^lPENTACOSA IS ^lS^lTETRAEIsn-l^-YL ARBONYL)- 4-PIPERIDINEC ARB OXYL ATE OR

METHYL 1 -((( 1 S,3'R,6'R,7'S,8'Z, 12'R)-6-CHLORQ-7'-HYDROXY~ 13', 13'- DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14] DIAZATETRACYCLO

[14,7.2.0 ³ ' ⁶ .0 ⁱ - ²⁴ ]PENTACOSA[8, 16, 1 8,24]TETRAEN]-12'-YL)C ARBONYL)- 4-PIPERIDINECARBOXYLATE OR

METHYL l-(((lS,3 ^! R,6'R,7'S,8'Z,12'S)-6-CHLORO-7'-HYDROXY-13',13'- DIOXID()-15 ^, -()XO-3,4-DIHYDR()-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[ 1,14] DIAZATETRACYCLO

[14.7.2.0 ³ -^0 ⁱ⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-12'-YL)CARBONYL)- 4-PIPERIDINECARBOXYLATE

STEP 1 : METHYL (2R)-(N,N-BIS(4-METHOXYBENZYL)

SULFAMOYL)HEX-5-ENOATE AND METHYL (2S)-(N,N-BIS(4- METHOXYB -

To a round bottom flask was added N,N-bis(4-methoxybenzyl)pent-4-ene- 1 -sulfonamide (Intermediate EE19, 3.40 g, 8.73 mmol) in THF (34.9 mL) at -78 °C, and butyllithium solution, 2.5 M in hexanes (3.84 mL, 9.60 mmol). The mixture was stirred for 5 nun and then added chlorocarbonic acid, methyl ester (1.01 mL, 13.09 mmol). The reaction mixture was stirred at this temperature for another 20 min and allowed to warm up to ambient temperature. The mixture was quenched with saturated aqueous NH4CI, and extracted with diethyl ether (2x). The combined organic layers were washed with brine, dried (MgSG-O, and filtered. The filtrate was concentrated to afford the title compound which was used without further purification. STEP 2 : (2R)-(N,N-BIS(4- ETHOXYBENZYL)SULFAMOYL)HEX-5-ENOIC

ACID AND (2S)-(N,N-BIS(4-ME ^r fflOXYBENZYL)SULFAMOYL)HEX~5" ENOIC ACI

To a round bottom flask charging with a mixture of methyl (2R)-(N,N- bis(4-methoxybenzyl)sulfamoyl)hex-5-enoate (3.90 g, 8.71 mmol) and methyl (2S)-(N,N-bis(4-methoxybenzyl)sulfamoyl)hex-5-enoate (3.90 g, 8.71 mmol) in THF (36 mL) was added sodium hydroxide (1.39 g, 34.9 mmol) in water (7.3 mL). The reaction mixture was stirred at 50 °C for 18 h and then neutralized with aqueous 1.0 N HC1. The mixture was extracted with EtO Ac (2x). The combined organic layers were washed with brine and dried (MgSC ), and filtered. The filtrated was concentrated and the resulting residue was chromatographed (silica gel, 0 to 100%, EtOAc+0.3%HOAc/hexane) to afford the title compounds. STEP 3: METHYL l-((2R)-( ,N-BIS(4-METHOXYBENZYL)SULFAMOYL) HEX-5 -ENOYL)PIPERIDINE-4-C ARBOXYL ATE AND METHYL 1 ~((2S)~ (N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEX-5-ENOYL)

PIPERlDfNE-4-CARBOXYLATE

To a solution of (2S)-(N,N-bis(4-methoxybenzv'l)sulfamoyl)hex-5-enoic acid and (2R)-(N,N-bis(4-methoxybenz l)sulfamoyl)hex-5-enoic acid (2.10 g, 4.84 mmol), HATU (3.68 g, 9.69 mmol) and N.N-diisopropylethylamine (2.53 mL, 14.53 mmol) in DMF (19.4 mL) was added methyl isonipecotate (1.38 g, 9.69 mmol). The reaction mixture was stirred at 40 °C for 18 h. The mixture was added water, and extracted with EtOAc. The organic layer was concentrated and chromatographed (silica gel, 0 to 30%, acetone/DCM) to afford the title compound as a mixture of two isomers (350 mg, 12.9%). m/z (ESI, +ve ion) 581.2 (M+Na) ⁺ .

STEP 4: METHYL l -((2R)-SULFAMOYLHEX-5-ENOYL)PIPERIDINE-4- CARBOXYLATE AND METHYL l -((2S)-SULFAMOYLHEX-5- ENOYL)PIPERIDINE-4-CARBOXYLATE

The title compounds were prepared from methyl l-((2R)-(N,N-bis(4- methoxybenzyl)sulfamoyl) hex-5-enoyl)piperidine-4-carboxylate and methyl 1- ((2S)-(N,N-bis(4-methoxybenzyl)sulfamoy3)hex-5-enoyl)piperid ine-4-carboxylate using a similar procedure described in Step 2 of Example 136. STEP 5: METHYL l -((S)-2-N-((S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l - HYDROXYHEX-2-EN - 1 - YL)C YCLOB UTYL)METHYL)-3 '4,4' ,5- TETRAHYDRO-2'H-SPIRO[ BENZO[B] [ 1 A OXAZEPINE-3, 1 ' - NAPHTHALENJ-7-YLCARBONYL) SULFAMOYL)HEX-5- ENOYL)PIPERIDINE-4-CARBOXYLATE AND

METHYL l-((R)-2-N-((S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL) METHYL)-3'4,4',5- TETRAHYDRO-2 'H-SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 ' - NAPHTHALEN]-7-YLCARBONYL)SULFAMOYL)HEX-5-ENOYL)

-4-C ARBOXYL ATE

The title compounds were prepared from methyl l-((2R)-sulfamoylhex-5- enoyl)piperidine-4-carboxylate and methyl l-((2S)-sulfamoylhex-5- enoyl)piperidine-4-carboxylate and (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l- hydrox>'hex-2-en-l -y])cyclobutyl)methy])-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (Intermediate AA12A) using a similar procedure described in Step 3 of Example 136.

STEP 6: METOYL l-(((lS,3'R,6'R,7 ^f S,8'E,12'R)-6-CHLORO-7'-HYDROXY- i;r ₅ 13' IOXII30-L5'-OXO-:i4-DmYI3RO-2H~SPIRO[NAPH HALENE-l,22 ^! ~ [20]OXA[ 13]THIA[1 4]DL ZATEII ACYCLO[14;7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA | 8,16,18,24]TETRAENj-12 ^! -YL)CARBONYL)-4- PIPERIDINEC ARBOXYL ATE OR METHYL !-((( 1 S,3'R,6'R,7'S,8'E, 12 ^* S)-6-CHLORO-7"-HYDROXY- 13', 13'- D10XlDO-15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALE E-l,22'- [20]OXA[ 13JTHIA [l,14]DIAZATETRACYCLO

[14.7.2.0 ³ - ⁶ .0 ^{i 9} - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]-.12'-YL)CARBONYL)- 4-PIPERIDINECARBOXYLATE OR

METHYL l"(((l S,3 ^, R,6'R,7'S,8 ^, Z,12 ^, R)"6-CHLORO-7'"HYDROXY-13 13'- DI()XIDO-15'-OX()-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1 , 14] DI AZ ATET AC YCLO

[14 .2i ^, -^0 ¹⁹ - ²⁴ ]PE TACOSA[8J6 8,24]TETRAEN]"12'-YL)CARBONYL)" 4-PIPERIDINECARBOXYLATE OR

METHYL 1 -(((! S,3'R,6'R,7'S,8'ZJ 2 ^f S)-6-CHLORO-7'-HYDROXY-I3', 13'- DiOXn30-15 ^! ~OXD-3,4 ^IHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'- [20] OXA[ 13]THI A[ 1,14] DIAZATETRACYCLO

[ 14:7.2 :) ³ ' ^{6 i9} - ²⁴ ]PENTACOSA[8,16J 8,24]TETRAEN]-12'-YL)CARBONYL)- 4-PIPERIDINECARBOXYLATE

A round bottom flask was charged with a mixture of methyl l-((S)-2-N- ((S)-6' -chloro-5-((( 1 R,2R)-2-((S,E 1 -hy droxyhex-2-en - 1 -yl)cy clobuty l)methyl)- 3'4,4',5-tetrahydro-2'H-spiro[benzo[b] [l,4]oxazepine-3,l '-naphthalen]-7- ylcarbonyl)sulfamoyl)hex-5-enoyl)piperidine-4-carboxylate and methyl 1 -((R)-2- N-((S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l- yl)cy clobuty l)methyl)-3 '4,4' ,5-tetrahy dro-2'H-spiro[ benzo[ b] [ 1 ,4] oxazepine-3, 1 ' - naphthalen]-7-ylcarbonyl)sulfamoyl)hex-5-enoyl)piperidine-4- carboxylate (0.125 g, 0.154 mmol) in AcOH (53.2 ml,). The mixture was stirred at ambient temperature and sparged Ar into the reaction flask for 15 min. To this homogeneous solution was added Hoveyda-Grubbs Π (0.019 g, 0.031 mmol). The mixture was stirred at ambient temperature under reduced pressure for 3 days after which time air was sparged into the flask for 10 min. Solvent was evaporated, and the residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford ihe title compound as the first eluting isomer. ¾ NMR (400MHz, CD2CI2) δ 7.71 (d, J=8.4 Hz, 1 H), 7.16 (dd, j 2.3. 8.7 Hz, 1 H), 7.09 (d, j 2.2 Hz, 1 H), 6.99 - 6.87 (m, 3 H), 5.69 (br s, 1 H), 5.55 - 5.47 (m, 1 H), 4.55 - 4.35 (m, 1 H), 4.35 - 4.19 (m, 2 H), 4.17 - 4.01 (m, 3 H), 3.84 (d, J=15.5 Hz, 1 H), 3.75 - 3.65 (m, 4 H), 3.48 - 3.28 (m, 1 H), 3.25 (d, j 1 .3 Hz, 1 H), 3.11 - 2,97 (m, 2 H), 2.83 - 2,70 (m, 2 H), 2.70 - 2.52 (m, 3 H), 2.50 - 2.27 (m, 5 H), 2.11 - 2.04 (m, 3 H), 2.015 - 1.87 (m, 6 H), 1.88 - 1.74 (m, 3 H), 1.74 - 1.60 (m, 3 H). m/z (ESI, +ve ion) 762.1 (M+Na) ⁺ . EXAMPLE 143. METHYL l-(((lS,3'R,6'R,7 ^, S,8 ^! Z,12 ^! R)-6-CHLORO-7'- HYDROXY-13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 12'-YL)C ARBONYL)-4- PIPERIDINECARBOXYLATE OR

METHYL l-(((lS,:rR,6'R,7'S,8 ^! Z,12¾)-6-CHLORO-7 ^! -HYDROXY-13',13'- DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALE E- 1 ,22'- [20]OXA[13]THIA[1,14]

DIAZATETRACYCLO[14,7.2.0 -^0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN|- '-YL)CARBONYL)-4-PIPERIDINECARBOXYLATE

The title compound was obtained as the third eluenting isomer from the reversed phase preparatorv' HPLC separation in Example 142. ^[ H NMR (400MHz, CDCI3) δ 8.61 (br s, 1 H), 7.73 (d, j 12. i Hz, 1 H), 7.63 (d, j 8.4 Hz, 1 H), 7.21 - 7, 13 (m, 1 H), 7, 1 1 (d, j 2.3 Hz, 1 H), 7.01 - 6.89 (m, 3 H), 5.67 - 5.58 (m, 1 H), 5,42 (dd, J=3, l, 10.4 Hz, 1 H), 4.60 - 4. 57 (m, 1 H), 4,50 - 4.10 (m, 6 H), 3,83 (d, .! 1 .3 Hz, 1 ill 3.75 - 3,70 (m, 4 H), 3.57 - 3,47 (m, ! H), 3.41 (d, 3=9.4 Hz, I H), 3.37 - 3.25 (m, 1 H), 3.24 - 3.05 (m, 1 H), 2.88 - 2.79 (m, 2 H), 2.63 - 2.44 (m, 3 H), 2.42 - 2.16 (m, 5 H), 2.14 - 1.98 (m, 3 H), 1.90 - 1.60 (m, 9 H). m/z (ESI, +ve ion) 762.1 (M+Na) ⁺ .

EXAMPLE 144. (IS,3'R,6'R,7'S,8'E,10'S,I rS)-6-CHLORO-7'-HYDROXY- 10^11 ^, -DIME^ΉYL-3,4-DIHYDRO-2H,14Ή-SPIRO[NAPH^ΉALENE-l ₅ 21 ^, - [19]OXA[12]THIA[1,13]DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ ' ²³ ]TETRACOSA

[8,15,17,23]TETRAEN]-14'~ ONE 13 ',13 '-DIOXIDE OR

(lS ₅ 3 ^, R,6 ^, R,7'S,8¾10 ^, S,ll ^, R)-6-CHLORO-7 ^, -IiYDROXY-10ir-DIMETHYL- 3 ,4-DIHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1,21'- [19]OXA[12]THIA[l,13]

DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹ - ^2J ]TETRACOSA[8,15 _: ,17 ₅ 23]TETRAEN]-

14'- ONE 13',13'-DIOXIDE OR(lS,3'R,6'R,7'S,8 ^* E,lQ ^* R,ll'R)-6-CHLORO-7'- HYDROXY- 10', I I '-DIMETHYL-3,4-DIHYDRO-2H, 14'H- SPIRO [NAPHTHALENE- 1,21'-

[19]OXA[ 12 ]THIA[ 1,13 jDIAZ ATETRACYCLO| 13.7.2.0 ³ - ⁶ .0 ¹⁸ - ² ]TETRACOSA [8,I5,17,23]TETRAEN]-14'- ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8Έ,10 ^, R,ll ^, S)-6-CHLORO-7 ^, -HYDROXY-10^1Γ-DIMETHYL- 3 ,4-DIHYDRQ-2H, 14'H-SPIRO [N APHTHALENE- 1,21'- [19]OXA[12]THIA[l,13]

DIAZATETRACYCLO[13J.2.0 ³ -^0 ¹⁸ ' ²³ ]TETRACOSA[8,15,17,23]TETRAEN]- 14·. ONE I3',13'-DIQXIDE

STEP 1 : (2S,3R)-3-METHYL-4-PENTENE-2-SULFONAMIDE AND (2S,3S)-3- METHYL-4-PENTENE-2-SULFONAMIDE AND (2R,3S)-3-METHYL-4- PENTENE-2- S ULFO AMIDE AND (2S,3R)-3-METHYL-4-PENTENE-2- SULFONAMIDE

The title compounds were prepared by a similar sequence described in EE22, using but-3-en-oi with (2S,3S)-3-methylhex-5-en-2-ol as the starting alcohol in Step 3.

STEP 2: (3S)-6'-CHLORO-5-((( 1 R,2R)-2-(( ! S,2E,4R,5S)- 1 -HYDROXY-4- METHYL-5-SULFAMOYL-2-HEXEN-l-YL)CYCLOBUTYL)METHYL)- 3 ^! ,4,4',5-TETRAHYDRO-2H-SPIRO[l,5-BENZOXAZEPINE-3,r- NAPHTHALENEj-7-CARBOXYLIC ACID AND

(3S)-6"-CFiLORO-5-(((lR,2R)-2 (l S,2E,4S,5S)-l -HYDROXY-4-MEraYL-5-

SULFAMOYL-2-HEXEN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5~

TETRAHYDRO-2'H-SPIRO 1 ,5-BENZOXAZEPINE-3.1 '-NAPHTHALENE] -7- CARBOXYLIC ACID (3S)-6"-CIiLORO-5-(((lR,2R)-2 (l S,2E,4S,5R)-l-IiYDROXY^-METHYL-5-

SULFAMOYL-2-HEXEN-l^L)CYCLOBUTYL)METHYL)-3',4,4',5~

TETRAHYDRO-2'H-SPIRO 1 ,5-BENZQXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLIC ACID

(3S)~6'~CHLQR0~5~(((1R,2R)~2-((1 S,2E,4R,5R)- 1 -ΗΥΙ«ΟΧΥ-4-ΜΈΊΉΥΙ.-5- SULFAMOYL-2"HEXE -l-YL)CYCLOBUIYL)METHYL)-3',4,4',5- TETP _^ 4I-iYDRO-2'H-SPIRO[ l,5-BENZ()XAZEPINT.-3,l'-NAPHTHALENE|-7- CARBOXYLIC ACID

A vial was charged with (S)-6'-chloro-5-(((l R,2R)-2-((S,E)- 1 -hy droxyhex-

2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spirojbenzojb] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic aci d (Intermediate AA12A, 180 nig, 0.353 mmoi) and a mixture of (2S,3R)-3-methyl-4-pentene-2- sulfonamide, (2S,3S)-3-methyl-4-pentene-2-sulfonamide, (2R,3S)-3-methyl-4- pentene-2-sulfonamide, (2S,3R)-3-methyl-4-pentene-2-sulfonamide (288 mg, 1.764 mmol) in DCE (5 mL). The mixture was sparged with Argon first for 10 min. To this mixture was added Hoveyda-Grubbs II (22.11 nig, 0.035 mmoi) at ambient temperature. The reaction was stirred and heated at 50 °C for 3 h, then air was sparged into the flask for 15 min. The mixture was filtered, and the filtrate was directly chromatographed (silica gel, 0 to 100%, EtOAc/hexane, and then to 100% EtOAc+1% HOAc/hexane) to afford the title compounds (106 mg, 49.8%). m/z (ESI, +ve ion) 603,2 (M+Na) ⁺ . STEP 3: (1S,3'R,6'R,7'S,8'E,10'S,1 rS)~6~CHLQRQ~7'~HYDRQXY-10',l 1 ^! - DIMETHYL-3,4-DIHYDRO-2H,14'H-SPIRO[NAPHTHALENE-l ,2V- [ 19]OXA[12]THIA[l ,13]

DIAZATETRACYCLO[13 .2.0 - ⁶ .0 ¹⁸ - ²³ ]TETRACOSA[8J 5,!7,23]TETRAEN]- 14'- ONE 13', 13'-D10XIDE OR (1S,3'R,6'R,7'S,8'E,10'S,1 l'R)-6-CHLORO-7'- HYDRQXY-10',l l'-DIMETHYL-3,4-DIHYDRO-2H,14'H- SPIRO INAPHTHALENE- 1,21'-

[19]OXA[ 12]THIA[1 3]DIAZATETRACYCIX)[ ! 3 .2 ³ '^0 ^1S - ²³ ]TETRACOSA [8,15,17,23]TETRAEN]-14'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R;7'S,8'E, l()'R,l l'R)-6-CHLORO-7' 3YDROXY-10' r-DlMETHYL- 3,4-ΟΙΗΥΌΚΟ-2Η,14Ή-8ΡΙΚΟ[ΝΑΡΗΤΗΑ1ΕΝΕ- 1,21 '-

[lQlOXAt^lTHIAtl SlDIAZATETRACYCLOIlS.T^.O^^ O^^JTETRACOSA [8,15,17,23]TETRAEN]-14'- ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,10'R,1 l'S)-6-CHLORO-7'-HYDROXY-l 0',1 l'-DTMETHYL- 3 ,4 -DIHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1 ,2 '-

[19]OXA[12]THIA[l,13]DIAZATETRACYCLO[13.7.2.0 ³ ^ 0 ¹⁸ - ² ]TETRACQSA [ 8,15,17,23 ]TETRAEN]-14'- ONE 13',13'-DIOXIDE

To a mixture of (3S)-6 ^* -chloro-5-(((lR,2R)-2-((l S,2E,4R,5S)-l-h droxy- 4-methyl-5-sulfamoyl-2-hexen-l -yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2'h- spiro| l,5-benzoxazepine-3,r-iiaphtlialene]-7-carboxylic acid, (3S)-6'-chloro-5- (((l R,2R)-2-((l S,2E,4S,5S)-l-hydroxy-4-methyl-5-sulfamoyl-2-hexen-l- yl)c Iobutyl)methyl)-3',4,4',5-tetrahydro-2'h-spiro[l,5-benzoxaze pine-3,r- naphthalene]-7-carboxyliic acid, (3S)-6'-chloro-5-(((lR,2R)-2-((l S,2E,4S,5R)-1- hydroxy-4-methyl-5-sulfamoyl-2-hexen-l-yl)cyclobutyl)methyl) -3',4,4',5- tetrahydro-2'h-spiro[l,5-benzoxazepine-3,.l '-naphthalene ]-7-carboxylic acid and (3S)-6'-chioro-5-(((J^2R 2~((l S,2E,4R,5^^

hexen-l-yl)cyclobut d)methyl)-3',4,4',5-tetrahydro-2'h-spiro[ l,5-beiizoxazepine- 3,1 '-naphthalene] -7-carboxy lie acid (110 mg, 0.182 mmol) was added N,N- dimethylpyridin-4-amine (DMAP) (44.6 rng, 0.365 mmol) and triethylamine (0,076 mL, 0.547 mmol) in DCM (100 mL) at ambient temperature. N-(3- dimethylaniinopropyl)-N'-ethylcarbodiiiriide hydrochloride (69.9 nig, 0.365 mmoi) was added slowly . The mixture was stirred at ambient temperature for 1 8 h. The reaction was then diluted with dichloromethane, washed with saturated sodium bicarbonate, saturated ammonium chloride, and brine. The combined organic layers were dried (MgS0 ₄ ), filtered and the filtrate was concentrated. The crude residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0, 1 % TFA, 30 min method) to afford the title compound as the second eluenting isomer. ^! H NMR (400MHz, CeDe) δ = 7.98 (br s, i 1 1 ). 7.72 (d, J==8.8 Hz, 1 H), 7.30 (dd, .1 2 1 . 8.3 Hz, 1 H), 7.18 (d, j 8.7 Hz, I H), 7.10 (d, J 2.2 Hz, 1 H), 6.96 (d, .! 6 9 Hz, 1 H), 6, 86 i s. 1 H), 5.84 (dd, J=4.3, 15.5 Hz, 1 H), 5.74 (dd, J=8.8, 15.8 Hz, i H), 4.16 - 4.05 (m, 3 H), 3.75 - 3.63 (m, 2 H), 3.45 - 3.20 (m, 3 H), 2.83 - 2.71 (m, 2 H), 2.56 - 2.46 (m, 1 H), 2.43 - 2.33 (m, 1 H), 2.09 - 1.80 (m, 6H), 1 ,68 - 1.58 (m, 3 H), 1.57 id, J 7.2 Hz, 3 H), 1.13 (d, J=6.8 Hz, 3 H). m/z (ESI, +ve ion) 585,2 (M+Na) ¹ .

EXAMPLE 145. ((l S,3'R,6'R,7'S,8 ^! E, 12 ^! S)-6-CHLORO-7'-HYDROXY-13 ^, , 13'- DIOXIDO- 15*-OXO-3,4-DIHYDRO-2H-SPIRO[N APHTHALENE- i ,22'- [20]OXA[13]THIA[1 ,14]

DL ZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^{i 9} - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN j- 12'-YL)ACETONTTRILE OR

((1 S,3'R,6 ^! R,7'S,8'E, 12'R)~6~CHLORO-7 ^! ~HYDROXY-l 3', 13'-DIOXIDO-l 5*- OXO-3,4~DIHYDRO-2H-SPlRO[NAPHTHALENE"l,22'- [20 |ΟΧΑ[13]ΤΗΙΑ|;ΐ , 14] DI AZATETRACYCLO [14.7.2.0 ³ - ⁶ .0 ¹⁹ · ²⁴ 1

PENTACOSA[8, 16, 1 8,24]TETRAEN]-12'-YL)ACETONITRILE OR

((i S,3 ^! R,6¾,7'S,8 ^, Z, i2 ^, S)-6-CHLORO-7'-HYDROXY -13V13'-DiOXIDO-15'- OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l _s 22'- [20]OXA[ 13 |THIA[ 1 , 14 j DI AZATETRACYCLO [ 14.7.2. > r ". () ^{! 9 24} ]

PENTACOSA[8, 16,18,24]TETRAEN]-12'-YL)ACETONlTRILE OR ((iS ¾ )'R 'S,8'Z, I 2'R)-6-CHIimO-7' iYDROXY-! 3Vi3'-DIOXIDO-15'- OXO-3,4-DlHYDRO-2H-SPIRO[NAPH ^r fflALENE-l,22'- [20]OXA[ 13 |THIA[ 1 , 14 j DIAZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PENTACOSA 8J 6,18,24]TETRAEN]-12'-

STEP 1 : (3S)-l-HYDROXY-N ₅ N-BIS(4-METHOXYBENZYL)-6-HEPTENE-3- SULFON AMIDE AND (3R)- 1 -HYDROXY-N,N-BIS(4-METHOXYBENZYL)- 6-HEPTENE-3-

To a solution of N ,N-bis(4-methox benzy l)pent-4-ene- 1 -sulfonamide

(Intermediate EE19, 2.55 g, 6.55 mmol) in THF (26 mL) was added butyllithium solution, 2.5 M in hexanes (2.88 mL, 7.20 mmol) at -78 °C dropvvise. The reaction mixture was stirred at -78 °C for 10 min, and then ethylene oxide gas was introduced into the reaction flask by sparging from a cylinder for 1 h at the same temperature. The reaction mixture was allowed to warm to ambient temperature. The mixture was then quenched with saturated aqueous NH ₄ C1, and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried

(Na ₂ S04), and filtered. The filtrate was concentrated. The resulting residue was chromatographed (silica gel, 30 to 60%, EtOAc/hexane) to afford the title compounds (1.80 g, 63.4%) as a colorless oil.

STEP 2: (3R)-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEPT-6- ENOIC ACID AND (3S)~(N,N~BIS(4~

METHOXYBENZYL)SULFAMOYL)HEPT-6-ENOIC ACID

In a round bottom flask equipped with an additional funnel was added (3S)-l-hydroxy-N,N-bis(4-methoxybenz ])-6-heptene-3-sulfonairade and (3R)-1- hydroxy-N,N-bis(4-methoxybenzyl)-6-heptene-3-sulfonamide (1.00 g, 2.31 mmol), KBr (27.4 mg, 0.231 mmol), 5% sodium bicarbonate in water (10.85 mL, 6.46 mmol), and TEMPO (396 mg, 2.54 mmol) in acetone (15 mL). To this mixture was added 6% sodium hypochlorite in water (2.07 mL, 1 .67 mmol) at 0 C° through the additional funnel. The resulting reaction mixture was stirred at this temperature for 1 h. The mixture was diluted with diethyl ether, added ice cold aqueous I .0 N HC1 (30 ml.) with brine (30 mL). The organic layer was washed with brine, dried (NaaSC ) and concentrated. The residue was chromatographed (silica gel, 0 to 100%, EtOAc + 0.5% HOAc/DCM) to afford the title compounds (530 mg, 51.3%) as a pale brown syrup.

STEP 3: (3R)-(N,N-BIS(4^1ETHOXYBENZYL)SULFAMOYL)HEPT~6-

E AMIDE AMD (3S)-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEPT-

6-EN AMIDE

To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)hept-6-enoic acid (530 mg, 1.18 mmol), and N,N-diisopropylethylamine (0.618 mL, 3.55 mmol) in DMF (1.00 mL) was added 7.0 N ammonia solution in methanol (0.846 mL, 5.92 mmol). The reaction mixture was stirred at 50 °C for 18 h. Solvent was evaporated, and the crude residue was chromatographed (silica gel, 0 to 40%, aeetone+10%MeOH/DCM) to afford the title compounds (50 mg, 9.45%).

STEP 4: (2S)-1 -CYANO-N,N-BIS(4-METHOXYBENZYL)-5-HEXENE-2- SULFONAMIDE AND (2R)-1 -CYANO-N,N-BIS(4-METHOXYBENZYL)- HEXENE-2-S

A solution of (3R)-(N,N-bis(4-methoxybenzv'l)sulfamoyl)hept-6-enoic acid and (3S)-(N,N-bis(4-methoxybenz} ⁱ -i)sulfamoyl)hept-6-enoic acid (50 mg, 0.1 12 mmol) and tri ethyl amine (0.078 mL, 0.560 mmol) in tetrahydrofuran (3 mL) was added tnfluoroacetic anhydride (0.039 mL, 0.280 mmol) and stirred from 0 °C to ambient temperature for 2 h. The mixture was quenched with H2O, and extracted with EtOAc (2x). The organic layer was washed with brine, dried (MgS0 ₄ ), and filtrated. The filtrate was concentrated. The resulting residue was chromatographed (silica gel, 0 to 50%, acetone/DCM) to afford the title compounds (45 mg, 94 %). STEP 5: (2S)-l -CYANO-5-HEXENE-2-SULF ON AMIDE AND (2R)-l-CYANO- 5-HEXE E-2-SULFO

_The title compoimds were prepared from a mixture of (2S)-l -cyano-N,N-bis(4- methoxybenzyl)-5-hexene-2-sulfonamide and (2R)-l -c ano-N,N-bis(4- methoxybenzyl)-5-hexene-2-sulfonamide using a similar procedure described in Step 2 of Example 137.

STEP 6: (3S)-6'-CHLORO-N-(((2S)-l -CYANO-5-HEXEN-2-YL)SULFONYL)- 5-(((l R,2R)-2-(( 1 S,2E)- 1 - HYDROXY -2,5-HEXADIEN- 1 -

YL)CYCIX)BUTYL)MF iYL)-3',4,4',5-TETRAHYDRO-2'H-SPIRO[ l,5- BENZOXAZEPINE-3, i '-NAPHTHALENE] -7-CARBOXAMIDE AND (3 S)-6 ^! ~ CHL0R0-N-(((2R) X:YAN0-5-HEXE -2-YL)SULF0NYL)-5-(((1R,2R)-2- ((l S,2E)-l-HYDROXY-2,5-HEXADIEN-l-YL)CTCLOBUTYL)METHYL)- ;r,4 4^5-TETRAHYDRO-2H-SPiRO[L5-BENZOXAZFJ ⁵ iNE~3 r

APHTH ALENE] -7 -C ARB OXAMIDE

To a mixture of (2S)-l-cyano-5-hexene-2-sulfonamide and (2R)-l-cyano- 5-hexene-2-sulfonamide was added N,N-Dimethylpyridin-4-amine (DMAP) (96 mg, 0,784 mmol), (S)-6'-chloro-5-(((lR,2R)-2-((S ₅ E)-l -hydroxyhex-2-en-l- yl)c> lobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (Intermediate AA12A, 200 mg, 0.392 mmol) and triethylamine (0. 164 mL, 1.176 mmol) in DCM (2 mL) at ambient iemperaiure. N-(3-dimethy]aminopropyl )-n'-ethylcarbodiimide hydrochloride (150 mg, 0.784 mmol) was added slowly and the reaction mixture was stirred at ambient temperature for 18 h. The mixture was diluted with dichloromethane. The organic layer was washed with aqueous 1.0 N HCI, brine and dried (MgS0 ₄ ) and filtered. The filtrate was concentrated and the resulting residue was chromatographed (silica gel, 10 to 100%, EtOAc+1% HOAc/hexane) to afford the title compounds (230 mg, 86%). m/z (ESI, +ve ion) 702.3 (M+Na) ⁺ .

STEP 7: ((1 S,3'R,6'R,7'S,8'E, 12'S)-6-CHLORO-7'-HYDROXY-l 3', 1 3'- DIOXIDO- 15 ^! -QXQ-3,4-DIHYDRQ-2H-SPIRQ[NAPfflYTALENE- 1 ,22'- [20jOXA[13]THiAj l ,14]

DIAZATETRACYCLO[14,7.2.0 -^0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]- 12'-YL)ACETONITRILE OR ((l S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'- HYDROXY - 13 ', 13 '-DIOXIDO- 15 '-OXO-3,4-DIHYDRO-2H- SPIRO I NAPHTHALENE- 1 ,22'-[20] OX A[ 13] THI A[ 1 , 14 j

DIAZATETRACYCLO[14.7,2.0 ³ - ⁶ .0 ³⁹ - ²⁴ ] PENTACOSA[8J 6,18,24]TETRAEN]~ 12'-YL)ACETONITRlLE OR

((l S,3'R,6'R,7'S,8 ^! Z, 12 ^! S)-6-CHLORO-7'-HYDROXY-13',13'-DIOXIDO-15'- OXO-3,4-DIT-rYDRO-2H-SPIRO[NAPHTOALENE-I,22'- [20]OXA[ 13]THI A[ 1 , 14] DIAZATETRACYCLO [14,7.2. ( V.0 ¹⁹ · ²⁴ ]

PENTACOSA[8,16,18,24]TETiL E ]-12'-YL)ACETONITi ILE OR

((I S _^ TR i'R^'S^'Z/^'R fi-CHLORO^'-HYDROXY- ' S'-DIOXIDO-l S'- OXO-3,4-DIHYDRO-2H-SPIRO| APHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14] DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTAC OS A [8, 16,18,24] TETRAEN] - 12'-YL) AC ETONITRILE

A round bottom flask was charged with (3S)-6'-chloro-N-(((2S)-l-cyano- 5-hexen-2-yl)sulfonyl)-5-(((lR,2R)-2-((l S,2E)-l -hydrox -2,5-hexadien-l - y )cyxiobut d)methy )-3',4,4',5 etraliydro-2'h-spiro[l,5-benzoxazepine-3,r- naphthalene]-7-carboxamide and (3S)-6'-chloro-N-(((2R)-l -cyano-5-hexen-2- yl)sulfonyi)-5-(((lR,2R)-2-((lS,2E)-l-hydroxy-2,5-hexadien-l - yl)cyciobutyl)methyl)^

naphthalene]-7-carboxamide (0.260 g, 0.382 mmol) in AcOH (132 mL). The mixture was stirred at ambient temperature and argon was sparged into the reaction flask for 15 min. To this homogeneous solution was added Hoveyda- Grubbs II (0.048 g, 0.076 mmol). The mixture was stirred at ambient temperature under reduced pressure for 18 h. Air was sparged into the reaction for 10 min. Solvent was removed and the crude residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient eiution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as the first eluenting isomer (8 rag, 3.43 %). Ή N .MR (400MHz, CD2CI2) δ 7,71 (d, J 8.4 Hz, I 1 1 ). 7.17 (dd, J 1 .8. 9,2 Hz, 1 H), 7.10 (d, J=1.8 Hz, 1 H), 7.03 - 6.88 (m, 3 H), 5.83 - 5.68 (m, 2 H), 4.35 - 4.40 (m, 1 H), 4.21 (t, J=4.7 Hz, 1 H), 4.15 - 4.02 (m, 2 H), 3.81 (d, .1 14.' ⁾ Hz, 1 H), 3.70 (d, j 14. ! Hz, 1 H), 3.26 (d, j 14.3 Hz, 1 H), 3.16 - 2,98 (m, 3 H), 2.91 - 2,70 (m, 2 H), 2.47 - 2.20 (m, 6 H), 2. 15 - 1.51 (m, 6 H), 1.42 (t, J=12.1 Hz, 2 H). m/z (ESI, +ve ion) 585,2 (M+Na) ⁺ .

EXAMPLE 146. (lS,3 ^, R ₅ 6 ^, R,7 ^, S.8 ^, E.12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(4-

MORPHOLINYLMETHYL)-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THL [1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,I6, I 8,24]TETRAEN1-15'- ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12'-(4-

MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]~15'~ ONE 13',13'-DIOXIDE

STEP 1 : (2R)l-HYDROXY-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2- SULFONAMIDE AND (2S)-1 -HYDROXY -N,N-BIS(4-METHOXYBENZYL)- -HEXENE-2-SULFONAMIDE

To a round bottom flask was added methyl 2-(N,N~bis(4~

methoxybenzyl)sulfamoyl)hex-5-enoate (from Example 142. Step 1, 0.82 g, 1.83 mmol), lithium borohydride (0.08 g, 3.66 mmol) in THF (9.16 mL), and a few drops of water at ambient temperature. The reaction mixture was stirred for 18 h and added aqueous 1.0 N HC1 (2 mL). The mixture was extracted with EtO Ac (2x). The combined organic layers were washed with water, brine, dried (MgSO- , and filtered. The filtrate was concentrated and the crude residue was chromatographed (silica gel, 20 to 60%, EtOAc/hexane) to afford the title compound.

STEP 2: (2S)-N ₅ N-BIS(4-METHOXYBENZYL)-l -OXO-5-HEXENE-2-

SULFONAMTDE AND

(2R)-N,N-BIS(4-M -l-OXO-5-HEXENE-2-SULFONAMIDE

To a solution of (2R)-.l -hydroxy-N,N-bis(4-methoxybenzyl)hex-5-ene-2- sulfonamide and (2S)-l-hydroxy-N,N-bis(4-methoxybenzyl)-5-hexene-2- sulfonamide (2.00 g, 4.77 mmol) in DCM (20 mL) was added Dess-Martin periodinane (4.04 g, 9.53 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 12 h. The mixture was then quenched with saturated aqueous Na2S ₂ Cb (15 mL), and extracted with Et ₂ 0 (2x). The combined organic layers were washed with saturated aqueous NaHCCb, brine, dried (MgSCH), and Filtered, the filtrate was concentrated, and the crude residue was chromatographed (silica gel, 10 to 40%, EtOAc/hexane) to afford the title compounds.

STEP 3: (2R)~N,N-BIS(4 lETHOXYBE ZYL)-l-(4-MORPHOLlNYL)-5- HEXEN E-2- SU LF ON AMIDE AND (2S)-N,N-B1S(4-METH0XYBE ZYL)-1 - (4-MORPH -5-HEXENE-2-SULFONAMIDE

To a mixture of (2S)-N,N-bis(4-methoxybenzyl)-l-oxo-5-hexene-2- sulfonami de, (2R)-N,N-bi s(4-methox benzyl)- 1 -oxo-5 -hexene-2-sul fon amide (1.60 g, 3.83 mmol), morpholine (0.84 mL, 9.58 mmol), and acetic acid (5 drops) in DCE (25 mL) was added sodium triacetoxyborohydride (2.44 g, 11.50 mmol) at ambient temperature. The mixture was stirred for 12 h, and additional morpholine and sodium triacetoxyborohydride (2,44 g, 1 1.50 mmol) were added to reach the completion. The reaction was quenched with saturated aqueous NH C!, and extracted with EtOAc. The organic layer was washed with brine, dried (MgS0 ₄ ) and concentrated. The residue was purified by the reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compounds (1.20 g, 64.1%). STEP 4: (2S)-l-(4-MORPHOLINYL)-5-HEXENE-2-SULFONAMlDE AND (2R)- 1 -(4-MORPHOL -5-HEXENE-2-SULFONA IDE

The title compounds were prepared from (2R)-N,N-bis(4-methoxy benzyl)- 1 -(4- ^η ιο 1ιο1ϊ ^η ν1)-5-1ΐ6Χ6η6-2-8η1Γο ^η α ^η Ίίά6 and (2S)-N,N-bis(4-methoxybenzyl)- 1-(4-ηιο ΗοΙϊη ^· 1)-5-1ΐ6 6η6-2-8η]ίοη3ηιίά6 using a similar procedure in Step 2 of Example 136. STEP 5: (3S)-6'-CHLORO-5-(((l R,2R)-2-((l S ₅ 2E)-l -HYDROXY-2-HEXEN-l - YL)CYCLOBUTYL)METHYL)-N-(((2S )- 1 -(4-MORPHOLINYL)-5-HEXEN-2-

YL)SULFONYL)~3V4,4',5-TETRAHYDRO-2 ^! H-SPIRO[l ,5- BENZOXAZEPlNE-3, -NAPHTHALENE]-7-CARBOXAMIDE AND (3S)-6'- CHLORO-5-(((l R,2R)-2-((l S,2E)-1 -HYDROXY -2-HEXEN- 1 - YL)CYCLOBUTYL)METHYL)-N-(((2R)- 1 -(4-MORPHOLINYL)-5-HEXEN-2-

YL)SULFONYL)-;r ₅ 4 4V5-TETRAHYDRO-2'H-SPiRO[l,5- -3,l'-NAPHTHALENE]-7-CARBOXAMIDE

To a mixture of (2R)-l-(4-morphoiinyl)-5-hexene-2-sulfonaniide and (2S)- 1-(4^ο ηο1ίην1)-5 ΐ6Χ6η6-2-8α1ίθΜίϊ β was added N,N-dimethylpyridin-4- amine (DMAP) (96 mg, 0,784 mmol), a solution of (S)-6'-chloro-5-(((lR,2R)-2- ((S,E)-l-hydrox\'hex-2-en-l-yl)c lobutyl)me l)-3^4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro] benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A, 200 mg, 0.392 mmol) and triethylamine (0.164 mL, .1.176 mmol) in DCM (2 mL) at ambient temperature. N-(3-dimethylaminopropyl)-n'- ethylcarbodiimide hydrochloride (150 mg, 0.784 mmol) was then added slowly. The mixture was stirred at ambient temperature for 18 h. The mixture was added water and diluted with dichloromethane. The organic layer was washed with aqueou 1.0 N HC1, brine, dried (MgS0 ₄ ) and filtered. The filtrate was concentrated and the resulting residue was chromatographed (silica gel, 10 to 100%, EtOAc+1% HOAchexane) to afford the title compounds (230 mg, 86%).

STEP 6: ( lS,3 ^f R,6'R,7'S,8'E,12'S)-6-CHLO O-7'-HYDROXY-l 2'-(4- MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSlTO Atl ^DIAZATET ACYCLOtl^y^.O'^.O'^lPE TACOSA

[8,16,18,24]TETRAEN]-15 ^! - ONE 13 I 3 '-DIOXIDE OR

(IS^' ^'R 'S^U^'Ri-e-CHLO O-T'-HYD OXY-^'^- MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2. · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

|8,16,18,24]TETRAENj-15'- ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'Z,12'S)-6-CHLORO-7'-HYDROXY-12'-(4- MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13|THIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ - ^f \0 ^l9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'- ONE 13', 13 -DIOXIDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, Z,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(4- MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-[20] OXA[ 13]THI A[ 1 , 14]

DIAZATETRACYCLO[14J.2.0 ³ -^0 ¹⁹ ' ² ]PEOTACOSA[8,16,18,24]TETRAEN]- 15'- ONE 13',13'-D10XIDE

A round bottom flask was charged with (3S)-6'-chloro-5-(((lR,2R)-2- ((1 S,2E)-1 iydroxy-2-hexen-l-yl)cyclobutyl)methyl)-N-(((2S)-l-(4- moφholiny])-5-he en-2-yl)sιdfonyl)-3',4,4 ^, ,5-tetrahydro-2Ή-spiro[l,5- benzoxazepine-3,r-naphthalene]-7-carboxamide and (3S)-6'-chloro-5-(((lR,2R)- 2-((lS,2E)-l½droxy-2-hexen-l-yl)cydobu1yl)me1hyl)-N-(((2R)- l-(4- mo holinyl)-5-hexen-2-yl)sulfon l)-3',4,4',5-tetrahydro-2 ^, h-spiroΓl,5- benzoxazepine-3, -naphthalene]-7-carboxamide (210 nig, 0.284 mmol) in DCE (142 mL). The mixture was stirred at ambient temperature and argon was sparged into the reaction flask for 30 mm. To this homogeneous solution was added Hoveyda-Grubbs TT (35.5 mg, 0.057 mmol) and stirred at ambient temperature under reduced pressure for 18 h. Solvent was evaporated and the crude residue was chromatographed ( silica gel, 10 to 100%», EtOAc+0.5%HOAchexane, and then 100% 10%MeOH/DCM) to afford an oil. Further purification of this oil by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column;

Phenomenex, Torrance, CA; gradient eiution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) afforded the title compound as the first eluenting isomer. ¾ NMR (400MHz, CD2CI2) δ 7.71 (d, j 8.5 Hz, 1 H), 7.16 (dd, J=2.2, 8.5 Hz, 1 H), 7.09 (d, J 2.2 Hz, 1 H), 7.03 (dd, j H.i.1.7 Hz, 1 H), 6.96 - 6.91 (m, 2 H), 5.81 - 5.72 (m, 1 H), 5.67 (dd, j 5.7. 15.5 Hz, 1 H),5.15-4.51 (br, 2 H), 4,49 (br s, 2 H), 4.34-4 I Mm.1 H), 4.14- 3.94 (m, 6 H), 3.82 - 3.57 (m, 3 H), 3.52 - 3.24 (m, 5 H), 3.11 (dd, J=8.3, 15.4 Hz, 1 H), 2.83 - 2.68 (m, 2 H), 2.47 - 2.30 (m, 3 H), 2.30 - 2.12 (m, 2 H), 2.06 - 1.98 {in.2 H), 1.98 - 1.60 (m, 6 H). m/z (ESI, +ve ion) 670.2 {\L\a) .

EXAMPLE 147. (lS,3 ^, R,6'R,7 ^! S,8'Z,12'R)-6-CHLORO-7'-HYDROXY-12'-(4-

MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YCT (>! i L7.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,12'S)-6-CHLORO-7'-HYDROXY-12'-(4-

MORPHOLINYLMETHYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[.1 ,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,1 -15'- ONE 13',13'-DIQX1DE

The title compound was obtained as the third eluenting isomer from the reversed phase preparatory HPLC separation in Example 146. ^! H NMR

(400MHz, CD2CI2) δ 7.72 (d, J=8.4 Hz, 1 H), 7.42 (dd, J=2.1, 8.3 Hz, 1 H), 7.38 (d, .! 3.7 Hz, 1 H), 7.16 (dd, j 2.2. 8.5 Hz, 1 H), 7.09 (d, j 2.2 Hz, 1 H), 6.97 (d, J==8.4 Hz, I H), 5.72 - 5,62 (m, 1 H), 5.58 (dd, j 6 I . 1 1.0 Hz, 1 H), 4.42 (t, J 7.2 Hz, I H), 4.17 (d, J 6. 7 Hz, 1 H), 4.13 (d, j 2 9 Hz, 2 H), 4,03 - 3.88 (m, 5 H), 3.83 (d, J=15.8 Hz, 1H), 3.65 (d, J=14.1 Hz, 1H), 3.50 - 3.29 (br, 2 H), 3.28 (d, j 4.3 Hz, 1 H), 3.24 (d, j 4.5 Hz, 1 H), 2.80 - 2.72 (in, 2 H), 2.67 - 2.52 (in, 2 H), 2.50 - 1.65 ( ns. 13 H), 1 .57 - 1.43 (ra, 2 H). m/z (ESI, +ve ion) 670.2 (M+Na) ⁺ .

EXAMPLE 148. (l S^'^e'R-T'S^'^^'S^e-CHLORO-l^-CYCLOPROPYL-?'- H YDROXY-3 ,4-DIHYDR0-2H, 15 'H-S PIRO [N APHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'- ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-I2'-CYCLOPROPYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]Tffl A[l J^DIAZATETRACYCLOlMJ^.O^^O'^jPENTACOSA [8,1 -15'- ONE 13',13'-DI0X1DE

STEP 1 : BIS (4-METHOX

To a three neck round bottom flask was added (4-methoxyphenyl) methanamine (35.7 g, 260 mmol) and 4-methoxybenzaldehyde (31.7 mL, 260 mmmol) in EtOH (300 mL, 200 proof). The reaction mixture was stirred and the internal temperature was increased to 41 °C. A precipitate was formed. After about 5 min, additional ethanol (300 mL) was added to the reaction while stirring. The reaction mixture was stirred for 1 h and NaBH ₄ (5.91 g, 156 mmol) was added portionwise in 40 min. The maximum internal temperature was about 33 °C. The reaction was then cooled in an ice bath, and the slurry was added concentrated HC1 (42 mL) dropwise maintaining internal temperature <15 °C. The reaction mixture was allowed to warm up to ambient tmeperature, and filtered. The solid was wash with ethanol and the resulting cake was dried under nitrogen to afford the title compound.

STEP 2: 1-CYCL0PR0PYL-N,N-BIS(4

METHOXYBENZYL)MET

To a solution of bis(4-methoxybenzyl)amine (3.02 g, 11.74 mmol) and triethylamine (5.71 mL, 41.1 mmol) in CH2CI2 (58.7 mL) at 0 °C was added cyclopropylmethanesulfonyl chloride (1.00 mL, 6.47 mmol) dropwise over 5 minutes. The cloudy mixture was stirred at 0 °C for 1 h and then diluted with CH2CI2. The mixture was washed twice with brine. The aqueous layer was back extracted with EtOAc and the combined organic layers were dried (MgS0 ₄ ), and filtered. Solvent was evaporated, and the crude orange oil was chromatographed (silica gel, 0 to 60 %, EtOAc hexane) to afford the title compound (2.49

56.5%). m/z (ESI, +ve ion) 398.2 (M+Na) ⁺ .

STEP 3 : 1 -CYCLOPROPYL-N,N-BIS(4-METHOXYBENZYL)PENT-4- SULFONA

To a solution of l-cyclopropyl-N,N-bis(4- methoxybenzyl)methanesulfonamide (2.10 g, 5.59 mmol) in THF (20 mL) was added butyllithium solution, 2,5 M in hexanes (2,46 ! mL, 6.15 mmol) at -78 °C dropwise. The reaction mixture was stirred at -78 °C for 10 min, and 4-bromo-l- butene (1.70 mL, 16.78 mmol) was added at this temperature. The reaction was stirred and then allowed to warm up to ambient temperature for 1 h. The mixture was quenched with saturated aqueous NT-LtCL and extracted with EtOAc (2X). The organic layer was washed with brine, dried (Na?.S04) and filtered. The filtrate was concentrated and the resulting residue was chromatographed (SiO?„ 10 to 40%, EtOAc/hexane) to afford the title compound (2.0 g, 83%) as a colorless oil. m / (ESI, +ve ion) 452.2 (M+Na) ⁺ .

STEP 4: (l R)-l-CYCLOPROPYL-4-PENTENE-l -SULFONAMIDE AND (1S)- 1 -C YCLOPROPYL- -PENTENE- 1 -SULFONAMIDE

The title compounds were prepared from above mixture of (IR)-l- cy clopropy 1-4-pentene- 1 -sulfonamide and (1 S)-1 -cy clopropy 1-4-pentene- 1 - sulfonamide using a similar procedure described in Step 2 of Example 36. STEP 5: (3S)-6'-CHLORO-N-(((l R)-l -CYCLOPROPYL-4-PENTEN-l- YL)SULFONYL)-5 - ((( 1 R,2R)-2-(( 1 S .2/. }·· 1 -HYDROXY-2-HEXEN - 1 - YL)CYCLOBUTYL)METHYL)-3',4.4',5-TETRAHYDRO-2H-SPIRO[ l,5- BENZOXAZEPINE-3, 1 '-NAPHTHALENE] -7-CARBOXAMIDE AND (3S)-6 - CHLORO-N-(((lS)-l-CYCLOPROPYL-4-PENTEN-l-YL)SULFONYL)-5- ((( 1 R,2R)-2-(( 1 S,2Z)~ 1 -HYDROXY-2-HEXEN - 1 -

YL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2'H-SPIR()|;i, 5- BE -3,r-NAPHTOALENE]-7-CARBOXAMIDE

A mixture of (l R)-l -cyclopropyi-4-pentene-l -su]fonamide and (I S)-l- cyclopropyl-4-pentene-l -sulfonamide was added N,N-dimethylpyridin-4-amine (DMAP) (47.9 mg, 0.392 mmol), a solution of (S)-6'-chloro-5-(((lR,2R)-2- ((S,E)-l-hydrox\'hex-2-en-l-yl)cydobutyl)methyl)-3',4,4',5-t etrahydro-2H,2'H- spirojbenzojb] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic aci d (Intermediate AA12A, 100 mg, 0.196 mmol) and triethylamine (0.082 ml,, 0.588 mmol) in DCM (2 mL). N-(3-dimethylarrdnopropyl)-N'-ethylcarbodiimide hydrochloride (75 mg, 0.392 mmol) was added slowly at last. The reaction mixture was stirred at ambient temperature for 18 h and then quenched with aqueous 1.0 N HC1. The mixture was diluted with dichioromethane. The organic layer was washed with brine, dried (MgSC ), and filtered. The filtrate was concentrated and the resulting residue was chromatographed (silica gel , 10 to 100%, EtOAc+ l%HOAc/hexane) to afford the title compounds, 130 mg (97%). m/z (ESI, +ve ion) 681.3 (M+H) ⁺ .

STEP 6: (lS,3 ^, R,6 ^, R.7 ^, S ₅ 8 ^, E ₅ 12 ^, S)-6-CHLORO-12 ^, -CYCLOPROPYL-7 ^, - HYDROXY-3,4-DIHYDRO-2H,I5'H-SPIRO[NAPHTOALENE-l,22'- [20] OXA[ 13]THI A[ 1 , 14] DIAZATETRACYCLO[14 .2 ^3/ \0 ¹⁹ - ² ]PENTACOSA[8,16,!8,24]TETRAEN]- 15'- ONE 13',13'-D10XIDE OR (lS,3 ^, R,6'R,7'S,8'E,12'S)-6-CHLORO-12'- CYCLOPROPYL-7'-HYDROXY-3,4-DIHYDRO-2H.15H- SPTRO[NAPHTH ALENE- 1 ,22'- |20jO.\A| 1311 HI Λ| I .. N |OI A/.\ Π·. ΓΗ. Αί ^' ΥΌ.01 i -i.7.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA [8,I6,18,24]TETiL E ]-15'- ONE 13',13 ^! "D10XIDE

A round bottom flask was charged with a mixture of (3S)-6'-chloro-n- (((lR.)-i-cyclopropyl-4-penien-l-yl)sLdfonyl)-5-(((iR,2R.)-^

2-hexen-l-yl)cyclobut>d)methyl)-3^4,4^5-tetrahydro-2'H -spiro[l,5- benzoxazepine-3, -naphthalene]-7-carboxamide and (3S)-6'-chloro-n-(((lS)-l- cyclopropyl-4-penten-l-yl)sulfonyl)-5-(((lR,2R)-2-((lS,2Z)-l -hydroxy-2-hexen- l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2'H-spiro[l,5-b enzoxazepine-3, - naphthalene]-7-carboxamide (0.090 g, 0.132 mmol) in AcOH (46 mL). The mixture was stirred at ambient temperature and argon was sparged into the reaction flask for 30 min. To this homogeneous solution was added Hoveyda- Grubbs II (0.017 g, 0.026 mmol) and the mixture was stirred at ambient temperature under reduced pressure for 18 h. Solvent was evaporated and the residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as the first eluenting isomer. ^! H NMR (400MHz, CD2CI2) δ 8.16 (s, 1 H), 7.70 (d, .! 84 Hz, 1 H), 7,17 (dd, J 2.2.8.5 Hz, 1 H), 7.09 (d, j 22 Hz, 1 H), 6.90 (s, 2 H), 6.85 (s, 1 H), 5.82 - 5.68 (m, 2 H), 4.22 (dd, j 3.9.7.0 Hz, 1 H), 4.07 (s, 2 H), 3.82 (d, J 1 .3 Hz, 1 H), 3.70 (d, J 14.! Hz, 1 H), 3.39 (dt, j 2.7.10.3 Hz, 1 H), 3.24 (d, j 14.1 Hz, 1 H), 3.02 (dd, j 97.15.4 Hz, 1 H), 2.82 - 2.69 (m, 2 H), 2.53 - 2.27 (m, 4 H), 2.06 - 1.90 (m, 4 H), 1.88 - 1.60 (m, 6 H), 1.39 (t, J=12.4 Hz, 1 H), 1.05 ·· 0.96 (m, 1 H), 0.90 - 0.74 (m 3 H), 0.44 (d, j 4.3 Hz, ill), m/z (ESI, +ve son) 611.3 (\Mli . EXAMPLE 149. (Ι 8,3'Κ,6' ,7'8,8Έ, 12'8)-6-α-ΙΙΧ) Ο-12'-CYCLOPROPYL-7'- HYDROXY -3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^! ~

|;20]OXA[ 13 iTHIA[ l 4jDIAZATETRACYCLO| 14.7.2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8 ₅ 16,18,24]TETRAEN]-15"- ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6'R,7'S,8 ^, E,12 ^, S)-6-CHLORO-12 ^, -CYCLOPROPYL-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[2()iOXA|;i3]THLA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [8J ~13'~ ONE 13', 13'-DIOXIDE

The title compound was obtained as the second eluenting isomer from the reversed phase preparatory HPLC separation in Example 148. ^! H NMR (400MHz, CD2CI2) δ 9.33 (br s, 1 H), 7.72 (d, J=8.6 Hz, 1 H), 7.27 (dd, 1=2.0, 8.2 Hz, 1 H), 7.17 (dd, ./ 2.3. 8.6 Hz, 1 H), 7.09 (d, j 2.3 Hz, 1 H), 6.99 - 6.87 (m, 2 H), 5.83 - 5.67 (m, 1 I s ). 5.59 (dd, J 8.0. i 1 .0 Hz, I H), 4.57 (dd, .1 5 6. 7.3 Hz, I H), 4.11 (s, 2 H), 3.91 (d, J=15.3 Hz, 1 H), 3.71 (d, J=14.3 Hz, IH), 3.28 (d, J=14.3 Hz, 1H), 3.22 ·· 2.99 (m, 2 H), 2.83 - 2.58 (m, 3 H), 2.46 - 2.18 (m, 3 H), 2.09 - 1.84 (m, 5 H), 1.82 - 1.62 (m, 3 H), 1 ,57 - 1.34 (m, 1 H), 1 ,34 - 1.15 (m, 2 H), 0.91 - 0,72 (m, 3 H), 0.39 - 0,31 (m, 1 H), rn/z (ESI, +ve ton) 611 ,2 ( VI H ) . EXAMPLE 150. (lS^^e^l l'S ^S^e-CHLORO-l l^l^-DIMETHYL-S^- DIHYDRO-2H,9'H,l 5'H-SPIRO[NAPHTH ALENE- 1 ,22'-[20]OXA[13]

THIA[1 ,8, 14] TRI AZ ATETRACY CLO

[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[16,18,24]TRIENE]-9',15'-DIONE 13',13'- DIOXIDE OR (l S,3'R,6'R,H 'R,12'S)-6-CHLORO-H',12'-DIMETHYL-3,4- DIHYDRO-2H,9'H, 15'H-SPIRO[NAPHTHALENE-l ,22'- [20] OXA[ 13]THIA[ 1,8, 4] TRI AZ ATETRAC YCLO [147.2 ³ -« 0 ¹⁹ ' ²⁴ ]PENTACOSA[16,18,24]TRIENE]-9",15'- DIONE 13',13'- DIOXIDE OR

(IS ^^'R l'R 'RVe-CHLORO-l l^^'-DIMETl-iYL-S^-DIHYDRO- 2H,9'H, 15'H-SPIRO[NAPHTHALENE-l ,22'- [20] OXA[ 13]THIA[ 1,8, 4] TRIAZATETRACY CLO

[ 14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSA[16,18,24]TRlENE]-9V15'- DIONE 13',13'~ DIOXIDE OR

(lS,3 ^, R ₅ 6 ^, R,l l ^, S 2 ^, R)-6-CHLORO-l l\12 ^, -DIMETOYL ,4-DIHYDRO-

2H,9'H,15'H~SPIRO[NAPHTHALENE-l,22 ^! ~

[20]OXA[ 13]THIA[ l,8,14]TRIAZATETRACYCLO

[14.7.2.0 ³ ' ⁶ .0 ^19,24 ]PENTACOSA[I 6,18,24]TRIENE]-9',15'- DIONE I

STEP 1: (2R,3R)-3-METHYLHEX-5-EN-2-OL AND (2S,3S)-3-METHYL-5- HEXEN-2-OL

To a solution of (+/-)-trans-2,3-dimethyloxirane (8.74 mL, 97 mmol) in Et ₂ 0 (48.5 mL) at -30 °C was added copper (I) iodide (5.55 g, 29.1 mmol) at first and then allylmagnesium bromide, 1.0 N solution in diethyl ether (194 mL, 194 mmol) dropwise in 1 h. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction was quenched with saturated aqueous ammonium chloride (300 mL), kept stirring for 1 h and extracted with ether (3x). The combined organic layers were dried (MgS0 ₄ ) and filtered. The filtrate was concentrated at 3 °C in a cold rotovap bath. The resulting residue was transferred to a smaller flask and distilled (137 °C) to afford the title compounds (10.1 g, 91%).

STEP 2: 2-(((2S,3R)-3-METHYL-5-HEXEN-2-YL)SULFANYL)PYRIMIDINE

AND

2-(((2R,3S)-3-METHY -5-HEXEN-2-YL)SULFANYL)PYRI IDINE

To a mixture of (2R,3R)-3-methylhex-5-en-2-ol and (2S,3S)-3-methyl-5- hexen-2-ol (10.0 g, 88 mmol) in Et ₂ 0 (175 mL) was added triethylamine (24.36 mL, 175 mmol) and methanesulfonyl chloride (7.45 mL, 96.0 mmol) at -78 °C. The mixture was stirred and then allowed to warm up to ambient temperature. The solid was filtered off and washed with diethyl ether (X3). The filtrate was washed with 1 .0 N HC1, brine, dried (MgS0 ₄ ), and concentrated. The resulting residue was dissolved in ethanol (60 mL) and added 21 % sodium ethoxide in ethanol (36.0 mL, 96 mmol). Pyrimidine-2-thiol (10.80 g, 96 mmol) was added. The reaction mixture was stirred for 18 h at 50 °C, concentrated, and then triturated in EfeO. The crude residue was chromatographed (silica gel, 5 to 40%, EtOAc/hexane) to afford the title compounds (8.90 g, 48.8%) as a colorless oil. m/z (ESI, +ve ion) 209.2 I 1 1 > ^" .

STEP 3: 2-(((2S,3R)-3 lETHYL-5-HEXEN-2~YL)SULFONYL)PYRlMIDiNE AMD 2 ((2R,3S)-3-METOYL-5 IEXEN-2-YL SULFONYL)PY iMIDINE

To a flask charged with 2-(((2R,3S)-3-methylhex-5-en-2- yl)thio)pyrimidine (3.45 g, 16.56 mmol) in DCM (2 mL) was added 3- chloroperoxy benzoic acid, 77% max. (7.61 g, 33.9 mmol) at 0 °C. The reaction was stirred at this temperature for 5 minutes and then was allowed to warm, up to ambient temperature. The reaction was kept stirring for 18 h. The mixture was quenched with sodium bicarbonate (300 mL), and extracted with diethyl ether (3 200 mL). The combined organic layers were dried (MgSC ), filtered and the filtrate was concentrated. The resulting residue was chromatographed (silica gel column, 0 to 100%, EtOAc/liexane) to afford the title compound (2.72 g, 68.3%) as an oil. m/z (ESI, +ve ion) 241.2 i \i f i ) .

STEP 4: (3S,4R)-3-METHYL~4-(PYRIMn3IN-2-YLSULFONYL)PENTANOIC ACID AND

(3S,4S)-3-METHYL-4-(2-PYRIMIDINYLSULFONYL) PENTANOIC ACID AND (3R,4S)-3-METOYL-4-(2-PYRiMIDINYLSULFONYL)PENTANOIC ACID AND (3R,4R)-3-METHYL-4-(2-PYRIMIDINYLSULFONYL)

PENTA

To a rapidly stirring solution of 2-(((2S,3R)-3-methyl-5-hexen-2- yl)sulfonyl)pyrimidine and 2-(((2R,3S)-3-methyl-5-hexen-2- yl)sulfonyl)pyrimidine (1 .1 g, 5.28 mmol) in water (19.50 mL) , acetonitrile (13.0 mL) and CCU (13.0 mL) was added sodium periodate (13.55 g, 63.4 rnmol). The reaction mixture was stirred vigorously at ambient temperature for 1 h. The mixture was acidified with 10% citric acid, and diluted with EtOAc. The organic layer was washed with brine, dried (Na ₂ S04) and concentrated to afford the title compounds (273 mg, 20.0%) which was used without further purification.

STEP 5: (S)-METHYL 5-(((lR,2R)-2-(AMlNOMETHYL)CYCLOBUTYL) METHYL)-6'-CHLORO-3 ^, ,4 ₅ 4 ^, ,5-TETRAHYDRO-2H,2H- SPIRO [BENZO [B][l ,4] ΟΧΑΖΕΡΓΝΕ-3 , ! '-NAPHTHALENE] -7- CARBOXYLATE

To a solution of ammoniumacetate (0.949 mL, 13.22 mmol) and (S)- methyl 6'-chloro-5-(((lR,2R)-2-formylcv'clobutyl)methyl)-3',4,4',5- tetrahydro- 2H,2'H-spiro[benzo[b] [1 ,4] oxazepine-3, 1 '-naphthalene]-7-carbox late

(Intermediate Intermediate AA1 1 Λ . Step 20A, 300 mg, 0.661 mmol) in MeOH (1.322 mL) was added sodium cyanoborohydride (1.00 g, 1.00 mmol). The reaction was stirred for 18 h at 30 °C. Solvent was evaporated to afford the title compound, m/z (ESI, +ve ion) 455.2 (M+H) ⁺ . STEP 6: (3S)-6'-CHLORO-5-(((lR,2R)-2-((((3R,4S)-3-METHYL-4-(2-

PYRJMIDINYLSULFONYL)PENTAN()YL)AMINO)METOYL)CYCL()BUTY L)METHYL)-3^4,4^5-TETRAIlYDRO-2TI-SPIRO[l ,5-BENZOXAZEPINE- 3, -NAPHTHALENE]-7-CARBOXYLIC ACID AND (3S)-6 ^! -CHLORO-5- (((lR,2R)-2-((((3R,4R)-3-METHYL-4-(2-PYWMmiNYLSULFONYL) PENT ANOYL) AMINO )METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-

TETRAHYDRO-^H-SPIROIl^-BENZOXAZEPINE-S '-NAPHTHALENE]-?- CARBOXYLIC ACID AND (3S)-6'-CHLORO-5-(((lR,2R)-2-((((3S,4S)-3- METHYL-4-(2-PYRIMIDINYLSULFONYL)

PENTANOYL)AMl O)METHYL)CYCLOBUTYL)METHYL)-3',4 ₅ 4'.5-

TETRAHYDRO-2Ti-SPIRO[l ,5-BENZOXAZEPINE-3,l '-NAPHTOALENE]-7- CARBOXYLIC ACID AND (3S)-6'-CHLORO-5-(((lR,2R)-2-((((3S,4R)-3- METHYL-4-(2-PYRIMlDINYLSULFONYL)

PEOTANOYL)AMINO)MEraYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5-

TETRAIIYDRO-21I-SPIRO[ l,5-BENZOXAZEPINE-3;i'-NAPHTOALENE]-7-

To a solution of (S)-methyl 5-(((lR,2R)-2- (aminomemyl)cydobutyl)memyl)-6'-chloro-3',4 _^

spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxylate (20 mg, 0.044 mmol) and a mixture of (3S,4R)-3-me1hyl-4-(pyrimidin-2-ylsulfonyl)pentanoic acid, (3S,4S)-3-methyl-4-(2-pyrimidinylsulfonyl)pentanoic acid, (3R,4S)-3- memyl-4-(2-pyrimidinylsulfonyl) pentanoic acid and (3R,4R)-3-methyl-4-(2- pyrimidinylsulfonyl)pentanoic acid (17.03 mg, 0.066 mmol) in DCM (2 mL) was added diisopropylethylamine (0.0593 mL, 0.341 mmol) and then 1- [bis(dimethylamino)methylene]-lh-benzotriazolium 3-oxide hexafluorophosphate (25,0! mg, 0,066 mraol). The reaction mixture was stirred at ambient temperature for 1 h. The mixture was diluted with DCM, washed with saturated sodium bicarbonate, dried (MgSCV), and filtered. The filtrate was concentrated and the resulting residue was chrornatographed (silica gel, 0 to 10%, MeOH/CttCh) to afford the title compounds(20 mg, 65,4%) as a light-yellow oil. m/z (ESI, +ve ion ) 7 1 7.2 ( M i l s ^' .

STEP 7: SODIUM (2S,3S)5-((((lR,2R)-2-(i(S)-6'-CHLORO-7- (METHOXYCARBONYL) ~3',4' 3IHYDRO-2H,2'H~

SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALEN] -5 (4H)- YL)METHYL)CYCLOBUTYL)METHYL)AMI O)-3-METHYL-5- OXOPENTANE-2-SULFINATE AND SODIUM (2S,3R)5-((((lR,2R)-2-(((S)-6 ^* - CHLORO-7-(METHOXYCARBONYL) -3',4 ^! ~DIHYDRO-2H,2'H~

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALEN j-5(4H)- YL)METHYL)CYCLOBUTYL)METHYL)AMINO)-3-METHYL-5-

OXOPENTANE-2-SULFINATE AND SODIUM (2R,3S)5-((((l ,2R)-2-(((S)-6 ^f - CHLORO-7-(METHOXYCARBONYL) -3',4'-DiHYDRQ-2H,2'H- SPIRO [BENZO | B j [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALEN] -5 (4H)- YL)METHYL)CYCLOBUTYL)METTHYL)AMINO)-3-METHYL-5- OXOPENTANE-2-SULFINATE AND SODIUM (2R,3R)5-((((lR,2R)-2-(((S)-6'- CHLORO-7-(METHOXYCARBONYL) -3',4'-DIHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALEN] -5 (4H)- YL)METHYL)CYCXOBUTYL)METHYL)AMINO)-3-METHYL-5- OXOPEN T AN E-2- SU LFIN ATE

A solution of (3S)-6'-chloro-5-(((lR,2R)-2-((((3R,4S)-3-methyl-4-(2- pyrimidinyl sulfonyl)pentanoyl)amino)methyl)cv'clobutyl)methyl)-3',4,4', 5- tetrahydro-2'h-spiro[l,5-benzoxazepine-3, -naphlhalene]-7-carbox lic acid and (3S)-6'-chloro-5-(((lR,2R)-2- ((((3R,4R)-3-metiiyl-4-(2- pyrimidinylsulfonyl)pentanoyl)amino)me^

tetTahydro-2'h-spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxylic acid and (3S)-6'-chloro-5-(((lR ₅ 2R)-2-((((3S ₅ 4S)-3-methyl-4-(2- pyrimidinylsulfonyl)pentanoyl)amino) methyl)cydobutyl)methyi)-3',4,4',5- tetrahydro-2'H-spiro l,5-benzoxazepine-3, -naphthalene]-7-carboxylic acid and (3S)-6"-(*loro-5 ((lR,2R)-2-((((3S,4R)-3-me M 2-pyrimidinyl

sulfonyl)pentanoyl)arnino)methyl)cyclobutyl)me^

spiro l,5-benzoxazepine-3, -naphthalene]-7-carboxylic acid (20 nig, 0.029 mmol) in MeOH (0.15 mL) was treated with sodium methoxide, 25 wt. % solution in methanol (0.0322 mL, 0.141 mmol). The reaction was stirred at ambient temperature for 1 h, then the solvent was evaporated and the resulting residue was taken into the next step without further purification.

STEP 8: (3S)-6'-CHLORO-5-(((lR,2R)-2-((((3R,4R)-3- ETHYL-4- SULFAM()YLPENTANOYL)AMIN())METHYL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5~TETRAHYDRO~2Ti-SPIRO[l ,5-BENZOXAZEPINE-3,l NAPHTHALENE] -7-CARBOXYLIC ACID AND (3S)-6'-CHLORO-5- (((lR,2R)-2-((((3R,4S)-3-METHYL^-SULFAMOYLPENTANOYL)

AM]NO)METHYL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2'H- SPTRO[ 1 ,5-BENZOXAZEPlNE-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (3 S)-6'-CHLORO-5 -((( 1 R,2R)-2-((((3 S ,4S)-3 -METHYL-4-

SULFAMOYLPENTANOYL) AM1N0)METHYL)CYCL0BUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2'H-SPIRO[ l,5-BENZOXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID AND (3S)-6'-CHLORO-5- (((lS,2R)-2-((((3R,4S)-3-METHYL-4-SULFAMOYLPE TANOYL)

AM]NO)METI-IYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAI-iYDRO- 2'H- SPTR -BENZOXAZEPINE-3, 1 '-NAPHTHALENEJ-7-CARBOXYLIC ACID

To a stirred solution of sodium (2S ₅ 3S)5-((((lR,2R)-2-(((S)-6 ^* -chloro-7- (methoxycarbonyl) -3',4'-dihydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, - naphthalen]-5(4H)-yl)methyl)c\ lobu1yl)methyl)amino)-3-methyl-5-oxopentane- 2-suIfinaie and sodium (2S,3r)5-((((lR,2R)-2-(((S)-6'-chloro-7-(methoxycarbonyl) -3',4'-dihydro-2H,2'H-spiro[benzo[b] [l,4] oxazepine-3, l'-naphthalen]-5(4H)- yl)methyl)cyclobutyl)methyl)an ^" iino)-3-methyl-5-oxopentane-2-sulfinate and sodmm (2R,3S)5-((((lR,2R)-2-(((S)-6'-chloro-7-(methoxycarbonyl) -3',4'- dihydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalen]- 5(4H)- yl)methyl)cyclobut>'l) methyl)amino)~3-methyl-5~oxopeniane~2~sulfinate and sodium (2R,3R)5-((((lR,2R)-2-(((S)-6'-chloro-7-(methoxycarbonyl) -3',4'- dihydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalen]- 5(4H)- yl)methyl)cyclobu1yl)me1hyl)amino)-3-methyl-5-oxopentane-2-s ulfinate (18 nig, 0.028 mmol) in water (0.860 mL) was added sodium acetate (4.62 mg, 0.056 mmol) and hydroxylamine-o-sulfonic acid (3.18 mg, 0.028 mmol). The reaction was stirred at ambient temperature for 18 h. The mixture was diluted with water and then extracted with diethyl ether (3X). The combined organic layers were dried (MgSC ), and filtered. The filtrate was concentrated and the residual was added toluene to azeotropically remove water (X3). The resulting oil was taken to the next step without further purification.

STEP 9: (1S,3'R,6'R,1 l'S,I2'S)-6-CHLORO-l l',l 2'-DIMETHYL-3,4-

Ο1ΉΥϋΚΟ-2Η,9Ή,15'Η-8ΡΙΚΟ[ΝΑΡΗ1ΉΑΙ.,Ε ΝΕ-1,22'-[20]ΟΧΑ[13]

TH1A[1 ,8, 14 jTRIAZATETRACYCLQ

[ 14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSA[16,18,24]TRJENE]-9 ^! ,15'- DIONE 13'.13'- DIOXIDE OR

(IS^l^e'RJ ll^n^^e-CHLO O-I I^^'-DlMETHYL-S^-DlHYDRO-

2H,9TI, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20] OXA[ 13] THI A[ 1 ,8,14] TRI AZ ATETRAC YCLO

[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]l TACOSA[16,18,24]imENE]-9 ^! ,15'- DIONE 13',13'- DIOXIDE

OR (1S,3'R,6'R,1 l'R,12'R)-6-CHLQRO-l l',12'-DIMETHYL-3,4-DIHYDRO-

2H,9TI, 15'H-SP1R0[NAPHTHALENE-1 ,22'-

[ 20] OXA[ 13] THI A[ 1 , 8, 14] TRI AZ ATETRAC YCLO

|;i4.7.2.0 - ⁶ .() ^!9 - ²⁴ ]PENTACOSA|;i6,18,24|TRIENE]-9',15 ^! - DIONE 13',13'- DIOXIDE

OR ( 1 S,3'R,6'R, 1 Γ S, 12 ^* R)-6-CHLORO-l Γ, 12'-DIMETHYL-3,4-DIHYDRO- 2Η,9Ή, 15'H-SPlRO[NAPHTHALENE-l ,22'-

[ 201 OXA[ 13] THI A[ 1 , 8, 14 ] TRI AZ ATETRAC YCLO

[ 14,7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[16,18,24]TRIENE]-9",15'- DIONE 13',13 ^* - DIOXIDE The title compound was prepared from a mixture of (3S)-6'-chloro-5- (((lR,2R)-2-((((3R,4R)-3-methyl-4- sulfamoylpentanoyl)ardno)methyl)cyclobutyl)methyl)-3 ^, ,4,4^5-tetrahydro- spiro[ 1 ,5-benzoxazepine-3, 1 '-naphtha! ene] -7-carboxylic acid, (3 S)-6'-chloro-5- (((] R,2R)~2-((((3R,4S)-3-methy -4-sulfamoylpentanoyl)

arnino)methyl)cyclobut\'l)methyl)-3 ^, ,4,4',5-tetrahydro-2'H-spiro[l,5- benzoxazepine-3, 1 '-naphthalene j-7-carboxy lie acid, (3S)-6'-chloro-5-(((l R,2R)-2- ((((3S,4S)-3-methyl-4-sulfamoylpentanoyl)amino)methyl)cyclob utyl) methyl)- 3^4,4',5 etrahydro-2^spiro[l,5-benzoxazepine-3, -naphthalene]-7-carboxyiic acid and (3S)-6'-chloro-5-(((l S,2R)-2-((((3R,4S)-3-methyl-4- sulfamoylpentanoyl)amino)methyl) cyclobu1yl)methyl)-3 ,4,4 ,5-tetrahydro-2'H- spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxylic acid (0.011 g, 0,058 mmol) using a similar procedure described in Step 3 of Example 144 and the reversed phase preparatory HPLC purification (Gemini™ Prep Cie 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) as the first eiuenting isomer. Ί I NMR (400MHz, CD2CI2) δ 11.68 (br s, 1/2 H), 10.79 (br s, ½ H), 7.73 (d, .1 H O Hz, 1 H), 7,43 (d, J 2.0 Hz, 1/2 H), 7,38 (dd, j 8.4. 2,0 Hz, 1/2 H), 7.32 - 7,26 (m, 1 H), 7, 17 (d, J=8,4 Hz, 1 H), 7.11 - 7.07 (m, 1 H), 6,92 (t, j 7 7 Hz, 1 H), 6.04 (br s, ½ H), 5.89 (br s, ½ H), 4.13 - 4.06 (m, 1 H), 3.99 - 3.87 (m, 1 H), 3.82 - 3.68 (m, 2 H), 3.65 - 3.57 (m, 1 /2 H), 3.42 - 3.24 (m, 2 H), 3.02 - 2.91 (m, 1 H), 2.85 - 2.77 (m, 1/2 H), 2.73 - 2,65 (m, 2 H i. 2.65 - 2,46 (m, 2 H), 2.46 - 2,06 (m, 2 H), 2.08 - 1.81 (m, 5 H), 1.80 - 1.72 (m, 3 H), 1.31(t j 7.0 Hz, 3 H), 1.30- 1.21 (m, 2 H), 1.09 (dd, j 4.O. 6.9 Hz, 3 H). m/z (ESI, +ve ion) 600.2 ί ΥΙ Π ) .

EXAMPLE 151. (1 S,3'R,6'R, i 1 'R, ! 2'R)-6-CHLORO- 11 ', 12'-DIMETHYL-3,4- DIHYD O-2H,9Ή,15'H-SPI O[NAPHTHALENE-l,22' 20]OXA[i3]

^ ! S AM .8J r! R! AZAli niL ( .OM 7.2. ^{i :} ! i ^{| ;} ' ^{: ,} | !>FN !V\( X)SA | I 6J 8.24 ! TRIENE]-9',15'- DIONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,1 l'R,12'S)-6- CHLORO - 1 Γ , 12'-DIMETHYL-3,4-DIHYDRO-2H,9'H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20] OXA[ 13] THIA[ 1,8,14] TR1 AZ ATETRAC YCLO

[14.7.2.0 - ⁶ .() ^!9 - ²⁴ ]PENTACOSA[16,18,24|TRIENE]-9',15'- DIONE 13',13'- DIOXIDE OR (1 S,3'R,6'R,1 l 'S, r2'R)-6-CHLORO-l l', 12'-DIMETOYL-3,4- DIHYDRO-2H,9'H, 15'H-SPIRQ[N APHTHALENE-1 ,22'- [20] OXA[ 13] THI Aj 1,8,14] TRIAZ ATETRAC YCLO

[ 14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ ' ²⁴ ]PENTACOSA[ 16, 18,24]TRIENE]-9',15'- DIONE 13', 13'- DIOXIDE OR

(lS,3'R,6'R,l l'S,12'S)-6-CHLORO-l l',12'-DLMETHYL-3,4-DIHYDRO- 2H,9'H, 15TI-SPIR()[NAPHTHALENE-1 ,22'-

[20] OX A[ 13] THIAf 1 ,8,14] TRI AZ ATETRAC YCLO

[14.7.2.0 ³ ' ⁶ .0 ^19,24 ]PENTACOSA[16,18,24]TRIENE]-9V15'- DIONE 13',13 ^! - D

STEP 1 : (S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-((METHYL AMINO)

METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

To a solution of (S)-methyl 6 ^! ~chloro-5-(((lR,2R)-2- formylcyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepme-3, ~naphthalene]-7-carboxylate (Intermediate Intermediate AA11A, Step 20A, 190 mg, 0.419 mmol) in DCE (4 niL) was added 2.0 M methyl amine solution in THF (2.51 mL, 5.02 mmol), sodium

triacetoxyborohydride (532 mg, 2.51 mmol) and 3 drops of HO Ac. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried (MgS04) and concentrated. The residue was chromatographed (silica gel, 0 to 10%, MeOH/CI-fcCb) to afford the title compound.

STEP 2: (S)-METHYL 6'-CHLORO-5-(((l R,2R 2-(((3R,4S)-N,3-DIMETOYL- 4-(PYRIMIDIN-2YLSULFONYL)PENTANAMIDO)METHYL)

CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RQ[BENZQ [B] [ 1 ,4] OXAZEPINE-3, 1 '- APHTHALENE] -7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-(((3R,4R)- N, 3 -DIMETHYL-4 -(P YRIMIDIN-

2YLSULFONYL)PENTANAMIDO)METHYL) CYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO| B] [ l,4] OXAZEPINE-3, Γ- NAPHTHALENE]-7-CARBOXYLATE AND { S}~\U . H IV 1 , 6'-CHLORO-5- (((lR,2R)-2-(((3S,4S)-N,3 3IMETHYL-4-(PYRiMrDrN- 2YLSULFONYL)PENTANAMIDO)METHYL) CYCLOBUTYL)METHYL)- 3 ⁱ .4.4 ^, .5-- ^' i ! ! ^' RA! !Y I}R(}-2I L2'! ! -SP!R()| Bi :NZ{)i B | | 1.4 ! OXAZEPINE-3, Γ- NAPHTHALENE] -7 -C ARB OXYL ATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-(((3S,4R)-N,3-DIMETHYL-4-(PYRIMlDIN- 2YL S ULFONYL)PENTANAMIDO)METHYL) CYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H,2TI-SPIRO[BENZO[B] [1 ,4] OXAZEPINE-3, 1 "- ΑΡΗ -7 -C ARB OXYL ATE

To a solution of (3S,4R)-3-methyl-4-(pyrimidin-2-ylsulfonyl)pentanoic acid and (3S,4S)-3-methyl-4-(2-pyrimidinylsulfonyl) pentanoic acid, (3R,4S)-3-methyl-4- (2-pyrimidinylsulfonyl)pentanoic acid, (3R,4R)-3-methyl-4-(2- pyrimidinylsulfonyl)pentanoic acid

(From Example 140, Step 4, 66.1 mg, 0.256 mmol) and (S)-methyl 6'-chloro-5- (((lR,2R)-2-((me1hylaiTdno)me1hyl)cyclobu1\d)methyl)-3',4,4' ,5-tetrahydro- 2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (80 mg, 0.171 mmol) in DCM (2 mL) was added diisopropyl ethylamine (0.0593 mL, 0.341 mmol) and then l -[bis(dimethylamino)methylene]-lh-benzotriazolium 3- oxide hexafluorophosphate (97 mg, 0.256 mmol). The reaction was allowed to stir at ambient temperature for 1 h. the mixture was diluted with DCM, washed with saturated sodium bicarbonate. The organic layer was dried (MgSC¼), filtered and concentrated. The crude residue was chromatographed (silica gel, 0 to 10%, MeOH/CHzC .) to afford the title compound (100 mg, 83%) as a light yellow oil. m/z (ES , +ve ion) 709.2 { \ I · Π } .

STEP 3: SODIUM (2S,3R)-5-((((lR,2R)-2-(((S)-6'-CHLORO-7

(METHOXYCARBONYL)-3',4'-DIHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALEN] -5 (4H

YL)METHYL)CYCLOBUTYL)MEraYL)(METHYL)AMINO)-3-METHYL-5-

OXOPENTANE-2-SULFINATE AND

SODIUM (2R,3R)-5-((((lR,2R)-2-(((S)-6'-CHLORO-7-

(METHQXYCARBQNYL)-3',4'-DiHYDRQ-2H,2'H-

SPIRO [BENZO [B j [ 1,4] OXAZEPINE-3 , l'-NAPHTHALEN] -5 (4H)-

YL)METT-ftl.)CYCLOBUWL)METHYL)(METIIYL)AMINO)-3-METOYL-5^

OXOPENTANE-2-SULFINATE AND

SODIUM (2S,3S)-5-((((lR,2R)-2-(((S)-6'-CHLORO-7-

(METHOXYCARBONYL)-3',4'-DIHYDR()-2H,2'H-

SPIRO [BENZO [B j [ 1 ,4] OX AZEPTNE-3 , 1 ^* -N APHTH ALEN] -5 (4H)-

YL)METHYL)CYCLOBUTYL)METHYL)(METHYL)AMlNO)-3-METHYL-5-

OXOPENTANE-2-SULFINATE AND

SODIUM (2R,3S)-5-((((lR,2R)-2-(((S)-6'-CHLORO-7-

(METHOXYCARBONYL)-3',4'-DIHYDRO-2H,2'H-

SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , Γ -NAPHTHALAN] -5(4H)-

YL)METI-n L)CYCL()BUTYL)METIlYL)(METHYL)AMINO)-3-METHYL-5-

OXOPENTANE-2-SULFINATE

A solution of (S)-methyl 6"-chloro-5-(((lR,2R)-2-(((3R,4S)-N ₅ 3-dimethyl- 4-(pyrimidin-2ylsulfonyl)pentanamido)methyl) cyelobutyl)niethyl)-3',4,4',5- tetrahydro-2H,2'H-spiro benzo b] l,4] oxazepine-3,l'-naph1halene]-7-carboxylate and (s)-methyl 6 ^f -chloro-5-(((IR,2R)-2 ((:m,4R)-N,3Hliraethyl-4-(p} _' -rimidin- 2ylsulfonyl)pentananiido)methyl) cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4] oxazepine-3,r-naphthalene]-7-carboxylate and (s)-methyl 6'- cWoro-5-(((lR.2R)-2-(((3S,4S)-N.3-cUmethyW-(pyrimidin- 2ylsulfonyl)pentanamido) methyl) cyclobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo [b] [l,4] oxazepine-3, -naphthalene]-7-carboxylate and (s)-methyl 6'- cWoro-5-(((l R,2R)-2-(((3S,4R)-N,3-dime l-4-(pyrimidin-2ylsulfonyl) pentanamido)methyl) cyclobu1yl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4] oxazepine-3,r-naphthalene]-7-carboxylate (100 mg, 0.141 nimoi) in MeOH (1 mL) was treated with sodium methoxide, 25 wt. % solution in methanol (0.0322 mL, 0.141 mmol) and the mixture was stirred at ambient temperature for 1 h. Solvent was evaporated and the resulting residue was obtained as the title compound and was used without further purification.

STEP 4: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-(((3R,4S)-N,3-DIMETOYL- 4-SULFAMOYLPENTANAMIDO) METHYL)CYCLOBUTYL)METHYL)- 3\4,4',5-TETl AHYDRO-2H,2'H~SPIRO[BENZO[B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2 ((3S,4R)-N,3-DTMETHYL-4-SULFAMOYLPENTANAMIDO) METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO| BENZO[B]|;L4iOXAZEPINE-3, l'-NAPHTHALENE]-7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-(((3R,4R)- N,3-DIMETHYL-4-SULFAMOYLPENTANAMIDO)

METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIR()[BENZO Bj[ l,4]()XAZEPINE-3,r-NAPHTHALENEl-7- CARBOXYLATE AND (S)-METHYL 6'-CHLO O-5-(((IR,2 )-2-(((3S,4S)-N,3-DIMETHYL-4- SULFAMOYLPENTANAM1DO) METHYL)CYCLOBUTYL)METHYL)- 3^4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B]|;i ,410XAZEPINE-3,r- -7 -C ARB OXYL ATE

To a stirred solution of sodium (2S,3R)-5-((((lR,2R)-2-(((S)-6'-chloro-7- (methoxyca,rbonyl)-3^4'~dihydro^

naph1h en]-5(4H)-yl)me1hyl)cyclobutyl)me^

oxopentane-2-sulfinate and sodium (2R,3R)-5-((((lR,2R)-2-(((S)-6'-chloro-7- (methoxycarbonyl)-3',4'-dihydro-2H,2'H-spiro | ^" benzo| ^" b] | ^' l,4]oxazepine-3,r- naphthalen]-5(4H)-yl)methyl)tyclobutyl)methyl)(methyl) amino)-3-methyl-5- oxopentane-2-sulfmate and sodium (2S,3S)-5-((((lR,2R)-2-(((S)-6'-chloro-7- (methoxycarbonyl)-3',4'-dihydro-2H,2'H-spiro benzo b] l,4]

naphthalen ]-5(4H)-yl)methyl)cyclobu1yl)methyl) (methyl)amino)-3-meth l-5- oxopentane-2-sulfmate and sodium (2R,3S)-5-((((lR,2R)-2-(((S)-6'-chloro-7- (methoxy arbonyl)-3',4 ^, -dihydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, - naphthalen]-5(4H)-yl)methyl)cyclobutyl)methyl)(methyl) amino)-3-methyl-5- oxopentane-2-sulfinate (92 mg, 0, 14 ! mrnol) in water (0.860 mL) was added sodium acetate (23.1 1 mg, 0.282 mmo!) and hydroxylamine-o-sulfonic acid (15,93 mg, 0, 141 mmol). The reaction mixture was stirred at ambient temperature for 17 h. The mixture was then treated with aqueous 15% NaOH, and extracted with EtOAc (x2). The combined organic layers were dried (MgS0 ₄ ) and filtered. The filtrate was concentrated to afford the title compound (91 mg, 100%) which was used without further purification.

STEP 5: (S)-6'-CHLORO-5-(((l R,2R)-2-(((3R,4S)-N,3-DIMETHYL-4- SULFAMOYL PENTANAMIDO)METHYL)CYCLOBUTYL)METHYL)- 3 4 4^5-TETRAHYD O-2H,2Ή-SPIRO[BENZO[B][L4]OXAZEPlNE-3,r~ NAPHTHALENE] -7-CARBOXYLIC ACID AND

(S)-6'-CHLORO-5-(((1 R,2R)-2-(((3S,4S)-N,3-DTMETHYL-4-SULFAMOYL PENTANAMIDO)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID AND

(S)-6'-CTiLORO-5-(((lR,2R)-2-(((3R,4R)-N,3-DIMETHYL-4-SUL FAMOYL PENTANAMIDO)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID AND

(S)-6 ^, -CHLORO-5-(((lR,2R)-2-(((3S,4R)-N,3-DIMETHYL-4-SULFAMO YL PENTANAMIDO)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5-

TETRAI IYDRO-2It2 ^* i-I-SPIROj BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID

To a solution of (S)-rnethyl 6'-cMoro-5-(((lR,2R)-2-(((3R,4S)-N,3- dimethyl-4-sulfamoylpentanamido) methyl)cyclobut 'l)m.ethyl)~3 ^! ,4,4',5- tetrahydro-2H,2'H-spiro [benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carbox\'late and (S)-methyl 6'-chloro-5-(((lR,2R)-2-(((3S,4R)-N,3-dimethyl-4- sdfamoylpentanarnido) meihyl)cyclobuly])methyi)-3^4,4V5 etrahydro-2I-I,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxy late and (S)-methy 1 6'- cMoro-5-(((lR,2R)-2-(((3R,4R)-N,3-dime l-4-sulfamoylpentanarrddo)methyl) cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b ] [ l,4] oxazepine- 3,l '-naphthalene]-7-carboxylate and (S)-methyl 6'-chloro-5-(((l R,2R)-2-

(((3S,4S)-N,3-dimethyl-4-sulfamoyl pentanamido)methyl) cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spif o| benzo | b] 1 1 ,4] oxazepine-3, 1 '-naphthalene ]-7- carbox late and (92 mg, 0. 142 rnmol) in THF (1 mL) and MeOH (1 mL) was added aqueous 2.0 N LiOH (2 mL). The reaction mixture was stirred at 50 °C for 1 h. The mixture was neutralized with 1.0 N HC1, and extracted with diethyl ether. The organic layer was dried (MgSC ), and filtered and the filtrate was

concentrated. The crude residue was used for the next step without further purification.

STEP 6: (1S,3'R,6'R, 1 l'RJ 2'R)-6-CHLORO-! I ',12'-DIMETOYL-3,4- D\ \ iYDRC ?.! 1 '! 1. ! - | !-SP! RO! VAPi Π 1 1ΛΙ j ^; \ L- 1 22'-i 20|OX,\i ! 3 | THIA[1 ,8, 14] TRI AZ ATETRAC Y CLO

[14 .2.0 ³ -^0 ¹⁹ - ²⁴ ]PE TACOSA[16,18,24]TRlENE]-9',15'~DlONE I.T.I.T- DIOXIDE OR

(1 S,3'R,6'R, 11 'R, 12'S)-6-CHLORO- 11 ', 12'-DlMETHYL-3,4-DIHYDRO- 2Η,9Ή, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20] OXA[ 1.·,Γ!!!!Λ| 1,8,14] TRI AZ ATETRAC YCLO

[14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSA[16,18,24]TRJENE]-9 ^! ,15'-DIONE 13',13'- DIOXIDE OR

(1S,3'R,6'R,1 l'S,12'R)-6-CHLORO-l l',12'-DlMETHYL-3,4-DlHYDRO- 2Η,9Ή, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20] OXA[ 13] THI A[ 1 ,8,14] TRI AZ ATETRAC YCLO

I 14.72.0 ^: ".0 ^{)': ,;} iPL\ lACOSAI Ι6.!8.2·ΙΙ R!L\Li~9\ I DIONL 13',13'- DIOXIDE OR

(lS,3 ^, R,6'R,ll ^, S,12 ^, S)-6-CHLORO-ll 12 ^, -DIMETHYL-3,4-DIHYDRO- 2H,9'H,15'H~SPIRO[NAPHTHALENE-l,22 ^! ~

[20] OXA[ 13] THIA[ 1,8,14] TRI AZ ATETRAC YCLO

|;i4.7.2.0 ³ - ⁶ .() ^!9 ' ²⁴ ]PENTACOSA|;i6,18,24]TRIENE]-9',15 ^! - DIONE 13',13'- DIOXIDE

N,N-dimethylpyridin-4-amine (9.66 mg, 0.079 mmol) was added to a solution of (l'S)-6 ^, -chloro-5-(((lR,2R)-2-(( ,3-dimethyl-4- sulfainoylpentananiido)niethyl)cyclobutyl)niethy3)-3',4,45-t et^

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid and triethylamine (0.082 mL, 0.592 mmol) in DCM (2 mL) at ambient temperature. The mixture was then added Nl-((ethylimino)methylene)-N3,N3- dimethylpropane-.l,3-diamine hydrochloride (0.015 g, 0.079 mrnol) slowly and stirred at ambient temperature for 17 h. The reaction mixture was diluted with dichloromethane and quenched with 1.0 N HC1. The combined organic layers w¾re washed w ^? iih brine, dried (MgSQ- , filtered and concentrated. The crude residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to afford the title compound as the first eluenting isomer. ¾ NMR (400MHz, CD2CI2) δ 11.58 (br s, 1 ! ! }. 7.73 (dd, J=2.9, 8.6 HZ, Hz, 1 H), 7.48 (d, j 5.2 Hz, 1 H), 7.38 (dd, j 2.2. 8.2 Hz, 1 ! ! }. 7.16 (dd, j 2.4. 9,8 Hz, 1 H), 7.08 (d, J 5.5 Hz, 1 ! !}. 6.90 (dd, j 4 5. 8.2 Hz, I H), 4.17 - 3.98 (m, 3 H), 3.87 (d, J 15.8 Hz, 1 H), 3.70 (d, J=14.9 Hz, 1 H), 3.50 id. J 7.4 Hz, 1 H), 3.38 (d, J 14.7 Hz, 1 H), 3.09 (dd, j 10.4. 15.3 Hz, 1 H), 3.01 - 2.96 (m, 2 H), 2.90 - 2.66 (m, 3 H), 2.64 - 2.26 (m, 3 H), 2.25 - 1.96 (m, 4 H), 1.96 (m, 10 H), 1.19 - 1.01 (m, 3 H), 0.99 - 0,76 (m, 3 H). m/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 152. (1 S,3'R,6'R, 11 'R, 12'R)-6-CHLORO - 11 12'-DIMETHYL-3,4- DIHYDRO-2H,9'H, 15'H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]THIA[1,8,14] TRlAZATETRACYCLO[ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PENTACQSA[16,18,24]TRIENE]-9 ^! ,15 ^* - DIONE 13',13'-DIGXIDE OR

(1 S,3 ^! R,6'R, 1 1 'R, 12'S)-6-CHLORO-l , 12'-DIMETHYL-3,4-DIHYDRO- 2H,9'H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ l,8,14]TRIAZATETRACYCLO

[14.7.2.0 ³ - ⁶ .0 ^!9,24 ]PEOTACOSA[16,18,24]TRIENE]-9',15'- DIONE 13',13'- DIOXIDE OR

(1S,3'R,6 ^! R,I rS,12'R)-6-CHLORO-l

2H,9'H,15'H-SPIRO|NAPHra:ALENE-l,22'- [20] OXA[ 13] THI A[ 1 , 8, 14] TRI AZ ATETRAC YCLO

[14.7.2.0 ^,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA[16,18,24]TRIENE]-9',15'- DIONE I .T. I .T- DIOXIDE OR

(1 S,3'R,6'R,I I'S,12 ⁱ S)-6-CHLORO-l r,12'-DIMETHYL-3,4-DIHYDRO- 2Η,9Ή, 15 Ή- SPIRQ [NAPHTHALENE- 1 ,22'- [20] OXA[ 1.·, Γ! ! !!Λ| 1,8,14] TRIAZATETRACYCLO

[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[16,18,24]TRIENE]-9',15'- DIONE 13',13'- DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 141. ¾ NMR (400MHz, Cel ) δ = 9.59 (d, J=8.6 Hz, 1 H), 9.42 (d, J=5.9 Hz, 1 H), 9.35 (dd, J=2.1, 8.3 Hz, 1 H), 9.03 (dd, j 2.2. 8.4 Hz, 1 H), 8.93 (dd, J=1.6, 6.0 Hz, 1 H), 8.78 (d, j 8.2 Hz, I H), 5.98 - 5.84 (m, 2 H), 5.78 - 5.62 (m, 2 H), 5.51 (d, J 1 .3 Hz, 1 H), 5.25 ·· 5.06 (m, 2 H), 4.84 - 4.74 (m, 4 H), 4.68 - 4.56 (m, 3 H), 4.43 (d, J=13.9 Hz, 1 I I ). 4.36 - 4.17 (m, 2 H), 4.07 (t, j 7.6 Hz, 1 H), 4.00 - 3.00 (m, 12 H), 2.95 (t, j 7.0 Hz, 3 I s ), m/z (ESI, +ve ion) 615.2 ( M I I ) .

EXAMPLE 153. (I S^'R^'R 'S^^^'Sj-e-CHLORO^'-HYDROXY-lS'-OXO- 3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1.22 ^, -[20]OXA[13]THIA[l ,14]

DIAZ A TETR A C YCLO [14.7,2.0 ³ · ⁶ .0 ³⁹ - ²⁴ ]

PENTACOS A[8, 16, 18,24] TETRAENE] - 12'-C ARBONITRILE 13', 13'-D10XIDE OR (lS,3'R,6'R,7 ^! S,8'Z,12'R)-6-CHL()R()-7'-HYDR()XY-15'-OX()-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PE -12'-CARBONITRILE 13', 13'-DIQXIDE

STEP 1 : METHYL (2S)-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)HEX-5-ENOATE AND METHYL (2R)- ( ,N-BIS(4- -5-ENOATE

To a round bottom flask was added N,N-bis(4-methoxybenzyl)pent-4-ene- 1 -sulfonamide (EE19, 3,40 g, 8.73 mmol) in THF (34,9 mL) at -78 °C, butyllithium solution, 2.5 M in hex arses (3.84 mL, 9.60 mmol), and followed by the addition of chlorocarbonic acid, methyl ester (1.01 mL, 13.09 mmol) after stirring for 5 min. The reaction mixture was stirred and then allowed to warm up to ambient temperature. The mixture was quenched with saturated aqueous NH4CI, and extracted with diethyl ether (2x). The combined organic extracts were washed with brine, dried (MgSC ), and filtered. The filtrate was concentrated to afford the title compound as a colorless oil without further purification.

STEP 2: (2S)-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEX-5-ENOIC

ACID AND (2R)-(N,N-BIS(4-METH()XYBENZYL)SULFAMOYL)HEX-5- ENOIC ACID

To a round bottom flask was added methyl 2-(N,N-bis(4- methoxybenzyl)sulfamoyl)hex-5-enoate (3.90 g, 8.71 mmol) in THF (36.3 mL), sodium hydroxide (1.39 g, 34.9 mmol) in water (7.26 mL). The reaction mixture was stirred at 50°C for 18 h. The reaction was neutralized with IO N HC1, extracted with EtOAc (2x). The organic extract was washed with brine, dried (MgSG- , and filtered. The filtrate was concenirated and chromatographed (silica gel, 0 to 100% EtOAc+0.3% HOAc /hexane) to afford the title compound (2.60 g, 69%).

STEP 3 : (2S)-( ,N-BIS(4-METHOXYBENZYL)S ULFAMOYL)HEX-5-

ENAMIDE AND

(2R)-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEX-5-EN AMIDE

To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)hex-5-enoic acid (1,00 g, 2.31 ramol), and N,N-diisopropylethylamine (1.20 mL, 6.92 mmol) in DMF (11.5 mL) was added ammonia, 7.0 N solution in methanol (0.49 mL, 3.46 mmol). The reaction mixture was stirred at 40 °C for 18 h. The mixture was washed with water, extracted with EtOAc. The organic layer was concentrated and chromatographed (silica gel, 0 to 40%, acetone/ DCM+10% MeOH) to afford the title compound (330 mg, 33.1%) as an off-white oil.

STEP 4: (1 S)-l -CYANO-N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE- 1 -

SULFONAMIDE AND (lR)~l~CYANO-N,N-BiS(4-METHOXYBENZYL)-4- PENTENE-1 -SULFONAMIDE

A mixture of 2-(N,N-bis(4-methoxybenz}'l)sulfamoyl)hex-5-enamide (400 mg, 0.925 mmol) in phosphorus oxy chloride (847 μΕ, 9.25 mmol) was heated at 60 °C for 2 h. The reaction mixture was cooled to ambient temperature and poured into ice water slowly. The combined organic layers were extracted with diethyl ether (3 x), dried (MgSC ), filtered and concentrated. The resulting residue was chromatographed (silica gel, 0 to 100%, acetone/DCM) to afford the title compound, (310 mg, 81 %) as a colorless oil.

STEP 5: (lS)-l-CYANOPENT-4-ENE-l-SULFONAMIDE AND

(1R)-1 -CYANOPENT- -ENE- 1 - S ULFON AMIDE AND

The title compounds were prepared from (1 S)-cyano-pent-4-ene-l - sulfonamide and (lR)-cyano-pent-4-ene-l -sulfonamide using a similar procedure described in Step 3 of Example 373.

STEP 6: (3S)-6'-CHLORO-N-(((lS)-l-CYANO-4-PENTEN-l -YL)SULFONYL)- 5-(((lR,2R)-2-((l S,2E)-1 -HYDROXY-2-HEXEN-l -

YL)CYCLOBUTYL)METHYL)-3^4,4^5"TETRAHYDRO-2'H"SPIRO[L5" BENZOXAZEPINE-3, -NAPHTHALENE]-7-CARBOXAMIDE AND (3S)-6'- CHLORO-N-((( 1 R)- 1 -CYANO-4-PENTEN- i -YL)SULFONYL)-5-((( 1 R,2R)-2- {{ ί S.2! ^; )- l ·! IYDROXY-2-! H !Xli 1 -YL ^' Yi ^' i .OBi Ί Y i .)\ lI ^; TI ΙΥ! . )-3'.4.4·.5 · TETRAHYDRO-2'H-SPIRO 1 ,5-BENZQXAZEPI E-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE

N,N-dimethylpyridin-4-amine (DMAP) (47.9 mg, 0.392 mmol) was added to a solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l - yl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxylic acid (Intermediate AA12A,] 00 mg, 0.196 mmol), triethylamine (0.082 mL, 0.588 mmol) and l-cyanopent-4-ene-l -sulfonamide (68 mg, 0.392 mmol) in DCM (2 mL) at ambient temperature. N-(3- Dimethylaminopropyl)-N'~ethylcarbodiimide hydrochloride (75 mg, 0.392 mmol) was added slowly and the reaction mixture was stirred at ambient temperature for 18 h. The residue was chromatographed (silica gel, 10 % to 100 %, EtOAc+LO % AcOH/hexanes) to afford the title compounds (130 mg, 100 % yield).

STEP 7: (lS,3 ^, R,6'R,7'S,8'E,12'S)-6-CHLORO-7 ^! -HYDROXY-l 5'-OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO [14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOS A[8, 16, 18,24] TETRAENE] - 12'-C ARBONITRILE 13', 13'-D10XIDE OR (lS,3'R,6'R,7 ^! S,8'E,12'R)-6-CHL()R()-7'-HYDR()XY-15'-OX()-3,4- DIHYDRO-2H-SPIRO[N APHTHALENE- 1 ,22'-[20] OXA [ 13JTHI A

[1,14]DIAZATETRACYCLO

|;14.7.2.0 ³ -^0 ^!9 ' ²⁴ 1PENTACOSA|;8,16,18,24]TETRAENE]-12 ^, -CARBONITRILE 13 ^f ,13'-DIOXIDE

A round bottom flask was charged with (TS)-6'-chloro-N-((l-cyanopent-4- en- 1 -yl)sulfonyl)-5-(((l R,2R)-2-((S,E)- 1 -hy droxyhex-2~en- 1 - yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b]| l ,4]oxazepine- 3,r-naphthalene]-7-carboxamide (0.130 g, 0, 195 mmol) in AcOH (67.3 mL). To the homogeneous solution was added Hoveyda-Grubbs 11 (0.024 g, 0.039 mmol) at room temperature. The mixture was stirred at ambient temperature under reduced pressure overnight and then air was bubbled through for 10 min. The reaction mixture was concentrated. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 35% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as a white solid (3 mg, 2.58 %). ^" Ή NMR (400 MHz, CD2CI2) δ 7.76 - 7.68 (m, I I I . 7.22 - 7.15 (m, 1 H), 7.12 - 7.06 (m, IH), 6,99 - 6.86 (m, 3H), 5.76 (ddd, J = 2.35, 3.91, 11.74 Hz, 2H), 5.24 (ddd, J = 3.33, 10.76, 14.09 Hz, 1H), 4.32 ·· 4.19 (m, i l l). 4.13 - 4.08 (m, 2H), 3.83 (d, J - 16.24 Hz, i l l . 3.68 id. J = 13.50 Hz, I I I ). 3.26 (d, J = 14.28 Hz, I I I ). 3.06 (dd, J - 9.39, 15.45 Hz, i l l ). 2.83 - 2.71 (m, 2H), 2.54 - 2.24 (m, 6H), 2,09 - 1.76 (m, 8H), 1.44 - 1.36 (m, 2H),

m/z (ESI, +ve ion) 596.2 (M+H) ⁺ . EXAMPLE 154. (lS^'R^'^TS^'^^'R^l^-iTERT-

BUTYLSULFONYL)ETHYL)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO-

2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20] OXA[ 13]THI A[ 1 , 14] DI AZ ATETR AC YCLO

i .V. l .T- DIOXIDE AND

(lS,3'R,6'R,7 ^, S,8'E, 12'S)-12'-(2-(TERT-BUTYLSULFONYL)ETHYL)-6- CHI RO-7' iYDROX ^r -3,4-Dim ^r DRO-2Fi,15Tl-SPiRO| siAPHTOALENE- 1 ,22'-[20] OX A[ 13] THI A[ 1 , 14] DIAZ ATETRAC YCLO

|;14.7.2.0 ³ - ⁶ .() ^!9 ' ²⁴ 1PENTACOSA [8,16,18,24jTETRAEN]-15'-ONE 13', 13'- DIOX

STEP 1 : (3R)-l-HYDROXY-N,N-BIS(4-METOOXYBENZYL)-6-HEPTENE-3- SULFQNAMIDE AND (3S)-l-HYDROXY-N,N-BIS(4-METHOXYBENZYL)- 6-HEPTENE-3-SU

To a solution ofN,N-bis(4-metiioxybenzyl)pent-4-ene-l-sulfonamide

(EE19, 4.85 g, 12.45 mmol) in THF (49.8 mL) was added butyllithium solution, 2,5 M in hexanes (5.98 mL, 14.94 mmol) -78 °C dropwise. After the reaction was stirred at -78 °C for 10 min, ethylene oxide gas (bp = 10.7 °) was sparged into the reation flask for 30 minutes at this temperature. The reaction was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH ₄ C1, and extracted with EtOAc(2X). The organic layers were washed with brine, dried (Na ₂ S0 ₄ ) and filtered. The filtrate was concentrated and chromatographed (silica gel, 30% to 65%, EtO Ac/Hex) to afford the title compounds (4.6 g, 85 %) as a colorless oil.

STEP 2: (3S)-N,N-BIS(4-METHOXYBENZYL)-l-((2-METHYL-2- PROPANYL)SULFANYL)-6-HEPTENE-3-SULFONAMIDE AND (3R)-N,N- BIS(4-METOOXYBENZYL)-l (2-MFmm _J -2-PRO A YL)SULFANYL)-6- HEPTENE-3-SULF

To a solution of (3R)-l-hydroxy-N,N-bis(4-methoxybenzyl)-6-heptene-3- sulfonamide and (3s)-l-hydroxy-N,N-bis(4-methoxybenz l)-6-heptene-3- sulfonamide (500 mg, 1.15 mmol) in toluene (2.31 mL) was added

cyanomethylenetri-n-butylphosphorane (0.84 mL, 3.46 mmol) and tert-butylthiol (0,39 mL, 3.46 mrnol). The reaction mixture was sealed and stirred for 18 h at 100 °C. The mixture was then cooled and concentrated. The crude material was chromatographed (silica gel, 0 to 100%», EtOAc /hexane) to afford the title compound (350 mg, 60.0 %) as a light yellow oil .

STEP 3: (3S)-N,N-BIS(4-METHOXYBENZYL)-l^(2-METHYL-2- PROPANYL)SULFONYL)-6-HEPTENE-3-SULFONAMIDE AND (3R)-N,N- ΒΙ8(4-ΜΕπΐΟΧΥΒΕΝΖΥΙ,)-1 (2-ΜΓ^^.-2-ΡΚΟΡΑΝΥΙ,)8υΐ.ΡΟΝΥΙ,)-6- HEPTENE-3-SULFONAMIDE AND (3R)-N,N-BIS(4-METHOXYBENZYL)-l- ((2-METHYL-2-PROPANYL)SULFONYL)-6-HEPTENE-3-SULFONAMIDE AND (3R)-N,N-BIS(4-METHOXYBENZYL)- 1 -((2-METHYL-2- PROPANYL)SULF -6-HEPTENE-3-SULFONAMIDE

To a solution of (3S)-N,N-bis(4-methoxybenzyl)-l-((2-methyl-2- propanyl)sulfanyl)-6-heptene-3-sulfonamide and (3R)-N,N-bis(4- methoxybenzj ⁷ l)-l-((2-methyl-2-propanyl)sulfanyl)-6-heptene-3-sulfo namide (320 mg, 0.633 mrnol) in DCM (3 mL) at 0 °C was added 3-chioroperoxybenzoic acid, 77% max. (312 mg, 1.39 mrnol). The reaction was stirred at this temperature for 15 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate, and extracted with DCM (3X). The combined organic layers were washed with brine, dried (MgS0 ₄ ), and filtered. The filtrated was concentrated and chromatographed (silica gel, 0 to 100%, EtOAc/hexane) to afford the title compound (210 mg, 61.7%) as an oil. STEP 4: (3R)-l-((2-METHYL-2-PROPANYL)SULFONYL)-6-HEPTENE-3- SULFGNAMIDE AND (3S)-1 -((2-METHYL-2-PROPANYL)SULFONYL)-6- HEPTENE-3-SULFON AMIDE

The title compounds were prepared from (3S)-N,N-bis(4-methoxybenzyl)- 1 ~((2-methyl~2~piOpanyl)sulfonyl)~6 ieptene-3~sulfoiiamide and (3R)-N,N-bis(4- methoxybenzjd)-l-((2-methyl-2-propanyl)sulfonyl)-6-heptene-3 -sulfonamide using a similar procedure described in Step 3 in Example 373.

STEP 5: (3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l-

YL)CYCLOBUTYL)METHYL)-N-(((3S)-l-((2-METHYL-2- PROPANYL)SULFONYL)-6-HEPTEN-3-YL)SULFONYL)-3 ^, ,4,4',5-

TETRAHYDRO-2'H-SPIRO[l ,5~BENZOXAZEPINE-: l'-NAPHTHALENE]-7- CARBOXAMIDE AND (3S)-6'-CHLORO-5-(((l R,2R)-2-((l S,2E)-1- HYDROXY-2-HEXEN- 1 -YL)CYCLOBUTYL)METHYL)-N-(((3R)-l -((2- METHYL-2-PROPANYL)SULFONYL)-6-HEPTEN-3-YL)SULFONYL)- S'^^' -TETRi^HYDRO^'H-SPIROtLS-BENZOXAZEPINE-S/l'- NAPHTHALENE] -7-CARBOXAMIDE

N,N-dimethylpyridin-4-amine (DMAP) (47.9 rng, 0.392 mmol) was added to a solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l - y^cyclobuty^methy^-S'^^'^-tetrahydro^H^'H-s irotbenzotblt l^Joxazepine- 3,1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A, 100 mg, 0.196 mmol), triethylamine (0.082 mL, 0,588 mmol) and (3R)-l-((2-methyl-2- propanyl)sulfonyl)-6-heptene-3-sulfonarnide and (3 S)- 1 -((2-methyl-2- propanyl)sulfonyl)-6-heptene-3-sulfonamide (117 mg, 0.392 nimois) in DCM (2 mL) at ambient temperature, N-(3-dime1hylaminopropyl)-N-ethylcarbodiirnide hydrochloride (75 mg, 0.392 mmol) was added slowly and the reaction mixture was stirred at ambient temperature for 18 h. The residue was chromatographed (silica gel, 10 % to 100 %, EtOAc+AcOH/hexane) to afford the title compound (130 mg, 84 %).

STEP 6: (IS,3¾,6'R,7'S,8T 12'R)-I2' 2 TERT-BUTYLSULFONYL)EmYL)- 6-CHLORO-7 ^, -HYDRO.XY-3,4 3IHYDRO-2H,15H~SPIRO[NAPHTHALENE- 1,22'-[20]OXA[13] THIA[l,14]DlAZATEm CYCLO[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ] PENTACOSA[8,16,18,24]TETRAENj-15'-ONE 13\13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R ₅ 7*S,8¾12 ^, S)-12 ^, -(2-(TCRT-BUWLSULFONYL)ET YT _J )-6-

C! U.O O-7 -ί iYDR()XY- .4-Di! !Y DR -211.1 V| !-SPlROjNAP! 111 l.\!J \i 1 ,22'-[20] OXA[ 13JTHIA

[1,14JDIAZ ATETRACYCLOi; 14.7.2.0 ³ ' .0 ¹⁹ - ²⁴ ]PENTACOS A[8, 16, 18,24]TETR AEN] - 15'-ONE 13 i 3 '-DIOXIDE

A round bottom flask was charged with (1 'S)-N-((l -(tert- butylsiilfonyl)hept-6-en-3-yl)sulfo^

hydroxyhex-2-en ~yi)cyclobutyi)rnethyl)-3 ^f ,4,4',5-tetrahydro-2H,21l- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide (0.130 g, 0.165 mmol) in AcOH (56,8 mL), To this homogeneous solution was added Hoveyda- Grubbs II (0.021 g, 0.033 mmol) at ambient temperature. The mixture was stirred at ambient temperature under reduced pressure for 18 h and then air was sparged into the flask for 10 min. The reaction mixture was concentrated. The crude oil was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 35% to 95% MeCN in water, where both solvents contain 0, 1% TFA, 30 min method) to afford the title compound as the second eluting isomer as a white solid (8 mg, 6.75%). ¾ NMR (400 MHz, CD ^• CI -} δ 7.72 (d, 8,61 Hz, 1H), 7.32 (dd, J = 2.05, 8,31 Hz, 1H), 7,16 (d, J = 2.35 Hz, 1H), 7.09 (d, J = 2,35 Hz, ill).6.98 (d, ,/ 8,22 Hz, 2H), 5.81 - 5.68 (m, 1H), 5.63 - 5.51 (m, IH), 4.52 (t, J = 6.85 Hz, 1H), 4.11 (s, 2H), 3.99 - 3.79 (m, 2H), 3.70 (d, J == 14.48 Hz, 1H), 3.44 - 3,10 (m, 4H), 2.86 - 2.72 (m, 2H), 2.67 - 2.53 (m, 2H), 2,46 - 2.16 (m, 5H), 2.12 - 1.91 (m, 6H), 1,75 - 1.57 (m, 4H), 1.43 (s, 9H). m/z (ESI, +ve ion) 719.2 (M+H) ⁺ .

EXAMPLE 155. (1 S,3'R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, R)-12 ^, -(2-(TERT- BUTYLSULFONYL)ETHYL)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO-

2H,15'H"SPIRO[NAPHTHALENE-L22'"[20]OXA[13]

THI A[ 1 , 14] DIAZATETRACYCLO

[ 14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13', 13'- DIOXIDE OR

(lS,3¾,6 ^, R,7^,8¾12'S)-12'-(2 TERT-BUT ' ^r LSULFONYL)ETHYL)-6-

CHLORO-7'-HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[ 13]THIA[ 1 , 14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN] 15'-ONE 13', 13 '-DIOXIDE

The title compound (16 mg, 13.5%) was obtained as the first eluting isomer from Example 154, Step 6. ¾ NMR {400 Mi!/. CD2CI2) δ 8.43 - 8.17 (ra, IH), 7.71 ( ^■ ±. I 8.61 Hz, 1H), 7.17 (dd, J = 2.35, 8.41 Hz, 1H), 7.09 (d, J = 2.35 Hz, IH), 6.95 - 6.84 (m, 3H), 5.94 - 5.65 (m, 2H), 4.39 - 4.26 (m, IH), 4.20 (dd, J - 4.01, 7.34 Hz, IH), 4.08 (s, 2H), 3.82 (d, 13.89 Hz, ill).3.70 (d, 14.09 Hz, IH), 3.36 (t, ./ 6.85 Hz, 2H), 3.25 (d, «/= 14.28 Hz, IH), 3.03 (dd, «/= 9.39, 15.26 Hz, IH), 2.85 - 2.62 (m, 2H), 2.54 - 2.19 (m, 6H), 2.10 - 1.90 (m, 4H), 1.81 (br. s., 611).1.43 (s, 9H). m/z (ESI, +ve ion) 719.2 iM H) . EXAMPLE 156. (Ι8,3Ί ,6¾,7'8,8Έ,12'8)-12'-(2-(ΤΕη-

BUTYLSULFONYL)ETHYL)-6-CHLORO-7'-METHOXY-3,4-DIHYDRO- [20]OXA[13]ΤΗΐΑ| 1 , ί 4 jDIAZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PENTACOSA[8,16,18,24]TET¾AEN]-15'-ONE 13',13'-DIOXIDE OR

(lS ₅ 3 ^, R,6 ^, R,7 ^, S,8¾12 ^, R)-12 ^, -(2-(TERT-BUTYLSULFONYL)E ^' raYL)-6-

CHLORO-7'-METHOXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-[20]OXA[13] TH [i;i4]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ ,0 ¹⁹ ' ²⁴ ] PEN - 15'-ONE 13', 13'-DIOXIDE

The title compound (3.4 mg, 67%) was prepared from

(lS,3 ^* R,6'R,7 ^! S,8'E,12'R)-12'-(2-(tert-butylsuta

3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l ,14]diazate1r^

n]-15'-one 13',13 ^! ~dioxMe or (1 S,3'R,6'R,7 ^f S,8'E, 12'S)-12'-(2-(tert- butylsulfon}d)ethyl)-6-chloro-7'-h}'droxy-3,4-dihydro-2H,15' H-spiro| ^" naphthalene- l,22'-[20]oxa[l 3]thia[l ,14]diazatetracyclo

[14.7.2.0 ⁵ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 155) using a similar procedure described in Example 718, Step 1. ^! H NMR (400MHz, CD2CI2) δ 7.70 (d, J = 8.61 Hz, i l l ). 7.17 (d l. J = 2.25, 8.51 Hz, H i ). 7.09 (d, J = 2.15 Hz, I I I ). 6.90 (s, 2H), 6.84 - 6.81 (m, IH), 5.81 (td, J = 6.50, 14.97 Hz, i l l ). 5,58 - 5.49 (m, i l l ). 4.43 - 4.28 (m, i l l ). 4,07 (s, 2H), 3.87 - 3.76 (m, 11 1 ). 3.70 (d, J = 14.28 Hz, IH), 3.63 (dd, J = 3.42, 8.90 Hz, IH), 3.45 - 3.29 { in. 2H), 3.25 (d, J == 14.28 Hz, IH), 3.01 (dd, J == 10.27, 15.36 Hz, IH), 2.81 - 2,72 (m, 2H), 2.55 - 2,25 (m, 7H), 2.05 - 2,01 (m, IH), 1.99 - 1.73 (m, 8H), 1.72 - 1.60 (m, 2H), 1.45 - 1.39 (m, 9H). mlz (ESI, +ve ion) 733.2 (M+H) ⁺ . EXAMPLE 157. (l S,3 ⁱ R,6'R,7 ^f S,8'E, 12'S)-6-CHLORO-12'-

(CYCLOPROPYLMETHYl,)-7'-HYDROXY-3,4-DIHYDRO-2H,15 ^! H-SPrRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8;i6,18,24]TETiL E ]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-12 ^, -(CYCLOPROPYLMETHYL)-7'- HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTOALENE-!,22'- [20] OXA[ 13]THI A[ 1 , 14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN 15'-ONE 13', 13 '-DIOXIDE OR

(lS ¾ )'R ^,8'Z, 12'S)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)-7'- HYDROXY-3 4 3IHYDRO-2H ₅ L5H~SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[ 13 ]THIA[ 1,14]

DIAZATETRACYCLO[14J.2.0 ³ -^0 ³⁹ ^ ⁴ ]PENTACOSA[8,16,18,24]TETRAENj 15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, Z,12 ^, R)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)-7'- HYDROXY ^-DIHYDRO^H S'H-SPIROI APHTHALENE-l^^- [20]OXA[13]THIA[1 ,14] DIAZATETRACYCLO[14,7.2.0 ^3/l .0 ¹⁹ - ²⁴ ]

PENTACO - 15'-ONE 13 VI 3'-DIOXIDE

STEP 1 : (2S)- 1 -CYCLOPROPYL-5-HEXENE-2-SULFON AMIDE AND (2R)-1- CYCLOPROPYL-5-HEXENE-2-SULFON AMIDE

The title compounds were prepared from N,N-bis(4-methoxybenzyl)pent-

-1 -sulfonamide (EE 19) using a similar procedure described in Step 1 and then 5 of Example 153, replacing chlorocarbonic acid methyl ester with

(bromomethyl)-cyclopropane in Step 1.

STEP 2: (lS,3¾,6¾,7'S,8T;,12'S)-6 ;HI RO-r2'^CYCLOPROPYLMETHYL)- 7 ^! ~HYDROXY-3,4-DlHYDRO-2H,15'H-SPIRO [NAPHTHALENE- 1 ,22 ^s - [20]OXA[13]THIA[1,14] DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACQSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DK)XIDE OR

(lS,3¾,6'R,7^,8 i,12'R)-6-CHLORO-12' CYCLOPROPYLMETHYL)-7'- HYDROXY-3,4 3IHYDRO-2H,L5H~SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[13]THIA [1,14]

DIAZATETRACYCLO[14.7,2.0 ³ ' ⁶ .0 ⁱ⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~ 15'-ONE 13',13'-D10XJDE OR (lS,3 ^! R,6'R,7'S,8'Z,12'S)-6-CHLORO-12'- (CYCLQPRQPYLMETHYL)-7'-HYDRQXY-3,4-DIHYDRQ-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]Tffl A[l ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,12'R)-6-CHLOR()-12 ^, -(CYCLOPROPYLMETHYL)-7'- HYDROXY-S^-DI-TroRO^H SH-SPIROINAPHTHALENE-l^*- |20jO.\A| 1311 HI Λ| I .. N |PI A/A Π·. I RAC VCi ()l i ·Ι 7.20 ^{' !'} .θ' ^: ' ^!| |Pi- ^" N i ACOS A [8,16,18,24]TETiL4EN]-15'-ONE 13',13'-D10X1DE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxyhex-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahyd ro-2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carbox lic acid (Intermediate AA12) using a similar procedure described in Example 153, Step 6 to 7, replacing 1 -cyanopent-4-ene-l -sulfonamide in Step 6 with I -cyclopropylhex-5-ene-2- sulfonamide. This crude oil of Step 7 was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Pheiiomenex, Torrance, CA; gradient eiution of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to afford the title compound as the first eluting isomer as a white foam (9 mg, 9.7%). ¾ NMR (400MHz, CD2CI2) δ 8.00 (s, 1H), 7.53 (d, J = 8.61 Hz, ill).6,99 (dd, J = 2,35, 8,61 Hz, 1H), 6,91 id. J = 2,35 Hz, ill).6.76 - 6,68 (m, 3H), 5.73 - 5.60 (m, ill).5.53 (dd, J = 7.63, 15.45 Hz, 2H), 3.90 (s, 4H), 3.65 (d, J = 13.89 Hz, Hi).3.53 (d, J = 14.28 Hz, lH), 3.07 (d, J - 14.28 Hz, ill .2.86 (dd, J = 9,29, 15,36 Hz, ill).2,68 - 2,48 (m, 2H), 2.06 (s, 4H), 1.94 - 1.72 (m, 6H), 1.61 (br. s., 6H), 0,92 - 0,79 (m, 1H), 0.41 (d, J = 7.83 Hz, 2H), 0.11 to -0.09 (m, 2H). m/z (ESI, +ve ion) 625.2 (M R)

EXAMPLE 158, (1 S,3'R,6'R,7'S,8'E, 12'S)-6-CHLORO- 12'- (CYCLOPROPYLAlETHYL)-7'-HYDROXY-3,4~DIHYDRO-2H,15 ^, H- SPIRO| APHTHALENE-1,22'-[20]OXA[13]THIA[1.14]DIAZATETRACYCLO

[14.7.2.0 ³ · ⁶ .0 ^!9 · ²⁴ ] PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE OR

(lS,3'R,61,7 ^, S,8 ^, E,12 ^, R)~6"CHLORO-12 ^! ~(CYCLOPROPYLMETHYL)-7'- HYDROXY-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTOALENE- 1 ,22'- [20]ΟΧΑ[13]ΤΗΐΑ[Ι,14] DIAZATETRACYCLO[14,7.2,0 ^3/l ,0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16,18,24]TETiL E ]-15'-ONE 13',13'-DIOXIDE OR

(lS,3 ^! R,6'R,7'S,8'Z,12'S)-6-CHLORO-12'-(CYCL()PROPYLMETOYL)- 7'- HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[13]TfflA[l,14] DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16,18,24]TETR,\EN]-15'-ONE 13',13'~DI0X1DE OR

(lS,3'R,6 ^! R,7'S,8'Z,12'R)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)-7'- HYDROXY-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTOALENE- 1 ,22'- [20]OXA[13]THIA[1,14]

DIAZATETRACYCL [14.7,2.() ³ -^() ⁱ⁹ - ²⁴ iPENTACOSA|8,16,18,24]TETRAENj- 15-ONE 13 ^* , 13'-DIOXIDE

The title compound (6 mg, 6.5%) was isolated as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 157. ^! H NMR (400MHz, CD2CI2) 68.17 (br. s., ill).7.67 (d, J = 8.61 Hz, 1H), 7.57 ·· 7.39 (m, 1H), 7.15 (dd, J = 2.35, 8.41 Hz, 1H), 7.10 (d, J = 2.35 Hz, 1H), 6.99 - 6.83 (m, 2H), 5,69 (dt, J = 4,70, 15,45 Hz, IH), 5,61 - 5,45 (m, 1H), 4.21 (s, 2H), 4.01 - 3,80 (m, 3H), 3.71 (d, J = 13.89 Hz, ill).3,40 (d, J = 14.08 Hz, H), 3.20 (d, J = 15.65 Hz, IH), 2.83 - 2.71 (ni, 2H), 2.56 - 2.41 (m, 2H), 2.38 - 2.26 (ni, ill).2.17 - 1.99 (m, 4H), 1.87 - 1.78 (m, SH), 1,78 - 1.55 (m, 4H), 1.08 - 0.93 (m, IH), 0,68 - 0,46 (m, 2H), 0.31 - 0.12 (m, 2H). m/z (ESI, +ve ion) 625,2 (M+H) ⁺ .

EXAMPLE 159. (lS,3 ^, R,6 ^, R,7 ^, S.8 ^, E.12 ^, S)-6-CHLORO-12'-

(CYCLOPROPYLMETOYL)-7'-HYDROXY-3,4-DII-IYDRO-2H,15'H-SPIR O [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8, 16, 18,24] TETRAEN] - 15 '-ONE 13',13'-DTOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,12'R)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)-7'- HYDROXY-3,4-DIHYDRO-2H,15'H-SPlRO[NAPHraALENE-l,22'- [20]ΟΧΑ[13]ΤΉΙΑ[1,14]

DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN 15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S,8'Z,12'S)-6-CHLORO-12 ^! - (CYCLOPROPYLMETHYL)-7'-HYDROXY-3,4-DIHYDRO-2H,15'H- SPIRO I NAPHTHALENE- 1 ,22'-[20] OXA[ 13] THI A[ 1 , 14 j DIAZATETRACYCLO[14,7.2.0 ³ - ^f \0 ¹⁹ - ² ]PENTACOSA [8,16,18,24]TETRAEN]- 15'-ONE 13',I3'-DIQX1DE OR (1S,3'R,6'R,7'S,8 ^! Z,12 ^, R)"6-CHL0R0-12'- (CYCLOPROPYLMETHYL)-7'-HYDROXY-3,4-DIHYDRO-2H,15H- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[ 1,14]

DiAZATETRACYCLO[L4;7,2A ⁾³ - ⁶ .0 ³⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]- 15'-O ', 13 '-DIOXIDE

The title compound (7 nig, 7.5%) was isolated as the third eluting isomer from the reversed phase preparatory HPLC separation in Example 157. ^! H NMR (400MHz, CD2CI2) δ 9.40 - 9.24 (m, IH), 7.72 (d, «/= 8.41 Hz, IH), 7.26 (dd, ./ = 1.96, 8.22 Hz, IH), 7.17 (dd, J = 2.15, 8.41 Hz, IH), 7.09 (s, 1H), 6.96 i d.

8.22 Hz, IH), 6.89 (d, ./ 1.96 Hz, IH), 5.81 - 5.66 (m, ! ! ! ). 5.64 - 5.53 (m, IH), 4,63 - 4.49 ( ns. IH), 4.10 (s, 2H), 3,91 (d. ./ 15.65 Hz, IH), 3,71 (d, ./ 14.48 Hz, IH), 3,27 (d, ./ 14.28 Hz, IH), 3,20 - 3.10 (m, IH), 3.09 - 2.98 (m, IH), 2,82 - 2.73 (m, 2H), 2.69 - 2.55 (m, IH), 2.50 - 2.36 (m, IH), 2.34 - 2.27 (m, IH), 2.24 - 2, 17 (m, IH), 2.05 (br, s,, 6H), 1 .78 - 1.64 (m, 4H), 1 ,54 - 1.39 (m, I H), 1 .26 (s, 2H), 0.95 - 0.82 (m, 2H), 0,80 - 0.69 (m, i l l ). 0.42 - 0.26 (m, IH). m/z (ESI, +ve ion) 625.3 (M+H) ⁺ . EXAMPLE 160. METHYL (lS,3'R,6'R,7 ^f S,8'E, 12'S)-6-CHLORO-7'-

HYDROXY-15'-OXO-:i4-DmYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[13]TOIA[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24] TETRAENE] - 12'-C ARBOXYL ATE 13 ',13 '-DIOXIDE OR METHYL (I S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7'-HYDROXY-15'-OXO-3,4- DIHYDRO-2H-SPIRO [NAPHTHALENE- 1 ,22'- [20] ()XA[ 13 jTHI A[ 1,14] DI AZ ATETRAC YCLO

[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]PENTACOSA [8, 16, 1 8,24 jTETRAENE]- 12'-CARBOXYL ATE 13Vi3'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxyhex~2-en~l~yl)cyclobuty4^

spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (Intermediate AA12A) using a similar procedure described in Example 153, Step 6 to 7, replacing l -cyanopent-4-ene-l -sulfonamide in Step 6 with methyl 2- sulfamoylhex-5-enoate. The crude oil of Step 7 was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 30 mm method) to afford the title compound the fastest eluting isomer (21 mg, 7.7%). ¾ NMR (400MHz, CD2CI2) δ 8.27 (s, IH), 7.70 (d, J = 8.6 Hz, H I ). 7.17 (dd, J = 2.3, 8.4 Hz, 1H), 7.09 (d, J - 2.3 Hz, i l l ). 6.96 - 6.87 (m, 3H), 5,73 (dd, J = 9,0, 14.1 Hz, i l l ). 5,05 (dd, J = 3,3, 10.6 Hz, i l l ). 4,20 (br. s . 1 1 1 ). 4,09 (s, 2H), 3,87 (s, 3H), 3,84 (d, J = 16,2 Hz, IH), 3.70 (d, J = 14,3 Hz, I H i. 3.25 (d, J = 14.1 Hz, IH), 3.04 (dd, J = 9.0, 15.7 Hz, IH), 2.81 - 2.72 (m, 2H), 2.49 - 2.27 (m, 4H), 2.04 (d, J = 13.5 Hz, 2H), 1.99 - 1.71 (m, 9H), 1.41 (t, J 12.2 Hz, IH). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ . EXAMPLE 161. METHYL (((lS,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-12'- CYCLOPROPYL- 13', 13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-1,22 ^, -[20]OXA[13]THIA [ 1, 14JDIAZ ATET ACYCLOi; 14.7.2,0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] -7'-YL)OXY) ACETATE OR METHYL

(((I S^ R^'RJ'S^ ^.^-e-CHLORO-n'-CYCLOPROPYL- ', !

15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]THIA[1, 14] DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16,18,24]TETR/\EN]-7 ^, -YL)OXY)ACETATE

To a solution of (l S,3'R,6 ^f R,7'S,8 ^, E, 12 ^, S)-6-Ghloro- i2 ^, -cyclopropyl-7'- hydroxy~3,4-dihydro-2H, 15'H-spiro[naphthalene-l,22'- [20] oxa[ 13 jthiaj 1 , 14] diazatetracy cio

|;i4.7.2.0 ³ -^0 ^!9 ' ²⁴ lpentacosa[8, 16J 8,241tetraen |-15'-one 13',13'-dioxide or (l S,3'R R,7'S,8 .;i2 ^, S)-6 .h]oro- 12'-cyclopropyl-7 ^, iydrox}'-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[ 13 ]thia[ 1,14] diazatetracy cio[ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa[8,16,18,24]tetraen]-15'-one 13', .13'-dioxide (Example 148, the first eluting isomer, 7.00 mg, 0.01 1 mmol) in THF (1.145 mL) was added sodium hydride, 60% dispersion in mineral oil (1.37 mg, 0.057 mmol). After 15 mm, bromoacetic acid methyl ester (0.002 mL, 0.023 mmol) was added. The reaction was stirred at ambient temperature. After 30 minutes the reaction was quenched with aqueous saturated ammonium chloride, brine and was extracted with diethyl ether (3X). The combined organic layers were concentrated. The crude residue was chromatographed (silica gel, 0% to 100%», EtOAc+0.5% acetic acid /hexane) to afford the title compound (4.6 mg, 58.8 %) as colorless glass. ¾ NMR (400 MHz, CD2CI2) 5 7.70 (d, J = 8.41 Hz, IH), 7.17 (dd, J = 2.45, 8.51 Hz, IH), 7.09 (d, J = 2.15 Hz, ill).6,92 - 6.88 (m, 2H), 6.79 (s, III).5.76 (ddd, J = 3.81, 9.10, 15.26 Hz, 1H), 5.56 (dd, J = 8.41, 15.06 Hz, 1H), 4.07 (d, J = 2.74 Hz, 2H), 3.97 (d, J = 4.11 Hz, 2H), 3.89 - 3.77 ins.2H), 3.72 (s, 3H), 3.44 (di, J = 2.35, 10.27 Hz, 111).3.25 (d, J = 14.28 Hz, 111).3,03 (dd, J = 10,47, 15.36 Hz, ill).2.80 - 2.72 (m, 2H), 2.61 - 2,48 (m, 2H), 2.32 (s, 3H), 1.99 - 1.90 (m, 2H), 1.88 - 1,77 (m, 5H), 1.74 - 1.64 (m, 2H), 1.07 - 0.96- (m, 2H), 0.75 - 0.82 (m, 2H), 0.48 - 0.39 (m, 2H). tii /. (ESI, +ve son) 683.2 (M+H) ⁺ .

EXAMPLE 162. (lS,3 ^, R,6'R,7 ^! S,8'E,12'R)-12'-(2-(BENZYLSULFONYL) ETHYL)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO-2H.15H-

SPIRO[NAPHTOALENE-l,22 ^f -[201OXA[I3]TOIA[l,14]DIAZATETRACYCLO [14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24] TETRAEN] - 15 '-ONE 13', 13'- DIOX1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,12'S)-12'-(2-(BENZYLSULFONYL)ETI-rX)-6-CHLORO-7 ^! - HYDROXY-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22 ^! - [20]OXA[13]THIA[1,14]

DIAZATETRACYCL [14.7.2.() ³ -^() ⁱ⁹ - ²⁴ iPENTACOSA[8,16,18,24]TETRAENj- 15-ONE I3'J3'-DIOXIDE

STEP 1 : (3R)-l-(BENZYLSULFANYL)-N,N-BIS(4-METHOXYBENZYL) -6- HEPTENE-3 - S ULFON AMIDE AND (3 S)- 1 -(BENZYLS ULF AN YL)-N ,N- BIS(4-METHO -6-HEPTE - -SULFONAMIDE

To a mixture of (3R)-1 -hydroxy-N,N-bis(4-methoxybenzyl)-6-heptene-3- sulfonamide and (3S)-l-hydroxy-N,N-bis(4-memoxybenzyl)-6-heptene-3- sulfonamide (Example 154, 500 mg, 1.15 mmol) in toluene (2.3 mL) was added cyanomethylenetri-n-butyiphosphorane (0.84 mL, 3.46 mmol) and benzyl thiol (0. 1 ml,, 3.46 mmol) at ambient temperature. The reaction was sealed, stirred and heated at 100 °C for 18 h. The mixture was cooled, concentrated and the crude residue was chromatographed (silica gel, 0 to 100%, EtOAc/hexane) to afford the title compound (456 mg, 73.3%) as a light-yellow oil. STEP 2: (3R)-1 -(BENZYLSULFONYL)-N,N-BIS(4-METHOXYBENZYL)-6- HEPTENE-3-SULFONAMIDE AND (3S)- 1 -(BENZYLSULFONYL)-N,N- BIS(4-METHO

To a mixture of (3R)-l-(benz>'lsulfanyl)-N,N-bis(4-methoxybenzyl) -6· heptene-3-sulfonamide and (3S)- 1 -(benzy lsulfany l)-N,N-bis(4-methoxybenzyl)-6- heptene-3-sulfonamide (420 mg, 0.78 mmol) in DCM (3 mL) at 0 °C was added 3-chloroperoxybenzoic acid, 77% max. (384 mg, 1.71 mmol). The reaction mixture was stirred for 15 minutes at this temperature and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM (3X) and the organic layer was washed with brine, dried (MgSCn), and filtered. The filtrate was concentrated and chromatographed (silica gel, 0 to 100%,

EtOAc/hexane) to afford the title compound (350 mg, 79%) as an oil.

STEP 3: (3S)-l-(BENZYLSULFONYL)-6-HEPTENE-3-SULFONAMIDE AND (3 S )- 1 -(BENZYLSULFONYL)-6-HEPTENE-3-SULFONAMIDE

The title compound was prepared from (3R)-l-(benzylsulfonyl)-N,N- bis(4-methoxybenzy])-6-heptene-3-sulfonamide and (3S)-l -(benz lsulfonyl)-N,N- bis(4-methoxybenzyl)-6-heptene-3-sulfonamide using a similar procedure in Step 5 of Example 153.

STEP 4: ( lS,3'R,6'R,7'S,8'E, 12'R)- 12'-(2-(BENZYLSULFONYL) ETHYL)-6- CHLORO-7 ^! -HYDROXY-:i4-DIHYDRO-2H i5'H-SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[ 13]THIA

[1, 14JDIAZ ATETRACYCLOi; 14.7.2.0 ³ ' .0 ¹⁹ - ²⁴ ]PENTACOS A[8, 16, 18,24] TETRAEN] - 15 '-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S,8'E, 12'S)-12'-(2- (BENZYLSULFONYL)ETHYL)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATFXRACYCIX)[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]ΤΈΤ¾ΑΕΝ]-15'-ΟΝΕ 13', 13 '-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxyhex-2-en-l -yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carbox lic acid (Intermediate AA12) using a similar procedure described in Example 153, Step 6 & 7, replacing l-cyanopent-4-ene-l-sulfonamide with (3S)-l-(benzylsulfonyl)-6-heptene-3- sulfonamide and (3S)-l-(benzylsulfonyl)-6-heptene-3-sulfonamide in Step 6, and the crude residue of Step 7 was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 50% to 90% MeCN in water, where both solvents contain 0. 1% TFA, 30 min method) to afford the title compound as the first eluting isomer (16 mg, 12.6%).

¾ NMR (400MHz, CD2CI2) δ 8.40 - 8.25 (m, IH), 7.75 (d, J = 8.61 Hz, IH), 7.55 - 7.43 (m, 5H), 7.21 (dd, J - 2.35, 8.61 Hz, IH), 7.14 (d, J - 2.35 Hz, IH), 6.99 - 6,88 (m, 3H), 5.86 - 5.67 (m, 2H), 4,35 (s, 2H), 4,33 - 4.20 (m, 2H), 4.13 (s, 2H), 3.86 (d, J = 13.50 Hz, i l l s. 3.74 (d, J = 14.28 Hz, 1H), 3.36 (t, J = 7.73 Hz, i l l ). 3.29 (d, J = 14.28 Hz, ! ! ! ). 3.08 (dd, J - 9.29, 15.36 Hz, IH), 2.85 - 2.76 { in. 2H), 2.54 - 2.30 (ra, 6H), 2,29 - 2.16 (m, 1 H), 2.13 - 2.04 (m, IH), 2,03 - 1.93 (m, 2H), 1.91 - 1.78 (m, 6H), 1.51 - 1.38 (m, 1H). m/z (ESI, +ve ion) 753.2 .

EXAMPLE 163. (l S,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E.12 ^, R)-12 ^, -(2-(BENZYLSULFONYL)

F^iYL)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE~l,22'- [20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, I 8,24]TETRAENl-15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^! R,7^,8iV 2'S)-12'-(2HBE ZYLSULFONYL)ETHYL)-6~CHLORO-7 ^! ~ HYDROXY-3 _s 4-DlHYDRO-2H 5H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1 ,14] DIAZATETRACYCLO

[14.7.2.0 ⁵ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'- DIO

The title compound (8 mg, 6.7%) was isolated as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 162. ^l H NMR (400MHz, CD2CI2) δ 7.72 (d, J = 8.41 Hz, 1 1 1 ). 7.42 (br. s., 5H), 7.31 (s, IH), 7.16 (br. s., IH), 7.09 (s, IH), 7.01 - 6.92 (m, 2H), 5.79 - 5.64 (m, IH), 5.61 - 5.46 (m, IH), 4.62 - 4.44 (m, IH), 4.31 (s, 2H), 4.11 (s, 2H), 3.95 - 3.82 (m, 2H), 3.74 - 3.62 (m, IH), 3,25 i d. J == 14,48 Hz, 4H), 2.77 (br. s., 21 1 ). 2,64 - 2,44 (m, 21 1 ). 2.28 (d, J = 6.06 Hz, 4H), 2.08 - 1.91 (m, 6H), 1.71 (br. s., 3H), 1.53 - 1.34 (m, IH). m/z (ESI, +ve ion) 753.2 (M+H) ⁺ . EXAMPLE 164. (l S,3'R,6'R,7'S,8'E, 10'S)-6-CHLORO-7'-HYDROXY-l Q'~ METHYL-3,4-DIHYDRO-2H, 14'H-SPIRO[N APHTHALENE-1 ,21 '- [19]OXA[ 12]THIA[ l,13]

DIAZATETRACYCLO[13J.2.0 ³ -^0 ³⁸ ^ ³ ]TETRACOSA[8,15,17,23]TETRAENj- 14'-ONE 12',12'-DiQXIDE OR (lS,3 ^! R,6'R,7'S,8'E,10'S)-6-CHLORO-7'-

HYDROXY- 10'-METHYL-3,4-DIHYDRO-2H, 14'H-SPIRQ [N APHTHALENE- 1,21 '-

[19]OXA[12]THIA[1 ,13]DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ - ²³ ]TETRACOSA

[8,15, 17,23]TETRAEN] -14'-ONE 12', 12'-DIOXIDE

STEP 1 : 2-(((2R)-2-METHYL-3-BUTEN- 1 - YL)S ULF ANYL)P YRIMIDINE AND 2-(((2S)-2-MEraYL- -BUTEN-l -YL)SULFANYL)PYRIMID] E

A solution of 2-methyl-3-buten-l-ol (2.395 mL, 23.22 mmol) and triethylamine (6.46 mL, 46.4 mmol) in Et ₂ 0 (46.4 raL) was cooled to -78 °C and treated with methanesulfonyl chloride (2. 156 mL, 27.9 mmol). The mixture was allowed to warm to ambient temperature and then filtered. The solid was washed with ether and the filtrate was concentrated. The crude mesylate was added to a solution of sodium ethoxide (10.40 mL, 27.9 mmol) and pyrimidine-2-thiol (3.13 g, 27.9 mmol) in EtOH (44 mL). The mixture was stirred for 17 h at 50 °C and then concentrated in vacuo. The residue was triturated in EfeO and the solid was removed. The filtraie was concentrated and the cmde oil was chromatographed (silica gel, 5% to 20%, EtOAc /hexane) to afford the title compound (3.59 g, 86 %) as a colorless oil. STEP 2 : 2-(((2Κ)-2-ΜΕΤΙ^.-3-ΒυΤΕΝ-1-ΥΙ.)8υΐ.ΡΟΝΥΕ )ΡΥΚΙΜΙΟΙΝΕ AND 2-(((2R)-2-METH -3-BUTEN-l~YL)SULFONYL)PYRlMlDINE

flask containing 2-(((2R)-2-methyl-3-buten- 1 -yl)sulfanyl)pyrimidine and 2-(((2S)-2-rnethyl-3-buten-l -} _' 1)8ulfan} _' 1)pyriiradine (3,59 g, 19.91 mmol) in DCM (1 mL) was added 3-chloroperox benzoic acid, 77% max. (9.15 g, 40.8 mmol) at 0 °C. The reaction was allowed to stir at this temperature for 15 minutes and then allowed to warm up to ambient temperature. The reaction was quenched with aqueou sodium bicarbonate (100 mL), and extracted with diethyl ether (3X). The organic layer was dried (MgS0 ), filtered and the filtrate was concentrated. The crude oil was chromatographed (silica gel, 0% to 100%, EtOAc/hexane) to afford the title compound (3.47 g, 82 %) as light-yellow oil .

STEP 3: SODIUM (2R)-METH YLB UT-3 -ENE- 1 - S ULFIN ATE AND SODIUM (2S)-METHYLBUT-3-ENE-l -SULFINATE

A mixture of 2-(((2R)-2-methyl-3-buten-l-yl)sulfonyl)pyrimidine and 2- (((2R)-2-memyl-3-buten-l -yl)sulfonyl)pyrimidine (3.47 g, 16.35 mmol) in MeOH was treated with sodium methoxide, 25 wt. % solution in methanol (3.74 mL, 16.35 mmol) and allowed to stir at ambient temperature for 1 h. The resulting mixture was concentrated in vacuo and the residue was triturated in Et20. The solid was filtered to afford the title compound which was used without further purification.

STEP 4: (2S)-METHYLBUT-3-ENE- 1 -S ULFON AMIDE AND (2R>

METHYLBUT-3-ENE- 1 -SULFONAMIDE

A mixture of sodium (2S)-methylbut-3-ene-l-sulfinate and sodium (2R)~ methylbut-3-ene-l-sulfinate (2.55 g, 16.33 mmol) in water (163 mL) was added sodium acetate (2.68 g, 32.7 mmol) followed by hydroxylamine-o-sulfonic acid (1.85 g, 16.33 mmol). The reaction was stirred at ambient temperature for 18 h. The reaction was cooled and treated with aqueous 1.0 N NaOH. The aqueous layer was extracted with EtOAc (2X). The combined organic extracts were dried (MgSC¼), filtered and the filtrate was evaporated in vacuo to afford the title compound (2.1 g, 86%).

STEP 5: (3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E,4R)-l-HYDROX ^ir -4- METHYL-5-SULFAMOYL-2-PENTEN-l-YL)CYCLOBUTYL)METI-IYL)- 3Vlv4^5-TETRAHYDRO-2 ^! H-SPIRO[l ,5-BENZOXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLIC ACID AND

(3S)-6 ^! -CHLORO-5-(((lR,2R)-2-((lS,2E,4S)-l-HYDR()XY-4-METHYL- 5- SULFAMOYL-2-PENTEN-I -YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAH YDRO-2'H-SPIRO [ 1 , 5-BENZOXAZEP1NE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLIC ACID

A vial was charged with (S)-6'-chloro-5-(((l R,2R)-2-((S,E)- 1 -hydroxyhex-

2-en-l -yl)cyclobutyl)methyl)-:r ₅ 4 4V5-tetrahydro-2H,2'H- spiroj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A, 180 mg, 0.353 mmol) and (2S)-methylbut-3-ene-l -sulfonamide and (2R)-methylbut-3-ene-l-sulfonamide (263 mg, 1.764 mmol) in DCE (5.097 mL). The mixture was sparged with argon and added Hoveyda-Grubbs 11 (22.11 mg, 0.035 mmol) at ambient temperature. The reaction was am at 50 °C for 18 h. The reaction mixture was bubbled with air for 15 minutes and filtered. The filtrate was directly chromatographed (silica gel, 0 to 100%, EtOAc+1.0% HO Ac /hexanes) to afford the title compound (106 mg, 51.0 %). MS (ESI) m'z: M+l] === ^: 589.2 STEP 6: (l S,3 ^! R,6^R,7'S,8T,, i 0^)-6-CHLORO-7 ^, -HYDROXY-10'-METHYL-3,4- DIHYDRO-2H, 14'H-SPIRO [N APHTH ALENE- 1 ,2V -[ 19]OXA[ 12]TH1A[1 , 13] DIAZATETRACYCLO [ 13.7.2.0 ³ · ⁶ .() ^{ϊ 8} ' ²³ ] TETRACOSA

[8, 15, 17, 23 ] TETR AEN] - 14'-ONE 12', 12 -DIOXIDE OR

(l S,3 ^, R,6'R,7 ^! S,8'E, 10'S)-6-CHLORO-7 ^! "HYDROXY-10 ^, -METHYL-3,4" DIHYDRO-2H.14H-SPIRO[NAPHTHALE E-l ,21 '- [ 19] OXA[ 12]Tffl A[ 1 , 13 ]DI AZ ATETRACYCLO

[13J.2.0 ³ ' ⁶ .0 ^!8 - ²³ ]TETRACOSA[8,15,17,23]TETRAEN]-14'-ONE 12',12'~ DIOXIDE N,N-dimethylpyridin-4-amine (DMAP) (41 .5 mg, 0.339 mmol) was added to a solution of (3S)-6'-chloro-5-(((lR,2R)-2-((lS,2E,4R)-l-hydrox>'-4-met hyl-5- sulfamoyl-2-penten-l-yl)cyclobutyl)methyl)-3\4,4'^

benzoxazepine-3, 1 '-naphthaleneJ-7-carboxylic acid, (3S)-6'-chloro-5-(((lR,2R)-2- ((1 S,2E,4S)-1 -hydroxy -4-methyl-5-sulfamoyl-2-penten-l -yl)cyclobutyl)methyl)- 3 ^, ,4,4 ^, ,5-tetrahydro-2 ^, h-spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxylic acid (100 mg, 0.170 mmol) and triethylamine (0.071 mL, 0.509 mmol) in DCM (2 mL) at ambient temperature. Then N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (65.1 mg, 0.339 mmol) was added slowly and it was stirred at ambient temperature for 18 h. The reaction mixture was diluted with dichlorornethane (1 0 mL) and washed with aqueous saturated sodium bicarbonate (5 mL), aqueous saturated ammonium chloride (5 mL), and brine (5 mL) separately. The combined organic layers were dried (MgS0 ₄ ), filtered and concentrated. The crude oil was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 ,u,m column; Phenomenex, Torrance, CA; gradient elution of 35% to 95% MeCN in water, where both solvents contain 0. 1% TFA, 30 min method) to afford the title compound as the first eluting isomer (4 mg, 3.9 %). Ή N.V1R (400 MHz, CD2CI2) δ 8.36 C or. s., 1H), 7.70 (d, J = 8.41 Hz, 1H), 7.24 - 7.05 (m, 3H), 7.01 - 6.87 (m, 2H), 5.75 (ddd, J - 5.67, 6.46, 18.39 Hz, 1 H), 4.13 (s, 2H), 3.98 (t, J = 6.16 Hz, 1H), 3.80 - 3.55 (m, 4H), 3.48 - 3.20 (m, 3H), 2.90 - 2.69 (m, 3H), 2.60 (d, J = 7,24 Hz, 2H), 2.03 - 1.76 (m, 9H), 1.17 (d, J = 6.85 Hz, 3H). m/z (ESI, +ve ion) 571.2 (M+H) ⁺ .

EXAMPLE 165. (l S,3'R,6'R,7'S,8'E, 10'S)-6-CHLORO-7'-HYDROXY-l Q'~ METHYL-3,4-DIHYDRO-2H, 14'H-SPIRO[NAPHTHALENE- 1 ,21'- [19]OXA[ 12jTHIA [1 ,13]

DIAZATETRACYCLO[13.7.2.0 ³ - ⁶ .0 ³⁸ ' ²³ ]TETRACOSA[8,15,17,23]TETRAENj- 14'-ONE 12',12'-DIQXIDE OR (lS,3 ^! R,6'R,7'S,8'E,10'S)-6-CHLORO-7'- HYDROXY- 10'-METHYL-3,4-DIHYDRO-2H, 14'H-SPIRO [N APHTHALENE- 1,21 '- [19]OXA[12]TfflA[l ,13]DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ - ²⁵ ]TETRACOSA [8,15, 17,23]TETRAEN] -14'-ONE 12', 12'-DIOXIDE

The title compound (1.9 mg, 1.8%) was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 164, Step 6. ^f H N .MR (400MHz, CD2CI2) δ 7.71 (d, J = 8,41 Hz, 1H), 7.23 (d, J = 2, 15 Hz, 1H), 7.18 (dd, J = 2.35, 8.41 Hz, 1H), 7.10 (d, J = 2.15 Hz, i l l ). 6.96 id,. J = 8.22 Hz, 1H), 6.88 - 6.81 (m, 1H), 5.84 (td, J = 3.52, 15.26 Hz, 1H), 5.68 (td, J = 8.41 , 16.04 Hz, i l l }. 4.12 id. J === 1.76 Hz, 3H), 3.76 - 3.51 i ns. 3H), 3.47 - 3.18 (m, 3H), 2.94 - 2.58 (m, 4H), 2.44 - 2.30 (m, 1 H), 2.00 (s, 9H), 1.12 (d, J = 6.85 Hz, 3H), m/z (ESI, +ve ton) 571 ,2 (M+H) ¹ . EXAMPLE 166, (I S,3'R,6'R,7'S,8'E, 10'S, 11 ^* R)-6-CHLORO-7'-HYDROXY- 10', 1 l'-DlMETHYL-3,4-DlHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1,21'- [19]OXA[ 12 ]THIA[ 1,13 jDIAZ ATETRACYCLOI 13.7.2.0 ³ - ⁶ .0 ¹⁸ - ²³ ]TETRACOS A

[8,I5, 17,23]TETRAEN]-14'-ONE 12', 12'-DIOXIDE OR

(lS^'R _^ e^T'S^^aO^irS^-CHLORO-T'-HYDROXY-lO^l l'-DIMETHYL- 3 ,4-DIHYDRQ-2H, 14'H-SPIRO [N APHTHALENE- 1,21'-

[ 19]OXA[12]THIA[1 ,13]DIAZATETRACYCLO[ 13.7.2.0 ³ ' ⁶ .0 ^{] 8} ' ²³ ]TETRACOSA

[8, 15, 17, - 14'-ONE 12', 12 -DIOXIDE

The title compound was obtained as the first eluting isomer (4 mg, 4.0%) from reversed phase preparator - HPLC in Example 144. Ή NMR (400MHz, CD2CI2) δ 8.64 - 8.51 (rn, IH), 7.68 (m, IH), 7.71 - 7.64 (m, IH), 7.23 (d, J = 8.41 Hz, IH), 7, 16 (dd, J = 2,45, 8.51 Hz, IH), 7.12 - 7,07 (m, 2H), 6.95 (d, J = 8.22 Hz, IH), 5.79 (ddq, J = 5.87, 7.82, 15.45 Hz, 2H), 4.25 - 4.03 (m, 3H), 3.75 - 3.65 (m, J = 7.04 Hz, IH), 3.61 - 3.42 (m, 3H), 2.85 - 2.39 (m, 5H), 2.07 - 1.67 (m, 7H), 1.35 - 1.30 (m, IH), 1 ,22 - 1.30 (m, 3H), 1.13 (d, J = 6.85 Hz, 31 1 ). 0.81 - 0.93 (m, IH). m/z (ESI, +ve ion) 585.2 { M l ! )

EXAMPLE 167. (1S,3'R,6'R,7'S,8'E, 1 rS,12'R)-6-CHLORO-7'-HYDROXY-H'- METHYL-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THIA[ 1 , 14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ^ ⁴ ]PENTACOSA[8,16,18 _S 24]TETRAEN]- 15 -ONE 13', 13 '-DIOXIDE OR (IS,3'R,6'R,7'S,8'E, 1 l ^, S,12'R)-6-CHLORO-7'- HYDROXY- 11 '-METHYL- 12'-((2R)-TETRAHYDRO-2-FURANYLMETHYL)- 3 ,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [ 20] OXA[ 13]THI A[ 1 , 14 |DI AZATETRACYCLO

[14,7.2.0 ³ ' .0 ¹⁹ - ² ]PENTACOSA [8,16, 18,24]TETRAEN]-I5'-ONE 13',13'- DIOXIDE OR (lS ¾ )'RJ^,8^11'S/I2'S)-6 ;HI RO-7' iYDROXY-ll'-METI-IYL-!2'- ((2S)-TETR^HYDRO-2-FURA^LMETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8,16,18,24] ^" rETRAEN]-15'-ONE 13 I 3 '-DIOXIDE OR

(lS,3'R,61 7 ^, S,8T l^J2'S)-6 mORO-7 ^, ~HYDROXY-ir-METHYL-12'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- ! ,22 ^* -[20] OXA[ 13]THIA[ 1 , ! 4]

DIAZATETRACYCLO [14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,1 -15'-ONE 13',13'-DIOXIDE

STEP 1 : (2S,3S)-N,N-BIS(4-METHOXYBENZYL)-3- ETHYL-l- (TETRAHYDRO-2-FURANYL)-5-HEXENE-2-SULFONAMIDE AND (2R,3S)- N,N-BIS(4- ETHOXYBENZYL)-3-METHYL-l-(TETRAHYDRO-2- FURANYL)-5-HEXE E-2-SULF ON AMIDE

The title compound was prepared from (2S)-N, N-bis(4-methoxybenzyl)- 2-methylpent-4-ene-l sulfonamide (Example 395, Step 3) using a similar procedure described in Example 395, Step 4, replacing ethylene oxide with 2- (bromomethyl) tetrahydrofuran.

STEP 2: (2S,3S)-3-METHYL-l-((2S)-(TETRAHYDRO-2-FURANYL)-5- HEXENE-2-SULFONAMIDE AND (2R,3S)-3-METHYL-l-((2S)- (TETRAHYDRO-2-FURANYL)-5-HEXENE-2-SULFONAMTDE AND (2S,3S)- 3-METHYL-l -((2R)-(TETRAHYDRO-2-FURANYL)-5-HEXENE-2-

SULFONAMIDE AND (2R, 3 S)-3 -METHYL- 1 -((2R)-(TETRAHYDRO-2- -5-HEXE E-2-SULFONAMIDE

The title compounds were prepared from (2S,3S)-N,N-bis(4- methoxybenzyl)-3-methyl-l-(tetrahydro-2-furanyl)-5-hexene-2- sulfonamide and (2R,3 S)-N,N-bis(4-methoxybenzyl)-3-melhyl - 1 -(tetrahy dro-2-furanyl)-5-hexene- 2-sulfonamide using a similar procedure in Step 5 of Example 153. STEP 3: (1 S,3'R,6'R,7'S,8'E, 1 l 'S, 12'R)-6-CHLORO-7'-HYDROXY-l 1 '- METHYL- 12'-((2 S)-TETRAHYDRO-2-FURAN YLMETHYL)-3 ,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20 j OXA[ 13] THIA [1,14]

DIAZATETRACYCLO[14.7,2.0 ³ ' ⁶ .0 ^{i 9} ' ²⁴ ]PENTACOSA [8, 16,1 8,24]TETRAEN]~ 15'-ONE 13 ',13 '-DIOXIDE OR (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-7 ^! - HYDROXY-i -METHYL-12'-((2R)-TETRAHYDRO-2-FURANYLMETHYL)- 3 ,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 , 22'- [20]OXA[13]TH1A[1 , 14]DI AZATETRACYCLO

[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-I5'-QNE 13',13'~ DIOXIDE OR (1S,3'R,6'R,7'S,8'E,1 l 'S,12'S)-6-CHLORO-7'-HYDROXY-l Γ- METOYL-12'-((2S)-TETRAIWDRO-2-FURANYLMETOYL)-3,4-DIHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1.22'-

| 2ί ί |ΟΧ Λ | 1 3 ΙΊ ! ! 1 Λ | L I 4 | ! ! A/.Vr! -;i ^' R A( Υ(·|..ΟΙ i 4.7.2.0 · ^, '.ί ^{) | :} ' ^{! 1} | P1 - M ^' .\C0S A

[ 8,16,18,24[TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

l'-METHYL-12'-

((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13] THIA[ 1 , 14 ]

DIAZ A TETR A C YCLO [14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-

1 - hydroxy hex-2-en-l -yl)cy clobut 'l)methyl)-3',4,4',5-tetrahy dro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]~7-carhoxylic acid (Intermediate AA12) using a similar procedure described in Example 164, Step 5 to 6, replacing

2- methylbut-3-ene-l -sulfonamide in Step 5 with

(2S,3S)-3-methyl-l -((2S)-(tetrahydro-2-furanyl)-5-hexene-2-sulfonamide and (2R,3S)-3-methyl-l-((2S)-(te1rahydro-2-furanyl)-5-hexene-2-s ulfonamide and (2S,3S)-3-methyl-l-((2R)-(tetrahydi -2-furanyl)-5-hexene-2-sulfoiian' de and (2R,3S)-3-methyl-l-((2R)-(tetrahydro-2-furanyl)-5-hexene-2-s ulfonamide. The crude residue of Step 6 was purified by reversed phase preparatory HPLC

(Gemini™ Prep Cis 5 ^im column; Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the first eluting isomer (29 mg, 12%). ¾ NMR (400MHz, CD2CI2) δ 8.33 - 8.13 (m, 1H), 7.70 (d. J = 8.41 Hz, III).7.17 (dd, J = 2.35, 8.41 Hz, 111).7.09 (d, J = 2,35 Hz, ill).7,05 - 6.96 (m, ill).6.91 (d, J = 0.98 Hz, 2H), 5.82 (ddd, J = 4.30, 8.61, 14,87 Hz, ill).5.68 (dd, J = 7.43, 15.06 Hz, III).4.23 - 4.02 - (m, 5H), 3.88 (s, 1H), 3.82 - 3.58 (m, 3H), 3.35 - 3.24 (m, 1H), 3.20 - 3.02 {in. III).2,77 (d, J = 4.89 Hz, 2H), 2.32 (d, J = 7.24 Hz, 3H), 2.22 - 1.75 (m, 12H), 1,59 - 1.42 (m, 5H), 1.05 (d, J = 6.65 Hz, 3H). m / (ESI, +ve ion) 669.2 (M ID

EXAMPLE 168. (1 S,3'R,6'R,7'S,8'E,1 i'SJ 2'R)-6-CHLORO-7'-HYDROXY-l 1 METHYL-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-

2H, 15'H"SPIRO| NAPHTHALENE-!, 22'-

[20]OXA[13]THIA[l,14]DIAZAraTRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PENTACOSA [8,16,18,24]TE,TRAEN]-15 ^! -ONE 13', 13 -DIOXIDE OR

(IS^l^e'R^'S^UirS/n^-e-CHLORO^'-HYD OXY-ll'-METHYL"^'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTOALENE-l,22 ^f -[201OXA[I3]TOIA[l,14]DIAZATETRACYCLO [14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,!6,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE O (lS^' ^'R^'S^'EJl'S/^'S^e-CHLORO^'-HYD OXY-ir- METHYL-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [8 ₅ 16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6¾,7'S,8¾irSJ2'S)-6-CHLORO-7' IYDROXY-ir-METHYL-12'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [8, 16, 18,24]TETRAENj~l 5'-ONE 13", 13-DIOXIDE

The title compound (16 mg, 6,7%) was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 167. ¾ NMR (400MHz, CD2CI2) δ 8.13 (br. s., 1H), 7.70 id. J = 8.6 Hz, 1H), 7.17 (dd, J - 2.3, 8.6 Hz, !!!).7.09 (d, J = 2.3 Hz, ill).6.94 (s, IH), 6.90 (s, 2H), 5.95 - 5.82 (m. III).5,71 (dd, J = 7.9, 15.2 Hz, ill).4,40 id,, J = 9.2 Hz, IH), 4,34 - 4,25 (m, 1H), 4.21 (dd, J = 4.1, 8,0 Hz, 1H), 4.12 - 4.06 (m, 2H), 3.88 - 3.71 (m, 3H), 3.67 (d, J = 14.3 Hz, ill).3.27 (d, J = 14.1 Hz, IH), 3.15 - 3.00 (m, 1H), 2.84 - 2.70 (m, 2H), 2.48 - 1.79 (m, 16H), 1,59 - 1.34 (m, 3H), 1.00 (d, J = 6.8 Hz, 3H). m/z (ESI, +ve ion) 669,2 (M+H) ⁺ .

EXAMPLE 169. (1 S,3'R,6'R,7'S,8'E,11'SJ 2'R)-6-CHLORO-7*-METHOXY-l 1 '- METHYL-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-

2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13 ] TH1A[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAENj-

15*-ONE 13',I3'-DIOXIDE OR (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-7'-

METHOXY- 11 '-METHYL- 12'-((2R)-TETRAHYDRO-2-FURANYLMETHYL)-

3 ,4-DlH YDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[ 13|THIA[1,14] DIAZATETRACYCLO

[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TET¾AEN]-15'-ONE 13',13'-

DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,ll'S,12'S)-6-CHLORO-7 ^! -METHOXY-ll'-METHYL-12'- ((2S)-TETRAIIYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,I5'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 ^* S, 12'S)-6-CHLORO-7'-METHOXY-l 1 '-METHYL- 12"- ((2R)-1\ETRAHYDR0-2-FURANYLMF;THYL)-3,4-DIHYDR0-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA

~15'-ONE 13", 13-DIOXIDE

The title compound (9.5 nig, 62%) was prepared from

(lS.S'R^^'S.S^ll'S.l^R^-chloro^'-hydro y-ir-met^l-lT-^S)- tetrahy dro-2-fttranylmethyl)-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy cio[ 14.7.2.0 ³ · ⁶ .0 ^{] 9} · ²⁴ Jpentacosa

[8,16,18,24]tetraen]-I5'-one 13",13'-dioxide or (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6- chloro-7'-hy droxy- 11 '-methyl- 12'-((2R)-tetrahy dro-2-furanylmethy l)-3,4-dihy dro- 2H, 15'H-spiro[naphthalene-l ,22'-[20]oxa[ 13]thia[ 1,14] diazatetracyclo

[14.7.2.0 ³ · ⁶ .0 ^ί9 · ²⁴ ] pentacosa[8,16,18,24]tetraen|-15'-one 13 ',13 '-dioxide or (lS 'R,6'R,7 ^f S,8'E,Il'S,12'S)-6-diloro-7'-hydroxy-l!'-methyl-12'-(( 2S)- tetrahy dro-2-furanylmethyl)-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13|thia| l,14|diazatetracyclo|14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa [8,16,18,24]tetraen]-15'-one 13',13'-dioxide or (^^"Ι ,ό'Κ,Τ'β,δΈ,ΙΙ'β,Ι^-ό- cMoro-7'-hydrox>'-ll ^, -melhyl-12 ^, -((2R)-tetrahydro-2-furanylmethyl)-3,4-dihydro- 2H, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[ 13]thia[l , 14]dia.zaietracydo[14,7.2,0 - ⁶ .0 ^l9 - ²⁴ ]per!tacosa

[8,16,18,24]tetraen]-15'-one 13',13'~dioxide (Example 167) using a similar procedure described in Example 95. ^! H NMR (400MHz, CD2CI2) δ 8.16 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.17 id. J = 8.4 Hz, 1H), 7.09 (s, 1H), 6.91 (s, 1H), 6.90 - 6,84 (m, IH), 5.87 - 5.72 (rn, IH), 5.51 (dd, J = 8.9, 15,4 Hz, IH), 4.32 - 4,15 (m, 2H), 4.12 - 4.04 (m, 2H), 3.97 - 3.60 (m, 6H), 3,32 - 3.13 (m, 4H), 3.04 (dd, J = 10.2, 15.1 Hz, IH), 2.76 (dd, J = 5.1, 10.4 Hz, 2H), 2.52 - 1.90 (m, 15!!}.1.70 - 1.63 (rn, IH), 1.55 - 1,46 (m, IH), 1.45 - 1.35 (m, IH), 1.06 (d, .1 7,0 Hz, 3H). m'z (ESI, +ve ion) 783.1 (M+H) ⁺ .

EXAMPLE 170. (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHL()RO-7'-METO()XY-ir- METHYL-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THIA[ 1 , 14]

DIAZATETRACYCLO[14.7.2.() ³ -^0 ⁱ⁹ - ²⁴ iPENTACOSA[8,16,18,24]TETRAENj- 15-ONE 13', 13 '-DIOXIDE OR flS,3'R,6'R,7'S,8'E,l l'S,12'R)-6-CHLORO-7'- METHOXY- 11 '-METHYL- 12'-((2R)-TETRAHYDRO-2-FURANYLMETHYL)- 3,4-DIHYDRO-2H,15 ^! H-SPIRO[NAPHTHALENE-l,22'- [ 20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[14.7.2.0 ⁵ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 l'S, 12'S)-6-CHLORO-7'-METHOXY- 11 '-METHYL- 12'- ((2S)-TETRAFT^DRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA [8,16,18,24]TETR _! 4EN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,Il'S,I2'S)-6-CHIimO-7'-METHOXY-l!'-METI-IYL-12'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [ -15'-ONE 13',13'-DIOXIDE

The title compound (7 mg, 53%) was prepared

fromO S,3'R,6'R,7'S,8'E, 11 'S,l 2'R)-6-chloro-7*-hydroxy-l 1 '-methyl- 12'-((2s)- tetrah dro-2-fiffanylmethyl)-3,4-dihydro-2H, 15'H-spiro [naphthalene- 1,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14.7.2.0 ³ · ⁶ . O ¹⁹ - ² ]pentacosa[ 8, 16, 18,24] tetraen]-15'-one 13',13'-dioxide or (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-chIoro-7'- hydroxy- 11 '-methyl- 12'-((2R)-tetrahydro-2-furanylmethy l)-3,4-dihydro-2H, 15Ή- spiro[naphthalene-l,22'-[20]oxa[13]thia[l,14] diazatetracy clo [14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ] pentacosa 8,16,18,24]tetraen]-15'-one 13',13'-dioxide or

(lS,3'R,6'R,7 ^f S,8'E,ll'S,12'S)-6-chloro-7'-hydroxy-ll'-rnethyl-12 ^f -((2S)- tetrahy dro-2-furanylmethyl)-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ¹⁹ - ² ]pentacosa

[8,16,18,24]tetraen]-15'-one 13 ',13 '-dioxide or

(lS^'^e'R 'S^^ll'S.n'S^-chloro^'-hydro -ll'-meth l-l^-^R)- tetrahydro-2-furanylmethyl)-3,4-dihydro-2H,15^spiro[naph

[20]oxa[13]thia[l,14] diazatetracy clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa

[8,16,18,24]tetraen]-15'-one 13 ',13 '-dioxide

(Example 168) using a similar procedure described in Example 95. ^" Ή NMR (400MHz, CD2CI2) δ 8.08 (s, IH), 7.71 (d, J = 8.6 Hz, IH), 7.17 (dd, J = 2.2, 8.6 Hz, IH), 7.09 (d, J == 2,2 Hz, UI).6.90 (s, 2H), 6.86 (s, !!!).5.87 (ddd, J == 2.9, 10,0, 15.0 Hz, i l l ). 5,50 (dd, J = 9,5, 15.6 Hz, i l l ). 4,51 i d. J = 8,8 Hz, ! ! ! }. 4,37 - 4.26 (m, IH), 4.08 (s, 2H), 3.87 - 3.59 (m, 5H), 3.25 (d, J = 14.3 Hz, 1H), 3.19 (s, 3H), 3.03 (dd, J = 10.2, 15.3 Hz, IH), 2.84 - 2.71 (m, 2H), 2.52 - 1.75 (m, 16H), 1 .52 (qd, J == 7.5, 12.1 Hz, I H), 1 .44 - 1.34 (m, IH), 1 ,01 (d, J = 6.8 Hz, 3H), m/z. (ESI, +ve ion) 783.2 (M+H) ⁺ .

EXAMPLE 176. (l S,3'R,6'R,7'S,8 ^! E, 12 ^! S)-6-CHLORO-7'-HYDROXY-12'-(2- PYRIDINYLMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

[20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,I6, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,12'R)-6-CHLORO-7 ^! -HYDROXY-12'-(2-

PYRJDINYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 22'- [20]OXA[13]Tffl A[l ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16 -15'-ONE 13', 13 '-DIOXIDE

STEP 1 : (R)-N,N-BlS(4-METHOXYBENZYL)-l-(PYRIDIN-2-YL)HEX-5- ENE-2-SULFONAMIDE AND (S)-N,N-BIS(4-METHOXYBENZYL)-l- (PYRIDIN-2- -5-ENE-2-SULFONAMIDE

To a solution ofN,N-bis(4-metiioxybenzyl)pent-4-ene-l-sulfonamide (1.34 g, 3.44 mmol. Intermediate EE19) at -78 °C in THF (17.2 mL) was added butyllithium solution, 2.5 M in hexanes (1.38 mL, 3.44 mmol). The reaction mixture was stirred at this temperature for 30 minutes. In a separate flask, charged with a solution of 2-(bromomethyl)pyridine hydrobromide (1.74 g, 6.88 mmol) in DCM (4 mL) was added saturated NaHCCb (4 mL) and the biphasic mixture was stirred for 15 minutes. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried (MgSC ) and filtered, toluene (10 mL) was added, and the mixture was concentrated to a 1 mL solution. This solution was then added to the first flask containing the nucleophile. The resulting reaction mixture was stirred at -78 °C. After 15 minutes, the reaction mixture was allowed to stir for an additional hour and then quenched with saturated aqueous NFLCl, The mixture was extracted with diethyl ether, the combined organic layers were washed with brine, dried (MgSOs), filtered and concentrated. The residue was injected into a 40 g 1SCO Gold column and purified by combi-flash, eluting with 0% to 100%» EtOAc/hexanes to give the title compounds (960 mg, 1.99 mmol) as a light yellow solid.

STEP 2. (R)-l -(PYRIDIN-2-YL)HEX-5-ENE-2-SULFONAMIDE AND (S)-l- (PYRTDIN-2-YL) -5-ENE-2-SULFON AMIDE

Following the same expeirment procedure as Example 153, Step 5, (R)- N,N-bis(4-memoxyberizyl)-l-(pyridin-2-yl)hex-5-ene-2-sulfona mide and (S)- N,N-bis(4-methoxybenzyl)-l-(pyridin-2-yl)hex-5-ene-2-sulfona mide was treated with anisole and TFA to afford the title compounds.

STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l- YL)CYCLOBLT L)METIiYL)-N-(((S)-l-(PYRIDIN-2-YL)HEX-5-EN-2-

YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2 ^! H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] ~7~

CARBOXAMIDE AND (S)-6'-CH.LORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN- 1 -YL)CYCLOBUTYL)METHYL)-N-(((R)- 1 - (PYRID]N-2^1.)HEX-5-EN-2-YL)SULFONYL)-3',4,4',5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

N,N-dimethylpyridin-4-amine (DMAP) (47.9 mg, 0.392 mmol) was added to a solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l -hydroxyhex-2-en-l- yl)c>'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[ benzo[b][l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (0.100 nig, 0.196 mmol, Intermediate AA12), triethylamine (0.082 mL, 0.588 mmol) and (R)-l-(pyridin-2-yl)hex-5-ene-2- sulfonamide and (S)-l-(pyridin-2-yl)hex-5-ene-2-sulfonamide (Example 176, Step 2) (0.094 g, 0,392 mmol) in DCM (2 mL). Then EDC (75 mg, 0,392 mmol) was added slowly in portions, and reaction mixture was stirred at ambient temperature overnight. The residue was injected into a 40g TSCO Gold column and purified by combi-flash, eluting with 10 % to 100 % EtOAc (containing 1.0 %

AcOH)/hexanes to give the title compounds (100 mg, 0.137 mmol).

STEP 4: (1 S,3'R,6'R,7'S,8'E,12 ^, S)-6-CHLORO-7'-HYDROXY-12'-(2- PYRIDrNYLMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

1,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(IS^'R^'R 'S^U^'Ri-e-CHLO O-T'-HYD OXY-^'^-

PYRJDI YLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1,22'- [20]QXA[13]THIA[U4]DL ZA

[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

A 100 mL round bottom flask was charged with the product from Example 176, Step 3 (0,100 g, 0.137 rnmol) in AcOH (47.1 mL). It was stirred at ambient temperature sparging Ar through the reaction mixture for 15 min. To the homogeneous solution was added Hoveyda-Grubbs II (0.017 g, 0.027 mmol). The mixture was stirred at ambient temperature under reduced pressure overnight and then air was sparged through for 10 min. The reaction mixture was concentrated. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci85 μιη column; Phenomenex, Torrance, CA; gradient elution of 35% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as white solid (0.0017 g, 0.0025 mmol). ^! H NMR (400MHz, CD2CI2) δ ppm 8.76 (d, ./ 5.5 Hz, 1H), 8.23 (t,■/ 7.3 Hz, II I). 7.82 id.,/ 8.0 !!/. !!!}.7.71 (m, ill).7,70- 7.68 (m, ill).7.16 (dd,J=2.1, 8.5 Hz, 1H), 7.09 (d, ,7=2,2 Hz, 1H), 6.93 - 6,87 (m, 3H), 5.86 (m, 1H), 5.74 - 5.66 (m, 1H), 4.63 (t, J=6.0 Hz, 1H), 4.21 (dd, ./ -1.3.7.8 Hz, Ml).4.07 (s, 2H), 3.81 (d, ./ 15.3 Hz, II I).3.72-3.58 (m, 3H), 3.25 (d, ./ 14.3 Hz, 1H), 3.04 (dd, J=9.6, 15.5 Hz, 1H), 2.81 - 2.24 (m, 6H), 2,10 - 1.88 (m, 5H), 1.88 - 1.72 (m, l).1.72 - 1,61 (m, 1H), 1.40 (t, ./ 12.9 Hz, 1H); m . (ESI, +ve ion) 662 (M+Na) ⁺ . EXAMPLE 186. (1 S,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12'- (TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14.7.2.() ³ ' ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12'-(TETRAH YDRO-2H- PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- L22'"

|;20]OXA[ 13 iTHIA[ l , 14jDIAZATETRACYCLO| 14.7.2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13*-DIOXIDE

STEP 1 : (S)-N,N-BIS(4-METHOXYBENZYL)-l-(TETRAHYDRO-2H-PYRAN- 4-YL)HEX-5-ENE-2-SULFONAMIDE AND (R)-N,N~B1S(4~

METHOXYBENZYL)-l-(TETRAHYDRO-2H-PYRA -4-YL)HEX-5-ENE-2-

SULFON

To a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l-suifonamide (2,40 g, 6. 16 mmol. Intermediate EE 19) in TOP (5 mL) was added butyllithium solution, 2.5 M in hexanes (3.20 mL, 8.01 mmol) at -78 °C dropwise. After being stirred at -78 °C for 10 min, 4-bromomethyltetrahydropyran (4.41 g, 24.6 mmol) was added into the reaction for 30 minutes at the same temp. After this time, the reaction was allowed to warm to room temperature. After being stirred at room temperature for 2 h, the reaction was quenched (sat.NH Cl), extracted (2 ^χ EtOAc), and washed (1 * brine). The combined organic la er were dried

(Na2S€>4) and concentrated under the reduced pressure. The residue was injected into a 40g ISCO Gold column and purified by combi-flash, eluting with 0 % to 30 % EtOAc /hexanes to give the title compound (1.5g, 3.08 mmol). STEP 2: (1 S,3'R,6'R,7'S,8'E, 12'S)-6-CHLORO-7'-HYDROXY-12'- (TETR/ HYDR0-2H-PY1 AN-4-YLMETHYL)-3,4-D1HYDR0-2H;15'H- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,12'R)~6"CHLORO-7 ^, ~HYDROXY-12'-(TEmAHYDRO-2H- PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPI-ITHALENE-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compounds was prepared from (S)-6'-chloro-5-(((l R,2R)-2- ((S,E)-l-hydroxyhex-2-en-l-yl)(^clobut\'l)methyl)-3',4,4',5- tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Intermediate AA12) by a procedure analogous to that described in Example 176, Steps 2 through 4, replacing (R)-N,N-bis(4~methoxybenzyl)-l -(pyridin-2-yl)hex-5-ene-2- sulfonamide and (S)-N,N-bis(4-methoxy benzyl)- 1 -(pyridin-2-yl)hex-5-ene-2- sulfonamide in Step 2 with (S)-N,N-bis(4-methoxybenz> )-l -(tetrahydro-2h- pyran-4-yl)hex-5-ene-2-sulfonamide and (R)-N,N-bis(4-methoxy benzyl)- 1 - (tetrahydro-2h-pyran-4-yl)hex-5-ene-2-sulfonarnide (Example 186, Step 1). The residue was injected into a 40g IS CO Gold column and purified by combi-flash, eluting with 10 % to 100 % EtOAc (containing 0.5 % AcOH)/ exanes to give a crude product as the faster eluting isomer. This crude product was purified by- reversed phase preparative HPLC (Gemini™ Prep Cie 5 μιη column;

Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0. 1% TFA, 30 min method) to provide one of the title compounds as a white foam. ¾ NMR (400MHz, CD2CI2) δ ppm 8.28 (br. s., 1H), 7.66 (d, ./ 8.4 Hz, 1 1 1 ). 7.48 (m, I I I ). 7.15 (dd, ,/ 2.2. 8.5 Hz, i l l ). 7.10 (m, i l l ). 6,99 - 6.88 (m, 2H), 5.72 - 5.60 (m, IH), 5,54 (m, IH), 4.20 (s, 2H), 4.07 - 3.81 (m, 5H), 3.70 (d, ,7=13,9 Hz, H), 3.50 - 3,31 (m, 3H), 3.20 (m, i l l ). 2.80 - 2.70 (m, 2H), 2.56 - 2.42 (m, 2H), 2,31 (m, IH), 2.13 (m, H), 2.06 - 1.64 (m, 13H), 1.60 - 1.44 (m, 2H), 1.39 - 1.23 (m, 2H); m/z (ESI, +ve ion) 669 (M+H) ⁺ .

EXAMPLE 187. (1 S,3 ^, R,6 ^! R,7'S,8 ^! E,12 ^! S)-6-CHLORO-7'-HYDROXY-12'- (TETOAHYDRO-2H-PYRAN-4-YL ETHYL)-3,4-DIHYDRO-2H,15H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '*0 ¹⁹ - ²⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-7'-HYDROXY-12'-(TETRAHYD R()-2H- PYRAN-4-YLMETHYL)-3,4-DlHYDRO-2H,15H-SPIROpviAPHTHALENE-

1,22'~

|2ujOXA| O ΙΊ ί Ι1Λ| I . I 4|Di A/.Yi ^' ! R AC YO.OI i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE

One of the title compounds was obtained as the second (slower) eluting isomer using combi-flash separation as described in Example 186. Ή NMR (400MHz, CD2CI2) δ ppm 8,24 (s, IH), 7,71 (d, «7=8.4 Hz, IH), 7.17 (dd, .7=2.2, 8.5 Hz, IH), 7.09 (d, J=2.2 Hz, IH), 6.94 - 6.87 (m, 3H), 5.83 - 5.68 (m, 2H), 4.19 (dd, ./ 4.0.7.3 Hz, !!!).4.16 - 4.05 (m, 3H), 4.00 - 3.88 (in, 2H), 3.82 (m, IH), 3.70 id../ 14 I Hz, IH), 3.41 (ra, 2H), 3,25 (d, J=14.3 Hz, IH), 3.03 (dd, J=9.4, 15.3 Hz, IH), 2.82 - 2.69 (m, 2H), 2.46 - 2.27 (m, 3H), 2.20 - 1.63 (m, 1 !!}.1.52 (ddd, ./ 3.9.8.9, 14.9 Hz, IH), 1.44 - 1.19 (m, 4H); m/z (ESI, +ve ion) 669 { \ I · Π } . EXAMPLE 188, (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-7'-HYDROXY-ir- ME ^r rHYL~12'-(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8,16,18,24] ^" rETRAEN]-15'-ONE 13 I 3 '-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, R;i2 ^, S)-6-CHLORO-7'-HYDROXY-ir-METHYL-12'- (TETRAHYDRO-2H-PYRAN-4-YLME^ YL)-3,4-DIHYDRO-2H 5H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,:r R 7'S,8Έ;Γί'SJ2'S)-6-CHLORO-7 ⁱ IYD OXΎ-ll'-METHYL-12'- (TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZAraT ACYCLO[147.2 ³ ' ^{6 ]9} ' ²⁴ ]PENTACOSA [8 ₅ 16,18,24]TETRAEN]-15 ^! -ONE 13', 13 -DIOXIDE OR

(Ιβ^'Κ,ό'Κ,Τ'β,δΈ,ΙΙ'Κ, 'Κ^ό-αΗίΟΚΟ-Τ'-ΗΥΟΚΟΧΥ-ΙΙ'-ΜΕΤΗΥ^Ι^- (TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2HJ5'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ4 |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 (Γ-''.O ¹ "··' ¹ |Pi-N i ACOSA [8,I -15'-ONE BVB'-DIQXIDE

STEP 1 : (2R,3R)-N,N-BIS(4-METHOXYBENZYL)-3-METHYL-l- (TETRAHYDRO-2H-PYRAN-4-YL)HEX-5-ENE-2-SULFONAMIDE AND (2S,3S)-N,N-BIS(4-METTHOXYBENZYL)-3-METHYL-l -(TETRAHYDRO-2H- PYRAN-4-YL)HEX-5-ENE-2-SULFONAMIDE AND (2S,3R)-N,N-BIS(4- METHOXYBENZYL)-3-METHYL-l -(TETRAHYDRO-2H-PYRAN-4- YL)HEX-5-ENE-2-SULFON AMIDE AND (2R,3 S)-N,N-BIS(4- METHOXYBENZYL)-3 -METHYL- 1 -(TETRAHYDRO-2H-PYRAN-4- -5-ENE-2-SULFON AMIDE

To a solution of (R)-N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-l- sulfonamide and (S)-N,N-bis(4-methoxybenz l)-2-methylpent-4-ene-I - sulfonamide (2.0 g, 4.96 mmol, Example 647, Step 7) at -78 °C in THF (24.8 mL) was added butyllithium solution, 2.5m in hexanes (2.39 mL, 5.90 mmol). After the reaction was stirred at the same temperature for 30 minutes. 4- bromomethyitetrahydropyran (3.55 mL, 19.8 mmol) was added. Then the reaction was allowed to warm to ambient temperature and stirred for 3 hours. The reaction was quenched (saturated aqueous NH ₄ C1), extracted (3 * Et?.0), and washed (brine). The combined organic layers were dried (NaaSO-i) and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 0% to 20%, EtOAc (containing 0.3% AcOHj/hexanes to give the title compounds (1.30g, 2.59 mmol).

STEP 2: (2R,3R)"3-METHYL-l-(TETiL' HYDRO-2H~PYR _J ' N"4-YL)HEX-5- ENE-2-SULFONAMIDE AND (2S,3S)-3-METHYL-l-(TETRAHYDRO-2H- PYRAN-4-YL)HEX-5-ENE-2-SULF ON AMIDE AND (2S,3R)-3-METHYL-l- { Π ·. 1 R .\HY i)I )-2l l-PY K AN-4-V 5 }H I X---:-.\ ! .-.?.-Si L! ONA YU DL AN D (2R,3 S)-3 -METHYL- 1 - (TETRAHYDRO-2H-P YRAN-4- YL)HEX-5-EN E-2- SULFONAMIDE

2H-pyran-4-yl)hex-5-ene-2-sulfonainide and (2S,3S)-N,N-bis(4-methoxybenzyl)-

3-methyl-l-(tetrahydro-2H-pyran-4-yl)hex-5-ene-2-sulfonat nide and (2S,3R)- N,N-bis(4-methoxybenz l)-3-methyl-l-(tetrahydro-2H-pyran-4-yl)hex-5-ene-2- sulfonamide and (2R,3S)-N,N-bis(4-methoxybenzyl)-3-methyl-l-(tetrahydro-2H- pyran-4-yl)hex-5-ene-2-sulfonamide (1.3 g, 2.59 mmol), trifluoroacetic acid (19.9 mL, 259 mmol) and anisole, anhydrous (28.2 ml., 259 mmol) was heated at 40 °C overnight. The crude mixture was cooled and concentrated under reduced pressure. The residue was injected into a 80 g 1SCO Gold column and purified by combi-flash, eluting with 30%) to 100% EtOAc (containing 0.3% AcOH)/hexanes to give the title compounds (540 mg, 2.06 mmol) as light-yellow oil.

STEP 3: (1 S,3'R,6'R,7'S,8'E,1 l 'S,12'R)-6-CHLORO-7'-HYDROXY-l 1'- METHYL- 12'-(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO- 2H, 15'H-SPlRO[NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[l 4]DIAZATCTRACYCLO|;i4 .2.0 ³ - ⁶ .0 ^l9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,l l ^, R;i2 ^, S)-6-CHLORO-7'-HYDROXY-i r-METHYL-12'- (TETOAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H,15H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 l'S, 12'S)-6-CHLORO-7'-H YDROXY- 11 '-METHYL- 12'- (TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DlHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20;|OXA[13]THIA[1,14]DIAZATCTRACYCLO[147.2 ³ ' ^{6 19} ' ²⁴ ]PE TACOSA

[8J 6, 18,24]TETRAENi-!5'-ONE 13', 13 '-DIOXIDE OR (lS ¾ )'R ^,8T I I 'R;i2¾)-6-CHIX)RO-7 ^f iYDROXY-i i'-METHYL-12'- (TETR/ HYDR0-2H-PY1 AN-4-YLMETHYL)-3,4-D1HYDR0-2H;15'H- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8, i 6, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXTDE

The title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)-2- ((S,E)- 1 -hy droxyhex-2-en- 1 -y l)c clobuty l)methy l)-3',4,4',5-tetrahy dr o-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, l '-naphthalene]-7-carboxy]ic acid (Intermediate AA12) by a procedure analogous to that described in Example 176, Steps 3-4, replacing l(R)-l-(pyridin-2-yl)hex-5-ene-2-sulfonamide and (S)-l-(pyridin-2- yl)hex-5-ene-2-sulfonamide in Step 3 with (2R,3R)-3-methyl-l -(tetrahydro-2H- pyran-4-yl)hex-5-ene-2-sulfonamide and (2S,3S)-3~methyl- 1 -(tetrahydro-2H- pyran-4-yl)hex-5-ene-2-sulfonamide and (2S,3R)-3-methyl-l-(tetrahydro-2H- pyran-4-yl)hex-5-ene-2-sulfonamide and (2R,3S)-3-methyl-l-(tetrahydro-2H- pyran-4-yl)hex-5-ene-2-su]fonamide (Example 179, Step 2). The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cm 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0. 1 % TFA, 30 min method) to provide one of the title compounds as the faster eluting isomer as a white foam. Ή NMR (400MHz, CD2CI2) δ ppm 8.29 (br. s., i l l ). 7.72 - 7.57 (m, 2H), 7.15 (d, ./ 8.7 Hz, 1H), 7.10 (m, 1H), 6.95 - 6.89 (m, 2H), 5.73 - 5.63 (m, 1 H), 5.60 - 5.46 (m, IH), 4.23 (s, 2H), 4, 18 - 4.07 (m, i l l ). 4.06 - 3.83 (m, il l ). 3,81 - 3.62 (m, I H i. 3.48 - 3.28 (m, 3H), 3.12 (m, IH), 2.80 - 2.69 (m, 2H), 2.58 - 2.35 (m, 3H), 2.20 - 2.11 (m, IH), 2,05 - 1.54 (m, 12H), 1.49 - 1.14 (m, 4H), 1.11 - 0.99 (m, 3H); m/z (ESI, +ve ion) 683 (M+H) ⁺ .

EXAMPLE 189. (1S,3'R,6'R,7'S,8 ^! E, 1 rS,12'R)-6-CHL()RO-7'-HYDR()XY-i r- METHYL - 12'-(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3 ,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ - ²⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 rR,12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL-12'- (TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1 ,22'-

|2ujOXA| ! jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.U ' ".ί ^)|: ' ^{! 1} |Ρ1·Ν I ^' ACOSA

[8,16,18,24]TETRAENj 5'-ONE 13',13'-DIOXIDE OR

(Ιβ^'Κ,ό^Τ'β,δΈ,Π'β,Ι^βί-ό-ΟίίίΟΚΟ-� �-ΙΙΥΟΚΟΧΥ-ΙΙ'-ΜΕΤΗΥί-ΙΪ- (TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(lS,3'R,6'R,7'S,8'E,irR,12'R)-6-CHLORO-7'-HYDROXY-ll'-MET HYL~12'" (TETOAHYDRO-2H-PYRAN-4-YLMETHYL)-3,4-DIHYDRO-2H,15H- SPIRO[NAPHTHALENE-l,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [ -15'-ONE 13',13'-DIOXIDE

One of the title compounds was obtained as the second (slower) eluting isomer using reversed phase preparatoiy HPLC as described in Example 188. ^] H NMR (400MHz, CD2CI2) δ ppm 10.28 (br. s., IH), 7.72 (m, IH), 7.43 (m, 1H), 7.28 - 7.13 (m, 2H), 7.10 (sm, IH), 6.97 (d, ./ 7.8 Hz, IH), 5.88 ·· 5.78 (m, IH), 5,57 - 5.40 (m, 1H), 4.45 (m, 1H), 4.17 - 4,10 (m, 2H), 3.99 - 3.90 (m, 2H), 3,75 (m, 1H), 3.63 (d, ./ 13.9 Hz, 1H), 3.49 - 3.33 (m, 2H), 3.32 - 3.15 (m, 2H), 3.08 (m, 1H), 2.82 - 2.70 (m, 2H), 2.52 (m, 1H), 2.30 (in, 1H), 2.24 - 2.07 (m, 3H), 2.06 - 1.93 (ra, 3H), 1,92 - 1.44 (m, 10H), 1.35 - 1.16 (ra, 4H), 1,16- 1.08 (m, 3H); m/z (ESI, +ve ion) 683 (M+H) ⁺ .

EXAMPLE 195. [(1 S,3'S,6'R)-6-CHLORO-3,4-DIHYDR()-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[7,13]DITHIA[l,14]DIAZATETOACYCLO[14.7.2.0 ³ -^0 ¹ ' ²⁴ ]PENrrAC OSA| 16,18,24jTRIEN]-15'-ONE 13 ^* ,13'-DIOXIDE] AND (lS,3'R,6'S)-6- CHLORO-3 ₅ 4-DlHYDRO-2H,15Ή-SPIRO| APH HALENE-l ₅ 22 ^, -

[20]OXA[7,13]DITHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTAC 0SA[16,18,24]TR1EN]-15'-0NE 13' _S 13'-DI0X1DE] OR [(lS,3'S,6'R)-6- CHLORO-3,4-DIHYDR()-2H,15 ^! H-SPIRO[NAPHTHALENE-l,22'- 12(ϊ|ί)ΧΛ| 7.1 ?!ΟΠ f ΠΛ| 1. Ι ΙΙΠΙΛΖΛ f I: s RACY ^' ? )| S 4. ? 2 ί 5 ^: -.0 ^{i ' !} | P!- N s AC OSA[16,18,24]TRIEN]-15'-ONE 13',13'-D10XIDE] AND (lS,3'R,6'R)-6- CHL()R0-3,4-DIHYDR0-2H,15'H-SPIR0|;NAPHTHALENE-1,22'- [20]OXA[7,13]DITHIA[1 ₅ 14]DTAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC QSA[16,18,24]TRiEN]-15'-ONE 13', 13 '-DIOXIDE] OR [(lS,3'S,6'R)-6- CHLORO-3 _s 4-DmYDRO-2H ₅ 15Ή-SPIRO[NAPHTHALENE-l,22 ^, - [20jOXA[7,13jDITHIA[l,14]DIAZATETRACY^

OSA[16,18,24]TRIEN]-15'-ONE 13',]3'-DIOXIDE] AND (lS,3'S,6'S)-6- CHLORO-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-I,22'- |;20]OXA[7,13]DITHIA|;i,141DIA ATETR,4CYCLO[14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTAC OSA[16,18,24]TRIEN]-15 ^* -ONE ', '-ΟΙΟΧΙΟΕ]

STEP 1 : BENZYL 2-CYCLOPROPYLIDENEACETATE

The cyclopropanone precursor, (1-ethoxycyclopropoxy) trimethylsilane (Wonda, 500 g, 2.866 mol), was dissolved in methanol (1.4 L) and the resulting solution was stirred at ambient temperature for two days. Methanol was removed in vacuo to provide the crude cyclopropanone ethyl hemiacetal intermediate. This material was redissolved in anhydrous chloroform (3 L), benzoic acid (63.7 g, 0.52 mol) was added, and the resulting reaction mixture was heated at reflux for 10 min under an atmosphere of dry nitrogen. A solution of benzyl 2-

(triphenylphosphoranylidene) acetate (Wonda, 1.07 kg, 2.61 mol) dissolved in the minimum volume of chloroform was then added to the reaction mixture dropwise. On completion of the reaction as assessed by TLC analysis, the mixture was allowed to cool to room temperature and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (60-120 mesh silica gel) using a solvent gradient of 0 to 5 % ethyl acetate in hexanes to afford the title compound (331 g, 61% yield) as a colorless oil.

STEP 2: (S)-BENZYL 2-HYDROXY-2-(l-HYDROXYCYCLOPROPYL) ACETATE, PREDOMINANTLY AND (R)-BENZYL 2-HYDROXY-2-(l- HYDROXYCYCLOPROPYL)ACETATE (PREDOMINANTLY (S))

minor enantiomer

To an ice-cooled solution of benzyl 2-cyclopropylideneaeetate (331 g, 1.76 mol) in a mixture of to -butanol (8.8 L) and water (8.8 L) was added AD-mix β (Aldnch, 2.45 kg). The resulting orange suspension was vigorously stirred at 0 °C. Ten minutes later, methanesulfonamide (Alfa Aesar, 167 g, 1.76 mol) was added and the reaction mixture was stirred at 0 °C for 16 h, after which time solid sodium sulfite (830 g, 6.58 mol) was added. Stirring at 0 °C for was continued for 15 minutes. The reaction mixture was diluted with ethyl acetate (10 L). Layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 3 L). The combined organic layers was washed with brine again, dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude material, which was purified by column chromatography (60-120 mesh silica), eiuting with a gradient of 0 to 40 % ethyl acetate in hexanes, to afford the title compound as a translucent oil (260 g, 66 % yield). Predominantly (S) benzyl 2-hydroxy-2-(l- hydroxycyclopropyl)acetate prepared in this manner typically had 86-89% enantiomeric excess as determined by chiral HPLC [Chiral pak IC column (250 mm x 4.6 mm); Mobile Phase: «~hexane:EtOH : 90: 10. Run Time: 20 mm. Flow rate: lml/min. Retention time (minor peak)- 9.35 (5.4%); Retention time (major peak)- 1 1.67 (94.6%)] and crystallized upon extended standing or cooling to give a white solid. An optional reciystaiiization procedure was implemented in some cases. For example, in one experiment, 37.9 g of predominantly (S) benzyl 2- hydroxy-2-(l -hydroxy cyclopropyl) acetate was dissolved in 400 mL hot hexanes to which was added the minimum volume of ethyl acetate required to produce a solution upon cooling. Diethyl ether (10 mL) was added to the solution, and it was stored at ca. -20 °C overnight. On the following day, the white crystals were collected by vacuum filtration, dried under vacuum, and found to weigh 29.3 g (77 % recovery for crystallization) and to have an enantiomeric excess of ca. 89 % as assessed by chiral HPLC.

STEP 3: (R)-l-(2-((TCRT-BUTYLDIPHENYLSILYL)OXY)-l- HYDROXYETHYL)CYCLOPROPANOL AMD (S)- 1 -(2-((TERT- BUTYLDIPHENYLSILYL)OXY)-l-HYDROXYETHYL)CYCLOPROPANOL

(PREDOMINANTLY (R))

minor enatitiomer

Predominantly (5) benzyl 2-hydroxy-2-(l -hydroxy cyclopropyl)acetate

(13.0 g, 58.5 mmol, recrystallized by the procedure described in Step 2) was dissolved in anhydrous tetrahydrofuran (200 mL) under an atmosphere of nitrogen and the resulting solution was cooled to °C in an ice water bath. Lithium borohydri.de (2 M solution in tetrahydrofuran, 120 ml, 240 mmol) was added to the reaction mixture over the course of ten minutes. The reaction mixture was then allowed to gradually warm to room temperature and aliquots were intermittently removed to facilitate reaction monitoring by NMR (aliquots were quenched by addition of methanol, acidified with acetic acid, concentrated to dryness, redissolved in THF-rfS, filtered, concentrated to dryness again, and finally redissolved in the desired NMR solvent, methanol -a?4). After 1 10 minutes, the reaction had gone to completion and the mixture was again cooled to 0 °C. After 45 minutes, the reaction was quenched by gradual addition of methanol (150 mL) followed by dropwise addition of a solution of ammonium acetate (119 g) in methanol (500 mL). The mixture was then acidified by addition of acetic acid (25 mL) and all volatiles were removed in vacuo. Three successive evaporations of methanol (250 mL) from the resulting residue were performed to remove boron byproducts as (volatile) trimethylborate. The boron-depleted residue was suspended in tetrahydrofuran and filtered under vacuum, washing the filter cake copiously with tetrahydrofuran (total volume of THF used = 1 L). The filtrate was concentrated in vacuo to provide 14.1 g of the crude trio! intermediate as a viscous, pale-yellow syrup containing benzyl alcohol and small amounts of residua] acetic acid.

The crude trio] was redissolved in anhydrous N,N-dimethylformamide (290 mL), and IH-imidazole (20.21 g, 297 mmol) and ten- butylchlorodiphenyisilane (37 mL, 144 mmol) were sequentially added to this solution. The resulting reaction mixture was stirred at ambient temperature for 19 hours under an atmosphere of dry nitrogen. On completion of the reaction (as assessed by GC analysis), the mixture was diluted in ether (250 mL) and washed with 5 % (w/w) aqueous LiCi (250 mL). The aqueous layer was back-extracted with three 100 mL portions of ether and the combined organics were subjected to a second wash with aqueous LiCl as described above. The organics were then sequentially washed with water (250 mL) and brine (250 mL), and were then dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography (330 g silica gel column eluted with a gradient of 0 to 40% ethyl acetate in hexanes) to provide the title compounds (17.7 g, 85 % yield from benzyl 2-hydroxy-2-(l -hydroxy cyclopropyl)acetate) as a waxy, white crystalline solid.

STEP 4: (S)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTANONE,

PREDOMINANTLY AND (R)-2-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTANONE

(PREDOMINANTLY (S), 78 - 81 % ee)

minor enantiomer

An oven-dried 500 mL RBF containing a stir bar was sealed with a septum and placed under an atmosphere of dry nitrogen using a dual-manifold. The flask was charged with l-(2-((ter/-butyldiphenylsilyl)oxy)-l - hydroxyethyl)cyclopropanol (predominantly (R) enantiomer mixture, 11.970 g, 33.6 mmol) and 300 mL pyridine. Once all of the dioi starting material had dissolved, the resulting solution was cooled in an acetonitrile/dry ice mixture to ca. -40 °C, and the nitrogen line was replaced with an Argon balloon.

Methanesulfonyl chloride (5.30 mL, 68.5 mmol) was added to the reaction mixture via syringe over the course of five minutes. The reaction mixture was stirred at -35 °C for 18 h inside a cryocool apparatus using acetone as the coolant medium. The reaction mixture was then allowed to warm to ambient temperature over the course of thirty minutes, after which time additional mesyl chloride (530 ί, 784 mg, 6.85 mmol) was added. Stirring at room temperature was continued for forty minutes. The reaction mixture was then cooled to ca -10 °C in an acetonitrile/dry ice slurry and poured into 250 mL of ice-water. The crude product was extracted into ether from the water layer via multiple rounds of extraction with fresh sol vent, with the total volume of ether used being 800 mL. The combined organics were then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude residue that was further purified by chromatography on a 220 g silica gel column eluted with a gradient of 0 to 25% ethyl acetate in hexanes to provide the title compounds (8.12 g, 71 % yield) as a semi-cry stall ine white solid. The cyclobutanone prepared in this manner typically had enantiomeric excesses ranging from 78-81% as assessed by Chirai SFC, corresponding to enantiomer ratios ranging from 8.1 : 1 to 9.5: 1. Absolute stereochemistry of the major enantiomer of the cyclobutanone was confirmed by stereospecific conversion to (lR,2R)-2-(((tert- butyldiphenyisiiyl)oxy )methyl)cy clobutanecarbaldeh de, reductive amination of the aldehyde with Intermediate AA1 1 A, Step 12B and subsequent desilylation to provide a sample of Intermediate AA11 A, Step 19B; the NMR spectral features of this material were identical to those of an authentic sample of Intermediate AAl l A, Step 19B.

STEP 5: (l S,2S)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOBUTANOL AND (1 R,2R)~ 2-(((ΤΕ¾Τ~ΒυΊΎΕΟΙΡΗΕΝΥΕ8ΙΕΥΕ)ΟΧΥ)Μ� �ΊΉΥΕ)εΥ€ ΟΒυΤΑΝΟΕ (PREDOMINANTLY (IS, 2S))

er

An oven-dried 100 mL round bottom flask was charged with 2-(((tert~ butyldiphenylsilyl)oxy)methyl)cyclobutanone (predominantly (5) with an enantiomer ratio of ca. 9: 1, prepared in Step 4, 1.20 g, 3.54 mmol) and placed under a nitrogen atmosphere. The cyclobutanone was dissolved in anhydrous tetrahydrofuran (35 mL) and the resulting solution was cooled to -78 °C in a dry ice/acetone bath. Z.-Selectride (1 M in THF, 5.40 ml, 5.40 mmol) was added via syringe, and the reaction mixture was allowed to gradually warm to ambient temperature. After 1 hour, 20 minutes, the reaction was quenched by cautious addition of saturated ammonium chionde and partitioned between ethyl acetate and saturated ammonium chloride, back-extracting the aqueous phase with several portions of ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude product, which was further purified by silica gel chromatography to provide the title compounds (1.14 g, 94 % yield). STEP 6: ((( 1 S ,2R)-2-(ALLYLTHIO)C YCLOBUTYL)METHOXY)(TERT- BUTYL)DIPHENYLSILA E AND (((lR,2S)-2- (ALLYLTHIO)CYCLOBUTYL)METHOXY)(TERT- BUTYL)DIPHENYLSILANE (PREDOMINANTLY (1 S,2R))

S

minor enantiomer

Methanesulfonyl chloride (0.270 mL, 3 ,49 mmol) was added to a stirred, ice-cooled solution of c7 ^' s~2~(((te7 -butyidiphenylsilyl)oxy)methyl)cyciobutaiiol (predominantly ( IS,2S) enantiomer mixture, prepared in Step 5, 1.13 g, 3.33 mmol) and N-ethyl-N-isopropylpropan-2-amine (Hunig's base, 1.2 ml, 6.89 mmol) in anhydrous dichioromethane (16 mL) under an atmosphere of nitrogen. The mixture was allowed to gradually warm to room temperature. After three hours, 35 minutes, the mixture was cooled again to °C in an ice-water bath.

Fifteen minutes later, the mixture was diluted in 75 mL of ice-cooled

dichioromethane and the resulting solution was washed with ice-cooled 1 M aqueous hydrochloric acid (2 X). The combined aqueous layers were back- extracted with two portions of dichioromethane and the combined organics were sequentially washed with ice-cooled water, ice-cooled saturated sodium bicarbonate, and brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the crude mesylate ester intermediate as a yellow syrup (1 .395 g, 100 % crude yiel d).

Technical grade prop-2-ene- l -thiol, (Sigma Aldrich, 1. 1 mL, 10,68 mmol) was added cautiously via syringe to a stirred slurry of sodium hydride (60 % dispersion in mineral oil, 0.36 g, 9.00 mmol) in ice-cooled, degassed anhydrous NiV-dimethyiformamide under an argon atmosphere. Once the addition was complete, the reaction mixture was allowed to warm to room temperature over the course of 22 minutes, after which a solution of the crude mesylate generated above (1.38 g, the amount remaining after analytical samples had been taken) in anhydrous, degassed N,N-dimethylformamide (12 mL) was added to the ally! thiolate solution. After five minutes, the resulting stirred reaction mixture was heated in an oil bath at 65 °C for two hours, 30 minutes. Upon cooling, 14 g of maleimide-functionalized silica gel (0.66 mmol/g maleimide loading; obtained from Silicycle) was added to the reaction mixture, giving a dark red slurry that was stirred at ambient temperature for 30 minutes and subsequently filtered, washing the filter cake with copious amounts of ethyl acetate. The filtrate was washed with 5% (w/w) aqueous LiCl, and the LiCl layer was back-extracted with two 75 mL portions of diethyl ether. The combined organics were washed sequentially with water, 15 % (w/w) aqueous citric acid, water (once more), saturated sodium bicarbonate (2X), brine, and were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude thioether product, which was further purified by chromatography on silica gel using an eluent gradient of 0 to 20 % ethyl acetate in hexanes. Fractions containing predominantly the desired product along with small amounts of nearly co-elutmg impurities were pooled and stripped of solvents in vacuo to give the title compound as 1.7 g of an oil, a mixture of compounds containing minor quantities of an unidentified impurity that was removed much more readily after Step 7.

STEP 7: ((l S,2R)-2-(ALLYLTHIO)CYCLOBUTYL)METHANOL AND

((lR,2S)-2-(ALLYLTOIO)CYCLOBUTYL)METOANOL (PREDOMINANTLY (1S,2R))

minor enantiomer

Tetrabutylammonium fluoride (1 M in THF, 5.40 ml, 5.40 mmol) was added to a stirred, ice-cooled solution of ra«s-((2-

(allylthio)cyclobutyl)methox5 _' ^, )(tert-butyl)diphenylsilane, predominantly { \ S.2R) (1.07 g, 2.70 mmol) in anhydrous tetrahydrofuran (18 mL) under an atmosphere of dry nitrogen. Following addition, the reaction mixture was allowed to warm to room temperature. After 4 h, the reaction mixture was partitioned between ether and saturated aqueous ammonium chloride. The aqueous layer was back- extracted with three portions of ether, and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude alcohol, which was further purified by flash chromatography (80 g silica gel column eluted with a gradient of 0 to 30 % ethyl acetate in hexanes) to provide 445 mg of a clear oil. NMR analysis showed this materia] to be the desired product, containing ca. 21 mol % residual ethyl acetate of

chromatography. The mass of desired product present in the sample could therefore be estimated as 387 mg, corresponding to a 91 % yield.

STEP 8: (S)-TERT-BUTYL 5-(((lS,2R)-2-

(ALLYLTHIO)CYCL()BUTYL)METHYL)-6'-CHL()RO-3',4,4',5- TETR.AHYDRO-2H,2'H-SPIRO[BENZO| B] | l ,4]OXAZEPINE-3, - NAPHTHALENE] -7-CARBOXYL ATE AND (S)-TERT-BUTYL 5-(((lR,2S)-2- (ALLYLra ^j :0)CYCLOBUTYL)METHYL)-6 ^, -CHLORO-3 ^, ,4 ₅ 4 ^, _s 5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [ 1 ₅ 4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYL ATE OR [(S)-TERT-BUTYL 5-(((l S,2R)-2- (ALLYLTHIO)CYCLOBUTYL)METHYL)-6 ^, -CHLORO-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-BUTYL 5-(((l S,2S)-2- (ALLYLTOIO)CYCLOBUTYL)METHYL)-6'-CHLORO-3',4,4 ^! ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPrNE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE OR [(S)-TERT-BUTYL 5-(((lS,2R)-2- (ALLYLTHiO)CYCLOBUWL)METHYL)-6'-CHLORO-3',4,4',5- TETRAHYDRO-2H,2 ^! H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYL ATE AND (S)-TERT-BUTYL 5-(((lR,2R)-2- (ALLYLTH10)CYCLOBUTYL)METHYL)-6'-CHLORO-3',4,4',5~

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALE -7-CARBOXYL ATE,

Water (50 μϊ_.) was suspended in a solution of tran -{2- (allylthio)cyclobutyl)methanol (predominantly (LS',2i?), prepared in Step 7, 222 mg, 1.403 mmol) in dichloromethane (13 mL), and the resulting biphasic mixtui'e was vigorously stirred at ambient temperature. After 15 minutes, the water appeared to be thoroughly dispersed throughout the reaction medium, and 1 ,1 ,1- Triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane, 1.18 g, 2.78 mmol) was added. The stirred reaction mixture was aged for 3.5 h and then diluted in additional dichloromethane. The excess oxidant was quenched by addition of 1 M aqueous sodium thiosulfate (a volume roughly equal to that of the organics). The resulting biphasic mixture was stirred at room temperature until both phases became clear and was then partitioned between ether and 1 M sodium thiosulfate. The organic phase was washed with sequentially with 1 M sodium thiosulfate, saturated sodium bicarbonate (6X) and brine, dried over magnesium sulfate and concentrated in vacuo cautiously (so as not to evaporate the desired aldehyde). The resulting oil weighed 16.1 mg and appeared by proton MR to contain principally the desired aldehyde intermediate, along with minor amounts of residual ether.

(S -fert-butyl e'-chloro-S'^^^S-tetrahydro- H^'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy late (Intermediate

AA11A, Step 12B, 237 nig, 0.593 mmol) and a solution of the crude intermediate aldehyde ira«s-2-(allylthio)cyclobutane carbaldehyde (predominantly (IS,2R), 151.7 mg, 0.884 mmol) were dissolved in a mixture of anhydrous

dichlorome thane (4400 uL) and acetic acid (2200 μΕ). The resulting stirred reaction mixture was cooled to 0 °C in an ice- water bath. After the mixture had been aged for 20 minutes at this temperature, a solution of sodium

cyanoborohydride (18.5 mg, 0.295 mmol) in anhydrous tetrahydrof an (500 μΕ) was added to it over the course of 90 minutes using a dry gas-tight syringe mounted on a syringe pump. The reaction mixture was then allowed to warm to ambient temperature and was aged for an additional 1 1 h, after which it was diluted in ethyl acetate and poured into a slurry of ca. 40 g of ice suspended in 70 mL 1 M aqueous sodium hydroxide. The crude product mixture was extracted into ethyl acetate and the aqueous layer was back-extracted with two portions of ethyl acetate. The combined organics were sequentially washed with two portions of pH 7 phosphate buffer and two portions of brine, dried over magnesium sulfate, filtered, and stripped in vacuo to gi e a residue which was further purified by flash chromatography (24 g silica gel column eluting with a gradient of 0 to 40 % (99: 1 ethyl acetate: acetic acid) in hex arses ) to provide the title compounds as a white foam (229 mg, 30 % combined yield over two steps based on tram -(2- (aUylthio)cyclobutyl)methanol, 72 % combined yield for the reductive amination based on Intermediate AA1 1 A, Step 12B).

STEP 9: (S)-TERT-BUTYL 6'-CHLORO-5-(((lS,2R)-2-((5- SULFAMOYLPENTYL)THIO)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [ 1 ₅ 4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-BUTYL 6 ^* -CHLORO- 5 ((lR 2S)-2-((5-SULFAMOYLPENTYL)THIO)CYCLOBUTYL)METOYL)- 3' ₅ 4 ₅ 4' ₅ 5.ΤΕΤΚ ΗΥϋΚΟ-2Η,2Ή-8Ρ11 0[ΒΕΝΖΟ[Β][1,4]ΟΧΑΖΕΡ1ΝΕ-3,Γ~ NAPHTHALENE] -7-CARBOXYLATE OR (S)-TERT-BUTYL 6'-CHLORO-5- (((l S,2R)-2-((5-SULFAMOYLPENTYL)TIflO)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H,2H-SPIRO[BENZO[B][l ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-B UTYL 6'-CHLORO- 5-(((l S,2S)-2-((5-SULFAMOYLPENTYL)THIO)CYCL()BUTYL)METOYL)- ;r,4,4 5-TETRAHYD O-2H,2Ή-S IRO[BENZO[B][ l,4]OXAZE INE-3,l '- NAPHTHALENE] -7-CARBOXYLATE OR (S)-TERT-BUTYL 6'-CHLORO-5- (((1 S,2R)-2-((5-SULFAMOYLPENTYL)TI-nO)CYCLOBUTYL)METIiYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO- 5-(((lR,2R)-2-((5-SULFAMOYLPENTYL)raiO)CYCLOBUTYL)ME ^r rHYL)- 3',4,4',5-TETRAHYDRO-2H,2TI-SPIRO[BENZO| B][ 1,4]ΟΧΑΖΕΡΙΝΕ-3,Γ- NAPHTHALENE] -7-CARBOXYLATE.

(l,3-Bis-(2,4,6-trime1hylphenyl)-2-irnidazolidinylidene)dich loro(o- isopropoxyphenylmethylene)ruthenium (Hoveyda-Grubbs catalyst, second generation, 153 mg, 0.244 mmol) was added to a room-temperature, stirred solution containing but-3-ene-l-sulfonamide (170 mg, 1.258 mmol) and a sample comprised of a ca. 6: 1 mixture of (S)-tert-butyl 5-(((15,2i?)-2- (dlylthio)cyclobutyl)methyl)-6 ^, -chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[6] [l,4]oxazepine-3,l '-naphthalene]-7-carboxylate and a minor diastereomer (mixture obtained in Step 8, 31.9 mg, 0.244 mmol total) in degassed dichloroethane (3.5 mL) under an argon atmosphere. Additional quantities of sulfonamide (51.4 mg, 0.38 mmol) and catalyst (7.0 mg, 0.01 1 mmol) were added at reaction times of 22 and 33 minutes, respectively. After a total reaction time of 90 minutes, the mixture was concentrated in vacuo and purified by silica gel chromatography, using a solvent gradient of 0 to 40% (99: 1 ethyl acetate: acetic acid) in hexanes, to provide a mixture of isomeric metathesis cross-coupling products as a semi-solid yellow residue (90.4 mg, 57 % material recovery).

A stirred solution of the isomeric mixture of olefinic metathesis products (90.4 mg, 0.140 mmol) in anhydrous, degassed dichloromethane (2 mL) was charged with (1 ,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)- iridium(I)hexafluorophosphate (Crabtree's catalyst, 22 mg , 0.027 mmol) and stirred under an atmosphere of hydrogen at ambient temperature. After ca.1.5 hours, an additional 1 mL of dichloromethane was added to the mixture, 20 h after the reaction was commenced, an additional 9 mg increment of Crabtree's catalyst was added to the solution. The reaction mixture was stirred for an additional 2 h before being concentrated in vacuo and purified by flash chromatography (12 g silica gel column eluted with a gradient of 0 to 40% [99: 1 ethyl acetate: acetic acid] in hexanes) to provide the title compounds as a semi-solid white residue (54.6 mg, 34 % overall combined yield, 60 % material recovery for the hydrogenation).

STEP 10: i !.S..T.V. '/V)-6-C: ! i .OIU -OIH YDRO-2//.1 7/- SPIRO [NAPHTHALENE- 1.22'-

[20]OXA[7,13]DITmA[l ₅ 14]DIAZATET ACYCLO[147.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PE TAC

QSA[16,18,24]TRiEN]-15 ^* -ONE 13 ^! ,13'-DI0X1DE AND (lS,3'R,&S ^r )-6- CHLORO-3,4-DmYDRO-2H 5^-SPlRO[NAPHTHALENE-l _s 22'-

[20iOXA|;7,131DITi«A[l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ -^( ⁾¹⁹ ' ² ]PE TAC OSA[16,18,24]TRIEN]-15 ^! -ONE 13 ',13 '-DIOXIDE OR (lS,3'S,6'R)-6-CHLORO- 3 ,4-DIH YDRO-2H, 15 'H-SPIRO [NAPHTHALENE- 1,22'-

|2Uj()XA|7.I iDiTinA| U4jD! A/ATI RACYCLOj i 4.7.2.0 ^; '\0 ^iu jPSiNTAC OSA[I6,l 8,24]TRIEN]-15'-ONE 13',13'-DTOXIDE AND (Κν,3'?,6'?)-6- CHLORO-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[7,13]DlTfflA[l,I4]DIAZATETR/\CYCLO[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTAC OSA[16,18,24]TRIEN]-15 ^* -ONE 13',13'-DIOXIDE OR [(kV,3',S67?)-6- CHLORO-3,4-DII-IYDRO-2H,15'H-SPIRO[NAPHTOALENE-l,22'- 120 jO A| 7.1 iD!Ti UA| 1.14!ί)1Λ/Α Π· ΗΑί Π 0| !4.?.2.0 ^: ·' ^' .0 ^! "·· ^!| |ΡΓΛ 1 AC OSA[16,18,24]TRIE ]-15'-ONE 13', 13 '-DIOXIDE AND CHLORO-3,4~DIHYDRO-2H15'H"SPIRO[NAPHTHALENE-l,22'"

[20]OXA[7 3]DITHIA[1 ₅ 14]DIAZATETOACYCLO[ 14 .2.0 ³ ' ^{6 19} ' ²⁴ ]PE TAC OSA[16,l 8,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE.

Trifluoroacetic acid (600 μΐ.,, 7.84 mniol) was added to a stirred, room- temperature solution of an isomer mixture containing (<S)-tert-butyl 6'-chloro-5- (((lS,2i?)-2-((5-sulfamoylpentyl)thio)cyd^

2H,2'H-spiro[benzo[i)] [ 1 ,4]oxazepine-3, 1 '-naphtha] ene]-7-carboxylate and a minor diastereomer (mixture obtained in Step 9, 17.3 mg, 0.027 mmol total) in dichloromethane (600 μΙ_). After 2 h, the reaction mixture was concentrated in vacuo and three aliquots of anhydrous toluene were evaporated from the resulting residue to remove moisture from the crude carboxylic acid intermediates prior to macrocyclization. The crude intermediates exhibited the mass of the desired carboxylic acid intermediate by LC-MS, and this material was used in the macrocyclization reaction without further characterization.

A solution of Nl-((ethyliiTdno)methylene)-N3 _y N3-dimethylpropane-l,3- diamine hydrochloride (12 mg, 0.063 mmol) in anhydrous dichloromethane (1 mL) was added portionwise over the course of seven minutes to an ice-cold, stirred solution of the crude carboxylic acid intermediates generated above and iV,N~dimethylpyridin~4~amiiie (6 mg, 0.049 mmol) in anhydrous dichloromethane (12 mL) under an atmosphere of dry nitrogen. The resulting stirred reaction mixture was allowed to gradually warm to rt and was aged for ca. 20 hours at this temperature, after which time it was partitioned between dichloromethane and 1 M aqueous hydrochloric acid. The organic lay er was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue that was further purified by flash chromatography (4 g silica gel column eluted with a gradient of 0 to 25 % [99: 1 ethyl acetate: acetic acid) in hexanes j to provide the title compounds as a flaky white solid (8.9 mg, 56 % overall combined yield). By comparison of NMR integrals and peak heights, the two isomers comprising the sample were present in a ratio of ca, 6: 1. Co-integration of NMR signals for the major and minor species supported the assignment of the minor compound as a diastereomer, consistent with expectations based on the means of preparation, the known enantiomer ratio of the cyclobuiane precursor described in Step 4, identical masses and retention times for both compounds observed by LC-MS and HPLC, respectively, and other considerations described in Step 7. ^! H NMR (500 MHz, CD2CI2) δ ppm 8.22 (br. s, 1 H), 7.72 (d, J=8.6 Hz, 0.13 H), 7.72 (d, J=8.6 Hz, 0.81 H), 7.16-7.20 (m, 1 H), 7.08-7.12 (m, 1.8 H), 7.08 (apparent d, ,/ 2.0 Hz, 0,07 H), 7,04-7.07 (m, 1 H), 6,95 id. ./ 8.3 Hz, 0,86 H), 6,95 (d, ./ 8.3 Hz, 0, 14 H), 4.23 id . «/= 12.0 Hz, 0.16 H), 4,08 - 4.14 (m, 1.84 H), 3.81 - 3.91 (m, 2 H), 3.72 (d, ,/ 14.2 Hz, 1 H), 3.34 (dt, ./ 14.8. 7.3 Hz, 1 H), 3.21 (d, ./ 14.2 Hz, 1 H), 3.01 - 3. 1 1 (ra, 2 H), 2.74 - 2.79 (m, 2 H), 2.57 - 2.67 (ra, 1 H), 2.49 - 2.55 (ra, 2 H), 2.01 - 2.12 (m, 4 H), 1.78 - 1.96 (m, 3 H i. 1.56 - 1.76 (m, 7 H), 1.39 - 1.47 (m, 1 H). m/z (ESI, +ve ion) 575.0 (M+H) ⁺ , 597.1 (M+Na) ⁺ .

EXAMPLE 196. (1 S,3'S,6'R)-6-CHLORO-3,4-DIHYDRO-2H, 15Ή- SP! ROj N APf I s 1 !Ai J I ί .22 -

[20]OXA[7,13]DITHIA[l,14]DIAZATETOACYCLO[14.7.2.0 ³ -^0 ¹ ' ²⁴ ]PENrrAC OSAj 16,18,24jTRIEN]-15 ^! -ONE 7',7',13',13'-TETRAOXIDE AND ( ! S. ' . ^, S }·· ί -( ! U .ORO-3.4-DI! !Y DRO-2! I. ! ! !~SPiRO| ΝΛΡ! i l l lAi.r.M .- 1.22'- [20]OXA[7,13]DITHIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTAC 0SA[16,18,24]TR1EN]-15'-0NE 7 ^, ,7 ^, ,13 ^, ,13 ^, -TETRAOXIDE OR (l S^'S^'R)^- CHLORO-3,4-DIHYDRO-2H.15Ή-SPIRO[NAPH HALENE-l,22 ^, - [20]OXA[7,13]DTTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[16,18,24]TRIEN]-15'-ONE 7'.7 ^' . i . i .I'-TE TR AOXI DS : AND i 1 S.3'S.6 ^' S )- 6-CHLOR()-3,4-DimORO-2H,15 ^, H-SPIRO|;NAPHTHALENE-l ,22'- [20]OXA[7,13]DITfflA[l ₅ 14]DTAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OSA[16,18,24]TRIEN]-15'-ONE 7 ^, ,7',13 ^, ,13 ^, -TETRAOXIDE OR [(lS,3'S,6'R)-6- CHLORO-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE-l,22'- [20iOXA|;7,131DITHIA[ l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PEN AC OSA[16, 18,24]TRIEN]-15'-ONE 7',7 ^f ,13',13'-TETRAOXIDE AND (1S,3'R,6'R)- -CI n .()RO-3.4-!)H !Y ORO-.?.! I. i !-SP!R()| \ APi Π H AI J ^: NI - i 22'- [20] OX A [7, 13] DITHI A[ 1 , 14]DI AZ ATETRAC YCLO [ 14.7.2,0

OS Ai 16, 18.241TRIEN1 - 15'-ONE 7'.7 ^! , 13', 13 '-TETRAOXIDE .

N-methylmorpholine oxide (30 mg, 0.256 mmoi) was weighed into a flask containing an mixture of (l,S,3 ,67?)-6-chloro-3,4-dmyclro-2H,15 ^, H- spiro[naphthalene-l,22'- 4|dia/aicu a s do! 14, 7, 2. ί! ^; " ϋ ^{1 "} |peniacosaj ! <S. ! 8.24 |u ie n]-15'-one 13', 13'-dioxide and a minor diastereomer (obtained in Step 10 of Example 195, 23.2 mg, 0.040 mmol total). A solution of osmium tetroxide (2.1 mg, 8.26 μηιοί) in 600 μΕ acetone was added followed by water (300 μΙ_.), and the resulting reaction mixture was vigorously stirred at ambient temperature for one hour. The oxidant was quenched by addition of 6 mL 1 M aqueous sodium thiosulfate and the crude product mixture was extracted into 1 :5.7

isopropanol:dichloromethane. The aqueous layer was back-extracted 3X with 1 :5.7 isopropanol:dichloromethane and the combined organs. cs were washed with 1 M aqueous sodium thiosulfate that had been saturated in sodium chloride followed by brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude residue that was further purified by flash chromatography (4 g silica gel column eluted with a gradient of 30 to 100 % [99: 1 ethyl acetate: acetic acid] in hexanes) to provide a mixture of the title compounds as a flaky white solid (16.7 mg, 68 % yield). Integration of aryl resonances in the proton NMR spectrum of this material showed it to be composed of a ca. 1 1 : 1 mixture of isomers containing the desired (3 S,6'R) diastereomer as the major compound along with a minor diastereomer inferred to arise from the minor enantiomer present in the cyclobutane starting material; however, as a purified sample of the minor compound was not obtained for exhaustive characterization, alternative structural assignments (as depicted above) for the minor diastereomer could not be definitively excluded. Co-integration of NMR sign als for the two compounds supported assignment of the minor component as a stereoisomer, consistent with expectations based on the considerations described in Steps 7 and 10 of Example 195. ¾ NMR (500 MHz, ; ); ^■ (.·()) δ ppm 10.26 (br. s„ 1 H), 7.80 (d, .7=8,6 Hz, 0.08 H), 7.75 (d, J=8.6 Hz, 0.91 H), 7.37 (d, J=1.7 Hz, 0.08 H), 7.30 (d, J=2.Q Hz, 0.91 H), 7.26 (dd, ./ 8.2. 2.1 Hz, 0.09 H), 7.23 (dd, ./ 8.4. 2.3 Hz, 0.95 H), 7.20 aid . ,/ HA . 2,0 Hz, 0.89 H), 7. 14 - 7. 15 (m, 0,08 H), 7. 1 1 -7.14 (m, 0.87 H), 6.95 (d, .7=8.1 Hz, 0.1 H), 6.94 (d, ,/ 8 i Hz, 0.85 H), 4.17 (s, 0.14 H), 4.14 (s, 0.17 H), 4.12 (s, 0.77 H), 4.10 (s, 0.71 H), 4.03 - 4.09 (m, 1 H), 3.87 (ddd, ./ 14.5. 9.9, 4.4 Hz, 1 H), 3.75 (d, ./ 14.2 Hz, 1 H), 3.66 (q, ./ 9 3 Hz, 1 H), 3.49 (s, 0.1 5 H), 3.29 - 3,43 (m, 2.82 H), 3,26 (dd, ./ 1 .9,, 10.3 Hz, 0.11), 3.03 - 3.20 (m, 3 H), 2.71 - 2.86 (m, 3 H; signal partially obscured by residual water peak), 2.19 - 2.35 (m, 2 H), 2.17 (dt, ./ 4.5. 2.3 Hz, 1 H), 2.08 - 2.16 (m, 2 H), 1.98 - 2.08 (m, 3 H; signal partially obscured by residual acetone peak), 1.86 - 1.98 (m, 5 H), 1 .68 - 1.86 (m, 3 H), 1.45 - 1.54 (m, 1 H). m/z (ESI, +ve ion) 607.2 { V! H i

EXAMPLE 197. (I S,3 ^, R,6'S,7 ^, E,9'S, 12 ^, R)-6-CHLORO-12'-E ^r fflYL-9 ^! - HYDROXY-3,4-DIHYDRO-2H,15'H-SPIR()[NAPHTHALENE-l ,22'-

[20]OXA[ 13]THIA[ 1 , 14]DIAZATETRACYCLO[ ! 4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [7, 16, 18,24]TETRAEN] - 15'-ONE l .T. 1 3 '-DIOXIDE OR

(lS,3'R,6 ^! S,7 ^, E,9 ^! R,12 ^, R)-6-CHLORO-12 ^! -ETHYL-9 ^, -HYDROXY-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [7, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

STEP 1 : ^■ TERT-BUTYL 4-HYDROXYHEXANOATE

Et

O.

"OH

Oi-Bu

The title compound was prepared in yields ranging from 49-51 % from (S)-2-ethyloxirane and te -butyi acetate by the method described in Journal of Organic Chemistry, 1989, 54, 2039, STEP 2: (R)-TERT-BUTYL 4-(PYRIMIDIN-2-YLTHIO)HEXANQATE

Methanesulfonyl chloride (2.1 mL, 27.1 mmol) was added dropwise to a stirred, ice-cooled solution of (S)-terf -butyl 4-hydroxyhexanoate (4.729 g, 25.1 mmol, prepared in Step 1) and N-ethyl-N-isopropylpropan-2-amine (9.0 mL, 53.1 mmol) in anhydrous dichloromethane (125 mL) under an atmosphere of dry nitrogen. The resulting reaction mixture was allowed to gradually warm to ambient temperature and was aged overnight for a total of 17 h. The mixture was diluted in DCM, washed sequentially with ice-cooled 1 M aqueous hydrochloric acid, satui'ated aqueous sodium bicarbonate and brine, and then the combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude mesylate intermediate as a reddish-orange oil weighing 6.88 g. Pyrimidine-2-thiol (3.24 g, 28.9 mmol) was suspended in degassed absolute ethanol (200 mL) under an argon atmosphere in a round-bottom flask equipped with a reflux condenser, and the resulting mixture was vigorously stirred at ambient temperature. Sodium ethoxide (21 % w/w in ethanol, 10.00 ml, 26.8 mmol) was gradually added to the slurry, inducing dissolution of the thiol as its sodium salt. After 13 minutes, a solution of the crude mesylate intermediate generated above in degassed ethanol (50 mL) was added the mixture over the course of five minutes. The reaction mixture was heated at 60 °C in an oil bath for ca. 2 h. The reaction temperature was then increased to 100 °C and maintained at this temperature for one hour, after which solvents were removed in vacuo. The residue was taken back up into diethyl ether (1 00 mL) and washed sequentially with 1 M aqueous sodium hydroxide (2X) and brine. The organics were dried over magnesium sulfate, filtered and concentrated to give the crude product, which was further purified by flash chromatography (330 g silica gel column eluted with a gradient of 0 to 20% ethyl acetate in hexanes) to give the title compound as an orange oil (3.20 g, 45 % yield).

STEP 3 : (R)-N -METHOXY-N-METHYL-4-(PYRlMIDIN-2- YLTHIO)HEXANAMIDE

Triiluoroacetic acid (10 mL, 130 mmol) was added to a stirred, room- temperature solution of (#)~ifer/-butyl 4-(pyrimidin-2-ylthio)hexanoate (3.09 g, 10.9 mmol) in dichloromethane (10 mL). After 2 h, the reaction mixture was concentrated to give the crude carboxylic acid intermediate. Trace moisture and residual triiluoroacetic acid were liberated from this material by successive azeotropic co-distillations of anhydrous toluene (4 X 24 mL) from the reaction pot using a rotary evaporator, giving a pinkish-orange syrup that was redissolved in anhydrous dichloromethane (30 mL). The resulting stirred, solution was cooled to 0 °C in an ice-water bath under an atmosphere of dr ' nitrogen, Triethylamine (12.2 mL, 88 mmol), N,0-dimethylhydroxylamine hydrochloride (1.32 g, 13.53 mmol) and lH-benzo[ii| [l,2,3]triazol-l -ol (2.24 g, 16.58 mmol) were added to the solution, followed by Nl-((ethylirnino)methylene)-N3^-dimethylpropane-l,3- diamine hydrochloride (EDO, 3.18 g, 16.59 mmol). An aliquot of anhydrous dichloromethane (3 mL) was used to rinse all solid reactants of the joint of the flask into solution. The stirred mixture was allowed to gradually warm to ambient temperature. After ca. 13.5 hours, the reaction mixture was partitioned between dichloromethane and 15 % (w/w) aqueous citric acid. The organics were sequentially washed with water, saturated aqueous sodium bicarbonate and brine, and were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was further purified by flash chromatography (220 g silica gel column eluted with a gradient of 50 to 80% ethyl acetate in heptanes) to provide the title compound as a pale pink oil (2.66 g, 90 % yield). STEP 4: (R)-5-(PYRIMIDIN-2-YLTHIO)HEPTAN-2-ONE

Methylmagnesium bromide (3M in diethyl ether, 7.4 mL, 22.20 mmol) was added over the course of six minutes to a stirred, -45 °C solution of (R)-N- methoxy-N-methyl-4-(pyrirnidin-2-ylthio)hexanarnide (1.958 g, 7.27 mmol) in a mixture of anhydrous diethyl ether (33ml) and anhydrous tetrahydrofuran (17 mL). After three hours, the reaction was quenched by cautious addition of saturated aqueous ammonium chloride (ca. 50 mL). The crude product was extracted into diethyl ether, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide a residue that was further purified by silica gel chromatography (eluent ^:=: 5 to 40% ethyl acetate in heptanes) to gi ve the title compound as a clear oil (968 mg, 54 % yield). STEP 5: (S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-((l S,6R)-l-HYDROXY-3- OXO-6-(PYRJMIDIN-2-YLTHIO)OCTYL)CYCLOBUTYL)METHYL)-

3^4,4^5-TETRAHYDRO-2ii2':H-SPIRO[BENZO[B]|;L410XAZEPINE-3 ,r- N APHTH ALENE J -7 -C ARB OXYL ATE AND (S)-METHYL 6 ^* -CHLORO-5- (((1 R,2R)-2-((l R,6R)-1 -HYDROXY-3-OXO-6-(PYRIMIDIN-2-

YLTHIO)OCTYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2H,2'H-SPIRO|;BENZO[Bi[ l,4]OXAZEPINE-3J ^, -NAPHTHALENE]-7-

CARBOXYLATE

N-butyllithium (2,5 M in hexanes, 295 μΕ, 0.738 mmol) was added dropwise over the course of four minutes to a stirred, -78 °C solution of diisopropylamine (108 ,uL, 0.770 mmol) in anhydrous diethyl ether (2.5 mL) under an atmosphere of dry nitrogen. Six minutes later, the solution was warmed to 0 °C and maintained at this temperature for 0.5 hours before being cooled again to -78 °C. A solution of (i?)-5-(pyrimidin-2-ylthio)heptan-2-one (157 mg, 0.700 mmol) in 1 : 1 diethyl ether:tetrahydrofuran (1 mL total) was added dropwise to the LDA solution over six minutes. The resulting ketone enolate solution was aged at -78 °C for ca. 1 hour, 45 minutes. A solution of (S)~methyl 6'~chloro~5~(((li?,2i?)- 2~formylcyclobut 'i)methyl)--3',4,4',5~tetrahydro-2H,2 ^! H~

spiro[benzo[6] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (Intermediate

AA1 1 A, Step 20A, 160 mg, 0.352 mmol) in anhydrous tetrahydrofuran (1.2 mL total volume) was then added to the ketone enolate over the course of 0.5 hours. The mixture was aged for an additional 36 minutes at -78°C and was then gradually cannulated while at this temperature into a vigorously stirred suspension of crushed ice (ca. 50 mL) in 0.5 M pH 7 phosphate buffer (25 mL). The crude product was extracted into ether and the organic layer was sequentially washed with 0,5 M pH 7 phosphate buffer and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a residue that was further purified by flash chromatography (12 g silica gel column eluted with a gradient of 10 to 70% (99: 1 ethyl acetate; acetic acid) in heptanes) to afford the product as a ca. 2.5; 1 mixture of diastereomeric alcohol epimers containing additional isomeric impurities at a total level of ca. 10% by NMR and HPLC. m/z (ESI, +ve ion) 678.2 (M+H) ⁺ ₅ 700.2 (M+Na) ⁺ .

STEP 6: (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((R,E)-3-OXO-6- (PYRlMIDiN-2-YLTOIO)OCT~l -EN-l-YL)CYCLOBUTYL)METHYL)~ S'^^'^-TET AHYDRO^H^'H-SPI OtBENZOP] [1 ,4]0XAZEP1NE-3,1 '- NAPHTHALENE] -7-CARBOXYLATE

Methanesulfonyl chloride (90 μΕ, 1.158 mmol) was added dropwise to a stirred, 0 °C solution of a mixture of (^-methyl &-c \ow-5-(((lR,2R)-2-((lS,6R)- 1 -hydroxy -3-oxo-6-(pyrimidin-2-ylthio)octyl)c lobu d)methyl)-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro [benzo \h } [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy late and (5)-methyl 6'-chloro-5-(((li?,2i?)-2-((li?,6i?)-l-hydrox '-3-oxo-6-(pyrimidin- 2-y]thio)octyl)cyclobutyl)methy])-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[6] [ 1 ,4] oxazepine-3 , -naphthalene] -7-carboxylate (748 mg, 1.103 mmol total) in anhydrous pyridine (7.8 niL). The mixture was allowed to gradually warm to ambient temperature. One hour later, an additional 900 μΕ aliquot of rnesyi chloride (1 1.6 mmol) was added dropwise over the course of three minutes. Stirring at ambient temperature was continued for one more hour, after which time the mixture was partitioned between water and methyl tot-butyl ether. The organic layer was washed sequentially with 15 % (w/vv) aqueous citric acid, water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude mixture of mesylate esters as a viscous yellow syrup. This material was redissolved in anhydrous benzene (10 mL) and the resulting stirred solution was cooled in an ice-water bath until it began to freeze. 1 ,8- Diazabicycioundec-7-ene (990 uL,, 6.62 mmoi) was added to this mixture dropwise over the course of seven minutes. After 1 h, 37 minutes, the mixture was diluted in ethyl acetate and washed sequentially with 15 % (w/wj aqueous citric acid, water and brine. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a residue that was further purified by flash chromatography (80 g silica gel column eluted with a gradient of 10 to 45 % (99: 1 ethyl acetate: acetic acid) in heptanes) to provide the title compound as a white foam (576 mg, 79 % overall yield).

STEP 7: (S)-METHYL 6'-CHLORO-5-(((l R,2S)-2-((R,E)-3-OXO-6- (PYRIMIDIN-2-YL SULFONYLjOCT- 1 -EN- 1 -

YL)CYCYLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO| BENZO[B;||;i,4|OXAZEPINE-3, l'-NAPHTHALENE]-7- CARBOXYLATE

Aqueous hydrogen peroxide (30 % w/w in water, 220 μΐ., 2.154 mrnol) was added dropwise over the course of ca. two minutes to a vigorously stirred, room temperature mixture of (5)-methyi 6'-chloro-5-(((li?,25)-2-(( ?,£)-3-oxo-6- (py iiidin-2-ylthio)oct-l -en- 1 -y ^

spiro [benzo [b ] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy 1 ate (558 mg, 0.845 mmoi), sodium tungstate dihydrate (27.9 mg, 0.085 mmol), tetrabutyl ammonium sulfate (50 weight % solution in water, 49 fiL, 0,085 mmol) and

phenylphosphonic acid (13.36 nig, 0.085 mmol) in toluene (3500 μί,): water (350 μ]_). When the addition was finished, the stirred reaction mixture was heated at 50-55 °C in an oil bath. After four hours, 41 minutes, the mixture was allowed to cool to room temperature and was partitioned between ethyl acetate and water. The combined organics were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a residue that was further purified by flash chromatography (50 g silica gel column eluted with a gradient of 15 to 60% (99: 1 ethyl acetate: acetic acid) in heptanes) to provide the title compound as a foamy white solid (478 mg, 82 % yield), m/z (ESI, +ve ion) 692.2 (M+H) ⁺ , 714.2 (M+Na) ⁺ .

STEP 8: (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((3S,6R,E)-3-HYDROXY-6- (PYMMDIN-2-YLSULFONYL)OCT-l-EN-l-YL)CYCLOBUTYL)METHYL)- ;r,4,4 5-TETP^HYD O-2H,2Ή-S IRO[BENZO[B][i,410XAZE INE-3,l ⁱ - N APHTH ALENE] -7 -C ARB OXYL ATE AND (S)-METHYL 6 ^f -CHLORO-5- (((l R,2S)-2-((3R,6R,E)-3-HYDROXY-6-(PYRIMIDIN-2-YLSULFONYL)OCT- 1 -EN- 1 - YL)C YCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETR AHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, i '-NAPHTHALENE]-7- CARBOXYLATE

A stirred solution of (5)-methyl 6'-ch3oro-5-(((lA 25 -2-((i?,i?)-3-oxo-6- (pyrimidin-2-ylsulfonyl)oct-l-en-l -yl)cycylobutyl)methyl)-3',4

2H,2'H-spiro[benzo[^][ l,4]oxazepine-3, -naphthalene]-7-carboxylate (480 nig, 0.693 mmol) in methanol (10.00 mL) and tetrahydrofuran (3000 μΕ) was cooled to ca. -10 °C in an ice/brine bath under an atmosphere of nitrogen. Cerium(III) chloride (188 mg, 0.763 mmoi) was added to the solution as the solid. Sodium borohydride (58.4 mg, 1.544 mmoi) was added to the reaction mixture

portionwise over the course of two minutes. The reaction mixture was aged for 1.5 h at -1 0 °C and was subsequently quenched by addition of 15% (w/w) aqueous citric acid (20 mL) and partitioned between ethyl acetate and brine. The orgaiiics were washed once more with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue that was further purified by flash chromatography (40 g silica gel column eluted with a gradient of 50 to 80 % (99: 1 ethyl acetate: acetic acid) in heptanes) to afford the desired alcohol epimer mixture as a white foam (363 mg, 75 % yield). By HPLC, the ratio of epimers appeared to be 57:43, m/z (ESI, +ve ion) 694.2 (M+H) ⁺ , 716,3 (M+Na) ⁺ .

STEP 9: (S)-METHYL 6'-CHLORO-5-(((l R,2S)-2-((3S.6R,E)-6-(PYRIMIDIN-2- YLSULFON YL)-3-((TRIISOPROPYLSILYL)OXY)OCT- 1 -EN- 1 -

YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETR^ HYDRO-2H,2 ^! H- SPIRO| BENZO[B;||;i,4|OXAZEPINE-3, l'-NAPHTHALENE]-7- CARBOXYLATE AND (S)-METHYL 6"-CHLORO-5-(((lR,2S)-2-((3R,6R,E)-6- { PY Ri Yii Di\~2-Y LSl Ι .Ι·Ό\Ύ Ι . Κ < ! R HSOPROPV LSH .YUOXV KX ^' i - ! -hV l-YL)CYX OBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR0[BENZ0|;B] [ 1,4]0XAZEPINE-3, 1 '-NAPHTHALENE|-7- CARBOXYLATE

Triisopropylsilyl trifluoromethanesulfonate (0.490 ml, 1.823 mmoi) was added dropwise to a stirred, 0 °C solution of (S)-methyl 6'-chloro-5-(((li?,2<S)-2- ((35,6i?^)-3-hydroxy-6-(pyrirnidin-2-ylsulfonyl)oct-l-en-l- yl)cyclobu1yl)methyl)-3 4,4^5-tetrahydro-2H,2 ^, H-spiro[benzo ¾][ l,4]oxazepine- 3,l'-naphthalene]-7-carboxylate and (<S -methyl 6'-chloro-5-(((l./?,25 -2- ((3i?,0i?,E)-3~hydroxy~6-(pyri^

yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[b enzo[i'][l,4]oxazepine- 3,1 '-naphthalene I -7-carboxy late (315.8 mg, 0.455 mmol total) and 2,6-iutidine (0,430 mL, 3.69 mmol) in anhydrous dichloromethane (4.5 ml.) under an atmosphere of dry nitrogen. After 19 minutes, the reaction was quenched by cautious addition of 20 mL saturated aqueous sodium bicarbonate. The resulting mixture was partitioned between dichloromethane and saturated sodium bicarbonate, washing the organic layer sequentially with 15% (w/w) aqueous citric acid and brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue that was further purified by flash chromatography (24 g silica gel column eluted with a gradient of 10 to 40% (99; 1 ethyl acetate: acetic acid) in heptanes) to provide a mixture of the title compounds as a white foam (348 mg, 90 %). m/z (ESI, +ve ion) 849.8 ( Yl · ! ! ) ^' .

STEP 10: (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((3S,6R,E)-6- SULFAMOYL-3-((TRIISOPROPYLSILYL)OXY)OCT-l-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _j! 4HYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((3R,6R,E)-6- SULF A OYL-3 - ((TRII SOPROP YL SIL YL)OXY)OCT- 1 -EN- 1 - YL)CYCL0BUTYL)METHYL)-3',4,4',5-TETRAHYDR0-2H,2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE

Potassium carbonate (312 mg, 2.258 mmol) was added as the solid to an ice-cooled solution of (5)-methyl 6'-c oro-5-(((li2,26>2-((35,6i?^-6-(pyrimidin- 2-ylsulfonyl)-3-((triisopropylsilyl)oxy)oct-l -en-l-yl)cyclobutyl)me1hyl)-3 4,4',5- tetrahydro-2H,2'H-spiro[benzo[6] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylate and ©-methyl 6'-chloro-5-(((li?,2^-2-((3/?,6/?,E)-6-(pyrirnidin-2-ylsulfo nyl)-3- ((triisopropylsilyl)oxy)oct-l -en- i-yl)cyc]obuty])methyl)-3

2H,2'H-spiro[benzo[&] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylate (382.6 mg, 0.450 mmol) in 8 mL 1 : 1 methanol :tetrahydrofuran and the resulting reaction mixture was vigorously stirred for 49 minutes. A solution of hydroxylamine-O- sulfonic acid (283 mg, 2.25 mmol) and sodium acetate (192 mg, 2.34 mmol) in water (4 mL) was added over the course of three minutes, and the mixture was stirred at room temperature. Additional increments of hydroxylamine-0-sulfonic acid (59.6 mg, 0.474 mmol) and sodium acetate (39.7 mg, 0.484 mmol) were added as a solution in water (0.4 mL) after one hour. Twenty minutes later, the mixture was partitioned between ethyl acetate and 15 % (w/w) aqueous citric acid. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a residue that was further purified by flash chromatography (24 g silica gel column eluted with a gradient of 25 to 70 % (99: 1 ethyl acetate: acetic acid) in heptanes and concentrated from dichloromethane to provide the desired epimer mixture as a white foam (335 mg, 95 % yield), m/z (ESI, +ve ion) 788,8 ( M i l ) .

STEP 11 : ¾-6 ^, HLORO-5-(((li?,2A 2-((3,S;6i?,£)-6-SULFAMOYL-3

((TRnSOPROPYLSILYL)OXY)OCT-i-EN-l-YL)CYCLOBUTYL)Mt : ,4,4 5-TETR^HYDRO-2H,2 -SPIRO[BENZOrø[ ,4]OXAZEPίNE-3, I '- ΑΡΗΊΉ ALENE j - 7 -C ARB OXYLIC ACID AND (^-e'-CHLORO-S-llCl/i .S)- 2-((3i?,6i?J¾-6-SULFAMOYL-3-((TRJISOPROPYLSILYL)OXY)()CT-l- EN-l- YL)CYCIX)BUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[5][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXYLIC ACID

A solution of (5)-methyl ff-chloro-S^l^^^-iiS^e i^-e-sulfainoyl- 3-((tjiisopropylsilyl)oxy)oct-l -en-l-yl)cyclobutyl)me1hyl)-3',4,4 5-teTjahydro- 2H,2'H-spiro[benzo[^][ l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((l/i25 2-((3i½iU^

((triisopropylsilyl)oxy)oct-l-en-l -yl)cyclob^^

2H,2'H-spiro[benzo[i][l,4]oxazepine-3,r-naphthalene]-7-carbo xylate (epimer mixture obtained in Step 10, 321.9 mg, 0.409 mmol) in tetrahydrofuran (2.0 niL) and methanol (1.0 mL) was charged with lithium hydroxide (49.0 mg, 2.05 mmol) and water (1.0 ml.) and the resulting reaction mixture was heated at 50 °C in an oil bath. After 2 h the temperature of the oil bath was increased to 60 °C. Five minutes later, an additional increment of lithium hydroxide (29.0 mg, 1.21 mmol) was added. The reaction mixture was heated for an additional period of 1.5 h. It was then combined with a mixture generated in the same way starting with a smaller quantity of (l'S)-methyl 6 ^, -chloro-5-(((lR,2S)-2-((6R,E)-6-sulfamoyl-3- ((triisopropylsilyl)oxy)oct-l -en-l-yl)c} ⁷ clobutyl)methyl)-3^4,4 5-tetrahydro- 2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (epimer mixture, 10.2 mg, 0.013 mmol) for joint work-up and purification. The combined mixtures were partitioned between ethyl acetate and 15 % (w/w) citric acid and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue which was further purified by silica gel chromatography (eluent ^:=: 15 to 100 % (99: 1 ethyl acetate: acetic acid) i heptanes) to give the desired epimer mixture as an off-white foam (318 mg, 97 % yield based on 0.422 mmol of the methyl ester), m/z (ESI, +ve ion) 774.8 ί M i l )

STEP 12: (18,3'Κ,6'8,7Έ,9'8,12Έ)-6-( ΗΕΟΚΟ-12·-ΕΤΗΥί-9'-

((TRIISOP OPYLSILYL)OXY)-3,4-DIHYDRO-2H,15'H-

SPIRO[NAPHTHAI.ENE~l,22'- [20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[7, 16, 18,24]TETRAEN]-15"-ONE 13', 13 ^* -DIOXIDE AND

(lS,3'R,6 ^! S,7'E,9'R, 12'R)-6~CHLORO-12 ^! ~ETHYL-9 ^! -

((TRIISOPROPYLSILYL)OXY)-3,4~DIHYDRO-2H,15'H"

SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[7, 16, 18,24]TETRAEN]-1 S'-ONE 13 ',13 '-DIOXIDE

A solution of Nl-((ethylin' no)methylene)-A ^i' 3^V ^r 3-dimethyipiOpane-l,3- diamine hydrochloride (126.4 mg, 0.659 mmol) in a anhydrous dichloromethane (37 ml.) was added dropwise over the course of 25 minutes to a stirred, ice-cooled solution of (S)-6'-chloro-5-((( lR,2S)-2-((3S, e i^-e-sulfamoyl-S- ((triisopropylsilyl)oxy)oct-l-en-l-yl)cyclobutyl)methyl)-3^4 ,4^5-tetrahydro- 2H,2'H-spiro benzo £> ] [ 1 ,4]oxazepine-3, 1 '-naphthalene |-7-carbox lie acid and (^)- 6'-chloro-5-(((li?,25)-2-((3i?,6i?,E)-6-sulfanioyl-3-((triis opropylsilyl)oxy)oct-l- en-l-yl)cyciobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[^][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (epimer mixture, 252 mg, 0.326 mmol) and N _j N-dimethylpyridin-4-amine (68.8 nig, 0.563 mmol) m anhydrous dichloromethane (123 mL). The reaction mixture was allowed to gradually warm to room temperature, and after ca. 15 hours, it was partitioned between ethyl acetate and 15 % (w/w) citric acid. The aqueous layer was saturated in sodium-chloride and back-extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue that was further purified by silica gel chromatography (eluent = 0 to 50% acetone in dichloromethane). Fractions containing predominantly the early diastereomer were pooled, concentrated in vacuo, and dried under high vacuum to give an off-white powder arbitrarily assigned as the 9 ^' S epimer (103 mg, 42 % yield), m/z (ESI, +ve ion) 755.9 (M+H)\ Fractions containing predominantly the late diastereomer were concentrated to obtain an off-white powder arbitrarily assigned as the 9'R epimer (73 mg, 30 % yield), m/z (ESI, +ve ion) 755.9 (M+H) ⁺ .

STEP 13: (lS,3'R,6'S,7'E,9'S,12'R)-6-CHLOR()-12 ^, -ETHYL-9'-HYDR()XY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7 .0 ^3> 60 ¹⁹ - ²⁴ ]PENTACOSA

[7,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'S,7'E,9'R, 12'R)-6-CHLORO-l 2'-ETHYL-9'-HYDROXY-3,4-

D\\ IYDR ~2i U 's i-SPIRO|N.\Pi ΠΉΛΙ.Ι ^: .\Ι ^: -1.22-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA [ 7, 16, 18,24 JTETRAEN] -15'-ONE 13', 13'-DIOXIDE

Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 1.33 mL., 1.330 mmol) was added to a stirred, ice-cooled solution of either

(L,3'#,6'S7'i,9'^

dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazaietracycio[14,7.2,0-^0 ^l9 - ²⁴ ]pentacosa[7,l^

n]-15'-one or ί I .Y.37. 7V.77-:.97«i. ! 27 )-6-cliior< ! 2 ^' -eihvj-9'~ ((trii sopropy Isily l)oxy )-3 ,4^

nj-15'-one 13',13'-dioxide (the early, major diastereomer from Step 12, 100 mg, 0.132 mmol) in

tetrahydrofuran (1.3 mL). The ice-bath was removed upon completion of the addition, and an additional aliquot of tetrabutylamrnonium fluoride (600 μΕ, 0.6 mmol) was added after ca. 1.75 hours. After a total reaction time of ca. 5 hours, the reaction mixture was combined with a mixture generated in same way starting with a smaller quantity (19.1 mg, 0.025 mmol) of the silyl ether for joint workup and purification. The combined reaction mixtures were partitioned between ethyl acetate and 15% (w/w) aqueous citric acid. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue that was further purified by silica gel chromatography, eiuting with a gradient of 10 to 40 % (99: 1 ethyl acetate: acetic acid) in heptanes, to provide the title compound as a white powder (66 mg, 70 % yield based on

0, 157 mmol of the silyl ether). ¾ NMR (500 MHz, CD2CI2) δ ppm 8.12 (br. s., 1 H), 7.71 (d, ./ 8.6 Hz, 1 H), 7.17 (d l.■/ 8.6. 2.4 Hz, 1 H), 7.09 (d,■/ 2.4 Hz, 1 H), 6.94 - 6.99 ( ns. 1 H), 6.90 - 6.93 (m, 1 ! ! }. 6.85 id. ,/ ! 7 Hz, 1 H), 6.09 (dd, J=15.5, 5.5 Hz, 1 H), 5.54 (ddd, .7=15.6, 7.6, 1.2 Hz, 1 H), 4, 14 - 4.21 (m, 1 H), 4.10 (s, 2 H), 3.76 - 3.87 (m, 2 H), 3.67 (d, J=14.2 Hz, 1 H), 3.18 (d, ./ 1 -1.2 Hz, 1 H), 3.07 (dd, ./ 15.7. 8.3 Hz, 1 H), 2.69 - 2.83 (m, 2 H), 2.56 - 2.66 (m, 1 H), 2.17 (dqd, ,/ 14.4. 7.4, 7.4, 7.4, 4.5 Hz, 1 I I ). 1 ,76 - 2.10 (m, I I H), 1.60 - 1.71 (m, 2 H), 1.54 - 1.57 (m, 1 H), 1.40 - 1.47 (m, 1 H), 1.15 (t, J=7.5 Hz, 3 H). m/z (ESI, +ve ion) 598.9 ( \\ H ) .

EXAMPLE 198. (1 S^'R.e'S 'E^'F _^ '^-e-CHLORO-l^-ETHYL-^- HYDROXY-S^-DlHYDRO^H SH-SPIROINAPHTOALENE-l^'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA

[7, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3¾,6'S,7¾9 ^, S,12 ^f R)-6-CHLORO-12'-ETHYL-9 ^f -HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[7,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

This compound was prepared in the same manner as in Step 13 of

Example 197, siarting instead from the late, minor diastereomer (85,2 mg, 0.113 mmol) from Step 12 of Example 197, and was obtained in the amount of 31 mg (46 % yield for the desilylation reaction). ¾ NMR (500 MHz, CD2CI2) δ ppm 8.01 (br. s., 1 H), 7.71 id. ./ 8.6 Hz, 1 ! ! }. 7.17 (dd, ./ X.4. 2.3 Hz, 1 ! ! }. 7.09 (d, ,/ 2 4 Hz, 1 H), 6,95 - 7.00 (m, 1 H), 6,91 - 6.94 (m, 1 H), 6,74 (d, ./ 1 .7 Hz, I H), 5,83 (dd, ./ 15.5.. 7.0 Hz, 1 H), 5,54 (dd, J=15.4, 6.1 Hz, I H), 4. 14 (quin, .7=5.6 Hz, 1 H), 4.05 - 4.12 (m, 2 H), 3.68 - 3.79 (m, 3 H), 3.27 (d, ./ 1 .4 Hz, 1 H), 3.14 (dd, ./ 1 .4. 9.3 Hz, 1 H), 2.70 - 2.84 (m, 2 ! ! }. 2.61 (quin, ./ 8.3 Hz, 1 H), 2.34 (quin, .7=8.6 Hz, 1 H), 2,09 - 2.19 (m, 1 H), 2,01 - 2,09 (m, 3 H), 1 ,80 - 1 ,97 (m, 5 H), 1.67 - 1,79 (m, 5 H), 1.40 - 1.48 (m, 1 H), 1.14 (t, ./ 7.5 Hz, 3 H). rn / (ESI, +ve ion) 598.9 { W W ) .

EXAMPLE 199. (l S,3'R,6 ^, S,7'E,9'S,12 ^! R)-6-CHLORO-12'-ETHYL-9 ^! - METHOXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[ 13]THIA[1,14]DIAZATETRACY ^T CLO[ !4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [7,16, 18 ,24]T ETRAEN] - 15'-ONE l .T. 13 '-DIOXIDE OR

(lS,3'R,6'S,7'E,9'R,12 ^, R)-6-CHLORO-12 ^! -ETHYL-9 ^, -METHOXY-3,4- DIHYDRO-2H, 15'H-SPIR()[NAPHTHALENE-1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ '* 0 ¹⁹ - ²⁴ ]PE TACOSA

[7,16,18,24]TETRAEN]~15'~QNE 13 ',13 '-DIOXIDE

An ice-cooled solution of either (15',3'i?,6' ₁ S ^, ,7'ii,9'5 ^' , 12'A ^, )-6-chloro-12'- ethyl-9'-hydro:^--3,4-dihy

[20]oxa[13]thia[l,14]diazatetn^

n]-15'-one 13',13'~dioxide or (15 ^, ,3 ^, /^,6 ^, S',7 ^, E ₅ 9 ^, R ₅ 12 ^, R)-6-chloΓO-12 ^, -ethyl-9 ^, - hydroxy-3,4-dihydro-2H, 15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[7,16,18,24]tetrae n|-15'-one 13', 13'-dioxide (Example 183, 14.6 mg, 0.024 mmol) in anhydrous tetrahydrofuran (500 μΕ) was charged with sodium hydride (60 % dispersion in mineral oil, 9.4 mg, 0.235 mmol) and the resulting stirred suspension was allowed to warm to room temperature. After seven minutes, iodomethane (8 μί,, 0.129 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 21 hours, after which time it was partitioned between ethyl acetate and saturated ammonium chloride. The orgamcs were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue that was further purified by silica gel chromatography (4 g silica gel column eluted with a gradient of 0 to 40 % (99: 1 ethyl acetate: acetic acid) in heptanes to provide the title compound as a white powder (8.7 mg, 58 % yield). ^! H NMR (500 MHz, CD2CI2) δ ppm 8.09 (s, 1 H), 7.63 (d,■/ 8. Hz, 1 H), 7.08 (dd, ./ 8.6. 2.2 Hz, 1 H), 7.01 (d, 2.2 Hz, 1 H), 6.87 - 6.91 (m, 1 H), 6.81 - 6.85 (m, 1 H), 6.79 (d, ./ 2.0 Hz, 1 H), 6.09 (dd, J=15.5, 5.3 Hz, 1 H), 5.27 (ddd, J=15.5, 8.3, 1.0 Hz, 1 H), 4.02 (s, 2 H), 3.70 - 3.78 (m, 2 H), 3.53 - 3.61 (m, 2 H), 3.11 (s, 3 H), 3.08 (d, ,/ 14 2 Hz, 1 H), 2,99 (dd, ./ ! 5.;\ 7.7 Hz, 1 H), 2.61 - 2,76 (m, 2 H), 2.51 - 2,60 (m, 1 H), 2,05 - 2.17 (m, 1 H), 1 ,88 - 1.97 (m, 4 H), 1 ,68 - 1.88 (m, 5 H), 1,52 - 1.68 (m, 3 H), 1.29 - 1.39 (m, 2 H), 1.06 (t, ./ 7.5 Hz, 3 H). m/z (ESI, +ve ion) 612.8 ( +H) ⁺ . EXAMPLE 200. (15,3^,6'5 7'iL ^' ,9',S i2'i?)-6-CHLORO-12 ^, -ETHYL-9'-(2- METHOXYETHOXY)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [7,16, 18,24] ^" rETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR { 1.V. / .6'.Y..7'/·. ' . 12' )- 6-CHLORO- 12'-ETHYL-942-METHQXYETHQXY)-3,4-DIH YDRQ-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[l ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ - ²⁴ ]PEKrACOSA [7, 16, 18,24]TETRAEN]-1 S'-ONE 13', 13'-DIOXIDE

A stirred, ice-cooled solution of either (lS'.S'R.e'S' 'E^'S ^' . ^'R^e-chloro- 12'-ethyl-9'-hydroxy-3,4-dihydro-2H, 15'H-spirofnaphthalene-l,22'- [20]oxa[13]thia[l, 14]diazatetra<y^

n]-15'-one 13',13'-dioxide or (15 3'^,6'Δ 7'£,9'Λ12'^)-6-ΰ1ι1θΓθ-12'-6Λν1"9'- hydroxy-3,4-dihydro-2H, 15'H-spiro|naphthalene-l,22'- [20]oxa[13]thia[l ,14]diazate1ra^^

n]-15'-one 13',13'~dioxide (Example 183, 15.2 mg, 0.025 mmol) in anhydrous N,N-dimethylforrnamide (0.50 mL) was charged with sodium hydride (60 % dispersion in mineral oil, 1 1 mg, 0.275 mmol), and the resulting suspension was allowed to warm to room temperature. After three minutes, l-bromo-2- methoxy ethane (12 μί, 0.128 mmol) was added via microsyringe. The resulting reaction mixture was stirred for 18 hours and then partitioned between partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was washed sequentially with 5 % (w/w) lithium chloride, 15 % (w/w) citric acid and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue that was further purified by silica gel chromatography (same method as in Example 185) to provide the title compound as a white powder (8.9 mg, 53 % yield). ¾ NMR (500 MHz, CD2CI2) δ ppm 8.19 (s, 1 H), 7.71 (d, ,/ 8. Hz, 1 H), 7.17 (dd. ,/ X f,. 2.2 Hz, 1 1 1 ). 7.09 (d, ,/ 2 2 Hz, ! H), 6.94 - 7.00 (m, 1 H), 6.89 - 6.93 (m, I H), 6.87 (d, ./ 2 0 Hz, 1 H), 6.16 (dd, ./ 15.6.. 5.4 Hz, 1 H), 5,38 (ddd, J=15.7, 8.4, 1.1 Hz, 1 H), 4.10 (s, 2 H), 3.74 - 3.87 (m, 3 H), 3.66 (d, J=14.2 Hz, 1 H), 3.56 (ddd, ./ 10.4. 6.3, 3.7 Hz, 1 H), 3.41 - 3.51 (m, 2 H), 3.32 (ddd, ,/ 10.5. 5,7, 3.8 Hz, 1 H), 3.30 (s, 3 H), 3.16 id. ./ 14.2 Hz, 1 ! ! }. 3.07 (dd, ,/ 1 5.5. 7.7 Hz, 1 H), 2.68 - 2.83 (m, 2 H), 2.58 - 2.68 (m, 1 H), 2.13 - 2.23 (m, 1 H), 1.96 - 2.07 (m, 3 ! ! }. 1.60 - 1.95 (m, 9 ! ! }. 1.39 - 1.48 (m, 2 I I ). 1.14 (t, ,/ 7.5 Hz, 3 H). m . (ESI, +ve ion ) 656.8 (M+H) ⁺ .

EXAMPLE 201. 2944012 (lS,3'R,6 ^, R,7 ^, S,8 ^, E,10 ^, S)-6-CHLORO-7'-HYDROXY- l()'-(HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIR()[NAPHTOALENE- 1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

STEP 1 : (S)-3-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4- EN-l-OL

PS

To a solution of (S)-methyl 3-(((tert-butyldiphenylsilyl)oxy)me1hyl)pent-

4-enoate (0.14 g, 0.366 mmoi) prepared according to the method of Helmchen et al. ³ dissolved in THF (4 mL) at room temperatiire was added lithium borohydnde (0.366 mL, 0.732 mmol) as a 2 M solution in THF all at once. After 5 minutes no reaction was observed by TLC. To the reaction was added methanol (0.059 mL, 1 .464 mmol). After 16 hours TLC indicated a small amount of starting material remained. An additional equivalent of lithium borohydride was added followed by an additional 2 equivalents of methanol. After 2 hours TLC indicated no starting material remained. To the reaction solution was added 5 ml saturated aqueous sodium bicarbonate solution and 5 ml water. The mixture was extracted with 2 x 25 ml diethyl ether. The combined organic extracts were washed with 20 ml brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford (S)-3-(((tert- butyldiphenylsilyl)oxy)methyl)pent~4-en-l-ol as a colorless oil (135mg, 0.37 mmol, 100% yield).

STEP 2: (S)-3-(((TERT-BUTYLDIPHElSIYLSILYL)OXY)METHYL)PENT-4- EN - 1 -YL METH ANESULFON ATE S

To a solution of (S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en-l -ol

(0.13 g, 0.367 mmol), 4-dimethylaminopyridine (1.344 mg, 11.00 μ ^η ιοΐ) and triethylamine (0.056 mL, 0.403 mmol) in DCM (3.67 mL) at room temperature was added neat methanesulionyl chloride (0.028 mL, 0.367 mmol). The reaction was stirred at ambient temperature for 60 minutes then partitioned between 20 mL each DCM and saturated aqueous ammonium chloride. The aqueous separation was extracted again with 20 ml DCM. The combined organic extracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford (S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en- 1-yl methanesulfonate as a colorless oil (156mg, 0.36 mmol, 98% yield).

¹ Helmchen et al. Synlett 2007, 790. STEP 3: (S)-3-(((TERT-BUTYLDIPHENYLSiLYL)OXY)METHYL

EN -1-YL)THI0)PYR1MIDINE

To a mixture of (S)~3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en-l -yl niethanesuifonate (0.15 g, 0.347 mmol) and 2-mercaptopyrimidine (0.047 g, 0.416 mmol) in DMF (3 mL) at room temperature was added potassium carbonate (0.025 mL, 0.416 mmol) all at once. The resulting yellow mixture was stirred at ambient temperature for 60 minutes then partitioned between 25 mL each 1 : 1 saturated aqueous ammonium chloride: water and diethyl ether. The aqueous separation was extracted again with 25 mL diethyl ether. The combined ethereal layers were washed with 25 mL water followed by 25 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a pale yellow oil (159 mg). The product was isolated by chromatography on 40g RediSep Rf column eluting with 20% ethyl acetate in hexane at 40 ml/min. to afford (S)-2-((3-(((tert-butyldiphenylsilyl)oxy)- methyl)pent-4-en~l-yi)thio)pynmidine as a colorless oil (127 mg, 0.28 mmol, 82% yield).

STEP 4: (S)-3-(((TERT-BUTYLDIPHENYLSTLYL)OXY)METHYL

EN - 1 -YL)SULFONYL)- PYRIMIDINE

To a mixture of sodium tungstate, dihydrate (0.016 mL, 0.158 mmol), phenylphosphonic acid (0.018 mL, 0.158 mmol) and tetrabutylammonium sulfate, 50 wt. % solution in water (0.182 mL, 0.158 mmol) was added hydrogen peroxide solution, 30% wt. % in water (0.485 mL, 4.75 mmol) all at once. The mixture was stirred for 5 minutes before a solution of (S)-2-((3-(((tert- butyldiphenylsilyl)oxy)memyl)pent-4-en-l-yl)mio)pyrimidine (0.71 g, 1.582 mmol) dissolved in toluene (4 mL) was added. The mixture was heated to 50 °C. After 60 minutes LLC indicated very little product. Heat was increased to 60 °C and the mixture was stirred overnight at this temperature. After 18 hours TLC indicated no starting material remained and LCMS confirmed complete consumption of SM and formation of desired product. The reaction was equilibrated to RT and partitioned between 30 mL each water and ethyl acetate. The aqueous separation was extracted again with 30 mL ethyl acetate. The combined organic extracts were washed with 30 ml brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless oil. The product was isolated by chromatography on 40g RediSep Rf Gold column eiuting with 33-50% ethyl acetate gradient in hexane at 40 ml/rnin to afford (S)-2-((3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en-l- yl)sulfonyl)- pyrirnidine as a colorless oil (600mg, 1.25 mmol, 79% yield).

STEP 5: (S)-3-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-

EN -1 -SULFONAMIDE S

To a solution of (S)-2-((3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en- l-yl)sulfonyl)pyrimidine (0.6 g, 1.248 mmol) dissolved in MeOH (12 mL) at room temperature was added sodium ethoxide, 21 w/w solution in ethanoi (0.466 mL, 1.248 mmol) all at once. The resulting solution was stirred at ambient temperature for 30 minutes then concentrated under reduced pressure. The sulfmate was dissolved in MeOH (3.00 mL) and water (3 mL) and this solution added ail at once to a solution of hydroxylamine-o-sulfonic acid (0.282 g, 2.496 mmol) and sodium acetate (0.134 mL, 2.496 mmol) dissolved in MeOH (3.00 mL) and water (3mL) heated to 50 °C. After 2 hours the reaction was concentrated under reduced pressure and the concentrate partitioned between 30 mL each water and ethyl acetate. The aqueous separation was extracted again with 30 mL ethyl acetate. The combined organic layers were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless oil. The product was isolated by chromatography on 40g RediSep Rf Gold column eiuting with 35% ethyl acetate in hexane at 40 ml/min to afford (S)~ 3-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-ene-l-sulfona mide as a colorless oil (405mg, 0.97 mmol 78% yield). -5-(((lR,2R)-2-((l S,4S,E>4-(((TERT-

N APHTHALENE] -7-C ARBOXYLIC ACID

A mixture of (S)-6'-chloro-5-(((l ,2R)-2-((S,E)-l -hydroxyhex-2-esn-l- yl)cyclobutyd)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxylic acid (0.1 g, 0.196 mmol, Intermediate ΑΑΓ1Α) and (S)-3-(((tert-butyldiphenylsilyl)oxj rnethyl)pent-4-ene-l-sulfonamide (0.279 g, 0.668 mmol, Step 5) dissolved in 1,2-dichloroethane (5 mL) was degassed with a stream of argon for 10 minutes before Hoveyda-Grubbs catalyst 2nd generation (0,018 g, 0.029 mmol) was added. The reaction was left stirring overnight at room temperature. After 18 hours 100 μΕ ethyl vinyl ether was added and air bubbled through the reaction solution for 10 minutes. The solution was concentrated under reduced pressure then purified by chromatography as described. The products were isolated by chromatography on 24g RediSep Rf Gold column eluting with 30 TO 100% ethyl acetate in hexane at 40 ml/mm to afford (S)-5-(((lR,2R)-2-((l S,4S.E)^-(((tert-butyldiphenylsilyl)oj-y)me l)-l- hydroxy-6-sulfamoylhex-2-en-l-yl)cy

tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid as a colorless film (50mg, 0.058 mmol, 30% yield).

STEP 7: (l S ₅ 3 ^, R,6'R,7 ^, S,8 ^, E,10 ^, S)-6-CHLORO-7 ^, -HYDROXY-10 ^, -((((2 METHYL-2-PROPANYL)(DTPHENYL)SILYL)OXY)METHYL)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - [20]OXA[ 13]THI A[l , 14]DIAZ ATETRAC YCLO-

[ 14.7.2.0 ³ ' ⁶ .0 ⁱ ' ² ]PENTACOSA[8,16,18,24]TETRAEN]-l 5'-ONE 13', 1 DIOXIDE DPS

A mixture of (S)-5-(((lR,2R)-2-((lS,4S;E)-4-(((tert- bu1yldiphenylsilyl)oxy)methyl)-l-hydroxy-6-sulfamoylhex-2-en -l- yl)c\xlobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3,r-naphthalene]-7-carboxylic acid (0.05 g, 0.058 mmol), 4-dimethylaminopyridine (0.012 g, 0.099 mmol) and l-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.022 g, 0.117 mmol) in DCM (29.2 mL) at room temperature was stirred for 4 days then concentrated under reduced pressure. The product was isolated by chromatography on 12g RediSep Rf Gold column eluting with 60% ethyl acetate in hexane + 0.5% acetic acid to afford (1 S,3'R,6'R,7'S,8'E, 10'S)-6-chloro-7'-hydroxy-l 0'-((((2-methyl-2- propanyl)(diphenyl)silyl)oxy)methyl)-3,4-dihydro-2H,15'H-spi ro[naphthalene-

1,22'-

[20]oxa[13]thia[l ,14]diazatefra<yclo[^^

n]-15'-one 13',13'-dioxide as a colorless film (17mg, 0.020 mmol, 35% yield).

STEP 8: (l S,3'R,6'R,7'S,8 l Q ^* S)-6-CHLOR()-7'-HYDROXY-10'- (HYDRCXXYMETHYL)~3,4-DTHYDRO-2H, 15'H-SPIRO [NAPHTHALENE - 1 ,22'-| 2 1 OXA| 1 3]THIA[ 1 , 14] - DIAZATETRACYTL()[14.7.2.() ³ -^() ^{i 9} - ²⁴ iPENTACOSA|;8,16, 18,24]TETRAENj- 15 -ONE 13', 13 '-DIOXIDE

To a solution of (lS^'^e'R-T'S^'E O'S^e-cMoro-T'-hydroxy-lO'-^- meth}d-2-propanyl)(diphenyl)silyl)oxy)methyl)-3,4-dihydro-2H ,15'H- spiro[naphthalene-l,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ -^0 ¹⁹ - ²⁴ ]pentaco

n]-15'-one 13',13'-dioxide (0.017 g, 0.020 mmol) dissolved in THF (2 mL) at room temperature was added tetrabutylammonium fluoride, 1.0m in

tetrahydrofuran (0.061 ml,, 0.061 mmol). The reaction was stirred at ambient temeperature overnight. After 24 hours the reaction was concentrated under reduced pressure then isolated by chromatography on 12g RediSep Rf Gold column eluting with 30% acetone in DCM at 35 ml/rain to afford

(1 S,3'R,6'R,7 ^! S,8'E, 10'S)-6-chloro-7'-hydroxy-l 0'-(hydroxymethyl)-3,4-dihydro- 2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l ,14]diazatefra<yc^

n]-15'-one 13',13'-dioxide as a colorless film. ¾ NMR (400 MHz, CD2CI2) δ ppm 7.75 (d, J=8.41 Hz, 1 H), 7.21 (dd, J=8.41, 2.35 Hz, 1 H), 7.14 (d, J=2.35 Hz, 1 H), 7.12 (br. s., 1 H), 7.00 - 7.05 (m, 1 H), 6.95 - 7.00 (m, 1 H), 5.73 - 5.83 (m, 1 H), 5.64 - 5.73 (m, 1 I I ). 4,35 (br. s,, 1 H), 4. 1 7 i s, 2 H), 3.98 (t, ,/ ! 1 .15 Hz, 1 H), 3,74 - 3.84 (m, 1 H), 3,59 - 3.73 (m, 3 H), 3,48 (dd, ./ 10.66. 6.75 Hz, 1 H), 3.34 (d, 14 4K Hz, 2 H), 3.21 (d, ./ I (..63 Hz, 1 H), 2.74 - 2,88 (ra, 2 H), 2.32 - 2,58 (m, 3 H), 1.52 - 1.78 (m, 12 H); m/z (ESI, +ve ion) 601.2 ( M H ) .

EXAMPLE 202. (1 S,3 ^! R,6 ^, R,7'S,8'E,10'R,12'R)-6-CHLORO-l()'-(2- HYDROXYETHYL)-7'-METHOXY- 12'-METHYL~3,4-DTHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22 ^! -

| 2u jOXA| 1 ΉΤί !1Α| Ι 4 4 |ΠίΑ/.ΥΠ:ΤΗ Α(ΎΠ.ϋΙ i 4.7.2. · ^, '.ί ^{) | :} ' ^{! 1} |P1-M ^' .\C<)SA [ 8,16,18,24 jTETRAEN] - 15'-ONE 13 ', 13 ' -DIOXIDE

STEP 1 : (4S,6S)-6-METHYL-4-VINYLTCTOAHYDRO-2H-PYRAN-2-ONE

Prepared according to the method of ICido et ah ² using (S)-(+)-parasorbic acid which is prepared by the method of Dupont and Donate. ³

STEP 2: (3R,5S)-3-VINYLHEX -l,5-DIOL

To a solution of (4S,6S)-6-methyl-4-vinyltetrahydro-2H-pyran-2-one

(0.677 g, 4.83 mrnol) in MeOH (24.15 mL) cooled by an ice bath was added solid sodium borohydride (0.851 mL, 24. 15 mmol) in portions over 10 minutes. After 15 minutes the cold bath was removed and the reaction equilibrated to room temperature. The reaction was stirred at room temperature for 2 hours then 3 mL

² Kido et al. Tetrahedron 1990, 46(13-14), 4887.

³ Dupont, J. and Donate, A..T. Tetrahedron: Asymmetry 1998, 9(6), 949. saturated aqueous sodium bicarbonate was added and the resulting mixture stirred for 15 minutes before the methanol was removed under reduced pressure on a rotary evaporator. The concentrate was pariitioned between 25 ml each water and ethyl acetate. The aqueous separation was extracted with 2 x 25 ml. ethyl acetate. The combined organic extracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford (3R,5S)-3- vinylhexane-l,5-diol as a colorless oil (618 mg, 4.29 mmol, 89% yield).

STEP 3 : (2S,4R)-4-(2-((TERT-BUTYLDIMETHYLSILYL)OXY)ETHYL)HEX- 5-EN-2-OL

To a solution of (3R,5S)-3-vinylhexane-l,5-diol (0.6 g, 4.16 mmol) and imidazole (0.274 mL, 4.16 mmol) in DMF (20.80 mL) cooled by an ice bath was added solid tert-butyldimethylsilyl chloride (0.627 g, 4.16 mmol) ail at once. The cold bath was removed and the reaction equilibrated to room temperature. The reaction was stirred at room temperature overnight. After ca. 18 hours the reaction was partitioned between 50 mL water and 30 mL hexane. The aqueous layer was extracted twice again with 30 ml hexane each. The combined organic extracts were washed with 3 x 20 mL water followed by 20 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless oil (1 g). The product was isolated by

chromatography on 80g RediSep Rf column eluiing with 20% ethyl acetate in hexane at 60 ml/min to afford (2S,4R)-4-(2-((tert- burylctomethylsilyl)oxy)ethyl)hex-5-en-2-ol as a colorless oil (670 mg, 2.59 mmol, 62% yield). STEP 4: (2S,4R)-4-(2-((TERT-BUTYLDIMETHYLSILYL)OXY)ETHYL)HEX- 5-EN-2-YL METHANESULFONATE

To a solution of (2S,4R)-4-(2-((tert-butyldimethy]silyl)oxy)ethyl)hex-5- en-2-ol (0.72 g, 2.79 mmol), triethyl amine (0.426 mL, 3.06 mmol) and 4- (dimethylamino)pyridine (0.017 g, 0.139 mmol) dissolved in DCM (18.57 mL) cooled by an ice bath was added neat methanesulfonyl chloride (0.226 mL, 2.92 mmol) all at once. The cold bath was removed and the reaction equilibrated to room temperature. TLC after 15 and 75 minutes was identical— starting material remained. After 90 minutes additional methanesulfonyl chloride (0.15 equiv) and triethylamine (0.2 equiv) was added to the room temperature solution. The reaction was stirred for an additional 60 minutes then TLC indicated no starting material remained. The reaction was washed with 30 mL 0. IN citric acid solution followed by 25 mL water and 25 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford (2S,4R)-4-(2-((tert-bulyl(Ume lsilyl)oxy)eft.yl)hex-5-en-2-yl methanesulfonate as a pale yello oil (950 mg, 2.82 mmol, 100% yield).

STEP 5: 2-(((2R,4R)-4-(2-((TERT-

BUTTYLDIMETHYLSILYL)OXY)ETHYL)HEX-5-EN-2-

Yl,)THIO)PYRlMIDINE

To a suspension of 2-mercaptopyrimidine (0.360 g, 3.21 mmol) in EtOH (8.9! mL) at room temperature was added sodium ethoxide, 21 % weight solution in ethanol (1.148 mL, 3.08 mmol) ail at once. The resulting orange, homogeneous solution was stirred at ambient temperatui'e for ten minutes before a solution of (2S,4R)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)hex-5-en-2- yl methanes ulfonate (0.9 g, 2.67 mmol) dissolved in EtOH (4.46 ml) was added ail at once. The reaction was heated to 50 °C overnight. After sixteen hours thin layer chromatography indicated no starting material remained. The reaction was concentrated under reduced pressure and the concentrate partitioned between 30 mL ethyl acetate and 30 mL 0. IN aqueous sodium carbonate solution. The aqueous layer was extracted again with 2 x 30 mL ethyl acetate. The combined organic extracts were washed with 30 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow oil (1 g). The product was isolated by chromatography on 80g RediSep Rf column eluting with 15% ethyl acetate in hexane at 60 mL/min to afford 2-(((2¾4R)-4-(2-((tert-butyldimethylsilyl)oxy)eftyl)hex-5-e n-2- yl)thio)pyrimidine as a colorless oil (667mg, 1.89 mmol, 71% yield).

STEP 6: 2-(((2R,4R)-4-(2-((TERT- BUTYLDIMETHYLSILYL)OXY)ETHYL)HEX-5-EN-2-

YL)SULFONYL)PYRIMTDTNE

into a 25 mL round bottom flask were charged sequentially sodium tungstate oxide dihydrate (0.019 mL, 0.184 mmol), phenvlphosphonic acid (0.021 mL, 0.184 mmol), tetrabutylammonium sulfate, 50% weight solution in water (0.212 mL, 0.184 mmol) and hydrogen peroxide 30% in water (0.471 mL, 4.61 mmol) at room temperature. The gummy mixture was aged for five minutes (NOTE: stir bar stopped for first couple minutes then returned to stirring as the mixture thinned and solids deposited on the inside of the reaction flask). To the mixture at room temperature was added a solution of 2-(((2R,4R)-4-(2-((tert- butyldimethylsilyl)oxy)ethyl)hex~5~en-2-yl)thio)pyrimidine (0.65 g, 1.843 mmol) dissolved in toluene (3.5 mL). The reaction mixture was heated to 50 °C with rapid stirring. After 90 minutes at 50 °C thin layer chromatography and LCMS indicated no starting material remained and a single product peak with mass corresponding to sulfone predominated. After two hours total reaction time the reaction was removed from heat and equilibrated to room temperature. The reaction mixture was partitioned between 25 mL each water and ethyl acetate. The aqueous layer was extracted again with 2 x 25 mL ethyl acetate. The combined organic layers were washed with 25 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford 2-(((2R,4R)-4-(2-((tert-butv'ldimethylsilyl)oxy)ethyl)hex-5- en-2- yl)sulfonyl)pyrimidine as a colorless oil (700 mg, 1.82 mmol, 99% yield).

STEP 7: (2R,4R)-4-(2-((TERT-

BUTYLDIMETHYLSILYL)OXY)ETHYL)HEX-5-ENE-2-SULFONAMIDE

To a room temperature solution of 2-(((2R,4R)-4-(2-((tert- butyldimethylsilyl)oxy)emyl)hex-5-en-2-yl)sulfonyl)pyrimidin e (0.65 g, 1.690 mmol) dissolved in MeOH (10 mL) was added sodium ethoxide, 21% weight solution in ethanoi (0.631 mL, 1.690 mmol) all at once. The solution was stirred at room temperature for 30 minutes then concentrated under reduced pressure. The sodium suifinate intermediate could not be precipitated with either diethyl ether or hexane. The concentrate was used without removal of the 2- methoxypyrimidine by-product. The concentrate was dissolved in MeOH (15 mL) and water (3 mL) and heated to 50 °C, at which temperature a solution of hydroxyiamine-o-sulphonic acid (0.382 g, 3.38 mmol) and sodium acetate (0.181 mL, 3.38 mmol) dissolved in water (5 mL) was added over one minute. A turbid solution developed within five minutes. Stirring at 50 °C was continued for 70 minutes after which time LCMS indicated no sulfmate remained. The reaction mixture was concentrated under reduced pressure and the concentrate partitioned between 25 mL each water and ethyl acetate. The aqueous separation was extracted again with 2 x 25 mL ethyl acetate. The combined organic layers were washed with 25 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a pale yellow oil (500 mg). The product was isolated by chromatography on 40g RediSep Rf Gold column eluting with 35-100% ethyl acetate gradient in hexane at 40 mL/min to afford (2R,4R)-4-(2-((tert-but\ dimethylsilyl)oxy)ethyl)hex-5-ene-2-sulfonamide as a colorless oil (324mg, 1.01 mmol, 60% yield).

STEP 8: (S)-5-((( 1 R,2R)-2-(( 1 S,4R,6R,E)-4-(2-((TERT- BUTYLDIMETHYLSILYL)OXY)ETHYL)- 1 -HYDROXY-6- SULFAMOYLHEPT-2-EN-l -YL)CYCLOBUTYL)METHYL)-6'-CHLORO- 3 ',4,4',5 -TETT AHYDRO-2H,2H-SPIRO [BENZO [b ] [ 1 ,4] OX AZEPINE-3 , 1. '- NAPHTHALENE] -7-CARBOXYLIC ACID

A solution of (2R,4R)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)hex-5-ene- 2-sulfonamide (0.32 g, 0,995 mmol) and (S)-6*-chloro-5-(((lR,2R)-2-((S)-l -

spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (0.14 g, 0.299 mmol, Intermediate AA1 1A ) dissolved in 1 ,2-dichloroethane (3 mL) was degassed by sparging a stream of argon through the solution at room temperature for ten minutes. To the solution was added solid Hoveyda-Grubbs catalyst 2nd generation (0.019 g, 0.030 mmol) all at once. The reaction was stirred at room temperature for 30 minutes after which time LCMS indicated no starting material remained. Air was sparged through the reaction for ten minutes at room temperature and the reaction was stirred open to air for two hours before concentrating under reduced pressure. The product was isolated by

chromatography on 24g RediSep Rf Gold column eluting with 35% acetone in hexane at 30 mL/mm to afford (S)-5-(((lR,2R)-2-((lS,4R )R;E)-4-(2-((tert- butyldimethylsilyl)oxy)ethyl)-l-hydrox>'-6-sulfamoylhept- 2-en-l- yl)c\xlobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthaler)e]-7-carboxylic acid as a colorless film (40mg, 0.053 mmol . 18% yield),

STEP 9: ( 1 S,3'R,6'R,7'S,8'E,10'R, 12'R)-6-CHLORO- 10"-(2-((DTMETHYL(2- METHYL-2-PROPA>n^L)SILYL)OXY)ETHYL)-7 ^, -HYDROXY-12'-METHYL- 3 ,4-DIHYDRO-2H, 15 ^! H-SPlRO [NAPHTHALENE- 1 ,22'- [ 20 |OXA[ 1 ΓΠ 1 , 14]DI AZ ATETRAC YCLO- [14.7.2.0 ⁵ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13', 13'- DIOXIDE

To a solution of 4-(dimethylamino)pyridine (0,022 g, 0.179 mmol) and (S)-5-(((lR,2R)-2-((l S,4R,6R,E)-4-(2-(^

hydrox\'-6-sulfarno} ⁷ lhept-2-en-l-yl)cyclobutyl)methyl)-6'-chloro-3',4,4',5 - tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyli c acid (0.08 g, 0.105 mmol) dissolved in DCM (52.5 niL) cooled by an ice bath was added solid l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.040 g, 0.210 mmol) all at once. The reaction slowly equilibrated to room temperature and was stirred overnight. After 20 hours the reaction was concentrated under reduced pressure and the concentrate partitioned between 25 niL each DCM and 0.1N aqueous citric acid solution. The aqueous separation was extracted again with DCM (2 x 15 mL), The combined organic extracts were washed with 2 x 15 mL water then 15 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film. The product was isolated by chromatography on 24g RediSep Rf Gold column eluting with 30% acetone in hexane at 40 mL/rnin to afford

(lS,3 ^, R,6 ^, R,7 ^, S,8¾ 0 ^, R,12 ^, R)-6-cWoro-10 ^, -(2-(((iimetfayl(2-methyl-2- propany sily^oxj ethy -T'-hydroxy-^'-meth l-S^-dihydro^H _j l S'H- spiro [naphtha] ene- 1 ,22'-

[20]oxa[l 3]thia[l, 14]diazatetra yclo[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]pentacosa- [8,16, 18,24]tetraen]-15'-one 13',13'-dioxide as a colorless film (55mg, 0.074 mmol, 70% yield).

STEP 10: (1 S,3'R,6'R,7'S,8¾,10¾,121 )~6"CHLORO-10 ^! ~(2"((D1METHYL(2- METHYL-2-PROPANYL)SILYL)OXY)ETI-r ^;" L)-7'-METH()XY-12 ^! -METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO-

|;14.7.2.0 ³ - ⁶ .() ^!9 ' ²⁴ 1PENTACOSA|;8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE

To a room temperature solution of ilS,3'R,6'R,7'S,8¾, 10'R,12'R)-6- chloro-l0'-(2-((dime1hyl(2-methyl-2-pro

methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- i;20]oxa[ 13]thia[l ,14]diazatetracyclo| 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa- [8,16, I 8,24]tetraen]-15'-one 13',13'-dioxide (0.04 g, 0,054 mmol) dissolved in THF (2.5 mL) was added sodium hydride, 60% dispersion in mineral oil (5.66 μί, 0.269 mmol) all at once. The mixture was stirred at room temperature for 30 minutes before neat iodomethane (0.017 mL, 0.269 mmol) was added all at once. The reaction mixture was stirred at room temperature for three hours, after which time TLC indicated no starting material remained and 10 mL saturated aqueous ammonium chloride solution was added followed by 10 mL water. The aqueous mixture was extracted with 2 x 25 mL ethyl acetate. The combined organic extracts were washed with 20 mL water then 20 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film (48 mg). The product was isolated by chromatography on 24 g RediSep Rf Gold column eluting with 25% ethyl acetate in hexane at 30 ml/min to afford (lS,3'R,6'R,7'S,8'E, 10'R,12'R)-6-chloro-10'-(2-((dimethyl(2- methyl-2-propanyl)silyl)oxy)ethyl)-7'-m

spiro [naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide as a colorless film (19 mg, 0.025 mmol, 47% yield).

STEP 1 1 : (l S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-CHLORO-10'-(2- HYDROXYETHYL)-7'-METHOXY- 12'-NffiTHYL-3.4-DIHYDRO-2H ₅ 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2( >X A | i ? I U Π Λ | ί i J l i^f AZ.Vf l : E R AC VCE C)l i J 7.2 0 ^{' !'} .ϋ ' " ^{! |} | Pi - N i ACOS A [8,16,18,24]TETRAEN]-15'-QNE 13 ',13 '-DIOXIDE

To a room temperature solution of (lS,3'R,6'R,7'S,8'E, 10'R,12'R)-6- chloro-10'-(2-((dimethyl(2-methyl-2-propanyl)silyl)oxy)ethyl )-7'-meth methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- i;20]oxa[ 13]thia|;i ,14]diazatetracycio| 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa- [8,16, 18,24]tetraen]-15'-one 13',13'-dioxide (0.017 g, 0,022 mmol) dissolved in THF (2 mL) was added tetrabutylammonium fluoride, 1.0 M in tetrahydrofuran (0.224 mL, 0.224 mmol) all at once. The reaction was stirred at room temperature for 4.5 hours then partitioned between 20 mL each ethyl acetate and 1 : 1 saturated aqueous ammonium chloride solution: water. The organic layer was washed with 3 x 10 mi, water followed by 10 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film. The product was isolated by chromatography on 12g RediSep Rf Gold column eluting with 10-25% acetone in dichloromethane at 30 ml/min to afford (1 S,3'R,6'R,7'S,8Ti,l Q'R,I2'R)~6~chloro-l 0 ^, -(2-hydroxyethyl)-7'-methoxy- 12-methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22 ^! - [20] oxa! 13 ] thia[ 1 , 14] diazatetracy cio [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ² ] - pentacosa8,16,18,24]tetraen]-15'-one 13',13'-dioxide as a colorless film (1 lmg, 0,017 mrnol, 76% yield). ¾ NMR (400 MHz, CDCb) δ ppm 8.93 (br. s., 1 H), 7.63 (d, ./ 8,4 ί Hz, 1 H), 7.19 (s, 1 H), 7.10 (dd, ./ 8. 1.2.05 Hz, 1 H), 7.01 (d, ./ 2.1 Hz, 1 !!}.6.80 - 6.96 (m, 2 !!}.6.74 (s, 1 H), 5.71 (dd, ./ 15.45.6.85 Hz, 1 III 5.42 (dd, 15.55.7.14 Hz, 1 H), 4.25 (br, s., ! H), 3.92 - 4. 1 (m, 2 H), 3.48 - 3.83 (m, 5 H), 3.22 (s, 3 H), 3.10 (d, .7=14.09 Hz, 1 H), 2.95 (dd, J=15.16, 8,71 Hz, 1 H), 2.60 - 2.80 (m, 2 H), 2.36 - 2.56 (m, 2 H), 2.13 - 2.28 (m, 2 H), 1.80 ·· 2.02 (m, 3 H), 1.28 - 1.79 (m, 11 H), m/z (ESI, +ve ion) 642.8 (M+H) ⁺ .

EXAMPLE 203. ((18,3¾,6 ^! ί ,7'8,8Έ,10Ί ,Ι2¾)-6-€ΗΕΟ1Ο-7'-ΜΕΊΉΟΧΥ- 12 ^* -METHYL-13', 13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( !ί>ΧΛ| i 3! ! Π!Λ| ί ! 1 |ί^!ΛΖΛ ί : ί AC YC i (>! i -17.2 (Γ·''. ( ⁾ '"··'' |Pi-N i ACOSA

[8, 16, 18,24]TETRAEN] - 10'-YL)ACETONITRILE

STEP 1: ((lS,3'R,6'R,7'S,8'E,I0'R,I2'R)-6-CHLORO-7'-METHOXY-12'- METHYL- 13 ', 13 '-DIOXJDO- 15'-OXO-3,4-DIHYDRO-2H- SPIRO[N APHTHALENE-1 ,22'-

[20]OXA[13]THIA[l,14]DIAZAraTRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA

[8, 16, 8,24]TETRAEN| - ! O'-YL) ACET ALDEHYDE

To a mixture of sodium bicarbonate (2.178 μΙ_, 0.056 mmol) and

(l S,3¾,6¾,7'S,8¾ 10¾, 12'R)-6-chlore^^^

methyl-3,4-dihydro-2H, 15'H-spiro[naphthalene- l ,22'- [20]oxa[13]thia[ l, 14]diazatetracyxio[l^ _^

n]-15'-one 13', 13'-dioxide (0.0072 g, 0.01 1 mmol, Example 202) in wet DCM (1.5 mL) cooled by an ice bath was added solid dess-martin periodinane (5.70 mg, 0.013 mmol) all at once. The rection mixture was stirred at 0-5 °C for ten minutes after which time TLC and LCMS indicated only starting material present. The reaction was equilibrated to room temperature and stirred for 90 minutes, after which time TLC indicated mostly starting material with a faint, less polar spot. An additional 1 equivalent of DM periodinane was added and stirring continued at room temperature. After 3.5 hours mostly starting material with a single less polar spot by TLC. An additional equivalent of DM periodinane was added (total = 3.2 equivalents) and stirring at room temperature continued. After 6.5 hours total time TLC and LCMS indicated no starting material remained and a single peak with mass corresponding to desired product predominated. To the reaction mixture was added 3 mL saturated aqueous bicarb solution, 3 mL saturated aqueous sodium thiosulfate solution and 3 mL DCM. This biphasic mixture was stirred rapidly for 30 minutes, after which time the phases were clear. The layers were separated and the aqueous layer extracted again with 2 x 10 mL DCM. The combined organic layers were washed with 10 mL bicarbonate solution then stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film (7.3 mg). The product was isolated by chromatography on 4g RediSep Rf Gold column eluting (manually) with 30% acetone in hexane in 5 ml volumes (by syringe) to afford ((1 S,3'R,6'R,7'S,8'E, 10'RJ 2'Κ)-6-οΐΊίθΓθ-7'-Γηε4οχγ- ! 2'-ιη6 1-13', 13'-dioxido-

15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[l ,14]cUazatetracyclon^^

n]-10'-yl)acetaldehyde as a coloriess film (7.2 mg, 0.011 mmol, 100%).

STEP 2: ((1 S,3'R,6'R,7 ^, S,8'E,10'R,12 ^, R)~6"CHLORO-7 ^, ~METHOXY-12'- METHYL - 13 ', 13 '-D I GXIDO- 15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24] TETRAEN j - 1 O'-yl) ACETONITRILE

A mixture of ((lS,3 ^, R ₅ 6 ^, R,7 ^, S,8Έ 0 ^, R,^ 2 ^, R)-6-chloΓO-7 ^, -me1hox -12 ^, - methyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthal ene-l,22'- [20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-l( ⁾ '-yi)acetaldehyde (4.9 mg, 7.64 μηιοΐ) and hydroxy I amine hydrochloride (1,590 μΕ, 0.038 mmol) in MeCN (0,8 mL) was heated for 20 minutes at 100 °C in a microwave reactor, after which time TLC and LCMS indicated no starting aldehyde remained and a single peak with mass corresponding to intermediate oxime predominated. The reaction mixture was partitioned between 10 mL each ethyl acetate and 2M aqueous sodium carbonate solution. The aqueous separation was extracted again with 2 x 10 mL ethyl acetate. The combined organic layers were washed with 10 mL brine and the brine back-extracted with 10 ml ethyl acetate. All combined organic layers were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film (5 mg). To a solution of triphenylphosphine oxide (3.71 μΐ,, 0.016 mmol) dissolved in CHCb (0.5 mL) at room temperature was added oxalyl chloride, 2.0 M solution in dichloromethane (4.97 μ1_,, 9.93 μηιοΐ) all at once. The resulting solution was stirred at ambient temperature for 5 minutes before a solution of the oxime in CHCb (0.5 mL) was added all at once. After 5 minutes TLC and LCMS indicated no starting material remained and a single less polar spot predominated with mass corresponding to desired nitrile. The reaction was stirred at room temperature for 60 minutes then concentrated under reduced pressure. The product was isolated by chromatography on 4g RediSep Rf Gold column eluting wtth 50% ethyl acetate in hexane + 1% acetic acid in 5 ml volumes (manually, by syringe) to afford ((1 S,3'R,6'R,7'S,8'E,I0'R, 12'R)-6- chloro~7 ^! ~methoxy-12'-niethyl-l 3',13 ^! ~dioxido~l 5 ^! -oxo-3,4~dihydro-2H- spiro [naphthalene- 1 ,22'-

[20ioxa| 13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ^{! 9} ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-10'-yl)acetonitrile as a colorless film (3.2mg, 0.005 mmol, 66% yield). ^* 'H N.V1R (400 MHz, CDCb) δ ppm 8.28 (br. s., 1 H), 7.62 (d, ./ 8. 1 Hz, 1 H), 7.10 (dd, ./ 8.5 ! . 2.25 Hz, 1 ! ! }. 7.01 (d, ,/ 2. 1 5 Hz, 1 H), 6.88 (s, 2 H), 6.72 (s, 1 H), 5.74 (dd, ,/ 15 65. 6.06 Hz, ! H), 5.57 (dd, ,/ 15.75. 6.75 Hz, 1 H), 4,28 (t, J=6.65 Hz, 1 H), 3.94 - 4.1 1 (m, 2 H), 3.56 - 3,79 (m, 3 H), 3.20 - 3,30 (m, 3 H), 3.1 1 (d, J=14.08 Hz, 1 H), 2.97 (dd, J=15.06, 9.00 Hz, 1 H), 2.58 - 2.80 (m, 3 H), 2.41 - 2.54 (m, 1 ! ! }. 2.39 id. ./ 6.85 Hz, 2 H), 2.21 - 2.32 (m, 1 H), 2.07 - 2.20 (m, 1 H), 1 ,79 - 2.03 (m, 4 H), 1 ,59 - 1.78 (m, 4 H), 1 ,43 - 1.59 (m, 3 H), 1,30 - 1.42 (m, 1 H);

m (ESI, +ve ion) 637.9 (M+H) ⁺ .

EXAMPLE 204. (l S,3'R,6 ^! R,7'S,8 ^! E,U ^)! R,12'R)-6-CHLORO-7'-METHOXY-10'- (2-METHOXYETHYL) - 12'-METHYL-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24] TETRAE - 15 '-ONE 1 3 . 13 ^' -DIOXIDE

To a solution of (lS,3 ^! R,6'R,7'S,8'E,10'R,12'R)-6-chloro-10'-(2- hydroxy ethyr)-7'-methoxy-12'-methy]-3,4-dihydro-2H,15'H-spiro[napht haIer! Y ^

[20]oxa[13]thia[l,14]diazateti^^

nj-15'-one 13',13'-dioxide (0.005 g, 7.77 μηιοΐ, Example 202) dissolved in THF (1.8 mL) at room temperature was added sodium hydride, 60% dispersion in mineral oil (6.32 μί.,, 0.300 mmol) all at once. The mixture was stirred at room temperature for 30 minutes before neat iodomethane (0.019 mL, 0.311 mmol) was added all at once. The reaction mixture was stirred at room temperature for 3 hours then 5 mL saturated aqueous ammonium chloride solution was added followed by 5 mL water. The mixture was extracted with 3 x 10 mL ethyl acetate volumes. The combined organic layers were washed with 10 mL brine, stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film (17 mg). The product was isolated by chromatography on 4g RediSep Rf Gold eluting with 25% acetone in hexane in 4 mL volumes, manually by syringe, to afford (18,3¾,6¾,7'8,8Έ,10¾,12¾)-6- chloro-7'-methoxy-l 0'-(2-methoxyethyl)-l 2'-methyl-3,4-dihydro-2H,15'H- spiro[naphthalene-l,22'-

n]-15'-one .13 ',13 '-dioxide as a colorless film (4.8mg, 0.0073 mmol, 94% yield). ¾ NMR (400 MHz, CDCh) δ ppm 8.72 (br. s., I H), 7.62 (d, ,/ 8 61 Hz, 1 H), 7.10 (dd, J=8.41, 2.15 Hz, 1 H), 7.01 (d, J=2.15 Hz, 1 H), 6.81 - 6.95 (m, 2 H), 6.77 (br. s., 1 H), 5.67 (dd, ./ 1 .55. 6.75 Hz, 1 ! ! }. 5.40 (dd, ./ 15.36. 7.53 Hz, 1 H), 4.20 (br. s,, 1 H), 3,93 - 4.12 (m, 2 H), 3,50 - 3,83 (m, 3 H), 3,23 - 3,43 (m, 2 H), 3.21 (s, 3 H), 3.05 - 3.17 (m, 4 H), 2.95 (dd, .7=15,26, 9.00 Hz, 1 H), 2.59 - 2.81 (m, 2 H), 2.45 (d,■/ 4. 1 1 Hz, 2 H), 2.16 (ddd, ./ 14.97. 8.51, 3.52 Hz, 2 H), 1 .80 - 1.99 ins. 3 H), 1.40 - 1.78 (m, 10 1 1 ). 1 .29 - 1.40 (ra, 1 1 1 ): m/z (ESI, +ve ion) 657.3 (M+H) ⁺ .

EXAMPLE 205. (lS,3'R,6 ^! R,7 ^, S,8 ^! E, 10 ^! R,12 ^, R)-6-CHLORO-10'-((2S)-2- HYDROXYPROPYL)-7'-METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15 ^f H- SPIRO [NAPHTHALENE- 1 ,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13' -DIOXIDE and

(18,3¾,6 ^, Κ,7 ,8Έ,10Έ, 12 ^! Κ)-6-εΐ1ΕΟΚΟ-1()'-((2Κ)-2 ΓΥθΜ)ΧΥΡΜ)ΡΥΕ)-7'- METHOXY- 12'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTH ALENE- 1.22'-! 201 OXA[ 13]THI A[ 1 , 14]DIAZATETRACYCLO-

[14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]ΡΕΝΤΑεθ8Α[8,16,18,24]ΤΕΤΚΑΕΝ]-15'-ΟΝ Ε 13',13'- DIOXIDE

To a solution of ((1 S,3'R,6 ^! R,7'S,8 ^! E, 10'R, 12'R)-6-chloro-7'-meihoxy- 12'- methyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro|naphthal ene-l ,22'- [20] oxa[ 13] thi a[ 1 , 14] diazatetracy clo-

[M ^.O^^O^^lpentacosatS^e.l S^ltetraenl-lO'-y acetaldehyde (0.0065 g, 10.14 μηιοΐ, Example 203, Step 1) dissolved in THF (2 mL) was added methylmagnesium bromide 3.0 M in diethyl ether (0.017 mL, 0.051 mmol) all at once. The reaction solution was stirred at room temperature for 5 minutes after which time LCMS indicated no starting material remained and a single peak with mass corresponding to desired product predominated. To the reaction mixture was added 5 mL each saturated aqueous ammonium chloride solution and water. The aqueous layer was extracted with 3 x 15 mL volumes ethyl acetate. The combined organic layers were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film (9.6 mg). The products were isolated by chromatography on 4g RediSep Rf Gold column eluting manually with 10 to 20% acetone in DCM to afford a mixture of (lS,3 ^, R,6 ^, R,7 ^, S _s 8¾10 ^, R,12 ^, R)-6-<^oro-10 ^, (2S)-2½droxypropyl)-7 ^, -methoxy- 12'-methyl-3,4-dihydro-2H, 15'H-spiro[naphtha]ene-l ,22'- |20jo\aj I |ihi«i| i J4|dia/aicua > ciol I4.7 .(! ^; '\( ^)1'i jpen!acosa|K.16.18.24 jieirae n]-15'-one 1 ^" .13 ^' -dioxide and (Ιβ^'Κ,ό'ΙΙ,Τ'β,δΈ,ΙΟ'Κ,Ι^-ό-οΜθΓθ-ΙΟ' -^Κ)- 2-1ιν(ΐΓθχ'ρΓορ} ⁷ 1)-7'-ηΐ6ΐηοχ5 ⁷ -12'-η6ΰι>Ί-3,4-(ϋ1ΐ}'(ΐΓθ-2Η,15Ή- spiro [naph thalene- 1 ,22'- 8.24i!cirac n]-15'-one 13 ^* ,13 '-dioxide as a colorless film(5.1mg, 0.0078 mmol, 77% yield). ^] H NMR (500 MHz, CDCb) δ ppm 7.64 (m, 2 H), 7.10 (m, 2 H), 7.01 (m, 2 H), 6,68 - 6.94 (m, 6 H), 5,82 (d, ./ ! 1.74 Hz, 1 !!}.5.59 (dd, ,/ 1528.7.46 Hz, 1 H),

5.33 - 5.50 (m, 2 H), 4.29 (br. s., 1 H), 4.10 - 4.22 (m, 1 H), 3.94 - 4.10 (m, 4 H), 3.87 (br. s., 1 H), 3.55 - 3.80 (m, 8 H), 3.22 (m, 6 H), 3.05 - 3.15 (m, 2 H), 2.86 -

3.03 (m, 2 H), 2.62 - 2.79 (m, 4 H), 2.56 (br, s., 2 H), 2,38 - 2.49 (m, 2 H), 2,03 -

2.34 (m, 5 H), 1.80 - 2.01 (m, 7 H), 1.67 - 1.79 (m, 5 H), 1.45 - 1.67 (m, 12 H), 1.27 - 1.45 (m, 2 H), 1.13 - 1.26 (m, 4 H), 1.05 - 1.12 (m, 6 H); m'z (ESI, +ve ion) 657.3 (VI II) .

EXAMPLE 206, ((1S,3 ^! R,6'S,7'E,9'R,1 l'S,12'R)-6-CHLORO-l l',12'- DlMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1.22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]- PENTACOSA[7,16,18,24]TETRAEN]-9'-YL)ACE ^' nC ACID or

((lS,3'R,6 ^! S,7¾,9'S,irS,121)-6-CHLORO-llV12'-DIMETHYL-13',13'- DIOXIDO-lS'-OXO-S^-DIHYDRO^-SPIROINAPHTHALENE-l^^- [20] OX A [13] ΤΗΐ A [ ! , ! 4] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] - PENTACOSA[7,16,18,24]TETiL EN]-9'-YL)ACETlC ACID

STEP 1 : (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-i r,12'-DIMETHYL-13',l

DIOXTDO-15'-OXO-3,4-DmYDRO-2H-SPIRO| SiAPHTHALENE-l ,22'-

[20]OXA[13]THIA[1,14]DIAZATERACYCLO-

[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-7'-YL ACETATE

To a mixture of ( S ^! R )¾,7'S,8T i rS,12'R)-6~chloro-7 ^! -lwdroxy- 11 12'-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[ 13]thia|T ,14]diazatetracyclo- [14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, 16,l 8,24]tetraen]-15'-one 13\13'-dioxide (0.05 g, 0.083 mmol, Example 719, Step 2), 4-dimethylaminopyridine (1.019 mg, 8.34 μηιοΐ) and triethylamine (0.041 mL, 0.292 mmol) in DCM (0.417 mL) at room temperature was added neat acetic anhydride (0.024 mL, 0.250 mmol) all at once. The reaction was stirred at room temperature for two hours then partitioned between 20 mL each DCM and water. The aqueous separation was extracted again with 20 mL DCM. The combined organic extracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film. The product was isolated by chromatography on 12g RediSep Rf Gold column eluting with 25% acetone in hexane at 30 mL/min to afford (lS,3 ^, RXVR,7 ^, S,8 ^! E,i rS,12'R)-6-chloro-i r,12'-dimethyl-13',13 ^! " dioxido- 15'-oxo-3,4-dihy dro-2H-spiro| naphthalene- 1,22'- [20] oxa[ 131 thi a[ 1 , 14] diazatetracy clo- [14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16,18,24]tetraen]-7'-yl acetate as a colorless film (47 mg, 0.073 mrnol, 88% yield).

STEP 2: ίί j S.3'R.6'S.7T.v R. i ! 'S. ! ?: H)-CH f()RO- ! i '. l 2'-!)! ΜΙ·: 1 HY l .- i .T. l .T- DIOXHX ⁾ - 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALE E- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]-

PENTACOSA[7,16J 8,24]TETRAEN]-9'-YL)ACETIC ACID or

((l S,31 ,6 ^, S,7U9'S rSa2'R)-6-CHLORO-l l 2'-DlMETHYL-13',13'- DIOXID()-15 ^, -()XO-3,4-DIHYDR()-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]- PENTACOS A[7J 6;i 8,24]TETRAEN]-9'-YL)ACETIC ACID

To a solution of (lS,3 ^, R,6 ^, R,7 ^, S _s 8 ^, E _s l l ^, S,12 ^, R)-6-chloro-i r,12 ^, -dimethyl- 13',13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[ I 3]thia[ 1, 14]diazatetracyclo-

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-7 ^, -yl acetate (0.045 g, 0.070 mrnol) and tert-butyl(chloro)dimethylsilane (0.053 g, 0.351 mrnol) dissolved in THF (2 mL) cooled by an acetone-dry ice bath was added a 1M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (0.21 1 mL, 0.21 1 mrnol) all at once. The reaction was left stirring at -78 °C for 3 hours then the cold bath was removed and the reaction equilibrated to room temperature over 30 minutes. The reaction was stirred at room temperature for 2 hours then partitioned between 20 mL each saturated aqueous ammonium chloride and ethyl acetate. The aqueous separation was extracted again with 20 mL ethyl acetate. The combined organic extracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film (49 mg). The crude product was dissolved in 2 mL methanol and 2 mL THF and a solution of 50 mg LiOH dissolved in 500 fiL water was added all at once at room temperature. After 30 minutes the reaction was concentrated under reduced pressure. The

concentrate was partitioned between 10 mL each IN aqueous hydrochloric acid and ethyl acetate. The aqueous separation was extracted twice again with 10 mL ethyl acetate. The combined organic extracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless film. The product was isolated by chromatography on 4g RediSep Rf Gold column eluting with 30% acetone in hexane at 18 mL/min to afford ίί I S.3'R.6'S.7 .v ^' R. i i'S.l 2 ^' R)-6-chiom- i ! '.12 ^' ~dime!hv!~ 1 '.1 ?-dioxido- 15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l ,22'-

[20] oxa[ 13] thi a| 1 , 14] di azatetracy ci o [14,7.2, 0 ³ · ⁶ .0 ^|9 · ²⁴ ] - pentacosa[7,16,18,24]tetraen]~9 ^! ~yl)acetic acid or ((1S,3'R,6'S,7 ^! E,9 ^! S,1 l'S,12*R)~ 6-chloro- H',1 ^-dimethyl- 13', 13'-dioxido- 15'-oxo-3,4-dihy dro-2H- spiro[naphthalene- 1 ,22'-| 20] oxa[ 13]thia- [lJ4]diazatetracyclo[14.7.2,0 ³ -^0 ^!9 - ²⁴ ]pentacosa[7,16,18,24

acid as a colorless film (20 mg, 0.031 mmol, 44% yield). ¾ N.V1R (400 MHz, CDCI3) δ ppm 8.19 (br. s., 1 H), 7.49 (d, ,/ 8.6! Hz, 1 H), 6.95 (dd, ,/ 8.5!.2.25 Hz, I H), 6.87 id. J=2.15 Hz, 1 H), 6.77 - 6.85 (ra, 2 H), 6.67 - 6.77 (ra, 1 H), 5.68 (dd, .7=15.45, 4.89 Hz, I H), 5.06 (dd, J=I5,06, 7,04 Hz, 1 H), 4.05 (d, .7=6.85 Hz, 1 H), 3.85 - 3.94 (m, 2 H), 3.62 (d, J=15.26 Hz, 1 H), 3.42 (d, J=14.09 Hz, 1 H), 2.97 (d, ./ 14.09 Hz, 1 H), 2.82 (dd, ,7=15.45, 8.41 Hz, 1 H), 2.49 - 2.63 (m, 2 H), 2,39 - 2.49 {Ml.1 H), 2,26 - 2.39 (m, 1 H), 2,13 - 2.24 (m, 1 II).2,06 (dd../ 15.94. 9,29 Hz, 2 H), 1.64 - 1.91 (m, 5 H), 1.46 - 1.64 (m, 2 H), 1.16 - 1.46 (m, 6 H), 1.00 - 1.14 (m, 2 II).0.77 (d, ,7=7.04 Hz, 3 H); mlz (ESI, +ve ion) 641.2 ( +H) ⁺ .

EXAMPLE 207. ((1 S,3'R,6'R,9'R,1 l'S,i2'R.)-6-CHLORO-ir,r2'-DIMETHYL- 13Vi3'~DIOXiDO~i5'~OXQ-3,4~DIHTm

|20jOXA| 1 ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 ".0 ^|u |P1 ^: N I ^' ACOSA [16,18,24]TRIEN]-9'-YL)ACETIC ACID or ((lS,3'R,6 ^f R,9'S,irS,12'R)-6- ( HI. ORG- 1 Γ, 12' -DIMETHYL- 13', 13 ^! -DIOXIDO- 15 ^! -OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-9'-YL)ACETIC ACID

Hydrogen gas was introduced by balloon to a mixture of

((Ι β,Β'Κ,ό'β,ΤΈ^ΊΙ,Ι Ι ,Ι^-ό-οΜθΓθ-Ι Ι^Π'-ά^ΛνΙ-ΙΒ^ '-άιοχ ο-^'-οχο^

3,4-dihydro-2H-spiroj naphthalene- 1,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]- pentacosa[7,16,18,24]tetraenh9'-yl)acetic acid or ((1 S,3'R,6'S,7'E,9'S,11'S,12'R)- 6-chloro- 1 1 ', 12'-dimethyl- 13', 13 '-dioxi do- 15 '-oxo-3 ,4-dihy dro-2H- spiro [naph thalene- 1 ,22'- [20 j oxa[ 13] thia-

[1, 14]diazatetracyclo[ 14.7.2,0 ³ ^0 ¹⁹ - ²⁴ ]pentacosa[7,l 6, 18,24]tetraen]-9'-yl)acetic acid (0.0067 g, 10.45 μηιοΐ, Example 206) and platinum (iv) oxide (4.75 mg, 0.021 mmol) in EtOAc (2 mL) at room temperature. The mixture was stirred at room temperature for 2 hours then filtered through a pad of celite, rinsing with ethyl acetate. The filtrate was concentrated under reduced pressure to afford ((18,3Ί ,6¾,9'ί ,11 ^* 8,12 ^! ί )-6-ΰωοΓ^^^ ^

dihydro-2H-spiro[naphtha]ene-l,22'-[20]oxa[13]tWa[l,14]di azatetracyclo- [14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa[16, 18,24]trien]-9'-yl)acetic acid or

((lS,3'R,6 ^! R,9'S,i rS,12'R)-6-chioro-i r,12'-dimethyi-13',13'-dioxido-15'-oxo-3,4- dihy dro-2H-spiro [naphthalene- 1 ,22'- [20 j oxa[ 13] thia[ 1,14] diazatetracy clo- [14.7.2.0 ³ ' ⁶ .0 ^l9 ' ² ]pentacosa[16,18,24]tTien]-9'-y])acetic acid as a colorless film (5.8 mg, 0.009 mmol, 86% yield). ¾ NMR (400 MHz, CDCb) δ ppm 8.18 (br. s., 1 ! ! }. 7.64 id. 8.61 Hz, 1 H), 7.10 (dd, J=8.41, 2.15 Hz, 1 H), 7.01 (d, J==1.57 Hz, 2 H), 6.82 - 6.97 (m, 2 H), 4.13 - 4.28 (m, 1 H), 3.96 - 4.11 (m, 2 H), 3.69 (d, J=15.26 Hz, 1 H), 3.59 (d, J=14.28 Hz, 1 H), 3.12 (d, =14.28 Hz, 1 H), 2.91 (dd, ./ 1 5.36. 8.31 Hz, 1 H), 2.61 - 2.77 (m, 2 H), 2.48 (dd, ./ 15.85. 2.74 Hz, 1 H), 2.14 - 2.35 (ra, 2 H), 1 .90 - 2.07 (m, 5 H), 1 .78 - 1.89 (ra, 3 H), 1.28 - 1.77 (ra, 11 H), 0.96 - i l l (m, 2 H), 0.91 (d, .7=6,85 Hz, 3 H); m/'z (ESI, +ve ion) 643.2

(M+H) ⁺ .

EXAMPLE 208, (l S,3'R ₅ 6 ^, R,7 ^, R,8 ^, E ₅ H ^, S,12 ^, R)-6-CHLORO-7 ^, -HYDROXY- i i \ ! 2'-Di YiLT! iY i - .4-Γ)! ΗΥ ΡΗ ⁽ )-2Ι 1. i V| !-SP!ROi \ ΛΡί Π H \i j ^' M - l 22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

STEP 1 : (S)-METHYL 6 ^, -CHLORO-5-(((lR,2R)-2-((R ₅ E)-l-HYDROXYHEX-2-

EN-l-YL)CYCLOBUT X)METHYL)-3 ^f ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7~

C ARB OXYL ATE

To borane dimethyl sulfide (0.522 mL, 5.51 mmol) in hexane (6 mL) under argon at 0 °C was added cyclohexene (1.116 mL, 1 1.01 mmol). After 3 h stirring at rt, pent-l-yne (0.543 mL, 5.51 mmol, Aldrich) was added and the reactio was allowed to warm up to rt for 30 min (during this period of time the cloudy mixture became a clear solution, and a slightly exothermal reaction occured). The reaction was cooled to -78 °C and treated with diethylzinc (1 M in hexanes, 5.51 mL, 5.51 mmol, Aldrich). The solution was warmed to 0 °C for ~3 min. then it was cooled back to -78 °C.

Separately, Intermediate ΑΑΓ1Α, Step 20A (500 mg, 1.10 mmol), and

(lR,2S,3S,4S)-l,7,7-trimethyl~3"morphoimobicycio[2.2. l]heptan-2-ol (52.7 mg, 0.220 mmol, Aldrich) were combined in hexane (6 mL) at 0 °C under argon. To this solution was added 8.4 mL of the prepared zinc reagent via syringe. After 50 minutes, the solution was warmed to rt for 10 minutes. The reaction was quenched with 20 mL sat. NftCl, diluted with 200 mL of EtOAc, and stirred at rt for -15 minutes to afford two clear and colorless layers. The layers were separated and the aqueous layer was extracted with ether. The combined ether layers were washed with brine, dried over MgSCK filtered, and concentrated to a pale yellow oil. The oil was deposited on 2.5 g silica gel and purified using an 80 g RediSep gold column eluted with 0 to 40% EtOAc:Hexanes to give (S)-methyl 6'-chloro-5- (((1R,2R)-2~((R,E)~1^

tetrahy dro-2H,2'H-spiro| benzoj b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (316 mg, 0.603 mmol, 27.4 % yield), miz (ESI, +ve ion) 524.2 ( M I I ) . STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((R,E)-l-HYDROXYHEX-2-EN-l- YL)CYCLOBUT L)METHYL)-3'.4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

(S)-methy 1 6'-chloro-5 -iii l R,2R)-2~((R,E)~ 1 -I droxyhex-2-en- 1 - icyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[ b][l,4]oxazepine- 3,1 '-naphthalene]-7-carboxylate (2, 10 g, 4,01 mmol) was dissolved in a 2: 1 mixture of MeOH (53.4 mL) and THF (26.7 mL), then lithium hydroxide (2 M; 20.03 mL, 40.1 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was partitioned between IN HC1 soln (-50 ml.) and EtOAc (3 x 150 mL). The combined organic layers were then washed with brine (1 x 25 mL) and dried over magnesium sulfate. The filtrate was concentrated to give (S)-6'-chloro-5- (((lR,2R)-2-((R,E)-l-h droxyhex-2-en-l-yl)(yclobutyl)melhyl)-3 4,4 5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (1.79 g, 3.51 mmol, 88 % yield), m/z (ESI, +ve ion) 510.2 (M+H) ⁺ .

STEP 3 : (S)-6'-CHLORO-5-((( 1 R,2R)-2-((R,E)- 1 -HYDROXYHEX-2

YL)CYCLOBUTYL)METHYL)-N-(((2R,3S)-3-METHYLHEX-5-EN

YL)SULFONYL 3 ^* ,4,4',5-TETRAHYDRO-2H,2TI-

SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

CARBOXAMIDE

4-Dimethyiaminopyridine (DMAP) (0.305 g, 2.500 mmol) was added to a solution of (S)-6'-chloro-5-((( 1 R,2R)-2-((R,E)- 1 -hy droxyhex-2-en- 1 - yl)cyclobu d)methyl)-3 4,4\5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxylic acid (0.75 g, 1.470 mmol) and (2R,3S)-3- methylhex-5-ene-2-sulfonamide (0.521 g, 2.94 mmol, Intermediate EE22) in dichioromethane (37 mL) cooled to 0 °C. EDC hydrochloride (EDC) (0.564 g, 2.94 mmol) was then added slowly. The mixture was stirred while allowing to reach rt overnight. The mixture was then washed with IN HC1 and brine and the aqueous layer was back-extracted with EtOAc. The combined organics were dried over MgS04, filtered and concentrated. The yellow oily residue was then purified by medium pressure chromatography (silica, 5 to 50% EtOAc (+0.3%

HGAc):Hexanes) to give (S)-6'-chloro-5-(((lR,2R)-2-((R,E)-l -hydroxyhex-2-en- l -yl)cyclobutyl)me l)-N-(((2R,3S^

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxamide (0.320 g, 0.478 mmol, 32.5 % yield), m/z (ESI, +ve ion) 669.3 (M+H) ⁺ .

STEP 4: ( 1 S,3'R,6'R,7'R,8'E, 1 1 ^f S, 12'R)-6-CHLORO-7 ^* -HYDROXY- 1 1 ', 12'- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13 ^* -DIOXIDE

(S)-6'-chloro-5-((( 1 R,2R)-2-((R,E)- 1 -hy droxyhex-2-en- 1 - yl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulf onyl)-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide (320 rng, 0.478 ramol) was weighed out into a 250 mL RB flask and purged with argon. 1,2-dichloroethane (255 mL) was added via cannula followed by the addition of (1 ,3-dimesityiimidazoiidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium(VI) chloride (Grubbs-Hoveyda Catalyst, 2nd Generation, Aldrich) (30.0 mg, 0.048 mmol) as a solid. The reaction mixture was heated to 80 °C and after 2 h, it was cooled to it. 2-(2-(vinyloxy)ethoxy)ethanol (0.026 mL, 0.191 mmol, Aldrich) was added and the resulting mixture was stirred for 20 min at rt and concentrated at 40 °C under vacuum. The crude product was purified by silica gel chromatography (40% to 90% EtOAc

(+0.3%HOAc):Hexanes) to give (l S,3'R,6'R,7'R,8'E,irS,12'R)-6-chloro-7'- hydroxy-ir,12'-dimethyl-3,4-dihydro-2h, 15'h-spiro[naphthalene-l,22'- [20]oxa[13]thia[l ,14]diazate1ra^^

n]-15'-one 13', 3'-dioxide (37 mg, 0.062 mmol, 12.92 % yield). ¾ NMR (400 MHz, CD3OD) δ 7.75 (d, J 8.6 Hz, 1 H), 7.50 (d, J 2.0 Hz, 1 H), 7.19 (dd, J 8.4. 2,2 Hz, ! H), 7. 14 (dd, .1 8 2. 2,0 Hz, 1 I s ). 7.1 ! (d, J 2.2 Hz, 1 H), 6.93 (d, .1 H 2 Hz, I H), 5.39-5.59 (m, 2 H), 4.08 (s, 2H), 3.88-4.00 (m, 2 H), 3.64-3.74 (m, 2H), 3,30 (d. J 145 Hz, 1 Is).3.04 (dd, J 15.6.5.0 Hz, I !!}.2.70-2,88 (m, 2 H), 2,51- 2.65 (m, 2 lis.2.14-2.28 (m, 1 lis.2.03-2.14 (m, 2 II).1.57-2.00 (m, 7 H), 1.42 (br. s, 1 H), 1.39 (d, j 7.2 Hz, 3 H), 1.32-1.36 (m, 1 H), 1.09 (d, j 6.8 Hz, 3 H). m/z (ESI, +ve ion) 599.2 (W W)

EXAMPLE 209. (1 S^'R^'l^yR^'Ei-e-CHLORO-T'-ETHOXY-S^-DlHYDRO- 2H, 15 Ή - SPIRO |N APHTHAE ENE- 1,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ '«0 ¹⁹ - ²⁴ ]PEOTACOSA

[8, 16, 18,24]TETRAEN] -15'-ONE 13', 13'-D10XlDE

A solution of ally lie alcohol (20 mg, 0.035 mmol, Example 952) in THF (1.00 mL) was cooled to 0 °C. Sodium hydride (60% dispersion) (14.01 mg, 0.350 mmol) was added and the resulting slum- was stirred for 30 minutes, lodoethane (0.014 mL, 0.175 mmol) was then added and the slurry was stirred overnight. The reaction was then acidified by adding IN HCl and this mixture was filtered. The crude material was purified by reverse-phase preparative HPLC using aPhenomenex L na column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 40% to 70%, over 20 mm to provide

(lS,3'R,6'R,7'R,8Ti)-6-chloro-7'-ethoxy-3,4-dihydro-2H,15'H- spiro[naphthalene- 1,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae nj-15'-one 13',13'-dioxide (6 mg, 10.01 μηιοΐ, 28.6 % yield). Ή NMR (40CMHz, CDCb) δ 8.57 (br, s.1 H), 7.72 (d, j H4 Hz, 1 H), 7,32 (d, J 1.8 Hz, 111).7.19 (dd, j 8.5..2.2 Hz, 1 H), 7.09 (d, j 2.2 Hz, 1 H), 7.07 (dd, j 8.1.1.9 Hz, 1 H), 6,95 (d. J 8.0 Hz, i 1 1 ). 5.78 (ill. j ! .\ 7. 5.4 Hz, 1 ! ! }. 5.49 (dd, j 15. 7 Hz, 8.0 Hz, 1 H), 4.06-4.17 (m, 2H), 3.94-4.05 (m, 2H), 3.63-3.78 (m, 3 H), 3.31-3.46 (m, 2 H), 3.19 (d, j 14.3 Hz, 1 H), 2.97 (dd, j 1 5.2. 9.1 Hz, 1 H), 2.68-2.86 (ni 2 H), 2,48-2.63 (m, 1 H), 2,39-2.48 (m, 1 H), 2.29-2.38 (m, 1 H), 2.00-2.13 (m, 3 H), 1.88-1.98 (m, 3 H), 1.77-1.87 (m, 1 H), 1.67-1.77 (m, 1 H), 1.53-1.66 (m, 1 H), 1.41-1.52 (m, 2 H), 0.78-0.97 (m, 5 H). m/z (ESI, +ve ion) 600.2 (M+H) ⁺ .

EXAMPLE 210. (lS,3 ^, R ₅ 6 ^, R,7 ^, R,8 ^, E)-6-CHLORO-7 ^, -(2-METHOXYETHOXY)- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

A solution of ally lie alcohol (20 nig, 0.035 mmol, Example 952) was dissolved in THF (LOO niL) and cooled to 0 °C. Sodium hydride (60% dispersion; 14.01 mg, 0.350 mmol) was added and the resulting slurry was stirred at 0 °C for 30 minutes. 2-bromoethyl methyl ether (0.016 mL, 0.175 mmol) was then added and the mixture was stirred overnight. LCMS indicated the reaction was -35% complete. Two more aliquots of sodium hydride (60% dispersion: 14.01 mg, 0.350 mmol) and 2-bromoethyl methyl ether (0.016 mL, 0.175 mmol) were added and the mixture was stirred for an additional three days at r.t. Another aliquot of each reagent was added and stirred for an addtional 2.5 days until -90% complete. The reaction mixture was then acidified with a few drops of IN HC1 and then diluted with DMSO and filtered. The crude material was purified by reverse- phase preparative HPLC using a Phenomenex Luna column, 5 micron, C8(2), 100 A, 150 x 21.2 mm, 0. 1% TFA in VM S ! ! ₂ 0. gradient 45% to 75% over 20 mm to provide (1 S,3 ^, R,6'R,7 ^, R,8 ^, E)-6-cMoro-7'-(2-methoxyelhoxy)-3,4-dihydro-

2H, 15'H-spiro[naphthalene-l ,22'-

[20]o¾i[13]thia[l ,14]diazatefr^

n]-15'-one 13',13 ^! ~dioxide (7.0 mg, 0.01 1 mmol, 32 % yield). ¾ NMR (400MHz, CDCh) δ 8.65 (br. s., 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.29 (d, J=2.0 Hz, IH), 7.19 (dd, J 8.4. 2.3 Hz, 1 H), 7.09 (d, J 2.2 Hz, 1 H), 7.06 (dd, J 8.2. 2.0 Hz, 1 H), 6,95 (d, J 8.0 Hz, 1 H), 5.8 ! (dt, j ! .\8. 5.4 Hz, 1 ! ! }. 5.48 (dd, j 15.9.8, 1 Hz, 1 H), 4.07-4.18 (m, 2 H), 4.03 (d, J=14.9, 1 H), 3,96 (ddd, J=15,0, 9.3, 5.2 Hz, 1 H), 3.85 (ddd, j 10.3. 4.7, 3.2 Hz, 1 H), 3.72-3.81 (m, 2 H), 3.61-3.71 (m, 2 H), 3.43- 3.51 (m, 1 H), 3.39 (s, 3 H), 3.18 (d, j 14, 1 Hz, 1 H), 2.96 (dd, j 1 5.3. 9.0 Hz, 1 H), 2.74-2,86 (m, 3 H), 2.44-2,59 (m, 2 H), 2.36 (dd, j 93. 5,6 Hz, I H), 2.12- 2.28 (m, 1 H), 1.88-2.09 (m, 4 H), 1.76-1.87 (m, 1 H), 1.66-1.76 (m, 1 H), 1.52- 1.66 (m, 1 H), 1.36-1.51 (m, 3 ! ! }. m/z (ESI, +ve ion) 629.2 (M+H) ⁺ . EXAMPLE 21 1. 3-(((lS,3 ^, R,6 ^, R,7 ^, R,8 ^, E)-6-CHLORO-13 ^, ,13 ^, -DIOXIDO-15'-

OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTOALENE-l,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

| 8,16, 18,24]TETRAENj-7'-YL)OXY)-N,N-DIMETHYLPROPANAMIDE

STEP 1 : 3-(((lS,3'R,6 ^! R,7¾,8T;)-6-CHLORO-13', 13'-D10XJDO-15'-OXO-3,4- ΟΙΗΥϋΚΟ-2Η-8ΡΙΚΟ[ΝΑΡΗΊΉΑΕΕΝΕ-1,22'-

[20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, I 8,24]TETRAEN]-7'-YL)O.XY)-PROPiONIC ACID

A solution of allylic alcohol (60 mg, 0, 1 1 mmol, Example 952) was dissolved in THF (1.00 mL) and sodium hydride (60% dispersion; 25.2 mg, 1.05 mmol) was added after cooling the solution to 0 °C. The slurry was stirred for 30 minutes then ethyl acrylate (0.057 mL, 0.525 mmol) was added and the reaction mixture was stirred overnight. After 16 hours, the mixture had congealed to a brown solid. Another 2 mL of THF was added to facilitate stirring. Another two aliquots of reagents were added and stirred for an additional 24 hours. The reaction was quenched with water, then acidfied with IN HC1 to pH~5 and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1 % TFA in

CH CN/H2O, gradient 40% to 70% over 25 min to provide 3- (((lS,3'R,6'R,7'R,8T,)-6-chioro-13 ^! ,13 ^, -dioxido-15'-oxo-3,4-dihydro-2h- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]mia[l,14]diazatetracyd

nj-7'-yl)oxy)-propionic acid (5.5 mg, 8.6 μιηοΐ, 8.1%) yield). ¾ NMR (400MHz, CDCb) 6 8,55 (br. s. 1 H), 7.71 (d, J 8.6 Hz, 1 ! ! }. 7.13-7.23 (m, 2 ! ! }. 7.09 id. J 2.2 Hz, 1 H), 6.84-7.00 (m, 2 H), 5.81 (dt, J=15,7, 5.3 Hz, 1 H), 5.44 (dd, j 1 5.7. 7.2 Hz, 1 H), 3.83-4.18 (m, 7 H), 3.71-3.78 (m, 1 H), 3.68 (d, j 1 .9 Hz, 1 H), 3.51-3.64 (m, 2 H), 3.26-3.35 (m, 3 H), 3.18 (d, J=13.9 Hz, 5 H), 2.94 (dd, 1- 15.5, 9.6 Hz, 2 H), 2,67-2.85 (m, 6 H), 2,33-2.60 (m, 5 H), 2,00-2.25 (m, 6 H), 1 ,67-1 ,98 (m, 8 H), 1 ,54-1.66 (m, 2 H), 1 ,37-1.48 (m, 2 H). m/z (ESI, +ve ion) 644.2 (Vl-il) .

STEP 2: 3-(((lS,3 ^, R,6 ^, R,7'R,8 ^, E)-6-CHLORO-13 ^, ,13 ^, -DiOXIDO-15 ^, -OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l ₅ 22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCIX)[!4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLPROPANAMIDE

The carboxylic acid (20 mg, 0.031 mmol) was dissolved in DMF (1.0 mL). HATU (28.4 mg, 0.075 mmol) was added followed by addition of dimethylamine (2M TOP solution; 0.311 mL, 0.622 mmol) along with a small amount of water (1 drop). The reaction was stirred for 3.5 h. The crude reaction mixture was purified by reverse-phase preparative HPLC using a Phenonienex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1% TFA in CH N/H^Q, gradient 40% to

80% over 25 mm to provide 3-(((18,3'Κ,6¾,7¾,8Έ)-6-ΰΜθΓθ-13',13'-ώοχ ο-15'- oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20joxa 13]thia[l,14]diazatetracycfo[14^

n]-7'-yl)oxy)-propionic acid (8.0 mg, 0.012 mmol, 38 % yield). ^! H NMR

(400MHz, CDCb) δ 8.62 (br. s.1 H), 7.72 (d, J=8.6 Hz, 1 H), 7.25 (d, J=1.8 Hz,

1 H), 7.19 (dd, j 8.4.2.3 Hz, 1 H), 7.09 (d, j 2.2 Hz, 1 H), 7.02-7.08 (ni, 1 H), 6.92-6.98 (in, 1 !!}.5.81 (dt, j 15.6.5.4 Hz, 1 !!}.5.48 (dd, J=15.9, 7.9 Hz, 1 H), 4.06-4.16 (m, 3 !!}.4.01 (ddd, .! 15.1, 9.8, 5.0 Hz, 1 H), 3.93 (d, J ! 5.3 Hz, 1 !!}. 3.86 (ddd, j=8.8, 6.3, 6.3 Hz, 1 H), 3.62-3.75 (m, 3 H), 3.25-3.39 (m, 5 H), 3.18 (d, J=14.1 Hz, 2 H), 3.11 (s, 3 H), 3.01-3.08 (m, 1 H), 2.94 (s, 3 H), 2.90-2.99 (m,

2 !!}.2,69-2.90 (m, 5 !!}.2.32-2.56 (m, 4 H), 1.88-2,26 (m, 8 H), 1.77-1,86 (m, 1 H), 1.67-1.76 (rn, 1 H), 1.49-1.65 (rn, 1 H), 1.36-1.45 (rn, 2 H). m/z (ESI, +ve ion) 670.3 (M+H) ⁺ .

EXAMPLE 212.2-(((18,3'Κ,6¾,7'Κ,8Έ)-6-εΗίΟΚΟ-13',13'-ΒΙΟ ΧΙΒΟ-15 ^! - OXO-3,4-DIHYDRO-2H-SPIRO[NAPH HALE^rE-l,22 ^, -

|2 ⁽ >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^{' !'} .ϋ'" ^!| |Pi-N i ACOSA

[8, 16, 18,24]TETRAEN] -7'-YL)OXY)-N-(2- (DIMETHYL AMINO)ETHYL)ACET AMIDE

The carboxylic acid (9.5 mg, 0.015 mmol, Example 211, Step 1) was dissolved in DMF (1.0 mL) and then N,N-dimethylethylenediamine (2.0 ,uL, 0.018 mmol), HATU (6.9 mg, 0.018 mmol) and a drop of water were added and the reaction mixture was stirred for 4.5 hours. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0. 1% TFA in CH ₃ CN H ₂ 0, gradient 20% to 60% over 25 min to provide 2-(((lS,3'R,6'R,7 ^, R,8 ^! E)-6-chloro-13', 13'-dioxido-15'-oxo- 3,4-dihy dro-2H-spiro| naphthalene- 1 ,22'-

[20joxa 13]thia[ l, 14]diazatetracycfo[14.7.2, 0 ³ ' ⁶ .0 ^{! 9} ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-7'-yl)oxy)-N-(2-(dimethy]amino)ethyl)acetamide (8.0 mg, 9,84 μτ ^η οΐ, 65.1 % yield. ¾ NMR (400MHz, CDCh) δ 11.26 (br. s. 1 H), 8.51 (br. s. I H), 7.70 (d, j 8.6 Hz, 1 H), 7.15-7.22 (m, 2 H), 7.10 (d, j 2.2 Hz, 1 H), 6.96 (s, 2 H), 5.88- 5.99 (m, 1 I s ). 5.54 (dd, J ! 5.9, 5.6 Hz, I H), 4.64-5,25 (m, 3 H), 4, 19-4.29 (m, 2 H), 3.99-4, 16 (m, 3 H), 3.80-3,90 (m, 2 H), 3.69 (d, .! 1 -I i Hz, 1 H), 3.41 (d, J=6.5 Hz, 2 H), 3.22-3.33 (m, 2 H), 3.18 (d, 1=14.3 Hz, 1 H), 2.88-3,06 (m, 6 H), 2.68-2.86 { in. 2 H), 2.44-2.60 (m, 2 H), 2.35 (d, j 1 .8 Hz, 1 H), 1.89-2.23 (m , 5 H), 1.79 (d, 3=9.6 Hz, 3 H), 1 .58-1.71 (m, I H), 1 .46-1.57 (m, 1 H), 1 .40 (t, J 1 1 .8 Hz, 1 H), m/z (ESI, +ve ion) 669.3 (M+H) ⁺ .

EXAMPLE 213. (l S,3 ^, R,6 ^, R,7'R,8 ^, E)-6-CHLORO-7 ^, -(2-(4- MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] PENT ACO S A [8, 16, 18,24]TETRAEN] -15'-ONE 13', 13'-DIOXIDE

The ally! alcohol (20 mg, 0.035 mmol, Example 952) was dissolved in THF (1.00 mL) and cooled to 0 °C. Sodium hydride (60% dispersion; 14.0 mg, 0.350 mmol) was added and the resulting slurry was stirred for 30 minutes. 4-(2- bromoethyl) morpholine hvdrobromide (48.1 mg, 0.175 mmol) was then added and the slurry was stirred overnight. To the slurry was added DMF (1.00 mL) followed by another aliquot of sodium hydride (60% dispersion: 14.0 nig, 0.350 mmol) and 4-(2-bromoethyl) morpholine hydrobromide (48.1 mg, 0.175 mmol) and stirred overnight. The reaction was then acidified by adding IN HC1 and this mixture was filtered. The crude material was purified by reverse-phase preparative HPLC usmg a Phenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1 % TFA in Π ! .( \ Η ,Ο. gradient 30% to 60% over 20 rain to provide (1 s,3Y,6 ^! r,7'r,8 ^! e)-6-chloro-7'-(2~ 4~morpholinyl)ethoxy)~3,4-dihydro- 2h, 15 'h-spiroj naphthalene- 1 , 22'-

[20]oxa[ 13]thia[l , 14]diazatetracyclo| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]pentacosa[8, 16, 18,24]tetrae n]- 15'-one 13', 13'-dioxide (14 mg, 0.018 mmol, 50 % yield). ^! H NMR (400 Mi !/. CDCb) δ 8,26 (br. s, 1 H), 7.70 (d, J 8.6 Hz, 1 H), 7.13-7.23 (m, 2 H), 7.10 (d, j 2.2 Hz, 1 ! ! }. 6.90-6.99 (m , 2 H), 5.75 (dt, j 1 .6. 4.5 Hz, 1 H), 5.36 (dd,

J=15.8, 8.2 Hz, 1 H), 4,07-4.22 (m, 2 H), 3 ,92-4.05 (m, 5 H), 3 , 81 -3.9 ! (m, 2 H), 3 ,60-3.76 (m, 5 H), 3 ,54 (br. s . 3 H), 3,02-3 ,22 (m, 3 H), 2,98 (dd, J=15 J , 8.6 Hz, 1 H), 2.66-2,88 (ni, 2 H), 2.34-2,58 (m, 3 H), 2.00-2,21 (m, 3 H), 1.87-1 ,99 (m, 3 H), 1.67-1 , 86 (m, 2 H), 1.50-1 ,66 (m, 1 H), 1.31 -1 ,49 (m, 2 H). m/z (ESI, +ve ion) 684.3 (M+H) ⁺ . EXAMPLE 214. (lS,3'R,6'R,7'R,8'E)-6-CHLORO-7 ^f -((3,5-DIMETHYL-4-

ISQXAZOLYL)METHOXY)-3,4-DIHYDRQ-2H,15 ^! H-

SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1 4]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The ally! alcohol (20 mg, 0.035 mmol, Example 952) was dissolved in THF (1.00 mL) and cooled to 0 °C. Sodium hydride (60% dispersion: 8.40 mg, 0.350 mmol) was added and the mixture was stirred for 30 minutes. 4- (chloromethyi)-3,5-dimethylisoxazo]e (0.022 mL, 0.175 mmol) was then added and the resulting mixture was stirred for 4.5 hours. Three more aliquot of reagents were added and the slurry was stirred at room temperature for 4.5 days. The reaction was quenched with water and acidified with IN HC3 to pH~5. The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1 % TFA in CH ₃ CN/H ₂ 0, gradient 50% to 80% over 25 min to provide (1 S,3 ^! R,6'R,7 ^! R,8'E)-

6-chloro-7'~((3,5-dimethyl-4 soxazolyl)methoxy)-3,4-dihydiO-2H,15 ^, H- spiro I naphthalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazate1r^

n]-15'-one 13',13 ^! ~dioxide (10 mg, 0.015 mmol 42 % yield). ¾ NMR (400MHz, CDCb) δ 8.16 (s, 1 H), 7.71 (d, J=8.4 Hz, 1 H), 7.30 (s, 1 H), 7.18 (dd, J 8.4. 2.3 Hz, 1 H), 7.09 (d, J 2.3 Hz, 1 H), 6.95 (s, 2 H), 5,72 (dt, .1 1 0 Hz, 4.7 Hz, 1 H), 5,46 (dd, J=15,8, 8.4 Hz, 1 H), 4.65 (d, j 12 ! Hz, 1 H), 4.13-4,26 (m, 1 H), 4, 1 1 (s, 2 i l l 4.03 (d, .1 1 2 1 Hz, 1 H), 3,96 (d. 1-14.7 Hz, 1 H), 3.59-3.71 (rn, 2 H), 3.19-3.30 (m, 1 H), 3.16 (d, j 14.3 Hz, 1 H), 2.86-2.98 (m, 1 H), 2.66-2.84 (m, 2 H), 2.42-2.58 (m, 2 H), 2.40 (s, 3 H), 2.32 (s, 3 H), 2.08-2.22 (m, 3 H), 1.85-2.07 (m, 4 H), 1.75-1.85 (m, 1 H), 1 .65-1.74 (m, 1 H), 1 .50-1.64 (m, 1 H), 1.38-1.47 (m, 2 H). m/z (ESI, +ve ion) 680,3 (M+H) ⁺ .

EXAMPLE 215. (lS,3'R,6 ^! R,7¾,8 ^r E)-6-CHLORO-7'-((l-MF; ^" fflYL-lH-l ,2,4-

TRIAZOL-3-YL)METHOXY)-3,4-DIHYDRO-2H.15H-

SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

All the reagents were first azeotroped with toluene to remove any residual water or acetic acid. The aliyl alcohol (27 mg, 0.047 mmol, Example 952) was dissolved in THF (0.3 mL) and cooled to 0 °C. Sodium hydride (60% dispersion; 1 1,3 mg, 0.47 mmol) was added and the resulting light pink slurry was strirred for 30 minutes. The 3-chloromethyl-l-methyl-lh-[l ,2,4]triazole, hydrochloride (0.029 mL, 0.24 mmol) was dissolved in DMF (0.5 mL) and added to the reaction mixture and allowed to warm to room temperature over a period of five hours. The reaction was quenched with water (hydrogen evolution occurred from residual hydride) and acidified with IN HC1 to pH~5. This mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with IN Li CI solution (I x 20 mL) and brine (1 x 20 mL). The organic layer was then dried over magnesium sulfate and the crude product was purified by medium pressure chromatgragphy (silica, 0 to 100% EtOAc (+0,3% HOAc):Hexanes) to give (l S,3¾,0l 7'R,8¾-6-chloro-7H(l-me

3,4-dihydro-2H, 15'H-spiro[naphthaIene-l ,22'- [20]oxa[13]thia[l ,14]diazatefra<yd^^

n]-15'-one 13',13 ^! ~dioxMe ( mg, 0.017 mmol, 35 % yield). ¾ NMR (400MHz, CDCb) δ 10.46 (br. s., 1 H), 8.10 { or. s., 1 H), 7.71 (d, J=8.4 Hz, 1 H), 7.29 (d, j I .H Hz, 1 H), 7.12-7.22 (m, 2 H), 7.08 (d, j 2.2 Hz, 1 H) , 6.94 (d, j 8.2 Hz, 1 H), 6.09 (dt, J i 5 7 , 5.8 Hz, I H), 5.53 (dd, .1 15 6. 6.8 Hz, 1 1 1 ). 4.85 (d, J 12. i Hz, 1 H), 4.49 (d, J I 1 .9 Hz, 1 H), 4.02-4.16 (m, 2 H), 3.99 (d, j 1 4 7 Hz, 1 H), 3.89 (s, 3 H), 3.67-3.77 (m, 2 H), 3.64 (d, j 14.3 Hz, 1 H), 3.19 (d, j 14.3 Hz, 1 H), 2.90-2,96 (m, 1 H), 2.68-2,83 (m, 2 H), 2.55-2,68 (m, 1 H), 2.23-2,53 (m, 3 H), 1.97-2, 17 (m, 4 H), 1.86-1 ,96 (m, 2 H), 1.67-1,86 (m, 2 H), 1.44-1,67 (m, 2 H), 1.36 (t, j 123 Hz, 1 H). m'z (ESI, +ve ion) 666.2 (M+H) ⁺ .

EXAMPLE 216. (l S,3'R,6'R,7 ^* R,8'E)-6-CHLORO-7'-(l ,3-THIAZC)L-2- YLMETHOXY)-3,4-DIHYDRO-2H 5H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14J .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] -15'-ONE 13', 13'-DIOXIDE

The allyl alcohol (20 mg, 0.035 mmol, Example 952) was dissolved in THF (1.00 mL) and cooled to 0 °C. Sodium hydride (60% dispersion; 8.40 mg, 0.350 mmol) was added and the mixture was stirred for 30 minutes. 2- (chloromethyl) thiazole hydrochloride (30.0 mg, 0.175 mmol) was then added and the resulting mixture was stirred at room temperature ovemight. LCMS now indicated reaction was -95% complete. The reaction was quenched with water and acidified with IN HC1 to pH~5. The mixture was extracted with ethyl acetate (2 x 30 rnL). The combined organic layers were washed with brine (1 x 20 mL) and dried over magnesium sulfate. The crude material was purified by reverse- phase preparative HPLC using a Phenomenex Luna column, 5 micron, CI 8(2), 100 A , 150 x 30 mm, 0.1% TFA in CH ₃ CN H ₂ 0, gradient 50% to 80% over 25 mm to provide (l S,3'R,6¾,7¾,8T;)-6-chloro-7'-((l-methyl-lH-l,2,4-tnazol-3- y l)methoxy )-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20ioxa| 13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-15'-one 13', 13'-dioxide (17 mg, 0,025 mmol, 73 % yield). 'H NMR (400MHz, CDCb) δ 8.20 (br, s., 1 H), 7,92 (d, J=3.3 Hz, 1 H), 7.71 (d, J=8.6 Hz, 1 H), 7.46 (d, j 3.5 Hz, 1 H), 7.33 (s, 1 ! ! }. 7.19 (dd, j 8.4. 2.2 Hz, 1 H), 7.10 (d, j 2.2 Hz, 1 H), 6,87-6.98 (m, 2 H), 5,82 (dt, j 1 0. 4.9 Hz, 1 H), 5.48 (dd, J=15.9, 8.3 Hz, 1 H), 5, 19 (d, J 14.3 Hz, 1 H), 4.85 (d, J 14.3 Hz, 1 H), 4.06-4,21 (m, 3 H), 4.02 (d, J=14.9 Hz, 1 H), 3.86 (dd, J=8.5, 3.2 Hz, 1 H), 3.68 (d, J=14.1 Hz, 1 H), 3.57 (t, j .3 Hz, 1 H), 3.23 (dt, j 10.4. 5.2 Hz, 1 ! ! }. 3.18 (d, j 14.3 Hz, 1 H), 3.00 (dd, J 1 .4. 8.5 Hz, I H), 2,67-2,88 (m, 3 H), 2.36-2,66 (m, 2 H), 1 ,88-2,28 (m, 5 H), 1.70-1.88 (m, 2 H), 1.55-1.69 (m, 1 H), 1.36-1.53 (m, 2H), m/z (ESI, +ve ion) 668.2 ( Vl - i l) .

EXAMPLE 217. ETHYL (((lS,3 ^, R,6 ^, R,7 ^, R,8'E)-6-CHLORO-13 ^, ₅ 13 ^, -DIOXIDO- 15 ^, -OX.O-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-.l ,22'- | 2( >X A| i 1 ! f Π Λ| ί i J l i^f AZ.Vf l: E RAC VCE C)l i J 7.2 0 ' ^!' .ϋ'" ^{! |} |Pi- N i ACOSA

[8, 16, 18,24]TETRAEN] -7'-YL)OXY)ACETATE

The ally! alcohol (40 mg, 0.070 mmol, Example 952) was dissolved in DCM (3.0 mL) and rhodium (ii) acetate dimer (6.2 mg, 0.014 mmol) along with ethyl diazoacetate (0.054 mL, 0.53 mmol) was added. The mixture was stirred at room temperature for two days. Upon adding the ethyl diazoacetate, rapid N2 evolution occurred. Over the two days of stirring three more aliquots of ethyl diazoacetate (0.054 mL, 0.525 mmol) and rhodium (ii) acetate dimer (6.2 mg, 0.014 mmol) were added to drive the reaction to completion. The mixture was then concentrated. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1 % TF A in CH^CN/H ₂ 0, gradient 50% to 80% over 25 min to provide ethyl

(((l s,:Tr,6 ^f r,7Y,8'e)-6-chloro-13', 13'-dioxido-15'-oxo-3,4-dihydro-2h- spiro [naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae nj-7'-yl)oxy)acetate (14.0 mg, 0.021 mmol, 29 % yield). ^j H NMR (400MHz, CDCh) δ 8.34 (s, I H), 7.71 i d. J = 8,6 Hz, ! H), 7.31 (d, J 1 .8 Hz, 1 ! ! }. 7.17 (dd, J=8.4, 2,3 Hz, 1 H), 6,95-7.15 (m, 3 H), 5.80 (id, J=15.9, 4.8 Hz, 1 H), 5.50 (dd, J=16.0, 8.4 Hz, 1 H), 4.30-4.41 (m, 1 H), 3.81-4.26 (m, 8 H), 3.60-3.75 (m, 1 H), 3.41 (ddd, j 1 5.3. 8.7, 6.9 Hz, 1 H), 2.90-3.18 (m, 5 H), 2.28-3.10 (m, 6 H), 1.52- 2,28 (m, I s ), ni . (ESI, +ve ion) 657.2 (M+H) ⁺ .

EXAMPLE 218. (((l S,3'R,6'R,7'R,8 ^! E)-6-CHLORO-13',13'-DIOXIDO-15'-OXO- 3,4-DIHYDRO-2H-SPTRO| AP^^THALENE-l ,22 ^, -

[20]OXA[13]TrHIA[l,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] -7'-YL)OXY)ACETlC ACID

The allylic alcohol (16 mg, 0,028 mmol, Example 952) was dissolved in THF (1.0 mL) and cooled to 0 °C. Sodium hydride (60% dispersion: 3.36 mg, 0.140 mmol) was added and the slurry was stirred for 30 minutes. Methyl broraoacetate (5.2 μί, 0.056 mmol) was then added and the mixture was slowly allowed to warm to room temperature over 3.5 hours. The intermediate methyl ester was only transient during the reaction and was quickly hydroizyed to the desired acid m situ. The reaction was quenched with IN HCl to acidify to pH~5 and then extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (1 x 15 mL) and dried over magnesium sulfate. The crude product was then purified by medium pressure chromatography (silica, 25 to 75% EtOAc (+0.3% HO Ac); Hexanes) to give (((l S,3'R,6' ,7'R,8'E)-6-chloro- 13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,2 2'- [20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)acetic acid (3.5 mg, 5.6 μηιοΐ, 20 % yield). ¾ NMR (4()0MHz, CDCh) δ 8.34 (s, 1 H), 7.71 (d, J=8,6 Hz, 1 H), 7.31 (d, J=l .6 Hz, 1 H), 7.19 (dd, J=8.5, 2.2 Hz, 1 H), 7.10 (d, J=2.3 Hz, 1 H), 6.98-7.02 (ni, 1 H), 6.92-6.97 (ni, 1 H), 5.81 (dt, j 1 5.9. 4.8 Hz, 1 H), 5.50 (dd, J=16.0, 8.4 Hz, 1 H), 4.32 (d, j 15. K Hz, I H), 4.03-4, 17 (m, 41 1 ). 3.96 (d, .! 1 .3 Hz, 1 H), 3.85 (dd, .1 H 2. 2.9 Hz, 1 H), 3.69 (d, j 1 4 3 Hz, 1 H), 3,21 -3.32 (m, 1 H), 3, 18 (d, J M . I Hz, I H), 3.01 (dd J=15.3, 8.4 Hz, 1 H), 2.68-2.86 (m, 2 H), 2.50-2.61 (m, 2 H), 2.42 (d, J=16.6 Hz, 1 H), 2.12-2.25 (m, 2 H), 1.89-2.05 (m, 4 H), 1.70-1.88 (m, 3 H), 1.57-1.69 (m, 2 H), 1,37-1.5 1 (m, 2 H). m/z (ESI, +ve ion) 629.2 ( W W ) .

EXAMPLE 219. 2-(((l S,3'R,6'R,7'R,8 ^! E)-6-CHL()RO-13', 13 ^! -DIOXIDO-15'- OXO-3,4-DIHYDRO-2H-SPIRO| APHTHALENE- 1 ,22'-

[8, 16, 18,24]TETRAEN] -7'-YL)OXY)-N,N- DIMETHYLETHANESULFONAMIDE

The ally! alcohol (30.0 mg, 0.053 mmol, Example 952) was dissolved in THF (1.5 mL) and cooled to 0 °C. Sodium hydride (60% dispersion; 13.0 mg, 0.53 mmol) was added and the resulting sluny was stirred at 0 °C for 30 minutes. The N,N-dimethylvinylsulfonamide (0.031 mL, 0.26 mmol) was then added and the reaction mixture was stirred overnight to completion. The reaction was quenched with water and then acidified with IN HC1 to pH~5. This mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1% TFA in

CH3CN/H2O, gradient 45% to 75% over 20 min to provide epimenc 2-

(((l S,3 ^! R,6 ^, R,7'R,8'E)-6-chIoiO-13',13'-dioxido-15'-oxo-3,4-dihydr o-2H- spiro [naph thalene- 1 ,22'- 8.24i !cirac n]-7 ^, -yl)oxy)-N,N-dimethylethanesulfonamide (17.0 mg, 0.023 mmol, 45 % yield). ^! ! 1 NMR (400MHz, CDCls) δ 8.22 (s, 1 I I I 7.71 id. j H. Hz, 1 H), 7.19 (dd, J 8.4. 2.2 Hz, I H), 7.10 (d, .1 2.2 Hz, 1 H), 6.89-7.01 (m, 2 H), 5.79 (dt, J 16.0. 4.9 Hz, 1 H), 5,42 (dd, J 16. 1. 8.1 Hz, 1 H), 3.93-4.19 (m, 5 H), 3.71-3.78 (m, 2 H), 3.68 (d, J=15.1 Hz, 1 H), 3.54-3.64 (m, 1 H), 3.42 (dt, J=14.5, 7.1 Hz, 1 H), 3.09-3.29 (m, 2 H), 2.94-3.05 (m, 2 H), 2.92 (s, 4 H), 2.82-2.86 (m, 1 H), 2,71-2.80 (m, 2 H), 2,31-2.61 (m, 5 H), 2.02-2.23 (m, 3 H), 1 .87-2.00 (m, 3 H), 1.76-1.86 (m, 1 H), 1.67-1.76 (m, 1 H), 1.51-1.66 (m, 1 H), 1.41 (q, J=10.5 Hz, 2 H). m/z (ESI, +ve ion) 706.2 ( +H) ⁺ . EXAMPLE 220, (1 S,3'R,6 ^, R,7 ^, R ₅ 8 ^, E)-6-CHLORO-7 ^, -(2-HYDROXYETHOXY)-

3,4"DlHYDRO-2H,15 ^, H-SPIRO[NAPH ^r fflALE E-l,22'-

[20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, 18,24]TETRAEN]-15"-ONE 13', 13 ^* -DIOXIDE

The ally! alcohol (33 rng, 0.058 mmol, Example 952) was dissolved in THF (1.50 ml.,) and cooled to 0 °C. Sodium hydride (60% dispersion; 23.0 mg, 0.57 mmol) was added and the resulting slurry was stirred for 30 minutes. 2-(2- bromoethoxy) tetrahydro-2H-p ran (60 mg, 0.29 mmol) was then added and the slurry was stirred overnight. The reaction was then acidified by adding IN HC1 and this mixture was filtered and concentrated in vacuo. The residue was dissolved in ether and 1 mL of 1 : 1 2N HC1:THF was added and the reaction was stirred for 2.5 days. LCMS indicated the reaction was -95% complete. The reaction was concentrated then dissolved in DMSO. The crude material was purified by reverse-phase preparative HPLC using a Plienomenex Luna column, 5 micron, C8(2), 100 A, 150 x 21.2 mm, 0.1% TFA in CH ₃ CN H ₂ 0, gradient 30% to 70% over 20 mm to provide (l S,3'R,6'R,7'R,8'E)-6-chloiO-7'-(2- hydroxyethoxy)-3,4-dihydro-2H, 15'H-spiro[naphthalene-l,22'- [20joxa[13]thia[ l, 14]diazatetracycfoH^

n]-15'-one 13', 13'-dioxide (10 mg, 0.016 mmol, 33% yield). ^! H NMR (400MHz, CDCh) δ 8.72 (br, s., 1 H), 7,71 (d, J=8.6 Hz, 1 H), 7.31 (s, 1 H), 7.18 (dd, J=8.4, 2.2 Hz, 1 H), 7.09 (d, j 2.2 Hz, 1 H), 6.96-7.05 (m, 1 H), 6.88-6.96 (m, 1 H), 5.78-5.86 (m, 1 H), 5.49 (dd, J=15.8, 7.4 Hz, 1 H), 3.98-4.20 (m, 4 H), 3.90 (br. s., 2 H), 3,77 (d, J 5. 1 Hz, 2 H), 3.67 id. J=13.9 Hz, I H), 3.49 (d, .1 8.8 Hz, 1 H ). 3, 10-3.31 (m, 2 H), 2,91 -3.04 (m, 1 H), 2,44-2.57 (m, 2 H), 2.40 i d J i d. Hz, 1 H), 1.98-2.22 (m, 3 H), 1.93 id. j 7.4 Hz, 2 H), 1.67-1.86 (m, 2 H), 1.53-1.66 (m, 1 H), 1.34-1.51 { in. 2 H), 1.24-1.33 { in. 3 H). m/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 221. (1 S ₅ 3 ^, R,6 ^, R,7 ^, R,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 14H-SPIRO| APHTHALENE-l,21 '-

[19]OXA[12]THIA[1,13]DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ - ²³ ]TETRACOSA

[ 8,15,17,23 ]TETRAEN]-14'-ONE 12 ^! ,12 ^* -DIOXIDE

STEP 1 : (S)-N-(BUT-3-EN-l-YLSULFONYL)-6'-CHLORO-5-(((lR,2R)-2- ((R,E l -HYDROXYHEX-2-EN-l -YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7 -C ARB OXAMIDE

(S)-6 ^, -chloro-5-(((lR,2R)-2-((R,E)-l-hydroxyhex-2-en-l- yl)cyclobu1yl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o b][ l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (89 mg, 0.17 mmol. Intermediate AA1 I B) was dissolved in DCM (6 mL) and cooled to 0 °C. But-3-ene-l -sulfonamide (59.0 mg, 0.436 mmol Intermediate EE15), triethylamine (0.073 mL, 0.523 mmol) and DMAP (36.2 mg, 0.297 mmol) were added followed by slow addition of EDC (67 mg, 0.35 mmol). The reaction was allowed to slowly warm to room temperature and stirred for 3.5 days to completion. The reaction mixture was then concentrated to dryness and the residue was purified by medium pressure chromatography (silica, 0 to 40% EtOAc(+0.3% HOAc):Hexanes) to give (S)-N- (but-3-en-l -ylsidfbnyl)-6 ^! -diloro^^^

yl)c lobutyl)methyl)-3 4,4 5-tetrahydro-2H,2^spiro[benzo[b][ l,4]oxazepine- 3,i'-naphthalene]-7-carboxamide (83 mg, 0. 13 mmol, 76 % yield), m/z (ESI, +ve ion) 627.3 (M+H) ⁺ .

STEP 2: (lS,3'R,6'R,7 ^! R,8 ^, E)-6-CHLORO-7 ^! -HYDROXY-3,4-DIH ^; ORO- 2H, 14'H-SPIROjNAPHTH ALENE- 1 ,21 ^* -

[19]OXA[12]THIA[1 ,13]DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ - ²³ ]TETRACOSA

[8,15,17,23]TETRAEN]-14'-ONE 12 2 ^! -DIOXIDE

(S)-N-(but-3"en-l-ylsuifonyl)~6 ^, ~chloro-5"(((lR,2R)"2-((R,E)-l- hydroxv'hex-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydr o-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxamide (83 mg, 0.13 mmol) was dissolved in AcOH (25 mL) and sparged with argon. Hoveyda-Grubbs 2nd generation catalyst (17.0 mg, 0.026 mmol) was then added and the reaction was stirred under reduced pressure overnight. Another 8.0 mg of the RCM catalyst was added and the reaction mixture was stirred for three days under reduced pressure. Another 8.0 mg of catalyst was added and stirred overnight.

The reaction mixture was concentrated under reduced pressure and purified by medium pressure chromatography (silica, 1 5 to 70% EtOAc(+0.3% HOAc):Hex) to give (1 S,3'R,6'R,7 ^, R,8 ^, E)~6"Chloro-7' iydroxy-3,4-dihydro-2H, 14Ή- spiro[naphthalene-l,21 '-

[19]oxa[12]thia[ U 3]diazate1ra^

]-14'-one 12', !2'-dioxide (35 mg, 0,063 mmol, 48% yield). ¾ NMR (400MHz, CD3OD) δ 7.75 (d, J 8,4 Hz, 1 H), 7.20 (dd, J=8.5, 2.2 Hz, 1 H), 7.13 (dd, J 3. 1. 2,3 Hz, 2 H), 7.07 (dd, j 8.2. 2.0 Hz, 1 H), 6.94 (d, j 8.2 Hz, 1 H), 5.45-5.72 (m, 2 H), 4,03-4.18 (m, 2 H), 3,84 (dd, J 15.6. 7.9 Hz, 1 H), 3.66-3,77 (m, 2 H), 3.51- 3.65 (m, 2 H), 3.26-3.33 (m, 1 H), 3.11 (dd, J=15.6, 3.6 Hz, 1 H), 2.69-2.91 (m, 2 H), 2.38-2.67 (m, 4 H), 2.08 (d, j 13.5 Hz, 1 H), 1.84-2.01 (m, 4 ! ! }. 1.75-1.84 (m, 1 H), 1,55-1.73 (m, 1 H), 1,39-1.52 (m, 1 H). m/z (ESI, +ve ion) 557.2 (M il)

EXAMPLE 222. (1 S,3¾,6'R,7¾)-6-CHLORQ-7'-HYDROXY-3,4-DIHYDRO- 2H, 14'H-SPIRO[NAPHTHALENE- 1 ,21 '-

I I !OXAl 121 Η1Λ| Ι..!3|ί)!Α/.\! :ΓΗ.Λ(·ν(·ί.()Ι 13.7.2 ί; ^: ' ^! '.0 ^{1S ,:} | I ^' i: ! RACOSA [15,17,23] TR1EN] - 14'-ONE 12', 12'-DIOXIDE

(18,3¾,6ΊΙ,71,8Έ)~6~οωοΓθ-7 ^! ιν(ΐΓθχγ-3,4-(1ί1ινί!Γθ-21ι,14 ^, 1ι- spiro[naphthalene-l,2 -

[ 19]oxa[ 12]thia[ 1, 13]diazatetracy clo[ 13.7.2.0 ³ ' ⁶ .0 ^]8 ' ²³ ]tetracosa[8,15,17,23]tetraen ]-14'-one 12',12'-dioxide (11 nig, 0,020 mmol, Example 207) was dissolved in EtOAc (1.0 mL) and then platinum (IV) oxide (4.5 mg, 0.020 mmol) was added. The reaction vessel was flushed with hydrogen and kept under balloon pressure for 4.5 hours. The reaction mixture was then directly loaded onto a column and purified by medium pressure chromatography (silica, 0 to 60% EtOAc(+0.3% HOAc):Hexanes) to give (lS,3'R,6'R,7'R)-6-chloro-7'-hydroxy-3,4-dihydro- 2H, ! 4'H-spiro[naphthalene- 1 ,2 Γ-

[19]oxa[12]thia[l,13]diazatetracyclo[13.7.2 ³ - ⁶ .0 ¹⁸ ' ²³ ]tetracosa[15,17,23]trien]- 14'-one 12',12'-dioxide (10.5 mg, 0.019 mmol, 95% yield). ¾ NMR (400MHz, CDCI3) δ 8.59 is.1 II).7.70 (d, j 8.6 Hz, 1 H), 7.18 idd. j 8.5.2.2 Hz, 1 H), 7.08 (d, j 22 Hz, 1 H), 7,00-7.06 (m, 2 H), 6.93 (d, J 7.8 Hz, 1 H), 4.11 (s, 2 H), 3.76-3.90 (m, 2 H), 3.72 (d, j 14..- Hz, 1 H), 3.45-3.52 (m, 1 H), 3.24-3.37 (m, 1 H), 3.20 (d, j 14.3 Hz, 1 II).3.08 (dd, j 1 .7.2.9 Hz, 1 H), 2.66-2.88 (m, 2 H), 2,31-2.50 (m, 2 H), 1,87-2.04 (m, 4 H), 1,64-1.85 (m, 4 H), 1,29-1.63 (m, 6 H). m/z (ESI, +ve ion) 559.2 (M R)

EXAMPLE 225. (1 S ₅ 3 ^, R,6 ^, R,7 ^, R,8 ^, E)-6-CHLORO-7 ^, -METHOXY-3,4- DIHYDRO-2H,14H-SPIRO| APHTHALENE-l,21 '-

[19]OXA[12]THIA[1,13]DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ - ²³ ]TETRACOSA

[ 8,15,17,23 ]TETRAEN]-14'-ONE 12 ^! ,12 ^* -DIOXIDE

(18,3¾,6ΊΙ,7Ί ,8Έ)~6-€ωοΓθ-7 ^! ιν(ΐΓθχγ-3,4-(1ι1ινί!Γθ-2Η,14Ή- spiro[naphthalene-l,21 '-

I i |o\a| I2|shia| U |dia/aieinu:vc!oj Κ /^.Ο^Ο ^{1 >;} iiesracos;)i8. !^.17.2 |ieiraen ]-14'-one 12',12'-dioxide (25 nig, 0.043 mmol, Example 221) was dissolved in THF (1.0 niL) and cooled to 0 °C. Sodium hydride (60% dispersion) (10.3 mg, 0.43 mmol) was added and the slurry was stirred at 0 °C for 20 minutes. The slurry was taken out of the ice bath for about three minutes to ensure anion formation (slurry turns slightly green in color) and iodomethane (0.013 mL, 0.214 mmol) was then added after reemerging in the ice bath. The slurry was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 25 mL) and dried over magnesium sulfate. The filtrate was concentrated and the residue was purified by medium pressure chromatography (silica, 0 to 40% EtOAc(+0.3%

HOAc):Hexanes) to give (lS,3 ^! R,6'R,7'R,8 ^, E)-6-chloro-7 ^, -methoxy-3,4-dihydro- 2H, 14'H-spiroj naphthalene- 1,21'- I i9|o\a| I2|shia| U |dia/aieinu:vc!oi 13.72..0 ^; ".0 ^{1 >;} |iesracosai8. !^.17.2 |ieiraen ]-14'-one 12', 12'-dioxide (15 mg, 0,026 mmol, 74 % yield). ^! H NMR (400MHz, CDC! ;) 5 8.36 (s, i i l }. 7.52-7.75 (m, i l l ). 6.97-7.17 (m, 3H), 6..78-6.95 (m, 2H), 5.27-5.56 (m, 2H), 3.93-4.13 (m, 3H), 3.51-3.76 (m, 4H), 3.12-3.28 (m, IH), 2.97- 3.09 (m, 4H), 2.70-2,77 (m, IH), 2.49-2.62 (ra, 2H), 2,30-2.46 (m, 2H), 1.94-2.08 (m, 3H), 1.81 -1.94 (m, 3H), 1.62- 1.81 (m, 3H). m/z (ESI, +ve ion) 571.2 (M+H) ⁺ .

EXAMPLE 226. (1 S,3'R,6 ^! R,7'R,8'E)-6-CHLORO-7'-METHOXY-3,4- DIHYDRO-2H, 14'H-S PIRO [NAPHTHALENE- 1 ,21'-

[19]OXA[12]THIA[1 ,13]DIAZATETRACYCLO[13.7.2.0 ³ - ⁶ .0 ^{] 8} ' ²³ ]TETRACOSA

[8,15,17,23]TE,TRAEN]-14 ^! -ONE 12',12 ^! -DIOXIDE

(lS,3 ^, R,6'R,7 ^, R,8 ^, E)-6-chloro-7 ^, -methoxy-3,4-dihydro-2H,14 ^, H- spiro [naphthalene- 1 ,2 Γ- [19]oxa[ 12]thia[l ,13]cUazatefracyc^

]-14'-one 12',12 -dioxide (11 mg, 0.019 mmol. Example 225) was dissolved in EtOAc (1.0 mL) and platinum(iv) oxide (4.4 mg, 0.019 mmol) was then added. The reaction vessel was flushed with hydrogen and kept under balloon pressure for 4.5 hours. The reaction mixture was then directly loaded onto a column and purified by medium pressure chromatography (silica, 0 to 60% EtOAc(+0.3% HOAc):Hexanes) to give (l S,3'R,6'R,7 ^, R,8'E)-6-chloro-7 ^! -methoxy-3,4-dihydro- 2H, 14'H-spiro[ naphthalene- 1 ,2 Γ- [19]oxa[12]thia[l ,13]diazatefra<^^

]-14'-one 12',12'-dioxide (9.0 mg, 0,016 mmol, 82 % yield). ¾ NMR (400MHz, CDCls) δ 8.74 (s, IH), 7.63-7.83 (m, IH), 7.09-7.27 (m, 4H), 6.89-7.05 (m, IH), 4.08-4.23 (m, 3H), 3.60-3.90 (m, 3H), 3.36-3.54 (m, IH), 3.15-3.40 (m, 5H), 2.98- 3, 16 (m, 2H), 2.67-2.88 (m, 2! I ). 2.34-2,59 (m, 21 1 ). 1.52-2. 1 1 (m, i 21 1 ), m/z (ESI, +ve ion) 573.2 (M+H) ⁺ .

EXAMPLE 227. (1 S,3'R,61V7'R,8¾-6-CHLQRO-7'-HYDRQXY-3,4- DIHYDRO-2H, 16H-SPIRO[NAPHTHALENE-l ,23'- [21 ]OXA[14]TfflA[l,15]DIAZATETRACYCLO[15.7.2.0 ³ ' ⁶ .0 ²⁰ - ^2S ]HEXACOSA

8,17, 19,25] TETRAEN] - 16'-ONE 14', 14'-DIOXIDE

STEP! : SODIUM HEX-5-ENE- 1 -SULFONATE

O ONa

A mixture of 6-bromo-l-hexene (2.1 mL, 13 mmol, Aldrich) and sodium sulfite (1.7 g, 14 mmol) in water (1 1 mL) was stirred at 110 °C for 10 hrs. The water was then removed under reduced pressure. The residue was triturated with acetone (10 mL) and the resulting slurry was filtered to collect sodium hex-5-ene- 1 -sulfonate as a white solid (2.3 g, 12 mmol, 95% yield). ^! H NMR (400MHz, DMSO-Λ)) δ 5.78 (tdd, J 6.8. 10.3, 17.0 Hz, 11 1 ). 5.00 (qd, .! 1 .7. 17.2 Hz, I I I ). 4,93 (id, .! 1 0. 10,2 Hz, 1H), 2.41 - 2,35 (m, 2H), 2.00 (q, J 7. 1 Hz, 2H), 1.60 - 1.51 (m, 2H), 1.43 - 1.33 (m, 2H).

STEP 2: HEX-5-ENE-1 -SULFONAMIDE

A mixture of sodium hex- 5 -ene-1 -sulfonate (1.6 g, 8.8 mmol) and phosphorus oxy chloride (32 mL, 350 mmol) was stirred at 130 °C for 6 hrs. The phosphorous oxy chloride was then removed under reduced pressure. The residue was triturated with CH CN (20 mL) and the precipitate was removed via filtration. To the filtrate was added a 30%, aqueous solution of NFL (15 mL) slowly at 0 °C, The mixture was stirred for 30 minutes. The mixture was then diluted EtOAc (240 mL) and then washed with brine and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was purified on a short silica gel plug eiuting with 1 : 1 EtOAc: hexanes to give hex-5-ene-l-sulfonamide (750 mg, 4.6 mmol, 52% yield). ^! H NM

(400MHz, DMSO-<¾) 5 6.73 (s, 2H), 5.88 - 5.67 (m, 1H), 5.04 (qd, J=1.8, 17.2 Hz, I I I ). 4.98 (tdd, ./ ! . ! . 2.2, 10.2 Hz, 1H), 3.01 - 2.91 (m, 2H), 2.10 - 2.00 (m, 2H), 1.75 - 1.63 (m, 2H), 1 ,52 - 1.42 (m, 2H).

STEP 3: (S)-6'-CHLORO-N-(HEX-5-EN-l -YLSULFONYL)-5-(((l R,2R)-2- ((R,E)-l-HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [ 1 ,4]GXAZEPINE-3, 1

NAPHTHALENE] -7-CARBOXAMIDE

(S)-6'-chloro-5-(((lR ₅ 2R)-2-((R,E)-l-hydrox>'hex-2-en-l- yl)c lobutyl)memyl)-3 4,4 5-tetrahydro-2H,2'H-spiro[benzo[b][ l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (89 mg, 0.174 mmol. Intermediate AAl lB) was dissolved in DCM (6 mL) and cooled to 0 °C. Hex-5-ene-l -sulfonamide (71 mg, 0.436 mmol; Example 227, Step 2), triethylamine (0.073 mL, 0.52 mmol), DMAP (36 mg, 0.297 mmol) were added followed by slow addition of EDC (67 mg, 0.35 mmol). The reaction was allowed to slowly warm to room temperature and stirred for 3.5 days to completion. The reaction mixture was then concentrated to dryness and the residue was purified by medium pressure chromatography (silica, 0 to 40% EtOAc(+0.3% HOAc):Hexanes) to give (S)~6'~ cWoro-N-(hex-5-en-l-ylsulfonyl)-5^^^

yl)cyclobutyl)methyl)-3 4,4 5-tetrahydro-2H,2'H-spiro[benzo b][ l,4]oxazepine- 3,l'-naphthalene]-7-carboxamide (83 mg, 0. 13 mmol, 73 % yield), m/z (EST, +ve ion) 655.3 (M+H) ⁺ .

STEP 4: (lS^'R.e'R.T'R.S'EJ-e-CHLORO-T'-HYDROXY ^-DIHYDRO-

2H, 16'H-SPIROjNAPHTH ALENE- 1 ,23'-

[21]OXA[14]TH1A[1,15]DIAZATEII ACYCLO[15.7.2.0 ³ -^0 ²⁰ - ²⁵ ]HEXACOSA[ 8,17, 19,25]TETRAEN]-16'-ONE 14',14'-DIOXIDE

(S)-6'-chloro-N-(hex-5-en- 1 -y lsulfonyl)-5-((( lR,2R)-2-((R)-l - hydroxyhex-2-en-l-yl)cyclobut d)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide (83 mg, 0.13 mmol) was dissolved in AcOH (25 mL) and sparged with argon. Hoveyda-grubbs catalyst 2 ^nd generation (16.0 mg, 0.025 mmol) was then added and the reaction was stirred under reduced pressure overnight. The reaction was complete and the reaction mixture was sparged with air to inactivate the catalyst. The reaction mixture was then concentrated to dryness and then purified by medium pressure chromatography (silica, 15 to 70% EtOAc (+0.3%HOAc):hexanes) to give (1 S,3'R,6 ^! R,7¾,8T;)-6-chloro-7'-hydroxy-3,4~dihydro-2H, 16H-spiro[naphthaleaie- 1,23'-

[21]oxa[14]thia[ l, 15]diazatetTacyclo[15.7.2.0 ³ ' ⁶ .0 ' ^u ' ^2:, ]hexacosa[8,17, 19,25]tetraen ]-16'-one 14', !4'-dioxide (44 mg, 0,075 mmol, 59% yield). ¾ NMR (400MHz, CD3OD) δ 7.76 (d, J=8.6 Hz, 1H), 7.29-7.43 (m, IH), 7.05-7.27 (m, 3H), 6.87- 7.00 (m, IH), 5.33-5.61 (m, 2H), 4.00-4.19 (m, 2H), 3.63-3.93 (m, 4H), 3.25-3.44 (m, 5H), 3, 17 (dd, ./ 5.2, 15.4 Hz, I H), 2.66-2.86 (m, 2H), 2,52-2.66 (m, IH), 2.46 (dq, J=3,2, 8.6 Hz, IH), 1,58-2.18 (m, 13H). m/z (ESI, +ve ion) 585.2 (M+H) ⁺ . EXAMPLE 228, (1 S ,3'R,6' ,7'R)-6-CHLO O-7'-HYD OXY-3,4-DiH ^T DRO- 2H, 16'H-SPIRO[NAPHTHALENE- 1 ,23'-

[21 ]OXA[ 14 |THIA[ 1,15 [DIAZ ATETRACYCLO[ 15.7.2.0 ³ - ⁶ .0 ²⁰ - ²⁵ ]HEXACOS Aj 17, 19,25 ]TRIEN] - 16'-0NE 14', 14'-DI0XIDE

(l S,3'R,6'R,7'R,8'E)-6-chloro-7 ^f iydroxy-3,4-dihydro-2H, 16'H- spiro [naphthalene- 1 ,23 '- [21]oxa[14]thia[ l, 15]diazatetra^

]-16'-one 14', 14'-dioxide (15 mg, 0,026 mrnol, Example 227) was dissolved in EtOAc (1.0 mL) and platinuni(iv) oxide (5.8 mg, 0.026 mmol) was then added. The reaction vessel was flushed with hydrogen and kept under balloon pressure for 4.5 hours. The reaction mixture was then directly loaded on a column and purified by medium pressure chromatography (silica, 0 to 60% EtOAc(+0.3% HO Ac) :Hexanes) to give (1 S,3 ^! R,6'R,7'R)-6-chloro-7'-hydroxy-3,4-dihydro- 2H, 16'H-spiro[naphthaiene- 1 ,23'- [21]oxa[l 4]thia[ 1, 15]diazatete^

16'-one 14', 14'-dioxide (8.5 mg, 0.014 mmol, 57 % yield). ). ¾ NMR (400MHz, CDCh) 5 9.49 (s, 1H), 7.72 (d, J 8.6 Hz, 1H), 7.36 (dd, J 8.3. 2.1 Hz, 1H), 7. 14- 7.21 (m, 2H), 7.09 id. j 2.2 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.10 (d, j 5.3 Hz, 2H), 3.74-3.88 (m, 2H), 3.71 (d, J 14.3 Hz, i l l ). 3,59 (dd, j 8.7. 3.2 Hz, 1H), 3.51 (dt, j 15.4. , 5,6 Hz, 1H), 3.23 (d, j 14 3 Hz, I I I ). 3.12 (dd, J 1 5. -. 6,8 Hz, 1H), 2.66-2.87 (m, 2H), 2.30-2.56 (m, 2H), 1.88-2.10 (m, 4H), 1.73-1.87 (m, 3H), 1.29-1.73 (m, I I I I ), m (ESI, +ve ion) 587.2 (M+H) ⁺ .

EXAMPLE 229, (1 S,3'R,6'R,7'R,8'E)-6-CHLORO-7'-METHOXY-3,4- DIHYDR.0-2H,16'H-SP1R0[NAPHTHALENE-1,23'- [21]OXA[14]THIA[1 ,15]DIAZATETRACYCLO[15.7.2.0 ³ ' ⁶ .0 ²⁰ - ²⁵ ]HEXACOSA| 8,17,19,25]TETRAEN] - 16'-ONE 14', 14 ^! -DlGXlDE

O

(l S ₅ 3¾,6'R,7 ^, R ₅ 8 ^, E)-6-chloro-7 ^, -hydroxy-3,4-dihydro-2H ₅ 16 ^, H- spiro [naphthalene- 1 ,23 '- [21 joxa[14]thia[ l, 15]diazatetracyclo^

]-16'-one 14', 14'-dioxide (25 mg, 0,043 mrnol, Example 227) was dissolved in THF (1.0 ml.) and cooled to 0 °C. Sodium hydride (60% dispersion; 17.0 mg, 0.43 mrnol) was added and the slimy was stirred at 0 °C for 20 minutes. The slurry was taken out of the ice hath for about three minutes to ensure anion formation (slurr ' turns slightly green in color) and the iodomethane (0.013 mL, 0.214 mrnol) was added after reemerging in the ice bath. The slum- was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 25 mL) and dried over magnesium sulfate. The filtrate was concentrated and the residue was purified by medium pressure chromatography (silica, 0 to 40% EtOAc(+0.3%

HOAc);Hexanes) to give (l S,3'R,6'R,7'R,8'E)-6-chloro-7'-methoxy-3,4-dihydro- 2H, 16'H-spiro[naphthalene- 1 ,23'-

[21]oxa[14]thia[ l,15]diazatetracycio[15.7.2.0 ³ ' ⁶ .0 ²⁰ ' ²⁵ ]hexacosa[8,17,19,25]tetraen ]-16'-one 14', 14'-dioxide (22 mg, 0.037 mrnol, 86 % yield). ^! H NMR (400MHz, CDCb) δ 9.35 (s, i l l ). 7.57-7.73 (m, i l l ). 7,29 (dd, J 2. 1. 8.3 Hz, i l l ). 7,21 (d, j 2.2 Hz, 1H), 7.11 (dd, 1=2.2, 8.5 Hz, 1H), 6.81-6.97 (m, M l ). 5.70 (td, J=15.0, 7.3 Hz, 1H), 5.42-5.55 (m, 1 1 1 }. 3.96-4, 10 (m, 2H), 3.69-3.81 (m, 1H), 3.57-3.69 (m, 2H), 3,50 (dd, J 8.3. 4.4 Hz, i l l ). 3.26-3.39 (m, 5H), 3, 13-3.24 (m, 1H), 2.97- 3, 10 (m, IH), 2.62-2,79 (m, 2H), 2.40-2.61 (m, 2H), 1 .49-2. 18 (ra, 13H). /z (ESI, +ve ion) 599.2 (M+H) ⁺ .

EXAMPLE 216. (l S,3'R,6 ^, R,7 ^! R)-6-CHLORO-7'-METHOXY-3,4-DlHYDRO- 2H, 16'H-SPIRO[NAPHTHALENE- 1 ,23'- [21 ]OXA[14]TfflA[l,15]DIAZATETRACYCLO[15.7.2.0 ³ - ⁶ .0 ²⁰ - ^2S ]HEXACOSA 17,19,25]TRIEN]-16 ^* -ONE 14'. ! i -OIOXU)} .

( 1 S ,3 'R,6¾, 7'R, 8Ti)-6-diloro-7'-methoxy -3 ,4-dihy dro-2H, 16Ή- spiro[naphthalene-l,23'- [21 ]oxa[ 14]thia[l ,15]cUazatetracyclo[^^

]-16'-one 14',14'-dioxide (19 mg, 0.032 mmol, Example 229) was dissolved in

EtOAc (1.0 mL) and platinum(iv) oxide (7.2 mg, 0.032 mmol) was then added.

The reaction vessel was flushed with hydrogen and kept under balloon pressure for 4.5 hours. The reaction mixture was then directly loaded on a column and purified by medium pressure chromatography (silica, 0 to 60% EtOAc(+0.3%

HOAc):Hexanes) to give (l S,3'R,6 ^, R,7 ^, R)-6-chloro-7 ^, -methoxy-3,4-dihydro-

2H, 16'H-spiro[naphthalene-l ,23'-

[21 ] oxa i 4] thi a[ I /I 5] di azaieto^

16'-one 14',14'~dioxide (12 mg, 0.020 mmol, 63 % yield). ¾ NMR (400MHz, CDCh) δ 9.62 (s, 1H), 7.59-7.74 (m, IH), 7.37-7.53 (m, IH), 6.99-7.15 (m, 3H), 6.79-6.97 (m, I H), 3.98-4.14 (m, 2H), 3.54-3.94 (m, 3H), 3.25-3.39 (m, IH), 2.97- 3.15 (m, 3H), 2.50-2,80 (m, 3H), 2.21 -2,45 (m, IH), 1 .36-2.08 (ra, 20H). /z (ESI, +ve ion) 601.2 (M+H) ⁺ . EXAMPLE 231. (IS,3'R,6'R,7 ^f R,8'E,ri'S)-6-CHLORO-7'-HYDROXY-l 1 ^* - ME ^r rHYL~3,4~DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE"l,22'- [20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8 ₅ 16, 18,24]TETRAEN]-15"-ONE !3',13'-DiOXIDE OR

(lS 'R,6 ^! R 7¾,8'E ₅ ] l'R)-6 HLORO-7'-HYDROXY-l ] ^! -ME ^' raYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA [8, 16, 18 , 24] TETR AEN 1 - 15'-ONE 13", 13 -DIOXIDE

STEP I : (S)-6 ^! -CHLORO-5-((( 1 R,2R)-2-{(R,E)- 1 -HYDROXYHEX-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-N-(((S)-2-METHYLPENT-4-EN-l- YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2 ^! H- SPIRO [BENZO [B ][1,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6 ^! ~CHLORO-5-(((lR,2R)-2~((R,E)-l - HYDROXYHEX~2"EN-l-YL)CYCLOBUTYL)METHYL)-N-(((R)-2~

METHYLPFi!SiT-4-EN-l -YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE

' and ^'

(S)-6'-chloro-5-(((lR ₅ 2R)-2-((R ₅ E)-l-hydroxyhex-2-en-l yl)cyclobu d)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,1 '-naphthalene] -7-earboxy lie acid (0.600 g, 1.18 mmol, Intermediate AA12B), a racemic mixture of (S)-2-methylpent-4-ene-l -sulfonamide and (R)-2-methylpent- 4-ene-l -sulfonamide (0.326 g, 2.000 mmol. Example 376, Step 2) and 4- dimethylaminopyridine (DMAP) (0.244 g, 2.000 mmol) were dissolved in DCM (12 mL). To the reaction mixture was added edc hydrochloride (EDC; 0.451 g, 2.35 mmol) and stirred overnight. The reaction mixture was then purified by medium pressiire chromatography with no work-up (silica, 10 to 60% EtOAc (+0.3% HOAc):Hexanes) to give (S)-6'-chloro-5-(((lR,2R)-2-((R,E)-l- hydrox 'hex-2-en-l-yl)cyclobutyl)methyl)-N-(((S)-2-methylpent-4-en- l - yl)sulfonyl)-3^4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, - naphthalene]-7-carboxamide and (S)~6'~chloro~5-(((l R,2R)-2-((R,E)- 1 - hy droxyhex-2-en- 1 -yl)cy clobutyl)methyl)-N-(((R)-2-methylpent-4-en- 1 - yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, - naphthalene] -7-carboxamide as a 1 : 1 mixture (390 mg, 0.60 mmol, 51 % combined yield) , m/z (ESI, +ve ion) 655,2 (M+H) ⁺ .

STEP 2: (lS,3'R,6'R,7 ^, R,8'E,i S)-6-CHLORO-7 ^, -HYDROXY-i -METHYL-

3,4-DIHYDRO-2H,15'i-I-SPIRO[NAPHTHALENE-l ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7'R,8'E,l l'R)-6-CHLORO-7'-HYDROXY-ir-METHYL-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE The 1 : 1 mixture of (S)-6'-chloro-5-(((lR,2R)-2-((R,E)-l-hydroxyhex-2-en- l-y )cycIobutyl)methyl)-N-(((S)-2-methylpent-4-en-l-yl)su3fonyl) -3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)-6'-chioro-5 -(((1 R,2R)-2-((R,E)- 1 -hydroxy hex-2-en- 1 - yl)c\xlobutyl)methyl)-N-(((R)-2-methylpent-4-en-l-yl)sulfony l)-3',4,4',5- tetrahy dro-2H,2H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxami de (390 mg, 0.595 mmol) was dissolved in 1,2-dichloroethane (300 mL) and the vessel was flushed with argon. (l,3-dimesitylirnidazolidin-2-ylidene)(3-phenyl- lH-inden-l-ylidene)ruthenium(VI) chloride (39.8 mg, 0.060 mmol) was then added and the solution was stirred at 80 °C for 2.5 hours (more catalyst was added as needed to drive the reaction to completion).2-(2-(vinyloxy)ethoxy)ethanol (0.024 mL, 0.18 mmol) was then added and the mixture was stirred for 30 minutes to quench the catalyst; the reaction was then concentrated and the residue was purified by medium pressure chromatography (silica, 30 to 80% EtOAc (+0.3% HOAc):Hexanes) to give (18,3·Κ,6'Κ,7¾,8Έ,1 rS)-6-chloro-7'-hydroxy-l Γ- methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- 8.24i!eirac n]-15'-one 13',13'-dioxide or (lS,31 ,6'R,7 ^! il,8'E,ir 6~chloro-7 ^! "hydiOxy-l Γ- methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[!3]thia[l,!4]diazatetra^

n]-15'-one 13',13'-dioxide (56 mg, 0.096 mmol, 16 % yield) ¾ NMR (400MHz, CDC!:.) δ 9.26 (br. s., lH), 7.61 (d, j 8.4 Hz, 1H), 7.28-7.48 (m, 1H), 6.95-7.17 (m, 3H), 6,74-6.93 (m, 1H), 5.67-5,90 (m, 1H), 5,48-5.66 (m, 1H), 3.79-4,12 (m, 5H), 3.57 (d, j 1 .3 Hz, 1H), 2.96-3.16 (m, 2H), 2,59-2.89 (m, 3H), 2.43 (br. s., 2H), 2.12-2.23 (m, III).1.38-2.07 (m, llH), 1.10 (d, j 6,3 Hz, 3H). m/z (ESI, +ve ion) 584.7 {M il} ,

EXAMPLE 232, (lS,3 ⁱ R,6'R,7'R,8'Z,i rR)-6-CHLORO-7'-HYDROXY-l Γ- METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPfflHALENE-l,22 ^! - [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(lS,3'R,6¾,7¾,8'ZJI'S)-6-CHLORO-7'-HYDROXY-ir-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2,0 ".i) ^|u |P1 ^: N I ^' ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13", 13-DIOXIDE

The title compound was obtained as the second eluting isomer from medium pressure chromatography (silica, 30 to 80% EtOAc (+0.3%

HOAc):Hexanes) in Example 231, Step 2 (32 mg, 0.055 mmol, 9.2 % yield). ¾ N.MR (400MHz, CDCb) δ 9,66 (d, J 17.6 Hz, ill).7.55-7,67 (m, 111).7.18-7.28 (m, III).7.08 (dd, j 2.3.8,4 Hz, I Hi.7.00 (d, j 23 Hz, III).6.74-6.93 (m, 2H), 5.43-5.82 (m, 2H), 4.47 (t J=6.0 Hz, IH), 3.84-4.14 (m, 3H), 3.48-3.73 (m, 4H), 3.32 (dd, j 3.5.15.7 Hz, IH), 2.87-3.16 (m, 2H), 2.27-2.77 (m, 6H), 1.48-1.98 (m, 8H), 1,00-1.09 (m, 3H). m/z (ESI, +ve ion) 584.7 i\\ U) . EXAMPLE 233. (1 S,3'R,6'R,7'R,8'Z, 11 'R)-6-CHLORO-7'-HYDROXY-l 1 '- METHYL-3 ₅ 4-DIHΎDRO-2H _s 15Ή-SPIRO[ APH^ΉALENE-l _s 22 ^, - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA

[8J6,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'Z, 11 'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL-3,4- DIHYDRO-2H, 15TI-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

The title compound was obtained as the third eluting isomer from medium pressure chromatography (silica, 30 to 80% EtOAc (+0.3% HOAc):Hexanes) in Example 231 , Step 2 (10 mg, 0.014 mmol, 2.4 % yield). ^" Ή NMR (400MHz, CDCb) 59.22 (s, 1H), 7.73 (d, J=8.4 Hz, lH), 7.21 idi. j 8.6.2.2 Hz, 2H), 7.11 (d, j 2.2 Hz, ill).6.83-7.08 (in, 2H), 5.79-5.94 (m, 1H), 5.69 (dd, j 6.5.11.2 Hz, ill).4.49 (t, J 5.9 Hz, 1H), 3.95-4.22 (m, 21 \) 3.67-3,90 (m, 3H), 3.40-3.59 (m, 1H), 3.01-3.29 (m, 2H), 2.69-2.90 (m, Mil 2.18-2,54 (m, 2H), 1.79-2.21 (m, 10H), 1.43 (t j 12.7 Hz, ill).1.24 (d, j 6.8 Hz, 3H). m/z (ESI, +ve ion) 584.7 { M · Π } ,

EXAMPLE 235, (1 S,3'R,6'R,7 ^f R,8'Z,12'S)-6-CHLORO-7'-HYDROXY-! 2'- METHYL-3,4-DIH DRO-2H,15'H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

|;8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE

STEP 1 : (S)-6'-CHLORO-N-((S)-HEX-5-EN-2-YLS ULFONYL)-5-(((lR,2R)-2-

((R,E)-l-HYDR()XYHEX-2-EN-l-YL)CYCL()BUTYL)METHYL)-3 ^, ,4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l ,4]OXAZEPINE-3, 1 '- NAPHTHALENEl-7-C

iSHV-chi( ---iii IR.2K}-2-ίίRJ:)-l-hvdπ¾x hcx-2-en-i-

, -naphthalene|-7-carboxylic acid (0.300 g, 0.588 mmol, Intermediate AA12B) (S)-hex-5-ene-2-sulfonamide (0,144 g, 0.882 mrnol. Intermediate EE202) and 4- dimethylaminopyridine (DMAP) (0.12 g, 1.00 mrnol) were dissolved in DCM (12 mL). To the reaction mixture was added EDC (0.23 g, 1.18 mrnol) and stirred overnight. The reaction mixture was then purified by medium pressure chromatography with no work-up (silica, 10 to 60% EtOAc (+0.3%

HOAc):hexanes) to give (S)-6'-chloro-N-((S)-hex-5-en-2-ylsulfonyl)-5-(((lR,2R)- 2-((R,E)-l-hydroxv'hex-2-en-l-yl)c lobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide (290 mg, 0,44 mrnol, 75% yield) . m/z (ESI, +ve ion) 655.2 {V! -ft) ^' .

STEP 2: ( 1 S,3'R,6'R,7'R,8'Z, 12'S)-6-CHLORO-7'-HYDROXY- 12"-METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA

[8,16,18,24]TETP^ENj-15'-C)NE 13 ^! ,13'-DIOXIDE (S)-6 ^, -chloro-N-((S)-hex-5-en-2-ylsulfonyl)-5-(((lR,2R)-2-(( R,E)-l- hydrox>'hex-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrah ydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide (290 nig, 0.44 mrnol) was dissolved in 1,2-dichloroethane (200 mL) and the vessel was flushed with argon. The (l,3-dimesitylimidazolidin-2-ylidene)(3-phenyl-lH-inden-l- ylidene)ruthenium(VI) chloride (29.6 mg, 0.044 mrnol) was then added and the solution was stirred at 80 °C for 2.5 hours (more catalyst was added as needed to drive the reaction to completion). The 2-(2-(vinyloxy)ethoxy)ethanol (0.024 mL, 0.177 mmol) was added and stirred for 30 minutes to quench the catalyst and the reaction was then concentrated and the residue was purified by medium pressure chromatography (silica, 30 to 80% EtOAc (+0.3% HOAc):Hexanes) to give

(lS,3 ^, R,6'R ^, R,8 ^, Z,12 ^, S)-6-chloro-7 ^, ½droxy-12 ^, -me l-3,4-dihydro-2H,15H- spiro [naphthalene- 1 ,22'-

n]-15'-one 13',13'-dioxide as the first eluting isomer (44 mg, 0.075 mmol, 17 % yield). ¾ NMR (400MHz, CDCh) δ 7.57-7.67 (m, 1H), 7.25-7.38 (m, 1H), 7,30 (dd, J 2. 1 . 8.3 Hz, IH), 7.07-7.17 (rn, H), 6,97-7.04 (m, l H), 6.93 (s, 2H), 6.76- 6.93 (m, 2H), 5.54-5.69 (m, IH), 5.41-5.54 (m, IH), 4.67-4.76 (m, M l). 4.47 (t, j 5.3 Hz, IH), 3.73-4.09 (m, 3H), 3.50-3.72 (m, 4H), 2.95-3.18 { in. I H), 2,56- 2,76 (rn, 3H), 2. 16-2,50 (m, 3H), 1.66-2.02 (ra, 7H), 1.46-1.56 (m, 3H). m/z (EST, +ve ion) 584.7 (M+H) ⁺ .

EXAMPLE 236. (l S,3 ^, R,6'R,7 ^, S,8'E)-6-CHLORO-7 ^, -HYDROXY-9 ^f -BROMO- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ^{] 9} ' ²⁴ ]PE TACOSA

[8, 16, 1 8 , 24] TETR AEN] - 15'-ONE 13 ', 13 ^" -DIOXIDE OR ( 1 S,3 ^! R,6'R,7'R,8 ^! E)-6- CHLQRQ-7'-HYDRQXY-9 ^! -BRQMQ-3,4-DlHYDRQ-2H,15'H- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCIX)[ 14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24] TETRAEN] - 15 '-ONE 13 ' , 13 ' -DIOXIDE.

STEP 1 : POTASSIUM (Z)-(2-BROMO-5-CHLOROPENT-l-EN-l-

YL)TRIFLUOROB ORATE

F I i

F Br

K ⁺

Boron iribromide (1.0 M in DCM) (23 ml,, 23 mmol) soln. was cooled to -78 °C. 5-chloropent-l-yne (2.4 g, 23 mmol) was dissolved in DCM (47 mL) and added dropwise to the boron iribromide solution. The reaction mixture immediately turned to a dark orange solution. This solution was stirred at -78 °C for one hour. Then, the diisopropylether (6.64 mL, 46.8 mmol) was added and the ice bath was removed and the solution was allowed to warm to room temperature and stirred for 2.5 days. The reaction mixture was then concentrated to give the desired crude product (Z)-diisopropyl (2-bromo-5-chloropent-l-en-l-yl)boronate. The crude isopropvl boronate ester (4300 mg, 14 mmol) was dissolved in THF (27 mL). 2 ml. of KFHF (400 mg/mL sola; 6500 mg, 83 mmol) was added and the resulting yellow solution was stirred overnight. The reaction mixture was then concentrated to dryness under reduced pressure and the residue was first slurried in warm acetone and filtered. The filtrate was then triturated with diethyl ether and a white precipitate formed that was filtered, washed with ether and dried to give potassium (Z)-(2-bromo-5-chloropent-l -en-l-yl)trifluoroborate (4.00 g, 13.8 mmol, 100 % yield), m/z (ESI, +ve ion) 269.9 ( Yl-k - H ) , 157.1 (M-K ⁺ -1 12) ⁺ (base peak).

STEP 2: (S)-METHYL-5-(((lR ₅ 2R)-2-((R^Z)-3-BROMO-6-CHLORO-l- HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'-CHLORO- 3 4,4 5-TETRAHYDRO-2H,2TI-SPIR()[BENZO| B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-C ARBOXYLATE OR (S)-METHYL-5-(((l R,2R)-2-((S,Z)- 3-BROMO-6-CHLORO-1 -HYDROXYHEX-2-EN-l -

YL)CYCLOBLrrYL)METHYL)-6 ^, -CHLORO-3',4,4',5-TETR^\HYDRO-2H,2 ^! H- SPIRO BENZO[B] [1 ,4 ]OXAZEPINE-3, 1 '-NAPHTHALENE]-7-

CARBOXYLATE

The (Z)-(2-bromo-5-chloropent-l-en-l-yl)trifluoroborate (2.2 g, 7.7 mmol) was slurried in 10 mL of DCM and cooled to 0 °C. The boron trifiuoride etherate (0.98 mL, 7.7 mmol) was added and the slurry was stirred at 0 °C for 10 minutes. Intermediate AAl lA, Step 20A (1.00 g, 2.20 mmol) was dissolved in 5 mL of DCM and added slowly at 0 °C. The ice bath was then removed and the mixture was allowed to warm to room temperature over 3.5 hours. The resulting yellow mixture was diluted with DCM (-100 mL) and water (45 mL) was added. The layers were separated and the aqueous layer was extracted (1 x 150 mL) with DCM. The combined organic layers were dried over magnesium sulfate and the crude product was purified by medium pressure chromatography (silica, 0 to 30% EtOAc:Hexanes) to give (S)-methyl 5-(((lR,2R)-2-((R,Z)-3-bromo-6-chloro-l- hydroxyhex-2-en-l-yl)cyclobutv'l)methyl)-6'-chloro-3',4,4',5 -tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-methyl 5- (((1 R,2R)-2-((S,Z)-3-bromo-6-chloro- 1 -hydroxyhex-2-en- 1 - yl)cyclobu1yl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox>'late (340 mg, 0.53 mmol. 24%) as the first eluting and major isomer. Further elution provided (S)- methyl 5-(((lR,2R)-2-((R,Z)-3-bromo-6-chloro-l-hydrox\'hex-2-en-l- yl)cvxlobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate or (S)-methyl 5- (((1 R,2R)-2-((S,Z)-3-bromo-6-chloro- 1 -hydroxyhex-2-en- 1 - yl)cyclobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [1,4] oxazepine-3 , Γ -naphtha! ene] -7-carboxy late (230 mg, 0.36 mmol, 16% yield) as the second eluting and minor isomer, m/z (ESI, +ve ion) 638.0 ( M i l s ^' .

STEP 3: (S)-METHYL 5-(((lR,2R)-2-((S,Z)"3-BROMO-l-HYDROXY-6- (PYRIMIDIN-2-YLTHIO)HEX-2-EN- 1 -YL)CY CLOBUTYL)METHYL)-6'- CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL 5-(((l R,2R)-2-((R-Z)-3-BROMO-l- HYDROXY-6-(PYRIMIDIN-2-YLTHIO)HEX-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-6 ^* -CHLORO-3^4,4\5-TETRAHYDRO-2H,2 ^, H-

SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE.

(S)-methyl 5-(((lR,2R)-2-((R,Z)-3-bromo-6-chloro-l -hydroxyhex-2-en-l - yl)cyclobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydfo-2H,2'H- spiro[benzo[b] [ l ,4]oxazepine-3, l.'-naphthalene]-7-carbox 'late or (S)-methyl 5- (((l R,2R)-2-((S,Z)-3-bromo-6-chloro-l-hydroxyhex-2-en-l- yl)cyclobulyl)methyl)-6 ^, -chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [ l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (280 mg, 0.44 mmol, Example 236, Step 2, second eluting isomer) was dissolved in DMF (9 mL) and potassium carbonate (240 mg, 1.8 mmol) and 2-mercaptopyrimidine (200 mg, 1.8 mmol) were added. The mixture was stirred for 4.5 hours to completion. The reaction was quenched with water and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude product was then purified by medium pressure chromatography (silica, 0 to 40%) EtOAcJiexanes) to give (S)-methyl 5- (((lR,2R)-2-((S,Z)-3-bromo- l -hydrox>'-6-(pyrimidin-2-ylthio)hex-2-en- l - yl)cyclobu1y'l)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H - spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylate or (S)-methyl 5- (((1 R,2R)-2-((R,Z)-3-bromo- l -hydroxy-6-(pyrimidin-2-ylthio)hex-2-en-.l - yl)c 'clobu1yl)methyl)-6 ^, -chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (190 mg, 0.26 mmol, 59% yield), m/z (ESI, +ve ion) 713.1 (M+H) ⁺

STEP 4: (S)-METHYL 5-(((lR,2R)-2-((R ₅ Z)-3-BROMO-l -HYDROXY-6- (PYRIMDIN-2-YLSULFONYL)HEX-2-EN- l-YL)CYCLOBUTYL)METHYL)-

6'-CHLORO-3',4,4',5"TETRAHYDRO-2H,2'H- SPIRO| BENZO[B;| |;i,4 |OXAZEPINE-3, l '-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 5-(((lS,2R)-2-((S,Z)-3-BROMO-l- HYDROXY-6-(PYRIMIDIN-2-YLSULFONYL)HEX-2-EN-l- YL)CYCLOBUTYL)METHYL)-6 ^, -CHLORO-3 ^, ,4.4',5-TETRAHYDRO-2H,2H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE.

Hydrogen peroxide 30% in water (0.24 mL, 2.3 nirnoi), phenylphosphonic acid (8.7 μΐ., 0.078 mrnol), sodium tungstate, dihydrate (8.0 μί, 0.078 mrnol) and tetra utylammonium sulfate, 50 wt. % solution in water (0.090 mL, 0.078 mmol) were added together and (S)-methyl 5-(((lR,2R)-2-((S,Z)-3-bromo-l-hydroxy-6- (pyrirnidin-2-ylthio)hex-2-en-l-yl)cv'clobutyl)methyl)-6'-ch loro-3',4,4',5- tetTahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalen e]-7-carboxylate or (S)-methyl 5-(((lR,2R)-2~((R,Z)~3-bromo-l~hydroxy-6-(pyrimidin-2- yltMo)hex-2-en-l-yl)cyclobut\'l)methyl)-6'-chloro-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (190 mg, 0.26 mmol, from step 3) dissolved in toluene (2.0 mL) was added. The mixture was heated to 60 °C and stirred for 3.5 hours to completion. The mixture was then cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (1 x 15 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatograpy (silica, 0 to 100% EtOAc:Hexanes) to give (S)-methyl 5- (((lR,2R)-2-((R,Z)-3-bromo-l -hydroxy -6-(pyrimi din-2-ylsulfonyl)hex-2-en-l - yl)cyciobutyl)methyl)-6'~chloro-3',4,4',5~tetraliydro-2H,2'H ~

spiro| benzo| bj [ l,4 |oxazepine-3, -naphthaIene]-7-carboxyiate or (S)-methyl 5- (((lS,2R)-2-((S,Z)-3-bromo-l -hydroxy-6-(pyrimidin-2-ylsulfonyl)hex-2-en-l- yl)cyclobutyl)methyl)-6'-chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiroj benzoj bj [ L4 |oxazepine-3, -naphthaIene]-7-carboxylate (46 mg, 0.062 mmol, 24 % yield), m/z (EST, +ve ion) 746.0 { V! H }

STEP 5: (S)-METHYL 5-(((lR,2R)-2-((R,Z)-3-BROMO-l -HYDROXY-6- SULFAMOYLHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-6'-CHLORO-

3' _; 4' ₅ 5-TETl AHYDRO-2H,2'H~SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYL ATE OR (S)-METHYL 5-(((lR,2R)-2-((S,Z)- 3-BROMO-l -HYDROXY-6-SULFAMOYLHEX-2-EN- 1 -

YL)CYCLOBLrrYL)METHYL)-6 ^, -CHLORO-3',4,4',5-TETR^\HYDRO-2H,2 ^! H-

SPIR0| BENZ0[B] |;L410XAZEPINE-3,1'-NAPHTHALENE]-7-

CARBOXYLATE,

(S)-methyl 5-(((lR,2R)-2-((R,Z)-3-bromo-l-hydroxy-6-(pyrimidin-2- ylsulfonyl)hex-2-en-l-yl)cyclobu1yl)methyl)-6'-chloro-3',4,4 ^, ,5-tetrahydfo- 2H,2'H-spiro[benzo[b] [1 ,4]oxazepine-3, l'-naphthalene]-7-carboxylate or (S)~ methyl 5 -((( 1 S,2R)-2-((S ,Z)-3 -bromo- 1 -hy droxy-6-(py rimidin-2-y 1 sulfony l)hex- 2-en-l-yl)cyclobutyl)methyl)-6 ^, -chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxylate (45 mg, 0.060 mmol, from step 4) was dissolved in MeOH (6.5 mL) and potassium carbonate (41.7 mg, 0.302 mmol) was added. The mixture was stirred for 1.5 hours. The hydroxylamine-o-sulfonic acid (34 mg, 0.30 mmol) was then added and the resulting cloudy reaction mixture was stirred for two hours. The reaction was concentrated and then partitioned between water (15 mL) and ethyl acetate (25 mL). The aqueous layer was extracted (1 x 25 mL) with EtOAc and the combined organic layers were washed with brine and dried over magnesium sulfate. The crade product was purified by medium pressure chromatography (silica, 30 to 100% EtOAc:Hexanes) to give (S)-methyl 5-((( lR,2R)-2-((R,Z)-3-bromo-l- hydroxy-6-sulfamoylhex-2-en-l -yl)cyclob

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylate or (S)-methyl 5-(((lR,2R)-2-((S,Z)-3-bromo-l-hydroxy-6-sulfamoylhex-2-en-l - yl)cyclobutyl)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate. (41 mg, 0.060 mmol, 100 % yield), m/z (ESI, +ve ion) 683.0 { M l I ) . STEP 6: (S)-5-(((lR,2R)-2-((R£)-3-BROMO-l -HYDROXY-6-

SULFAMOYLHEX-2-EN-l -YL)CYCLOBUTYL)METHYL)-6'-CHLORO-

3',4,4',5-TETRAHYDRO-2H,2'H-SPlRO[BENZO[B] [ 1 ,4] OXAZEPINE-3 , 1 '- NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)~5~(((1R,2R)~2~((S,Z)~3~ BROMO - 1 -HYDROXY -6-S ULF AMO YLHEX-2-EN- 1 - YL)CYCLOBUT L)METHYL)-6'-CHLORO-3 ^, .4,4 ^, .5-TETRAHYDRO-2H,2 ^, H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID.

(S)-raethyl 5-(((IR,2R)-2-((R,Z)-3-brorao-I-hydroxy-6-su]famoylhex-2- en- l-yl)c>'clobut>'l)methyl)-6 ^, -chloro-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [ l,4]oxazepine-3,r~naphthalene]-7-carboxylate or (S)-methyl 5- (((1 R,2R)-2-((S,Z)-3-bromo- 1 -hy droxy-6-sulfamoylhex-2-en- 1 - yl)cyclobut 'l)methyl)-6'-chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7 -carboxy 1 ate (41 mg, 0.060 mmol) was dissolved in a 2: 1 mixture of MeOH (3.00 mL) and THF (1.5 mL). To the solution was added lithium hydroxide (2 M; 0.30 mL, 0.60 rnmol) and the resulting mixture was stirred for overnight. The reaction was then heated to 50 °C and stirred for 7.5 hours. The reaction mixture was then concentrated to a reduced volume in vacuo. The residue was then acidified to pH~5 and this mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (1 x 15 mL) and dried over magnesium sulfate to give (S)-5~ (((lR,2R)-2-((R,Z)-3-bromo-l-hydroxy-6-sulfamoylhex-2-en-l- yl)cyclobutyl)methyl)-6'-chloro-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid or (S)-5- (((1 R,2R)-2-((S,Z)-3-bromo- 1 -hy droxy-6-sulfamoylhex-2-en- 1 - yl)c 'clobutyl)methyl)-6 ^, -chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, ~naphthalene]-7-carboxylic acid (40 mg, 0.060 rnmol, 100 % yield), m/z (ESI, +ve ion) 669.1 { M l ! ) .

STEP 7. (1 S,3'R,6 ^, R,7 ^, S.8 ^, E)-6-CHLORO-7 ^, -HYDROXY-9 ^, -BROMO-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13' -DIOXIDE OR (lS,3'R,6'R,7'R,8'E)-6- CHL()R()-7'-HYDROXY-9'-BROM()-3,4-DlHYDRO-2HJ 5'H- SPTRO[NAPHTH ALENE- 1 ,22'- | 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 0 ' ".U ^{1 *} ' · ¹ |PH\ i ACOSA

[8,16,18,24] TETRAEN] - 15 '-ON E 13 ' , 13 ' -DIOXIDE.

EDC (34 mg, 0.18 rnmol), triethylamine (36 mg, 0.36 rnmol), DMAP (22 mg, 0.18 rnmol) and (S)-5-(((l R,2R)-2-((R,Z)-3-bromo-l -hydroxy-6- sulfamoymex-2-en-l -yl)cyclobutyl)methyl)-6'-cM

spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid or (S)-5- (((1 R,2R)-2-((S,Z)-3-bromo- 1 -hy droxy-6-sulfamoylhex-2-en- 1 - yl)cyclobutyl)meihyl)-6'-chlorc :r,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (40 mg, 0.60 rnmol) were combined in DCM (12 mL) and stirred overnight at room iernperaiure. The reaction mixture was concentrated. The crude material was purified by reverse-phase preparative HPLC using a Plienomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 40% to 70% over 20 mm to provide (lS,3'R,6'R,7'S,8'E)-6-chloro-7'-hydroxy-9'- bromo-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae nj-15'-one 13',13'-dioxide or (l S,3'R,6'R,7'R,8 ^! E)-6-chloiO-7'-hydroxy-9 -hromo- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacos

n j - 15 '-one 13 ' , 13 ' - di oxide. (5.1 mg, 7.9 μιηοΐ, 13 % yield). ^! i i NMR (400 MHz, CDCI3) 6 ppm 8.76 (br. s„ 11 1 ). 7,68 (d, J 8.4 Hz, i l l ). 7, 18 (dd, J 8Λ 2.2 Hz, 1H), 7.13-7.16 (m, IH), 7.07-7.13 (m, 21 \ l 6.96 (d, j 8 0 Hz, I H i. 5.96 (d, j 7 8 Hz, IH), 4.51 (dd, j 7.6. 5.1 Hz, IH), 4.06-4.24 (m, 2H), 3.85-4.02 (m, IH), 3.40- 3.71 (m, 4H), 2.57-2.87 (m, 5H), 2.08-2.20 (m, 3H), 1.97-2.07 (m, IH), 1.69-1.96 (m, 6H), 1 .49-1.67 (m, IH), 1 ,30-1.45 (m, I H). m/z (EST, +ve ion) 651.1

EXAMPLE 238, (1 S,3'R,6'R,7'R,8'E)-6-CHLORO-7'-HYDROXY-9'-METHYL- 3 ,4-DlH YDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[ l 4]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, 18,24]TETRAENl-15'-ONE 13' ₅ 13'-DTOXIDE OR (l S,3'R,6'R,7'S,8'E)-6- CHLORO-7 ^! -HYDROXY-9'-METHYL-3,4-DIHYDRO-2H, 15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATET ACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA

[8,16,18,24] TETR AEN] - 15 '-ONE 1 . 1 -DIOXIDE.

The vinyl bromide (IS 'R,6'R,7'S,8'F~0~chloro~7 ^f -hy droxy-9'-hromo-3,4~ dihy dro-2h, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[U4]cUazatetxacyc^

n]-15'-one 13',13'-dioxide or (lS,3 ^f R,6'R,7'R,8'E)-6-chloro-7'-hydroxy-9 ⁱ -brorao- 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (9.0 mg, 0.014 mrnol, Example 236) was dissolved in 1,4-dioxane (0.3 ml.) and cesium carbonate (16 mg, 0.048 mrnol), PdCl ₂ (dppf)- CH2CI2 (2.3 mg, 2.8 μηιοΐ) and methaneboronic acid (2.5 nig, 0.042 mrnol) were then added and the reaction was heated at 100 °C for one hour. The reaction was then cooled and diluted with EtOAc, The mixture was then fitered and the filtrate was concentrated to dryness. The crude product was purified using SFC chromatography (AS column, 35% MeOH/C02) to give (Ι8,3Ί ,6¾,7'ί,8Έ)-6- chloro-7'-hydroxy-9'-methyl-3,4-dihydro-2H,15H-spiro[naphtha lene-l,22'- |20jo\aj I3|ihi«i| i. I4|dia/aieuac> ciol I4.7.2.(! ^; ''.(! ^1'i jpenlacosa|K.!6JS.2-ljleirae n]-15'-one I.V.I 3 ^' -dioxide or (lS,3 ^! R,6'R,7'S,8'E)-6-chloi -7'-hydroxy-9'-methyl- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]uiia[l,14]diazate1r^

n]-15'-one 13',13'-dioxide (2.3 mg, 28%). ^" Ή NMR (400 MHz, (1X1;) δ ppm 7.79 (d, J 8.6 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J 7.6 Hz, 1H), 7.18 (dd, J=8.5, 2.2

Hz, ill .7.12 id. j 2.2 Hz, 1H), 6.81 (d, j HO Hz, III).5.74 (d, j 9.6 Hz, III).

4,32 (d. J 7.6 Hz, ill).4.05-4,11 (m, 111).3.93-4.02 (ra, ill).3,67-3.8! (m, 21!}.

3,38-3.51 (m, 2H), 3.38-3.52 (m, 2H), 3.17 (dd, J=15.0, 10.7 Hz, ill).2.70-2.97

(m, 4H), 2.49-2.63 (m, 1H), 2.25-2.42 (m, 1H), 2.00-2.20 (m, 3H), 1.87-1.99 (m, ill). 1.82 (t, .1 7. Hz, 2H), 1.68- 1.72 (n, 3H), 1.39- 1 , 54 ( m, 1 H). m/z (ESI, + ve ion) 585.1 (M+H) , 567,3 (M-H ₂ 0+H) (base peak).

EXAMPLE 239. (1 S,3'R,6 ^! R,7'R,8'E)-6-CHI,ORO-7'-HYDROXY-9'-METHYL- 3,4-DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE-l,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ '*0 ^]9 ' ²⁴ ]PEOTACOSA [8,16,18,24]TETRAEN]-15 ^! -ONE 13',13 ^" -DIOXJDE OR (lS,3 ^! R,6'R,7'S,8'E)-6- CHLORO-7'-HYDROXY-9 ^f -METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, 18 ,24] TETR AE ] - 15 '-ONE 13 \ 13 ' -DIOXIDE,

STEP 1 : (1 S,:rR,6'R,7 ^! S,8'E)-6-CHLORO-7'-HYDROXY-9'-BROMO-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA

[8, 16, 1 8 , 24] TETR AEN] - 15'-ONE 13 13 ' -DIOXIDE OR ( 1 S,3 ^! R,6'R,7'R,8 ^! E)-6-

CHLQRQ-7'-HYDRQXY-9 ^! -BRQMQ-3,4-DlHYDRQ-2H,15'H-

SPIRO INAPHTHALENE- 1.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8,16, 18 ,24] TETR AEN] - 15 '-ONE 13', 13 ' -DIOXIDE.

The title compound was obtained from Example 236 Step 3, first eluting isomer following a similar procedure as outlined in example 236, Steps 4-7,

STEP 2 : (l S,3'R,6'R,7'R,8Ti)-6-CHLORO-7'-HYDROXY-9'-METI-TYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,I6, 18,24]TETRAEN]-15'-ONE 13' ₅ 13'-DTOXIDE OR (I S,3'R,6'R,7'S,8'E)-6- CHLORO-7'-HYDROXY-9 ^f -METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18 ,24] TETR AEN] - 15 '-ONE 13 ' , 13 ' -DIOXIDE, The vinyl bromide (1 S,3'R,6'R,7'S,8'E)-6-chloro-7'-hydroxy-9 ^f -bromo-3,4- dihydro-2h, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14 7.2.0 ³ ' ⁶ .0 ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-15'-one 13',13'-dioxide or (1 S,3'R,6'R,7'R,8'E)-6-chloro-7'-hydroxy-9'-bromo- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[I,14]diazatetn^

n]-15'-one 13',13'-dioxide (55 mg, 0.085 mmol, Example 238, step 1) was dissolved in 1 ,4-dioxane (2.0 mL) and cesium carbonate (96 mg, 0.30 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ (14 mg, 17 μηιοΐ) and methaneboronic acid (15 mg, 0.250 mmol) were then added and the reaction was heated at 100 °C for one hour. The reaction was then cooled and diluted with EtOAc. The mixture was then fitered and the filtrate was concentrated to dryness. The crude product was purified using SFC chromatography (AS column, 35% MeOH/C02) to give

(lS,3 ^! R,6·R,7'R,8Έ)-6-chloro-7'-hyd oxy-9'-methyl-3,4-dlhyd o-2H,15Ί-I- spiro [naph thalene- 1 ,22'-

n]-15'-one 13 ^" ,13 '-dioxide or (l S,3'R,6'R,7 ^* S,8 ^! E)-6-chloro-7 ^* -hydroxy-9'-methyl- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

[20]oxa[I 3]thia[ l, I 4]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 1 ^" . 1 3 ^' -dioxide (5.0 mg, 33%). Ή N.V1R (400 MHz, CDCb) δ ppm 1.79 (t, ,/ 8.02 Hz, 2 H) 1.85 - 1.99 (m, 4 1 1 ) 1.99 - 2.17 (m, 4 H) 2.24 - 2.36 (m, 1 H) 2.49 - 2.6 ! (m, 1 IT) 2.69 - 2.97 (m, 4 H) 3.14 (dd, ,/ 14.87. 10.56 Hz, 1 I I ) 3.37 - 3.49 (m, 2 H) 3,65 - 3.78 (m, 2 H) 3.92 - 4.00 (m, 1 H) 4,03 - 4.13 (m, 1 H) 4.30 (d, ./ 7.63 Hz, 1 H) 5.71 (d, ./ 9.59 Hz, 1 H) 6.58 - 6.66 (m, 1 H) 6.78 (d, ./ 8.02 Hz, 1 1 1 ) 7.09 (d, ,/ 2. 1 5 Hz, 1 H) 7.16 (dd, ./ 8.6 ! . 2, 15 Hz, 1 H) 7.33 (d, J=7.63 Hz, 1 H) 7.47 (s, 1 H) 7.71 - 7.81 (m, 1 H). m/z (ESI, +ve ion) 585.3 EXAMPLE 240, (lS,3'R,6 ^, R,7 ^, S,9 ^, S)-6-CHLORO-7 ^, -HYDROXY-9'-METHYL- 3,4-DlHYDRQ-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [16,I8,24]TRIEN]-15'-ONE 13',13'-DIOXIDE AND (1 S,3'R,6'RJ'S ,9'R)-6- CHLORO-7 ^! -HYDROXY-9'-METHYL-3,4-DIHYDRO-2HJ5'H~

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '* 0 ^{] 9} ' ²⁴ ]PE TACOSA

[16J 8,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R,9'S)-6- CHLQRQ-7'-HYDRQXY-9'-METHYL-3,4-DIHYDRQ-2H,I5'H- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1 4]DIAZATETRACYCIX)[!4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TR1EN]-15'-0NE 13',13'-D10XIDE AND (lS,3'R,6'R,7'R,9'R)-6- CHLQRQ-7'-HYDRQXY-9 ^* -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]Tffl A[l ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

To a solution of (lS,3 ^, R,6'R,7'R,8'E)-6-chloro-7 ^, -hydroxy-9 ^, -methyl-3,4. dihydro-2H,15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazatetra<y^

n]-15'-one 1 ^" .1 3 ^' -dioxide or (lS,3'R,6'R,7'S,8'E)-6-chloi -7'-hydroxy-9'-methyl- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'- |20jo\aj I |ihi«i| ! 4jdia/aicira > clo! 14.7.2.0 ^; -' ¹ ^ jpen!acosa|K.16.18.24 jieirae n]-15'-one 13 ',13 '-dioxide (40 mg, 0.062 mmol, Example 238) in EtOAc (2.0 mL) and MeOH (1.0 mL) was added platinumuv) oxide (34.9 mg, 0.154 mmol) and the reaction flask was flushed with hydrogen and kept under balloon pressure overnight. LCMS indicated -70% conversion, so another aliquot of platinum(iv) oxide (35 mg, 0.15 mmol) and MeOH (1.0 mL) was added and the mixture was stirred again under hydrogen for an additional 5.5 hours to completion. The slurry was then filtered and then concentrated to dryness. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, C 18(2), 100 A , 150 x 30 mm, 0.1 % TFA in CH ₃ CN/H ₂ 0, gradient 40% to 70% over 20 mm to provide (lS,3 ^, R,6 ^, R,7'S,9'S)-6-chloro-7'-hydroxy-9'- methy 1 -3 ,4-dihy dro-2h, 15 'h-spiro[naphthalene- 1 , 22'-

[ 20] oxa[ 13 ]thia[ U 4] diazatetracyxi^ ^

15'-one 13',13'-dioxide and (18,3¾,6¾,7'8,9¾)-6-ΰωοΓθ-7 ^! ¾χΐΓθχν-9'-ιη6 1- 3,4-dihydro-2h,15'h-spiro[naphthalene-l,22'-

[20]oxa[13]mia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide or (lS,3'R,6 ^, R,7'R,9 ^! S)-6-chioro-7'~hydiOxy-9'-methyl"3,4- dihy dro-2h, 15 'h-spiro [naphthal ene- 1 ,22'- |20jox;iί i 3|thia| i. i4|dia/aielracveioj 14.7.20 ^i: '.0 ^{1;i ,:} ipenlacosa| 1 .18.2-1 |irieni~ 15'-one 13',13'-dioxide and (18,3'ί,6¾,7¾,9Ί)~6"ΰωοΐΌ-7'½^Γθχν-9'-ηΐ6 1- 3,4-dihy dro-2h, 15'h-spiroj naphthalene- 1 ,22'- [20]oxa[I3]mia[l,I4]diazatetTacyclo^

15'~one 13',13'-dioxide as the first eluting isomer (12.0 mg, 0.020 mmol, 33% yield). ^! H NMR (400 MHz, CHLOROFORM^ δ ppm 9.81 (br. s.1H), 7.68 (d, J 8.4 Hz, 1H), 7.34 id. j X.2 Hz, 1H), 7.17 (dd, .1 H 5.2.2 Hz, ill).7,04-7, 13 (m, 2H), 6.93 (d, j 82 Hz, ill).4.01-4.14 (m, 211).3,84 (br. s. Ml).3,44-3.76 (m, 4H), 3.03-3.43 (m, 2H), 2.61-2.90 (m, 2H), 2.06-2.18 (m, 2H), 1.73-2.05 (m, 9H), 1.60-1.72 (m, 1H), 1.38-1.59 (m, 4H), 1.28-1.38 (m, 1H), 0.90-1.03 (m, 3H). m/z (ESI, +ve ion) 587,2 (VI Π)\ EXAMPLE 241 , (1 S,3 ^! R,6'R,7'S,9 ^, S)-6-CHLORO-7'-HYDROXY-9 ^! -METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

|;i6,18,24]TRIEN]-15'-()NE 13'.13'-DIOXIDE AND (l S,3'R,6'R,7'S,9'R)-6- CHLORO-7'-HYDROXY-9 ^* -METOYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

| 2u jOXA| 1 3 ΙΊ ! !1Λ| l . l 4 |! !A/.Vr!-;i ^' R A( ^' Y(-l.()l i 4.7.2.0 ^' ' ) ¹ *' · ¹ |PHNTAC0SA [ 16,18,24] TRS EN] -15 '-ONE 13',13'-DIOXIDE OR (18,3Έ,6¾,7¾,9'8)-6- CHLORO-7'-HYDROXY-9 ^f -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[l ₅ 14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [16,18,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE AND (l S,3'R,6'R,7'R,9'R)-6- CHLORO-7 ^! -HYDROXY-9'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA [16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from reverse- phase preparative HPLC using a Phenomenex Luna column, 5 micron, C18(2), 100 A , 150 x 30 mm, 0.1% TFA in C! ! ₃ CN I ! ₂ 0. gradient 40% to 70% over 20 mm m Example 240 (6.0 mg, 0.020 mmol, 17 % yield). ¾ N .MR (400 Ml 1/.

CDCh) δ 9.93 (br. s., lH), 7.49-7.63 (m, 1H), 7.15-7.34 (m, 2H), 6.90-7.11 (m, 2H), 6.67-6.82 (m, 1H), 3.80-4.12 (m, 2H), 3.32-3.70 (m, 4H), 2.86-3.26 (m, 3H) _: 2,51-2.74 (m, 3H), 2.11-2.47 (m, 5H), 0.96-2.05 (m, ΠΗ), 0.75-0.88 (m, 3H). m/z (ESI, +ve ion) 587.2 (M R)

EXAMPLE 242. (1 S,3 ^, R,6 ^, R,7 ^, S,9 ^, S)-6-CHLORO-7 ^, -HYDROXY-9'-METHYL-

3,4-DIHYDRO-2H,15 ^, H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1 4]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[ 16, 18,24]TRIEN] - 15 ^* -ONE 13', 13'-DIOXJDE AND (1 S,3'R,6'R,7 ^! S,9'R)-6- CHLORQ-7'-HYDROXY-9 ^* -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TWEN]-15'-ONE 13',13'-DI0X1DE OR (lS,3'R,6'R,7'R,9'S)-6- CHLORO-7 ^, -HYDROXY-9'-METHYL-3,4-DIHYDRO-2H,15 ^, H- SPTRO[NAPHTHALENE-l,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20--M> ^l "-' ^, |PHNT.\( ^' OS.-\

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE AND (lS,3'R,6'R,7'R,9 ^* R)-6- CHLORO-7'-HYDROXY-9 ^f -METHYL-3,4-DIHYDRO-2H,15'H- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

To a solution of (1 S,3'R,6'R,7'R,8T,)-6-chloro-7'-hydroxy-9 ^! -methyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

[20]oxa[I3]1hia[l,I4]diazatetTacyclo[14.7.2.0 ³ '^0 ^]9 ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]~15'~one 1 ^' .13 ^' -dioxide or (lS,3 ^! R,6'R,7'S,8'E)-6-chloro-7'-hydroxy-9'-methyS- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

n]-15'-one 13',13'-dioxide (40 mg, 0.062 mrnol, Example 239) in EtOAc (2.0 mL) and MeOH (1.0 rnL) was added platinum(iv) oxide (35 mg, 0.15 mrnol) and the reaction flask was flushed with hydrogen and kept under balloon pressure overnight. LCMS indicated -70% conversion, so another aliquot of platinuni(iv) oxide (35 mg, 0.15 mrnol) and MeOH (1.0 mL) was added and the mixture was stirred again under hydrogen for an additional 5.5 hours to completion. The slurry- was then filtered and then concentrated to dryness. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, CI 8(2), 100 A , 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 40% to 70% over 20 min to provide (iS,3'R,6'R,7 ^! S,9'S)-6~chloro-7 ^! -hydroxy-9'- methyl-3,4-dihydro-2h,15'h-spiro[naphthalene-l,22'- [20joxa[13]thia[l,14]diazatetracycio[14.^ _^

15'-one 13', 13'-dioxide and (1 S,3'R,6'R,7'S,9'R)-6-chioro-7'-hydroxy-9'-methy - 3,4-dihy dro-2h, i 5'h-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[i,14]diazatetracycio[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]tn

15'-one 13',13'-dioxide or (lS,3'R,6'R,7'R,9'S)-6-chioro-7 ^! -hydroxy-9'-methyl-3,4- dihy dro-2h, 15 'h-spiro [naphthal ene- 1,22'- [20]oxa[13]thia[l,14]diazatetracycio[14.7.2.0 ³ -^0 ¹⁹ - ² ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide and (lS,3'R,6'R,7'R,9'R)-6-chloro-7'-hydroxy-9'-methyl- 3,4-dihydro-2h,15'h-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]trien]- 15'-one I3',13'-dioxide as the first eluting isomer (1.3 mg, 2.2 μηιοΐ, 2.6% yield). ¾ NMR (400 MHz, CDC ) δ 9.15-9,34 (m, 1H), 7.60-7.71 (m, 1H), 7.27-7.37 (m. III).7,04-7.13 (m, 2H), 7.02-7,16 (m, 3H), 6,88-6.96 (m, 1H), 3.83-4,12 (m, 3H), 3.63-3,77 (m, 2H), 3.06-3.36 (m, 4H), 2.59-2.84 (m, 4H), 2.26-2.48 (m, 3H), 1.37-1.81 (m, 9H), 1.13-1.28 (m, 5H). m/z (ESI, +ve ion) 587.2 (M H) .

EXAMPLE 243. (1 S,3'R,6 ^! R,7 ^, S,9 ^! S)-6-CHLORO-7'-HYDROXY-9'-METHYL- 3.4-DiRYOR -2i 1. i Ί f-SP!RO|\API Π 1! \i J-Nl - ! 22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A I 16.!H.24| I ^' RIhXI-l^'-ON!; 13',13'-DIOXIDE AND (lS,3'R,6'R,7'S,9'R)-6- CHL()R()-7'-HYDROXY-9'-METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'- [20]QXA[13]THIA[U4]DiAZATEm

[16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE OR (lS,3'R,6'R7'R,9'S)-6~ CHLORQ-7'-HYDROXY-9 ^* -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13'.13'-DIOXIDE AND (lS,3'R,6'R,7'R,9'R)-6- CHLORO-7'-HYDROXY-9 ^* -METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N ΆΡΗΤΗ ALENE- 1.22 ^' -

|2ujOXA| ! jTIUA| U4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA [ 16,18,24] TRI EN] -15 '-ONE 13',13'-DIOXIDE

The title compound was obtained as the second eluting isomer from reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, C18(2), 100 A , 150 x 30 mm, 0.1% TFA in CH ₃ CNH ₂ 0, gradient 40% to 70% over 20 rain in Example 242 (12.0 mg, 0.020 mmol, 24 % yield). ¾ NMR (400 MHz, CDCh) δ 8.79 (br. s., 1H), 7.50-7.66 (m, lH), 7.12-7.19 (m, 3H), 7.06 (ddd, ./ 2.15.8.36, 12.18 Hz, 2H), 6.91-6.99 (m, ill).6.73-6.87 (m, 1H), 3.94-3.97 (m, 2H), 3.67-3.83 (m, 2H), 3.50-3.67 (m, 2H), 3.32-3.45 (m, 1H), 3.04 (d,J=14.28 Hz, ill).2,93 idd. 8.22.15.26 Hz, 1H), 2.58-2.71 (m, 2H) 2.26-2,41 (m, 3H), 1.26-2.02 im. !3il).0.71-0.83 (m, 3H). m/z (ESI, +ve ion) 587.2 (M+H) ⁺ .

EXAMPLE 244. DIMETHYL ((lS,3'R,6 ^, R,7'S,9'S,irS,12'R)-6-CHLORO-7'- HYDROXY- 11', 12'-DIMETHYL-13', 13'-DIOXIDO- 15'-OXO-3,4-DIHYDRO- 2H-SPIRO [NAPHTHALENE- 1 ,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ' ".U ^1* ' · ¹ |PH\ i ACOSA [ 16,18,24]TRIEN;|-9'-YL)PR0PANEDI0ATE OR DIMETHYL

((IS,3'R,6'R,7'S,9'S, 11 *R, 12'R)-6-CHLORO-7*-HYDROXY-l 1 ', 12'-DIMETHYL- i;r,13'-DIOXIDO-15'-OXO-:i4-DmYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18 ₅ 24]TRIEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((1 S,3'R,6'R,7'S,9'R,1 l ^, S,12'R)-6-CHLORO-7 ^, -HYDROXY-l 1 12'-DIMETHYL- 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIH YDRO-2H-SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA

[16,18,24]TRTEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((lS,3 ^! R,6'R,7'R,9'R,irR,12'R)-6-CHLORO-7'-HYDROXY-llV12'-DiM ETHYL- 13',13'-D10XIDO-15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALENE-l,2 2'- [20]OXA[13]THIA[l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-9 ^, -YL)PROPANEDTOATE

STEP 1: (lS,3'R,6'R,8 ^, E,12 ^, S)-6-CHLORO-12 ^, -METHYL-3,4-DIHYDRO- 2Η,7Ή, 15'H-SPI O[NAPHTO ALENE-1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, 18 ,24] TETRAENE] -7', 1 S'-DIONE 13', 13'-DI()XIDE

The ally! alcohol (310 rng, 0.520 ramol. Example 719, Step 2) was dissolved in DCM (6.0 ml.) and cooled to 0 °C. Dess-Martm periodmane (270 mg, 0.63 mmol) was then added and the reaction mixture was stirred for 1.5 hours. Another 90 mg of Dess-Martm reagent was added at 0 °C and stirred for an additional 45 minutes. The reaction was quenched with 20 mL of 1M Na_S203 and allowed to warm to room temperature. The mixture was extracted (3 x 40 mL) with DCM. The combined organic layers were washed with water (1 x 30 mL) and then dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 10 to 100% EtOAc (+0.3%

HOAc):Hexanes) to give (lS,3'R,6'R,8 ^, E,12 ^, S)-6-chloro-12 ^, -methyl-3,4-dihydro- 21 1.7 1.15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l ,14]diazate1ra^

ne]-7',15'-dione 13', 13'-dioxide (230 mg, 0,385 mmol, 74.0 % yield). 'f t NMR (400 MHz, CDCh) δ 8.32-9.05 (m, 1H), 7.69-7.90 (m, 1H), 7.35-7.48 (m, 1H), 7, 17-7.27 (m, 1H), 7.06-7.16 (m, 1H), 6.81 -6.99 (m, 2H), 6.59-6,72 (m, 1H), 5.93 (d, .7=15.65 Hz, 1H), 4.01-4.24 (m, 3H), 3,74-3.97 (m, 3H), 3.26 (d, ,7=14,48 Hz, 1 1 1). 2.92-3.16 (m, 2H), 2.69-2,89 (m, 2H), 1.70-2.26 (m, 9H), 1.48-1.56 (m, 3H), 1.35-1.46 (m, 1H), 1.29 (t, ./ 7. 14 Hz, 1H), 1.07-1.19 (m, 3H). m/z (ESI, +ve ion) 596.7 ί \! · 11) .

STEP 2: 1 S,3'R,6'R,9'S,1 1 'S, 12'R)~6~CHLORO~9'~

(DIMETHYLPROPANEDIOATE)- 1 I ', 12'-DIMETHYL-3,4-DIHYDRO- 2Η,7Ή, 15'H~SPIRO[NAPHTH ALENE-1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA j l6,18,24]TRIENEj-7', 15'-DIONE 13',13'-DI()XIDE AND/OR

(1 S,3'R,6'R,9'R, 1 1 'S, 12 ^* R)-6-CHLORO-9'-(DlMETOYLPROP ANEDIOATE)- 11 ^12'-ΟΙΜΕΤΉΥΕ-3,4-ΟΜΥΒΚΟ-2Η,7Ή,15Ή-8ΡΙΚ� �ΕΝΑΡΗ ΗΑΕΕΝΕ-

1 ">"><-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA [16,18,24]TRIENE]-7',15'~DIONE 13',13'~DIOXIDE

(lS,3'R,6'R,8'E,12'S)-6-chloro-12'-methyl-3,4-dihydro-2H, 7'H,15'H spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae nej-7',15'-dione 13',13'-dioxide (30 mg, 0.050 mmol, Step 1) was dissolved in THF (1 .0 raL). Dimethyl malonaie (0.057 ml,, 0.50 mmol) and DBU (0,075 mL, 0,50 mmol) were then added and the reaction was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in DMSO. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ C /H ₂ 0, gradient 50% to 95% over 40 mm to provide (lS,3 ^, R,6'R,9'S,l l'S,12 ^, R)-6-chloro-9 ^! -(dimethylpropanedioate)-ir,12'- dimethyl-3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]mia[l, 14]diazatetracyclo[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide and/or (l S,3'R,6'R,9'R,l l'S,12'R)-6-chloro-9'- (dimethylpropanedioate)-i r,12'-dimethyl-3,4-dihydfo-2H,7'H,15'H- spiro [naphtha! ene- 1 ,22'- [20]oxa[13]thia[U4]diazatetracy^^

7',15'-dione 13', 13 '-dioxide as the first eluting isomer (13 mg, 0.015 mmol, 31 % yield). ^! H NMR (400 MHz, CD3OD) δ 7.75 (d, 86! Hz, 111).7.10-7.40 (ra, 3H), 6.89-7.04 (m, IH), 6.80 (d, «7=1.96 Hz, 1H), 4.09-4.30 (m, Ml).3.57-3,90 (m, 5H), 3.04-3.43 (m, 8H), 2.51-3.08 (m, 5H), 1.78-2.44 (m, 8H), 1.47-1.71 (m, 2H), 1.45 (d, ./ 7.24 Hz, 3H), 1.26-1.37 (m, 2H), 0.99-1.11 (m, 311). m/z (ESI, +ve ion) 728.7 (M+H) ⁺ .

STEP 3: DIMETHYL ((1S,3'R,6 ^! R,7'S,9 ^! S,1 l'S,12*R)-6-CHLORO-7- HYDROXY- 11 ', 12'-DIMETHYL-13', 13'-DIOXIDO-l 5'-OXQ-3,4-DIHYDRO- 2H-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[ 16,18,24]TRlEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((1 S,3'R,6'R,7'S,9'S, 11'R, 12 ^, R)-6-CHLORO-7'-HYDROXY- 11 ', 12'-DIMETHYL- 13'J3'-DIOXTDO-15'-OXO-3,4-DIHYDRO-2H-SPTRO[NAPHTHALENE-l,22 '- [20]OXA[13]Tffl A[l ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18 ₅ 24]TRIEN]-9'-YL)PROPANED10ATE OR DIMETHYL

((1 S,3'R,6'R,7'S,9'R,1 l'S,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-l r.lZ-DIMETHYL- 13 I 3'-DTOXIDO- 15 '-OXO-3 ,4-DTHYDRO-2H-SPIRO [NAPHTHALENE- 1 ,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ' ".0 ^|: ' ^{! 1} |PH\ i ACOSA [ 16,18,24]TRlEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((1 S,3'R,6'R,7'R,9'R, 1 l'R,l 2'R)-6-CHLORO-7'-HYDROXY-l 1 ', 12*-DIMETHYL- 13'J3'-DIOXTDO-15'-OXO-3,4-DIHYDRO-2H-SPTRO[NAPHTHALENE-l,22 '- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24] TRIEN] -9'- YL)PROP ANEDIO ATE

The ketone (7.0 mg, 8.30 μιηοΐ, Example 244, Step 2) was dissolved in MeOH (1.0 mL) and cooled to 0 °C. Sodium borohydride (3.1 mg, 0.083 mmol) was then added and the solution was stirred for 30 minutes. The reaction was quenched by adding a few drops of IN HCI solution and then concentrated under reduced pressure. The residue was then purified by medium pressure

chromatography (silica, 20 to 60% EtOAc (+0.3% HOAc):Hexanes) to give exclusively a single isomer of the alcohol (4.3 mg, 5.9 μηιοΐ, 71 % yield). ^] H NMR (400 MHz, Solvent) δ ppm 7.77 (d, J 8.4 Hz, 1H), 7,44-7.59 (m, 1H), 7.07- 7.28 (m, 3H), 6.88-7,01 (m, 1H), 4.00-4.24 (m, 4H), 3,59-3.90 (m, 9H), 3.27 (d, J=14.1 Hz, lH), 3.06 (dd, J=15.3, 9.0 Hz, IH), 2.71-2.90 (m, 2H), 2.39-2.63 (m, 3H), 1.49-2.19 (m, 12H), 1.41-1.47 (m, 3H), 1.23-1.34 (m, 3H), 0.98-1.07 (m, 3H). m/z (ESI, +ve ion) 730.6 (W \\) .

EXAMPLE 245. DIMETHYL ((1S,3'R,6'R,7 ^! S,9'S,1 l'S,12'R)-6-CHLORO-7 ^f - HYDROXY- 11 ', 12'-DIMETHYL-13', 13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO- 2H-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCIX)[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRlEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((1 S,3'R,6'R,7'S,9'S, 11'R, 12'R)-6-CHLORO-7'-HYDROXY- 11 ', 12'-DIMETHYL- 13 13 ^, -DIOXroO-15 ^, -OXO-3,4-DIHYDRO-2H-SPTRO| APHTHALENE-l,22 ^, - [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18 ₅ 24]TRIEN]-9'-YL)PROPANED10ATE OR DIMETHYL

((1 S,3'R,6'R,7'S,9'R,1 l'S,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-l r.l2'-DIMETHYL- 13 I 3'-DIOXIDO- 15 '-OXO-3 ,4-DIHYDRO-2H-SPIRO [NAPHTHALENE- ,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ^' ".O ^{1 ! 1} |PL\ i ACOSA

[16,18,24]TRlEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((1 S,3'R,6'R,7'R,9'R, 11 'R, 12'R)-6-CHLORO-7'-HYDROXY-l 1 ', 12*-DIMETHYL- 13'J3'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-L22' - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24] TRIEN] -9'- YL)PROP ANEDIO ATE

STEP 1: IS,3'R,6'R,9'S,ll'S,12'R)-6-CHLORO-9'- (DIMETHYLPROPANEDIOATE)- 11 12'-DIMETHYL-3,4-DIHYDRO- 2Η,7Ή,15Ή-8Ρ110[ΝΑΡΗΊΉΑΕΕΝΕ-1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA

[16,18,24]TRIENE]-7V15'-DIONE 13',13'~DIOXIDE OR

(lS,3 ^, R,6'R,9 ^! R,irS,12 ^! R)"6-CHLORO-9'-(DlMETHYLPROPANEDIOATE)~ 11^12'-DIMETHY -3,4-DIHYDRO-2HJli 5'H-SPIRO[NAPHTHALENE- 1,22'- |20i()XA| Γ, ΐΗ1Λ| Ι,,! |ί)!Λ/Λ! :ΓΗ.Λ( ^' , 01117.2 (Γ·''. ( ⁾ '"··'' |Pi-N i ACOSA [16,18,24]TR1ENE]-7',15'-D10NE 13',13'-D1QXIL)E

The title compound was obtained as the second eluting isomer from reverse-phase preparative HPLC using a Plienomenex Luna column, 5 micron, C18(2), 100 A , 150 x 30 mm, 0.1% TFA in CH ₃ CNH ₂ 0, gradient 50% to 95% over 40 rain in Example 244, Step 2 (8.5 rng, 10 μηιοΐ, 20 % yield), ¾ NMR (400 MHz, ( i) ; ⁽ )!)) δ 7.66-7.91 (m, H), 7.06-7,38 (m, 3H), 6.65-6.99 (m, 2H), 4.06- 4.18 (m, 2H), 3.64-3.91 (m, 10H), 3.38-3.48 (in, 2H), 3.20-3.33 (m, 2H), 2.54- 2,95 (rn, 6H), 2.41 (dd../ 2.74.19.17 Hz, ill).2.14-2.27 (m, !H), 1.97-2,13 (m, 2H), 1.71-1.96 (m, 4H), 1.44-1.61 (m, H), 1.30-1,43 (m, 4H), 1.19-1.29 (m, H), 1.08-1.16 (m, 2H). m/z (ESI, +ve ion) 728.7 ί M H ) . STEP 2: DIMETHYL ((1 S,3'R,6'R,7'S,9'S, 11 *S, 12'R)-6-CHLORO-7'- HYDROXY-11 12'-DIMETHYL-13', 13'-DiOX!DQ-l 5'-OXO-3,4-DIHYDRO- 2H-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16, 8,24]TRIEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((lS,3'R,6'R,7'S,9 ^, S,ll'R,12'R)~6"CHLORO-7'~HYDROXY-ir,12'-DlMETHYL- 13^13 ^, -DIOXIDO-15 ^, -OXO-3,4-DfflYDRO-2H-SPIRO| APH HALENE-l,22 ^, - [20]OXA[13]TO A[1,14]DIAZATETT ACYCLO[147 .0 ³ '*0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-9 ^, -YL)PROPANED10ATE OR DIMETHYL

((1 S,3'R,6'R,7'S,9'R,1 l'S,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-l r.l2'-DIMETHYL- 13',13'-DTOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO| APHTHALENE-l,22'- |20jO.\A| 1311 HI Λ| I N |OI A/A Π·. ΓΚΑί ^' ΥΌ.01 i -1.7.2 (Γ·''. ( ⁾ '"··'' |Pi-N iACOSA [16,18,24]TRlEN]-9'-YL)PROPANEDIOATE OR DIMETHYL

((lS,3'R,6'R,7'R,9'R,irR,12'R)-6-CHLORO-7'-HYDROXY-lT,12' -DIMETHYL- i;r,13' IOXIDO-15'-OXO-3,4-DmYDRO-2H~SPIRO[NAPHTHALENE-l,22 ^! ~

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16, 18,24 ] TRIEN] - 9'- YL)PROP ANEDIO ATE

The ketone (8.0 mg, 9.5 μιηοΐ; from step 1) was dissolved in MeOH (1.0 mL) and cooled to 0 °C. The sodium borohydride (3.6 mg, 0.095 mmol) was added and the solution was stirred for 30 minutes to completion. The reaction was quenched with a few drop of IN HC1 solution and then concentrated under reduced pressure. The residue w ^? as taken up in DMSO and filtered into a

Preparative LC vial. The crude material was purified by reverse-phase preparative HPLC using a Phenonienex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 50% to 85% over 40 min to provide a

65:35 alcohol mixture of the title compound (1.3 mg, 1.5 μιηοΐ, 16 % yield). ). ^l H NMR (400 MHz, MeOD) δ ppm 7.65 (d, j 86 Hz, 1H), 7.01-7.14 (m, 3H), 6,90 (d, J=6.5 Hz, 1H), 6.82-6.87 (m, lH), 6.76 (d, j 2.0 Hz, IH), 3.98-4.08 (m, 2H), 3.92 (d, j 12.! Hz, IH), 3.67-3.79 (m, Ml).3.63 (d, j 2.7!!/.3H), 3.37-3.50 (m, IH), 3,27-3.37 (m, 3H), 1.88-2,81 (m, 15H), 1.70-1.81 (rn, 3H), 1.27-1,31 (m, 5H), 0,98-1.03 (m, 3H), m/z (ESI, +ve ion) 730.6 { \i · ! ! } ^' ,

EXAMPLE 246. (18,3'Κ,6¾.,7¾,8Έ,1 Γ8,12¾)-6-εΗ1,ΟΚΟ-7'-ΜΕΤΗΟΧΥ- 1 V, 12'-DlMETHYL-3 ,4-DIH YDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1,22'- [20]OXA[ 13]THIA[ l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8 ₅ 16, 18,24]TETRAEN]-15"-ONE 13', 13 '-DIOXIDE

The ally lie alcohol (4.0 mg, 6.7 μιηοί, Example 208) was dissolved in THF (0,5 mL) and cooled to 0 °C. To the solution was added sodium hydride (60% dispersion; 2.7 mg, 0.067 mmol) and the mixture was stirred for 30 minutes. Iodomeihane (2.1 ,uL, 0.033 mmol) was then added and the mixture was remo ved from the ice hath and stirred for three hours. The reaction was then acidified with a few drops of IN HC1 solution and then diluted with water. The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 0 to 50% EtOAc (+0.3% HOAc):Hexanes) to give ( ! S.3'R.6'R.7'R.8'i i. I i 'S. 1 2'R )-6-chloro- 7'-methoxy-i r,12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l, 14]diazatetra<^

n]-15'-one 13',13'-dioxide (3.3 mg, 5.4 μηιοΐ, 81 % yield). ¾ NMR (400 MHz, CHLOROFORMS) δ ppm 8.08 (br. s., Hi), 7.72 (d, j 8.4 Hz, IH), 7.45 (d, j 1 .4 Hz, 1 1 1 ). 7.19 (dd, J 8.4. 2.3 Hz, I I I). 7.09 id. .1 2.3 Hz, 1 1 1 ). 6.83-6.96 (ra, 21 1 ). 5.26-5.50 (m, 2H), 4,02-4.15 (m, 3H), 3.96 (dd, 1=15.5, 4.1 Hz, IH), 3.68 (d, j 1 -1.5 Hz, IH), 3.16-3.24 (m, 2H), 2.95 (dd, 1=15.4, 6.7 Hz, IH), 2.69-2.87 (m, 31 1 ). 2.52 (br. s., 21 1 ). 2.17 (d, j 18.0 Hz, 1 1 1 ). 2.11 (dd, j 4.7. 1.6 Hz, I H), 2.03 (dd, .1=15.6, 4.1 Hz, IH), 1.85-1 .99 (m, 3H), 1.77-1.84 (m, IH), 1 .64- 1 .77 (ra. Ml).1.45 id J 7.2!!/.3H), 1,31-1.43 (m, 3H), 1.09 (d, .1 68 Hz, 3H). m/z (EST, +ve ion) 612.7 (V! R)

EXAMPLE 247. (IS^'R^'l^yS^'SJl'S/ 'Ri-e-CHLORO^'- (DIMETHYLAMINO)-7'-HYDROXY-11^12'-DIMETIiYL-3,4-DIHYDRO- 2H, 15H-SPIRO[N APHTHALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ' ".U ^1* ' · ¹ |PL\ i ACOSA [16,18,24]TRIE ]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7 ^* S,9'S,1 l'R,12'R)- 6-CHLORO-9'-(DIMETHYLAMINO)~7'~HYDROXY~l Γ, 12'-DIMETHYL~3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R,9'S,irS,12'R)- 6-CHLORO-9'-(DIMEmYLAMINO)-7'-HYDROXY-ll 12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTHALENE - 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13', 13-DIOXIDE OR (1S,3'R,6'R,7'R,9'R,I l'S,12'R.)- 6-CHLORO-9'-(DIMETHYLAMINO)-7'-HYDROXY- 1 I ', 12'-DIMETHYL~3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16, 8,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The ketone (16.5 mg, 0.019 mmol, Example 244, Step 1) bis- trifluoroacetate was dissolved in MeOH (1.5 niL) and sodium borohvdride (7.2 mg, 0.190 mmol) was added. The reaction was complete after 10 minutes and the mixture was allowed to stir at room temperature over the weekend. The reaction was then concentrated and the residue was dissolved in DMSO. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1% TFA in

CH CN/H2Q, gradient 25% to 75% over 30 min to provide

(lS,3¾,6'R,7^,9'S,l l'S,12'R 6-chloro-9'-(dimethylamino)-7' iydroxy-l l 2'- dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'-

15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,9'S, l l ^! R,12'R)-6-chiorQ-9'-

(dimethylamino)-7'-hydroxy-l l',12'-dimethyl-3,4-dihydro-2H,15'H- spiro [naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyxlo[14.7.2^

15'-one 13', 13'-dioxide or (1S,3'R,6'R,7 ^! R,9 ^* S, 1 l'S,12'R)-6-chfoiO-9 ^* - (dimethylamino)-7'-hydroxy-l r,12'-dimethyl-3,4-dihydro-2H, 15'H- spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1,14] diazateti^

15'-one 13',13'-dioxide or (1S,3'R,6'R,7'R,9'R,1 1 'β.Π'^-ό-οΜθΓθ-θ'- (dimethylamino)-7'-hydroxy-nV12'-dimethyl-3,4-dihydro-2H,15' H- spiro [naphthalene- 1,22'-

[20joxa[13]thia[ l, 14]diazatetracycfo[14^^

15'-one 13', .13'-dioxide as the first eluting isomer (2,8 mg, 3.2 μηιοΐ, 17 % yield). ³ H NMR (400 MHz, MeOD) δ ppm 1.21 (s, 2 H) 1.40 - 1.51 (m, 2 H) 1.54 (d, ./ 7.24 Hz, 3 H) 1.65 - 2.02 (m, 11 H) 2.04 - 2.17 (m, 3 H) 2.26 - 2.41 (m, 1 H) 2,68 - 2.84 (m, 3 H) 2.87 (s, 3 H) 2.92 (s, 3 H) 3.1 1 (dd, ./ 1 5.26. 9.39 Hz, 1 H) 3.35 - 3.43 ( ns. 1 H) 3,55 (br. s . I H) 3.70 (d, J=14.28 Hz, 1 H) 3.88 (dd. ,/ 7 14. 3.42 Hz, 1 H) 3.95 - 4.14 (m, 3 H) 6.91 - 6.99 (m, 1 H) 7.00 - 7.07 (m, 1 H) 7.13 (d,■/ 245 Hz, 1 H) 7.15 - 7.23 (m, 2 H) 7.73 (d, ./ 8. 1 Hz, 1 H). m'z (ESI, +ve ion) 643.8 (M+H) ⁺ . EXAMPLE 248, (1 S,3'R,6 ^! R,7'S,9'S,1 l 'S,12'R 6~CHLORO~9'~ (DIMETHYL AMINO)-7'-HYDROXY- 11 ', 12'-DIMETHYL-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIE ]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'S,9'S,1 l'R,12'R)~ 6-Π U. RO-v-{!)]\H. Π iVL AMINO}-?'-! !YDROXY-i i'.12~D!Ylh Π 1Y1.-3.4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZAraTRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7 ^f R,9'S,ll'SJ2'R)- 6-CHLORO-9'-(DIMETHYLAMI O)-7 ^! -HYDROXY-H',12'-DIMETHYL-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE I T. ! -O!OXID! . OR (1S,3'R,6'R,7'R,9'R,1 rS,12'R)- 6-CHLORO-9 ^, -(DIMETHYLAMlNO)-7'-HYDROXY- 11 ', 12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]Tffl A[l ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 25% to 75% over

30 min in Example 247 (6.3 mg, 7.2 μιηοΐ, 38 % yield). ¾ NMR (400 MHz, MeOD) δ ppra 7.75 (d, .! 8.6 Hz, Hi).7.35 (d, J 7.H Hz, 1H), 7.14 (d, J==9.6 Hz, IH), 7,10 (d, J 11.0 Hz, 2H), 6,81 id. J=8.0 Hz, H), 4,58 (br. s . !!!).4.21 (dd, j 5.8.3.6 Hz, IH), 3.96-4.09 (m, 2H), 3.73-3.89 (m, .21 i).3.59 (d, J=13.9 Hz, IH), 3.25 (d, j 13.7 Hz, IH), 3.18 (br. s., IH), 3.04 (dd, j 14.8.9.5Hz, IH), 2.66- 2.88 (m, 2H), 2.46 (br. s., 6H), 2.33-2.43 (m, IH), 2,22-2,32 (m, IH), 1.52-2.19 (m, I IH), 1.44 (t, J=13.0 Hz, IH), 1.37 (d, J=6.8 Hz, 3H), 1.13 (t, J= 11.5 Hz, IH), 1.05 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 643.8 {M l!)

EXAMPLE 249. (1S,3'R,6'R,7'S,9'S,1 rS,12'R)-6-CHLORO-9'- (DIMETHYLAMINO)-7'-HYDROXY- 11 ', 12'-DIMETHYL-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'S,9'S,1 l'R,12'R)- 6-CHLORO-9'-(DIMEmYLAMINO)-7'-HYDROXY-ll 12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXTDE OR (lS,3'R,6'R,7 ^f R,9'S,ll'S,12'R)- 6-CHLORO-9'-(DIMETHYLAMINO)-7'-HYDROXY- 1 I ', 12'-DIMETHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [16, 8,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R,1 l'S,l 2'R)- -C! U.ORO-9 -{!)]\H. Π IV 5.\VU\0}-7'-! IY!)R()XY-i i'. ! 2 -0! \Π·. Π iVL-3.4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

STEP 1 : (1S,3 ^! R,6'R,9'S,1 l'S,12'R)-6-CHLORO-9HDlMETHYLAMlNO)- 11 ', 12'-DIMETHYL-3,4-DIHYDRO-2H ,7'H, 15TI-SPIRG[NAPHTHALENE- 1,22'- | 2( >X A| i ? I ! f Π Λ| ί i J l i^f AZ.Vf l: E RAC YCE C)l i J 7.2 0 ^' ".U ^{1 *} ' · ¹ |PH\ i ACOSA

[ 16,18,24]TRIENE]-7',15'-DIONE 13',13'-DIGXIDE AND

(1 S,3'R,6'R,9'R, 11 ^* S, 12'R)-6-CHLORO-9' -(DIMETHYL ΑΜΙΝΟ)-1 Γ, 12"- DIMETHYL-3,4-DIHYDRO-2H,7'H, 15 Ή- SPIRO [NAPHTHALENE - 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIENEi-7', 15'-DIONE 13',13'-DI()XIDE

The enone (30 nig, 0,050 mmol, Example 244, Step 1) was dissolved in THF (1.00 mL) and dimethyiamine (2.0 M in THF: 2.0 mL, 4.0 mmol) was added and the solution was stirred for 30 minutes. The reaction mixture was then concentrated to dryness and the residue was taken up in DMSO. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1% TFA in

CH3CN/H2O, gradient 25% to 75%) over 30 min to provide a mixture of

(1 S,3'R,6'R,9'S,1 l'S,l 2 ^f R)-6-chloro-9'-(dimethylaraino)-l 1 ', 2'-dirnethyl-3,4- dihydro-2H,7'H, ! ^ ^' H-spiro| nap !halene- i .22'- [ 20] oxa[ 13 ]thia[ 1 , 14] diazatetra^

7 ^* ,15'-dione 13',13'-dioxide and (1 S,3'R,6'R,9'R, 1 l'S,12'R)-6-chloro-9 ^f - (dimethylamino)-l 1 ^12'-dimethyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene- 1,22'-

[20]oxa[ 13]thia[l ,14]cUazatetracyc^

7', 15'-dione 13',13'-dioxide (19 mg, 0.022 rnmol, 44 % yield), m/z (EST, +ve ion) 641.7 (M+H) ⁺ .

STEP 2: (1 S3 ^! R,6'R,7'S,9'S, 11 'S, 12'R)-6-CHLORO-9 ^, -(DiMETHYLAMiNQ)~7 ^! - HYDROXY- 1 1 ', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18 ₅ 24]TRIE ]-15'-ONE 13',13'-DIQXIDE OR (1S,3¾,6'R,7 ^! S,9'S,1 l'R,12'R 6-CHLORO-9'-(DIMETHYL AMINO)-7'-HYDROXY- 1 1 ', 12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή-SPTRO [NAPHTHALENE- 1 ,22'-

| 20 jOX A| I 31 1 HI Λ| I .. N | OI A/A Π·. f ^' RAC YCf .Oj I -1.7.2 0 ' ".O ¹ " · ¹ |PLNT. S A [ 16,18,24] TRI EN] -15 '-ONE 13',13'-DIOXIDE OR (1 S,3'R,6 ^! R,7 ^* R,9'S,11'S,12'R)- 6-CHLORO-9'-(DIMETHYLAMINO)-7'-HYDROXY- 11 12'-DTMETHYL~3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13', 13'-DTOXIDE OR (1 S,3'R,6'R,7'R,9'R,1 l'S,12'R)- 6-CHLORO-9'-(DIMEmYLAMINO)-7'-HYDROXY-l l ',12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s -

;20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14J.2 ³ '^0 ¹⁹ ' ²⁴ ]PENTACOSA

16, 18,24]TRTEN]-15'-ONE 13',13'-DIOXTDE

The title compound was synthesized from (lS,3'R,6'R,9'S,i rS,12'R)-6-chloro-9 ^! - (dimethylamino)-l 1 ', 12'-dimethy l-3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-

1,22'- [20]oxa[13]thia[U4]diazatetra<yclo^

7',15'-dione 13',13'-dioxide or (l S,3'R,6'R,9'R,l l ^* S, 12'R)-6-chloro-9'- (dimethylamino)-l 1 ^12'-dimethyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-

[20]oxa[13]tMa[l,14]diazatetracyclo^

7',15'-dione 13',13'-dioxide (Step 1) by a procedure similar to the one described in Example 247 and it was obtained as the only eluting isomer from reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, C I 8(2), 100 A , 150 x 30 mm, 0.1% TFA m Π ί ( \ 1 1,0. gradient 40% to 70% over 20 mm. (3.1 nig, 3.6 μ ^η ιοΐ, 52 % yield). ^l H NMR (400 MHz, MeOD) δ ppm 1.14 - 1.21 (m, 6H) 1.46 - 1.54 (m, 5H) 1.70 - 1.81 (m, 4H) 1.83 - 2, 16 (m, 5H) 2. 19 - 2,30 (m, 3H) 2.35 - 2.47 (m, 2H) 2.74 - 2.95 (m, 6H) 3.38 - 3.45 (m, 1H) 3.68 - 3.89 (m, 4H) 3.89 - 3.99 (m, 1H) 4.03 - 4.11 (m, 1H) 4.11 - 4.23 (m, 2H) 6.90 - 7.00 (m, i l l ) 7,04 (d, J 2.0 Hz, IH) 7.06 - 7, 16 (m, 2H) 7.16 - 7,27 (m, i l l ) 7.70 - 7,82 (m, 1H). m/z (ESI, +ve ion) 643.8 (M+H) ⁺ . EXAMPLE 256. (1 S,3'R,6 ^! R,7'S,9'S,1 l 'S,12'R.)-6-CHLORO-7'-HYDROXY- 7', 11 ^, ,12'-TRIMETHYL-9'-(METHYLAMINO)-3,4-DIi-IYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18 ₅ 24]TRIE ]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R,1 l'S,12'R)- 6-CHLORO-7'-HYDROXY-7', 1 1 ', 12'-TRIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[147 .0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIQXIDE OR (1 S,3'R,6'R,7'R,9'S,11'S,12'R)- 0-CHL()R()-7'-HYDROXY-7', 1 1 ', 12'-TRIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]QXA[13]miA[U4]DL^

[16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE OR (1 S,3'R,0'R,7'R,9'R,1 l'S,12'R)- 6-CHLORO-7'-HYDROXY-7' ₅ 11 ', 12 ^, -TRIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13 ', 13 '-DIOXIDE

STEP 1 : (1S,3'R,6'R,9'S,1 l ^, S ₅ 12 ^, R)-6-CHLORO-9 ^, -(DlMETHYLAMlNO)-

11 ^12 ^, -DIME^ΉYL-3 ₅ 4-DIHYDRO-2H,7Ή 5Ή-SPIRO[NAPHTHALENE-

1,22'-

[20]QXA[13]miA[U4]DL^

116,18,24]TRIENE]-7',15'-DIONE 13',13'-DIOXIDE AND/OR

(1 S,3'R,6'R,9'R, 11 'S, 12'R)-6-CHLORO-9' -(DIMETHYL ΑΜΙΝΟ)-1 Γ, 12'-

DIMETHYL-3,4-DIHYDRO-2H,7'H, 15 Ή- SPIRO [NAPHTHALENE - 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIENE|-7', 15'-DIONE 13',13'-DIOXIDE

The enone (30 mg, 0.050 mmol, Example 244, Step 1) was dissolved in THF (1.0 mL). Methylamine (2.0 M in THF; 1.0 mL, 2.0 mmol) was then added and the reaction was stirred overnight. Another aliquot of methylamine (2.0M in THF; 1.0 mL, 2.0 mmol) was added to drive the reaction to completion within another 30 minutes. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in DMSO and filtered into a Preparative LC vial. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C 18, 100 A, 150 x 30 mm, 0.1% TFA in CH CN/H2O, gradient 30% to 60% over 40 min to provide ketone

(lS,3'R,6'R,9'S,i rS,12'R)-6-chioro-9 ^! dimethyIainino)-l l ',12'-dimethyl-3,4- dihydro-2H,7'H, 15'H-spirornaphthalene-.l ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide and (18,3'R,6'R,9'R, l l ^! S,12'R)-6-chloro-9 ^* - (dimethylamino)-l 1 ',12'-dimethyl-3,4-dihydro-2H,7'H,l 5'H-spirofnaphthalene-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]m 7', 15'~dione 13',13'-dioxide) as the first eluting isomer (17 mg, 0.020 mmol, 40% yield), m/z (ESI, +ve ion) 627.7 (M+H) ⁺ . STEP 2: (1 S,3'R,6'R,7'S,9'S,11 'S, 12'R)-6-CHLORO-7'-HYDROXY-7', 11 ', 12'- TRIMETHYL-9'-(METHYLAMINO)-3,4-DlHYDRO-2H, 15 Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ '* 0 ¹⁹ - ²⁴ ]PEOTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13 ^! -D1GX1DE OR (18,3Ί ,6¾,7 ^! 8,9¾,11 ^! S,12'R 6-CHL()R()-7'-HYDROXY-7', 1 1 ', 12'-TRIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'S, 11'S,12'R)- 6-CHLORO-7'-HYDROXY-7', 1 1 ', 12'-TRIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s -

| 2u jOXA| ! 3 jTI UA| U 4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2.U ' ".ί ^{) | :} ' ^{! 1} |Ρ1·Ν I ^' ACOSA [ 16J 8,24]TRIENj-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7 ^* R,9'R, 1 l'S,12'R)- 6-CHLORO-7'-HYDROXY-7', 11 ', 12'-TRIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16, 8,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The ketone (60 mg, 0,070 mmol, Step 1 ) was dissolved in MeOH (2.0 mL) and cooled to 0 °C. Sodium borohydnde (26 mg, 0.70 mmol) was then added and the mixture was allowed to stir for 30 minutes. The reaction went from a clear solution to forming a white precipitate upon completion. The mixture was then quenched with saturated sodium bicarbonate solution and concentrated under reduced pressure and then extracted between organic (EtOAc, DCM,

DCM/MeOH) and water (15 mL). It was noted that a white precipitate was never solubilized throughout the workup and was saved. The combined organic layers were dried over magnesium sulfate and concentrated. The material was purified by Preparative LC, but low recovery was observed. The white insoluble precipitate from the work up was then analyzed and determined to be the free base of the desired product. This material was then dissolved in DMSO and combined with the material collected after the first purification. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C 18, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 35% to 48% over 40 min to provide (1S,3'R,6'R,7'S,9'S,1 l'S,12'R)-6-enloro-7 ^! - hydroxy-?', H',12'-trimethyl-9'-(methy lamino)-3,4-dihy dro-2H, 15Ή- spiro [naphtha] ene- 1 ,22'-

15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,9'R,i rS,12'R)-6-chioro-7 ^! -hydi xy- T, 11 ', 12'-trimethyl-9'-(methy]amino)-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1,22'-

[20]oxa[13]thia[l,14]diazatetracycio^

15'-one 13', 13'-dioxide or (1S,3'R,6'R,7'R,9'S, 1 l'S,12'R)-6-chIoro-7'-hydroxy- 7', 1 1 ', 12'-trimethyl-9'-(methylamino)-3,4-dihydro-2i-1, 15'H-spirofnaphthalene- l.z -

[20]oxa[13]thia[l,14]diazatetn^

15'-one 13',13'-dioxide or (1 S,3'R,6'R,7'R,9'R,1 l 'S, 12'R)-6-chloro-7'-hydroxy- 7', 11 ', 12'-trimethy -9'-(methylamino)~3,4-dihydro-2H, 15'H-spiro[naphthalene- 1,22'-

[20ioxa| 13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ³ ' ^f 0 ^!9 ' ²⁴ |pentacosa[ 16,18,24]trien]- 15 ^* -one 13', 13'-dioxide (27 mg, 0,031 mraol, 44.9 % yield). ^! H NMR (400 MHz, MeOD) δ ppm 1 , 15 (d, J=6,9 Hz, 2H) 1.46 - 1.52 (m, 3H) 1.57 (d, J 1 3. 1 Hz, 1H) 1.63 - 2.18 (m, 10H) 2.23 - 2.49 (m, 2H) 2.69 - 2.91 (m, 4H) 3.05 - 3.21 (m, 1H) 3.23 - 3.36 ins. 4H) 3.40 - 3.54 (m, 1H) 3.62 (d, j 1 3.9 Hz, 1 1 1 ) 3,65 - 3.74 (m, 1H) 3,76 - 3.79 (m, 1H) 3.77 - 3.88 (m, I H i 3.98 (d, J=15.1 Hz, i l l ) 4.02 - 4. 17 (m, 3H) 4.20 (dd, ./ 1 1 .3. 5.6 Hz, M l ) 6.94 - 7.03 (m, M l ) 7.05 - 7.15 (m, 2H) 7.17 - 7.26 (m, 2H) 7.73 - 7.78 (m, 1H). m/z (ESI, +ve ion) 629.8 { M · Π } .

EXAMPLE 257. (lS,3'R,6 ^! R,7'S,9'S,i rS,12'R)-6-CHLORO-7' iYDROXY- 11^12'-DIMETHYL-9 ^, -(METHYLAMINO)-3,4-DIHYDRO-2H, 15 ^, H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (18,3¾,6¾,7'8,9Έ,1 l'S,12'R 6-CHLORO-7'-HYDROXY-l 1 V12'-DIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

| 2u jOXA| ! 3 jTI UA| U 4 |niA/ATI:TR A( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^{) | :} ' ^{! 1} |Pl-N i ^' AC<)SA

[ 16,18,24] TRS EN] -15 '-ONE 13',13'-DIOXIDE OR (1 S,3'R,6 ^! R,7 ^* R,9'S,11'S,12'R)- 6-CHLORO-7'-HYDROXY- 1 1 ', 2'-DIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ l ₅ 14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]- 15'-ONE 13', 13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R,1 l'S,l 2'R)- 6-CHLORO-7'-HYDROXY-11^ 12'-DIMETHYL-9'-(METHYLAMINO)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20;|OXA[13]THIA[1 ,14]DIAZATET ACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PENTACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 mi cron, C18, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 30% to 60% over

30 mm in Example 256, Step 2 (15 mg, 0.017 mmol, 74.8 % yield). ^! H NMR (400 MHz, Solvent) 6 ppm 1.10 - 1.21 (m, 3H) 1.42 - 1 ,64 (m, 5H) 1 ,64 - 1 ,82 (m, 3H) 1.86 - 2.15 (m, 7H) 2. 15 - 2.27 (m, 1H) 2.31 - 2,47 (m, 1H) 2.64 - 2,90 (m, 4H) 3.20 (t, 3=9 Hz, 1H) 3.26 - 3.46 (m, 7H) 3.66 - 4.02 (m, 3H) 4.02 - 4.21 (m, 2H) 6.93 - 7.01 (m, ill) 7.04 - 7.16 (m, Ml) 7.19 (dd, .1 H 4.2.2 Hz, IH) 7.75 (d, J=8.4 Hz, IH). m/z (ESI, +ve ion) 629.8 (M+H) ⁺ .

EXAMPLE 259. (lS,3 ^, R,6'R,7 ^! S,9'S,irS,12 ^! R)"6-CHLORO-7'"HYDROXY- 9', 1 Γ, 12'-TRIMETHYL-3,4-DIHYDRO-2H.15 Ή- SPI O |N APHTH ALENE- 1,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ' ".U ^1* ' · ¹ |PL\ i ACOSA [16,18,24]TRIE ]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R,11 ^* S,12'R)- 6-CHLORO-7'-HYDROXY-9', 11 ', 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRQ[NAPHTHALENE~1,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R,9'S,irS,12'R)- 6-CHLORO-7 ⁱ -IYD OXY-9 II^ί2'-T ΐMEπm _J -3,4-DIHYDRO-2HJ5 ^f H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [16,18,24]TRIEN]-15'-ONE 13', '-DIOXTDE OR (1S,3'R,6'R,7'R,9'R,1 l'S,12'R.)- 6-CHLORO-7'-HYDROXY-9', 1 Γ, 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA

[16, 8,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

STEP 1 : (1S,3 ^! R,6'R,9'S,1 l'S,12'R)-6-CHLORO-9 ^f ,l l',12'-TRIME ^" fflYL-3,4- DIHYDRO-2H,7'H, 15'H-SPIRO[N APHTHALENE-1 ,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A [16,18,24]TRIENE]"7',15'-DIONE 13',13'-DI0X1DE AND

(1S,3'R,6 ^* R,9'R,1 l'S,12'R)-6-CHLORO-9',l l',12'-DIMETHYL-3,4-DIHYDRO- 2H,7'H, 15'H-SPIRO[NAPHTHALENE-l ,22'- |2 ⁽ >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^{' !'} .ϋ'" ^!| |Pi-N i ACOSA

[16,18,24]TR1E E]-7',15'-D10NE 13',13'-D1QXIDE

A stock solution of methyl cuprate was made by slurrying copper (I) iodide (48 μΐ,, 1.4 mmol) in 1.0 ml. of Et ₂ 0 and cooling to -78 °C and adding methyllithium (1.6 M solution in diethyl ether; 1.8 ml,, 2.9 mmol) dropwise forming a bright yellow slurry. The mixture was stirred at -78 °C for 10 minutes. The enone (17 mg, 0.028 mmol, Example 244, Step 1) was dissolved in 1.0 mL of THF and cooled to -78 °C. 0.6 mL of the cuprate stock solution was added to the THF solution and the resulting bright yellow solution was stirred at -78 °C for 30 minutes. The mixture was then warmed to 0 °C and stirred for an additional 1.5 hours. The reaction was quenched with saturated ammonium chloride and the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 15 to 40% EtOAc (+0.3% HOAc):hexanes) to give a mixture of

(1 S,3'R,6 ^! R,9'S, 11 'S.12'R)-6-chloro-9', 11 12'-trimethyl-3,4-dihydro-2H,7 ^! H, 15Ή- spiro [naphthalene- 1 ,22'-

[20joxa[13]thia[l,14]diazatetracycf^^

7',15'-dione 13',13'-dioxide and (1S,3'R,6'R,9'R,1 l'S,12'R)~6-ehloro-9Vi Γ,12'- dimethyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazateto^^

82,9 7',15'-dione 13',13'-dioxide (11 mg, 0.018 mmol, 63% yield), m/z (ESI, +ve ion) 612.7 (Vl-il) .

STEP 2: (1 S,3'R,6'R,7'S,9'S, 11 'S, 12'R)-6-CHLQRQ-7'-HYDRQXY-9', 11 ',12'- TRiMETHYX.-3,4-DIHYDRO-2HJ51i-SPIRO|NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15 ^* -ONE 13',13'-DIQXTDE OR (1S,3'R,6 ^! R,7'S,9'R,1 l'S,12'R)~ 6-CHLORO-7'-HYDROXY-9' ₅ 11 ', 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE OR (1S,3'R,6'R,7'R,9'S,11'S,12'R)- 6-CHLOR()-7'-HYDROXY-9', 11 ', 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YCT (>! i 47.20--M> ^l "-' ^, |PHNT.\( ^' OS.-\

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'R,1 l'S,12'R)- 6-CHLORO-7'-HYDROXY-9', 11 ', 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

(lS,3'R,6'R,9'S,ll'S,12'R)-6-chloro-9',ir,12' riineihyl-3,4-dihydiO- 2H,7'H, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[l,14]diazate1rac lo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15 ^* -dione 13',13'-dioxide and (Ιβ^'^ό^^ΙΓβ,Ι^-ό-ο ^η ΙθΓθ- ',ΙΙ'.ΙΪ- dimethyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]1hia[l,14]diazatetracyclo[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione I3',13'-dioxide (11 mg, 0.018 mmol) was dissolved in MeOH (1.0 mL) and cooled to 0 °C. Sodium borohydride (1.4 mg, 0.036 mmol) was added and the mixture was stirred for 10 minutes. LCMS showed -20% conversion. The mixture was warmed to room temperature and another aliquot of sodium borohydride (1.4 mg, 0.036 mmol) was added and stirred for 30 minutes. The reaction was then quenched with saturated amraoniura chloride solution and then extracted with ethyl acetate (2 x 20 mL). The material was purified by reverse- phase preparative HPLC using aPhenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1 % TFA in CH ₃ CN/H ₂ 0, gradient 20% to 70% over 40 mm to provide (lS,3'R,6¾7'S,9^,ll¾,12¾ 6 hloro-7'½drox}-9Vi ,12'- trimethyl-3,4-dihydro-2H,15 ^, H-spiro[naphthalene-l,22'- [20]oxa|;i3]ftia[U4]flazatetra^

15'-one 13',13'-dioxide or (iS,3'R,6'R,7'S,9'R,l l'S,12'R.)-6-chloro-7'-]tydroxy- 9'. ] ! ! 2'-trimcihyi-3.4-dih> dro-2i 1.1 Ί !~spiro|naphiha!ene~ 1.22 ^' - [20]oxa[13]tMa[l,14]cUazate1rac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]trien]- 15-one 13', 13 ^* -dioxide or (1 S,3'R,6'R,7'R,9'S, 1 ! ^* S, 12'R)-6-chioro-7'-hydroxy~ 9', 11 12'-trimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracycio[147 _^

15'-one 13',13'-dioxide or (lS,3'R,6'R,7 ^! R,9 ^, R,ll'S,12'R)-6-chioro-7'-hydroxy- 9',11 ',12'-trimethyl-3,4-dihydro-2H,l 5'H-spirofnaphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14 .0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide as the first eluting isomer (0.5 nig, 0.7 μηιοΐ, 3% yield). ¾ NMR (400 MHz, CDC 13) δ 7.62 (d, j 8.4 Hz, ill .6.90-7.16 (m, 2H), 6.54-6.89 (m, 3H), 3,77-3.80 (m, 4H), 3.59-3.95 (m, 5H), 2,54 (s, 2H), 2,01-2.44 (m, 6H), 1.48-1.96 (m, 15H), 0.84-1.00 (m, 4H). m/z (ESI, +ve ion) 614.8 (M R)

EXAMPLE 260. (1 S,3'R,6'R,7'S,9'S, 11 'S, 12'R)-6-CHLORO-7'-HYDROXY- 9', 11 ^* , 12'-TRlMETHYL-3,4-DlHYDRQ-2H, 15 Ή-S PIRO [NAPHTHALENE- l. -

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R,1 l'S,12'R 6-CHLORO-7 ⁱ -HYDROXY-9',ll',i2'-TRiMETOYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ujOXA| !3jTIUA| U4|niA/A ETRA( ^' YCl.Oj i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |Pl-N i ^' AC<)SA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6 ^! R,7 ^* R,9'S,11'S,12'R)- 6-CHLORO-7 ^, -HYDROXY-9 ^, ₅ ir,12 ^* -TRIMETHYL-3,4-DIHYDRO-2H,15 ^, H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'R,1 l'SJ2'R)- 6-CHLORO-7 ⁱ -HYDRO Y-9 11^ί2'-TRΐMEπm _J -3,4-DIHYDRO-2HJ5 ^f H- SPIRO[NAPHTHALENE- 1 ,22'-

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: ' ^{! 1} |Pl-N i ^' AC<)SA [ 16,18,24] TRS EN] -15 '-ONE 13',13'-DIOXIDE

The title compound was obtained as the second pure eluting isomer (other two isomers could not be completely purified) from reverse-phase preparative HPLC using a Phenonienex Luna column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1% TFA in CH-CN/H ₂ 0, gradient 20% to 70% over 40 min in Example 259,

Step 2 (0.3 mg, 0,4 μιηοΐ, 2.0 % yield. ^l H NMR (400 MHz, CDsOD) δ 7.66 (d, J 8.4 Hz, IH), 7.33 (d, j 2.2 Hz, IH), 6.99-7,15 (m, 3H), 6.85 (d, J 8.2 Hz, 1H), 4.87 (s, IH), 3.87-4.12 (m, 3H), 3.67 (d, j 9.8 Hz, ill).3.55 (d, j 13.9 Hz, IH), 3.16 (d, j 1 .7 Hz, IH), 2.97 (dd, j H.8.15.3 Hz, IH), 2.64-2.77 (m, 2H), 2,30- 2,50 (m, 2H), 1.90-2.13 (m, 5H), 1.85 (s, 8H), 1.47-1.83 (m, 7H), 1.08 (t, J 11.5 Hz, 2H), 0,91-0,97 (m, 2H). rrv'z (ESI, +ve ion) 614.8 (M+H) . EXAMPLE 261. (lS,3 ^, R,6 ^, R,7 ^, S,9 ^, S,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-9 ^, ,12'-

DIMETHYL-3,4-DIHYDR()-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,i8,24]TRIEN]-15'-ONE 13', 13'-DIOXJDE OR (1 S,3'R,6'R,7'S,9'R, 12'R)-6- CHLORO-7'-HYDROXY-9', 12'-DlMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,0'R,7'R,9 ^* S,12'R)-6- CHLORO-7'-HYDROXY-9 ^* , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/Λ Π:ΤΗΛ(Ύα.ί)Ι i 4.7.2. ^' ' ) ¹ *' · ¹ |PHNT.\i SA [16,18,24]TRIE ]-15'-ONE 13',I 3 ^* -DIOXIDE OR (lS,3'R,0'R,7'R,9'R,12'R)-6- CHLORO-7'-HYDROXY~9 ^f , 12'-DTMETHYL-3 ₅ 4-DlHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [16, 8,24] TRIEN] - 15 '-ONE 13 13 '-DIOXIDE

STEP 1: (IS,3'R,6'R,9'S,!2'R)-6-CHI RO-9',12 ⁱ -DIMETHYL-3,4-DII-IYDRO- 2H,7¾15H-SPIRO[NAPHTHALENE-l,22'-

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/Λ Π:ΤΗΛ(Ύα.ί)Ι i 4.7.2.0 ^' ' ) ¹ *' · ¹ |PHNT.\i S A [16,18,24]TRIENE]-7',15'-DIQNE 13',13'-DIOXIDE AND (1S,3'R,6'R,9'R,12'R 6-CHLORO-9'J2 ^f -DIMETHYL-3,4-DIHYDRO-2H,7'H,15'H- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24]TRIENE]-7', 15'-DIONE 13', 13'-DIOXIDE

A stock solution of methyl cuprate was made by slurrying copper (I) iodide (270 mg, 1.4 rnmol) in 1.0 mL of Et ₂ 0 and cooling to -78 °C and adding methyllithium (1.8 mL, 2.8 mmol) dropwise forming a bright yellow slurry. The mixture was stirred at -78 °C for 10 minutes. ( l S,3'R,6'R,8'EJ 2'R)-6-chioro-12'- methyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae nej-7',15'-dione 13',13'-dioxide (33 mg, 0.057 mmol. Example 604) was dissolved in 1.0 mL of THF and cooled to -78 °C. 1.0 mL of the cuprate stock solution was added to the THF solution and the resulting bright yellow solution was stirred at - 78 °C for 30 minutes. The reaction was quenched with saturated ammonium chloride and the mixtrue was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 10 to 60% EtOAc (+0.3% HOAc):hexanes) to give a mixture of (1 S,3'R,6'R,9'S, 12'R)-6-chloro-9 ^* , 12'-dimethyi-3,4-dihydro- 2Η,7Ή, 15'H-spiro[naphthalene-l .22'-

[20]oxa[13]tMa[l,14]cUazate1rac lo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]triene]- T, 15'-dione 13', 13'-dioxide and ( 1 S,3'R,6'R,9'R, 12'R)-6-chloro-9', 12'-dimethyl- 3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l .22'-

[20]oxa[13]thia[l ,14]diazatetrac>'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide (22 mg, 0.037 mmol, 65% yield), m/z (ESI, +ve ion) 598,8 ( V! 1 1

STEP 2: i lS,3 ^f R,6'R,7'S,9'S,12'R)-6-CHLORO-7 ^f -HYDROXY-9', 12'- DIMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE~l,22'-

|;20]OXA[ 13 iTHL4[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (l S,3'R,6'R,7'S,9'R, ! 2'R)-6- CHLORO-7'-HYDROXY-9 ^! , 12'-DIMETHYL-3,4-DIHYDR0-2H, 15Ή- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15 ^* -ONE J 3', li -DIOXIDE OR (1S,3'R,6 ^! R,7'R,9 ^! S, 12'R)~6~ CHLQR0-7'-HYDRQXY-9', 12'-DlMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-D10X1DE OR (I S,3'R,6'R,7'R,9'R,12'R)-6- CHL()RO-7'-HYDR()XY-9', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2( >X A| i ? I U Π Λ| ί i J l i^f AZ.Vf l: E RAC YCE C)l i J 7.2 0 ' ^! '.ϋ'" ^{! |} |Pi- N i ACOSA [16,18,24]TRIEN]-15'-0NE 13', 13 '-DIOXIDE

The mixture of (1 S,3'R,6'R,9'S,12'R)-6-chloro-9',12'-dimethyl-3,4- dihy dro-2H,7'H, ! 5 Ή-spiro [naph thai ene- 1 ,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14 .2.0 ³ '^0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide and (lS,3'R,6'R,9'R,12'R)-6-chloro-9',12'-dimethyl- 3,4-dihydro-2H,7'H, 15'H-spiro| naphthalene- 1 ,22'-

| 2ίί |<¾χ;!ΐ I 3 |ihia| I . i 4 |di;!/aielracvci<¾| 14.7.2 0 ^{; :} '.U ^{| 1! ; i} ipcniacosa| 16. i 8.24 |incnel- 7',15 -dione 13 ^! ,13 -dioxide (11 mg, 0.018 mmol, Step 1) was dissolved in MeOH (1.0 mL) and cooled to 0 °C. Sodium borohydride (1.4 mg, 0.036 mmol) was added and the mixture was stirred for 10 minutes. LCMS showed -20% conversion. The mixture was warmed to room temperature and another aliquot of sodium borohydride (1.4 mg, 0.036 mmol) was added and stirred for 30 minutes. The reaction was then quenched with saturated ammonium chloride solution and then extracted with ethyl acetate (2 x 20 mL). The material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C8(2), 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 20% to 70% over 40 mm to provide (l S,3'R,6'R,7'S,9'S, 12'R)-6-chloro-7'-hydiOxy-9 ^, ,12'- dimethyl-3,4-dihydro-2H, 15'H-spirofnaphthalene- 1 ,22'- |20jo\aj I |ihi«i| ! . ! 4|diaya!cua > c!o! 14.7.2. ⁽ ϊ ^; -'.O ^1' ' jpen!acosa| i . ί 8.24|nien i- 15'-one 13',13'-dioxide or (lS^'R^l^T'S^'^^'Ri-e-chloro-T'-hydroxy-g^n'- dimethyl-3,4-dihydro-2H,15'i-I-spiro|naphihaiene-l,22 ^! -

[20]oxa[ jthiaj 1 ,14]diazatetracyclo| 44,7.2,Q ³ ^ 0 ^l9 - ²⁴ ]pesntacosa[l 6,18,24]trien]- 15 ^f -one 13',13'-dioxide or (lS rR,6'RJ ^! R ^4.2¾)~6-chloro-7'4iydroxy-9',12'- dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20joxa[13[thta[l,14[diazatetracycfo[14 _^

15*-one 13',13'-dioxide or ( iS,3'RX.¾ 'R,9¾,12'R)-6-chloro-7'4iydroxy-9'J2 ^f - dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- |2 ⁽⁾ jox.ij I3|thia| 1 J4|dia/.aletracyc!oj !4.7.2 ^)ί: '.Ο ^ι " ^Ipcnlacosal i . S 8.24|tnen !-·

15'-one 13',13'-dioxide as the first eiuiing isomer (2,3 mg, 3.8 μπιοΐ, 10% yield).

¾ NMR (500 MHz, CDsOD) δ 7.66-7.83 (m, IH), 7.19 (dd, J 2.2.8.6 Hz, 1H),

7.06-7.15 (ni, 2H), 7.01 (s, IH), 6.96 id../ 8.1 Hz, IH), 4.05-4.16 (m, 2H), 3.90-

4.00 (m, IH), 3.75-3.90 (m, 2H), 3.64-3.75 (m, IH), 3.25 (d../ 14.2 Hz, 211), 2,70-2.89 (m, 2H), 2.27-2.40 (m, IH), 2. 6-2.25 (m, H), 1.99-2.16 (m, 3H), 1.93-

1,99 (m, 2H), 1.56-1.91 (m, 6H), 1.44-1.53 (m, 3H), 1.25-1.44 (m, 5H), 0,95-1.02

(m, 3H). m/z (ESI, +ve ion) 600.7 { \ I · Π } .

EXAMPLE 262, (lS,3 ^! R,6 ^, R,7'S,9'S,12'R)-6-CHLORO-7 ^! -HYDROXY-9 ^, ,12'- DIMETHYL-3,4-DII-IYDRO-2H,15'H-SPIRO[ API-ITHALENE-l,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC4 (>! i 47.2 ϋ ' ".U ^1* ' · ¹ |PH\ iACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-D10XIDE OR (18,3'ίΙ,6Ί ,7'8,9¾,12¾ 6- CHLORO-7'-HYDROXY-9 ^f , 12'~DIMETHYL~3,4~DIHYDRO~2H, 15Ή- SPIRO [NAPHTHALENE- ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24] TRIEN] - 15 ' -ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R,9'S,12'R)-6- CHLORO-7'-HYDROXY-9*, 12 ^, -DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|2ujOXA| 1ΉΤί!1Λ| Ι44|ΠίΛ/Α Π:ΤΗΑ(Ύα.ΟΙ i 4.7.2.0 ".0 ^|u |Pi ^: NTAi S A [16,18,24]TRIEN]-15'-ONE 13", 13'-DIOXIDE OR (18,3Έ,6¾,7¾,9Έ,12¾)-6- Cffl..ORO-7'-HYDROXY-9 12'-DIMETHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, CI8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 20% to 70% over

40 min in Example 261 , Step 2 (13 mg, 21 μηιοΐ, 57% yield). ^" Ή NMR (500 MHz, CDCb) δ 9.94-10.20 (m, 1H), 7.67 (s, ill).7.59-7.69 (m, 1H), 7.33-7.40 ins.1H), 7.10 (dd, ./ 2.32.8.44 Hz, ill).6.98-7.06 (m, III .6.85-6.89 (m, III). 3.93-4.05 (m, 3H), 3,41-3.68 (m, 3H), 2.99-3.19 (m, 2H), 2.61-2,84 (rn, 3H), 2.43- 2.56 (m, 1H), 1.90-2,04 (m, 4H), 1.64-1.90 (rn, 8H), 1,06-1.31 (m, 9H). m/z (ESI, +ve ion) 600.7 { M · H ) . EXAMPLE 263. (lS,3'R,6'R,7'S,9'S,12'R)-6-CHL()R()-7'-HYDR()XY-9',12'- DIMETOYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S,9'R,12'R)-6- CHLORO-7'-HYDROXY-9 ^* , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTH ALENE- 1 ,22'-

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|D!A/.Vri-;i ^' RA( ^' YCi..()l i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |Pl-N i ^' AC<)SA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'S,12'R 6- CHLORO-7'-HYDROXY-9', 12'-DTMETHYL-3,4-DlHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A

[16,18,24]TRIEN]-15'-ONE 13',13'-DIQXIDE OR (l S,3'R,6'R,7'R,9'R,12'R)-6- CHL()R0-7'-HYDR()XY-9', 12'-DIMETHYL-3,4-DIHYDR0-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ^

[16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the third eluting isomer from reverse- phase preparative HPLC using a Phenomenex Luna column, 10 micron, C I 8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 20% to 70% over 40 min in

Example 261, Step 2 (1.1 mg, 1.5 μηιοΐ, 4.2% yield). ^! H NMR (400 MHz,

CDCb) δ 7.69-7.79 (ra, IH), 7,42 (d, J 2.0 Hz, IH), 7.20 (dd, .1 2 3. 8.5 Hz, IH), 7.1 1 (d, J 2.4 Hz, IH), 7.00-7,08 (m, IH), 6.95 (d, 1=8.2 Hz, IH), 4.08-4.19 (m, 3H), 4.02 (d, J=15.3 Hz, IH), 3.82 (dd, J=3.8, 10.1 Hz, IH), 3.68 (d, J=14.3 Hz, IH), 3.20 (d, j 14. ! Hz, I H), 3.05 (dd, j 8.6. 15.3 Hz, IH), 2.66-2.86 (m, 2H), 2.37-2.59 (m, 2H), 2.12 (s, IH), 1 ,58-2.09 (m, 10H), 1.52-1.58 (m, 4H), 1.37-1.47 (ni, 2H), 1.26-1.34 (m, 2H), 1.10-1.21 (m, IH), 0.92-0.98 (m, 3H). m/z (ESI, +ve ion) 600.7 (M+H) ⁺ . EXAMPLE 264. (lS,3'R,6'R,7'S,9 ^! S,12'R)-6-CHL0R0-7'-HYDR0XY-9',12'- DIMETHYL-3,4-DlHYDRO-2H,15Ή-SPIRO[ APH HALENE-l ₅ 22 ^, - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3> 6 0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-0 E 13',13'-DI0X1DE OR (lS,3'R,6'R,7'S,9'R,12'R)-6- CHL()R0-7'-HYDR()XY-9', 12'-DIMETHYL-3,4-DIHYDR0-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R,9 ^* S,12'R)-6- CHLORO-7'-HYDROXY-9*, 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: ' ^{! 1} |Pl-N i ^' AC<)SA [16,18,24]TRIE ]-15'-ONE 13',13 ^* -DIOXIDE OR (lS,3'R,6'R,7'R,9'R,12'R)-6- CHLORO-7'-HYDROXY-9', 12'-DTMETHYL-3,4-DlHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE~l,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the fourth eluting isomer from reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 20% to 70% over

40 min in Example 261, Step 2 (2,0 mg, 2.8 μιτιοΐ, 7.6% yield), Ή NMR (500 MHz, ( !) ;()!)) δ 7,69-7,85 (m, 1H), 7.06-7.28 (m, 2H), 6,82-7.06 (m, 3H), 4.03- 4.23 (m, 2H), 3.36-3.87 (m, 5H), 3.11-3.25 (m, 1H), 2.72-2.92 (m, 3H), 1.85-2.21 (m, 9H), 1.58-1,85 (m, 5H), 1.44-1.58 (m, 3H), 1.17-1.41 (m, 6H). m/z (ESI, +ve ion) 600,7 (M+H) ⁺ .

EXAMPLE 265 , (1 S,3 ^! R,6'R,7'S,9'S, 12 ^, R)-6-CHLORO-7'-HYDROXY-9', 12'- DIMETHYL-3 ,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ^l9 - ²⁴ ]PE TACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R, !2'R)-6- CHLORO-7'-HYDROXY-9 ^! , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE J 3',13'-DiQXIDE OR (1S,3'R,6 ^! R,7'R,9 ^! S,12'R)~6~ CHLQRO-7'-HYDRQXY-9', 12'-DlMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7,2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIQXIDE OR (lS,3'R,6'R,7'R,9'R,12'R)-6- CHL()RO-7'-HYDR()XY-9', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i() A| 1311 HI Λ| I . ! -i |PI.\/A Π·. ΓΚΑίΎί ^' ί.01 i -1.7.2 (Γ·''. ( ⁾ '"··'' |Ρ1·Ν i ACOS A

[16,18,24]TRLEN]-15'-ONE 13', 13 '-DIOXIDE

STEP 1: (lS,3'R,6'R,8'E,12'S)-6-CHLORO-12'-METHYL-3,4-DIHYDRO- 2H,7TI, 15'H~SPIRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PEOTACOSA [8, 16, 18,24]TETRAENE] -7', 15'-DIO E 13', 13'-DIOXlDE

ί !SJ'R..6'R.? ^' R.K'h. I 2 ^' S)-6-chioro-7 ^' -hvdrovi ~ 12'~n':oi.h} 1-3.-1 -dihvdro- 2H,15'H-spiro[naphthalene-l,22'- | 20 jo\aj I |ihi«i| ! . ! 4|diaya!cu a > c!o! 14.7.2.(ϊ ^; -'.i ^{) 1 '} ' jpen!acosa| K. i 6J 8.2-s jieirae n]-15'-one 13',13'-dioxide (67 nig, 0.12 mmol, Example 995) was dissolved in DCM (2.0 ml) and cooled to 0 °C. Dess-Martin periodinane (97 mg, 0.23 mmol) was added and the reaction mixture was stirred for 45 minutes. The reaction was then diluted with dichloromethane (2.5 ml.) and then quenched with saturated Na ₂ S ₂ 03 (15 niL). The layers were separated and the aqueous layer was extracted with dichloromethane (1 x 25 mL). The combined organic layers were then dried over magnesium sulfate. The crude produci was purified by medium pressure chromatography (silica, 20 to 100% EtOAc (+0,3% HOAc):hexanes) to give (18,3¾,6'Κ,8Έ,12 )-6-ΰΜθΓθ-12'^6 ·1-3,4^¾'άΓθ-21ι,7¾,15¾- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetrac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16, 18,24]tetrae ne]-7',15'-dione 13 ',13 '-dioxide (39 mg, 0.067 mmol, 58% yield) that was used in the next reaction, m/z (ESI, +ve ion) 582.7 (M+H) ⁺ .

STEP 2: (lS,3' ,6'R,9 ^, S,12'S)-6-CHLORO-9',I2'-DIMETHYL-3,4-DIHYD O- 21 1.7 1.15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIENE]-7', 15'-DIONE 13',13'-DIOXIDE AND (1 S,3'R,6 ^! R,9'R, 12'S 6-CHLORO-9',12'-DIMETHYL-3,4-DIHYDRO-2H,7'H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIENE]-7',15'-DIONE 13',13'-DIOXIDE

A stock solution of 3 mmol of Cu(LiMe) ₂ in 5 mL of solvent (-0.6M solution) was formed at -78 °C. In a separate flask the enone (5.0 mg, 8.6 μηιοΐ, Step 1) was dissolved in 0.5 ml. of THF and cooled io 0 °C. 0.5 niL of the cuprate stock solution was added and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine and dried over magnesium sulfate. The crude product was then purified by medium pressure chromatography (silica, 20 to 60% EtOAc (+0.3% HOAc):hexanes) to give a mixture of (lS,3'R,6'R,9'S,12'S)-6-chloro-9',12'- dimethyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]ftia[l,14]diazatefra<yd

7 ^* ,15'-dione 13',13'-dioxide and (lS,3 ^, R,6 ^, R,9 ^, R,12 ^, S)-6-chloro-9 ^, ₅ 12 ^, -dimethyl- 3,4-dihy dro-2H,7'H, 15'H-spiro[naphthalene-l ,22'- 8.2-1 |lrionci- 7',15'-dione 13',13'-dioxide (3.2 mg, 6.3 μηιοΐ, 64% yield), m/z (ESI, +ve ion) 598.8 (M+H) ⁺ .

STEP 3: (lS,3'R,6'R,7'S,9'S,12'R)-6-CHLORO-7'-HYDROXY-9',12'- DTMETHYL~3,4-DiHYDRO-2H/i5 ~SPTRO[N^^

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-QNE 13',13'-DIOXIDE OR ί18,3¾,6¾,7'8,9'ίΙ,12Ί )-6- CHLORO-7'-HYDROXY-9', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| I ?! ! ί U Ai i I -J |? !,\ Ά ! : I AC YC ^' fOl 147.20 ' ".ί) ^|: ' ^{! 1} |Ρ1·Ν i ^' ACOSA

[16,18,24]TRIENj-15'-ONE 13',13'-DIOXIDE OR (18,3¾,6'^7¾,9'8,12Τ< 6- CHLORO-7'-HYDROXY-9', 12'-DTMETHYL-3,4-DlHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3TL6 ^* R,7'R,9'R,12'R)-6- CHLORO-7'-HYDROXY-9' ₅ 12'-DIMETHYL-3 ₅ 4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE

A mixture of (1 S,3 ^, R,6 ^, R,9 ^, S,12 ^, S)-6-chloro-9^12 ^, -dime l-3,4-dihydro-

2Η,7Ή, 15'H-spii [iiaphthalene-l ,22 ^, -

7\15 ^* -dione 13',13'~dioxide and flS,3'R,6'R. ,9'R, 12 ^, S)-6-chloro-9',12 ^, -dimethyl- 3,4~dihydro-2H,7'H, 15'H-spiro[naphthalene-l .22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene|- 7',15'-dione 13',13'-dioxide (16 mg, 0.027 mmol; Step 2) was dissolved in MeOH (1.0 mL) and sodium borohydride (10 mg, 0.27 mmol) was added (or enough to drive the reaction to completion). The reaction mixture was concentrated to dryness and then diluted with ethyl acetate and IN HCI soln. (5 mL). The mixture was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 10-60% EtOAc (+0.3% HOAc):Hexanes) to give the title compound as the first eluting isomer (0.2 mg, 0.3 μ ^η ιοΐ, 1.2% yield). Ή NMR (500 MHz, CDsOD) δ 7.70-7.86 (m, 1H), 7.07-7.37 (m, 3H), 6.88-6.99 (m, 1H), 5.68-5.94 (m, 1H), 4.97-5.20 (m, 2H), 4.00-4.20 (m, 2H), 3.43-3.85 (m, 4H), 2.58-3.06 (m, 3H), 1.76-2,35 (m,10H), 1.41-1.76 (m, 6H), 1.33-1.41 (m, 3H), 0.90-1.03 (m, 4H). m!z (ESI, +ve ion) 600.8 (M+H) ⁺ .

EXAMPLE 266, (IS,3 ⁱ R,6'R,7'S,9'S,I2'R)-6-CHLORO-7 ⁱ -HYDROXY-9'J2'- DIMETHYL-3,4-DiHYDRO-2H,15'H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13 ^! -DI()XIDE OR (lS,3'R,6'R,7'S,9'R,12 ^! R)-6- CHLORO~7'~HYDROXY-9', 12'-DIMETHYL-3,4-DIHYDRO-2H ₅ 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 ".i ^)|u |P1 ^: N I ^' ACOSA

[16,18,24]TRIEN]-15'-ONE !3',13'-DIOXIDE OR (lS,3'R,6'R,7 ^f R,9'S,12'R)-6- CHI RO-7'-HYDROXY-9 12'-DIMETHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA jl6,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6 ^* R,7'R,9'R,12'R)-6- CHLORO-7'-HYDROXY-9*, 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l ,22'-

|2ujOXA| 1ΉΤί!1Λ| Ι.Ι4|ΠίΑ/.ΥΠ:ΤΗΑ(ΎΠ.ϋΙ i 4.7.2.U ^' ".ί) ^|: ' ^{! 1} |Ρ1·Ν I ^' ACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE

The title compound was synthesized as described in example 265, step 3 and was obtained as the second eluting isomer (6.0 mg, 10.0 μηιοΐ, 37% yield). ¾ NMR (400 MHz, CD3OD) δ 7.67-7.87 (m, 1H), 7.11-7.25 (m, 2H), 7.05-7.42 (m, 2H), 6,88-7.03 (m, 1H), 3.97-4,25 (m, 3H), 3.71-3.85 (rn, 1H), 3.41-3,71 (m, 2H), 3.24-3.41 (m, 5H), 3.15 (dd, j 7.6.15.4 Hz, 1H), 2.68-2.98 (m, 2H), 2.45-2.65 (m, 1H), 2.19-2.45 (m, IH), 2.08-2.19 (m, 2H), 1.99-2.08 (m, 2H), 1.61-1.99 (m, 8H), 1.41-1,61 (m, 6H). m/z (ESI, +ve ion) 600.8 (M+H) ⁺ .

EXAMPLE 267. (lS,3'R,6 ^f R,7'S,9 ⁱ S,12'R)-6-CHLORO-7'-HYDROXY-9',12'- DiMF;THYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [16,18,24]TRJEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7 ^f S,9'R,12'R)-6- CHLORO-7'-HYDROXY-9 ^! , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l ₅ 14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13"-DIOXIDE OR (lS,3'R,6'R,7'R,9'S,12'R)-6- CHLORO-7'-HYDROXY~9 ^f , 12'-DTMETHYL-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13' ₅ 13 ^* -DIOXIDE OR (1 S,3'R,6'R,7'R ,9'R,12'R)~6- CHLQRQ~7'~HYDRQXY-9', 12'-DiMETHYL-3,4-DiHYDRO-2H, 1 ^'i !- SPIRO[N APHTHALENE-1 ,22'-

[20;|OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PENTACOSA [16,18,24]TRTEN]-15'-ONE 13',13'-DIOXIDE

The title compound was synthesized as described in Example 265, Step 3 and was obtained as the third eluting isomer (2.0 mg, 3.3 μιτιοΐ, 13% yield). ^l H NMR (400 MHz, CD3OD) δ 7.70-7.88 (ra, 1H), 7,09-7.33 (m, 3H), 6.82-7.04 (m, 2H), 4.60 (br. s., 1H), 3.97-4.26 (m, 3H), 3.62-3.87 (m, 3H), 3.14 (dd, j 9.7. 15.4 Hz, 1H), 2.67-2.96 (m, 2H), 1.65-2.47 (m, 1 1H), 1.24-1.54 (m, 9H), 0.97-1.06 (m, 3H), 0.86-0,89 (m, 1H). m!z (ESI, +ve ion) 600.8 (M+H) ⁺ .

EXAMPLE 268. (18,3¾,6Έ,7'8,9'8,1 1 'S)-6-CHLORO-7'-HYDROXY-9', 1 Γ- DiMETHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [16,18,24]TRJEN]-15'-ONE 13', ! 3'-DIOXIDE OR (lS,3'R,6'R,7 ^f S,9'R, i l 'S)-6- CHLORO-7'-HYDROXY-9 ^! , 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[l ₅ 14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-I 5'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'S,1 l'S)-6- CHLORO-7'-HYDROXY-9' ₅ 11 *-DTMETHYL-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,I8,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R,1 l'S)-6- CHLQRO~7'~HYDRQXY-9', 11 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA [16,18,24]TRJEN]-15'-ONE 13',13'-DIOXIDE

STEP 1: (lS ₅ 3 ^, R,6 ^, R,8 ^, E,ll ^, S)-6-CHLORO-12 ^, -METHYL-3,4-DIHYDRO- 2H, 7Ή, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/Ar!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 " ^)1* ' · ¹ |PLNTAC0SA

[8,16,18,24]TETP^ENE]-7',15'-DIONE 13 ',13 '-DIOXIDE

(18,3Έ,6¾ Έ,8Τ^,11'8)-6-οΗίθΓθ-7'-ΚνάΓθχγ-12^Μ6 1-3,4-(1 άΓθ- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (53 mg, 0.091 mmol, Example 231) was dissolved in DCM (2.0 ml) and cooled to 0 °C. Dess-Martin periodinane (77 mg, 0.18 mmol) was added and the reaction mixture was stirred for 45 minutes. The reaction was then diluted with dichloromethane (25 mL) and then quenched with saturated Na_S ₂ 03 (15 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (1 x 25 mL). The combined organic layers were then dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 20 to 100% EtOAc (+0.3% HOAc):hexanes) to give (lS,3 ^, R,6'R,8¾l l ^, S)-6-cWoro-12 ^, -me l-3,4-dihydro-2h,7 ^, h,15¾- spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ^{! 9} - ²⁴ ]pentacosa[8, 16, 18,24]tetrae ne]-7',15'-dione 13',13'-dioxide (32 nig, 0.055 mmol, 61% yield) that was used in the next reaction, m/z (ESI, +ve ion) 582.7 (M+H) ⁺ .

STEP 2: (1 S,3'R,6'R,9 ^! S,1 l 'S)-6-CHLORO-9',l l'-DIMETHYL-3,4-DIHYDRO-

2H,7'H,15'H-SPlRO[NAPHraALENE-l,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA

[16,18,24]TRIENE]-7',15'-DIONE 13',13'-DI0X1DE AND (lS,3 ^! R,6'R,9'R,irS)~ 6-CHLGRO-9', 11 ^! -DlMETHYL-3,4-DlHYDR( 2H,7'H, 15Ή- SPIRO INAPHTHALENE- 1.22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIENE]-7', 15 ^* -DIONE 13',13'-DIOXJDE

A stock solution of the methyl cuprate solution was made by slurrying copper (1) iodide (270 mg, 1.4 mmol) in 1.0 mL of EtaO and cooling to -78 °C and adding methyllithium (1.8 mL, 2.8 mmol) dropwise forming a bright yellow slurry. The mixture was stirred at -78 °C for 10 minutes. The enone (33 mg, 0.057 mmol, Step 1) was dissolved in 1.0 mL of THF and cooled to -78 °C. 1.0 mL of the cuprate stock solution was added to the THF solution and the resulting bright yellow solution was stirred at -78 °C for 30 minutes. The reaction was quenched with saturated ammonium chloride and the rnixtrue was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 10 to 60% EtOAc (+0.3%

HOAc):Hexanes) to give a mixture of (lS,3 ^! R,6'R,9'S,irS)-6-chloro-9',ir- dimethyl-3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l ,22'- ! 20 j oxaj 13 ] thi a[ 1 , 14] diazatetra^

7',15'-dior!e I3',13'-dioxide and (1S,3'R,6'R,9'R,1 l'S)-6-chloro-9',! I'-dimethyl- 3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]mia[l,14]cUazatetra^

7',15'-dione 13',13'~dioxide. m/z (ESI, ^■ sc ion) 598.8 { M II } .

STEP 3: (1S,3'R,6'R,7'S,9'S,1 l'S)-6-CHLORO-7'-HYDROXY-9',ir- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N ΑΡΗΊΉ ALEN E- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13', ! 3'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R, ! l'S)~6~ CHLORO-7*-HYDROXY-9', 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16, 8,24]TRIEN]- I5'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'S,1 l'S)-6- CHLORO-7'-HYDROXY-9', 11 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13 ^! -DIOXIDE OR (1S,3'R,6'R,7'R,9'R,1 l*S)-6- CHLORO-7'-HYDROXY-9', 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16, 18,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE

The mixture of ketones (25 mg, 0.042 mmol, Step 2) was dissolved in MeOH (2.0 mL) and sodium borohydnde (16 mg, 0.42 mmol) was added and stirred for 30 minutes. (More NaBH4 was added as needed to push the reaction to completion). The reaction mixture was then concentrated and extracted between EtOAc (2 x 20 mL) and IN HCI (10 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over magnesium sulfate. The filtrate was concentrated and the residue was purified by medium pressure

chromatography (silica, 20 to 75% EtOAc (+0.3%HOAc):hexanes) to give (lS,3¾,6'R,7^,9'S,l l'S)-6-chloro-7'-hydroxy-9^11'-dimethyl-3,4-dihydro- 2H, 1 5'H-spiro[naphthalene-l ,22'-

| 20 jo\aj I 3 |shia| U 4|dia/aieinu:vc!o| 14.7 2.0 ⁵ · ^ί, .0 ^{| ,} ' jpentaeosa| 16. i 8.24|tnen |- 15'-one 13',13'-dioxide or (1S,3'R,6'R,7'S,9'R,1 l ^, S)-6-chloro-7 ^, -hydroxy-9',l Γ- dimethyl-3,4-dihydro-2H,15'H-spiro| naphthalene-!, 22'-

15'-one 13',13 ^* -dioxide or (lS,3'R,6'R,7'R,9'S,l l ^, S)-6-chloro-7 ^, -hydi xy-9',i r~ dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ -^0 ¹⁹ - ² ^

15'-one 13',13'-dioxide or (lS,3'R,6'R,7'R,9 ^! R,H'S)-6-chloro-7'-hydroxy-9',i r- dimethy3-3,4-dihydro-2H,15'H-spiro|naphthalene-l,22 ^! -

| 20 jox«ij I 3 |t ia| U 4 |dia/aielracveioj 14.7.2 O ^{; :} '.0 ^{| 1! ; i} ipemacosa| 16. i 8.24|inen j~ 15'-one 13',13'-dioxide (2.4 mg, 4.00 μτηοΐ, 9.6 % yield) as the first eluting isomer. M i NMR (500 MHz, CDCls) δ 10.41 (br. s., 1H), 7.56-7.74 (m, 1H), 7.34- 7.50 (m, 1H), 7.23-7.31 (m, 1H), 6.82-7.10 (m, 3H), 3.90-4.06 (m, 2H), 3.46-3.79 (m, 2H), 2.94-3.17 (m, 3H), 2,58-2.70 (m, 2H), 2.15-2.53 (m, 3H), 1.74-2.10 (m, 6H), 1.22-1.41 (m, 7H), 0.82-1.04 (m, 9H). m'z (ESI, +ve ion) 600.8 (M+H) ⁺ .

EXAMPLE 269. (l S,3'R,6'R,7 ^! S,9'S,l l'S)-6-CHLORO-7'-HYDROXY-9',l l'- DIMETHYL-3,4-DIHYDR()-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15 ^* -ONE 13', 13'-DIOXJDE OR (1 S,3'R,6'R,7'S,9'R, 1 l'S)-6- CHLORO-7'-HYDROXY-9', 11 '-D1METHYL-3.4-D1HYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13\13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'S, 11 'S)-6- CHLORO-7'-HYDROXY-9 ^! , 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15*-ONE 13', 13 '-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R,1 l'S)~6~ CHLQRO-7'-HYDRQXY-9', 11 '-D1METHYL-3.4-D1HYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer using medium pressure chromatography (silica, 20 to 75% EtOAc

(+0.3%HOAc):Hexanes) in Example 268, Step 3 (1.5 mg, 2,5 jimol, 6.0 % yield). ¾ NMR (500 MHz, CDCh) δ 9.75 (s, IH), 7.58-7.75 (m, 1H), 7.37-7.53 (m, IH), 6.80-7.17 (m, 4H), 3.90-4.11 (m, 3H), 3.47-3.82 (m, 3H), 2.91-3.24 (m, Ml).2,59-2.78 (m, 2H), 2.07-2,48 (m, Ml).2.04-2.07 (rn, IH), 1.60-2,01 (m, 6H), 1,19-1.39 (m, 7H), 0.87-1.01 (m, 6H). m/z (ESI, +ve ion) 600.8 (M+H) ⁺ .

EXAMPLE 270, (IS,3'R,6'R,7'S,9'S,I I'S)-6-CHLORO-7'-HYDROXY-9',ir- DIMETHYL-3,4-DIHYDR()-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15*-ONE 13', 13'-DIOXIDE OR (1 S,3'R,6'R,7'S,9'R, 1 l'S)-6- CHLORO-7'-HYDROXY-9', 11 '-D1METHYL-3.4-D1HYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A [16,18,24]TRIEN]-15'-ONE 13',13'-DIQXiDE OR (lS,3'R,6'R,7 ^! R,9'S,ll'S)-6- CHL()RO-7'-HYDR()XY-9', 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^

[16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE OR (1S,3'R,6'R,7'R,9 ^! R,1 l'S)-6- CHLORO-7'-HYDROXY-9' ₅ 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was obtained as the third eluting isomer using medium pressure chromatography (silica, 20 to 75% EtOAc (+0.3%HOAc):Hexanes) in Example 268, Step 3 (18 mg, 0.030 mmol, 72% yield). ¹ !-] NMR (400 MHz, CDCI3) 68,93 (br. s., 1H), 7.57-7.99 (m, !H), 7.36-7,55 (m, Hi).6.88-7.26 (ra, 4H), 3.80-4.31 (m, 5H), 3.57-3.74 (m, IH), 3.11-3,34 (m, 2H), 2.90-3.11 (m, 2H), 2.67-2.88 (m, 3H), 2.38-2.67 (m, 21 i).1.48-2.02 (m, 12H), 1.10-1.19 (m, 41 i). 0.90-1.00 {in.3H). m/z (ESI, +ve ion) 600.8 i\i Π) .

EXAMPLE 271 , (IS,3'R,6'R,7'S,9'S, 11 'S)-6-CHLORO-7'-HYDROXY-9', 11 '- DIMETHYL-3 ,4-DIHYDRO-2H, 15 ^! H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S,9'R,irS)-6- CHLORO-7'-HYDROXY-9', 11 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE OR (l S,3'R,6'R,7'R,9 ^* S, l l'S)-6- CHLORO-7'-HYDROXY-9 ^* , 1 1 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

| 2u jOXA| ! jTI UA| U 4 |niA/A ETR A( ^' YCl.Oj i 4.7.2 U ' ".ί ^{) | :} ' ^{! 1} |Ρ1·Ν I ^' ACOSA [ 16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7 ^* R,9'R, 1 l'S)-6- CHLORO-7'-HYDROXY-9', 11 '-DTMETHYL-3,4-DlHYDRO-2H, 15Ή- SPIRQ[NAPHTHALENE~1,22'- [20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the fourth elutmg isomer using medium pressure chromatography (silica, 20 to 75% EtOAc

(+0.3%HOAc):Hexanes) in Example 268, Step 3 (1.0 tng, 1 .7 μηιοΐ, 4.0% yield). ¾ NMR (500 MHz, CDCh) δ 9,32 (br. s. , IH), 7.56-7.75 (m, IH), 7.39- 7.39 (m, IH), 7.33-7.45 (m, IH), 6.81-7.16 (m, 3H), 3.99-4.31 (m, 3H), 3.46-3.86 (m, 4H), 2.90-3.22 (m, 3H), 2.60-2.75 (m, 2H), 1.66-2.30 (m, 10H), 1.28-1.36 (m, 4H), 0,96-1 .13 (m, 8H). nvz (ESI, +ve ion) 600.8 (M+H) ⁺ .

EXAMPLE 272, (lS,3'R,6 ^, R,7 ^, S,9 ^, S,H ^, R)-6-CHLORO-7 ^, -HYDROXY-9 ^, ,l 1 '- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [16,18,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE OR ( 1S,3'R,6'R,7'S,9'R, 1 l'R)-6- CHLORO-7'-HYDROXY-9' ₅ 11 ^* -DTMETHYL-3,4-DlHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,I8,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'S, 1 l'R)-6- CHLQRO~7'~HYDRQXY-9', 1 1 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA

[16,18,24]TRTEN]-15'-ONE 13", 13'-DIOXIDE OR (I S,3'R,6'R,7'R,9'R, 1 l'R)-6- CHLQRQ-7'-HYDRQXY-9 ^! , 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16, 1 8,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE

The ketone derived in essentially the same manner as described in

Example 268, Step 1 from the alcohol (10 mg, 0,017 mmol, Example 233) was dissolved in MeOH (1.0 mL) and sodium borohydnde (6.3 mg, 0.17 mmol) was added (or enough to drive the reaction to completion). The reaction mixture was concentrated to dryness and then diluted with ethyl acetate and IN HCl soln. (5 mL). The mixture was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude product was purified by a combination of medium pressure chromatography (silica, 10-60% EtOAc (+0.3% HOAc):hexanes) and reverse- phase preparative HPLC using a Phenomenex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH3CN/H20, gradient 40% to 75% over 30 mm to give (lS,3 ^, RXVR,7^,9 ^! SjrR)-6-chloro-7'½droxy-9',ir-dimethyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

|20iox!j I3|t ia| iJ4|dia «leiracydoj 14.7.2 O ^;: '.0 ^|1!;i ipemacosa| 16. i 8.24|inenj~ 15 ^f -one 13',13'-dioxide or (1S,3'R,6'R,7 ^! S,9'R,1 rR)-6-chloro-7'-hydroxy-9',i - dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20ioxa|13jthia[l,14jdiazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ^!9 ' ²⁴ ipentacosa[ 16,18,24]trien]- 15'-one 13*,13*-dioxide or (1S,3'R,6'R,7'R,9'S,1 l'R)-6-Gh]oro-7'-hydiOxy-9',l I '- dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- |20jox.ij I3|thia| I J4|dia/.aletracye!oj !4.7.2.0 ^i: '.0 ^l " ^lpcnlacosal 16. i 8.24|inersj- 15'-one 13',13'-dioxide or (1S,3'R,6'R,7'R,9'RJ I'R)-6-chloro-7'-hydroxy-9',ir- dimethyl-3,4-dihydro-2H,15'H-spiro[naphtiialene-l,22'- [20]oxa[13]ihia[l,14]diazatefracyd^

15'-one 13',13'-dioxide (1.2 mg, 1.7 μπιοΐ, 10% yield) as the first eluting isomer by HPLC. ^" Ή NMR (500 MHz, CDsOD) δ 7,74 (d, J=8.56 Hz, IH), 7.25-7.46 (m, 2H), 7.06-7.23 (m, 2H), 6.87-7.06 (m, IH), 4.04-4.28 (m, 2H), 3.71-3.84 (m, 2H), 3.61-3.71 (in, IH), 3.54 (dd, j 9.1.15.2 Hz, IH), 3.35-3.39 (m, 211), 2.72-2.90 (m, 2H), 2,29-2.41 (m, IH), 2.14-2.28 (m, 2H), 2,04-2.13 (m, 21 \) 1.84-2,03 (m, 4H), 1.72-1.82 (m, 2H), 1.51-1.67 (m, 2H), 1.22-1,44 (m, 4H), 1.14 (d, J=6.9 Hz, 3H), 0.98-1.04 (m, 3H), 0.86-0.96 (m, IH). m/z (ESI, +ve ion) 600.8 (M+H) ⁺ .

EXAMPLE 273. (lS,3'R,6 ^! R,7'S,9 ^, S,ll'R)-6-CHLORO-7'-HYDROXY-9 ^! ,i - DIMETHYL-3,4-DIHYDRO-2H,15H-SPIRO|7 ^> iAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-QNE 13',13'-DI0X1DE OR (lS,3'R,6'R,7'S,9'R,irR)-6- CHLORO-7'-HYDROXY-9', 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|20jOXA| I 311 HI Λ| I , N |OIA/.\ Π·. f ^' RACYCf .Oj I -1.7.20 ' ".U ^1* ' · ¹ |PL\ i ACOS A [16,18,24]TR1EN]-15'-0NE 13', '-D10XIDE OR (lS,3'R,6'R,7'R,9 ^! S,irR)-6- CHLORO-7'-HYDR.OXY~9 ^f , 11 '~DIMETHYL~3,4~DIHYDRO~2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [16,18 ₅ 24]TRIE ]-15'-ONE 13',13 ^! -D1GX1DE OR (1 S,3'R,6'R,7'R,9'R,1 l'R)-6- CHL()RO-7'-HYDR()XY-9', 1 1 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'- | 20 jOX A| Π Ι Η1 Λ| I , i ! | PIA/.\ Π·. ΓΗ. ΑίΎί ^' ί ,ΟΙ i -i .7.2 0 ' ^! '.ϋ'" ' ¹ |Ρ1· N i ACOS A [16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer by HPLC in the separations described in Example 272 (2.0 mg, 2.8 μηιοΐ, 17% yield). ¾

NMR (500 MHz, CDsOD) δ 7.66-7.85 (m, I H), 7.25-7.64 (m, IH), 7.07-7.23 (m, 3H), 6.84-7.01 (m, IH), 4.10-4.35 (m, 2H), 3.90-4,04 (m, IH), 3.50-3.69 (m, 3H), 2.98 (dd, j=9.8, 14.9 Hz, i l l ). 2.59-2.91 (m, 3H), 1.80-2.23 (m, 8H), 1.61-1 ,80 (m, 3H), 1.21-1.61 (m, 5H), 1.17 (d, j 6,4 Hz, 3H), 0.90-1.01 (m, 5H). m/z (ESI, +ve ion) 600.8 ( +H) ⁺ .

EXAMPLE 274, (lS,3'R,6'R,7'S,9'S,i rR)-6-CHLORO-7'-HYDROXY-9'J 1 '- DIMETHYL-3 ,4-DIHYDRO-2H, 15 ^! H-SPlRO [NAPHTH ALENE- 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24jTRIEN]-15'-ONE 13', 13 ^! -DIOXIDE OR (lS,3'R,6'R,7'S,9'R,i rR)-6- CHLORO-7'-HYDROXY-9', 1 1 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14J.2.0 ³ - ^{6 19} ' ²⁴ ]PE TACOSA [16,18,24]TRIE ]-15'-ONE 13',13'-DIOXIDE OR (l S,3'R,6'R,7'R,9'S, l 'R)-6- CHLORO-7'-HYDROXY-9 ^! , 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R,1 l'R)-6- CHLORO-7'-HYDROXY-9*, 11 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1 ,22'-

|2ujOXA| 1 ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.U ^' ".ί) ^|: ' ^{! 1} |Ρ1·Ν I ^' ACOSA [ 16,18,24] TRS EN] -15 '-ONE 13',13'-DIOXIDE

The title compound was obtained as the third eluting isomer by HPLC in the separations described in Example 272 (0.9 mg, 1.5 μτηοΐ, 9.0% yield). ^! H NMR (400 MHz, CDsOD) 67,76 (d, J=8.4Hz, 111).7.16-7.23 (ra, 2H), 7,09-7.15 (m, 2H), 6.93 id. j 8.2 Hz, ill).4.03-4.13 (m, 2H), 3.99 (d, j 1 .3 Hz, 1 H), 3.73 (d, j 1 .9 Hz, I I I).3.58-3.68 (m, 1H), 3.52 (dd, j 15.0.6.2 Hz, 1H), 3.24-3.29 (m, 1H), 3.12-3.21 (m, 1H), 2,72-2.9! (m, 3H), 2.19-2.34 (m, 2H), 2.07-2.19 (m, 3H), 1,96 (d, j=9.4Hz, i l l).1.88 (br. s., 111).1.66-1,80 (m, 2H), 1.55-1.65 (m, IH), 1.42-1.55 (m, 2H), 1.18-1.28 (m, 2H), 1.15 (d, j 6.8 Hz, 3H), 1.07 (d, J=6.5 Hz, IH), 0.92 (d, .! 6.7!!/.3H), 0.84-0.89 (m, IH). m/z (ESI, +ve ion) 600.8 (W W) . EXAMPLE 275. (1 S,3'R,6'R,7'S,9'S,1 l'R)-6-CHLORO-7'-HYDROXY-9',i Γ- DIMETHYL-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [16J8,24]TRiEN]-15'-ONE 13', ! 3'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R, Π 'R)-6- CHLORO-7'-HYDROXY-9 ^! , 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R,9 ^* S,ll'R)-6- CHLORO-7'-HYDROXY-9 ^* , 11 '-DIMETHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

|2ujOXA| 1ΉΤί!1Λ| l.l4|DiA/AiTTRAC ^' Ya.i)i i 4.7.2.U ' ".ί ^)|: ' ^{! 1} |Ρ1·Ν I ^' ACOSA

[16,18,24]TRIEN]-15'-ONE 13',13 ^* -DIOXIDE OR (1S,3'R,6'R,7'R,9'R,1 l'R)-6- CHLORO-7'-HYDROXY-9', 11 '-DIMETHYL-3,4-Dn-I TJRO-2H, 15Ή- SPIRQ[NAPHTHAi.ENE~l,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the fourth eluting isomer by HPLC in the separations described in Example 272 (0.5 mg, 0.7 μηιοΐ, 4.2% yield). ^l H NMR (500 MHz, CD3OD) δ 7.7.5 (d, J=8,56 Hz, ΓΗ), 7.06-7.25 (m, 2H), 6.74- 7.06 (m, 3H), 3.94-4.26 Cm.2H), 3.73-3.84 (m, 1H), 3.62-3.73 (m, Ml).3.40-3.55 (m, 2H), 2.73-2.91 (m, 1H), 2.68 (s, 1H), 2.42-2.54 (m, 1H), 2.29-2,42 (m, 1H), 1.97-2.14 (m, 2H), 1,47-1.97 (m, 11H), 1.17 (br. s., 3H), 0,97-1.12 (m, 4H), 0.92- 1.04 (m, 4H), m/z (ESI, +ve ion) 600, 8 ί VI · H )

EXAMPLE 276. (1 S,3'R,6'R,9 ^, R)-6-CHLORO-9 ^, -METHYL-3,4-DIHYDRO- 2H, 15 Ή - SPIRO | N APHTH AL ENE- 1,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A [16,18,24]TRIEN]-15'-QNE 13',13'-DIQXiDE AND (lS,3'R,6'R,9'S)-6- CHLORO-9'-METHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-

1 ,22'- | 2( >X A| i ? I U Π Λ| ί i J l i^f AZ.Vf l: E RAC VCE C)l i J 7.2 0 ' ^! '.ϋ'" ^{! |} |Pi- N i ACOSA [16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE.

The vinyl bromide (l S,3'R,6'R,7'S,8'E)-6-chloro-7'-hydroxy-9 ^f -bromo-3,4- dihydro-2h, 15'H-spiro[naphthalene-l ,22'- | 2o jo\aj I 3 |lhia| ! J 4 |dia/aieiruc> ck>i U^ ^ O - ) ¹ '' ^peniacosu| 8J J 8.24j teirae n]-15'-one 13',13'-dioxide or (1 S,3'R,6'R,7'R,8'E)-6-chloro-7'4iydroxy-9'-bromo- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazateti^

nj-15'-one 13',13'-dioxide (9.0 mg, 0.014 mmol. Example 236) was dissolved in 1 ,4-dioxane (0.3 mL) and the cesium carbonate (I 5.79 mg, 0.048 mmol),

PdCl ₂ (dppf)-CH2Cl ₂ (2.261 mg, 2.77 μιτιοΐ) and methaneboronic acid (2.486 mg, 0.042 mmol) were added and the reaction was heated at 100 °C for one hour. The reaction was then cooled and diluted with EtOAc. The mixture was then fitered and the filtrate was concentrated to dryness. The crude product was purified using SFC chromatography (AS column, 35% MeOH/C02) To give an unidentified mixture of products (7 mg). The product mixture (7.0 mg, 0.012 mmol) was dissolved in EtOAc (1.0 mL). The platinum (IV) oxide (2,7 mg, 0.012 mmol) was added and the reaction vessel was flushed with hydrogen and stirred over night under balloon pressure. The reaction mixture was then filtered and the filtrate was concentrated and the residue was taken up in DMSO. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column. 10 iracron, C8(2), 100 A, 150 x 30 mm, 0.1% TFA ra CH ₃ CN/H ₂ 0, gradient 50% to 70% over 20 mm to provide (lS,3'R,6^R,9 ^, R)-6-chloro-9'-meihyS-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'- [2Q]oxa[13]thia[l,14]diazatetra^

15'-one 13',13'-dioxide and (lS,3 ^! R,6'R,9'S)-6-chk)ro-9'-m.ethyl-3,4-dihydro- 2H,15'H-spiro[naphthalene-l,22'- [20joxa[13]thia[l,14]diazatetracycfo[14.7.2X^^^

15'-one 13',13'-dioxide. (0.9 mg, 0.8 μτηοί, 6.6% yield) as the third eluting isomer. 'HNMR (400 MHz, CDCb) δ 7.79-8.02 (m, IH), 7.47-7,66 (m, IH), 6.64-6.72 (m, IH), 6.64-7.08 (m, 4H), 3.81-4.16 (m, 2H), 3.47-3.69 (m, 2H), 3.22-3.47 (m, ill).2.98-3.22 (m, IH), 2.87 (dd, J 8.1.15.4 Hz, !!!).2.55-2,70 (m, 2FI), 1.96- 2.28 (m, 2H), 1.89-1,96 (m, IH), 1.74-1.89 (m, 3H), 1,27-1.53 (m, 9H), 0.65-0.87 (m, 7H). m/z (ESI, +ve ion) 571.3 (M R)

EXAMPLE 279. (lS^'R.e'^'S^'S l'S mVe-CHLORO-T-HYDROXY- ll 2'-DIMETHYL-9'-(4-MORPHOLINYL)-3,4-DIHYDRO-2FI,15 ^, H- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R,1 l'S,12'R 6-CHLORO-7'-FIYDROXY-H',!2'-DIMETFiYL-9'-(4-MORPHOLINYL)-3,4 - DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |Pl-N i ^' AC<)SA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS^'R.e'^^ 'S l'S R)- 6-CHLORO-7'-HYDROXY-l 1 ', 12'-DIMETHYL-9'-(4-MORPHOLiNYL)-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-.l 5'-ONE 13', 13'-DTOXIDE OR (1 S,3'R,6'R,7'R,9'R, 11'S, 12'R)- 6-CHLORO-7'-HYDROXY- 11 ', 12 ^* -DIMETHYL-9 ^, -(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

STEP 1 : (lS,3TL6'R,9'S,l l'S,12 ^* R)-6-CHLORO-l l',12'-DIMETHYL-9'-(4- MORPHOLmYL)-3,4-DmYDRO-2H TT/15H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[13]THIA[1,14]DL ZATETRACYCLO[14,7.2,0 ³ - ⁶ .0 ¹⁹ - ² ^

[ 16,18,24]TR1E E]-7',15'-D10NE 13',13'-D1QXIDE AND

(1S,3'R,6'R,9'R, 1 l'S,l 2'R)-6-CHLORO-l 1 ',12'~DIMETHYL-9'-(4- MORPHOL.rNYL)-3,4-DIHYDRO-2H,7'H ₅ 15'H-SPIRO[NAPHTHALENE- 1 ,22 ^! ~ [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |;i6,18,24]TRIENE|-7' '-DIONE 13',13'-DIOXIDE

The enone (50 mg, 0.084 mmol, Example 244, Step 1) was dissolved in THF (2,5 mL) and morpholine (0.15 mL, 1.7 mmol) was added and the resulting solution was stirred for 2.5 hours to completion. The reaction mixture was then concentrated and placed under high vaccum. The residue was dissolved in MeOH (2.0 mL) and cooled to 0 °C. The sodium borohydride (16 mg, 0.42 mmol) was added and the reaction was stirred for 15 minutes to completion. The mixture was concentrated to dryness and the residue was taken up in EtOAc (20 mL) and washed with saturated sodium bicarbonate solution (1 x 10 mL). The organic layer was washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a

Plienomenex Gemini column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1% TFA in CH3CN/H2O, gradient 35% to 55%) over 45 min to provide

(lS,3¾,6 ^, R,9^,irS,12'R)-6-chloro-11^12'-dimethyi-9' 4-morpholinyl)-3,4- dihydro~2H,7'H, !^ ^' H-spiro|nap !halene-i.22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide or (lS^^&R-^R-lVS-l^RJ-e-chloro-ir-n'- dimethyl-9'-(4-mo holinyl)-3,4-dih dro-2H,7Ή,15Ή-spirofnaphthalene-l,22'- [20]oxa[13]mia[l,14]diazatetracyclo[14 .2^

7',15'-dione 13',13'-dioxide (45 mg; 0.049 mmol, 59%) as the first eluting isomer. Further elution provided 1 S,3'R,6'R,9'S, 11 'S, 12'R)-6-chloro- H',12'-dimeth 1-9'- (4-mo holinyl)-3,4-dihydro-2H,7Ή,15Ή-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide or (lS,3'R,6'R,9'R,ll ^* S,12'R)-0-chloro-ll',12'- dimethyl-9'-(4-moφholinyl)-3,4-dih dro-2H,7Ή,15Ή-spirofnaphthalene-l,22'- [20]oxa[13]mia[l,14]diazatetracyclo[14 .2.0 ³ '^0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13 ',13 '-dioxide (14 mg; 0.015 mmol, 18%) as the second eluting isomer. STEP 2 : (1S,3'R,6'R,7'S,9'S,1 l'S,12'R)-6~CHLORO-7'~HYDROXY-l Γ,12'- DIMETHYL-9'-(4-MORPHOLINYL)-3,4-DIHYDRO-2H.15H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DI0X1DE OR (1S,3'R,6'R,7'S,9'R,1 l'S,12'R 6-CHLORO-7'-HYDROXY-llV!2'-DIMETFiYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

|2uj XA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA [ 16,18,24] TRI EN] -15 '-ONE 13',13'-DIOXIDE OR (1S,3'R,6 ^! R,7'R,9'S,H'S,12'R)- 6-CHLORO-7"-HYDROXY- 11 ', 12 ^, -DIMETHYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A [16,18,24]TRIEN]-15'-QNE 13 ',13 '-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R,11'S;12'R)- 6-CHLORO-7 ^, -HYDROXY-11^ 12 ^, -DIMETHYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO

[16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE

The ketone (Example 279, Step 1 , first eluting isomer) (38 mg, 0.042 mmol) was dissolved in MeOH (2.0 mL) and cooled to 0 °C. The sodium borohydride (15.76 mg, 0.417 mmol) was added and the reaction was stirred for 15 minutes to completion. The mixture was concentrated to dryness and the residue was taken up in EtOAc (20 ml) and washed with saturated sodium bicarbonate solution (1 x 10 mL). The organic layer was washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C 18, 100 A, 150 x 30 mm, 0.1 % TF A in CH ₃ CN/H ₂ 0, gradient 35 % to 55 % over

45 ram to provide (1 S,3'R,6'R,7'S,9'S, 1 l 'S,12'R)-6~chloro~7'~hydroxy-l l',12 ^e - dimethyl-9'-(4-morpholiny1)-3,4-dihydro-2H,15'H-spiro[naphth alene-l,22'- 12ί> ! χίΐ! i jihial I J 4|di.i/.alL racye!oj ! 4.7.2.0 ^{i '} '.O ^l " ^ Ipenlacosal 16. i 8.24|iners j- 15'-one 13', 13'-dioxide or (1 S,3'R,6'R,7'S,9'R, 11 ^* S, 12'R)-6-chioro-7'-hydroxy~ l lV12'-dimethy1-9'-(4~morpholinyl)-3,4-dihydro-2H, 15'H-spiro[na

[20]oxa[13]thia[ l,14]diazatetracyxlo[14.7.2.0 ³ -^0 ¹⁹ - ² ]pentacosa[16,18,24]trien]- 15'-one 13', 13'-dioxide or (1S,3'R,6'R,7'R,9 ^* S,1 l'S ₅ 12 ^, R)-6-chloro-7 ^, -hydroxy- 1 r,12'-dimethyl-9'-(4-morpho!^

[20]oxa[13]thia[I,14]diazatetracyclo[14.7.2.0 -^0 ¹⁹ - ²⁴ ]pentacosa[16,18,^

15'-one 13',13'-dioxide or (1 S,3'R,6'R,7'R,9'R,1 l 'S,12'R)-6-chloro-7'-hydroxy-

1 l 12'-dimethyl-9'-(4-morpholinyl)-3,4-dihydro-2H,15H-spiro[nap hthalene-l,22'-

15'-one 13',13'-dioxide as the first eluting isomer (5.0 mg, 5.5 μηιοΐ, 13% yield). ¾ NMR (400 MHz, CD3OD) δ 7.75 (d, ,/ 8.6 Hz, 1H), 7.31-7.36 (m, 1H), 7.06- 7,31 (m, 3H), 6.93-7.06 (m, 2H), 3.40-4,47 (m, 1 1H), 3.04-3.30 (m, 3H), 2,74- 2,91 (m, 2H), 2.61-2,74 (m, 2H), 2.34-2,53 (m, 2H), 1.67-2.21 (ra, 13H), 1.37- 1.63 (m, 5H), 1.07-1.25 (m, 311). m/z (ESI, +ve ion) 685.8 (M+H) ¹

EXAMPLE 280. (lS,3 ^, R,6'R,7 ^! S,9'S,irS,12 ^! R)-6-CHLORO-7'-HYDROXY- ir,12'-DIMETHYL-9'-(4-MORPHOLINYL)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTHALENE-l ,22'-

|2 ⁽ >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ' ".U ^1* ' · ¹ |PL\ l ACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7 ^* S,9'R,11 ^* S,12'R)- 6-CHLORO-7"-HYDROXY- 11 ', 2'-DIMETHYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'S,11'S,12'R)- 6-CHLORO-7'-HYDROXY-l r,12'-DIMETHYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'R,11*S,12'R)- 6-( 1 l!.ORO-7 -! fVDROXY-1 i '.

D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16, 8,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer using reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0 ₅ gradient 35% to 55% over

45 min in Example 279 (6.0 mg, 8.7 μιηοΐ, 21 % yield). ^l H NMR (400 MHz, MeOD) δ 7.75 (d, ,7=8,41 Hz, IH), 7.17-7.25 (m, IH), 7. 4 (d, .7=2.15 Hz, 1H), 7.08 (dd, J=1.86, 8.12 Hz, IH), 6.93-7.01 (m, 2H), 4.09-4.22 (m, 3H), 4.01-4.09 (m, IH), 3.63-4.01 (m, 6H), 3.14-3.58 (m, 17H), 2.71-2.91 (m, 2H), 2.41 (hr. s., IH), 2,01-2.22 (m, 5H), 1.70-2,01 (m, 7H), 1.44-1.67 (rn, 5H), 1.11-1.24 (m, 3H). m/z (ESI, +ve ion) 686.3 (M+H) ⁺ . EXAMPLE 281. (lS,3 ^, R,6'R,7 ^! S,9'S,irS,12 ^! R)-6-CHLORO-7'-HYDROXY- H',12'-DIMETHYL-9'-(4-MORPHOLINYL)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHrrHALENE-l,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 (Γ·''. ( ⁾ '"··'' |Pi-N i ACOSA

[16,18,24]TRIEN]-15'-ONE 13' _s 13'-DIOXIDE OR (1S,3'R,6 ^! R,7'S,9'R,1 l'S,12'R)- 6-CHLORO-7 ^! -HYDROXY-ll',12'-DIMETHYL-9'-(4-M()RPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R,9'S,irS,12'R)- 6-CHLORO-7'-HYDROXY-n^l2 ^, -DIMETHYL-9'-(4-MORPHOLIrm.)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 12 -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (18,3Έ,6¾,7¾,9¾,1 l'S,12'R)- 6-CHLORO-7'-HYDROXY-l 1 ',12'-DIMETHYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24] TRIEN] - 15 '-ONE ! 3 ', 13 '-DIOXIDE

The ketone (Example 279, Step 1, second eluting isomer) (14 mg, 0.015 mmol) was dissolved in MeOH (1.0 mL) and cooled to 0 °C. The sodium borohydride (5.6 mg, 0.15 mmol) was added and the reaction was stirred for 15 minutes to completion. The mixture was concentrated to dryness and the residue was taken up in EtOAc (20 ml) and washed with saturated sodium bicarbonate solution (1 x 10 mL). The organic layer was washed with brine (1 x 10 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ Q, gradient 35% to 55% over 45 min to provide (1S,3'R,6 ^! R,7'S,9'S,1 rS,12'R)-6-chloro-7 ^* -hydroxy-l r,12'-dimethyl~9'"(4- morpholmyl)~3,4~dihydro-2H,lSH-sp

|20ioNai Π|ί!¾κί| U-i|dia/:Ueiracyeiol !-!.?.2 O ^i: '.o ^{1;i ,:} ipenlacosa| !6.I8.2-I|lrienj- 15 ^! -oiie 13',13'-dioxide or (lS^^e^yS^R-irS ^R^e-chloro-T^hydro y- ll 12'-dime l-9 ^, -(4-morpholinyl)-3,4-dihydro-2H,15H-spiro|naphthalene- l,22'- [20]oxa[ 13]thia[ i, 14]diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ^]9 ' ²⁴ ]pentacosa[16,18,24]trien]- lS'-one 13',13'-dioxide or (1S,3'R,6'R,7'R,9 ^! S,1 i'S,12'R)-6-chloro-7 ^! ~hydroxy- 11^12'-dimethyl-9'-(4-morphoiinyl)-3,4-dihydro-2H,15H-spiiO[ naphthaIene-l,22'- |2( ⁾ joxsij I3|t ia| i. i4|dia/aielracveioj 14.7.20 ^;: '.0 ^|1!;i ipcniacosa| 16. i H.24|iricn|- 15 ^! -one 13',13'-dioxide or { ! 8.:νκ.. ¾.7Ί . ί. ii'S. ! 2 <}-6-chk)ro-7M> droxv- ll\12'-dimethyi-9 ^, 4~morpholmyl)~3,4-dihydiO-2H,15H-spiro[naphthaiene-l _^ [20joxaj 15'-one 13',I3'-dioxide as the first eluting isomer (7.0 rag, 0.0077 mmol, 52 % yield). ¾ NMR (400 MHz, CDsOD) δ 7.77 (d, J=8.02 Hz, IH), 7.43 (br. s., 2H), 6.72-7.19 (m, 3H), 5.13-5.46 (m, IH), 3.96-4.22 (m, 4H), 3.60-3.75 (m, 5H), 2.42- 3.17 (m, 9H), 1.63-2,19 (m, !OH), 1.32 (s, 5H). ra/z (ESI, +ve ion) 686.3 ( M II) . EXAMPLE 282. (1 S,3'R,6'R,7'S,9'S,1 l'S,12'R)-6~CHLORO-7'-HYDROXY- 1 Γ , 12'-DIMETHYL-9'-(4-MORPHOLINYL)-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[N APHTHALENE-1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '*0 ^]9 ' ²⁴ ]PE TACOSA

[16,18,24]TRIEN]~15'~ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'S,9'R,1 l'S,12'R)- 6-CHLORO-7'-HYDROXY-ll',12 ^, -DIMETHYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15TI-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE OR (1S,3'R,6'R,7'R,9'S,1 l'S,I2'R)- 6-CHLORO-7'-HYDROXY-ll',12'-DIMETHYL-9'-(4-M()RPHOLINYL)-3,4 - DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]Tffl A[l ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-QNE 13 ',13 '-DIOXIDE OR (1S,3'R,6'R,7'R,9'R,1 l'S,I2'R)- 6-CHLORO-7'-HYDROXY-ir,12'-DIMETHYL-9'-(4-MORPHOLINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ' ".ϋ ^|: ' · ¹ |PH\ i ACOSA

[16,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer using reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0. gradient 35% to 55% over

45 min in Example 281(0.7 mg, 0.7 μτηοΐ, 5 % yield). ^! H NMR (500 MHz,

CD3OD) δ 7.60 (dd, .7=5.50, 8.44 Hz, IH), 6,97-7.06 (m, 3H), 6.86-6,94 (m, IH), 6.76-6.83 (m, ill).3.89-4.05 (m, 5H), 3.53-3.73 (m, 7H), 3.26-3.31 (m, 4H), 2.56- 2.74 (m, IH), 2.27-2.42 (m, IH), 2.14 (br. s., 1H), 1.95 (d, J==9.29 Hz, 2H), 1.77- 1,88 (m, 11H), 1.60-1.70 (rn, 4H), 1.29-1,39 (m, 5H), 1.00-1.09 (m, 4H). m/z (ESI, +ve ion) 686,3 (M il) . EXAMPLE 283. (lS,3 ^, R,6'R,7 ^! S,9'S,irS,12 ^! R)-6-CHLORO-7'-HYDROXY- ir,12'-DIMETHYL-9'-(l-PIPERIDINYL)-3,4-DIHYDRO-2H,15'H-

SPIRO[NAPHTH ALENE- 1 ,22'-

|2( >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^{' !'} .ϋ'" ^!| |Pi-N i ACOSA [16,18,24]TRIEN]-15'-ONE 13' _s 13'-DIOXIDE OR (1S,3'R,6 ^! R,7'S,9'R,1 rS,12'R)- 6-CHLORO-7 ^! -HYDROXY-ll',12'-DIMETHYL-9'-(l-PIPERIDINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22*-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13 ^! -DIOXIDE OR (lS,3'R,6'R,7'R,9'S,irS,12'R)- 6-CHLORO-7-HYDROXY- 11 ', 12'-DIMETHYL~9'~( 1 -PIPERIDINYL)-3 ,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: ' ^{! 1} |P1-M ^' .\C<)SA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (18,3Έ,6Έ,7¾,9ΊΙ,1 l'S,12'R)- 6-CHLORO-7'-HYDROXY-ll',12'-DIMETHYL-9'-(l-PIPERIDINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [16, 8,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The enone (50 mg, 0,084 mraol, Example 230, Step 1) was dissolved in THF (2.5 ml.) and piperidine (0,17 mL, 1,7 mmol) was added and the resulting solution was stirred for 2,5 hours to completion. The reaction mixture was then concentrated and placed under high vaccum. The crude ketone (-50 mg) was dissolved in MeOH (2 mL) and sodium borohydride (32 mg, 0.84 mmol) was added and stirred for 20 minutes. The mixture was then concentrated and then quenched with saturated sodium bicarbonate after diluting with ethyl acetate. The mixture was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over magnesium sulfate. The residue was then dissolved in DMSO. The crude material was purified by reverse- phase preparative HPLC using a Phenomenex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mm, 0.1% TFA in CH3CN/H20, gradient 35% to 55% over 45 min to provide (lS,:rR,6 ^, R,7^,9^,ll^,12¾)~6-chloro-7'½-droxy-ir,12'- dimethyl-9'-(l-piperidinyl)-3,4-dihydro-2H,15'H-spiro[naphth alene-l,22'- |20jox«ij I3|t ia| U4|dia/aielracveioj 14.7.20 ^;: '.0 ^|1!;i ipcniacosa| 16. i 8.24|irienj~ 15 ^f -one 13', 13'-dioxide or (1 S,3'R,6'R,7'S,9'R, 11 'S, 12'R)-6-chloro-7'-hydroxy- 1 Γ, 12'-dimethy l-9'-(l -piperidinyl)-3,4-dihy dro-2H, 15'H-spiro [naphthalene- 1 ,22'- [20ioxa|13jthia[l,14jdiazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ^!9 ' ²⁴ ipentacosa[ 16,18,24]trien]- lS'-one 13',13'-dioxide or (1S,3'R,6'R,7'R,9'S,1 l'S,12'R)-6-chloro-7'~hydroxy- 11 ', 12'-dimethyl-9'-(l -piperidiiiyl)-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- |20jox.ij I3|thia| I J4|dia/.alL racye!oj !4.7.2.0 ^i: '.0 ^l " ^lpcnlacosal 16. i 8.24|iners|- 15'-one 13',13'~dioxide or (1S,3'R,6'R,7'R,9'R,1 l'S,12'R)-6-chloro-7'-hydroxy- I l\12'-dimethyl-9'-(l-piperidinyl)-3,4^

[20]oxa[13]thia[l,14]diazatetracy^^

15'-one 13',13'-dioxide as the first eluting and minor isomer (11 mg, 0.016 mmol, 19% yield). ^" Ή NMR (400 MHz, ( ;()! ^') ) δ 7,77 id../ 8.4 Hz, IH), 7.53 (d, J=l .4 Hz, IH), 7.31-7.36 (rn, IH), 7.21 (dd, J=2.3, 8,5 Hz, IH), 7.12 (d, J=2,2 Hz, 1H), 6.82 (d, j 8,2 Hz, IH), 3.96-4.17 (m, 3H), 3.78-3.89 (m, IH), 3.62 (d, J=14.5 Hz, IH), 3.37-3.56 (m, Ml).3.32 (d, j 14.7 Hz, !!!).3.12-3.22 (m, 2H), 2.98-3.08 (m, 2H), 2.42-2,60 (m, 5H), 2,23-2.4! (m, 5H), 1.89-2.10 (m, 9H), 1.68-1.77 (rn, IH), 1,36-1.43 (rn, 4H), 1.29 (d, J=7.2 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H). m/z (ESI, +ve ion) 683.7 (M+H) ⁺ .

EXAMPLE 284. (1 S,3'R,6'R,7'S,9'S,1 l'S,12'R)-6-CHL()RO-7'-HYDROXY-

I I ^f ,12'-DIMETHYL-9'-(l -PIPERIDINYL)-3,4-DlHYDRO-2H,l 5Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13",13'-DIOXIDE OR (lS,3'R,6'R,7 ^f S,9'R,l l'S,!2'R)- 6-CHI RO-7 ^, -HYDRO.XY-11^12'-DIMETHYL-9'-(l-PlPERIDINYL)-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZATCTRACYCLO|;i4.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-I5'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'S,1 l'S,12'R)- 6-CI U O -7 -ί iYOROXY- i I ' i 2'-ί)ί VU: ! i !Y!.-9'-i 1 ~PU ^! i;RU)l\YI.}- 4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20iOXA|;i3]THLA|;i,14]DlAZATETRACYCL )[14.7.2.0 ³ '^0 ^!9 ' ²⁴ ]PENTACOSA [16J8,24]TRIEN]-15'-ONE 13',13 ^! -DiOXIDE OR (1S,3'R,6'R,7 ^! R,9'R,1 !'S,12'R)~ 6-CHLORO-7'-HYDROXY-l 1 ', 12'-DIMETHYL-9'-(l -PlPERIDlNYL)-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16, 18,24] TRIEN] - 15 '-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the second eluting and major isomer using reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 35% to 55% over 45 min in Example 283 (16 mg, 0.023 mmol, 28 % yield). ¾ NMR (400 MHz, CD3OD) δ 7.66-7.87 (m, IH), 7.25-7,51 (m, 1H), 6.99-7.25 (m, 3H), 6.76-6.99 (m, IH), 4.37 (d, J=10.2 Hz, IH), 3.98-4.19 (m, 3H), 3,72-3.94 (m, 3H), 3.43-3.66 (m, 2H), 3.13-3.28 (m, 2H), 3.07 (dd, J=8.6, 15.3 Hz, IH), 2,66-2,96 (m, 4H), 2.27-2.51 (m, 3H), 1,57-2.12 (m, 18H), 1.27-1.57 (m, 6H). m/z (ESI, +ve ion) 683.7 (M+H) ⁺ .

EXAMPLE 285. (lS,3 ^, R,6'R,7 ^! S,9'S,irS,12 ^! R)-6-CHLORO-7'-HYDROXY- 11 ', 12'-DIMETHYL-9'-(3-OXO-4-MORPHOLINYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'- |2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.20 ' ".U ^1* ' · ¹ |PH\ i ACOSA [16,18,24]TRIE ]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7 ^* S,9'R,11 ^* S,12'R)- 6-CHLORO-7"-HYDROXY-l ! ', 12'-DIMETHYL-9'-(3 -OXO-4- MORPHOLiNYL)-3,4-DIHYDRO-2H,15H-SPlRO[NAPHTHALENE-l,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13 ^! -D10XIDE OR (lS,3'R,6'R,7'R,9'S,irS,12'R)- 6-CHLORO-7'-HYDROXY-l V,\ 2'-DIMETHYL-9'-(3 -OXO-4- MORPHOLlNYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALEM E- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [ 16, 1 8,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R, I l 'S,12'R.)- 6-CHLQRQ-7'-HYDRQXY-l l ', 12'-DIMETHYL-9'-(3-QXO-4- MORPHOLINYL)-3,4-DIHYDRO-2H.15H-SPIRO[NAPHTHALENE-l ,22'-

[20]OXA[ 13]THIA[ 1 4]DIAZATETRACYCLO[ 14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16, 1 8,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE

The enone (48 nig, 0,080 mmol, Example 244, Step 1) was dissolved in THF (2.5 mL) and morpholin-3-one (8.94 mg, 0.088 mmol) was added followed by dropwise addition of lithium bis(trimethylsilyl)amide, l .OM solution in tetrahydrofuran (0. 1 7 mL, 0. 1 7 mmol). The reaction was stirred for 90 minutes until completion. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (1 x 15 mL) and dried over magnesium sulfate to give crude ketone. The crude ketone was dissolved in MeOH (2 mL) and sodium borohydride (30.4 mg, 0.804 mmol) was added. The reaction was stirred for 45 minutes then concentrated to dryness. The residue was take up in EtOAc and acidified with TFA. The mixture was concentrated. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C I 8, 100 A, 150 x 30 mm, 0.1% TFA in (Ί \ ( ^' Η ,Ο. gradient 50% to 85% over 45 min to provide aS,3'R,0'R,7 ^! S,9'S,l l ^* S, 12'R)-0-diloro-7'- hydroxy-1 rj 2 ^f -dimethyl-9'-(3-oxo-4-mo jholinyl)-3,4-dihydro-2H,I 5'H- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]tMa[l,14]cUazatetracyclo^

15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,9'R,irS,12'R)-6-chIoro-7 ^! -hydroxy- 11 V12'-diraethyl-9'-(3 )xo-4-morpholinyl)-3,4-dihydro-2H,l 5Ή- spiro [naphthalene- 1 , 22'-

[20]oxa[13]thia[l,14]diazatetracyclo[147.2XJ ³ -^0 ¹⁹ - ² ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide or (1S,3'R,6'R,7'R,9 ^* S,1 l'S,12'R)-6-chIoro-7'-hydroxy- 11 12'-άΪΜβ 1-9 ^, -(3-οχο^^ο Ηο1^1)-3,4-ά <ΐΓθ-2Η ₅ 15Ή- spiro[naphthalene-l,22'- 12ί>! χίΐ! i jihial U4|di.i/.alL racye!oj 14.7.2 (I'Mi^ ^i cnlac sal 16. i 8.24|inersj- 15'-one 13',13'-dioxide or (1S,3'R,6'R,7'R,9'R,1 l'S,12'R)-6-chloro-7'-hydroxy- 11 ',12'-dimethy1-9'-(3 )xo-4-morphohnyl)-3,4-dihydro-2H,l 5Ή- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracycfo[14J _^

15'-one 13',13'-dioxide as the first elirting and minor isomer (4.4 mg, 5.40 μηιοΐ, 6.7 % yield). ^; l! NMR (400 MHz, V!eOl I ·.;';! δ 7.76 (d, J=8.6 Hz, 1H), 7.20 (dd, ./ 2.3.8.5 Hz, ill).7.13 (d,J=2.2Hz, 1H), 6.97-7.01 (m, 1H), 6.94-6.97 (m, 1H),

6.93 (d, ,/ i.6 Hz, 1H), 4.64-4,80 (m, ill).4.12-4.18 (rn, 3H), 3.99 id../ 12. i Hz, 1H), 3.87-3.97 (m, 4H), 3.80 (d, «7=14.1 Hz, 1H), 3.35-3.46 (m, 5H), 3.25-3,32 (m, 1H), 2.73-2.90 (m, 2H), 2.44-2.55 (m, J=3.9 Hz, lH), 2.01-2.28 (m, 5H), 1.84-

1.94 (m, 2H), 1.70-1.82 (m, 2H), 1.61-1.69 (m, 111).1.46-1.54 (m, 2H), 1.43 (d, ,/ 724 Hz, 3H), 1.14 (d, J=6.65 Hz, 3H), m/z (ESI, +ve ion) 699.7 (M+H) ⁺ .

EXAMPLE 286, (lS,3'R,6'R,7 ^! S,9'S,i rS,12 ^! R)-6-CHLORO-7'-HYDROXY- 11 ', 12'-DlMETHYL-9'-(3-OXO-4-MORPHOLlNYL)-3,4-DlHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15*-ONE 13 ^! ,13'-DIQXiDE OR (1S,3'R,6 ^! R,7'S,9'R,1 l'S,12'R)~ 6-CHLORO-7'-H YDROXY- 1 Γ, 12'-DlMETHYL-9'-(3 -OXO-4- M()RPHOLINYL)-3,4-DIHYDRO-2H, 15'H-SPIR()[NAPHTHALENE-1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R,7'R,9'S, I rS, 12'R)- 6-CHLQRQ-7'-HYDRQXY-l l',12'-DIMETHYL-9'-(3-QXO-4- MORPHOLINYL)-3,4-DIHYDRO-2H.15H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[I4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'R,7'R,9'R, 1 l'S,12'R)- 6-CHLORO-7'-H YDROXY- H',12'-DlMETHYL-9'-(3 - OXO-4- M()RPHQLINYL)-3,4-DIHYDRQ-2H, 15'H-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ - ²⁴ ]PE TACOSA [16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as the second eluting and major isomer using reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1% TFA in (Ί Ι ₃ ( ^' \ i !-,0. gradient 35% to 55% over 45 min in Example 285 (19.5 mg, 0.024 mmol, 29.8 % yield). ^! H NMR (400 MHz, MeO! !-:./;) δ 7.76 (d, J 8.4 Hz, IH), 7,55 (d, J 1.6 Hz, IH), 7.18 (dd, J=8.5, 2,3 Hz, IH), 7.10-7, 15 (m, 2H), 6.95 (d, 1=8.2 Hz, IH), 4,02-4.25 (m, 6H), 3.81-3.94 (m, 2H), 3.64 (d, .1 14. 1 Hz, IH), 3.47-3.54 (m, I H), 3.37-3.46 (m, IH), 3.24 (d, j 14. 1 Hz, IH), 3.13-3.20 (m, .1=1.6 Hz, IH), 3,04 (dd, .1=8.9, 15.2 Hz, IH), 2.70-2,88 (m, 2H), 2.42-2.60 (m, 2H), 1.57-2, 14 (m, 13H), 1.48 (d, j 2.2 Hz, IH), 1.43 (d, j 7.0 Hz, 3H), 1.10 (d, 1=6.9 Hz, 3H). m/z (ESI, +ve ion) 699.7 { \ I · Π } . EXAMPLE 287. N-((lS,3'R,6 ^, R,7 ^! S,9'S,irS,12 ^! R)~6-CHLORO-7 ^! -HYDROXY- ir,12'-DlMETHYL-13',13'-D10XIDO-15'-OXO-3,4-DlHYDRO-2H~

SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCIX)[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [ 16, 18,24]TRIEN] -9'-YL)-N-METHYLGLYCINE OR N-

((lS,3'R,6'R,7'S,9'R,ll'S,12'R)-6-CHLORO-7'-HYDROXY-ll',1 2'-DIMETHYL- 13 13 ^, -DIOXroO-15 ^, -OXO-3,4-DIHYDRO-2H-SPTRO| AP^m^ALE3SlE-l,22 ^, - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRlEN]-9'-YL)-N-METHYLGLYClNE OR N-

((1 S,3'R,6'R,7'R,9'S,1 l'S,12'R)-6-CHLORO-7'-HYDROXY-l l',12'-DIMETHYL- 13^13 ^, -DT0Xro0-15 ^, -0X0 ₅ 4-DlHYDR0-2H-SPIR0[NAPHTHALENE-l,22"- |20jOXA| I 311 HI Λ| I .. ! -I |OI A/A Π·. f ^' RACYCf .Oj N.7.20--M> ^l "-' ^, |PHNTA( ^' OS.-\ [16,18,24]TRIEN I -9'-YL)-N-METHYLGLYCINE OR N- ((lS,3'R,6'R,7'R,9'R,ll'S,12'R)-6-CHLORO-7'-HYDROXY-ll',!2'- DIMETHYL- i;r,13'-DIOXJDO-15'-OXO-3,4-DrHYDRO-2H-SPIRO[NAPHTHALENE-l,2 2 ^! - [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |;i6,18,24]TRIEN]-9'-YL)-N-METHYLGLYCINE

The methyl amino alcohol (12 rag, 0.0.14 mmol, Example 256) was dissolved in 1,2-dichloroethane (140 μί) and a drop of acetic acid (0.80 μί, 0.014 mmol) was added followed by ethyl glyoxalate, ca 50% soln. in toluene (5.5 ,uL, 0.028 mraol) and sodium triacetoxyborohydride (5.9 mg, 0.028 mmol). The mixture was stirred for several days after adding several more equivalents of ethyl glyoxalate, ca 50% soln. in toluene (5.5 μΙ_, 0.028 mmol) and sodium triacetoxyborohydride (5.9 mg, 0.028 mmol). Sodium cyanoborohydride (0.88 mg, 0.014 mmol) and MeOH was then added and the reaction was completed after stirring overnight. The reaction was then quenched with saturated sodium bicarbonate solution and extracted with EtOAc to give 6.5 mg of a crude mixture. This mixture (6.5 mg, 9.07 μιηοΐ) was dissolved in THF (1.0 mL) and sodium hydroxide (5 N soin.) (0.5 mL, 2.5 mmol) was added and the mixture was stirred overnight. The reaction was then acidified by addition of TFA (0.21 mL, 2.7 mmol). The mixture was concentrated and then dissolved in DMSO. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 A, 150 x 30 mm, 0.1 % I FA in CH3CNH2O, gradient 20% to 50% over 30 min to provide N- ((lS,3'R,6'R,7'S,9^,irS,12'R)-6-chloro^^

dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetra<^

9'-yl)-N-methylglycine _or Ν-((18,3·Κ,6'Κ,7'8,9'Κ,1 l'S,12 ^! R)-6-chloro-7'-hydroxy- 1 r,12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[ naphthalene-l,22'- |20ioNai n|iha| U4|dia/aie!racyeioj N.7.2 O ^i: '.o ^{1;i ,:} ipenlacosa| !6.I8.2-I|lrienj- 9'-yl)-N-me1hylglycine or N-((1S,3 ^! R,6'R,7'R,9'S,1 l'S,12 ^, R)-6-chloro-7 ^, -hydroxy- i ,12'-dimethyi-13',13'-diQxido-15'-oxo-3,4-dihy

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]pentacosa[16,18,24]tnen]- 9Lyi) ^„ N-methylglycine or N-((1S,3'R,6 ^* R,7'R,9 ^! R,11'8,12Ί)"6-ΰΜοΐΌ-7'½^Γθχν- 11^12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-l,22'- |20ioxaj I3|lhia| U |dia/aielracveioj 14.7.2 O ^;: '.0 ^|1!;i ipemacosa| 16. i 8.24|irienj~ 9'-yl)-N-methylglycine as the first eluting and major isomer (0.6 mg, 0.6 μηιοΐ, 7 % yield). '!! NMR (400 MHz, MeOi !··>/,} δ 7.75 (dd, J=3.30, 8.44 Hz, ill).7.35 (s, 1H), 7.19 (dd, J=l.96, 8.31 Hz, IH), 7.12 (t, ./ 2.45 Hz, IH), 6.98 (d, ./ 1.7! Hz, IH), 6,94-6.97 (m, IH), 4.16 id. ,/ 1223 Hz, IH), 4.08-4.13 (m, IH), 3.90- 4,05 (m, 3H), 3.77-3.89 (m, 2H), 3,66 (d, ./ 14.67 Hz, H), 3,42 (d, J=14. 8 Hz, 1H), 2.94 (s, 3H), 2.72-2.91 (m, 4H), 2.34 (br. s„ 1 H), 2.07-2.16 (m, 3H), 1 .86- 2.01 (m, 6H), 1.55-1.83 (m, 5H), 1.48 (d, J=7.09 Hz, M l ). 1.14 (d, J=6.60 Hz, 3H). m/z (ESI, +ve ion) 687.7 i M H ) .

EXAMPLE 288. N-((1S,3'R,6'R,7'S,9'S,1 l 'S, 12'R)-6-CHLORO-7'-HYDROXY- 1 1 ^f ,12'-DIMETHYL-l 3',13'-DIOXIDO-15'-OXO-3,4-DIH ^r DRO-2H- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PE TACOSA [ 16, 18,24]TRIEN] -9'-YL)-N-METHYLGLY CINE OR N-

((l S,3'R,6'R,7'S,9'R,i rS,12'R)-6-CHLORO-7'-HYDROXY-l l',12'-DIMETHYL- 13 ^, ,13 ^, -D10XIDO-15 ^, -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ₅ 22'- [20]OXA[ 13]THIA[ 1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-9'-YX)-N-METHYLGLYCINE OR N-

((l S,3'R,6 ,7'R,9'S,irS,121 )-6-CHLORO-7 ^, -HYDROXY-ir,12'-DlMETHYL- 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIH YDRO-2H-SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA [ 16, 18,24]TRIEN] -9'- YL)-N-METHYLGLYCINE OR N-

((l S,3 ^, R,6'R,7'R,9'R,l l'S,12'R)-6-CHLORO-7 ^, -HYDROXY-l l',12'-DlME ^' raYL- 13',13'-DIOXIDO-15'-OX()-3,4-DIHYDRO-2H-SPIR()[NAPHTHALENE-l ,22 ^! - [20]OXA[ 13]THIA[1,14]DIAZATFXRACY ^T CLO[ !4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-9'-YL)-N-METHYLGLYClNE

The title compound was obtained as the second eluting and minor isomer using reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, CI 8, 100 A, 150 x 30 mra, 0.1% TFA in CH ₃ CN/H ₂ 0, gradient 20% to

50% over 30 mm in Example 287 (0.3 mg, 0.3 μιηοΐ, 4 % yield), ¾ NMR (500 MHz, MeOH-cU) δ 7.74 (d, ./ K.56 Hz, III).7.35 (d, ./ 1.71 Hz, 1H), 7.17 (d, ./ 8.31 Hz, 111).7,11 (d, J=2.20 Hz, !!!).7.08 (dd,J=1.96, 8,31 Hz, ill).6.94 (d, ./ 8.07 Hz, III).4, 10 (dd, J=2.93, 4,16 Hz, 2H), 3.97-4.03 (m, .7=17.12 Hz, 2H), 3.87-3.96 (m, ill).3.67-3.79 (m, 2H), 3.65 (d, ./ 13.69 Hz, 1H), 3.07 (dd, J=9.05, 15.89 Hz, IH), 2.92 (s, 3H), 2.73-2.82 (m, 2H), 2.54-2.63 (m, 1H), 2.47 (s, 1H), 2.04-2.13 (m, ./ 13.20 Hz, 3H), 1,95-2.00 (m, 3H), 1.57-1,91 (m, 9H), 1,50 (d, J=7,34 Hz, 3H), 1.12 (d, ,7=6,85 Hz, 3H), m/z (ESI, +ve ion) 687,7 (M+H) ⁺ . EXAMPLE 292. (((lS,3 ^, R,6 ^, R,7'S,8'E,irS,12 ^, R)-6-CHLORO-ir,12'- DIMETHYL-13',13'-DIOXID()-l ,5'-OXO-3,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| i 1 U ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.20 ^{' !'} .o' ^: ' ^!| |Pi- ^" N i ACOSA

[8, 16, 18,24]TETRAEN] -7'-YL)OXY)ACETIC ACID

STEP 1: (((1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-ir,12'-DIMETHYL- i;r,13'-DIOXIDO-15'-OXO-:i4-DmYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA | 8,16,18,24]TETRAENj-7'-YL)OXY)ACETIC ACID ETHYL ESTER AND ETHYL ((1S,3'R,6'R,7'S,8'E,1 l ^f S,r2'R)-6-CHLORO-7'-(2-ETHOXY-2- OXOETHOXY)- 11 ', 12'-DIMETHYL- i.V.l 3 ^! -ΟίΟΧΓΟΟ- 15 ^! -OXO-3,4- DIHYDRO-2H-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOSA [8, 16, 18 , 24] TETR AEN] - 17'-YL)ACETATE

To a stirred solution of (1S,3'R,6'R,7'S,8 ^! E,1 l'S,12'R)-6-chloro-7'- hydroxy-1 l 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro[naphtha]ene-l ,22'- [20]oxa[13]thia[l,14]diazatetracyclo^^

n]-15'-one 13',13'-dioxide (304 nig, 0.507 mmol, Example 719, Step 2) and rhodium (ii) acetate dimer (44.8 mg, 0.101 mmol) in DCM (5.0 ml.) was added dropwise ethyl diazoacetate (0.263 mL, 2.54 mmol). Note that strong bubbling occurred during and after the addition. The mixture was stirred at rt for a period of 1 h 10 min at which time the LC-MS showed complete conversion. The mixture was loaded onto silica gel precolumn and subjected to combi-flash column chromatography (EtOAc/Hexanes, 30 mm from 0 to 60%, 24 g ISCO silica gel column) to give a mixture of the title compounds (290 mg, 0.423 mmol, 83 % yield) as a orange-colored solid, impure and taken onto the next step directly. Note that the mono-ester was the major product.

STEP 2: (((1S,3'R,6'R,7'S,8'E,1 l 'S,12 ^! R)-6-CHLORO-ir, 12'-DIMETHYL- 13'J 3'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ > ⁶ 0 ¹⁹ - ²⁴ ]PENTACOSA |;8,16, 18,24]TETRAENj-7'-YL)OXY)ACETIC ACID

To a stirred suspension of the impure mixture of

(((18,3¾,6¾,7'8,8Έ,1 Γ8,12ΊΙ)-6-ΰΜθΓθ-11^12'^^6 1-13',13 ^! ~άιοχίάο-15'- oxo-3,4-dihydro-2H-spiro|naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16, 18,24]tetrae n]-7'-yl)oxy)acetic acid ethyl ester and ethyl ((1 S,3'R,6 ^! R,7'S,8'E,1 l'S,12'R)-6- chloro-7'-(2-ethoxy-2-oxoethoxy )- 1 , 12' -dimethyl- 1 3', 13'-dioxi do- 15'-oxo-3,4- dihy dro-2H-spiro [naphthalene- 1 ,22'-

n]- l 7'-yl)aceiate (0.290 g, 0.423 mmol) in a mixed solvent comprising MeOH (5.0 mL), THF (5.0 mL), and water (1 .0 mi.) was added lithium hydroxide

nionohvdrate (0.044 g, 1.058 mmol) at rt. The resulting mixture was stirred at 50 °C in a preheated oil bath for a period of 1 h 20 min. The LC-MS showed clean completion. The volume was reduced and the residue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cig 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, the title compound (120 nig, 0.152 mmol, 43 % yield) as the second eluting fraction as an off-white solid. ^] H NMR (500MHz, CDCh) δ 8.03 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 7.10 (d, J=2,2 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.83 (d, ./ 1 .2 Hz, 1H), 5.97 - 5.88 (m, 1H), 5.57 (dd, ./ 9.4. 15.0 Hz, i l l . 4.33 (q, ./ 6.8 Hz, I I I ). 4.14 - 3.97 (m, 4H), 3.95 (dd, ./ 3.3. 9,4 Hz, IH), 3.83 (d, 15.2 Hz, 1H), 3.70 (d, ./ 14.2 Hz, IH), 3.23 id, ./ 14.4 Hz, IH), 3,03 (dd, ./ 1 0.3. 1.5.2 Hz, IH), 2.87 - 2.50 (m, 4H), 2,34 (td, .1=9.1 , 1 8.3 Hz, I H ). 2.24 - 1.78 (m, 8H), 1.69 (qum, ./ 9.6 Hz, IH), 1.51 (d, ./ 7.3 Hz, 3H), 1.40 (t, ./ 1 3.0 Hz, IH), 1.07 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 657,2 ( X I I I )

EXAMPLE 293. ((1 S,3'R,6 ^! R,7'S,8'E, 1 rS,12'R)-7'-(CARBOXYMETHOXY)-6- CHLORO- 1 Γ, 12' -DIMETHYL- 13', 13'-DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 17'-YL)ACETIC ACID

The title compound (6.5 mg) was obtained as an off-white solid as the first eluting isomer from preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column: Phenonienex, Torrance, CA; gradient elution of 45-95% acetonitriie in water, where both solvents contained 0.1% TFA, 30 min method) in Example

292. 'HNMR (400MHz, (1X1.) δ 10.79 is. ill).7,66 id../ 8.6 Hz, ill).7,16 (dd, J=2.2, 8.6 Hz, 1H), 7.09 (d, ,/ 22 Hz, I Hi..6.80 (s, 1H), 6.70 (s, 1H), 5.99 - 5.78 (m, IH), 5.58 (dd, J=9.3, 15.2 Hz, 1H), 4.23 (q, J=6.8 Hz, 1H), 4.09 - 3.99 (m, 5H), 3.91 (dd, ./ 3.!.9.6 Hz, III).3.83 - 3.59 (m, 3H), 3.27 (d, ./ 14.3 Hz, !!!). 3,05 (dd../ 10.7.15.4 Hz, IH), 2.89 - 1.77 (ra, 13H), 1.75 - 1,64 (m, 1H), 1.50 (d, ,/ 72 Hz, 3H), 1.39 (t, ,/ 129 Hz, IH), 1.09 (d, ,7=6,3 Hz, 3H). m/z (ESI, +ve ion) 715.0 .

EXAMPLE 294.2-(((l S,3'R,6'R,7 ^! S,8Ti 1 l'S,l 2'R)-6-CHLORO-l 1 12'- DIMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-7'-Y CETAMlDE

To a stirred solution of impure (((1S,3'R,6'R,7'S,8'E,1 l'S,12¾)~6~chloro~

1 l',12'-dime1hyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-l,22'-

n]-7'-yl)oxy)acetic acid (10 mg, 0.015 mmol. Example 292) and HATU (11.57 mg, 0.030 mmol, in excess) in DMF (1.2 mL) was added methylamine, 2,0 M solution in tetrahydrofuran (0.076 mL, 0.152 mmol) (0.4 mL, actual) at rt. The resulting mixture was stirred at rt for a period of 0.5 h. The crude mixture was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 5.0 mg of the title compound as an off-white solid. ¾ N.MR (400MHz, CDCb) δ 7,97 (s. 111).7,69 (d, ./ 8.4 Hz, Hi).7. 9 (dd, 23. 8,4 Hz, 1H), 7.10 (d, .7=2.2 Hz, IH), 6,97 - 6,79 (m, 3H), 5.93 - 5.79 (m, IH), 5,56 (dd, J=8.9, 15.6 Hz, IH), 4.43 - 4.26 (m, IH), 4.17 - 3.96 (m, 4H), 3.90 - 3.78 (m, 2H), 3.71 (d, ./ 14.3 Hz, IH), 3.23 (d, ./ 14.3 Hz, IH), 3.09 - 2.94 (m, 7H), 2.87 - 2.73 (rn, 2H), 2.65 - 2,54 (m, !!!).2.3! (quin,J=8.9 Hz, 111).2.24 - 1.76 (m, 711). 1.74 - 1.58 (m, ill).1,50 (d, J=7.2 Hz, 3H), 1.45 - 1.31 (m, IH), 1.06 (d, .7=6.8 Hz, 3H). m/z (ESI, +ve ion) 670.1 { M I i

EXAMPLE 295, 2-(((lS,3'R,6'R,7 ^, S,8'E,irS,12 ^! R)~6-CHLORO-ir,12'- DlMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1.22 ^J -

|2( >X A| I ?! ! ί U Ai i 4 J |? !,\ Ά ! : I AC VC fOl 147.20 ^{' !'} .ϋ'" ^!| |Pi-N i ACOSA [8, 16, 18,24]TETRAEN] -7'- YLACET AMIDE

The title compound was synthesized according to the procedure exemplified in Example 294. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient eiution of 20-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after Ivophilization, 4.5 nig of the title compound as an off-white solid. ¾ NMR (4()0MHz, CDCb) δ 7.97 (s, 1H), 7.69 (d, ,/ 8.4 Hz, IH), 7. 19 (dd, 2.3. 8.4 Hz, IH), 7.10 (d, ./ 2.2 Hz, 1 1 1 ). 6.97 - 6,78 (m, 3H), 5.94 - 5.77 (m, IH), 5.56 (dd, .7=8.9, 15.6 Hz, IH), 4.43 - 4.26 (m, IH), 4.17 ·· 3.96 (m, 4H), 3.88 - 3.78 (m, 2H), 3.71 (d, ./ 1 -1.3 Hz, IH), 3.23 (d, ./ 14.3 Hz, IH), 3.07 - 2.95 (m, 7H), 2.87 - 2.73 (m, 2H), 2,70 (s, 2H), 2,66 - 2.54 (m, IH), 2,41 - 1.74 (m, 8H), 1 ,72 - 1.59 (m, I H), 1.50 (d, 7.2 Hz, 3H), 1.43 - 1.33 (m, IH), 1.06 (d, J=6,8 Hz, 3H). m/z (ESI, +ve ion) 684.0 (M+H) ⁺ .

EXAMPLE 296. 2-(((l S,3'R,6'R,7'S,8'E,l l ^,12¾)-6-CHLORO-i rj 2'- DIMETHYL- 13' , 13 '-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRQ-2H~

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ^{] 9} ' ²⁴ ]PE TACOSA

[8,16, 18 ,24] TETR AEN] ~7 ^! ~YL)QXY)-N-( 1 -METHYLETHYL) ACET AMIDE

The title compound (6,5 mg as an off- white solid) was synthesized and purified according to the procedure exemplified in Example 294. ¾ NMR (400MHz, CDCb) δ 7.99 (s, IH), 7.70 (d, ./ 8.4 Hz, IH), 7.19 (dd, ./ 2.2. 8.5 Hz, I H), 7.10 (d, 2.2 Hz, H), 6.97 - 6,88 (m, 2H), 6.84 (s, H i ). 6.33 (d, ,/ 7 0 Hz, IH), 6.02 - 5.82 (m, IH), 5.54 (dd, ./ 9.2. 14.5 Hz, IH), 4.33 (q, ./ 7. 1 Hz, IH), 4.20 - 4.02 (m, 3H), 3.95 - 3.63 (m, 5H), 3.24 (d, ./ 14.3 Hz, ! ! ! ). 3.03 (dd, ,/ i 0 2. 15,3 Hz, H), 2.87 - 2,64 (m, 2H), 2.55 - 2.42 (rn, H), 2.41 - 2,26 (m, IH), 2,25 - 1.76 (m, 91 ! j. 1.75 - 1.64 (m, IH), 1 ,51 (d, ./ 7.2 Hz, 3H), 1.41 (t, ./ 1 .6 Hz, IH), 1.19 (t, J=6.1 Hz, 6H), 1.06 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 698.0 ( +H) ⁺ . EXAMPLE 297.2-(((lS,3'R,6 ^, ,7'S,8 ^, E;irS,12 ^, R)~6"CHLORO-ll ^! ,12'- DIMETHYL-13\13'-DIOXID()-15'-OXQ-3,4-DIHYDR()-2H- SPTRO[NAPHTH ALENE- 1 ,22'- |2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 1 |ί^!ΛΖΛ ί : ί AC YC i (>! i -17.2 (Γ·''. ( ⁾ '"··'' |Pi-N i ACOSA

[8, 16, 18,24]TETRAEN] -7'-YL)OXY)-N-(2,2,2- TRIFLUOROETHYL)ACE

The title compound was synthesized according to the procedure exemplified in Example 294. Mote that triethylamine was used as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cie 5 μτ column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 7.0 mg of the title compound as an off-white solid. Ή NMR (500MHz, CDCb) δ 8.01 (s, ! 11 ).7.70 (d, ,7=8,3 Hz, IH), 7.19 (dd, J=2.2, 8.6 Hz, 1H), 7.10 (d, ,7=2.0 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.83 (d, ,7=1.2 Hz, 1H), 6.75 (br. s., IH), 5.99 - 5.84 (m, III).5.55 (dd, ,/ 9.5.15.2 Hz, 111).4.32 (q, ,/ 72 Hz, IH), 4.14 - 4.06 (m, 2H), 4.04 - 3.86 (m, 5H), 3.82 (d, J=15.2 Hz, IH), 3,71 (d, J=14.2 Hz, IH), 3.24 (d, .7=14.2 Hz, IH), 3.03 (dd, ./ 10.3.15.2 Hz, IH), 2.87 - 2.71 (m, 2H), 2.55 - 2,44 (m, IH), 2.36 (qum,■/ 9,2 Hz, IH), 2,23 - 1,62 (m, 10Π).1.5! id.,/ 73 Hz, 3H), 1.44 - 1.37 (m, IH), 1,06 (d, .7=6.8 Hz, 3H). rrv'z (ESI, +ve ion) 738.0 {M l I) .

EXAMPLE 298.2-(((lS,3 ^, R,6 ^, R,7'S,8 ^, E,l rS,12 ^! R)-6-CHLORO-ir,12'- DIMETHYL- 13',13-DIOXIDO-l 5-0X0-3 ,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-7'- YETHYL)ACETAMIDE

The title compound (6.0 mg as a white solid) was synthesized and purified according to the procedure exemplified in Example 294. ¾ NMR (500MHz, CDC! :.) δ 8.02 is. i l l . 7.70 id. ./ 8.6 ! !/. IH), 7.19 (dd, ./ 2.3. 8.4 Hz, I I I ). 7.10 (d, ./ 2.2 Hz, 1H), 6,97 - 6.80 (m, 4H), 5.97 - 5.83 (ra, 1H), 5,54 (dd, J-9.8, 14.7 Hz, 1H), 4.38 - 4.26 (m, IH), 4.15 - 4,03 (m, 2H), 3.97 - 3.89 (m, IH), 3,88 - 3,77 (m, 3H), 3.70 (d, J=14.2 Hz, 1H), 3.52 - 3.44 (m, 4H), 3.39 (s, 3H), 3.24 (d,

./ 14.2 Hz, I I I ). 3.02 (dd, J=10.0, 15.2 Hz, I I I . 2.89 - 2.67 (m, 2H), 2.56 - 2.44 (m, 1H), 2.35 (quin, J=9.1 Hz, 1H), 2.24 - 2.13 (m, 1H), 2.1 1 - 1,60 (m, 9H), 1.5 ! (d, J=7.3 Hz, 3H), 1.40 (t, J=12.8 Hz, IH), 1.06 (d, J=6.8 Hz, 3H). m'z (ESI, +ve ion) 714.1 ( +H) ⁺ .

EXAMPLE 299. 2-(((l S,3'R,6'R,7'S,8'E, 1 l 'S,l 2'R)-6-CHLORO-l 1 12'- DIMETHYL- 13', 13 '-DIOXIDO- 15 '-OXO-3 ,4-DIHYDRO-2H-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)-N-(2-METHOXYETHYL)-N- METHYLACET AMIDE

The title compound (5.0 mg as a white solid) was synthesized and purified according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. ^! H NMR (400MHz, CDC ) δ 8.00 (s, ill).7.69 (d, J=8.6 Hz, ill).7.18 (dd, ./ 2.2.8.5 Hz, Hi).7.10 (d, J 22 Hz, III). 6.97 - 6.76 (m, 3H), 5,98 - 5.74 (m, III).5.66 - 5.46 (m, IH), 4,33 (q, ./ 7.2 Hz, 1H), 4.22 - 3.96 (ni, 4H), 3.83 (d, J=13.7 Hz, 2H), 3.74 - 3.62 (m, 2H), 3.61 - 3.55 {in. III).3.54 - 3.42 ins.2H), 3.37 (d, J=5.1 Hz, 311).3.23 (d,J=14.3 Hz, III). 3,09 - 2.95 {ni.4H), 2,88 - 2.68 (m, 2H), 2,60 (d, ./ 8.4 Hz, !!!).2.39 - 2,24 (m, IH), 2,24 - 1.74 (m, 9H), 1.65 (quin, «7=9.4 Hz, IH), 1.50 (d, ,/ 70 Hz, 3H), 1.39 (t, J=12.7 Hz, IH), 1.06 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 728.1 (M+H) ⁺ .

EXAMPLE 300.2-(((i S,3'R,6'R,7'S,8Ti 1 V S, 12'R)-6-CHLORO- 11 12'- DIMETHYL- 13', 13 '-DIOXIDO- 15 '-OXO-3 ,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-l ₅ 22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '*0 ¹⁹ - ²⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-7'-YL)OXY)-N-(2-(DlMETHYLAMlNO)ETHYL)-N - METHYLACET AMIDE

The title compound was synthesized according to the procedure exemplified in Example 294. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Ci8 5 μπι column; Phenomenex, Torrance, CA; gradient eiution of 30-95% acetonitrile in water, where both solvents contained 0.1 % TFA, 30 min method) to give, after lyophilization, 6.5 mg of the title compound as a off-white solid. 'H NMR (500MHz, CDsOD) δ 7.72 (d, J=8.6 Hz, 1H), 7.17 (dd, J=2.2, 8.6 Hz, IH), 7.11 (d, J=2.2 Hz, IH), 7.05 (dd,

J=2.0, 8. 1 Hz, IH), 6.93 { O. J 8 I Hz, I H), 6.86 id. ./ ! .? Hz, i l l ). 5,88 - 5,76 (m, IH), 5.60 (dd, .7=9,2, 15.3 Hz, IH), 4,24 - 4.02 (m, 5H), 3.92 (dd, .7=2,9, 9.3 Hz, IH), 3.85 - 3.69 (ni, 3H), 3.65 (d, J=14.2 Hz, IH), 3.37 (t, J=6.0 Hz, 2H), 3.33 - 3.26 (m, 3H), 3.11 (dd, J=10.3, 15.4 Hz, IH), 3.07 (s, 3H), 2.97 (s, 6H), 2.86 - 2,70 (m, 2H), 2.6 ! - 2.50 (m, H), 2,31 (quin, ,/ 9 3 Hz, IH), 2.24 - 1.66 (m, HI I ). 1 ,53 - 1.38 (m, 4H), 1.06 (d, .7=6,8 Hz, 3H), m/z (ESI, +ve ion) 741 , 1 (M+H) ⁺ .

EXAMPLE 301. 2-(((l S,3'R,6'R,7'S,8 ^* E,I S,12 ^! R)-6-CHLORQ-H',12'- DIMETHYL- 13' , 13 '-DIOXIDO - 15 '-QXO-3 ,4-DIHYDRQ-2H~

SPIRO[NAPHTHALENE- 1 ,22 ^! -

[20]OXA[13]THIA[1 ,14]DIAZATET ACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]-7'-YL)OXY)-N-METHOXYACETAMIDE

The title compound was synthesized according to the procedure exemplified in Example 294, Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cie 5 μτη column; Phenomenex, Torrance, CA; gradient eiution of 45-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 2,0 mg of the title compound as an off- white solid. Ή NMR (400MHz, CDCis) δ 8,79 (br, s,, IH), 7.99 (s, IH), 7.69 (d, ./ 8.4 Hz, IH), 7.19 (dd, ./ .2.2. 8.5 Hz, IH), 7.10 (d, ./ 2.2 Hz, IH), 6.99 - 6.73 (m, 3H), 5.98 - 5.83 (m. 111).5,52 (dd, J=\O.Q, 15.1 Hz, 111).4.44 - 4.24 (ra, ill). 4.16 - 4.04 im.2H), 4.03 - 3.86 (ni, 2H), 3.86 - 3.77 (m, 5il).3.70 (d, =14.7 Hz, ill).3.23 (d, ./ 14.3 Hz, 1H), 3.03 (dd, ./ 10.0.15.3 Hz, III).2.88 - 2.66 (m, 3H), 2,54 - 2.27 (ra, 2H), 2,25 - 1.57 (m, 9H), 1.55 - 1.34 (ra, 4H), 1,07 id, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 686.1 (M+H) \

EXAMPLE 302.2-(((lS,3'R,6'R,7'S,8'E,irS,12'R)-6-CHLORO-ir,12'- DIMETHYL-13', 13"-DIOXIDO-l 5'-OXO~3,4-DIHYDRO-2H- 8ΡΙΚΟ[ΝΑΡΗΤΗΑΙ.ΕΝΕ~1,22'- [20]OXA[13]THIA[l 4]DIAZATCTRACYCLO|;i4 .2 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,I6,I8,24]TETRAEN]-7'-YL)OXY)-N,N-BIS(2- METHOXYETHYL)ACET

The title compound (5.5 mg as an off-white solid) was synthesized and purified according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. ^] H NMR (500MHz, CDCh) δ 7.99 (s, 1H), 7.73 - 7.67 (m, IH), 7,18 (dd, .7=2.3, 8.4 Hz, IH), 7.10 (d, .7=2,2 Hz, III). 6.95 - 6.81 (m, 3H), 5.93 - 5.76 (ni, IH), 5.57 (dd, J=9.2, 14.8 Hz, IH), 4.34 (q, ./ 6.9 Hz, IH), 4.24 - 4.17 (m, IH), 4.13 - 4.01 (m, 3H), 3.90 - 3.78 (m, 2H), 3.70 (d, ./ 14.2 Hz, IH), 3.66 - 3.44 (m, 8H), 3.35 (d, ./ 7.6 Hz, 6H), 3.23 (d, ./ 14.4 Hz, IH), 3.01 (dd, .7=10,5, 15,4 Hz, IH), 2.87 - 2,55 (m, l).2.31 (quin, .7=9.0 Hz, IH), 2.24 - 1.72 (m, 9H), 1.70 - 1.59 (m, IH), 1.50 (d, ./ 7 ! Hz, 3H), 1.38 (t, ,7=12.7 Hz, IH), 1.06 id. ,7=6.8 Hz, 3H). m/z (ESI, +ve ion) 772,0 (M+H) ⁺ . EXAMPLE 303, 2-(((lS,3 ^, R,6'R,7 ^, S ₅ 8 ^, E ₅ ll ^, S,12 ^, R)-6-CHLORO-l 1' ₅ 12'- DIMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7 ^, ^l.)OXY)-N-3-OXETANYLACETAMIDE

The title compound (3.0 nig as an off-white solid) was synthesized and purified according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction, ³ H NMR (400MHz, CDCh) δ 8.01 (s, lH), 7.70 (d, J=8.6 Hz, 1H), 7.19 (dd, ./ 2.3.8.4 Hz, ill).7.10 (d, ./ 2.2 Hz, ill).7.06 - 6.87 (m, 3H), 6.84 (s, lH), 5.99 - 5.84 (m, 1H), 5.56 (dd, J=9.1, 15.6 Hz, 111).5.18 - 5.05 (m, ill).5,02 - 4,90 (m, 2H), 4.54 (dt, ./ 4.2.6.3 Hz, 2H), 4.32 (q, ,7=7,2 Hz, H), 4.16 - 4,03 (m, 2H), 3.98 - 3.61 (m, 5H), 3.25 (d, .7=14.3 Hz, IH), 3.05 (dd, J=10.4, 15.1 Hz, 1H), 2.87 ·· 2.71 (m, 2H), 2.60 - 2.45 (m, IH), 2.37 (quin, ,7=9.0 Hz, IH), 2.25 - 1.61 (m, 10H), 1.51 (d, ,/ 7.2 Hz, Ml).1.41 (t, J=12.9 Hz, IH), 1.07 (d, ,7=6,8 Hz, 3H), m/z (ESI, +ve ion) 712, 1 (M+H) ⁺ .

EXAMPLE 304. (1 S,3 ^! R,6 ^* R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2-(3- HYDROXY- 1 -AZETIDINYL)-2-OXOETOOXY)-l Γ,12'-DIMETOYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί <Λ( ^' Υ(·ί..ΟΙ i 4.7.2.0 ".i ^)|u |P1 ^: N I ^' ACOSA [8,16,18 ₅ 24]TETRAEN]-15'-ONE 13 ^! ,13'-DIOXIDE

The title compound (6.0 mg as a white solid) was synthesized and purified according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. ^" Ή NMR (400MHz, CDCh) δ 8.15 - 7.96 (m, M i ). 7.71 (d, J=8.6 Hz, IH), 7.20 (dd, J=2.2, 8.4 Hz, IH), 7.11 (d, .7=2,2 Hz, IH), 6.99 - 6.79 (m, 3H), 5.96 - 5.72 (m, IH), 5.62 - 5.45 (m, IH), 4.71 (br. s., H I ). 4.49 (d, ./ 6.3 Hz, IH), 4.40 - 4.24 (m, 2H), 4.21 - 3.64 (m, 9H), 3.24 (d, ,/ 14 3 Hz, IH), 3.04 (dd, J=10.5, 15.0 Hz, IH), 2,91 - 2,64 (m, 2H), 2.54 (d, ,/ 8 4 Hz, IH), 2.40 - 2.26 (m, IH), 2,25 - 1.75 (m, I OH ). 1.74 - 1.58 (m, IH), 1.52 (d, J=7.2 Hz, 3H), 1.41 (t, J=12.6 Hz, IH), 1.08 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 712. 1 i .V! H ) .

EXAMPLE 305. (1 S,3'R,6 ^! R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2-(3- HYDROXY-3-METHYL- 1 -AZETIDINYL)-2-OXOETHOXY)- 11 ', 12'- DIMETI-IYL-3,4-DiHYDRO-2H,15'H-SPIRO[NAPHTOALENE-l ,22'~

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16.18,24]TETRAEN]-15'- ',13'-DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 3.0 mg of the title compound as an off- white solid. Ml NMR (400MHz, CDCb) δ 8.16 - 7.93 (m, ill).7.69 (d, J=8.4 Hz, ill).7.19 Kk!.,/ 2.2.8.4 Hz, 111).7,10 (d, J=2.2 Hz, Hi).6.98 - 6.76 (m, 3H), 5.98 - 5.71 (m, ill).5,52 (dd, J=9.0, 14.9 Hz, 1H), 4.42 - 4.23 (m, IH), 4,22 - 3.77 (m, 11H), 3.70 (d, J=14.9 Hz, IH), 3.22 (d, J=U3 Hz, IH), 3.09 - 2.94 (m, IH), 2.88 - 2.70 (m, 2H), 2.52 (br. s., IH), 2.37 - 2.26 (m, IH), 2.23 - 1.74 (m, 9H), 1 ,73 - 1.63 (m, IH), 1.57 (d, 4.3 Hz, 3H), 1.50 id. J=7.0 Hz, 3H), 1 ,40 (t, ,/ 12 Hz, ill).1.06 (d, ,7=6,8 Hz, 3H), m/z (ESI, +ve ion) 726,0 (VI ·Π)

EXAMPLE 306. (1 S,3 ^! R,6 ^* R,7'S,8'E,1 rS,12'R)-6-CHLORO-7'-(2-(3- HYDROXY-3-(TRIFLUOROMETHYL)-l-AZEllDiNYL)-2-OXOETHOXY)- 1 Γ , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA[l,14]DIAZATETRACYCL )[14.7.2.0 ³ ' ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN]~15'-ONE 13", 13-DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45-95%) acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 3.0 mg of the title compound as an off- white solid. Ή NMR (400MHz, CDC ) δ 8.11 - 7.96 (m, IH), 7.69 (d, ./ 8.6 Hz, ill).7,19 !dd../ 2.2, 8.5 Hz, III).7.10 id.,/ 2,2 !!/, IH), 6.99 - 6,78 (m, 3H), 5.98 - 5.74 (m, IH), 5.52 (dd, J=9.0, 15.3 Hz, IH), 4.62 - 4.48 (m, IH), 4.37 - 4.21 (m, 3H), 4.11 - 3.91 (m, 5H), 3.88 - 3.66 (m, 3H), 3.23 (dd, ./ 3.2.14.4 Hz, IH), 3.09 - 2.96 (m, IH), 2,88 - 2.71 (m, 2H), 2.50 (dd, ,/ 7,6.16.0 Hz, IH), 2,39 - 1,57 (m, 12H), 1.50 (dd, «/=3.9, 7,0 Hz, 3H), 1.40 (t, .7=12,5 Hz, ill).1.07 (d, ./ 6.7 Hz, 3H). m/z (ESI, +ve ion) 779.9 (M+H) ⁺ .

EXAMPLE 307, iIS,3'R,6'R,7'S,8'E,l l ^, S ₅ 12'R)-6-CHLORO-7'-(2-(3- ΜΕΤΉΌΧΥ- 1 - ΑΖΕΤΓΟΓΝΥΕ)~2-ΟΧΟΕΊΉΟΧΥ)- 1 Γ, 12'-DIMETHYL-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1 ^' .13 ^* ~DIOXIDE

The title compound (6.0 nig as a white solid) was synthesized and purified according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. ¾ N.V1R (400MHz, CDCb) δ 8.02 (d, ./ 14.9!!/. IH), 7.69 (d, J=8.6Hz, IH), 7.19 (dd, =2.1, 8.5 Hz, IH), 7.10 (d, =2.0 Hz, IH), 6.96 - 6.78 (m, 3H), 5.95 - 5.79 (m, IH), 5,60 - 5.43 (m, IH), 4.48 - 4,29 (m, 2H), 4.27 - 4.17 (m, 2H), 4.15 - 3,66 (m, 9H), 3.32 (s, 3H), 3.23 (d, J=14.3 Hz, IH), 3.01 (dd, J=10.2, 15.3 Hz, IH), 2.87 - 2.69 (m, 2H), 2.51 (d,

./ K.6 Hz, IH), 2.33 (d, ./ 7.4 Hz, IH), 2.25 - 1.74 (m, 9H), 1.73 - 1.59 (m, IH), 1,50 (d, ./ 7.0 Hz, 3H), 1.40 (t, ./ 1 .6 Hz, IH), 1,06 (d, ,/ 6.7 Hz, 3H). m/z (ESI, +veion) 726.1 {V! Hi EXAMPLE 308, (1 S,3'R,6'R,7'S,8'E, I l'S,12'R)~6~CHI,ORO~7'~(2~(3,3~

DIFLU ORO- 1 -AZETIDIN YL)-2-OXOETHOXY)- 1 Γ, 12'-DIMETH YL-3 ,4- DIHYDRO-2H, 15H-SPIRO[NAPHTHALENE-l ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Mote that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 45-95% acetoiiitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 4.5 mg of the title compound as an off- white solid, ^" Ή NMR (400MHz, CDC! 3) δ 8.02 (s, IH), 7.69 (d, .7=8.4 Hz, IH), 7.19 (dd, J=2.2, 8.5 Hz, IH), 7.10 (d, J=2.2 Hz, 1H), 6.97 - 6.88 (m, 2H), 6.83 (s, IH), 5.98 - 5.84 (m, IH), 5.51 (dd, J=9.6, 15.1 Hz, I H), 4.57 ( ',. ./ i I .H Hz, 2H), 4.43 - 4.28 (ra, 3H), 4, 19 - 4.02 (m, 3H), 3.99 - 3.89 (m, IH), 3,86 - 3.78 (m, 2H), 3.71 (d, ,7=14,3 Hz, IH), 3.23 (d, .7=14,3 Hz, IH), 3.02 (dd, .7=10.3, 15.4 Hz, IH), 2.88 - 2.69 (m, 2H), 2.55 - 2.42 (m, IH), 2.35 (qum, J=9.2 Hz, IH), 2.25 - 1.60 { in. 10H), 1.51 (d, ,7=7.2 Hz, 3H), 1.40 (t, ./ 12.7 Hz, IH), 1.07 (d, ,7=6.8 Hz, 3H). m/z (EST, +ve ion) 732.0 { M · H )

EXAMPLE 309. (1 S,3'R,6 ^* R,7'S,8'E,1 l'S,12'R)-6-CHLORO-l l',12'-DIMETHYL- 7 ^f 2-OXO-2-(3-(!-PYRROLIDINYL)-l-AZETIDlNYL)ETHOXY)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'- [20] OX A [13] ΤΗΐ A [ 1 , 14] DI AZ ATETR A C YCLO [ 14.7.2.0 ³ · ⁶ .0 ^19,24 ] PENT ACO S A [8, 16, 18,24]TETRAEN]-1 '-ONE 13', 13'-DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 30-95% acetonitrile in water, where both solvents contained 0. 1% TFA, 30 min method) to give, after lyophilization, 3.0 mg of the title compound as an off- white solid. ¾ NMR (500MHz, CDsOD) δ 7.73 (d, J=8.6 Hz, 1H), 7.17 (dd,

./ 2.3. 8.4 Hz, H i ). 7.11 (d. ./ 2.2 I I/. 1H), 7.05 id. ./ 8. 1 Hz, i l l . 6.93 i d. J 8.3 Hz, IH), 6.86 (d, ,/ 3 4 Hz, 1 H), 5.93 - 5.79 (m, IH), 5.66 - 5.53 (m, 1H), 4.73 - 4.63 (m, IH), 4.47 - 4,34 (m, 2H), 4.29 - 3.51 (m, 13H), 3.30 - 3,25 (m, 2H), 3.10 (dd, ./ 10.3. 15.4 Hz, IH), 2.87 - 2.70 (m, 2H), 2.61 - 2.49 (m, IH), 2.40 - 1.67 { in. 15H), 1.53 - 1.39 (m, 4H), 1.06 (d, ./ 6.K Hz, 3H). m/z (ESI, +ve ion) 765.2 ί M I i )

EXAMPLE 310. (1S,3'R,6'R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2-((3S)-3- HYDROXY-i-PYRROLIDINYL)-2-OXOETHOXY)-l Γ, 12"-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - [20]QXA[13]THL\[1,14]DL ZATCT^^

[8, 16, 18,24]TETRAEN]-15'-ONE 13", 13 -DIOXTOE

The title compound was synthesized according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 ₍ um column; Phenomenex, Torrance, CA; gradient elution of 40-95%) acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophihzation, 1.2 mg of the title compound as an off- white solid. Ή NMR (500MHz, CDCis) δ 8, 17 - 7.87 (m, 1H), 7.69 (d, .7=8.3 Hz, 1H), 7.18 (dd, ./ 2.2. 8.6 Hz, i l l ). 7.10 (d, ./ .2.2 Hz, IH), 6.97 - 6.81 (m, 3H), 5,87 - 5.75 (m, I H), 5.57 (dd, ,/ 9 3. 14.9 Hz, IH), 4,63 - 4,49 (m, IH), 4.29 (dd, J=3,4, 7.1 Hz, IH), 4.15 - 3,94 (m, 4H), 3.84 (d, J=l i ,7 Hz, 2H), 3.76 - 3.42 (m, 5H), 3.23 (d, J=14.4 Hz, IH), 3.02 (dd, J=10.5, 15.4 Hz, IH), 2.91 - 2.70 (m, 2H), 2.66 - 2.53 (m, IH), 2.42 - 1.59 (m, 14! ! }. 1.50 (dd, ./ 4.4. 7.1 Hz, 3H), 1.44 - 1 .34 (m, IH), 1.06 (d, ./ 6.8 Hz, 3H). m/z (EST, +ve ion) 726.1 { \i · H ) .

EXAMPLE 311. (18,3'Κ,6Ίν7'8,8Έ,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2-((3R)-3- HYDROXY- 1 -PYRROLIDINYL)-2-OXOETHOXY)- 1 1 ', 12'-DIMETHYL-3 ,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 ₍ um column; Phenomenex, Torrance, CA; gradient elution of 40-95%) acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 4.5 mg of the title compound as a white solid, ¾ NMR (500MHz, CDCb) δ 7.99 (d, J=7.8 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.18 (d, ./ 8.6 Hz, IH), 7.10 (d,■/ 2.2 Hz, I I I ). 6.98 - 6.80 (m, 3H), 5.87 - 5,76 (m, H i ). 5.58 (br, s., ! H), 4.70 - 4,47 (m, IH), 4.31 (quin, 7.2 Hz, i l l ). 4.14 - 4.00 (m, 4H), 3.97 - 3.39 (m, 10H), 3,23 id. ./ 14.4 Hz, IH), 3.03 (dd, J=i0.1, 15.3 Hz, IH), 2.85 - 2.70 (m, 2H), 2.61 (br. s., IH), 2.36 - 1.57 (m, 9H), 1.53 - 1.34 (m, 6H), 1.06 (d, ./ 6.K Hz, 31 1 ). m/z (ESI, +ve ion) 726.1 ( +H) ⁺ . EXAMPLE 312. (1 S,3'R,6'R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2-(4-

HYDROXY- 1 -PIPERIDINYL)-2-OXOETHOXY)- 11 ', 12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents contained 0.1% T ^' FA, 30 min method) to give, after lyophilization, 2.5 mg of the title compound as an off- white solid. ^" Ή NMR (400MHz, CDC ) δ 7.99 (d, 12.3 Hz, IH), 7.69 (d, ./ 8.6 Hz, IH), 7.19 (dd, J=2.2, 8.5 Hz, 1H), 7.10 (d, .7=2.2 Hz, IH), 6.98 - 6.81 (m, 3H), 5.92 - 5.74 (m, IH), 5.56 (dd, J=8.8, 15.3 Hz, IH), 4.31 (dd, J=7.5, 13.8 Hz, IH), 4.19 - 3.64 (m, 10H), 3.31 - 3.09 (m, 3H), 3.03 (t, ./ I I .H Hz, IH), 2.88 - 2,70 (m, 2H), 2.59 (br. s„ IH), 2,39 - 1 ,54 (m, 16H), 1.50 (d, ,/ 7 2 Hz, 3H), 1.39 (t, 1 2.9 Hz, IH), 1.06 (d, J=6,8 Hz, 3H). m/z (ESI, +ve ion) 740. 1 { Yi i ί ) . EXAMPLE 313. (I S,3'R,6'R,7'S,8'E, 1 l'S,I2'R)~6~CHI,ORO~l ! ', 12'-DIMETHYL- 7 ^, -(2-(4-MORPHOLINYL)~2-OXOETHOXY)-3,4~DIHYDRO-2H, 15'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13 ^* -DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Mote that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini ^m Prep Cis 5 μηι column; Phenomenex, Torrance, C A; gradient elution of 45-95% acetomtriie in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 3.5 mg of the title compound as an off- white solid, ^" Ή NMR (400MHz, CDC! 3) δ 7.97 (s, IH), 7.69 (d, .7=8.4 Hz, IH), 7.19 (dd, J=2.2, 8.5 Hz, IH), 7.10 (d, J=2.2 Hz, 1H), 6.96 - 6.81 (m, 3H), 5.97 - 5.78 (m, IH), 5.55 (dd, ./ 8.4.15.3 Hz, !!!).4.39 - 4.28 (m, IH), 4.16 - 3.95 (m, ■ill).3.87 - 3.79 (m, 2! I ).3,78 - 3.56 (m, 8H), 3.50 (br. s., 211).3,23 id../ 14.3 Hz, IH), 3.02 (dd, .7=10,3, 15,2 Hz, H), 2.88 - 2,70 (m, 2H), 2.62 - 2.48 (m, IH), 2.39 - 2.26 (m, IH), 2.25 - 1.60 (m, 9H), 1.51 (d, ./ 7.2 Hz, 3H), 1.39 (t, ./ 12.9 Hz, IH), 1.06 (d, J=6.8 Hz, 3H). m/z (EST, +ve ion) 726.0 {\i · H) ,

EXAMPLE 314. (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-l 1',12'-D1METHYL- 7'-(2-()XO-2-(3-OX()-l-PIPERAZINYL)ETHOXY)-3,4-DIHYDRO-2H,15 'H- SPlROfNAPHTHALENE- 1 ,22'-

|20i()XA| Γ. ΐΗ1Λ| Ι..! |ί)!Λ/Λ ! :ΓΗ.Λ( ^' .()Ι 117.20--M> ^l "-' ^, |PHNT.\( ^' OS.-\ [8,16,18,24]TETRAEN1-15'-C)ME 13 ^! ,13 ^* -DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 ₍ um column; Phenomenex, Torrance, CA; gradient elution of 40-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 3.5 mg of the title compound as an off- white solid. Ή MR (400MHz, CDC ) δ 8.53 - 7.93 (m, 1H), 7.68 (d, ./ 8.4 Hz, 1H), 7.19 (dd, ./ 2.2.8.5 Hz, III).7.09 (d, ,/ 2.0 Hz, 1H), 6.94 - 6.50 (m, Ml). 5,98 - 5.77 (m, 1H), 5.64 - 5.47 (m, IH), 4,36 - 3.66 (m, 12H), 3.47 (br, s., 2H), 3,23 (d, ./ 14.3 Hz, IH), 3.04 (dd, «/=9.6, 15.1 Hz, ill).2.86 - 2.69 (m, 2H), 2,67 - 2.43 (m, IH), 2.34 (t, ./ 8.6 Hz, IH), 2.25 - 1.59 (m, 11H), 1.51 (d, J=7.0 Hz, 3H), 1.39 (t, ,/ 13.! Hz, IH), 1.06 (d, .7=6.8 Hz, 3H). m /. (ESI, +ve ion) 739.0 i\i Π) . EXAMPLE 315. (lS,3'R,6 ^! R,7'S,8 ^, E,ll'S,12'R)-6-CHLORO-7'-(2-(4,4-

DIFLU()RO-l-PIPERIDINYL)-2-OXOETHOXY)-ir,12'-DIMETHYL-3,4 - DIHYDRO-2H, 15 'H-SPIRO [NAPHTHALENE- 1 ,22*-

[20]OXA[13]TrHIA[l,14]DIAZATETRACYCLO[14 .0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was synthesi zed according to the procedure exemplified in Example 294. Note that DIEA was utilized as the general base in the reaction. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cie 5 iim column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitriie in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 6.0 mg of the title compound as an off- white solid. Ή NMR (400MHz, CDCis) δ 8,04 (s, IH), 7.69 (d, «/=8.6 Hz, 1H), 7.19 (dd, J=2.3, 8.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.97 - 6.79 (m, 3H), 5.95 - 5.79 (m, H i ). 5.54 (dd,■/ 9.4. 15.3 Hz, 1H), 4.46 - 4.26 (m, 1H), 4.18 - 3.96 (m, 4H), 3, 89 - 3.50 (m, ?! ! }. 3.23 (d, 1 .3 Hz, IH), 3.07 - 2,98 (m, ! ! ! ). 2.85 - 2,74 (m, 2H), 2.68 - 1.76 (m, 15H), 1 ,73 - 1.60 (m, I H), 1.50 (d, ,7=7,2 Hz, M i l 1.39 (t, J=i2.5 Hz, IH), 1.06 (d, =6.8 Hz, 3H). m/z (ESI, +ve ion) 760.0 (M+H) ⁺ .

EXAMPLE 316. (1 S,3'R,6 ^! R,7'S,8 ^! E, 1 rS, 12'R)-6-CHLORO-l 1 ', 12'-DIMETHYL- 7'-(2-(4-METHYL- 1 -PIPERAZlNYL)-2-OXOETHOXY)-3,4-DJHYDRO- 2H, 15'H-S PIRO | N APHTH AL ENE- 1 ,22'-

[20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[ 14.7.2.0 ³ '^0 ^{] 9} ' ²⁴ ]PE TACOSA [8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was synthesized according to the procedure exemplified in Example 294. The crude mixture was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 35-95% acetonitriie in water, where both solvents contained 0.1 % TFA, 30 min method) to give, after lyophilization, 5.5 mg of the title compound as a white solid. M l NMR (400MHz, CDCh) 5 8, 1 2 (br. s . H i ). 7.69 (d, J=8.4 Hz, IH), 7.19 (dd, «/=2.2, 8,6 Hz, H), 7. 10 (d, .7=2.2 Hz, IH), 6,99 - 6.78 (m, 3H), 6.08 - 5,60 (m, 1H), 5.53 (dd, 8.4. 15,5 Hz, I H), 4.72 (br. s„ IH), 4.42 - 1.58 (m, 34H), 1.49 (d, =5.1 Hz, 3H), 1.45 - 1.35 (m, lH), 1.07 (d, ./ 6.5 Hz, M l ), m/z (ESI, +ve ion) 739.1 (M+H) ⁺ . EXAMPLE 317. (1 S,3'R,6 ^! R,7'S,8 ^! E, 1 rS, 12'R)-6-CHLORO-l l ', 12 ^! ~DIMETHYL- 7'-(2-PYRIMIDIN YLMETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[ 147.2 ³ '« 0 ¹⁹ - ²⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN]-15'- ', 13'-DIOXIDE

To a stirred solution of iI S,3'R,6'R,7'S,8'E, l l 'S. l^R^-chloro-T- hydrox>'-11^12'-dimethyl-3,4-dihydro-2H,15H-spiro[naphtha lene- [20]oxa[ 13]thia[l, 14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16

n]-15'-one 13', 13'-dioxide (22 nig, 0.037 mmol, Example 719, Step 2) in DMT (1.5 ml.) was added sodium hydride, 60% in mineral oil (7.34 mg, 0.184 mmol) (in excess) at rt. The resulting mixture was stirred at it for a period of 20 min before 2-(chrloromethyl)pyrimidine (14. 16 mg, 0.1 10 mmol) was added. The resulting mixture was stirred at rt for a period of 19 h. The desired product was only the minor. The reaction was quenched with MeOH and the crude mixture was taken up in DMSO and subjected to preparative reverse-phase HPLC

(Gemini™ Prep Cig 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitriie in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 0.5 mg of the title compound as a colorless film. ^l H NMR (500MHz, CDCb) δ 8.89 (d, J=4.2 Hz, 2H), 7.92 (s, I H), 7.70 (d, ,7=8,3 Hz, IH), 7.37 (br. s„ IH), 7.19 (dd, ./ 2.3. 8.4 Hz, I H), 7.10 (d, ./ 2.2 Hz, IH), 6.97 - 6.83 (m, 3H), 5.99 - 5.80 (m, IH), 5.65 (dd, J=9.4, 15.0 Hz, 1H), 4,83 - 4.72 (m, 1H), 4.70 - 4,54 (m, 1H), 4,31 (q, ,/ 6.X Hz, 1H), 4.15 - 4.04 ί η ·. 2H), 4.01 (d, J=8.8 Hz, 1H), 3.83 (d, J=14.9 Hz, 1H), 3.71 (d, ./ 14.4 Hz, i l l ). 3.24 (d, ,/ 14,4 Hz, 1H), 3.02 (dd, ,/ 10.4. 15.0 Hz, i l l ). 2.87 - 2.66 { in. 3H), 2.41 - 2,29 (m, ! ! ! ). 2.25 - 1.56 (m, 10H), 1.50 (d, 7.3 Hz, 3H), 1 ,39 (t, J=13.0 Hz, 1H), 1.07 (d, ,7=6,8 Hz, 3H), m/z (ESI, +ve ion) 691.0 (M+H) ⁺ .

EXAMPLE 318. (3R,6R,7S,8E, 1 l R,16R,26S)-6'-CHLORO-7-HYDROXY- DIHYDRO-2'H, 19H-SPIRO[ 13,24-DIOXA- 17-THI A- 1 ,18- DIAZAPENTACYCLO[18.7.2.0 ³ ' ⁶ .0 ¹¹ ' ¹⁶ .0 ²³ ' ²⁸ ]NONACOSA-8,20 _S 22,28- TETRAENE-26, 1 '-NAPHTH ALEN] - 19-ONE 17, 17-DIOXIDE

STEP I : (R)-3-ALLYLDIHYDRO-2H-PYRAN-4(3H)-ONE AND (S)-3- ALLYLDIHYDRO-2H-P -4(3H)-ONE

racemate

Into a single-necked round-bottomed 250-mL flask were placed allylpaliadiumill) chloride (0,630 g, 1.722 mmol), 4,5-bisidiphenylphosphino)- 9,9-dimethylxanthene (1.993 g, 3.44 mmol), and dl-proline (1.189 g, 10.33 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen. Then tetrahydropyran-4-one (9,54 mL, 103 mmol), ally! alcohol (2.342 mL, 34.4 mmol), and DMSO (100 mL) were introduced sequentially at rt under nitrogen. The resulting mixture was stirred at rt for 10 min and 75 °C for a period of 24 h. After cooled, the crude mixture was poured into ice and saturated sodium bicarbonate aqueous solution and extracted with 25% i-PrOH/DCM (3 X). The combined organics were washed with water (2 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 8 mm at 0% and 35 mm from 0 to 40%», 80 g ISCO silica gel column) to give a racemic mixture of (R)-3- allyldihydro-2H-pyran-4(3H)-one and (S)-3-allyldihydro-2H-pyran-4(3H)-one

5 (3.85 g, 27.46 mmol, 80 % yield) as a colorless liquid, impure and directly taken onto the next step.

STEP 2: (3R,4S)-3-ALLYLTETRAHYDRO-2H-PYRAN-4-OL AND (3S,4R)-3- ALLYLTETRAHYDRO- -PYRAN-4-OL

j o racemate

To a stirred solution of impure 3-allyldihydro-2H-pyran-4(3H)-one (3.100 g, 22.11 mmol) in THF (60 ml.) cooled in an MeOH-dry ice bath (- 78 °C) was slowly added L-selectride, 1.0 M solution in tetrahydrofuran (31.0 mL, 31.0 mmol) via a syringe. After the addition was complete, the resulting mixture was

15 stirred at - 78 °C for 1 h. The MeOH-dry ice was replaced with ice- water bath a d the mixture was stirred for 15 min before carefully quenched with saturated ammonium chloride aqueous solution. The mixture was further diluted with saturated ammonium chloride aqueous solution and extracted with 25% i- PrOH/DCM (3 X). The combined organics were dried over anhydrous sodium 0 sulfate and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 5 min at 0% and 35 min from 0 to 60%, 40 g ISCO silica gel column) to give a racemic mixture of (3R,4S)-3- allyltetrahydro~2H-pyran-4-ol and (3S,4R)-3-allyltetrahydro-2H-pyran-4-ol (2.60 g, 18.28 mmol, 83 % yield) as a colorless liquid, impure and directly taken onto 5 the next step. STEP 3: (3R,4S)-3-ALLYLTETRAHYDRO-2H-PYRAN-4-YL

METHANESULFONATE AND (3 S,4R)-3- ALLYLTETRAHYDRO-2H- PYRAN-4-YL METHANE

racemate

To a stirred ice-cooled solution of impure racemic (3R,4S)-3- allyltetrahydro-2H-pyran-4-ol and (3S,4R)-3-allyltetrahydro-2H-pyran-4-ol (2.00 g, 14.07 mmol) and anhydrous triethylamine (4,30 mL, 30.9 mmol) in DCM (30 mL) was slowly added methanesulfonyl chloride (1.667 mL, 21.10 mmol) through a syringe. The resulting mixture was stirred at 0 °C for a period of 1 h 20 min. The crude mixture was poured into ice and I N aqueous HC1 solution and extracted with DCM (2 X). The combined organics were washed once again with 1 N aqueous HC1 solution followed by brine (2 X), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a racemic mixture of (3R,4S)-3- allyltetrahydro-2H-pyran-4-yl methanes ulfonate and (3S,4R)-3-allyltetrahydro- 2H-pyran-4-yl methanesulfonate (2.8 g, 12.72 mmol, 90%) as a colorless oil, impure and taken onto the next step without purification.

STEP 4: 2-(((3R,4R)-3-ALLYLTETRAHYDRO-2H-PYRAN-4- YL)TH10)PYR1M1D1NE AND 2-(((3S,4S)-3-ALLYLTETRAHYDRO-2H- P YRAN-4- YL )THI 0)P YRIMIDINE

racemaie

A mixture of 2-mercapto-pyrimidine (2.467 g, 21 ,99 mmol) and potassium carbonate anhydrous (4.47 g, 32.3 mmol) in DMF (30 mL) was stirred at rt for 10 min before a solution of the impure racemic mixture of (3R,4S)-3-allyltetrahydro- 2H-pyran-4-yl methaxiesulfonate and (3S,4R)-3-allyltetrahydro-2H-pyran-4-yl methanesulfonate (2.85 g, 12.94 mmol) was added at rt. The resulting mixture was stirred at rt for 10 min, at 75 °C for a period of 1 h, 85 °C for 1.5 h, and at 95 °C for 1 h. The crude mixture was poured into ice and saturated sodium carbonate aqueous solution and extracted with EtOAc (2 X). The combined organics were washed with saturated sodium carbonate aqueous solution (1 X) followed by water (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/hexanes, 40 min from 0 to 60%, 40 g ISCO silica gel column) to give 0.58 g of a racemic mixture of 2-(((3R,4R)-3-allyltetrahydro-2H-pyran-4-yl)thio)pyrimidine and 2- (((3S,4S)-3-allyltetTahydro-2H-pyran-4-yl)thio)pyrimidine as a colorless film, impure and taken onto the next step.

STEP 5: 2-(((3R,4R)-3-ALLYLTETRAHYDRO-2H-PYRAN-4- YL)SULFONYL)PYRTMIDINE AND 2-(((3S,4S)-3-ALLYLTETRAHYDRO- 2H-PYRAN-4-YL)SULFO

racemaie

To a stirred ice-cooled solution of the impure racemic mixture of 2- (((3R,4R)-3-allyltetrahydro-2H-pyran-4-yl)thio)pyrimidine and 2-(((3S,4S)-3- allyltetrahydro~2H-pyran-4-yl)thio)pyrimidine (0.58 g, 2.454 mmol) in DCM (10 mL) and DMF (0.5 mL) was added 3-chlorobenzoperoxoic acid (1.155 g, 5.15 mmol) in 2 portions as a solid over 5 min. The resulting mixture was stirred at 0 °C for 10 min. The ice bath was then removed and the mixture was stirred at rt for 2 h 15 min. The crude mixture was directly loaded onto a silica gel precolumn and subjected to combi-flash column chromatography (EtOAc/Hexanes, 5 min at 0% and 40 min from 0 to 100%, 40 g ISCO silica gel column) to give a racemic mixture of 2-(((3R,4R)-3-allyltetrahydro-2H-pyran-4-yl)sulfonyl)pyrimi and 2-(((3S,4S)-3-allyltetrahydro-2H-pyran-4-y])sulfonyl)pyrimid ine (0.3! g, 1.155 mmol, 47.1 % yield) as a colorless oil.

m (ESI, +ve ion) 269.1 (M+H) ⁺ . STEP 6: (3R,4R)-3-ALLYLTETRAHYDRO-2H-PYRAN-4-SULFONAMIDE AND (3S,4S)-3-ALLYL -2H-PYRAN-4-SULFONAMIDE

The 1 ^st step: To a stirred solution of the racemic mixture of 2-(((3S,4S)-3- allyltetrahydro-2H-pyran-4-yl)sulfonyl)pyrimidine and 2-(((3R,4R)-3- ailyltetrahydi -2ITpyran-4-yl)sidfonyl)pyrimidine (0.31 g, 1.155 mmol) in

MeOH (8 raL) was added at rt sodium methoxide, 25 vvt % solution in methanol (0.257 mL, 1.155 mmol) via a syringe. The resulting mixture was stirred at rt for 40 min when LC-MS showed near completion. The volatiles were removed in vacuo and the residue was subjected to high vacuum.

The 2 ^ne step: To the above residue was added at rt water (8 mL) followed by- sodium acetate trihydrate (0.217 mL, 2.311 mmol) and amidoperoxymonosulfunc acid (0.261 g, 2.31 1 mmol). The resulting clear solution was stirred at 75 °C in a preheated oil bath for a period of 40 min. The mixture was cooled, basified using ice cold saturated sodium carbonate, and extracted with 20% i-PrOH/DCM (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 3 min at 0 and 40 min from 0 to 80%, 24 g ISCO silica gel column) to give a racemic mixture of (3R,4R)-3-allyltetrahydro- 2H-pyran-4-sulfonamide and (3S,4S)-3-allyltetrahydro-2H-pyran-4-sulfonamide (0.20 g, 0.974 mmol, 84 % yield) as a colorless oil, directly taken onto the next step. STEP 7: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -HYDROXY-4-((3R,4R)-4-

SULFAMOYLTETRAHYDRO-2H-PYRAN-3-YL)BUT-2-EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-4-((3S,4S)-4- SULFAMOYLTETRAHYDRO-2H-PYRAN-3-YL)BUT-2-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACI

To a 25 mL single-necked round-bottomed flask were placed (S)~6 ^f - chloro-5-((( 1 R,2R)-2-((S,E)~ 1 -hydroxyhex-2-en- 1 -y cyclobul methy -S'A^S- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (150 mg, 0.294 mmol, Intermediate AA12A), a racemic mixture of (3R,4R)- 3-allyltetrahydro-2H-pyran-4-sulfonamide and (3S,4S)-3-allyltetrahydro-2H- pyran-4-sulfonamide (121 mg, 0.588 mmol), and 2 ^nd generation hoveyda-grubbs catalyst (18.43 mg, 0.029 mmol). T he flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (4.5 mL) was introduced through a syringe under nitrogen. The resulting mixture was stirred at it under nitrogen for a period of 3 h. The crude mixture was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography ((10%

MeOH/DCM with 0.3% AcOH)/DCM), 30 mm from 0 to 70%, 24 g ISCO silica gel column) to give a mixture of the title compounds (73 mg, 0.113 mmol, 38.5 % yield) as an off-white solid. STEP 8: (3R,6R,7S,8E,1 1 R,16R,26S)-6'-CHLORO-7-HYDROXY-3',4'- DIHYDRO-2'H, 19H-SP1R0[ 13,24-DIOXA- 17-Tffl A-l , 18- DS A/APkNTAi YCLOi 1 .7.2. ^: '.0 ^{! ! ;} " ' ^K |X()\AC()SA-H.20.22.2H- TETRAENE-26, 1 '-N APHTH ALEN] - 19-ONE 17, 17-DIOXIDE OR

{3R.6R.7S.8I·. 1 1 S,l 6S,26S)-6 ^, -CHLORO-7-HYDROXY-3',4 ^, -DIHYDRO- 2Ή, 19H-SPIRQ [ 13,24-DIOXA- 17-THIA- 1,18-

DIAZAPENTACYCLO|;i 8.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹ .0 ²³ ' ²⁸ ]NONACOSA-8,20,22,28- TETRAENE-26, 1 ^* -N APHTH ALEN] - 19-ONE 17, 7-DIOXIDE To a stirred ice-cooled solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydrox '-4-((3R,4R)-4-sulfamoyltetrahydro-2H-pyran-3-yl)but-2-en-l- y^cyclobut methy^-S'^^'^-tetrahydro^H^'H-s irotbenzotblt l^Joxazepine- 3,l'-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxy-4-((3S,4S)-4-sulfamoyltetrahydro-2H-pyran-3-yl)but-2 -en-l- yl)c> lobu1yl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3, -naphthalene]-7-carboxylic acid (73 mg, 0.113 mmol), N,N-dimethylpyridin- 4-amine (30.4 mg, 0.249 mmol) in DCM (60 mL) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54.2 mg, 0.283 mmol) in one portion. The resulting mixture was stirred at 0 °C for 20 mill and at ambient temperature for 4 h. The volatiles were removed in vacuo. The crude residue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after Iyophiiization, 23 mg of the title compound as the first eluting fraction (Example 318) as a white solid. ¾ NMR (400MHz, CDCb) δ 8.46 (br. s., 1H), 7.70 (d, ./ K.6 Hz, 1H), 7.19 (dd, ,/ 2.2. 8.5 Hz, 1H), 7.09 (d, ,/ 2 2 Hz, i l l ). 7.00 - 6.92 (m, 2H), 6,79 (s, i l l ). 5,93 (td, ./ 7.( 14.6 Hz, ! ! ! ). 5,70 (dd, J=8.0, 15.3 Hz, 1H), 4.29 - 4.17 (m, 2H), 4, 14 - 3.99 (m, 3H), 3.92 (dd, ./ 4.0. 11.8 Hz, 1H), 3.74 (dd, J=14.8, 19.1 Hz, 2H), 3.64 - 3.54 (m, 1H), 3.31 (dd, ./ 8.0. 1 1 .9 Hz, i l l ). 3.23 (d, ,/ 1 .3 Hz, ! ! ! ). 3.03 (dd, ,/ 9.0. 15,5 Hz, 1H), 2,85 - 2.73 (m, 2H), 2,50 - 1.75 (m, 1 1 1 ). 1,67 (q. ./ 9.5 Hz, ! ! ! ). 1.41 { I. 1 . 1 Hz, 1H). m/z (ESI, +ve ion) 627.0 { V! ! ! }

Further elution provided the title compound (29 mg) as the second eluting fraction (Example 319) as a white solid. Ή NMR (400MHz, CDCh) δ 8,46 (br. s,, 1H), 7.66 (d, ,7=8,4 Hz, 1H), 7. 17 (dd, .7=2.2, 8.5 Hz, 1H), 7.12 - 6.99 (m, 3H), 6.95 (d, ./ 8.2 Hz, IH), 6.11 - 5.61 (m, 2H), 4.41 - 1.34 (m, 30H). m/z (ESI, +ve ion) 627.0 ( VI I I ) .

EXAMPLE 320. (3R,6R,7S,8E,1 lR,16R,26S)-6'-CHLORQ-7-METHQXY-3',4'- DIHYDRO-2'H, 19H-SPIRO[ 13,24-DIOXA- 17-THI A-l , 18-

DIAZAPENTACYCLO[18.7.2.0 ³ - ⁶ .0 ^{3 3} ' ^!6 .0 ²³ ' ²⁸ jNONACOSA-8,20,22,28- TETRAENE-26, 1 '-ΝΑΡΗΊΉ ALEN] - 19-ONE 17, 17-DlOXIDE OR

(3R,6R,7S,8E,l l S,16S,26S)-6'-CHLORO-7-METHOXY-3 ^! ,4'-DIHYDRO- 2Ή, 19H-S PIRO [ 13,24-DIOXA- 17-THI A- 1 ,18- DIAZAPENTACYCLO[18,7.2,0 ³ - ⁶ .0 ¹¹ - ¹⁶ .0 ²³ - ^2S ]NONACOSA-8,20,22,28- ΤΕΤ^\Ε -26, 1 '-ΝΑΡΗΤΗ ALEN] -19-ONE 17,17-DIQXIDE

To a stirred ice-cooled solution of a mixture of

(3R,6R,7S,8E,l lR,16R,26S)-6 ^, -chloro-7-hydroxy-3',4'-dihydro-2 ^, H,19H- spiro|;i3,24-dioxa-17-mia-l,18-diazapentacyclo|;i 8.7.2.0 ' ⁶ .0 ¹¹ - ¹⁶ .0 ²³ ' ²⁸ ]nonacosa- 8,20,22,28-tetraene-26,.r-naphthalen]-19-one 17, 17-di oxide and

(3R,6R,7S,8E,l l S,16S,26S)-6 ^, -chloro-7-hydroxy-3 ^, ,4 ^, -dihydro-2¾19H- spiro[ 13,24-dioxa-17-thia-l,18-diazapentac clo[l 8.7.2.0 ^{3 j} .0 ^!i ' ⁱ⁶ .0 ²³ ' ²⁸ jnonacosa- 8,20,22,28-tetraene-26,l'-naphthalen]-19-one 17,17-dioxide (not weighed, Examples 318) in DMF (2 mL) was added sodium hydride, 60 % dispersion in mineral oil (in excess) at rt. The resulting mixture was stirred at 0 °C for 10 min and at rt for 20 min before iodomethane (in excess) was added at rt. The resulting mixture was stirred at rt for a period of 1.5 h. The reaction mixture was cooled in an ice-water bath before quenched with methanol. It was taken up in DMSO andsubjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenonienex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 0.6 mg of the title compound as the first eluting fraction as a white solid, ^" Ή NMR (500MHz, CDCh) δ 8.12 (s, IH), 7.71 (d, .7=8,6 Hz, IH), 7.20 (dd, J=2.2, 8.6 Hz, IH), 7.1 1 (d, J=2.2 Hz, IH), 6.98 - 6.89 (m, 2H), 6.74 (d, J=1.5 Hz, I I I ). 5.97 - 5.83 (m, IH), 5.55 (dd, ,7=9.0, 15.4 Hz, IH), 4.39 (dt, ./ 4.9. 9.0 Hz, IH), 4, 1 7 - 4.03 (m, 3H), 3.93 (dd, ./ 4.0. 1 1 .9 Hz, IH), 3 ,80 (d, ./ ! 5.2 Hz, IH), 3.73 (d, ./ 1 4.2 Hz, IH), 3.69 (dd, ./ 3.7. 9,0 Hz, IH), 3.60 - 3.53 (m, IH), 3.33 (dd, J=8.8, 11.7 Hz, IH), 3.27 (s, 3H), 3.20 (d, J=14.2 Hz, IH), 2.99 (dd, J=10.3, 15.2 Hz, IH), 2.86 - 2.73 (m, 2H), 2.59 (d, ./ 1 5.4 Hz, IH), 2.50 - 1.53 (m, 13H), 1 .40 (t, ,/ 1 2. 7 Hz, I H). m/z (ESI, +ve ion) 641 .0 ( M i l ) .

EXAMPLE 32 . (3R,6R,7S,8E, 11 S, 16S,26S)-6'-CHLORO-7-METHOXY-3',4'~ DIHYDRO-2'H, 19H-SPIRO[ 13,24-DIOXA- 17-THI A-l , 18- DIAZAPENTACYCLO[18.7.2.0 ³ - ⁶ .0 ¹¹ - ¹⁶ .0 ²³ - ²⁸ ]NONACOSA-8,20,22,28- TETRAENE-26, 1 '-NAPHTH ALEN] - 19-ONE 17, 17-DIOXIDE OR

(;«,6R,7S,8E, l l R, 16R,26S)-6'-CHLORO-7-METHOXY-3',4'-DIHYDRO- 2Ή, 19H-SPlRO[l 3,24-DIOXA-l 7-TH1A- 1 ,18-

DIAZAPENTACYCLO[18.7.2.0 ³ - ⁶ .0 ⁿ ' ¹⁶ .0 ²³ ' ²⁸ ]NONACOSA-8.20,22 ₅ 28- TETRAENE-26, 1 '-NAPHTH ALEN] - 1 9-ONE 17, 1 7-DIOXIDE

The title compound (0.8 mg) was obtained as a white solid as the second eluting isomer from preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenonienex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 320. 'HNMR (500MHz, CDCh) δ 8.12 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.24 (d, ./ 9.0 Hz, III).7.19 (dd, ./ 2.!.8.4 Hz, 1H), 7.09 (d, ./ 2.0 Hz, 1H), 6.98 (d, ./ 8.3 Hz, ill).6,60 (hr. s . 111).6.09 - 5.93 (ra, ill).5,56 (dd, ./ 8.3. 15.2 Hz, 1H), 4.22 - 4.08 (m, 2H), 4,07 - 4.01 (m, ill).3.98 - 3.88 (m, 2H), 3,69 id.. «7=14.4 Hz, 1H), 3.64 (dd, J=3.4, 8.1 Hz, 1H), 3.57 (d,J=14.9Hz, Ml).3.51 Cut../ 1.6. 11.4 Hz, 1H), 3.37 - 3.24 (m, 4H), 3.18 - 3.03 (m, 2H), 2.86 - 2.71 (in, 2H), 2.52 - 2,30 (m, 4H), 2.28 - 2,16 (m, !!!}.2.14 - 1.58 (m, 9H), 1.44 (t, ./ !2.i Hz, ill). m/z (ESI, +ve ion) 641.0 (M · f i

EXAMPLE 322. (3R,6R,7S,8E,1 lR,16R,26S)-6'-CHLORO-7-(2- ME HOXYETHOXY)-3',4 ^! -DIHYDRO-2 ^! H,19H-SPiRO[13,24-D10XA-r7- ΤΗΙΑ ,18-ΟΙΑΖΑΡΕΝΤΑεΥεΕΟ[18.7.2.0 ³ ·^0 ^η · ¹⁶ .0 ²³ · ²⁸ ]ΝΟΝΑ€Ό8Α- 8,20,22,28-TETRAENE-26, 1 '-N APHTHALEN] - 19-ONE 17, 17-DIOXIDE OR (3R,6R,7S,8E,llS,16S,26S)-6 ^, -CHLORO-7-(2-METHOXYETHOXY)-3 ^, ,4 ^, - DIHYDRO-2'H, 19H-SPIRO[ 13,24-DIOXA- 17-THI A-l ,18- DIAZAPENTACYCL [18.7.2.() ³ - ⁶ .() ⁱⁱ - ^!6 .0 ²³ - ²⁸ jNONACOSA-8,20,22,28- TETRAEN -26, 1 *-N APHTH ALEN] - 19-ONE 17,17-DIOXIDE

To a stirred solution of a mixture of (3R,6R,7S,8E,llR,16R,26S)-6'- chloro-7-hydroxy-3',4'-dihydro-2'H,19H-spiro[13,24-dioxa-17- thia-l,18- dsazapentacy clo [ 18.7.2, Q ³ ^ 0

naphthalen]-19-one 17,17-dioxide and (3R,6R,7S,8E,1 lS,16S,26S)-6'-chloro-7- i 3.24..dioxa- ! 7 -ihia- 1.18- diazapeniacyclo[18.7.2.() ³ ' ⁶ .0 ^IIJ ^0 ² - ²⁸ ]nonacosa-8,20,22,28-tetraene-26,r- naphthalen]-19-one 17,17-dioxide (6.2 mg, 9,89 μτηοΐ, Example 318) in DMF (1 mL) was added sodium hydride, 60 % dispersion in mineral oil (3.95 mg, 0.099 mmol) (in excess) at rt. The mixture was stirred at rt for 25 min before 2- bromoethyl methyl ether (9.30 μΐ, 0.099 mmol) (in excess) was added. The resulting mixture was stirred at rt for 2.5 h. The reaction mixture was cooled in an ice-water bath before quenched with methanol, it was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μτη column; Phenornenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 5.0 mg of the title compound as a white solid. ¾ NMR (400MHz, CDCb) δ 8.47 (br. s., 1H), 7.69 (d, ./ 8.6 Hz, 1H), 7.18 (dd, ./ 2.3.8.4 Hz, 1H), 7,09 (d, ./ 2.3 Hz, ill).6.93 (s, 2H), 6.72 (s, ill).5.9! (td, ./ 7.2.14.6 Hz, 111). 5,54 (dd, J=8.3, 15.4 Hz, 1H), 4.30 (dt, ./ 4.7.9.0 Hz, ill).4.15 - 4.00 (m, 3H), 3.90 (dd, J=4.1, 11.7 Hz, 1H), 3.81 (dd, J=3.3, 8.4 Hz, 1H), 3.79 - 3.67 (m, 2H), 3.64 - 3.49 (m, 4H), 3.48 - 3.42 (m, 1H), 3.39 (s, 3H), 3.32 - 3.15 (m, 2H), 2.96 idd../ 10.4.15.3 Hz, 111).2,86 - 2.69 (m, 2H), 2.54 - 1.51 (m, 1 11).1,39 (t, J=\ 2.4 Hz, 1H). m/z (ESI, +ve ion) 685.1 (M+H) ⁺ .

EXAMPLE 323, (lS,3'R,6'R,7 ^f S,8'E, I l'R,l 5'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 18 Ή- SPIRO [NAPHTHALENE- 1 ,25'-

[23]OXA[16]THL [l,17]DIAZAPENTACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹ 0 ²² ' ²⁷ ]OCTAC OSA| 8,19,21,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR

(1 S,3'R,6 ^! R,7'S,8'E, 11 'S, 1 'S)-6-( l U RO-7 -ί iYOR XY-U-DH !Y i)RO- 2H,18'H-SPIRO[NAPHTHALENE-l,25'-

|23i()XA| !( ^' Ϊ ^" ΗΙ,\| Ι.Ι7|Ι)!ΛΖΛΡΙί\Ί·Λί Υ('Ι.θ _! 17.7.2. ϊ ·'.ί ^{η !} \·;:· ^Λ "Ίθ(··ΓΛ(· OSA[8,19,21 ,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE

STEP 1: ( 1 R,2S)-2-ALLYLCYCLOPENTANOL AND (lS,2R)-2- ALLYLCYCLOPENTANOL

racemaie

To allylmagnesium bromide, 1.0 M solution in diethyl ether (100 mL, 100 mmol) stirred at - 10 to - 18 °C in a 500-mL single-necked round-bottomed flask was added slowly 1 ,2-epoxycyclopentane (4.12 mL, 47.6 mmol) through a syringe over a period of 30 rain. The resulting mixture was stirred at this temperature and allowed to slowly warm up to rt and stirred at rt overnight (18 h). The reaction mixture was thoroughly cooled in an ice bath before slowly and very carefully quenched with ice cold saturated ammonium chloride aqueous solution. Strong gas evovlution was observed. Some chunky and gummy precipitate formed at the bottoms of the flask. This mixture was further diluted with ether and ice cold ammonium chloride aqueous solution. It was stirred and occassionally sonicated to give a clear two-phase mixture. The layers were separated and the aqueous phase was extracted with ether (2X). The combined organies were combined and washed with saturated ammonium chloride aqueous soultion (I X), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a racemic mixture of (l R,2S)-2-allyicyclopentanoi and (lS,2R)-2-allylcyclopentanol (6.6 g, 52,3 mmol, 110 % yield) as a colorless oil.

STEP 2: (1 S,2R)-2-ALLYLCYCLOPENTYL METHANESULFO ATE AND (lR,2S)-2-ALLYLCYCLO ONATE

racemate

To a stirred ice-cooled solution of a racemic mixture of (l S,2R)-2- allylc clopentanol and (l S,2R)-2-allylcyclopentanol (3.0 g, 23.77 mmol) and triethylarnine (7.27 mL, 52.3 mmol) in DCM (50 mL) was slowly added methanesulfonyl chloride (2.82 mL, 35.7 mmol) through a syringe. The resultinj mixture was stirred at 0 °C for a period of 1 h. The crude mixture was poured into ice and 1 N aqueous HC1 solution and extracted with DCM (2 X). The combined organics were once again washed with 1 N aqueous HQ solution followed by brine (2 X) and dried over anhydrous sodium sulfate. The residue after concentration invacuo gave a racemic mixture of (lS,2R)-2-allylcyclopentyl niethanestiifonate and (lR,2S)-2-allylcyclopentyl methanesulfonate (5.0 g, 24.48 mmol, 103 % yield) as a nearly colorless oil, directly taken onto the next step.

STEP 3 : 2-(((l R,2R)-2-ALLYLCYCLOPENTYL)THIO)PYRIMIDESiE AND

(((l S,2S)-2-ALLYLCYCL DINE

racemte

To a stirred mixture of 2-mercapto-pyrimidine (3.64 g, 32.5 mmol) and potassium carbonate anhydrous (5.52 g, 39.9 mmol) in DMF (20 mL) was added at rt a solution of a racemic mixture of (1 S,2R)-2-allyicy clopentyi

methanesulfonate and (lR,2S)-2-allylcyclopentyl methanesulfonate (5.1 g, 24.96 mmol) in DMF (20 mL). The resulting mixture was stirred at rt for a period of 17 h. Withm the first 1.5 h or so, the reaction mixture got so creamy that the stirring became nearly ineffective. More DMF (3 X 10 mL) was added and the mixture was stirred at rt overnight. It was observed the next morning the sirring had been disabled due to the fact that the mixture became a very thick paste. The crude mixture was poured into ice and saturated sodium bicarbonate aqueous solution and extracted with ether (3 X). The combined organics were washed with water (1 X) followed by brine (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/Tiexanes, 20 mm at 10%, 80 g ISCO silica gel column) to give 4.3 g of an impure racemic mixture of 2-(((l R,2R)-2- allylcyclopentyl)thio)pyrimidine and 2-(((l S,2S)~2~

allylcyclopeniyl)thio)pyrimidine, directly taken onto the next step.

STEP 4: 2~(((1 R,2R)-2-ALLYLCYCLOPENTYL)SULFONYL)PYRIMIDINE AND 2-(((lS,2S)-2-ALL YL)PYRIMIDINE

racemte

To a stirred ice-cooled solution of the above impure racemic mixture of 2- (((lR,2R)-2-allylcyclopentyl)thio)pyrimidme and 2-(((l S,2S)-2- allylcyclopentyl)thio)pyrimidine (2.1 g, 9.53 mmol) in DCM (30 mL) was added 3-chlofobenzoperoxoic acid (3.45 g, 20.02 mmol) in two portion over a period of 10 min. The resulting mixture was stirred at 0 °C for about 2 h. (Note that there was a major peak on LC-MS which gave rise a mass consistent with the intermediate sulfoxide. So the reaction was allowed to go for a much extended duration). The reaction mixture appeared a white heterogeneous paste. DMF (1.0 mL) was added and the reaction mixture became a clear solution and it was stirred at rt for 2.5 h. The reaction mixture was then poured into ice and saturated sodium bicarbonated aqueous solution and extracted with DCM (3 X). The combined organics were washed with ice-cold sodium bicarbonate aqueous solution (1 X) followed by brine (1 X), dned over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography

(EtOAc/hexanes, 35 mm from 0 to 100% and 10 min at 100%, 40 g ISCO silica gel column) to give 1.05 g of a racemic mxture of 2-(((lR,2R)-2- ailylcyciopentyl)suifonyl)pyrimidiiie and 2-(((lS,2S)-2- allylc clopentyl)sulfonyl)pyrimidine as a colorless oil. STEP 5: ( 1 R,2R)-2- ALLYLCYCLOPENT ANE- 1 -SULFONAMIDE AND (lS,2S)-2-ALLYLCYC E

racemte

To a stirred solution of a racemic mixture of 2-(((lR,2R)-2- allylcyclopeiiryl)sulfonyl)pyrimidine and 2-(((lS,2S)-2- allylcydopentyl)sulfonyl)pyrimidine (0.641 g, 2.54 mmol) in MeOH (15 mL) was added at rt potassium carbonate (1.053 g, 7.62 mmol) in one portion as a solid. The resulting mixture was stirred at rt for 75 min. The LC-MS indicated the complete consumption of the sm. Amidoperoxymonosulfuric acid (1.436 g, 12.70 mmol) was added at rt in one portion as a solid followed by water (1 8 mL). The resulting mixture was stirred at rt for 2 min and at 90 °C in a preheated oil bath for 5 min and at rt for 1 h 45 min. The mixture was poured into ice and 1 N sodium hydroxide aqueous solution and extracted with EtOAc (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give an impure mixture of the title compounds with the major contaminant being 2-methoxypyrimidine, directly taken onto the next step.

STEP 6: (S)-6 ^! -CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-4-((lS,2S)-2- SULF AMOYLC YCLOPENTYL)BUT-2-EN - 1 -YL)C YC LOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S,E)-l-HYDROXY-4-((lR,2R)-2-SULFAMOYLCYCLOPENTYL)BUT-2- EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

To a 25 mL single-necked round-bottomed flask were placed (S)~6 ^! - cWoro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en^^^

tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (0.085 g, 0.167 mmol, Intermediate AA12A) and the impure racemic 2- allylcyclopentane-l-sulfonaniide (0.095 g, 0.500 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (2.1 mL) was introduced via syringe under argon at rt. To this stirred solution was added via a syringe a solution of 2 ^na generation hoveyda-grubbs catalyst (10.44 mg, 0.017 mmol) in DCE (1.2 mL) at rt under argon. The resulting mixture was stirred at rt under argon for a period of 1 h 45 mm. The crude mixture was loaded onto a silica gel precoiurnn and subjected to combi-flash column chromatography ((10% MeOH/DCM with 0.3% AcQH)/DCM, 20 min from 50 to 100% and 20 mm at 100%, 24 g 1SCO silica gel column) to give a mixture of the title compounds (30 mg, 0.048 mmol, 28.6 % yield) as a gray film, taken onto the next step.

STEP 7: (lS,3 ^! R,6¾,7'S,8T,,l l¾J 5'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 18 Ή- SPIRO [N APHTH ALENE - 1 ,25'-

[23]OXA[16]TO A[l ,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ' ^{, 5} .0 ²² ' ²⁷ ]OCTAC OSA[8, 19,21 ,27]TETRAEN]-18'-QNE 16',16'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,i rS,15'S)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 18'H-SPIRO[N APHTH ALENE- 1 ,25'-

[23]OXA[ ;i6]THIA[ 1, 17]DIAZAPENTACYCLO[ 17,7.2,0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² - ²⁷ ]OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16',16'-DIOXlDE

To a stirred ice-cooled solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxy-4-((l S,2S)-2-sulfamoykyclope^^ 3 4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid and (S)-6 ^, -chloro-5-(((lR,2R)-2-((S,E)-l-hydroxy-4-((lR,2R)-2- sulfamoylcycIopentyl)but-2-en-l -y^

2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,l '-naphthalene]-7-carboxylic acid (30 mg, 0.048 mmol) and N,N-dimethylpyridin-4-amine (12.81 mg, 0.105 mmol) (14 mg actual) in DCM (25 mL) was added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (22.85 mg, 0.1 19 mmol) in two portions over a period of 5 rain. The resulting mixture was stirred in the ice bath for 40 min at ambient temperature for a period of 15 h. The LC-MS and HPLC spectra indicated an epimeric ratio of 3:2. The volatiles were removed. The residue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 55-95%

acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 4.0 mg of the title compound as the first eluting fraction as a white solid. ' ! ! NMR (500MHz, CDCb) δ 8.87 (br. s., IH), 7.69 (d, ./ K.3 Hz, IH), 7.21 - 7.12 (m, 2H), 7.10 (d, ,/ 2.2 Hz, i l l ). 6.95 (d, ./ N. I Hz, 2H), 6,06 - 5.93 (m, IH), 5.71 (dd, ,/ 7.0. 15.5 Hz, IH), 4,38 ( id. 5.5. 8.1 Hz, IH), 4, 18 (dd, J=3.8, 6.5 Hz, i l l ). 4.16 - 4.07 (m, 2H), 3,61 (t, .7=14.5 Hz, 2H), 3.43 - 3.18 (m, 2H), 2.86 - 2.71 (m, 2H), 2.58 - 2.39 (m, 4H), 2.38 - 2.14 (m, 3H), 2.04 - 1.64 (m, 12H), 1.56 - 1.44 (m, I H). m/z (ESI, +ve ion) 611.2 (M+H) ⁺ .

EXAMPLE 324. (1 S,3'R,6'R,7'S,8'E,1 rS,15'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, I 8'H-SPIRO[NAPHTHALENE-l,25'-

| 23 !ΟΧ Λ| Ι 6 | Η1 Λ| I J 7 | i)|,\/.\Pi-::\ ΓΛίΎΠ .ΟΙ i , 7.2 0 ^: ' ''.O ^{1 1} ^.ϋ" ' ^~ |OC l AC OSA[8,19,21,27]TETRAEN]-18'-O E 16',16'-DIQXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,i rR,15 ^, R)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 18'H-SPIROjNAPHTHALENE- 1 ,25'- pSlOXAtieiTHIAtl^TlDIAZAPE TACYCLOin-T^-O^^O ^{! !} -^-O^^OCTAC OS A| 8, 19,21,27]TETRAEN]-18'-ONE 16', 16'-DI OXIDE

The title compound (4.0 nig) was obtained as a white solid as the second eiuting isomer from preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 55-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 323. 'HNMR (400MHz, CDCb) δ 8.16 (br, s., ill).7.71 (d, ./ 8.6 Hz, ill).7,24 (d, J=7.8 Hz, 1H), 7.19 (dd, J=2,3, 8.4 Hz, IH), 7.09 (d, J=2.2 Hz, IH), 6.97 (d, ./ 8,2 Hz, IH), 6.75 (br. s., ill).6.09 - 5.94 (m, IH), 5.73 (dd, J=5.8, 15.4 Hz, IH), 4.33 - 4.19 ins. IH), 4.17 - 4.00 (m, 3H), 3.74 (d, ./ 14.5 Hz, IH), 3.65 (d, ./ 12.9 Hz, 111).3,35 (d, ./ 14.5 Hz, !!!).3.18 (dd, ,/ 8,7.14,6 Hz, IH), 2.87 -

2.71 (m, 2H), 2.68 - 2,49 (m, 2H), 2.46 - 2.14 (m, 5H), 2.05 - 1,63 (m, 12H), 1.46 (t, ./ 12.0 Hz, IH). m/z (ESI, +ve ion) 611.2 { \ i -If) .

EXAMPLE 325. (18,3'Κ,6'Κ,7'8,8Έ,1 l'S,15'R)-6~CHLORO-7 ^, -HYDROXY-3,4" DIHYDRO-2H, 18 Ή- SPI RO [ NAPHTHALENE- 1,25'-

[23]OXA[16]THIA[l 7]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ^ll - ^ls .0 ²² ' ²⁷ ]OCTAC

OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16', 16'-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8 ^, E,ll ^, R,15'S)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 18'H-S PIRO | N APHTH AL ENE- 1 ,25'- pSJOXAtieiTO At^niDIAZAPENTACYCLOtnj^-O^^O ^!! -^^^OCTAC OS A[8, 19,21 ,27]TETRAEN]- 18'-ONE 16', 16'-DIOXIDE

STEP 1 : (I S,2S)-2-ALLYLCYCLOPENTYL FORMATE AND (lR,2R)-2-

ALLYLCYCLOPENT E

racemate

To a stirred ice-cooled solution of a racemic mixture of (l R,2S)-2- allylcyclopentanol and (lS,2R)-2-allylcyclopentanol (3.5 g, 27.7 mmol) and triphenylphosphine (9.09 g, 34.7 mmol) in THF (100 mL) was added 98% formic acid (1.308 mL, 34.7 mmol) followed by slow addition of (E)-diisopropyl diazene-l ,2-dicarboxylate (6.87 mL, 34.7 mmol) through a syringe. The resulting mixture was stirred at 0 °C for 15 min and at ambient temperature for a period of 16 h. After the voiatiles were removed in vacuo, the residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 5 un at 0 % and 25 min from 0 to 5 %, 80 g ISCO silica gel column) to give a racemic mixture of (1S.2S)- 2-allylcyclopentyl formate and (lR,2R)-2-allylcyclopentyl formate (3.25 g, 21.08 mmol, 76 % yield) as a colorless oil, taken onto the next step.

STEP 2: (1S,2S)-2~ALLYLCYCL0PENTAN0L AND (! R,2R)-2- ALLYLCYCLQPENTAN

racemate

To a stirred solution of a racemic mixture of (l S,2S)-2-allylcyclopentyl formate and (lR,2R)-2-allylcyclopentyl formate (3.25 g, 21.08 mmol) in MeOH (40 mL) was added ammonia hydrate, 27% aqueous solution (4.0 mL, 21.08 mmol) via a syringe at rt. The resulting mixture was stirred at rt for a period of 4 h when TLC showed completion. Note that more commercial ammonium hydroxide (about 10 mL) was added over the course of the reaction. The mixture was poured into ice and saturated ammonium chloride aqueous solution and extracted with EbO (3 X). The combined organics were dried over anhydrous sodmm sulfate and concentrated in vacuo. The residue appeared rather wet and was subjected to comhi-flash column chromatography (EtOAc/Hexanes, 5 min at 0 % and 25 min from 0 to 30 %, 40 g ISCO silica gel column) to give a racemic mixture of (l S,2S)-2-allylcyclopentanol and (lR,2R)-2-allylcyclopentanol (2.30 g, 18.23 mmol, 86 % yield) as a colorless oil, taken onto the next step.

STEP 3: (1 S,2S)-2-ALLYLCYCLOPENTYL METHANESULFONATE AND (lR,2R)-2-ALLYLCYCL ONATE

race mate

To a stirred ice-cooled solution of a racemic mixture of (l S,2S)-2- allylcyclopentanol and (lR,2R)-2-allylcyclopentanol (2.3 g, 18.23 mmol) and triethylamine (5.58 mL, 40. 1 mmol) in DCM (60 mL) was slowly added methanesulfonyl chloride (2.160 mL, 27.3 mmol) through a syringe. The resulting mixture was stirred at 0 °C for a period of 1.5 h. The crude mixture was poured into ice and 1 N aqueous HCI solution and extracted with DCM (2 X). The combined organics were washed once again with 1 N aqueous HCI solution followed by brine (2 X) and dried over anhydrous sodium sulfate. Concentration in vacuo gave a racemic mixture of (l S,2S)-2-allylcyclopentyl methanesulfonate and (lR,2R)-2-allylcyclopentyl methanesulfonate (3.83 g, 18.75 mmol, 103 % yield) as a nearly colorless oil, taken onto the step.

STEP 4: 2-(((1R,2S)-2-ALLYLCYCL0PENTYL)THI())PYRI:MIDINE AND 2- ((( 1 S ,2R)-2~ ALL YLC YCLOPENTYL)TTOO)P YRJMIDINE

racemte

A mixture of 2-mercapto-pyrimidine (3.15 g, 28.1 mmol) and potassium carbonate anhydrous (4.4 g, 31.9 mmol) in DMF (40 mL) was stirred at rt for 10 rain before a solution of amixture racemic mixture of (1 S,2S)-2-aJiylcyclopentyi methanesulfonate and (lR,2R)-2-allylcyclopentyl methanesulfonate (3.83 g, 18.75 mmol) in THF (40.0 mL) was added at rt. The resulting mixture was stirred at rt for 10 min and at 70 °C for a period of 16 h. The crude mixture was poured into ice and saturated sodium carbonate aqueous solution and extracted with EtOAc (3 X). The combined organics were washed with saturated sodium carbonate aqueous solution (1 X) followed by water (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/¾exanes, 5 min at 0 % and 25 min from 0 to 30%, 80 g ISCO silica gel column) to give a racemic mixture of 2-(((l.R,2S)-2- lylcyclopentyl)tmo)pyrirnidine and 2-(((l S,2R)-2- ailylcyciopentyl)thio)pyrimidine (1.92 g, 8.71 mmol, 46.5 % yield) as a colorless oil, taken onto the next step.

STEP 5: 2-(((lR,2S)-2-ALLYLCYCLOPENTYL)SULFONYL)PYRIMIDINE

AND 2-(((lS,2R)-2-ALL YL)PYRlMIDINE

racemte

To a stirred ice-cooled solution of a racemic mixture of 2-(((lR,2S)-2- allylcyclopentyl)thio)pyrimidine and 2-(((l S,2R)-2- allylcyclopentyl)thio)pyrimidine (0.87 g, 3.95 mmol) in DCM (20 mL) and DMF (2.00 mL) was added 3-chlorobenzoperoxoic acid (1.858 g, 8.29 mmol) in 3 portions as a solid over 10 min. The resulting mixture was stirred at 0 °C for about 1 h 15 min. The ice bath was then removed and the mixture was stirred at rt for 2 h. The reaction was then poured into ice and saturated sodium carbonate aqueous solution and extracted with DCM (3 X). The combined organics were washed with ice-cold sodium carbonate aqueous solution (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-fiash column chromatography (EtOAc/Hexanes, 25 min from 0 to 100%, 24 g ISCO silica gel column) to give a racemic mixture of 2~(((lR,2S)-2~ allylcydopentyl)sulfonyl)pyrimidine and 2-(((lS,2R)-2- allylcyclopentyl)sulfonyl)pyrimidine (0.90 g, 3,57 mmol, 90 % yield) as a colorless oil, taken onto the next step. STEP 6: ( 1 R,2S )-2- ALLYLCYCLOPENTANE- 1 -SULFONAMIDE AND (IS, 2R)-2- ALL YLC Y CLOPENTANE- 1 - SULF ON AMIDE

racemte

The 1 ^st step: To a stirred solution of a racemic mixture of 2-(((l R,2S)-2- allylcyclopentyl)sulfonyl)pyrimidine and 2-(((l S,2R)-2- allylcyclopentyl)sulfonyl)pyrimidine (0.90 g, 3.57 mmol) in MeOH (35 mL) was added at rt sodium methoxide, 25 wt % solution in methanol (0.795 mL, 3.57 mmol) via a syringe. The resulting mixture was stirred at rt for 25 mm and on rotavap at 52 °C for 10 min to remove the volatiles. The residue was subjected to high vacuum.

The 2 ^nd step: To the above residue was added water (30 mL) followed by sodium acetate trihydrate (0.67 mL, 7.13 mmol) and amidoperoxymonosulfuric acid (0.81 g, 7.13 mmol) at rt. The resulting clear solution was stirred at 50 °C in a preheated oil bath for a period of 40 rain. The LC-MS showed this time that the desired product was the minor while still the intermediate sulfmate was the overwhelmingly major. The temperature was raised to 95 °C and the reaction mixture was sirred at this temperature for 1 0 min. The LC-MS showed this time that the desired product became the major with some of the intermediate sulfmate still remaining. The reaction was put back into the 95 °C oil bath and stirred for 10 min. The LC-MS showed the reaction stalled with some of the fulfmate still remaining. After briefly cooled, one equivalent each of sodium acetate and amidoperoxymonosulfuric acid was added. The mixture was stirred at 95 °C for 10 min and became cloudy upon cooling. It was basified using ice cold saturated sodium carbonate and extracted with 20% i-PrOH/DCM (5 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to combi-flash column chromatography

(EtOAc/Hexanes, 20 min from 0 to 70%, 24 g ISCO silica gel column) to give, as a colorless crystalline solid, 0.61 g of a mixture of the title compound and 2- methoxypyrimidine (the by-product) in a ratio of 3.5 to 1. This was triturated with EtOAc/hexanes to give a pure racemic mixture of (lR,2S)-2-allylcyclopentane-l - sulfonamide and (lS,2R)-2-allylcyclopentane-l-sulfonamide (0.4668 g, 2.69 mmol, 76 % yield) as a white solid.

STEP 7: (S)-6 ^, -CI-ILOR()-5-(((l R,2R)-2-((S,E)-l T-IYDROXY-4-((lS,2R)-2- SULFAM0YIX:YCL0PENTYL)BUT-2-EN-1 -YL CYCL0BU L)METHYL)- 3 4, ^5-TETRAHYDRO-2H,2Ή-SPIRO[BENZO[B] [ L4]OX EPINE-3,r~ NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2R)- 2-((S,E)~ 1 -HYDROXY-4-(( 1 R,2S)-2-SULF AMOYLC YCLOPENTYL)BUT-2- EN-l -YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ][ ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

To a 25 rnL single-necked round-bottomed flask were placed (S)-6'- chloro-5-((( lR,2R)-2-((S,E)-l -hydroxyhex-2-en- 1 -yl)cy dobutyl)meihy )-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (0.194 g, 0.380 mmoi, Intermediate AA12A), a racemic mixture (lR,2S)-2- a!ly Icy clopentane- 1 -sulfonamide and ( 1 S,2R)-2-aI3y Icy clopentane- 1 -sulfonamide (0.180 g, 0.951 mraol), and 2 ^nd generation hoveyda-grubbs catalyst (0.024 g, 0.038 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (5 mL) was introduced through a syringe under nitrogen. The resulting mixture was stirred under nitrogen at rt for a period of 4 h. The crude mixture was loaded onto a silica gel precolumn and subjected to combi- flash column chromatography ((10% MeOH/DCM with 0.3% AcOH)/DCM), 25 min from 0 to 100%, 24 g ISCO silica gel column) to give a mixture of the title compounds (0.19 g, 0.302 mmol, 79 % yield) as a gray solid, taken onto the next step.

STEP 8: (I S,3'R,6'R,7'S,8'EJ l 'S,15'R)-6-CHLORO-7'-HYDROXY-3,4~

DIHYDRO-2H, 1 8 Ή- SPIRO [NAPHTHALENE- 1 ,25'-

[23]OXA[ 16]TH1A[1,17]DIAZAPENTACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹⁵ .0 ²² - ²⁷ ]OCTAC OSA| 8,19,21,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR

(l S,3'R,6'R,7'S,8¾i rR, 15'S)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 18'H-SPIRO[N APHTHALENE- 1.25'-

| 23 i()XA| Ι ΓΠ I IA| I . i 71 Di ΛΖΛΡΙ ΐΝ ^" ΓΛ€ Y .0! i 7.7.2. ⁽ i ^; " o ^{1 !} \0 ^Λ " ^' |Ο(Ύ.\<· OSA[8, 19,21 ,27]TETRAEN]-18'-ONE 6',16'-DTOXTDE

To a stirred ice-cooled solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydrox\'-4-((lS,2R)-2-sulfamoylcyclopentyl)but-2-en-l-yl)cy' clobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxylic acid and (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l-h droxy-4-((lR,2S)-2- sulfamoy cyciopentyl)but-2-en-l-yi)cyxlobu^

2H,2'H-spiro| benzoj b] [ 1 ,4] oxazepine-3 J '-naphthalene] -7-carboxylic acid ( 190 mg, 0,302 mrnol) and N,N-dimethylpyridin-4-amine (8.1 mg, 0.664 mmol) in DCM (150 niL) was added l-(3-dimethylanTinopropyl)-3-ethylcarbodiimide hydrochloride (145 mg, 0.755 mmol) in one portion. The resulting mixture was stirred at 0 °C and gradually warmed up to ambient temperature overnight (12 h). The volatiles were removed in vacuo. A portion (1/3) of the crude residue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep 5 μπι column; Phenomenex, Torrance, CA; gradient elution of 55-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 10 mg of the title compound as the first eluting fraction as an off-white solid. Ή NMR (500MHz, CDCb) δ 8.33 (br. s., ill).7.70 (d, .7=8.6 Hz, IH), 7.18 (dd, J=2.2, 8.6 Hz, 1H), 7.09 (d, J=2,2 Hz, 1H), 7.01 - 6.89 (m, 3H), 5.82 - 5.73 (m, 1H), 5.72 - 5.62 (m, IH), 4.25 (td, J=6.4, 8.8 Hz, HI).4.18 (dd, ./ 5.!.7.1 Hz, IH), 4.14 - 4.03 (m, 2H), 3.81 (dd, ./ 2.2.15.2 Hz, IH), 3,72 (d, ,/ 14.4 Hz, ill).3.23 (d, 14.4 Hz, IH), 3.04 (dd, ,/ H 4.15,3 Hz, IH), 2,86 - 2.71 (m, 2H), 2.54 - 2.22 (m, 6H), 2.19 - 1.58 (m, 12H), 1.55 - 1.45 (m, IH), 1.42 (t, J=12.5 Hz, IH). m/z (ESI, +ve ion) 611.3 {M ID .

EXAMPLE 326. (1S,3'R,6 ^! R,7'S,8'E,1 l'S,15'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 18'H-SPIR()[NAPHTHALENE-1 ,25'-

[23]OXA[16]TO A[l,17]DIAZAPE TACYCLO[17.7.2.0 ³ ' ⁶ .0 ' ^,5 .0 ²² ' ²⁷ ]OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16', 16'-D10XIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'E,ll'R,15 ^! S)-6-CHLORO-7'-HYDROXY-3,4-DlHYDRO- 2H, 18H-SPIRO[N APHTH ALENE- 1,25'-

[23]OXA[16]THIA[1,.17]DIAZAPENTACYCLO[.17.7.2.0 ³ ' ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]OCTAC OSA[8, 19,21 ,27]TETRAEN]-18'-O E 16',16'-DIOXlDE

The title compound (15 mg) was obtained as an off-white solid as the second eluting isomer from preparative reverse-phase HPLC (Gemini ^rM Prep Cis 5 Ltm column; Phenomenex, Torrance, CA; gradient elution of 55-95%

acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 325. ^! H N.YiR (500MHz, CDCb) 6 8. 1 8 is. i l l ). 7.66 id. ./ 8. Hz, IH), 7,54 (br. s . 1H), 7.16 (dd, ,/ 2 2. 8.6 Hz, IH), 7.10 (d, J=2.4 Hz, IH), 6,98 - 6.84 (m, 2H), 5.72 (dd, J=5.1, 15.7 Hz, IH), 5.54 (br. s., IH), 4.29 - 4.16 (m, 2H), 4.11 - 3.94 (m, 2H), 3.69 (br. s., I H), 3.49 - 3.10 (m, 2H), 2.81 - 2.73 (m, 2H), 2,62 - 2.35 (ra, 4H), 2,27 (did. ,/ 6. ! . 8.8, 14.9 Hz, IH), 2.20 - 1 .63 (m, 1 ! ! }. 1.51 - 1 ,34 (m, 2H). m/z (ESI, +ve ion) 61 1.3 (M+H) ⁺ .

EXAMPLE 328, (I S,3'R,6'R,7'S,8'E, 1 l'S,I5'R)-6-CHLORO-7'-((l -METHYL- 1H- 1 ,2,4-TRIAZOL-3-YL)METOOXY)-3,4-DIHYDRO-2H, 18Ή- SP1RO [NAPHTHALENE- 1,25'-

|;23]OXA[ 16iTHIA[ l, 17jDIAZAPENTACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹ l0 ²² ' ² ']OCTAC OS A[8, 19,21 ,27]TETRAEN] - 18'-ONE 16\16'-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8^E,l l^R, 15 ^, S)-6-CHLORO-7'-((l-METHYL~lH-l,2,4- TRIAZOL-3-YL)METHOXY)-3,4-DIHYDRO-2H ₅ 18Ή- SPIRO [NAPHTHALENE- 1 ,25"-

E23]OXA[16]THIA[1,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ - ³⁵ .0 ²² ' ²⁷ ]OCTAC OS A[8, 19, -18'-ONE 16', 16'-DIOXIDE

To a stirred solution of ilS,3'R,6'R,7 ^f S,8'E,l l'S,15'R)-6-chloro-7'- hy droxy-3,4-dihy dro-2H, 18'H-spiro[naphthalene- 1 ,25'- j;23]oxa[16]thiaj;i,17]diazapentacyx

etraen]-18*-one 16',16'-dioxide and (lS,3'R,6'R,7 ^f S,8'E,l 1¾,15Έ)~6~Α1ΟΓΟ~7'~ hydroxy -3,4-dihydro-2H, 18'H-spiro[naphthalene-l,25'-

[23]oxa[16]thia[l,17]diazapentacyelo[17.7.2.0^

etraen]-18'-one I6',16'-di oxide (14 mg, 0.023 mmol, Examples 326) in DMF (2 mL) was added sodium hydride, 60 % dispersion in mineral oil (9.16 mg, 0.229 mmol) (20 mg actually) at rt. The resulting mixture was stirred at rt for 30 min before 3-chloromethyl-l-methyl-lh-[ l,2,4]triazole, hydrochloride (0.014 mL,

0.115 mmol) was added as a solid at rt. The resulting mixture was stirred at rt for a period of 3 days. Note that more NaH (not weighed) was added after 6 h. The reaction was quenched with methanol and the resulting mixture was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetomtrile in water, where both solvents contained 0.1% TEA, 30 min method) to give, after lyophilization, 2.0 mg of the title compound as the first eluting fraction as a white solid. Ή NMR (400MHz, CDCb) δ 8,33 (s, ill).8,20 (s, IH), 7,70 (d, «/=8.6 Hz, IH), 7.18 (dd, J=2.3, 8.4 Hz, IH), 7.09 (d, J=2.2 Hz, IH), 6.93 - 6.81 (m, 2H), 6.77 (s, IH), 5.92 - 5.75 (m, IH), 5.59 (dd, ./ 9.0.15.3 Hz, IH), 4.67 - 4.55 (m, IH), 4.50 - 4.38 (m, 2H), 4,13 - 4.01 (m, 2H), 3.99 (s, 3H), 3.86 (dd,J=3.8, 8.7 Hz, IH), 3.81 - 3.68 (m, 2H), 3,17 (d, J=14.3 Hz, IH), 2,96 (dd, J=9.6, 15.3 Hz, IH), 2.84 - 2.69 (m, 2H), 2.60 - 2.20 (m, 6H), 2.08 - 1.72 (m, 9H), 1.68 - 1.49 (m. Ml).1,38 (t, ./ 12.6 Hz, IH), m/z (EST, +ve ion) 706,3 ! M il)

EXAMPLE 329. (1 S,3 ^! R,6'R,7'S,8'E,1 rR,15'S)-6-CHLORO-7'-((l-METHYL- lH-l,2,4-TRJAZOL-3-YL)METOOXY)-3,4-DIHYDRO-2H,18'H- SPIRO[N APHTHALENE- 1 ,25'~

[23iOXA|;i6]THLA|;i,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ^!! - ⁱ l0 ² - ⁷ jOCTAC OSA[8,19,21 ,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR (IS^l^e'RJ^^'EjrS/lS'R e-CHLORO-T'-iCl-METHYL-lH-l^^- TRIAZOL-3-YL)METHOXY)-3,4-DIHYDRO-2H, 18Ή- SPTRO[NAPHTH ALENE- 1 ,25'-

[23]OXA[16]THIA[l,17]DIAZAPENTACYCLO[17.7.2,0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² - ²⁷ ]OCT, OSAjH.19, -18'-O E 16',16'-DIQXIDE

The title compound (2.0 mg) was obtained as a white solid as the second eluting isomer from preparative reverse-phase HPLC (Gemini™ Prep CJS 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 328. ^! il NMR (5()()MHz, CDCh) δ 8.27 (br. s., 2H), 7.68 (d, ./ 8.6 Hz, IH), 7.21 - 7,16 (m, 2.3.8.4 Hz, IH), 7.09 (d, ,/ 2.0 Hz, IH), 6.98 (d, ,/ H Hz, IH), 6.90 id..7=8.1 Hz, IH), 6.84 (br. s., IH), 6.00 - 5,82 (m, IH), 5.54 (dd, .7=7.9, 15,3 Hz, IH), 4.66 - 4.56 (m, IH), 4.50 (d, J=12.5 Hz, IH), 4.13 - 4.02 (m, 2H), 3.98 (s, 3H), 3.88 (br. s., IH), 3.77 - 3.54 (m, 3H), 3.31 (d, ./ 14.4 Hz, IH), 3.16 (br. s., IH), 2.86 - 2.69 (m. l).2.51 - 1.55 (m, 16H), 1.49 - 1.34 ins.2H). m/z (EST, +ve ion) 706.3 (M+H) ⁺ . EXAMPLE 330, (1 S,3'R,6'R,7'S, 11 'R, 15'R)-6-CHLORO-7*-HYDROXY-3 ₅ 4- DIHYDRO-2H, 18 Ή- SPIRO [NAPHTHALENE- 1 ,25'-

[23]OXA[16]TH1A[1,17]DIAZAPENIACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹ 0 ²² ' ²⁷ ]OCTAC OSA|;i9,21 ₅ 27]TRIEN]-18'-ONE 16',16'-DIOXIDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S,irS,15 ^, S)-6-CHLORO-7 ^, -HYDROXY-3,4-DIHYDRO-2H ₅ 18 ^, H- SPIRQpM APHTHALENE- 1 ,25'-

[23iOXA|;i6]THIA|;i,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ^!! - ⁱ l0 - ⁷ jOCTAC OSA[19,21,27]TRIEN]-l 8'-ONE 16',16'-DIOXIDE

A mixture of (1 S,3 ^! R,6'R,7'S,8'E,1 l'S,l 5'R)-6-chIoo-7 ^! -hydroxy-3,4- dih do-2H,18Ή-8piro[ aphtha]ene-l,25 ⁱ - [23]oxa[16]thia[l,17]diazapenta^

etraen]-18'-one 16',16'-dioxide or (1S,3'R,6'R,7'S,8'E,1 l'R,15'S 6-chloro-7 ^! - hydroxy' -3,4-dihydro-2H, 18'H-spiro[ naphthalene- 1,25'- [23]oxa[16]thia[l,17]diazapenta^

etraen]-18'~one 16',16'-dioxide (12 nig, 0.020 mmol, Example 326) and platinum (iv) oxide (0.892 mg, 3.93 μηιοΐ) (in excess) in EtOAc (8 mL) was degassed and purged with hydrogen for multiple times and baioon hydrogenated for a period of 3.5 h. The reaction was quenched with DCM. The solid was filtered off and the residue after concentration in vacuo was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cie 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 55-95% acetonitriie in water, where both solvents contained 0.1% TFA, 30 mm method) to give, after iyophilization, 3.5 mg of the title compound as a white solid, 'HNMR (400MHz, CDCh) δ 9.27 (br. s., IH), 7.68 (d, .7=8.6 Hz, IH), 7.41 (d, ,7=1.6 Hz, 1H), 7.22 (d, J=7.8 Hz, ill). 7.17 (dd, ./ 2.3.8.4 Hz, ill).7.09 (d, ./ 2.2 Hz, 1H), 6.95 (d, J=8.2 Hz, IH), 4.19 - 4.03 (m, 2H), 3.86 (td, J=6.6, 9.5 Hz, IH), 3.78 - 3.58 (m, 3H), 3.39 - 3.11 (m, 2H), 2,85 - 2.71 (m, 2H), 2.55 - 1.18 (m, 24!!). m/z (EST, +ve ion) 706.3 {M H)

EXAMPLE 331. (1 S,3 ^! R,6 ^* R,7'S,8'E,1 rS,16'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H,19Ή-SPIRO| APHTHALENE-l,26 ^, -

|24i()XA| Γ7Ι Η1Λ| 1..Ι8|ί)!Λ/.\Ρ1·::\ ΓΛίΎΠ.ΟΙ 18.7.2 (r-.O ¹¹ "\0 ^,5 -' ^K |\ONAC OSA[8,20,22,28]TETRAEN]-19'-ONE 17',17'-DI0X1DE

STEP 1 : ( 1 R,2S)-2~ALLYLC YCLOHEXANOL AND (lS,2R)-2-

ALLYLCY CLOHEXANO

racernaie

To a stirred ice-cooled allylmagnesmm bromide, 1.0 M solution in diethyl ether (44.9 mL, 44.9 mmol) was slowly added a solution of cyclohexene oxide (2, 165 mL, 21.40 mmol) in diethyl ether (45 mL) via a syringe over a period of 10 min. The resulting mixture was stirred at 0 °C for a period of 0.5 h. The reaction mixture was carefully quenched and further diluted with ice cold saturated ammonium chloride aqueous solution and extracted with E†.20 (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give a racemic mixture of (lR,2S)-2-allylcyclohexanol and (lS,2R)-2- ailylcyciohexanol (3.1 g, 22.1 1 mmol, 103 % yield) as a colorless oil, taken directly onto the next step.

STEP 2: (lS,2S)-2-ALLYLCYCLOHEXYL FORMATE AND (lR,2R)-2

ALLYLCYCLOHEXY

racemate

To a stirred ice-cooled solution of a racemic mixture of (lR,2S)-2- ailylcyciohexanoi and (lS,2R)-2-ailylcyclohexanol (3.100 g, 22.11 mmol) and triphenylphosphine (7.25 g, 27.6 mmol) in THF (100 mL) was added 98% formic acid (1.043 mL, 27,6 mmol) followed by slow addition of (E)-d sopropyi diazene-l,2-dicarboxylate (5.48 mL, 27.6 mmol) through a syringe over a period of 15 mm. Note that the mixture turned cloudy toward the end of the addition. The ice bath was removed upon the completion of addition. The resulting mixture was stirred at ambient temperature for a period of 20 h. Note that the cloudy mixture gradually became clear within the first hour or so and the reaction did not go to completion by the time of workup. After the volatiles were removed in vacuo, the residue was subjected to combi-flash column chromatography

(EtOAc/Hexanes, 5 mm at 0 % and 30 min from 0 to 30 %, 80 g ISCO silica gel column) to give a racemic mixture of (1 S,2S)-2-allylcyclohexyl formate and

(l R,2R)-2-allylcyclohexyl formate (2.0 g, 11 .89 mmol, 53.8 % yield) as a nearly colorless oil, taken onto the next step.

STEP 3: (l S,2S)-2-ALLYLCYCLOHEXANOL AND (l R,2R)-2- ALLYLCYCLOHEXANO

racemaie

To a stirred solution of a racemic mixture of (lS,2S)~2~aliy cyclohexyl formate and (lR,2R)-2-allylcyclohexyl formate (2.0 g, 11.89 mmol) in MeOH (70 mL) was added ammonia hydrate, 27% aqueous solution (10 mL, 1 1.89 mmol) via a syringe at rt. The resulting mixture was stirred at rt for a period of 18 h when TLC showed completion. The volatiles were removed and the residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 4 min at 0 % and 25 min from 0 to 30 %, 40 g ISCO silica gel column) to give a racemic mixture (l S,2S)-2-allylcyclohexanol and (lR,2R)-2-allylcyclohexanol (1.13 g, 8.06 mmol, 67.8 % yield) as a colorless oil, taken onto the next step.

STEP 4: (l S,2S)-2-ALLYLCYCLOHEXYL METHANESULFONATE AND (lR,2R)-2-ALLYLCYCLOHEXYL METHANESULFONATE

racemate

To a stirred ice-cooled solution of a racemic mixture of (l S,2S)-2- ailylcyciohexanol and (lR,2R)-2-allylcyclohexanol (1.13 g, 8.06 mmol) and triethylamine (2.47 mL, 17.73 mmol) in DCM (40 mL) was slowly added methanesulfonyl chloride (0.955 mL, 12.09 mmol) through a syringe. The resulting mixture was stirred at 0 °C for a period of 1.5 h. The crude mixture was poured into ice and 1 N aqueous HCl solution and extracted with DCM (2 X). The combined organics were once again washed with 1 N aqueous HCl solution followed by brine (2 X) and dried over anhydrous sodium sulfate. Concentration in vacuo gave a racemic mixture of (lS,2S)-2-ailylcyciohexyi methanesulfonate and (l R,2R)-2-aliylcyclohexyf methanesulfonate (1.83 g, 8.38 mmol, 104 % yield) as a colorless oil, directly taken onto the step.

STEP 5: 2-(((lR,2S)-2-ALLYLCYCLOHEXYL)THIO)PYRlMlDINE AND 2- (((1 S,2R)-2-ALLYLCYCL INE

racemaie

A mixture of 2-mercapto-pyrimidine (1.598 g, 14.25 mmol) and potassium carbonate anhydrous (1.265 mL, 20.96 mmol) in DMF (30 mL) was stirred at rt for 15 mm before a solution of a racemic mixture of (l S,2S)-2-allylcyc3ohexyi methanesulfonate and (l ,2R)-2-aliylcyclohexyl methanesulfonate (1.830 g, 8.38 mmol) THF (30 mL) was added at rt. The resulting mixture was stirred at rt for 30 min and at 75 °C for a period of 5 h. The crude mixture was poured into ice and saturated sodium carbonate aqueous solution and extracted with EtOAc (2 X). The combined organics were washed with saturated sodium carbonate aqueous solution (1 X) followed by water ( 1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/hexanes, 5 min at 0 % and 25 mm from 0 to 30%, 40 g silica gel, 18 mm tubes) to give a racemic mixture of 2-(((l ,2S)~2- allylcyclohexyl)thio)pyrimidine and 2-(((lS,2R)-2- allylcyclohexyl)thio)pyrimidine (not weighed) as a colorless oil, directly taken onto the next step.

STEP 6: 2-(((lR,2S)-2-ALLYLCYCLOHEXYL)SULFONYL)PYRIMIDINE AND 2-(((lS,2R)-2-ALL YL)PYRIMIDINE

raoerrsate

To a stirred ice-cooled solution of a racemic mixture of 2-(((lR,2S)-2- allylcyciohexyi)thio)pyrimidine and 2-(((l S,2R)-2~

ailylcyciohexyi)thio)pynmidine (0.27 g, 1.152 mmol) in DCM (6 mL) and DMF (0.2 mL) was added 3-chlorobenzoperoxoic acid (0.542 g, 2.419 mmol) in one portion as a solid. The resulting mixture was stirred at 0 °C for 5 min and at rt for a period of 3 h 40 min. The mixture was directly loaded onto silica gel precolumn and was subjected to combi-flash column chromatography (EtOAc Hexanes, 25 min from 0 to 100%, 24 g ISCO silica gel column) to give a racemic mixture of 2- (((lR,2S)-2-allylcyclohexyl)sdfonyl)pyrimidine and 2-((( TS,2R)-2- allylcyclohexyl)sulfonyl)pynniidine (0.224 g, 0.841 mmol, 73.0 % yield) as a colorless oil, taken onto the next step.

STEP 7: (lR,2S)-2-ALLYLCYCLOHEXANE-l -SULFONAMIDE AND

(lS,2R)-2-ALLYLCYCLOHEXANE-l-SULFONAMlDE

The 1 ^st step: To a stirred solution of a racemic mixture of 2-(((lR,2S)-2- allylcy clohexyl)sulfony])pyrimidine and 2-(((I S,2R)-2- allylcyclohexyl)sulfonyl)pyrimidine (0.224 g, 0.841 mmol) in MeOH (9 mL) was added at rt sodium methoxide, 25 wt % solution in methanol (0.187 mL, 0.841 mmol) via a syringe. The resulting mixture was stirred at rt for 30 min when LC- MS showed completion. The volatiles were removed in vacuo and the residue was subjected to high vacuum.

The 2 ^nd step: To the above residue was added water (9 mL) followed by sodium acetate trihydrate (0. 158 mL, 1.682 mmol) and amidoperoxymonosulfuric acid (0. 190 g, 1.682 mmol) at rt. The resulting clear solution was stirred at 75 °C in a preheated oil bath for a period of 40 min. The mixture became cloudy upon cooling. It was basified using ice cold saturated sodium carbonate and extracted with 20% i-PrOH/DCM (5 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.27 g of the crude product. This was subjected to combi-flash column chromatography (EtOAc/Hexanes, 3 min at 0 and 27 min from 0 to 60%, 24 g silica gel column, 13 mm tubes) to give a racemic mixture of (lR,2S)-2-allylcyclohexane-l-sulfonamide and (lS,2R)-2- allylcyclohexane-1 -sulfonamide as a colorless solid, taken onto the next step.

STEP 8: (S)-6'-CHLORO-5-(((IR,2R)-2-((S,E)-l -HYDROXY-4-((l S,2R)-2- SULFAMOYLCYCLOHEXYL)BUT-2-EN-l-YL)CYCLOBUTYL)METHYL)- 3^4,4^5-TETRAH:YDRO-2H,2TLSPIRO[BENZO[B]|;i ,4jOXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S,E)-l-HYDROXY-4-((lR,2S)-2-SULFAMOYLCYCLOHEXYL)BUT-2- EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2H- SPIRO [BENZO [B][ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE j -7-C ARBOXYLI C ACID

To a 25 mL single-necked round-bottomed flask were placed (S)-6'- cWoro-S-CCCl R^Ri^-CCS^-l -hydroxyhex^-en-l-ylJcj'clobut methyl)^'^^'^- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyli c acid (0.20 g, 0.392 mmol. Intermediate AA12A), racemic (l R,2S)-2~

ailylcyciohexane-1 -sulfonamide (0.128 g, 0.627 mmol), and 2 ^nd generation hoveyda-grubbs catalyst (0.025 g, 0.039 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (5 mL) was introduced through a syringe under nitrogen. The resulting mixture was stirred under nitrogen at rt for a period of 3 h. The crude mixture was loaded onto a silica gel precolumn and subjected to combi -flash column chromatography ((10% MeOH/DCM with 0.3% AcOH)/DCM), 25 mm from 0 to 60%, 24 g ISCO silica gel column) to give a mixture of the title compounds (0.15 g, 0.233 mmol, 59.5 % yield) as an off-white solid, taken onto the next step.

STEP 9: (1 S,3'R,6'R,7'S,8Ti 1 V S, 16 ^* R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 19'H-SPIRO [NAPHTHALENE- 1 ,26'-

[24]OXA[ 17;|^ΉIA[ l 8]DIAZAPE^ΓΓACYCLO|;l 8.7.2.0 ^3■ ^0 ^{l l} · ¹ 0 ^23■28 ]NONAC OSA[8,20,22,28]TETRAE ]-19'-ONE 17',17'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,l l ^, R,16 ^, S)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 19'H-S PIRO | N APHTHAE ENE- 1.26'-

[24]OXA[17]TO A[l ,18]DIAZAPE TACYCLO[18.7.2.0 ³ ' ⁶ .0 ' ^, .0 ²³ ' ²⁸ ]NONAC

OSA[8,20,22,28]TETRAEN]-19'-ONE 17',17'-DIOXIDE To a stirred ice-cooled solution of (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l- hydroxy-4-(( ^' lS,2R)-2-sulfanioylcyclohexyl)but-2-en-l -yl)cyclobutyl)methyl)- 3',4,4',5-tetr ally dro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene | -7- carboxylic acid and (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l-h droxy-4-((lR,2S)-2- sulfamoylcyclohexy^but^-en-l -y^cyclobuty methy^-S'^^'jS-tetrahydro- 2H,2'H-spiro| benzoj b] [ 1 ,4] oxazepine-3 J '-naphthalene] -7-carboxylic acid ( 150 mg, 0,233 mrnol) and N,N-dimethylpyridin-4-amine (62.7 mg, 0.513 mrnol) in DCM (120 niL) was added l -(3-dimethylanTinopropyl)-3-ethylcarbodiimide hydrochloride (1 12 mg, 0.583 mmol) in one portion. The resulting mixture was stirred at 0 °C and gradually warmed up to ambient temperature overnight (16 h). The volatiles were removed in vacuo. The crude residue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, C A; gradient elution of 55-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after Ivophilization, 20 mg of the title compound as the first eluting fraction as an off- white solid. Ί I NMR (500MHz, CDCb) δ 8.16 (s, I I I ). 7.70 (d, ,/ 8.6 Hz, i l l ). 7.19 (dd, J=2,2, 8.6 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.93 (s, 2H), 6.78 (s, 1H), 5.94 - 5.82 (m, M l ). 5.67 (dd, J=8.2, 15.0 Hz, 1H), 4.24 (dd, J=3.8, 8.2 Hz, 1H), 4.15 - 4.00 (m, 3H), 3.79 (d, ,/ 1 5.2 Hz, 1H), 3.71 (d, ./ 14.2 Hz, 1H), 3.20 (d, ,/ 1 4 2 Hz, 1 H), 3.00 (dd, ,/ 9.8. 15.4 Hz, 1H), 2, 85 - 2.71 (m, 2H), 2.49 - 2.23 (m, 5H), 2.13 - 1.58 (m, 13H), 1.51 - 1.29 (m, 4H). m/z (ESI, +ve ion) 625.2 ( M R )

EXAMPLE 332. (1 S,3'R,6¾,7'S,8 ^! E, 1 rR, 16'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 19'H-SPIRO[ APHTHALENE-l ,26 ^! -

[24 iOXA| r7]THIA|;i , 18]DIAZAPENTACYCLO[ 18.7.2.0 ³ ' ⁶ .0 ^{! !} - ⁱ ^0 ²³ - ²⁸ jNONAC OSA[8,20,22,28]TETRAEN]- 19'-ONE 17', 17'-DIOXIDE

The title compound (30 mg) was obtained as an off-white solid as the second eluting isomer from preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA: gradient elution of 55-95%

acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 331. ¾ NMR (500MHz, CDCh) δ 8.25 (br. s., 1H), 7.66 (d, J=8.6 Hz, IH), 7.17 (dd, J=2.2, 8.6 Hz, 1H), 7.10 (d, ./ 2.2 Hz, 1H), 7,02 id, ./ 7.1 Hz, 1H), 6.93 (d, ,7=8,1 Hz, IH), 5.94 - 5.41 (m, 2H), 4.29 - 3.88 (m, 4H), 3.73 - 3,21 (m, 3H), 2.76 (br. s., 2H), 2.66 - 1.31 (m, 23H). m/z (ESI, +ve ion) 625.2 (M+H) ¹ . EXAMPLE 333, ilS,3'R,6'R,7'S,l l'S,16'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 19'H-SPIRO [NAPHTHALENE- 1 ,26'-

[24]OXA[17]TH1A[1,18]DIAZAPENIACYCLO[18.7.2.0 ³ -^0 ¹¹ - ¹ ^0 ²³ - ²⁸ ]NONAC OSA[2(),22,28jTRIEN]-19'-QNE I7 ^* ,17'-DiGXIDE OR

(lS,3'R,6 ^! R,7'S,ll¾,16'S)-6-CHI RO-7 ^, -HYDROXY-3,4-DIHYDRO-2H,19 ^! H- SPIRO [NAPHTHALENE- 1,26'-

[24iOXA|r7]THIA|;i,18]DIAZAPENTACYCLO[18.7.2.0 ³ ' ⁶ .0 ^!! - ⁱ ^0 ²³ - ²⁸ jNONAC OSA[20,22,28]TRIEN]-19 ^f -ONE 17', 17'-DIOXIDE

A mixture of (1 S,3'R,6'R,7 ^! S,8'E, H'S,i 6'R)-6-chloro-7'-hy droxy-3,4- dihy dro-2H, 19'H-spiro[naphthal ene- 1 ,26'-

[24]oxa[17]thia[i,18]diazapeniacyclo[ 18,7.2.0 ³ - ⁶ ,0 ^liJ6 .0 ²³ - ^2S ]nonacosa[8,20,22,28 tetraen]-19'-one 17*,17'-dioxide and (ΙΒ^Ι^,ό^^ ,ΒΈ,ΙΙ'ί ,Ιό ί-ό-ΰΙιΙθΓθ^'- hydroxy-3,4-dihydiO-2H,19'H-spiro[naphtha3ene-l,26'-

|24i<¾x;il i?|ihia| I. i 8|di;!/apc!ii;!C> clo| 18.72.0 ^; ".(! ^{;! !} " 0 ^{>; iK} |iK>nac s;!l 8.20.22.28 tetraen]-19'-one 17',17'~dioxide (8.0 mg, 0,013 mmol, Examples 331) and platinum (iv) oxide (0.581 mg, 2.56 μηιοΐ) (in excess) in EtOAc (8 mL) was degassed and purged with hydrogen for multiple times and baloon hvdrogenated for a period of 2 h. The reaction was quenched with DCM. The solid was filtered off and the residue after concentration in vacuo was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cie 5 lira column; Phenomenex, Torrance, CA; gradient elution of 55-95% acetomtrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 1.5 mg of the title compound as the first eluting fraction as a white solid. ¾NMR (400MHz, CDCb) 69.59 {or. s., 111).7.69 (d, J=8.4 Hz, III).7.31 (d,■/ 7.8 Hz, III).7.22 - 7.14 (m, 2H), 7.09 (d, ./ 2.2 Hz, lH), 6.96 (d, ,/ 8.2 Hz, 1H), 4,21 - 3.99 (m, 2H), 3.79 - 3.46 (m, 4H), 3,40 - 3.09 (m, 2H), 2.86 - 2.72 (m, 2H), 2,61 - 2.37 (m, 2H), 2.36 - 2.15 (m, 211).2.13 - 0.97 (m, 20H). m/z (ESI, +ve ion) 627.3 (M+H) ⁺ .

EXAMPLE 334. (1 S,3'R,6 ^! R,7'S,1 rR,16'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 19'H-SPIRO[N APHTHALENE-1 ,26'-

[24iOXA|r7]THIA|;i,18]DIAZAPENTACYCLO[18.7.2.0 ³ ' ⁶ .0 ^!! - ⁱ ^0 ²³ - ²⁸ jNONAC OSA[20,22,28]TRIE ]-19'-ONE 17*,17'-DIOXIDE OR

ί 1 S..TR.6 ^' K.7 ^' S. ! ! ^' S.16'R)-6~( j II O ( ⁾ -7'-i IYDROXY-3.4-DH IV DRO-211.1 'Π I-

SP1RO [NAPHTHALENE- 1,26'- |;24]()XA[17|THIA[l,18jDIAZAPENTACYCLO[18.7.2.0 ³ -^0 ^ll - ¹ ^0 ²³ ' ^2S ]NONAC OSA[20,22,28]TRrEN]-19'-ONE 17'. i 7'-Ι)!ί)ΧΗ)Ι· ^'

The title compound (3.5 mg) was obtained as a white solid as the second elutmg isomer from preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 55-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 333, l N V!R (400MHz, CDCb) δ 10.52 (br, 8., I H ). 7.70 (d, ./ 8.6 Hz, i l l ). 7,59 - 7.50 (m, IH), 7.25 (br. s., IH), 7.17 (dd, J=2.3, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.98 (d, ,/ 8.4 Hz, IH), 4.19 - 3.98 (m, 2H), 3.87 - 3.69 (m, 2H), 3.62 - 3.45 (m, 2H), 3, 14 (d, ./ ! 4. i Hz, 2H), 2.85 - 2.71 (m, 2H), 2.55 (d, J= \ 1.9 Hz, IH), 2. 1 - 0.88 (m, 25H), m/z (ESI, +ve ion) 627,3 i V! H )

EXAMPLE 335. (l S,3'R,6¾,7'S,8 ,irR, 13'R, 15'R)-6-CHLORO-7',13'- DiHYDROXY-3,4 IHYDRO-2H,18H-SPIRO[NAPHTHALENE-l,25'- | 2 jOXA| 1 ΙΊ I Ι1Λ| I . i 7 |Π!Λ/ΛΡ! ^: ΝΤΛ(ΎΟ.ί)Ι i 7.7.2.ϋ ^; ·".0' ^{1 !} \0 ^Λ " ^' |Ο(Ύ.\<· OSA[8, 19,21 ,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR

(1 S,3'R,6'R,7 ^! S,8'E, 1 1 'S, 13'S, 15 ^! S)-6-CHLORO-7', 1 S'-DIHYD OXY-S^- D1HYDRO-2H, 18'H-SPIRO [NAPHTHALENE- 1 ,25 '-

|;23]OXA[ 16iTHIA[ l, 17jDIAZAPENTACYCLO[17.7.2.0 ³ -^0 ¹¹ - ¹ l0 ²² ' ² ']OCTAC OS A[8, 1 - 18'~ONE 16', 6'~DIOXTDE

STEP 1 : TERT-BUTYL(CYCLOPENT-3-EN-l -YLOXY)DIMETHYLSILANE

To a stirred ice-cooled solution of 3-cyclopentene-l-ol (3.60 mL, 42.8 mmol) in DCM (80 mL) was added imidazole, 99+%, cr 'stalline (6.70 g, 98 mmol) followed by slow addition of teri-butyldimethylsilyl chloride, 1.0 M solution in dichloromethane (47.1 mL, 47.1 mmol) via a syringe. The resulting mixture was stirred at 0 °C for 0.5 h and at ambient temperature overnight (16 h). The reaction was poured into ice water and extracted with DCM (3 X). The combined organics were washed with brine (1 X), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes, 5 min at 0 % and 30 min from 0 to 10 %, 80 g ISCO silica gel column) to give tert-butyl(cyclopent-3-en-l -yloxy)dimethylsilane in nearly quantitative yield as a colorless liquid, taken directly onto the next step.

STEP 2: ((lR,3S,5S)-6-OXABICYCLO[3.1.0]HEXAN-3-YLOXY)(TERT- BUTYL)DIMETHYLSILANE and ((1R,3R,5S)~6~

OXABICYCLO[3.1.0]HEXAN-3-YLOXY)(TERT- BUTYL)DIMETHYLSILANE

To a stirred ice-cooled solution of tert-butyl(cyclopent-3-en-l- yloxy)dimethylsilane (8.49 g, 42.8 mmol) in DCM (150 mL) was added 3- chlorobenzoperoxoic acid (11.99 g, 53.5 mmol) in 3 portions as a solid over 10 min. The resulting mixture was stirred at 0 °C and allowed to warm up to rt gradually overnight (18 h). It appeared to be a milky white suspension. DMF (3 mL) was added resulting in a clear solution. The mixture was stirred at rt for an additional 5 h and then poured into ice and 10 % NaHSCte aqueous solution and extracted with DCM (2 X). The combined organics were washed sequentially with 10 % NaHSCte aqueous solution (1 X), saturated sodium bicarbonate aqueous solution (2 X), water (I X) and brine (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo to give 9.15 g of a crude product mixture of two stereoisomers. This was subjected to combi -flash column chromatography

(EtOAc/Hexanes, 25 min from 0 to 20 %, 80 g ISCO silica gel column) to give, as the first peak out, pure ((l R,3S,5S)-6-oxabicyclo| .1.0]hexan-3-yloxy)(tert- butyl)dimethylsilane (1 .78 g, 8.30 mmol, 19.40 % yield) as a colorless liquid, which solidified upon standing at rt, and, as the second peak out, ((lR,3R,5S)-6- oxabicyclo[3.1.0]hexan-3-yloxy)(tert-bui ⁷ I)dimethylsilane (5.28 g, 24.63 mmol, 57.5 % yield) as a colorless liquid contaminated with the first peak in a ratio of 12; 1 . The stereochemistr ' was assigned according to the reference of Bull. Chem. Soc, Jpn, 1990, 63, 1402-1408, (ref : Bull. Chem, Soc. Jpn, 1990, 63, 1402-1408; J. Med. Chem. 2008, 51, 5176-5197) STEP 3: (lR,2R,4R)-2-ALLYL-4-((TERT-

BUTYLDIMETHYLSILYL)OXY)CYCLOPENTANOL AND (lS,2S,4S)-2- ALLYL-4-((TCRT- OPENTANOL

racemate

To a stirred ice-cooled allylmagnesium bromide, 1.0 M solution in diethyl ether (51.7 mL, 51 .7 rnmol) was slowly added a solution of ((lR,3R,5S)-6- oxabicyclo[3.1.0]hexan-3-yloxy)(tert-butyl)dimethylsilane (5.28 g, 24.63 rnmol) in THF (70 mL) via a cannula over a period of 20 min. The resulting mixture was stirred at 0 °C for a period of 0.5 h. The reaction mixture was carefully quenched and further diluted with ice cold saturated ammonium chloride aqueous solution and extracted with Et ₂ 0 (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give a racemic mixture of

(1 R ₅ 2R,4R)-2-a]lyl-4-((tert-butyldimethylsily])oxy)cyclope ntanol and (1 S,2S,4S)~ 2-allyl-4-((tert-butyldimethylsilyl)oxy)cyclopentanol (6.39 g, 24.92 rnmol, 101 % yield) as a colorless oil, taken directly onto the next step.

STEP 4: (l S,2R,4R)-2-ALLYL-4-((TERT-

BUTYLDIMETHYLSILYL)OXY)CYCLOPENTYL FORMATE AND

( 1 R,2 S,4S)-2-ALL YL-4-((TERT-

BUTYLDIMETH E

racemate

To a stirred ice-cooled solution of a racemic mixture of (l R,2R,4R)-2- allyl~4-((tert-butyldimeihylsilyi)oxy)cyclopentanol and (l S,2S,4S)~2~allyS-4-((tert~ butyldiniethylsilyl)oxy)cyclopentanol (6.39 g, 24.92 rnmol) and triphenylphosphine (8.17 g, 31.1 rnmol) in THF (100 ml.) was added 98% formic acid (1.175 mL, 31.1 rnmol) followed by slow addition of (E)-diisopropyl diazene-l ,2-dicarboxylate (6.17 mL, 31.1 rnmol) through a syringe over a period of 15 min. The resulting mixture was stirred at 0 °C for 30 min and at ambient temperature for a period of 10 h. After the volatiles were removed in vacuo, the residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 5 min at 0 % and 25 min from 0 to 5 %, 80 g ISCO silica gel column) to gi ve a racemic mixture of (1 S,2R,4R)-2-allyl-4-((tert-butyldimethylsilyl)ox ')c clopenty 1 formate and (lR,2S,4S)-2-aliyl-4-((tert-butyldimethylsilyl)oxy)cyclopent yl formate (6.48 g, 22.78 rnmol, 91 % yield) as a nearly colorless liquid, taken directly onto the next step.

STEP 5: (lS ₅ 2R,4R)-2-ALLYL-4-((TERT-

BUTYLDIMETHYLSILYL)OXY)CYCL()PENTANOL AND (1 R,2S,4S)-2- ALLYL-4-((TERT-B LOPE TANOL

racemate

To a stirred solution of a racemic mixture of (lS,2R,4R)-2-allyl-4-((tert- butyldimethylsilyl)oxy)cyclopentyl formate and (lR,2S,4S)-2-allyl-4-((tert- butyldimethylsilyl)oxy)cyclopentyl formate (6.480 g, 22.78 rnmol) in MeOH (70 mL) was added ammonia hydrate, 27% aqueous solution (15 mL, 22.78 rnmol) via a syringe at rt. The resulting mixture was stirred at rt for a period of 12 h when TLC showed completion. The volatiles were removed and the residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 5 min at 0 % and 30 min from 0 to 30 %, 80 g ISCO silica gel column) to give a pure racemic mixture of (1 S,2R,4R)-2-ally l-4-((tert-butyldimethylsilyl)oxy)cy clopentanol and (l R,2S,4S)-2-allyl-4-((tert-butyldimethylsilyl)oxy)cyciopentar !ol (4.81 g, 1 8.76 rnmol, 82 % yield) as a colorless oil, take onto the next step. STEP 6: (I S,2R,4 )-2-ALLYL-4-((TERT-

BUTYLDIMETHYLS1LYL)0XY)CYCL0PENTYL METHANES ULFON ATE AND ( 1 R,2S,4S)-2-ALLYL-4-((TERT-

BUTYLDIMETHY NESULFONATE

racemate

To a stirred ice-cooled solution of a racemic mixture of (1 S,2R,4R)~2- allyl-4-((tert-butj _' 'ldimethylsilyl)oxy)cyclopentanol and (lR,2S,4S)-2-allyi-4- ((tert-butyldimethylsiiyl)oxy)cyc3opentanol (4.81 g, 18.76 mniol) and

triethyl amine (5.74 mL, 41.3 mmol) in DCM (70 mL) was slowly added methanesulfonyl chloride (2.223 mL, 28.1 mmol) through a syringe. The resulting mixture was stirred at 0 °C for a period of 1 h. The crude mixture was poured into ice and 1 N aqueous HCl solution and extracted with DCM (2 X). The combined organics were once again washed with 1 N aqueous HCl solution followed by brine (2 X) and dried over anhydrous sodium sulfate. Concentration in vacuo gave a racemic mixture of (1 S,2R,4R)-2-ailyl-4-((teri- butyldimethy]silyl)oxy)cyclopentyl methanesulfonate and (l.R,2S,4S)-2-all l-4- ((tert-butyldimethylsilyl)ox\')cyclopentyl methanesulfonate (6.56 g, 19.61 mmol, 105 % yield) as a nearly colorless oil, directly taken onto the step.

STEP 7: 2-(((lR,2R,4R)-2-ALLYL-4-((TERT-

BUTYLDIMETHYLSILYL)OXY)CYCLOPENTYL)THIO)PYRIMIDINE AND 2-(((l S,2S,4S)-2-ALLYL-4-((TERT-

BUTYLDIMETHYLSILYL)OXY)CYCLOPENTYL)THIO)PYRIMIDINE

racemate

A mixture of 2-mercapto-pyrimidine (3.74 g, 33.3 mmol) and potassium carbonate anhydrous (2.96 mL, 49.0 mmol) in DMF (70 mL) was stirred at rt for 10 rain before a solution of a racemic mixture of (1 S,2R,4R)-2-allyl-4-((tert- butyldimethylsilyl)oxy)cyclopentyl methanesulfonate (6.560 g, 19.61 mmol) and (lR,2S,4S)-2-ailyl-4"((tert-but dimethylsilyl)oxy)cyclopent 'l methanesulfonate in THF (70 mL) was added. The resulting mixture was stirred at rt for 10 min and at 75 °C for a period of 20 h. The crude mixture was poured into ice and saturated sodium carbonate aqueous solution and extracted with EtOAc (2 X). The combined organics were washed with saturated sodium carbonate aqueous solution (1 X) followed by water ( X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to eomhi-flash column chromatography (EtOAc/hexanes, 5 min at 0 % and 25 mm from 0 to 30%, 80 g ISCO silica gel column) to give a racemic mixture of 2-(((lR,2R,4R)-2-allyl-4- ((tert-butyidimeihylsilyi)oxy)cyclopentyl)thio)pyrimidine and 2-(((l .S,2S,4S)-2- ally 1 -4-((tert-butyldimethylsilyl)oxy)cy clopentyl)thio)pyrimidine (4.17 g, 11.89 mmol, 60.7 % yield) as a colorless oil, taken onto the next step.

STEP 8: 2-(((lR,2R,4R)~2-ALLYL-4~((TERT- BUTYLDIMETHYLSlLYL)OXY)CYCLOPENTYL)SULFONYL)PYRIMlDIN

E AND 2-(((lS,2S,4S)-2-ALLYL-4-((TERT-

UTYLDIMETHYLSILYL)OXY)CYCLOPEN L)SULFONYL)PYRIMIDI E

racemate

To a stirred ice-cooled solution of a racernic mixture of 2-(((l R,2R,4R)-2- allyl-4-((tert-but dime1hylsilyl)oxy)cyclopentyl)¾io)pyrimidine and 2- (((lS,2S,4S)-2-allyl-4-((tert-butyldimethylsilyl)oxy

(1.05 g, 2.99 mmol) in DCM (20 mL) and DMF (2,00 mL) was added 3- chlorobenzoperoxoic acid (1.4 0 g, 6.29 mmol) in 2 portions as a solid over 10 min. The resulting mixture was stirred at 0 °C for about 2 h and at rt for a period of 5.5 h. The reaction stalled without completion. The reaction mixture was cooled again in an ice-water bath. Based on LC-MS estimate, 0.48 g more of m- CPBA was added and the resulting mixture was stirred at 0 °C and allowed to warm up gradually to rt overnight (11 h). It was poured into ice and 10 %

NaHSOs aqueous solution and extracted with DCM (2 X). The combined organics were washed sequentially with 10 % NaHSCb aqueous solution (1 X), saturated sodium bicarbonate aqueous solution (1 X) and brine (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 25 min from 0 to 100%, 40 g ISCO silica gel column) to give a racernic mixture of 2-(((l R,2R,4R)-2-allyl- 4-((tert-but 'ldimethylsilyl)oxy)cyclopent\ )sulfonyl)pyrirnidine and 2- (((lS,2S,4S)-2-allyl-4-((tert- butyldimethy]silyl)oxy)cyclopent d)sulfonyl)pyrirnidine (1.04 g, 2.72 mmol, 91 % yield) as a colorless oil which solidified upon standing at rt over time, taken onto the next step.

STEP 9: ( lR,2R,4R)-2-ALLYL-4-HYDROXYCYCLOPENTANE- 1 -

SULFONAMIDE AND (1 S,2S,4S)-2-ALLYL-4-HYDROXYCYCLOPENTANE- 1 -SULFO AMIDE

racemate

The 1 ^st step: To a stirred solution of a raeemic mixture of 2-ίίί I R.2K .4R)- 2-aliyl-4-((tert iutyklimethylsilyl)oxy and 2-

(((lS,2S,4S)-2-allyl-4-((tert- butyldimethylsilyl)oxy)cyclopen d)sidfonyl)pyrirnidine (1.04 g, 2.72 mmol) in MeOH (40 ml,) was added at rt sodium methoxide, 25 wt % solution in methanol (0.606 mL, 2.72 mmol) via a syringe. The resulting mixture was stirred at rt for 30 min when LC-MS showed completion. The volatiles were removed in vacuo and the residue was subjected to high vacuum.

The 2 ^nd step: To the above residue was added water (40 mL) followed by sodium acetate trihydrate (0.510 mL, 5.44 mmol) and amidoperoxymonosulfuric acid (0.615 g, 5.44 mmol) at rt. The resulting clear solution was stirred at 75 °C in a preheated oil bath for a period of 3 h. Note that the mixture remain clear after cooled. It was basified with ice cold saturated sodium carbonate and extracted with 25% i-PrOH/DCM (5 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to combi- flash column chromatography ((10% MeOH/DCM with 0.3% AcOi l } iX .Vl. 25 min from 0 to 70%), 24 g ISCO silica gel column) to give a raeemic mixture of (lR,2R,4R)-2- lyl-4-hydroxycyclopentane-I -sulfonamide and (1 S,2S,4S)-2-allyl- 4-hydroxycyclopentane-l-sulfonamide (0.46 g, 2.241 mmol, 82 % yield) as a colorless sticky oil, taken onto the next step.

STEP 10: (S)-6'-CHLORO-5-(((lR,2R)-2 (S,E)-l-HYDROXY-4-((lR,2R,4R)-4- HYDROXY^-SULFAMOYLCYCLOPENTY^BUT^-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _j! 4HYDRO-2H,2 ^, H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-4-((l S,2S,4S)- 4-HYDROXY -2-SULFAMOYLCY CLOPENTYL)BUT-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETR^ HYDRO-2H,2 ^! H-

SPIRO|BENZO[B]|;i,4iOXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXY LIC

ACID

To a 25 rriL single-necked round-bottomed flask were placed (S)-6'- chloro-5-((( lR,2R)-2-((S,E)-l -hydroxyhex-2-en- 1 -yl)cy dobutyl)methy )-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (0.145 g, 0.284 mmol, Intermediate AA12A), a racemic mixture of

(lR,2R,4R)-2-allyl-4-hydroxycyclopeniane-l-sulfonamidemid (lS,2S,4S)-2-allyl- 4 iydroxycyclopentane-l-sulfonarnide (0.093 g, 0.455 mmol), and 2 ^nd generation hoveyda-grubbs catalyst (0.018 g, 0,028 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (4 mL) was introduced through a syringe under nitrogen. The resulting mixture was stirred at rt under nitrogen for a period of 4 h. The crude mixture was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography ((10% MeOH/DCM with 0.3% AcOH)/DCM), 50 min from 0 to 100%, 24 g ISCO silica gel column) to give a mixture of the title compounds (0.0884 g, 0. 37 mmol, 48.2 %) as a gray solid.

STEP 11: (1S,3'R,6'R,7'S,8'EJ l'R,13'R,15'R)-6-CHLORO-7',13'-DIHYDROXY- 3.4-DiRYORO-2i 1. i S'l f-SP!RO|\API Π 1! \1 J ^' NI - ! 25'-

[23]OXA[16]TH1A[1,17]DIAZAPENTACYCLO[17.7.2.0 ³ -^0 ¹¹ - ^I 0 ²² - ²⁷ ]OCTAC OSA| 8,19,21,27]TETRAEN]-18'-ONE 16',16'-DIOXIDE OR

(lS,3'R,6'R,7'S,8¾irS,13'S,15'S)-6-CHLORO-7',13 ⁱ -DIHYDROXY-3,4- DIHYDRO-2H, 18 Ή- SPIRO [N APHTH ALENE- 1 ,25'- pSlOXAti eiTHIAtl

OS A[8, 19,21,27]TETRAEN]-18'-ONE 16', 16'-D!GXIDE

To a stirred ice-cooled solution of (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l - hydroxy -4-((lR,2R,4R)-4-hydroxy~2~su^

yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[b enzo[b][l,4]oxazepine- 3,r-naphthalene|-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydrox '-4-((l S,2S,4S)-4-hydroxy-2-sulfamoylcyclopent ' ^, l)but-2-en-l- yl)cyclobu1\d)methyl)-3',4,4^5-tetrahydro-2H,2'H-spiro[benzo [b][l ,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (88 nig, 0.136 mmol) and N,N- dimethylpyridin-4-amine (36,7 mg, 0.30 mmol) in DCM (70 ml.) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65.4 mg, 0.341 mmol) in one portion. The resulting mixture was stirred at 0 °C for 0.5 h and at ambient temperature for 5.5 h. The volaiiles were removed in vacuo. The crude residue was taken up in DMSO and subjected to preparative reverse-phase HPLC

(Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0. 1% TFA, 30 min method) to give, after lyophilization, 7 mg pure of the title compound as the first eluting fraction as an off-white solid. About 10 mg slightly impure of this title compound was collected in the second crop. ^l H NMR (5()()MHz, CDCb) δ 8.56 (br. s., IH), 7.70 id. ./ 8.6 Hz, IH), 7, 18 (dd, ./ 2.0. 8.6 Hz, i l l ). 7.10 (d, J=1.7 Hz, IH), 7.03 - 6.90 (m, 3H), 5.88 - 5.75 (m, IH), 5.74 - 5.66 (m, IH), 4.43 (br. s., IH), 4.32 - 4.24 (m, IH), 4.23 - 4.18 (m, IH), 4.16 - 4.03 (m, 2H), 3.76 (d, J=14.9 Hz, IH), 3.69 (d, ,/ 14.4 Hz, IH), 3,25 (d, ./ 13.9 Hz, IH), 3,09 (dd, J=7,6, 14.7 Hz, IH), 2.89 - 1.54 (m, 20H), 1.44 (t, J=12.3 Hz, IH). m/z (ESI, +ve ion) 627.3 (M+H) ⁺ .

EXAMPLE 336. (l S,3'R,6 ^! R,7'S,8 ^, E, l l ^, S,13'S,15 ^, S)-6-CHLORO-7',13 ^, ~

DIHYDROXY-3,4-DIHYDRO-2H,18'H-SPIRO|NAPHTHALENE-l ,25'- pSlOXAtieiTHIAtl

QSA[8,19,21,27]TETRAEN]-18'-QNE 16',16'-D1QX1DE OR

(IS 'R^'R ^^T r S'RJS^-e-CHLORO-y' S'-DIHYDROXY-S^- DIHYDRO-2H,18'H-SPIRO[NAPHTHALENE-l,25'- [23]OXA[16]THIA[l,17]DIAZAPENTACYCLO[17 ,7.2,0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² - ²⁷ ]OCTAC OSAI8. -18'-O E 16',16'-DIQXiDE

The title compound (18 mg) was obtained as an off-white solid as the second eluting isomer from preparative reverse-phase HPLC (Gemini™ Prep Cie 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95%

acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 335. About 10 mg impure of the title compound was harvested in the second crop. ¾ NMR (500MHz, CDCh) δ 8.56 (br. s., 1H), 7.67 (d, J=8.6 Hz, ill).7, 17 (dd, ./ 2.2.8.6 Hz, III).7.10 id. ,/ 2.0 Hz, IH), 7.02 (d, ./ 8.3 Hz, ill). 6,94 (d, ./ 8.1 Hz, IH), 5.72 (br, s., 2H), 4.44 (d, ,7=2,7 Hz, IH), 4.26 - 4.12 (m, 2H), 4.10 - 3.90 (m, 2H), 3.84 - 3.23 (m, 4H), 2.76 (br. s., 3H), 2.67 - 2.42 (m, 4H), 2.32 - 1.39 (m, 14H). m/z (ESI, +ve ion) 627.3 (M+H) ⁺ .

EXAMPLE 337. { ! S..VR.iVR.7'S.8T:. I ! i 3'K. ! 5'R)-6-.( ! U.OKO-7'. ! ;V- DIMETHOXY-3,4-DJHYDRO-2H, 18'H-SPIRO[NAPHTHALENE-l ,25'-

[23iOXA|;i6]THIA|;i,17]DlAZAPENTACYCL)[17.7.2.0 ³ '^0 ^!! ' ⁱ 0 ²² - ²⁷ ]OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16', 16'-D10XJDE OR

(lS,31,6'R,7 ^! S,8'E,irS,13'S,15 ^! S)-6-CHLORO-7',13'-DlMETHOXY-3,4- DIHYDRO-2H, 18 Ή- SPI RO [ NAPHTHALENE- 1,25'- [23]OXA[16]TOIA[l,17]DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ^ll - ^ls .0 ²² ' ²⁷ ]OCTAC OS A[8, 19,21 ,27]TETRAEN]-18'-ONE 16', 16 ^! -D10XIDE

To a stirred ice-cooled solution of{ ! S.3 ^' R.6'R.7'S.8'H. I ! 'R. I 3 ^' R. ! 5'R)-6- cMoro-7',13'-dihydroxy-3,4-dihydro-2H,18'H-spiro[naphthalene -l,25'-

[23joxajl6]thia[l,17]diazapentacyclQ[17.7.2.0^

etraen]-! 8'-one 16",16-dioxide or (1S,3'R,6'R,7'S,8'E,1 l's,13'sj 5's)-6-chloro- 7', 13'-dihydroxy-3,4-dihydro-2H, 18'H-spiro[naphthalene-l ,25'- 12 !οχα| I6|thia| U7|dia/upeniacycIo| 17,7.2.0 ^; θ ^{;! !} \( ^{) Ι : '} lociacosajH.1 .2i.27|t etraen|-18'-one 16',16'-dioxide (not weighed. Example 335) in DMF (2 mL) was added sodium hydride, 60 % dispersion in mineral oil (in excess). The resulting mixture was stirred at 0 °C for 10 min and at rt for 20 mm before iodomethane (in excess) was added. The resulting mixture was stirred at rt for a period of 1 h. It was cooled in an ice-water bath before quenched with methanol. The crude mixture was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 5.5 nig of the title compound as a white solid. Ή NMR (400MHz, CDCh) δ 8.23 (s, III).7.70 (d, ./ 8.6 Hz, 1H), 7.18 (dd, ./ 2.3.8.6 Hz, 111).7.09 (d, ,/ 23 Hz, 1H), 6.98 - 6.85 (m, 2H), 6.77 (s, 1H), 5.86 - 5,74 (m, 1H), 5.56 (dd, «/=8.4, 14.7 Hz, 1H), 4.45 (q, .7=9.3 Hz, 1H), 4,07 (q, ./ 12.2 Hz, 2H), 3.91 - 3.66 (m, 4H), 3.31 (s, 3H), 3.26 (s, 3H), 3.18 (d, ./ 14.3 Hz, 1H), 2.98 (dd../ 10.3.15.2 Hz, 1H), 2.85 - 2.60 (m, 4H), 2.57 - 1.55 (m, 14H), 1,39 (t, ./ 12.7 Hz, IB), m!z (EST, +ve ion) 655,0 !V! I!)

EXAMPLE 338.(1 S,3 ^! R,6'R,7'S,8'E, 1 l'R, 15'S)- 13'- ACETYL-6-CHLORO- HYDROXY-3,4-DIHYDRO-2H,18'H-SPIRO[NAPHTOALENE-l,25'- [23]OXA[16]TfflA[l,13,17]TRIAZAPENTACYCLO[17.7.2.0 ³ - ^r 0 ¹¹ ' ¹ ^0 ²² ' ² ACOSA[8,19,21,27]TETRAEN]-18'-ONE 16',16'-DI0X1DE OR (1 S,3'R,6'R,7'S,8'E, 1 1 'S, 15'R)-13'-ACETYL-6-CHLORO-7'-HYDROXY-3,4 D1HYDRO-2H, 18H-SP1R0[NAPHTHALENE-1 ,25'- | 23 j()XA| ! A j H S iAj 1. 13. 1 7 |Ί ^' ΚΙΛ/ΛΡΙ ίΝΊ ^' Λ(Ύ( .()Ι i 7.7.2.0 ^; ".0 ^{1 1} ' · ^' \( ⁾ ·· ^{, '} :T ACQS A[8, 19,21 ,27]TETRAEN] - 18 ^* -ONE 1 ό', 16'-DTOXIDE

STEP 1 : (3R,4S)~TERT-BUTYL 3-ALLYL-4-HYDROXYPYRROLIDINE-1- CARBOXYLATE AND (3S,4R)-TERT-BUTYL 3-ALLYL-4- HYDROXYPYRROLI Y

racemate

To a heat-gun-dried single-necked round-bottomed flask (250 mL) was charged dry diethyl ether (20 mL) and allylmagnesiurn bromide, 1.0 M solution in diethyl ether (11.34 mL, 11.34 mmol). The mixture was cooled to 0 °C in an ice bath. To this was slowly added a solution of 3-boc-6-oxa-3-aza- bicyclo[3.1.0]hexane (1.0 g, 5.40 mmol) in dry ethyl ether (20 ml.) via a syringe. A white precipitate formed immediately upon addition. After the addition was complete, the mixture was stirred for 15 min at 0 °C before quenched with saturated ammonium chloride aqueous solution (25 mL, slow addition with caution). The resulting mixture was extracted with diethyl ether (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give a racemic mixture of (3 ,4S)-tert-butyi 3-allyl-4- hydroxypyrrolidine-l-carboxylate and (3S,4R)-tert-butyi 3-all l-4- h droxypyrrolidine- 1 -carboxylate (1.2 g, 5.28 mmol, 98 % yield) as a nearly colorless oil, directly taken onto the next step. STEP 2: (3 ,4R)-TERT-BUTYL 3-ALLYL-4-(FORMYLOXY)PYRROLIDINE- 1-CARBOXYLATE AND (3S,4S)-TERT-BUTYL 3-ALLYL-4- (FORMYLOXY)P Y - 1 - C ARBOXYL ATE

racemate

To a stirred ice-cooled solution of a racemic mixture of (3R,4S)~tert-hutyl

3-allyl-4-hydroxypyrrolidine-l-carboxylate and (3S,4R)-tert-butyl 3-allyl-4- hydroxypyrrolidine-l -carboxylate (0,980 g, 4.31 rnmol) and triphenylphosphine (1.414 g, 5,39 mmol) in THF (28 mL) was added 98% formic acid (0.203 mL, 5.39 mmol) followed by slow addition of (E)-diisopropyl diazene-1,2- dicarbox late (1.068 mL, 5.39 mmol) through a syringe. The resulting mixture was stirred at ambient temperature for a period of 26 h. After the volume was reduced, the crude mixture was subjected to combi-flash column chromatography (EtOAc/Hexanes, 25 min at 20%, 40 g ISCO silica gel column) to give a racemic mixture of (3R,4R)-tert-butyl 3-allyl-4-(formyloxy)pyrrolictone-l-carboxylate and (3S,4S)-tert-butyl 3-allyl-4-(formyloxy)pyrrolidine-l-carboxylate (0.75 g, 2.94 mmol, 68.1 % yield) as a colorless film, directly taken onto the nexts tep.

STEP 3: (3R,4R)-TERT-BUTYL 3-ALLYL-4-HYDROXYPYRROLIDINE- CARBOXYLATE AND (3S,4S)-TERT-BUTYL 3-ALLYL-4- HYDROXY PYRROLI - 1 -CARB

racemate

To a stirred ice-cooled solution of a racemic mixture of (3R,4R)-tert-butyl 3-allyl-4-(formyloxy)pyrrolidine-l-carboxylate and (3S,4S)-tert-butyl 3-allyl-4- (formyloxy)pyrrolidine-l-carboxylate (1.0 g, 3.92 mmol) in MeOH (15 mL) was added ammonia hydrate, 27% aqueous solution (1.1 mL, 3.92 mmol) via a syringe. The resulting mixture was stirred at rt for a period of 1.5 h. The volatiles were removed and the residue was subjected to high vacuum to give a racemic mixture of (3R,4R)-tert-butyl 3-allyl-4-hydroxypyrrolicUne-l -carboxylate and (3S,4S)-tert-butyl 3-ally 1-4-hydrox yrrolidine- 1 -carboxy late (0.94 g, 4.14 mmol, 106 % yield) as a colorless film, directly taken onto the next step.

STEP 4: (3 R,4R)-TERT-BUTYL 3-ALLYL-4-

((METHYLSULFONYL)OXY)PYRROLIDINE-l-CARBOXYLATE AND (3 S,4S)-TERT-BUTYL 3 -ALL YL-4-

((METHYLSULFONY -l -CARBOXYLATE

racemate

To a stirred ice-cooled solution of a racemic mixture of (3R,4R)-tert-butyl 3-allyl-4-hydroxypyrrolidine-l -carboxylate and (3S,4S)-tert-butyl 3-ally 1-4- hydroxy pyrrolidine- 1 -carbox late (0.940 g, 4.14 mmol) and triethylamine (1.265 mL, 9.10 mmol) in DCM (15 mL) was slowly added methanesulfonyl chloride (0.490 mL, 6.20 mmol) through a syringe. The resulting mixture was stirred at 0 °C for a period of 1.5 h. The crude mixture was poured into ice and 1 N aqueous HC1 solution and extracted with DCM (2 X). The combined organics were once again washed with 1 N aqueous HC1 solution followed by brine (2 X) and dried over anhydrous sodium sulfate. Concentration in vacuo gave a racemic mixture of (3R,4R)-tert-buty 1 3 -aliyi-4-((methy Isuifony l)oxy)py rroiidme- 1 -carboxylate and (3S,4S)-tert-butyl 3-allyl-4-((methylsulfonyl)oxy)pyrrolidine-l-carbox late (1.22 g, 3.99 mmol, 97 % yield) as a nearly colorless oil, directly taken onto the step.

STEP 5: (3R,4S)-TERT-BUTYL 3-ALLYL-4-(PYRIMIDIN-2- YLTHIO)PYRROLIDINE-l -CARBOXYLATE AND (3 S,4R)-TERT-BUTYL 3- ALLYL-4-(PYWMIDIN-2-YLTHIO)PYRROLIDINE-l-^

racemate

A mixture of 2-mercapto-pyrimidine (0.582 g, 5.19 mmol) and potassium carbonate anhydrous (0.94 g, 6.79 mmol) in DMF (15 mL) was stirred at rt for 10 min before a racemic mixture of (3R,4R)-tert-butyl 3-allyl-4- ((methylsulfonyl)oxy)pyrroiidine- 1 -carboxylate and (3S,4S)-tert-butyl 3-allyi-4- ((methylsulfonyl)oxy)pyrrolidine-l-carboxylate (1.220 g, 3.99 mmol) in DMF (15.0 mL) was added at rt. The resulting mixture was stirred at rt for 10 min and at 80 °C for a period of 3 h. The crude mixture was poured into ice and saturated sodium carbonate aqueous solution and extracted with ether (3 X). The combined organics were washed with water (I X) followed by brine (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi -flash column chromatography (EtOAc/hexanes, 20 min from 0 to 100%, 24 g ISCO silica gel column) to give a racemic mixture of (3R,4S)-tert-butyl 3- allyl-4-(pyrimidin-2-ylthio)pyrrolidine-l -carboxylate and (3S,4R)-tert-butyl 3- allyl-4-(pyrimidin-2-ylthio)pyrrolidine~l -carboxylate (0.69 g, 2.147 mmol, 53.7 % yield) as a yellow oil, directly taken onto the next step.

STEP 6: 2-(((3S,4R)-4-ALLYLPYRROLIDlN-3-YL)TOIO)PYRIMIDINE 2, TRIFLUORO ACETATE AND 2-(((3R,4S)-4-ALLYLPYRROLIDIN-3- YL)THIO)PYRIMI -TRIFLUOR

racemate To a stirred solution of a racemic mixture of (3R,4S)-tert-butyl 3-allyl-4- (pyrirnidin-2-ylthio)pyrrolidine-l-carboxylate and (3S,4R)-tert-butyl 3 -ally 1-4- (pyrimidin-2-ylthio)pyrrolidine-l (0.69 g, 2.147 mmol) in DCM (10 mL) was added triiluoroacetic acid (0.638 mL, 8.59 mmol) at rt. The resulting mixture was stirred at rt for a period of 1.5 h. The LC-MS indicated the majority was still the sm. More TFA (2.0 mL) was added and the mixture was stirred for 1.5 h, at which time the reaction became complete. The voaltiies were removed and the residue was subjected to high vacuum to give a crude racemic mixture of 2-(((3 S,4R)-4-allylpyrrolidin-3-yl)thio)pyrimidine 2,2,2-trifluoroacetate and 2- (((3R,4S)-4-allyipyrrolidin-3-yi)thio)pyrimidine 2,2,2-trifluoroacetate as a light orange oil, directly taken onto the next step.

STEP 7: l-((3R,4S)-3-ALLYL-4-OPYRIMIDIN-2-YLTH10)PYRROLIDIN-l- YL)ETHANONE AND 1 -((3S,4R)-3-ALLYL-4-(PYRIMIDIN-2- YLTHIO)PYRROLTDIN- - YL )ETH ANONE

racemate

To a stirred ice-cooled solution of the above crude racemic mixture of 2- (((3S,4R)-4-allylpyrrolidin-3-yl)thio)pyrimidine 2,2,2-trifluoroacetate and 2- (((3R,4S)-4-allyipyrrolidin-3-yi)thio)pyriiriidine 2,2,2-trifluoroacetate (0.475 g, 2.147 mmol) in DCM (12 mL) was added triethylamine (0.747 mL, 5.37 mmol) followed by 2,5-dioxopyrrolidin-l -yl acetate (0.405 g, 2.58 mmol). The resulting mixture was stirred at ambient temperature for 15 h. The LC-MS showed that there was still a bit sm remained. More Et3N (0.2 mL) was added followed by more of 2,5-dioxopyrrolidin-l-yl acetate (90 mg). The resulting mixture was stirred at rt for 20 min, at which time it reached completion. After the volatiles were removed, the residue was subjected to combi-flash column chromatography (EtOAc/hexanes, 15 min from 20 to 100 % and 20 min at 100 %, 24 g ISCO silica gel column) to give a racemic mixture of l-((3R,4S)-3-allyl-4-(pyrimidin-2- ylthio)pyrrolidin-l -yl)ethanone and 1 -((3S,4R)-3-allyl-4-(pyrimidin-2- ylthio)pyrrolidin-l-yl)ethanone (0.54 g, 2,05 mmol, 96 % yield) as a colorless oil, directly taken onto the next step.

STEP 8: l-((3R,4S)-3-ALLYL-4-(PYRlMlDIN-2-

YLSULFONYL)PYRROLIDIN-l-YL)ETHANONE AND 1 -((3S,4R)-3-ALLYL- 4-(PYRIMIDIN-2-YLSU -l-YL)ETHANONE

raoemale

To a stirred ice-cooled solution of a racemic mixture of 1 -((3R, S)-3-allyl-

4-(pyrimidin-2-ylthio)pyrrolidin-l-yl)ethanone and l-((3S,4R)-3-allyl-4- (pyrimidin-2-ylthio)pyrrolidin-l-yl)ethanone (0.54 g, 2.05 mmol) in DCM (12 mL) was added 3-chlorobenzoperoxoic acid (0.965 g, 4.31 mmol) in one portion as a solid. The resulting mixture was stirred at 0 °C for about 1 h. DMF (1.2 mL) was added to attain complete dissolution and the mixture was further stirred at 0 °C for 45 min. Note that the reaction was closely monitored by LC-MS and went through a few rounds of adding more m-CPBA as follows. More m-CPBA (0.6 g) was added at 0 °C and the mixture was stirred at this temperature for 20 min before the ice bath was removed. It was stirred at rt for 20 min. The mixture was cooled again in an ice bath and more m-CPBA (0.55 g) was added and the mixture was stirred at 0 °C for 1 h. Again, more m-CPBA (0.26 g) was added at 0 °C and the mixture was stirred at this temperature for 1 h. The reaction mixture was then poured into ice and saturated sodium bicarbonate aqueous solution and extracted with DCM (3 X). The combined organics were washed with ice cold sodium bicarbonate aqueous solution (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography ((10%MeOH/DCM)/DCM, 35 min from 0 to 60%, 40 g ISCO silica gel column) to give a racemic mixture of l-((3R,4S)-3-allyl-4-(pyrimidin-2- ylsulfonyl)pyrrolidin-l-yl)ethanone and l-((3S,4R)-3-allyl-4-(pyrimidin-2- ylsulfonyl)pyrrolidin-l-yl)ethanone (0.436 g, 1 .476 mmol, 72.0 % yield) as a colorless film, taken onto the next step.

STEP 9: (3S,4R)-l-ACETYL-4-ALLYLPYRROLIDINE-3-SULFONAMIDE AND (3R,4S)~ 1 -ACETY -4-ALLYLPYRROLTDINE-3-SULFONAMIDE

racemaie

The 1 ^st step: To a stirred solution of a racemic mixture of 1-((3R,4S)~3~ allyl-4-(pyrimidin-2-ylsulfonyl)pyrrolidin-l-yl)ethanone and l-((3S,4R)-3-allyl-4- (pyrimidin-2-ylsulfonyl)pyrrolidin-l-yl)ethanone (0.203 g, 0.687 mmol) in MeOH (4 mL) was added at rt sodium methoxide, 25 wt % solution in methanol (0. 153 mL, 0.687 mmol) via a syringe. The resulting mixture was stirred at rt for 35 min. The volatiles were removed in vacuo and the residue was subjected to high vacuum.

The 2 ^nd step: To the above residue was added water (5 mL) followed by sodmm acetate tnhvdrate (0.129 mL, 1.375 mmol) and amidoperoxymonosulfuric acid (0.155 g, 1.375 mmol) at rt. The resulting clear solution was stirred at 50 °C in a preheated oil bath for a period of 40 min. No precipitation occurred after cooling. The mixture was basified using ice cold saturated sodium carbonate. Initial multiple extractions using EtOAc was not effecti ve and some of the desired product remained in the aqueous layer. Then the extraction was earned out with 20% i-PrOH DCM (4 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to combi- flash column chromatography ((10% MeOH/DCM)/DCM, 25 min from 10 to 100%, 12 g ISCO silica gel column) to give a racemic mixture of (3S,4R)-1- acet l-4-allylpyrrolidine-3-sulfonajtnide and (3R,4S)- 1 -acetyl-4-allylpy rrolidine-3- sulfonamide (0.120 g, 0.517 mmol, 75 % yield) as a colorless film, taken onto the next step. STEP 10: (S)-5-(((lR,2R)-2-((S,E)-4-((3R,4S)-l-ACETYL-4-

S ULF AMOYLP YRROL1DIN - 3- YL) - 1 -H YDROXYBUT-2-EN - 1 - YL)CYCLOBUTYL)METHYL)-6'-CHLORO-3 ^, .4,4 ^, .5-TETRAHYDRO-2H,2 ^, H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-5-(((lR,2R)-2-((S,E)-4-((3S,4R)-l -ACETYL-4- SULF A OYLPYRROLIDIN-3-YL)- 1 -HYDROXYBUT-2-EN- 1 -

YL)CYCIX)BUTYI MF^iYL)-6'-CHLORO-3',4,4',5-TETRAi-IYDRO-2H,2'H- SPIRO[BENZO[B][l 4]OXAZEPINE-: l'-NAPHTOALENE]-7-CARBOXYLIC ACID

To a 25 mL single-necked round-bottomed flask were placed (S)-6'- chloro-5-((( lR,2R)-2-((S,E)-l -hydroxyhex-2-en- 1 -yl)cy clobutyl)methy )-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (0.135 g, 0.265 mmol, Intermediate AA12A), a racemic mixture of (3S,4R)- l-acetyl-4-allylpyrrolidine-3-sulfonamide and (3R,4S)-l-acetyl-4-aliylpyrroiidine- 3 -sulfonamide (0. 123 g, 0.529 mmol), and 2" ^d generation hoveyda-grubbs catalyst (0.017 g, 0.026 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (3.2 mL) was introduced via a syringe under nitrogen. The resulting mixture was stirred under nitrogen at rt for a period of 3.5 h. The crude mixture was loaded onto a silica gel precolumn and subjected to combi-fiash column chromatography ((10% MeOH/DCM with 0.3%

AcOH)/DCM)), 20 mm from 0 to 100%, 24 g ISCO silica gel column) to give a mixture of the title compounds (105 mg, 0.156 mmol, 59.0 % yield) as a gray solid. The material was azetroped with toluene and dried on high vacuum before taken onto the next step.

STEP 11 : (1 S,3'R,6'R,7'S,8'E, 11 ^* R, 15'S)- 13'- ACETYL-6-CHLORO-7'- HYDROXY-: 4 31HYDRO-2H;i 8H-SPIRO[NAPHTHALENE-l,25'-

[23]OXA[16]THIA[1 _S 13,17]TRIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ ' ¹⁵ .0 ²² - ²⁷ ]OCT ACOS A[ 8, 19,21 ,27 jTETRAEN] - 18'-ONE 16', 16'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 1 'S, 15'R)-13'-ACETYL-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 1 8 Ή- SPIRO [NAPHTHALENE- 1 ,25'- | 2 j()XA| ! 6 | Η ΠΑ| 1. 13. 1 71 ^' I ^' RIA/AFI iNTACYCI.OI i 7.7.2. * ^; ' ^' . ⁾ ' ^{1 l :} \U - j()( ^' T ACQS A[8, 19,21 ,27]TETRAEN] - 18 ^* -ONE 16 ^f , 16'-DIOXIDE

To a stirred ice-cooled solution of (S)-5-(((l R,2R)-2-((S,E)-4-((3R,4S)- ^' l- acetyl-4-sulfamoylpyrrolidin-3-yl)-l-hydroxybut-2-en-l-yl)cy clobut^ )methyl)-6'- chloro-3\4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [ 1 ,4 joxazepine-3, 1 '- naphthalene] -7-carboxylic acid and (S)-5-(((lR,2R)-2-((S,E)-4-((3S,4R)-l-acetyl- 4-sulfamoylpyrrolidin-3-yl)-l-hydrox\'but-2-en-l-yl)c} lobutyl)methyl)-6'- chloiO-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'i-I-spiro| benzo| b] | l ,4 |oxazepine-3,l'- naphthalene]-7-carboxylic acid (105 mg, 0.156 mmol) and N,N-dimethylpyridin- 4-amine (42.0 mg, 0.344 mmol) in DCM (75 mL) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiirnide hydrochloride (74.9 mg, 0.390 mmol) in one portion. The resulting mixture was stirred at ambient temperature for 12 h. The volatiles were removed and the residue was subjected to preparative reverse- phase HPLC (Gemini™ Prep Cm 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents

contained 0.1% TFA, 30 min method) to give in major bands, after lyophilization, 15 mg of the title compound as the first eluting fraction as an off-white solid. 'H NMR (500MHz, CDCh) δ 9.03 - 8.26 i ns. i l l ). 7.70 (d, ./ 8.6 Hz, ! ! ! ). 7.19 (dd, J=2.2, 8.6 Hz, 1H), 7.10 (d, ,/ 2 0 Hz, 1H), 7.04 - 6.90 (m, 3H), 5.86 - 5.65 (m, 2H), 4.74 - 4.54 (m, i l l ). 4.34 - 3.99 (m, 5H), 3.94 - 3.74 (m, 2H), 3.70 (dd, ./ 6.0. 14.3 Hz, i l l . 3.36 (dd, ./ 5.7. 11.9 Hz, ! ! ! ). 3.31 - 3.14 (m, 2H), 3.14 - 2,97 (m, IH), 2.86 - 2,65 (m, 3H), 2.54 - 2,30 (m, 3H), 2.27 - 1.59 (m, 11H), 1.50 - 1.35 (m, 1H). m/z (ESI, +ve ion) 654.3 (M+H) ⁺ .

EXAMPLE 339. (lS,3 ^, R,6 ^! R,7'S,8'E,irS,15'R)-13'-ACETYL-6-CHLORO-7'- HYDROXY-S^-DlHYDRO^H SH-SPIROINAPHTHALENE-l^S'-

ACOS A[ 8, 19,21 ,27]TETRAEN| - 18'-ONE 16 ^* , 16'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^! S,8'E,ll'R,15 ^! S)-13 ^, -ACETYL-6-CHLORO-7 ^, -HYDROXY-3,4" DIHYDRO-2H, 18 Ή- SPI RO [ NAPHTHALENE- 1,25'-

[23]OXA[16]THIA[1,.13,17]TRTAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ^1] ' ^]5 .0 ²² ' ²⁷ ]OCT ACOSA -18'-ONE 16Y16'~DIOXIDE

The title compound (19 mg) was obtained as an off-white solid as the second eluting isomer from preparative reverse-phase HPLC (Gemini™ Prep Cis 5 um column; Phenomenex, Torrance, CA; gradient elution of 45-95%

acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) in Example 338. '!! NMR (500MHz, (Ό(Ί·.) ό 9.20 - 8.27 (m, IH), 7.63 (dd, ./ 4.6.8.6 Hz, IH), 7.15 (dd, ./ 2.1.8.4 Hz, IH), 7.10 (d, ./ 2.2 Hz, IH), 7.04 (d, ,/ H I Hz, IH), 7.00 - 6.96 (m.111).6,95 - 6.90 (m, IH), 5.77 (dd,J=3.7, 15.4 Hz, IH), 5,54 (d, J=18.8 Hz, IH), 4.62 - 4.49 (m, H), 4.42 - 1.29 (m, 30H). m/z (ESI, +ve ion) 654.3 (M+H) ⁺ .

EXAMPLE 340. (1 S,3'R,6'R,7'S,8'E, 11 'R, 15'S)- 13'- ACETYL-6-CHLORO-7'- METHOXY-3,4-DIHYDRO-2H, 18 Ή- SP1RO [NAPHTHALENE- 1,25'- |2 i()XA| I I. i 3. ! 7ΓΓΚ!ΛΖΑ! :Ν ! A(-Y( ^' !.0| i 7.7.2.0 ^; ".0 ^{n '} " ^' ΧΊ ^' ACOS A[ 8, 19,21 ,27]TETRAEN| - 18'-ONE 16 ^* , 16'-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E, 11 'S, 15'R)-13'-ACETYL-6-CHLORO-7'-METHOXY

D1HYDRO-2H, 18H-SP1R0[NAPHTHALENE-1 ,25'- i 23 jOXAj !ΑΠΊ!ΙΛ| 1.13.17 |Ί ^' ΚΙΛ/ΛΡΕΝ ^' ΓΛ(Ύ( .()Ι i 7.7.2.0 ^; ".0 ¹¹ '-".(f

- 18*-ONE 1 G, 16'-DTOXIDE

To a stirred solution of impure (1S,3'R,6'R,7'S,8'E,1 l'R,15'S)-13'-acetyI-6- chloro-7'-hydroxy-3,4-dihydro-2H,18'H-spiro[naphthalene-l,25 '- [23]oxa[16]thia[l,13,17]triazapentacyclo^^

27]tetraen]-18'-one 16',16'-dioxide or (1S,3'R,6'R,7'S,8 ^! E,1 l ^! S,15'R)-13'-acetyl-6- chloro-7'-hy droxy-3,4-dihy dro-2H, 18'H-spiro[naphthalene- 1 ,25'- [23]oxa[16]thia[l,13,17]triazapentac^^

27]tetraen]-18'-one 16',16'-dioxide (8.0 nig, 0.012 mmol, Example 338) in DMF (2 ml.) was added sodium hydride, 60 % dispersion in mineral oil (4.89 mg, 0.122 mmol) (in excess) at rt. The resulting mixture was stirred at rt for 30 min before iodomethane (0.760 μΐ, 0.012 mmol) (not weighed, much in excess) was added. The resulting mixture was stirred at rt for a period of 1.5 h. The reaction was quenched with methanol and the resulting mixture taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 0.7 mg of the title compound as an off-white solid. ¾ NMR (500MHz, CD3OD) δ 7.73 (d, ,/ 8.6 Hz, 1H), 7.17 (dd,■/ 2.2.8.6 Hz, 1H), 7.10 hi.,/ 2.0 H . 111).7.03 id.,/ 8 I Hz, !H), 6.93 id../ 8.1 Hz, ill).6,88 (s, ill). 5,96 - 5.80 (m, III).5.62 (dd, ,/ 90.14.7 Hz, 1H), 4,79 - 4,65 (m, 1H), 4.21 -

3.59 (m, 8H), 3.40 - 3.32 (m, 2H), 3.25 - 3.21 (m, 3H), 3.13 - 3.01 (m, 1H), 2.87 - 2,61 (m, 4H), 2.56 - 2,25 (m, 4H), 2.16 - 2,02 (m, 4H), 1.99 - 1.67 (m, 6H), 1.50 - 1.39 (m, IH). m/z (ESI, +ve ion) 668.3 (M+H) ^H \

EXAMPLE 341. (1 S,3'R,6'R,7'S,8'E)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 13 Ή- SPIRO [N APHTH ALENE- 1 ,20 ^! -

[18]OXA[11]THL\[1J2]DL\ZATETRACYCLO[12.7.2.0 ³ -^0 ¹⁷ - ²² ]TRICOSA[8,1 4, 16,22] TETRAEN] - 13 '-ONE 1 Γ, 1 1 '-DIOXIDE

STEP 1 : (S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((l R,2R)-2-

HYDROXYHEX-2-EN-l^'L)CYCLOBUTYL)METHYL)-3',4,4 ^! ,5

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '

NAPHTHALENE] -7-CARBOXAMIDE

To a stirred ice-cooled solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydrox 'hex-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2' H- spiro|benzo|b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (69 mg, 0.135 mmol, Intermediate AA12A), prop-2-ene-l -sulfonamide (82 mg, 0.676 mmol), and N,N-dimethylpyridin-4-amine (36.4 mg, 0.298 mmol) in DCM (8 mL) was added l-(3-dimethylarninopropyl)-3-ethylcarbodiimide hydrochloride (64.8 mg, 0,338 mmol) in one portion. The resulting mixture was stirred at 0 °C and allowed to gradually warm up to ambient temperature overnight (18 h). The volatiles were removed in vacuo. The residue was subjected to combi -flash column chromatography ((EtOAc with 0.3% AcOH /Hexanes, 25 min from 0 to 40%, 24 g ISCO silica gel column) to give 50 mg of the title compound as a white solid.

STEP 2: (1 S,3'R,6' ,7'S,8'E)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H.13'H-SPIRO[N APHTHALENE- 1 ,20'-

I !8jOXA| 1 ί ΙΊ Η1ΛΙ l.l2|! !A/.Vn-;i ^' RA( ^' YCI.()l i .7.2.0 ^' ' ^{)1 " ! !} |TRiC()SA| 8. ί 4, 16,22] TETRAEN] - 13 '-ONE H',1 l'-DIOXIDE

To a 25 mL single-necked round-bottomed flask were placed (S)-N- (allylsulfonyl)-6'-chloro-5-(((lR,2R)-2-((S,Z)-l-hydroxyhex- 2-en- ^' l- yl)cyclobutyl)methyl)-34,4',5-tetrahydro-2H,2'H-spiro[benzob ][l,4]oxazepine- 3,l'-naphthalene]-7-carboxamide (25 mg, 0.041 mmol) and 2 ^nd generation hoveyda-grubbs catalyst (5.11 mg, 8.15 μηιοΐ). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCM (20 mL) was introduced through a syringe under nitrogen. The resulting mixture was stirred at 45 °C in a preheated oil bath under nitrogen for a period of 20 h. The crude mixture was subjected to combi-flash column chromatography ((EtOAc with 0.3% AcOH)/Hexanes, 60 min from 0 to 100%, 24 g silica gel column, 13 mm tubes) to give the title compound as an off-white solid, ^! !l \Y1R (500 Mi!/. CDCh) δ 8.35 (br. s., IH), 7,71 (d, «7=8.6 Hz, IH), 7.19 (dd, .7=2.0, 8,6 Hz, IH), 7.14 - 7.07 (m, 2H), 6.96 (d, ./ 8.! Hz, IH), 6.58 (br. s., 1H), 6.02 (br. s., 2H), 4.41 - 3.89 (m,

5H), 3.77 - 3.61 (m, 2H), 3.32 (d, ./ 14.2 Hz, 2H), 2.89 - 2.68 (m, 2H), 2.59 - 1.53 (m, 10H), 1.45 (t, ,/ 12.5 Hz, IH). m/z (ESI, +ve ion) 543.2 ( M II) .

EXAMPLE 342. (1 S ₅ 3'R,6 ^, R,7 ^, S)-6-CHLORO-7 ^, -HYDROXY-3,4-DIHYDRO- 2H, 13 Ή-S PIR O [NAPHTHALENE- 1 ,20'-

I l8iOXA| i ! I I 111, \| I„! 2|ί)Ι.\/.νΠ·. ΓΗ. AC VCi, 0112,7.20 ^{; !'} .O ^r "| ΓΚ 08,\| 14. 16,22]TRIEN]-13'-ONE 1 l',l l'-DIOXIDE

A mixture of (1 S,3'R,6 ^! R,7'S,8'E)-6-chloiO-7 ^, -hy droxy-3,4-dihydro- 2H, 13'H-spirofnaphthalene- 1 ,20'-

[ 18]oxa[ 1 1 ]thia[ 1 , 12] diazatetracy clo[ 12, 7.2.0 ³ · ⁶ .0 ¹⁷ - ²² ]tricosa[8, 14, 1 6,22]tetraen] - 13'-one 1 Γ,Ι Γ-dioxide (not weighed, Example 341) and platinum (iv) oxide (in excess) in EtOAc (8 mL) was degassed and purged with hydrogen for multiple times and baloon hydrogen ated for a period of 3 h. The reaction was quenched with DCM. The solid was filtered off and the residue after concentration in vacuo was taken up in DMSO and subjected to preparative reverse-phase HPLC

(Gemini™ Prep Cie 5 iim column; Phenomenex, Torrance, CA; gradient elution of 40-95% acetonitriie in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 2.5 mg of the title compound as a white solid, ^" Ή NMR (400MHz, CDCb) δ 9.52 (br. s., i l l ). 7.70 i d. ./ 8.4 Hz, IH), 7.33 (d, J=8.0 Hz, IH), 7.18 (dd, J=2.2, 8.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 2H), 6.98 (d, J=8.2 Hz, IH), 4.27 - 4.17 (m, 1H), 4.16 - 4.08 (m, IH), 3.87 - 3.27 (m, 7H), 2.88 - 2.73 (m, 2H), 2.66 (br. s„ IH), 2,37 - 2.16 (m, 2H), 2.12 - 1.35 (m, 12H). m/z (ESI, +ve ion) 545,2 ( M i l ) ,

EXAMPLE 343. (3R,6R,7S,8E,1 lR,26S)-6'-CHLORO-7-HYDROXY-3',4'- DIHYDRO-2'H, 19H-SPIRO[ 13,24-DIOXA- 17-THIA- 1 , 16, 18- TRIAZAPENTACYCLO[18.7.2.0 ³ - ⁶ .0 ¹¹ ' ¹⁶ .0 ²³ ' ²⁸ ]NONACOSA-8,20,22,28- TETRAENE-26, 1 '-NAPHTH ALEN] - 19-ONE 17,17-DIOXIDE

STEP 1 : (R)-3-ALLYLMORPHOLINE-4-SULFONAMIDE

A mixture of (R)-3-allylniorpholine hydrochloride (0.700 g, 4.28 mmol), sulfamide (1.233 g, 12.83 mmol), and potassium carbonate (0.258 mL, 4.28 mmol) in 1,4-dioxane (20 mL) was stirred under nitrogen at 85 °C (a preheated oil bath) for a period of 16.5 h. Some sm was still remaining. More sulfamide (not weighed) was added and the stirring continued at 85 °C for another 2 h. After the volatiles were removed, saturated ammonium chloride aqueous solution was added to the residue. The mixture was extracted with DCM (3 X). The combined organics were dried over anydrous sodium sulfate and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 35 niin from 0 to 100%, 40 g ISCO silica gel column) to give (R)-3- allylmorpholine-4-sulfonamide (0.422 g, 2.046 mmol, 47.8 % yield) as a colorless oil, taken onto the next step. STEP 2: (S)-N-(((R)-3-ALLYLMORPHOLINO)SULFONYL)-6'-CHLORO-5-

(((1Κ,2 )-2-((8)-1-ΗΥΒΚΟΧΥΑΙ .ΥΤ)€ΥεΕΟΒυΤ Χ)ΜΕΤΗΥΙ.)-3',4,4',5- TETRAHYDRO-2H,2'H-STEP 3. SPiRQ[BENZO[B][l,4]QXAZEPiNE-3,l ^! - NAPHTHALENE1-7-CARBOXAMIDE

To a stirred ice-cooled solution of impure (S)-6'-chloiO-5-(((lR,2R)-2- ((S)-l-hydroxya31yl)cyc3obuty3)methyl)-3^4,4^54etrahydro-2H, 2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'lic acid (190 mg, 0.406 mmol, Intermediate ΑΑΓ1Α), (R)~3~al3ylmoq3ho!ine-4-sulfonamide (126 mg, 0,609 mraol) (140 rng actual), and N,N-dimethylpyridin-4-amine (124 rng, 1.015 mmol) in DCM (8 mL) was added l-(3-dimethylaminopropyl)-3- ethyicarbodiimide hydrochloride (195 mg, 1.015 mmol) (210 mg actual) in one portion. The resulting mixture was stirred at ambient temperature for a period of 2.5 h. The crude mixture was subjected to combi-flash column chromatography ((EtOAc with 0.35% AcOH)/Hexanes, 35 min from 0 to 70%, 24 g ISCO silica gel column) to give 150 mg of impure title compound as a colorless film, taken onto the next step. STEP 3. (3R,6R,7S,8E, 1 lR,26S)-6 ^, -CHLORO-7-HYDROXY-3 ^, ,4'-DIHYDRO- 2Ή, 19H-SPIRO[l 3,24-DIOXA- 17-THIA-l , 16, 18-

TRIAZAPENTACYCLO[18.7.2.0 ⁵ - ⁶ .0 ^U ' ¹⁶ .0 ²³ ' ²⁸ ]NONACOSA-8,20,22,28- TETRAENE-26, 1 '-NAPHTHALEN]-19-ONE 17, 17-DlOXIDE

To a 250-mL single-necked round-bottomed flask was placed (S)-N-(((R)- 3-allylmoφholino)sulforι ])-6 ^, -chloro-5-(((lR ₅ 2R)-2-((S)-l-

spiroj benzoj b][ T,4]oxazepine-3, -naphthalene]-7-carboxamide (150 mg, 0.229 mmol) and 2 ^nd generation hoveyda-grubbs catalyst (14.32 mg, 0.023 mraol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen followed by addition of DCM (100 mL). The mixture was stirred at rt for a period of 8 h. The unreacted sm appeared to be the major in the crude reaction mixture. The volume was reduced and the crude was directly loaded onto a silica gel precolumn and subjected to combi-flash column chromatography ((EtOAc with 0.35%) AcOH)/Hexanes, 50 min from 0 to 100%, 24 g ISCO silica gel column) to give, in the major band, 10 mg of the title compound as the second eluting fraction as an off-white solid. ¾ NMR (400MHz, CDCh) δ 8.61 (br, s., IH), 7.69 (d, J=8.4 Hz, IH), 7.18 (dd, ./ .2.2. 8.5 Hz, 1H), 7.11 - 7.05 (m, 2H), 6.93 (d, ./ 8.2 Hz, i l l . 6.87 (br. s., 1H), 5.98 - 5.78 (m, 1H), 5.72 (dd, ./ 7.8. 15.6 Hz, IH), 4.15 - 3.85 (m, 6H), 3.80 - 3,57 (m, 5H), 3.46 (dt, ./ 3. 1 . 12.8 Hz, 1 1 1 ). 3.36 (d, ,/ 14 3 Hz, IH), 3,23 (br. s. , IH), 2.87 - 2.70 (m, 2H), 2.68 - 2.50 (m, 2H), 2.41 (br. s., 2H), 2, 1 1 (s, ! 1 1 ). 2,02 - 1 .75 (m, 5H), 1.73 - 1.59 (m, 2H), 1 ,51 - 1 .43 (m, 1 m/z (ESI, +ve ion) 628.0 ( M R )

EXAMPLE 344. (3R,6R,7S,8Z,1 lR,26S)-6'-CHLORO-7-HYDROXY-3',4'- DIHYDRO-2'H, 19H-SPIRO[ 13,24-DIOXA- 17-THIA- 1 , 16, 18~

TRIAZAPENTACYCLO[18.7.2.0 ³ - ⁶ .0 ¹¹ ' ¹⁶ .0 ²³ ' ²⁸ ]NONACOSA-8,20,22,28- TETRAENE-26, 1 '-NAPHTH ALEN] - 19-GNE 17, 17-DIOXIDE

The title compound was synthesized as described in example 343 and was isolated as the first eluting isomer. This material was dissolved in DMSO and further purified by preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 20-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 2.1 mg of the title compound as a white solid. ^l H NMR (400MHz. CDCh) δ 10.41 (s, IH), 7.73 (d, J=8.4 Hz, I H), 7.55 (dd, ,7=2, 1 , 8.3 Hz, i l l ). 7.21 (d, ./ 2,0 Hz, IH), 7.18 (dd, ./ 2.3. 8.4 Hz, i l l ). 7.09 (d, ./ 2.2 Hz, IH), 6.99 (d, ./ 8.2 Hz, IH), 5.90 - 5.77 (m, IH), 5.70 (dd, ./ 7.7. 10.3 Hz, IH), 4.50 (t, ./ 7.5 Hz, I H), 4.20 - 4. 11 (rn, IH), 4,09 - 4,03 (m, I H), 4.02 - 3.88 (rn, 3H), 3.85 - 3 ,56 (ni, 5H), 3 ,47 - 3.30 (m, i l l ). 3.14 - 2.98 (m, 2H), 2, 85 - 2.66 (m, 4H), 2.29 - 2.12 (m, 2H), 2.10 - 1.59 (m, 7H), 1.52 - 1.31 (m, 2H). m/z (ESI, +ve ion) 628.0

{ \ I · Π }

EXAMPLE 345. (lS,3 ^, R,6'R,7 ^! S,8'E,i rS)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 18 Ή- SPI RO [ NAPHTHALENE- 1 ,25'- [23]OXA[ ; 16]THIA[ 1, 15, 17]TRTAZAPENTACYCLO[ 17.7.2.0 ³ · ⁶ .0 ^{J !} · ^{! 5} .0 ^2? - ²⁷ ]OCT AC0SA[8, 19,21 ,27]TF;TRAEN]-18'-0NE 16V16'-DI0XIDE

STEP 1 : (S)-2-ALLYLPYRROLI -l -SULFONAMIDE

A mixture of (S)-2-allylpyrrolidine hydrochloride (1.00 g, 6.77 mmol), sulfamide (2.60 g, 27.1 mmol), and triethylamine (1.41 mL, 10.16 mmol) in 1,4- dioxane (20 mL) was stirred under nitrogen at 85 °C (a preheated oil bath) for a period of 17 h. The volatiles were removed and the residue was subjected to combi-ffash column chromatography (EtOAc Hexanes, 35 min from 0 to 100%, 40 g ISCO silica gel column) to give (S)-2-allylpyrrolidine-l-sulfonamide (0.80 g, 4.20 mmol, 62.1 % yield) as a white crystal solid, taken onto the next step.

STEP 2: (S)-6'-CHLORO-5-(((l R,2R)-2-((S,E)-l -HYDROXY-4-((S)-l- SULF AMOYLP YRROLIDIN-2-YL)BUT-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO I BENZO [B] [1 ,4 ]OXAZEPINE-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC

ACID

To a 25 mL single-necked round-bottomed flask were placed (S)-6'- cMoro-5-(((l R,2R)-2-((S,E)-l ½droxyhex^

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyli c acid (75.5 mg, 0.148 mmol, Intermediate AA12A), (S)-2-ailylpyrrolidme~l~ sulfonamide (84 mg, 0.444 mmol), and 2" ^d generation hoveyda-grubbs catalyst (9.28 mg, 0.015 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (2.0 mL) was introduced through a syringe under nitrogen. The resulting mixture was stirred under nitrogen at rt for a period of 4 h. The crude mixture was subjected to combi -flash column chromatography ((EtOAc with 0.35% AcGH)/Hexanes, 35 min from 0 to 100%, 24 g 1SCO silica gel column) to give 90 mg of the title compound as a colorless film, impure and directly taken onto the next step. STEP 3: (lS,3'R,6'R,7^,8^,i rS)-6-CHLORO-7 ^! -HYDROX ^ir -3,4-DIHYDRO- 2H, 18 ^* H-SPIRO[N APHTHALENE- 1 ,25'-

[23]OXA[16]THIA[1, 15,17]TRIAZAPENTACYCLO[17.7.2.0 ³ " ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]OCT

ACOS A[ 8, 19,21 ,27]TETRAEN]-18'-ONE 16 ^! , 16'-DIGXlDE

To a stirred ice-cooled solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxy~4~((S)~l ~sulfamoylpyrro^^

3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-na phthalene]-7- carbox lic acid (95 mg, 0.151 mmol) and N,N-dimethylpyridin-4-amine (55.2 mg, 0.452 mmol) in DCM (75 mL) was added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (87 mg, 0.452 mmol) in one portion. The resulting mixture was stirred at at 0 °C for 10 min and at ambient temperature for a period of 6 h. After the volume was reduced, the crude mixture was subjected to combi-flash column chromatography ((EtOAc with 0.35% AcOH)/Hexanes, 35 min from 10 to 100%, 24 g 1SCO silica gel column) to give the title compound as the second eiuting fraction which was not pure. This was further purified by preparative reverse-phase HPLC (Gemini™ Prep Cie 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 40-95% acetonitriie in water, where both solvents contained 0.1 % TFA, 30 min method) to give, after lyophilization, 12 mg of the title compound (Example 345) as a white solid. ¾ NMR (500MHz, CDCb) δ 8.94 (br. s., 1H), 7.70 (d, ./ 8. Hz, 1H), 7.18 (dd, ./ 2.2. 8.6 Hz, i l l ). 7.09 (d, ./ 2.0 Hz, 1 1 1 ). 7.01 (d, ./ 7.8 Hz, 11 1 ). 6.92 (d, ./ H. I Hz, 1H), 6.77 (br. 8., IH), 5.95 (ddd, 4.2.10.3, 14.9 Hz, 111).5.73 (dd, H 8.15,2 Hz, !!!}.4.28 (dd, ./ 3.2.8.6 Hz, 1H), 4.16 ·· 4.00 (m, 3H), 3.97 - 3.81 (m, 2H), 3.76 ·· 3.62 (m, 2H), 3.23 (d, ./ 14.2 Hz, 1H), 3.08 (br. s., IH), 2.85 - 2.69 (m, 2H), 2.63 - 1.71 (m, 15H), 1,70 - 1.60 (m, III).1.43 (I.,/ 12.3 Hz, 111), m/z (ESI, +ve ion) 612.0 \\\-U) .

EXAMPLE 346. (1S,3'R,6'R,7 ^* S,8'E,1 l'S 6-CHLORO-16',16'-DIOXIDO-18'- OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,25'-

[23]OXA[16]THIA[1,15,17] RIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ^U ' ¹⁵ .0 ²² - ²⁷ ]OCT ACOSA|8,19,21,27]TETRAENj-7 ^! -YL ACETATE

The first eluting fraction from combi -flash column chromatography

((EtOAc with 0.35% AcOHVHexanes, 35 rain from 10 to 100%, 24 g ISCO silica gel column) in Example 345 gave the impure title compound. It was further purified by preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column: Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 2 mg of the title compound as a white solid. Note that the title compound was formed in situ by reacting under the reaction condition with the residual acetic acid brought in with the stalling material. ¾ NMR (400MHz,

CDC! ^: .) δ 8.28 is. ill .7.71 id../ 8.6 Hz, IH), 7.18 (dd, ./ 2.3.8.6 Hz, III).7.09 (d, ./ 2.3 Hz, IH), 6,95 - 6.84 (m, 2H), 6.74 (d, ,/ 1,8 Hz, IH), 6.04 - 5,90 (m, IH), 5.63 - 5,51 (m, IH), 5,31 (dd, ./ 3.7.9,0 Hz, IH), 4.16 (dd, ,7=4,0, 8.1 Hz, IH), 4.12 ·· 3.96 (m, 3H), 3.90 - 3.79 (m, 2H), 3.73 (d, ./ 1-1.3 Hz, IH), 3.18 (d, ./ 14.3 Hz, IH), 2.98 (dd, ,/ v.9 15.2 Hz, IH), 2.86 - 2.71 (m, 2H), 2.68 - 2.59

(m, IH), 2.48 - 2.25 (m, 2H), 2,20 - 1.52 (m, 15H), 1.45 - 1.34 (m, IH), m/z (ESI, +ve ion) 654.1 (M+H) ⁺ . EXAMPLE 347. (1 S,3'R,6'R,7 ^! S,8'E,1 rR)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 18 Ή- SPI RO [ NAPHTHALENE- 1,25'-

[23]OXA[ ; 16]THIA[ 1, 15, 17]TRTAZAPE TACYCLO[ 17.7.2.0 ³ · ⁶ .0 ^{J !} · ^{! 5} .0 ^2? - ²⁷ ]OCT ACOSA[8,19,21,27]TETRAEN]-18'-ONE 16Y16'~DIOXIDE

STEP 1 : (R)-2-ALLYLPYRROLI -l -SULFONAMIDE

A mixture of (R)-2-ailylpyrrolidine hydrochloride (1.00 g, 6.77 mmol), sulfamide (1.953 g, 20.32 mmol), and triethylamine (1.413 mL, 10.16 mmol) in 1,4-dioxane (20 mL) was stirred under nitrogen at 85 °C (a preheated oil bath) for a period of 16 h. It appeared that still some sm was remaining. The volume was reduced in vacuo and the residue was subjected to combi-flash column chromatography (EtOAc/Hexanes, 35 min from 0 to 100%, 40 g 1SCO silica gel column) to give (R)-2-allylpyrrolidine-l -sulfonamide (0.75 g, 3.94 mmol, 58.2 % yield) as a white crystalline solid, taken onto the next step.

STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -HYDROXY-4-((R)-l - SULF AMOYLP YRROLIDIN-2-YL)BUT-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,l ^, -NAPHTHALENE]-7-CARBOXYLIC ACID

To a 25 niL single-necked round-bottomed flask were placed (S)~6 ^! - cWoro-5-(((lR,2R)-2-((S,E)-l-hydrox 'hex-2-en-l-yl)cyclobutyl)methyl)-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (74.0 mg, 0.145 mmol. Intermediate AA12A), (R)-2-allylpyrrolidine-l- sulfonamide (83 mg, 0.435 mmol), and 2 ^nd generation hoveyda-grubbs catalyst (9.09 mg, 0.015 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before DCE (2.0 niL) was introduced through a syringe under nitrogen. The resulting mixture was stirred under nitrogen at rt for a period of 3 h. The crude mixture was subjected to combi -flash column chromatography ((EtOAc with 0.35% AcOH)/Hexanes, 35 min from 0 to 100%, 24 g ISCO silica gel column) to give 70 mg of the title compound as a colorless film, impure and taken onto the next step directly. STEP 3: (lS,3'R,6'R,7'S,8'E,irR)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 18'H-SPIRO[N APHTHALENE- 1 ,25'-

[23]OXA[16]THIA[1 _S 15 ₅ 17]TRIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]OCT

ACOS A[ 8, 19,21 ,27 jTETRAEN j- 18'-ONE 16', 16'-DIOXIDE

To a stirred ice-cooled solution of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydrox '-4-((R)-l-sulfamoylpyrrolidin-2-yl)but-2-en-l -yl)cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r- naphthalene]-7- carboxylic acid (70 mg, 0.1 1 1 mmol) and N,N-dimethylpyridin-4-amine (40.7 mg, 0.333 mmol) in DCM (55 ml,) was added l-(3-dimethylaminopropyl)-3- ethyicarbodiimide hydrochloride (63.9 mg, 0.333 mmol) in one portion. The resulting mixture was stirred at 0 °C for 10 min and at ambient temperature for a period of 7 h. After the volume was reduced, the crude mixture was subjected to preparative reverse-phase HPLC (Gemini ^lM Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 mm method) to give, after lyophilization, 4.5 mg of the title compound as a white solid. ¾ NMR (4()()MHz, CDCh) δ 8.84 (s, IH), 7.71 (d, J=8.6 Hz, 1H), 7.18 (dt, ,/ 22.8.5 Hz, 2H), 7,09 (d, ./ 2.2 Hz, 1H), 6.96 (d, ,7=8,2 Hz, H), 6.74 (s, H), 6.30 -6,13 (m, IH), 5.73 (dd, «7=6.9, 15,6 Hz, IH), 4.23 (dd, ,7=2.8, 7.1 Hz, IH), 4.14 - 3.81 (m, 5H), 3.75 - 3,57 (ni, 2H), 3.32 (d,■/ 14.5 Hz, IH), 3.13 (dd, ,7=10.3, 15.0 Hz, IH), 2.89 - 2.59 (m, l).2.50 - 1,60 (m, 15!!).1.45 {I. 11.911/. IH). m/z (EST, +ve son) 612.0 (\f ·!!} ^' , EXAMPLE 348. (^ ' ,ό'Κ^ ,δΈ,ΙΓΚ^ό-ΟΗΕΟΚΟ-Ιό',Ιό'-ΟΙΟΧΙΟΟ-Ιδ '- OXO-3,4-DIHYDRO-2H-SPIRO| APHTHALENE- 1 ,25'-

[23]OXA[16]THIA[1,15,17]T1¾IAZAPENTACYCLO[17.7.2.0 ³ " ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]OCT

ACOSA[8,19,21,27]TETRAEN |-7'-YL ACETATE

The title compound (7.0 mg) was obtained as a white solid as the second eiuting isomer from preparative reverse-phase HPLC (Gemini™ Prep Cis 5 um column; Phenomenex, Torrance, CA; gradient elution of 45-95% acetonitrile in water, where both solvents contained 0,1% TFA, 30 min method) in Example 347, Note that the title compound was formed in situ by reacting under the reaction condition with the residual acetic acid brought in with the starting material. ¾ NMR (500MHz, CDCb) δ 8,51 (br. s,, IH), 7.70 (d, .7=8,6 Hz, IH), 7.19 (dd, J=2.2, 8,3 Hz, IH), 7.09 (d, ,7=2.0 Hz, IH), 7.04 (d, ,7=8.1 Hz, IH), 6,94 (d, ./ 8.1 Hz, IH), 6.77 (br. s., IH), 6.12 - 5.97 (m, IH), 5.59 (dd, ./ 5.9.15.4 Hz, 1 IT), 5.27 (br. s., IH), 4,16 - 4,01 (m, 3H), 3.92 - 3.79 (ra, 2H), 3,69 id../ 14.2 Hz, IH), 3.61 (d, ,7=14.9 Hz, IH), 3.30 (d, ,7=14.2 Hz, IH), 3.17 - 3,06 (m, IH), 2.88 - 1.58 (m, 2011).1.45 (t, ,/ 12.5 Hz, IH). m/z (ESI, +ve ion) 654.1 (M+H) ⁺ . EXAMPLE 349, (1 S,3'R,6'R,8'E, 1 I'S, 12"R)-6-CHLORO- H',12'-DIMETHYL- 3 ,4-DIH YDRQ-2H, 7Ή, 15 Ή-SPIRO [ APHTHALENE- 1 ,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAENE]~7', 15"-DIONE 13', 13'-DIOXIDE

To a stirred ice-cooled solution of (1S,3 ^! R,6'R,7 ^! S,8'E,1 l'S,12'R)-6-chloro- 7'-hy droxy- 1 , 12'-dimethyl-3,4-dihy dro-2H, 15'H-spiroj naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]cUazatetracyclo^^

n]-15'-one 13',13'-dioxide (550 mg, 0.918 mniol. Example 719, Step 2) in DCM (10 mL) was added dess-martin periodinane (401 mg, 0.918 mmol) in one portion as a solid. The resulting mixture was stirred at 0 °C for a period of 0.5 h. The crude mixture was loaded onto a silica gel pre-column and subjected to combi- flash column chromatography (EtGAc/Hexanes, 40 mm from 0 to 60%, 40 g ISCO silica gel column) to give the title compound (483.4 mg, 0.809 mmol, 88 % yield) as a crystalline white solid. ^] H NMR (500MHz, CDCh) δ 8.02 (s, 1H), 7.76 (d, J=8.3 Hz, IH), 7,36 (d, J=2.0 Hz, 1H), 7.20 (dd, «/=2.3, 8,4 Hz, 1H), 7.08 (d, ./ 2.2 Hz, IH), 6.88 - 6.81 (m, 1H), 6.77 (dd, J=2.0, 8.1 Hz, IH), 6.69 - 6.58 (m, HI).5.91 (d, ,/ 15.7 Hz, IH), 4.21 - 3.98 (m, 3H), 3.94 - 3.81 (m, 2H), 3.76 (q, ,/ 95 Hz, IH), 3.25 (d,J=14,4Hz, H), 3.12 - 3,01 (m, IH), 2.98 (dil.J 3 I.15,5 Hz, IH), 2,85 - 2,66 (m, 2H), 2.25 - 1.53 (m, lOH), 1.50 (d, J=7.3 Hz, 3H), 1,43 - 1.35 (m, IH), 1.15 (d, J=5.9 Hz, 3H). m'z (ESI, +ve ion) 597.1 {W W) .

EXAMPLE 350. (1 S,3'R,6'R,9'R, I I'S,12'R)-6-CHLORO-l r,12'-DIMETOYL-9'- ((1 E)- 1 -PROPEN- 1 -YL)-3,4-DrHYDRO-2H,7'H, 15'H-SPIRO [N ^" APHTH ALE E- 1 ">"> ^< -

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ^]9 ' ²⁴ ]PE TACOSA

[ 16, 18,24]TRIENE] -7', 15'-DIONE 13', 13'-DIOXlDE

To a 25 -mL single-necked round-bottomed flask were placed

(1 S,3'R,6'R,8'E, 11 'S,12'R)-6-chloro-l 1 ', 12'-dimethyl-3,4-dilwdro-2H,7'H,l 5Ή- spiro [naphthalene- 1 ,22'- [20]oxa|; i 3]thia[ U4]diazatetra^

ne]-7',15'-dione 13', 13'-dioxide (190 mg, 0.318 mmol, Example 349), trans- propenylboronic acid (137 mg, 1.591 mmol),

(acetylacetonato)bis(ethylene)rhodium (i) (16.43 mg, 0.064 mmol), and (R)-(+)- 2,2'-bis(diphenylphosphino)-l , l '-binaphthyl (39.6 mg, 0.064 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before dioxane (2.0 mL) was added followed by water (0.2 mL). The resulting mixture was stirred at 100 °C under nitrogen for a period of 5 h. After cooled, the mixture was filtered through a layer of celite and the cake was washed with EtOAc. The filtrate was concentrated in vacuo. The residue was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography

(EtO Ac/Hexanes, 40 min at 20%, 40 g silica gel, 13 mm tubes) to give a major peak, which contained 3 compounds, presumably the desired product(s), the unreacted sm, and an unknown product. This was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA: gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1 % TFA, 30 min method) to give, after lyophilization, 28 mg of the title compound as an off-white solid, 'H MR (500MHz, CDCh) δ 8.21 (s, ! H), 7.68 (d, ./ 8.6 Hz, 1H), 7.19 (dd, J=2.2, 8.6 Hz, lH), 7.09 (d, ./ 2.2 Hz, 1H), 7.03 - 6.80 (m, 3H), 5.27 - 5.02 (m, 2H), 4.19 - 4.04 (m, 2H), 3.88 (dq, J=2.7, 7.3 Hz, 1 H), 3.81 - 3.66 (m, 2H), 3,32 - 3.17 (m, 3H), 2.91 - 2.69 (m, 3H), 2,50 - 2.25 (m, 3H), 2.22 - 2. 12 (m, i l l ). 2,07 - 1.64 (m, 11 1 ). 1.56 (d, .7=5,6 Hz, 3H), 1.51 - 1 ,38 (m, 4! i ). 1 .28 - 1.24 (m, 2H), 1 ,03 (d, ./ 6.8 Hz, 3H). m/z. (ESI, +ve ion) 639.0 ί M H )

EXAMPLE 353. (l S^'R.e'^ 'S^ l'S RJ-e-CHLORO-i r ^-DIMETHYL-Q'- ((1 E)- 1-PROPEN- 1 -YL)-3,4-DIHYDRO-2H,7'H, 15'H-SPIRO[NAPHTHALENE- 1.22'-

| 2u jOXA| 1 ΉΤί !1Λ| Μ 4 |ΠίΛ/.ΥΠ:ΤΗ Λ(Ύα.ί)Ι i 4.7.2.0 · ^, '.ί ^{) | :} ' ^{! 1} |P1-M ^' .\C<)SA [ 16,18,24]TRIENE]-7',15'-D ',13'-DIGXIDE

To a 25 -mL single-necked round-bottomed flask were placed

(1S,3'R,6 ^! R,8'E,1 rS,12'R)-6-chloro-l l ^* ,12 ^, -dimethyl-3,4-dihydro-2H,7 ^, H,l 5Ή- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetracyclo[14.7 _^

ne]-7',15'-dione 13',13'-dioxide (294 mg, 0.492 mmol, Example 349), trans - propenylboronic acid (211 mg, 2.46 mmol),

(acetylacetonato)bis(ethylene)rhodium (i) (25 mg, 0.098 mmol), and (s)-(-)-2,2'- bis(diphenylphosphino)-l ,l'-binaphthyl (6.1 mg, 0.098 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with nitrogen before dioxane (3.0 mL) was added followed by water (0.3 mL). The resulting mixture was stirred under nitrogen at 100 °C for 5.5 h. After cooled, the mixture was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography (EtOAc/Hexanes, 40 min at 20%, 40 g ISCO silica gel column) to give a major peak, which contained 3 compounds, presumably the desired product, the unreacted sm, and an unknown product. This was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give 65 mg of the title compound as an off-white solid. *H NMR (500MHz, CDCh) δ 8.24 (s, IH), 7.70 (d, J=8.6 Hz, ill).7,22 - 7.16 (m, 2H), 7.09 (d, 2.2 Hz, ill).7.02 - 6,94 (m, IH), 6.94 - 6.90 (m, IH), 5.44 - 5.34 (m, IH), 5.17 (ddd, J=1.5, 7.9, 15.3 Hz, IH), 4.20 - 4.14 (m, IH), 4.13 - 4.06 ins.2! I ).3.86 (dd, ./ 5.7.15.5 Hz, IH), 3.68 (d, ,/ 14.4 Hz, IH), 3.28 - 3.14 (ns.2H), 3,03 (dd, ./ 5.6. 15.7 Hz, IH), 2.90 - 2.69 (ra, 311).2,64 - 2.54 (m, IH), 2.33 - 2.16 (m, 2H), 2.07 - 1.67 (m, 8H), 1.57 (dd, J=1.5, 6.4 Hz, 3H), 1.51 - 1.37 (m, 5H), 1.22 (ddd, J=2.8, 11.6, 14.5 Hz, IH), 1.02 (d,J=6.8Hz, 3H). m/z (ESI, +ve ion) 639.0 (M+H) ⁺ .

EXAMPLE 357. ETHYL (2S)-((lS,3 ^! R,6'S,7'E,9 ^, S,irS,12'R)-6-CHLORO- 1 l',12'-DIMETHYL-l 3',13'-DIOXIDO-15'-OX()-3,4-DIH ^ir DRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^{' !'} .ϋ'" ^!| |Pi-N i ACOSA [7,16,18,24] TETRAEN] - 9'- YL)(METHOXY)ETHANO ATE

STEP 1: (!S,3'R,6'R,7'S,8Til rS,12'R)-6-CHLORO-7'-METHOXY-l l',12 ^! ~ D1METHYL-3 ,4-DlHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ^l9 - ²⁴ ]PE TACOSA

[8, 16, 18,24]TETRAEN] - 15'-GNE- 13', 13'-DIOXIDE

To a slurry of ( 18,3¾ ^'8,8Έ^ Γ8, ί2'Κ)-6-Λ1οΐΌ-7'-1ιν*οχν- 1 Γ, 12'- dimethyl-3,4~dihydro-2h, 15'h-spiro[naphthalene-l ,22 ^! ~

[20]oxa[13]thia[ l, 14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16, 18,24]tetrae n|-15'-one 13', 13'-dioxide (Example 719, Step 2; 32.6 g, 49. 1 mmol) (containing 9.8% toluene, starting materi al was not completely soluble in Me-THF) and Mel (15,2 ml, 245 mmol) in Me-THF (820 ml) was added KHMDS (1 .0 M in THF, 167 ml, 167 mmol) dropwise for 30 mm while maintaining reaction temperature between - 44 °C and - 38 °C under N2. After the mixture was stirred at - 44 °C for 30 min, the reaction was allowed to warm to ambient temperature and stirred for 1.5 h (LCMS confirmed the reaction was complete). The reaction mixture was cooled to 5 °C, quenched ( 170 mL of saturated aqueous NH4CI and 170 mL of water) carefully while maintaining temperature between 5 °C and 14 °C, and acidified (340 mL of 10% aqueous citric acid). The organic layer was separated and the aqueous layer was back-extracted with EtOAc (500 mL). The combined organic layers were washed with brine (3 500 mL), dried (MgSC ), and concentrated under reduced pressure to provide a crude target compound (30.1 g, 49.1 mmol, quantitatively) (purity >98% with no over 1 % major impurity from HPLC) as a bright yellow solid. After the same scale reaction was repeated for four times, all the crude products (4 ^χ 49.1 mmol = 196 mmol) were dissolved in EtOAc, combined, and concetrated under reduced pressure. Then the combined crude product was recrystailized as follows: ethanol (800 mL) was added to the cmde product and the resulting slurry solution was shaked well while heating the solution for 20 min. Water (250 ml.) was added dropwise for 30 min at rt and the slurry was cool down to 0 °C. After the slurry was kept in ice bath for 4 h, the solid product was filtered through filter paper. The filter cake was rinsed with ice- cold 30% water in EtOH (300 mL) and air-dried for 2 days. The product was further dired under high vacuum at 40 °C for 4 days to provide the pure target compound (1 15 g, 188 mmol, 96% yield) as a white solid: ¾ NMR (600 MHz, DMSG-ife) δ 1 1.91 (s, 1 H), 7.65 (d, ,/ 8.6 Hz, 1 H), 7.27 i dd. ./ 8.5, 2,3 Hz, 1 H), 7.17 (d, J = 2.4 Hz, 1 H), 7.04 (dd, J= 8.2, 2.0 Hz, 1 H), 6.90 (d, J = 8.2 Hz, 1 H), 6.76 i d. ./ 1.8 Hz, 1 H), 5.71 (ddd, ,/ 15.1, 9.7, 3.5 Hz, 1 H), 5.50 (ddd,■/ 15.2, 9.2, 1 , 1 Hz, 1 H), 4.08 (qd, ,/ 7.2, 7,2, 7.2, 1.5 Hz, 1 H), 4.04 (d, 12,3 Hz, 1 H), 3.99 (d, J = 12.3 Hz, 1 H), 3.73 (d, J = 14.9 Hz, 1 H), 3.56 (d, J = 14.1 Hz, 1 H), 3.53 (dd. J 9.1, 3.3 Hz, 1 H), 3.19 (d, J = 14.1 Hz, 1 H), 3.09 (s, 3 H), 3.03 (dd, J ------ 15.4, 10.4 Hz, 1 H), 2.79 (dt, ./ 17.0, 3.5, 3.5 Hz, 1 H), 2.69 (ddd, J ------ 17.0, 10,7, 6.3 Hz, 1 H), 2.44-2.36 (m, 1 H), 2.24-2. 12 (m, 2 ! ! }. 2.09 (ddd, ,/

15,5, 9.6, 2.3 Hz, 1 H), 1.97 (dt, ./ = 13.6, 3,6, 3.6 Hz, 1 H), 1.91-1.80 (m, 4 H), 1.80-1.66 (m, 3 H), 1.38 (td, ./ 12.3, 12.3, 3.5 Hz, 1 H), 1.33 (d, ./ 7.2 Hz, 3 H), 0.95 (d, ,/ 6.8 Hz, 3 H); [a jo (24 °C, c - 0.0103 g/mL, DCM) - - 86.07 °; m.p. 222.6 - 226.0 °C; FT-IR (KBr): 3230 (b), 2931 (b), 1688 (s), 1598 (s), 1570 (s), 1505 (s), 1435 (s), 1384 (s), 1335 (s), 1307 (s), 1259 (s), 1155 (s), 1 1 13 (s), 877 is ). 736 (s) cm ^'1 ; Anal, Calcd. for C33H41CIN2O5S: C, 64,64; H, 6.74; N, 4,57; CI, 5,78; S, 5.23, Found: C, 64.71 ; H, 6.81 ; N, 4.65; CI, 5.81 ; S, 5.11; HRMS (ESI) m/z 613.2493 | Y1 + H] ⁺ (C33H41CIN2O5S requires 613.2503).

The mother liquor was concentrated under reduced pressure and further purification of the residue by flash column chromatography (200 g S1O2, 10% and 10% to 45% and 45%> EtQA-'hexanes w/ 0.3% AcOH, gradient elution) provided additional pure product (3.1 g, 5.1 mmol, 2.6%) as a off-white soild.

STEP 2: ETHYL (2R)-((lS,3'R,6'S,7'E,9'S,i rS,12'R)-6-CHLORO-l l',12 ^! - DIMETHYL-13',13'-DIOXlDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [7,16,18,24] TETRAEN] - 9'- YL)(METHOXY)ETHANO ATE

To a stirred solution of (l S,3¾,6 ^* R,7^,8'E,i rS,12'R)-6-chioro-7 ^! - methoxy-1 Γ,12'-dimethyl-3,4-dihydro-2HJ 5Tl~spirojna,phthalene~l,22'-

[20] oxa[ 13] thia[ 1 , 14] diazatetracy cl 0 [ 14, 7.2, O^ ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13', 13'-dioxide (152 mg, 0.248 mmol) and rhodium (ii) acetate dimer (11 rag, 0.025 mmol) in DCM (3 mL) was added dropwise a solution of ethyl diazoacetaie (0.077 mL, 0.74 mmol) in DCM (2 mL) at ambient temperature over 6 min. The resulting mixture was stirred at ambient temperature for 1 h 20 min. The reaction stalled and the mixture was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography (EtOAc/Hexanes, 30 rain from 0 to 100%, 24 g 1SCO silica gel column) to give an impure product mixture. This was taken up in DMSO and subjected to preparative reverse-phase HPLC

(Gemini ^1M Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetoiiitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give 7.0 mg of the title compound as the first eluting fraction as a light orange solid. ^! H NM (400MHz, CD2CI2) δ 8.01 (s, IH), 7.71 id. ./ 8.4 Hz, IH), 7.16 (dd, J=2.2, 8.5 Hz, i l l ). 7.09 (d, ,7=2,2 Hz, IH), 7.01 - 6,87 (m, 3H), 5.90 (dd, ./ 4.7. 15.5 Hz, IH), 5.28 - 5.16 (m, IH), 4,25 - 4.02 (m, 6H), 3.82 (d, ./ 1 5.5 Hz, IH), 3.66 - 3.58 (m, 2H), 3.34 (s, 3H), 3.23 - 3, 14 (m, IH), 3.07 (dd, J=8.0, 15.5 Hz, IH), 2.80 - 2.71 (ra, 2H), 2,56 (dt, ./ 4.3. 8.7 Hz, 2H), 2.22 - 1.56 (111, 7H), 1 ,52 - 1.39 (m, 5H), 1.31 - 1.23 (m, 5H), 0,98 (d, «/=6.8 Hz, 3H). m/z (ESI, +ve ion) 699.1 < M 1 0 . EXAMPLE 358, ETHYL (2R)-((1 S,3'R,6 ^! S,7'E,9'S, i l'S,12 ^! R)-6-CHLORO- i r,12'-DlMETHYL-13',13'-D10XIDO-15'-OXO-3,4-DlHYDRO-2H~

SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[7, 16, 18,24]TETRAEN] -9'-YL)(METHOXY)ETHANOATE

The title comppund (4,0 mg) was obtained as the second eluting fraction as a light orange solid from the to preparative reverse-phase HPLC purification in Example 357, Step 2. ^; l ! NMR (400MHz, CD2CI2) 6 7.99 (s, IH), 7.71 (d, ./ 8.6 Hz, I H), 7.16 (dd,■/ 2,3. 8.4 Hz, IH), 7,09 id. ./ 2.3 Hz, IH), 7.03 - 6.89 (m, 3H), 5.95 (dd. ,/ 4 4. 15.6 Hz, IH), 5,22 (ddd. ./ 1 .6. 8.5, 15,4 Hz, IH), 4.21 - 3,97 (m, 6H), 3.83 (d, .7=15,5 Hz, IH), 3.62 (d, .7=14.5 Hz, IH), 3,50 (d, J=6.5 Hz, IH), 3.32 (s, 3H), 3.18 (d, J=14, l Hz, IH), 3.06 (dd, J=8.2, 15.5 Hz, IH), 2.83 - 2.70 (m, 2H), 2,54 (br, s . 1 1 1 ). 2.48 - 2.35 (ra, i l l ). 2,23 - 1 ,57 (m, 71 1 ). 1 .52 - 1.20 (ra, 10H), 0.97 (d, ,7=6,8 Hz, 3H), rn/z (ESI, +ve ion) 699, 1 (M+H) ⁺ .

EXAMPLE 359. (2S)-((1 S,3'R,6'S,7'E,9'S,1 rS, 12'R)-6-CHLORO-l Γ,12'- DIMETHYL -1.3', 13"-DIOXIDO-l 5"-OXO-3,4-DIHYDRO-2H- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]THIA[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [7, 16, 18,24]TETRAEN]-9'-YL)(METHOXY)ETHANOIC ACID

To a stirred solution of Ethyl (2S)-((1 S,3'R,6'S,7 ^! E,9'S,1 l'S,12'R)-6- chloro-i r,12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracyd^^

n]-9'-yl)(methoxy)ethanoate (3.0 mg, 4.3 μηιοΐ, Example 357) in a mixed solvent comprising MeOH (0.5 mL), THF (0.5 mL), and water (0, 1 mL) was added lithium hydroxide monohydrate (0.45 mg, 11 μηιοΐ) at rt. The resulting mixture was stirred at 50 °C for 2 h and left stirred at ambient temperature over the weekend. The volatiles were removed, the residue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give 0.3 mg of the title compound as a white solid. ¾ NMR (500MHz, CD2CI2) δ 7,99 (s, i l l ). 7,71 (d, ./ 8,6 Hz, IH), 7.16 (dd, ./ 2,3. 8.4 Hz, i l l ). 7,09 (d, ./ 2.2 Hz, IH), 7.02 - 6.87 (m, 31 ! }. 6.00 (dd, ./ 4.5. 15.5 Hz, IH), 5.28 (d,■/ 8.8 Hz, I H), 4.19 - 4.09 (m, 2H), 4,09 - 4.02 (m, IH), 3.83 (d, ,/ 15.4 Hz, IH), 3,69 (d, ./ 3.9 Hz, IH), 3.61 (d, ,7=14,2 Hz, IH), 3.47 (s, 3H), 3. 18 (d, .7=13,9 Hz, IH), 3,07 (dd, J=8.2, 15.5 Hz, IH), 2.82 - 2.68 (m, 2Π).2.58 (d, 5. ! Hz, 2H), 2.21 - 1,33 (m, 15!!). 0.99 (d, ,7=6,8 Hz, 3H). m/z (ESI, +ve ion) 671.0 (VI 11) .

EXAMPLE 360. (2R)-((1S,3 ^, R,6 ^, S,7 ^, E,9 ^, S,1 l'S ₅ 12'R)-6-CHLORO-l l',12'- DIMETHYL -13', 13"-DIOXIDO-l 5"-OXO-3,4-DIHYDRO-2H-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TOIA[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [7, 16, 18,24]TETRAEN]-9'- OIC ACID

The title compound (0.4 nig) was prepared as a white solid from Ethyl

(2R)-((1 S,3'R,6'S,7'E,9'S,1 l'S,I2'R)-6-chloro-l l ^f ,12'-diraethyl-! 3',13'-dioxido- 15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[7,16

n]-9'-yl)(methoxy)ethanoate (Example 358) following the procedure described for Example 359. ^l H NMR (400MHz, CD2CI2) δ 8.00 (s, IH), 7.71 (d, ,/ H4 Hz, 1H), 7.16 (dd, J=2,3, 8.4 Hz, IH), 7,09 (d, ./ 2.2 Hz, 1H), 7.02 - 6.89 (m, 3H), 6.01 (dd, =4.8, 15.4 Hz, IH), 5.26 (dd, J=8.0, 15.7 Hz, IH), 4.21 - 4.08 (m, 2H), 4.03 (d, J=4.9 Hz, IH), 3.83 (d, ./ 15.3 Hz, IH), 3.68 - 3.56 (m, 2H), 3.43 (s, Ml).3.19 (d, ,/ i 43 Hz, IH), 3.08 (dd, ,/ HO.15,7 Hz, IH), 2.85 - 2,69 (m, 2H), 2.63 - 2.47 (m, 2H), 2.24 - 1.29 (m, 15H), 0,99 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 671.0 I 11 > ^" .

EXAMPLE 361. (2S)-2-((l S,3'R,6 ^! S,7'E,9'S,i i'S,12 ^! R)-6-CHLORO-l 1 ^! ,12'- DIMETHYL- 13', 13 '-DIOXIDO- 15 '-OXO-3 ,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [7, 16, 18,24]TETRAEN] -9'-YL)-2-METHOXY-N-METHYLETHAN AMIDE OR (2Κ)-2-((18 ₅ 3¾,6 ^, 8 ₅ 7Έ ₅ 9 ^, 8,11 ^, 8,12 ^, Κ)-6-ΟΗίΟΚΟ-11\12 ^, -ΟΙΜΕΤΉΥί-13 ^, ,13'-

DIOXIDO-15'-OXO ,4-DIHYDRO-2H-SPIRO[ APH^

|2( ⁾ jOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/.ΥΠ:ΤΗΛ(ΎΠ.ϋΙ i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' AC<)SA

-9'-YL)-2-METHOXY-N-METHYLETHANAMIDE

STEP 1: SODIUM (2S)-((1S,3 ^! R,6'S,7 ^! E,9'S,1 l'S,12 ^, R)-6-CHLORO-ir,12'- DIMETHYL-13 ^! ,13'-DIOXID()-15'-OXO-3,4-DIHYDR()-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 (Γ ".O ¹ " ^M |PH\ i ACOSA [7,16,18,24]TETRAEN]-9'-YL)(METHOXY)ETHANOATE AND SODIUM (2R)-((lS,3'R,6'S,7¾9^,ll^,12'R)-6-CHL()RO-ir,12 ^! -DIMETHYL-13',13'- DIOXIDO-lS'-OXO-S^-DlHYDRO^-SPmorNAPHTHALENE-l^^- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [7, 16, 18,2 -9'-YL)(METHOXY)ETHANO ATE

A mixture of ethyl (2S)-((lS,3'R,6'S,7'E,9'S,i rSJ2'R)-6-chloro-l l',12'~ dimethyl- 13', 13'-dioxido~ 15'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1 ,22 ^! ~

[2C)joxa[13]thia[l,14]diazatetra^

n]-9 ^, -yl)(methoxy)ethanoate and ethyl (2R)-((iS,3'R,6'S,7 ^f E,9'S,! I'S,12'R)-6- chloro-ll 2'-diniethyi-13 13 ^! ~dioxido-l5'-oxo-;^4-dihydro-2H- spiro [naphthalene- 1 ,22'- j;2Q]oxa[13]thiajl,14]diazatetra^^^ n]-9'-yl)(methoxy)ethanoate (54 mg, 0.080 mmol, Examples 357 and 358) and lithium hydroxide monohydrate (15 mg, 0.36 mmol) in a mixed solvent of MeOH (1 mL), THF (1 mL), and water (0.1 mL) was stirred at 50 °C for 20 min. The reaction appeared going rather slowly. More lithium hydroxide monohydrate was added followed by a bit more water. The mixture was stirred for another 40 min. The volatiles were removed, the residue was subjected to high vacuum before taken onto the next step.

STEP 2: (2R)~2-((l S,3¾ VS,7T;,9 ^, S,l l^,12 ^! R)-6-CHLORO-1 1 ^12' miETHYL- 13 ', 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI M.T^.O'^.O^^lPE TACOSA [ , 16, 18,24]TETRAEN] -9'-YL)-2-METHOXY-N-METHYLETHAN AMIDE OR (2S)-2-((l S,31 ,6 ^, S,7T,9 ^, S,i rS,12'R)-6-CHLORO-l l 2'-DlMETHYL-13 ^, ,13'- D10XlDO-15 ^, -OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [7,16, 18,24]TETRAEN]-9'-YL)-2-METHOXY-N-METHYLETH AN AMIDE

To a stirred solution of a mixture of sodium (2S)- ((l S,3'R,6'S,7T,9^,l l^, 12'R)-6-chloro-11^ 12 ^, -dimeihyl-13',13'-dioxido-15 ^, -oxo- 3,4-dihy dro-2H-spiro| naphthalene- 1 ,22'- [20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[

n]-9 ^, -yl)(methoxy)ethanoate and sodium (2R)-((1 S,3'R,6'S,7'E,9'S,1 l 'S, 12'R)-6- chloro-1 r,12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H- spiro [naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[7,16,18,24]tetrae n]-9'-yl)(methoxy)ethanoate (55 mg, 0.080 mmol) and hatu (91 mg, 0.24 mmol) in DMF (2 mL) was added methylamine, 2,0 M solution in THF (0,20 mL, 0.40 mmol) at ambient temperature followed by diisopropylethylamine (0.14 mL, 0.80 mmol). The resulting mixture was stirred at ambient temperature for 20 min. The volatiles were removed in vacuo and the residue was dissolved in DMSO/DMF and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 40-95%) acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give 8.0 mg of the title compound as the second eluting fraction as a light yellow solid. Ή NMR (500MHz, CD2CI2) δ 7.99 (s, 1H), 7.71 (d, =8.3 Hz, 1H), 7.16 (dd, =2.4, 8.6 Hz, 1H), 7.09 (d, ./ 2.2 Hz, 111.7.02 - 6.95 (m, 2H), 6.94 - 6.89 (m, ill .6.64 (q, ,/ 42 Hz, 111).5.92 (dd, ,/ 50.15.5 Hz, ill).5.27 (dd, ./ 7.7.16.0 Hz, III). 4.19 - 4.06 (m, 2H), 4.04.3.95 ( _m , !}{).3,82 (d, ./ 15.-1 Hz, IH), 3.62 (d, .7=14.2 Hz, 1H), 3.49 (d, ./ 5.1 Hz, IH), 3.36 (s, 3H), 3.18 (d, .7=14.2 Hz, lH), 3.08 (dd, J=8.1, 15.4 Hz, 111).2.82 (d, ,7=4,9 Hz, 3H), 2.79 - 2.72 (m, 2H), 2,63 - 2.39 (m, 2H), 2.13 (quin, «7=8.9 Hz, IH), 2.04 - 1.75 (m, 7H), 1.69 - 1,57 (m, IH), 1.53 - 1.42 (m, 2H), 1.39 - 1.24 (m, 4H), 0.97 (d, ./ 7.1 Hz, 3H). m/z (ESI, +ve ion) 684.1 (M+H) ⁺ .

EXAMPLE 362. (2R)-2-((l S,3'R,6'S,7'E,9'S, 11 'S, 12'R)-6-CHLORO- 11 ', 12'- DlMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( >X A| I ?! ! ί U Ai i 1 -J |? !,\ Ά ! : I AC VC ^' fOi 147.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA [7,16,18,24]TETRAEN]-9'-YL)-2-METHOXY-N-METHYLETHANAMIDE AND (2S)-2-((lS,3'R,6 ^! S,7'E,9'S,l l'S,12'R)-6-CHLGRO-l l',12'-DIMETHYL- 13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,2 2'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA [7,16,18, -9'-YL)-2-METHOXY-N-METHYLETHANAMIDE

The first eluting fraction from the preparative reverse-phase HPLC purification in Example 361, Step 2 provided 5.0 mg of the title compound as a light yellow solid. It was a mixture of two epimers of a ratio of 44 to 56 (the first one eluting out of the reverse-phase HPLC column to the second one). ¾ NMR (500MHz, CD2CI2) δ 8.01 (br. s„ ill).7,7! id../ 8.611/.1H), 7.16 Uld. ,/ 2.3.8,4 Hz, 1H), 7.09 (d, ,/ 22 Hz, I Hi.7.03 - 6.85 (m, 3H), 6,61 (q, J=4.6 Hz, 0.56H) [from the second epimer coming out the reverse-phase HPLC column], 6.51 (br. s., 0.44H) [from the first epimer coming out of the reverse-phase HPLC column], 5,92 (dd, J=5.0, 15.5 Hz, 111).5.30 - 5.22 (ra, ill).4.22 - 3.94 (m, 311).3.82 (d, J=15.4 Hz, I Hi.3.67 - 3.57 (m, ill).3,55 - 3.44 (m, III).3.39 (s, 1.3211) [from the first epimer coming out of the reverse-phase HPLC column], 3.36 (s, 1.68H) [from the second epimer coming out of the reverse-phase HPLC column], 3.18 (d, 14.2 Hz, III).3,08 (dd, ./ 8.1.15.2 Hz, III).2.85 - 2.71 (m, 5H), 2,62 - 1.19 (ni, 1 !!).1.07 - 0.92 (m, 4H). m/z (ESI, +ve ion) 684.1 (M+H) ⁺ .

EXAMPLE 363, (2S)-2-((lS,3 ^, R ₅ 6 ^, S,9 ^, R ₅ ll ^, S,12 ^, R)-6-CHLORO-n ^, ₅ 12 ^* - DlMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-9'-YL)-2-METHOXY-N-METHYLETHANAMIDE OR (2R)- 2 (lS,3 ^, R,6'S,9'R,irS,12'R)-6-CHLORO-ir,12'-DlME ^' raYL-i3 ^, ,13'- DIOXIDO-lS'-OXO-S^-DIHYDRO^-SPIROINAPHTHALENE-l^^- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [16,18,2 -9'-YL)-2-METHOXY-N-METHYLETHAN AMIDE

A vigorously stirred mixture of (2R)-2-((lS,3'R,6'S,7 ^! E,9 ^! S,l i'S,12'R)-6- chloro-ir,12'-dimethyl.l3',13'-dioxido-I5'-oxo-3,4-dihydiO-2 H- spiro[naphthalene-l,22'- [20]oxa[!3]thia[i,!4]diazatetracyclo[14.7,2.0 ^3>6 0 ^!9 ^

n]-9'-yl)-2-m.ethoxy-N-methylethanamide or (2S)-2- ((l S,:rR,6^ T 9'S, l l'S;i2¾)-6-chk)ro-l l V12'-dimethyl-1 3VI 3'-dioxido- 15'H)xo- 3,4-dihydro-2H-spiro[naphthalene- 1 ,22'-

n]-9'-yl)-2-me1hoxy-N-methylethanamide (not weighed, Example 361) and platinura (iv) oxide (in excess) in EtOAc (5 ral.) was baloon-hydrogenated over a period of 2.5 h. The crude mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in DMF/DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient eiution of 50-95% acetonitrile in water, where both solvents contained 0.1 % TFA, 30 min method) to give 2.0 mg of the title compound as a white solid. Ή NMR (500MHz, CD2CI2) δ 8,01 (s, IH), 7,72 (d, ./ 8.6 Hz, IH), 7.17 (dd, J=2.2, 8.6 Hz, IH), 7.1 1 - 7.04 (m, 2H), 6.99 - 6.88 (m, 2H), 6.64 (d, ./ 4.9 Hz, IH), 4.12 (q, ./ 1 2.0 Hz, 2H), 4.02 - 3.93 (m, IH), 3.82 - 3.72 (m, 2H), 3 ,66 (d, ./ 14.4 Hz, IH), 3.38 (s, M l ). 3.20 (d, 1 .2 Hz, IH), 3.06 - 2,97 (m, IH), 2, 85 (d, «/=4.9 Hz, 3H), 2.79 - 2.72 (m, 2H), 2.41 - 2,23 (m, 2H), 2.09 - 1.34 (m, 14H), 1.32 - 1.20 (m, 4H), 1.10 - 1.02 (m, IH), 0.93 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 686.1 (M+H) ⁺ .

EXAMPLE 364. (l S,3'R,6'lV7'S, 12'S)-6-CHLQRO-7'-HYDRQXY-3,4- DIHYDRO-2H, 15'H-SPIR0[NAPHTHALENE-1 ,22'-

[20]OXA[13]TO A[1 , 14]DIAZAPEOTACYCLO[ 14.7.2.1 ⁸ " ¹² .0 ³ - .0 ¹⁹ ' ² ]HEXACO SA[16, 18,24]TRIEN] - 15'-ONE 13 ,13'-DIOXIDE OR (1 S,3'R,6'R,7'S, 12'R)-6- CHLORO-7'-HYDROXY-3,44C)IHYDRO-2H,15'H-SPlRO[NAPHTHALENE- 1,22'- [20]OXA[ 13]THIA[ 1 , 14]DI AZ APENTACYCLO[ 14,7.2, 1 ^{8J 2} .0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]HEXACO S A[ 16, 18,24] TRIEN] - 15 '-ONE 13', 13 '-DIOXIDE

STEP 1 : (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-((R)-CYCLOHEX-2- EN-l -YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

3-Bromocyclohexene (1.37 niL, 11.0 mmol) was added dropwise to a stirred suspension of indium (0.708 g, 6.17 mmol) in DMF (15 mL) under nitrogen at ambient temperature. The mixture was stirred at ambient temperature for 10 min before a solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2- formylcyclobu1yl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (2.00 g, 4.41 mmol, Intermediate AA11A, Step 20 A) in DMF (10 mL) was added via a cannula. The resulting mixture was stirred at ambient temperature for 0.5 h. The mixture was poured into ice and saturated ammonium chloride aqueous solution and extracted with EiOAc (2 X). The combined organics were washed with water and saturated ammonium chloride aqueous solution successively, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (EtOAc Hexanes, 5 min at 0%, 5 rain from 0 to 10% and 35 min at 10%, 80 g ISCO silica gel column) to give the title compound (0.328 g, 0.612 mmol, 14% yield) as a white solid. It was the last one among the total four isomeric products coming out of the silca gel column.

STEP 2: (S)-METHYL 5-(((lR,2R)-2-((R)-((TERT- BUTYLDIMETHYLSILYL)OXY)((R)-CYCLOHEX-2-EN-l- YL)METHYL)CYCIX)BUTYL)METOYL)-6'-CHLORO-3',4,4

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE

APHTH ALENE1 -7 - C ARB OXYL ATE

To a stirred solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-((R)- cyciohex-2-en-l-yl)(hydroxy)methy3)cyclobulyl)met

2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-caxbox late (0.303 g, 0.565 mmol) and 2,6-dimethylpyridine (0.138 ml,, 1.19 mmol) in DCM (10 mL) cooled at - 40 °C was added dropwise (l,l-dimethylethyl)dimethylsilyl trifluoromethanesulfonate (0.195 mL, 0.848 mmol) via a syringe. The resulting mixture was stirred at this temperature for 4 h. The crude mixture was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography (EtOAc/Hexanes, 25 min from 0 to 15%, 40 g ISCO silica gel column) to give the title compound (0.320 g, 0.492 mmol, 87% yield) pure as a white solid.

STEP 3: (S)-METHYL 5-(((lR,2R)-2-((R)-((TERT-

BUTYLDIMETHYLSILYL)QXY)((lR,3S)-3- HYDROXYCYCLOHEXYL)METI-IYL)CYCLOBUTY ^T L)METHYL)-6 ^f -

CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7-

CARBOXYLATE AND (S)-METHYL 5-(((lR,2R)-2-((R)-((TERT-

BUTYLDIMETHYL S IL YL)OXY)(( 1 R, 3 R)- 3 - HYDROXYCYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] ~7~

CARBOXY

To a stirred ice-cooled solution of (S)-methyl 5-(((lR,2R)-2-((S)-((tert- butyldimethylsilyl)oxy)((R)-cyclohex-2-en-l~yl)methy

chloro-3',4,4',5-tetrahy dro-2H,2'H-spiro[benzo[b ] [ 1 ,4]oxazepine-3, Γ- naphthalene]-7-carboxylate (0.320 g, 0.492 mmol) in THF (5.0 niL) was added borane dimethyl sulfide complex, 1.0 M solution in THF (0.1 97 mL, 0. 197 mmol) via a syringe under nitrogen. The resulting mixture was stirred at ambient temperature for 16 h. The mixture was cooled in ice-water bath before quenched with water (5.0 mL) followed by hydrogen peroxide, 30% aqueous (5.0 mL) and sodium hydroxide, 2 N aqueous (5.0 mL). The mixture was stirred at 0 °C for 5 min and at ambient temperature for 1.5 h. The mixture was diluted with water and extracted with EtOAc (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue (0.33 g) as an off-white solid, directly taken onto the next step. STEP 4: (S)-METHYL 5-(((lR,2R)-2-((R)-((TERT- BUTYLDrMETHYLSILYL)OXY)((lR,3S)-3-

((METHYLSULFONYL)OXY)CYCLOHEXYL)ME ^r rHYL)CYCLOBLnTL)ME TH:YL)-6'-CFIL()R0-3',4,4',5-TETR,4HYDR0-2H:,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (S)-METHYL 5-((( 1 R,2R)-2-((R)-((TERT- BUTYLDIMETHYLSILYL)OXY)((lR,3R)-3-

((METTWLSULF0NYL)0XY)CYCL0HEXYL)METHYL)CYC 0BUTYL)ME

THYL -6 ^, -CHLORO-3V^4 ^, ,5~TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '- APHTHALENE] - 7- CARBOXY

To a stirred ice-cooled solution of crude (S)-rnethyl 5-(((lR,2R)-2-((R)- U !en-buh idm eii^ isiK ! )ON> Mi i K .3S)-3- hydiOxycydohexyl)methyl)cyclobuty^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carbox 'late and (S)- methyl 5-(((lR ₅ 2R)-2-((R)-((tert-butyldimethylsilyl)oxy)((lR,3R)-3- hydroxycyxk>hexyl)methy1)cy^^

2H,2'H-spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy late (0.343 mL, 2,47 rnmol) in DCM (8 mL) was slowly added methanesulfonyl chloride (0,078 mL, 0.99 mmol) through a syringe. The resulting mixture was stirred at 0 °C for 1.5 h. The crude mixture was directly subjected to combi-flash column chromatography (EtOAc/Hexanes, 30 min from 0 to 60%, 24 g ISCO silica gel column) to give a mixture of the title compounds (107 mg, 0.143 mmol, 29% yield) as a colorless film, taken onto the next step. Note that they were the major regio-isomeric product and the second regio-isomer peak coining out of the silica gel column.

STEP 5: (S)-METHYL 5-(((lR,2R)-2-((R)"((TERT-

BUTYLDIMETHYLSILYL)OXY)((lR,3S)-3-(PYRIMIDIN-2-

YLTOIO)CYCLOHEXYI METHYL)CYCLOBUWl METm _J )-6'-CHLORO- ;r,4,4^5-TET¾AHYDRO-2H,2H-SPIRO[BENZO[B][l,4]OXAZEPlNE-3,r~ APHTH ALENE] -7 - C ARB OXYL ATE AND (S)-METHYL 5-(((lR,2R)-2-((R)- ((TCRT-BUTYLDIMETOYLSILYL)OXY)((lR,3R)-3-(PYRT DIN-2- YLTHIO)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-6'-CHLORO- 3' _; 4' ₅ 5.TETl AHYDRO-2H,2'H~SPIRO[BENZO[B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE

A mixture of 2-mercapto-pyrimidine (28 mg, 0.25 mmol) and potassium carbonate anhydrous (51 mg, 0.37 mmol) in DMF (3 ml.) was stirred at rt for 10 mm before a solution of (S)-methyl 5-(((lR,2R)-2-((R)-((tert- butyldimethylsilyl)oxy)((lR,3S)-3- ((meihylsulfonyl)oxy)c\x]ohexyl)methyl)c\ lobutyl)methyl)-6'-chloro-3 ^f ,4,4' tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (S)-methy 1 5 -((( 1 R,2R)-2-((R)-((tert-but ldimethy isily i)oxy )(( 1 R,3R)-3- ((methylsulfonyl)oxy)cyclohexy

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (110 mg, 0.147 mmol) in THF (4 mL) was added at ambient temperature. The resulting mixture was stirred at 75 °C in a preheated oil bath for 7 h. After cooled, the mixture was poured into ice and saturated sodium carbonate aqueous solution and extracted with DCM (2 X). The combined organics were washed with the same aqueous solution (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo.

The residue was subjected to combi-flash column chromatography

(EtOAc/hexanes, 4 mm at 0% and 30 mm from 0 to 30%, 24 g ISCO silica gel column) to give a mixture of the title compounds (57 mg, 0.075 mmol, 51% yield) as a colorless film, not pure and directly taken onto the next step.

STEP 6: (S)-METHYL 5-(((lR,2R)-2-((R)-((TERT- BUTYLDIMETHYLSlLYL)OXY)((lR,3S)-3-(PYmMIDIN-2-

YLSULFONYL)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-6'-

CHLQRQ-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

CARBOXYLATE AND (S)-METI-FYL 5-(((l R,2R)-2-((R)-((TERT-

BUTYlT3IMETHYLSILYL)OXY)((lR,3R)-3-(PYRIMIDI -2-

YLSULFONYL)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-6'-

CHL()R()-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7-

CARBOXYLATE

To a stirred ice-cooled solution of (S)-methyl 5-(((lR,2R)-2-((R)-((tert- buty ldimethy lsily l)oxy )(( 1 R,3 S)-3 ~(py rimidin-2- ylthio)cyclohexyl)methyl)cyclob^

2H,2'H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)- methyl

yltMo)c clohex )methyl)cyclobu1yl)methyl)-6 ^, -cUoro-3 ^, ,4,4 ^, ,5-tetrahydro- 2H,2'H-sptro[ benzoj b] [ l,4]oxazepine-3,r-naphthalene|-7-carbox late (57 mg, 0.075 mmol) in DCM (4 mL) was added 3-chloroperbenzoic acid (37 mg, 0.15 mmol) in one portion as a solid. The resulting mixture was stirred at 0 °C for 10 min and at ambient temperature for 5 h. The crude reaction mixture was directly subjected to cornbi-flash column chromatography (EtOAc/Hexanes, 40 min from 0 to 70%, 24 g ISCO silica gel column) to give a mixture of the title compounds (30 mg, 0.038 mmol, 51% yield) as a colorless film.

STEP 7: (S)-5-(((lR,2R)-2-((R)-((TERT- BUTYLDlMETHYLSILYL)OXY)((lR,3S)-3-

SULFAMOYLCYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H- SPs ROi 5· /ΟΙ P || i .4 !i >X ΛΖ! · P i \ !· -3.1 Λ Fi ! Π !Λ1 J N !: !-7~C \\R! )X Y I ACID AND (S)-5-(((l ,2R)-2-((R)-((TERT"

BUTYLDIMETHYLSILYL)OXY)((lR,3R)-3-

SULFAMOYLCYC OHEXYL)METHYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][ l,4]OXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXYLlC ACID

The 1 ^st step: To a stirred solution of (S)-met yl 5-(((l R,2R)-2-((R)-((tert- buty ldimethy 1 sily l)oxy )(( 1 R,3 S)-3 -(py rimi din-2- ylsijlfonyl)cyclohexyl)methyl)cyclobutyl)meihyl)-6'- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 5-(((lR,2R)-2-((R)-((tert-butyldimethylsilyl)oxy)((l R,3R)-3-(pyrimi ylsulfonyl)eyclohexyl)methyl)w^

2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine- 3 , 1 '-naphthalene] -7-carboxy late (30 mg, 0.038 mmol) in MeOH (3 mL) was added at rt sodium methoxide, 25 wt % solution in methanol (8.4 μΐ, 0.038 mmol) (in excess) via a syringe under nitrogen. The resulting mixture was stirred at ambient temperature for 45 min when LC-MS showed completion. The volatiles were removed in vacuo and the residue was subjected to high vacuum.

The 2" ^d step: To the above residue was added water (4 mL) followed by sodium acetate trihydrate (15.4 mg, 0.113 mmol) and amidoperoxymonosulfuric acid (14.2 mg, 0.113 mmol) at ambient temperature. The resulting clear solution was stirred at 55 °C for 1.5 h. The sulfmate intermediate was completely consumed. The reaction crude mixture was directly taken onto the next step.

The 3rd step: To the above reaction mixture was added lithium hydroxide monohydrate (16 mg, 0.038 mmol). The resulting mixture was stirred at 85 °C for 1 h. After cooled, the mixture was poured into ice-cold saturated ammonium chloride aqueous solution with some 2 N acqueous HC1 added, and extracted with 25% i-PrOH/DCM (4 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to combi- flash column chromatography ((10% MeOH/DCM with 0,3% AcOH)/DCM), 35 min from 0 to 70%, 12 g 1SCO silica gel column) to give 15 mg of a mixture of the title compounds as a colorless film, which was directly taken onto the next step,

STEP 8: (l S,3'R,6'R,7'S,12'S>6-CHLOR()-7'-(TERT- BUTYLDIMETOYLSILYL)OXY-3,4-DiHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THlA[l 4]DL ZAPENTACYCLO[14.7.2:i ⁸ - ^l 0 ³ -^() ^!9 - ²⁴ lIiEXACO SA[16, 18,24]TR1EN]-15'-0NE 13",13'-DIOXIDE AND (lS,3'R,6'R,7'S,12'R)-6- CHLORO-7'--(TERT-BUTYLDIMETHYLSILYL)OXY-3,4-DIHYDRO- 2H, 15'H"SPIRO| NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOIA[l,14]DIAZAPENTACYCLO(14.7.2.1 ^8>l2 .0 ^3>6 .0 ⁱ⁹ - ²⁴ ]HEXACO S A[l 6, 18,24] -.l 5'-ONE 13', 13'-DTOXIDE

To a stirred ice-cooled solution of (S)-5-(((l R,2R)-2-((R)-((tert- hutyldimethylsilyl)oxy)((l R,3S)-3- sulfamoylcyclohexyl)methyl)cyclobut}4)methyl)-6'-chloiO-3',4 ,4',5"tetrahydro- 2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy lie acid and (S)-5 ((lR,2R)-2-((R.)-((tert-butyldimethylsilyl)oxy)((!R _^

sulfamoy1cyxlohexyl)methyl)cy

2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (15 mg, 0.020 mmol) and N,N-dimethylpyridin-4-amine (5.5 mg, 0.045 mmol) in DCM (1 1 mL) was added l -(3-dimethylaminopropyl)-3-ethylcarbodiimide

hydrochloride (9.8 mg, 0.051 mmol) in one portion. The resulting mixture was stirred at ambient temperature for 5 h. Then the reation solution was concentrated under reduced pressure and directly loaded onto a silica gel precolumn and subjected to combi -flash column chromatography (((10% MeOH with 0.35% AcOH)/DCM)/DCM, 30 mm from 0 to 60%, 12 g silica gel) to give 12 mg of a mixture of the title compounds (12 mg, 0.01 7 mmol, 84% yield) as a colorless film.

STEP 9: (l S ₅ 3'R,6 ^, R,7 ^, S, 12 ^, R)-6-CHLORO-7 ^, -HYDROXY-3 ₅ 4-DIHYDRO- 2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[l ,14]DIAZAPENTACYCLO[14.7.2.1 ⁸ ' ⁱ² .0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]HEXACO SA[ 16, 18,24]TRIENj-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6 ^! RJ'S, 12'S 6- CHLORO-7 ⁱ -i-IYDROXY-3,4-DIi-IYDRO-2H,15'H-SPIRO[NAPHTOALENE- 1,22'- [20]OXA[13]THlA[ia4]DL\ZAl TACYCLO[ 14.7.2.1 ⁸ 0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]HEXACO

S A[ 16, 18,24]TRIEN] - 15'-ONE 13', 13'-DIOXIDE

To a stirred solution of (l S.S'R^'R.T'S ^S^e-chloro-T^itert- butyldimethylsilyl)oxy-3,4-dihydro-2H,15'H-spiro[naphthalene - l ,22'-

en]-15*-one 13', 13'-dioxide and (l S ₅ 3 ^, R,6 ^, R,7 ^, S, 12 ^, R)-6-chloro-7 ^, -(tert- butyldimethylsilyl)oxy-3,4-dihy dro~2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[U4]diazapentacyelo[ 14.7.2

en]-15'-one 13', 13'-dioxide ( 12 mg, 0.017 mmol) in THF (2.5 mL) was added tetrabutylammonium fluoride, 1.0 M in tetrahydrofuran (0.17 rnL, 0.17 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 17 h. Both LC-MS and HPLC showed still some sm was remaining. More tetrabutylammonium fluoride, 1.0 M in tetrahydrofuran solution (1.2 mL) was added and the mixture was stirred at ambient temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the reidue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 55-95% acetomtrile in water, where both solvents contained 0. 1 % TFA, 30 min method) to give 4.5 mg of the title compound as the first eluting fraction as a white solid. It was the major epimeric product. ¾ NMR (400MHz, CDCb) δ 8.67 (s, 1H), 7,72 (d, ./ 8. 4 Hz, 1H), 7.20 (dd, J=2.2, 8.4 Hz, 1H), 7.15 - 7.07 (m, 2H), 7.00 - 6.91 (m, 2H), 4.23 - 4.07 (m, 2H), 4.00 (d, ./ 1 3.3 Hz, I I I ). 3.74 (d, ,/ 1 4.5 Hz, 1 1 1 ). 3.58 (d. ./ 5. 1 Hz, W D. 3.37 (d, ,/ 1 .5 Hz, H i ). 3.29 - 3.12 (rn, 2H), 2.88 - 2,71 (m, 2H), 2.53 (br. s., lH), 2.39 (d, J=\ 1.9 Hz, 1H), 2.32 - 2.17 (m, 2H), 2.15 - 1.32 (m, 16H). m/z (ESI, +ve ion) 585.2 (M+H) ⁺ . EXAMPLE 365, (1 S,3'R,6'R,7'S, 12"S)-6-CHLORO-7*-HYDROXY-3 ₅ 4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[ 1 , 14]DIAZAPENTACYCLO[14.7.2.1 ⁸ - ^I 0 ³ -^0 ^!9 - ²⁴ 1HEXACO SA[ 16, 1 8,24]TR1EN]-15'-0NE 13", 1 3'-DIOXIDE AND (l S,3'R,6'R,7'S, 12'R)-6- CHLORO-7 ^! -HYDROXY-:i4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-

[20]OXA[13]TOIA[l ,14]DIAZAPENTACYCLO( 14.7.2.1 ^8>l2 .0 ^3>6 .0 ⁱ⁹ - ²⁴ ]HEXACO S A[l 6, 18,24]T - 15'-ONE 13', 13'-DTOXTDE

Further elution from the preparative reverse-phase HPLC purification in Example 364, Step 9 provided the title compound (1.2 mg) as the second eiuting fraction as a white solid, which was an l l -to-9 mixture of the two epimeric products. ^l H NMR (500MHz, CDCb) δ 8.71 (br, s., 0.45H) [from the first epimer coming out of the reverse-phase HPLC column], 8.24 (br. s., 0.55H) [from the second epimer coming out of the reverse-phase HPLC column], 7.71 (d, J=8.6 Hz, 1H), 7.23 - 7.07 (m, 3H), 7.03 - 6.89 (m, 2H), 4.19 - 4.03 (m, 2H), 4.00 - 3.30 (m, A W ). 3,27 - 3.10 (m, 2H), 2.91 - 2.69 (m, 2! I ). 2,61 - 1 .01 (m, 2211). m/z (ESI, +ve ion) 585.2 (M+H) ⁺ .

EXAMPLE 366. (1 S,3'R,6 ⁱ R,7'S,8'R, 12'S)-6-CHLORO-7'-METHOXY ^T -3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s -

[20]OXA[13]TfflA[l,14]DIAZAPEOTACYCLO[14.7.2.1 ^8>l2 .0 ^3>6 .0 ⁱ⁹ - ²⁴ ]HEXACO SA[16, 18,24]TRIEN]-15'-ONE 13', 13"-DIOXIDE OR (1 S,3'R,6'R,7'S,8'R, 12'R)- 6-CHLORO-7'-METHOXY-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1,22'-

|20!()ΧΛ| Ι | Η1Λ| υ·Ι|ί)!,\/.\ΡΗΝ ΓΑίΎΠ.ΟΙ i L7.2 i^.O^.O ¹ '' 'MHhXAC SA[16,18,24]TRIE ]-15'-ONE 13',13'-DiQXIDE OR (IS^' ^'R^'R^'S,^^)- 6 HL0R0-7 ^! -METH0XY-3,4-DIHYDR0-2I-L15'H-SPIR0|NAPH™:ALENE-

[20]OXA[13]THIA[l,14]DIAZAPENTACYCLO[14.7.2.1 ⁸ ' ⁱ² .0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]HEXACO SA[16,18,24]TRIENj-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6 ^! RJ'R,8'S,12'S)-6- CHLORO-7'-METHOXY-3,4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTHALENE-

1,22'- [20]OXA[13]ra ^j :A[l _s 14]DIAZAPE rrACYCLO[14J.2.1 ⁸ ' ¹² .0 ³ '^0 ¹⁹ ^ ⁴ ]HEXACO SA[16,18,24]TRIEN]-15'-ONE 13'.13'-DIOXIDE OR (18,3¾,6Έ,7'8,8'8,12¾)-6- CHLORO-7'-METHOXY ,4-DIHYDRO-^ _^

1,22'-

|2( ⁾ j()XA| 13jTIIIA| Μ4|Ι)ΙΑΖΛΙ ΎΑ(ΎΠ.<>! 14.7.2. I^- O'^O^ ' ¹ !! !kXACO SA[16,18,24]TRIEN]-15'-ONE 13', '-DIOXIDE OR (lS,3'R,6'R,7'S,8'S,12'S)-6- C! U.O ()-7'-Vn :n K)XY- .4-DlRYi}RO-2i 1. i | |-SPlR()i\ API Π H \i J \!-

122'-

[20]OXA[13]THIA[1,14]DIAZAPE TACYCLO[14.7.2.1 ⁸ ' ¹² .0 ³ -.0 ¹⁹ ' ² ]HEXACO S -.l 5'-ONE 13', 13'-DIOXIDE

STEP 1: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)-((R)-CYCLOHEX- l-YL)(^DROXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4 ^, .5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((R)-((S)-CYCLOHEX-2-EN-l-

YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2 ^f H-SPIRO[BENZO[B][!,4]OXAZEPiNE-3, l '-

N APHTH ALENE] -7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5 - (((1 R,2R)-2-((S)-((S)-CYCLOHEX-2-EN- 1 -

YL)(HYDROXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]QXAZEPiNE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

The title compound (0,38 g as a white solid) was synthesized and purified in Step 1 of Examples 364. It was the third isomeric product coming out of the silica gel column described therein.

STEP 2: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)-((R)-CYCLOHEX-2-EN- l-YL)(METHOXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDR0-2H,2'H-SPIR0|;BENZ0[B] [ 1 ,4]OXAZEPINE-3, 1

NAPHTHALENE] -7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5- (((1 R,2R)-2-((R)-((S)-C YCLOHEX-2-EN-] -

YL)(METHOXY)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5- ((( 1 R,2R)-2-((S)-((S)-C YCLOHEX-2-EN - 1 -

YL)(METHOXY) ETHYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- -7 -C ARB OXYL ATE

To a stirred ice-cooled solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-

((R)-cyclohex-2-en-l-yl)(hydroxy)rnethy

2H,2'H-spiro [benzo[b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] -7-carboxylate or (S)- methyl 6'-chloro-5-(((l R,2R)-2-((R)-((S)-cyclohex-2-en- 1 - yl)(hydroxy)methyl)cyclobut 'l)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiroj benzoj bj [ L4 |oxazepine-3, -naphthalene]-7-carboxyiate or (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-((S)-cyclohex-2-en-l- yl)(hydroxy)methyl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate (380 mg, 0.709 mmol) in THF (30 mL) was added sodium hydride, 60% dispersion in mineral oil (43 mg, 1.06 mmol). The resulting mixture was stirred at 0 °C for 10 min and at ambient temperature for 30 min before iodomethane (0.053 mL, 0.85 mmol) was added. The resulting mixture was stirred at 60 °C overnight. Essentially no reaction occurred. After cooled to rt, more sodium hydride (not weighed) was added. About 10 min later, more methyl iodide (not weighed) was added followed by more anhydrous DMF (20 mL). T he mixture was heated up to 90 °C for 3.5 h. The reaction went to clean completion. The mixture was cooled in an ice-water bath and carefully quenched with methanol. The resulting mixture was poured into ice water and extracted with DCM (3 X). The combined organics were washed with water (1 X) followed by brine (1 X), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude mixture was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography

(EtOAc Hexanes, 5 min at 0% and 3 min from 0 to 30%, 40 g 1SCO silica gel column) to give the title compound (352 mg, 0.640 mmol, 90 % yield) as a colorless film.

STEP 3: {(S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)-((lR,3S)-3- HYDROXYCYC OHEXYL)(METHOXY)METHYL)CYCLOBUTYL)METHY

L)~3V4 ₅ 4^5-TETUAHYDRO-2H,2H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- APHTH ALENE] -7 -C ARB OXYL ATE AND (S)-METHYL 6'-CHLORO-5-

(((lR,2R)-2-((S)-((lR,3R)-3-

HYDROXYCYCLOHEXYL)(METHOXY)METHYL)CYCLOBUTYL)METHY L)-3^4,4^5-TETR _J ' HYDRO-2H,2 ^, H-SPlRO[BE ZO[B][l,4]OXAZEPlNE-3,r~ NAPHTHALENE] -7-CARBOXYLATE} OR {(S)-METHYL 6'-CHLORO-5- {{•;iR.2R)-2-;!RW(!S.3R)-3-

HYDROXYCYCLOHEXYL)(METHOXY)METHYL)CYCLOBUTYL)METHY

L)~3\4,4^5-TETlAHYDRO-2H,2'H"SPIRO[BENZO[B][l,4]OXAZEPINE -3;r- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((R)-((lS,3S)-3-

HYDROXYCYCLOHEXYL)(METHOXY)METHYL)CYCLOBUTYL)MEraY

NAPHTHALENE] -7-CARBOXYLATE} OR {(S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S)-((l S,3R)-3-

HYDROXYCYCLOHEXYL)(METHOXY)METHYL)CYCLOBUTYL)METHY L)-:r,4,45-TETRAH ^' D O-2I-L2Ή-S IRO[BENZO[B][l,4]OXAZE INE-3J ⁱ - NAPHTHALE E] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S)-((lS,3S)-3- HYDROXYCYCLOHEXYL)(METOOXY)METHYL)CYCLOBUTYL)METOY L)-3 ^f ,4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE -3,l'- NAPHTHALENE] -7-CARBOXYLATE}

To a stirred ice-cooled solution of (S)-methyl 6'-chloro-5-(((l R,2R)-2-((S)- ((U)-c\ lohex-2-en-l-yl)(me1hox\ memyl)c> lobu1yl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate or (S)-methyl 6'-chloro-5-(((lR,2R)-2-((R)-((S)-cyclohex-2-en-l- yl)(methoxy)methyl)cyclobutyl)me1hyl)-3^4,4 5-tetTahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate or (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-((S)-cyclohex-2-en-l- yl)(methoxy)methyl)cyclobut )methyl)-3',4,4 ^, ,5-tetrahydfo-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late (300 mg, 0.545 mmol) in THF (5.0 mL) was added borane dimethyl sulfide complex, 1.0 M solution in THF (0.218 mL, 0.218 mmol) via a syringe under nitrogen. The resulting mixture was stirred at ambient temerature for 13.5 h. TLC showed some sm was still remaining. The mixture was cooled in ice bath and more borane dimethyl sulfide complex, 1.0 M solution in THF (0.218 mL, 0.218 mmol) was added. The resulting mixture was stirred at ambient temperature for 1 h. TLC showed complete consumption of the sm. The mixture was cooled in an ice-vvater bath before quenched with water (5.0 mL) followed by sodium hydroxide, 2 N aqueous (5.0 mL) and hydrogen peroxide, 30% aqueous (5.0 mL). The mixture was stirred at 0 °C for 5 rain and at ambient temperature for 1 h. The mixture was diluted with water and extracted with EtOAc (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.29 g of a crude mixture of the title compounds as a white solid, directly taken onto the next step.

STEP 4: {(S)-METHYL 6 ^* -CHLORO-5-(((lR,2R)-2-((S)-METHOXY((l R,3S)-3- ((METHYLSULFONYL)OXY)CYCLOHEXYL)METHYL)CYCLOBUTYL)ME THYL)-3 4,4 5-TETRAHYD O-2H,2Ή-SPIRO[BE ZO[B][ l,410XAZEPINE- 3, 1 '-NAPHTHALENE]-7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S)-METHOXY((lR,3R)-3-

((METHYLSULFONYL)OXY)CYCLOHEXYL)METHYL)CYCLOBUTYL)ME TFIYL)-3',4,4 ^f ,5-TETRAFiYDRO-2FI,2'H-SPIRO[BENZO[B][l ,4]OXAZEPlNE- 3, 1 '-NAPHTHALENE]-7-C ARBOXYLATE} OR {(S)-METHYL 6'-CHLORO- 5-(((lR,2R)-2-((R)-METHOXY((lS,3R)-3- ((METHYLSULFONYL)OXY)CYCLOHEXYL)METOYL)CYCLOBUT ^r L)ME raYL) \4,4\5-TOTRAHYDR0-2H,2 ^, H-SPIR0[BENZ0[B][l,4]0XAZEPINE- 3,l'-NAPHTHALENE]-7-CARBOXYLATE AND (S)-METHYL 6'"CHLORO-5- (((lR,2R)-2-((R)-METO()XY((lS,3S)-3-

((METiiYLSULFONYL)OXY)CYCLOFIEXYL)METHYL)CYCLOBUTYL)ME raYL)-3^4,4 ^f ,5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE- 3, 1 '-NAPHTHALENE]-7-C ARBOXYLATE} OR {(S)-METHYL 6'-CHLQRQ- 5-(((l R,2R)-2-((S)-METHOXY(( 1 S,3R)-3-

((METHYLSULFONYL)OXY)CYCLOHEXYL)METHYL)CYCLOBUTYL)ME

THYL)-3^4,4^5"TETRAHYDRO-2H,2'H-SPlRO[BENZO[B][L4]OXAZEPl NE- 3, 1 '-NAPHTHALENE]-7-C ARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S)-METHOXY((l S,3S)-3-

((ΜΕΤΉΥί8^ΡΟΤ^.)ΟΧΥ)ΟΥ^ΟΗΕΧ^)ΜΕΤΗΥ ί)ΟΥΟίΟΒυΤΥί)ΜΕ

IHYL)-3\4,4\5-TETl AHYDRO-2H,2'H~SPIRO[BENZO[B] [ l,4]OXAZEPINE- 3, -NAPHTHALENE]-7-C ARBOXYLATE}

To a stirred ice-cooled solution of a mixture of {(S)-methyl 6'-chloro-5- (((lR,2R)-2-((S)-((lR,3S)-3- hydroxycyclohexyl)(methoxy)methyl)ty^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((lR,2R)-2-((S)-((lR,3R)-3- hydroxyxyclohexyl)(methoxy)me

2H,2'H-spiro [benzo[b] [ 1 ,4] oxazepine- 3 , 1 '-naphthalene] -7-carboxylate} or {(S)- methyl 6'-chloro-5-(((lR,2R)-2-((R)-((l S,3R)-3- hydroxy cyclohexyl)(raethoxy)nieihyl)cyclobuly])nieihyl)-3',4,4',5-t etrahydro- 2H,2'H-spiro[benzo[b][l,4]oxazepine~3, -naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((lR,2R)-2-((R)-((lS _s 3S)-3- hydroxycyclohexy )(meihoxy)raethyl)cyclobutyl)raethyl)-3',4,4',5^

2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate} or {(S)~ methyl 6'-chloro-5-(((lR,2R)-2-((S)-((lS,3R)-3- hydroxycyc3ohexy3)(methoxy)methyl)cyclobutyl)methyi)-3',4,4

2H,2TI-spiro[benzo[b |[l ,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)- methyl 6'~chloro~5~(((lR,2R)~2-((S)~((l S..3S)-3- hydroxycyclohexyl)(methoxy)methyl)cyclob^ 2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,l '-naphthalene]-7-carboxylate} (290 mg, 0.510 mmol) and triethylamine (0,355 mL, 2.55 mmol) in DCM (15 mL) was slowly added methanesulfonyl chloride (0.081 mL, 1.02 mmol). The resulting mixture was stirred at 0 °C for 2 h. The crude mixture was directly subjected to combi-flash column chromatography (EtOAc/Hexanes, 5 min at 0% and 40 min from 0 to 70%, 40 g ISCO silica gel column) to give a mixture of the title compounds (121 mg, 0.187 mmol, 37% yield) as a colorless film. It was the second one of two regio-isomeric products coming out of the silica gel column. STEP 5: {(S)-METHYL 6 ^, -CHLORO-5-(((lR,2R)-2-((S)-METHOXY((iR,3S)-3- (PYRIMIDIN-2-

YLTOIO)CYCLOHEXYL)METOYL)CYCLOBUWL)METHYL)-3',4,4',5- ΤΕΤΚΑΗΥϋΚΟ-2Η,2Ή-8ΡΙΚΟ[ΒΕΝΖΟ[Β][1,4]Ο ΧΑΖΕΡΙΝΕ-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((l R,2R)-2-((S)-METHOXY((lR,3R)-3-(PYRIMIDIN-2-

YLTHIO)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3' ₅ 4,4 ^, ,5- TETRAHYDRQ-2H,2'H-SPiRQj BENZQ[B ] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE} OR {(S)-METHYL 6'-CHLORO-5- ((iiR,2R)-2-i(R)-MEmOXY((lS,3R)-3-(PYRIMIDiN-2- YLTHIO)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3 ^, ,4 ₅ 4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6 ^* -CHLORO-5- (((lR,2R)-2-((R)-ME ^r raOXY((lS,3S)-3-(PYRIMiDIN-2- YLTHIO)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5- TETR,4HYDRO-2I-L2'H-SPIRO BENZO[Bl [ 1 ₅ 4]OXAZEPINE-3.1 '-

NAPHTHALENE] -7-CARBOXYLATE} OR {(S)-METHYL 6'-CHLORO-5- (((iR,2R)-2-((S)-METHOXY((l S,3R)-3-(PYRIMIDlN-2- YLTHIO)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S)-METHOXY((lS,3S)-3-(PYRlMlDlN-2- YLTOiO)CYCIX)HEXYL)MF^m CYCLOBUT¾X)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- AP -7 -C ARB OXYL ATE }

A mixture of 2-mercapto-pyrimidine (53 mg, 0.468 mmol) and potassium carbonate anhydrous (91 mg, 0.66 mmol) in DMF (3 ml.) was stirred at ambient temperature under nitrogen for 10 min before a solution of {(S)-methyl 6'-chloro- 5-(((lR,2R)-2-((S)-methoxy((l R,3S)-3- ((methylsulfonyl)oxy)cyclohexyl)memyl)cyd^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((lR,2R)-2-((S)-methoxy((lR,3R)-3- ((methylsulfony])oxy)cyck ⁾ hexy

2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate} or {(S)- methyl 6 ^, -chloro-5-(((lR,2R)-2-((R)-methoxy((lS,3R)-3- ((methylsulfonyl)oxy)c> ⁷ clohexyl)memyl)cyclobutyl)memyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)- methyl 6'-chloro-5-(((lR,2R)-2-((R)-methox>'((lS,3S)-3- ((methylsulfonyl)oxy)cyclohexyl)methyl)cyd^ 2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,l '-naphthalene]-7-carboxylate} or {(S)~ methyl fc'-cliloiO-5-{{{ I K .2R )-2-ii S)-me!hoxyii I S.3R )-3- ((methylsulfonyl)oxy)cyclohexyl)memyl)cycto^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carbox\'late and (S)- methyl 6'-chloro-5-(((l R,2R)~2~((S)~methoxy((l S,3S)-3- ((methylsulfonyl)oxy)cyclohe

2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate} (121 mg, 0.187 mmol) in THF (4 ml.) was added. The resulting mixture was stirred at 75 °C for 18 h. After the reaction mixture was concentrated under reduced pressure, the residue was directly subjected to combi-flash column chromatography

(EtOAc/hexanes, 6 min at 0% and 35 min from 0 to 70%, 40 g ISCO silica gel column) to give a mixture of the title compounds (50 mg, 0.075 mmol, 40% yield) as a colorless film. STEP 6: {(S)-METHYL 6 ^* -CHLORO-5-(((l R ₅ 2R)-2-((S)-METHOXY((lR,3S)-3-

(PYRJMIDIN-2-

YLSULFO YL)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)- 3 4,4 5-TETP^HYDRO-2H,2 -SPIR()|;BENZO| B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S)-METOOXY((l R,:m)-3-(PYRLMIDIN-2-

YLSULFONYL)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3 , 1 '- NAPHTHALENE] -7-CARBOXYLATE } OR {(S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((R)-METHOXY((lS,3R)-3-(PYRIMlDIN-2- YL S LT.FON YL)C YCLOHEXYL)METHYL)C YCLOBUTYL)METHYL)- ;r,4,4',5-TETRAHYDRO-2H,2TI-SPIRO[BENZO[B][ l,4]OXAZEPINE-3,l '- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6 ^f -CHLORO-5- (((lR,2R)-2-((R)-METHOXY((lS,3S)-3-(PYRIMlDlN-2- YLSULFONYL)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)- 3Vl',4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE} OR {(S)-METHYL 6'-CHLORO-5- (((1 R,2R)~2-((S)~METHOXY((l S,3R)-3-(PYRIMIDIN-2- YLSULFONYL)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)- S'^^^S-TETl AHYD O^H^'H-SPI OtBE ZOtBlt l^JOX^EPINE-S,!'- NAPHTHALENE] -7-CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5- (((lR,2R)-2-((S)-METHOXY((l S,3S)-3-(PYRIMIDIN-2-

YLSULFONYL)CYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)- S'^^'j-TETR ^HYD O^H^'H-SPl OtBE ZOtBll l^iOXAZEPl E-S,!'- NA -7-CARBOXYLATE}

To a stirred ice-cooled solution of {(S)-methyl 6'-chloro-5-(((lR,2R)-2-

((S)-mel oxy((lR,3S)-3-(p rimidin-2- yl1hio)c\ lohexyl)me1hyl)c\ lobutyl)me1hyl)-3 ^, ,4,4\5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-methoxy((l R,3R)-3-(pyrimidm-2- ylthio)cyclohexyl)methyl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylate} or {(S)-methyl 6'- chloro-5-(((lR,2R)-2-((R)-methoxy((lS,3R)-3-(pyrimidm-2- ylthio)cyc]ohexy])methyl)cyc]ob^ spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((R)-methoxy((l S,3S)-3-(pyrimidin-2- yltMo)cyclohexyl)methyl)cyclobut 'l)methyl)-3',4,4^5-te1rahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate} or {(S)-methyl 6'- (*loro-5-(((lR,2R)-2-((S)-methoxy((l S,3R) -(pyrimidin-2- ylthio)cyclohexyl)methyl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((l R,2R)-2-((S)-methoxy((lS,3S)-3-(pyrimidin-2- yl1hio)c\ lohexyl)me1hyl)c\ lobutyl)me1hyl)-3 ^, ,4,4\5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate} (50 mg, 0.075 mmol) in DCM (4 mL) was added 3-chloroperbenzoic acid (41 mg, 0.166 mmol) in one portion. The resulting mixture was stirred at 0 °C for 5 min and at ambient tmeperature for 2 h. The crude reaction mixture was directly subjected to combi- flash column chromatography (EtOAc/Hexanes, 40 min from 0 to 70%, 24 g ISCO silica gel column) to give a mixture of the title compounds (31 mg, 0.045 mmol, 59% yield) as a colorless film.

STEP 7: {(S _, )-6'-CHLORO-5-(((lR,2R)-2-((S _, )-METHO,W((lR,3S)-3- SULFAMOYIX:YCLOHEXYL)METHYL)CYCLOBUTYL)METOYL)-3',4,4',5- TETRAHYDRO-^^'H-SPIROIBENZOPIII^IOXAZEPINE-S, ! '- APHTH ALENE] -7 - C ARB OXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((S)-METHOXY((lR,3R)-3-

SULFAMOYLCYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID} OR {(S)-6'-CHLORO-5-(((l ,2R)- 2-((S)-METHOXY((l R,3R)-3-

SULFAMOYLCYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2R)- 2-((R)-METHOXY(( 1 S, 3 S)-3 -

SULFAMOYLCYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID} OR {(S)-6'-CHLORO-5-(((lR,2R)- 2-((S)-METHOXY((l S,3R)-3-

SULFAMOYLCYCLOHEXYL)METHYL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5- TETRAHYDRO-2H,2T-I-SPIRO[BENZO[B][!,4]OXAZEPiNE-3, l '-

N APHTHALE E] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2R)-

2-((S)-ME ^r fflOXY((lS,3S)-3-

SULFAMOYLCYC OHEXYL)METHYL)CYC OBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]ΟΧΑΖΕΡΓΝΕ-3, 1 '- NAPH -7-CARBOXYLIC ACID}

The title compounds were synthesized from {(S)-methyl 6'-chloro-5- (((l R,2R)-2-((S)-methoxy((lR,3S)-3-(pyrimidm-2- ylsulfonyl)cyclohexyl)methyl)cycta

spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-methoxy((l R,3R)-3-(pyrimidin-2- ylsulfony )cyelohexyl)methy^

spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylate} or {(S)-methyl 6'- cWoro-5-(((l R,2R)-2-((R)-me1hoxy((lS,3R)-3-(pyrimidin-2- ylsu]fonyl)cyclohexyl)rnethyl)cyclobuiyi)methyl)-3',4,4',5- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate and (S)-methyl 6 - cWoro-5-(((lR,2R)-2-((R)-methoxy((l S,3S)-3-(py

ylsulfonyl)cyxlohexyl)inethyl)cydob^

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate} or {(S)-methyl 6'- (^oro-5-(((lR,2R)-2-((S)-methoxy((l S,3R)-3-(pyriraidin-2- ylsulfonyl)cyclohexyl)me1hyl)cyclobutyl)meth^

spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late and (S)-methyl 6'- chloro-5-(((lR,2R)-2-((S)-methoxy((lS,3S)-3-(pyrimidin-2- ylsulfonyl)eydohexyl)methyl)eydob^

spi ro [ benzo [ b] [ 1 ,4 ] oxazepine-3 , Γ -naphtha! ene | - 7 -car boxy 1 ate } following the procedure described for Step 7 in Examples 364 and 365.

STEP 8: (lS,3 ^, R _s 6 ^, R,7 ^, S,8 ^, R,12 ^, S)-6-CHLORO-7 ^, -METHOXY-3 ₅ 4-DIHYDRO- 2H, 15 ^* H-SPIRO[N APHTHALENE- 1 ,22'-

| 20i()XA| Ι | Η1 Λ| I J -l |i)!A/.\PHN ΓΑίΎΠ.ΟΙ i 17.2 i ^.O ^.O ^{1 '} ' ' MH hXAC SA[16,18,24]TRIEN]-15'-ONE 13',13'-D1QXIDE OR (1 S,3 ^, R,6 ^, R,7 ^, S _: ,8 ^, R ₅ 12 ^, R)- 6 HLORO-7 ^! -METHOXY-3,4-DIHYDRO-2I-L15'H-SPIRO|NAPHraALENE- [20]OXA[13]THIA[l,14]DIAZAPENTACYCLO[14.7.2.1 ⁸ ' ⁱ² .0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]HEXACO SA[ 16,18,24]TRIENj-15'-ONE 13',13'-DIOXIDE OR (1S,3'R,6 ^! RJ'R,8'S,12'R)- 6-CHLORO-7 ⁱ -METHOXY-3,4-DIHYDRO-2H,i5'H-SPIRO[NAPHTOALENE- 1,22'-

[20]QXA[13]raL\[U4]DL4 LAP^

SA[16,18,24]TRIEN]-15'-ONE 13'.13'-DIOXIDE OR (18,3¾,6Έ,7¾,8'8,12 ^! 8)-6- CHI RO-7'-METHOXY-3,4-DimTJRO-2HJ 5 -SPiRO|NAPHTHALENE- l. -

[20]OXA[13]THlA[l,14]DIAZAPENIACYCLO[14.7.2:i ⁸ - ^l 0 ³ -^0 ^!9 - ²⁴ lIiEXACO SA[16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S,8'S,12'R)-6~ C! U .O ()-7'-Vn :n iOXY- -..4-f)!HY i)RO-2l 1. i | i-SPlR()i \ API Π H \i J N! - [20]OXA[ 13]THI A[ 1 , 14]DI AZ APENT AC YCLO[ 14,7.2, 1 ^{8 i 2} .0 ³ · ⁶ .0 ¹⁹ - ²⁴ ]HEXACO SA[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S,8'S,12'S)-6-

CHLORO-7'-METHOXY-3,4-DlHYDRO-2H;i5'H-SPlRO[NAPHTHALE E- 1 22'- [20]OXA[13]THTAj 1 ,14]DIAZAPE TACYCLO[ 14.7.2.1 ⁸ - ¹² .0 ³ 0 ¹⁹ - ²⁴ ]HEXACO S A[ 16, 18,24]TRIEN] - 15'-ONE 13', 13'-DIOXIDE

To a stirred ice-cooled solution of {(S)-6'-chloro-5-(((l R,2R)-2-((S)- methoxy((lR,3S)-3-sulfamoylcyclohexyl)me^

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((S)-me1hoxy((lR,3R)-3- sulfamoylcv lohexyl)methyl)c^xlobutyl)methyl)-3',4,4',5-tetrahydro-2H,2' H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid} or {(S)-6 - chloro-5-(((lR,2R)-2-((S)-methoxy((lR,3R)-3- sulfamoylcyclohexyl)methyl)cyclobut^ )methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox dic acid and (S)-6'- chloro-5-(((lR,2R)-2-((R)-methoxy((l S,3S)-3- sulfamo}4cyclohexyl)methyl)cyclobut}4)methyi)-3',4,4',5 etrahydro-2H spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid} or {(S)-6'- chloro-5-(((lR,2R)-2-((S)-methoxy((l S,3R)-3- sulfamoylcyclohexyl)me&yl)cyclobu^

spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)-6'- chloro-5-(((lR,2R)-2-((S)-methoxy((l S,3S)-3- sulfamoylc>xlohexyl)methyl)c} lobutyl)rnethyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid} (23 mg, 0.036 mmol) and N,N-dimethylpyridin-4-amine (10 mg, 0.080 mmol) in DCM (20 mL) was added Nl -((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (17 mg, 0.091 mmol) in one portion. The resulting mixture was stirred at 0 °C for 5 min and at ambient temperature for 27 h. The reaction mixture was concentrated in reduced pressure and the residue was directly loaded onto a silica gel precolumn and subjected to combi-flash column chromatography ((EtOAc with 0.35% AcOH)/hexanes, 70 min from 0 to 100% and 15 mm at 100%, 24 g ISCO silica gel column) to give 8,0 mg of the title compound as the first eluting fraction as a white solid. Ή NMR (500MHz, CDCb) δ 7,85 (br. s . 1H), 7.70 (d, J=8.6 Hz, 1H), 7.19 (dd, J=2.3, 8.4 Hz, IH), 7.09 (d, J=2.2 Hz, 1H), 7.03 - 6.91 Or, 2H), 6.89 (d, ,/ H.3 Hz, 1H), 4.15 - 4.10 (m, 1H), 4.07 - 3.99 (m, ill).3,72 (br. s .2H), 3.51 (s, 311).3.39 - 3.28 (rn, ill).3,07 id../ 2.4 Hz, ill). 2,91 - 2.70 (m, 3H), 2.39 - 1.16 (m, 20H). m/z (ESI, +ve ion) 617.1 {V! Hj

EXAMPLE 367. (18,3¾,6'Κ,7'8,8'Κ,12'Κ)-6-α-Π,ΟΚΟ-7'-ΜΕΉ-ΙΟΧ Υ-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTHALENE- 1 ,22'- [20]OXA[13]THIA[l,14]DL ZAI TACYCLO[14.7.2.1 ⁸ 0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]HEXACO SA[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7 ^! S,8'R,12 ^! S)-6- CHLORO-7'-METHOXY-3,4-DIHYDRO-2H,15Ti-SPIRO|SiAPHTHALENE- 1,22'-

|20!()X.\| !3ΓΠ!1Λ| iJ4|D!AZ,\PLNrACYCi.()i 14.7.2.1'^'.O^^.O^' ' ¹ !! HXACO SA[ 16,18,24]TRIEN]-15'-ONE 13",13-DIOXIDE OR (1S,3'R,6 ^, R,7 ^, R ₅ 8 ^, S,12 ^, R)- 6-CHLORO-7'-METHOXY-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-

1 ">"><-

[20]OXA[13]THIA[1,14]DIAZAPE TACYCLO[14.7.2.1 ⁸ ' ¹² .0 ³ - .0 ¹⁹ ' ² ]HEXACO SA[16,18,24]TRIEN]-15'-ONE 13',13'-DI0X1DE OR (1 S,3'R,6'R,7'R,8 ^f S,r2'S)-6- CHLORO-7'-METHOXY-3,4-DIHYDRO-2H,15 ^! H-SPIRO[NAPHTHALENE" 1,22'-

[20]OXA[ 13]THIA[ 1 , 14]DI AZ APENT AC YCLO[ 14.7.2, 1 ^{8 i2} .0 ³ · ⁶ .0 ¹⁹ - ²⁴ ]HEXACO SA[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7 ^! S,8'S,12'R.)-6- CHLORO-7'-METHOXY-3,4-DlHYDRO-2H,15'H-SPIRO[N APHTHALENE- 122'-

[20]OXA[13]TO A[1,14]DIAZAPEOTACYCLO[14.7.2.1 ⁸ " ¹² .0 ³ - .0 ¹⁹ ' ² ]HEXACO SA[16,18,24]TRIEN]-15'-ONE 13 ^! ,13'-DIOXJDE OR (lS,3'R,6'R,7'S,8'S,12 ^! S)-6~ CHL()R()-7'-METHOXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'- |20i()XA| Ι | Η1Λ| l,.i-l|i)!A/.\PHN I AC VCi, Ol i -1,7.2 i ^x "u^.O ¹ " 'MHhXAC S A[ 16, 18,24] TRIEN] - 15 '-ONE 13', 13 '-DIOXIDE

Further eiution from the combi-flash column chromatography in Example 366, Step 8 provided the title compound as the second eluting fraction which was not pure. This was subjected to preparative reverse-phase HPLC (Gemini™ Prep Ci8 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 60-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give, after lyophilization, 1 .7 mg of the pure title compound in Example 367 as a white solid. 'H NMR (500MHz, CDCb) δ 7.63 (br. s., 2H), 7.17 (d, ,7=8,6 Hz, 1H), 7.10 (d, ./ 2.2 Hz, 1H), 6.91 (d, ./ 7.8 Hz, i l l ). 6.81 (br. s., 1H), 4.16 (br. s., M l ). 3.57 (d, ./ 8.6 Hz, 3H), 3.26 - 2,93 (m, 1H), 2.75 (br. s., 2H), 2.47 (t, ./ 8.2 Hz, 21 1 ). 2.17 - 0,89 (m, 2 1 ! ! ). m/z (ESI, +ve ion) 617.1 { M · 1 1 ) .

EXAMPLE 368. (3R,6R, 12R,22S)-6 ^, -CHLORO-12-ETHYL-3 ^, ₅ 4 ^, -DIHYDRO- 2Ή, 15H-SPIRO[8,20-DIOXA- 13-THIA-l , 14-

DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ³⁹ - ²⁴ P

NAPHTHALEN] - 15 -ONE -DIGX!DE

STEP 1 : (S)-TERT-BUTYL 5-(((lR,2R)-2-

((ALLYLOXY)METHYL CYCLOBUTYL)METHYL)-6'-CHLORO-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

To a stirred solution of (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2- (hydroxyme l)cyclobut54)methyl)-3',4,4',5 etrahydro-2H,2'H- spiroj benzoj bj [ L4 |oxazepine-3, -naphthaIene]-7-carboxylate (0.240 g, 0.482 mmol, intermediate AA11A, Step 19B) in THF (5 mL) was added at rt sodium hydride, 60% dispersion in mineral oil (0.014 g, 0.58 mmol) under nitrogen. The mixture was stirred at ambient temperature for 20 min before ally! bromide (0.044 mL, 0.506 mmol) was added. The resulting mixture was stirred at ambient temperature for 19 h. As LC-MS showed that the sm was still the major, the reaction mixture was then heated up to 70 °C for 2 h. LC-MS showed that the desired product was the major with still some sm remaining. The temperature was then raised to 80 °C and the mixture was stirred at this temperature for 1 h. After cooled, the mixture was poured into ice and brine and extracted with EtOAc (2 X). The combined organics were dried over anhydrous sodium sulfate and

concentrated in vacuo. The crude residue was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography (EtOAc/Hexanes, 30 min from 0 to 30%, 24 g ISCO silica gel column) to give the title compound (0.239 g, 0.444 mmol, 92%) yield) as a clear film, directly taken onto the next step.

STEP 2: (S)-5-(((lR,2R)-2-

((ALLYLOXY)METHYL)CYCLOBUIYL)METHYL)-6 ^, -CHLORO-3',4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [ 1 ,4]GXAZEPINE-3, 1

NAPHTHALENE] -7-CARBOXYLTC ACID

To a stirred solution of (S)-tert-butyl 5-(((lR,2R)-2- ((allyloxy)methyl)cyclobutyl)methyl)-6^

spirojbenzojb] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxylate (0.239 g, 0.444 mmol) in THF (5.0 mL), MeOH (10.0 mL), and water (5.0 mL) was added lithium hydroxide monohydrate (0.380 g, 8.88 mmol) at ambient temperature. The mixture was heated at reflux (105 °C) for 18 h. After cooled, the mixture was poured into ice and saturated ammonium chloride aqueous solution with a small volume of saturated citric aqueous solution added, and extracted with EtOAc (3 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vauo to give the title compound (0.180 g, 0.373 mmol, 84% yield) as a white solid, directly taken onto the next step.

STEP 3: (S)-5-(((l R,2R)-2- ((ALLYLOXY)METHYL)CYCLOBUTYL)METHYL)-6'-CHLORO-N-((S)- PENT-l-EN-3-YLSULFONYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2H,2H- SP1RO [BENZO[B] [ 1 ,4] GXAZEP1NE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-5-(((lR,2R)-2-

((ALLYLOXY)METHYL)CYCLOBUTYL)METHYL)-6'-CHLORO-N-((R)- PENT-l-EN-3-YLSULFONYL)-3',4,4',5~TETiLAHYDRO-2H,2'H- SPIR()[BENZO B][ l,4]()XAZEPINE-3,r-NAPHTHALENE]-7- CARBOX

To a stirred solution of (S)-5-(((lR,2R)-2-

((allyloxy)rnethyl)cyciobut5 )rnethyl)-6'-chloro-3 ^f ,4,4',5-teirahydro- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'lic acid (85 mg, 0.18 mmol), pent- 1 -ene-3-sulfonamide (53 mg, 0.35 mmol), and N,N-dimethyipyridin- 4-amine (65 mg, 0.53 mmol) in DCM (10 mL) was added l-(3- dimethylaminopfopyl)-3-ethylcarbodiimide hydrochloride (101 mg, 0.529 mmol) at ambient temperature. The mixture was stirred at rt for a period of 3 h. The crude mixture was loaded onto a silica gel precolumn and subjected to combi -flash column chromatography (EtOAc/Hexanes, 4 mm at 0% and 26 mm from 0 to 100% and 15 min at 100%, 40 g ISCO silica gel column) to give a mixture of the title compounds (87 mg, 0.14 mmol, 78% yield) as a colorless film.

STEP 4: (3R,6R,12R,22S)-6'-CHLORO-12-ETHYL-3',4'-DIHYDRO-2'H,15H- SPIRO[8,20-DIOXA - 13-THIA- 1 , 14-

DIAZATETRACYCLO[ 14.7.2.0 - ⁶ .0 ¹⁹ ' ^M ]PENTACOSA-16, 18,24-TRIENE-22, 1 '- N APHTHALEN ] - 15 -ONE 13,13-DIOXIDE

The 1st step: To a 50-mL single-necked round-bottomed flask were placed

(S)-5-(((l R,2R)-2-((allylox n ethyl)cyclobutyl)methyl)-6'-chloro-N-((S)-pent-l- en-3-ylsulfonyl)-3',4,4',5-tetrahydro-2H,2 ^, H-spiro[benzo[b][l,4]oxazepine-3, - naphthalene]-7-carboxamide and (S)-5-(((lR,2R)-2-

((allyloxy)memyl)c lobut>d)memyl)-6 ^, -chloro-N-((R)-pent-l -en-3-ylsulfonyl)- 3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxamide (45 mg, 0.073 mmol) and hoveyda-grubbs catalyst second generation (9.2 mg, 0.015 mmol). The flask was subjected to evacuation and backfilling with nitrogen (3 X). AcOH (24 mL) was added at rt under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature under house vacuum for 23 h. The reaction mixture was concentrated under reduced pressure. The residue was loaded onto a silica gel precolumn and subjected to combi-flash column chromatography ((10% MeOH/DCM with 0,2% AcOH)/'DCM, 30 min from 0 to 100%, 24 g ISCO silica gel) to give 25 mg of a diastereomeric mixture of products, directly taken onto the next step.

The 2nd step: A vigorously stirred mixture of the above impure product mixture and platinum(lV) oxide (15 mg) in EtOAc (15 mL) was balloon hydrogenated at ambient temperature for 3 h. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was subjected to preparative reverse-phase HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 40-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 mm method) to give 1.2 mg of the title compound as an off-white solid (the first eluting fraction). ¾ NMR (500MHz, CDCb) δ 8.16 (s, 111).7.73 (d, ,/ H (> Hz, IH), 7.19 (dd, ,/ 2.3.8.4 Hz, IH), 7,09 id..7=2.2 Hz, IH), 7.03 - 6.98 (m, 2H), 6,95 - 6.90 (m, IH), 4.17 - 4.04 (m, 2H), 3.85 - 3.67 (m, 3H), 3.60 - 3.51 (m, 2H), 3.42 (td, J=5.1, 9.9 Hz, IH), 3.35 (dd, ./ 5.1.10.5 Hz, IH), 3.24 (d, ./ 142 Hz, IH), 3.04 (dd, ,/ 9,5.15.4 Hz, IH), 2.87 - 2,71 (m, 2H), 2.68 - 2.57 (m, IH), 2.29 - 1,25 (m, 15H), 1.15 (t, ./ 7.5 Hz, Ml). m/z (ESI, +ve ion) 587.2 (M+H) ⁺ .

EXAMPLE 369. (3R,6R,12S,22S)-6'-CHLORG-l 2-ETHYL-3 ^* ,4'-DIHYDRQ- 2Ή, 15H-SPIRO [8,20-DIOX A - 13 -THI A - 1,14- DIAZATTETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ ' ² ]PEOTACOSA 6,18,24-TRffiNE-22,r- N APHTHALEN ] - 15 -ONE 13,13-DlOXIDE

Further elution from the to preparative reverse-phase HPLC purification in Example 368, Step 4 provided 0.7 mg of the title compound as an off-white solid (the second eluting fraction). Ή NMR (500MHz, CDCb) δ 8,50 (s, IH), 7,72 (d, J=8.6 Hz, IH), 7.20 (ddd, J=2.2, 8.3, 10.3 Hz, 2H), 7.09 (d, J=2.4 Hz, IH), 6.97 (d,J=8.3Hz, IH), 6.85 (d, J=2.0 Hz, IH), 4.16-4.11 (m, IH), 4.10 - 4.04 (m, IH), 3.75 (d, ,/ 14.2 Hz, 2H), 3.67 (qd, 4.7.9.2 Hz, IH), 3.6! - 3.52 (m, 2H), 3.49 - 3.43 (m, IH), 3,42 - 3.33 (m, 2H), 3.24 (dd, J=9,4, 15.3 Hz, IH), 2,85 - 2.71 (m, 2H), 2.57 - 2.47 (m, 111}.2.31 - 1.26 (m, 15H), 1.13 (t, ./ 7.6 Hz, Ml). m/z (ESI, +ve ion) 587.2 {M H}

EXAMPLE 370. (lS,3'R,6'R)-6-CHLORO-3,4-DIHYDRO-2H,9'H, 15Ή- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 ,8, 14] TRI AZ ATETR AC YCL O [ 14.7.2.0 ³ ' ⁶ ,Q ⁱ⁹ - ²⁴ ]PENTACO SA[16 ₅ ] 8,24]TRIENE]-9V15'-DIONE 1 '. 1 -l>!OXi i>l ^; .

STEP 1 : (S)-METHYL 6'-CHLORO-5-(((.lR,2R)-2-(((4- METHOXYBENZYL)AMINO)METHYL)CYCLOBUTYL)METHYL)- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE! -7-CARBOXYLATE

A mixture of (S)-methyl 6 ^! -chloro-5-(((lR,2R)-2- formylcyclobutyl)methyl)-3^4,4^54etrahydro-2H,2'H- spiroj benzoj bj [ L4 |oxazepine-3, -naphthaIene]-7-carboxylate (120 mg, 0.264 mmol, Intermediate AA11A, Step 20A) and 4-methoxybenzylamine (0.051 mL, 0.40 mmol) in DCM (3.0 mL) was stirred at ambient temperature for 15 min before sodium triacetoxyborohydride (168 mg, 0.793 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was subjected to combi-flash column chromatography ((10% MeOH/DCM with 0.5 % commercial ammonium hydroxide)/DCM, 35 min from 20 to 100%, 24 g ISCO silica gel column) to give the title compound (150 mg, 0.261 mmol, 99% yield) as a colorless film.

STEP 2: (S)-METHYL 6'-CHLORO-5-(((l R,2R)-2-((N-(4- METHOXYBENZYL)-4-

SULFAMOYLBUTANAMIDO)METHYL)CYCLOBUTYL)METHYL)-3 ^, ₅ 4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

To a stirred mixture of (S)-methyl 6'-chloro-5-(((lR,2R)-2-(((4- methoxybenz>'l)amino)methyl)cyclobutyl)me1hyl)-3',4,4 5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylate (150 nig, 0.261 mmol) and 3-carboxypropanesulfonamide (46 mg, 0.27 mmol) in DCM (5 mL) was added HATU (104 mg, 0.274 mmol) at ambient temperature followed by n,n- diisopropylethylamine (0.054 mL, 0.313 mmol). The resulting mixture was stirred at ambient temperature for 1 h. The crude mixture was subjected to combi-flash column chromatography ((0.2% AcOH in EtOAc)/Hexanes), 40 min from 0 to 100%, 24 g ISCO silica gel column) to give the title compound (53 mg, 0.073 mmol, 28% yield) as a colorless film.

STEP 3: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((N-(4-METHOXYBENZYL)-4- SULFAMOYLBUTANAMIDO)METHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPrNE-3, 1 '- NAPHTHALENE j -7-C ARBOXYLIC ACID

A mixture of (S)-methyl 6'-chloro-5-(((lR,2R)-2-((N-(4-methox>'benzyl)- 4-sdfamoylbutanamido)methyl)cyclobutv'l)methyl)-3',4,4',5-te trahydro-2H,2'H- spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxylate (54 mg, 0.075 mmol) and lithium hydroxide hydrated (9.4 mg, 0.22 mmol) in a mixed solvent consisting of MeOH (3.0 mL), THF (1.0 mL) and Water (1.0 mL) was stirred at 80 °C for 2 h. After the reaction mixture was concentrated under reduced pressure, the residue was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini ^1M Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 20-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give 16 mg of the title compound as a white solid. STEP 4: (lS,3 ^! R,6 ^, )-6~CHLORO-8 ^, -(4~METHOXYBENZYL)-3,4-DlHYDRO- 2H,9'H,15'H-SPIRO|NAPHTHALENE-l,22'-

[20]OXA[13]TraA[l ₅ 8, 14]raAZATCTRACYCLO[147.2.0 ³ f0 ¹⁹ " ²⁴ ]PENTACO

SA[16,18,24]TRIENE]-9', 15'-DIONE 13',13'-DIOXIDE

To a stirred solution of (S)-6'-chloro-5-(((l R,2R)-2-((N-(4- methoxybenzyl)~4~sulfamoylbutananiido)m

tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carbox lic acid (30 mg, 0.042 mmol) in DCM (30 mL) was added EDCI HC1 salt (20 mg, 0.13 mmol) at ambient temperature followed by N,N-dimethylpyridin-4-amine (15.5 mg, 0.127 mmol). The resulting mixture was stirred at ambient temperature for 4 h. After the reaction mixture was concentrated under reduced pressure, the residue was subjected to combi -flash column chromatography ((0.2% AcOH in EtOAc)/hexanes, 3 min at 0% and 40 min from 0 to 70%, 24 g ISCO silica gel column) to furnish 10 mg of the title compound as an off-white solid.

STEP 5: (1 S,3'R,6'R)-6-CHLORO-3,4-DIHYDRO-2H,9'H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TfflA[l,8,14]TmAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ ' ²⁴ jPENTACO S A[ 16, 18,24]TRIENE]-9', 15'-DTONE 13 ^f , 13'-DTOXIDE

A solution of (1 S,3 ^, R,6 ^, R)-6-chloro-8 ^, -(4-methoxybenzyl)-3,4-dihydro- 2Η,9Ή, 15'H-spiro[naphthalene-l ,22'- 3 |ihuij i .8 4 |iria/.atemie> cl j i 4.7.2. o ^; ".0 ^{| u} |peniaco:>aj ! 6. I .24|inene ]-9',15'-dione 13',13'-dioxide (not weighed) in 2,2,2-trifluoroacetic acid (3.0 mL) was heated at reflux for 2 h. The crude mixture was taken up in DMSO and subjected to preparative reverse-phase HPLC (Gemini™ Prep Cm 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 20-95% acetonitrile in water, where both solvents contained 0.1% TFA, 30 min method) to give 4.5 mg of the title compound as a white solid. ^l H NMR (500MHz, DMSO-de) δ 7.75 (t, ./ 4.8 Hz, ill).7,66 id../ 8.6 Hz, IH), 7,26 (dd, ./ 2.3.8.4 Hz, III).7.17 id. ,/ 2.2 Hz, IH), 7,03 - 6.94 (m, 2H), 6.89 (d, .7=8.1 Hz, IH), 3.91 (ddd, .7=5.5, 8.9, 14.7 Hz, III).3.71 (d, ./ !5.7 Hz, IH), 3.57 (d, J=13.9 Hz, IH), 3.49 -3.15 (m, 5H), 3.08 - 2,92 (m, 2H), 2.83 - 2.65 (m, 2H), 2.45 - 2,32 (m, 2H), 2.27 - 2.07 (m, 2H), 2.02 - 1.59 (m, 9H), 1.49 - 1,34 (m, IH). m/z (ESI, +ve ion) 572,3 ( M II) .

EXAMPLE 371. (1 S,3'R,6'R,I0'E)-8'-ACETYL-6-CHLORO-3,4-DIHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,8 4]TMAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACO SA[1Q,16,18,24]TETRAEN]-15 ^! -0NE 13',13'-DIOXIDE AND (1S,3'R,6'R,10'Z)- 8*-ACETYL-6-CiiLORO-3,4-DIHYDRO-2H 5H-SPIRO[N APHTHALENE- l. -

[20]OXA[ 13]THIA[ l,8,14]TRIAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ jPENTACO S A[ 10, 16, 18,24]TETRAEN] - 15-ONE 13*, 13'-DIOXIDE

STEP 1: (S)-METHYL 5-(((lR,2R)-2-

((ALLYLAMINO)METHYL)CYCLOBUTYL)METHYL)-6'-CHLORO- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLATE

A mixture of (S)-methyl 6'-chloro-5-(((lR,2R)-2- formylc 'clobutyl)rnethyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (1 10 mg, 0,242 mmol, Intermediate AAl 1A, Step 2 OA) and allylamine (0.036 mL, 0.485 mmol) in DCM (3.0 mL) was stirred at ambient temperature for 30 rain before sodium triacetoxyborohydride (154 mg, 0.727 mmol) was added in one portion. After the resulting mixture was stirred at ambient temperature for 1 h, the reaction mixture was concentrated under reduced pressure and the residue was directly taken onto the next step.

STEP 2: (S)-5"(((lR,2R)-2-

((ALLYLAMINO)METHYL)CYCLOBU L)METHYL)-6'-CHLORO- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-C ARBO

To the above crude residue was added lithium hydroxide monohydrate (150 mg, 3.63 mmol) followed by MeOH (5.0 mL), THF (2.0 mL) and water (2.0 mL). The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was directly taken onto the next step.

STEP 3: ( S )-5-!(( i R.2R}-2-(( \-

ALLYLACETAJVnDO)METHYL)CYCLOBUTYL)METHYL)-6'-CHLORO- 3 ^f ,4,4',5-TETRAHYDRO-2H 2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE~3, 1 "- NAPHTHALENE] -7 -C ARB

The above crude residue was dissolved in DMF (3.0 mL) and 2-Propanol (1.0 mL). To this stirred mixture was added 2,5-dioxopyrrolidin-l-yl acetate (1 14 mg, 0.727 mmol) followed by diisopropylethylamine (0.126 mL, 0.727 mmol). The resulting mixture was sonicated and stirred at ambient temperature for 1 h. Still some unreacied sm was observed. DMSO (1.500 mL) was added to facilitate the dissolution later followed by more 2,5-dioxopyrrolidin-l-yl acetate (not weighed). The mixture was stirred at ambient temperature for another 1.5 h. Upon workup, the mixture was poured into ice and saturated ammonium chloride. The pH of the resulting mixture was adjusted with 2 N aqueous HQ followed by extraction with EtOAc (2 X). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue (0.21 g) was taken onto the next step without purification.

STEP 4: (S)-5-(((lR,2R)-2-((N-

ALLYLACETAMDO)METHYL)CYCLOBUTYL)METHYL)-N- (ALLYLSULFONYL)-6 ^, -CHLORO-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2"

SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXAMIDE

To a stirred mixture of (S)-5-(((lR,2R)-2-((N- ailylacetarnido)methyl)cyciobut d)methyl)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'lic acid (48 mg, 0.092 mmol) and prop-2-ene-l -sulfonamide (33 mg, 0.28 mmol) in DCM (2.0 ml.) was added at rt EDC1 HC1 salt (43 mg, 0.28 mmol) followed by N,N-dimethylpyridin- 4-amine (34 mg, 0.28 mmol). The resulting mixture was stirred at rt for a period of 16 h. The crude mixture was subjected to combi-flash column chromatography ((0.2% AcOH in EtOAc)/hexanes), 35 mm from 0 to 100%, 24 g ISCO silica gel column) to furnish 30 mg of the title compound as a colorless film, directly taken onto the next step. STEP 5: (lS,3 ^, R,6 ^, R,10 ^, E)-8'-ACETYL-6-CHLORO-3,4-DIHYDRO-2H,15 ^, H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TraA[l ₅ 8, 14]raAZATCTRACYCLO[14.7.2.0 ³ ^0 ¹⁹ - ²⁴ ]PENTACO

SA[ 10,16,18,24]TETRAEN]-15'-QNE 13',13'-DIQX1DE AND (18,3Ί ,6¾,10'Ζ)- S'-ACETYL-e-CHLORO-S^-DIHYDRO^lSH-SPIROtNAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,8,14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACO S A[ 10, 16,18,24] TETRAEN]-15'-ONE 13',13'-D10XIDE

A 250 mL single-necked round- bottomed flask charged with (S)-5- (((lR,2R)-2-((N-allyiacetam^

chloro-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene]-7-carboxamide (25 mg, 0.040 mmol) was subjected to 3 cycles of evacuation and back-filling with nitrogen. Toluene (40 mL) was introduced under nitrogen. The resulting mixture was stirred at ambient temperature for 10 min to allow the starting material to dissolve (but it didn't completely dissolved) before 2 ^nd generation hoveyda-grubbs catalyst (5.0 mg, 8.0 μηιοΐ) was added. The resulting mixture was stirred at 106 °C for 75 min. After the volatiles were removed, the crude residue was subjected to combi-flash column chromatography ((0.2% AcOH in EtOAc/hexanes), 35 min from 0 to 100%, 24 g ISCO silica gel column) to furnish 5 mg of a nearly i-to-I mixture of the title compounds as an off-white solid. ¾ NMR (400MHz, CDCh) δ 8,27 (br. d, J=l .0 Hz, i l l ). 7,70 (t, J=8.9 Hz, IH), 7.41 (s, 0.5H), 7.37 (s, 0.5H), 7.20 (td, J=3.0, 8.5 Hz, IH), 7.12 - 7.06 (m, IH), 7.00 - 6,88 (m, 2H), 5.69 - 5.43 (m, 2H), 4.75 - 4,57 (m, IH), 4.20 - 4.04 i s 4H), 4.00 - 3,90 (m, 2H), 3.83 - 3.68 (m, 2H), 3.22 (dd, .1=1 1.2, 14.3 Hz, 2H), 3.05 (dd, J=9.0, 14.3 Hz, M l ). 2.86 - 2.65 (m, 4H), 2.31 - 1.37 (m, ί i l l ), m/z (ESI, +ve ion) 598.3 ( VI I D ^' .

EXAMPLE 372. (18,3Ί ,6'8,7Έ,9Έ,1 rS,12 ^! R)-6-CmQRQ-l l',12'-DIMEraYL- 3 ,4-DlH YDRQ-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [7,9, 16, 18,24]PENTAEN ~15'-ONE 13', 13'-DIOXIDE

To a stirred solution of bis(2,2,2-trifluoroethoxy)triphenylphosphorane (11.52 nig, 0.025 mmol) in a mixed solvent comprising DCM (0.6 mL) and EteO (0.6 mL) was added a solution of (1 S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-chloro-7 ^! - methoxy- 1 Γ, 12'-dimethy 1-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- ^' ' ⁿ ]pen!acosa| H. I 6. i 8.24 ]icirae n]-15'-one 13',13'-dioxide (15 nig, 0.025 mmol, Example 357, Step 1) in DCM (0.3 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h. More bis(2,2,2-trifluoroethoxy)triphenylphosphorane (not weighed) was added to the solution and the stirring continued for 2 h. After the reaction mixture was concentrated under reduced pressure, the residue was taken up in DMSO, and subjected to preparative reverse-phase HPLC (Gemini™ Prep Ci8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 55-95% acetonitnle in water, where both solvents contained 0.1% TFA, 30 min method) to give 4.0 mg of the title compound as a white solid. ^! H NMR (400MHz, CDCb) δ 7.71 - 7.61 (m, 2H), 7.21 (ddd, .7=2.2, 8.4, 19.6 Hz, 2H), 7.10 (d, ,/ 2 2 Hz, i l l ). 6.96 (d, J=8.2 Hz, 1H), 6.65 (d, ./ 2.0 Hz, IH), 6.28 (dd, ./ 1 0.2. 15.3 Hz, 1H), 6.07 (dd, ./ i o.2. 16.0 Hz, IH), 5.91 (dd, ./ 6.8. 16.0 Hz, ! ! ! ). 5.53 (dd, ./ 9.3. 15.2 Hz, WD.4.19 - 4.02 (m, 2H), 3.76 - 3.66 (m, 2H), 3.57 (d, J=15.5 Hz, Hi). 3.36 - 3.19 (m, 2H), 2,88 - 2.74 (m, 2H), 2.71 - 2.54 (m, 2H), 2,31 (quin, ,7=8,5 Hz, 1H), 2.17 - 1.66 Cm.6H), 1.60 id../ 7.2 Hz, 3H), 1.58 - 1.45 (m, 21 i).1.17 (d, ./ 6,8 Hz, 3H). m'z (ESI, +ve ion) 581.1 (M+H) ⁺ .

EXAMPLE 373. (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(l ₅ 3- THIAZOL-2-YLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[1,14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ³⁹ - ²⁴ ]PENTACOSA [8,16,18,24]

TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E ₅ 12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(l,3-THIAZOL-2- YLMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THI A[ 1 , 14] DIAZATETRACYCLO

[14.7.2.0 -^() ^!9 - ²⁴ lPENTACOSA|8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE

STEP 1 : 2-(BROMOMETHYL)THIAZOLE ^- ^Br

To a suspension of l,3-thiazol-2-ylmethanol (1.52 g, 12,8 mmol) in Et ₂ 0, carbon tetrabromide (1,37 mL, 14.1 mmol) and triphenylphosphine (3.69 g, 14.1 mmol) was added at ambient temperature. The mixture was stirred for 2 h, and a white precipitate was formed. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographed (silica gel, hexane/EtOAc, 9:1 to 1:1) to afford the title compound as a colorless liquid which was used immediately for the next reaction without further purification m/z (ESI, +ve ton) 178,2 { M H )

STEP 2: (2S)-N ₅ N-BIS(4-METHOXYBENZYL)- 1 -( 1 ,3-THIAZOL-2-YL)-5- HEXENE-2-SULFON AMIDE AND

(2R)-N,N-BIS(4-METHOXYBENZYL)-l-(l,3-THIAZOL-2-YL)-5-HEXENE- 2- SULFONAM

To a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l -sulfonamide

(Intermediate EE19, 1.00 g, 2.57 mmol) in THF (10 mL) at -78 °C was added n- butyllithium, 2.5 M solution in hexanes (1.03 mL, 2.57 mmol). The mixture was stirred at this temperature for 30 minutes, and then added a solution of 2- (bromomethyl)thiazole (0.914 g, 5.13 mmol) in THF. The mixture was continued stirring at -78 °C for 1 h and then quenched with saturated aqueous NHUCl. The mixture was diluted with EtOAc, the organic layer was washed with water, brine and dried (MgSC ). Solvent was evaporated, the crude residue was

chromatographed (silica gel, hexane/EtOAc, 9: 1 to 1 : 1) to afford a light oil as the title compounds.

STEP 3: (2R)-i ~(1 ,3-THIAZOL-2-YL)-5-HEXENE-2-SULFON AMIDE AND (2S)- 1 -(l,3-THIAZO -2-YL)-5-HEXENE-2-SULFONAMIDE

A solution of (2S)-N,N-bis(4-methoxybenzyl)-l-(thiazol-2-yl)hex-5-ene-2- sulfonamide and (2R)-N,N-bis(4-methoxybenz 1)-1 -(thiazol-2-yl)hex-5-ene-2- sulfonamide (740 mg, 1.52 mmol) in 2,2,2-trifluoroacetic acid (13.9 ml, 122 mmol) was heated with anisole (8.26 ml, 76.0 mmol) at 40 °C for 18 h. The mixture was cooled, concentrated and the residue was chromatographed ( silica gel, hexane/EtOAc,l:0 to 3: 1 to 0: 1) to afford the title compounds as a colorless oil. STEP 4: (3S)-6'-CHLORO-5-(((lR,2S)-2-((l S,2E)-1 -HYDROXY-2-HEXEN- 1 - YL)CYCLOBUTYL)METHYL)-N-(((2S)-l-(l,3-THIAZOL-2-YL)-5-HEXE -2- Y^SULFONY^-S'^^'^-TETRAHYDRO^H-SPIROIl^- BENZOXAZEPTNE-3,l'-NAPHTHALENE]-7-CARBOXAMIDE AND

(3 S)-6'-CHLORO-5-((( 1 R,2S)-2~(( 1 S ,2E)- 1 -HYDROXY -2-HEXEN- 1 - YL)CYCLOBUTYL)MEraYL)-N-(((2R)-l-(l,3-THIAZOL-2-YL)-5-HEXEN- 2- YL)SULFONYL)-3 ^, ,4.4 ^, ,5-TETRAHYDRO-2 ^, H-SPIRO|;i,5- BENZOXAZEPrNE-3,l.'-NAPHTHALENE]-7-CARBOXAMIDE

(S)-6'-Chloro-5-(((l R,2S)-2-((S,E)-l-hydroxyhex- yl)c lobutyl)methyl)-3 4,4 5-tetrahydro-2H,2^spiro[benzo[b][ l,4]oxazepine- 3 , 1 -naphthalene] -7-carboxy He acid (Intermediate AA12A, 100 mg, 0,20 mmol) in CH2CI2 (1 mL) was mixed with (2S)-l-(l,3-thiazol-2-yl)-5-hexene-2-sulfonamide, (2R)-l-(l,3-thiazol-2-yl)-5-hexene-2-sulfonamide (97 mg, 0.39 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide HCl (75 mg, 0.39 mmol), 4- dimethyl amino pyridine (48 mg, 0.39 mmol) and triethylamine (0.068 ml,, 0.49 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 days and quenched with water. The mixture was diluted with CH2CI2, and the organic layer was dried (MgSC>4), filtrated and concentrated. The resulting residue was chromatograplied (silica gel, hexane/EtOAc, 9: 1 to 1 : 1) to afford the first eluting isomer as one title compound, m/z (ESI, +ve ion) 738.2 (M+H) ⁺ ; and the second eluting isomer as the other title compound, m/z (ESI, +ve ion) 738.2 (M+H) ⁺ . STEP 5: ί I S ..TR.6'R.7'S.X'i -.. 1 2'S )-6-CI ! LORO-7 -} i V DR()XY- ! 2'-i i .3- THIAZOL-2-YLMETHYL)-3,4-DlHYDRO-2H, 15H-SPIRO[NAPHTHALENE- l,22'-| 20jOXA[ 13]THIA

[ 1, 14]DIAZATETRACYCLO[ 14.7.2,0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8, 1 6, 18,24]TETR AEN]-15'-ONE 13', 13 '-DIOXIDE OR

(l S,3'R,6'R,7'S,8'E, 12'R 6-CHLOR()-7'-HYDROXY-12'-(l ,3-TOIAZOL-2- YLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[13]THIA[1 , 14] DIAZATETRACYCLO

[ 14.7.2.0 ³ · ⁶ .0 ^ί9 · ²⁴ ]ΡΕΝΤΑ€Ο8Α[8, 16, 18,24]ΊΈΊ^ ΕΝ]-15'-Ο Ε 13', 13'- DIOXIDE

A round bottom flask was charged with the first isomer (50 mg, 0.068 mmol) in AcOH (40 ml,). After bubbling argon gas into the flask for 15 min, the homogeneous solution was added Hoveyda-Grubbs catalyst 11 (22 mg, 0.034 mmol) and stirred at ambient temperature under reduced pressure (with a intermediate needle going through a septum into the flask and its other end connecting to the house vacuum) for 18 h. The mixture was quenched with ultrapure silica gel (loading-0.61mmol/l g), stirred for 20 min, and filtered. The filtrate was concentrated, and the crude residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to afford the title compound as a white solid. H NMR (500 MHz, (1X 1 ; ) δ ppm 8.45 (br s, 1 H), 7.78 (d, j 3 4 Hz, 1 H), 7,70 (d, J=8.3 Hz, 1 H), 7.35 (d, J=3.4 Hz, 1 H), 7.18 (dd, J=2.2, 8.6 Hz, 1 H), 7.12 - 7.06 { i n. 1 H), 6.96 - 6.90 (m, 3 H), 5.86 - 5.78 (m, 1 H), 5.67 (dd, j 7.2. 15.3 Hz, 1 H), 4.64 -4.76 (m, 1 H), 4.22 (dd, j 4 3. 6,7 Hz, ! H), 4.15 - 4.05 (m, 3 H), 3 ,91 (d, j 5.7. 15,5 Hz, 1 H), 3,79 (d, J=15.4 Hz, 1 H), 3.70 (d, J 1 4.2 Hz, 1 H), 3.59 (dd, J=7.0, 15.5 Hz, 1 H), 3.25 (d, J=14.2 Hz, 1 H), 3.06 (dd, J=8.7, 15.0 Hz, 1 H), 2.83 - 2.71 (m, 2 H), 2.50 - 2.25 (m, 6 H), 2.25 - 1.60 (m, 5 H), 1.42 (m, 2 H). m/z (ESI, +ve ion) 668.2 (M+H) ⁺ . Example 374. (18,3¾,6'Κ,7'8,8'Ζ,12'8)-6-α-Π.Λ¾0-7'-ΗΥΟΚΟΧΥ- !2'-(1,3- THL Z0L-2-YLMF;THYL)-3,4 ^IHYDR0-2H,15H-SPIR0[NAPHTHALENE- 1 ,22'-[20] OXA[ 13]THI A[ 1 , 14]DIAZ ATETRAC YCLO

[14.7.2.0 ³ - ⁶ .0 ^I9 - ²⁴ ]PENTACOSA[8,16J 8,24] TETRAEN ] - 15 '-ONE 13',13'- DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'Z,12'R 6-CHLORO-7'-HYDROXY-12'-(l,3~THL' ZOL-2- YLMETHYL)-3,4-DIHYDRO-2HJ5'H~SPIRO[ APHTHALENE-L22'"

[20] OXA[ 13]THI A[ 1 , 14] DI AZ ATET AC YCLO

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18 ₅ 24] TETRAEN] - 15 '-ONE 13',13'- DIOXIDE

The title compound was prepared from the second eluting isomer in Step 5 of Example 373, using a similar procedure described in the S tep 5. ¾ NMR (500 MHz, CDCI δ ppm 7.77 (d, J 3,4 Hz, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 7.44 (dd, j 2.0.8.3 Hz, 1 !!}.7.33 (d, j 3.4 Hz, 1 H), 7.18 (dd, j 2.3.8.4 Hz, 2 !!}.7.10 (d, j 2.2 Hz, 1 Is).7.07 - 7.03 (rn, ! H), 7.00 (d, J 8.3 Hz, 1 H), 5.68 (dt, J 5.1.10.6 Hz, 1 H), 5.51 (dd, J=7,l, 10.8 Hz, 1 H), 4.51 (t, J=5.6 Hz, 1 H), 4.28 - 4.20 (m, 1 H), 4.17 - 4.04 (m, 3 H), 4.04 - 3.83 (m, 3 H), 3.97 (dd, j 3.9.15.2 Hz, 1 H), 3.89 (d, J 14.9 Hz, 1 !!}.3.75 - 3.60 (m, 1 H), 3.49 (dd, j 10.6.15,3 Hz, 1 H), 3,28 - 3.19 (m, 1 H), 3.13 (dd, j S .15.7 Hz, I H), 2.80 - 2.70 (m, 2 H), 2.38 - 1.73 (m, 6 H), 1.73 - 1.57 (m, 2 H), 1.53 - 1.37 (m, 2 H). m/z (ESI, +ve ion) 668.2 (M+H) ⁺ .

EXAMPLE 375. (1 S,3'R,6 ⁱ R,7'S,8'E, ri'R)-6-CHLORO-7'-(2- METHOX ΥΕΊΉΟΧΥ)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 ^

[8,16,18,24]TETRAEN]-15'-QNE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,ll'S)-6-CHLORO-7'-(2-METOOXYEra:OXY)-ir- METOYL-3,4-DIHYDRO-2I-I,15'H-SPTRO| JAPHTHALENE-l ,22'- [20]OXA[ 13]THI A[ 1 , 14] DIAZATETRACYCLO

[14.7.2.0 - ⁶ .0 ^!9 - ²⁴ 1PENTACOSA|;8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE

STEP 1: (1S,3'R,6'R,7'S,8'E,11'R)-6-CHL0R0-7'-HYDR0XY-11'-ME™YL- 3,4-DlHYDRO-2H,15^SPIRO[NAPHTHALENE-l,22'-

|20i() A| 1311 HI Λ| I .. ! -I |ΡΙΛ/.\ Π·. ΓΗ. Λί ^' ΥΌ.01 i -i.7.20 ' ".U ^1* " ¹ |PL\ i ACOSA

[8,16,18,24]TETRAENj-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8^11'S)-6-CHIX)RO-7'-HYDROXY-ri'-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATEII ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was synthesized as described for Example

(lS,3'R,6'R,7'S,8'E,irR)-6-chloiO-7 ^, -hydroxy-ir-methyl-3,4-dihydro-2H,15'H- spiro [naph thalene- 1 ,22'-

n|-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,H'S)-6-chloro-7'-hydroxy-l Γ- methyl-3,4-dihydro-2H,15'H-spirofnaphthalene-l,22'- [20]oxa[13]thia[l,14]diazatefra^

n]-15'-one 13',13'-dioxide was isolated as the second eluting major isomer (12 mg, 0.020 mmol, 21% yield). ^! ll NMR (400MHz, CD2CI2) δ 8.44 (br. s., IH), 7.71 (d, ./ K.4 Hz, 1H), 7.17 (dd, ,/ 2.3.8.6 Hz, III).7.09 (d, ,/ 2.3 Hz, IH), 6.95 - 6.90 (m, 2H), 6.89 (s, ill).5.82 (ddd,J=5.1, 7.6, 15.1 Hz, IH), 5.70 (dd. J 8.2.15,3 Hz, H), 4,24 (dd, J=3.9, 12.3 Hz, IH), 4.20 (dd, «7=4.7, 8,8 Hz, IH), 4.10 - 4,05 (m, 2H), 3.82 (d, J=14.9 Hz, IH), 3.69 (d, J=14.3 Hz, IH), 3.25 (d, J=14.3 Hz, 1 IT), 3.05 (dd, .7=9,6, 15.1 Hz, IH), 2,98 (dd,J=8.0, 15.3 Hz, IH), 2.84 - 2.67 (ra, 2H), 2.41 (ddd, ,7=4,3, 9.8, 18.0 Hz, IH), 2.36 - 2.28 (m, IH), 2.24 (ddd, .7=2.2, 7.9, 15.2 Hz, IH), 2.08 - 1.99 (m, 2H), 1.98 - 1.87 (m, 3H), 1.87 - 1.74 (m, 4H), 1.68 (dd../ 9.4.18.8 Hz, IH), 1.46 - 1.35 (m, IH), 1.15 (d../ 6.5 Hz, Ml). MS (ESI, +ve ion) rn/z 585.1 (M l!) .

STEP 2: ( 1S,3'R,6'R,7'S,8'E,1 rR)-6-CHLORO-7'-(2-METHOXYETHOXY)-l Γ- MEra^L-3,4-DIHYDRO-2H ₅ 15^SPmO[NAPHTHALENE-l,22"-

|2 ⁽ !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24]TETiL E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,ll'S)-6-CHLORO-7'-(2-METOOXYEra:OXY)-ir- METOYL-3,4-DIHYDRO-2Il,15'H-SPTRO| JAPHTHALENE-!,22'- [20]OXA[13]THIA[1 ,14] DIAZATETRACYCLO

[14.7.2.0 - ⁶ .0 ^!9 - ²⁴ 1PENTACOSA|;8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE

To a round bottom flask was added sodium hydride, 60% dispersion in mineral oil (21 mg, 0.51 mmol) and DMF (1 mL) at 0 °C.

(lS,3¾,6 ^, R,7'S,8¾,ll'R)-6-cMoro-7 ^, ½drox -ll'-me i-3,4-dihydro-2H,15^ spiro[naphtha] ene- 1 ,22'-[20] oxa[ 13] thia[ 1 , 14] diazatetracy clo

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15 ^, -on or

(lS,3¾,6 ^, R,7^,8¾irS)-6-chloro-7' iydroxy-ll'-meth}4-3,4-dihydro-2H,15'H- spiro [naph thai ene- 1 ,22'- [20] oxa[ 13] thia[ 1 , 14]

diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-on ( the first isomer, 30 mg, 0.051 mmol) was then added. After the reaction mixture was stirred at 0 °C for 30 min, 2-bromoethyl methyl ether (36 mg, 0,26 mmol) was added. The reaction mixture was allowed to warm up to ambient temperature and stirred for 18 h. The mixture was quenched with 1,0 N aqueous HCl, and diluted with EtOAc. The organic layer was dried (MgSC ) and concentrated. The resulting residue was chromatographed (silica gel, 0-50%, EtOAc+0.5%

HOAc/hexane) to afford a solid, 30 mg. This solid was further purified by- reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column;

Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound, ¾ NMR (500 MHz, CDCb) ό ppm 8.32 (s, 1 H), 7,68 (d, J 8.6 Hz, 1 H), 7.17 (dd, j 2.2. 8.6 Hz, 1 H), 7.09 (d, J=2.0 Hz, 1 H), 7.05 - 6.97 ins. 1 ! ! }. 6.92 (d, J=8.1 Hz, I H), 5.94 - 5,85 (m, I H), 5.51 (dd, .1 7 0. 15.3 Hz, 1 H), 4.17 - 4.04 (m, 2 H), 3.75 - 3.68 (m, 2 H), 3.66 - 3.46 (m, 7 H), 3.44 - 3.34 (m, 4 H), 2.80-2.72 (m 2 H), 2.45 - 2.40 (m, 2 H), 2.22 - 2.10 (m, 3 H), 2.00 - 1.75 (m, 6 H), 1.75-1.55 (m, 2 H), 1.53-1.48 (m, 1 H), 1.18 (d, j 6.4 Hz, 3 ! ! }. m /. (ESI, +ve ion) 643.2 (M+H) ⁺ .

EXAMPLE 376. (1 S,3'R,6 ^* R,7'S,8'E,1 l'S)-6-CHLORO-7'-(2- METHOXYETHOXY)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]raJA[l,14]DIAZATETRACYC^

[8,16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(1S,3¾,6'R,7¾,8¾,1 l ^, R)-6-CHLORO-7'-(2-METHOXYETHOXY)-l 1'- METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[1,14]

DIAZATETRACYCLO[14.7.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15'-ONE 13', 13'-DIOXJDE

STEP 1 : (S)-N,N-BIS(4-METHOXYBENZYL)-2-METHYLPENT-4-ENE-l - SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)-2- METHYLPEN -4-ENE-l -SULFONAMIDE

N,N-bis(4-memoxybenzyl)methanesulfonainide (intermediate EE12; 1.05 g, 3.13 mmol) was azeotroped in PhMe under vacuum for 12 h, then, under Ar, THF (21 mL) was added and the solution was cooled to -78 °C. Butyllithium solution, (2.5 M in hexanes; 1.63 mL, 4.07 mmol) was then added and the mixture (turned immediately dark) was stirred at -78 ° C for 30 mm. Pent-4-en-2-yl 4- methylbenzenesulfonate (prepared according to the procedure by Sigman, M. S. et ai. - J. Am. Chem. Soc , 2012, !34(2 ), 1 1408-11411; 1.3 g, 5.41 mmol) was then added as a solution in 1.5 mL THF. After complete addition the mixture was allowed to warm to ambient temperature and stir overnight. LC/MS analysis showed 50% conversion to the desired product; prolonged stirring for a further 24 h did not improve the conversion. The mixture was then quenched with sat.

NH4CI, and extracted with EtOAc, dried over MgS04 and concentrated. The cmde material was purified by chromatography through a 24 g IS CO col umn, eluting with 10 % to 20 % to 60% EtOAc in hexanes, to provide a racemic mixture of (S)~ N,N-bis(4-methoxybenz l)-2-methy lpent-4-ene- 1 -sulfonamide and (R)-N,N- bis(4-memoxybenz l)-2-memylpent-4-ene-l-sulfonamide (408 mg, 1.01 mmol, 32% yield). STEP 2: (S)-2-METHYLPENT-4-ENE-l -SULFONAMIDE AND (R)-2-

METHYLPENT-4-E -l -SULFONAMIDE

The title compounds were synthesized from (S)-N,N-bis(4- methoxybenzyl)-2-methylpent-4-ene-l -sulfonamide and (R)-N,N-bis(4- methoxybenzyl)-2-methylpent-4-ene-l -sulfonamide (506 mg, 1.25

mmol) following the procedure described for Example 26, Step 2, (S)~2~ methylpent-4-ene-l -sulfonamide and (R)-2-methylpent-4-ene-l -sulfonamide were obtained as a racemic mixture (152 mg, 0.930 mmol, 74%» yield).

STEP 3: (TS)-TERT BUTYL 6 ^, -CHLORO-5-(((lR,2R)-2-((lS,5S,E)-l- HYDROXY-5-METHYL-6-SULF AMOYLHEX-2-E - 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _j! 4HYDRO-2H,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (l'S)-TERT BUTYL 6'-CHLORO-5-(((lR,2R)-2- ((l S.5R,E)-l-HYDROXY-5-METHYL-6-SULFAMOYLHEX-2-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE

A vial was charged with ((S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l- hy droxyhex-2-en- 1 -y l)cy clobuty l)methy l)-3 ',4 ,4',5 -tetrahy dro-2H,2 ^! H- spiro [benzo [b J [1,4] oxazepme-3 , -naphthalene] -7-carboxy late (Intermediate AA12A, Step IB, first eluting isomer; 120 mg, 0.212 mmol) and a racemic mixture of (S)-2-methylpent-4-ene-l -sulfonamide and (R)-2-methylpent-4-ene-l- sulfonamide (156 mg, 0.954 mmol) in 1,2-DCE (3.03 niL). The solution was sparged with argon and Hoveyda-Gmbbs TT (13.28 mg, 0.021 mmol) was added as a solution in 1.5 mL 1,2-DCE at ambient temperature. The mixture was stirred (sparging with Ar and venting the vial) at ambient temperature (the clear solution becomes increasingly darker) for 1.5 h (70% conversion by LC/MS analysis). The reaction mixture was then sparged with air for 5 min, concentrated and directly injected into a 24 g ISCO Gold column, and purified eluting with 0-20-50-100% EtOAc/hexane over 16 min to give a mixture of (l 'S)-tert butyl 6'-chloro-5- ((( 1 R,2R)~2-(( 1 S,5 S,E)- 1 -hy droxy-5-methy l-6-sulfamoylhex-2-en- 1 - yl)c>'clobu1yl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[ benzo[b] [l,4]oxazepine- 3,l '-naphthalene]-7-carboxylate and (l 'S)-tert butyl 6'-chloro-5-(((lR,2R)-2- ((l S,5R,E)-l -hydroxy-5-methyl-6-sulfamoylhex-2-en-l -yl)cyxlobut 'l)methyl)- 3\4,4 5-tetrahydro-2H,2 ^, H-spiro[benzo[b] [ l ,4]oxazepine-3,.r-naphthalene]-7- carboxylate (63 mg, 0.096 mmol, 45 % yield). STEP 4: (S)-6*-CHLORO-5-(((lR,2R)-2-(( l S,5S )-l-HYDROXY-5-NlETHYL- 6-SULFAMOYLHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [l ,4]OXAZEPfNE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-((( lR,2R)- 2-((l S,5R,E)- l -HYDROXY-5-METHYL-6-SULFAMOYLHEX-2-EN-l - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SP1RO [BENZO [B] [ 1 ,4] OXAZEPlNE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

To a solid mixture of (l 'S)-tert butyl 6'-chloro-5-(((lR,2R)-2-((l S,5S,E)-l hydroxy-5-methyl-6-sulfanioylhex-2-en-l -yl)cyclobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b J [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate and (1 'S)-tert butyl 6'-chloro-5-((( lR,2R)-2-((l S,5R,E)- 1 -hydroxy-5-methyl-6- sdfamoylhex-2-en-l-yl)cyclobut 4)me1hyl)-3 ^, ,4,4 5-tetTahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepme-3 , Γ-naphthal ene] -7-carboxy late (63 mg, 0.096 mrnol) and lithium hydroxide monohydrate (0.013 mL, 0.48 mmol) was added a 1 : 1 mixture of Dioxane/MeOH (1.9 mL). The reaction was heated to 70 °C. Virtually no reaction was observed after 1.5 h; water (-0.4 mL) was added and the mixture was stirred for 40 h (still incomplete reaction). The mixture was then quenched with 1 N HCl (1.0 mL), diluted with brine, extracted with EtOAc, dried over MgS04 and concentrated. The crude material thus obtained (containing traces of starting material) was taken on to the next step without further purification.

STEP 5. (1 S,3'R,6'R,7'S,8'E,1 l ^* S)-6-CHLORO-7 ^* -HYDROXY-l l '-METHYL- 3,4-DIHYDRO-2H,15^SPIRO|TSiAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DL ZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAENl-15'-ONE 13', 13'-D )XIDE OR

(lS,3'R,6'R,7'S,8'E,i R)-6-CHLORO-7'-HYDROXY-i -METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.() ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [8, 16, 18,24]TETR ~15'-ONE 13", 13 -DIOXIDE

The title compound was synthesized from (S)-6'-chloro-5-(((l R,2R)-2- ((l S,5S,E)-l-hydroxy-5-me1hyl-6-sulfam

3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((l S,5R,E)-l-hydroxy-5-methyl- 6-sdfamoylhex-2-en-l-yl)cj'clobutyl)methyl)-3^4,4 5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, ~naphthalene]-7-carboxylic acid (57 mg, 0.095 mmol) following the procedure described for Example 323, Step 7. The crude material was purified by chromatography through a 12 g ISCO gold column, eluting with 10-50 % EtOAc (containing 0.3% AcOH) in hexanes over 24 min, to provide (1S,3 ^! R,6¾,7'S,8'E, 1 l'S)-6-chk>ro-7'-hydroxy~l r-methyl-3,4-dihydro- 2H,15'H-spiro[naphthalene-l,22'- [20]oxaj l3]thia[ l, 14]diazatetracycfo[14.7^ _^

n]-15'-one lS^n^dio ide or il S^^ff^TS^^i rR^e-chloro-T-hydrox -l l ^* - methyl-S^-dihydro^H _j lS'H-spirofnaphthalene-l^'-

[20]oxa[13]tMa[l,14]diazatetrac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'-dioxide as the first eluting minor isomer (1 1 mg, 0.019 mmol, 20% yield, 90% purity). ¾ NMR (400MHz, CD2CI2) δ 8.41 (s, 1H), 7.66 (d, J=8.4 Hz, IH), 7.50 (br. s., 1H), 7.15 (dd, J=2.3, 8.4 Hz, i l l ). 7.10 (d, J=2.3 Hz, H I ). 6.95 (dd, ./ 2.0. 8.2 Hz, I I I ). 6.90 (d, ,/ 8.0 Hz, IH), 5.69 (dd, ./ 4.3. 15.8 Hz, H), 5,63 - 5,54 (m, 1 1 1 ). 4.20 (s, 2H), 4.04 (d, ,/ 1 5 3 Hz, IH), 3.94 (dd, ,/ 2 2. 5.2 Hz, IH), 3.89 - 3,81 (m, IH), 3.74 - 3.63 (m, H), 3.39 (d, J=15.3 Hz, IH), 3.26 - 3.17 (m, IH), 3.09 - 2.96 (ni, IH), 2.81 - 2.71 (m, 2H), 2.57 - 2.41 (ni, 2H), 2.16 (dd, ,/ 6,5. 1 1 .7 Hz, IH), 1 ,92 - 1.76 (m, 6H), 1 .75 - 1.63 (m, 3H), 1 ,62 - 1 ,41 (m, 2H), 1.19 id. .7=6.1 Hz, 3H). MS (ESI, +ve ion) m/z 585, 1 (M+H) ⁺ .

STEP 6: (1 S,3'R,6'R,7'S,8 ^* E,1 l ^, S)-6-CHLORO-7 ^, -(2-METHOXYETHOXY)-l l'- METHYL-3,4-DIHYDRO-2H,15^SPIRO|NAPHTHALENE-.l ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,1 l ^, R)-6-CHLORO-7'-(2-METHOXYETHOXY)-l Γ-

MEraYL-3,4-DIHYDRO-2H,15^SPIRO|NAPHTHAL-ENE-l,22'-

[20] OXA[ 13]THI A| 1,14]

DLAZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA[8,16,18,24]TETRAEN]- 15 ^* -ONE 13',I3'-DIOXIDE

The title compound was prepared from (l S,3'R,6'R,7'S,8'E,Ti'S)-6-chloro- 7'-hy droxy- 1 l'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'~ i;20]oxa[ 13]thia|;i ,14]diazatetracycio| 14.7.2,0 ³ -^0 ^l9 - ²⁴ ]pentacosa[8,I6, l ^ n]-15'-one 13',13 ^! -dioxide or (1 S,3'R,6'R,7 ^! S,8'E, 1 rR)-6-chloro-7'-hydroxy-ir- niethy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20] oxai 3] ihi a[ I/ 4] ds aza ^^

n]-15'-one 13',13'-dioxide (30 mg, 0,051 mmol) using a similar procedure described in Example 375, Step 2, reacting with 2-bromoethyl methyl ether (36 mg, 0.26 mmol). Purification by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μίη column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeC in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as a white solid. ¾ NMR (500 MHz, CDCb) δ ppm 8.22 (s, 1 H), 7,70 (d. J 8.6 Hz, 1 H), 7.18 (dd, J 2.!.8.4 Hz, 1 H), 7,09 id. J 2,0 Hz, 1 H), 6,95 - 6,88 (m, 2 H), 6,83 (s, I H), 5.88 - 5.80 (m, I H), 5.56 (dd, J 9.0. 15.2 Hz, 1 H), 4.36 (dd, j 4.8.15.3 Hz, 1 H), 4.14 - 4.04 (m, 2 H), 3.85 - 3.78 (m, 2 H), 3.71 (d, j 14.2 Hz, 1 H), 3.60 - 3.48 (m, 3 H), 3.45 - 3.34 (m, 4 H), 3.23 (d, .! 14.4 Hz, 1 H), 3.09 - 2,91 (m, 2 H), 2,84 - 2,71 (m, 2 H), 2,53 - 2,44 (m, 1 H), 2,36 - 2.23 (m, 2 H), 2,13 - 1.92 (m, 5 H), 1,89 - 1.74 (m, 3 H), 1,69 - 1.54 (m, 1 H), 1.39 (t, J 1 .6 Hz, 1 H), 1.16 (d, J 6.6 Hz, 3 H). m/z (ESI, +ve ion) 643.2 (WW) .

EXAMPLE 377. (1S,3'R,6 ^! R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2-(2- METHOXYETHOXY)ETHOXY)- 1 Γ, 12 ^, -DIMETHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO[NAPHTOALENE-l,22'-[20]OXA[131TOiA[I,14]DIAZATETRACY CLO [14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PE TACOSA[8,16,18,24]TET1 AEN]"15'"ONE Β',Β'- DIOXIDE

A mixture of dry (lS,3 ^, R ₅ 6 ^, R ₅ 7 ^, S,8 ^, E,irS _s 12 ^, R)-6-chloro-7 ^, -hydroxy i ,12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene- 1 ,22' [20] oxa[ 13]thia[ 1 , 14] diazatetracyclo [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] pentacosa[8, 16, 1 8,24]tetTaen]-15'-one 13', 13'-dioxide ( 15 mg, 0.025 mmol) from Examples 719, Step 2 and sodium hydride, 60% dispersion in mineral oil (9.9 mg, 0.43 mmol) in DMF was stirred under argon for 10 min. l -(2-bromoethoxy)-2- methoxyethane (22.6 mg, 0.124 mmol) was added at ambient temperature. The reaction mixture was stirred for 8 h, quenched with saturated aqueous NH4CI, and extracted with EtOAc (X3). The combined organic layers were dried { YlgSO i ) and concentrated. The residue was chromatographed (silica gel, 0-50%,

EtOAc+0.3%HOAc/hexane) to afford the title compound as a white solid. ¾ NMR (400 MHz, CDCh) δ ppm 8.09 (s, 1 H), 7,70 (d, J=8,6 Hz, 1 H), 7. 8 (dd, J=2.2, 8.5 Hz, 1 H), 7.09 (d, J=2.2 Hz, 1 H), 6.95 - 6.87 (m, 3 H), 5.82 (ddd, j 3.2. 9.4, 15.1 Hz, 1 H), 5.54 (dd, j v. I . 15.2 Hz, 1 H), 4.35 - 4.24 (m, 1 H), 4.16 - 4.05 (ra, 2 H), 3.87 - 3.74 (m, 2 H), 3.70- 3.54 (m, 8 H), 3 ,45 - 3.44 (m, 1 H), 3.40 (s, 3 H), 3.23 (d, J=14.3 Hz, 1 H), 2.99 (dd, J 1 0.2. 15.3 Hz, 1 H), 2, 84 - 2.71 (m, 2 H), 2.53 - 2.42 (m, 1 H), 2.38 - 2.24 (m, 1 H), 2.15 - 1.93 (m, 4 H), 1.90 - 1.72 (m, 3 H), 1.72 - 1.57 (m, 3 H), 1.49 (d, j 7.2 Hz, 3 H), 1 .42-1.35 (m, 1 H), 1.05 id, J 6.8 Hz, 3 H). m/z (ESI, +ve ion) 701.2 i .V! H ) .

EXAMPLE 378. (l S,3 ^! R,6 ^, R,7'S,8'E,i rS,12'R)-6-CHLORO-7'-(2-(2-(2- METOOXYETHOXY)ETHOXY)ETHOXY)- ! ! 12'-DIMETHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - [20] OXA[ 13]THI A[ 1 ,14] Dl AZ ATETRAC Y CLO

[ 14.7.2.0 ³ ' .0 ¹⁹ ' ² ]PENTACOSA[8, 16, 1 8,24]TETRAEN]- 1 5'-ONE 13', 13'- DIOXIDE

The title compound was prepared from (l S,3'R,6'R,7'S,8'E, i S,12 ^! R)~6- chloro-7'-hydroxy-l lVI2'-dimethyl-3,4-dihydro-2H,15 ^, H-spiro|naphthalene- l,22'[20]oxa|;i3 ]thia[ 1.14] diazatetracyclo[ 14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]

pentacosa[8, 16, 18,24]tetraen]-15'-one 13',13'-dioxide (Examples 719, Step 2) using a similar procedure described in Example 377 replacing 1 -(2-bromoethoxy)- 2-methoxy ethane with l-bronio-2-|2~(2-methoxyethoxy)ethoxy | ethane. ¾ MR (400 MHz, CDCh) δ ppm 7.97 (s, 1 H), 7,70 (d, J 8.4 Hz, 1 1 1 ). 7.19 (dd, .! 2.2. 8,4 Hz, 1 H), 7.10 id . j 2.0 Hz, 1 H), 6.95 - 6.87 (m, 3 H), 5.86 - 5.75 (m, 1 H), 5.54 (dd, J=9.0, 15.1 Hz, 1 H), 4.35 - 4.22 (m, 1 H), 4.13 - 4.05 (m, 2 H), 3.86 - 3.76 (m, 2 H), 3.72 - 3.63 (m, 7 H), 3.63 - 3.54 (m, 5 H), 3.44 - 3.42 (m, 1 H), 3.40 (s, 3 H), 3,23 (d, J 1 .3 Hz, 1 H), 2.99 (dd, J=10.1, 15.4 Hz, I H), 2.84 - 2.71 (m, 2 H), 2.48 (d, J 10.6 Hz, 1 H), 2.38 - 2.26 (m, 1 H), 2.21 - 1.90 (m, 4 H), 1.89 - 1.72 (m, 3 H), 1.70 - 1.58 (m, 3 H), 1.50 (d, J=7.2 Hz, 3 H), 1.45-1.32 (m, 1 H), 1.06 (d, j 6.8 Hz, 3 ! ! }. m (ESI, +ve ion) 745.2 (M+H) ⁺ .

EXAMPLE 379. (1 S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-l 1',12'-D1METHYL- 7'-(3,6,9,12-TETRA()XATRlDE{ l -YLOXY)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTOALENE-l,22 ^f -[201OXA[ 13]TOIA[l, 14]DIAZATETRACYCLO [14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSA[8,16,18,24] TETRAEN] - 15 '-ONE 13', 13'- DIOXIDE

The title compound was prepared from (l S,3'R,6'R,7'S,8'Ej rS,12'R)--0- chloro-7'-hydroxy-l 1 ', 12'-dimethyl-3,4-dihydro-2H, 15'H-spiro|naphthaiene- 1 ,22' [20] oxa[ 13] thia[ , 14] di azatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Exaple 719, Step 2) using a similar procedure described in Example 377, replacingl-(2-bromoethoxy)-2- methoxyethane with triethylene glycol 2-bromoethyl methyl ether. H NMR (400 MHz, CDCb) δ ppm 8.02 (s, 1 H), 7.70 (d, J 8.6 Hz, 1 H), 7.19 (dd, j 2.2. 8,4 Hz, 1 H), 7.09 id. j 2.2 Hz, 1 H), 6.94 - 6.88 (m, 3 H), 5.85 - 5.77 (m, 1 H), 5.54 (dd, j K.5. 15.4 Hz, 1 H), 4.31 (q, j 7.4 Hz, 1 H), 4.09 (s, 2 H), 3.85 - 3.75 (m, 2 H), 3.74 - 3.62 (m, 1 1 H), 3.62-3.50 (m, 5 H), 3.45 - 3.42 (m, 1 H), 3.39 (s, 3 H), 3.23 (d, j 14.3 Hz, 1 H), 3.03 - 2,95 (m, 1 H), 2.83 - 2,72 (m, 2 H), 2.52 - 2,43 (m, 1 H), 2.32 (t, J=9.5 Hz, 1 H), 2.21 - 1.92 (m, 4 H), 1.90 - 1.74 (m, 3 H), 1.68 - 1.56 (m, 3 ! ! }. 1.50 id. j 7.2 Hz, 3 H), 1.40 (t, j 13.2 Hz, 1 H), 1.06 (d, j 6.8 Hz, 3 H). m/z (ESI, +ve ion) 789.2 (M+H) ⁺ .

Example 385. (lS,3'R,6'R,7 ^! S,8'E,H'S,12'R)-6-CHLORO-12'- (CYCLOPROPYLMETHYL)-7'-(2-METHOXYETHOXY)-l 1 '-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]D1AZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

PENTACOSA[8, 16, 18,24]TETRAE ]-15'-ONE 13',13'-DIOXIDE OR (18,3¾ Κ^'8,8Έ;Γί'8^2'8)-6-€ΗΕΟΚΟ-!2'-(€Υα.ΟΡΚΟ� �ΥΕΜΕΤΗΥΙ,)-7'- (2-METHOXYETHOXY)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRGpM APHTHALENE-1 ,22'~

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6'R 'S,8'Eai'R 2'R)"6-CHLORO-12'-(CYCLOPROPYLMETHYL)-7'- (2-METHOXYETHOXY)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTHALENE-l,22'-

|2θ!() Λ| I 311 HI Λ| I .. N |PIA/A Π·. E R.AC VC ^' E C)i i J 7.2 ίΓ".ϋ ^1: ' |ΡΗ\ i ACOSA [8,I6,18,24]TETiL4EN]-15'-ONE 13 I 3 '-DIOXIDE OR

(lS,3'R,6'R;7'S,8'E l'RJ2'S)-6-CHLOR()-12'-(CYCLOPROPYLMETHYL 7'- (2-METHOXYETHOXY)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TOIA[1 4]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8 ₅ 16,18,24 -15"-ONE 13',13'-DIOXIDE

STEP 1 : (2S)-N,N-BIS(4-METHOXYBENZYL)-2-METHYLPENT-4-ENE-l - SULFONAMIDE AND (2R)-N,N-BIS(4-METHOXYBENZYL)-2-METHYL-4- PENTE E- 1 - S ULFON AMIDE

The title compound was prepared from Intermediate EE 12 and pent-4-en- 2-yl 4-methylbenzenesulfonate following a similar procedure described in Example 434, Step 1. STEP 2: (2S,3R)-l-CYCLOPROPYL-N,N-BIS(4-METHOXYBE ZYL)-3- METHYL-5-HEXENE-2-SULFONAMIDE AND

(2R,3 S)- 1 -CYCXOPROPYL-N,N-BlS(4-METHOXYBENZYL)-3-METHYL-5- HEXENE-2-SULFONAMIDE AND

(2R,3R)-l-CYCLOPROPYL-N,N-BIS(4-METHOXYBENZYL)-3-METHYL-5- HEXENE-2-SULFONAMIDE AND

(2S,3S)-l-CYCLOPROPYL-N,N-BIS(4-METHOXYBENZYL)-3-METHYL-5- HEXENE-2

To a solution of (2S)-N,N-bis(4-metiioxybenzyl)-2-methyipent-4-ene- 1 - sulfonamide and (2R)-N,N-bis(4-methoxybenzyl)-2-memylpent-4-ene-l- sulfonamide (600 mg, 1.49 mmol) in THF was added butylliihium solution, 2.5 N in hexanes (0.624 mL, 1.56 mmol) at -78 °C under N ₂ . After the reaction was stirred at this temperature for 15 min, a solution of (bromomethyl)-cyclopropane (0.288 mL, 2.97 mmol) in THF (1 mL) was added. The reaction mixture was stirred at -78 °C for 1 h and then allowed to warm up to ambient temperature. The mixture was quenched with water, and extracted with EtOAc. The organic layer was washed with water and dried (Na ₂ S0 ₄ ). Solvent was evaporated, the resulting residue was chromatographed (silica gel, 10 to 50%, EtOAc/Hexanes) to afford the title compounds as a colorless liquid. STEP 3: (2S, 3S)-l-CYCLOPROPYL-3-METHYLHEX-5-ENE-2- SULFONAMIDE AND

(2S, 3R)-l-CYCLOPROPYL-3-METHYLHEX-5-ENE-2-SULFONAMIDE AND (2R, 3S)-1 -CYCLOP ROPYL-3-METHYLHEX-5-ENE-2-SULFONAMIDE AND (2R, 3R)- 1 -CYCLOPROPYL-3-METHYLHEX-5-E E-2-SULFONAMIDE

A mixture of (2S,3R)-l-Cyclopropyl-N,N-bis(4-methoxybenzyl)-3- methyl-5-hexene-2-sulfonamide and (2R,3S)-l-cyclopropyl-N,N-bis(4- methoxybenzyl)-3-methyl-5-hexene-2-sulfonamide and (2R,3R)-l-cyclopropyl- N,N-bis(4-methoxybenzyl)-3-methyl-5-hexene-2-sulfonamide and (2S,3S)-1- cyclopropyl-N,N-bis(4-methoxybenzyl)-3-methyl-5-hexene-2-sul fonamide (510 mg, 1.11 mmol) was treated with anisole (1 .81 g, 16.7 mmol) in 2,2,2- trifluoroaceiic acid (3.81 g, 33.4 mmol). The mixture was stirred, heated at 40 °C for 18 h and then concentrated. The resulting residue was chromatographed (silica gel, hexane/EtOAc, 9: 1 to 1 : 1 ) to afford the title compounds as a light brown oil.

STEP 4: (3S)-6'-CHLORO-N-(((2R,3S)-l-CYCLOPROPYL-3-METHYL-5~ HEXEN-2-YL)SULFONYL)-5-(((lR,2R)-2-((lS,2E)-l-HYDROXY-2-HEXE N- 1 -YL)CYCLOBUTYL)METHYL)^

BENZOXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXAMIDE AND

(3S)-6'-CHLORO-N-(((2R,3R)-l-CYCLOPROPYL-3-METHYL-5-HEXEN -2- YL)S ULFONYL)-5 -((( 1 R,2R)-2-(( 1 S ,2E)- 1 -HYDROXY-2-HEXEN- 1 - YL)CYCLOBUTYL)METFIYL)-3',4,4',5-TETRAI-iYDRO-2TI-SPIRO[l ,5- BENZOXAZEPIN¾-3,r-NAPHTHAL;ENE]-7-CA.^^

(3S)-6'-CHLORO-N-(((2S,3S)-l-CYCLOPROPYL-3-METHYL-5-FffiXEN- 2- YL)SULFONYL)-5-((( 1 R,2R)-2-(( 1 S,2E 1 -HYDROXY-2-HEXEN- 1 - YL CYCLOBUTYL)METFrY ^r L)-3',4,4',5-TETRAFrY ^r DRO-2'H-SPIRO[l,5- BENZOXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXAMIDE AND (3S)-6'-CHLORO-N-(((2S,3R)-I -CYCLOPROPYL-3-METOYL-5-HEXEN-2- YL)S ULFONYL)-5 -((( 1 R,2R)~2~(( 1 S ,2E)- 1 -HYDROXY -2-HEXEN- 1 - YL)CYCLOBUTYL)METHYL)-3^4,4^5-TETRAHYDRO-2H-SPIRO[l,5-

BE -3,1 '-NAPHTHALENE] -7-CARBOXAMIDE

A mixture of (2S, 3S)-l-cyclopropyl-3-methylhex-5-ene-2-sulfonamide, (2S, 3R)-l-cyclopropyl-3-methylhex-5-ene-2-sulfonamide, (2R, 3S)-1- cyclopropyl-3-methylhex-5-ene-2-sulfonamide, and (2R, 3R)-l-cyciopropyl-3- methylhex-5-ene-2-sulfonamide (160 mg, 0.74 mmol) was added (S)-6'-chloro-5- ((( 1 R,2S)-2-((S ,E) - 1 -hydroxy hex-2-en- 1 -y l)cy clobuty l)methy l)-3 ',4,4 ^* , 5 - tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A 250 mg, 0.49 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (141 mg, 0,74 mmol), 4-dimethylaminopyridine (90 mg, 0.74 mmol) and triethylamine (0.20 mL, 1.5 mmol) in CH2CI2 (1 mL). The reaction mixture was stirred at ambient temperature for 3 days. The mixture was then diluted with CH2CI2, and added water. The organic layer was dried (MgS04), and concentrated. The resulting residue was chromatographed (silica gel, 1 : 0 to 1 : 1, hexane/EtOAc+0.5%HOAc) to afford the title compounds.

STEP 5: (1 S,3'R,6'R,7'S,8'E,1 l 'S, 12'R)-6-CHLORO-12 ^, -(CYCLOPROPYL METHYL)-7'-HYDROXY-i -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO I NAPHTHALENE- 1 ,22'-[20] OX A[ 13] THIA[ 1 , 14 ] DI AZATETRACYCLO [14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-QNE 13', 13'- DIOXIDE OR (18,3¾ Κ^'8,8Έ;Γί'8^ 2'8)-6-€ΗΕΟΚΟ-!2'-(€Υα.ΟΡΚΟΡΥΕΜΕΤΗΥΙ ,)-7'- HYDROXY-i -METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[ 13]ΊΉΙΑ

[ 1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA 8,16,18,24]TETR AEN]-15 ^* -ONE 1343 '-DIOXIDE OR

(lS^^ffR-T^^^l l^l^^-e-CHLORO-^^iCYCLOPROPYLMETHYL)-?'- HYDROXY - 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTHALENE- 1 ,22'-[20]OXA[13]THIA

[1,14]DIAZATETRACYCLO[14.7.2.0 ⁵ ' ⁶ .0 ¹⁹ ' ² ]PENTACOSA[8,16,18,24]TETR AEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3¾,6'R;7^,8T,l l'RJ 2 ^, S)-6-CHLOR()-12'-(CYCLOPROPYLMETHYL 7'- HYDROXY- 1 1 '-METHYL-3,4-DIHYDRO-2H, 15 'H-SPIRO [NAPHTHALENE- L22'-[20]OXA[13]THIA

[L14]DIAZATETiLACYCLO[ 14 .2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTACOSA[8,16,18,24]TETR AEN]-15'-ONE ', 13 '-DIOXIDE

A round bottom flask was charged with above mixture of (3S)-6'-chloro-n- (((2R,3S)-l-cyclopropyl-3-methyl-5-hexen-2-yl)sulfonyl)-5-(( (l R,2R)-2- ((1 S,2E)-1 -hydro?^'-2-hexen-l-yl)cyc1obulyl)me1hyl)-3^4,4 5 etTahydro-2 ^, H- spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carboxamide, (3S)-6'-chloro-n- (((2R,3R)-l-c clopropyl-3-methyl-5-hexen-2-yl)sulfonyl)-5-(((l R,2R)-2- ((I S,2E)-l-hydroxy-2-hexen-l -yl)cyck)butyl)methyl)-3',4,4',5-ietrahydro-2T spiro[l,5-benzoxazepine-3, 1 '-naphthalene]-7-carboxamide, (3S)-6'-chloro-n- (((2S,3S)-l-cyclopropyl-3-methyl-5-hexen-2-yl)sulfonyl)-5-(( (lR,2R)-2-( 1 -hydroxy -2-hexen-l-yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2'H-spiro[ 1,5- benzoxazepine-3, -naphthalene]-7-carboxamide and (3S)-6'-chloro-n-(((2S,3R)- l-cyclopropyl-3-methyl-5-hexen-2-yl)sulfonyl)-5-(((lR,2R)-2- ((lS,2E)-l- hydro y^-he en-l-y c^ lobuty methy -S'^^'.S-tetrahydro^H-spiroll _j S- benzoxazepine-3, -naphthalene]-7-carboxamide (210 nig, 0.30 mmol) in DCE (100 mL). After bubbling into the flask with Argon for 15 min, the homogeneous solution was added Hoveyda-Grubbs catalyst II (65 mg, 0.35 mmol) and stirred at 50 °C for 18 h. The reaction mixture was cooled and introduced air by bubbling air into the flask for 2 min. Solvent was evaporated, and the crude residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the title compound as the first eluenting isomer. ¾ NMR (500 MHz, CDCh) δ ppm 8.08 (s, 1 H), 7.70 (d, J K.3 Hz, 1 H), 7.19 (dd, .! 2.2.8.6 Hz, 1 H), 7.10 (d, J 2.0 Hz, 1 !!}.6.99 (br s, 111).6.97 - 6.89 (ra, 2 H), 5.97 - 5.88 (rn, 1 H), 5.72 (dd, J 8.!. 15.2 Hz, 1 H), 4.30 - 4.22 (m, 2 H), 4.10 (s, 2 H), 3.82 (d, J=14.9 Hz, 1 H), 3.69 (d, j 14.2 Hz, 1 H), 3.26 (d, j 14.2 Hz, 1 H), 3.06 (br s, 1 H), 2.85 - 2.71 (m, 2 III 2.53 - 2.39 (m, 1 !!}.2.33 (quisn, J 8.7 Hz, 1 !!}.2,27 - 2.12 (m, 2 !!}.2,09 - 1.86 (m, 5 H), 1.86 - 1.77 (m, 3 H), 1.75 - 1.61 (m, 1 H), 1.50 - 1.31 (m, 2 H), 1.23 - 1.12 (m, 1 H), 1.05 (d, i=6.8 Hz, 3 H), 0.63 (d, J=7.8 Hz, 2 H), 0.35 - 0.25 {in.1 H), 0.13 - 0.06 {in.1 H). m/z (ESI, +ve ion) 639.2 {M il} . STEP 6: (1S,3'R,6'R,7*S,8'E,1 l ^! S,12'R)-6-CHLORO-I2'-

(CYCLOPROPYLMETHYL)-7'-(2-METI-IOXYETHOXY)-ir-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO [14.7,2.0 ³ · ⁶ 0 ¹⁹ · ²⁴ ]

PENTAC OS A[8, 16, 18,24] TETRAE ] - 15 '-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^, S,8'E,ll'S,12'S)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)-7'- (2-METHOXYETHOXY)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPi ( ⁾ i\AFHill. {.! \i:-1.22-

[20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-D )XIDE OR

(lS,3 ^, R,6'R,7'S,8'E,irR,12'R)-6-CHLORO-12'-(CYCLOPROPYLMETHY L)-7'- (2-METHOXYETHOXY)- 1 l'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13 13'-D10X1DE OR

(lS,3¾,6'R;7^,8T l'RJ2^)-6-CHL()R()-12'-(CYCLOPROPYLMETHYL 7'- (2-METHOXYETHOXY)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1 4]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24] - 15"-ONE 3', 13 ^* -DIOXIDE

The title compound was prepared from (lS,3'R,6'R,7'S,8'Ej S,12 ^! R)-6- chloro-12'-(cyclopropylmethyl)-7'-hydroxy-l -methyl-3,4-dihydro-2h,.15'h- spiro[naphthalene-l,22'-[20]oxa[13]thia[l,14]diazatetracyclo [14,7.2.0 ³ · ⁶ ,0 ¹⁹ · ²⁴ ] pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide or

methyl-3,4-dihydro-2h,.l 5'h-spiro[naphthalene-.l ,22'-[20]oxa[13]thia| 1 ,14] diazatetracyclo[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]peiitacosa[8,16,18,24]tetraen]-15'~one 13',13'- dioxide or(lS,3¾,6 ^, R,7 ^, S.8Έ ΓR,12 ^, R)-6-cωoΓO-12 ^, -(c clopΓopylme1h l)-7 ^, - hydroxy-1 r-methyl-3,4-dihydro-2h,15'h-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14, 7.2, 0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide or

(lS,3¾,6 ^, R,7'S,8¾,ll'R,12¾)-6-chIoro-12Hcyclopropylmethyl)-7 ^, ½cifoxy r methyl-3,4-dihy dro-2h, 15'h-spiro[naphthal ene- 1 ,22'-f 20] oxa[ 13] thia[ 1 , 14] diazatetracyclo[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹²⁴ ]peiitacosa[8,16,18,24]tetraen]-15'~one 13',13'- dioxide (Step 5) by a similar procedure described in Example 720, replacing 4-(2- bromoethyl)morpholine hydrobromide with 2-bromoethyl methyl ether (0.012 mL, 0.125 mmol), ^" Ή NMR (400MHz, CDCh) δ ppm 8.05 (s, 1 H), 7,70 (d, J=8.6 Hz, I H), 7.18 (dd, .1 2 2. 8.5 Hz, I H), 7.09 id. .! 2.2 Hz, I H), 6.96 - 6,90 (m, 3 H), 5.91 - 5.83 (m, 1 H), 5.56 (dd, J=9.0, 15, 1 Hz, 1 H), 4.30 (dd, J 4.5. 7.2 Hz, 1 H), 4.09 (s, 2 H), 3.87 - 3.79 (m, 2 H), 3.74 - 3.67 (m, 1 H), 3.59 - 3.50 (m, 3 H), 3.48 - 3.41 Or, 1 H), 3.41 - 3.35 (s, 3 H), 3.23 (d, j 14.5 Hz, 1 H), 3.00 (dd, .! 10.2. 15.3 Hz, 1 H), 2,84 - 2.71 (m, 2 H), 2,50 id. J=10.6 Hz, 1 H), 2.37 - 2, 16 (m, 3 H), 2, 13 - 1.92 (m, 4 H), 1.91 - 1.73 (m, 3 H), 1.71 - 1.52 (m, 2 H), 1,51 - 1.34 (m, 2 H), 1.23 -1.14 ( m, 1 H), 1.05 (d, J=6.8 Hz, 3 H), 0.67 - 0.58 (m, 2 H), 0.29 (dd, .! 4.4. 9, 1 Hz, 1 H), 0,08 (dd, J 4. ! . 9.0 Hz, 1 H). m/z (ESI, +ve ion) 697.3 (M+H) ⁺ .

EXAMPLE 386. (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-12'- (CYCLOPROPYLMETHYL)- 11 '-METHYL-7 ^* -(2-(4- MORPHOLrNYL)ETHOXY)-3,4-DmYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8 ^, E,l l ^, S,12'S)-6-CHLORO-12 ^! -(CYCLOI¾OPYLMETHYL)-l l'-

METHYL-7'-(2-(4-M()RPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]TOIA[1,14]DL ZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S,3'R,6 ^f R,7'S,8¾ rR,12'R)-6-CHLORO-I2'-(CYCLOPROPYLMETHYL)-

11 ^! -METOYL-7'-(2-(4-MORPHOL/lNYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAt^MlDIAZATET ACYCLOI MJ^.O'^.O^^lPE TACOSA

[8J 6,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8Έ, l l ^, R,12 ^, S)-6-CHLORO-12 ^, -(CYCLOPROPYLMETHYL)-l l ^, - METHYL-7'-(2-(4-MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H,15 ^, H- SPTRO[NAPHTH ALENE- 1 ,22'- | 2( >X A| i ? I U Π Λ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.2 0 ^; ".O ¹ " ^M |PH\ i ACOSA [8, 16, 18,24]TETRAEN] -15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (lS,3'R,6'R,7'S,8'E,i rS,12'R)-6- chloro-i2'-(cydopropylnieihyi)-7'- spiro[naphthalene-l,22'-[20]oxa[13]thia[l ,14]diazatetracyclo [14.7,2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide or

(1 S,3'R,6'R,7'S,8'E, 1 l'S, 12'S)-6-chloro- 12'-(cy clopropylmethyl)-7'-hy droxy- 1 1'- methy 1 -3 ,4-dihy dro-2h, 15 'h-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracycio [14.7.2.0 · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa 8,16,18,24]tetraen]-15'-one 13', 13'-dioxide or

(1 S,3'R,6'R,7'S,8'E, 1 1 'R, 12'R)-6-chloro- 12 ^* -(cyclopropy lmethyl)-7-hy droxy- 11 '- methyl-3 ,4-dihy dro~2h, 15'h-spiro[naphthalene- 1,22'- [20]oxa[13]thia[l,14]diazatetracycio[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

pentacosa[8, 16, 18,24]tetraen]-15'-one 13',13'-dioxide or

(1 S,3'R,6'R,7'S,8'E, i i 'R, 12'S)-6-chloro- 12'-(cy clopropylmethyl)-7'-hy droxy- 11'- methyl-3,4-dihy dro-2h, 15¾-spiro[naphthalene- 1 ,22'-[20] oxa[ 13] thia[ 1,14] diazatetracyclo|;i4.7.2.0 ³ - ⁶ .() ^{i 9} ' ²⁴ i pentacosa| 8,16,18,24]tetraen]-15 ^! -one 13',13'- dioxide (Example 385, Step 5, 11 mg, 0.017 mmol) by a similar procedure described in Example 720, replacing 4-(2-bromoethyl)morpholine hydrobromide with 4-(2-bromoethyl)morpholine hydrobromide . ¾ NMR (500 MHz, CDCh) δ ppm 8.03 (s, 1 H), 7,70 i d. j 8.6 Hz, 1 H), 7.19 (dd, J 2.2. 8.6 Hz, 1 H), 7, 10 id.

2.0 Hz, 1 H), 6.95 - 6.89 (m, 3 H), 5.92 - 5.83 (m, 1 H), 5.54 (dd, j 8.9. 15,3 Hz, 1 H), 4.30 - 4.20 (m, 1 H), 4.10 (s, 2 H), 3.88 - 3.66 (m, 7 H), 3.58 (br s, 1 H), 3.46 (br s, 1 I I I 3.23 id. j 14.2 Hz, 1 H), 3.01 (dd, J 10. 1. 15.3 Hz, 1 H), 2.97 (s, 1 ! !}. 2,89 (s, 1 H), 2,84 - 2.63 (m, 2 H), 2,60 - 2.48 (m, 4 H), 2,46 - 2.40 (m, 1 H), 2,37 - 2.28 (m, 1 H), 2,28 - 2.15 (m, 2 H), 2,13 - 1.91 (m, 5 H), 1,89 - 1.73 (m, 3 III 1.70 - 1.60 (m, 1 H), 1,53 - 1.35 (m, 2 H), 1.25 - 1.15 (m, 1 H), 1,05 (d. J 7.1 Hz, 3 H), 0.66 - 0,58 (m, 2 H), 0.32 - 0,26 (m, 1 H), 0.11 - 0,04 (m, 1 H). m/z (ESI, +ve ion) 752.3 (M il) . Example 387. (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6~CHLORO-12'~

(CYCLOPROPYLMETHYL)- 11 '-METHYL-7'-(((2R)-2-(4- MORPHOLINYL)PROPYL)OXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[ 1,14]

DIAZATE RACYCLO[14 .2.0 ³ '* 0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13', 13 '-DIOXIDE AND

(lS,3¾,6'R,7^,8T,ll'S,12'S)-6-CHLORO-12'-(CYCLOPROPYLMETHYL )-ir- MEπm..-7 ^f -(((2 )-2-(4-MO HOLINYL)PROP X)OXY)-3,4-DIHYD O- 2H,15 ^! H-SPrRO [NAPHTHALENE-1,22'-

[20]OXA[13]TfflA[l,14]DIAZATETlACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8J6,18,24]TETRAEN]-15'-ONE 13',13-DIOXIDE AND

(lS,3 ^, R,6 ^! R,7'S,8iVl'R/12'R)-6-CHLORO-12'-(CYCLOPROPYLMETHYL)- ir-METHYL-7'-(((2R)-2-(4-MORPHOLINYL)PROPYL)OXY)-3,4-DIHYDRO -

2H, 15 Ή - SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]THL4[1 ,14]DIAZATETRACYCLO

[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-

DIOXIDE AND

(1 S,3'R,6'R,7'S,8'E, 11 'R,12'S)-6-CHLORO- 12"-(CYCLOPROPYLMETHYL)- 11 ^* -

METH L-7'-(((2R)-2-(4-MORPH01JNYL)PROPYL)OXY)-3,4-DiHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [ 20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[14.7.2.0 ³ ' ⁶ ,0 ⁱ⁹ - ²⁴ ]PENTACOSA[8,I6,l 8,24]TETRAEN]-15'-ONE 13',I3'- DIOXIDE

STEP 1 : (R)-2-MORPHOLINOPROPAN-l -OL

ΓΛ

0 N— ?

\ _^^ \— _Qj --j

2-Bromoethyl ether (8.20 mL, 35.4 mniol) in DCM was added (R)-2- aminopropan-l-ol (13.3 g, 177 mmol) at ambient temperature with vigorous stirring. The highest internal temperature was 42 °C after 19 min. The reaction mixture was stirred for 24 h and diluted with dichloromethane (10 mL). The mixture was quenched with saturated aqueous potassium carbonate (10 mL), and extracted with dichloromethane. The combined organic layers were dried (MgSQ*), and filtered. The filtrate was concentrated, and ehrornatographed (silica gel, 0 to 20%, MeOH/DCM) to afford the title compound.

STEP 2: (R)-4-(l -CHLOROPROPAN-2-YL)MORPHOLINE

HYDROCHLORIDE

HCI

(R)-2-Morpholinopropan-l-ol (2.85 g, 19.6 mmol) was dissolved in toluene (15 mL) and added sulfurous dichloride (1.71 mL, 23.6 mmol). The reaction mixture was heated at 80 °C for 3 h. cooled, and concentrated under reduced perssure. Additional anhydrous toluene was added and concentrated. This process was repeated with toluene three times and then switched to isohexane (1 X). The resulting residue was slurried in diethyl ether, filtered, and the solid was washed with copious amount of diethyl, ether. The stick solid was dried under vacuum at ambient temperature to afford the title compound (1.60 g, 50%). STEP 3: (1S,3'R,6'R,7'S,8'E,1 rS,12 ^! R)-6-CHLORQ-12'- (C YCLOPROPYLMETHYL)- 11 '-METHYL-7 ^, -(((2R)-2-(4- M()RPHOLI]sr¾' ^r L)PROPYL)()XY)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-1,22 ^* -[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO

[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA [8,16,18,24] TETRAEN] - 15 '-ONE 13',13'- DIOXIDE AND

(l S^^ffR.T'S^^l l'S^ yS^-CHLORO- '-iCYCLOPROPYLMETOYL)-! ! '- METHYL-7H((2R)-2-(4-MORPHOLINYL)PRO

2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[ 20] OXA[ 1 ΓΠ 1 , 14]DI AZATETRACYCLO

[ 14,7.2.0 ³ · ⁶ ,0 ¹⁹ · ²⁴ ]ΡΕΝΤ ACQS A[8, l 6, 1 8,24]TETRAEN]-15'-ONE 13', I 3'- DIOXIDE AND

(1S,3'R,6'R,7'S,8'E,1 rR,12'R)-6-CHL()RO-12'-(CYCL()PROPYL METHYL)- 1 1 ^, -METOYL-7'-(((2R)-2-(4-MORPHOLINYL)PROP YL)OXY)-3,4-DIHYDRO-

2H, 15 Ή-SP!RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]D1AZATETRACYCLO [14.7.2.0 · ⁶ .0 ¹⁹ · ²⁴ ]

PENTACOSA[8,16,l 8,24] TETRAEN]-! 5 '-GNE 13',13'-DIOXIDE AND

(lS,3 ⁱ R,6'R,7 ^f S,8'E, l l 'R,12 ^f S)-6-CHLORO-12 ⁱ -(CYCLOPROPYLMETHYL)-l l ^f - METHYL-7'-(((2R)-2-(4-MORPHOLINYL)PROPYL)OXY)-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'~ DIOXIDE

The title compound was prepared from (l S,3'R,6'R,7'S,8'E,irS,12'R)-6- chloro-12'-(cyclopropylmethyl)-7'-hydrox '-l.r-methyl-3,4-dihydro-2H, L spiro[naphthalene-l,22'-[20]oxa[13] thia[l,14]diazatetracyclo [14,7.2.0 · ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide or

(1 S,3'R,6'R,7'S,8'E,1 l'S,l 2'S)-6-chloro-l 2 ^, -(cyclopropylmethyl)-7 ^, -h droxy-l 1"- methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo | 14.7,2.0 ' ^b .0 ^l - ²⁴ ]pentacosa [8,I6,18,24]teiraen]-15'-one 13',13'-dioxide or (Ι β^ΊΙ,όΊΙ,Τβ,δΈ, Ι l'R^'RJ-e- cMoro-^^cyclopropylmethy^-T'-hydroxy-l r-methyl~3,4-diliydro-2H,15 ^! H- 3ρίΓθ[ιι ρΜ1ιαΐ6ηθ-1,22' 20]οχ [13]Αία[ΐα4^ι ζ3ΐθΐΓαονε1ο[14:7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] pentacosa[8,16,18,24]tetraen]-15'-one 13', 13'-dioxide or

(lS,3'R,6'R,7 ^f S,8'E,i rR,12'S)~6~^^

methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-[20]ox a[13] thia[l ,14] diazatetracyelo[ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] pentacosa[8, 16,18,24]tetraen|-15'-one 13',13'- dioxide (Example 385, Step 5, 22 mg, 0.034 mmol) by a similar procedure described in Example 720, replacing 4-(2-bromoethyl)morpholine hydrobromide with (R)-4-(l -chloropropan-2-yl)morpholine hydrochloride . ^! H NMR (500 MHz, CDCls) δ ppm 8.11 (br s, 1 H), 7.69 (d, J 8.6 Hz, 1 ! ! }. 7.23 - 7.17 (m, 1 ! ! }. 7.10 (d, J 2.0 Hz, 1 ! ! }. 6.96 - 6.84 (m, 3 ! ! }. 5.98 - 5.92 (m, 1 ! ! }. 5.54 (d l. j 9.3. 15,2 Hz, 1 H), 4.29 - 4.19 (m, 1 H), 4.10 (s, 2 H), 4.07 - 3.92 (m, 4 H), 3.84 - 3.69 (m, 4 H), 3.55 (br s, 1 H), 3.51 - 3.35 (m, 3 H), 3.23 (d, J=14.4 Hz, 2 H), 3.16 - 2.98 (m, 2 H), 2,85 - 2.67 (m, 2 H), 2,50 - 2.40 (m, 1 H), 2,38 - 2.15 (m, 4 H), 2.14 - 1.60 (m, 10 H), 1.50 - 1.41 (m, 1 H), 1. 39 (d, j 6 8 Hz, 3 H), 1.25 - 1.20 (m, 1 H), 1.15 - 0.99 (m, 3 H), 0.65 - 0.58 (m, 2 H), 0.29 (dd, j 4.4. 9.0 Hz, 1 H), 0.09 - 0.04 (m, 1 H). m/z (ESI, +ve ion) 766.2 ( M i l ) ^' . EXAMPLE 393. (1S,3'R,6'R,7'S,8'E,1 rS,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12'- (2-METHOXYETHYL)-l 1 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[ 13] THIA [1, 14] DIAZ ATETR ACYCLO [14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TE1¾AEN]-15'-ONE 13',13'~ DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,l l'R,12 ^, S)-6-CHL()RO-7'-HYDR()XY-12'-(2- METHOXYETHYL)-l ] '-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-[20]OXA[13]TfflA[l ,14]

DIAZATETRACYCLO[14.7.2.0 ³ .6 0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15 -ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,irS,12'S)-6-CHLORO-7 ^! -HYDROXY-12'-(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[ 1,14]

DIAZATE RACYCLO[14 .2.0 ³ '* 0 ³⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13', 13 '-DIOXIDE OR

(lS^'R^'R-TS^'E l'I^ 'R^e-CHLORO-T-HYDROXY-l^^- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-1,22'-[20]OXA[13]THIA[1,14]

DIAZATETRACYCLO[14 .2.0 ³ .« 0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAE j- 15 -ONE 13'J 3'-DIOXIDE

STEP 1: (3R,4S)-l-HYDROXY-N ₅ N-BIS(4-METHOXYBENZYL)-4-METHYL- 6-HEPTENE-3-SULFON AMIDE AND

(3R,4S)-l-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-6- HEPTENE-3-SULFO AMIDE AND

(3R,4S)-l-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-6- HEPTENE-3 -SULFONAMIDE AND

(3R,4S)-l-HYDROXY-N,N-BlS(4-METHOXYBENZYL)-4-METHYL-6- -3-SULFO

The title compounds were prepared from (2S)-N, N-bis(4-methoxybenz l)-

2-methylpent-4-ene-l -sulfonamide and (2R)-N, N-bis(4-methoxybenzyl)-2- methylpent-4-ene-l -sulfonamide using a similar procedure described in Step 2, of Example 380, replacing (bromomethyl)-cyclopropane with ethylene oxide gas. STEP 2: (3R,4S)- 1 -METHOXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL- 6-HEPTENE-3-S ULFON AMIDE AND

(3R,4S)-l -METHOXY-N,N-BIS(4-METHOXYBENZYL)-4-METHYL-6- ΗΕΡΤΈΝΕ-3-SULFONAMIDE AND

(3R ₅ 4S)-] -ME;raOXY-N ₅ N-BIS(4-METHOXYBF;NZYL)-4-METHYL~6- HEPTENE-3-SULFONAMlDEAND

(3R,4S)-l-METHOXY-N,N-BIS(4-METHOXYBENZYL)-4-METFIYL-6- HEPTE E- -S ULFON AMIDE

To a suspension of sodium hydride, 60% in oil (0,086 mL, 4.09 mmol) in

THF at 0 °C, was added a solution of (3R,4S)-l-hydroxy-N,N-bis(4- rnethoxybenzyl)-4-methyl-6-heptene-3-sulfonamide, (3 R,4S)-1 -hydrox -N,N- bis(4-methoxybenzyl)-4-methyl-6-heptene-3-sulfonamide, (3R,4S)-1 -hydroxy - N,N-bis(4-methoxybenzyl)-4-methyl-6-heptene-3-sulfonamide and (3R,4S)-1- hydroxy-N,N~bis(4-methoxybeiizy'l)"4"methyl-6~hepteiie-3-sul fonamide (610 nig, 1 .36 mmol) in THF. The mixture was stirred for 25 min at 0 °C, and then iodomethane (0.169 mL, 2.73 mmol) was added. The mixture was allowed to warm up to ambient temperature and kept stirring for 1 day. The mixture was quenched with aqueous saturated NH4CI, and diluted with EtOAc. The organic layer was washed with water, dried (Na_S04) and concentrated. The crude residue was chromatographed (silica gel, hexane/EtOAc, 9: 1 to 3: 1) to afford the title compounds as an oil. STEP 3: (3R,4S)-l-METHOXY-4-METHYL-6-HEPTENE-3-SULFONAMIDE

AND

(3R,4S)-l-METHOXY-4-METHYL-6-HEPTENE-3-SULFO AMIDE AND (3R,4S)-l -METHOXY-4-METHYL-6-HEPTENE-3-SULFONAMIDE AND (3R,4S)- 1 -METHOXY-4-METHYL-6-HEPTENE-3-SULFONAMIDE

The title compounds were prepared from a mixture of (3R,4S)-1 -methoxy- N,N-bi .s(4-me1hoxybenzv'l)-4-methyl-6-heptene-3-sulfonarnide and (3R,4S)~ 1 - methoxy-N ,N-bis(4-methoxy benz l)-4-methy l-6-heptene-3 -sulfonamide and (3R,4S)-l -methoxy-N,N-bis(4-methoxybenzyl)-4-methyl-6-heptene-3- sulfonamide and (3R,4S)-l-methoxy-N,N-bis(4-methox>' ^, benzyl)-4-methyl-6- heptene-3-sulfonamide using a similar procedure described in Step 3, of Example 380.

STEP 4 : (3 S)-6'-CHLORO-5 -(((1 R,2S)-2-(( 1 S ,2E)- 1 -HYDROXY-2-HEXEN- 1 - YL)CYCLOBUTYL)METHYL)-N~(((3R,4S)-l-METHOXY-4-MEraYL"6- HEPTE -3-YL)SULFONYL)-3 ^, ,4,4 ^, .5-TETRAHYDRO-2H-SPIRO[l,5- BENZOXAZEPINE-3,1 '-NAPHTHALENEj-7-CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2S)-2-((l S,2E)-1 -HYDROXY-2-HEXEN-l -

YL)CYCLOBUTYL)METHYL)~N-(((3R,4R)-l-METHOXY-4-METHYL~6" IIEPTEN-3-YI SULFONYL)-3',4,4',5-TETRAI-IYDRO-2'H-SPiRO[l ,5- BENZOXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2S)-2-((lS,2E)-l -HYDROXY -2-HEXEN-l- YL)CYCLOBUTYL)METI-IYL)-N-(((3S,4S)-l-METHOXY-4-METHYL-6- HEPTEN-3^)SULF0NYL) \4,^5

BENZOXAZEPrNE-3, -NAPHTHAL-ENE]-7-CARBOXAMIDE AND

(3 S)-6'-CHLORO-5-((( 1 R,2 S)-2-(( 1 S ,2E)- 1 -HYDROXY-2-HEXEN - 1 -

YL)CYCLOBUTYL)METHYL)-N-(((3S,4R)-l-METOOXY-4-METOYL-6- HEPTCN-3-YL)SULFONYL)-3 ^, ₅ 4,4',5-TETRAHYDRO-2H-SPTRO[l,5- BENZOXA '-NAPHTH XAMIDE

The reaction of (S)-6'-chloro-5-(((lR,2S)-2-((S,E)-l-hydroxyhex-2-en-l- y^cyclobut ^methy^-S'^^'^-tetrahydro^H^'H-s irotbenzotblt l^Joxazepi e- 3,1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A, 300 mg, 0.59 mmol) with l -(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (192, rng, 1.00 mmol), 4-dimethylaminopyridine (122 mg, LOO mmol), triethylamine (179 mg, 1.76 mmol), and a mixture of (3R,4S)-l-methoxy-4-methyl-6-heptene-3-sulfonamide and (3R,4S)-1 -methoxy-4-meth l-6-heptene-3-sulfonamide and (3R,4S)-1 - methoxy-4-methyl-6-heptene-3-sulfonamide and (3R,4S)-l-methoxy-4-methyl-6- heptene-3-sulfonamide (221 mg, 1.00 mmol, Step 3) in CH2CI2 (2 mL) was stirred at ambient temperature for 3 days. The mixture was quenched with water, and diluted with CH2CI2. The combined organic layers were concentrated and chromatographed (silica gel, 9: 1 to 1 : 1, hexane/EtOAc+0.5%HOAc) to afford the title compounds as an oil.

STEP 5: (I S^' _^ e'R.T'S^'E l 'SJ^RH-CHLORO-T'-HYDROXY-l^- METHOXYETHYL)-ir-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO I NAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,l LR,12 ^, S)-6-CHLORO-7'-HYDROXY-12 ^! -(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-1,22'-[20]OXA[13]THIA[1 ,14] DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,0'R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-7'-HYDROXY- 12'-(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22' -[20] OXA[ 13]THIA[1 ,14]

DIA/A Π . i R Ai ^' YO .Oi ! 17.2 () ' ·'. i ) ¹ " j Pj ^: \,TAC ^' 0S | 8. i . ! 8.2-1 ITHTRALN | - 15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,11 'R, 12'R)-6-CHLORO-7'-HYDROXY- 12'-(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1 ,22'-[20] OXA[l 3]THIA[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(:()SA[8,16,18,24|TETRAEN]- 15 ^* -ONE 13',I3'-DIOXIDE

A mixture of (3S)-6 ^, ~chloro-5 ^» (((lR,2S)-2~((lS,2E)~l~hydiOxy-2-hexen-l- yl)c lobutyl)methyl)-N-(((3R,4S)-l-methoxy-4-methyl-6-hepten-3-yl )sulfonyl)- 3',4,4',5-tetrahydro-2'H-spiro[l ,5-benzoxazepine-3, 1 '-naphthalene]-7- carboxamide, (3S)-6'-chloro-5-(((lR,2S)-2-((lS ₅ 2E)-l-hydroxy-2-hexen-l- yl)c^ lobut5d)methyl)-N-(((3R,4R)-l-methoxy-4-methyl-6-hepten-3-yl )sulfonyl)- 3',4,4',5-tetrahydro-2'H-spiro[.l ,5-benzoxazepine-3, -naphthalene]-7- carboxamide, (3S)-6'-chloro-5-(((lR,2S)-2-((lS,2E)-l-hydroxy-2-hexen-l- yl)cyclobutyl)methyl)-N-(((3S,4S)-l-methoxy-4-methyl-6-hepte n-3-yl)sulfonyl)- 3',4,4',5-tetrahydro-2^spiro[l,5-benzoxazepine-3,r-naphthale ne]-7 -carboxamide and (3S)-6 ^! -chloro-5-(((l R,2S)-2-((lS,2E)-l-hydroxy-2-hexen-l- yl)cyclobutyl)methyl)-N-(((3S,4R)-l-methoxy-4-memyl-6-hepten -3-yl)sulfonyl)- 3',4,4',5-tetrahydro-2'H-spiro| l ,5-benzoxazepine-3,l'-naphthalene]-7-carboxamide (310 mg, 0.44 mmol) in 1,2-dichloroethane (120 mL) was introduced argon by bubbling argon into the flask for 10 min. Hoveyda-Grubbs catalyst II was added and the reaction mixture was heated at 50 °C for 48 h. The reaction mixture was then introduced air by bubbling air into the flask for 5 min. the crude material was concentrated and chromatographed (silica gel, , 9: 1 to 0: 1,

hexane/EtOAc+0.5%HOAc) to afford an oil. This oil was further purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μχη column;

Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to afford the first eluenting isomer as the title compound (23 mg, 8.2%) as a white solid., ^] H NMR (400 MHz, CDC] 3) δ ppm 8.00 (s, 1 H), 7,73 - 7.68 (m, 1 H), 7, 19 (d, J 8.7 Hz, 1 H), 7.10 (d, j 2.2 Hz, 1 H), 7.02 - 6.95 (m, 1 H), 6.95 - 6.80 (m, 2 H), 5.93 - 5.78 (m, 1 ! ! }. 5.71 (dd, j 8.0. 15.5 Hz, 1 H), 4.32 (d, j 9.0 Hz, 1 H), 4.25 (dd, j 4.4. 7.9 Hz, 1 I I I 4. 15 - 4.07 (m, 2 H), 3.81 (d, j 1 7 Hz, 1 H), 3,76 - 3,64 (m, 3 H), 3.40 (s, 3 H), 3,27 (d, J i -! .3 Hz, I H), 3.08 (br s, 1 H), 2.84 - 2.71 (m, 2 H), 2.46 (dd, J=4.1, 8.0 Hz, 1 H), 2.39 - 2.23 (m, 2 H), 2.20 - 2.06 (m, 1 H), 2.06 - 1.88 (m, 7 H), 1.88 - 1.77 (m, 2 H), 1.73 - 1.61 (m, 1 H), 1.52 - 1.36 (m, 1 H), 1.07 (d, .! 6.3 Hz, 3 H), m/z (ESI, +ve ion) 643.2 ( VI 1 1 ) .

EXAMPLE 394. (18,3 ^! ,6 ^, Κ,7'8,8'Ζ,1 Γ8,12¾)-6-(:ΗίΟΚΟ-7'-ΗΥΟΚΟΧΥ-12·- (2-METHOXYETHYL) - 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

| 20 jOXA| 1 ΉΤί !1Λ| U 4 |DiA/A iTTR AC ^' Ya.Oi i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |Pl-N i ^' AC<)SA [ 8,16,18,24]TETP^EN]-15'-ONE 13 ^! ,13'-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'Z,l l 'R,12'S)-6-CHLORO-7'-HYDROXY-12'-(2- METHOXYETHYL)-i r-METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-[20] ()XA| 13] ! ! !!AI 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'Z,l l'S,12'S)-6-CHLORO-7 ^, -HYDROXY-I2'-(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- ! ,22'-[20] OXA[ 13]THI A[ ! , 14]

DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ¹⁹ - ² ]PEOTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z,11 'R, 12"R)-6-CHLORO-7 ^* -HYDROXY- 12'-(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3]THIA[ 1,14] DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16, 18,24]TETRAEN; 15'-ONE 13', 13'-DIQXIDE

The title compound was obtained as the third eluenting isomer from the reversed phase preparatory HPLC separation in EXAMPLE 393. ¾ MR (400 MHz, CDCb) δ ppm 7.72 (d, j H.4 Hz, 1 H), 7.54 - 7.37 (m, 1 H), 7.23 - 7.12 (m, 2 H), 7.12 - 7.07 (m, 1 H), 6,99 (d, J 8.2 Hz, 1 H), 5.76 (br s, I H), 5.52 (dd, j 2.4. 11.8 Hz, 1 H), 4.41 (br s, 1 H), 4.25 - 4.04 (m, 2 H), 3.89 (d, J=15.5 Hz, 1 H), 3.78 - 3.57 (m, 4 H), 3.50 (s, 3 H), 3.21 - 2.96 (m, 2 H), 2.91 - 2.67 (m, 2 H), 2,39 - 2.11 (m, 2 H), 2, 10 - 1.88 (m, 2 H), 1,73 -1.50 (br s, 10 H), 1.50 - 1.40 (ra, 1 H), 1.08 - 1.03 (d, J=6.8 Hz, 3 H). m/z (ESI, +ve ion) 643.2 (M+H) ⁺ .

Example 395. (1S,3'R,6'R,7 ^! S,8'E,1 l'S,12 ^, S)-6-CHLORO-7'-HYDROXY-12 ^, -(2- METHOXYETHYL)- 1 1 '-METHYL~3,4~DIHYDRO-2H, 15 ^f H-SPIRO

[NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]

PENTACOSA[8, 16,l 8,24]TETRAE ]-15'-ONE 13',13'-DIOXIDE OR

(lS,3¾,6 ^, R,7 ^! S,8'E, l I'S, 12'R)-6-CHLORO-7'-HYDROXY-12'-(2- METHOXYETHYL)- 11 '-METHYL-3.4-DIHYDRO-2H, 15Ή- SPIRO j NAPHTHALENE- 1 ,22'-[20] OX A[ 13] THI A[ 1 , 14 j

DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ³⁹ " ²⁴ ]PENTACOSA[8,16, 18,24]TETRAEN]- 15'-ONE 13'.13 '-DIOXIDE

STEP 1 : (R)-PENT-4-E -2-YL-4- NZENESULFONATE

To a solution of/ oluenesulfonyl chloride (12.2 g, 63.9 mmol) and DMAP (3.55 g, 29.0 mmol) in DCM (150 mL) at 0 °C was added triethyiamine (16.2 mL, 116 mmol), and then followed by the drop wise addition of (R)-(-)-4- penten-2-ol (2) (5.97 mL, 58.1 mmol) in DCM (100 mL). The reaction mixture was stirred and allowed to reach ambient temperature. After completion, the mixture was washed with 1.0 N HC1, saturated aqueous NaHCCb and H2O. The organic layer was dried (MgSO- , filtered, concentrated and chromatographed (silica gel, 0 to 70 %, EtOAc/hexane) to afford (R)-pent-4-en-2-yl 4- methylbenzenesulfonate (11.0 g, 79%). m/z (ESI, +ve ion) 263.2 (M+Na)\

STEP 2: N,N-BIS(4-METHOXYBENZYL)METHANESULFON AMIDE

X ,ΡΜΒ

PMB

To a solution of methanes ulfonamide (6.30 g, 66.2 mmol) in 2-butanone (331 mL) was added potassium iodide (1.10 g, 6.62 mmol), anhydrous potassium carbonate (36.6 g, 265 mmol), and PMBCi (22.5 mL, 166 mmol) successively. The resulting mixture was stirred at 81 °C for 18 h and then cooled, filtered through Celite to remove solids. The filter cake was washed with DCM and the filtrate was concentrated. Ether was added to the residue and a solid was formed to afford the title compound (18.0 g, 81%). m/z (ESI, +ve ion) 358.2 (M+H) ⁺ . STEP 3: (S)-N,N-BIS(4-METHOXYBENZYL)-2-METI-IYLPENT-4-ENE-l - SULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (8.00 g, 23.9 mmol) in THF (68 mL) under N ₂ at -78 °C was added but llithium solution, 2.5 M in hexanes (10.5 mL, 26.2 mmol). This mixture was stirring for 10 min and then added a solution of (R)-pent-4-en-2-yl 4-methyl benzene sulfonate (8.60 g, 35.8 mmol) in THF (6 mL). The resulting mixture was stirred for 20 h from -78 °C to ambient temperature, and then added saturated aqueous NFUCl. The mixture was extracted with diethyl ether twice, and the combined organic layers were concentrated. The residue was chromatographed (silica gel, 0 to 60%,

EtOAc/Hexane) to afford the title compound (3.0 g, 31%). m/z (ESI, +ve ion)

STEP 4: (3S,4S)-1 -HYDROXY -N,N-BIS(4-METHOXYBENZYL)-4-METHYL- 6-HEPTENE-3-SULFONAMIDE AND

(3R,4S)-l-IWDROXY-N,N-BlS(4-METOOXY ^T BENZYL)-4-METHYL-6- HEPTENE-3-SULFON AMIDE

To a solution of (S)-N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-l - sulfonamide (2.80 g, 6.94 mmol) in THF (15 mL) was added n-buiyllithiuni solution, 2.5 M in hexanes (3.05 mL, 7.63 mmol) at -78 °C dropwise. The mixture was stirred at -78 °C for 5 min, and ethylene oxide, 2.5 M solution in THF (5.55 mL, 13.9 mmol) was then added. The mixture was allowed to warm up to ambient temperature and stirred for 18 h. The mixture was quenched with saturated aqueous NH4Q, and extracted with EtOAc (2X). The organic layer was washed with brine, dried (MgS0 ₄ ), and filtered. The filtrate was concentrated and the resulting residue was chromatographed (silica gel, 20 to 60%, EtOAc/Hexane) to afford the title compounds (2.3 g, 74%). m/z (ESI, +ve ion) 470.2 { W W ) .

STEP 5 : (3S,4S )- 1 -METHOXY-N,N-BIS(4-METHOXYBENZYL)-4- METHYLHEPT-6-ENE-3-SULFON AMIDE AND

(3R ₅ 4S)-l -METHOXY-N,N-BIS(4-METHOXYBENZYL)-4~METHYLHEPT-6~ ENE-3-S ULFONA

To a suspension of sodium hydride, 60% in oil (0.570 g, 14.3 mmol) in THF (10 mL) was added a solution of (3R,4S)-l-hydroxy-N,N-bis(4- methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide and (3S,4S)- 1 -hydroxy -N,N- bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfonarnide (2.13 g, 4.47 mmol) in THF (4 mL). The mixture was stirred for 20 min at ambient temperature, and iodomethane (0.59 mL, 9.52 mmol) was added. The mixture was stirred at this temperature for 4 h and monitored by LCMS. More NaH and Mel were added in portions to reach the completion of the reaction. The mixture was quenched with saturated aqueous NH4CI, and extracted with EtOAc. The organic layer was washed with water, dried (MgSC ) and concentrated. The resulting residue was chromatographed (silica gel, hexane EtOAc, 1 :0 to 1 : 1) to afford the title compounds as a yellow oil (1.87 g, 91%). m/z (ESI, +ve ion) 484.2 (M+H) ⁺ .

STEP 6: (3S, 4S )- 1 -METHOXY -4-METHYLHEPT-6-ENE-3-SULF ON AMIDE

AND

(3R, 4S)-l -METHOX -4-METHYLHEPT-6-ENE-3-SULFONAMIDE A mixture of (3R, 4S)-l-methoxy-N,N-bis(4-methoxybenzyl)-4- methylhept-6-ene-3-sulfonamide and (3S, 4S)-l-methoxy-N,N-bis(4- methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide (1.86 g, 4.03 mmol) in TFA (23.0 g, 201 mmol) and anisole (22.0 g, 201 mmol) was stirred at 40 "C for 18 h. Then the reaction mixture was cooled and concentrated under reduced pressure and the residue was chromatographed (silica gel, hexane/EtO Ac, 1 :0 to 0: 1) to afford the title compounds as an oil (0.81 g, 91%). m/z (ESI, +ve ion) 244.2 ( W W ) . STEP 7: (3S)-6'-CHLORO-5-(((lR,2R)-2-((lS,2E _: ,5S _s 6R)-l-HYDROXY-8- METHOXY-5-MEra:YL-6-SULFAM()YL-2-()CTEN-l- YL)CYCLOBUTYL)METFIYL)-3',4,4',5-TETRAHYDRO-2TI-SPIRO[l ,5- BENZOXAZEPrNE-3,T-NAPHTHAL-ENE]-7-CARBOXYLIC ACID AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E ₅ 5S _s 6S)-l-HYDROXY-8-METHOXY-5- METFFYL-6-SULFAMOYL-2-OCTEN- 1 - YL)C YCLOBUTYL)METHYL)- 3Vlv4^5-TETRAHYDRO-2 ^! H-SPrRO[l ,5-BENZOXAZEPINE-3,r- NAPHTH -7-C ARBOXYLIC ACID

A mixture of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l -hydroxyhex-2-en-l - yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b] [l,4]oxazepine- 3,r-naphthalene |-7-carbox lic acid (Intermediate AA12A, 200 mg, 0.39 mmol) and (3R, 4S)-l-methoxy-4-methylhept-6-ene-3-sulfonamide and (3S, 4S)- 1 - methoxy~4~methylhept-6-ene-3-sulfonamide (304 mg, 1.37mmol, Step 6) in 1 ,2- dichloroethane (2 mL) was introduced argon by bubbling argon into the reaction flask for 10 mm. Hoveyda-Grubbs catalyst II (61 mg, 0.098 mmol) in 1,2- dichloroethane (2 ml.) was added and the reaction was stirred at ambient temperature for 1.5 h. Air was then introduced by bubbling air into the reaction for 3 min. The mixture was then concentrated, and the resulting residue was chromatographed (silica gel, 9: 1 to 0: 1 , hexane EtOAc+0.3%HOAc) to afford the title compounds.

STEP 8: (18,3'Κ,6¾,7'8,8Έ,11 Έ,12'8)-6-(:ΗΕ0 0-7'-ΗΥ0Κ0ΧΥ-12'-(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAEN]-15'-ONE 13', 13'-D )XIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO-7'-HYDROXY-12 ^f -(2- METHOXYETHYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-1.22'-[20]OXA[13]THIA|;i ,14]

DIAZATETRACYCLO[14,7.2.0 ^3/ \0 ¹⁹ - ² ]PENTACOSA[8,16,! 8,24]TETRAEN]- 15'-ONE 13 ',13 '-DIOXIDE

A mixture of (3S)-6 ^, -chloro-5-(((lR ₅ 2R)-2-((l S,2E,5S.6R)-l-hydroxy-8- methoxy-5-methyl-6-sulfamoyl-2-octen- 1 -yl)cyclobutyl)methyl)-3',4,4',5- tetrahydro-2'H-spiro[l,5-benzoxazepine-3,r-naphthalene]-7-ca rbox lic acid and (3S)-6 ^, -chloro-5-(((lR,2R)-2-((lS,2E,5S,6S)-l-hydroxy-8-metho x\'-5-methyl-6- sulfamoyl-2-octen-l-yl)cvxlobut5d)me1hyl)-3',4,4',5-tetrahyd ro-2'H-spiro[ l,5- benzoxa.zepine-3, ! '-naphthalene|-7-ca,rbox lic acid (250 mg, 0.38 mmol) was reacted with l -(3-dimethylaminopropyl)-3-ethylcarbodiimide HC1 (145 nig, 0.76 mmol) and 4-dimethylaminopyridine (92.0 mg, 0.76 mmol) in DCM (150 mL) at ambient temperature for 3 days. Concentrated, the crude residue was

chromatographed (silica gel, hexane/ EtOAc+0.3%HOAc, 9: 1 to 1 :9) to afford a grey oil. This oil was further purified by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 25% to 75% MeCN in water, where both solvents contain 0. 1% TFA, 30 min method) to afford the title compound as the second eluenting isomer (15 mg, 6.2%) as a white solid. ¾ NMR (500 MHz, CDC ) δ ppm 8.25 (br s, 1 H), 7.69 (d, .1 H I Hz, 1 H), 7,20 (s, 1H), 7, 19 (d, .1=8.0 Hz, 1 1 1 ). 7.10 id. j 2.2 Hz, I H), 7.00 - 6.91 (m, 1 H), 6.68 (br s, 1 H), 6.04 (br s, 1 H), 5.67 (dd, J 6.4. 15.4 Hz, 1 H), 4.20 (br s, 1 H), 4.17 - 4.01 (m, 2 H), 3.90 (br s, 1 H), 3.78 - 3.59 (m, 4 H), 3.50 - 3.41 (ra, 1 H), 3.40 (s, 3 H), 3,29 - 3.01 (m, 1 H), 2,85 - 2.72 (m, 2 H), 2,61 - 2,47 (m, 2 H), 2.41 - 2,32 (m, 1 H), 2.31 - 2,20 (m, 2 H), 2.15 - 1.80 (m, 8 H), 1.78 - 1.62 (m, 1 H), 1.52 - 1.40 (ni, 1 H), 1.17 - 1.09 (d, .1 7, 1 Hz, 3 H). m/z (ESI, +ve ion) 657,2 ( VI I D ^' .

EXAMPLE 396. (IS^'R^'R 'S^'EJ l'S/ 'Si-e-CHLORO^'-METHOXY-^'- (2-METHOXYETHYL) - 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTOALENE-l,22 ^f -[201OXA[ 13]TOIA[l, 14]DIAZATETRACYCLO [MJ^.O^^O'^lPENTACOSAtSJ^lS^lTETRAENl-lS'-ONE 13',13'- DIOXIDE OR

(lS,3Έ,6 ^! ,7Έ,8Έ,Π 'S,12' )-6-CHLO O-7'-METHOXY-12'-(2-

METHOXYETHYL)-l. r-METHYL-3,4-DIHYDRO-2H,15'H-

SPIRO[NAPHTHALENE-l,22'-[20]OXA[13]TfflA[l ,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^{i 9} - ²⁴ jPENTACOSA[8,16, 18,24]TETRAEN]- 15 -ONE 13', 13'

To a suspension of sodium hydride, 60% in oil (8.7 nig, 0.22 mmoi) in DMF at 0 °C was added a solution of (18,3¾,6¾,7 ^! 8,8Έ,1 Γ8,12'8)-6-ΛΙοίΌ-7·- hydroxy-12'-(2-methoxyethyl)-l 1 '-methyl-3,4-dihydro-2H, 15Ή- spiro[naphthalene-l,22'-[20]oxa[13]thia[l ,14] diazatetracyelo

[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraen|-15'-one I3',13'-dioxide or (18,3¾,6¾,7 ,8Έ,1 Γ8,12¾)-6-οωοΓθ-7 ^! ½άΓθ ^χ ν-12'-(2^6Λο ^χ ν6Λνί)-1 Γ- methyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-.l ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 1 -1.7.2 0 "'.0 ¹⁹ · ²⁴ ]

pentacosa[ 8,16,18,24jtetraenj-15'-one 13',13'-dioxide (the first eluenting isomer in Example 395,12 mg, 0.019 mmol) in DMF. The mixture was stirred for 20 min at this temperature, and iodomethane (5.8 μΐ, 0.093 mmol) was added. The ice bath was then removed and the mixture was allowed to stir at ambient temperature for 18 h. The reaction was quenched with water, and added EtOAc. The organic layer was washed with water (3X), dried (MgS04), and filtered. The filtrate was concentrated and chromatographed (silica gel, 9: 1 to 1 : 1 ,

hexane/EtOAc+0.5%HOAc) to afford an oil. Further purification of the oil by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column;

Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) afforded the title compound as a white solid. ¾ NMR (500 MHz, CDCh) δ ppm 7.95 (s, 1 H), 7.70 (d, j 8.6 Hz, I H), 7. 19 (dd, .1 2 1. 8.4 Hz, 1 H), 7.13 - 7.06 (ra, 1 H), 6.96 - 6.86 (m, 3 H), 5.92 - 5.85 (m, 1 H), 5.52 (dd, J=10.6, 15.3 Hz, 1 H), 5.31 (s, 1 H), 4.40 (d, j 7.8 Hz, 1 H), 4.10 (s, 2 H), 3.82 (d, j 15.2 Hz, 1 H), 3.76 - 3.63 (m, 4 H), 3.41 (s, 3 H), 3.28 - 3.18 (m, 4 H), 3.01 (dd, J=10.3, 15.2 Hz, 1 H), 2.84 - 2.72 (m, 2 H), 2,50 - 2.4 ! (m, 1 H), 2,38 - 2.19 (m, 3 H), 2, 1 1 - 1.90 (m, 6 H), 1,89 - 1 ,80 (m, 3 H), 1.75-1 ,40 (m, 1 H), 1.44 - 1 ,35 (m, 1 H), 1.09 - 1,03 (d, J 6.8 Hz, 3 H). m/z (ESI, +ve ion) 657.2 (M+H) ⁺ .

EXAMPLE 397. (1 S,3'R,6'R,7'S,8 ^! E,1 rS,12'R)-6-CHLORO-7 ^* -(2- METHOX YETHOXY)- 12'-(2-METHOXYETHYL) - 11 '-METHYL-3,4- DIHYDRO-2H, 15'H-SPIR()[NAPHTHALENE-1 ,22'- [20]OXA[13]THIA[1 , 14]DI AZATETRACYCLO

[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA[8,16,18,24]TETRAEN]-15'-ONE ', '- DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 l'S,l 2 ^, S)-6-CHLORO-7'-(2-METHOXYETHOXY)-12'-(2- METHOXY ETHYL)-ir-METHYL-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA [13]THIA[ 1,14]

DIAZATETRACYCLO[14.7.2,0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[ 8, 16,18,24] TETRAEN]- 15 ^* -ONE 13 ^f ,I3'-DIOXIDE

The title compound was prepared from (Ι β^'ΙΙ,ό'Κ,Τ'β,δΈ,Ι l ^, S,12 ^, S)-6- cMoro-7'-hydroxy-12 ^, -(2-methoxye l)-l -methyl-3,4-dihydro-2H,15Ή- spiro [naphthalene- 1 ,22'-[20] oxa[ 13 jthiaj 1 ,14] diazatetracy clo

[ 14.7.2.() ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa| 8,16,18,24]tetraenj-15 ^! -one 13',13'-dioxide or (lS ¾ )'R ^,8^ 1 1 'S/12¾.)-6-chloro-7' iydroxy-12' 2-meihox} _' eihyl)-l l'- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1 , 14 [diazatetracy clo

[14.7.2.0 ³ - ⁶ .0 ^{i 9} - ²⁴ ]pentacosa[8,16,l 8,24]tetraen]-15'-one 13', 13'-dioxide (the first eluenting isomer in Example 395) by the similar procedure described in Example 396, replacing iodomethane with 2-bromoethyl methyl ether. ¾ NMR (500 MHz, CDCh) δ ppm 8.03 (s, 1 H), 7.70 (d, J==8.6 Hz, 1 H), 7.18 (dd, j 2.3. 8.4 Hz, 1 H), 7,09 (d, J 2.2 Hz, 1 H), 6.94 - 6.88 (rn, 3 H), 5.85 (ddd, J 3. 1 . 9.8, 15,2 Hz, 1 H), 5.54 (dd, j 9.2. 15.3 Hz, 1 H), 4.37 (d, j 8. 1 Hz, 1 H), 4.09 (s, 2 H), 3.85 - 3.77 (m, 2 H), 3.76 - 3.67 (m, 3 H), 3.60 - 3.48 (m, 3 H), 3.44 - 3.40 (m, 4 H), 3.39 (s, 3 H), 3,23 (d, J 14.2 Hz, 1 H), 2.99 (dd, J ! 0.3, 15.2 Hz, I H), 2,83 - 2,72 (m, 2 H), 2.53 - 2.45 (m, 1 H), 2.37 - 2.20 (m, 3 H i. 2.07 - 1.92 (m, 6 H), 1.91 - 1.74 (m, 3 H), 1.68 - 1.50 (m, 1 H), 1.39 (t, j 1 2.7 Hz, 1 H), 1.05 (d, j 6.8 Hz, 3 H). m/z (ESI, +ve ion) 701 ,2 ( VI I D ^' . EXAMPLE 398. (I S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-12'-(2-

METHOXYETHYL)-n ^, -METHYL-7'-(2-(4- ORPHOLI YL)ETHOXY)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[ 14.7.2.0 ³ ·^0 ^ί9 · ²⁴ ]ΡΕΝΤΑ€Ο8Α[8,16,18,24]ΊΈΊ^ ΕΝ]-15'-Ο Ε 13',13'- DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 1 'S , 12'S )-6-CHLORO- 12 ' -(2-METHOXYETHYL)- 1 1 '- METHYL-7'-(2-(4-MORPHOLINYL)ETHOXY)-:i4-DmYDRO-2H, 15'H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13 iTHL4[ l,14jDIAZATETRACYCLO[14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DiOXIDE

The title compound was prepared from (l S,3'P 6 ^, R,7'S,8'E,i rS,12'S)-6- chloro-7'-hydroxy-12'-(2-methoxyethyl)-l l'-methyl-3,4-dihydro-2h, 15'h- spiro[naphthalene- 1 ,22'-[20] oxa[ 13]thia[ 1 , 14] diazatetracy clo

[ 14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa| 8,16,18,24]tetraenj-15 ^! -one 13',13'-dioxide or (lS ¾ )'R ^,8^ 1 1 'S/i2¾.)-6-chloro-7' iydroxy-12' 2-meihoxyeihyl)-l l'- methyl-3,4-dihydro-2h, 15'h-spirojnaplithalene- 1,22'- [20] oxa[ 13 jthiaj 1 , 14] diazatetracy clo

|;i4 .2.0 -^() ^!9 ' ²⁴ lpentacosa[8,16,18,241tetraen |-15'-one 13',13'-dioxide, the first eluenting isomer in Example 395 by a similar procedure described in Example 396, replacing iodomethane with 4-(2-bromoethyl)morpholine hydrobromide. ¾ NMR (500MHz, CDCb) δ = 7.70 id. j H.3 Hz, 1 H), 7.18 (dd, j 2.2. 8.6 Hz, 1 H), 7.09 (d, J 2.2 Hz, 1 H), 6.93 (s, 2 H), 6,88 (s, 1 H), 5.90 - 5.83 (m, 1 H), 5.53 (dd, 3=9.2, 15.3 Hz, 1 H), 4.34 (d, .7=8.3 Hz, 1 H), 4.14 - 4.06 (m, 2 H), 3.85 - 3.65 (m, 9 H), 3.60 (br s, 1 H), 3.47 (br s, 1 H), 3.41 (s, 3 H), 3.24 (d, J=14.2 Hz, 1 H), 3.01 (dd, j i O. I . 15.3 Hz, 1 H), 2.84 - 2.71 (m, 2 H), 2.60 (br s, 6 H), 2.49 - 2.40 (m, 1 H), 2.39 - 2.19 (m, 3 H), 2.08 - 1 .91 (rn, 6 H), 1.88 - 1 .76 (m, 3 H), 1.64 (t, J=9.7 Hz, 1 H i. 1.39 (t, 1=12.8 Hz, 1 H i. 1.05 (d, .! 6 8 Hz, 3H). rrv'z (ESI, +ve ion) 756.2 (M+H) ⁺ .

EXAMPLE 399, (1 S,3'R,6 ^! R,7'S,8 ^! E, 1 l'S.l 2 ^* R)-6-CHLORO-7'-HYDROXY-l 2'- (2-(2-METHOXYETHOXY)ETHYL)-i r-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO|NAPHTHALENE-1,22'-[20]OXA[ 13]THIA[ 1, 14]DIAZATETRACYCLO [14.7.2.0 ³ -^0 ^! ^ ⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE OR

(I S,3 ^, R,6 ^, R,7 ^! S,8 ^, E,i rS,I2'S)-6-CHLORO-7'-HYDROXY-12 ^, -(2-(2- METHOXYETHOXY) ETHYL)- 1 l'-METHYL-3,4-DIHYDRO-2H,15'H- 8ΡΚΟ[ΝΑΡΗΤΗΑ1,ΕΝΕ~1,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R;7 ^, S,8 ^, E,i rR,12'R)-6-CHLORO-7'-HYDROXY-12'-(2-(2- METHOXYETHOXY) ETHYL)- 1 l'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S^'^e'R 'S^^l l'R^^SJ-e-CPILORO-T-HYDROXY-ir^-iZ- METHOXYETHOXY) ETHYL)-i r-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1 ,22'-[20] QXA[ I 3]TH1A[ 1,14]

DIAZATETRACYCLO| 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16 ₅ 18,24]TETRAEN]- 15 ^* -ONE ^f ,13'-DIOXIDE

STEP 1: (3R,4S)-N,N-BIS(4-METHOXYBENZYL)-l-(2- METHOXYETHOXY)-4-METHYL-6-HEPTENE-3-SULFON AMIDE AND

(3R,4R)-N,N-BIS(4-METHOXYBENZYL)-l-(2-METHOXYETHOXY)-4- METHYL-6-HEPTENE-3-SULFONAMIDE AND

(3S,4S)-N,N-BIS(4-METHOXYBENZYL)- 1 -(2-METHOXYETHOXY)-4- METHYL-6-HEPTENE-3-SULFON AMIDE AND

(3S,4R)-NN-BIS(4-METHOXYBENZYL)-I-(2-METHOXYETHOXY)-4- -6-HEPTENE-3-SULFONAMIDE

To a suspension of sodium hydride, 60% in oil (164 mg, 4.09 mmol) in THF at 0 °C was added a solution of (3R,4S)-1 -hydroxy -N,N~bis(4~

methoxybenzyl)-4-methyl-6-heptene-3 -sulfonamide, (3 R,4S)-1 -hydroxy -N,N- bis(4-methoxybenzyl)-4-methyl-6-heptene-3-sulfonamide, (3R,4S)-1 -hydrox - N,N-bis(4-methoxybenzyl)-4-methyl-6-heptene-3-sulfonarnide and (3R,4S)~1 - hydroxy-N,N-bis(4-methoxybenzyl)^-methyl-6-heptene-3-siilfon (From Example 393, Step 1, 610 mg, 1.36 mmol) in THF. The mixture was stirred for 25 min at this temperature, and 2-bromoethyl methyl ether (0.256 mL, 2.73 mmol) was added. The mixture was allowed to warm up to ambient temperature and stirred for 3 day. The mixture was quenched with saturated aqueous NH4CI, and diluted with EtOAc. The organic layer was dried (MgSC ), filtered and the filtrate was concentrated. The resulting residue was chromatographed (silica gel, 9: 1 to 3:2, hexane/EtOAc) to afford the title compound as an oil.

STEP 2: (3S, 4R)-l-(2-METHOXYETHOXY)-4-METHYLHEPT-6-ENE-3- SULFONAMIDE AND

(3R, 4R)-l-(2-METHOXYETHOXY)-4-METHYLHEPT-6-ENE-3- SULFONAMIDE AND

(3S, 4S)- 1 -(2-METOOXYETHOXY)-4-METHYLFiEPT-6-ENE-3- SULFONAMIDE AND

(3R, 4S)- 1 -(2-METHOXYETHOXY)-4-METHYLHEPT-6-ENE-3-

SULFON

The title compounds were prepared from a mixture of (3R,4S)~N,N~bis(4- methoxybenzy )-l-(2-methoxyethoxy)-4-methyl-6-heptene-3-sulfonamide, (3R,4R)-N,N-bis(4-methoxybenzyl)-l-(2-methoxyethoxy)-4-methy l-6-heptene-3 sulfonamide, (3S,4R)-N,N-bis(4-methoxybenz>'l)- ! -(2-methoxyethoxy)-4-methyl 6-heptene-3-sulfonamide and (3S,4S)-N,N-bis(4-methoxybenzyl)-l- (2- methoxyethoxy)-4-methyl-6-heptene-3-sulfonamide by using a siinilar procedure described in Step 3 of Example 393.

STEP 3: (3S)-6'-CHLORO-5-(((l R,2R)-2-((l S ₅ 2E)-l-HYDROXY-2-HEXEN-l - YL)CYCLOBUTYL)METHYL)-N-(((3R,4S)- 1 -(2-METHOXYETHOXY)-4- METHYL-6-HEPTEN-3-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2'H- SP1R0[ 1 , 5-BENZOXAZEPINE-3, -NAPHTHALENE] -7-CARBOXAMlDE

AND

(3S)-6 ^! -Cm,ORO-5-(((lR,2R)-2~((] S,2E)-l-HYDROXY-2-HF EN~l~ YL)CYCLOBUTYL) METHYL)-N-(((3S,4S)-l-(2-METHOXYETHOXY)-4- METHYL-6-HEPTEN-3-YL)SULFONYL)-3 ^, ,4,4',5-TETRAHYDRO-2 ^, H- SPIRO[ 1. ,5-BENZOXAZEPINE-3, 1 '-NAPHTHALENE] -7-CARBOX AMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((l S ₅ 2E)-l-HYDROXY-2-HEXEN-l- YLjCYCLOBUTYL) METHYL)-N-(((3R,4S)- 1 -(2-METHOXYETHOXY)-4-

METH L-6-HE;PIEN-3-YL)SULF0NYL)-3^4,4 ^! ,5-TETRAHYDR0-2'H- SPIRO[ L5-BENZOXAZEPINE-3, Γ - APHTHALENE] -7-CARBOXAMIDE AND

(3S)-6'-CHLORO-5-(((lR,2R)-2-((l S,2E)-l-HYDROXY-2-HEXEN-l- YL)CYCLOBUTYL) METHYL)-N-(((3S lR)-l-(2-METHOXYETHOXY)-4 METHYL-6-HEPTEN-3-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2'H- SPT -BENZOXAZEPlNE-3, 1 '-NAPHTHALENE] -7-CARBOXAMIDE

The title compounds were prepared from a mixture of (3S, 4R)-l-(2- methoxyethoxy)-4-methylhept-6-ene-3-sulfonamide, (3S, 4R)-l-(2- methoxyethoxy)-4-methylhept-6-ene-3-sulfonamide, (3S, 4R)-1 -(2- methoxyethoxy)-4-methylhept-6-ene-3-sulfonamide and (3S, 4R)-l-(2- methoxyeihoxy)-4-rnethylhepi-6-ene-3-siilfonaniide with Intermediate AA12A by a similar procedure described in Step 4 of Example 380. STEP 4: (! S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-7'-HYDROXY-12'-(2-(2- ΜΕΤΉΌΧΥ ETHOXY)ETHYL)-l i'-METHYL~3,4-DIHYDRO-2H,15 ^! H~ SP1RO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1 , 14] DI AZ ATETRACYCLO [

14;7.2I) ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA [8,i6J 8,24]TETRAEN]-15'-ONE 13',!3'- DIOXIDE OR

(l S,3 ^! R,6 ^, R,7'S,8'E,irS,12'S)-6-CHLOR()-7'-HYDROXY-12'-(2-(2- METHOXYETHOXY) ETHYL)- 1 l"-METHYL-3,4-DIHYDRO-2H,l 5Ή- SPIRO[NAPHTHALENE-1,22'-[20]OXA[13]

THIA[L14]DlAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ jPENTACOSA

[8,I6,! 8,24]TETRAEN]-15'-ONE !3',13'-D )XIDE OR

(1 S,3'R,0'R,7'S,8'E, 11 'R, 12 ^, R)-6-CHLORO-7'-HYDROXY- 12 ^* -(2-(2-

METHOXYETHOXY) ETHYL)- 11 '-METHYL- 3.4-D1HYDRO-2H, 15 Ή-

SPIRO [NAPHTHALENE- 1 ,22'- [ 20] OXA[ 13 ]

THIA[ 1 , 14] DIAZ ATETRACYCLO

[14 .2i ^, -^0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETl AEN]-15'-ONE I3',13'-

DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,11'R, 12 ^* S)-6-CHLORO-7 ^* -HYDROXY-l 2'-(2-(2-

ΜΕΤΗΟΧΎΕΤΗΟΧΥ) ETHYL)-! r-METHYL-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]

THIA[ 1,14] DIAZ ATETRACYCLO [ 14.7.2.0 ³ · ⁶ . () ^!9 - ²⁴ ]PENTACOS A

[8, 16, 18,24]TETRAEN]-15'-ONE 13", 13'-DIOXTDE

The title compound was prepared from a mixture of (3S)-6'-chloro-5-

(((1 R,2R)-2-((l S,2E)-I -hydroxy -2 -liexen- 1 -yl)cy clobut>'l)methyl)-N-(((3R,4S)- 1 -

(2-methoxyethoxy)-4-methyl-6-hepten-3-yl)sulfonyl)-3 ^, ,4,4',5-tetrahydro-2'H- spiro[!,5~benzoxazepine-3, -naphthalene]-7-carboxamide, (3S)-6'-chloro-5-

(((1 R,2R)-2-((l S,2E)-1 -hydroxy -2-hexen- 1 -yi)cy dobutyl)methyl)-N-(((3S,4S)- 1 - (2-methoxyethoxy)-4-methyl-6-hepten-3-yl)sulfonyl)-3^4,4',5- tetrahydro-2'H- spiro[ l ,5-benzoxazepine-3, -naphthalene]-7-carboxaniide, (3S)-6'-chloro-5-

(((1 R,2R)-2-((l S,2E)-1 -hydroxy -2-hexen- 1 -yl)cy clobutyl)methyi)-N-(((3R,4S)- 1 - (2-methoxyethoxy)-4-methyl-6 iepien-3-yl)sulfonyl)-3',4,4',5 etrahydro-2TI- spiro[ l,5-benzoxazepine-3, l '-naphthalene]-7-carboxamide and (3S)-6'-chloro-5-

(2-methoxyethoxy)-4-methyl-6-hepten-3-yl)sulfonyl)-3',4,4',5 -tetrahydro-2'H- spiro[ l ,5-benzoxazepine-3, -naphthalene]-7-carboxamide by a similar procedure described in Step 5 of Example 380, and as the first eluenting isomer from the reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column;

Phenomenex, Torrance, CA; gradient elution of 25% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method). . ¾ NMR (500 MHz, CDCb) 5 ppm 8.05 (br s, 1 H), 7.70 (d, J=8.6 Hz, 1 H), 7.18 (dd, J 2.0. 8.6 Hz, 1 H), 7.12 - 7.06 (m, 1 H), 7.01 - 6.86 (m, 3 H), 5.92 - 5.80 (m, 1 H), 5.71 (dd, J 7.6. 1 5.2 Hz, 1 ! ! }. 4.39 i d. j 8 6 Hz, 1 H), 4,28 (br s, I H), 4. 10 (s, 2 H), 3.85 - 3.76 (m, 3 H), 3.73 - 3.57 (m, 6 H), 3.45 - 3.40 (m, 3 H), 3.25 (d, j 14.2 Hz, 1 H), 3.06 (br s, 1 H), 2.86 - 2.71 (m, 2 H), 2.50 - 2.40 (m, 1 H), 2.37 - 2.21 (m, 3 H), 2.20 (m, 6 H), 1.92 - 1.75 (m, 2 H), 1.73 - 1.62 (in, 1 H), 1.42 (t, j 1 2.6 Hz, 1 H), 1 , 1 3 - 1.00 (d, J 6.6 Hz, 3 H) m/z (ESI, +ve son) 687.2 (M+H) ⁺ .

Example 400. ( 1 S,3'R,6'R,7 ^! S,8'Z, 1 1'8, 12'Κ)-6-(:ΗΕΟΜ)-7· ίΥΟΜ)ΧΥ-12'-(2- (2-METHOXYETHOXY)ETHYL)-l l'-METHYL-3,4-DIHYDRO-2H, l 5Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1 ,14]DL\ZATCTRACYCLO[ 14.7.2.0^ ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8, 16, 18,24]TETRAEN]- 15'-ONE 13' ₅ 13'-DIOXIDE OR

(l S,3'R,6 ^f R,7'S,8'Z,i rSJ2'S)-6-CHLORO-7 ⁱ -HYDROXY-I2'-(2-(2-

ΜΕΤΉΌΧΥΕΤΗΟΧΥ) ETHYL)-! r-METHYL-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]

THIA|;i, 14]DIAZATETRACYCLO[ 14.7.2.() ³ ' ⁶ ,0 ⁱ⁹ - ²⁴ ]PENTACOSA

[8, 16, ! 8,24]TETRAEN]-! 5'-ONE 13 ^! , 13'-DIOXIDE OR (1 S,3'R,6'R,7'S,8'Z, 11 ^* R, 12'R)-6-CHLORO-7'-HYDROXY- 12'-(2-(2- METHOXYETHOXY) ETHYL)-i -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]

THI A[ 1,14] DIAZ ATETRAC YCLO [ 14.7.2.0 ³ · ⁶ . () ^!9 - ²⁴ ]PENTACOS A

[8J 6,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

( 1 S,3'R,6'R,7'S,8'Z, 11 'R, 12'S)-6-CHLORO-7'-HYDROXY- 12'-(2-(2- METHOXYETHOXY) ETHYL)-1 l'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [ APHTHALENE- 1 ,22'- [20] OXA

[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18, 24] TET '-ONE 13 ',13 '-DIOXIDE OR

The title compound was obtained as the second eluenting isomer from the reversed phase preparatory HPLC separation in Example 399. ^! H NMR (400 MHz, CDCb) δ ppm 8.99 (br s, 1 H), 7.71 (d, J 8.4 Hz, 1 H), 7.19 (d, J=8.5 Hz, 2 H), 7.10 (s, 2 H), 6.95 (d, j K.3 Hz, 1 H), 5.78 (br s, 1 H), 5.66 (dd, j 7.0. 1 1.3 Hz, I H), 4.45 (t, J 5.9 Hz, 1 H), 4.18 - 4.10 (m, 1 H), 4.10 (s, 2 H), 3.89 - 3.73 (m, 3 H), 3.73 - 3.57 (m, 6 H), 3.46 - 3.39 (m, 3 H), 3.30 - 3.10 (m, 2 H), 2.84 - 2,71 (m, 2 H), 2.50 - 2,36 (m, 1 H), 2.35 - 2.24 (m, 2 H), 2.12 (br s, 1 H), 2.09 - 1 .96 (m, 4 H), 1.92-1.61 (m, 5 H), 1.45 (t, J 12.4 H/. 1 I I). 1.15 - 1 .04 id. j 6 ! Hz, 3 H), m/z (ESI, +ve ion) 687,2 (M+H) ⁺ .

Example 401. (1S,3'R,6'R,7'S,8'E,1 l'S,12 ^* R)-6-CHLORO-7'-HYDROXY-12'-(2- (2-METHOXYETHOXY)ETHYL)-l l '-METHYL-3,4-DIHYDRO-2H,I5'H- SP1RO [ APHTHALENE- 1 ,22'- [20]OXA[ 13 |THIA[ l,14jDL4ZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8, 16, 18,24] TETRAEN] - 15 '-ONE 13',13'-DIOXIDE OR (l S ¾ )'R,7 ^f S,8'E,l l 'S,12'S)-6-CHLORO-7'-HYDROXY-12'-(2-(2- METHOXYETHOXY) ETHYL)-i -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]

THIA[ 1,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA|;8,16,18.24]T ETRAEN]- 15'-ONE ! 3', 13'-DiOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'E,i rR,12'R)-6-CHLORO-7 ^! -HYDROXY-12 ^, -(2-(2- METHOXYETHOXY) ETHYL)-i r-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [ APHTHALENE- 1 ,22'- [20] OX A[ 13]

THlA[i;i4]DIAZATETRACYCLO[14 .2X) ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,] 8,24]T ETRAEN]-15'-ONE ',13 ^! -D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E, l l'RJ 2 ^, S)-6-CHLORO-7'-HYDROXY-12'-(2-(2-

METHOXYETHOXY) ETHYL)- 1 l'-METHYL-3,4-DIHYDRO-2H,l 5Ή-

SPIRO [NAPHTHALENE- 1 ,22' - [20] OX A

[13]THlA[ia4]DlAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]

PENTACOSA[8,l 6,18,24] TETRAEN] - 15 '-ONE 13', 13'-DTOXIDE

The title compound was obtained as the third eluenting isomer from the reversed phase preparatory HPLC separation in Example 399. ^l H NMR (500 MHz, CDCb) δ ppm 8.28 (br s, 1H), 7.70 (d, j 8 6 Hz, 1 H), 7.21 - 7.14 (m, 2 H), 7.14 . 7.06 (m, 1 H), 6.96 (d, j 8.6 Hz, i l l ). 6.69 (br s, 1 l i s. 6.05 (br s, 1 H), 5.67 (dd, j 5.4. 15.2 Hz, 1 H), 4.24 - 4.00 (m, 4 H), 3.95 - 3.52 (m, 9 H), ), 3.47 - 3.37 (m, 4 H), 3.34 - 3. 15 (m, 1 H), 2.86 - 2.70 (m, 2 H), 2.61 - 2.45 (m, 2 H), 2.38 (br s, I H), 2.26 (br s, 2 H), 2, 15 - 1.65 (m, 8 H), ! .47 (m 1 H), 1.13 (d, J 7. 1 Hz, 3 H). m/z (ESI, +ve ion) 687.2 (M+H) ⁺ . Example 402. (1 S,3'R,6'R,7'S,8'E, 11 'S, 12 ^* R)-6-CHLORO-7'-HYDROXY-l 2"-(2- (2-METHOXYETHOXY)ETHYL)-r -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-L22 ^! ~[20]OXA[13]raiA[l,14]DlAZATETRACYCLO [14.7.2.0 ³ · ⁶ .0 ^ί9 · ²⁴ ] PENTACOSA[8,16,18,24jTETRAEN|-15*-ONE 13',13'- DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8 ^, E,ll ^, S,12'S)-6"CHLORO-7 ^, ~HYDROXY-12 ^, -(2~(2"

METHOXYETHOXY) ETHYL)-n'-METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| Γ. ΐΗ1Λ| Ι..! |ί)!Λ/Λ! :ΓΗ.Λ( ^' . 1117.20 ^;ί' .ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 1 ^' .1 -DIO.XIDE OR

(lS,3'R,6 ^! RJ ^, S,8'EJl'R,12'R)-6-CHLOR()-7 ^, -HYDROXY-12'-(2-(2-

METHOXYETHOXY) ETHYL)- 1 l"-METHYL-3 ₅ 4-DlHYDRO-2H,l 5Ή-

SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3] 1Η1Λ! 1 , 14]

DIAZATETRACYCLO[14 .2.0 ³ .«0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15-ONE 13 ^* , 13'-DIOXIDE OR

(lS,3 ^, R,6'R,7'S,8 ^, E,irR,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^f -(2-(2-

METHOXYETHOXY) ETHYL)- 11 '-METHYL- 3.4-D1HYDRO-2H, 15 Ή-

SPIRO [NAPHTHALENE- 1 ,22'- [ 20] OXA[ 13 ]

THIA[ 1 , 14] DIAZ ATETRAC YCLO

[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA[8,16,18,24]TETRAEN]-15'-ONE ', '-

DIOXIDE

The title compound was obtained as the fifth eluenting isomer from the reversed phase preparatory HPLC separation in Example 399. ¾ NMR (400 MHz, CDCb) δ ppm 8.24 (br s, I H), 7.75 (br s, 1 H), 7,64 (d, J 8.4 Hz, I 11). 7,15 (dd, J 2.2.8.5 Hz, 1 H), 7.10 (d, j 2.2 Hz, 1 H), 6,94 - 6,88 (m, 2 H), 5,75 (dd, .1 3 7. 15,7 Hz, i I s ). 5.5 ! (m, 1 H), 4,32 (d, J 7.6 Hz, 1 H), 4.30 - 4.19 (ra, 2 H), 4. 12 (br s, 1 H ). 3.94 - 3.68 (m, 7 H), 3.65 - 3.58 (m, 1 H), 3.50 - 3.37 (m, 3 H), 3.30 (d, J=14.3 Hz, 1 H), 3.10 (d, J=16.0 Hz, 1 H), 2.75 (m, 2 H), 2.61 - 2.39 (m, 2 H), 2.37 - 2.13 (m, 1 H), 2.06 - 1.60 (m, 1 1 H), 1.50 - 1.34 (m, 1 H), 1.07 (d, .! 5.9 Hz, 3 H), m/z (ESI, +ve ion) 687,2 (M+H) ⁺ .

EXAMPLE 403. (Ι β^ΊΙ,ό'Κ,Τβ,δΈ,Ι Ι'β,Ι ^-ό-Ο^ΟΚΟ-Τ-ΜΕΤΗΟΧΥ-Ι Ϊ- (2-(2-METHOXYEraOXY)ETHYL)-l r-METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-[20] OXA[ 13] Π 11 Al 1,14] DIAZ ATETRAC YCLO |;i4.7.2.0 - ^f () ^!9 - ²⁴ ]PENTACOSA| 8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 1 'S, 12'S)-6-CHLORO-7'-HYDROXY-l 2 ^* -(2-(2- METHOXYETHOXY) ETHYL)- 11 '-METHYL- 3.4-D1HYDRO-2H, 15 Ή-

SPIRO [NAPHTHALENE- 1 ,22'- [ 20] OXA [ 13]THI A[ 1 , 14 j

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTACOSA[8,16,18,24] TETRAEN]- I S'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,H'R, 12'R)-6-CHLORO-7'-HYDROXY-12'-(2-(2- METHOXYETHOXY ) ETHYL)- ^' ! l.'-METHYL-3,4-DIHYDRO-2H, 15'H- SPIRO [NAPHTHALENE- 1 ,22'-[20] OXA[l 3] THIA[ 1 , 14]

DL ZATET¾ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA[8,16,18,24]TETRAEN|- 15 ^* -ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E, l l'R,12'S)-6-CHLORO-7'-HYDROXY-12'-(2-(2- METHOXYETHOXY) ETHYL)-1 l'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22 ^* -j 2Q] ()XA[ 13] THIA[ 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared from (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6- chloro-7'-hydroxy-12'-(2-(2-methoxyethoxy)ethyl)-rr-methyl-3 ,4-dihydro- 2H, 15'H-spiro[naphthalene-l ,22'-[20]oxa[ 13]thia[ 1,14] diazatetracy clo

[14.7.2.0 ³ · ⁶ .0 ^ί9 · ²⁴ ] pentacosa[8,16,18,24]tetraenj-15'-one 13', 13 '-dioxide or (lS ¾,6'R ^,8^11'S,12'S)-6-chloro-7'-hydroxy-12 ^f -(2-(2-methoxyethoxy) ethyl)- 1 Γ-methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[ 13]tnia[ 1 , 14] diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ^{] 9} · ²⁴ ] pentacosa

[8,16,18,24]teiraen]-!5'-one 13',13'-dioxide or (1S,3'R,6'R,7'S,8'E,1 l'RJ2'R)-6- chloro-7'-hydroxy-12'-(2-(2-methoxyethoxy) ethyl)-! !'-m.ethyl-3,4-dihydro- 2H, 15'H-spiro[naphthalene-l ,22'-[20]oxa[13] thia[l , 14]diazatetracyclo

[14.7.2.() ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa| 8,16,18,24]tetraen]-15 ^! -one 13',13'-dioxide or (lS ¾,6'RJ^,8T^!!'R;i2^)-6-chloro-7'-hydroxy-r2'-(2-(2-methoxye ethyl)- 1 Γ-methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20] oxa[ 13 ] thia[ 1,14] diazatetracy clo [14.7.2.0 ³ - ⁶ .() ⁱ⁹ ' ²⁴ ipentacosa[8,16,18,24iietraen|-15'-one 13',13'-dioxide (from Example 399) by a similar procedure described in Example 396. ¾ NMR (500 MHz, CDCb) δ ppm 8.00 (s, 1 H), 7.70 (d, ./ 8.6 Hz, 1 H), 7.19 (dd, J=2.2, 8.6 Hz, 1 H), 7.10 (d, J=2.2 Hz, 1 H), 6.96 - 6.85 (m, 3 H), 5.92 - 5.85 (m, 1 H), 5.55 - 5.49 (d, j 8.3.14.4 Hz, 1 H), 4.36 (d,J=9.3 Hz, 1 H), 4.09 (s, 2 H), 3.91 -3,86 (m, 1 H), 3.86-3.6! (m, 7 H), 3.60 - 3,57 (m, 2 H), 3.45 - 3,36 (m, 3 H), 3.29 - 3,18 (m, 4 H), 3.0! (dd, ./ 10.3.15.4 Hz, 1 H), 2.84 - 2.72 (m, 2 H), 2.46 (m, 1 H), 2.39 - 2.25 (m, 3 H), 2.08 - 1.92 (m, 6 H), 1.90 - 1.75 (m, 2 H), 1.75 - 1.63 (m, 1 H), ! .46 - 1.25 (m, 1 H), 1.05 (d, J-6.8 Hz, 311} m/z (ESI, +ve ion) 623.2 (M+Na) ⁺ .

EXAMPLE 404. 2-(((lS,3 ^, R ₅ 6'R,7 ^, S ₅ 8 ^, E ₅ 12 ^, R)-6-CHLORO-12 ^, -METHYL- 13 ^, ₅ 13 ^, -DIOXIDO-15 ^, -OXO-3 ₅ -DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^, - | 2u jOXA| ! 3 jTI UA| U 4 | ni A/A I :TR A( ^' YCl.Oj i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |P1-M ^' .\C<)SA [ 8,16,18,24 jTETRAEN] -7'-YL)OXY)-N-METHYL ACET AMIDE

STEP 1 : (l S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12 ^, -METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 719, Step 2 using a mixture of (R)~hex-5-ene-sulfonaniide

(Intermediate EE20) and of (S)-hex-5-ene-sulfonamide (Intermediate EE202), and the desired product, (l S,3'R,6'R,7'S,8'E,12'R)-6-chloro-7'-hydroxy-12'-meth l- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'- i 8.24i !cirac n]-15'-one 13', 13'-dioxide (the 1st epimer out of preparative reverse phase HPLC) and (1 S,3'R,6'R,7'S,8'E, 12 ^* S)-6-chloro-7 ^, -hydroxy-12 ^, -methyl-3,4-dihydro- 21 i.15'H-spiro[naphthalene- 1,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (the 2nd epimer out of preparative reverse phase HPLC) were isolated. (1 S,3'R,6'R,7'S,8'E, 12'R)-6-chloro-7'-hydroxy-12'-raethyl-3,4- dihydro^H. l S'H-spirotnaphthalene-l^'-

[20]oxa[13]thia[l ,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'~dioxide: ¾ NMR (400MHz, CD3OD) δ 7.74 (d, J=8.0 Hz, IH), 7.19 (dd, J=3.5, 11.5 Hz, I H), 7.12 (d, J=1.8 Hz, IH), 7.01 (d, J=9.2 Hz, IH), 7,01 (d, ./ 7.6 Hz, i l l ). 6.94 (d, 8.0 Hz, IH), 6.88 (s, IH), 5.89 - 5.81 (m, i l l ). 5,73 (dd, ./ 7. -L 14.5 Hz, IH), 4.22 (dd, ,/=3.5, 7,6 Hz, IH), 4.18 - 4, 12 (m, IH), 4.09 (d, J=2.0 Hz, 2H), 3.85 (d, J=15.1 Hz, IH), 3.85 (d, J=15.3 Hz, IH), 3.68 (d, ./ 14. 1 Hz, 11 1 ). 3,08 (dd, J=10.2, 15. 1 Hz, IH), 2.87 - 2.73 (ra, 21 1 ). 2,48 - 2.18 (m, 4H), 2.1 1 (d, J=13.7 Hz, IH), 2.05 - 1.65 (m, 8H), 1.52 (d, .7=6.8 Hz, 3H), 1.47 - 1.41 (m, IH). m/z (ESI, +ve ion) 585.2 ( V! R )

STEP 2: 2 ((l S,3¾,6'R,7^,8T^ I 2'R)-6-CHLORO-12'-METHYL-13',13'- D10XlDO-15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALE E-I,22'- |;20]OXA[ 13 iTHIA[ l,14jDL4ZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, I 8,24]TETRAEN]-7'-YL)OXY)-N-METHYLACETAMIDE

To a 5-mL round-bottomed flask were added (lS,3'R,6'R,7'S,8'E,12'R)-6- chloro-7'-hy droxy- 12'-methyl-3,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20ioxa| 13jthia[ l, 14jdiazatetrac clo[14.7.2.0 ^3>, 0 ^{! 9} ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-15'-one 13', 13'-dioxide (15 mg, 0.026 mrnol, Example 404, Step 1 ) and sodium hydride, 60% dispersion in mineral oil (3.1 mg, 0.13 mmol) in 1 mL of THF at 0°C. The reaction mixture was stirred at 0°C for 30 min, and then 2-chloro-N- methylacetamide (8.3 mg, 0.077 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was queched with saturated NH ₄ C1 aqueous solution, and diluted with 40 mL of EtOAc, The organic layer was separated and concentrated. The crude product was purified by the reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column:

Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0. 1 % TFA, 30 min method) to provide the title compound. The structure was confirmed by the co-crystal structure of Example 404 with Mcl-1. ¾ NMR (400 MHz, CDCh) δ 8.12 (s, IH), 7.70 (d, J=8.4 Hz, 1 H), 7. 19 (dd, .7=8,5, 2.4 Hz, 1 H), 7.07 - 7.12 (m, 1 H i. 6.88 - 6.95 (m, 2 H), 6.80 (1 II.8), 5.87 (ddd, ,/ 1 .3.9.2, 4,3 Hz, 1 H), 5.55 (dd, J=15.7, 9,4 Hz, ! H), 4.22 - 4,32 (m, 1 H), 4.02 - 4,14 (m, 2 H), 3.69 - 3,96 (m, 5 H), 3.23 (d, .7=14.5 Hz, I H), 3.00 (dd, J=15.2, 10.3 Hz, 1 H), 2.86 (d, J=5.1 Hz, 3 H), 2.71 - 2.82 (m, 2 H), 2.44 - 2.54 (m, 1 H), 2.20 - 2.41 (m, 3 H), 1.91 - 2.10 (m, 3 H), 1.63 - 1.89 (m, 7 H), 1.59 (d, ,/ 7.0 Hz, 3 H), m/z (EST, +ve ion) 656,2 !YM!)

EXAMPLE 405. (1 S,3'R,6¾,7^,8¾12¾)-6-CHLC)R()-7'-(2- METHOXYETHOXY)- 12'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22 ^! ~

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/Α Π:ΤΗΑ(Ύα.ί)Ι i 4.7.2.0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24]TETRAENj 5'- ',13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using l-bromo-2-methoxyethane instead of 2-chloro-N- methylacetaraide. ^! H NMR (400 MHz, CD3OD) δ 7.72 (d, J 8.6 Hz, 1 H), 7.16 (dd, j K.5.2.2 Hz, 1 H), 7.10 (d, j 2.2 Hz, 1 H), 6.98 (d, j N.3 Hz, 1 H), 6.91 (d, j 8.2 Hz, 1 Is).6.85 (d, J !.H Hz, 1 H), 5.80 - 5.87 (m, 1 H), 5.58 (dd, j 8,8 Hz, 1 H), 4.03 - 4,18 (m, 3 H), 3.80 - 3,86 (m, 2 H), 3.41 - 3,68 (m, 5 H), 3.35 (s, 3 H), 3.06 (dd, j 15.3.10.4 Hz, 1 H), 2.70 - 2.81 (m, 2 H), 2.24 - 2.53 (m, 4 H), 2,09 (d, J 13.7 Hz, 1 H), 1.68 - 1.96 (m, 7 H), 1.50 (d, J 7.0 Hz, 3 H), 1.39 - 1.47 (m, 2 H). m/z (ESI, +ve ion) 643.2 {M l!)

EXAMPLE 406, (1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-12'-METHYL-7'-(2-

(METHYLSULFONYL)E ^r rHOXY)-3,4-DIHYDRO-2H,15'H-

SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using 2-bromoethyl methyl sulfone instead of 2-chloro-N- methylacetamide. ^! H NMR (500 MHz, CDCb) δ 7.91 (s, 1 H), 7,70 id. j 8.6 Hz, 1 H), 7.19 (dd, j 8.6. 2.2 Hz, 1 H), 7.08 (1 H, s), 6.87 - 6.95 (m, 2 H), 6.79 (d, j 1.7 Hz, 1 H), 5.87 (ddd, j 15.2. 9.3, 3.9 Hz, 1 H), 5.56 (dd, j 15.2. 9.3 Hz, 1 H), 4.19 - 4,31 (m, 1 H), 4.01 - 4.16 (m, 2 H), 3.77 - 3.91 (m, 3 H), 3.63 - 3.77 (m, 2 H), 3, 14 - 3.27 (m, 3 H), 2,95 - 3.00 (m, 4 H), 2,72 - 2.84 (m, 2 H), 2,25 - 2.48 (m, 4 H), 1.73 - 2.06 (m, 9 H), 1.65 - 1.73 (m, 1 H), 1.59 (d, j 7. 1 Hz, 3 H). m / (ESI, +ve ion) 691.2 ( VI I D ^' ,

EXAMPLE 407. (((lS,3'R,6'R,7'S,8 ^! E, 12 ^! R)-6-CHLORO-12'-METHYL-13',13'- DIOXIDO-lS'-OXO-S^-DlHYDRO-ZH-SPmorNAPHTHALE E-l^^-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] -7'-YL)OXY)ACETlC ACID

The title compound was prepared in an analogous manner to that described in Example 404 using brornoacetic acid instead of 2-chloro-N-methylacetamide. ³ H NMR (500 MHz, CD3OD) δ 7.73 (d, j 8.6 Hz, 1 H i. 7.17 (dd, j 8 -1. 2,3 Hz, 1 I I I 7.1 1 (1 I I. d, J 2.2 Hz, 1 ! ! }. 6.91 - 6.99 (m, 2 ! ! }. 6.82 id. j 2 0 Hz, 1 I I ). 5.84 - 5.90 ins. 1 H), 5.60 (del .! 15.2. 9.3 Hz, 1 H), 4,04 - 4.20 (m, 3 H), 3,99 (s, 2 H), 3,93 (dd, J 9.2. 3.5 Hz, 1 H), 3.84 (d, j 1 9 Hz, 1 H), 3,67 (d, J=14.2 Hz, I H), 3.08 (dd, J=15.3, 10.4 Hz, 1 H), 2.72 - 2.85 (m, 2 H), 2.54 - 2.63 (m, 1 H), 2.26 - 2.46 Or, 3 H), 2.10 (d, j 1 .4 Hz, 1 H), 1.71- 2.02 (m, 9 H), 1.51 i d. j 6.8 Hz, 3 H). m/z (ESI, +ve ion) 643,2 (M+H) ⁺ .

EXAMPLE 408. METHYL (((lS,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-CHLORO-12'- METHYL- 13 13 '-DIOXIDO- 15 '-OXO-3,4-DIHYDRO-2H- SP1RO [NAPHTHALENE- 1 ,22'- |;20]OXA[ 13 iTHIA[l,14jDL4ZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAEN]-7"-YL)OXY)ACET ATE

The title compound was prepared in an analogous manner to that described in Example 404 using methyl 2-bromoacetate instead of 2-chloro-N- methylacetaraide. ^! H NMR (500 MHz, CD3OD) δ 7.72 (d, ,/ H 56 Hz, 1 H), 7, 17 (dd, ./ 8.56. 2.20 Hz, 1 ! ! }. 7.11 (s, 1 H), 6.98 (d, ./ 8.29 Hz, 1 H), 6.90 - 6.94 (m, 1 H), 6,82 (s, 1 H), 5.81 - 5,88 (m, 1 H), 5.58 (dd, ./ 15 16. 9.29 Hz, 1 H), 4.12 - 4.19 is 1 H), 4.05 - 4.09 (m, 2 H), 4.01 - 4.05 (m, 2 H), 3.87 - 3.94 (m, 1 H), 3.83 (d, J=14.92 Hz, 1 H), 3.74 (s, 3 H), 3.66 (d, =14.18 Hz, 1 H), 3.07 (dd, ./ 15.4 ! . 10.27 Hz, 1 H), 2.72 - 2.85 (m, 2 H), 2.51 - 2.60 (m, 1 H), 2.24 - 2.43 (m, 3 H), 2, 10 (d, J=13.69 Hz, 1 H), 1.79 - 1.97 (m, 7 H), 1.69 - 1.78 (m, 2 H) 1.51 (d, J=6.85 Hz, 3 H). m/z (ESI, +ve ion) 657.2 (M+H) ⁺ . EXAMPLE 409. (1 S,3'R,6'R,7 ^! S,8'E, 12'R)-6-CHLORO-7'-((3,5-DIMETHYL-4- ISOXAZOLYL)METHOXY)- 12'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 ⁽ Γ ".O ¹ " ^M |PH\ i ACOSA [8, i 6, 18,24]TETRAEN]-15'- '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using 4-(chloromethyl)-3,5-dimethylisoxazole instead of 2- chloro-N-rnethylacetamide. ¾ NMR (500 MHz, CD ₃ OD) δ 7.72 (d, j 86 Hz, IH), 7.17 (dd, j 8.6.2,2 Hz, IH), 7.10 (d, .1 22 Hz, IH), 6.98 (dd, j HA.2,0 Hz, IH), 6.92 (d, j 83 Hz, IH), 6.84 (d, j 1.7 Hz, IH), 5.82-5.88 (m, IH), 5,62 (dd, j 15.4.8.8 Hz, IH), 4.32 (d, j 12.0 Hz, IH), 4.13-4.21 (m, 2H), 4.03-4.09 (m, 2H), 3.79-3.87 (m, 2H), 3.65 (d, j 14.2 Hz, IH), 3.06 (dd, j 1 .3.10.1 Hz, IH), 2,71-2.84 (m, 2H), 2.39-2.49 (m, 2H), 2.37 (s, 3H), 2.25-2.36 (m, 2H), 2.22 (s, 3H), 2,09 (d, j 1 .7 Hz, IH), 1,64-2.01 (m, 8H), 1.52 (d, j 6,8 Hz, 4H), 1.43 (br, s., IH). in . (ESI, +ve son) 694.2 (M+H) ⁺ .

EXAMPLE 410. (IS^'R^'RJ'S^U^'Ri-e-CHLORO- '-METHYL-T'-^l- METHYL-lH-l,2,4-TRIAZOL-3-YL)METHOXY)-3,4-DIHYDRO-2H,15 ^, H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[l,i4]DLAZATETRACYCLO[14,7.2,0^V0 ¹⁹ - ²⁴ ^

[8,16,18,24]ΤΕΤΡ^ΑΕΝ]-15'- ',13'-DIOXIDE

The title compound was prepared in an analogous manner to that described ample 404 using 3-(chloromethyi)- 1 -methyl-lH- 1 ,2,4-triazole hydrochloride instead of 2-chloro-N-methylacetarnide. ¾ NMR (500 MHz, CDsOD) δ 8,53 (s, IH), 7.72 (d, ,7=8,6 Hz, IH), 7. 17 (dd, .7=2.3, 8.4 Hz, IH), 7.10 (d, .7=2,2 Hz, I H), 6.97 (dd, ./ 2,0. 8.1 Hz, i l l ). 6.90 (d, J=8. i Hz, IH), 6.79 (d, ./ 1 .7 Hz, IH), 5.89 - 5.83 (m, IH), 5.59 (dd, ./ 8.9. 15.3 Hz, IH), 4.58 - 4.50 (m, IH), 4.49 - 4.34 (m, IH), 4,20 - 4.14 (m, I H), 4.09 - 4,02 (m, 2H), 3 ,97 (s, l ). 3, 89 (dd, ./ 3.4 , 8,8 Hz, IH), 3,80 - 3 ,72 (m, IH), 3.65 (d, ,/=14.2 Hz, IH), 3.26 (d, .7=13 ,9 Hz, IH), 3.05 (dd, J=10.3, 15.4 Hz, IH), 2.84 - 2.71 (m, 2H), 2.53 - 2.47 (m, IH), 2.45 - 2.37 (m, IH), 2.35 - 2.27 (m, 2H), 2.08 (d,■/ 13.7 Hz, I H), 1.95 - 1.78 (m, 71 1 ). 1 .77 - 1.69 (ra, 2H), 1 ,52 (d, .7=7.1 Hz, 3H). ni , (ESI, +ve ion) 680.2 (M+H) ⁺ .

EXAMPLE 41 1. (1 S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-l 2'-METHYL-7*-((5- METHYL-3-ISOXAZOLYL)METHOXY)-3,4-DIHYDRO-2H, 15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20 iOXA|;i3]THIA|;i ,14]DIAZATETRACYCL )[ 14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8, 1 6, 18,24]TETRAEN]-15'- ", 13'-DIOXTDE

The title compound was prepared in an analogous manner to that described in Example 404 using 3-chloromethyS-5-methylisoxazole instead of 2-chloro-N- methylacetamide. ¾ NMR (500 MHz, CD3OD) δ 7.71 (d, J=8.3 Hz, IH), 7.17 (dd, J 2.1, 8.4 Hz, IH), 7.10 (d, 1=2.2 Hz, IH), 6.98 (dd, J 1 .8. 8.2 Hz, IH), 6.91 (d, 1=8.1 Hz, IH), 6.83 (d, J=1.7 Hz, IH), 6.11 (s, IH), 5.89 - 5.82 (m, IH), 5.60 (dd, J=8.9, 15.3 Hz, IH), 4.46 (d, j 12.7 Hz, IH), 4.39 (d, 1=13.0 Hz, I H), 4.16 (ddd, .1 3 3. 6,7, 9.8 Hz, IH), 4,09 - 4.02 (m, 2H), 3.90 (dd, j 3.8. 8,9 Hz, IH), 3.81 (d, j 14. ·! Hz, IH), 3.65 (d, 1=14.2 Hz, IH), 3.27 (d, 1=14.2 Hz, IH), 3,05 (dd, .1 100.15,4 Hz, IH), 2.84 - 2.71 (m, 2H), 2.56 - 2,46 (m, IH), 2.44 - 2,28 (m, 6H), 2,08 (d, J 1 .7 Hz, IH), 1,97 - 1,79 (m, 6H), 1.76 - 1.70 (m, 2H), 1.51 (d, J=6.8 Hz, 3H), 1.48 - 1.36 (m, IH). m/z (ESI, +ve ion) 680.2 (M+H) ⁺ . EXAMPLE 412. (lS,3 ^, R,6¾,7'S,8 ^, E,12 ^, R)-6-CHLORO-12 ^f -METHYL-7 ^, -((5-

METHYL-l,3,4-OXADlAZOL-2-YL)METHOXY)-3,4-DIHYDRO-2H,15'H~ SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'- ', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using 2-(chloromethyl)-5-methyl-l,3,4-oxadiazole instead of 2- chloro-N-mel ylacetamide. ¾ NMR (500 MHz, CD3OD) δ 7.74 (d, ./ 8.6 Hz, IH), 7.19 (dd, J=2.3, 8.4 Hz, IH), 7.12 (d, J=2.2 Hz, IH), 7.00 (dd, J=2.0, 8.1 Hz, IH), 6.92 (d, ./ 8.! Hz, IH), 6.86 (d, ./ 2.0 Hz, IH), 5.95 - 5.89 ins. IH), 5.61 (dd, .7=8 ,9, 15,3 Hz, ill).4.66 - 4,61 (m, IH), 4.61 - 4.54 (m, H), 4,22 - 4,16 (m, IH), 4,09 - 4.05 (m, 2H), 3.99 (dd, ,/ 38.8.9 Hz, IH), 3,85 (d, ./ 14.9 Hz, IH), 3,68 (d, ./ ί 4.2 Hz, IH), 3.32 - 3.28 (m, IH), 3.28-3.31 (m,l H), 3.08 (dd, ./ 10.3.15.4 Hz, IH), 2.86 - 2,73 (m, 2H), 2.58 - 2.55 (m, 4H), 2.46 - 2,27 (m, 3H), 2.11 (d, ./ 1 .7 Hz, IH), 1,98 - 1.81 (m, ?!!}.1.79 - 1.71 (m, 2H), 1,54 id../ 7.1 Hz, 3H). ra-'z (ESI, +ve ion) 681.2 (M+H) ⁺ .

EXAMPLE 413. (lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-12 ^, -METHYL-7'-(((3S)- 2-OXOTETRAHYDRO-3 -FURANYL)OXY)-3,4-DIHYDRO-2H, 15 Ή- SPIRO[N APHTHALENE- 1 ,22 ^! -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2,0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24]TETR _! 4ENl-15'-ONE 13 ^! ,13'-DIOXIDE

STEP 1 : (R)~3~AZTDODIHYDROFURAN~2(3H)~ONE AND (S)~3~

AZIDODIH YDROF URA

To a 25-mL round-bottomed flask were added alpha-bromo-gamma- butyrolactone (0.168 mL, 1.82 mmol) and sodium azide (177 mg, 2.73 mmol) in DMSO (6.1 mL). The mixture was stirred at ambient temperature for 2 days. The reaction mixture was diluted with saturated NaHCCb solution (10 mL) and extracted with Et20 (2x10 mL).The organic extract was washed with saturated NaCl (10 mL) and dried over MgSCk The solution was filtered and concentrated in vacuo to give the title compound (200 mg, 87%) as a colorless oil. ^l H NMR (500 MHz, CDCb) δ 4.41-4.51 (m, 1H), 4.25-4,37 (m, 2H), 2.59 (dddd, «7=3.67, 6.72, 8.47, 13.17 Hz, 1H), 2.12-2.28 (m, 11 1 ).

STEP 2: 2,5-DIOXOPYRROLIDlN-l-YL 3- (DIPHENYLPHOSPHINO)PROPANOATE

To a 100-mL round-bottomed flask were added 3-

(diphenylphosphino)propanoic acid (2.50 g, 9.68 mmol) and n- hydroxysuccinimide (1.23 g, 10.7 mmol) in DCM (19.4 ml), and then Ν,Ν'- methanediylidenebis(propan-2-amine) (1.34 g, 10.7 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with Et?.0 and the solid was remo ved by filtration. The filtrate was concentrated. The residue was redissolved in a mixture of EtOAc and hexane, and solid was precipitated. Filtration provided the title compound (2.00 g, 58%). m/z (ESI, +ve ion) 356.1 (M+H) ⁺ . STEP 3: 3-DIAZODIHYDROFURAN-2(3H)-ONE

To a 25-mL round-bottomed flask were added 2,5-dioxopyrrolidin-l-yl 3- (diphenylphosphino)propanoate (288 mg, 0.810 mmol, Step 2) and (R)-3- azidodihydrofuran-2(3H)-one and (S)-3-azidodihydrofuran-2(3H)-one (100 mg,

0.787 mmol, Step 1) in THF (1.4 ml,) and water (0.21 mL). The mixture was stirred at ambient temperature for 3 h, and then 3 mL of saturated NaHCCb aqueous solution was added. After stirred another 15 rain, the solution became yellow. The reaction mixture was diluted with saturated NaCl aqueous solution, extracted with DCM. The combined DCM solution was dried over MgSC¼, filtere and concentrated. The residue was purified by chromatography using DCM as an eluent to provide the title compound (70 rag, 79%). Ή NMR (400 MHz, CDCb) δ 4,38-4.46 (m, 2H), 3.36-3.43 (m, 2H). STEP 4: (lS,3'R,6¾,7 ^, S,8'E,12'R)-6-CHLORO-12'-METHYL-7 ^, -(((3S)-2- OXOTETRAHYDRO-3 -F URAN YL)OXY)-3 ,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

To a 25-mL round-bottomed flask were added (l S,3 ^, R,6'R,7'S,8 ^! E,12'R)-6- chloro-7'-hydroxy-12'-methyl-3,4-dm^

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,^ n]-15'-one 13',13'-dioxide (12 mg, 0.021 mmol, Example 404, Step 1) and rhodium (ii) acetate dimer (2.7 rag, 6.2 μπιοΐ) in DCM (680 μΐ), and then 3- diazodihydrofuran-2(3H)-one (5.8 mg, 0.051 mmol, Step 3). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered, filtrate was concentrated. The crude product was purified by the reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 40% to 95%» MeCN in water, where both solvents contain 0.1 % TFA, 30 rnin method) to provide the title compound as the second eluting isomer, ¾ NMR (500 MHz, MeOH) δ 7.74 (d, J=8.31 Hz, IH), 7.19 (dd, J=2.20, 8.56 Hz, IH), 7.12 (d, ,/ 2.20 Hz, IH), 6.99-7.02 (m, IH), 6.92-6.95 (m, IH), 6.91 id../ I.? I Hz, IH), 5,86-5.94 (m, IH), 5.61 (dd,J=8.80, 15.16 Hz, IH), 4,30-4,40 (ni, 3H), 4,21-4.27 (m, IH), 4.14-4,21 (m, IH), 4.05-4.12 (m, 2H), 3.88 (d, J=13.45 Hz, IH), 3.68 (d, ./ 14.18 Hz, IH), 3.35-3.40 (m, IH), 3.28-3.31 (ni, IH), 3.10 (dd, ./ 9.90.15.28 Hz, IH), 2.73-2.88 (m, 2H), 2.59 (dq, ./ 3. 1.9.21 Hz, IH), 2,36-2.48 (m, 3H), 2,27-2,35 (m, IH), 2.09-2.15 (m, IH), 2,01-2,08 (m, IH), 1,80-2.00 (m, 6H), 1.71-1,80 (m, 2H), 1.53 (d,«/=6.85 Hz, 3H), 1.41-1.49 (m, IH). m/z (ESI, +ve ion) 669.2 (M+H) ⁺ .

EXAMPLE 414. (IS^'R^'RJ'S^U^'Ri-e-CHLORO- '-METHYL-?'-^^- 2-()XOTETRAJiYDRO-3-FURANYL)OXY)-3,4-DIHYDR()-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2θ!()ΧΛ| I 311 Η1Λ| I„ i i |OI.\/.\ Π·. f ^' RACYCf ,Oj I -1.7.20·".ϋ ^{|:, !|} |ΡΗ\ i ACOSA [8,16,18,24]TETRAENj-15'- ^! ,13'-DIOXIDE

The title compound was obtained as the first eluting isomer from the reversed phase preparatory HPLC separation in Example 413, Step 4. Ή NMR (500 MHz, CD3OD) δ 7,75 (d, ./ 8.3! Hz, !!!).7.19 (dd, ,/ 2.2Π, 8,56 Hz, IH), 7.13 id../ 1.9611/. IH), 7.01 {dd../ 1.83.8.19 Hz, 111).6.91-6.96 (m, IH), 6.86 {±■/ i .7! Hz, IH), 5.88-5.98 (m, IH), 5.62-5.73 (m, IH), 4.38-4.45 (m, 2H), 4.27 (dt,J=6.36, 9.41 Hz, !!!).4.15-4.23 (m, IH), 4,03-4,13 (m, 311).3.87 {O.J 15 1 Hz, IH), 3.69 (d, .7=14.18 Hz, 1 H), 3.34-3.38 (m, 1H), 3,28-3.34 (m, 1H), 3.09 (dd, .7=10.27, 15.16 Hz, IH), 2,73-2.87 (m, 2H), 2.61-2.69 (m, i l l ). 2,48-2.56 (m, IH), 2.40-2.48 (m, IH), 2.28-2.40 (m, 2H), 2.08-2.22 (m, 2H), 1.81-1.99 (m, 6H), 1.71 -1.80 { in. 2H), 1.53 (d, ,7=6.85 Hz, 3H), 1.42-1.50 (m, ! ! ! ). m (ESI, +ve ion) 669,2 ( V! 1 1) .

EXAMPLE 415. (l S,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E.12 ^, R)-6-CHLORO-7 ^, -(((2R)-2,3-

DIHYDROXYPROP YL)OXY)- 12'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-

SP1RO [NAPHTHALENE- 1 ,22'- |;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8,16, 18,24]TETRAEN]-15"-ONE 13', 13'-DiOXIDE AND

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-(((2S)-2,3-

DIHYDROXYPROPYL)OXY)-12'-METHYL-3,4-DlHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8, 16, 18,24 -1 S'-ONE 13 ',13 '-DIOXIDE

To a 25-mL round-bottomed flask were added (1 S,3'R,6'R,7'S,8'E,12'R)- 6-ch]oro-7'-hydroxy-12'-methyl-3,4-dih} _' -dro-2H,15'H-spiro[naphthalen

[20]oxa[13]thia[l,14]diazatetra yclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosaE8,16,18,24]^ n]-15'-one 13',13'-dioxide (40 mg, 0.068 mmol, Example 404, Step 1) and sodium hydride, 60% dispersion in mineral oil (27 mg, 0.68 mmol) in I mL of THF at ambient temperature. The reaction mixture was stirred for 30 min, and then (+)/(- )-epichiorohydrin (53.5 μΐ, 0.684 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with 2 N HCl. The crude material was purified by chromatography through a Redi-Sep pre- packed silica gel column (12 g), eluting with a gradient of 0% to 45% EtOAc in hexane to provide the product as the precursor of the title compound. The compound obtained above was dissolved in 100 mL of water/ACN mixture with 0.3%» HO Ac, and stirred at ambient temperature for 6 hours. The mixture was concentrated, and repeated twice. The crude material was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex,

Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0. 1 % TFA, 30 min method) to provide the title compound. Ή NMR (500 MHz, CD3OD) δ 7,75 (d, J=8.56 Hz, IH), 7.19 (dd, ./ 2.32. 8.44 Hz, IH), 7.12 (d, ./ 2.20 Hz, 1H), 6.97-7.03 (m, IH), 6.90-6.96 (m, IH), 6.87 (d, ./ i .7 1 Hz, IH), 5.80-5.92 (m, IH), 5.61 (dd, J=9.29, 15.41 Hz, I H), 4.14-4.24 (m, I H), 4.03-4. 13 (m, 2H), 3, 80-3.92 (m, 2H), 3.65-3.77 (m, 2H), 3.55-3.62 (m, IH), 3,28-3.34 (m, 2H), 3.35-3,40 (m, IH), 3.28-3.33 (m, H), 3,08 (dd, .7=10.39, 15.28 Hz, IH), 2.73-2.88 (m, 2H), 2.48-2.58 (m, IH), 2.26-2.47 (m, 3H), 2.12 (d, ./ 1 3.69 ! !/. IH), 1 ,79-2.01 (m, 6H), 1 .69-1.79 (m, 2H), 1.52 id, J=6.85 Hz, 3H), 1.46 (t, ./ 14, 18 Hz, IH). m/z (ESI, +ve ion) 659.2 (M+H) ⁺ .

EXAMPLE 416. (1 S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-l 2'-METHYL-7*-(( l- YU . H iV ^' i - 1 1 !- ! .2. ·- 1 R! A/Οί ---Y L )\ j h Π ίΟΧΥ }- .4-ί)! Ι !Y i)R( ?.l 1. 1 V| !- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13 ^! -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using 5-(chloromethyl)-l-methyl-lH-l ,2,3-triazole hydrochloride. T-I NMR (400 MHz, DCCb) δ 8.01 (s, IH), 7.69 (d, ,/ 8, 4 ! Hz, IH), 7.64 (s, IH), 7.19 (del.,/ 235.8.61 Hz, IH), 7.10 id../ 2.15 Hz, IH), 6,88-6.96 (m, 2H), 6.80 (d, .7=1.56 Hz, IH), 5,84-5.94 (m, IH), 5.59 (dd, ,/ 929.15.36 Hz, IH), 4,54 (d, J=12.52 Hz, IH), 4.40 (d, J=12.52 Hz, IH), 4.22-4.32 (m, IH), 4.03-4.13 (m, 5H), 3.89 (dd, ./ 3.33.9.00 Hz, IH), 3.68-3.84 (m, 211 ).3.50 (q, J=7.04 Hz, IH), 3.22 (d, I4.4X Hz, IH), 2.99 (dd, J=10.17, 15,06 Hz, IH), 2,71-2,81 (m, 2! I ).2.21- 2,48 (m, 3H), 1.92-2.12 (m, 3H), 1,75-1,87 (m, 5H), 1.63-1,71 (m, IH), 1,61 id. J=7.04 Hz, 3H), 1.40 (t, J=12.72 Hz, IH). m/z (ESI, +ve ion) 680.2 {M il) ,

EXAMPLE 417. (lS^ ^, R,6 ^, R,7 ^, S,8¾12 ^, R)-6-CHLORO-12 ^, -METHYL-7'-((l- METHYL-lH-l,2,3-TRIAZOL-4-YL)METHOXY)-3,4-DIHYDRO-2H,15 ^, H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| i 1 ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 ' ".U ^1* " ¹ |PH\ i ACOSA

[8, 16, 18,24]TETRAEN]-15'- ', 13'-D10XlDE

The title compound was prepared in an analogous manner to that described in Example 404 using 4-(chloromethyi)- 1 -methyl-lH- 1 ,2,3-triazole hydrochloride. ¾ MR (500 MHz, CDsOD) 67.88 (s, IH), 7.66-7.76 (m, IH), 7.19 (dd, ./ 2.32. 8.44 Hz, IH), 7.12 (d, ./ 2.20 Hz, IH), 7.00 (dd, ./ 1.96.8.31 Hz, IH), 6.93 (d, ,/ H07 Hz, IH), 6.86 (d, J=l,96 Hz, IH), 5,81-5,92 (m, IH), 5.63 (dd, 856. 15,41 Hz, IH), 4.54-4,60 (m, IH), 4.47 (d, «7=11.98 Hz, IH), 4.09-4.19 (m, 4H), 4.04-4.09 (in, 2H), 3.94 (dd, ./ 3.67.8.56 Hz, IH), 3.82 (d, J=15.16 Hz, IH), 3.66 id../ 14.1 Hz, IH), 3,25-3,32 (m, IH), 3.07 (dd, .7=10.03, 15.1611/. IH), 2.72- 2.87 (m, 2H), 2,26-2,55 (m, 4H), 2.10 (d, ,/ 1 69 Hz, IH), 1.68-1.99 (m, 8H), 1.54 (d, =6.85 Hz, 3H), 1.40-1.49 (m, IH). m/z (ESI, +ve ion) 680.2 (M+H) ⁺ .

EXAMPLE 418. (lS,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^! -METHYL-7 ^, -(2-(4- MORPHOLlMYL)E ^r fflOXY)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7^

[8, 16, 18,24]TETRAEN]-15'- '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using 4-(2-bromoethyl)morpholine hvdrobromide. ¾ NMR (500 MHz, CDCh) δ 8.22 (br, s., IH), 7.70 (d, .7=8.56 Hz, IH), 7.19 (dd, J=2.20, 8.31 Hz, IH), 7.09 (d, J=1.96 Hz, IH), 6.86-6.96 (m, 2H), 6.77 (s, IH), 5.84-5.96 (m, IH), 5.52 (dd, ./ H.8U. 14.92 Hz, IH), 4.24 (dd, ./ 7.09. 12,72 Hz, IH), 3.94-4.12 (m, 6H), 3,86 (br. s,, IH), 3.68-3.82 (ra, 3H), 3,60-3.66 (m, 2H), 3.16-3.33 (m,

3H), 2.88-3.04 (m, 2H), 2.70-2.85 (m, 2H), 2.26-2,48 (m, 4H), 1.92-2.07 (m, 5H), 1.74-1.87 (m, 5H), 1.62-1.70 (m, IH), 1.58 id. ./ 6.85 Hz, 3H), 1.39 it. ./ 1 .96 Hz, IH), m/z (ESI, +ve ion) 698.2 ! M l ! } ^' EXAMPLE 419. (2S)-2-(((l S,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -METHYL- 13^ 13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPTRO| APH HALENE-l ,22 ^, -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETl AEN]-7'-YL)OXY)- ,N-DlMETHYLBUTANAMIDE OR (2R)-2-(((l S,3Έ,6¾,7Έ,8Έ, 12'R)-6-CHLO O-12 ^! -METHYL-13 ^, ,13'-DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTH ALENE- .1 ,22'-

| 2( >X A| i 1 ! f Π Λ| ί i J l i^f AZ.Vf l: E RAC YCE C)l i J 7.2 ' ".U ^{1 *} " ¹ |PH\ i ACOSA

[ 8,16,18,24 jTETRAENj -7'-YL)OXY)-N,N-DIMETHYLBUTANAMIDE

STEP 1 : (R)-2-BROMO-N,N-DTMETHYLBUTANAMIDE AND (S)-2- BROMO-N _s N-DIMETHYLBUTAN AMIDE

o o \ Br \ Br

To a 100-mL round-bottomed flask were added 2-(lh-benzotriazol-l -yl)-

1,1 ,3,3-tetraniethyluronium hexafluorophosphate (5,79 g, 15.3 mmol), DIEA

(3.56 ml, 20.4 mmol), 2-bromo butyric acid (1.70 g, 10.2 mmol) and

dimethylamine, 2.0 M solution in tetrahydrofuran (7.63 ml, 15.3 mmol) in THF (40.7 rnl). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with CH2CL2 (2 x 30 mL). The organic solution was concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed sihca gel column (40 g), eluting with a gradient of 0% to 65% EtOAc in heptane, to provide the title compound (1.10 g, 56% ). 'H N R (400 MHz, CDCh) δ 4.31-4.42 (m, 1H), 3.13 (s, 3H), 3.03 (s, 3H), 2,00-2.28 (m, 2H), 1.04 (t, ./ 7.24 Hz, 3H).

STEP 2: (2S)-2-(((lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-12'-METHYL-13 ^! ,13'- DIOXTDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO| SiAPHTHALENE-l ,22'- | 2( !ί>Χ Λ| i 3 ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]ΊΈΤΚΑΕΝ]-7'-ΥΕ)ΟΧΥ)-Ν,Ν-ϋ1ΜΕΊ� �ΥΤΒυΤΑΝΑΜΙΟΕ OR (2R)-2-(((lS,3'R,6¾,7'S,8¾12'R)-6-CHL()R()-12^METHYL-13',1 3'-DI()XIDO- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[ 13]TH1A[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLBUTANAMIDE

The title compound was prepared in an analogous manner to that described in Example 404 using (R)-2-bromo-N,N-dimethylbutanamide and (S)-2-bromo- Ν,Ν-dimethylbutanamide (Step 1), and was isolated as the first eluting isomer from the reversed phase preparatory HPLC separation. ^" Ή NMR (500 MHz, CDCb) δ 7.90-7.98 (m, !il}.7.65-7.73 (m, ill).7.18 (dd../ 2.20.8.56 Hz, IH), 7.09 (d, ./ 2.2(5 Hz, 1H), 6.89-6.94 (m, 1H), 6.85-6.88 (m, 1H), 6.78 (d,■/ i.7! Hz, ill).5,69-5,78 (m, 111).5.55 (dd, ,/ ' ^■ ) I 7.15,53 Hz, !!!}.4.21-4,30 (m, !!!). 4,01-4.13 (m, 3H), 3.81 (d, ,7=15,16 Hz, IH), 3.66-3,74 (m, 2H), 3.22 id../ 14. IS Hz, 2H), 3,10-3.15 (m, 3H), 3.06 (s, 3H), 2.92-3.01 (m, 2H), 2.70-2.84 (m, 2H), 2.50-2,58 (m, IH), 2,34-2.43 (m, IH), 2,22-2,32 (m, 2H), 2.04 (d, J=13.94 Hz, IH), 1.91-2.00 (m, 2H), 1.73-1.87 (m, 4H), 1.61-1,72 (m, 2H), 1.58 (d, .7=6,85 Hz, 3H), 1.37 (t, J=12.72 Hz, IH), 0.93 (t, J=7.46 Hz, 3H). m/z (ESI, +ve ion) 698.2 { \ I · Π ) .

EXAMPLE 420.2-(((lS,3'R,6'R,7 ^, S,8 ^! E,12 ^! R)-6-CHLORO-12'-METHYL-13 ^! ,13'- DIOXIDO- 15'-OXO-3,4-DTHYDRO-2H-SPIRO[N APHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'- YLACET AMIDE

The title compound was prepared in an analogous manner to that described in Example 404 using 2-chloro-N, -dimethylacetamide instead of 2-chloro-N- methylacetamide. ¾ NMR (4()0MHz, CD3OD) 07.75 (d,■/ 8,4 Hz, IH), 7.19

(dd, ,/ 2.2, 8,6 Hz, IH), 7.12 (d, ./ 2.2 Hz, IH), 7.01 (dd, ./ 1.6, 8.2 Hz, IH), 6.93 (d, J=8.0 Hz, ill}.6.86 (d, ./ 1.8 Hz, IH), 5.95 - 5.86 (m, IH), 5.62 (dd, J=9.2, 15.3 Hz, IH), 4.23 - 4.04 (m, 5H), 3.90 (dd, ,7=3.5, 9.0 Hz, IH), 3.86 (d, ./ 1 .5 Hz, 111).3.68 id.,/ 14 I Hz, IH), 3.11 (dd, ,7=10,6, 1 .0 I i/, ill).3,06 - 3,01 (m, 3H), 2.97 (s, 3H), 2.88 - 2.72 (m, 211).2,64 - 2.54 (m, ill).2.48 - 2.26 (m, 311). 2,12 id. ,/ 135 Hz, 1H), 1.99 - 1.71 (m, 9H), 1.53 (d, ,/ 7.0 Hz, 3H), 1.50 - 1.41 (m, 1H) m/z (ESI, +ve ion) 670.2 {Vi H ) .

EXAMPLE 421. (2R)-2 ((lS,3¾,6'R,7 ^f S,8'E,I2'R)-6-CHLORO-12'-METHYL- 13V13'-DIOXIDO-15'-OXO-3,4-DLHYDRO-2H-SPIRO[NAPHTHAI^

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ -«0 ¹⁹ ^ ⁴ ]PE rrAC [8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLBUTANAMIDE OR (2S)-2-(((lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -METHYL-13 ^, ,13 ^, -DIOXIDO- 15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHraALENE-l,22'- |;20]OXA[13iTHLA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8,24]TETRAEN]-7 ^, -YL)OXY)-N,N-DIMETHYLBUTANAMIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 419, Step 2, Ή NMR (500 MHz, CDCLs) δ 7.91-7.96 (m, 1H), 7.67-7.73 (m, 1H), 7.19 (dd, ./ 2.20. 8.56 Hz, 1H), 7.09 (d, ./ 2.20 Hz, 1H), 6.90-6.94 (m, ill).6.85-6.89 (m, III .6.79 hi.,/ i 7! Hz, IH), 5.79-5.89 (ra, 1H), 5,52-5.61 (m, 1H), 4.22-4.31 (m, 1H), 4,02-4.12 (m, 2H), 3.98 (dd, ,7=5,62, 8.07 Hz, IH), 3,78-3.87 (m, 2H), 3.68-3.75 (m, IH), 3.23 (d, ./ 1-1.43 Hz, IH), 3.07-3,14 (m, 3H), 2.96-3.06 (m, 2H), 2.94 (s, 3H), 2.70-2.84 (m, 3H), 2.47-2.57 (m, IH), 2.25-2.34 (m, 2H), 2.09-2.19 (m, IH), 1.87-2.08 (m, 3H), 1,73-1.85 (m, 4H), 1,62-1,72 (m, 2H), 1.58 (d,J=6.85 Hz, 3H), 1.38 (t, «7=12.59 Hz, IH), 0.99 (t, J=7.34 Hz, 3H). m/z (ESI, +ve ion) 698.2 (M+H) ⁺ .

EXAMPLE 422.2-(((lS,3'R,6'R,7 ^, S,8 ^! E,12 ^! R)-6-CHLORO-12'-ETHYL-13',13'- DIOXIDO-15'-OX()-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-Y LETHYL)ACETAMIDE

STEP 1: (18,3¾,6'Κ,78,8Έ, 12'R)-6-CHLORO- 12'-ΕΤΉΥΕ-7'-ΗΥΒΚΟΧΥ-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]()XA[13iTHIA[l 4jDIAZATETRACYCLO|14 ³ - ^f \0 ¹⁹ - ²⁴ ;|PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13*-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 719, Step 1 and Step 2 using a racemic mixture of (R)-hept-6-ene-3- sulfonamide (Intermediate EE21) and (S)-hept-6-ene-3-sulfonamide (Intermediate EE212), and the desired products, (lS^TR/R 'S^'E.n'i^-b-chioro- '-ethyl.?*- hydrox'-3,4-dihydro-2H,15 ^, H-spiro|naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracy^

n] - 15 '-one 13 ', 13 '-dioxide as the first eiuting maj or isomer out of preparative reverse phase HPLC. ^! ii NMR (4()()MHz, CD3OD) δ 7.75 (d, J=8.4 Hz, 1H), 7.19 (dd, ,/ 2.0.8,8 Hz, IH), 7.12 (d, 2.2 Hz, IH), 7,00 (dd, ./ I.H.8.0 Hz, IH), 6.93 (d, .7=8.2 Hz, IH), 6.87 (d, ,/ i 6 Hz, IH), 5.90 - 5.82 (m, IH), 5.73 (dd, «7=7.8, 15.1 Hz, IH), 4.21 {dd../ 3.7.7.8 Hz, IH), 4.09 (dd, J=12.I, 14.7 Hz, 2H), 4.02 (dd,J=6.5, 13.5 Hz, IH), 3.85 (d, =15.1 Hz, IH), 3.68 (d,J=14.1 Hz, IH), 3.29 (d, ./ 14.3 Hz, ill).3,08 (dd, ./ 10.( 15.3 Hz, !!!).2.88 - 2,73 (m, 21 \) 2.46 - 2.22 (m, 4H), 2.16 - 2,05 (m, 2H), 2.02 - 1.79 (m, 8H), 1.73 (dd, .7=9.0, 17.6 Hz, ill).1.46 (t, i 26 Hz, 111).1.20 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 599.2 (M+H) ⁺ .

STEP 2: 2-(((l S,3'R,6'R,7'S,8'E,I2'R)-6-CHLORO-i2'-ETHYL-13',13'- DIOXIDO-15'-OXO-3,4-STEP 2: DIHYDRO-2H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O'^lPE TACOSA

[8, 16, 18 ,24] TETR AEN] -7'-YL)OXY)-N-( 1 -METHYLETHYL) ACET AMIDE

The title compound was prepared in an analogous manner to that described in Example 404 using (1 S,3 ^! R,6 ^, R,7'S,8'E,12'R)-6-ch3oro-12'-ethyl-7'-hydiOxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'-

12 ⁽ j aj i |thia| U4|dia/aie!racycioj N.7.2 ⁽ r'-.o ¹¹ ' ^!| !penlacosa|8. i6J8.24i!cirac n]-15'-one 13',13'-dioxide (Example 422, Stepl) and 2-bromo-N- isopropylacetamide, and isolaied by chromatography eluting with a gradient of 0% to 100% EtOAc (containing 0.1 % AcOH) in hexane. ¾ NMR (500 MHz, CD3OD) δ 7.75 (d, J=8.56 Hz, 1H), 7.19 (dd, ./ 2.32.8.44 Hz, 1H), 7.12 (d, ./ 2.20!!/.1H), 6.96-7.03 (m, 1H), 6.91-6.95 (m, Hi), 6.83 (d, J=1.96 Hz, 1H), 5.86-5.96 (m. 111).5,59-5.69 (m, 1H), 4.02-4,10 (m, AW).3.92 (dd, ,/ .167.9,05 Hz, 1H), 3.83-3.88 (m, 3H), 3,68 (d,J=14.18 Hz, ill).3,30 id,../ 14.18 Hz, 1H), 3.09 (dd, J=10.39, 15.28 Hz, 1H), 2.73-2.87 (m, 2H), 2.55-2.64 (m, 1H), 2.39-

2.48 (m, 1H), 2.28-2.38 (m, 2H), 2.07-2.17 (m, 2H), 1.92-2.02 (m, 3H), 1.82-1.92 (m, 5H), 1.72-1.81 (m, IH), 1,41-1.49 (m, 1H), 1.17-1.22 (m, 9H). m/z (ESI, +ve ion) 698.2 (M+H) ⁺ . EXAMPLE 423, (1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-12'-ETHYL-7'-((l-

METHYL-lH-l,2,4-TRIAZOL-3-YL)METHOXY)-3,4-DIHYDRO-2H,15'H - SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE i.T.i 3'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using (lS,3¾ VR7^,8T^.2 ^! R)-6-chlori 12'-e l-7'-hydroxy- 3,4-dihydro-2H,15'H-spiro[naphthalene-L22'- [20joxa[13]thia[l,14]diazatetracycfo[14^

n]-15'-one 13',13'-dioxide (Example 422, Step I ) and S-chloromethy -l-methyl- lH-l^-triazole hydrochloride, ¾ NMR (500 MHz, CD3OD) δ 8,39-8.57 (m, IH), 7.74 (d, ./ 8.56 Hz, IH), 7.19 (dd, ./ 2.32.8.44 Hz, IH), 7.12 (d, J=2.20 Hz, 1 IT), 6.96-7,02 (m, IH), 6.87-6.95 (m, H), 6,81 id../ I.? I Hz, IH), 5,85-5,94 (m, IH), 5.61 (dd, .7=8,93, 15.28 Hz, IH), 4,41-4.57 (m, 2H), 4.03-4.12 (m, 3H), 3,99 (s, 3H), 3.90 (dd, J=3.67, 8.80 Hz, IH), 3.75-3.81 (m, IH), 3.67 (d, J=14.18 Hz, IH), 3.24-3.30 (m, IH), 3.07 (dd, ,7=10.03, 15.41 Hz, IH), 2.71-2.86 (m, 2H), 2.53 (dq,J=3.55, 9,33 Hz, IH), 2.39-2,47 (m, IH), 2.26-2.38 (m, 21 \) 2.06-2,19 (m, 2H), 1,85-2.02 (m, 6H), 1.82 (dd, .7=8,19, 10.39 Hz, 2H), 1,67-1.78 (m, IH), 1.39- 1.50 (m, IH), 1.23 (t, J=7.46 Hz, 3H). m/z (ESI, +ve ion) 694.2 (M+H) ⁺ .

EXAMPLE 424. (lS,3 ^, R,6'R,7 ^! S,8'E,12'R)-6-CHLORO-12'-EraYL-7'-(((3R)-2- OXOTETRAHYDRO-3-FURANYL)OXY)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATCTRACYC^

[8,16,18,24]TETiL E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3¾,6'R,7^,8^I2'R)-6-CHLOR.O-12'-ETI-I X-7'-(((3S)-2- OXOTETRAHYDRO-3-FURANYL)OXY)-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15'-ONE 3', 13'-DTOXIDE

The title compound was prepared in an analogous manner to that described in Example 413, Step 4 using (lS^'I^e'I^TS^'EamH-chloro-l^-ethyl-T- hydroxy-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- !2C)joxa 13]thia[l,14]diazatetrac^

n]-15'-one 13',13'-dioxide (Example 422, Step 1), and isolated as the first eluting isomer from the reversed phase preparatory HPLC. ^! H NMR (500 MHz, CD3OD) 67.75 (d, J=8.56 Hz, IH), 7.18-7.22 (m, ill).7.12 (d, ./ 2.20 Hz, IH), 6.98-7.03 (m, IH), 6,92-6.97 (m, IH), 6.86 (d, .7=1.96 Hz, IH), 5,88-5,99 (m, IH), 5.68 (dd, ./ 8.9,115.28 Hz, IH), 4.35-4.45 (m, 2H), 4,23-4,30 (m, IH), 4.00-4.13 (m, 4H), 3.86 (d, ,7=14,67 Hz, IH), 3.68 (d, .7=14,18 Hz, IH), 3.26-3,33 (m, IH), 3.09 (dd, J=10.15, 15.28 Hz, IH), 2.73-2.88 (m, 2H), 2.63 (dddd, ,/ 2.HL 6.36, 7.89, 12.53 Hz, IH), 2,53 (dq,J=3.67, 9.21 Hz, IH), 2.40-2.48 (rn, IH), 2,29-2,39 (m, 2H), 2,07-2.22 (m, 3H), 1.80-2,04 (m, 8H), 1.68-1.79 (m, IH), 1.41-1,50 (m, IH), 1.21 (t, J=7.58 Hz, 3H). m/z (ESI, +ve ion) 683.2 (M R) .

EXAMPLE 425. (lS,3 ^, R,6'R,7 ^! S,8'E,12'R)-6-CHLORO-12'-EraYL-7'-(((3S)-2- OXOTETRAHYDRO-3-FURANYL)OXY)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'- |2θ!() Λ| I 311 HI Λ| I , N |OIA/.\ Π·. E R.AC VC ^' E C)i 147.20 ^;ί '.ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,12'R)-6-CHLORO-12 ^! -ETHYL-7'-(((3R)-2- OXOTETTRAHYDRO-3-FURANYL)OXY)-3,4-DIHYDRO-2H ₅ 15'H- SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1.14]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13 ^* -DIOXIDE

The title compound was obtained as the later eluting isomer from the reversed phase preparatory HPLC separation in Example 424. ^l H NMR (500 MHz, CD .00} δ 7.74 (d,J=8.56 Hz, IH), 7.16-7.22 (m, IH), 7,12 (s, IH), 7,00 (dd, ./ 1.22.8.07 Hz, IH), 6.89-6.95 (m, 2H), 5.83-5.94 (m, IH), 5.61 (dd,

./ 8.56.15.16 Hz, !!!).4.28-4.40 (m, 3H), 4.24 (dt,J=6.72, 9.11 Hz, IH), 4.05- 4.11 (m, 2H), 4.02 (quin, .7=5.93 Hz, IH), 3.87 id. ,/ 1418 Hz, H), 3.67 (d, 14.18 Hz, IH), 3,29 (d, ./ 14.18 Hz, IH), 3.09 (dd, «7=9.66, 15.28 Hz, IH), 2.72-2.87 (m, 2H), 2.60 (dq, ./ 4.1 .9.05 Hz, IH), 2.35-2.48 (m, 3H), 2.26-2.35 (m, IH), 1.80-2.16 (m, 11H), 1.69-1.79 (m, IH), 1.45 it. J 11.98 Hz, IH), 1.21 (t, ,/ 746 Hz, 3H). m/z (ESI, +ve ion) 683.2 i \\ U) .

EXAMPLE 426, (lS,3¾,6'R,7^,8'E,12'R)-6-CLiLORO-12'-ETHYL-13',13 ^f - DIOXIDO-15'-OXO-3,4-DIHYD O-2H-SίlRO[NAPHlΉALENE-l,22'- [20]OXA[13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24] TETR AEN j - 7 '- YL ACETATE

To a 25-mL round-bottomed flask were added (lS,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6- cMoro-12'-ethyl-7'-hydroxy-3,4-dihydro-2H,15H-spiro^

[20]o¾i[13]thia[l,14]diazatefr^

n]-15'-one 13',13'-dioxide (20 mg, 0.033 mmol, Example 422, Step 1) and acetic anhydride (100 μΐ , 1.06 mmol) in DCM(500 μΐ), and pyridine (200 μΐ, 2.48 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with IN HCl (5mL) and extracted with EtOAc (2 xl 0 mL). The organic solution was separated and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 45%» EtOAc in hexane, to provide the title compound as a white powder. ¾ NMR (400 MHz, CDCh) δ 7.88 (s,

111).7.71 id. J=8.41 Hz, lH), 7.20 (dd, J=2.35, 8.41 Hz, 1H), 7.10 (d, =2.35 Hz, ill).6.84-6.97 (m, 2H), 5.88-5.98 (m, 1H), 5.66 (dd, ./ 8.3!.15.36 Hz, ill).5.33 idd../ 4.2!.8.31 Hz, 111).4,01-4.17 (m, 3H), 3.92 id../ 1 .69 Hz, !H), 3.69-3,77 (ni. 3,22 (d, ./ 14.08 Hz, IH), 3.00 (dd, ./ 9.-19.15.36 Hz, 1H), 2.72-2.85 (m, 2H), 2.50 (dd,J=4.11, 9.39 Hz, IH), 2.17-2.42 (m, 3H), 1.88-2.16 (m, 7H), 1.75- 1.87 (m, 3H), 1.62-1.72 (m, IH), 1.33-1.46 (m, 2H), 1.17-1.26 (m, 3H), 0.80-0.95 (m, 3H). m/z (ESI, +ve ion) 641.2

EXAMPLE 427, (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)~6~CHLORO~! ! ',12'-DIMETHYL- 7 ^, -(((3S)-2-OXOTCTRAHYDRO-3-FURANYL)OXY)-3,4-DIHYDRO-2H, 15 ^! H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE !3',13'-D )XIDE OR

(1 S,3'R,6 ^! R,7'S,8'E, 11 'S.12'R)-6-CHLORO- 11 ', 12 ^! -DLMETHYL-7'-(((3R)-2- OXOTETRAHYDR()-3-FURANYL)OXY)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24] -1 S'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 413, Step 4 using ilS,3'R,6'R,7'S,8'E,H'S,12'R)-6-chloro-7'-hydroxy- 1 Γ.12'-dimethyi-3,4~dihydro~2H,l 5'H-spiro[naphthalene-l,22'- [20] οχα Ι 3 ] ihi a[ U 4] ds aza ^^

n]-15'-one 13',13'-dioxide ( Example 719, Step 2), and isolated as the second elutmg isomer from the reversed phase preparatory HPLC. ¾ NMR (400 MHz, CDCh) δ 8.14 (br. s., IH), 7.69 id. ./ 8.4 ! Hz, IH), 7.18 (dd, J=2.25, 8.51 Hz, IH), 7,09 (d, J-----2A5 Hz, ! ! ! ). 6.84-6.98 (m, 3H), 5.80-5,98 (m, 1 1 1 ). 5.55 (dd, J=9.00, 15.26 Hz, IH), 4.28-4.43 (m, 3H), 4.13-4.26 (m, 2H), 4.03-4.12 (m, 2H), 3.90 (d, J=15.26 Hz, IH), 3.70 (d, J=14.28 Hz, IH), 3.23 (d, J=14.28 Hz, IH), 3.02 (dd. ,/ 10 1 7. 15,26 Hz, IH), 2.65-2,86 (m, 3H), 2.53-2.64 (m, IH), 2.25- 2.45 (m, 2H), 2.08-2,24 (m, 3H), 1.91-2.08 (m, 3H), 1,74-1.90 (m, 31 ! ). 1.60-1.72 (m, IH), 1.50 (d, J=7.24 Hz, 3H), 1.32-1.46 (m, IH), 1.06 (d, J=6.85 Hz, 3H). m/z (ESI, +ve ion) 683.2 ( VI I D ^' .

EXAMPLE 428. (1 S,3'R,6 ^! R,7'S,8'E,1 l'S,12'R)-6-CHLORO-l l',12'-DLMETHYL- 7'-(((3R)-2-OXOTETRAHYDRO-3-FURANYL)OXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(l S,3'R,6 ^, R ₅ 7 ^, S,8¾l l ^, S, 12 ^, R)-6-CIiLORO-l l \12 ^, -DIMETHYL-7 ^, -(((3S)-2- OXOTETRAHYDRO-3-FURANYL)OXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THLA|;i ,14]DIAZATETRACYCLO[ 14.7.2.0 ^3> ^0 ^{! 9} - ²⁴ ]PENTACOSA [8, 16, 18 , 24] - 15 ^! -ONE 13', 13 ^! -DIOXIDE

The title compound was obtained as the first eluting isomer from the reversed phase preparatorv- HPLC separation in Example 427. ¾ NMR (400 MHz, CDCb) δ 8.00 (s, IH), 7.63-7.75 (m, IH), 7.19 (dd, J=2.35, 8.41 Hz, IH), 7.10 (d, ./ 2. 1 Hz, IH), 6.89-6.99 (m, 2H), 6.87 (d, ./ i .56 Hz, IH), 5.82-5.94 (m.111).5,68 (dd, J=9.29, 15.55 Hz, Hi).4.43 (ill../ 2.H4.8.85 Hz, 111).4.27- 4.34 is Mi).4.18-4,27 (m, 2H), 4.12-4.18 (m, IH), 4,05-4.12 (m, 2H), 3.92 (dd, J=3.23, 9.29 Hz, IH), 3.83 (d, J=14.87 Hz, IH), 3.71 (d, J=14.28 Hz, IH), 3.20- 3.27 (m, IH), 3.02 (dd, J=10.07, 15,36 Hz, IH), 2.72-2,84 ins.2H), 2.52-2.63 (m, IH), 2,41-2.51 (m, IH), 2,30-2,40 (m, IH), 2.11-2.25 (m, 3H), 1.96-2,05 (m, 3H), 1,82-1.95 (m, 3H), 1.62-1.71 (m, IH), 1.47-1.52 (m, 3H), 1.35-1,44 (m, IH), 1.06 (d, J=6.85 Hz, 3H). m / (ESI, +ve ion) 683.2 {M ID

EXAMPLE 429. (2S)-2-(((lS,3'R,6 ^, R,7'S,8'E,l l'S,12 ^, R)-6-CHLORO-l Γ,12'- DIMETHYL-13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPTRO[NAPHTHALENE-l,22'-

|20i() A| I 3111 II Λ| I„ I -I |ί)Ι.\/.νΠ: I RAC VCiOl I -1,7.20 ' ".O ¹ '" ¹ |Pi-:N l ACOS A [8, 16, 18,24]TETRAEN] -7'-YL)OXY)-N,N,4-TRlMETHYLPENTAN AMIDE OR (2R)-2-(((lS,3'R,6 ^, R ₅ 7 ^, S,8¾irS,12 ^, R)-6-CHLORO-ll\12 ^, -DIMETOYL-13 DIOXIDO-15'-OXO-3,4-DIHYD O-2H-SίlRO[NAPHTΉAJ,ENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24] '-YL)OXY)-N,N,4-TRIME ^r rHYLPENTANAMIDE

STEP 1 : (R)- 1 -(DIMETHYL AMINO)-4-METHYL- 1 -OXOPENT AN-2-YL

METOANESULFONATE AND (S)- 1 -(DIMETHYL AMINO)-4-METHYL- 1 OXOPENTAN-2-

To a mixture of methanesulfonyl chloride (0.408 ml, 5.28 mmol) and 2- hydroxy-N,N,4-trimethylpentana,mide (0,800 g, 5.02 mmol) in 10 niL of DCM i a 100-mL round-bottomed flask at 0 °C was added a mixture of triethylamine (1 .05 ml, 7.54 mmol) and N,N-dimethylpyridin-4-amine (0.307 g, 2.5 ! mmol) in 10 mL of DCM through an addition funnel. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with IN HCl (10 mL) and extracted with Et?,0 (3 x 20 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over MgSCH. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound (0.250 g, 21 %) as a white solid, m/z (ESI, +ve ion) 238.2 (M+H) ⁺ .

STEP 2: (R)-2-BROMO-N,N,4-TRTMETTHYLPENTANAMIDE AND (S)-2- BROMO-N,N,4-TRIMETHYLPENTANAMIDE

\ Br \ Br

To a 25-fflL round-bottomed flask were added (R)- l -(dimethylamino)-4- methyl-1 -oxopentan-2-yl methanesulfonate and (S)- 1 -(dimethylammo)~4~methyl- l -oxopentan-2-yl methanesulfonate (100 mg, 0.421 mmol) and bromide salt of sodium ( 131 mg, 1.26 mmol) in DMF (4.2 mL). The reaction mixture was stirred at 50°C overnight. The reaction was quenched with aq. NH ₄ C1 (5 mL) and extrated with EtOAc (2x10 mL). The organic layer was combined and dried over MgS0 ₄ . The solvent was removed. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 40% EtOAc in hexane, to provide the title compound (76 mg, 81 %) as a colorless oil. 'H NMR (500 MHz, CDCh) δ 4.47-4,59 (m, 1H), 3 ,09-3.20 (m, M l ). 2.95-3.05 (m, 3H), 1.94-2.05 (m, 2H), 1.72-1 , 85 (m, IH), 0.89- 1.00 (m, 6H).

STEP 3. (2S)-2-(((l S,3 ^, R,6'R,7 ^! S,8 ^, E,i rS,12'R)-6-CHLORO-i r, 12'- DIMETHYL-13 ^! ,13'-DIOXID()-15'-()XO-3,4-DIHYDR()-2H- SPTRO[NAPHTH ALENE- 1 ,22'- | 2 ⁽ >X A | i ? I U Π Λ | ί i J l i^f AZ.Vf l : E R AC VCE C)l i J 7.2 ϋ ^{; ί'} .ϋ | ΡΗ\ i ACOS A [8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N,4-TRIMETHYLPENTANAMIDE OR (2R)-2-(((lS,3 ^, R,6 ^, R,7 ^, S,8Έ,ll ^, S,12 ^, R)-6-CHLORO-11 12 ^, -DIMETHYL-13 ^, ,13 ^, -

DIOXIDO- 15'-QXQ-3,4-DIHYDRQ-2H-SPiRQ[NAPHTHALENE- 1 ,22'- [2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N,4-TRIMETHYLPENTANAMIDE

The title compound was prepared in an analogous manner to that described in Example 404 using (lS^'R^'R 'S^'E,! l'S^'RK-cMoro^'-hydroxy-l l',12'- dirnethyl-3,4-dihydro-2H,15'H-spirofnaphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetrac ^

n]-15'-one 13',13'-dioxide ( Example 719, Step 2) and (R)-2-bromo-N,N,4- trimethylpentanamide and (S)-2-bromo-N,N,4-trimethylpentanamide (Step 2), and isolaied as the major isomer from the reversed phase preparatory HPLC. ¾-I N.V1R (500MHz, CDCb) δ 7.92 (s, ill).7.69 (d, J=8.3 Hz, IH), 7.18 (dd, J=2.2, 8.6 Hz, 1H), 7.09 (d, ,/ 2.2 Hz, IH), 6.94 - 6.91 (m, ill .6.89 - 6.86 (m, ill).6.82 (d, ./ 1.7 Hz, IH), 5,80 - 5.69 (m, IH), 5.53 (dd, ,/ 95. 15.2 Hz, H), 4,36 - 4,28 (m, IH), 4,23 (dd, ./ 2.7.10.8 Hz, III).4.12 - 4.02 (m, 2H), 3,81 (d, ./ 15.2 Hz, IH), 3.70 (d, ./ 1-1.4 Hz, IH), 3.64 (dd, ./ 3.2.9.3 Hz, lit).3.22 (d, ./ 14.2 Hz, IH), 3.10 (s, 3H), 3.05 (s, 3H), 3.02 - 2.93 (m, IH), 2.86 - 2.70 (m, 2H), 2.61 - 2,52 (m, IH), 2.34 - 2.23 (m, H), 2,21 - 1,58 (m, I3H), 1.50 (d, J=7.3 Hz, 3H), 1.41 - 1.34 (m, IH), 1.07 (d, .7=6,8 Hz, Mil 0.91 (d, .7=6.8 Hz, 3H), 0,85 (d, J=6.4 Hz, 3H). m/z (ESI, +ve ion) 740.4 (M+H)+.

EXAMPLE 430. (2S)-2-(((lS,31 ,6'R,7'S,8'E,l rS,12'R)-6-CHLORO-l l',12'- DIMETHYL-13 ^! ,13'-DIOXID()-15'-OXO-3,4-DIHYDR()-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZATETRACYCLO[14,7.2,0 ³ '^0 ¹⁹ - ²⁴ ]i ^{^} ^^

18. i 6. i 8.24! r!-;i-RA!:N I-7'.ΥΙ. )XY }··Ν.Ν··01 \!!·ΊΊ ΙΥΙ Bl l ANAVIU)!: OR

(2R)-2 ((lS,3'R,6¾,7'S,8¾irS,12 ^, R)-6 :HLORO-11^12'-DIMETHYL-13',13'-

DIOXIDO- 15'-OXO-3,4-DTHYDRO-2H-SPIRO[NAPHTH ALENE- 1 ,22'- [20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLBUTANAMIDE

The title compound was prepared in an analogous manner to that described in Exampie 404 using (l S,3 ^, R,6 ^, R,7'S,8'E,i rS,12'R)-6~chloro-7 ^, ~hydiOxy-l l ^, ,12'- dimethy3-3,4-dihydro-2H,15'i-I-spiro|naphthalene-l,22 ^! - [20]oxa[13]thia[l ,14]diazatetrac>'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'-dioxide ( Example 719, Step 2) and (R)-2-bromo-N,N- dimethylbutanamide and (R)-2-bromo-N,N-dimethylbutanarnide (Exampie 419, Step 1), and isolated as the first eluting isomer out of reversed phase preparatory HPLC, ³ H NMR (400MHz, CDsOD) δ 7.72 (d, .7=8.4 Hz, H), 7.17 (dd, J=2.2, 8.5 Hz, 1H), 7.10 (d, ./ 2.2 Hz, i l l ). 7.03 (dd, J=1.9, 8.1 Hz, IH), 6.91 (d, ./ 8.2 Hz, I H), 6.86 (d, ./ 1 .8 Hz, IH), 5.90 - 5.78 (m, IH), 5.60 (dd, ./ 9.4. 15.5 Hz, I H), 4.25 - 4.17 (m, IH), 4,09 - 4.03 (m, 3H), 3.88 (dd, ./ 2.9. 9.4 Hz, 11 1 ). 3,81 (d, .7=14.3 Hz, 1 1 1 ). 3,67 - 3,62 (m, IH), 3.27 (s, IH), 3.16 - 3.05 (m, 4H), 2,91 (s, 3H), 2.87 - 2.72 (m, 2H), 2.58 - 2.47 (m, IH), 2.35 - 2.25 (m, IH), 2.15 - 1.57 (m, 1 1 1 ). 1.43 (d, ./ 7.2 Hz, 3H), 1.04 (d,■/ 6.5 Hz, 3H), 1.00 (t, ./ 7.4 Hz, 31 1 ). m (ESI, +ve ion) 712,3 (M+H) ⁺ .

EXAMPLE 431 , (2R)-2-(((l S,3'R,6'R,7'S,8'E, 11 ^* S, 12'R)-6-CHLORO- 1 1 ', 12'- DIMETHYL-1.T. 1 3 '-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8, ^' 16, 18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLBUTANAMIDE OR (2S)-2-(((lS,3'R,6 ^! R,7'S,8 ^, E,i rS,12'R)-6-CHLORO-l l',12 ^! -DIMETHYL-13',13'- DIOXIDO-15'-OX()-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLBUTANAMIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 430. 'HNMR (400MHz, C }}<()}>) δ 7.72 id..7=8.4 Hz, ill).7.16 (dd, J=2,2, 8.5 Hz, Ui).7,10 (d, J=2.3 Hz, IH), 7.03 (dd, J=1.9, 8.1 Hz, IH), 6.90 (d, ./ 8.2 Hz, IH), 6.84 (d, ./ i.8 Hz, Ml). 5.82 - 5.67 (m, IH), 5.62 - 5.52 (m, IH), 4.25 - 4.13 (m, 2H), 4.07 (s, 2H), 3.77 (d, ./ 15.3 Hz, IH), 3,70 (dd, ./ 3.!.9,0 Hz, IH), 3.63 id. ,/ \ A 7 Hz, IH), 3.15 (s, 3H), 3.13 - 3.04 (m, IH), 3.02 (s, 3H), 2.86 - 2.67 (m, 2H), 2.59 - 2.47 (m, IH), 2.39 - 1.56 (m, 15H), 1.43 (d, ./ 7.2 Hz, 3H), 1.06 (d, ./ 6.8 Hz, 3H), 0.92 (t, ./ 7.3 Hz, 3H). m/z (ESI, +ve ion) 712.3 (M+H) ⁺ .

EXAMPLE 432. (1 S,3¾,6¾,7'S, 12 ^! S)-6 :HLQR0-7'-HYDRQXY-12 ^* - (TRIFLUOROMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- l. - [20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |;i6,18,24jTRIEN]-15'-()NE 13',13 ^! -DI()XIDE OR (1S,3'R,6'R,7 ^! S,12'R 6- CHLORO-7 ⁱ -HYDROXY-12'-(TRIFLUOROMETHYL)-3,4-DIHYDRO- 2H, 15 Ή-S PIRO | N APHTH ALEN E- 1 ,22' -

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',!3'-DIOXiDE

STEP 1: 2,2 ₅ 2-TRIFLUORO-N,N-BIS(4- METHOXYBENZYL)ETHANESULFONAMIDE

To a 250-mL round-bottomed flask were added bis(4- methoxybenz l)amine (4.23 g, 16.4 mmol, Inermediate EE11) and triethylamine (4,57 mL, 32.9 mmol) in DCM (40 mL). 2,2,2-trifluoroethanesulfonyl chloride (2.00 g, 1.0 mmol) was added to the solution at 0°C slowly. The white precipitate came out. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with IN HC1 (10 mL) and extracted with EtOAc (2x50 mL). The combined EtOAc solution was concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eiuting with a gradient of 10% to 60% EtOAc in hexane, to provide the title compound (1.10 g, 25 % yield), m/z (ESI, +ve ion) 406.0 (M+Na) ⁺ .

STEP 2: (S)-l,i,l-TRlFLUORO-N,N-BIS(4-METHOXYBENZYL)PENT-4- ENE-2-SULF ON AMIDE AND (R)-l ₅ l. l-TRIFLUORO-N,N-BIS(4- METHOXYBENZYL)PENT-4-ENE-2-SULFONAMIDE

To a dried vial containing 1.0 g of mol ecular sieve 5 A were added tns(dibenzyiideneaeetone)dipaliadiuni (0) chloroform adduct (32 mg, 0.031 mmol), allyl methyl carbonate (0.173 mL, 1.49 mmol), 2,2,2-trifluoro-N,N-bis(4- methoxybenzyl)ethanesulfonamide (500 mg, 1.24 mmol) and (-)-binap (77 nig, 0.12 mmol) in 3 mL of THF. The mixture was stirred at 50 °C for 6 hrs. The mixture was cooled to ambient temperature and filtered through a pad of celite. The filtrate was concentrated. The crude material was pun lied by chromatography ihrough a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 20% to 40% EtOAc in hexane, to provide the title compound (500 mg, 91 % yield) as slight yellow oil m/z (ESI, +ve ion) 466.0 (M+Na) ⁺ .

STEP 3: (S)~ 1, 1 , 1 -TRIFLUOROPENT-4-ENE-2-SULFON AMIDE AND (R)- 1,1,1 -TRIFLUOROPE -4-ENE-2-SULFONAM1DE

To a solution of (S)- 1,1,1 -trifluoro-N,N-bis(4-methox>'benzyl)pent-4-ene- 2-sulfonamide and (R)- 1,1,1 -trifluoro-N ,N-bis(4-methoxybenzy l)pent-4-ene-2- sulfonamide (300 mg, 0.676 mmol) in 6 mL of DCM was added thioanisole (0.794 mL, 6.76 mmol), followed by trifluoroacetic acid (2.0 ! mL, 27. 1 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 24 h, and concentrated. The crude material was purified by chromatography through a Redi- Sep pre-packed silica gel column (40 g), eluting with a gradient of 20% to 80% EtOAc in hexane, to provide the title compound (96 mg, 70% yield) as a white solid. ¾ NMR (400 MHz, CDCh) δ 5.78-6.06 (m, 1H), 5.15-5.39 (m, 2H), 4.96 (br. s., 2H), 3.68-3.90 (m, IH), 2.74-3.02 (m, 2H).

STEP 4: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l -HYDROXYBUT-3-EN-l- YL)C YCLOBUTYL)METHYL)-N-(((S)- 1,1,1 -TRIFLUOROPENT-4-EN-2- YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l -HYDROXYBUT- 3-EN-l -YL)CYCLOBUTYL)METHYL)-N-(((R)- 1,1,1 -TRIFLUOROPENT-4- EN-2-YL)SULFONYL)-3',4,4' ₅ 5-TETRAHYDRO-2H,2H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- C

To a solution of (S)-6 ^, ~cliloro-5~(((lR,2R)~2 ^» ((S)-l-hydroxybut-3-en-l- yl)cyclobutyl)methyl)-3 4,4 5-tetrahydro-2H,2'H-spiro[benzo b][ l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (50.0 mg, 0.104 mmoi, Intermediate AA13A) and (S)~ 1,1,1 -trifluoropent-4-ene-2-sulfonamide and (R)- 1 ,1,1 -trifluoropent-4- ene-2-sulfonamide (42.2 mg, 0.207 mmoi) in 3 mL of DCM (5 niL) at 0°C were added N,N~dimethylpyridin-4-amine (DMAP) (25.3 mg, 0.207 mmoi) and n-(3- diniethylaniinopropyl)-n'-ethylcarbodiimide hydrochloride (39.8 mg, 0.207 mmoi). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc (30ml), washed with IN HC1 (5ml), brine (3ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g), eluting with a gradient of 0% to 100% EtOAc in hexane

(containing 0.1% HOAc), to provide the title compounds (50.0 mg, 72 %). m/z (ESI, +ve ion) 667,0 ί VI H ) . STEP 5: (lS,3 ^f R,6'R,7'S,9'Z,I2'S)-6-CHLORO-7'-HYDROXY-12'-

(TRIFLUOROMETHYL)-3,4-DIHYDRO-2H ₅ 15 ^, H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.() ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [9, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13 ^! -DIOXIDE AND

(lS,3 ^, R,6'R,7 ^! S,9'Z,12'R)-6-CHLORO-7'-HYDROXY-12'-

(TRJFLUOROMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9, 16, 18,24]TETRAEN] - 15'-ONE l .T. 13 '-DIOXIDE AND

(Ιβ^'Κ,ό'Κ,Τ'β^Έ,η ί-ό-εΗΕΟΚΟ-Τ'-ΗΥΟΚΟΧΥ-^'- (TRIFLUOROMETHYL)-3,4-DIHYDRO-2I-L15'H-SPIRO[NAPHTHALENE- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [9,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE AND

(l S^'R _^ e'R^'S^'^^'^-e-CHLORO-T'-HYDROXY- '- (TRIFLUOROMETHYL)-3,4-DIHYDRO-2H,15 ^, H-SPIRO[NAPHTHALENE- 1,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [9, 16, 18,24]TETRAEN]-15'-ONE 13", 13 -DIOXIDE A 50 mL round bottom flask was charged with (S)-6'-chloro-5-(((l R,2R)~

2- ((S)~ 1 -hydroxybut-3-en- 1 -yl)cy clobuty l)methyl)-N-(((S)- 1,1,1 -trifluoropent-4- en-2-yl)sulfon}4)-3',4,4',5 etraliydro-2H,2H-spiro[benzo[b] [ l,4]oxazepine-3,r- naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-

3- en-l -yl)cyclobutyl)methyl)-N-(((R)-l, I ,l-trifluoropent-4-en-2-yl)sulfonyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxamide (50 mg, 0.075 mmol) in toluene (30 mL), and the solution was subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs 2 ^nd generation (9.4 mg, 0.015 mmol) in toluene (1 mL) at room temperature. The mixture was stirred at 101 °C under nitrogen for 60 min. Air was blown through the solution for 5 min to deactivaie the catalyst, and then the mixture was concentrated. The crude dark oil was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10 % to 50% EtOAc (containing 0.1% AcOH) in hexanes to provide the title compounds (30 mg, 63 %). m/z (ESI, +ve ion) 639.0 (M+H) ⁺ .

STEP 6: (l S,3'R,6'R,7'S,12'S>6-CHLOR()-7'-HYDROXY-12'- (TRIFLUOROMETHYL)-3,4-DIHYDRO-2H, 15 Ή-SPTRO [ APHTHALENE- l. -

[20]OXA[13]TO1A[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [16,18 24]TRIEN]-15'-ONE 13', 13"-DIOXIDE OR ( ! S,3'R,6'R,7'S, 12'R)-6- CHLORO-7 ^! -HYDROXY-12'-(TM:FLUOROMETHYL)-3,4~DiHYDRO- 2H, 15'H"SPIRO| NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i ,14]DlAZATETRACYCLO[ 14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13 -DIOXIDE

A mixture of (l S,3'R,6'R 7 ^, S,9 ^, Z,12 ^, S)-6-chloro-7 ^, -hydroxy-12'- (trifluorornethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,2 2'- [20]oxa[13]thia[l ,14]diazatetra<yclo^

n]-15'-one 13',13'-dioxide and (lS,3'R,6 ^, R,7'S,9'Z,12'R)-6-cliioro-7 ^, ~hydiOxy-12'- (trifluoromethyl)-3,4-dihydfo-2H,15'H-spiro[naphthalene-l,22 '- [20]oxa[13]thia[ l, 14]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[9, 16,18,24]tetrae n]-15'-one 13 ^* ,B'-dioxide and (l S,3 ^, ,6'R,7 ^! S,9Έ,12 ^, S)"6"Chlol -7 ^, -hydroxy-12 ^, - (trifluoromethyl)-3,4-dihydro-2H,15'H-spifo[naphthalene-l,22 '- [20]oxa[13]thia[l ,14]diazate1ra^

n]-15'-one 13',13 ^! ~dioxide and (l S,3'R ) ^! R 7'S,9^E/12^R)-6~chk)ro-7 ^! -hydroxy-12'- (trifluoromethy l)-3 ,4-dihy dro-2H, 15 'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[ l, 14]diazatetra^^

n]-15'-one 13', 13'-dioxide (30 mg, 0,047 mmol) and platinum (iv) oxide (6.4 mg, 0.028 mmol) in EtOAc (2 mL) were stirred under H ₂ at ambient temperature for 30 min. The solid was filtered off and filtrate was concentrated. The crude material was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μΐΏ column; Phenomenex, Torrance, CA: gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compound as the first eluting isomer. ^l H NMR (400MHz, CDCb) δ 9.71 (br. s., Mi).7.66 (d, J=8.6 Hz, IH), 7,35 - 7.26 (m, 2H), 7.18 (dd, ,7=2,2, 8.5 Hz, IH), 7.10 (d, J=2.3 Hz, IH), 6.98 (d, J=8.2 Hz, IH), 4.53 - 4.34 (m, IH), 4.22 - 4.05 (m, 2H), 3.70 (d, ./ 6.7 Hz, IH), 3.65 - 3.50 (m, 2H), 3.38 (d, ,/ 13, 1 Hz, 2H), 2,85 - 2.68 (m, 2H), 2.51 (br. s„ IH), 2,40 - 1.14 (m, 1811). m/z (ESI, +ve ion) 6 1.0 (M+H) ⁺ .

EXAMPLE 433. (1 S^'R _^ e'R 'S. 'R^e-CHLORO-T'-HYDROXY-^'- (TRIFLUOROMETHYL)-3,4-DIHYDRO-2H,15 ^, H-SPIRO[NAPHTHALENE- 1,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15'-ONE 13",13'-DIOXIDE OR (lS,3'R,6'R,7'S,12'S)-6- CHLORO-7'-HYDROXY-12'"(TRlFLUOROMETHYL)-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 18,24] TRIEN] - 15 '-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 432, Step 6. Ή NMR (400MHz, CDCb) δ 10.61 (br. s., IH), 7,70 (d, J=8.4 Hz, IH), 7,49 (dd, ./ 2.0. 8.2 Hz, IH), 7.32 - 7.25 (m, IH), 7.18 (dd, ,/ 2.3.8.4 Hz, IH), 7.09 (d, ./ 2.2 Hz, IH), 6,98 (d, ,/ 8.4 Hz, IH), 4.39 (br, s., !H), 4.16 - 4.08 (m, IH), 4.07 - 3.98 (m, IH), 3,81 (d, ./ 1 .7 Hz, IH), 3.69 - 3.57 (m, 2H), 3.20 - 3,04 (m, 2H), 2.77 (br, s., 2H), 2.40 - 1.15 (m, 1 !!). m/z (ESI, +ve ion) 641.0 (M il) .

EXAMPLE 434. (1 S,3'R,6 ^f R,7'S,8 ⁱ E,12 ⁱ S)-6-CHLORO-7'-HYDROXY-12'- (METHOXYMETHYL)-3,4-DIHYDRO-2HJ5'H-SPIRO[NAPHTHALENE- 1 ,22'-

| 2( >X A | i ? I ! f Π Λ | ί i J l i^f AZ.Vf l : E R AC VCE C)l i J 7.2 ϋ ^{; ί'} .ϋ | ΡΗ\ i ACOS A

[ 8, 16, 18,24]TETRAEN]- '-ONE 13 VI 3'-DIOXIDE

STEP I : ( )-METHYL 2-(N,N~BIS(4~

METHOXYBENZYL)SULFAMOYL)HEX-5-ENOATE AND (S)-METHYL 2- (N,N-BIS(4-

To a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l-sulfonamide (3,00 g, 7.70 mmol Intermediate EE 19) in THF (40 mL) at -78 °C was added butyllithium solution, 2.5 M in hexanes (3.39 ml,, 8.47 mmol). The resulting mixture was stirred at -78 °C for 5 min, and then chlorocarbonic acid, methyl ester (0.583 mL, 7.55 mmol) was added. The reaction was stirred at -78 °C for another 20 min, and allowed to warm up to ambient temperature overnight. The reaction mixture was diluted with saturated NH Cl (lOmL), and extracted with EtOAc (2 x30 mL). The organic extract was washed with satui ^' ated NaCl ( 10 mL) and dried over MgSCH, filtered and concentrated in vacuo to give the title compound as a colorless oil (3,40 g, 99%). m/z (ESI, +ve ion) 470.2 (M+Na) ⁺ . STEP 2: (R)-l -FTYDROXY-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2- SULFONAMIDE AND (S)-l -HYDROXY -N,N-BIS(4- METHOXYBENZYL)HEX-5-ENE-2-SULFON AMIDE

To a 100-mL round-bottomed flask were added (R)-methyl 2-(N,N-bis(4- methoxybenzyl)sulfamoyl)hex-5-enoate and (S)-methyl 2-(N,N-bis(4~ methoxybenzyl)sulfamoyl)hex-5-enoate (2.20 g, 4,92 mmol) and lithium borohydride (0.214 g, 9.83 mmol) in THF (24.6 ml). A few drop of water was added. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with IN HCI (10 mL) and water, and extracted with EtOAc (2 x20 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgS04, filtered and concentrated in vacuo to give the crude material. The cmde material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 20% to 60% EtOAc in hexane, to provide the title compound (1.30 g, 63%). m/z (ESI, +ve ion) 442.2 (M+Na) .

STEP 3: (R)-l-METHOXY-N,N-BTS(4-METI-IOXYBENZYL)HEX-5-ENE-2- SULFONAMIDE AND (S)-l -METHOXY-N,N-BIS(4- METHOXY BENZ YL)HEX-5 -EN E-2- SL ⁵ LFON AMIDE

To a 25 -mL round-bottomed flask were added (R)~ 1 -hydroxy -N,N-bis(4- methoxybenzyl)hex-5-ene-2-sulfonamide and (S)-l -hydroxy -N,N-bis(4- methoxybenzyl)hex-5-ene-2-sulfonamide (190 mg, 0.453 mmol) and iodomethane (0.563 mL, 9.06 mmol) in THF (5.7 mL), and then potassium tert-butoxide, 1.0 M solution in tetrahydrofuran (0.444 mL, 0.444 mmol) slowly over 30 min. The reaction mixture was stirred for lh. The reaction mixture was diluted with IN HCl (lOmL), and extracted with EtOAc (2 x l OmL). The organic solution was concentrated. The crude material was purified by chromatography through a Redi- Sep pre-packed silica gel column (40 g), eluting with a gradient of 20% to 40% EtOAc in hexane, to provide the title compound (0.170 g, 87 % yield), m/z (ESI, +ve ion) 456.2 (M+Na) ⁺ .

STEP 4: (R)-l-METHOXYHEX-5-ENE-2-SULFONAMlDE AND (S)-l- METHOXYHEX-5- -2-SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 3 using (R)-l-methoxy-N,N-bis(4-memoxybenzyl)hex-5- ene-2-sulfonamide and (S)-l-methoxy-N,N-bis(4-rnethoxybenzyl)hex-5~ene-2~ sulfonamide . m/z (ESI, +ve ion) 194.2 { \ I · I ! )

STEP 5: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l -

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(((S)-l-METHOXYHEX-5- EN-2-YL)SULFONYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SPIRO BENZO[B] [1 ,4 ]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE AND (S)-6"-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(((R)-l-METHOXYHEX-5- EN-2-YL)SULFONYL)-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO B j [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)c lobu d)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (Intermediate ΑΑΓ1Α) and (R)-l-methoxyhex-5-ene-2 -sulfonamide and (S)-l-methoxyhex-5- ene-2-sulfonamide. m/z (ESI, +ve ion) 643.2 (M+H) ⁺ .

STEP 6: (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12'- (METHOXYMETHYL)-3,4-DIHYDRO-2H,15 ^, H-SPIRO|NAPH ^r THALENE-

1,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ' ".U ^1* " ¹ |PH\ i ACOSA [ 8, 16, 18,24 JTETRAEN] -15'-ONE 13 ^! , 13 ^* -DIOXIDE

The title compound was prepared in an analogous manner to that described m Example 432, Step 5 using (S)-6'-chloro-5-(((lR ₅ 2R)-2-((S)-l- hydrox\'allyl)cyclobutyl)methyl)-N-(((S)-l-methoxyhex-5-en-2 -yl)sulfonyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7- carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobuiyl)m.ethy

3',4,4',5~tetraliydro-2H,2'H spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7- carboxamide, and isolated as first eluting isomer from the reversed phase preparatory HPLC separation. ¹ 11 NMR (400MHz, CDCb) δ 8,19 (s, IH), 7,70 (d, ./ 8.4 Hz, IH), 7.19 (dd, J=2.2, 8.4 Hz, IH), 7.09 (d, ./ .2.2 Hz, IH), 6.97 - 6.86 ins.3H), 5.87 - 5.76 (m, IH), 5.75 - 5.66 (m, IH), 4.29 (dd, ./ 4.O.8.9 Hz, IH), 4.20 (dd, ,/ 45.6.7 Hz, IH), 4, 15 - 3.99 (m, 3H), 3.96 - 3.88 (ra, IH), 3,82 (d, J=15.5 Hz, IH), 3,71 id.../ 14.- Hz, IH), 3.45 (s, 3H), 3.24 id../ 14.3 Hz, IH), 3.03 (dd,J=8.5, 15.4Hz, ill).2,86 - 2,66 (m, 211).2.51 - 1.58 (ra, 1 !!).1.41 (t, J=12.2 Hz, 1H). m/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 435. (lS^'^e'i^T'S^'Ea^^-e-CHLORO-T'-HYDROXY- '- (METHOXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8 ₅ 16.18,24]TETRAEN]-1 '-ONE 13',13'-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 434, Step 6. Ή NMR (400MHz, CDCb) δ 8.33 (br. s., 1H), 7.64 (d, J=8.4 Hz, 2H), 7.15 (dd, J=2.2, 8.4 Hz, 111).7.10 (d, ,/ 22 Hz, ill).6.99 - 6.86 (m, 2H), 5,68 (dd, ./ 4.5.15.8 Hz, I Hi.5.56 - 5.38 (m, ill).4.31 - 4.10 (m, 3H), 4.04 (dd, ,7=4,1, 10.6 Hz, 2H), 3,97 - 3.86 (m, 2H), 3.76 (d, J=14.7 Hz, 1H), 3.46 (s, 3H), 3.38 - 3.25 (m, 1H), 3.14 (d, ./ 15.8 Hz, III).2.86 - 2.67 ins.2H), 2.60 - 2.43 (m, 2H), 2.40 - 1.05 ins.13H). m/z (ESI, +ve ion) 615.2 {M H}

EXAMPLE 436. (iS,3'R,6 ^, R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-N,N~ DIMETHYL- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |Ρ!·Λ l ACOSA [8, 16, 18,24]TETRAENE] - 12'-CARBOXAMIDE 13', 13'-D10XIDE

STEP 1 : (R)-2-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL

ENOIC ACID AND (S)-2-(N,N-BIS(4- METHOX -5-ENOIC ACID

To a 100-niL round-bottomed flask were added (R)-methyl 2-(N,N-bis(4- methoxybenzyl)sulfamoyl)hex-5-enoate and (S)-methyl 2-(N,N-bis(4- methoxybenzyl)sulfamoyl)hex-5-enoate (1.10 g, 2.46 mmol, Example 434, Step 1) in THF (10.2 ml) and sodium hydroxide (0.393 g, 9.83 mmol) inWater (2.05 ml). The reaction mixture was stirred at 50°C overnight. The reaction mixture was cooled to ambient temperature and neutralized with IN HC1, and extracted with EtOAc (2 x20 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSCu, filtered and concentrated in vacuo to give the crude material. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc (containing 0.1% AcOH) in hexane, to provide the title compounds (0.64 g, 60%). m/z (ESI, +ve ion) 456.2 (M+Na) ⁺ .

STEP 2: (R)-2-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-N,N- DIMETHYLHEX-5-EN AMIDE AND (S)-2-(N,N-BIS(4- METHOX AMIDE

To a 250-mL round-bottomed flask were added (R)-2-(N,N-bis(4- methoxybenzyl)sulfamoyl)hex-5-enoic acid and (S)-2-(N,N-bis(4- methoxybenz l)sulfamoyl)hex-5-enoic acid (228 mg, 0.526 mmol), dipea (184 μΐ, 1.05 mmol), 2-(lh-benzotriazol-l-yl)-l,l,3,3-tetrameth} ⁷ luronium

hexafluorophosphate (299 mg, 0.789 mmol) and dimethylamine, 2.0 M solution in tetrahydrofuran (789 ul, 1.58 mmol) in DMF (5.3 ml). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (l OOmL), and extracted with DCM (2 xl OOmL). The organic solution was concentrated. The crude material was purified by chromatography through a Redi- Sep pre-packed silica gel column (40 g), eluting with a gradient of 30% to 80% EtOAc in hexane to provide the title compound (200 mg, 83% yield), m/z (ESI, +ve ion) 483.2 (M+Na) ⁺ .

STEP 3: (R)-N,N-DIMETHYL-2-SULFAM:0YLHEX-5-ENAMIDE AND (S)- N,N-DIMETHYL-2- -5-ENAMTDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 3 using (R)-2-(N,N-bis(4-methox\'benzyl)sulfamoyl)-N,N- dimethylhex-5-enamide and (S)-2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N- dimethylhex-5-enamid. m/z (ESI, +ve ion) 221.2 (M+H) ⁺ .

STEP 4: (S)-6'-CHLORO-N-(((S)-l -(DIMETHYLAMINO)- 1 -OXOHEX-5-EN- YL)SULFONYL)-5-(((lR,2R)-2-((S)-l -

HYDR0XYAL;LYL)CYCL0BU L)METHYL)~3V4,4',5-TETRAHYDR0~ 2H,2'H-SP1R0 [BENZO [B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE AND (S)-6'-CHLORO-N-(((R)-l-(DIMETHYLAMINO)-l- OXOHEX-5-EN-2-YL)SULFONYL)-5-(((lR,2R)-2-((S)-l - HYDROXY ALLYL)CYCLOBU L)METHYL)-3',4,4',5-TETRAfTYDRO-

2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE-3, -NAPHTHALENE]-7-

CARBOXAMIDE

The title compounds were prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S)-l - h}'-droxyallyl)cyclobu 4)m.ethyl)~3 ^! ,4,4',5-tetrahydro-2H,2 ^! H- spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (Intermediate, AAl 1 A) and (R)-N,N-dimethyi-2-sdfamoylhex-5-enamide and (S)-N,N- dimethyl-2-sulfamoylhex-5-enamide. m/z (EST, +ve ion) 670.2 (M+H) ⁺ .

STEP 5: (lS,3 ^, R,6'R,7'S,8'E,12'S)-6-CHLORO-7 ^! -HYDROXY-N,N-DIMETHYL-

15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'-

| 20 j X A| Π Ι 1 HI A| I .. i 1 | OI.\/.\ Π·. ΓΚΑίΎί ^' ί .01 i -1.7.2 0 ^; ".ϋ ^{1 :} ' |ΡΗ\ i ACOSA

[8, 16, 18,24] TETRAEN E] - 12'-CARBOXAMIDE 13', 13'-D10XIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-6'-ch]oro-N-(((S)-l -(dimethylamino)-l -oxohex- 5-en-2-y!)sulfonyS 5 ((lR,2R)-2~((S^

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3,r-naphthalene]-7- carboxamide and (S)-6'-chloro-N-(((R)- 1 -(dimethyl amino)- 1 -oxohex-5-en-2- yl)sulfonyl)-5-(((l R,2R)-2-((S)-i -hydroxy altyl)cyclobutyl)methyl)-3 ^, ,4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b | [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxamide, and isolated as first eluting isomer from the reversed phase preparatory HPLC separation. ¹ 1 1 NMR (500MHz, CDCb) δ 8,35 (br. s., iH), 7.70 (d, J=8.6 Hz, IH), 7.19 (dd, J-2.2, 8.6 Hz, i l l ). 7.10 (d, ./ 2.2 Hz, IH), 6.98 - 6.80 (m, 3H), 5.83 - 5.68 (m, 2H), 5.58 (dd,■/ 2.7. 10.3 Hz, IH), 4.32 - 4.23 (m, ill).4.17 - 4.05 (m, 2! I ).3,84 (d, ,/ 1 .2 Hz, Hi).3.72 (d, 14.4 Hz, III).3.38 (s, Mi).3.24 (d, .7=14.2 Hz, IH), 3.11 (s, 3H), 3.01 (dd, 7=9.3, 15.4 Hz, 1H), 2.87 - 2.64 (m, 3H), 2.53 - 2.25 (m, 3H), 2.09 - 1.49 (m, 10H), 1.41 (t, J=12.7 Hz, 1H). EXAMPLE 437, (1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7'-HYDROXY-N,N- DIMETHYL-15'-OXO-3,4-DIHYDRO-2H-SPIRO[ ^

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18 ,24]TETRAENE] - 12'-C ARBOX AMIDE 13 ', 13 '-DIOXID

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 436, Step 5. ^" Ή NMR (500MHz, CDCh) δ 8.92 (br. s., IH), 7.72 (br. s., IH), 7.64 (d, J=8.6 Hz, IH), 7.15 (dd, J=2.1, 8.4 Hz, IH), 7.11 (d, J=2.0Hz, IH), 7.03 -6.97 (m, IH), 6.95 - 6.90 (m, IH), 5.66 (dd, ./ 4.2.15.6 Hz, !!!).5.47 - 5.29 (m, 2H), 4.35 - 4.22 (m, 2H), 4.19 - 4.06 (m, IH), 3,90 (d, ,/ 4.6 Hz, IH), 3.82 (d, =7=13.9 Hz, IH), 3.42 (s, 3H), 3.29 (d, .7=13,9 Hz, IH), 3.18 - 3,03 (m, 4H), 2.89 - 2.70 (m, 3H), 2.65 - 1,20 (m, 1 !!).

EXAMPLE 438, (1 S,3'R,6'R,7'S,8'E, 12"S)-6-CHLORO- 12'- (DIFLUOROMETHYL)-7'-HYDROXY-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13 13'-DIOXIDE OR

(1S,3'R,6 ^! R,7'S,8 ^, E,12 ^, R)~6~CHL0R0-12 ^! ~(D1FLU0R0METHYL)~7 ^, ~

HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO|NAPH ^r rHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

STEP 1 : (R)-N,N-BIS(4-METHOXYBENZYL)-l-OXOHEX-5-ENE-2- SULFONAMIDE AND (S)-N,N-BIS(4-METHOXYBENZYL)-l-OXOHEX-5- ENE-2-SU

In a 250 mL round-bottomed flask with stirbar was charged with (R)-l- hydroxy-N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide and (S)-l -hydroxy - N,N-bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide (0.730 g, 1.74 mmol, Example 434, Step 2) in 20 mL of DCM. To this solution was added dess-martin periodinane (1.11 g, 2.61 mmol). The reaction mixture was stirred at ambient temperature for 4 hrs. The reaction mixture was diluted with saturated Na_S2C solution (30mL), and extracted with Et ₂ 0 (2 x50 mL). The combined organic solution was further washed with saturated NaHCCb and brine, and dried over MgS€>4, concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 50% EtOAc in hexane, to provide the title compound (0.700 g, 96% yield) as a cololess oil. m/z (ESI, +ve ion) 440.2 (M+Na) ⁺ .

STEP 2: (R)-l , l-DIFIXORO-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2- SULFONAMIDE AND (S)-l ,l-DIFLUORO-N,N-BIS(4- METHOXYBENZYL)HEX-5-ENE-2-SULFONAMlDE

To a 100-mL round-bottomed flask were added (R)-N,N-bis(4- methoxy benzyl)- 1 -oxohex-5-ene-2-sulfonamide and (S)-N,N-bis(4- methoxybenzyl)-.l -oxohex-5-ene-2-sulfonamide (0.230 g, 0.55 ! mmol) and diethylaminosulfur trifluoride (0.29 ml, 2.2 mmol) in DCM (5.5 ml), and then

EtOH, 200 proof, tax-free (3.22 μΐ, 0.055 mmol). The reaction mixture was stirred at ambient temperature overnight, and neutralized with saturated NaHCC solution, and extracted with EtOAc (2 x 20mL). The organic extract was washed with saturated NaCl (10 mL), dried over MgSC filtered and concentrated in vacuo to the title compound as a yellowish oil. m/z (ESI, +ve ion) 462.2 (M+Na) ⁺ .

STEP 3: (R)- 1 , 1 -DIFLUOROHEX-5-ENE-2-S ULFON AMIDE AND (S)-l,l- DIFLUOROHEX-5-EN -2-SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 3 using (R)-l,l-difluoro-N,N-bis(4-methoxybenzyl)hex-5- ene-2-sulfonamide and (S)-l,l-difluoro-N,N-bis(4-methoxybenzyl)hex-5-ene-2- sulfonamide. ¾ NMR (400 MHz, CDCh) δ 5.80 (tdd, ,/ 6.65. 10,32, 17,07 Hz, 1H), 4.99-5.24 (m, 2H), 4.55-4.82 (m, 2H), 3.48 (dtdd, .7=3.33, 5,97, 7.46, 19.34 Hz, 1H), 2.51-2.70 (m, i l l ). 2.28-2.47 (m, 21 1 }. 2.00-2.20 (m, 2H).

STEP 4: (S)-6'-CHLORO-N-(((S)-l , 1 -DIFLUOROHEX-5-EN-2- YL)SULFONYL)-5 -((( 1 R,2R)-2-((S)- 1 - HYDROXY ALLYL)CYCLOBU L)METHYL)-3',4,4',5-TETRAlTY ^' DRO- 2H,2H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7- C ARBOXAM1DE AND (S)-6'-CHLORO-N-(((R)- 1 , 1 -DIFL UQRQHEX-5 - YL)S ULFONYL)-5 -((( 1 R,2R)-2-((S)- 1 -

HYDROXY ALLYL)CYCLOBUTY ^T L)METHYL)-3',4,4',5-TETRAHYDRO-

2H,2H-SPIRO[BENZO[B] [L4]OXAZEPINE-3,r~NAPHTHALENE]~7~

CARBOXAMIDE

The title compound was prepared in an analogous manner to that described m Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)c 'clobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, ~naphthalene]-7-carboxylic acid (Intermediate, AA11A) and (R)-l, l -difluorohex-5-ene-2-sulfonamide and (S)-l,l-difluorohex-5- ene-2-sulfonamide. m/z (ESI, + ve ion) 649.2 i .Yi H ) .

STEP 5: (lS,3'R,61l,7^,8¾12 ^! S)-6~CHLORO-12'~(DIFLUOROMETHYL)-7 ^, ~ H YDROXY-3.4-DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACQSA [8,I6,18,24]TETiLAEN]-15'-QNE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7 ^, S,8'E, 12'R)-6-CHLORO-12'-(DIFLU()R()METOYL)-7 ^! - HYDROXY-3,4-DIHYDRO-2H, 15 Ή-SPTRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-1 S'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-6'-chloro-N-(((S)-l, l-difluorohex-5-en-2- yl)suIfonyl)-5-(((l R,2R)-2-((S)-l -hydroxy altyl)cyclobutyl)methyl)-3 ^, ,4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)~6 ^! -chloro-N~(((R)-l,l~d^

1 -hydroxy allyl)cyclobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, l'-naphthalene]-7-carboxamide, and isolated as first eluting isomer from the reversed phase preparatory HPLC separation. ^! H N.V1R (500MHz, CDCb) δ 8.80 (br. s., 1H), 7.70 (d, ./ 8.6 Hz, 1H), 7.19 (dd, ./ 2. 1 . 8.4 Hz, 1 H), 7.22 - 7.16 (m, I I I . 7.10 id. J=2.0 Hz, Hi), 7.04 - 6.89 (m, 3H), 6.75 - 6.29 (m, 1H), 5,86 - 5.50 (m, 2H), 4.54 - 4.36 (m, 1H), 4.22 - 4.06 (m, 3H), 3.82 - 3.63 (m, 2H), 3,27 (d, «7=13.9 Hz, 1H), 3.11 (d, J=9.8 Hz, 1H), 2.87 - 2.67 (m, 2H), 2.52 - 1.06 (m, 15H). m/z (ESI, +ve ion) 621.2 (M+H) ^f .

EXAMPLE 439, ( 1 S,3'R,6'R,7'S,8'E, 12"S)-6-CHLORO- 12'- (ETHOXYMETHYL)-7'~HYDROXY-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ I4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6~CHLORO-12 ^, ~(ETHOXYMETHYL)-7 ^, -HYDROXY- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtl SJTO Atl ^DIAZATETRACYCLOtl^y^.O'^.O^^lPE TACOSA [8,16,18,24]TETR^\EN]-15'-ONE 13',13 ^! "D10X1DE

STEP 1 : (R)- 1 -ETHOXY-N,N-BTS(4-METHOXYBENZYL)HEX-5-ENE-2- SULFONAMIDE AND (S)-l-ETHOXY-N,N-BIS(4-METHOXYBENZYL)HEX- 5-ENE-2-SULFONAMIDE AND N,N-B1S(4-METH0XYBENZYL)HEXA-1,5- DIENE-2-SULFONAMIDE

The title compounds were prepared in an analogous manner to that described in Example 434, Step 3 using lodoethane. m/z (ESI, +ve ion) 470.2 (M+Na) ⁺ and m/z (ESI, +ve ion) 424.2 { \\ ^■ \a) ^' .

STEP 2: (R)-l-ETHOXYHEX-5-ENE-2-SULFON AMIDE AND (S)-l- ETHOXYHEX-5-ENE-2-S ULFON AMIDE AND HEXA- 1 ,5-DIENE-2-

SULFON

The title compound were prepared in an analogous manner to that described in Example 432, Step 3 using (R)-l -ethoxyhex-5-ene-2-sulfonamide and (S)-l-ethoxyhex-5-ene-2-sulfonamide and hexa-l,5-diene-2-sulfonamide. m/z

\ e ion) 208,2 (M+H) ⁺ and m z (ESI, +ve ion) 184.2 (M+Na) ⁺ . STEP 3: (S)-6 ^* -CHLORO-N-(((S)-l-ETHOXYHEX-5-EN-2-YL)SULFONYL)-5- (((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL) - 3' _; 4' ₅ 5-TETl AHYDRO-2H,2'H~SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE ] -7 -C ARB OXAMI D E AND (S)-6'-CHLORO-N-(((R)- 1 - ETOOXYHEX-5-EN-2-YL)SULFONYX)-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMIDE AND (S)-6'-CHLORO-N-(HEXA-l,5- DIEN-2-YLSULFONYL)-5 - ((( 1 R,2R)-2-((S,E)- 1 -HYDROXYHEX-2-EN- 1 - YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en-l-yl)cyckjbutyr)methyl)-3',4,4',5-tetrahydro-2H,2 ^f i-I- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (Intermediate, AA12A) and (R)-l-ethoxyhex-5-ene-2-sulfonamide and (S)-l-ethoxyhex-5-ene-2- sulfonamide and hexa-1 ,5-diene-2-sulfonamide. m/z (ESI, +ve ion) 699.2 (M+H) ⁺ and m/z (EST, +ve ion) 653,2 { V! H} ^'

STEP 4: (lS,3 ^, R,6'R,7 ^, S,8 ^! E,12 ^! S)-6~CHLORO-12'~(ETHOXYMETHYL)-7'- H YDROXY-3.4-DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACQSA [8,I6,18,24]TETiLAE ]-15'-QNE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-12'-(ETHOXYMETHYL)-7'-HYDROXY- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '6 0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-6'-chloi -N-(((S)-l-ethoxyhex-5-en-2- y l)suifony f)-5 -((( 1 R,2R)-2-((S,E)- 1 -hy droxyhex-2-en- 1 -y l)cy ciobut}' l)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, l '-naphthalene j~7~ carboxamide and (S)-6'-chloro-N-(((R)-l-ethoxyhex-5-en-2-yl)sulfonyl)-5- (((IR,2R)-2-((S,E)-l-hydroxyhex-2-en-l-yl)cyclobuty )methyl)-3',4,4 ^* ,5- tetrahy dro-2H,2'H-spiro| benzoj b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)-6'-chloro-N-(hexa-l,5-dien-2-ylsulfony])-5-(((lR ₅ 2R)-2-((S,E)-l- hy droxyhex-2-en- 1 -y l)cy clobuty l)methy l)-3 ',4 ,4',5 -tetrahy dro~2H,2 ^! H~

spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide, and isolated as the second eluting isomer from the reversed phase preparatoiy HPLC separation. ³ H NMR (400MHz, CDCh) δ 8.18 (s, H), 7.70 (d, ./ 8.4 Hz, ill).7, 19 (dd, ./ 2.2, 8.5 Hz, 1H), 7.09 (d, ./ 2.2 Hz, IH), 6.96 - 6.88 (m, 3H), 5.90 - 5.77 (m, ill).5.75 - 5.63 (m. III).4.28 (qd, ./ 4.2.8.8 Hz, III).4.21 (dd, ,/ 4.3.6.8 Hz, ill).4.15 - 3.94 (m, 4H), 3,82 (d, ,/ 1 .7 Hz, IH), 3.7! (d, 14.3 Hz, III).3.66 - 3.55 is 2H), 3.25 (d, J=14.3 Hz, IH), 3,04 (dd, J=8.5, 15.4 Hz, IH), 2.89 - 2.65 (m, 2H), 2.52 - 1.59 (m, 14H), 1.42 (t, J=11.6 Hz, IH), 1.24 (t, J=7.0 Hz, 3H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 440. (18,3¾,6¾,7 ^! 8,8Έ,12¾)-6-0ΗίΟ*Ο-12'- (ETHOXYMETHYL)-7'~HYDROXY-3,4-DIHYDRO-2H,15 ^, H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( !ί>ΧΛ| i 3! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ^;ί '.ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-DI0X1DE OR

(lS,3¾,6 ^! R,7^,8T,12'S)-6-CHLORO-12'-(ETHOXYMETHYL)-7' -r¾' ^r DROXY- 3,4-DIHYDRO-2H, 15 ^* H-SPIRO[NAPHTH ALENE- 1 ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16.18,2 -15'-ONE 13',13'-DIOXIDE

The title compound was obtained as the third eluting isomer from the reversed phase preparatory HPLC separation in Example 439, Step 4. Ή NMR (400MHz, CDCb) 68.10 (br. s., IH), 7.68 - 7.49 (m, 2H), 7.16 (dd, ./ 2.2.8.5 Hz, IH), 7.10 (d, ./ 2.3 Hz, IH), 6.93 (s, 2H), 5.74 - 5.62 (m, IH), 5.48 id../ 14.5 Hz, IH), 4,28 - 3.92 (m, 8H), 3.76 (d, ./ 1 .9 Hz, H), 3.65 - 3,56 (m, 2H), 3.33 (d. J=14.9 Hz, 111).3.15 id, ./ Hz, !!!).2.85 - 2.69 (m.2H), 2.61 - 2,44 (m, 2H), 2.40 - 1.06 (m, 15H). m/z (ESI, +ve ion) 629,2 iV! H)

EXAMPLE 441. (lS,3'R,6 ^! R,7 ^* S,8 ^! E)-6-CHL()R()-7'-HYDROXY-12'- METHYLIDENE-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N ΑΡΗΤΉ ALENE- 1 ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE

The title compound was obtained as the first eluting isomer from the reversed phase preparatory HPLC separation in Example 439, Step 4. ^" Ή NMR (500MHz, CDCb) δ 8.33 (s, 1H), 7.70 (d, «/=8.6 Hz, 1H), 7.18 (dd, J=2.2, 8,3 Hz, IH), 7.09 (d, J=2.0 Hz, 1H), 6.99 - 6.91 (m, 2H), 6,87 (br. s., 1H), 6.73 (s, 1H), 6.04 (s, III).5.83 - 5.60 ins.2H), 4.16 (dd, ./ 4.2.7,3 Hz, III).4.09 (q, ./ 12,2 Hz, 2H), 3.75 - 3,63 (m, 2H), 3,27 (d, ,/ 1 .2 Hz, IH), 3.12 (br, s., III).2.86 - 2,71 (m, 2H), 2.67 - 2.54 (m, 2H), 2.47 - 2,29 (m, 4H), 2,05 - 1.19 (m, 9H). m/z (ESI, +ve ion) 583.2 { \ I · Π } .

EXAMPLE 442, (lS,3 ^! R,6'R,7'S,8 ^, E,12 ^, S)-6-CHLORO-7'-HYDROXY-12 ^! ~(2- METHOXYETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- |;20]OXA[13iTHL4[l,14jDL4ZATETRACYCLO|14.7.2,0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,12'R)-6-CHLORO-7 ^! -HYDROXY-12'-(2- METHOXYETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-L22'- [20]OXA[13]THIA[1,14]DIAZATCTRACYCLO[14.7.2.0 ³ '«0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

STEP 1 : 3-CHLORO-N,N-BIS(4-METHOXYBENZYL)PROPANE-l-

SULFON AMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step I using 3-chloropropanesulfonyl chloride, m/z (EST, +ve ion) 420.2 (M+Na) ⁺ .

STEP 2: 3-METHOXY-N,N-BIS(4-METHOXYBENZYL)PROPANE- 1 - SULFONAMIDE

To a 100-mL round-bottomed flask were added sodium methoxide, 0.5 M in methanol (23.4 mL, 11.7 mmol) and 3-chloro-N,N-bis(4- methoxybenzyl)propane-l -sulfonamide (3.10 g, 7.79 mmol) in DMSO (10 mL). The reaction was stirred at 50 °C overnight. The reaction mixture was diluted with IN HC1 (10 mL), and extracted with Et ₂ 0 (2 x30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgS0 ₄ , filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 30% to 70% EtOAc in hexane, to provide the title compound (2.40 g, 78 % yield) as a yellow oil. m/z (ESI, +ve ion) 416.2 (M+Na) ⁺ .

STEP 3 : (R)-l -METHOXY-N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-3- SULFONAMIDE AND (S)-l -METHOXY-N,N-BIS(4- METHOX -6-ENE-3-SULFON AMIDE

The title compound was prepared in an analogous manner to that described in Example 434, Step 1 using 3-methoxy-N,N-bis(4-methoxybenzyl)propane-l- sulfonamide and 4-bromobut-l -ene, and purified by chromatography eluting with a gradient of 15% to 40% EtOAc in hexane. m/z (ESI, +ve ion) 470.2 (M+Na) ⁺ .

STEP 4: (R)- 1 -METHOXYHEPT-6-ENE-3-SULFONAMIDE AND i S}- 1 · METHOXYHEPT-6- -3-SULFONAMTDE

The title compound were prepared in an analogous manner to that described in Example 432, Step 3 using (R)-l-methoxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (S)-l -methoxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide. m/z (ESI, +ve ion) 230.2 (M+Na) ⁺

STEP 5: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -HYDROXYHEX-2-EN- 1 - YL)C YCLOB UTYL)METHYL)-N-(((S) - 1 -METHOXYHEPT-6-EN-3 - YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAM1DE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN- 1 -YL)CYCLOBUTYL)METHYL)-N-(((R)- 1 - METOOXYHEPT-6-EN-3-YL)SULFONYL)-3^4,4^5-TETRAHYDRO-2H,2TI- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en-l-yl)c 'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo[b] [ 1 ,4] oxazepine-3 , 1 '-naphthal ene] -7-carboxy lie acid (Intermediate, AA12A) and (R)-l-methoxyhept-6-ene-3-sulfonamide and (S)-l-methoxyhept-6- ene-3-sulfonamide. m / (ESI, +ve ion) 699.2 (M+H) ⁺ .

STEP 6: (l S,3'R,6'R,7'S,8'E,12'S)-6~CHLORO-7 ^! ~HYDROXY-i2'-(2- ME ^r rHOXYETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22 '- pOlOXAI lSlTHIAI l.MlDIAZATETRACYCLOiM.T^.O'^.O^^lPENTACOSA [8, i 6, 18,24]TETRAEN] - 15'-ONE 13 ^! , 13'-DiOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-

ME^ΉOXYETHYL)-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPH HALE^ ^Γ E-l ₅ 22 ^, - [20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[147 ³ "* 0 ^{] 9} ^ ⁴ ]PENTACOSA [8, 16, 18 , 24] TETRAEN] - 15 ^! -ONE 13', 13 ^! -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l -hydroxj'hex-2- en-l-yl)c lobu d)methyl)-N-(((S)-l-methoxyhept-6-en-3-yl)su]fonyl)-3',4,4', 5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxamide and (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l -hydroxyhex-2-en-l- yl)(yclobu1yl)me l)-N-(((R)-l-methoxyhept-6-en-3-yl)sulfonyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxamide, and isolated as the first eluting isomer from the reversed phase preparatory HPLC separation. ^! H NMR (400 Mi!/. ΠΧ i.) δ 8, 19 (s, IH), 7,70 (d, ./ 8.4 Hz, Hi).7.19 (dd, =2.3, 8.4 Hz, IH), 7.09 (d, ./ .2.2 Hz, IH), 6.92 (s, 3H), 5.94 - 5.81 (m, IH), 5.77 - 5.67 (m, IH), 4.33 - 4.18 (m, 2H), 4.14 - 4.03 (m, 2H), 3.82 (d, ,/ 141 Hz, IH), 3.75 - 3.60 (m, Ml).3.40 (s, Ml).3.24 (d, 143 Hz, IH), 3.03 (dd, ,7=9,3, 15.4 Hz, IH), 2,88 - 2.67 (m, 2H), 2.51 - 1.60 (m, 16H), 1,41 (t, ./ 12.4 Hz, IH). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 443. (1 S,3'R,6 ^! R,7 ^* S,8'E, 12'R)-6-CHLORO-7'-HYDROXY-l 2'-(2- METOOXYETOYL)-3,4-DTHYDRO-2H,15'I-I-SPIRO[NAPT-m-iALENE-l,22 '- [20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 12'S)-6-CHLORO-7'-HYDROXY- 12"-(2-

METHOXYETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22' - |2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2.0 · ^, '.0 ^|: " ¹ |P1-M ^' .\C<)SA [ -15'-ONE 13 ^! ,13'-DIOXIDE

The title compound was obtained as the second elutmg isomer from the reversed phase preparatory HPLC separation in Example 442, Step 6. 'H NMR (400MHz, CDC] 3 δ 8.12 (br. s„ IH), 7,68 - 7,47 (m, 2H), 7.16 (dd, ,/ 22.8.4 Hz, IH), 7.10 (d, ,7=2,2 Hz, IH), 6.93 (s, 2H), 5.73 (dd../ 4.5.15.8 Hz, IH), 5.55 - 5.34 (m, IH), 4.32 - 4.18 (m, 2H), 4.15 - 3.88 (m, 4H), 3.83 - 3.59 (m, 4H), 3.42 (s, Ml).3.40 - 3.28 (m, 2H), 3.17 (d, ./ 1 .0 Hz, IH), 2.80 - 2.72 (m, 2H), 2.56 - 2,36 (m, 4H), 2.25 (br, s., H), 2, 10 - 1.35 (m, 9H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ , EXAMPLE 444. (1 S,3'R,6'R,7'S,8'E, 12'S)~6~CHLQRO~7'~METHQXY- 12'- (METHOXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE-

122'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOtM.y^.O'^.O^^lPE TACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using (iS,3'R,6'R,7'S,8'E,i2'S)-6-chloro-7'-hydroxy-12 ^! - (methoxyniethyl)-3,4-dihydro-2H,15'H-spiro|napiithalene-l,22 '- [20]oxa[13]thia[l,14]cUazatetracyclo^

n]-15'-one 13',13'-dioxide ( Example 434, Step 6, the first eluting isomer) and iodomethane. ¾ N.V1R (500MHz, CDCh) δ 7.99 (s, Ml).7.70 (d, ./ 8. Hz, 1H), 7.19 (dd, ./ 2.3.8.4 Hz, III).7.09 (d, ./ 2.0 Hz, 1H), 6.96 - 6.91 (m, III).6.90 - 6,86 (m, Hi).6.8! (d, ,/ i 7 Hz, III).5.90 - 5.78 (m, ill).5,55 (dd, ./ 8.7.15.3 Hz, IH), 4,48 - 4,37 (m, 1H), 4.16 - 4.02 (m, Ml).4.00 - 3,92 (m, 1H), 3.82 (d, J=I4.9 Hz, IH), 3.71 (d, J=14.2 Hz, 1H), 3.65 (dd, J=3 , 8.8 Hz, 1H), 3.45 (s, 3H), 3.29 - 3.18 ins.4H), 2.99 (dd, J=10.1, 15.3 Hz, IH), 2,85 - 2.69 (m, 2H), 2.54 - 1.17 (m, 14H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 445. (1 S,3'R,6'R,7'S,8'E, 12'S)-6-CHLORO-7'-HYDROXY-12'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE-

[20]OXA[13]THL [1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE

STEP 1 : (R)-l-HYDROXYHEX-5-ENE-2-SULFONAMIDE AND (S)-l- HYDROXYHEX-5-E

The title compound was prepared in an analogous manner to that described in Example 432, Step 3 using (R)-l-hydroxy-N,N-bis(4-methoxybenzyl)hex-5- ene-2-sulfonarnide and (S)-l-hydroxy-N,N-bis(4-methoxybenz l)hex-5-ene-2- sulfonamide (Example 434, Step 2), and isolated from chromatography through a Redi-Sep pre-packed silica gel column, eluting with a gradient of 50% to 100% EtOAc in hexane. m/z (ESI, +ve ion) 202.1 { \\ · \a) ,

STEP 2: (R)-l-((TERT-BUTYLDIMETHYLSILYL)OXY)HEX-5-ENE-2- SULFONAMIDE AND (S)- 1 -((TERT-BUTYLDIMETHYLSlLYL)OXY)HEX- 5-ENE-2-SULFON

To a solution of (R)- 1 -hydroxyhex-5-ene-2-sulfonamide and (S)- 1 - hydroxyhex-5-ene-2-sulfonamide (170 nig, 0.948 mmol) in 6 mL of DCM was added tert-butyldimethyisiiyl chloride (157 mg, 1.04 mmol), followed by imidazole (71.0 mg, 1.04 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated. The residue was diluted with IN HCi (lmL) and water (10 mL), extracted with Et ₂ 0 (2 x20 mL). The organic extract was washed with saturated NaCl (10 ml.) and dried over MgS0 ₄ , filtered and concentrated in vacuo to give the title compound (270 mg , 97%) as a colorless oil. m/z (ESI, +ve ion) 316.3 (M+Na) ⁺ . STEP 3: (1 S,3'I^6 ^, R,7 ^, S,8U12'S)-6-CHLORO-12'-(((DIMETHYL(2-METHYL- 2-PROPANYL)SILYL)OXY)METHYL)-7'-HYDROXY-3,4-DIHYDRO-

2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE AND

(lS,3 ^, R,6 ^, R,7 ^, S,8i 2 ^, R)-6-CHLORO-12 ^, -(((DlMETHYL(2-METHYL-2-

PROPANYL)SILYL)OXY)MEra:YL)-7'-HYDROXY-3,4-DIHYDRO-2H,15' H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxyhex-2-en-l-yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spirojbenzojb] [ 1 ,4]oxazepine-3, 1 '-naphihalene]-7-carboxylic acid (Intermediate, AA12A) and (R)-l -((tert-butyldimethylsilyl)oxy)hex-5-ene-2-sulfonamide and (S)-l-((tert-bu v'ldimethylsilyl)oxy)hex-5-ene-2-sulfoiiamide by similar procedures described in Example 432, Steps 4-5, and isolated from

chromatography through a Redi-Sep pre-packed silica gel column, eluting with a gradient of 20% to 50% EtOAc (containing 0.1% AcOH) in liexane. m/z (ESI, +ve ion) 715.2 ( +H) ⁺ .

STEP 4: ί I S.3'R.6'R.7'S.X'i -.. I 2'S )-6-C! i! .ORO-7 ^' -i IV OROXY- 12'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-

|20|() Λ| I 311 HI Λ| I 14 j Of A A ΓΓ. E .AC VC ^' E C)i i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13 VI 3'-DIOXIDE

To a solution of (lS.3 ^, R,6 ^, R,7 ^, S,8¾12 ^, S)-6-chloro-12 ^, -(((dimethyl(2- me1hyl-2-propanyl)silyl)oxy)me1hyl)-7'-hydrox>'-3,4-dihyd ro-2H,15'H- spiro[naphthalene-l,22'-

[20]oxa[13]tMa[l,14]cUazate1rac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13', ! 3'-dioxide and (18,3¾,6'Κ,7'8,8Έ,12Έ)-6-Λ1οΐΌ-12'- (((dimethyl(2-m.ethyl~2~propany

2H,15'H-spiro[naphthalene-l,22'-

[20joxa[13]thia[l,14]diazatetracycfo[14.7

n]-15'-one 13',13'-dioxide (0.038 g, 0.053 mmol) in tetrahydrofuran (0.53 ml) at 0°C was added tetra-N-butylammonium fluoride, 1M solution. In THF (0.106 ml, 0.106 mmol) dropwise, and the reaction mixture was stirred at ambient temperature for lh. The reaction mixture was concentrated. The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μπι column; Phenomenex, Torrance, CA; gradient eiution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide the title compound as the first eluting isomer, ¾NMR (500MHz, CDCh) δ 8.27 (br. s., IH), 7.70 (d, ./ 8.6 Hz, IH), 7.19 (dd, ./ 2,1.8.4 Hz, IH), 7.10 (d, ./ 2.0 Hz, IH), 6.99 - 6.84 (m, 3H), 5.86 - 5.77 (m, IH), 5.76 - 5.66 (m, IH), 4.26 (d, ./ ! i.O Hz, 1 IT), 4.23 - 4.05 (m, 5H), 3,86 - 3.68 (m, 4H), 3.25 (d, 14,4 Hz, IH), 3.04 (dd, J=8.9, 15.3 Hz, IH), 2.86 - 2.68 (m, 2H), 2,50 - 1,36 (m, 14H). m . (ESI, +ve ion) 601.2 (M+H) ⁺ .

EXAMPLE 446, (1 S,3'R,6' ,7'S,8'E, 12"S)-6-CHLORO- 12'- (HYDROXYMETHYL)-7'-METHOXY -3,4-DIHYDRO~2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]()XA[13|THIA[l,14jDL4ZATETRACYCLO|14.7.2.0 ³ -V0 ^l9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-i5'-ONE 13 I 3 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8 ^, E,12 ^, R)~6"CHLORO-12 ^! "(HYDROXYMEraYL)-7'- METHOXY ,4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTHALENE-1,22 ^* -

| 20 !ΟΧ Λ| ΐ : ΐ ! !1 Λ| Κ. ! | ί)!Λ/Λ ! : ΓΗ.Λ( ^' Χ)Ι 1 17.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8, 16, 18, -15'-ONE 13 VI 3'-DIOXIDE

To a 5-mL round-bottomed flask were added sodium hydride, 60% dispersion in mineral oil (3.4 mg, 0.084 mmol) and (Ι β^'Ι ,ό'Κ,Τβ,δΈ,Ι ϊβ)^- chloro~] 2 ^! -(((dimethyl(2-methyl-2-propanyl)silyl)oxy)methyl)-7'- hydro dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa|;i3]thia[ U4]diazatetr^

n]-15 ^* -one l 3', 13'-dioxide and (l S,3'R,6'R,7 ^f S,8'E, 12'R)-6-chloro-i2'-

(((dimethyl(2-methyl-2-propanyl)silyl)oxy)methyl)-7'-hydr oxy-3,4-dihydro

2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[U4]cUazatetracyc^

n]-15'-one 13',13'-dioxide (20 mg, 0.028 mmol, Example 445, Step 3) in 2 mL of THF at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then Mel (3.50 μΐ, 0.056 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with IN HCl (5 mL), and extracted with EtOAc (2 xiO mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgS0 ₄ , filtered and concentrated in vacuo to give the crude material . The crude material was redissolved in 1 mL of THF and treated with tetrabutylammonium fluoride, 1.0 M solution in tetrahydrofuran (0.056 mL, 0.056 mmol) and the mixture was stirred overnight. The reaction mixture was concentrated, and the residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, C A; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide the title compound as the first eluting isomer. Ή NMR (500MHz, CDCb) δ 8.05 (br. s,, i l l ). 7.70 (d, ,/ 8 6 Hz, 1H), 7.19 id. J=8.6 Hz, H), 7.10 (s, IH), 6.96 - 6,80 (m, 3H), 5.84 (d, 4 Hz, IH), 5.56 (dd, J=9.0, 14.9 Hz, IH), 4,38 - 4,27 (m, 2H), 4.24 - 4.16 (m, IH), 4,14 - 4.03 (m, 2H), 3.82 (d, ./ 14.7 Hz, IH), 3.72 (d, J=13.9 Hz, IH), 3.64 (d, ./ 6.1 Hz, IH), 3.24 (s, 4H), 3.06 - 2.94 (m, IH), 2.87 - 2.67 (m, 2H), 2.56 - 1.21 (m, 15H). m/z (EST, +ve ion) 615.2 {\i · H)

EXAMPLE 447. (lS,3'R,6'R,7'S,8'E,12'S)-6-CHL )RO-7'-HYDROXY-12'-((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'- |2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2,0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETP^ENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS,3¾,6'R,7^,8'Fi,12'R)-6-CHLORO-7'-HYDROXY-12'-((2- METHOXYETHOXY)METHYL)-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, Z,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15 ^, H- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,12'R)-6-CHLORO-7'-HYDROXY-12'-((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAtl ^DIAZATCT ACYCLOIMJ^.O'^.O^^lPE TACOSA

[8, 16, 18,24]TETRAEN]- 5'-ONE 13", 13-DIOXIDE

STEP 1 : (R)-N,N-BIS(4-METHOXYBENZYL)-l -(2- METHOXYETHOXY)HEX-5-ENE-2-SULFONAMIDE AND (S)-I

METHOXYBENZYL)- 1 -(2-METHOXYETHOXY)HEX-5-ENE-2-

SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 434, Step 3 using 2-methoxyethyl methanesulfonate. m/z (EST, +ve ion) 500.2 (M+Na) ⁺ .

STEP 2 : (R)-l-(2-METHOXYETHOXY)HEX-5-ENE-2-SULFONAMIDE AND

(S)-l -(2-METHOXYETOOXY)HEX-5-ENE-2-SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 3 using (R)-N,N-bis(4-methoxybenzyl)-l-(2- methoxyethoxy)hex-5-ene-2-sulfonamide and (S)-N,N-bis(4-methoxybenzyl)-l- (2-methoxyethoxy)hex-5-ene-2-sulfonamide. m/z (ESI, +ve ion) 238.2 (M+H) ⁺ . STEP 3: (S)-6*-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l- YL)CYCLOBUTYL)METHYL)-N-(((S)-l-(2-METHOXYETHOXY)HEX-5- EN"2-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR0[BENZ0|;B] [ 1 ,4]0XAZEPINE-3,1 '-NAPHTHALENE]-7- CARBOXAMTDE AND (S)-6'-CHLORO-5-(((l R,2R)-2-((S,E)-l-

HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-N-(((R)-l-(2- METHOXYETHOXY)HEX-5-EN-2-YL)SULFONYL)-3',4,4',5- TETRAHYDRO-2H,2*H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- -7 -C ARB OXAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en ^» yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spir oj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate, AA12A) and (R)-l -(2-me†hoxye†hoxy)hex-5-ene-2-sulibnarnide and (S)-l-(2- methoxyethoxy)hex-5-ene-2-sulfonamide. m/z (ESI, +ve ion) 729.3 (M+H) .

STEP 4: (1 S,3'R,6'R,7'S,8'E, 12 ^, S)-6-CHLORO-7'-HYDROXY-12'-((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14]DIAZATETRACYCLO] 14.7.2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R _s 7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15 ^, H-

SPIRO [NAPHTHALENE- 1,22'- [20]OXA[ 13]THIA[ 1 , 14]DIAZATETRACYCLO[ 14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(l S,3 ^, R,6 ^, R,7 ^, S,8 ^, Z,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8, 16.18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(l S,3'R,6 ^, R ₅ 7 ^, S,8 ^, Z, 12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'~

[20 iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8, 1 6, 18 , 24] TETR AEN 1 - 15'-ONE 13", 13 -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l -hydroxyhex-2- en-l-yl)c^ lobu1\d)me1hyl)-N-(((S)-l -(2-methoxyethoxy)hex-5-en-2-yl)sulfonyl)- 3',4,4',5-tetr ally dro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene j -7- carboxamide and (S )-6'-chloro-5-((( 1 R,2R)-2-((S,E)- 1 -hydroxy hex-2-en- 1 - yl)cyclobu d)methyl)-N-(((R)-l -(2-methoxyethoxy)hex-5-en-2-yl)sulfonyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3,r-naphthalene]-7- carboxamide, and isolated as the first eiuting isomer from the reversed phase preparatory HPLC separation. ^l H NMR (400MHz, CDCh) δ 8.47 (br, s., 1H), 7.70 (d, J=8.6 Hz, IH), 7.18 (dd, J=2.2, 8.5 Hz, 1H), 7.09 (d, J=2,2 Hz, 1H), 7.02 - 6.85 (m, 3H), 5.88 - 5.77 (m, IH), 5.73 - 5.60 (m, IH), 4.27 - 4.18 (m, 2H), 4.15 - 4.01 (m, 4H), 3.86 - 3.65 (m, 4H), 3.61 - 3.55 (m, 2H), 3.41 (s, M l ). 3.27 (d,

,/ 1 4 5 Hz, I H), 3. 15 - 3.03 (m, IH), 2.89 - 2.64 (m, 2H), 2.51 - 1.55 (m, 14H), 1.43 (t, .7=12.0 Hz, IH). m/z (ESI, +ve ion) 659,2 (M+H) ¹ .

EXAMPLE 448. (1 S,3'R,6 ⁱ R,7'S,8'Z,!2'R)-6-CHLORO-7'-HYDROXY-12'-((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, Z,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2- METHOXYE ^r rHOXY)METHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2- METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12 ^, ~((2"

METHOXYETHOXY)METHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTH ALENE- 1 ,22'- [20]QXA[13]THiA[l,14]DL^

[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was obtained as the third eluting isomer from the reversed phase preparatory' HPLC separation in Example 447, Step 4. ¾ NMR (400MHz, CDCh) δ 7.72 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.18 (dd, J=2.0, 8.6 Hz, ill).7.09 (d, ./ 1.8 Hz, 1H), 7.01 (s, 1H), 6.96 id../ 8.2 Hz, IH), 5.66 (hr. s., 1H), 5.56 - .5.41 (m, ill).4,67 (br. s .1H), 4.16 - 4.04 _(m .3H), 3.97 (d, J=13.9 Hz, 3H), 3.79 - 3.53 (m, 5H), 3.38 (s, 3H), 3.26 (d, J=14.3 Hz, IH), 3.11 (dd, J=10.0, 14.9 Hz, IH), 2.90 - 2.65 (in, 3H), 2.43 - 1.18 (m, 14H). m/z (ESI, +ve ion) 659.2 {M il} EXAMPLE 449. 4-(((l S,3'R,6'R 'S,8'E,12'S)-6-CHLORO-7'-METHOXY- 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI M.T^.O'^.O^^lPENTACOSA

[8, 16, 18,24] TETR AEN] - 12'- YL)C ARBONYL)-N,N-DIMETHYL- 1 -

PIPERAZINESULFONAMIDE OR 4-(((l S,3'R,6'R,7'S,8'E,I2'R)-6-CHLORO-7'- METHOXY - 13 ', 13 '-DIOXIDO- 15 '-OXO-3 ,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 ( Γ ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24] TETRAEN] - 12'- YL)C ARBON YL)-N ,N-DIMETHYL- 1 -

PIPER

STEP 1 : N,N-DIMETHYLPIPERAZINE-1 -SULFONAMIDE

HYDROCHLORIDE

To a solution of tert-butyl 4-(cmorosulfonyl)piperazine-l -carboxylate (1.00 g, 3.51 mmol) in DCM (17.6 ml) were added triethylamine (0,977 ml, 7.02 mmol), 4-dimethylaminopyridine (0.215 g, 1.76 mmol) and dimethylamine, 2.0 M solution in tetrahydrofuran (3.51 ml, 7.02 mmol). The solution was stirred at room temperature overnight. The reaction mixture was diluted with IN HCl (lOmL) and extracted with EtOAc (2 xlO mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgS04, filtered and concentrated in vacuo. The crud material was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (1.35 ml, 17.6 mmol). The mixture was stirred overnight, and concentrated. The residue was dissolved in 10 mL of IN HCl and freeze to dry to give the title compound (0.806 g, 100%). m/z (ESI, +ve ion) 194.1 ( M i l ) . STEP 2 : (R)-4-(2-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEX-5- ENOYL)-N,N-DIMETHYLPIPERAZINE-l -SULFONAMIDE AND (S)-4-(2- (N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEX-5-ENOYL)-N,N- DIMETHYL - 1 - SULFONAMIDE

To a 250-mL round-bottomed flask were added (R)-2-(N,N-bis(4- methoxybenz}'l)sulfamoyl)hex-5-enoic acid and (S)-2-(N,N-bis(4- memoxybenzyl)sulfamoyl)hex-5-enoic acid (0.650 g, 1.50 mmol, Example 436, Step 1 ). dipea (0.786 ml, 4.50 mmol), 2-(lh-benzotriazol-l -yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (0.853 g, 2.25 mmol) and N,N- dimethylpiperaziiie-l-sulfonamide hydrochloride (0.344 g, 1.50 mmol) in DMF (10 ml). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with IN HCl (lOmL) and extracted with EteO (2 x 30mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgS04, filtered and concentrated in vacuo to give the title compound (0.852 g, 93%). m/z (ESI, +ve ion) 631.2 (M+Na) ⁺ .

STEP 3: (R)-N,N-DIMETHYL-4-(2-SULFAMOYLHEX-5-

ENO YL)P I PERAZINE- 1 -SULFONAMIDE AND (S)-N,N-DIMETHYL-4-(2-

SULFAMOYLHEX-5-ENOYL)PIPERAZINE- 1 -SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 3 using (R)-4-(2-(N,N-bis(4-methoxybenzyl)sulfamoyl)hex- 5-enoyl)-N,N-dimethylpiperazine- 1 -sulfonamide and (S)-4-(2-(N,N-bis(4- me1hoxybenz\d)sulfamoyl)hex-5-enoyl)-N,N-dimethylpiperazine- l -sulfonamide, m/z (ESI, +ve ion) 391.1 ( +Na) ⁺ .

STEP 4: (S)-6 ^* -CHLORO-N-(((S)-l -(4-( ,N-

DIMETHYLSULFAMOYL)PlPERAZIN-l-YL)-l-OXOHEX-5-EN-2- YL)SULFONTYl.)-5-(((l R,2R)-2-((S,E)-l -METHOXYPE T-2-EN-l-

YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^f H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6'-CHLORO-N-(((R)-l-(4-(N,N- DIMETHYLSULFAMOYL)PIPERAZIN-l-YL)-l-OXOHEX-5-EN-2- YL)SULFONYL)-5 ((lR,2R)-2 (S,E) -METOOXYPENT-2-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '- APHTHALENE] -7-

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-methoxyhex-2- en-l-yl)cyciobuiyi)rnethyl)-3^4,4',5-tetrahydro-2H,2 ^f i-I- spiro [benzo [b] [ 1 ,4] oxazepme-3 , Γ-naphthal ene] -7-carboxy lie acid (Example 724, Step 1) and (R)-N,N-dimethyl-4-(2-sulfamoylhex-5-enoyl)piperazine-l- sulfonamide and (S)-N,N-dimethyl-4-(2-sdfamoylhex-5-enoyl)piperazine-l- sulfonamide.

STEP 5: 4-(((lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^! -METHOXY-13 ^, ,13'- DIOXIDO-lS'-OXO-S^-DIHYDRO^H-SPIROI APHTHALENE-l^^- |2 ⁽ !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24] TETRAEN] - 12'-YL)CARBONYL)-N ,N-DIMETHYL- 1 -

PIPERAZINESULFONAMIDE OR 4-(((lS,3'R,6'R,7'S,8'E,12'R)-6-CHL()RO-7'- METHOXY- 13 ', 13 '-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18 ,24] TET AEN] - 12'-YL)CARBONYL)-N,N-DIMETHYL- 1 - PIPERAZINESULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-6'-chloro-N-(((S)-l-(4-(N,N- dimethylsulfaraoyl)piperazin- 1 -yl)-l -oxohex-5-en-2-yl)sulfonyl)-5-(((l R,2R)-2- ((S,E)-l-methox>φent-2-en-l-yl)c clobut l)meΛyί)-3 ^! ,4,4 ^! ,5-tetrahydro-2H,2Ή- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide and (S)-6'-chloro- N-(((R)-l-(4-(N,N-dimethylsulfaraoyl)piperazin-.l-yl)-l-oxoh ex-5-en-2- yl)sulfonyl)-5-(((lR,2R)-2-((S,E)-l-methoxypent-2-en-l-yl)cy clobufyl)me ^{^} 3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7- carboxamide, and isolated as the first eluting isomer from the reversed phase preparatory HPLC separation. ^! H NMR (500X1!!/. CD3OD) 67.73 id../ 8.6 Hz, IH), 7,17 (dd, ./ 2.1.8.4 Hz, ill).7.11 (s, ill).7.03 - 6.97 (m, ill).6,95 - 6.91 (m, IH), 6.87 (s, IH), 5.81 - 5.71 (m, ill).5.64 (dd, ./ 3.5.9.7 Hz, IH), 5.57 (dd, ./ 8.2.15.3 Hz, IH), 4.19 (d, J=13.9 Hz, IH), 4.12 - 4.01 (m, 3H), 3.91 - 3.78 (m, 2H), 3.74 (dd, ,7=3,4, 7.8 Hz, IH), 3,67 (d, J=14.2 Hz, IH), 3.60 - 3.52 (m, H), 3.45 - 3.36 (m, 3H), 3.28 (s, IH), 3.23 (s, 3H), 3.21 - 3.13 (m, IH), 3.07 (dd, ./ Ι ίί. Ι . 15.3 Hz, Ι Π ). 2.89 - 2,82 (m, 6H), 2.82 - 2,72 (m, 2H), 2.59 - 2.29 ( ni 4H ). 2.14 - 1 ,99 (m, 2H), 1 ,92 (dd, J=7. L 13.4 Hz, 4H), 1.81 - 1.65 (m, 3H), 1 ,44 (t J=12.2 Hz, 1H). EXAMPLE 450, (l S,3'R,6'S,8'E,12'S)-6-CHLORO-12'-(HYDROXYMETOYL)- 3,4-DIHYDRO-2H,15^SPIRO|NAPHTHALENE-l,22'-

[20]OXA[13]TfflA[l,14]DIAZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ⁹ - ²⁴ ]PENTACOSA[ 8,I6, 18,24]TETRAEN]- 15'-ONE 13', 13'-DIOXIDE OR (l S,3'R,6'S,8'Z, I 2'S)-6- CHLORO-12 ^! ~(HYDROXYMETHYL)-3,4-DIHYDRO-2HJ 5'H~

SPIRO[NAPHTHALENE-l,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI M.T^.O'^.O^^lPE TACOSA

[8J 6,18,24]TETRAEN]~iS'~ONE 13', 13 '-DIOXIDE OR (1 S,3'R,6'S,8'E, I 2'R)-6- CHLQRQ-12'-(HYDRQXYMETHYL)-3,4-DIHYDRQ-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0 - ⁶ .0 ⁹ - ²⁴ ]PENTACOS A[ 8,16, 18,24]TETRAEN]- 15 ^* -ONE 13', 13'-DIOXIDE OR (1 S,3'R,6'S,8'Z, 12'R)-6- CHLORO - 12'-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147.2 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

STEP 1 : (S)-TERT-B UTYL 6'-CHLORO-5-(((lR,2R)-2-((E)-2-

METHOXYVINYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 -NAPHTHALENE] - 7-

CARBOXYLATE AND (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2-((Z)-2- METHOXY TNYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

A solution of (methoxymethyl)triphenylphosphonium chloride (1 ,74 g, 5.08 mmol) in THF (10 mL) was cooled to -78 °C. The 2.5 M butyllithium in THF solution (1.36 mi, 3.40 mmol) was added dropwise and the mixture was stirred at -78 °C for 30 min. and then (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2- formylcyciobtm4)methyl)-3',4,4',5--tetrahydro-2H,2'H- spiroj benzoj b] [ 1,4 joxazepine-3, 1 '-naphthalene]-7-carboxylate (0.420 g, 0.847 mmol, intermediate, Intermediate AA1 1 A, Step 20B) in THF (5 ml) was added slowly. The resulting mixture was stirred at -78 °C overnight. Water (lOmL) was added to quench the reaction. The mixture was extracted with diethyl ether (2x30 mL). The combined organics were concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eiuting with a gradient of 0% to 30% EtOAc in hexane, to provide the title compound as a white powder, m/z (ESI, +ve ion) 524.2 (M+H) ⁺ .

STEP 2: (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2S)-2-(2-

OXOE^WL)CYCLOBUTYL)METI-iYL)-3',4,4',5-TETRAIiYDRO-2I-i,2 'i-I- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARB OXYL ATE

To a 25-mL round-bottomed flask were added (S)-teri-butyl 6'-chloro-5- (((l R,2R)-2-((E)-2-methoxyvinyl)c lobutyl)me l)-3 ^, ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate and (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((Z)-2-methoxyvinyl)cyclobuty])me l)-3 4,4\5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, Γ -naphthalene] -7-carboxylate (180 mg, 0.343 mmol), 1 N HC1 (0.515 ml, 0.515 mmol) in 1,4-dioxane (4 ml) and sodium iodide (257 mg, 1.72 mmol). The reaction mixture was stirred at ambient temperature ovemght. The reaction mixture was treated with sodium thiosulfate solution until mixture became clear. The reaction mixture was diluted with water (lOmL) and extracted with Et ₂ 0 (2 xlO mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgS0 ₄ , filtered and concentrated in vacuo to give the crude material. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eiuting with a gradient of 0% to 40% EtOAc in hexane, to provide the title compound (170 mg, 97 % yield) as a colorless oil. m/z (EST, +ve ion) 501.2 (M+H) ⁺ . STEP 3: (S)-5-(((lR,2S)-2-ALLYLCYCLOBUTYL)METHYL)-6'-CPILORO-

3Vlv4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-C AR

To a solution of methyl phenylphosphonium bromide (490 mg, 1.37 mmol) in THF (3 ml) was added potassium tert-butoxide, 1.0 M solution in THF (0.823 ml, 0.823 mmol) and stirred at ambient temperature 30 min, and the mixture was cooled to 0 °C. To this solution was added (S)-tert-butyl 6'-chloro-5- (((l T^2S)-2-(2-oxoethyl)cyclobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate (140 mg, 0.274 mmol) in THF (1.5 ml) slowly. The resulting mixture was stirred at 0 °C for 30 min and then at ambient temperature overnight. The reaction mixture was diluted with IN HC1 (10 mL) and extracted with Et?.0 (2 x30 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over MgSC¼, filtered and concentrated in vacuo. The residue was dissolved in 5 mL of DCM and treated with 2 mL of TFA. The mixture was stirred at ambient temperature for 2h, and then concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide the title compound (100 mg , 81%) as a clear oil. m/z (ESI, +ve ion) 452.2 (M+H) ⁺ .

STEP 4: (S)-5-(((lR,2S)-2-ALLYLCYCLOBUTYL)METHYL)-6'-CHLORO-N- (((S)-l-HYDROXYHEX-5-EN-2-YL)SULFONYL)-3 ^, ,4,4 ^, _: ,5-TETRAHYDRO- 2H,2'H-SPIRO[BENZO B] [ l,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXAMTDE AND (S)-5-(((l R,2S)-2-ALLYLCYCLOBUTYL)METHYL)- 6 ^, -CHLORO-N-(((R)-l-HYDROXYHEX-5-EN-2-YL)SULFONYL)-3 ^, ,4,4 ^* ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- -7 -CARBOXAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)~5-(((lR,2S)-2~all}'1cyclobutyl)methyl)-6'-chloro- 3',4,4',5 etraliydro-2H,2'H~spiro[benzo[b] [l,4]oxazepme-3, -naphthalene|-7- carboxylic acid and (S)-l -((tert-butyldimethyisilyl)oxy )hex-5-ene-2-sulfonamide and (R)-l~((tert-bur 4dimethylsilyl)oxy)hex-5-ene-2-sulfonamide (Example 445, Step 2), and then the crude material was treated with tetrabutylammonium fluoride m THF. m/z (ESI, +ve ion) 613.2 i M H ) .

STEP 5: (lS,3¾,6^,8L;,12 ^! S)-6~CHLORO-12'-(HYDROXYMETHYL)"3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]ΟΧΑ[13]ΤΉ Α[1 4]DIAZATETRACYCLO[147.2 ³ "* 0 ⁹ - ²⁴ ]PENTACOSA[ 8,16, 18,24]TETRAEN]- .15'-ONE 13', 13"-DIOXIDE OR (1 S,3'R,6'S,8'Z, 12'S)-6-

CHLORO-12 ^! ~(HYDROXYMETHYL)-3,4-DIHYDRO-2HJ5'H~

SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR i i S.3 ^' .6'S.H ^' H.12 ^' R )-6- CHLQRQ-12'-(HYDRQXYMETHYL)-3,4-DIHYDRQ-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ⁹ ' ²⁴ ]PENTACOSA[ 8,16, 18,24]TETRAEN]- 15*-ONE 13', 13'-DIOXIDE OR (1 S,3'R,6'S,8'Z, 12'R)-6- CHLORO - 12'-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-5-(((IR,2S)-2-allylc' ^, clobutyl)methyl)-6 ^, -chloro- N ((S)-l½dro he -5-en-2-yl)sιdf«Mlyl)-3 4,4^5 etΓahydΓO-2H,2Ή- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-5- (((1 R,2S)-2-ally Icy clobutyl)methy l)-6'-chl oro-N-(((R)- 1 -hy droxy hex-5-en-2- yl)sulfonyl)-3',4,4',5-tetrahydrc 2H,2'I-I-spiro[benzo[b][l,4[oxazepine-3,r- naphthalene] -7-carboxamide, and isolated as the first eluting isomer from the reversed phase preparatory HPLC separation. ^! H NMR (500MHz, CDC ) δ 8.12 (s, !!!}.7.73 (d, ./ 8.6 Hz, ill).7,29 (d, J=2.Q Hz, !!!).7.20 (dd, ,/ 2.2.8,3 Hz, 1H), 7.09 (d, .7=2,2 Hz, IH), 6.96 - 6,90 (m, 1H), 6.89 - 6.85 (m, IH), 5.45 (td, ./ 6.9.14.2 Hz, IH), 5.27 - 5.13 (m, IH), 4.24 - 4.05 (m, 6H), 3.81 (dd, ./ 6.4. 15.4 Hz, IH), 3.72 (d, ./ 14.2 Hz, IH), 3.22 id../ 14.4 Hz, IH), 2.95 (dd, ./ 5.9. 15,4 Hz, IH), 2.84 - 2.69 (m, 2H), 2.44 - 0.65 (m, 16H). m/z (ESI, +ve ion) 585.2 (M+H) ^_i ,

EXAMPLE 451. (1 S,3'R,6'S,8'Z, 12'R)-6-CHLORO- ^"-(HYDROXYMETHYL)- 3 ,4 -DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'-

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.i4|! !A/.Vr!-;i ^' RACYCi..()l i4.7.2,U' ^, '.i ^{)|:, !|} |Pl-N I ^' ACOSA [8,I6,18,24]TETRAEN]-15'-ONE 13',13 ^* -DIOXIDE OR (lS,3'R,6'S,8'E,12'S)-6-

CHLORO-12 ^! ~(HYDROXYMETHYL)-3,4-DIHYDRO-2HJ5'H~

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZAraT ACYCLO[147.2 ³ ' ^{6 9} ' ^M ]PENTACOSA[ 8,16,18,24]TETRAEN]-15'-ONE 13", 13'-DIOXIDE OR (lS,3'R,6'S,8'Z,12'S)-6- CHLQRQ-12'-(HYDRQXYMETHYL)-3,4-DIHYDRQ-2H,15'H- SPIRO [NAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR (lS,3'R,6'S,8'E,12'R)-6- CHLORO - 12'-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSJTO At^MlDIAZATET ACYCLOtMJ^.O'^.O'^lPENTACOSAt

8, 16, 18,24] TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 450, Step 5. *H NMR (400MHz, CDCb) δ 8.31 (br. s., ill).7.71 (d, ./ 8.4 Hz, !!!).7.23 - 7.15 (m, 2H), 7.09 (d, ,/ 2.2 Hz, !!!}.6.98 (d, ./ 8.2 Hz, ill).6,70 is. ill).5,48 (br. s .2H), 4.20 - 4,02 (m, 4H), 3.86 (dd, «7=4.5, 8,2 Hz, IH), 3.78 - 3,66 (m, 2H), 3.30 id..7=14.5 Hz, IH), 3.10 (dd, J=8.0, 15.5 Hz, 1H), 2.87 - 2.69 (m, 2H), 2.60 - 2.46 (m, 1H), 2,39 - 1.56 (m, 15H), 1.44 (t, ,/ 12.3 Hz, IH). m/z (ESI, +ve ion) 585.2 i.YMir.

EXAMPLE 452. (IS,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-METHOXY-N,N- DIMETHYL- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24] TETRAE E] - 12'-C ARBOXAMIDE 13', 13'-D10XIDE OR

(1S,3'R,6'R,7'S,8'E,12'R)-6-CHL0R0-7'-METH0XY-N,N-DIME™ YL-15'- OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTOALENE-I,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [ - 12'-C ARBOX AMIDE 13 ', 13 '-DIOXIDE

STEP 1 : (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -HYDROXY-6-

SULFAMOYLHEX-2-EN-l^L)CYCLOBUTYL)METHYL)-3',4,4',

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE! -7-C A

100 mL flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxyhex-2-en-l -yl)cyclobut 'I)methyl)~3',4,4',5~tetrahydro-2H,2'H~ spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Iniermediate AA12A; 500 mg, 0.980 rnmol), pent-4-ene-l -sulfonamide (Intermediate EE 19; 878 mg, 5.88 rnmol), and DCE (14 mL). The solution was sparged with argon for 15 min at which time Hoveyda-Grubbs II (61 mg, 0.098 rnmol) was added as a 0.2 mL solution in DCE at it. The mixture was stirred at rt and sparged with argon (the vial was vented) for 2 h. The reaction mixture was then bubbled with air for 5 minutes and filtered to separate the insoluble sulfonamide homodimer. The crude product was purified on a Combifiash® (24g gold SiC column), eluting with 50% - 90% EtOAc in heptanes + 0.2% AcOH) to give (S)-6'-chloro-5- (((I ,2R)-2-((S,E)-l-hydroxy-6"SuIfamoylhex-2-en -yI)cyclobut}4)methyI)- 3',4,4',5-tetrahydro-2h,2'h-spiro[benzo[bl [l,4]oxazepine-3,r-naphtha3ene|-7- carbox lic acid (439 mg, 0.745 rnmol, 76 % yield) as a white solid. STEP 2: (1 S,3'R,6' ,7'S,8'E)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H. 15'H-SPIRO[N APHTHALENE- 1.22'-

| 20 jO.\ ,\ | ! 3 jTI U A | I 4 | ni A/ATI :TR A( ^' YCl .Oj i 4.7.2.U ' ".i ^{) 1} '" ¹ | Ρ1·Ν I ^' ACOSA [ 8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

To a 1 L flask containing (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxy-6- sulfamoylhex-2-en-l-yl)cyclobutyl)me1hyl)-3^4,4 ^, ,5-tetrahydro-2H,2'H- spiro benzo b] l,4]oxazepine-3,l'-naphthalene|-7-carboxylic acid (from Step 1, 449 mg, 0.745 mmol), which was previously dried by azeotroping twice with 10 mL of toluene, was added N,N-dimethylpyridin-4~amine (155 mg, 1.27 mmol) and 400 mL of DCM. The reaction mixture was cooled to 0 °C at which time N- (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (286 mg, 1.490 mmol) was slowly added. The reaction was then stirred at rt for 18 h. The mixture was quenched with 200 mL of IN HCl and extracted with 600 mL of EtOAc. The organic layer was dried over anhydrous Na?,S()4, filtered, and concentrated by rotary evaporation. The crude product was purified on a

Combiflash® (24g gold SiCte column), eluting with 30% - 70% EtOAc in heptanes, to give the titie compound as a white solid. ^] H NMR (500MHz, CD3OD) δ 7.75 (d, J=8.3 Hz, 1H), 7.20 (dd, ,/ 2 9. 7.6 Hz, 1H), 7, 12 (d, ./ 3.7 Hz, IH), 7,00 (dd, ./ 1 .7. 8.8 Hz, IH), 6.94 (d, ,7=8,3 Hz, IH), 6.88 (d, J=2.2 Hz, i l l ). 5.95 - 5.86 (m, IH), 5.70 (dd, J=8.8, 15.9 Hz, IH), 4.25 - 4.19 (m, IH), 4.22 (dd, ./ 4.4. 8.6 Hz, I H), 4.14 - 4.06 (m, 31 1 4.14 - 4.05 (m, 3H), 3.84 (d, J=15.2 Hz, I H), 3.68 (d, ,/ ! :\2 Hz, IH), 3.09 (dd, 8.3. 15.9 Hz, IH), 2.87 - 2.74 (m, 2H), 2.45 - 2.30 (m, 3H), 2, 14 - 1.88 (m, 5H), 1.86 - 1.69 (m. H i ), m/z (ESI, +ve ion) 571.2 (M+H) ⁺ .

STEP 3: (lS,3 ^, R,6'R,7 ^, S,8 ^, E)-6-CHLORO-7 ^, -METHOXY-3,4-DIHYDRO- 2H, 15'H-SPlRO[NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

100 mL flask was added (lS,3'R,6'R,7'S,8'E)-6-chloro-7'-hydroxy 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

[20]oxa[ 13]thia[l ,14]cUazatetracyclo^

n]-15'-one 13',13'-dioxide (from Step 2, 138 mg, 0,242 mmol), THF (10 mL), and sodium hydride (29.0 mg, 1.208 mmol). The reaction was stirred at rt for 15 min at which time Mel (0.092 mL, 1.480 mmol) was added. The reaction was stirred at rt for 2 h at which time additional sodium hydride (58.0 mg, 2.42 mmol) and Mel (0.092 mL, 1.480 mmol) were added and the reaction was stirred at rt for an additional 16 h. The reaction was quenched with 100 mL of satd NH ₄ C1 and extracted with 400 mL of EtOAc. The organic layer was dried over Na?.S04, filtered, and the solvent was removed by rotary evaporation. The crude product was purified on a Combiflash® (12g gold SiCte column), eluting with 10% to 50% EtOAc in heptanes, to give (l S,3'R,6 ^! R,7'S,8'E)-6-chloiO-7'-methoxy-3,4-dihydi - 2H, 1 5'H-spiro[naphthalene- 1 ,22'-

n]-15'-one 13',13'-dioxide (120 mg, 0.205 mmol, 85 % yield) as an off white solid. ¾ NMR (400MHz, CDCb) 0 8.02 (s, 1H), 7.70 (d,■/ 8.6 Hz, 1 I I ). 7.19 (dd,

./ 2.2. 8.5 Hz, 1 1 1 ). 7.10 (d, ,/ 2 2 Hz, 1 H), 6.97 - 6.87 (m, 2H), 6.84 (d, 1 .6 Hz, 1H), 5.88 (ddd, ,7=5,2, 8.1, 15.1 Hz, IH), 5.53 (dd, «/=8.7, 15.4 Hz, I H i,. 4.30 (ddd, ./ 4.8. 9.8, 15.0 Hz, IH), 4.15 - 3.98 (m, 2H), 3.84 - 3.69 (m, 2H), 3.67 (dd, ./ 3.8. 8.7 Hz, 1H), 3.36 - 3.21 (m, 2H), 3.25 (s, 3H), 3.01 (dd, ./ 10.3. 15.2 Hz, I I I ). 2,87 - 2.64 (m, 2H), 2.52 - 2.29 (m, 3H), 2.25 - 1.91 (m, 5H), 1 .88 - 1.75 (ra, 3H), 1.71 - 1.60 (m, 2H), 1.41 (t, ./ 12.-1 Hz, IH). m/z (ESI, +ve ion) 585.0 { M l ! ) STEP 4: ( 1 S,3'R,6'R,7'S,8'E, 12'S)-6-CHLORO-7 ^* -METHOXY-N ₅ N-DIMETHYL-

15 ^! -OXO-3,4 1iHYDRO-2H-SPIRO[NAPHTHALENE-l ,22 ^! - | 2u jOXA| O ΙΊ ί Ι1Λ| I„ I 4 |Di Α/.ΥΠ Ί ^' Η Λ(ΎΟ.ϋΙ i 4.7.2.0 ^• ^ 0 ^{| :, ! 1} |PH\,T.\i SA [ 8, 16, 18,24 JTETRAENE] - 12'-C ARBOX AMIDE 13 ', 13 '-DIOXIDE OR

(lS ¾,6'R ^,8 ^ 12'R)-6-CHLORO-7'-METOOXY-N,N-DIMETOYL-I5'- OXO-3,4 3IHYDRO-2H-SPiRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DL ZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18 ,24]TETRAENE] - 12'-C ARBOX AMIDE 13', 13 '-DIOXIDE

To a solution of diisopropylamine (96 μΕ, 0.68 mmol) in THF (2 mL) at - 78 °C under argon was added butyllithium solution, 2.5 M in hexanes (273 μΕ, 0.684 mmol) dropwise and the resulting mixture was stirred at -78 °C for 10 min, at 0°C for 30 min then recooled to -78 °C, This solution (~ 0.55 M; 0.15 mL 3 eq.) was then added to a solution of (1 S^'R^'R^'S^'E^e-chloro-T'-memoxy-S^- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [2Q]oxa[13]thia[l ,14]diaza ^^

n]-15'-one 13',13'-dioxide (from Step 3, 10 mg, 0.017 mmol) in 0,5 mL THF at - 78 °C under argon. The mixture was stirred at -78 ° for 30 min, and

(dimethylamino)carbonyl chloride (16 μΕ, 0.17 mmol) was added. The resulting mixture was stirred at -78 °C for 20 min. The reaction was quenched with 2 N HCi solution and mixture concentrated. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column;

Phenornenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0. 1% TFA, 30 min method) to provide the title compounds as the first eiuting isomer. 'H NMR (400MHz, CDCb) δ 8.33 (br. s., H I ). 7.70 (d, ,/ 8.4 Hz, IH), 7.19 (dd,■/ 2.2. 8.5 Hz, 1H), 7.10 (d, ./ 2.2 Hz, i l l ). 6,98 - 6.86 { Ml. 2H), 6.82 (s, I I I ). 5.88 - 5.71 (m, i l l ). 5,65 (dd, ./ 2.9. 10.4 Hz, IH), 5,56 (dd, J=8.5, 15.2 Hz, I I I ). 4.17 - 4.03 (m, 2H), 3,82 (d, ./ 14.7 Hz, IH), 3.76 - 3.61 (m, 2H), 3.37 (s, 3H), 3.35 - 3.29 (m, IH), 3.25 (s, 3H), 3.24 - 3.19 (m, IH), 3.12 (s, 3H), 3.11 - 3.06 (m, IH), 3.00 (dd, ,/ 10.5. 15.2 Hz, I H), 2.85 - 2.68 (m, 3H), 2,54 - 1.55 (m, 10H), 1.40 (t, «7=12.3 Hz, IH). m/z (ESI, +ve ion) 656.1 (M+H) ⁺ . EXAMPLE 453. (1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7'-METHOXY-N,N-

DIIVIETHYL-15 ^, -OXO-3,4-DIHYDRO-2H-SPIRO| APH^HALE E-l ₅ 22 ^, -

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOIM.T^.O'^.O^^lPE TACOSA

[8J6,18,24]TETRAENEl-12'-CARBOXAMiDE 13',13'-DIOXIDE OR

(lS,31 ,6'R ^,8Ea2'S)-6-CHLORO-7 ^! "METHOXY-N,N-DIMEraYL-15'- OXO-3,4-DlHYDRO-2H-SPIRO[NAPH ^r fflALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

- 12'-C ARBOX AMIDE 13 ', 13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 452, Step 4. *H NMR (400MHz, CDCb) δ 8.52 (br. s., ill).7.65 (d, ./ 8.4 Hz, !!!).7.43 (br. s., III). 7.16 (dd. ,/ 22.8.5 Hz, ill).7,10 (d,J=2.2Hz, IH), 7.03 - 6.96 (m, 1H), 6.94 - 6.90 (m, IH), 5.71 (td, ,7=5,3, 15.6 Hz, IH), 5,37 - 5.16 (m, 2H), 4.28 - 4.07 (m, 2H), 3.77 - 3.61 (ni, 2H), 3.51 - 3.19 (m, 9H), 3.10 (s, 3H), 2.76 (br. s., 2H), 2.67 - 2.54 (m, IH), 2.51 - 1.48 (m, 13H). rn/z (ESI, +ve ion) 656.1 (M+H) ⁺ .

EXAMPLE 454. (IS,3'R,6'R,7'S,8'E,1 l'S,I2'R 6~CHLORO-7'-HYDROXY-ir- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YCT (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [8,I6,18,24]TETiL EN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,ll'R,12'R 6-CHLOR()-7' IYDROXY-ir-METHOXY-12'- METHYL-3,4-DlHYDRO-2H,l 5'H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]THL [1,14]DIAZATETRACYCLO[14.7,2.0 ³ -^0 ¹⁹ - ²⁴ ]PENIACOSA [8 ₅ 16, 18,24]TETRAEN]-15"-ONE 13', 13'-D )XIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S.12'S)-6-CHLORO-7'-HYDROXY- 1 1 '-METHOXY -12'-

METHYL-3,4-D1HYDR0-2H;15'H-SP1R0[NAPHTHALE E-1,22'- [20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,l l'R,12 ^! S)-6-CHLORO-7'-HYDROXY-i r-METHOXY-12'- METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACY ^T CLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

STEP 1 : (2R,3S)-3-METHOXYHEX-5-ENE-2-SULFONAMlDE AND (2S,3S)- 3 -METHOXYH EX-5 -ENE-2- S UL FON AMIDE AND (2R,3R)-3- METHOXYHEX-5-ENE-2-SULFONAMIDE AND (2S,3R)-3-METHOXYHEX- -ENE-2-SULFONAMI

To a 25 -mL round-bottomed flask were added iodomethane (0.477 mL, 7.63 mmol) and (2R,3S)-3~hydroxy-N,N-bis(4-methoxybenz 'l)hex-5~ene-2~ sulfonamide and (2S,3S)-3-hydroxy-N,N-bis(4-methoxybenz>'l)hex-5-ene-2- sulfonamide and (2R,3R)-3-hydroxy-N,N-bis(4-methoxybenz l)hex-5-ene-2- sulfonamide and (2S,3R)-3-hydroxy-N,N-bis(4-methoxybenz 'l)hex-5~ene-2~ sulfonamide (400 mg, 0.953 mmol, Example 714, Step 4) in THF (5 mL), and then sodium hydride, 60% dispersion in mineral oil (114 mg, 2.86 mmol). The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with IN HC1 (5 mL) and extracted with EtOAc (2 xlO mL). The organic extract was washed with saturated NaCl and dried over MgS0 ₄ , filtered and concentrated in vacuo to give the crude material. The crude material was dissolved in 3 mL of DCM and treated with 3 mL of TFA. The mixture was stirred overnight, and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 60% EtO Ac in hexane, to provide the title compound. m/z (EST, +ve ion) 194.2 { \i · H )

STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((S )-l-I-r ^;" DROXYHEX-2-EN-l-

YL)CYCIX)BUTYL)MEWIYL)-N-(((2R,3S)-3-METHOXYHEX-5-EN-2-

YL)SULFONYL)-3' ₅ 4,4',5-TETRAHYDRO-2H,2 ^! H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-E - 1 -YL)CYCLOBUTYL)METHYL)-N-(((2S,3 S)-3 - METHOXYHEX~5-EN-2-YL)SULFONYL)~3V4 ₅ 4V5-TETRAHYDRO-2H,2 ^, H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE AND (S)-6"-CHLORO-5-(((lR,2R)-2-((S,E)-l-

HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-N-(((2R,3R)-3- METHOXYHEX-5-EN-2-YL)SULFONYL)-3 ^, ,4,4 ^, _: ,5-TETRAHYDRO-2H ₅ 2 ^, H- SPIR0[BENZ0|;B] [ 1 ,4]0XAZEPINE-3,1 '-NAPHTHALENE]-7- CARBOXAMTDE AND (S)-6'-CHLORO-5-(((l R,2R)-2-((S,E)-l- HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-N-(((2S,3R)-3- ETHOXYHEX-5-EN-2-YL)SULFONYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en-l-yl)cyciobuty3)methyl)-3',4,4',5-tetrahydro-2H,2'FI- spirojbenzojb] [ 1 ,4]oxazepine-3, ! '-naphthalene]-7-carboxylic acid (Intermediate, AA12A) and (2R,3S)-3-methoxyhex-5-ene-2-sulfonamide and (2S,3S)-3- methoxyhex-5-ene-2-sulfonamide and (2R,3R)-3-methoxyhex-5-ene-2- sulfonamide and (2S,3R)-3-methoxyhex-5-ene-2-sulfonamide. m/z (ESI, +ve ion) 685.2 (M+H) ⁺ . STEP 3: (IS,3¾,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-7'-HYDROXY-l Γ-

\H ^" H !ΟΧΥ-!2'-.Υ1Ι· ^" Π !YL~3. l-P!HYDRO-2} i-SSMR()|\ API 1 Π ί,\5 Ι ·.- L22'"

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(Ιβ^'Κ,ό'Κ,Τ'β,δΈ,ΙΓΚ, 'Κ ό-ΟΗίΟΚΟ-Τ'-ΗΥΟΚΟΧΥ-ΙΙ'-ΐνΐΕΤΗΟΧΥ- Ι^- ΜΕΊΉΥΕ-3,4-ΟΙΗΥΟΚΟ-2Η,15Ή-8ΡΙΚΟ|ΝΑΡΗ� �ΗΑΕΕΝΕ-1,22'- [20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE B', 13 '-DIOXIDE OR

(lS,3'R,6'R ^,8¾irS,12'S)-6-CHLOR()-7'-HYDROXY-ir-METHOXY-12 ^! - MEraYL-3,4-DIHYDRO-2H ₅ 15^SPmO[NAPHTHALENE-l,22"-

|2 ⁽ >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: ί RAC YCi C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8,I6,18,24]TETiL E ]-15'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R, 7 ^* S,8'E, 11 'R, 12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHOXY- 12'- METTiYL-3,4-DIHYDRO-2IlJ5Ti-SPIRO| JAPHTHALENE-l,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)~6 ^! -chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en-l-yl)cyciobut\d)methyl)~N~(((2R,3S)-3-methoxyhex-5-en-2-y l)sulfonyl)- 3;4,4',5 etraliydro-2H,2 ^! H-spiro[benzo[bi[l,4joxazepine-3,l'-naphthalene|-7- carboxami de and (S )-6'-chloro-5-((( I R,2R)~2~((S,E)~ I -hydroxy hex -2-en- 1 - yl)c lobut\d)me l)-N-(((2S,3S)-3-methox\'hex-5-en-2-yl)sulfonyl)-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and(S)-6 ^, -chloro-5-(((lR,2R)-2-((S,E)-l-hydro3^hex-2-en-l- yl)cyclobutyl)meihyl)-N-¾^

tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxarnide and (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l -hydroxyhex-2-en-l- yl)cyclobu1yl)methyl)-N-(((2S,3R)-3-methoxyhex-5-en-2-yl)sul fonyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxamide, and isolated as the first eluting isomer from the reversed phase preparatory HPLC separation. ^! H NMR (400X1! !/. CDCb) 6 8, 1 8 is. i l l ). 7,70 id. J=8.6 Hz, 1H), 7.18 (dd, J=2.2, 8.5 Hz, IH), 7.10 (d, J=2.2 Hz, 1H), 7.02 - 6.86 (m, 3H), 5.87 - 5.77 (m, IH), 5.72 - 5.60 (m, IH), 4.31 - 4.09 (m, 4H), 3.82 (d, ./ 15.5 Hz, IH), 3.72 (d, J=14.5 Hz, IH), 3.5 ! (d, J=10.2 Hz, IH), 3.39 (s, 3H), 3.26 (d, ,7=14,3 Hz, IH), 3.07 (br. s„ IH), 2,87 - 2.68 (m, 2H), 2.58 - 1.63 (m, 12H), 1.58 (d, ./ 7.2 Hz, 3H), 1.42 (t, ./ 1 2.2 Hz, IH). m'z (ESI, +ve ion) 615.2 { M · Π ) .

EXAMPLE 455. (18,3Ί ,6¾,7 ^! 8,8Έ,1 l'S,12'S)-6-CHLORO-7'-HYDROXY-12'- (METHOXYMETHYL)-i -METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2( >X A| = 3 ! ! ί U Ai i 1 -J | ? !,\ Ά ! : I AC YC ^' f Ol 1 4 7.2 0 ^; ". ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN]- '-ONE 13', 13'-DIOXIDE

STEP 1 : (2S,3S)-l-METOOXY-3-METHYLHEX-5-ENE-2-SULFONAMIDE AND (2R,3S)-l-METHOXY -METHYLHEX-5-ENE-2-SULFONAMIDE

The title compound was prepared from (S)-N,N-bis(4-methoxybenzyl)- methylpent-4-ene-l -sulfonamide (Example 395, Step 3) by similar procedures described in Example 434, Steps 1 -4. m/z (ESI, +ve ion) 208.2 ( +H) ⁺ . STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l- YL)CYCLOBUΊΎL)MEΊΉYL)-N ((2S,3R)- MEΊΉOXY-3-MEΊΉYLHEX" 5-EN-2-YL)SULFONYL)-3 ^! ,4,4',5-TETRAHYDRO-2H,2TI- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARBOXAMIDE AND (S)-6'-CHLORO-5 -((( 1 R,2R)~2-((S,E)~ 1 - HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-N-(((2R,3R)-l- METOOXY-3-MF^iYLHEX-5-EN-2-YL)SULFONYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]QXAZEPiNE-3, 1 '- NAP -7-C ARBOXAMIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 4 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2- en- 1 -y l)c clobuty l)methy l)-3 ',4,4',5-tetrahy dr o-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (Intermediate, AA12A) and (2S,3S)-l-methoxy-3-methylhex-5-ene-2-sidfonarnide and (2R,3S)- l-methoxy-3-methylhex-5-ene-2-sulfonamide. m/z (ESI, +ve ion) 699.2 ( M R ) .

STEP 3: (1S,3 ^! R,6'R,7'S,8'E,1 1 'S. 1 2'S}-6-( 1 U .()R()-7'-i !YDROXY- i T- (METHOXYMETHYL)- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 432, Step 5 using (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l -hydroxyh en- 1 ~y!)ey clobuty l)methy!)~N^

y l)sulfony i)-3 ',4,4',5 -tetrahy dro-2H,2'H-spiro [benzo [b] [ 1,4 ] oxazepine- 3 , 1 '- naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l - hydroxyhex-2-en-l-yl)c^ lobut'l)me1hyl)-N-(((2R,3R)-l-methoxy-3-me1hylhex-

5-en-2-yl)stdfonyl)-3',4,4',54etrahydro-2H,2H^

naphthalene] -7-carboxamide, and isolated as the first eluting isomer from the reversed phase preparatory HPLC separation. Ή NMR (400MHz, CDCh) 58,15 (s, lH), 7.69 id. J=8.4 Hz, 1H), 7.18 (dd, ./ 2.3.8.4 Hz, ill).7.10 (d, ./ 2.2 Hz, 1H), 7.06 - 6.98 (m, 1H), 6.96 - 6.87 (m, 2H), 5.94 - 5.81 (m, IH), 5.69 (dd, ./ 7.3.15.2 Hz, IH), 4.47 - 4.35 (m, ill).4,25 - 4,18 (m, IH), 4.15 - 4.02 (ra, 3H), 3.98 - 3.91 (m, IH), 3,77 (d, ./ 15.1 Hz, IH), 3.66 (d, «7=14.1 Hz, IH), 3.41 (s, 3H), 3.29 (d, J=14.3 Hz, IH), 3.13 (br. s., IH), 2.87 - 2.67 (m, 2H), 2.51 - 1.36 (m, 14H), 1.14 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 456. (1S,3'R,6'R,7'S,8'E,1 l'S,I2'R 6~CHLORO-7 ^, -HYDROXY-12'- (METHOXYMETHYL) - 11 '-METHYL- 3 ,4-DJH YDRO-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'~

|2( !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |Ρ!·Λ i ACOSA [8,I6,18,24]TETIL4E ]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'Z,ll'S,12'S)-6-CHLORO-7 ^! -HYDROXY-12'- (METHOXYMETHYL)- 11 ^* -METHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPi ( ⁾ i\APHiHA!J\i:-l.22-

[20]OXA[13]THL4[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24] - 15"-ONE 13', 13 ^* -DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 455, Step 3. Ή NMR (400MHz, CDCb) 68.02 (br. s., IH), 7.67 (d, J=8.4 Hz, IH), 7.18 (d, ./ 8.6 Hz, ill).7.14 - 7.07 (m, 2! I ).6,95 (d, 8.0 Hz, 111).6.86 (br, s., !H), 5.87 (br. s„ 1H), 5.66 (dd, ,7=5,3, 15.8 Hz, ill).4,19 - 4.07 (m, 3H), 4.03 - 3.83 (m, 3H), 3,66 (d, J=15.5 Hz, 1H), 3.53 - 3.33 (m, 6H), 2.79 (br. s., 2H), 2.65 - 1.41 (m, 14H), 1.20 (d, ./ 7.0 Hz, 3H). m/z (ESI, +ve ion) 629.2 (M ill .

EXAMPLE 457. (1S,3'R,6'R,7'S,8'Z,1 rS,12'R 6~CHLORO-7 ^, -HYDROXY-12'- (METHOXYMETHYL) - 11 '-METHYL- 3 ,4-DIH YDRQ-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PL\ i ACOSA [8,I6,18,24]TETiL4E ]-15'-QNE 13', 13 '-DIOXIDE

The title compound was obtained as the third eluting isomer from the reversed phase preparatory HPLC separation in Example 455, Step 3. Ή NMR (400MHz, CDC] 3) δ 9.70 (br. s„ ill).7,72 id../ 8.4 Hz, !!!).7.45 (dd, ,/ 2.0.8.2 Hz, 1H), 7.19 (dd, .7=2.2, 8.5 Hz, Mi).7.09 (d, J=2.2 Hz, IH), 7.06 (s, IH), 6,99 (d, ./ 8.2 Hz, ill).5.74 (d, ./ 8.6 Hz, IH), 5.54 (ddd, J=2.3, 5.2, 11.8 Hz, IH), 4.42 (br. s., IH), 4.17 - 3.95 (m, 4H), 3.92 - 3.82 (m, 2H), 3.67 (d, ,7=14.3 Hz, IH), 3,43 (s, i).3,20 (d, ,/ 14.1 Hz, ill).3.15 - 3.02 (m, 2H), 2.93 - 2,69 (m, 3H), 2,40 - 1.35 (m, 12H), 1.16 (d, ,7=6,8 Hz, 3H), m/z (ESI, +ve ion) 629,2 (M R)

EXAMPLE 458. { ! .3 ^' R.6'R.7'S.81-:. ! I ^' S.12'R )-6-( ^' l il.OKO- ! 2 ^' ~\: 11 i V i -7 - HYDROXY- 1 r-METHQXY-3,4-DIHYDRQ-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E,ri 'R ,12 ^* S)-6-CHLORO- 12"-ETHYL-7'-HYDROXY-l 1 '- METHOXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- |2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥΠ:ΤΡΑ(ΎΠ.ϋΙ i 4.7.2 U · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24]TETP^ENj-15'-ONE 13 ^! J3 ^* -DIOXIDE OR

(IS ,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-CHLORO-12'-ETHYL-7'-HYDROXY-l V- METHOXY-34 3IHYDRO-2H ₅ ]5H~SPIRO[NAPHTHALENE-l,22 ^! ~

[20]OXA[13]TH1A[1 4]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8 ₅ 16,18,24]TETRAEN]-15"-ONE i3',13'-DIOXIDE OR

(1S,3 ^, R,6'R,7'S,8 ^, E,1 l^^^-e-CHLORO-l^-ETHYL-T-HYDROXY-l Γ- VII · Ι ΙΟΧΥ-3.4-ΠΗ !YDRO-2! I. ί } l-SPIROj \ΛΡί I l l 1Λ!.ί:ΝΗ-Ι.22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOIM.T^.O'^.O^^lPE TACOSA

AEN] - 15'-ONE 13", 13-DIOXIDE

STEP 1 : (S)-ETHYL 2-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)BUTANOATE AND (R)-ETHYL 2- N- BIS(4-MET YL)

The title compound was prepared in an analogous manner to that described in Example 432, Step 1 using (R)-ethyl 2-(chlorosulfonyl)butanoate and (S)-ethyl 2-(chlorosulfonyl)butanoate. m/z (ESI, +ve ion) 458.2 (M+Na) ⁺ . STEP 2: (S)-l -HYDROXY-N,N-BTS(4-METHOXYBENZYL)BUTANE-2- SULFONAMIDE AND (R)-l -HYDROXY-N,N-BIS(4- METHOXYBENZYL)BUTANE-2-SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 434, Step 2 using (S)-ethyl 2-(N,N-bis(4- methoxybenzyl)sulfamoyl)butanoate and (R)-ethyl 2-(N,N-bis(4- methoxybenzyl)suIfamoyl)butanoate. m/z (ESI, +ve ion) 416.2 (M+Na) ⁺ .

STEP3 : (S)-N ₅ N-BIS(4-METHOXYBENZYL)- 1 -OXOBUTANE-2- SULFON AMIDE AND (R)-N ₅ N-BIS(4-METHOXYBENZYL)-l - OXOBUTANE-2-SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 438, Step 1 using (S)-l-liydroxy-N,N~bis(4~nietlioxybenz}4)btitane-2- sulfonamide and (R)-l -hydroxy -N,N-bis(4-methoxybenzv'l)butane-2-sulfonamide. m/z (ESI, +ve ion) 414,2 (M+Na) ⁺ .

STEP 4: (3S,4S)-4-HYDROXY-N,N-BIS(4-METOOXYBENZYL)HEPT-6-ENE- 3 -SULFONAMIDE AND (3S,4S)-4-HYDROXY-N,N-BIS(4- METHOXYBENZYL)HEPT-6-ENE-3-SULFONAMIDE AND (3S,4R)-4- H YDROXY-N ,N-BI S (4 -METHOXYBENZ YL)HEPT-6-ENE - 3 - SULFONAMIDE AND (3R,4S)-4-HYDRQXY-N,N-BIS(4- METHOXYBENZYL)HEPT-6-ENE-3-SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 714, Step 4 using (S)-N,N-bis(4-methoxybenzyl)-l-oxobutane-2- sulfonamide and (R)-N,N-bis(4-methoxybenz 'i)-l-oxobutane-2~sulfonamide. m/z (ESI, +ve ion ) 456.2 (M+Na) ⁺ .

STEP 5: (3S,4S)-4-METHOXYHEPT-6-ENE-3-SULFONAMIDE AND (3R,4R)~ 4-METHOXYHEPT-6-ENE-3-SULFONAMIDE AND (3 S,4R)-4- METHOXYHEPT-6-ENE-3-SULFON AMIDE AND (3R,4S)-4- -6-ENE-3-SULFON AMIDE

The title compound was prepared from (3S,4S)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (3S,4S)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (3S,4R)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (3R,4S)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide by similar procedures described in Example 434, Steps 3-4. m/z (ESI, +ve ion) 208.2 (M+H) ⁺ . STEP 6: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((l S,5R,6R ₅ E)-l -HYDROXY-5- METHOXY-6-SULFAMOYLOCT-2-EN-l-YL)CYCLOBUTYL)METHYL)- S'^^^S-TETl AHYD O^H^'H-SPI OtBE ZOtBlt l^JOX^EPINE-S,!'- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((l S,5S,6S,E)- 1 -HYDROXY-5-METHOXY-6-SULF AMOYLOCT-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2R)-2-((l S,5R,6S,E)-l-HYDROXY-5- METHOXY-6-SULFAMOYLOCT-2-EN-l-YL)CYCLOBUTYL)METHYL)- 3\4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((lS,5S,6R,E)-l-ilYDROXY-5-METHOXY-6-SULFAMOYLOCT-2-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPlRO[BENZO[B][l,4]OXAZEPlNE-3, -NAPHTHALENE]-7-C ARBOXYLIC ACID

To a 25 mL single-necked round-bottomed flask were placed (S)-6'~ chloro-5-(((lR,2R)-2-((S)-l-hydroxydlyl)cyclobutv'l)me l)-3^4,4^5-tetrahydro- 2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (70 mg, 0.15 mmol, Intermediate, AA11A) and (3S,4S)-4-methoxyhept-6-ene-3- sulfonamide and (3R,4R)-4-methoxyhept-6-ene-3-sulfonamide and (3S,4R)-4- methoxyhept-6-ene-3-sulfonamide and (3R,4S)-4-methoxyhept-6-ene-3- sulfonamide (155 rng, 0.748 mmol) in DCE (2 mL). The mixture was stirred under argon for 10 mill before Hoveyda-Grubbs catalyst 2nd generation (19 mg, 0.030 mmol) was added, and then the resulting mixture was stirred under argon at ambient temperature for 2 h. The reaction mixture was bubbled with air for 10 min and then concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient 50% to 100% EtOAc (containing 0,3% AcOH) in hexane, to provide the title compound (52 mg, 54%). m/z (ESI, +ve ion) 647.2 (M+H) ^f . STEP 7: (1S,3'R,6'R,7'S,8'E,1 l ^f S,12'R)-6-CHLORO-12'-ETHYL-7'-HYDROXY- ll ^, -METHOXY-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TH1A[1,14]DIAZATEIIACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18,24]TETRAENl-15'-ONE 13',13'-D )XIDE OR

(1 S,3'R,0 ^! R,7'S,8'E, 11 'R,12'S)-6-CHLORO- 12'-H 111YI.-7'-! IYDROXY-11 ^! - VII · Ι ΙΟΧΥ-3.4-ΠΗ !YDRO-2! I. ί } l-SPIROj \ΛΡί I l l 1ΛΙ.ί:Ν!>Ι.22'-

[20iOXA|13]THIA|144]DIAZATETRACYCLO[14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]~1S'~0NE 13'J3'-DIOXTDE OR

(IS^'R^'R 'S^'EjrS/ 'Si-b-CHLORO-^'-ETHYL^'-HYDROXY-ir- METHOXY-3,4-DIHYDRO-2H,15'H~SPIRO[NAPHTHALENE-l,22 ^! ~

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,61 7 ^, S,8T,lll;i2 ^, R)-6-CHLORO-12'-ETHYL-7 ^, -HYDROXY-ir- ME^ΉOXY ,4-DIHYDRO-2H 5Ή-SPIRO| APH HALENE-l,22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 323, Step 7 using (S)-6'-chloro-5-(((lR,2R)-2-((lS,5R ₅ 6R,E)-l- hydroxy-5-methoxy-6-sulfamoyloct-2-en-l-yl)cyclobutyl)methyl )-34,4',5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid and (S)-6'-chloro-5-(((lR2R)-2-((lS,5S,6S,E)-l-hydrox\'-5-methox y-6- sulfamoyloct-2-en-l-yl)cyclobutd)methyl)-3',4,4',5-tetrahydr o-2H,2'H- spiro[benzo[b] [1,4] oxazepine-3, Γ-naphthalene] -7-carboxylic acid and (S)-6'- chloro-5-(((lR,2R)-2-((lS,5R,6S,E)-l-hydroxy-5-methoxy-6-sul famoyloct-2-en- 1 -y l)c clobuty l)methy l)-3',4,4',5-tetrahy dr o-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)~6 ^! - cMoro-5-(((lR,2R)-2-((lS,5S,6R,E)-l -hydroxy' -5-methoxy-6-sulfamoyloct-2-en- l-}'1)cyclobutyl)meihyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid, and isolated as the first eiuting isomer from the reversed phase preparatory HPLC separation. Ή NMR (500MHz, CD3OD) δ 7.73 (d, ./ 8.6 Hz, 1H), 7.17 (dd, ,/ 2.2.8.6 Hz, 1H), 7,11 (s. 111).7,05 (dd, ./ 2.0.8.1 Hz, 1 !!}.6.93 id. ,/ 81 Hz, IH), 6.87 (d, 1.5 Hz, 1H), 5.82 (dd, .7=8.3, 15.2 Hz, IH), 5.74 - 5.61 (m, 1H), 4.18 (dd, J=3A, 8.1 Hz, IH), 4.08 (s, 2H), 3.99 (dt, =2.1, 4.6 Hz, Ml).3.81 (d, ./ 15.2 Hz, IH), 3.65 id../ 14.4 H/. IH), 3,54 id../ 10.3 Hz, IH), 3,35 (s, Ml).3.08 (dd, J=9.9, 15.3 Hz, IH), 2.87 - 2.68 (m, 2H), 2,60 (ddd, .7=2.7, 8.7, 15.0 Hz, IH), 2.45 - 2.24 (m, 3H), 2.18 - 1.79 (m, 8H), 1.72 (td, ,1=9.5, 18.7 Hz, IH), 1.49 - 1.40 (m, IH), 1.35 - 1.30 (m, 2H), 1.24 (t, ./ 7.5 Hz, Ml), m/z (ESI, +ve ion) 629.2 ( +H) ⁺ .

EXAMPLE 459. (1S,3'R,6'R,7'S,8'E,1 l'R,12 ^! S 6~CHLORO-12'~ETHYL-7'- HYDROXY - 11 '-METHQXY-3,4-DIHYDRQ-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'~

|2 ⁽ >X A| i 1 ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^{:' i'} .0 ^li ' |Pi-:N i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-D10X1D OR

(18,3Έ,6¾,7Έ,8Έ, 11 'S, 12'R)-6-CHLORO- 12'-ETHYL-7'-HYDROXY- 11 '- METHOXY-3,4-DIHYDRO-2H, 15 Ή- SPTRO [N ΑΡΗΤΉ ALENE- 1 ,22' - pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,11*S,12 ^, S)-6-CHLORO-12'-ETHYL-7'-HYDROXY-l 1*- METHOXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- |2ίί|ΟΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2. · ^, '.ί ^)|: " ¹ |P1-M ^' .\C0SA [8,16,18,24]TETR _! 4ENl-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 l'R,l 2'R)-6-CHLORO-l 2'-ETHYL-7'-HYDROXY-l Γ- METHOXY-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, ! 8,24]TETRAEN] - 15"-ONE 13', 13*-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 458, Step 7. Ή NMR (500MHz, CDCh) δ 8.31 (br. s„ ill).7,64 (d, J=8.6 Hz, 2H), 7.16 (dd, ./ 2.3.8,4 Hz, 1H), 7.10 (d, ./ 2.2 Hz, 1H), 7.03 - 6.96 (m, III).6.96 - 6.90 (m, 1H), 5.75 (dd,J=3.9, 15.7 Hz, 1H), 5.46 (br. s.. III .4.37 - 4.18 (m, 111).4.16 - 3.91 (m, Ml).3,76 (d, J-----12.Q Hz, !!!).3.49 (d, 86 Hz, III).3.38 (s, 3H), 3.37 - 3.29 (m, IH), 3.14 (d, «7=15.4 Hz, 1H), 2.81 - 2.72 (m, 2H), 2,65 - 1.13 (m, 18H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 460. (18,3 ^, Κ,6 ^ί Κ,7 ,8Έ,1Γ8,12'8)-6~€Η1,ΟΚΟ-7 ^! ~ΜΕΊΉΟΧΎ-12'- (METHOXYMETHYL)- 11 '-METHYL-3 ,4-DIHY DRQ-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7,2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(IS 'R^'R 'S^'EarSJ^^-e-CHLORO^'-METHOXY-l^'- (METHOXYMETHYL)-I l'-METHYL-3,4-DlHYDRO-2H,15'H- SPIRO[N ΆΡΗΤΗ ALENE- 1 ,22'- |2ujOXA| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί <Λ( ^' Υ(·ί,.ΟΙ i 4.7.2,0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18, -15'-ONE 13',13 ^* -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404, Step 2 using (1S,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-chioro-7'-hydroxy- 12'-(methoxy methyl)- ir-methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-.l, 22'- [20] oxai 3] ihi a[ I/ 4] ds

n]-15'-one 13',13 ^! -dioxide or (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)~6~chloro~7'~hydroxy- 12'-(methoxymethyi)- 1 r-methyl"3,4-dihy dro-2H, 15'H~spiro[naphthalene-l ,22'- [20joxa[13]thia[l,14]diazatetracycfo[14.7 _^ ^

n]-15'-one 13',13'-dioxide or (18,3¾,6Έ,7'8,8'Ζ, Γ8,12'8)-6-Λ1οΐΌ-7' ΐ}^Γθχν- 12'-(methoxyniethyl)- 1 -methyl-3,4-dihy dro-2H, 15'H-spiroj naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracy^

n]-15'-one 13',!3'~dioxide or (1S,3'R,6'R,7'S,8'Z, I l'S,12'R.)-6-chloro-7'-hydroxy- 12 ^! -(methoxymethyl)- 11 '-methyl-3,4-dihy dro-2H, 15 ^! H-spiro[naphthalene-l ,22'- IKJ4jtctrao n]-15'-one 13',13'-dioxide (Example 455, Step 3, the crude material before HPLc purification) and iodomethane, and isolated as the first eluting isomer from the reversed phase preparatory HPLC separation. ¾ N.V1R (500MHz, CDCh) δ 7.99 (s, 1H), 7.70 (d, ./ 8. Hz, ill).7.19 (dd, ./ 2.2.8.6 Hz, III).7.10 (d, ./ 2.0 Hz, ill).6.96 - 6.87 (m, 2! I ).6,85 (d, ,/ 1.5 Hz, 111).5.93 - 5.83 (m, IH), 5.52 (dd, J=9.4, 15.3 Hz, IH), 4.53 - 4.45 (m, IH), 4.18 - 3,99 (m, 4H), 3.82 (d, J=15.2 Hz, IH), 3.74 - 3.61 (m, 2H), 3.44 (s, 3H), 3.29 - 3.16 (m, 4H), 3.00 (dd, J=10.3, 15.4 Hz, IH), 2.87 - 2.67 (m, 2H), 2.54 - 1.18 (m, 13!!}.1.14 id. 6.8 Hz, 3H). m/z (ESI, +ve ion) 643,2 (VI 11) .

EXAMPLE 461. (1 S,3'R,6 ^* R,7'S,8'E,1 l'S,12'R)-6-CHLORO-7'-METHOXY-12'- (METHOXYMETHYL)- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ujOXA| 1ΉΤί!1Λ| Ι.Ι4|ΠίΑ/ΛΠ:ΤΗΛ(Ύα.ΟΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,ll'S,12'S)-6-CHLORO-7'-METHOXY-12'- (METHOXYMETHYL)- 11 '-METHYL-3 ,4-DIHYDRQ-2H, 15 Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13|THL4[l,14jDL4ZATETRACYCLO[14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 I 3 '-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 460. ^! H NMR (400MHz, CDCb) δ 8.22 (br, s., IH), 7.66 (d, 8.4 Hz, IH), 7, 18 (dd, ./ 2.3.8.4 Hz, 2H), 7,10 (d, ./ 2.2 Hz, IH), 6.97 (d, «7=8.2 Hz, ill).6.72 (br, s., IH), 5.92 (br. s„ ill). 5.48 (dd, J=7.9, 15.6 Hz, IH), 4.15 - 4.01 (m, 3H), 3.95 - 3.81 (m, 2H), 3.70 (d, ./ 14.7 Hz, IH), 3.63 - 3.52 (m, 2H), 3.41 (s, 3H), 3.35 (d, ./ 14.5 Hz, IH), 3.27 (s, 3H), 2.89 - 2.71 (m, 2H), 2.70 - 2,43 (m, 3H), 2.42 - 2.27 (m, 2H), 2.1 I - 1.76 (m, 7H), 1,66 (quin, .7=9,1 Hz, H), 1.49 (t, J=ll,7 Hz, IH), 1.20 (d, .7=7.0 Hz, 3H). m/z (ESI, +ve ion) 643.2 (M+H) ⁺ .

EXAMPLE 462, (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6~CHLORO-12 ^! ~ETHYL-7',l Γ- DIMETHOXY-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(lS,3'R,6Ί ,7 ^, S,8Έ,lΓR,12'S)-6-CHLO O-12'-ETHYL~7 l -MEΊΉOXY-3,4" DIHYDRO-2H, 15'H-SPIR()[NAPHTHALENE-1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 -DIOXIDE or

(lS,31,6 ^, R,7 ^! S,8'E,irS,I2'S)-6-CHLORO-12 ^, -ETHYL-7',ll ^, -METHOXY-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,I6,18,24]TETiL E ]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7 ^* S,8'E, 11 'R, 12'R)-6-CHLORO- 12'-ETH YL-7', 11 '-METHOXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404, Step 2 using (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-chloro-12'-ethyl-7'- hydroxy-1 r-methoxy-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- 12 ⁽ j aj i |thia| U4|dia/.alclraeycioj N.7.2 ⁽ r'-.o ¹¹ ' ^!| ipenlacosa|8. !6J8.24i!cirac nj-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,irR,12 ^! S)-6-chloro-12 ^! -ethyI-7'- hydroxy-11 '-methoxy-3,4-dihydro-2H, 15'H-spirofnaphthalene-l ,22'- [20]oxa[13]thia[l,14]diazatetra<y^

n]-15'-one 13 ^* , '-dioxide or (lS,3 ^, R,6 ^, R7'S,8 ^, E,irS,12'S)-6~chloro-12'"ethyl-7'- hydroxy-1 -methoxy-3,4-dihydro-2H, 15'H-spiroj naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatefra<^

n]-15'-one 13',13'-dioxide or (1S,3'R,6'R,7 ^! S,8'E,1 l'R,12 ^! R)-6-chloro-12'-ethyl-7'- hydroxy-ir-methox>'-3,4-dihydro-2H,15H-spiro[naphthalene- l,22'- [20]oxa[13]thia[l,14]diazatetracy^^

nj~1.5'~one 13',13'-dioxide (Example 458, Step 7) and iodomethane, and isolated as the first eluting isomer from the reversed phase preparatoiy HPLC separation. ¾ NMR (500MHz, CDCb) 58.18 (s, 1H), 7.70 (d,■/ 8.6 Hz, 1 II).7.18 (dd,

./ 2.3.8.4 Hz, 111).7. 0 (d, ,/ 22 Hz, 1H), 6.94 (s, 21 \) 6.85 (s, !H), 5.77 - 5.67 (m, IH), 5,66 - 5.59 (m, ill).4.15 - 4.08 (m, 3H), 3,81 (d, ./ 1 .2 Hz, IH), 3.73 (d, ./ 14.2 Hz, IH), 3.66 (dd, ./ 3.4.8.6 Hz, IH), 3.55 - 3.50 (m, IH), 3.37 (s, 3H), 3.26 - 3.21 (m, 4H), 3.01 (dd, ,/ 10.0.15.2 Hz, IH), 2.85 - 2.71 (m, 2H), 2,61 - 2.53 (m, H), 2.51 - 2,40 (m, 2H), 2.33 (quin, .7=9.0 Hz, IH), 2.24 (quind, J=7,5, 15.2 Hz, IH), 2.16 - 1.60 (m, 8H), 1.41 (t, ./ 12.7 Hz, IH), 1.30 (t, ./ 7.5 Hz, 3H). m (ESI, +ve ion) 643.2 (M+H) ⁺ . Example 463. ( ! S,3'R,6'R,7'S,8'E,1 'S,l 2'S)-6-CHLORO-7'-(2- METHOXYETHOXY)-12'-(METHOXYMETHYL)-i -METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[2()iOXA|;i3]THIA|;i,14]DlAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,irS,12 ^, R)-6-CHLORO-7'-(2-METHOXYETHOXY)-12'- (METHOXYMETHYL)-i -METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[N APHTH ALENE- 1 ,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^{:' i'} .0 ^li ' |Pi-:N i ACOSA

[8, -15'-QNE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404, Step 2 using (1S,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-chioro-7'-hydroxy- 12'-(meihoxymethyl)-r!'-methyl~3,4-dihydro-2H,15'H-spiro[nap hthalen

[20]oxa[13]thia|;i,14]diazatetracycio[14;7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24] nj-15'-one 13 ',13 '-dioxide or (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-chIoro-7'-hydroxy- 12'-(methoxymethyl)- 11 '-methyl-3,4-dihydro-2H, 15'H-spiro| naphthalene-! ,22'- [20]oxa[13]thia[l,14]diazatet^

n]-15'-one 13',13'-dioxide or (lS,3*R,6'R,7 ^! S,8'Z,ll'S,12'S)-6-chloro-7'-hydroxy- 12'-(methoxymethyl)-i -methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[I3]1hia[l,I4]diazatetTacyclo[1 J.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-I5'-one 13 ',13 '-dioxide or (18,3¾,6Ί ,7'8,8*Ζ,11*8,12'ί )-6-ΰωοΐΌ-7'¾^Γθχν- 12'-(methoxymethyl)- 1 l'-methyl-3,4-dihy dro-2H, 15'H-spiro| naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazate1ra^ n]-15'-one 13',13'-dioxide (Example 455, Step 3, the crude materia] before HPLC purification) and 2-bromoethyl methyl ether, and isolated as the first eluting isomer from the reversed phase preparatorv' HPLC separation. ¾ NMR (400MHz, CDCls) δ 8.05 (s, i l l ). 7.70 (d, ./ K.6 Hz, I I I ). 7.18 (dd, ,/ 2.2. 8.4 Hz, i l l ). 7.09 (d, ,/ 2 2 Hz, 11 1 ). 6.95 - 6.84 (ra, 3H), 5,94 - 5.79 (m, 11 1 ). 5.64 - 5.48 (ra, i l l ). 4.45 (dt, J=2A, 5.2 Hz, IH), 4.11 - 3.97 (m, 4H), 3.88 - 3.75 (m, 2H), 3.70 (d, J=I4.3 Hz, IH), 3.62 - 3.54 (m, IH), 3.53 - 3.48 (m, 2H), 3.46 - 3.40 (m, 4H), 3.39 (s, 3H), 3.22 id. ,/ 14 3 Hz, I H), 2.98 (dd, 10.2. 15.5 Hz, IH), 2,87 - 2.67 (111, 2H), 2,56 - 0.60 (m, 16H). m z (ESI, +ve ion) 687.2 .

EXAMPLE 464. (1 S,3'R,6'R,7'S,8'E, 1 l'S,12'R)-6-CHLORO-7'-(2- METHOXYETHOXY)- 12'-(METHOXYMETHYL)- 1 1 '-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, I 8,24]TETRAENl-15'-ONE 13', 13'-DTOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-7'-(2-METHOXYETHOXY)- 12'- (METHOXYMETHYL)- 11 '-METH YL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 463. ^! H NMR (400MHz, CDCh) δ 8.29 (br, s., IH), 7.66 (d, J=8.6 Hz, IH), 7, 18 (dd, J=2.4, 8.5 Hz, 2H), 7,09 (d, ./ 2.2 Hz, IH), 6.96 id . «/=8.0 Hz, IH), 6.74 (br, s., IH), 5.91 (br. s„ IH), 5.49 (del ,/ 75.15.6 Hz, ill).4,20 - 4,01 (m, 311).3.95 - 3.82 (ra, 211), 3,79 - 3.49 (m, 6H), 3.47 - 3,32 (m, 8H), 3.30 - 3.17 (m, H), 2.87 - 2,45 (m, 5H), 2.33 (d, ,1=5.5 Hz, 2H), 2,12 - 1.76 (m, 6H), 1.71 - 1.59 (m, ill).1.49 (t, ./ I 1.9 Hz, HI).1.19 (d, ./ 7.2 Hz, 3H). nvz (ESI, +ve ion) 687,2 (M il) ^' ,

EXAMPLE 465. (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-12'-ETHYL-l Γ- ME ^r fflOXY-7'"(2-(4-MORl ⁵ HOLINYL)ETHOXY)-3,4-DlHYDRO-2H,15 ^, H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 (Γ ",Ο ¹ " ^M |Ρ!·Λ iACOSA [8,16,18,24]TETiL4E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3¾,6'R,7^,8T,ll'R,12^)-6 :HL()RO-12'-ETHYL r-METH()XY-7 ^! -(2-(4- MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8 ₅ 16,18,24]TETRAEN]-15"-ONE 13',13'-D )XIDE OR

(1 S,3'R,6 ^! R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-12'-ETHYL-l 1 '-ΜΕΊΉΟΧΥ-7'-(2-(4- MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS.3'R,6 ^, R,7 ^, S,8¾ll ^, R 2 ^, R)-6-CHLORO-12 ^, -ETHYL-ll ^, -METHOXY-7 ^, -(2-(4- MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|2ujOXA| !3jTIUA| l.l4|niA/A I:TRA( ^' YCl.Oj i 4.7.2,0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA

'-ONE 13 ^! ,13 ^* -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404 using ((lS,3¾ VR ^,8T,,irS,12'R)-6-chloro-12'-ethyl~7 ^! ~ hydroxy -1 -methoxy-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- !2C)joxa 13]thia[l,14]diazateto^^

n]-15'-one 13',13'-dioxsde or (1 S,3'R,6'R,7'S,8'E,1 l'R,12'S)-6-chloro-12'-ethyl-7'~ hy droxy - 1 -methoxy - 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1,22'- [20]oxa[13]thia[l,14]diazatetracy^

n]-15'-one I3',13'~dioxide or (1S,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-chloro-12'-ethyl-7'- hydroxy-r -methoxy-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

n|-15'-one 13',13'-dioxide or (lS,3 ^! R,6'R,7'S,8'E,irR,12 ^! R)-6-chloro-12'-ethy3-7'- hydroxy-11 '-methoxy-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[U4]diazatetracy^^

n]-15'-one 13',13'-dioxide (Example 458, Step 7) and 4-(2-bromoethyl)morpholine hydrobromide. ^! !l NMR (400MHz, CDCb) δ 8.57 (br, s., !!!}.7.70 (d, ./ 8. Hz, IH), 7.18 (dd, ,7=2,2, 8.4 Hz, IH), 7,10 (d, J=2.2 Hz, 1H), 7.00 - 6.90 (m, 2H), 6.79 (s, IH), 5.89 - 5.74 (m, Ml).5.60 (dd, J=8.5, 15.0 Hz, IH), 4.16 - 3.94 (m, 7H), 3.85 - 3.58 (m, 7H), 3.54 - 3.45 (m, IH), 3.35 (s, 3H), 3.31 - 1.74 (m, 20H), 1,73 - 1.57 (m, IH), 1.40 (t, ,/ 12.4 Hz, IH), 1.28 (t, ./ 7.4 Hz, 3H). m / (ESI, +ve ion) 742.4 (M+H) ⁺ .

EXAMPLE 466. (1 S,3'R,6'R,7'S,8'E, 11*S,12'S)-6-CHLORO-l 2'-

{\ ^: Ύ\ !OXV VI!·. Π iVL)-7 -l fVDROXY-l i'-.VU- ^' Tf IYI.-.VM>II IYDRO-21 U 1 !-

SPIRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOIM.T^.O'^.O^^lPE TACOSA

[8J6,18,24]TETRAEN]~1S'~0NE 33', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irS,12'R)-6-CHLORO-12'-(E;fflOXYMETOY L)-7'- HYDROXY-ir-METHYL-3,4-DIHYDRO-2H,15TI-SPIRO[NAPI-ITHALENE- 1,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ^; ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE i.T.i 3'-DIOXIDE

STEP 1 : (2R,3S)-l-HYDROXY-N ₅ N-BIS(4-METHOXYBENZYL)-3- METHYLHEX-5-ENE-2-SULFONAMIDE AND AND (2S,3S)-i -HYDROXY - N,N-BIS(4- -3-METHYLHEX-5-ENE-2-SULFON AMIDE

The title compound was prepared from (S)-N,N-bis(4-methoxybetizyl)-2- methylpent-4-ene-l -sulfonamide (Example 395, Step 3) by similar procedures described in Example 434, Steps 1-2. STEP 2: (2S ₅ 3S)-l-ETHOXY-3-METHYLHEX-5-ENTE-2-SULFONAMIDE

AND (2R,3S)-l-ETHOXY-3-METHYLHEX-5-ENE-2-SULFONAMIDE AND (S)-3- -l,5-DIENE-2-SULFON AMIDE

The title compound was prepared from (2R,3S)~l~hydroxy-N,N-bis(4~ methoxybenz l)-3-methylhex-5-ene-2-sulfonamide and and (2S,3S)-l-hydroxy- N,N-bis(4-memoxybenzyl)-3-memyIhex-5-ene-2-sulfonamide by similar procedures described in Example 439, Steps 1-2.

STEP 3: (lS,3'R,6'R,7'S,8T:,l l'S,12^)-6-CIlL()RO-12'-(ETI-IOXYMETHYL)-7'- HYDROXY- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTH ALENE- 1,22'-

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14J.2 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8 ₅ 16,18,24]TETRAEN]-15"-ONE 13',13'-D )XIDE OR

(Ιβ,Β'Κ,ό'Κ,Τ'β,δ'Ε,ΙΙ'β, 'Κνό-ΟΗίΟΚΟ-Ι^-ίΕΤΗΟΧΥΜΕΤΗΥ^-Τ- HYDROXY-i -METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 122'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was prepared from (2S,3S)-l-ethoxy-3-methylhex-5- ene-2-sulfonamide and (2R,3S)-1 -ethoxy-3-methylhex-5-ene-2-sulfonamide and (S)-3-methylhexa-l,5-diene-2-sulfonamide by similar procedures described in Example 458, Steps 6-7, and isolated as the second eluting isomer from the reversed phase preparatory HPLC separation. Ή NMR (4()(MHz, CDCh) δ 8.14 (br, s., !!!}.7.69 (d, J=8.4 Hz, !!!}.7.18 (dd, ./ 2.!.8.5 Hz, !!!).7.10 (d, 20 Hz, 2H), 6.92 (s, 2H), 5.95 - 5.83 (m, 1H), 5.67 (dd, ./ 6.6.15.2 Hz, 1H), 4.47 - 4.35 (m, IH), 4.20 (br. s., 1H), 4.15 - 4.03 (m, 3H), 3.94 (br. s., 1H), 3.79 - 3.47 (m, 4H), 3,39 - 3.11 (m, 2H), 2.88 - 2.68 (m, 2! I ).2,51 - 1.05 (m, 20!!}. m/z (ESI, +ve ion) 643.2 (M+H) ⁺ .

EXAMPLE 467. (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHL()RO-12'- (ETHOXYMETHYL)-7'-HYDROXY-i -METHYL-3,4-DIHYDRO-2H,.15'H- SPi ()i\AFHiH. !J \!:-l.22-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E ₅ lΓS,12 ^, S)-6-CHLORO-12 ^, -(ETHO YMETHYL)-7 ^, - HYDROXY-1 r-METHYL-3,4-DIHYDRO-2H,l 5'H-SPIRO[ APHTHALENE- 122'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ "*0 ^]9 ^ ⁴ ]PE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15 ^! -ONE 13', 13 ^! -DIOXIDE

The title compound was obtained as the third eluting isomer from the reversed phase preparatory HPLC separation in Example 466, Step 3. Ή NMR (400MHz, CDCb) 68.28 (br. s., Ml).7.67 (d, J=8.4 Hz, lH), 7.18 (dd, J=2.2, 8.5 Hz, ill .7.14 - 7.09 (m, 2H), 6.95 (d, J=8.2 Hz, 1H), 6.85 (br. s., ill).5.90 (br. s., 1H), 5,65 (dd, ./ 5.7.15.5 Hz, 1H), 4.21 - 3.96 (ra, 7H), 3,85 (br. s,, !H), 3.66 (d, ,/ 1 -I 3 Hz, I Hi.3.59 - 3.22 (m, 7H), 2,93 - 2.70 (m, 3H), 2.58 (br. s., 2H), 2,47 (d, J=3.9 Hz, 1H), 2.36 - 1.08 (m, 12H). m/z (ESI, +ve ion) 643.2 {M il) .

EXAMPLE 468. (1 S,3'R,6 ^! R,7'S,8 ^! E,1 l'S)-6-CHLORO-7'-HYDROXY-l Γ- ΜΕΊΉΥΕ-12'-ΜΕΊΉΥΕ10ΕΝΕ-3,4-01ΗΥΟίΙΟ-2Η ,15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PEOTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was obtained as the first eluting isomer from the reversed phase preparatory HPLC separation in Example 466, Step 3. ^" Ή NMR (400MHz, CDCb) δ 8.30 (s, 1H), 7.70 (d, ./ 8.4 Hz, 1H), 7.18 (dd, ./ 2.2.8.5 Hz, ill).7.09 (d, ./ 2.0 Hz, 1H), 6.92 (s, 2H), 6.86 is. ill .6.79 id../ 0.8 Hz, 1H), 6.03 (s, 1H), 5.78 - 5.56 (m, 2H), 4.20 - 4.02 (m, 3H), 3.78 (d, ./ 133 Hz, !H), 3.70 (d, .7=14,1 Hz, 1H), 3.21 (d, .7=14,3 Hz, IH), 3.01 (dd, .7=8.9, 15.4 Hz, 1H), 2.87 - 2.64 (m, 3H), 2.49 - 2.22 (m, 4H), 2.08 - 1.57 (m, 8H), 1.40 (t, J=12.6 Hz, 1,28 (d, J=7.0 Hz, 3H). m (ESI, +ve ion) 597.2 (M il) .

EXAMPLE 469. (IS^'R^'R 'S^'EjrS/ 'S e-CHLO O- '- (ETHOXYMETOYL)-7'-METHOXY-l l'-METHYL-3,4-DIHYDRO-2H,15TI- SPTRO[NAPHTH ALENE- ! ,22'-

|2( >X A| i i ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)i i J 7.20 ^' ".O ¹ '' ' ¹ |Pi-NT.\( SA

[8,16,18,24]TETR _! 4ENl-15'-ONE 13 ^! ,13'-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E,I 1 ^* S J 2 ^f S)-6-CHLORO- 12'-(ETHOXYMETHYL)-7'-

METOOXY-ir-METHYL-3,4-DIHYDRO-2H, 15H-SPIRO[NAPHTHALENE-

1 ">"><-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA

~1S'~0NE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described m Example 404, Step 2 using (l S,3'R,6'R,7'S,8'E,l l'S,12'S)~6~chloro~12'~ (ethoxymethyl)-7' iydroxy-i -meth}4-3,4-dihydro-2H,15'H-spiro[naphthaiene- 1,22'-

[20]oxa[13]thia[l ,14]diazatefra<^

n]-15'-one 13',13'-dioxide or { i S 'R.6 ^' K .7'S^'|{J i 'S. i 2'R i-6-ch!oro- 1 2 ^' - (ethQxyniethyl)-7'-hydroxy-ir-m

1,22 ^« -

n]-15'-one 13', 13 '-dioxide (Example 466) and iodomethane. ¾ NMR (400MHz, CDC! :.) δ 7.82 (s, i l l . 7.50 id. ./ 8.6 Hz, 1H), 6.99 (dd, ./ 2.2. 8.5 Hz, I I I ). 6.90 (d, ./ 2.3 Hz, IH), 6,77 - 6.62 (m, 3H), 5.76 - 5.62 (ra, IH), 5,32 (dd, J=9.2, 14.9 Hz, IH), 4.30 (ddd, .7=2.4, 4,4, 6.7 Hz, IH), 4,00 - 3.83 (m, 4H), 3.62 (d, .7= 15,3 Hz, IH), 3.54 - 3.44 (m, 2H), 3.43 - 3.33 (m, 2H), 3.11 - 2.99 (m, 4H), 2.81 (dd, ./ H U . 15.4 Hz, IH), 2.68 - 2.48 (m, 2H), 2.42 - 1.35 (m, 19H). m /. (ESI, +ve ion) 657.2 (M+H) ⁺ . EXAMPLE 470. (l S,3'R,6'R,7'S,8'E,H'S,12'R)-6-CHLORO-12'-ETHYL-7'- HYDROXY- 11 '~(2~METHOXYETHOXY)-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[N APHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R 7 ^, S,8 ^, E,irS,12 ^! S)-6-CHLORO-12 ^, ~ETHYL-7 ^, -HYDROXY-i r-(2- METHOXYETHOXY)-3,4-DIHYDRO-2H,l .5'H-SPIRO|NAPHTHALENE-l ,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'R,12'R)-6-CHLORO-12'-ETHYL-7'-HYDROXY- 1 1 '-(2- METHOXYETHOXY)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 ^^^

[8,16,18,24]TETiL4E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8T,l l'R,12 ^, S)-6-CHLORO-12'-ETHYL-7'-HYDROXY-i r-(2- METHOXYETHOXY)-3 ₅ 4-DlHYDRO-2H,l 5H-SPIRO[NAPHTH ALENE-1 ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

'-ONE 13'.13'-DIO

STEP 1 : (3S,4S)-4-(2-METHOXYETHOXY)HEPT-6-ENE-3-SULFONAMIDE

AND (3R,4R)-4-(2-METHOXYETOOXY)HEPT-6-ENE-3-SULFONAMiDE AND (3S,4R)-4-(2-METHOXYETHOXY)HEPT-6-ENE-3-SULFONAMIDE

The title compound was prepared from (3S,4S)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (3S,4S)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3 -sulfonamide and (3S,4R)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (3R,4S)-4-hydroxy-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide (Example 458, Step 4) and 2- bromoethyl methyl ether by similar procedures described in Example 434, Steps 3-4. m/z (ESI, +ve ton) 252.2 (M+H) ⁺ . STEP 2: (1 S,3'R,6'R,7'S,8'E,1 l 'S, 12'R)-6-CHLORO-12'-ETHYL-7'-HYDROXY- 11 '~(2~METHQXYETHOXY)-3 ,4-DIHYDRO-2H, 15 Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - i 5'-ONE 13', 13'-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 rS,12 ^! S)-6-CHLORO-12'-ETHYL-7'-HYDROXY-l Γ-(2-

ME^ΉOXYETHOXY)-3 ₅ 4-DIHYDRO-2H,15Ή-SPIRO|NAPHTHALENE-l ,22 ^, - [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'R,12'R)-6-CHLORO-12'-ETHYL-7'-HYDROXY- 1 1 '-(2- METHOXYETHOXY)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l ,22'- | 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]TETiLAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E, l l'R,12'S)-6-CHLORO-12'-ETHYL-7'-HYDROXY-i r-(2- METHOXYETHOXY)-3 ₅ 4-DlHYDRO-2H,l 5H-SPIRO[NAPHTH ALENE-1 ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)-I - hydroxyallyl)cyclobut\ )m.ethyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4]oxazepme-3, 1 '-naphthalene] -7-carboxylic acid (Intermediate, AA11 A) and (3S,4S)-4-(2-methoxyethoxy)hept-6-ene-3-sulfonamide and

(3R,4R)-4-(2-methoxyethoxy)hept-6-ene-3-sulfonamide and (3S,4R)-4-(2- methoxyethoxy)hept-6-ene-3-sulfonamide and (3R,4S)~4-(2-m.ethoxyethoxy)hept- 6-ene-3-sulfonamide by similar procedures described in Example 432, Steps 4-5, and isolated as the major isomer from the reversed phase preparatory HPLC separation. ¾ NMR (400MHz, CDCb) δ 8.95 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.18 (dd, J=2.2, 8.5 Hz, i l l ). 7.10 (d, ./ 2.2 Hz, 1H), 6.99 - 6.81 (m, 3H), 5.89 - 5.78 (m, 1H), 5.77 - 5,64 (m, 1H), 4.26 (dd, ,/ 44.7,1 Hz, !H), 4.18 - 4,03 (m, 21 \ ).3.90 (dd, ,7=3,9, 8.0 Hz, ill).3,83 (d, ./ 15.1 Hz, 1H), 3.77 - 3.66 (m, 4H), 3.60 - 3.51 (m, IH), 3.43 - 3.35 (m, 1H), 3.29 - 3.21 (m, 4H), 3.10 - 2.99 (m, 1H), 2.87 - 2.69 (m, 2H), 2.54 - 0.74 (m, 18H). nVz (ESI, +ve ion) 673.2 ( +H) ⁺ .

EXAMPLE 471. (Ιβ^'Κ,ό'Κ^'β,δΈ,ΙΟ'Κ,Π'βνό-ΟΉΕΟΚΟ^'-Η ΥΒί ΟΧΥ-η'- (METHOXYMETHYL) - 10'-METHYL- 3 ,4-DIH YDRG-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,l()'S,12'S)-6-CHLORO-7 ^! -HYDROXY-12'- (METHOXYMETHYL)- 10'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή- 8ΡΚΟ[ΝΑΡΗΊΉΑ1,ΕΝΕ-1,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13*-DIOXIDE

STEP 1: (2R,4S)- 1 -METHOXY-4-METHYLHEX-5-EN-2-OL AND (2R,4R)-1- METHOXY-4-METHYLHEX-5-EN-2-OL

To 1 -methyl-2-propenylmagnesium chloride (95.0 ml, 47.7 mniol), 0.5 M solution in THF stirred at -10°C to -18°C in a 500-mL single-necked round- bottomed flask was added slowly (r)-(-)-glycidyl methyl ether, 97% (2.00 ml, 22.7 mniol) in THF (45.4 ml) over 1 h. The resulting mixture was allowed to slowly warm up to ambient temperature and stirred overnight. The reaction mixture was cooled in an ice bath before slowly quenched with ice-cold saturated ammonium chloride aqueous solution. This mixture was further diluted with ether and ice- cold water. The organic layer was separated and concentrated. The residue was purified by chromatography eluting with a gradient of 0% to 35% EtOAc in hexane to give the title compound (3.21 g, 98 % yield). R NMR (400 MHz, CDCh) δ 5.61-5.87 (m, 1H), 4.90-5.13 (m, 2H), 3.78-3.94 (m, 1H), 3.35-3.48 (m, 4H), 3, 18-3.32 (m, I H), 2.34-2,52 (m, 1H), 2.23-2.34 (m, IH), 1.44-1.62 (m, IH), 1.26-1.39 (m, IH), 1.01-1.10 (m, 3H).

STEP 2: (2S,4S)-l -METHOXY-4-METHYLHEX-5-ENE-2-SULFON AMIDE AND (2S,4R)-l-METHOXY-4-METHYLHEX-5-ENE-2-SULFONAMIDE

The title compound was prepared from (2R,4S)- 1 -methoxy-4-methylhex- 5-en-2-ol and (2R,4R)-l-methoxy-4-methylhex-5-en-2-ol by similar procedures described in Example 703, Steps 3-5. m/z (ESI, +ve ion) 230.2 (M+Na) ⁺ .

STEP 3: (lS,3'R,6'R,7'S,8'E,I0'R,12'S)-6-CHLQRQ-7'-HYDRQXY-12'- (METHOXYMETHYL) - 10'-METHYL-3 ,4-DIH YDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ 0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETR^\EN]-15'-ONE 13 ',13 '-DIOXIDE OR

(l S,3'R,6 ⁱ R,7'S,8'E,10'SJ 2'S)-6-CHLORO-7'-HYDROXY-I2'- (METHOXYMETHYL)- 10'-ΜΕΤΉ YL-3 ,4 -DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAt^MlDIAZATET ACYCLOI l^T^.O'^.O^^lPE TACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13", 13'-DIOXTDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2~((S,E)- l-hydroxyhex-2-en-l-yl)cyclobutj _' )niethyl)-3',4,4',5-tetrahydiO-2H,2'H- spiroj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate, AA12A) and (2S,4S)-! -rnethoxy-4-methylhex-5-ene-2-sulfonamide and (2S.4R)- 1 -methoxy-4-methylhex-5-ene-2-sulfonamide by similar procedures described in Example 458, Steps 6-7, and isolated as the first isomer from the reversed phase preparatory HPLC separation. ¾ NMR (400MHz, CD3OD) δ 7.73 (d, J=8.6 Hz, 1H), 7.16 (dd, ./ 2.3. 8.4 Hz, I I I ). 7.10 (d, ,/ 2.2 Hz, 1H), 7.00 - 6.95 (m, IH), 6,95 - 6.91 (ni, 1 H), 6.80 (d, ,/ 1 .6 Hz, IH), 5.80 (dd, J=5.5, 15.8 Hz, IH), 5,68 - 5,54 (m, 1H), 4.39 - 4.30 (m, H), 4.29 - 4,24 (m, 1H), 4.15 - 4.00 (m, 2H), 3.90 - 3.74 (m, 3H), 3.63 (d, J=I3.9 Hz, IH), 3.37 (s, 3H), 3.19 (d, J=U. l Hz, 1H), 3.04 (dd, J=9.4, 15.3 Hz, IH), 2.86 - 2.68 (m, 2H), 2.58 - 1.60 (m, 12H), 1 ,52 - 1.40 (m, IH), 1 ,07 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 472. (l S,3'R,6 ^! R,7 ^, S,8 ^! E, 10 ^! S,12'S)-6-CHLORO-7'-I-ri ^ir DROXY-12'- (METHOXYMETHYL)- 10'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAENl-15'-ONE 13', 13 ^* -DIOXIDE OR

(lS,3'R,6 ^! R,7^,8'E,10'R,12'S)-6-CHLORO-7'-HYDROXY-12 ^! - (METHOXYMETHYL)- 10'-METH YL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147.2 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 471, Step 3. Ή NMR (400MHz, CD3OD) δ 7.73 (d, .7=8,6 Hz, H), 7.16 (dd, J=2.3, 8.4 Hz, IH), 7.10 (d, ./ 2.2 Hz, i l l ). 7.05 - 7.00 (m, IH), 6.97 - 6.89 (m, 2H), 5.93 - 5.84 (m, IH), 5.63 (ddd, ./ 1 .6, 6.7, 15.8 Hz, IH), 4.28 - 4.17 (m, 2H), 4.11 - 4.07 (m, 2H), 4.00 - 3.89 (rn, 2H), 3.82 (d, ./ 14.9 Hz, i l l ). 3,65 (d, ./ 14. 1 Hz, IH), 3,40 (s, l ). 3,09 (dd, J=9.5, 15.4 Hz, IH), 2.89 - 2.64 (m, 21 1 ). 2,49 - 1.55 (m, 13H), 1.50 - 1.39 (m, IH), 1.09 (d, ./ 6.7 Hz, 3H). m/z (ESI, +ve ion) 629.2 { W W ) . EXAMPLE 473. (1 S,3'R,6'R,7'S,8'E,10'R,12'S)-6-CHLORO-7'-METHOXY-12'- (METHOXYMETHYL) - 10'-METH YL-3 ,4-DIHYDRO-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

| 20 i()X A| ΐ : ΐ Η1 Λ| Κ. ! | ί)!Λ/Λ ! : ΓΗ.Λ( ^' Χ)Ι 1 17.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-DIGXiDE OR

(lS,3'R,6 ^! R;7 ^, S,8'E, l()'S,12'S)-6-CHLORO-7 ^! -METHOXY-12'- (METHOXYMETHYL)- 10'-METHYL-3 ,4-DIHYDRO~2H, 15 Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, - 15"-ONE 13', 13 ^* -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404, Step 2 using (l S^'R^'R^'S^lOlU^S^e-d-loro^'^dro y^ 12'-(methoxymethyl)-10'-methyl-3,4-dihydro-2H,151i-spiro[nap hthalene-l ,2

[20]oxa[13]thia[ l, 14]diazatetTacy^^

n]-15'-one 13', 13'-dioxide or (lS,3'R,6 ^! R,7'S,8'E,10'S,12 ^! S)-6~chloro-7 ^! ~hydroxy- 12'-(methoxymethyl)- 10'-methyl-3,4-dihy dro-2H, 15'H-spir o| naphthalene- 1 ,22'- [20]oxa[ 13]thia[l ,14]cUazatetracyc^

n]-15'-one 13',13'-dioxide (Example 471) and iodomethane. ³ H NMR (500MHz, CD3OD) δ 7.72 (d, J=8.6 Hz, IH), 7.16 (dd, J=2.2, 8.6 Hz, IH), 7.10 (d, J=2.2 Hz, IH), 6.98 - 6.95 (m, IH), 6.93 - 6.91 i ns. IH), 6.79 (d, ,/ 1.7 Hz, IH), 5.95 (dd, ,/ 4 8. 15,5 Hz, IH), 5.46 (ddd, ./ 1 .5, 8.2, 15.5 Hz, I H), 4.50 - 4.36 (ra, IH), 4, 12 - 4.01 (m, 2H), 3.88 - 3,83 (m, 2H), 3.77 (dd, .7=3.8, 8,2 Hz, IH), 3.64 (d, .7=14.2 Hz, IH), 3.37 (s, 3H), 3.25 (s, 3H), 3.20 (d, J=14.2 Hz, IH), 3.05 (dd, ./ 9.7. 15.3 Hz, I H), 2.86 - 2.65 (m, 2H), 2.60 - 2.43 (m, 2H), 2.39 - 1.65 (m, 11H), 1.49 - 1.39 (m, IH), 1.10 (d, J=6.6 Hz, 3H). m/z (ESI, +ve ion) 657.2 (M+H) ⁺ .

EXAMPLE 474. (lS,3'R,6'R,7'S,8 ^! E, l() ^! R,12 ^, S)-6-CHL()RO-7'-HYDR()XY-l()'- METHYL-12'-(l -METHYLETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ iACOSA

[8,16,18,24]TETiL E ]-15'-ONE BVD'-DIQXIDE OR

(lS,3 ^, R,6'R,7 ^, S.8 ^, E.10 ^, S ₅ 12 ^, S)-6-CHLORO-7 ^, -HYDROXY-10 ^, -METHYL-12 ^, -(l- METHYLETHYL)-3,4-DIHYDRO-2H,15H-SPIROP^APHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R,7'S,8Έ;l0'SJ2'R)-6 ;HI RO-7' iYD OXY-10 ^f -METHYL-12' !- METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- |2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/Α Π:ΤΗΑ(Ύα.ί)Ι i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAEN1-15'-0NE 13 ^! ,13 ^* -DIOXIDE OR

(18,3Έ,6¾,7Έ,8Τ ϊ0¾, 2Έ)-6Χ4Τ^

ME ^r rHYLETHYL)~3,4-DlHYDRO-2H,15H-SPlRO[NAPHTHALENE~l,22'~ |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA

"-ONE 13',13'-DTOXIDE

STEP 1: (S)-3-METHYLPENT-4-EN-l-OL AND (S)-3-METHYLPENT-4-EN-l-

OL

To a 500-mL round-bottomed flask was added 3-methyl-4-pentenoic acid (6.38 ml, 52.6 mmol) in THF (210 ml). The solution was cooled to 0°C, and lithium aluminum hydride, 1.0 M solution in tetrahvdrafuran (60.0 ml, 60.0 mmol) was added to the solution through an addition funnel. The resulting mixture was stirred at this temperature for 4 h. The reaction was quenched by addition of 2.28 mL of water, 4.56 mL of 10% NaOH, and 6.84 mL of water in order. The solid was filtered off, and the solution was dried over MgSOt, filtered and concentrated to provide the crude title compound as colorless oil (3.40 g, 65%). ^! H NMR (400 MHz, CDCb) δ 5,63-5.88 (m, i l l ). 4.86-5. 11 (m, 2H), 3 ,57-3.77 (m, 2H), 2.24- 2.43 (m, 1H), 1.54-1.71 (m, 2H), 0.95-1.09 (m, 31 1 ). STEP 2: (S)-3-ME -4-ENAL AND (R)-3-METHYLPENT-4-ENAL

To a solution of oxalyi chloride (12.7 ml, 25.5 mmol) in DCM (50 mL) at - 78°C was added dimethyl sulfoxide anhydrous (3.61 ml, 50.9 mmol) under N ₂ . After the solution was stirred for 2 min, a solution of (S)-3-methylpent-4-en- l -ol and (S)-3-methylpent-4-en-l -ol (1.70 g, 17.0 nimol) in DCM (10 mL) was added, and the resulting mixture was stirred at this temperature for 15 min. Triethylamine (11 ,8 ml, 85.0 mmol) was added, and the mixture was stirred at ambient temperature for 20 min. The reactio mixture was diluted with DCM, washed with 1 M HC1 aqueous solution, saturated NaHCCb aqueous solution, saturated NaCl solution, dried over MgSC¼ and concentrated to give the title compound (1.30 g, 78 % yield), ^" Ή NMR (400 MHz, CDCb) δ 9,28-9.97 (m, 1 H), 5.80 (ddd, ,/ 6 85. 10.37, 17.22 Hz, 1H), 4.91-5.14 (m, 2H), 2.68-2.86 (m, 1H), 2.30-2.54 (m, 2H), 1.10 (d, J==6.85 Hz, M l ). STEP 3: (3S,5S)-2,5-DIME ^" fflYLHEPT-6-EN-3-OL AND (3S,5R)-2,5-

DIMETHYLHEPT-6-EN-3-OL AND (3R,5S)-2,5-DIMETHYLHEPT-6-EN-3- OL AND (3R,5R)-2,5-DIMETHYLHEPT-6-EN-3-OL

To the solution of (S)-3-methylpent-4-enal and (R)-3-methylpent-4-enal (1.50 g, 15.3 mmol) in THF (61.1 ml) in a 250-mL round-bottomed flask at -78 °C was added isopropylmagnesium chloride (15.3 ml, 30.6 mmol). The resulting mixture was stirred at this temperature for 1 h and gradually warmed up to ambient temperature. The reaction mixture was diluted with saturated NH4CI (20 mL), and extracted with EtOAc (2 x30 mL), The organic extract was washed with saturated NaCl (10 mL), and dried over MgSC . The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g). eluting with a gradient of 0% to 35% EtOAc in hexane to provide the title compound (1.10 g, 51 % yield) as colorless oil. ¾ NMR (500 MHz, CDCh) δ 5.55-5.91 (m, 1H), 4.84-5.13 (m, 211), 3.33-3.53 (m, 1H), 2.28-2.47 (m, 1H), 1.58- 1.72 (m, 1H), 1.35-1,51 (m, 2H), 1.04 (dd,J=5.87, 6,85 Hz, 3H), 0.83-0,94 (m, 6H).

STEP 4: (3S,5S)-2,5-DIMETHYLHEPT-6-ENE-3-SULF()NAMIDE AND (3S,5R)-2,5-DIMETHYLHEPT-6-ENE-3-SULFONAMIDE AND (3R,5S)-2,5- DIMETHYLHEPT-6-ENE-3-SULFONAMIDE AND (3R,5R)-2,5- -6-ENE-3 -S ULFONAMIDE

The title compound was prepared from (3S,5S)-2,5-dimethylhept-6-en-3-ol and (3S,5R)-2,5-dimethylhept-6-en-3-ol and (3R,5S)-2,5-dimethylhept-6-en-3-ol and (3R,5R)-2,5-dimethylhept-6-en-3-ol by similar procedures described in Example 703, Steps 3-5. m/z (ESI, +ve ion) 206.6 (M+H) ⁺ .

STEP 5: (lS,3 ^, R,6'R,7 ^, S,8'E,10'R,12 ^, S)-6-CHLORO-7'-HYDROXY-10'- METHYL- 12'-( 1 -METHYLETHYL)-3 ,4-D IHYDRO-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'- |2 ⁽ >X A| i 1 U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24]TETRAEN]-15'-QNE 13',13'-D10X1DE OR

(lS,3¾,6 ^! R,7^,8T,l()'S,12'S)-6-CHLORO-7 ^! -HYDROXY-10'-METHYL-12'-(l- METOYLETOYL)-3,4-DIHYDRO-2H, 15H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]TH1A[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR (18,3¾ Κ,7'8,8Έ;0'842¾)-6-εΗΙ Ο-7' ίΥΟΚΟΧΥ-10'-ΜΕΤΗΥΙ.-12'-(!- METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- |2 ⁽⁾ jOXA| O ΙΊ ί Ι1Λ| I . I 4|ΠΙΛΖ.\ Ι: f AC YCE.OI i 4.7.2 U · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA

[8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE OR

(!S,3¾,6¾,7^,8Tvl0'R,12¾)-6-CHLORO^

METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TH1A[1 4]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13*-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- 1 -hydroxyhex-2-en-l -yl)cyclobut'l)methyl) ^» 3',4,4',5~tetrahydro-2H,2'H~

spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxyl ic acid (Intermediate, AA12A) and (3S,5S)-2,5-dimethylhept-6-ene-3-sulfonamide and (3S,5R)-2,5- dimethylhept-6-ene-3-sulfonamide and (3R,5S)-2,5-dimethylhept-6-ene-3- sulfonamide and (3R,5R)-2,5-dimethylhept-6-ene-3-sulfonamide by similar procedures described in Example 458, Steps 6-7, and isolaied as the first isomer from the reversed phase preparatory HPLC separation. Ή NMR (400MHz,

CDCb) δ 8.21 (br. s., 1H), 7.71 id../ 8. Hz, 1H), 7.18 (dd, ./ 2.3.8.4 Hz, ill). 7.09 (d, J 2.3 Hz, !!!).6.94 (s, 2H), 6.78 (s, !!!).5.80 (dd, ,/ 5.3.15.5 Hz, 1H), 5,67 - 5.57 (m, 1H), 4.38 - 4.31 (m, IH), 4,17 - 4.00 (m, 3H), 3.80 (d, ,/ 1 i Hz, IH), 3,71 (d, J=13.9 Hz, IH), 3.17 (d, .7=14.1 Hz, IH), 3.02 (dd, J=9,0, 15.1 Hz, IH), 2.88 (dtd, J=2.6, 6.9, 13.8 Hz, IH), 2.82 - 2.69 (m, 2H), 2.53 - 0.78 (m, 23!!}. m/z (ESI, +ve ion) 627.2 i \\ U ) .

EXAMPLE 475. (IS,3 ^, R,6 ^, R,7'S,8'E,10'S,I2'S)-6-CHLORO-7 ^, -HYDROXY-10'- METHYL- 12'-( 1 -METHYLETHYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(lS,3'R,6¾,7'S,8¾10¾,12'S)-6-CHIX)RO-7'-HYDROXY-10 ^f -METIWL-I2'-(l^ METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0^^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(Ιβ,Β'Κ,ό'Κ,Τ'β,δΈ,ΙΟ'β, 'Κνό-ΟΗίΟΚΟ-Τ'-ΗΥϋΚΟΧΥ-ΙΟ'-ΜΕΤΗΥί-� �^-ίΙ- METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[2()iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 12 ^, R)"6"CHLORO-7'"HYDROXY-10'-METHYL-12'-(I - ME ^r rHYLETHYL)~3,4-DIHYDRO-2H,15H-SPnO[NAPHTHALENE~l,22'~ [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

'-ONE 13', 13'-DiOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 474, Step 5. ^" Ή NMR (400MHz, CDCb) δ 8.51 (br. s„ ill).7,71 (d, J=8.6 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.09 (d, J=1.8 Hz, 1H), 7.03 - 6.98 (m, lH), 6.97 - 6.91 (m, 1H), 5.74 - 5.50 (m, 2H), 4.24 - 3.97 (m, 3H), 3.91 - 3.77 (m, 2H), 3.73 (d, ,/ 14.7 Hz, 111).3.27 (d, ,/ 143 Hz, III).3.08 (dd, ,/ 6.3.15.5 Hz, ill).2,85 - 2.60 (m, 3H), 2.58 - 2.42 (m, 2H), 2.25 (br. s., 1H), 2,07 - 1,59 (m, 10H), 1.44 (t, ./ 12.3 Hz, 1H), 1.24 (d, J=6.8 Hz, 3H), 1.18 (d, J=7.0 Hz, 3H), 1.06 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 627.2 iVI-!ll .

EXAMPLE 476. (lS,3'R,6'R,7'S,8'E,10 ^, S,12'R)-6-CHLORO-7'-HYDROXY-10'" METHYL- 12'-( 1 -METHYLETHYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ⁱ R,7'S,8¾10'R,12'S)-6-CHIORO-7'-HYDROXY-10'-METIWL-I2' -( METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]D1AZATETRACYCLO[14.7.2.0 ³ ^^0 ¹⁹ - ²⁴ ]I TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

{ I S.3'R. ⁽ V .7 ;.8'i-:. lO'S.12' K-n U ORO~? ~i iYPROXY- 1 U'~V1! . f s V ! - i 2 -{ i - METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[2()iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN] S'~ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 12 ^, R)"6"CHLORO-7'"HYDROXY-10 ^, -METHYL-12'-(I - ME ^r rHYLETHYL)~3,4-DIHYDRO-2H,15H-SPnO[NAPHTHALENE~l,22'~ [20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

'-ONE 13', 13'-DiOXIDE

The title compound was obtained as the third eluting isomer from the reversed phase preparatory HPLC separation in Example 474, Step 5. Ή NMR (400MHz, CDCb) δ 8.17 (s, 1H), 8.03 - 7.68 (m, 1H), 7.65 (d, «7=8.6 Hz, 1H), 7.19 - 7.13 (m, IH), 7.10 (d, J=2.3 Hz, lH), 6.99 - 6.86 (m, 2H), 5.70 (dd, J=5.5, 15.8 Hz, IH), 5.18 (br. s., ill).4.42 - 1.19 (m, 2811).1.10 (d,J=6.7 Hz, 3H), 1.00 (d, 67 Hz, 3H). m/z (ESI, +ve ion) 627.2 i \ 1 II) .

EXAMPLE 477. (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,12 ^! S)-6-CHLORO-7 ^, -HYDROXY-12'- (2-METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,I0'S,I2'S)-6-CHLORO-7'-HY ^T DROXY-12'-(2- METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13|TfflA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(lS,3'R,6 ^, R,7'S,8 ^, E,10'S,12'R)-6-CHLORO-7'-HYDROXY-12 ^! "(2- METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| 1ΉΤί!1Λ| Ι.Ι4|ΠίΛ/.ΥΠ:ΤΗΛ(ΎΠ.ϋΙ i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PH\,T.\i SA [8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12'-(2- METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

STEP! : (3R,5S)-l-METHOXY-5-METHYLHEPT~6-EN-3-OL AND (3R,5R)~1- METHOXY-5-METHYLHEPT-6-EN-3-OL AND (3S,5R)-l-METHOXY-5- METHYLHEPT-6-EN-3-OL AND (3S,5S)-1 -METHOXY-5-METHYLHEPT-6- -3-OL

A mixture of magnesium (1.49 g, 61.4 mmol) in THF (10.0 mL) with a catalytic amount of iodine and 1,2 dibromoethane (0.176 ml, 2,05 mmol) was sonicated for 35 min. ^' To this suspension solution was added one fifth amount of 4-bromo-3-methylbut-l-ene (6.10 g, 40.9 mmol) in THF (20 ml) at 50 °C over 30 min, and rest of 4-bromo-3-methylbut-l-ene was dropwise added at 20-30°C, and the resulting mixture was stirred at ambient temperature for 1.5 h. The mixture containing (2-methylbut-3-en-l-yl) magnesium bromide was used to next step directly.

To 3-methoxy-propionaldehyde (3.61 ml, 4.1.0 mmol) in THF (2 mL) at ~15 C was added (2-methylbut-3-en-l-yi) magnesium bromide prepared above (7.11 g, 40.9 mmol) in THF (14 ml) slowly over 1 h. The resulting mixture was allowed to warm up to arabieni temperature and stirred overnight. The reaction mixture was cooled in an ice bath, and quenched with ice-cold saturated ammonium chloride aqueous solution. This mixture was further diluted with ether and ice-cold water. The organic layer was separated and concentrated. The residue was pun i led by chromatography through a Redi-Sep pre-packed silica gel column (24g), eluting with a gradient of 0% to 35% EtOAc in hexane to provide the title compound (3.00 g, 46 % yield) ¾ NMR (400 MHz, CDCh) δ 5.60-5.88 (m, Hi), 4.83-5.11 (m, 2H), 3,87 (tdd, 3.62. 12.59, 16.55 Hz, IH), 3.49-3.69 (m, 2H), 3.30-3,42 (m, 3H), 2,69-2.89 (m, I H i. 2.30-2,51 (m, IH), 1.64-1.80 (m, 2H), 1.53 (dt, J=4.69, 9.19 Hz, IH), 1.25-1.45 (m, IH), 1.05 (dd, J=2.64, 6.75 Hz, 3H).

STEP 2: 2-(((3R,5S)-l -METHOXY-5-METHYLHEPT-6-EN-3- YL)THIO)PYRIMIDINE AND 2-(((3R,5R)-l-METHOXY-5-METHYLHEPT-6- EN-3 - YL)THIQ)P YRIMIDINE AND 2-(((3S,5R)-l-METHOXY-5- METOYLHEPT-6-EN-3-YL)TOIO)PYRIMIDINE AND 2-(((3S,5S)-l- -5-METHYLHEPT-6-EN-3-YL)THIO)PYRIMIDINE

To an ice-cold solution of tributylphosphme (3.98 ml, 16.1 mmol) in 15 mL of anhydrous and degassed THF was added diethyl azodicarboxylate, 40% w/w in toluene (7.34 ml, 16.1 mmoi) dropwise. During the addition, the mixture became the orange color immediately. To this solution was added (3R,5S)-i- methoxy-5-methylhept-6-en-3~ol and (3R,5R)-l~methoxy-5-methylhept~6~en-3-ol and (3S,5R)-i-methoxy-5-methylhept-6-en-3-ol and (3S,5S)-l-niethoxy-5- methyihepi-6-en-3-oi (1.50 g, 9.48 mmol) dropwise via a syringe. The resulting mixture was aged at 0 °C for 1 h, and then a suspension of pyrimidine-2-thiol (2.66 g, 23.7 mmol) in 15 mL of anhydrous THF was added. The reaction mixture was stirred at ambient temperature overnight. The yellow solid was filtered off, and the filtrate concentrated. The residue was purified by

chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 35% EtOAc in hexane, to provide the title compound (1.85 g, 77 % yield) as colorless oil. m/z (ESI, +ve ion) 253,2 (M+H) ⁺ .

STEP 3: (3R,5S)-l-METHOXY-5-METHYLIiEPT-6-ENE-3-SULFONAMIDE AND (3 ,5R)- 1 -METHOXY-5-METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3S,5R)-l-METHOXY-5-METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3 S,5S)- 1 -METHOXY-5-METH YLHEPT-6-ENE-3-S ULFON AMIDE The title compound was prepared from 2-(((3R,5S)-l-methoxy-5- methylhept-6-en-3-yl)thio)pyrirrucline and 2-(((3R,5R)-l-methoxy-5-methylhept- 6-en-3-yl)thio)pyrimi dine and 2-(((3S,5R)-l -methoxy-5-methylhept-6-en-3- yl)thio)pyrimidine and 2-(((3S,5S)-l-methoxy-5-methylhept-6-en-3- yl)thio)pyrimidine by similar procedures described in Example 703, Steps 4-5. m/z (ESI, +ve ion) 244.2 (M+Na) ⁺ .

STEP 4: (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2- METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1 ,22'- | 2 ⁽ !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 0 ' ".O ¹ '' ' ¹ |Pi-NT.\( SA

[ 8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS,3¾,6'R,7 ^f S,8'E, 10'S,I2'S)-6-CHLORO-7'-HYDROXY-12'-(2- METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ l 4]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ^l9 - ²⁴ ]PE TACOSA [8,I6, 18,24]TETRAENl-15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8 ^, E,10 ^, S,12'R)-6-CHLORO-7'-HYDROXY-12 ^! -(2- METHOXYETHYL)- 1 Q'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 O'R, 12'R)-6~CHLORO-7'~HYDRQXY- 12*-(2- METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxyhex-2-en-l-yl)cyclobutyl)me1hyl)-3^4,45-tetTahydro- 2H,2'H- spiro[benzo[b][l,4]oxazepine-3, ~naphthalene]-7-carboxylic acid (Intermediate, AA12A) and (3R,5S)-l-methoxy-5-methylhept-6-ene-3-sulfonamide and (3R.5R)- 1 -methox -5-methylhept-6-ene-3-sulfonamide and (3S,5R)-l-methoxy-5- methylhept-6-ene-3-sulfonamide and (3S,5S)-l-methoxy-5-methylhept-6-ene-3- sulfonamide by similar procedures described in Example 458, Steps 6-7, and isolated as the first isomer from the reversed phase preparatoiy HPLC separation. ¾ NMR (500MHz, CDCb) δ 8.48 (br, s,, III).7.71 id. J=8.6 Hz, H), 7.18 (dd, J=2.1, 8.4 Hz, 1H), 7.09 (d, J=2,0 Hz, 1H), 7.01 (d, .7=7.8 Hz, H), 6,97 - 6.91 (m, 1H), 6.86 (br. s., ill).5.94 (dd, J=5.6, 15.4 Hz, IH), 5.66 (dd, J=7.0, 15.5 Hz, IH), 4.40 - 4.25 (m, 2H), 4.18 - 4.02 (m, 2H), 3.76 (d, ./ 15.2 Hz, IH), 3.69 (d, ./ 142 Hz, IH), 3.63 (t, ,/ 64 Hz, 2H), 3.39 (s, 3H), 3.22 id../ 142 Hz, H), 3.14 - 3.03 (m, IH), 2.87 - 2.68 (m, 2H), 2,57 - 2.41 (m, 3H), 2.40 - 2.28 (m, IH), 2.18 (ddd, ./ 3.3.9.4, 15.2 Hz, IH), 2.07 - 1.59 (m, lOH), 1.45 (t, ./ 12.3 Hz, ill). 1.06 (d, ./ 6,6 Hz, 3H).jm/z (ESI, +ve ion) 643.2 (V! 11) .

EXAMPLE 478. (lS,3'R,6'R,7'S,8'E,10'S,12'S)-6-CHLORO-7'-HYDROXY-12'- (2-METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ 0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(18,3¾,6Έ,7'8,8Έ,10Έ,12'8)-6-α-ΪΙ^Ο-7'-ΗΥ™.Ο ΧΥ ^τ -12'-(2- METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6'R,7 ^, S,8 ^, E,10 ^, S,12'R)-6-CHLORO-7'-HYDROXY-12 ^! "(2- METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,10'R, 12"R)-6-CHLORO-7 ^* -HYDROXY- 12'-(2- METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

- 15'-ONE 13", 13 -DIOXIDE The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 477, Step 4. ^! H NMR (400MHz, CDCb) δ 8. 1 I (s, 1H), 7.71 (d, J==8.6 Hz, 1 1 1 ). 7.18 (dd, J=2.2, 8,5 Hz, IH), 7, 12 - 7.03 (m, 2H), 6.97 - 6.86 (m, 2H), 5,83 - 5.73 (m, I H i. 5.67 - 5.54 (m, IH), 4.24 - 4.07 (m, 4H), 3.83 (dd, J=3.2, 15.4 Hz, IH), 3.77 - 3.65 (m, 3H), 3.39 (s, 3H), 3.26 (d, ./ 14. 1 Hz, IH), 3.06 (dd, ./ 8.0. 15.5 Hz, IH), 2.88 - 2,67 (m, 2H), 2.52 - 1.54 (m, 15H), 1 ,42 (t, .7=12.5 Hz, IH), 1.08 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 643.2 (M+H) ^H" . 120954-23

EXAMPLE 479,

(2-METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO[14.7.2,0 ³ - ⁶ .0 ^l9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,12 ^, S)-6-CHLORO-7'-HYDROXY-12 ^! -(2- METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| 1ΉΤί!1Λ| Ι.Ι4|ΠίΑ/ΑΠ:ΤΗΑ(Ύα.ΟΙ i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PL\,TAi SA [8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE OR

(lS ¾,6'RJ^,8^I0'S,12'S)-6-CHLORO-7'-HYDROXY-12'-(2- METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,10'R,12'R)-6-CHLORO-7 ^, -HYDROXY-12'-(2- METHOXYETHYL)- 1 Q'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

'-ONE 13',13'-DIOXIDE

The title compound was obtained as the third eluting isomer from the reversed phase preparatory HPLC separation in Example 477, Step 4. Ή NMR (500MHz, CDCb) δ 8.17 (s, 1H), 7.81 (hr. s,, 1H), 7.64 id. J=8,6 Hz, !H), 7.16 (dd, «/=2.2, 8,3 Hz, 1H), 7.11 (d, .7=2.2 Hz, IH), 6.97 - 6,82 (m, 2H), 5.73 (dd,

./ 4.6.15.9 Hz, IH), 5.10 (br. s., 1H), 4.39 - 4.22 (m, 2H), 4.08 (br. s., ill).3.93 - 3.78 (m, 2H), 3.74 - 3.61 (m, 2H), 3.43 (s, 3H), 3.27 (d,■/ 14.4 Hz, IH), 3.08 (d, ./ 1 .9 Hz, IH), 2,75 (t, ./ 5.6 Hz, 2H), 2,65 - 2.54 (m, IH), 2,52 - 2.38 (m, 2H), 2.24 - 1.11 (m, 14H), 0,99 (d, J=6.6 Hz, 3H). m/z (ESI, +ve ion) 643.2 (M+H) ⁺ .

EXAMPLE 480, (IS,3 ⁱ R,6'R,7 ^f S,8'E,I0'R,12'R)-6-CHLORO-7'-HYDROXY-10 ⁱ -

METHYL-12 ^! -(2-METHYLPROPYL)-3,4-DiHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDL4ZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS 'R,6 ^! R7^,8iV10'S ₅ ]2'R)-6 HLORO-7'-HYDROXY-10 ^! lETHYL-12'-(2- ΜΕΤΗΥίΡΚΟΡΥί)-3,4-ΟΙΗΥΟΚΟ-2Η,15Ή-8ΡΙ� �Ο[ΝΑΡΗΤΗΑίΕ Ε-1,22'- [2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, ,6'R 'S,8ΈJ0'R 2'S 6 ΉLORO-7 ^, -HYDROXY-10'-MEΊΉYL"12'-(2- ME ^r rHYLPROPYL)-3,4-DlHYDRO-2H;i5'H-SPIRO[NAI ^J HTHALE E-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(lS,3'R,6 ^, R7'S,8 ^, E 0 ^, SJ2'S)-6 mORO-7 ^, ~HYDROXY-I0'-METHYL-12'-(2- METHYLPROPYL)-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPH^ΉALENE-1.22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

STEP 1: (4S,6S)-2 ₅ 6-DI ETHYLOCT-7-EN-4-OL AND (4S,6R)~2,6- DIMETHYLOCT-7-EN-4-OL AND (4R,6S)-2,6-DIMETHYLOCT-7-EN-4-OL

-2,6-DIMETHYLOCT-7-EN-4-OL

The title compound was prepared in an analogous manner to that described in Example 471, Stepl using 2-isobutyloxirane. 'HNMR (400 MHz, CDCb) δ 5.59-5.94 (m, 1H), 4.79-5.18 (m, 2H), 3.77 (did, ./ 4.40.8.40, 16.55 Hz, 1H), 2,29-2.53 (m, 1H), 1.69-1.92 (m, 1H), 1.31-1.56 (m, 4H), 1.19-1.30 (m, 1H), 1.02- 1,09 (m, 3H), 0.90-0.98 (m, 6H),

STEP 2: (4S,6S)-2,6-DIMETHYLOCT-7-E E-4-SULFONAMIDE AND

(4S,6R)-2,6-DIMETHYLOCT-7-ENE-4-SULFONAMIDE AND (4R,6R.)-2,6- DIMETHYLOCT-7-ENE-4-SULFON AMIDE AND (4R,6S> -7 -ENE -4 - SULF ON AMIDE The title compound was prepared from (4S,6S)-2,6-dimethyloct-7-en-4-ol and (4S,6R)-2,6-dimethyloct-7-en-4-ol and (4R,6S)-2,6-dimethyloct-7-en-4-ol and (4R,6R)-2,6-dimethyloct-7-en-4-ol by similar procedures described in Example 477, Steps 2-3. m/z (ESI, +ve ion) 220.2 (M+H) ⁺ . STEP 3: (l S,3'R,6'R,7'S,8'EJ 0'R, 12'R)-6-CHLORO-7'-HYDROXY-I0'- METHYL~12 ^! -(2-METOYLPROPYL)-3,4~DIHYDRO-2H,i5'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHL4[l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8 ₅ 16,18,24]TETRAEN]-15"-ONE !3',13'-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^, S,8 ^, E,10 ^, S,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-10 ^f -METHYL-12'-(2- METHYLPROPYL)-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPHTHALE E-l,22 ^, -

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.() ³ >^0 ^{! 9} - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,12'S 6-CHLORO-7'-HYDROXY-10'-METHYL-12'-(2- ME^WLPROPYL)-3,4-DIHYDRO-2Ii,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - i 5'-ONE 13', 13'-DiOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,10'S,12'S)-6-CHLORO-7 ^, -HYDROXY-10'-METHYL-12'-(2- METHYLPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]Tffl A[l .MIDIAZATETRACYCLOIMJ^.O^^O'^IPENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l -hydroxyhex-2-en-l-yl)cyclobutyl)me1hyl)-3^4,4 5-tetTahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (Intermediate, AA12A) and (4S,6S)-2,6-dimethyloct-7-ene-4-sulfonamide and (4S,6R)-2,6- dirnethyloct~7~ene~4~sulfona,mide and (4R,6R)-2,6-dimethyloct-7-ene-4- sulfonamide and (4R,6S)-2,6-dimethyloct-7-ene-4-sulfonamide by similar procedures described in Example 458, Steps 6-7, and isolated as the first isomer from the reversed phase preparatory HPLC separation. ^! H NMR (500MHz, CDCb) δ 8.38 (br, s., H), 7.71 (d, 8.6 Hz, IH), 7, 18 (dd, ./ 2.2.8.3 Hz, 1H), 7.10 (d, ./ 2.0 Hz, IH), 7.02 (d, ./ 8.1 Hz, IH), 6.97 - 6.91 (m, ill).6.84 (br. s., IH), 6.01 (dd, ,/ 5.4.15.7 Hz, IH), 5.68 (dd, ./ 6.K.15.9 Hz, IH), 4.30 (dd, J=3.9, 7.1 Hz, IH), 4.25 - 4.17 (m, IH), 4.16 - 4,06 (m, 2H), 3.82 - 3.66 (m, 2H), 3.22 (d, J=13.9 Hz, IH), 3,16 - 3.02 (m, I Hi.2.83 - 2.69 (m, 2H), 2,50 - 2.32 (m, 3H), 2.18- 1.16 (m, 1 11).1.06 (d, ./ 6.6 Hz, 3H), 1.04 (d, ./ 6.6 Hz, 3H), 0.99 (d, ./ 6,4 Hz, 3H). m'z (ESI, +ve ion) 641.2 (M+H) ⁺ .

EXAMPLE 481. (lS,3'R,6 ^! R,7'S,8E,10'S,12'R)-6-CHLORO-7'-HYDROXY-10'- METHYL- 12'-(2-METHYLPROP YL)-3 ,4-DIHYDRO-2H, 15 Ή- SPTRO[NAPHTH ALENE- I ,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.2 ^; ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24]TETiLAE ]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3¾,6 ^! R,7^,8E,10'R,12'R 6-CHLOR()-7 ^, -HYDROXY-10'-METHYL-12'-(2- METHYLPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[N APHTHALENE- ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(lS,3'R,6¾,7'S,8E,10¾,12'S)-6-CHLORO-7'-HY ^T DROXY-10 ^f -METHYL-12'-(2- METHYLPROPYL)-3,4-DIHYDRO-2H,l 5'H-SPIRO[N APHTHALENE-1, 22'- |2ίί!<)ΧΛ| 13ΙΊ !!1Λ| Ι.14|! !Λ/.νΓ!·Ί <Λ( ^' Υ(·ί..ΟΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETR _J! AEN1-15'-0NE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,10'S,I2'S)-6-CHLORO-7'-HYDROXY-10'-METI-IYL-12 ⁱ -(2- ME^ΉYLPROPYL)-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPHTHALENE-l,22 ^, - [20]OXA[13]THIA[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15'-ONE 3', 13*-DIOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 480, Step 3. ^! H NMR (400MHz, CDCb) δ 8. 18 (s, IH), 7.71 (d, J=8.6 Hz, 11 1). 7.18 (dd, ,/ 2 2. 8,4 Hz, IH), 7, 12 - 7.05 (m, 2H), 6.98 - 6.82 (m, 2H), 5,88 - 5.73 (m, I H i. 5.70 - 5.57 (m, IH), 4.18 (t, .7=5.7 Hz, IH), 4.11 (s, 2H), 4.07 - 3.96 (m, IH), 3.85 (dd, =2.9,

15.3 Hz, IH), 3.73 i ± 14.3 Hz, IH), 3.25 (d, J=14.3 Hz, IH), 3.04 (dd../ H. I .

15.4 Hz, IH), 2.90 - 2.65 (m, 2H), 2.53 - 1.55 (m, 15H), 1 ,49 - 1.36 (m, 2H), 1.08 (d, .7=6.7 Hz, 3H), 1.02 (t, .7=5.8 Hz, 6H). m/z (ESI, +ve ion) 641 ,2 (M+H)

EXAMPLE 482, (18,3¾,6'Κ,7'8,8Έ,10'Κ,12'8)-6-€:ΗΕΟ Ο-7'-ΗΥΟ ΟΧΥ-10'- METHYL~12 ^! -(2-METHYLPROPYL)-3,4~DiHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- |;20]OXA[ 13 iTHIA[l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, I 8,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(1 S,3'R,6 ^! R,7'S,8'E, 10'R, 12'R)-6-CHLORO-7'-HYDROXY- 10'-METHYL-12 ^! ~(2-

METHYLPROPYL)-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPHTHALENE-1.22 ^, -

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15 ^! -ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'S,I2'R)-6~CHLORO-7'-HYDROXY-10'-METHY L"12'-(2- ME^WLPROPYL 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,l()'S,12'S)-6-CHLORO-7 ^! -IiYDROXY-10'-METHYL-12'-(2- METHYLPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the third eluting isomer from the reversed phase preparatory HPLC separation in Example 480, Step 3. ^! H NMR (400MHz, CDCb) δ 8. 15 (s, IH), 7.68 (d, J=8.6 Hz, 1 1 1 ). 7.18 (dd, ,/ 2 2. 8,5 Hz, IH), 7, 12 - 7.04 (m, 3H), 6.95 (d, .7=8.2 Hz, IH), 5.95 (dd, .7=5.7, 15.3 Hz, IH), 5.66 (dd, ./ 4.2. 15.7 Hz, IH), 4.19 - 4.08 (m, 3H), 4.01 (br. s., IH), 3.63 - 3.54 (m, IH), 3.52 - 3.35 (m, 2H), 2,78 (br. s., 2H), 2.69 - 2.48 (m, 2H), 2.35 (d, ./ 5.3 Hz, IH), 2.23 - 2, 10 (m, IH), 2,02 - 1 ,52 (m, 14! ! ). 1.10 (d, ./ 6 8 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H), 0,99 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 641.2 (M+H) ⁺ .

EXAMPLE 483, (l S,3¾,6'R,7 ^f S,8'E, 10'S,12'S)-6-CHLORO-7'-I-I ^r DROXY-! 0'- METHYL~12 ^! -(2-METHYLPROPYL)-3,4~DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- |;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2,0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-CHLORO-7'-HYDROXY- 10'-METHYL-12 ^! ~(2-

METHYLPROPYL)-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPHTHALENE-1.22 ^, -

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8,16, i8,24]TETRAEN]-15 ^! -ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'S,I2'R)-6~CHLORO-7'-HYDROXY-10'-METHY L"12'-(2- ME^WLPROPYL 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(1S,3'R,6 ^! R,7'S,8'E,1()'R,12'S)-6 :HL()R0-7'-HYDR0XY-1()'-METHYL-12'-(2- METHYLPROPYL)-3,4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the fourth eluting isomer from the reversed phase preparatory HPLC separation in Example 480, Step 3. ^! H NMR (400MHz, CDCb) δ 8. 15 (s, IH), 7.68 (d, J=8.4 Hz, 1 1 1 ). 7.18 (dd, ,/ 2 2. 8,4 Hz, IH), 7, 12 - 7.02 (m, 3H), 6.95 (d, .7=8.2 Hz, IH), 5.95 (dd, .7=6.0, 16.7 Hz, IH), 5.66 (dd, J=5.8, 15.9 Hz, IH), 4.24 - 4.06 (m, 3H), 4.01 (br. s., IH), 3.63 - 3.54 (m, IH), 3.52 - 3.40 (m, 2H), 2.78 (br. s., 2H), 2.69 - 2.48 (m, 2H), 2.36 (br. s., I H), 2.23 - 2.10 (m, IH), 2,01 - 1.49 (m, 14H), 1 .10 (d, ,/ 6,8 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 0.99 (d, J=6.5 Hz, 3H). m/z (ESI, +ve ion) 641.2 (M+H) ¹ .

EXAMPLE 484, (1 S,3'R,6'R,7'S,8'E, 10'R, 12'S)-6-CHLORO-7'-METHOXY- 12'-

(2-METHOXYETHYL)-10'-METHYL-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'- |;20]OXA[ 13 iTHIA[ l,14jDL4ZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E, 10'S,12'S)-6~CHLORO-7 ^! ~METHOXY-12'-(2- METHOXYETHYL)- 1 Q'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,l()'S,12'R)-6-CHLORO-7'-METHOXY-12'-( 2- METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ⁱ⁹ ^ ⁴ |PENTACOSA [8, 16, 18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E, 10'R,12'R)-6-CHLORO-7'-METHOXY-12'-(2- METHOXYETHYL)- 10'-METHYL-3,4-DlHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404, Step 2 using (l S,3'R,6 ^, R,7 ^, S,8 ^, E,10'R,12'S)-6"Chloi -7'-hydroxy- 12'-(2-methoxyethyl)-lQ'-methyf-3,4-d

[20]oxa[13]thia[l ,14]diazate1r^

n]-15'-one 13',13'~dioxide or (lS,3¾,6¾.,7 ^! S,8'E, 10'S,12'S)-6-chloro-7'-hydroxy- 12'-(2-methoxy ethyl)- 10'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20joxa 13]thia[ l, 14]diazatetracycfo[14J _^

n]-15'-one 13', 13 '-dioxide or (1 S,3'R,6'R,7'S,8'E, 10'S,12'R)-6-chloro-7'-hydroxy- 12'-(2-methoxy ethyl)- 10'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- |;20]oxa[ 13]thia|;i ,14]diazatetracycio| 14.7.2,0 ³ - ^f \0 ¹⁹ - ²⁴ ]peniacosa|;8,16, 18,24 n] - 15'-one 13', ! 3'~dioxide or (1 S,3'R,6'R,7'S,8'E, 10'R, '^-e-chloro-T'-hydro y-

12'-(2-m.ethoxyethyl)-10'-methyl-3,4-dihydro-2H,i5'H-spir o[naphth

[20joxa 13]thia[ l, 14]diazatetracycfo[14J _^

n]-15'-one ! 3', 13'-dioxide (Example 477) and iodomethane. 'H NMR (400MHz, CDCh) δ 8.07 (br, s., IH), 7.70 (d, .7=8.4 Hz, IH), 7.18 (dd, J=2.2, 8.6 Hz, 1H),

7.09 (d, J=2.2 Hz, 1H), 6.97 - 6.87 (m, 2H), 6.78 (s, 1H), 6.00 (dd, J=4A, 15.6 Hz, IH), 5.55 - 5.41 (m, IH), 4.47 (dd, J=3.0, 7.3 Hz, IH), 4.14 - 4.01 (m, 2H), 3.83 - 3.67 (m, 3H), 3.66 - 3,53 (m, 2H), 3.33 (s, 3H), 3.27 (s, 3H), 3.17 (d, ,/ 14 3 Hz, IH), 3.01 (dd, .7=9,3, 15.2 Hz, IH), 2,84 - 2.69 (m, 2H), 2.60 - 2.35 (m, 3H), 2,27 - 2.11 (m, 2H), 2.07 - 1.17 (m, 1 OH), 1.10 (d, ./ 6.7 Hz, 3H). m/z (ESI, +ve ion) 657.2 (M+H) ⁺ .

EXAMPLE 485. (l S,3'R,6'R,7'S,8'E,10'S,12'S)-6-CHLORO-7'-METHOXY-12'- (2-METHOXYETHYL)-l 0'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DL4ZATETRACYCLO[147.2X) ³ '^0 ¹⁹ - ²⁴ ]

[8,16,18,24]TETiLAE ]-15'-QNE 13', 13 '-DIOXIDE OR

(lS,3 ^, R ₅ 6 ^, R,7 ^, S.8 ^, E,10 ^, R,12 ^, S)-6-CHLORO-7 ^, -METHOXY-12 ^, -(2- METHOXYETHYL)- 10'-METHYL-3.4-DIHYDRO-2H, 15Ή-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1 4]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-D )XIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E ₅ 10 ^, S,12 ^, R)-6-CHLORO-7 ^, -METHOXY-12 ^, -(2- METHOXYETHYL)- 1 G'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,12'R)-6-CHLORO-7'-METHOXY-12'-(2 - METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTH ALENE- 1.22 ^' -

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' AC<)SA

'-ONE 13',13 ^* -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404, Step 2 using (lS ₅ 3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E,10 ^, S.12 ^, S)-6-chloro-7 ^, -hydroxy- 12'-(2-me&oxyethyl)-10'-methyl-3,4-dih^

n]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,10'R,12'S)-6-chloro-7'-hydroxy- 12'-(2-methoxyethyl)-10'-methyl-3,4-dihydro-2H,15H-spirofnap hthalene-l,22'^

[20]oxa{13]thia[l,14]diazatetra<y^

n]-15'-one 13 ',13 '-dioxide or (lS,3'R,6'R,7'S,8'E,10'S,12'R)-6-chioro-7'-hydroxy- 12'-(2-methoxyethyl)-10'-methyl-3,4-dihydro-2H,15'H-spiro[na phthalene-l,22'- [20]oxa[13]thia[l,14]diazatefra^

n]-l 5'-one 13*, 13'-dioxide or (1 S,3'R,6'R,7 ^! S,8'E, 10'R, 12 ^! R)~6-chloro-7'-hydroxy- 12'-(2-methoxy ethyl)- 10'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20joxa|13]thia[l,14]diazatetracycfo[^^

n]-15'-one !3',13'-dioxide (Example 478) and iodomethane. ¾ NMR (400MHz, CDC!;) δ 8.03 (br. s., IH).7.71 (d, ./ 8.4 Hz, ill).7.18 (dd, ./ 2.2.8.4 Hz, IH), 7.09 (d, ,/ 2.0 Hz, IH), 6.95 - 6.86 (m, l).5.95 (dd, ,/ 3.2.15.7 Hz, IH), 5.53 - 5.41 (rn, IH), 4.32 (t, J=8.3 Hz, IH), 4.10 (s, 2H), 3.82 (d, ./ 15.! Hz, IH), 3,76 - 3.62 is 4H), 3,38 (s, 3H), 3,25 is. Ml).3,15 id../ 6.7 Hz, IH), 3.01 (dd, J=9.9, 15.2 Hz, IH), 2.87 - 2.68 (m, 2H), 2.54 - 2.36 (ni, 3H), 2.30 - 2.22 (m, IH), 2.13 - 1.23 (m, 1 !!!).1.12 (d,■/ 6.7 Hz, 31!}. m /. (ESI, +ve ion) 657.2 (M+H) ⁺ .

EXAMPLE 486. (IS^'R^'R^'S^'EJO'S/n'RVe-CHLORO^'-METHOXY-n'- (2-METHOXYETHYL) - 10'-METHYL-3,4-DlHYDRO-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ^

[8,I6,18,24]TETiLAE ]-15'-QNE 13', 13 '-DIOXIDE OR

(lS,3 ^, R ₅ 6 ^, R,7 ^, S.8 ^, E,10 ^, R,12 ^, S)-6-CHLORO-7 ^, -METHOXY-12 ^, -(2- METHOXYETHYL)- 10-METHYL-3 ,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,I6,18,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(18,3¾,6¾,7 ,8Έ,Κ)'8,12'8)-6~€ΗΙ-^0-7 ^! ~ΜΕΊΉΟΧΥ-12'-(2- METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 -DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-CHLORO-7'-METHOXY- 12'-(2- METHOXYETHYL)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 404, Step 2 using (l S,3'R,6'.R,7'S,8'E,10'S,12 ^! R)~6-chloro-7'-hydroxy- 12 ^, -(2-methoxyethyl)-10'-methyl-3,4-dihydro-2H,15 ^, H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[l ,14]cUazatefracy^

n] - 15'-one 13', 13'-di oxide or (1 S,3'R,6'R,7'S,8'E, 10'R, 12'S)-6-chloro-7'-h droxy- 12 ^f -(2-metttoxyetttyi)-10 -methyl-3,4-dihydro-2H,15H-spiro[n

i H.2- - j ictrao n]-15'-one 13', 13"-dioxide or (l S,3'R,6 ⁱ R,7'S,8'E, 10'SJ 2 ^f S)-6-chloro-7' tydroxy- 12'-(2-methoxy ethyl)- 10'-methy 1-3 ,4-dihy dro-2H, 15 'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]tMa[l,14]cliazatetracy^

n]-15'-one 13',13'-dioxide or (lS,3'R.6 ^, R,7 ^, S.8 ^, E.10 ^, R,12 ^, R)-6-chloro-7 ^, -hydroxy- 12'-(2-methoxy ethyl)- 10'-methyl-3,4-dihy dro-2H, 15'H-spiro [naphtha] ene- 1 ,22'- i 8.2 j !eirae n|-15'-one 13', 13'-dioxide (Example 479) and iodomethane. ¾ NMR (5()0MHz, CDCb) δ 8.05 (br, s., ! H), 7.67 i d. ./ 8.3 Hz, i l l ). 7,22 - 7.03 (m, 31 1 ). 7.01 - 6.81 (m, 21 ! ). 5.74 (d, ,7=13,0 Hz, 1H), 5.40 (dd, .7=8.1, 15.6 Hz, IH), 4, 19 - 4.04 (m, 2H), 3.85 - 0.61 (m, 34H). m/z (ESI, +ve ion) 657.2 { M · H ) .

EXAMPLE 487. (1 S,3'R,6'R,7'S,8'E,10'R,12'R)-6-CHLORO-7'-HYDROXY-10'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.0 ^3> ^0 ^{! 9} - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,12'S 6-CHLORO-7'-HYDROXY-10'-METHOXY-12'- METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

STEP 1 : (2S,4R)-4-HYDROXY-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE- 2-SULFONAMIDE AND (2R,4R)~4~HYDRQXY-N,N~BIS(4~

METHO -5 -EN E-2- SO LFON AMIDE

To a solution of N,N-bis(4-methoxybenzyl)ethanesulfonaniide (1.00 g, 2.86 mmol, Intermediate, EE13) in THF (9.5 ml) in a 150-mL round-bottomed flask at -78 °C was added butyllithium, 2.5 M solution in THF (1,26 ml, 3.15 mmol) slowly. The resulting mixture was stirred at this temperature for 15 min, and then (r)-2-vinyl-oxirane (0.346 mi, 4.29 mmol) was added. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with saturated NH ₄ C1 ( I OmL) and extracted with EtOAc (2 x 20mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSCk The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 35% EtOAc in hexane, to provide the title compound (0.42 g, 35%). ¾ N.V1R (500 MHz, CDCh) δ 7.20- 7.24 (m, 4H), 6.86-6.91 (m, 4H), 5.79 (ddd,■/ 6 ! ! . 10.58, 17.06 Hz, 1H), 5.14- 5.32 (rn, 2H), 4.37-4,47 (m, 3H), 4.17-4.22 (ra, 2H), 3,82-3.86 (m, 6H), 3.18 (sxt, J=6.75 Hz, I I I ). 2.19 (td, .7=5.96, 14.24 Hz, i l l ). 2,03-2.07 (m, i l l ). 1.71-1.81 (m, 1H), 1.32 (d, ./ 7.09 Hz, 3H). STEP 2: (2S ₅ 4R)-4-METHOXYHEX~5-ENE-2-SULFONAMIDE AND (2R,4R)~ 4-METHOXY -5-ENE-2-SULFONAMIDE

The title compound was prepared from (2S,4R)-4-hydroxy-N,N-bis(4- methoxybenzyl)hex-5-ene-2-sulfonamide and (2R,4R)-4-hydroxy-N,N-bis(4- methoxybenzyl)hex-5-ene-2-sulfonamide by similar procedures described in Example 434, Steps 3-4. m'z (ESI, +ve ion) 216.2 (M+Na) ⁺ . STEP 3 : ( 1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6~CHLORO-7 ^! ~HYDROXY- 10'-

METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15H-SPIROpiAPHTHALENE- 1,22'-

|20i()XA| ΐ: ΐΗ1Λ| Ι..! |ί)!Α/Λ! :ΓΗ.Λ( ^' .01117.2 (Γ ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]TETRAEN]-15'-QNE 13',13'-D10X1DE OR

(lS,3¾,6 ^! R,7^,8T,l()'R,12^)-6-CHL()RO-7'-HYDROXY-l()'-METHOXY-1 2'- METHYL-3,4-DlHYDRO-2H,15^SPIRO|NAPHTHALENE-.l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxyhex-2-en~l~yl)cyclobu^

spiro [benzo [b] [1,4] oxazepme-3 , -naphthalene] -7-carboxy lie acid (Intermediate, AA12A) and (2S,4R)-4-methoxyhex-5-ene-2-sulfonamide and (2R,4R)-4- methoxyhex-5-ene-2-sulfonamide by similar procedures described in Example 458, Steps 6-7, and isolated as the first isomer from the reversed phase preparatory HPLC separation. ^! H NMR (50GMHz, CDCb) δ 8.37 (br. s., 1H), 7.71 id../ 8.6 H . ill).7,19 (dd,J=2.3, 8.4 H .111).7.09 {O.J 2 11/.1H), 7.02 (s, 1H), 6.95 - 6.86 (m, 2H), 5,90 (dd, ./ 6.1.15.4 Hz, III).5.63 (dd, ,/ 64.15.4 Hz, 1H), 4.28 (t, J=5.5 Hz, 1H), 4.16 - 4.03 (m, 2H), 3.99 (dt, ./ 4.3.7.5 Hz, IH), 3.85 (dd, ,/ 3.3.15.3 Hz, IH), 3.70 (d, ./ 14.4 Hz, IH), 3.67 - 3.61 (m, !!!).3.18 (s, 3H), 3.02 (dd, ,/ H i . 15.4 Hz, i l l ). 2,84 - 2.69 (m, 2H), 2,55 - 2.44 (m, i l l ). 2,43 - 2,31 (m, IH), 2.26 - 1.63 (m, 1 IH), 1.59 (d, .7=6.8 Hz, M l ). 1.40 (t, .7=13,2 Hz, 1H). m/z (ESI, +ve ion) 615.2 (M+H) ⁺ . EXAMPLE 488, (IS ,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E, 10 ^, R,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-10 ^* - METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(IS^'R^'l^T'S^'E O'^^'R^e-CHLORO-T'-HYDROXY-lO'-METHOXY-n'" ME^ΉYL-3 ₅ 4-DIHYDRO-2H,15Ή-SPI O| APH^ΉALENE-l ,22 ^, - [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was obtained as the later eluting isomer from the reversed phase preparatory HPLC separation in Example 487, Step 3. Ή NMR (500MHz, CDCb) 6 8.10 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.58 (br. s., lH), 7.16 (dd, ./ 2.4. 8.6 Hz, 1H), 7.10 (d, ./ 2.2 Hz, I I I . 6.96 - 6.89 (m, 11 1 ). 5.83 - 5.78 (m, IH), 5.75 - 5.66 (m, IH), 4,34 - 4.25 (m, IH), 4.23 (s, 2H), 4.08 (d, .7=8.3 Hz, IH), 3.95 - 3.89 (m, IH), 3.37 - 3.28 (m, IH), 3.23 (s, 3H), 3.20 - 3.03 (m, 2H),

2,79 - 2.73 (m, 2H), 2.55 (d, ./ 8.3 Hz, IH), 2.34 (quia ./ 8.9 Hz, IH), 2.22 - 1.38 (m, 15H), m/z (EST, +ve ion) 615,2 { V! H }

EXAMPLE 489. (l S,3'R,6'R,7'S,8'E,10'S,12'R)-6-CHLORO-7'-HYDROXY-10'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR (18,3¾ Κ,7'8,8Έ;ΐ0'8^ 2'8)-6-α«-,ΟΚΟ-7'-ΗΥΟ ΟΧΎ-10'-ΜΕΤΗΟΧΥ-12'-

METHYL-S^-DIHYDRO-ffl^S^SPIROI APHTHALENE-l^^-

| 2ίί !0ΧΛ| O ΙΊ ί Ι1Λ| I„ I 4 |Πί Α/Λ T! R AC YO OI i 4.7.2.0 " ) ¹ *" ¹ |PHNT.\C0S A

[ 8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE

The title compound was prepared from (s)-2-vinyloxirane by similar procedures described in Example 487, Steps 1-3, and isolated as the first isomer from the reversed phase preparatory HPLC separation. ^" Ή NMR (500MHz, CDCb) δ 8,21 (br. s., 1H), 7.70 id . «7=8.3 Hz, 1H), 7.18 (dd, ,/ 2 1. 8.4 Hz, IH), 7.10 (d, =2.0 Hz, 1H), 7.02 - 6.89 (m, 3H), 5.96 - 5.87 (m, 1H), 5.85 - 5.74 (m, i l l ). 4,38 - 4.22 (m, 2H), 4.16 - 4,04 (m, 2H), 3,89 (t, ./ 5.3 Hz, i l l ). 3,83 (d, J=15.2 Hz, i l l ). 3.70 (d, ,7=14,4 Hz, H), 3,25 (s, 3H), 3,06 (dd, .7=8.3, 15.4 Hz, IH), 2,86 - 2.70 (m, 2H), 2.61 - 2,46 (m, IH), 2,37 (t, .7=8.2 Hz, IH), 2.18 - 1.56 (m, 14H), 1,43 (t, ./ 12.6 Hz, IH), m/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 490. (1 S,3'R,6 ^! R,7'S,8 ^! E, 10 ^! S, 12'S)-6-CHLORO-7'-HYDROXY-l 0'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7^,8¾10'S,12'R)-6-CHLORO-7'-I-r OROXY-10'-METHOXY-12'-

METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20] O A 113]THI A[ 1 , 14] DIAZATETRA

CYCLO[ 14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ ]PENTACOSA[8,16,18,24]TETRi EN]-15 ^, -ONE 13',13'-DIOXIDE

The title compound was obtained as the later eluting isomer from the reversed phase preparatory HPLC separation in Example 489. ¾ NMR (500MHz, CDCh) δ 8.16 (s, IH), 7.77 (br. s., IH), 7.63 (d, J=8.6 Hz, IH), 7.15 (dd, J=2.2, 8.6 Hz, 1H), 7.11 (d, ,/ 2.2 Hz, IH), 6.95 - 6.88 (m, 211 ).5.92 (dd, ./ 4.4.16.1 Hz, ill).5.24 (dd, ,/ 7.9.16.0 Hz, IH), 4,31 - 4.15 (m, 3H), 3.97 (dd, ,/ 40.9.7 Hz, IH), 3.91 - 3.80 (m, 2H), 3,55 - 3.45 (m, ill).3.28 (d, .7=14,4 Hz, IH), 3.20 (s, 3H), 3.08 (dd, J=3.3, 16.0 Hz, IH), 2.75 (t, J=5.7 Hz, 2H), 2.68 - 2.58 (m, IH), 2.55 - 2.45 (m, ./ 8.8 Hz, IH), 2.03 - 1.66 (m, 1011).1.63 id../ 7.1 Hz, 3H), 1.42 - 1,31 (m, IH). m/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 491. (1 S 'R^'R 'S^'EJO'Ri-e-CHLORO^'-HYDROXY-lO'- METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'- |2( >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ' ".U ^1* " ¹ |PH\ i ACOSA [8,16,18,24]TETRAENj-15'-C)NE 13',13 ^* -DIOXIDE OR

(lS,3'R ₅ 6 ^, R,7 ^, S,8¾10 ^, S)-6-CHLORO-7 ^, -HYDROXY-10 ^, -METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOLA[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared from oxirane by similar procedures described in Example 480, Steps 1-3, and isolated as the first isomer from the reversed phase preparatory HPLC separation. Ή NMR (500MHz, CDCh) δ 8.16 (s, !!!).7.68 (d, 86 Hz, 1 !!}.7.18 (dd, ,/ 23.8.4 Hz, ill).7, 10 id../ 2.2 Hz, IH), 6.98 - 6.86 (m, 2H), 5.74 - 5.51 (m, 2H), 4.21 - 4.09 (m, 3H), 3.90 {or. s., IH), 3.68 - 3.22 (m, 5H), 2.85 - 2.70 (m, 2H), 2.56 - 2.34 (m, 3H), 2.22 - 1.24 (m, 1 IH).1.04 (d, ,/ 6.8 Hz, 3H). m/z (ESI, +ve ion) 585,2 (M+H) ⁺ . EXAMPLE 492. (lS^'R-e'R-T'S^'E O'S^e-CHLORO-T'-HYDROXY-lO'- ME^ΉYL-3 ₅ 4-DIHYDRO-2H,15Ή-SPI O| APHTHALENE-l,22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R)-6-CHLOR()-7'-HYDROXY-l()'-METOY L-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE i.T.i 3'-DK)XIDE

The title compound was obtained as the later eluting isomer from the reversed phase preparatory HPLC separation in Example 49.1. 'HNMR (500MHz, CDCh) 58.19 (br. s., IH), 7.69 (d, ./ 8. Hz, ill).7.18 (dd, ./ 2.2.8.6 Hz, IH), 7.10 (d, ./ 2.2 Hz, 2H), 6.95 (s, 2H), 5.87 (dd, ./ 5.1.14.9 Hz, IH), 5.64 (ddd, ./ 1.3.6.1, 15,8 Hz, IH), 4.25 (br. s„ IH), 4,19 -4,10 (m, 211).4.00 id.,/ Hi 8 II/. IH), 3.65 (d, ,7=14,9 Hz, 2H), 3.50 - 3.19 (m, 3H), 2.85 - 2.68 (m, 2H), 2.44 (br. s .2H), 2.29 (br, s., !i!).2.06 - 1.43 (m, !!!!).1,09 id ,/ 6.S Hz, 3H). ra/z (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 493. (1 S,3'R,6'R,7'S,8'E, 10'S)-6-CHLORO-7'-HYDROXY- 10'Jl ',1 r-TRIMETHYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

[20]OXA[13]THIA[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8 ₅ 16,18,24]TETRAEN]-15"-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 10'S)-6-CHLORO-7'-HYDROXY- 10', 11 ', 11 '-TRIMETHYL- S^-DIHYDRO^H S'H-SPIROfNAPHTHALENE-l^^-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA

[8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,10'R)-6-CHLORO-7'-HYDROXY-10',ir,ll'-TllMETHYL- 3 ,4-DlH YDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 10'S)-6-CHLORO-7'-HYDROXY- 10', 11', 11 '-TRIMETHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

STEP 1: (S)-2,2,3~TRIMETHYLPENT-4-EN-I-OL AND (R)-2,2,3- TRIMETHYLPENT-4-EN- 1 -Ol. The title compound was prepared from (S)-2,2,3-trimethylpent-4-enoic acid and (R)-2,2,3-trimethylpent-4-enoic acid (prepared according to reference: Tetrahedron, 63(51), 12616-12620, 2007) by the similar- procedure described in Example 474, Step 1 , m/z (EST, +ve ion) 129.2 ! V! ! ! }

STEP 2: (S)-2,2,3-TRIMETHYLPENT-4-ENE-l -SULFONAMIDE AND (R)- 2,2,3-TRIMETHYLPENT-4-ENE- 1 -SULFONAMIDE

The title compound was prepared from (S)-2,2,3-trimethylpent-4-en-l-ol and (R)-2,2,3-trimethylpent-4-en-l-ol by similar procedures descnbed in Example 703, Steps 3-5. m/z (ESI, +ve ion) 192.1 ( +H) ⁺ .

STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCL()BUT iX)METHYL)-N-(((R)-2,2,3- TRIMETHYLPENT-4-EN-l -YL)SULFON ⁱ i L)-3',4,4 ⁱ ,5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B] [L4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(((S)-2,2,3- TRIMETHYLPE T-4-EN-l-YL)SULFONYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO- 2H,2'H-SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '- APHTHALENEJ-7- CARBOXAMIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)c clobutyl)methyl)-3',4,4',5-tetrahydfo-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid ( Intermediate, AA11A) and (S)-2,2,3-trimethylpent-4-ene-l -sulfonamide and (R)-2,2,3- trimethylpent-4-ene-l -sulfonamide by the similar procedure described in Example 432, Step 4. m!z (ESI, +ve ion) 641.2 ( Μ - Π ) .

STEP 4: (S)-5-(((l R,2R)-2- ACRYLO YLCYCLOB l Ί Y L )MI:TI iY! .}-- ^' ~

CHLORO-N-(((R)-2,2,3-TRIMETHYLPENT-4-EN-l-YL)SULFONYL)-3' ,4,4',5- TETRAHYDRO-2H,2 ^f H-SPIRO[BENZO[B][!,4]OXAZEPINE-3, l '- NAPHTHALENE] -7-C ARBOXAMIDE AND (S)~5-(((l R,2R)-2- ACRYLO YLCYCLOBUTYL)METHYL)-6 ^, -CHLORO-N-(((S)-2,2, 3-

TRIMETHYLPENT-4-EN-l-YL)SULFONYL)-3 ^, ,4,4',5-TETRAHYDRO- 2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

To a solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- h}'-droxyallyl)cyclobuiyl)m^

3',4,4',5 etraliydro-2H,2H~spiro[benzo[b][l,4]oxazepme-3, -naphthalene|-7- carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox'ally])cyclobutyl)methyl)-N-(((S)-2,2,3-trimethylpent- 4-en-l-yl)sulfo^ 34,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-n aphthalene]-7- carboxamide (0.430 g, 0.671 mmol) in DCM (6.7 ml) was added dess-martin periodinane (0.341 g, 0.805 mmol). The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was loaded on the column and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eiuting with a gradient of 0% to 30% EtOAc in hexane, to provide the title compound (0.250 g, 58%). mix (ESI, + ve ion) 639.2 i.Yl H) .

STEP 5: (lS,3 ^* R,6'R,8'E,10'R)-6-CHLORQ-10',l l',l l'-TRIMETHYL-3,4- DIHYDRO~2H,7'H, 15'H-SPIRO[NAPHTHALENE-l ,22'-

|20i()X A| I 311 HI Λ| I .. N |OI A/A Π·. ΓΚΑίΎί ^' ί. Ol i -1.7.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOS A [8, 16, 18,24]TETRAENE] -7', 15'-DION 13', 13'-DIOX!DE AND

(lS,3 ^, R.6'R,8¾10 ^, S)-6-CHLORO-10^11 ll ^, -TTUMETHYL-3,4-DIHYDRO- 2H,7TI, 15 Ή-SPTRO [N APHTH ALENE- 1 ,22'- |20jOXA| Ι3ΓΓ!Π.\| i.l4|5)!A .A ^' ! n RAC YCi.Oi 14.7 .0 ^; "O ¹ '" ¹ |P1 ^: N I ^' ACOSAi 8, 16, 18,24]TETRAENE] -7', 1 S'-DIONE 13', 13'-DI()XIDE

The title compound was prepared from (S)-5-(((lR,2R)-2- acr>Toylcyclobuty'l)methyl)-6'-chloro-N-(((R)-2,2,3-trime thylpent-4-en-l- y l)sulfony i)-3 ',4,4',5 -tetrahy dro-2H,2'H-spiro [benzo [b] [ 1,4 ] oxazepine- 3 , naphthalene]-7-carboxamide and (S)-5-(((lR,2R)-2-actyloylcyclobutyl)methyl)-

0 ^! -ehloro-N~(((S)~2,2,3-trimethylpeM

2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine- 3 , 1 '-naphthalene] -7-carboxamide by the similar procedure described in Example 432, Step 5. m/z (ESI, +ve ion) 611.2 {\i · H)

STEP 6: (IS^'R^'R 'S^'E O'Sl-e-CHLORO-T'-HYDROXY-lO',! Γ,11'- TRIMETHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 (Γ ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]TETiL EN]-15'-ONE 13',13'-DIQXIDE OR

(1 S,3'R,0 ^! R,7 ^* R,8'E, 10'S )-6-CHLORO-7'-HYDROXY- 10', 1 Γ, 11 '-TRIMETHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8 ₅ 16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6 ⁱ R,7'S,8'E,10'R)-6-CHLORO-7'-HYDROXY-10Vl !',! 1 '-TRTMETHYL- 3.4-OIHYDRO-2I !.Ι ^' ί i-Si ^! IR()| ΝΛΡ! ί Γ! !.\ί Ι·.\! .-!.22'-

|2ίί|0ΧΛ| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥίΤΤΗΑ(ΎΠ.ΟΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS,3Έ )' ,7¾,8Έ/10'S)-6-CHI O-7'-HYDROXY-10 ^l -TRIMETHYL- 3.4-DiRYORO-2i 1. i Ί f-SP!RO|\ ^' .\PI Π ΗΛΙ.ΓΝΙ - 1.22'-

[20]OXA[13]THL [1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 3', 13*-DIOXIDE

To a solution of (lS,31 ,6'R,8¾10 )-6-chloro-10',ir,ir rimethyl-3,4- dihydro-2H,7¾15H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[14.7.2.0 ³ * ⁶ .0 ^{!9 <24} ]pentacosa[8,16,18,24]tetrae ne]-7',15'-dion 13',13'-dioxide and (lS,3'R,6'R,8 ^! E,10 ^! S)-6-chloro-10Vi ,l Γ- trimeihyl-3,4-dihydro-2H,7'H,15'H-spiro[naphthalene-l,22'-

|2 ⁽⁾ joxsij I3|t ia| U4|dia/aielracveioj 1

e]-7',15'-dione 13',13'-dioxide (70 mg, 0.12 mmol) in 3 mL of THF under N ₂ at

0°C was added borane tetrahydrofuran complex, 1.0 M in tetrahydrofuraii (0.17 mL, 0.17 rnmol). Hie reaction mixture was stirred at 0°C for Ih, and then queched with MeOH at 0°C. The reaction mixture was diluted with saturated NH4CI soution and 30 mL of EtOAc. The organic layer was separated and concentrated. The residue was purified by chromatography, eluting with a gradient of 0% to 40% EtOAc (containing 0.3% AcOH) in hexane to provide the title compound as the first eluting isomer (12 mg, 34%). Ή N.V1R (400MHz, CDCb) δ 8.99 (br. s., IH), 7.73 (d, ./ 8.4 Hz, I H ). 7.26 - 7.21 (m, 2H), 7.18 (d l.■/ 2.3. 8.4 Hz, IH), 7.10 id. ,/ 2.3 Hz, IH), 6.96 (d, 8.6 Hz, IH), 6,01 - 5,90 (m, IH), 5.86 - 5.76 (m, IH), 4,31 (br. s . IH), 4.1 1 (s, 2H), 3.99 (d, J=15.1 Hz, IH), 3.91 (d, ,7=15,8 Hz, IH), 3.68 (d, J=14.3 Hz, IH), 3.58 (d, J=15.8 Hz, IH), 3.22 (d, J=14.3 Hz, IH), 3.02 (dd, ./ 8.7. 15.4 Hz, I H), 2,85 - 2.69 (m, 2H), 2.65 - 2.44 (m, 3H), 2,26 - 2.14 (m, IH), 2.08 - 1.37 (m, 8H), 1.24 (s, 3H), 1.09 (s, 3H), 1.0 ! (d, 6 8 Hz, 3H). m/z (ESI, +ve ion) 613.2 (M+H) ⁺ . EXAMPLE 494. (1 S,3'R,6'R,7'R,8'E, 10'S)~6-CHLORO~7'~HYDROXY-

10', 1 i '. i i '-TRIMETHYL-3,4-DIHYDRO-2H, 15 Ή-S PIRO [N APHTH ALENE-

1 ">"> ^< -

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCL )[ 14.7.2.0 ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,10'S)-6-CHLORO-7'-HYDROXY-10',l Γ,11 ' -TRIMETHYL- 3,4-DIHYDRO-2H,l 5'H-SPIRO[N APHTH ALENE-1 , 22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1 ^' . 13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R)-6-CHLORO-7'-HYDROXY- 10', 11 ', 11 '-TRIMETHYL- S^-DIHYDRO^H.lS'H-SPIROINAPHTHALENE-l^^-

[20]ΟΧΑ[13]ΤΉ Α[1 4]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 10'S)-6-CHLORO-7'-H YDROXY- 10', 1 1 ', 11 '-TRIMETHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l ,22'- | 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA

[8, 16, 18,24]TETRAEN] -15'-ONE 13', 13'-DIOXIDE

The title compound was obtained as the second eluting isomer from chromatography separation in Example 493, Step 6 (2.2 mg, 6%). ^l W NMR

(500MHz, CD3OD) δ 7.71 (d, ,/ 8.6 Hz, IH), 7.16 (dd,■/ 2. ! . 8.4 Hz, 1H), 7.10 (d, 2 0 Hz, 11 1 ). 7.05 (br. 8., H), 6.97 (d, ./ 8. 1 Hz, i l l ). 6,90 (d, ./ 8. ! Hz, IH), 5,98 (d, J=9.5 Hz, IH), 5.52 - 5.44 (m, H), 4.08 (s, 2H), 4.01 (t, ,7=7,0 Hz, IH), 3.87 (d, ./ 1 .9 Hz, IH), 3.62 (d, ./ 14.7 Hz, 2H), 3.50 - 3.39 (m, 2H), 2.88 - 2.69 (m, 2H), 2.63 - 2.53 (m, IH), 2.36 - 2.20 (m, 2H), 2.10 - 1.68 (m, 8H), 1.50 (t, J=U2 Hz, ΓΗ), 1.29 (s, 3H), 1.22 (s, 3H), 1.02 (d, .7=7.1 Hz, 3H). m/z (ESI, +ve ion) 613.2 (M+H) ⁺ . EXAMPLE 495, (l S,3'R,6'S,8'E)-6-CHLORO-3,4-DIHYDRO-2H,15'H- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8,16, 18,24]TETRAEN]-15'-ONE 13\13 ^* -DTOXIDE AND EXAMPLE 496.

(1 S,3'R,6 ^! R,9'E)-6-CHLORO-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[10,16, 8,24]TETRAEN]-15'-ONE 13 ^* , 13'-DIOXIDE AND EXAMPLE 497.

(1 S,3'R,6'R, 10'Z)~6~CHLORO~3,4-DmYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'- |;20]()XA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA

[10,16,18,24]TETRAEN]-15'-ONE 13V13'-DIOXIDE AND EXAMPLE 498,

(1 S,3'R,6'R, 10'E)-6-CHLORO-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147.2 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [10,16,18,24]TETRAEN]-15"-ONE 13',13'-DTOXIDE AND EXAMPLE 499, (1 S,3 ^, R,6 ^! R,9'Z)-6-CHLORO-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DlAZATETRACYCLO[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [9J 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

498 499

STEP1 : (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((E)-3-OXOPROP-l-EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((Z)-3- OXOPROP-l -EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO- 2H,2TI-SPIRO[BENZO[B][I,410XAZEPINE-3,1 '-NAPHTHALENE]-7- CARBOXYLATE

A solution of (l,3-dioxolan-2-ylmethyl)tripheny]phosphonium bromide (2.18 g, 5.09 mmol. Avocado Research) in 1.5 mL of THF was cooled to -78 °C, butyllithium solution, 2.5 M in hexanes (1.45 ml, 3.63 mmol, Aldrich) was added dropwise. The reaction mixture was stirred at -78 °C for 25 min, (S)-methyl 6'- chloro-5-(((lR,2R)-2-formylc ]obutyl)me l)-3 4,4^5-tetTahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylate (0.330 g, 0.727 mmol, Intermediate, Intermediate AA11A, Step 20A) in THF (0.5 ml) was added slowly and it was stirred at -78 °C for 30 min and then r.t. overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic solution was concentrated, and the residue was dissolved in 10 mL of THF and was treated with 2 mL of IN HC1 aq solution, stirred at ambient temperature for 2 hrs. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic extract was washed with saturated aqueous NaCl (30 mL) solution and dried over MgS04. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 60% EtOAc in hexane to provide a mixture of the title compound (0.260 g, 75%) as a white solid, m/z (ESI, +ve ion) 480.2 { \ I · Π } .

STEP 2: (S)-METHYL 6'-CHLORO-5-(i(lR,2S)-2-(3- ilYDROXYPROPYL)CYCLOBUTYL)METIiYL)-3',4,4',5-TETRAi-IYDRO- 2H,2H-SPIR0[BF;NZ0[B] [1 ,4]0XAZEPINE-3,1'-NAPHTHALENE]-7- CARBOXYLATE

12JZ

A mixture of (S)-methyl 6'-chloro-5-(((lR,2S)-2-((E)-3-oxoprop-l -en-l- yl)cyclobutyl)methyl)-3 4,4 5-tetrahydro-2H,2'H-spiro[benzo b] [ l,4]oxazepine- 3,l '-naphtha] ene]-7-carboxylate and (S)-methyl 6'-chloro-5-(((l R,2S)-2-((Z)-3- oxoprop-l -en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylate (0.260 g, 0.542 mmol) from Step 1 above and platinum (iv) oxide (60 mg, 0.26 mmol. Omega) in EtOAc (10 mL) were stirred under H ₂ at ambient temperature for 3 h. The solid was filtered off and the filtrate concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0 % to 100 % EtOAc in hexane, to provide the title compound (0.240 g, 92%). m/z (ESI, +ve ion) 484.2 (M+H) ⁺ .

STEP 3: (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-(3-

OXOPROPYL)CYCLOBUTYL)METHYL)-3',4,4;5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

A flask charged dimethyl sulfoxide (0.352 mL, 4.96 mmol, Aldrich) and (1 mL) was cooled to -78 °C, oxalyl chloride, 2.0 M solution in dichloromethane (1 .24 mL, 2.48 mmol, Aldrich) was added dropwise and the reaction stirred for 30 rnin. A solution of (S)-methyl 6'-chloro-5-(((lR,2S)-2-(3- hydroxypropyl)cyclobur}'i)methyl)~3',4,4',5~tetrahydro-2H,2' H~

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyla te (240 mg, 0.496 mmol) from Step 2 above in DCM (1 ml) was added dropwise and the reaction was stirred at -78 °C for 30 min, and then triethylamine (1.38 mL, 9.92 mmol, Aldrich) was added dropwise and it was stirred for 10 min at -78 °C and then ambient temperature for 30 min. The reaction mixture was quenehed with water (5 ml), extracted with EtOAc (50 ml). The organic layer was washed with IN HCl aq solution and brine, dried over anhydrous sodium sulfate, and concentrated and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0 % to 60 % EtOAc in hexane to give the title compound (0.220 g, 92%). m/z (ESI, +ve ion) 482.2 (M+H) ^" . STEP 4: (S)-METHYL 5-((( 1 R,2R)-2-(BUT-3-EN~ 1 -

YL)CYCLOBLrrYL)METHYL)-6 ^, -CHLORO-3',4,4',5-TETR/\HYDRO-2H,2 ^! H- SPIRG j BENZO[B] [1 ,4 ]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE

A solution of methyl phenylphosphonium bromide (741 mg, 2.08 mmol, Avocado Research) in THF (10 ml) was added potassium tert-butoxide, 1.0 M solution in tetrahydrofuran (1.25 ml, 1.25 mmol, Aldrich) and stirred at ambient temperature for 30 min. (S)-methyl 6'-chloro-5~(((lR,2S)-2-(3~

oxopropy )cyclobuty )methyi)-3',4,4',5 etrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate (200 mg, 0.420 mmol) from Step 3 above in THF (1.5 ml) was added slowly and the resulting mixture was stirred at 0 °C for 30 min and then ambient temperature overnight. The reaction mixture was diluted with IN HC1 (10 mL) and extracted with Et ₂ 0 (2 x 30 mL). The organic extract was washed with saturated aqueous NaCl solution (20 mL) and dried over MgS04. The solution was filtered and concentrated in vacuo to give the crude title compound as a white solid, m/z (ESI, +ve ion) 480.2 I 1 1 > ^" .

STEP 5 : (S)-5 - ((( 1 R,2R)-2-(BUT-3 -EN- 1 - YL)C Y CLOBUTYL)METHYL)-6'- CHLORO-3',4,4',5-TETRALIYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

A mixture of (S)-methyl 5-(((lR,2R)-2-(but-3-en-l-yl)cyclobutyl)methyl)- 6'-chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, - naphthalene]-7-carboxylate (180 mg, 0.375 mmol) from Step 4 above and lithium hydroxide monohy drate (142 mg, 3.37 mmol, Aldrich) in 1 mL of water dissolved in MeOH (2 mL) and THF (3.00 mL) was stirred at 40 °C overnight, and then the solvents were removed, acidified with 1 N HC1 aq soultion to pH 2-3, extracted with EtOAc (3x60 ml), washed with brine (3 ml), dried over anhydrous sodium sulfate, and then concentrated to give the title compound (0.175 g, 100%). m/z (ESI, +ve ion) 466.2 (M+H) ⁺ .

STEP 6: (S)-5-((( lR,2R)-2-(BUT-3-EN- 1 -YL)CYCLOBUTYL)METHYL)-N-

(BUT-3-EN-l-YLSLT..FONYL)-6'-CHLORO-3',4,4',5-TETRAHYDRO- 2H,2'H- SPIRO [BENZO [B][l ,4] OXAZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

N,N-dimethylpyridin-4-amine (DMAP) (78.0 mg, 0.638 mmol, Aldrich) was added to a solution of (S)-5-(((lR,2R)-2-(but-3-en-l-yi)cyc]obuty])methyl)- 6'-chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxa zepine-3,r- naphthalene]-7-carboxylic acid (0.175 g, 0.375 mmol) from Step 5 above and but- 3-ene-l-suifonamide (0.203 g, 1.50 mmol Intermediate, EE15 ) in DCM (13 ml) at 0 °C, and then n-(3-dimethylaminopropyl)-n'-ethylcarbodiimide hydrochloride (0.144 g, 0.750 mmol, Aldnch) was added at ambient temperature! on by portions slowly and the reaction mixture was stirred at ambient temperature overnight. The reaction was diluted with EtOAc (60 ml), washed with IN HO aq solution (2x5 ml), brine (3 ml), dried over anhydrous sodium sulfate, concentrated. The residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0 % to 20 % EtOAc in hexane to provide the title compound (0.175 g, 80%). m/z (EST, +ve ion) 583.2 {V! H} STEP 7: ( 1 S,3 ^f R,6'S,8'E)-6-CHLORO-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTH ALENE- 1.22 ^' -

|2ujOXA| O ΙΊ ί Ι1Λ| I„ I 4|ΠίΛ/Λ T! RAC YO C)! i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]ΤΕΤΡ^ΑΕΝ]-15'-ΟΝΕ 13',13'-DIOXIDE AND (lS,3'R,6'R,9'E)-6- CHI RO-3,4-DmYDRO-2H,15'H-SPIRO[NAPI-ITHALENE-l,22'- [20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ' ²⁴ ]PENTACOSA [10,16,18,24]TETRAEN]-15'~ONE 13',13'"D10XIDE AND (lS,3'R,6'R,10'Z)-6- CHL()RO-3,4-DIHYDRO-2H,15'i-I-SPIRO|NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [ 10, 16, 18,24] TETRAEN] - 15'-ONE 13', 13'~DIOXIDE AND ( 1 S,3'R,6'R, 10Έ)-6- CHLORO-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE"l,22'- [2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [ 10, 16, 18,24]TETRAEN]-!5'-ONE 13',13 -DIOXIDE AND (1 S,3'R,6'R,9'Z)-6- CHLORO-3,4~DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [9, 16, 18 ,24]TETRAEN] - 15"-ONE 13 ', 13 '-DIOXIDE A lOOmL round bottom flask was charged with (S)-5-(((lR,2R)-2-(but-3- en-l-yl)c clobutyl)methyl)-N-(but-3-en-l-ylsulfonyl)-6'-chloro-3',4,4' ,5- tetrahy dro-2H,2TI-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxami de

(135 mg, 0.230 mmol) from Step 6 in 20 ml, of toluene. The solution was stirred at ambient temperature for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs 2 ^nd generation (29 mg, 0.046 mmol, Aldrich) in toluene (10 mL) at room temperature. The mixture was stirred at 106 °C under nitrogen for 70 min. Air was blown for 10 min to deactivate the catalyst, and then concentrated. The residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100 % EtOAc to give two fractions with the desired mass. The first fraction was further purified by the reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give (lS,3'R,6'S,8'E)-6-chloro-3,4-dihydro-2H,15'H- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]mia[l,14]diazatetracyc

n]-15'-one 13',13'-dioxide (Example 495, 14 mg, 0.025 mmol) as the first eluting major isomer, (lS,3'R,6'R,9'E)-6-chloro-3,4-dihydro-2H,15'H-spiro[naphthal ene- 1.22'-

12 j / en]-15'-one 13',13'-di oxide (Example 496, 10 mg, 0.018 mmol) as the third elutmg major isomer, (1 S,3'R,6'R, 10'Z)-6-chloro-3,4-dihydro-2H, 15H-spiro[naphthalene-

1 ">"> ^< -

[20]oxa[13]thia[l,14]diazatetracycfo[14.7

en]-15'-one 13',13'-dioxide (Example 497, 10 rng, 0.018 mmol) as the second eiuting major isomer, (1 S,3'R,6'R, 10'E)-6-chloro-3,4-dihy dro-2H, 15Ή- spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazate1ra<^

en]-15'-one 13',13'-dioxide (Example 498, 23 mg, 0.041 mmol) as the fourth elutmg major isomer. The second fraction from chromatography purification was also further purified by the reversed phase preparatory HPLC (C jemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give (lS,3 ^, R,6 ^, R,9 ^! Z)-6-chloro-3,4-dihydro-2H,15'H-spiro|naphthalene-l,22 ^, ~

[20]oxa[13]thia[l,14]diazate1r^

n]-15'-one 13',13 ^! -dioxide (Example 499, 5 mg, 0.009 mmol). { IS. ΪΚ. ⁽ ^ ΑΊ -.)- ^(■ .- chloro-3,4-dihydro-2H,15'H-spiro[naphthalene-L22'-

[20ioxa|13jthia[l,14jdiazatetracyclo[14.7.2.0 ^3>6 .0 ^!9 ' ²⁴ |pentacosa[ 8,16,18,24]tetrae n]-15'-one 13',13'-dioxide: ^l H NMR (500MHz, CDCb) δ 8.00 (s, lH), 8.04 - 7.96 (m, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.19 (dd, J=2.2, 8.6 Hz, 1H), 7.08 (dd, J=2.0, 8.3 Hz, 2H), 6.95 - 6.91 (m, 1H), 6.90 - 6.86 (m, 1H), 5.55 - 5.40 (m, 2H), 4.18 - 4.03 (m, 3H), 3,82 - 3.66 (m, 2H), 3.37 - 3.20 (m, 2H), 2,98 (dd, J=8.1, 15.4 Hz, 111). 2.85 - 2.69 (m, 2H), 2,37 - 2.18 (m, 4H), 2.12 - 1.21 (m, 12H). m/z (ESI, +ve ion) 555.2 (M+H) ⁺ ; (lS,3'R,6 ^, R,9 ^, E)-6-chioiO-3,4"dihydro-2H,15 ^, H"Spiro[naphthalene- 122'-

[20] oxa[ I 3 ] thi a[ 1,14] diazatetracy cl ol 14.7.2.0 ³ · ⁶ 0 ^{! 924} ] pentacosa[ 10, ! 6, ! 8,24] tetra en]~15 ^! -one 13',13'-dioxide: Ί1 NMR (500MHz, CDCb) δ 8,04 (s, IH), 7,73 (d, ./ 8.6 Hz, IH), 7.21 (ddd, ./ 2.1.8.2, 14.9 Hz, 2H), 7.09 (d, ./ 2.2 Hz, IH), 6.97 (d, ./ 8.3 Hz, IH), 6,83 (d, ./ ! .7 Hz, IH), 5.62 (td, ./ 7.2. 1 .7 Hz, IH), 5.45 - 5.33 (m, IH), 4.19 - 4,04 (m, 3H), 3.85 (ddd, ./ 2.7.10,2, 15.5 Hz, IH), 3.78 - 3.61 (m, 3H), 3.20 (d, J=14.4 Hz, IH), 3.05 (dd, J=5.5, 15.5 Hz, IH), 2.86 - 2.51 (m, 4H), 2,34 - 1.23 (m, 13H). m /, (ESI, +ve ion) 555.2 i.V! H) ;

(lS,3'R,6 ^! R,10'Z)-6-chloro-3,4~dihydro^^

en]-15'-one 13',13'-dioxide: Ή NMR (500MHz, CDCb) δ 7.90 (s, IH), 7.71 (d, ,/ 86 Hz, IH), 7.19 (dd, ,/ 2.3.8.4 Hz, IH), 7.07 (dd, ./ 1.7.19.1 Hz, 2H), 6.95 -

6.90 (m, 2H), 5.79 (dt,J=3.L 10.8 Hz, IH), 5.48 (dt,J=3.3, 11.1 Hz, IH), 5.07 -

4.91 (m, IH), 4.18 - 4.07 (m, 2H), 3.85 (d, ./ 15.4 Hz, ill).3.77 - 3.62 (m, 2H), 3.17 (d, ,/ 142 Hz, IH), 2.99 (dd, 6.7.15.3 Hz, 111).2,84 - 2.66 (m, 211).2.37 - 1.06 (m, 1 » I) m/z (ESI, +ve ion) 555.2 (M+H) ⁺ ; (lS,3'R,6'R,10'E)-6~chloro-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracycfo[½

en]-15'-one !3',13'-dioxide: Ή NMR (500MHz, CDCb) δ 8,04 (s, IH), 7,70 (d, ,7=8.6 Hz, IH), 7.18 (dd, J=2.3, 8.4 Hz, IH), 7.14 (dd, J=2.G, 8.1 Hz, IH), 7.09 (d, ./ 2.2 Hz, IH), 6.97 (d, ,/ 8.1 Hz, IH), 6.74 (d, ./ i.7 Hz, IH), 5.89 (id.■/ 7.5. 15.1 Hz, IH), 5.56 (id, ./ 7.4.15.2 Hz, !!!).4.31 - 4.23 (rn, IH), 4.22 -4,16 (m, IH), 4.14 - 4.07 (m, 2H), 3,69 (d, ./ 14.2 Hz, IH), 3.60 id..7=15.7 Hz, IH), 3.28 - 3.14 (m, 2H), 2.85 - 2.69 (m, 2H), 2.25 - 1.20 (m, 16H). m/z (ESI, +ve ion) 555.2 { \ I · Π } : lS,3'R,6 ^! R,9'Z)-6-chloro-3,4-dihydiO-2H,15 ^! H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[ 1, 14]diazatetracy clo[14.7,2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]pentacosa[9,16,18,24]ietrae n]-15'-one 13',13'-dioxide: ¾ NMR (400MHz, CDCb) δ 7.98 (br. s., IH), 7.71 (d, ./ 8.6 Hz, IH), 7.19 (dd, ./ 2.2.8.6 Hz, IH), 7.12 - 7.04 (m, 2H), 6.98 id. ./ 8.2 Hz, IH), 6.89 (s, IH), 5.62 - 5.49 (m, IH), 5.41 - 5.31 (m, IH), 4,22 - 4.02 (m, 2H), 3,80 - 3.53 (m, 4H), 3.34 (d, ,7=14,3 Hz, IH), 3.18 (dd, .7=8.8, 15.5 Hz, IH), 2.90 ·· 2.69 (m, 2H), 2.66 - 1.17 (m, 16H). m/z (ESI, +ve ion) 555.2 {W W) .

EXAMPLE 500, (1 S,3'R,6'S,9'R, 10"E)-6-CHLORO-9'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[10,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR (1 S,3'R,6'S,9'S,I0'E)-6- CHLORO-9 ^! -HYDROXY-:i4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 122'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[ 10, 16, 18,24] TETR AEN] - 15'-ONE 13', 13'-DIOXIDE

STEP 1 : (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2S)-2-(3- OXOPROPY UCVC i OBL TYUYl h ! 1 1 Υ 1.)-3'.4. ^. Γ. - ^' Π·. 1 R A! !Y ORO-21 f.2'J !- SP1RO [BENZO [B] [ 1 ,4] QXAZEP1NE-3, 1 '-NAPHTHALENE] -7-

CARBOXYLAT

The title compound was prepared in an analogous manner to that described in Example 495 from Step 1 to Step 3 using Intermediate AA11A, Step 20B. (S)- tert-butyl 6'-chloro-5-(((l R,2S)-2-(3-oxopropyl)cyclobutyl)me 1)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylate. m/z (ESI, +ve ion) 524.2 (M+H) ⁺ . STEP 2: (S)-6 ^f -CHLORO-5-(((lR,2S)-2-((R)-3-HYDROXYPENT-4-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2S)-2-((S)-3-HYDROXYPENT-4-EN-l-

Y ! . )i VC i OBL TY UYl h ! 1 1 Y ! .)-3'.4. I\5- Π ·. 1 R A! !Y I>RO-2l i.2'1 !-

SPIRO [BENZO [B ] [ 1,4] OXAZEPINE-3 , l'-N APHTHALENE] -7-C ARBQXYLIC

ACID

To a 100 ml round-bottomed flask was added (S)-tert-buryl 6'-chloro-5- (((lR,2S)-2-(3-oxopropyl)c\ lobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro benzo b] |l,4]oxazepine-3,r-naphthalene]-7-carboxjlate (180 mg, 0.343 mmol) from Step 1 above in THF (3 ml.), and the solution was cooled to -78 °C, vinylmagnesium bromide, 1.0 M solution in tetrahydrofuran (0.446 mL, 0,446 mmol, Aldrich) was added dropwise. The reaction mixture was allowed to warme up to ambient temperature, and stirred for 3 h. The reaction mixture was diluted with ether, and quenched with the saturated aqueous NH4C1 solution. The organic layer was separated, and washed with brine, concentrated. The residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0 % to 50 % EtOAc in hexane to give the desired intermediate. The intermediate was treated with 4 mL of 50 % TFA/DCM. The mixture was stirred at ambient temperature for 4h, and then concentrated. The residue was dissolved in MeCN and water, and then a few drop of NaHCCe was added. The resulting mixture was stirred at ambient temperature for 2 h, and then the organic solvent was removed. The mixtue was acidified with IN HC1 aq soultion to pH 2-3, extracted with EtOAc (3x60 mL). The organic solution was separated and washed with brine (3 ml), dried over anhydrous sodium sulfate, and then concentrated to give the title compound (0.045g, 26%). nvz (ESI, +ve ion) 496.2 (M+H) ⁺ .

STEP 3: (S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((l R,2S)-2-((R)-3- HYDROXYPENT-4-EN- l-YL)CYCLOBUTYL)METHYL)-3',4,4',5- ΤΕΤΚΑΗΥΟΚΟ-2Η,2Ή-8ΡΙΚΟ[ΒΕΝΖΟ[Β][1,4]Ο ΧΑΖΕΡΙΝΕ-3, 1 '- APHTH ALENE] -7 - C ARB OXAMIDE AND (S)-N-(ALLYLSULFONYL)-6 ^* - CHLORO-5-(((l R,2S)-2-((S)-3-HYDROXYPENT-4-EN-l - Y ! .)i VC i OBL TYUYl h ! 1 1Y ! .)-3'.4. I .5- Π·. ! R A! !Y I>RO-2l i.2'1 !- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

The title compounds were prepared in an analogous manner to that described in Example 495, Step 6 using (S)-6'-chloro-5-(((lR,2S)-2-((R)-3- hydroxypent-4-en-l-yl)cv'clobutyl)methyl)-3',4,4',5-tetrahyd ro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid and (S)-6'- chloro-5-(((lR,2S)-2-((S)-3-hydroxypent-4-en-l-yl)cyclobutyl )methyl)-3 ^, ,4,4',5- tetrahy dro-2H,2'H-spiro| benzoj b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyiic acid from Step 2 above and prop-2-ene-.l -sulfonamide (perpared according to the procedure by Hanson, Paul R. ; Jimenez-Hopkins, Maria; Organic Letters, 2008, 10, 2223-2226). m/z (ESI, +ve ion) 599.2 (M+H) ⁺ .

STEP 4: (lS,3 ^! R,6'S,9 ^! R,10'E)-6-CHLORO-9'-HYDROXY-3,4-DIHYDRO- 2H, 15'H-S PIRO [N APHTH AL ENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [10,16,18,24]TETRAEN]-15'-ONE 13 ', 13 '-DIOXIDE OR (1S,3'R,6'S,9'S,10'E)- 6-CHLORO-9'-HYDROXY-3,4-DlHYDRO-2H,15H-SPlRO[NAPHTHALENE-

122'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[10,16, 18,24] TETRAEN] - 15 '-ONE 13', 13'-D10XIDE

The title compound was prepared from (S)-N-(allylsulfonyl)-6'-chloro-5- (((lR,2S)-2^(R)-3-hydroxypen -en-l-yl)(yclobutyl)methyl)-3 ^, ,4 ₅ 4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)-N-(allylsulfonyl)-6'-(^oro-5-(((lR,2S)-2 (S)-3-hydroxypeiit-4-eii-l- yl)cyclobut'i)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l,4]oxazepine- 3,r-naphthalene]-7-carboxamide by the similar procedure described in Example 432, Step 5, and isolated as the second eluting major isomer from the reversed phase preparatory HPLC separation. ¾ NMR (500MHz, CD2CI2) δ 8.13 (br. s,, 1H), 7.71 (d, .7=8,6 Hz, IH), 7.17 (dd, J=2.3, 8.4 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.95 (d, J=8.3 Hz, 1H), 6.72 (d, J=2.0 Hz, IH), 5.92 (dd, J=5.9, 15.4 Hz, IH), 5.83 - 5.74 (m, IH), 4.34 - 4.18 (m, 3H), 4.09 (s, 2H), 3.74 - 3.54 (m, 2H), 3.27 - 3,07 (m, 2H), 2.84 - 2,65 (m, 2H), 2.25 - 0,76 (m, 15H). m!z (ESI, +ve ion) 571.2 (M il)

EXAMPLE 501. (1 S,3'R,6'S,9'S,10'E)-6-CHLORO-9'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

|2uj XA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' .\COSA [1C),16,18,24]TETP _^ AEN]-15'-0NE 13 ',13 '-DIOXIDE OR (lS,3'R,6'S,9'R,10'E)-6- CHLORO-9'-HYDROXY-3,4-DlHYDRO-2H,15'H-SPIRO[N APHTH ALENE- l. "

[20]OXA[13]TOIA[1,14]DL ZATEIIACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [10,16,18,24]TETRAEN]-15"-ONE 13\13'-DTOXIDE

The title compound was obtained as the first eluting isomer from the reversed phase preparatory HPLC separation in Example 500, Step 4. ¾ NMR (500MHz, CD2CI2) δ 8.05 (s, IH), 7.68 (d, J=8.6 Hz, 1H), 7.16 (dd,■/ 2.3.8.4 Hz, 1H), 7,09 (dt, ./ 2.2.4.0 Hz, 2H), 6.95 (d, 8.1 Hz, 1H), 6.78 (d, ,/ 20 Hz, 1H), 5,96 (dd, J=6.4, 15.7 Hz, 1H), 5.82 - 5.71 (m, IH), 4,31 - 4.17 (m, 2H), 4.16 - 4.05 (m, 3H), 3.65 (d, J=I4.4 Hz, IH), 3.53 (d, J=15.7 Hz, 1H), 3.34 - 3.23 (m, 2H), 2.84 - 2.65 ins.2H), 2.11 - 0.50 (m, 15H). m /. (ESI, +ve ion) 571.2 iM Π) .

EXAMPLE 502. (1 S,3'R,6'S,9'R)-6-CHLORO-9'-HYDROXY-3,4-DIHYDRO- 2H, 15'H-S PIRO | N APHTH AL ENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ "*0 ^]9 ^ ⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13', 3 ^! -ΟίΟΧΓΟΕ OR (18,3Έ,6'8,9'8)-6-αΗΙ^Ο- 9'-HYDROXY-3,4-DIHYDRO-2H,15'H~SPIRO[NAPHTHALENE-l,22 ^! " |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ - ⁶ .0 ^l9 ' ²⁴ ]PENTACOSA [16, 18,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE

A mixture of (1 S,3'R,6'S,9'R, 10'E)-6-chloro-9'-hydroxy-3,4-dihydro- 2H, 15 Ή-spiro [naphthalene- 1 ,22' -

en]-15'-one 13',13'-dioxide or (lS,3'R,6'S,9'S,10'E)-6-chloro-9'-hydroxy-3,4- dihydro-2H,15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazatetr^

en]-15'-one 13',13'-dioxide (Example 500, 15 mg, 0.026 mmol) and platinum (iv) oxide (3.6 mg, 0.0 ! 6 mmol) in EtOAc (1 ml.) was stirred was stirred under an atmosphere of H ₂ (balloon) at ambient temperature for 45 min. The reaction mixture was then filtered through a syringe filter and. The crude product was further purified by the reversed phase preparatory HPLC (Gemini™ Prep Cm 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give the title compound as a white solid. ^! H NMR (500MHz, CDCb) δ 8.08 (s, 1H), 7.72 (d, J=8.3 Hz, IH), 7.19 (dd, ./ 2.2.8.6 Hz, 1H), 7.10 (d, .7=2,0 Hz, 1H), 7.00 - 6,94 (m, 2H), 6.91 (s, III).4.16 - 3.97 (m, 3H), 3.79 - 3.67 (m, 3H), 3.46 - 3.35 (m, HI).3.20 (d, ./ !4.4 Hz, !!!).3.02 (dd,■/ 7. .15.4 Hz, 1H), 2.84 - 2.69 (m, 2H), 2,34 - 1.21 (m, 19H). m/z (ESI, + ve ion) 573.2 (M il) . EXAMPLE 503. (1 S ₅ 3 ^, R,6 ^, S.9 ^, S)-6-CHLORO-9 ^, -HYDROXY-3 ₅ 4-DIHYDRO-

2H, 15 Ή-S PIR O [NAPHTHALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC4 (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA

[16,18,24]TR1EN]-15'-0NE 13 ',13 '-DIOXIDE OR (lS,3'R,6'S,9'R)-6-CHLORO- 9'-HYDROXY-3,4-DIHYDRO-2H, 15'H-SPIRQ[NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE JTACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 502 using (lS,:rR,6'S,9'S,10'E)-6-chloro-9'-hydroxy-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

en]-15'-one 13',13'-dioxide or (lS,3'R,6 ^! S,9'R,10'E)-6-chIoi -9'-hydroxy-3,4- dihy dro-2H, 15 Ή-spiro [naphtha] ene- 1 ,22'-

[20]oxa[13]thia|;i,14]diazatetracyclo[14;7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[10,

en]-15'-one 13',13'-dioxide (Example 501). H NMR (500MHz, CDCh) δ 8.10 (s, ill).7.71 (d, J=8.6 Hz, ill).7.20 (dd, ./ 2.2.8.3 Hz, ill).7.13 - 7.08 (m, 2H), 7.00 - 6.89 (m, 2H), 4.17 - 4.04 (m, 2H), 3.95 - 3.85 (m, ill).3,79 - 3.47 (m, 4H), 3.31 id../ 1141!/.1H), 3.13 {dd../ 6.!.15.4 Hz, ill).2.86 - 2.70 (m, 2H), 2.31 - 1.14 (m, 19H). m/z (ESI, +ve ion) 573.2 (M+H) ⁺ .

EXAMPLE 504. (lS,3'R,6'S,8'E,ll'S,12 ^! R)-6-CHLORO-ll'-HYDROXY-12 ^! - METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(ΙΒ,Β'Κ,ό'Β,δΈ,Ι l'S,12'S)-6-CHLORO-l r-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15'H-SPIR()[NAPHTHALENE-1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'S,8'E,1 l'R,12'R)-6-CHLOR()-I l'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |Ρ!·Λ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13', 13 '-DIOXIDE OR (lS,3' S,8T ll' ;i2^)-6-CHLORO-ri'-I-IYDROXY-12'-METOYL-3,4- D\\ IYDR ~2i ί ! ! l-SPiRO|\APi ΓΙ ΠΛΙ.Ι .Μ·-! .22'-

|2ujOXA| 1ΉΤί!1Α| l.l4|DiA/AiTTRAC ^' Ya.i)i i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PHNTAi S A

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE

The title compound was prepared from (S)-5-(((lR,2S)-2- allylcyciobu )rnethyl)-6'-chloro-3^4,4^5 etrahydro-2H,2 ^f H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 450, Step 3) and (2R,3S)-3-hydroxyhex-5-ene-2-sulfonamide and (2S,3S)-3 hydroxyhex-5-ene-2-sulfonamide and (2R,3R)-3-hydroxyhex-5-ene-2- sulfonamide and (2S,3R)-3-hydroxyhex-5-ene-2-sulfonamide (Example 714, Step 5) by similar procedures described in Example 432, Steps 4-5, and isolated as the third eluting isomer from the reversed phase preparatory HPLC separation. ¾ N.MR (400MHz, CDCb) δ 8,17 (s, 1H), 7,72 (d, ./ 8.4 Hz, Hi).7.20 (dd, 22. 8,4 Hz, H), 7.16 - 7,06 (m, 2H), 6.96 - 6.83 (m, 2H), 5.62 - 5.50 (m, 1H), 5.29 - 5.14 (m, IH), 4.26 (q, J=7.1 Hz, IH), 4.15 - 4.03 (m, 3H), 3.87 - 3.76 (m, IH), 3.71 (d, J=13.9 Hz, IH), 3.22 (d, ./ 14.3 Hz, IH), 2.95 (dd, ./ 6.6.15.4 Hz, IH), 2,86 - 2.66 (ra, 2H), 2,44 - 1.17 (m, 18H). m/z (ESI, + ve ion) 585.2 (W W) .

EXAMPLE 505. (lS,3'R,6'S,8'E,irS,12'S)-6-CHLOR()-ir-HYDROXY-12'- METOYL-3,4-DIHYDRO-2Il,15'H-SPTRO| JAPHTHALENE-l,22 ⁱ - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'S,8'E,irS,12'R)-6-CHLORO-ir-HYDROXY-12'-METHYL- 3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [8 ₅ 16, 18,24]TETRAEN]-15"-ONE 13',13'-DIOXIDE OR

(ΙΒ,Β'Κ,ό ,δΈ,Ι Ι'Κ,^^-ό-ΟΗΕΟΚΟ-ΙΓ-ΗΥΟΚΟΧΥ- '-ΜΕΤΗΥί-Β^- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8J 6,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6'S,8'E,i rR,12'S)-6-CHLORO-l l'-HYDROXY-12'~METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 504. ¾ NMR (400MHz, CDCls) δ 8.22 (br. s., 1H), 7.70 (d, ./ 8.4 Hz, 1H), 7.19 (dd, ./ 2.2. 8.6 Hz, H i). 7.12 - 7.03 (m, 2H), 6.96 (d, ,/ 8.2 Hz, IH), 6.68 (br. s„ 1H), 5,73 - 5.6 ! (m, 1H), 5,60 - 5.51 (m, I I I ). 4.29 (t «/=6.7 Hz, 1H), 4.18 - 4.03 (m, 2H), 3.91 - 3.77 (m, IH), 3.68 (t, J=14.5 Hz, 2H), 3.28 (d, J=14.3 Hz, IH), 3.16 (dd, J=7.6, 15.3 Hz, IH), 2.89 - 2.65 (m, 2! I ). 2.53 - 1.06 (m, 19H). m (ESI, +ve ion) 585.2 i \i Π ) .

EXAMPLE 506. (lS^'R.e'S^'E l'R.l^R^e-CHLORO-l l'-HYDROXY-l^-

ME^ΉYL-3 ₅ 4-DIHYDRO-2H,15Ή-SPIRO| APHTHALENE-l,22 ^, -

[20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]~15'~QNE 13 ',13 '-DIOXIDE OR

(lS,3 ^, R,6'S,8'E,i rS,12'R)-6-CHLORO-l l'-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0 ³ ^ 0 ¹⁹ - ²⁴ ]PENTACQSA [8,I6,18,24]TETiL E ]-15'-QNE 13', 13 '-DIOXIDE OR (lS,3'R S,8Tll'S;i2'S)-6 ;HI RO-ir iYDROXY-12'-METI-IYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

|2ujOXA| !3jTIUA| Μ4|ηΐΛ/Λ Ι·: ^' ΠίΛ(ΎΠ.Ο! i 4.7.2.0 " ) ¹ *" ¹ |PLNT. SA

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS ¾ )'S,8 .;ri¾ 2'S)-6 ;HLORO-ll' iYDROXY-12'-METOYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13 ^* -DIOXIDE

The title compound was obtained as the first eluting isomer from the reversed phase preparatory HPLC separation in Example 504. ¾ NMR (400MHz, CDCb) δ 8.10 (br. s., 1H), 7.71 (d, ./ 8. Hz, 1H), 7.20 (dd, ./ 2.2.8.4 Hz, ill).

7.09 (d, ./ 2.ϊ Hz, !!!).6.98 - 6.85 (m, 2H), 6.78 (s, 1H), 5.64 - 5.52 (m, 1H), 5.50 - 5.36 (rn, IH), 4.28 (d, ./ (..? Hz, ill).4,16 - 3.96 (m, 3H), 3.88 - 3.73 (ra, 211). 3,24 (d, ./ 14.3 Hz, IH), 3.04 (dd, J=8.4, 15, 1 Hz, ill).2.89 - 2.67 (m, 2H), 2,66 - 2.55 (m, IH), 2.44 - 1.13 (m, 17H). m/z (ESI, +ve ion) 585.2 (M+H) ⁺ .

EXAMPLE 507. (1S,3'R,6'S,8'E,1 l'R,l 2'S)-6-CHLORO-l i'-HYDROXV-LT- METHYL-3,4-DrHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[l,14]DIAZATCTl^CYCLO[147.2 ³ ' ^{6 19i4} ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(1S,3'R,6'S,8'E,1 l'S,12 ^f R)-6-CHLORO-l l'-HYDROXY-12 ^f -METHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTA(X)SA

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(lS^^e'S^'E,! l'S,12'S)-6-CHLORO-l r-HYDROXY-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.20 ^;ί' .ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-QNE 1 ^' .1 -DIO.XIDL OR

(1 S,3'R,6'S,8'E, 11 'R, 12'R)-6-CHLORO-l 1 '-HYDROXY- 12'-METHYL-3, 4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22*- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8.16 ,18,241TETRAEN1-15 ^! -0NE 13'.13'-DIOXIDE

The title compound was obtained as the fourth eluting isomer from the reversed phase preparatory HPLC separation in Example 504. ^l H NMR (400MHz, CDCb) δ 8,09 (br. s., 1H), 7.65 id. «/=8.4 Hz, 1H), 7.16 (dd, ,/ 20.8.4 Hz, 1H), 7.10 (d, ./ 1.8 Hz, 1H), 6.99 (s, 1H), 6.95 - 6.82 (m, 2H), 5.55 - 5.42 (m, 1H), 5.36 - 5.20 (m, 1H), 4.26 - 4.02 (m, 4H), 3.72 - 3.38 (m, 3H), 3.26 (d, ./ 14.1 Hz, III . 2,76 (br. s .2H), 2.43 - 1.18 (m, 18!!} m/z (ESI, +ve ion) 585,2 (V! 11) ^' ,

EXAMPLE 508. (IS^' ^'RJ'S^U^'Ri-e-CHLO O-T'-HYD OXY-^'-^R)- 2-METHOXYPROPYL)-3,4-DIHYDRO-2H.15 Ή- SPI RO [ N APHTH ALENE-

1,22'-

|20i() A| I 311 HI A| I , N |OI.\/.\ Π·. ΓΗ. ΛίΎί ^' ί, l i -1,7.2 ' ' ) ¹ *' ' ¹ |PLNT.\i S A [8,16,18,24]TETP^ENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12'-((2R)-2- METHOXYPROPYL S^-DIHYDRO^H S^SPIROINAPHTHALENE-l^'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

STEP 1 : (2R,4R)-2-HYDROXY-N ₅ N-BIS(4-METHOXYBENZYL)OCT-7-ENE- 4-SULFONAMIDE AND (2R,4S)-2-HYDROXY-N,N-BIS(4- METHOXYBENZYL)OCT-7-ENE-4-SULFON AMIDE

To a -78 °C solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l- sulfonamide (from Intermediate EE 19) (2,00 g, 5. 13 mmol) in THF (20 mL) under argon was added n-butyllithium, 2.5 M solution in hexane (2.47 mL, 6.16 mmol) over 5 minutes. The mixture was stirred at -78 °C for 2 hours (solution turned red-pink) at which time (R)-(+)-! ,2~epoxypropane (Sigma- Aldrich, Milwaukee, WI)(0,540 mL, 7.70 mmol) was added and sti rred at 0 °C for 17 hours. The reaction was then quenched with 100 ml of saturated ammonium chloride and extracted with 300 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified on a Comhif!ash (40g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give [(2R,4R)-2-hydrox\'-N,N-bis(4-methoxybenzyl)oct-7- ene-4-sulfonamide and (2R,4S)-2-hydroxy-N,N-bis(4-methoxybenzyl)oct-7-ene- 4-sulfonamide] (1.85 g, 4.13 mmol, 80 % yield) as a light yellow oil.

STEP 2: (2R,4S)-2-((TERT-BU ^r n LDIPHENYLSILYL)OX -N,N-BIS(4- METHOXYBENZYL)OCT-7-ENE-4-SULFON AMIDE OR (2R,4R)-2-((TERT- BUTYLDIPHENYLSILYL)OXY)-N,N-BIS(4-METHOXYBENZYL)OCT-7- ENE-4-SULFONAMIDE

To a 100 nil flask was added [(2R,4R)-2-hydroxy~N,N~bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide and (2R,4S)-2-hydroxy-N ,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonarnide] (from Step 1) (2.58 g, 5.76 mmol), DMF (40 ml), imidazole (785 mg, 11.5 mmol) and tert-butylchlorodiphenylsilane (2.25 ml, 8.65 mmol). The reaction was stirred at 65 °C for 16 hours at which time reaction was then quenched with 200 ml of saturated ammonium chloride and extracted with 600 ml of diethyl ether. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was first purified on a Combiflash (40 g gold silica column), eluting with 10% to 30% EtOAc in heptanes. The racimic mixture (1 : 1) was then purified by preparatory SCF chromatography (ChiralPak AD 250mm x 30mm column, Phenomenex, Torrance, CA; 16g/minute EtOH + (20mM Ammonia) + 64g/minute CO?. (20% co-solvent) on Thar 80 SFC; outlet pressure = 100 bar; temperature = 22 °C; wavelength = 220 nm; used 1.0 mL injections of 3647mg/41mL (89 mg/mL) sample solution of MeOH (35mL) and DCM (5mL); run time = ^: 13 minutes & cycle time 10 minutes) to provide [(2R,4S)-2~((tert- butyldiphenylsilyl)oxy)-N,N-bis(4-methoxybenzyl)oct-7-ene-4- sulfonamide or (2R,4R)-2-((tert-butyldiphenylsilyl)oxy)-N,N-bis(4-methoxy benz l)oct-7-ene-4- sulfonamide] (1651 mg, 2.407 mmol, 46 % yield) as the faster eluting isomer as a yellow liquid (ΐκ = 1.10 minutes on analytical SFC; AD-H column; 15% EtOH in CO?.).

STEP 3: (2R,4S)-2-HYDROXY-N,N-BIS(4-METHOXYBENZYL)OCT-7-ENE- 4-SULFON AMIDE OR (2R,4R)-2-HYDROXY-N,N-BIS(4- METHOXYBENZYL)OCT-7-ENE-4-SULFON AMIDE

To a 100 ml flask was added (2R,4S)-2-((tert-butyldiphenylsilyl)oxy)- N,N-bis(4-methoxybenz}d)oct-7-ene-4-sulfonamide or (2R,4R)-2-((tert- but diphenylsilyl)oxy)-N,N-bis(4-methoxybenzyl)oct-7-ene-4-sulfo naiTiide] (from Step 2) (600 mg, 0.875 mmol) and tetrabutylammonium fluoride, 1.0 M in tetrahydrofuran (10 ml, 10 mmol). The reaction was stirred at room temperature for 3 hours at which time the reaction was quenched with 100 ml of brine and extracted with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The crude product was purified on a Combifiash (12 g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give [(2R,4S)-2-hydroxy~N,N~bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide or (2R,4R)-2-hy droxy- ,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide] (313 mg, 0.699 mmol, 80% yield) as a clear oil.

STEP 4: (2R,4S)-2-METHOXY-N ₅ N-BIS(4-METHOXYBENZYL)OCT-7-ENE- 4-SULF ON AMIDE AND (2R,4R)-2-METHOXY-N,N-BIS(4- -7-ENE-4-SULFONAMIDE

To a 100 ml flask was added [(2R,4S)-2-hydroxy-N,N-bis(4- methoxybenzy3)oct-7-ene-4-sulfonamide or (2R,4R)-2-hydroxy-N,N-bis(4- methoxybenzyl)oct-7-ene~4-sulfonamidel (from Step 3) (313 mg, 0.699 mmol), THF (5 mL) and NaH (50 mg, 2.1 mmol). The reaction was stirred at room temperature for 15 minutes at which time Mel (0.066 ml, 1.1 mmol) was added. The reaction was stirred at room temperature for an additional 3 hours and then the reaction was quenched with 100 ml of saturated ammonium chloride and extracted with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give [(2R,4S)-2-methoxy-N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide and (2R,4R)-2-methoxy-N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide] (255 mg, 0,552 mmol, 79% yield) as a light yellow oil.

STEP 5: (2R,4S)-2-METHOXYOCT-7-ENE-4-SULFONAMIDE OR (2R,4R)-2- -7-ENE-4-SULFONAMIDE

To a 100 ml flask was added [(2R,4S)-2-methoxy-N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide and (2R,4R)-2-methoxy-N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide] (from Step 4)(255 mg, 0.552 mmol) anisole (0.603 ml, 5.52 mmol), DCM (8 ml) and then TFA (4 ml). The reaction was stirred at 22 °C for 6 hours at which time the solvent was removed. The crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give [ (2R,4S)-2-methoxy oct-7-ene-4- sulfonamide or (2R,4R)-2-methoxyoct-7-ene-4-sulfonamide] (21 mg, 0.096 mmol, 17% yield) as the faster eluting isomer as a yellow liquid.

STEP 6: (S)-6'-CHLORO-5-(((l R,2R)-2-((l S,6R,8R,E)- 1 -HYDROXY-8- METHOXY-6-SULFAMOYLNON-2-EN-l-YL)CYCLOBUTYL)METFiYL)-

S'^^'j-TETR-^HYD O^H^'H-SPl OtBE ZOtBll l^iOXAZEPlNE-S,!'- NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lR,2R)-

((l S,6S,8R,E)-l~HYDROXY-8-METHOXY-6-SULFAMOYLNON-2~EN-l - YL)CYC OBUTYL)METHYL)-3',4,4',5~TETiLAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

To a 100 ml flask was added (S)-6'-chloiO-5-(((lR,2R)-2-((S,E)-l - hydroxyhex^-en-l-y^cyclobuty methy^-S'^^'^-tetrahydro^H^'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (from

Intermediate AA12A) (20 mg, 0,039 mmol), [(2R,4S)~2~methoxyoct-7-ene-4- sulfonamide or (2R,4R)-2-methoxyoet-7-ene-4-sulfoiiamide] (from Step 5)(22 mg, 0.098 mmol) and DCE (2 mL). The solution was sparged with argon for 15 minutes at which time (l,3-dimesityiimidazolidm-2-ylidene)(2- isopropoxybenzylidene)mthenium(VI) chlonde (2.5 mg, 3.9 μηιοΐ) was added as a 0.2 mL solution in DCE at room temperature. The mixture was stirred at room temperature for additional 16 hours. Note: the clear solution becomes slowly darker. The reaction mixture was then bubbled with air for 5 minutes and filtered. The solvent was removed from the filtrate and was directly purified on a

Combiflash (4g gold silica column), eiuting with 50%) - 90% EtOAc in heptanes + 0.2% AcOH, to give [(S)-6'-chloro-5-(((lR,2R)-2-((lS,6R ₅ 8R,E)-l-hydroxy-8- methoxy-6-sulfamoylnon-2-en-l-yl)c> lobu1yl)methyl)-3\4,4 5-tetrahydro- 2H,2'H-spiro[benzo[b] [L4]oxazepine-3,r-naphthalene]-7-carboxylic acid or (S)- 6 ^! -chloro-5-(((lR,2R)-2-((l S,6S,8R,E)-1 iydroxy-8-methoxy-6-sidfamoylnon-2- en-l -yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7 -carboxy lie acid] (25.9 mg, 0.039 mmol, 100 % yield) as white solids. Rf 0.16 eiuting with 90% EtOAc in heptanes.

STEP 7: (lS,3 ^! R,6 ^, R,7'S,8'E,12'R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-2- METHOXYPROPYL)-3.4-DIHYDRO-2H,15^SPIRO[NAPHTHALE E-l,22'- [20]OXA[13]Tffl A[l .MIDIAZATETRACYCLOIMJ^.O^^O'^IPENTACOSA [8,I6, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(lS,3 ^* R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-2-

METHOXYPROPYL)-3,4-DfflYDRO-2H,15^SPIRO[N

[2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE

To a 100 ml flask containing [((S)-6'-chloro-5-(((lR,2R)-2-((l S,6R,8R,E)- l -hydroxy-8-methoxy-6-sulfamoylnon-2-en-l-y^

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid or (S)-6 ^, -chloro-5-(((lR ₅ 2R)-2-((l S,6S _s 8R ₅ E)-l-hydroxy-8-methoxy-6- sulfamoylnon-2-en-l-yl)cj'clobut l)rnethyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, l '-naphthalene]-7-carboxylic acid] (from Step 6)(26 mg, 0.039 mmol), which was previously dried by rotovaping twice with 10 ml of toluene, was added N,N-dimethylpyridin-4-amine (DMA! ⁵ ) (8.1 mg, 0.067 mmol), 45 ml of DCM and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15 mg, 0.078 mmol). The reaction was stirred at room

temperature for 18 hour at which time the mixture was quenched with 100 ml of IN HC3 and extracted with 300 ml of EtOAc. The organic layer were dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified on a Combiflash (4 g gold silica column), eluting with 30% - 70% EtOAc in heptanes, to give the title compound (6.8 mg, 11 μηιοΐ, 27 % yield) as a white solid. Ή NMR (400MHz, CDCb) δ 8.21 (br. s,, 1H), 7.77 - 7.68 (m, IH), 7.64 (d, J=8.4 Hz, IH), 7.20 - 7.14 (m, IH), 7.10 (d, ,7=2,2 Hz, IH), 6.92 (s, 2H), 5.78 (dd, J=4.3, 15.8 Hz, i l l ). 5.48 - 5.33 (m, IH), 4.24 (m, 3H), 4.15 - 4.05 (m IH), 3.92 (br. s., I H), 3.87 - 3.71 (m, 2H), 3.51 (s, 3H), 3.41 - 3.24 (m, IH), 3.12 (d, J=15.5 Hz, IH), 3.01 - 2.93 (m, IH), 2.78 - 2.72 (m, 2H), 2.61 - 2,41 (m, 2H), 2.31 - 2.14 (m, 2H), 2.12 - 1,97 (m, IH), 1.90 - 1.61 (m, 8H), 1.39 (d, ./ 9 8 Hz, 2H), 1.31 - 1.24 (m, i l l ). 1.21 (d, ./ 6. i Hz, 3H). m/z (ESI, +ve ion) 643.0 (M+H) ⁺ .

EXAMPLE 509. (1 S,3'R,6'R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(3- HYDROXYPROPOXY)- 11 ^* , 12'-DIMETHYL-3 ,4-DIHYDRO-2H, 15Ή- SP!K()iN, PHTi!A!.!-.Ni-:-!.2?:-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i.()l i 4.7.2 U · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24]TETRAE -15'-ONE 13 ^! ,13 ^* -DIOXIDE

STEP 1: (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-l l^n'-DIMETHYL^'-CS- ((2S)-TETTlAHYDRO-2H-PYRAN-2-YLOXY)PROPOXY)-3.4-DIHYDRO-

2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND

(1 S,3'R,6'R,7'S,8'E, 11 ^* S, 12'R)-6-CHLORO- 11 !2'-DIMETHYL-7'-(3-((2R)- TETRAHYDRO-2H ^> YRAN-2-YLOXY)PROPOXY)-3,4-DIHYDRO-2HV15 ^, H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.( ⁾³ - ⁶ .() ^!9 - ²⁴ ]PENTACOSA [8, 16, 18 , 24] TETR AEN 1 - 15'-ONE 13", 13-DIOXIDE

To a 100 ml round-bottomed flask was added

(lS,3'R,0'R,7'S,8'E,irS,12'R)-6-chloro-7'-h^

2H, 15'H-spiro[naphthaiene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracy ^

n]~15'~one 13', 13 '-dioxide (from Example 719, Step 2) (88.0 nig.0.147 mmol), 15 mL of DMF and then sodium hydride, 60% dispersion in mineral oil (0.031 ml, 1 .469 mmol). The reaction mixture was stirred at room for 15 minutes at which time 2-(3-bromopropoxy)tetrahydro-2h-pyran (0.125 ml, 0.734 mmol) (Sigma- Aldnch, Milwaukie, Wl) was added. The reaction mixture was then stirred at 50 °C for 16 hours and at 60 °C for 4 hours. The reaction was then quenched with 100 ml of saturated aqueous ammonium chloride and 100 ml of 1 N HQ and then extracted with 400 ml, of diethyl ether. The organic layer was back extract twice with 100 ml brine. The organic layer was dried over sodium sulfate, concentrated by rotary evaporation and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 0% - 50% EtOAc in heptanes, give a 1 to 1 mixture of [(18,3ΊΙ,61 ,7 ,8Έ,11 ,12¾)-6-ΰωοΐΌ-11^12 ^! ~ά^6Λν1"7'-(3-((28)- tetrahydro-2H-pyrmi-2-yloxy)propoxy)-3,4-dihydro-2H,15 ^, i-I-spiro|naphthalene-

[20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa

n]-15'-one 13',13'-dioxide and (1 S,3'R,6 ^! R,7 ^* S,8'E, 1 l'S,12'R)-6-chfoiO-l l ^* ,12'- dime1hyl-7 ^, -(3-((2R)-tetrahydro-2H-pyran-2-y]ox ')propoxy)-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n|-15'-one 13', 13'-dioxide| (39 mg, 0.053 mmol, 36% yield) as a white solid. STEP 2: (1 S,3'R,6'R,7'S,8'E,1 l 'S, 12 ^, R)-6-CHLORO-7 ^, -(3-

HYDROXYPROPOXY)-l l',12'-DlMETHYL-3,4-DlHYDRO-2H,15'H- SPTRO[NAPHTHALENE-l ,22'-

| 2( !ί>Χ Λ| i 3 ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE i .T. i 3'-DIOXIDE

To a 25 -mL round-bottomed flask was added

| { 1 S.:VR.6'K .7'S.8 ^' 5 :. ! ! ^' S. 1 2'R )~6~ch!oro~ 1 Γ. 1 2'-dimci!n !-7'-(3-{{2S )-ieinshydro- 2H-pyran-2-yloxy)propoxy)-3,4-dihydro-2H,15'H-spiro[naphthal ene-l,22'- i;20]oxa[ 13]thia|;i ,14]diazatetracycio| 14.7.2.0 ³ -^0 ^l9 - ²⁴ ]pentacosa[8,l^

n]-15'-one 13',13 ^! ~dioxide and (1 S,3'R,6 ^! R,7'S,8'E, 1 l'S,12'R)-6-chloro-l Γ,12'- dimethyl-7'-(3-((2R)-tetrahydro-2H-pyran-2-yloxy)propoxy)-3, 4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxidej (from Step 1)(39 nig, 0.053 mmol), 1 ml of THF and 1 mL of 1 N aqueous HCl. The reaction mixture was heated to 55 °C for 60 minutes at which time the reaction was diluted with 100 rnl of EtOAc and washed with 50 ml of IN HCl and 50 ml of brine. The aqueous layer was back extracted with 100 ml of EtOAc and the combined organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified on a Combiflash (4g gold silica column), eluting with 50% - 90% EtOAc in heptanes, to give the title compound (13 mg, 0.020 mmol, 38 % yield) as a white solid. Ί I NMR (400MHz, CD2CI2) δ 8.28 (br. s., Hi).7.70 (d, ./ K.4 Hz, III). 7,16 (dd,J=2.2, 8.4 Hz, 111).7.09 id.,/ 2011/. !H), 6.92 (s, 2H), 6.86 (s, 1H), 5.89 - 5.75 (m, 1H), 5.54 (dd, J=9.2, 14.3 Hz, 1H), 4.33 - 4.22 (m, 1H), 4.08 (s, 2H), 3.89 - 3.65 (m, 5H), 3.60 (ddd, J=4.9, 6.7, 9.3 Hz, 1H), 3.43 (ddd, J=4.8, 6.6, 9.3 Hz, 1H), 3.25 (d, 14.3 Hz, 111).3.03 (dd, 1 2.15,3 Hz, !H), 2.85 - 2.60 (m, 2H), 2,52 - 2.39 (m, ill).2.39 - 2.27 (111, 2H), 2,26 - 2.02 (m, 3H), 2.00 - 1.63 (m, 8H), 1.45 (d, ./ 7.2 Hz, 3H), 1.40 - 1.34 (m, 1H), 1.02 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 657.3 (VI ID ^' . EXAMPLE 510. (lS,3'R,6 ^! R,7'S,8'E,irS,12'R)-6-CHLORO-ir,12 ^! ~

DIMETHYL-7'-((2R)-TETRAHYDRO-2-FURANYLMETHOXY)-3,4- DTHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN]-15'- '-DIOXIDE

STEP 1: (R)-(TETRAHYDROFURAN-2-YL)METHYL 4-

METHYLBENZENESULFONATE

To a solution of 4-methylbenzene-l-sulfonyl chloride (2.05 g, 10.8 mmol) and N,N-dimethylpyridin-4-amine (0.598 g, 4.90 mmol) in 30 mL DCM, cooled to 0 °C was added triethylamine (2.05 ml, 14.7 mmol) followed by the drop wise addition (R)-tetrahydrofurfuryl alcohol (ASTATECH, INC., Bristol, PA)(0.949 ml, 9.79 mmol) as a solution in 5 mL DCM. The solution was stirred at room temperature for 24 hours at which time the reaction was filtered and concentrated. The crude material was resuspended in 200 ml of EtOAc and was then washed with 100 ml of 1 N HC1, 100 ml saturated sodium bicarbonate and 100 ml of brine. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude oil was purified on a Combiflash (40 gram gold silica column), eluting with 0% to 50% EtOAc in heptanes to give (R)- (tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (2.20 g, 8.58 mmol, 88% yield) as a clear oil.

STEP 2: (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-l 1',12'-Β1ΜΕΊΉΥΕ-7'- ((2R)-TETRAHYDRO-2-FURANYLMETHOXY)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

| 20 jOX,\| O ΙΊ ί Ι1Λ| I„ I 4 |ΠίΛ/Λ T! R AC Y i OI i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |Pl-N i ^' AC<)SA [ 8,16,18,24]TETP^ENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

To a 25 -mL round-bottomed flask was added

(18,3¾,6¾,7 ^! 8,8Έ,11'8,12¾)-6-Λ1ΟΓΟ-7'^

2H, 15'H-spiro[naphthalene-l ,22'- | 20 iox !j I 3 |thia| i . i 4 |di !/aielracveioj 14.7.2 0 ^{; i} '.o ^pi i peniacosa| 8. i 6J 8.24i !eirac n]-15'-one 13',13'-dioxide (from Example 719, Step 2) (9.0 mg, 0.015 mmol), 2 ml of DMT and sodium hydride, 60% dispersion in mineral oil (6.0 mg, 0.15 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes at which time (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (from Step i)(19 mg, 0.075 mmol) was added. The reaction mixture was stirred at 50 °C for 4 hours and at 60 ° for 2 hours, and was then quenched with 1 ml of MeOH and 50 ml of 1 N HC1. The quenched reaction was extracted with 200 mL of EtOAc, the organic layer dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μπι column; Phenomenex, Torrance, CA; gradient el u lion of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (2.4 mg, 3.5 μηιοΐ, 23% yield) as a white fil M l NMR (400MHz, CD2CI2) 6 8,08 is. i l l ). 7,71 id. ./ 8.6 Hz, IH), 7.17 (dd, J=2,2, 8.6 Hz, 1H), 7.09 (d, J=2.2 Hz, IH), 6.91 (d, «/=0, 8 Hz, 2H), 6.85 (s, i l l s. 5.79 (ddd, ./ 3.2. 9.5, 15.0 Hz, IH), 5.61 - 5.44 (m, 1H), 4.34 - 4.14 (m, IH), 4.08 (s, 2H), 3.97 - 3.88 (m, IH), 3.87 - 3.65 (m, 5H), 3.37 (dd, J=10.0, 4.1 Hz, H), 3,30 - 3.15 (m, 2H), 3.02 (dd, J=10.3, 15,4 Hz, IH), 2.84 - 2,63 (m, 2H), 2,53 - 2.41 (m, IH), 2.32 (m, IH), 2.25 - 2,02 (m, 3H), 2.01 - 1.90 (m, 4H), 1 ,89 - 1.76 (m, 6H), 1.58 - 1.48 (m, 2H), 1.45 (d, J=7.2 Hz, 3H)1.02 (d, J=6.8 Hz, 3H). m/z (ESI, + ve ion) 682.9 (M+H) ⁺ .

EXAMPLE 511. (1 S,3'R,6'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO-7'-(2- CHLOROETHOXY)- 1 1 ', 12'-DIMETHYL-3,4-DIHYDRO-2H.15Ή- SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAEN]-15 ^! - ',13'-DIOXIDE

To a 1 dram pressure relief vial was added (lS,3'R,6 ^! R,7'S,8'E,i rS,12 ^! R)- 7'-(2-bromoethoxy)-6-chloro-l 1 ', 12'-dimethyl-3,4-dihydro-2H, 15Ή- spiro [naphtha] ene- 1 ,22'-

n]-15'-one 13', 13 '-dioxide (from Example 14) (20 mg, 0.028 mniol), 1 ml of DMSO, (R)-3-(methoxymeth}-])moipholme hydrochloride (Frontier Scientific, Logan, UT) (23 mg, 0.14 mmol) and DIE A (0.023 ml, 0.14 mmol). The reaction was sealed with a pressure release fitted cap and heated to 55 °C for 16 hours. The crude was purified by reversed phase preparatory HPLC (Gemini™ Prep C is 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (2.9 mg, 4.4 μηιοΐ, 15% yield) as a white films. ¾ NMR (40()MHz, CD2CI2) 6 8.07(s, 1 1 1 ). 7.70 (d, ,/ H (> Hz, I I I ). 7.17 (d l. ,/ 2.2. 8.5 Hz, i l l ). 7,09 (d, J=2.2 Hz, IH), 6.91 (d, J=1.0 Hz, 2H), 6.85 (s, 1H), 5.84 - 5.78 (m, 1H), 5.55 (dd, J=9 , 15.7 Hz, IH), 4.34 - 4.20 (m, IH), 4.09 (s, 2H), 3.88 - 3.77 (m, 2H), 3.70 (d, ./ 14.3 Hz, IH), 3.67 - 3.61 (m, IH), 3.60 - 3.56 (m, 2H), 3.56 - 3.49 (m, IH), 3,25 (d, ,/ 14.3 Hz, ! ! ! ). 3.04 (dd, J=10. 1, 15,4 Hz, I H), 2.73 - 2.60 (m, 2H), 2,44 - 2.32 (m, IH), 2.31 - 2. 18 (m, IH), 2, 17 - 1.93 (m, 4H), 1.93 - 1.81 (m, 3H), 1.79 - 1.68 (m, 2H), 1.65 - 1.53 (m, IH), 1.37 (d, J=7.0 Hz, 3H), 1.31 (s, IH), 0.95 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 661.3 ( M i l ) .

EXAMPLE 512. (1 S,3'R,6'R,7'S,8 ^! E, 1 rS ₅ 12'R)-6-CHLORO-7'-(3- METHOXYPROPOXY)- H',12"-DIMETHYL-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13 ^* -DIOXIDE

To a 100 ml round-bottomed flask was added

(18,3¾,6¾,7 ^! 8,8Έ,11'8,12¾)-6-ΰΜθΓθ-7^

2H, 15'H-spirofnaphthalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16, 18,24]tetrae n]"15'-one 13',13'-dioxide (from Example 719, Step 2) (50 mg, 0.083 mmol), 5 mL of DMF and then NaH (60% in mineral oil, 33 mg, 0.83 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes at which time l-bromo-3-methox propane (Matrix Scientific, Columbia, SC) (0.048 ml, 0.42 mmol) was added. The reaction mixture was stirred at 60 °C for 24 hours. The reaction was then quenched with 20 ml of saturated aqueous ammonium chloride and 20 ml of 1 N HC1 and then extracted with 100 mL of diethyl ether. The organic layer was back extract twice with 50 ml brine. The organic layer was then dried over sodium sulfate, concentrated by rotary evaporation and the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA: gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (12 mg, 0.17 mmol, 20% yield) as a white solid. ^; l! NMR (400MHz, CD2CI2) 68.12 {or. s., 111).7.70 (d, J=8.4 Hz, ill).7.17 (dd, ,/ 2.3.8.4 Hz, 1H), 7.09 (d, ./ 2.3 Hz, 111).6.91 (d,■/ i O Hz, 2H), 6.86 (s, 1H), 5.77 (ddd, ./ 33.9.5, 15.2 Hz, 1H), 5.58 - 5.42 (m, 1H), 4.34 - 4.20 (111, 4,08 (s, 2H), 3,82 id,,./ 15.1 Hz, 1H), 3.76 - 3.59 (m, 2H), 3.50 - 3,35 (m, 3H), 3.33 - 3.23(m, 5H), 3.02 (dd, J=10.3, 15.4 Hz, 1H), 2.86 - 2.64 (111, 2H), 2.48 - 2.38 (m, 111).2.32 (quin, ./ 9.0 Hz, 111).2.22 - 2.01 (m, 3H), 1.99 - 1.90 (m, 3H), 1.89 - 1.61 (m, 6H), 1,44 (d, =7.2Hz, 3H), 1.41 - 1.34 (m, !!!}.1.02 id. J=6,8 Hz, 3H). m/z (ESI, +ve ion) 671.3 (M+H) .

EXAMPLE 513. (18,3¾,6'Κ,7'8,8'Ε, Γ8,12¾)-6-α-ΙΙ.Ο Ο-7'-(2- (DLMETHYL AMINO)ETHOXY)- 11 ', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]- 5'- ", 13-DIOXIDE

To a 2 dram pressure relief vial was added (18,3¾,6Έ,7'8,8Έ,Π'8,12¾)- 7'-(2-bromoethoxy)-6-chioro-l 1

spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracycfo[14J _^

n]-15'-one 13 ',13 '-dioxide (from Example .14) (47 mg, 0.067 mmol), 2 ml of

DMSO and dimethvlamine (2.o M in THF, 0.15 ml, 0.30 mmol). The reaction was sealed with a pressure release fitted cap and heated to 55 °C for 16 hours. The reaction was then quenched with 20 ml of 1 N HC1 and extracted with 100 ml of EtOAc, The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The crude was purified on a Combiflash (4 g gold silica column), eluting with 10% MeOH in DCM), to give the title compound (27 rag, 0.040 mmol, 60% yield) as a white solid, ^" Ή NMR (400MHz, CD ₂ Cb) δ 7.72 (d, J=8.4 Hz, 1H), 7.20 - 7.03 (m, 3H), 6.97 (s, ills.6.82 (d, ./ 8.0 Hz, Ml). 6.13 - 5.84 (m, IH), 5.53 (dd, ./ 8.2.15.1 Hz, IH), 4.02 (s, 2H), 3.93 - 3.63 (m, 5H), 3.63 - 3.52 (m, IH), 3,26 (d, ,/ 14.1 Hz, IH), 3.08 - 2,88 (m, 3H), 2.82 - 2,72 (m, 2H), 2,66 (s, 6H), 2,49 - 2.35 (m, 2H), 2.20 - 1.98 (m. Hi).1,88 - 1.61 (m, 4H), 1.35 (d, ./ 7.2 Hz, 3H), 1.37 - 1.29 (m, 3H), 0.99 (d, J=5.3 Hz, 3H). m/z (ESI, +ve ion) 670.4 (VI ID ^' . EXAMPLE 514. (lS,3'R,6'R,7 ^! S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12'-((2R 2-METHOXYPROPYL)-3,4-DIHYDRO-2H,15 ^, H-SPIRO[NAPHTHALENE-

1,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YCT (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12'-((2R)-2-

METOOXYPROP^ ^-DIHYDRO^H S^SPIROINAPHTHALE^l^*- [20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE

STEP 1 : (2R,4S)-2-METHOXYOCT-7-ENE-4-SULFONAMIDE OR (2R,4R)-2- -7-ENE-4-SULFONAMIDE

(2R,4S)-2-methoxyoct-7-ene-4-sulfonamide or (2R,4R)-2-methoxyoct-7~ ene-4-sulfonamide was obtained as the slower eluting isomer in Example 508, Step 5. STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((l S,6R,8R,E)-l-HYDROXY-8-

METHOXY-6-SULFAMOYLNON-2-EN-l-YL)CYCLOBUTYL)METHYL)-

3^4,4^5-TETRAHYDRO-2TI,2'H-SPIRO[BENZO[B]|;L410XAZEPINE-3 ,r- NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lR,2R)-2- ((l S,6S,8R,E)-l-HYDROXY-8-METHOXY-6-SULFAMOYLNON-2-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _j! HYDRO-2I-L2 ^, H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC

To a 100 ml flask was added (SVff-chloro-S-CftlR^R^-^E)-!- hydro j'hex^-en-l-y cj lobut methy -S'^^'^-tetrahydro^H^'H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid (from

Intermediate AA12A) (20 mg, 0.039 mmol), [(2R,4S)-2-methoxyoct-7-ene- sulfonamide or (2R,4R)-2-methoxyoct-7-ene-4-sulfonamide] (from Step ! )(22 mg, 0,098 mmol) and DCE (2 mL). The solution was sparged with argon for 15 minutes at which time (l,3-dimesitylirmdazolidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium(VI) chloride (2.5 mg, 3.9 μηιοΐ) was added as a 0.2 mL solution in DCE at room temperature. The mixture was stirred at room temperature for additional 16 hours. Note: the clear solution becomes slowly darker. The reaction mixture was then bubbled with air for 5 minutes and filtered. The solvent was removed from the filtrate and was directly purified on a

Combiflash (4g gold silica column), eluting with .50% - 90% EtOAc in heptanes + 0.2% AcOH, to give [(S)-6'-chloro-5-(((lR,2R)-2-((l S,6R,8R,E)-1 -hydroxy-8- methoxy-6-suifamoylnon-2-en-l-yl)cyc3obutyl)methyl)-3',4,4', 5-tetrahydro- 2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3,r-naphthalene]-7-carboxylic acid or (S)- 6 ^, -chloro-5-(((lR,2R)-2-((l S,6S,8R,E)-i½droxy-8-m.ethoxy-6-sul&^^ en^-y cyclobuty methy -S'^^'J-tetrahydro^H^'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid] (19 mg, 0.029 mmol, 73% yield) as white solids.

STEP 3: (l S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12 ^, -((2R)-2- METOOXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTOALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S,3'R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-2- METHOXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1.22'- | 2u jOXA| 1 ΉΤί !1Λ| Μ 4 |ΠίΑ/.ΥΠ:ΤΗ Α(ΎΠ.ϋΙ i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |Pl-N i ^' AC<)SA [ 8,16,18,24]TETRAENj 5'-C)NE 13 ^! ,13 ^* -DIOXiDE

To a 100 ml flask containing [((S)-6'-chloro-5-(((lR,2R)-2-((l S,6R,8R,E)-

1 iydroxy-8-methoxy-6-sulfamoyliion^

tetrahy dro-2H,2'H-spiro| benzoj b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid or (S)-6'-chloro-5-(((lR,2R)-2-((lS,6S,8R,E)-l-hydrox>'-8-me thoxy-6- sulfamoylnon-2-en-l-yl)cyclobuty )me†Jiyl)-3 ^, ,4,4 ^, ,5-teTjahydro-2H,2 ^, H- spiro[benzo[b][l ,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid] (from Step 2)(19 mg, 0,029 mmol), which was previously dried by rotovaping twice with 10 ml of toluene, was added N,N-dimethylpyridin-4-amine (6.0 mg, 0.049 mmol), 45 ml of DCM andN-(3-dimethylaminopfopyl)-N'-ethylcarbodiimide hydrochloride (11 mg, 0.057 mmol). The reaction was stirred at room temperatiire for 18 hour at which time the mixture was quenched with 100 ml of IN HCl and extracted with 300 ml of EtOAc. The organic layer were dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified on a Combiflash (4g gold silica column), eluting with 30% - 70% EtOAc in heptanes, to give the title compound (1.5 mg, 2.3 μηιοΐ, 8% yield) as a white solid Rf 0.16 eluting with 50% EtOAc in Heptanes. ^] H NMR (400MHz, CDCb) δ 8,20 (s. 111).7,70 (d, ./ 8.6 Hz, 1H), 7.19 (dd, ./ 2.3.8,4 Hz, !H), 7.09 (d, 2.2 Hz, 1H), 6.96 - 6.83 (m, 3H), 5.90 - 5.81 (m, 1H), 5.76 - 5.64 (m, 1H), 4.22 (dd, ./ 4.2.7.5 Hz, 2H), 4.14 - 4.02 (m, 3H), 3.87 - 3.68 (m, 3H), 3.36 (s, 3H), 3.24 (d, ./ 1 .3 Hz, 111).3,03 (dd, ./ 9.!. [5.4 Hz, III).2,85 - 2.68 (ra, 211).2,53 - 2.19 (m, 5H), 2,08- 1.74 (m, 8H), 1,49 - 1.35 (m, 2H), 1.28 (d, .7=6.1 Hz, 3H), m/z (ESI, +ve ion) 643.0 < M 10.

EXAMPLE 515. (lS,3'R,6 ^f R,7'S,8'E,irSJ2'R)-6-CHLORO-7'-(2-(3,3- ? !! 5 LO O- 1 ~P!Fl-; U iNY!.)l II OXV}- 1 i ' ! 2'-i)f Μ1· ΓΪ ΙΥί.-3 -j-DH !YO O- 2H, 15'H-SPlRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1 ^' .13'-DIOXIDE

To a 4 ml vial was added (((1S,3'R,6'R,7'S,8'E,1 Ι^,η'Κ^ό-οΜθΓθ-ΙΙ',ΙΪ- dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphth alene-l,22'- [20] oxa i 3] ihi a[ I / 4] ds

n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (20 mg, 0.031 mmol), DCE (4 ml), 3,3-difluoropiperidine hydrochloride (Frontier Scientific, Logan, UT)(19 mg, 0.13 mmol) and tnethylamine (0.017 ml, 0.13 mmol). The reaction was heated at 50 °C for 5 minutes, at which time the reaction was cooled to room temperature and sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added. The reaction was then stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by- reversed phase preparatory HPLC (Gemini™ Prep Cie 5 jim column;

Phenomenex, Torrance, CA: gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (1.6 mg, 2.1 μτηοΐ, 6.9% yield) as an amorphous solid. 'H NMR

(400MHz, CD2CI2) δ 8. 14 (br.s., 1H), 7.70 (d, ,7=8,6 Hz, 1H), 7. 17 (dd, .7=2.4, 8.5 Hz, 1H), 7.09 (d, ./ 2.2 Hz, 1H), 6.91 (d, J=1.0 Hz, 2H), 6.83 (s, 1H), 5.98 - 5.80 (m, 1H), 5.65 - 5.46 (m, 1H), 4.32 - 4.22 (m, 1 H), 4.16 (d, ./ 16.8 Hz, 1H), 4.08 (s, 2H), 3.89 - 3.75 (m, 3H), 3.69 (d, ./ 14.7 Hz, 1H), 3,64 - 3,56 (m, 1H), 3.50 - 3,38 (m 2H), 3.37 - 3,32 (m, 2H), 3.25 (d, .7=14.3 Hz, 2H), 3.04 (dd, J=10,2, 15,5 Hz, 1H), 2.83 - 2.66 (m, 2H), 2.52 - 2.39 (m, 1H), 2.34 (t, J=8.8 Hz, 1H), 2.23 - 1 .90 (m, 1 ! ! }. i 45 i d. 7.2 ! !/. 3H), 1.41 - 1.32 (m, 11 1 ). 1.03 (d, J=6,8 Hz, 3H). m/z (ESI, +ve ion) 746.3 ( +H) ⁺ .

EXAMPLE 516. iI S,3'R,6' ,7'S,8'E, l l'S,I2'R)-6-CHLORO-7'-(2- HYDROXYETHOXY)- 11 ', 12'-DIMETHYL~3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[2 ]()XA[ 13 iTHIA[ l,14jDIAZATETRACYCL[ 14.7.2.() ³ '^0 ⁱ⁹ - ²⁴ lPENTACOSA[8 , 16, 18,24]TETRAEN] - 15'-GNE ! .?. 13'-DIOXIDE

To a 25-mL round-bottomed flask was added a mixture of

(18,3¾,6Ίν7'8,8Έ,11 ^* 8,12'ί )-6-ΰωοΐΌ-11^ _^

2H-pyran-2-y 1 oxy)ethoxy)-3,4-dihy dro-2H, 15'H-spiro[naphthal ene- 1 ,22'- ⁿ j pen!aco a| K. i 6J 8.2.j jietrae n]-15'-one 13 ^* ,13'-dioxide and (18,3¾,6¾,78,8¾1 l'S,12'R)-6-chloro-l l',12'- dime1hyl-7'-(2-((2R)-tetrahydro-2H-pyran-2-ylox} e1hox} -3,4-dihydro-2H,15 ^, H- spiro [naph thai ene- 1 ,22'- 8.24i !eirae n]-15'-one 13',13'-dioxide (from Example 517 ) (185 mg, 0.254 mmol), 2 ml THF, and of 2 mL 2 N aqueous HQ , The reaction mixture was heated to 55 °C for 45 minutes at which time the reaction was diluted with 100 ml of EtOAc and washed with 50 ml of IN HC1 and 50 ml of brine. The aqueous layer was back extracted with 200 ml of EtOAc and the combined organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude material was purified on a Combiflash (12 gram gold silica column), eluting with 50% - 90% EtOAc in heptanes to give the title compound (107 mg, 0.166 mmol, 65% yield) as a white solid. Rf = 0.51 eluting with 90%, EtOAc in heptanes. ¾ NMR (400MHz, CD2CI2) δ 8.05 (br. s., 1H), 7.63 (d, J=8,4 Hz, IH), 7.09 (dd, .7=2.3, 8.6 Hz, 1H), 7.01 (d, J=2.2 Hz, IH), 6.88 - 6.75 (m, 3H), 5.73 (ddd, J=3.4, 9.5, 15.1 Hz, i l l ). 5.47 (dd, =9.2, 15.3 Hz, 1 1 1 }. 4.17 i ns. IH), 4.00 (s, 2H), 3.80 - 3.67 (m, 2H), 3.65 - 3.48 (m. 3H ). 3,42 ! ddd. ./ 3.2. 6.2, 9,8 Hz, IH), 3.27 (ddd. J 3.4. 6.1, 9.9 Hz, IH), 3.17 (d, J=14.1 Hz, IH), 2.95 (dd, .7=10.2, 15.3 Hz, IH), 2.78 - 2.50 (m, 2H), 2.46 - 2.33 (m, IH), 2.26 (m, IH), 2.15 - 1.82 (m, 6H), 1.80 - 1.68 (m, 4H), 1.66 - 1.53 (m, IH), 1.36 id. ./ 7.2 Hz, 3H), 0.95 id. ./ 6.8 Hz, 3H). m (ESI, +ve ion) 643,0 (M+H) ⁺ . EXAMPLE 517. (1 S,3'R,6'R,7'S,8'E,1 I'SJ 2'R)-6-CHLORO-l l',12'-DIMETHYL- 7'-(2-((2S)-TETRAHYDRO-2H-PYRAN-2-YLOXY)ETHOXY)-3,4-DIHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE AND

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO- H',12 ^, -DIMETHYL-7'-(2-((2R)-

TETRAHYDRO-2H-PYRAN-2-YLOXY)ETHOXY)-3,4-DIHYDRO-2H ₅ 15'H-

SPTRO[NAPHTHALENE-l,22'-

|20jOXA| I 311 HI Λ| I .. N |PI.\/.\ Π·. E R.AC VC ^' E C)i i J 7.2 ϋ ^{; ί'} .ϋ |ΡΗ\ iACOSA

-15'-QNE 13', 13 '-DIOXIDE

To a 250 ml round-bottomed flask was added

(18,3¾,6¾,7 ^! 8,8Έ,11'8,12¾)-6-Λ1ΟΓΟ-7*^

2H,15'H-spiro|naphthalene-l,22'- [20]oxa[13]thia[l,14]diazate1r^

n]-15'-one 13',13'-dioxide (from Example 719, Step 2) (650 mg, 1.09 mmol), 60 mL of DMF and then sodium hydride, 60% dispersion in mineral oil (434 mg, 10.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes at which time 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.819 ml, 5.42 mmol) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction was then quenched with 100 ml of saturated aqueous ammonium chloride and 100 ml of 1 N HC1 and then extracted with 400 mL of diethyl ether. The organic layer was back extract twice with 100 ml brine. The organic layer was then dried over sodium sulfate, concentrated by rotary evaporation and was purified on a Combiflash (12 gram gold silica column), eluting with 10% - 50% EtOAc in heptanes, to give a mixture of title compounds (650 mg, 1.09 mmol) as a white solid. ¾ NMR (400MHz, CD2CI2) 68.07 (d, J=6.3 Hz, WD.7.71 (d, ,/ 8,6 Hz, 111).7.17 (dd, 23.8.4 Hz, ill).7,09 id. J=2.3 Hz, IH), 6.93 - 6.90 (m, 21!).6.87 (s, I Hi.5.89 - 5,74 (m, ill).5,62 - 5.47 (ni, 111).4.63 - 4.54 (m, IH), 4.32 - 4.20 (ni, Ml).4.15 - 4.00 (m, 2H), 3.91 - 3.65 {in.5H), 3.60 - 3.36 ins.4H), 3.26 !d../ 14.3 Hz, !!!).3.03 {dd.,/ 10.!.15.4 Hz, IH), 2,85 - 2.66 (m, 2H), 2.53 - 2,41 (m, IH), 2,33 (m, IH), 2.25 - 2.02 (ra, 3H), 2,02 - 1.89 (m, 31!).1.87 - 1.76 (m, Hi).1,75 - 1.62 (m, 211).1.59 - 1.49 i v.. H ). 1.45 (d, J=7.2 Hz, 3H), 1.40 - 1.37 (m, IH), 1.03 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 727.4 i.V! H) . EXAMPLE 518. (1S,3'R,6 ^! R,7'S,8'E,1 l'S,12'R)-6-CHLORG-l 1' ₅ 12'-DIMETHYL- 7 ^! -(2-(2-OXA-6-AZASPIRO[3.3]HEPT-6-YL)ETOOXY)-3,4-DIHYDR O- 2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DiAZATETRACYCLO[14.7,2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA |;8,16,18,24]TETRAEN]-15 ^! - ',13'-DIOXIDE

To a 100 nil flask was added (((lS,3'R,6'R,7 ^! S,8'E,irS,12'R)-6-chloro- 11^12'-dinieihyi-13 i3'~dioxido~15 ^{^}

[20]oxa[13]thia[l,14]diazatetra yclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosaE8,16,18^^^ n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (10 nig, 0,016 mmol), DCE (2 ml), 2~oxa-6~azaspiro[3.3 jheptane (AMRI, Albany, NY) (6.37 mg, 0.064 mmol), and sodium triacetoxyborohydride (17 mg, 0.080 mmol). The reaction was stirred at 55 °C for 5 hours at which time the reaction was quenched with 0.5 ml of MeOH and 100 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 300 ml of EtOAc and the EtOAc layer was washed with 100 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (1.6 nig, 2.1 μηοΐ, 13% yield) as a white film. ^; l! NMR (400MHz, CD2CI2) δ 8.12 (br. s., 111).7.70 id. ./ K.6 Hz, 1H), 7.17 (dd, ,/ 2.3.8.4 Hz, I I I).7.09 (d, ,/ 2.3 Hz, Hi).6.91 (s, 2H), 6,81 (s, 111).5,94 - 5.78 (m, III).5.58 - 5.44 (ra, ill).4,84 (s, 211).4,69 (s, 211). 4,62 (s, 211).4.31 - 4.17 (m, ill).4.08 (s, 211).3.98 (d, ,7=11,0 Hz, 2H), 3.84 - 3.62 (m, 4H), 3.48 (s, 1H), 3.25 (d, J=14.3 Hz, 1H), 3.19 (s, 2H), 3.03 (dd, ./ 10.( 15.3 Hz, III). 2.87 - 2,66 (m, 2H), 2.50 - 2.38 (m, 1H), 2.36 - 2,23 (m, 1H), 2.20 - 2,09 (111, 211).1,86 - 1.77 (m, 611).1.74 - 1,63 (m, 2H), 1,44 (d, ./ 7.2 Hz, 3H), 1.41 - 1.41 (m, 1H), 1.02 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 724.3 { \ I · Π } .

EXAMPLE 519. (IS^'R^'R^'S^'EJl'S/ ' Ve-CHLORO^'-^R)^-

METHOXY PROP Y L)OXY)- 1 Γ , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'~

|2( >X A| I ?! ! ί U Ai I 1 -J |? !,\ Ά ! : I AC YC ^' fOl 147.20 ^; ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN] -15'-ONE 13', 13'-DIOXlDE AND

(lS,3'R,6 ^! R,7 ^, S,8 ^, E,ll ^, S,12'R)-6-CHL()RO-7'-(((2S)-2-

METHOXYPROPYL)OXY)-l 1 ^f ,I2'-DiMETHYL-3,4-DIHYDRO-2H,l 5Ή- SPs O!N AF! ! s ! 1Λί.Ι ^" \Ί-:- 1.22 -

[20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8, 16, 18,24] - 15"-ONE 13', 13*-DIOXIDE

STEP !: (IS,3'R,6'R,7'S,8'E,1 l ^, S,12 ^, R)-6-CHLORO-7*-(((2R)-2-

HYDROXYPROPYL)OXY)~ 1 V , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15 ^! H- SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE AND

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,i rS,12 ^! R)-6-CHLORO-7 ^, -(((2S)-2- HYDROXYPROPYL)OXY)- 11 12'-DIMETHYL-3,4-DffiYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAE -15'-ONE 13',13'-DIOXIDE

To a 100 ml flask containing (((l S,3'R,6'R,7'S,8¾l l ^! S,12'R)-6-chloro- l l 2'-dimethyi-13\13'-diQxido-15'-oxo-3,4-dihydro^^

[20]oxa[13]1hia[ l, 14]diazatetTacyclo[147.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (240 mg, 0,374 mmol) was added 20 ml of THF and the reaction was cooled to -78 °C at which time methylmagnesium bromide 3.0 M in diethyl ether (0.37 ml, 1.1 mmol) was added. The reaction was stirred at room temperature for 1 hour, then quenched with 100 ml of saturated ammonium chloride and extracted once with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude was pun i led on a Combiflash (12g gold silica column), eluting with 10% - 70% EtOAc in heptanes) to give

[(l S ₅ 3 ^, R _s 6 ^, R ₅ 7 ^, S,8Έ _s l ΓS 2 ^, R)-6-chloΓO-7 ^, -(((2R)-2-hydΓoxypro yl)oxy)-l l ^, _s 12 ^, - dimethyl-3,4-dihydro-2h, 15 ^, h-spiro[naphthalene-l,22'- [2Q]oxa i3]thia[l , Mjdiazateto

n]-15'-one 13',13 ^! -dioxide and (1 S,3'R,6 ^! R,7'S,8'E,1 rS,12'R)-6-chloro-7 ^* -(((2S)-2- hydroxypropyl)oxy)-11^12'-dimethyl-3,4-dihydro-2h,151i-spiro |naphthalene- 1,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ^{! 9} ^]pen^^^

n]-15'-one 13',13'-dioxide] (26 mg, 0.040 mmol) as a white solid. Step 2: (1 S,3'R,6'R,7'S,8'E,11'S ,12'R)-6-CHLORO-7 ^* -(((2R)-2- METHOXYPROPYL)OXY)-H',12'-DIMETHYL-3,4-DlHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND

(lS.3 ^, R,6 ^, R,7 ^, S,8 ^, E,l l ^, S,12 ^, R)-6-CHLORO-7 ^, -(((2S)-2- METHOXYPROPYL)OXY)-l 1 ^* ,12'-DIMETHYL-3,4-DIHYDRO-2H, 15'H- SPIRO[N APHTHALENE- 1 ,22'- | 2u jOXA| ! 3 jTI UA| U 4 | ni A/A ETR A( ^' YCl.Oj i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |P1-M ^' .\C<)SA [ 8,16,18,24]TETRAENj-15'-C)NE 13',13 ^* -DIOXIDE

To a 100 ml flask was added [(lS,3'R,6'R,7'S,8'E,irS,12'R)-6-chloro-7'- (((2R)-2-hydroxypropyl)oxy)-l 1 ', 12'-dimethyl-3,4-dihydro-2h, 15'h- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetracyclo^^

n]-15'-one 13 ',13 '-dioxide and (l S,3'R,6'R,7'S,8 ^* E,H ^* S,12'R)-6-chloiO-7'-(((2S)-2- hydroxypropyl)oxy)-ir,12'-dimethyl-3,4-dihydfo-2h,15'h-spiro |naph^ [20]oxa[13]thia[l,14]diazatetra^

n]-15'-one 13',13'-dioxide] (from Step 1 ) (26 mg, 0.040 mmol), DMF (2 mL) and NaH, 60% in oil (50.3 mg, 2.098 mmol). The reaction was stirred at room temperature for 20 minutes at which time Mel (0.025 ml, 0.40 mmol) was added. The reaction was then stirred at room temperature for 4 hours at which time the reaction was quenched with 50 ml of saturated ammonium chloride and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0. 1% TFA, 45 minute method) to give a 1 : 1 mixture of the title compounds (4.0 mg, 6.0 μιηοΐ, 15% yield) as a white solid. ¾ MR (400MHz, CD2CI2) δ 8.08 (s, I H ). 7.71 id. ./ 8.4 H/. i l l ). 7. 17 (dd. ./ 2.3. 8.4 Hz, 1H), 7.09 (d, .7=2,2 Hz, H), 6.91 (m, 2H), 6.86 (s, IH), 5.86 - 5.68 (m, H), 5.61 - 5.45 (m, IH), 4.34 - 4.19 (m, IH), 4.08 (s, 2H), 3.82 (d, J= .l Hz, IH), 3.77 - 3.64 (m, 2H), 3.45 - 3.35 (m, 1.5, H), 3.33 (s, 1.5H), 3.32 (s, 1.5 H), 3.30 - 3.21 (m, 2H), 3.17 (dd, ./ 3.8. 9.5 Hz, 0,5 H), 3,03 (dd, ./ 10.5. 15.2 Hz, ! ! ! ). 2.87 (s, IH), 2,83 - 2.71 (m, 2H), 2.51 - 2.39 (m, IH), 2,38 - 2.26 (m, IH), 2.23 - 2.01 (m, 3H), 2.00 - 1.90 (m, 3H), 1.88 - 1.77 (m, 3H), 1.45 (d, J=7.2 Hz, 3H), 1.39 (m, I H), 1.09 (d, ./ 5 2 Hz, 1.5H), 1.07 (d, 5 2 Hz, 1.5! I ). 1.03 i d. J-6.8 Hz, l ). m/z (ESI, +ve ion) 671.5 (M+H) ⁺ .

EXAMPLE 520, ilS,3'R,6'R,7'S,8'E, l 1 'S,12'R)-6-CHLORO-l 1",12'- DIMETHYL-7'-(2-((lS,4S)-2-OXA-5-AZABICYCLO[2.2.1]HEPT-5-

YL)ETHOXY)-3,4-DIHYDRO-2H,15'H-SPIRO|NAPI-m-IALENE-l,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ 14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13 ^! , 13'-DIOXIDE 2,2,2-TRIFLUOROACE ^' nC ACID

To a 4 ml vial was added (((18,3Έ,6¾,Τ8,8Έ,1 l'S,12'R)-6-chloro-l Γ,12'- dime1hyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphth alene-l,22'- [20]oxa[ 13]thia|;i ,14]diazaietracyclo[14,7.2,0 -^0 ^l9 - ²⁴ ]peniaco

n]-7'-}'-])oxy)acetaldehyde (from 527, Step 1) (20 mg, 0.031 mmol), DCE (4 ml), (lS,4S)-2-oxa-5-azabicyelo[2.2.1 jheptane hydrochloride (4.2 mg, 0.031 mmol) (Frontier Scientific, Logan, UT) and tnethylamine (0.017 ml, 0.13 mmol). The reaction was heated at 50 °C for 5 minutes, the reaction was cooled to room temperature and sodium triacetoxyborohydride (33 mg, 0.16 mmol) was then added. The reaction was stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saiurated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparator' HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA: gradient elution of 10% to 90% MeC in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (2.1 mg, 2.5 μτηοΐ, 8% yield) as an amorphous solid. 'HNMR

(400MHz, CD2CI2) δ 8.07 (br. s„ IH), 7,62 id. J=8.6 Hz, IH), 7.09 (dd, ./ 2.3.8,4 Hz, IH), 7.01 (d, J=23 Hz, IH), 6.88 - 6.82 (m, 2H), 6.74 (s, IH), 5.86 - 5.67 (m, IH), 5.53 - 5.35 (m, IH), 4.63 - 4.43 (m, IH), 4.39 - 4.28 (m, IH), 4.27 - 4.03 (m, Ml).4,02 - 3.93 (m, 2H), 3.83 - 3.54 (m, 6H), 3,44 (d, ,/ 10.2 Hz, ill).3.39 - 3.31 (m, ill).3.26 (d, ,7=6,5 Hz, H), 2,98 - 2,86 (m, 2H), 2.72 - 2.59 (m, 2H), 2,40 - 2.31 (m, IH), 2.26 (d, J=9.8 Hz, 2H), 2.11 (d, J=12.1 Hz, 2H), 2.03 - 1.89 (m, 5H), 1.78 - 1.70 (m, 2! I ).1,68 - 1.49 (m, 2H), 1.36 (d, 7.2 Hz, 3H), 1.33 - 1,27 (m, IH), 0,94 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 724,4 (M+H) ⁺ .

EXAMPLE 521. (1S,3'R,6'R,7'S,8 ^! E,1 l ^! S,12'R)-6-CHL()RO-l r,12 ^! -DIMETHYL- 7"-(2-((lR,4R)-2-OXA-5-AZABICYCLO[2.2.1]HEPT-5-YL)ETHOXY)-3, 4- DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THL [1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,I8,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE 2,2,2-TRIFLUOROACETIC ACID

To a 4 ml vial was added (((1S,3'R,6'R,7'S,8'E,1 Γ8,12Έ.)~6~Α1ΟΓΟ~11',12'- dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphth alene-l,22'- [20] oxa i 3] ihi a[ I / 4] ds

n]-7'-yj)oxy)acetaldehyde (from 527, Step 1) (20 mg, 0.031 mmol), DCE (4 ml), (lR,4R)-2~oxa-5~azabicyclo[2.2.1]heptane hydrochloride (4.2 mg, 0.031 mmol) (Frontier Scientific, Logan, UT) and tnethylamine (0.017 ml, 0.13 mmol). The reaction was heated at 50 °C for 5 minutes the reaction was cooled to room temperature and sodium triacetoxyborohydride (33 mg, 0.16 mmol) was then added. The reaction was stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saiurated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparator ' HPLC (Gemini™ Prep Cis 5 μχ column; Phenomenex, Torrance, CA: gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (1.7 mg, 2.0 μτηοΐ, 6.5% yield) as an amorphous solid. ^] H NMR

(400MHz, CD2CI2) δ 8. 15 (br. s„ IH), 7,69 (d, J=8.4 Hz, 1H), 7.16 (dd, ./ 2.3. 8,4 Hz, IH), 7.08 (d, J=2.3 Hz, IH), 6.90 (s, 2H), 6.81 (s, IH), 5.92 - 5.71 (m, i l l ). 5.59 - 5.40 (m, I H), 4.61 - 4.42 (m, 2H), 4.34 - 4.12 (m, 2H), 4.07 (s, 2H), 3.86 - 3,73 (m, 5H), 3.68 (d, 14 5 Hz, I H), 3.62 - 3.53 (ra, IH), 3,41 (d, ./ 4.7 Hz, IH), 3,36 - 3.17 (m, 2H), 3.07 - 2.92 (m, 2H), 2,83 - 2.66 (m, 2H), 2.47 - 2.28 (m, 3H), 2.19 - 2.00 (m, 5H), 1.97 - 1.87 (m, 6H), 1.43 (d, ./ 7.2 Hz, 3H), 1.39 (m, I H), 1.01 (d, ,/ 6,8 Hz, 3H). m/z (ESI, +ve ion) 724(M+H) ⁺ .

EXAMPLE 522. (1 S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-l l',12'~DIMETHYL- 7'-(2-(3-OXETANYLAMINO)ETHOXY)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ ' ⁶ 0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE 2,2,2-TRIFLUORO ACETIC ACID

To a 4 ml vial was added (((Ι β,Β'ίΙ,ό'Κ,Τ'β,δ'Ε, Ι Ι , Γ, η'" dimethyl-13', 13 ^, -dioxido- 15'-oxo-3,4-dihydro-2H-spiro| naphthalene-l,22'- [20]oxa[ 13]1hia[ l, 14]diazatetTacyclo[147.2.0 ³ ^ 0 ^{] 9} ' ²⁴ ]pentacosa[8, 16, 18,24]tetrae n]-7'-yl)oxy)acetaldelwde (from 527, Step 1) (20 mg, 0,031 mmol), DCE (4 ml), oxetan-3-amine hydrochloride (14 mg, 0.13 mmol)(Frontier Scientific, Logan, UT) and triethylamine (0.017 ml, 0.13 mmol). The reaction was heated at 50 °C for 5 minutes at which time the reaction was cooled to room temperature and sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added. The reaction was stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep C is 5 urn column; Phenomenex, Torrance,

CA: gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1 % TFA, 45 minute method) to give the title compound (5.8 mg, 7.1 μιηοΐ, 23% yield) as an amorphous solid as an amorphous solid. ^" Ή NMR (500MHz, CD2CI2) δ 8.41 (br, s., IH), 7.69 (d, ,7=8,6 Hz, IH), 7. 17 (dd, J=2.3, 8.4 Hz, 1H), 7.09 (d, ./ 2.4 Hz, I I I ). 6.99 - 6.89 (m, 2H), 6.82 (s, 1H), 5.95 - 5.75 (m, 1H), 5.60 - 5.46 (m, 1H), 4.90 - 4.75 (m, 4H), 4.41 - 4.33 (m, 1H), 4.29 - 4.17 (m, 1H), 4.06 (s, 2H), 3.86 - 3.75 (m, 2H), 3,72 - 3.61 (m, 2H), 3.49 (d, .7=7,6 Hz, IH), 3.24 (d, .7=14.4 Hz, IH), 3.21 - 3.14 (m, 1H), 3.10 (d, =3.7 Hz, 1H), 3.02 (dd, J=10.5, 15.4 Hz, IH), 2.85 - 2.68 (m, 2H), 2.52 - 2.42 (m, IH), 2.33 (td, =9.2, 18.2 Hz, IH), 2.21 - 1 .90 (m, M l ). 1 .88 - 1.76 (m, 3H), 1 ,73 - 1 .61 (m, I H), 1.44 (d, 7. ! Hz, 3H), 1 ,39 (t, .7=12,8 Hz, IH), 1.02(d, .7=6.8 Hz, 3H). m/z (ESI, +ve ion) 698,4 (M+H) ^"

EXAMPLE 523. (lS,3 ^, R,6 ^, R,7'S,8'E,i rS,12'R)-6~CHLORO-l l ',12'- DIMETHYL-7'-(2^(3R)-3-MEraYL-4-MORPHOLINYL)ETHOXY)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* - pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'- ',13'-DIOXIDE

To a 100 nil flask were added (((1S,3 ^* R,6'R,7'S,8 ^! E, 1 l ^! S,12'R)-6-chloro- l l\ 12 ^, -dime l-13\13'-dioxido-15 ^, -oxo^

[20]oxa[13]thia[l, 14]diazatetra<yclo^

n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (16 mg, 0.025 mmol), DCE (2 ml), (R)-3-methylmorpholine (J & W PharmLab, Levittown, PA) (5.8 μΐ, 0.051 mmol) and sodium triacetoxyborohydride (27 mg, 0.13 mmol). The reaction was stirred at 55 °C for 5 hours at which time the reaction was quenched with 0.5 ml of MeOH and 100 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 300 ml of EtOAc and the EtOAc layer was washed with 100 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance,

CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (2.9 mg, 4.0 μιηοΐ, 16% yield) as a white film. Ί I NMR (400MHz, CD2CI2) δ 8.19 (br. s., i l l ). 7.70 (d, ,/ H (, Hz, 1 H), 7.17 (dd, ,/ 2.3. 8.4 Hz, IH), 7.09 (d, ,/ 2.2 Hz, H i ). 6.92 (s, 2H), 6,83 (s, IH), 5,96 - 5.80 (m, I I I ). 5.62 - 5.44 (m, i l l ). 4.26 (q, J=6.8 Hz, IH), 4.08 (s, 2H), 4.02 - 3.90 (m, 2H), 3.81 (d, J=14.3 Hz, 4H), 3.74 - 3.65 (m, 2H), 3.60 - 3.51 (m, IH), 3.45 (t, ,/ 1 1 .4 Hz, 2H), 3.32 - 3.21 (m, 3H), 3.19 - 3.10 (m, IH), 3.05 (del.,/ H!O.15.5 Hz, 1H), 2.84 - 2,71 (m, 2H), 2.51 - 2.40 (rn, 1H), 2.40 - 2.28 (m, IH), 2.26 - 2,15 (m, 1H), 2.15 - 2.01 (m, 2H), 2.01 - 1,89 (m, 2H), 1.88 - 1.76 (m, 5H), 1.45 (d, ./ 7.2 Hz, 3H), 1.41 - 1.38 (m, IH), 1.33 (d, ./ 6.5 Hz, 3H), 1.03 (d, ./ 6.7 Hz, 311). m/z (ESI, +ve ion) 726.3 (M+H) ⁺ .

EXAMPLE 524. (lS,3 ^, R,6 ^, R,7'S,8'E,ll'S,12' 6-CHLORO-7 ^, -(2~(l,l- DIOXIDO-4-THIOMORPHOLINYL)ETHOXY)- 11 ', 12'-DlMETHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PL\ i ACOSA

[8,16,18,24]TETiLAE ]-15'-ONE 13',13'-D10X1DE

To a 100 ml flask was added (((1S,3'R,6'R,7'S,8'E,11'β,Π'^-ό-οΙιΙθΓθ- llV12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-l,22'-

n]-7'-yl)oxy)acetaldehyde (Example 527, Step 1) (10 mg, 0.016 mmol), DCE (2 ml), thiomorpholine dioxide (TCI America, Portland, OR) (8.7 mg, 0.064 mmol) and sodmm triacetoxyborohydride (17 mg, 0.080 mmol). The reaction was stirred at 55 °C for 5 hours at which time the reaction was quenched with 0.5 ml of MeOH and 100 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 300 ml of EtOAc and the EtOAc layer was washed with 100 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (1.7 mg, 2.2 mmol, 14% yield) as a white film. ^" Ή NMR (400MHz, CD2CI2) δ 8,03 (br. s,, IH), 7.62 (d. ./ 8.4 Hz, W D. 7.09 (dd, ./ 2.3. 8.4 Hz, i l l ). 7.01 (d, 2.2 Hz, 1H), 6.83 (s, 2H), 6.74 (s, i l l ). 5.89 - 5.71 (m, i l l ). 5,52 - 5.36 (m, i l l ). 4,23 - 4.09 (m, I I I ). 4.00 (s, 2H), 3.79 ·· 3.57 C m. 8H), 3.56 - 3.47 (m, i l l ). 3.39 (s, 4H), 3.24 ·· 3.10 (m, 31 1 ). 2.96 (dd, ./ 10.3. 15.4 Hz, 1H), 2.76 - 2,62 (m, 2H), 2.43 - 2.32 (m, 1H), 2.31 - 2.21 (m, IH), 2.14 - 1 .81 (m, 6H), 1.79 - 1.56 (m, 5H), 1.37 hi. ,/ 7 0 ! !/. 3H), 0,95 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 760.3 (M+H) ⁺ .

EXAMPLE 525. (1 S,3' ,6'R,7'S,8'E, 'SJ 2'R)-6-CHLORO-7'-(2-(3- METHOXY- 1 -AZETIDINYL)ETHOXY)- 11 ', 12'-DIMETHYL-3,4-DIHYDRO- 2H, 15'H"SPIRO| NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]- 5 -ONE 13", 13'-DIOXTDE 2,2, 2-TRIFLUORO ACETIC ACID

To a 4 ml vial was added (((1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-emoro-l 1\12 ^! ~ dime1hyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphth alene-l,22'- [20]oxa[13]thia[l ,14]diazatefra^

n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (19 mg, 0.030 mmol), DCE (4 ml) and 3-methoxyazetidine (Frontier Scientific, Logan, UT)(10 nig, 0.12 mmol). The reaction was heated at 50 °C for 5 minutes, was cooled to room temperature and sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added. The reaction was stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (2.8 nig, 3.4 μιηοΐ, 11% yield) as an amorphous solid. ^] H NMR (400MHz, CD2CI2) δ 8.17 (br. s., 1H), 7,70 (d, ./ 8.6 Hz, ill).7. 7 (dd, ,/ 2.2.8,4 Hz, IH), 7.09 (d, 2.3 Hz, ill).6,91 (s, 2H), 6.82 (s, 1H), 5.93 - 5.75 (m, 1H), 5.51 (dd, J=8.7, 14.4 Hz, 1H), 4.62 - 4.64(m, 2H), 4.33 (d, ./ 6.1 Hz, ill).4.29 - 4.16 (m, 2H), 4.08 (s, 2H), 3.84 - 3.59 (m, 5H), 3,54 - 3.45 (m, 2H), 3.37 - 3.20 (m, 5H), 3,03 (dd, ./ iO.3, 15.4 Hz, IH), 2.85 - 2.70 (m, 2H), 2,44 (d, ./ 9.6 Hz, IH), 2.32 (td, J=8.8, 17.7 Hz, IH), 2.22 - 1.72 Cm.9H), 1.71 - 1.62 (m, IH), 1.44 (d, ./ 7.2 Hz, 3H), 1.41 - 1.32 (m, IH), 1.02 (d, ./ 6.K Hz, 311). m/z (ESI, +ve ion) 712.4 (M+H) ⁺ .

EXAMPLE 526. (lS,3 ^, R,6 ^, R,7 ^! S,8'E,ll'S,12'R)-7 ^, -(2~(l"

AZETIDINYL)ETHOXY)-6-CHLORO- IV, 12'-DIMETHYL-3 ,4-DTHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1.22'-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAEN]-15'-C)NE 13',13'-DIOXIDE 2,2,2-TRIFLUORGACETIC ACID

To a 4 ml vial was added (((1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-chloro- ! V,12'~ dimethyl- 13', 13'-dioxido- 15'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1 ,22'- i;20]oxa[13]thia|;i,14]diazatetracyclo|14.7.2.0 ³ - ^f \0 ¹⁹ - ²⁴ ]peniacosa|;8,16,18,^ n]-7'-y])oxy)acetaldehyde (from 527, Step 1) (19 mg, 0.030 mmol), DCE (4 ml), azetidine hydrochloride (Frontier Scientific, Logan, UT) (11 mg, 0.12 mmol) and triethylamiiie (0.016 ml, 0.12 mmol). The reaction was heated at 50 °C for 5 minutes, the reaction was cooled to room temperature and sodium

triacetoxyborohydride (31 mg, 0, 15 mmol) was added. The reaction was stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% 1 FA. 45 minute method) to give the title compound (1.6 mg, 2.0 μηιοΐ, 6.8 % yield) as an amorphous solid. ^] H NMR (400MHz, CD2CI2) δ 8.11 (br. s., 1H), 7.70 (d, ,/ 86 Hz, 1H), 7.17 (dd, ,/ 2.3.8.4 Hz, 1H), 7.09 (d, ,/ 2.2 Hz, Hi).6.98 - 6.88 (m, 2H), 6.82 (s, 1H), 5.93 - 5.74 (m, ill).5.56 - 5.47 (m, 1H), 4.39 - 4.29(m, 2H), 4.25 (d, J=8.0 Hz, 1H), 4.08 (s, 2H), 3.94 - 3.73 (m, 4H), 3.69 (d, J=14.3 Hz, 2H), 3.51 - 3.41 {in. !!!}.3.24 (d, J=14.5 Hz, 3H), 3.02 (dd, 10.3.15.2 Hz, 1H), 2.82 - 2.64 (m, 3H), 2,44 (d, ./ 6.7 Hz, 1H), 2.36 - 2.24 (m, 2H), 2.22 - 2,01 (m, 3H), 2.01 ·· 1.49 (m, 7 H), 1.44 (d, J=7.0 Hz, 3H), 1.40 - 1.35 (m, 1H), 1.02 (d, ./ 6,8 Hz, 3H). m!z (ESI, +ve ion) 682.4 { \ I · Π } .

EXAMPLE 527. (18,3 ^! ,6·Κ,7'8,8Έ,1Γ8,12¾)-6-α-ΪΕΟΜ)-7'-(((2Κ)-2- HYDROXYPROPYL)OXY)-ll\12'-DIMEra^L-3,4-DIHYDRO-2H ₅ 15H- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ujOXA| 1 ΙΊ !!1Λ| l.l4|! !A/.Vn-;i ^' RA( ^' YCi,.()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24]TETRAENj-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6' ,7'S,8'E, 11 'S, 12*R)-6-CHLORO-7'-(((2S)-2- HYDROXYPROPYL)OXY)~ 1 V , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHL4[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13V13'-DIOXIDE

STEP 1 : (((lS,:rR,6'R,7^ ₅ 8¾i rS;i2¾)-6-CHLORO-ir,12' 31ME ^' raYL- 13 ^, ,13 ^, -D10XIDO-15 ^, -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ₅ 22'- [20]OXA[ 13]THIA[ l 4]DIAZATCTRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN]-7'- DE

To a 100 ml flask containing ί 1 S.:VR.6'R .7'S.8 ^' h. ! I ^' S. I 2'R )-6-ch!oro-7'-{2- hydroxyethoxy)-l lV12'-dimethyl-3,4-di^

j;2Q]oxa[ 13]thiaj;i ,14]diazate^

n]-15'-one 13',13'-dioxide (from Example 516) (380 mg, 0.591 mmol) was added 30 ml of wet DCM, the reaction was cooled to 0 °C and then dess-martin periodinane (501 mg, 1.18 mmol) was added. The white slurry was stirred at 0° C for 30 minutes at which time the ice bath was removed and the reaction was stirred for an additional 8 hours. The reaction was then quenched with 100 ml of saturated aqueous sodium bicarbonate and extracted with 400 niL of EtOAc. The organic layer was extracted once more with 100 ml of brine, dried o ver sodium sulfate, concentrated by rotary evaporation and was purified on a Combiflash (12 gram gold silica column), eluting with 10% - 50% EtOAc in heptanes, to give (((18,3¾,6¾,7'8,8Έ,1 Γ8,12ΊΙ)-6-ΰΜθΓθ-11^12'^^6 1-13^13 ^! ~άιοχίάο-15'- oxo-3,4-dihydro-2H-spiro|naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2,0 ³ - ⁶ .0 ^{! 9} ' ²⁴ ]pentacosa[8,16,18,24]ietrae n]-7'-yl)oxy)acetaldehyde (240 nig, 0.374 mmol, 63% yield) as a white solid. STEP 2: (lS,3 ^f R,6'R,7'S,8'E,l 1 ^* S,12'R)-6-CHLORO-7'-(((2R)-2- HYDROXYPROPYL)OXY)-ll\12'-DIMEra^L-3,4-DIHYDRO-2H ₅ 15H- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| 1ΉΤί!1Λ| U4|DiA/.YiTTRAC ^' Ya.Oi i 4.7.2,0 ^• ^0 ^{|:, ! 1} |PH\,T.\i SA [8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12*R)-6-CHLORO-7'-(((2S)-2-

HYDROXYPROPYL)OXY)- 1 Γ,12'-DIMETHYL~3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

To a 100 ml flask containing (((lS,3'R,6'R,7'S,8¾ll^,12'R)-6-chloro- 1 r,12'-dimethyl-13^1J'-dioxido-15'-oxo-3,4-dify

[20]oxa[13]thia[l,14]diazatetracyclo[14;7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[

n]-7'-yl)oxy)acetaldehyde (from Step 1) (240 mg, 0.374 mmol) was added 20 ml of THF and the reaction was cooled to -78 °C at which time metliylmagnesium bromide 3.0m in diethyl ether (0.374 ml, 1.12 mmol) was added. The reaction was stirred at room temperature for 1 hour, then quenched with 100 mi of saturated ammonium chloride and extracted once with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude was first was purified on a Cornbiflash (12 gram gold silica column), eluting with 10% - 70% EtOAc in heptanes. Rf = 0.19 eluting with 50% EtOAc in heptanes. The racimic mixture (1:1) was then purified by preparatory SCF chromatography (ChiralPak AD-H 4.6 x 250 mM column, Phenomenex, Torrance, CA; elution of 35% EtOH in liquid CO?.; flow rate = 3mL/minute, 100 Bar BPR; 20 minute method, 0.5 mL stacked injections,

6mg/mL) to provide the title compound (40 mg, 0.061 mmol, 33% yield), as the slower eluting isomer as a white solid (ta = 7.7 minutes). ¾ NMR (400MHz, CD2CI2) δ 8.20 (br. s., IH), 7.62 (d, ,/ 8.4 Hz, ill).7.08 (dd,■/ 2.2.8.6 Hz, ill . 7.01 (d, ,/ 2.0 FIz, H), 6.89 - 6,72 (m, Ml).5.71 (ddd, ,/ 3.3.9,6, 15,1 Hz, H), 5.46 (dd, ,/ 90.15.1 Hz, IH), 4,25 - 4,09 (m, 1H), 4.05 - 3.90 (m, 2H), 3,85 -

3.69 (m, 3H), 3.61 (d,J=14.1 Hz, IH), 3.24 - 3.05 (m, 3H), 2.95 (dd,J=10.1, 15.4 Hz, 111).2.76 - 2,59 (m, 211).2,43 - 2,32 (m, 111).2.25 {id../ 8.9.18.2 Hz, III). 2.17 - 1.93 (m, 4H), 1,93 - 1.71 (m, 6H), 1.65 - 1.55 (m, 1H), 1,36 id. J=7.0 Hz, 3H), 0.99 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 657.3 { M · Π } .

EXAMPLE 528. (18,3'Κ,6 ^! Κ,7'8,8Έ,1 l'S,12'R)-6-CHLORO-7'-(((2R)-2- HYDROXYPROPYL)OXY)- 1 Γ, 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|20jOXA| I 311 HI Λ| I , N |OIA/.\ Π·. f ^' RACYCf ,Oj N.7.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL4E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8 ^, E,ll ^, S,12'R)-6-CHLORO-7'-(((2S)-2- HYDROXYPROPYL)OXY)-l 1 \12'-DlMETHYL-3 ₅ 4-DlHYDRO-2H,l 5Ή-

8ΡΚΟ[ΝΑΡΗΊΉΑΙ,ΕΝΕ-1,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8 ₅ 16,18,24] -15"-ONE 13',13'-D )XIDE

To a 100 ml flask containing (((ISJ'R^' ^'S^^irS^'R -chloro- 1 l 12'-dime1hyl-.13^13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[napht alene-l,22'-

[20]oxa[ 13]thia[ 1,1

n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (240 nig, 0.374 mmol) was added 20 ml of THF and the reaction was cooled to -78 °C at which time methylmagnesium bromide 3.0m in diethyl ether (0,374 ml, 1.12 mmol) was added. The reaction was stirred at room temperature for 1 hour, then quenched with 100 ml of saturated ammonium chloride and extracted once with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude was first was purifi ed on a Combiflash (12 gram gold silica column), eluting with 10% - 70% EtOAc in heptanes. Rf = 0.19 eluting with 50% EtOAc in heptanes. The racimic mixture (1:1) was then purified by preparatory SCF chromatography (ChiralPak AD-H 4.6 x 250 mM column, Phenomenex, Torrance, CA; elution of 35% EtOH in liquid CO?.; flow rate =

3mL/minute, 100 Bar BPR; 20 minute method, 0.5 mL stacked injections, 6mg/mL) to provide the title compound (25 mg, 0.038 mmol, 20% yield), as the faster eluting isomer as a white solid, (TR = 6.5 minutes). ¾ NMR (400MHz, CD2CI2) δ 8.20 (br. s., IH), 7.62 (d, ,/ 8.4 Hz, 1H), 7.08 (dd,■/ 2.2.8.6 Hz, 1H), 7.01 (d, ,/ 2.0 Hz, IH), 6.89 - 6,76 (m, Ml).5.71 (ddd, ,/ 3.3.9,6, 15,1 Hz, IH), 5.46 (dd, ,/ 90.15.1 Hz, IH), 4,18 (q, ./ 7.3 Hz, IH), 4.00 (s, 2H), 3.85 - 3.67 (m, 3H), 3.61 (d, J=14.1 Hz, IH), 3.21 - 3.13 (m, 2H), 3.13 - 3.04 (m, IH), 2.95 (dd, ./ 10.2.15.3 Hz, IH), 2.76 - 2.56 (m, 2H), 2.45 - 2.32 (m, IH), 2.25 (td,J=8.9, 18,1 Hz, IH), 2.19 - 1.82 (m, 7H), 1.81 - 1.68 (m, 2H), 1.64 - 1.48 (m, 2H), 1.36 (d, .7=7.2 Hz, 3H), 0.99 (d, J=6,3 Hz, 3H), 0.97 - 0.89 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 657.3 (V! li) .

EXAMPLE 529. (1 S,3'R,6'R,7'S,8'E,1 rS,12'S)-6-CHLORO-7 ^! ~HYDROXY-12'- ((2R)-2-METHOXYPROPYL)- 1 l'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]ΟΧΑ[13]ΤΉ Α[1 4]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irS,12'R)-6-CHLORO-7'-HYDROXY-12'-((2R)- 2- METHOXYPROPYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTH ALENE- 1.22 ^' -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18 -15'-ONE 13',13'-DIOXIDE

STEP 1 (2R,4S,5S)-2-HYDROXY-N, N-BIS(4-METHOXYBENZYL)-5- METHYLOCT-7-ENE-4-SULFONAMIDE AND (2R,4R,5 S)-2-HYDROXY- N,N-BIS(4-M NAMIDE

To a -78 °C solution of (S)-N,N-bis(4-methoxybenz l)-2-methylpent-4- ene-1 -sulfonamide (from Example 395, Step 3) (700 mg, 1 ,74 mmol) in THF (10 mL) under argon was added n-butyllithium (2.5M solution in hexane, 0.833 mL, 2.08 mmol) over 5 minutes. The mixture was stirred at -78 °C for 1 hours at which time (R)-(+)-l,2-epoxy ropane (Sigma- Aldrich, Milwaukee, Wl)(0.182 mL, 2.60 mmol) was added and stirred at 0 °C for 5 hours. The reaction was then quenched with 100 ml of saturated ammonium chloride and extracted with 300 ml of

EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude was purified on a Combiflash (24 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give a 2: 1 mixture of [(2R,4S,5S)-2-hydroxy-N,N-bis(4-methoxybenzyl)-5-methyloct-7 -ene- 4-sulfonamide and (2R,4R,5S)-2-hydroxy-N,N-bis(4-methoxybenzyl)-5- methyloct-7-ene-4-sulfonamide] (570 mg, 1.24 mmol, 71% yield) as light yellow oils.

STEP 2: (2R, 4S, 5S)-2-METHOXY-N,N-BIS(4-METOOXYBENZYL)-5- METHYLOCT-7-ENE-4-SULFONAMIDE AND (2R, 4R, 5S)-2-METHOXY- N,N-BIS(4-METHOXYBENZYL)-5-METHYLOCT-7-ENE-4-SULFONAMlDE

To a 100 ml flask was added [(2R,4S,5S)-2-hydroxy-N,N-bis(4- methoxybenzyl)-5-methyloct-7-ene-4-sulfonamide and (2R,4R,5S)-2-hydroxy N,N-bis(4-methoxybenzyl)-5-methyloct-7-ene-4-sulfonamide] (from Step 1 ) ( mg, 1.24 mrnol) and THF (10 mL). The reaction flask was cooled to 0 °C and NaH (50 mg, 2.1 rnmol) was added. The reaction was stirred at room temperature for 20 minutes at which time Mel (0.066 ml, 1.0 mmol) was added. The reaction was then stirred at room temperature for 4 hours then the reaction was quenched with 100 ml of saturated ammonium chloride and extracted with 400 ml of

EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The crude was purified on a Conibiflash (24 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give a 1 : 1 mixture of [(2R, 4S, 5S)-2-methoxy-N,N-bis(4-melhoxybenzyl)-5-methyloct- 7-ene-4-sulfonamide and (2R, 4R, 5S)-2-methoxy-N,N-bis(4-methoxybenzyl)-5- methyioci-7-ene-4-suifonamide] (510 mg, 1.07 mmol, 87% yield) as a light veilow oil.

STEP 3: (2R,4R,5S)-2-METHOXY-5-METHYLOCT-7-ENE-4-SULFONAMIDE OR (2R,4S,5S)-2-ME -5- ETHYLOCT-7-ENE^-SULFONAMIDE

To a 100 ml flask was added [(2R, 4S, 5S)-2-methoxy~N,N~bis(4- methoxybenzyl)-5-methyloct-7-ene-4-sulfonamide and (2R, 4R, 5S)-2-methoxy- N,N-bis(4-methoxybenzyl)-5-methyloct-7-ene-4-sulfonamide] (from Step 2) (500 mg, 1.05 mmol), anisole (1 .15 ml, 10,5 mmol), DCM (10 ml), and then TFA (4 ml). The reaction was stirred at 22 °C for 8 hours at which time the solvent was removed. The crude was purified on a Combiflash (12 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes) to give (2R,4R,5S)-2-methoxy-5- methyloct-7-ene-4-sulfonamide or (2R,4S,5S)-2-methoxy-5-methyloct-7-ene-4- sulfonamide](108 mg, 0.459 mmol, 87% yield) as the faster eluting isomer, as a light yellow oil.

STEP 4: (S)-6 ^! -CHLORO-5~(((l R,2R)~2-((l S,5S,6S,8R,E)-l-HYDROXY-8- ETHOXY-5-METHYL-6-SULFAMOYLNON-2-EN-1- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO [B] [ 1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6 ^, -CHLORO-5-(((lR,2R)-2-((l S,5S _: ,6R,8R,E)-l-HYDROXY-8- METHOXY-5-METH YL-6-SULF AMOYLNON-2-EN- 1 - YL)CYCI BUTYL)METHYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^f H-

SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

To a 100 ml flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l - hydroxyhex-2-en-l-yl)cyclobut d)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepme-3 , Γ-naphthal ene] -7-carboxy lie acid (Intermediate AA12A) (51.6 mg, 0.101 mmol), [(2R,4R,5S)-2-methoxy-5-methyloct-7-ene-4- sulfonamide or (2R,4S,5S)-2-methoxy-5-methyloct-7-ene-4-sulfonamide| (from Step 3)(71 .4 mg, 0.303 mmol), and DCE (4 mL). The solution was sparged with argon for 15 minutes at which time Hoveyda-Grubbs II (6.3 mg, 10 μπιοΐ) was added as a 0.2 mL solution in DCE at room temperature. The mixture was stirred at room temperature for 16 hours. Note: the clear solution becomes slowly darker. The reaction mixture was then bubbled with air for 5 minutes and filtered. The solvent was removed from the filtrate and was directly purified on a Combiflash (12 gram gold silica column), eluting with 50% - 90% EtOAc in heptanes + 0.2% AcOH, to give [(S)-6'-chloro-5-(((lR,2R)-2-((lS,5S,6S,8R,E)-l-hydroxy-8- me1hoxy-5-methyl-6-sulfamoylnon-2-en-l -yl)cyclobut 'l)methyl)-3',4,4',5- tetrahydro-2H,2'H-spiro| benzoj bj [ l,4]oxazepine-3,r-naphihaIene]-7-carboxy lie acid or (S)-6'-chloro-5-(((lR,2R)-2-((lS,5S,6R,8R,E)-l -hydroxy-8-methoxy-5- methyl -6-sidfamoylnon-2-e^

spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid] (46 mg, 0.068 mmol, 67% yield) as white solids. STEP 5: (lS,3 ^, R ₅ 6 ^, R,7'S ₅ 8 ^, E ₅ l l ^, S,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-2-

METHOXYPROPYL)~] ] '-METHYL-3,4-DIHYDRO-2H,15 ^! H- SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J 6, 18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(IS^' ^'RJ'S^'EJ l'S/ ^-e-CHLO O-T'-HYD OXY-n'-^ )^- METHOXYPROPYL)-! Ι'-ΜΕΊΉΥΕ-3,4~ΟΙΗΥΟί Ο-2Η,15Ή- SPTRO[NAPHTH ALENE- 1 ,22'- [20]QXA[13]THIA[U4]DL^

[8,I6,18,24]TETiL EN]-15'-ONE 13 VI 3 '-DIOXIDE

To a 25 ml flask containing [(S)-6'-chloro-5-(((lR,2R)-2-

((l S,5S,6S,8R E)-l~hydrox}'--8-methoxy-5~methyl-6

y^cyclobuty^methy^-S'^^'^-tetrahydro^H^'H-s irotbenzotblt l^Joxazepine- 3,l'-naphthalene]-7-carboxylic acid or (S)-6'-chloro-5-(((lR,2R)-2- ((l S,5S,6R,8R,E)-l-hydroxy-8-methoxy-5-methyl-6-s

yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[b enzo[b][l,4]oxazepine- 3, -naphthalene|-7-carbox lic acid] (from Step 4) (46 mg, 0.068 mmol) which was previously dried by rotovaping twice with 5 rnl of toluene, was added N.N- dimethylpyridin-4-amine (DMAP) (14 mg, 0. 12 mmol) and 100 ml of DCM. The reaction mixture was cooled to 0 °C at which N-(3-dimethylaminopiOpyl)-N ^' '- ethylcarbodiimide hydrochloride (26 mg, 0, 14 mmol) was slowly added. The reaction was stirred at room temperature for 18 hour. The mixture was then quenched with 50 ml of IN HCi and extracted with 200 ml of EtOAc. The organic layer were dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (7.6 mg, 0.0.12 mmol, 17% yield) as a white solid. ¾ NMR (400MHz, CDCb) δ 8,22 (br. :s . 1H), 7.70 (d, J=8.6 Hz, i l l ). 7.19 (dd, J=2.3, 8.4 Hz, 2H), 7.10 (d, ./ 2.2 Hz, 1H), 6.97 (d, ./ 8.2 Hz, ill).6,78 - 6.62 (m ill).6,10 - 5.97 (m, ill).5.67 (dd, 6.3.15.5 Hz, I Hi. 4,23 - 3.99 (m, 41! ).3.88 - 3.69 (m, 2H), 3,62 (d, «7=13.9 Hz, 1H), 3.48 - 3.44 Cm. HI).3.43 (s, 3H), 3.34 - 3.15 (m, IH), 2.89 - 2.67 (m, 2H), 2.61 - 2.39 (m,2H), 2.34-2.11 (m, 3H), 2.08 - 1.67 (m, 9H), 1.49 id../ ! 1.7 i!/.1H), 1.21 (d, 61 Hz, 3H), 1.11 (d, ,/ 70 Hz, 3H). ni / (ESI, +ve ion) 657.0 (M+H) ⁺ .

EXAMPLE 530. (1S,3'R,6'R,7'S,8'E,1 l ^, S,12'R)-6-CHLORO-7 ^, -(2-((3R)-3-

(METHOXYMETHYL)-4-MORPHOLINYL)ETHOXY)- H',12'-DIMETHYL-

3 ,4 -DIHYDRO-2H, 15 ^! H-SPIRO [NAPHTHALENE- 1 ,22'- |2ujOXA| 1 Γ1Ή1Λ| Ι.Ι4|ΠίΛ/ΛΠ:ΤΗΛ(Ύα.ί)Ι i 4.7.2.0 · ^, \0 ^{|:, ! 1} |PHNT.\i SA

[8,16,18,24]TETRAENj-15'-C)NE 13',13'-DIOXIDE AND

(lS,3 ^, R,6'R,7 ^f S,8'E,Il'S,I2'R)-6-CHLORO-7'-(2-((3S)-3-

(METHOXY¾lETHYL)-4-MORPHOLlNYL)ETHOXY)-ir,12'-L)IMETHYL-

3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8, 16, 18,24] - 15'-ONE 13 ^! , 13'-DIOXIDE

To a 100 ml flask was added i( ( 1 S..VR.6'R.7 ^' S.8'! ^; ..1 I'S.12 ^' )-6-i;hio!-o- ir,12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro [naphthalene-l _^ i;20]oxa[13]thia|;i,14]diazatetracyclo|14.7.2.0 ³ - ^f \0 ^l9 - ²⁴ ]peniacosa|;8,16 _^ n]-7'-y])oxy)acetaldehyde (from Example 527, Step 1) (10 mg, 0.016 mmol), DCE (2 mi), 3-(methoxymethyl)morpholine hydrochloride (Frontier Scientific, Logan, UT)(11 mg, 0.064 mmol), and sodium triacetoxyborohydride (17 mg, 0,080 mmol). The reaction was stirred at 55 °C for 5 hours at which time the reaction was quenched with 0.5 ml of MeOH and 100 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 300 ml of EtOAc and the EtOAc layer was washed with 100 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give a 1:1 mixture of the title compounds (1,8 mg, 2.4 μιηοΐ, 15% yield) as a white film. ¾ NMR (400MHz, CD2CI2) δ 8.11 (br. s., 1H), 7.70 (d, J=8.6Hz, 1H), 7.17 (dd, ./ 2.2.8.5 Hz, ill).7.09 (d,J=2.3 Hz, 1H), 6.91 (s, 2H), 6.83 (s, 1H), 5.98 - 5.77 (m. 111).5,62 - 5.45 (m, III).4.26 (d, ,/ 7.4 Hz, IH), 4.08 is.2H), 4.01 - 3,89 (m, 4H), 3.88 - 3.73 (m, 5H), 3,69 (d, «7=14.5 Hz, 2H), 3.64 - 3.43 (m, 4H), 3.37 (m, 1.5H), 3.36 (m, 1.5H), 3.24 (d, J=14.3 Hz, 2H), 3.04 (dd, J=10.1, 15.4 Hz, 1H), 2.84 - 2.69 (m, 2H), 2,49 - 2.39 (m, IH), 2.38 - 2.26 (m, IH), 2,23 - 1.89 (m, 6H), 1,88 - 1.75 (m, 3H), 1.75 - 1.62 (m, IH), 1.45 (d, J=7.0Hz, 3H), 1.42 - 1.35 (m, IH), 1,08 - 0.91 (m, 3H). m/z (ESI, +ve ion) 756.4 ί\ί H) . EXAMPLE 531. (1 S,3'R,6'R,7'S,8'E,1 I'SJ 2'R)-6-CHLORO-l l',12'-DIMETHYL- 7 ^! ~(2-((3R)-3-(l-METHYLETHYL)~4 lORPHOLiNYL)ETHOXY)-3,4~ DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ^3>, 0 ^!9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15-ONE 13", 13-DIOXIDE 2,2, 2-TRIFLUORO ACETIC ACID AND (lS,3 t,6'R,7 ^! S,8'E,l l'S _s 12'R)-6-CHLORO-l r,12'-DIMETHYL-7'- (2-((3S)-3-(l-MEraYLETHYL)-4-MORPHOLINYL)ETHOXY)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|2 ⁽ >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^; ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXlDE 2,2,2-TRIFLUORO ACETIC ACID

To a 4 ml vial was added ((( 1 S,3'R,6'R,7'S,8'E, 1 l'S,l 2'R)-6-chloro-l l'J 2 - dimethyl- 13', 13'-dioxido~ 15'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (20 mg, 0.031 mmol), DCE (4 ml), 3-isopropylmorpholine hydrochloride (Frontier Scientific, Logan, UT)(21 mg, 0.13 mmol) and tri ethyl amine (0.017 ml, 0.13 mmol). The reaction was heated at 50 °C for 5 minutes at which time the reaction was cooled to room temperature and sodium triacetoxyborohydnde (33 mg, 0. 16 mmol) was added. The reaction was stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give a 1 : 1 mixture of th e title compounds (1.8 mg, 2.1 μιηοΐ, 6.7% yield) as an amorphous solid. ¾ NMR (400MHz, CD2CI2) δ 8.20 (br. s., H i ). 7.70 (d, ./ 8. Hz, 1H), 7.17 (dd, ./ 2.2. 8.5 Hz, 1H), 7.09 (d, ,/ 2 3 Hz, 1 H), 6.92 (s, 2H), 6.83 (s, 1 H), 5.99 - 5.79 (m, 1H), 5.63 - 5.46 (m, 1 H), 4,27 (q, J=6.9 Hz, 1H), 4.2 - 4.1 (m, 0.5 H), 4.08 (s, 2H), 4.04 - 3,89 (m, 3,5 H), 3.82 (d, J=14.3 Hz, 3H), 3.69 (d, J=14.3 Hz, 2H), 3.57 - 3.47 (m, 1.5 H), 3.46 - 3.37 (m, 1.5 H), 3.24 i d. ./ 14. ! Hz, 2H), 3,20 i s. i l l ). 3.10 - 2,97 (m, 1 1 1 ). 2.84 - 2.67 (m, 3H), 2.44 (s, 2H), 2.38 - 2,27 (m, 1H), 2.24 - 1.90 (m, 9H), 1.46 (d, ./ 7.0 Hz, 1.5 H), 1.45 (d, ./ 7.0 Hz, 1.5 1 1 }. 1.33 - 1.27 (m, 1H), 1.04 (id. J=4.7, 6.8 Hz, 9H). m/z (ESI, +ve ion) 698.4 i \i H ) .

EXAMPLE 532, (1S,3'R,6'R,7'S,8'E, 1 l ^, S,12'R)-6-CHLORO-7 ^, -(2-(3-FLUORO- 1 -AZETIDINYL)ETHOXY)-l 1 ', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'- | 2( !ί>Χ Λ| i 3 ! 1 Π! Λ| ί 1 1 | ί^!ΛΖΛ ί : ί AC YC i (>! i -1 7.2 ^; ".O ¹ " ^M |Ρ!·Λ i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE i .T. i 3'-DIOXIDE

To a 8 ml vial was added (((1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-chloro-ir,12 ^! - dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphth alene-l,22'- [20]oxa[13]thia[l,14]diazatetra<yclo^

n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (19 mg, 0.030 mmol), DCE (4 ml), 3-fluoroazetidine hydrochloride (Frontier Scientific, Logan, UT)(13 mg, 0.12 mmol) and tnethyiarnine (0.016 ml, 0.12 mmol). The reaction was heated at 50 °C for 5 minutes and sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added. The reaction was stirred at 50 °C for 16 hours at which time the reaction was quenched with 0.2 ml of MeOH and 50 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 100 ml of EtOAc and the EtOAc layer was washed with 50 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solveni removed by rotary evaporation. The crude was purified on a Combiflash (4 gram gold silica column), eluting with 2% - 10% MeOH in DCM, to give the title compound (9.0 mg, 0.011 mmol, 37% yield) as an off white solid. Ri ^" 0.28 elutmg with 10% MeOH m DCM. Ί I NMR (400MHz, CD2CI2) δ 7.71 (d, 86 Hz, 111).7.17 (dd, ,/ 22.8.5 Hz, ill).7.09 id../ 2.3 Hz, ill). 6,99 - 6.93 (m, III).6.92 - 6.82 (m, 2H), 5,89 - 5.71 (m, 1H), 5.52 (dd, ,7=9,1, 15.4 Hz, 1H), 5,19 (dq, JH,F= 57.7 & J=5.2, 1H), 4.26 - 4.15(m, IH), 4.07 (s, 2H), 3.88 - 3,63 (m, 5H), 3.50 - 3.38 (m, 2H), 3.31 -3,18 (m, 5H), 3.02 (dd, ,/ 10.0.15,3 Hz, IH), 2.81 (d, ,/ i Hz, 2H), 2.72 - 2.62 (m, 2H), 2.48 - 2.28 (m, 2H), 2.20 - 1.74 (m, 7H), 1.73 - 1.62 (m, IH), 1.42 id../ 7.0!!/,.3H), 1.38 (m,lH), 1.01 (d, ./ 6,8 Hz, 3H), m/z (ESI, +ve ion) 700.4 (M+H) ⁺ . EXAMPLE 533, 2-(((iS,3'R,6'R,7'S,8 ^! E,irS,12'R)-6-CHLORO-l l',12'- DIMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N,N-TRIETHYLETHANAMINlU M

2,2,2-TRIFLUOROACETATE

To a 1 dram pressure relief vial was added (1S,3'R,6'R,7'S,8'E,1 i'S,12'R)-

7'-(2-bromoe1hoxy)-6-cMoro-11^12 ^, -dimethyl-3,4-dihydro-2H,15 ^, H- spiro I naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazate1r^

n]-15'-one 13',13'-dioxide (from Example 14) (10 nig, 0.014 mmoi), 0.5 mi of DMSO and 6-oxa-l-azaspiro 3.3]heptane (Synthonix, Wake Forest, NC)(14 mg, 0.14 mmol). The reaction was sealed with a pressure release fitted cap and heated to 70 °C for 2 hours then triethylanime (40 μ\, 0.28 mmol) was added and heated to 70 °C for an additional 16 hours The reaction was then quenched with 0.2 ml of MeOH and was directly by reversed phase preparatory HPLC (Gemini™ Prep Ci85 μηι column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (2.1 mg, 2.5 μιηοΐ, 18% yield) as clear film. 'HNMR (400MHz, CD2CI2) δ 7.70 (d, J=8.4 Hz, 111).7.17 (dd, 24.8,5 Hz, 1H), 7.09 (d, .7=2,3 Hz, 1H), 7.00 - 6.85 (m, 2H), 6,80 (s, ill).6,00 - 5.81 (m, III).5.61 - 5.44 (m, 1H), 4.31 - 4.19 (m, 1H), 4.13 - 4.02 (m, 2H), 3.90 - 3.77 (m, 2H), 3.69 (d, ./ 14.9 Hz, 2H), 3,60 (m, 2H), 3.36 - 3.21 (m, 8H), 3.10 - 2,98 (m, 1H), 2.74 - 2.64 (rn, 2H), 2.38 - 2,20 (m, 2H), 2.16 - 1.98 (rn, 3H), 1.98 - 1.82 (m, 4H), 1.81 - 1.58 (m, 3H), 1,37 (d,J=7.2Hz, 3H), 1,34 - 1.28 (m, ill).1.23 (t, «7=7.1 Hz, 9H), 0.95 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 726.5 (M+H) ⁺ .

EXAMPLE 534, (1S,3 ^! R,6'R,7'S,8'E,1 rS,12'R)-6~CHLORO-l 1 ', 12'-DIMETHYL- 7'-(2-((3S)-3-METHYL^-MORPHOLI TYL)ETHOXY)-3 ₅ 4-DlHYDRO- 2H.15'H-SPIRO[N APHTHALENE- 1.22'-

|2ujOXA| O ΙΊ ί II A| I . I 4|Di A/A T! R AC YO.OI i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PHNTAi S A

[8,16,18,24]TETRAENj 5' ^! ,13 ^* -DIOXIDE

To a 100 ml flask was added (((1S,3'R,6'R,7'S,8'E,1 l'S,12 ^! R)-6-chloro- 1 r,12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[ naphthalene

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)acetaldehyde (from 527, Step 1) (16 mg, 0.025 mmol), DCE (2 ml), (S)-3-methylmorpholine (Frontier Scientific, Logan, UT) (5.1 mg, 0.051 mmol), and sodium triacetoxyborohydride (27 mg, 0.13 mmol). The reaction was stirred at 55 °C for 5 hours at which time the reaction was quenched with 0.5 ml of MeOH and 100 ml of saturated sodium bicarbonate. The aqueous solution was extracted with 300 ml of EtOAc and the EtOAc layer was washed with 100 rnl of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (2.7 mg, 3.7 μηιοΐ, 15% yield) as a white film. Ή NMR (400MHz, CD2CI2) 58.16 (br. s., 1H), 7.71 (d, ./ 8.4 Hz, ill).7.17 (dd, ./ 2.3.8.4 Hz, ill).7.09 (d, 2.3 Hz, H), 6.92 (s, 2H), 6.83 (s, IH), 5.96 - 5.77 (m, Ml).5.61 - 5.42 (m, IH), 4.27 (d, ./ 6.8 Hz, 1H), 4.09 (s, 2H), 4.05 - 3.87 (m, 3H), 3.87 - 3.59 (m, 6H), 3.52 - 3.10 (m, 6H), 3.04 (dd, ,/ i(>3.15,4 Hz, H), 2.85 - 2,68 (m, 2H), 2.45 (d, 90 Hz, IH), 2.39 - 2.27 (m, IH), 2,23 - 2.01 (m, 2H), 2.01 - 1.90 (111, 3H), 1,90 - 1.75 (m, 2H), 1.73 - 1.62 (111, IH), 1.45 (d, ./ 7.2 Hz, 3H), 1.41 - 1.39 (m, IH), 1.33 (d, ./ 6.7 Hz, 2H), 1.36 - 1.29 (m, 3H), 1.03 id../ 6.7 Hz, 3H). m (ESI, +ve ion) 726.3 I 11 > . EXAMPLE 535. (1 S,3'R,0 ^! R,7'S,8'E,1 rS,12'R)-6-CHLORO-7'-METHOXY-12'- ((2R)-2-METHOXYPROPYL)- 1 l'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[.1,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS.3 ^, R,6 ^, R,7 ^, S,8 ^, E,ll ^, S,12 ^, S)-6-CHLORO-7 ^, -METHOXY-12 ^, -((2R)-2- METHOXYPROPYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ujOXA| !3jTIUA| I 4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,1 -15'-ONE 13',13 ^* -

To a solution of [(1S,3'R,6'R,7'S,8'E,1 l'S,12'S)-6~chloro~7'~hydroxy-12'- ((2R)-2-methoxypropyl)- 11 '-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 122'-

[ 20] ox a[ ! 3 ] thi a[ 1 , ! 4] di azatetracy cl o [ 14.7 , 2, 0 ³ · ⁶ .0 ^{! 9} ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13', 13 '-dioxide or (lS,3'R,6 ^! R,7'S,8'E,irS,12'R)-6-chloro-7'-hydroxy- 12'-((2R)-2-methoxy propyl)- 11 '-methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene-

1,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14,7.2,0 ³ ' ⁶ .0 ¹⁹ ' ² '¾

n]-15'-one 13',13'-dioxide] (from Example 540)(16 mg, 0.024 mmol) in 1 ml of THF cooled to 0 °C was added NaH (5.8 mg, 0.24 mmol). After 15 minutes, Mel (7.6 μΐ, 0.12 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 45 minutes at which time the reaction was quenched with 25 ml of saturated ammonium chloride and extracted with 100 ml of EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude was purified on a Combiflash (4 gram gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give the title compound (8.0 mg, 0.012 mmol, 49% yield), ¾ NMR (400MHz, CDCh) δ 8.05 (s, I H), 7.70 (d, J=8.4 Hz, IH), 7.19 (dd, ./ 2.2. 8.5 Hz, I H i.. 7.10 (d, .7=2,3 Hz, H), 6.99 - 6,82 (m, 3H), 5.86 (ddd, J=3.0, 9.4, 15.2 Hz, IH), 5.54 (dd, ./ 9.2. 15.3 Hz, IH), 4.31 { dd. ,/ 3. . 8,5 Hz, IH), 4. 10 (s, 2H), 3.91 - 3,77 (m, 2H), 3.74 - 3.62 (m, 2H), 3 ,39 (s, 3H), 3 ,29 - 3.18 (m, I H), 3.23 (s, 3H), 3.01 (dd, J=10.2, 15.3 Hz, i l l ). 2,85 - 2.66 (m, 2H), 2.57 - 2.41 (m, 2H), 2,38 - 2.18 (m, 2H), 2.17 - 2. 10 (m, IH), 2.09 - 1.92 (m, 4H), 1.88 - 1.75 (m, 3H), 1.75 - 1.57 (m, 2H), 1.40 (t, J=12.6 Hz, 1 IT), 1.28 (d, 6, 8 Hz, 3H), 1 .08 (d, 6 8 Hz, 3H). m/z (EST, +ve ion) 671.0 \ \\ - U ) .

EXAMPLE 536. (l S,3'R,6'R,7'S,8 ^! E, l() ^! S)-6-CHLORO-7'-HYDROXY-10 ^, - METHOXY-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N ΑΡΗΤΉ ALENE- 1 ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

|;8, 16, 18,24]TETRAEN]-15 ^! -ONE 13', 13'-DIOXIDE

STEP 1 : (S) -HYDR0XY-N,N-BIS(4-METH0XYBENZYL)PENT-4-ENE-l- SULFONAMIDE

To a -78 °C solution of N,N-bis(4-methoxybenzyl)methanesulfonamide

(from Example EE12)(2.00 g, 5,96 mmol) in THF (25 mL) under argon was added n-butyl lithium (2.5 M solution in hexane, 3,58 mL, 8.94 mmol) over 5 minutes. The mixture was stirred at -78 °C for 2 hours (solution turned red-pink) at which time (R)-2-vinyl-oxirane (Sigma- Aldrich, Milwaukee, WI)(0, 84 mL, 10 mmol) was added and stirred at 0 °C for 16 hours. The reaction was then quenched with 100 ml of saturated ammonium chloride and extracted with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude was purified on a Combiflash (40 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give (S)-3- hydroxy-N,N-bis(4-methoxybenzyl)pent-4-ene- 1 -sulfonamide (1.35 g, 3.34 mmoi, 56% yield) as light yellow oils.

STEP 2: (S)-3-METHOXY-N,N-BTS(4-METHOXYBENZYL)PENT-4-ENE- SULFONAMIDE

To a 100 ml flask was added (S)-3-hydroxy-N,N-bis(4- methoxybenzyi)pent-4-ene-l -sulfonamide (from Step 1) (200 mg, 0.493 mmoi) DMF (4 mL) and NaH (59 mg, 2,5 mmoi). The reaction was stirred at room temperature for 15 minutes at which time iodomethane (0.092 ml, 1.5 mmoi) was added. The reaction was then stirred at room temperature for 2 hours, the reaction was quenched with 50 ml of saturated ammonium chloride and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude was purified on a Combiflash (12 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give (S)-3-methoxy-N,N-bis(4-methoxybenzyl)pent-4-ene-l- sulfonamide (91 mg, 0.22 mmoi, 44% yield) as an off white solid.

STEP 3: (S)-3-METHOXYPENT FONAMIDE

To a 100 ml flask containing (S)-3-methoxy-N,N-bis(4- methoxybenzyl)pent-4-ene-l -sulfonamide (from Step 2)(91.3 mg, 0.218 mmoi, 44.1 % yield) was added DCM (8 ml), anisole (0.539 ml, 4.93 mmoi) and then TFA (2 ml). The reaction was stirred at 22 °C for 5 hours at which time the solvent was removed. The crude was purified on a Combifiash (12 gram gold silica column), during with 10% to 50% EtOAc in heptanes, to give ((S)-3- methoxypent-4-ene-l -sulfonamide (24.9 mg, 0.139 mmol, 64% yield) as white solid.

STEP 4: (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l-

YL)C YCLOBUTYL)METHYL)-N-(((S)-3 -METHOXYPENT-4-EN- 1 - YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2 ^! H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPI E-3 , 1 '- APHTHALENE] -7- CARBOXAMIDE

To a 100 ml flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S _s E)-l- hydroxyhex-2-en-l~yl)cyclobutyi)rnethyl)-3',4,4',5-tetrahydr o-2H,21-I- spiro[benzo[b][l ,4]oxazepme-3, ~naphthalene]-7-carboxylic acid (from Example AA12A) (30 mg, 0.059 mmol), (S)-3-methoxypent-4-ene-l-sulfonamide (from Step 3) (25 mg, 0.14 mmol), N,N-dimethylpyridin-4-amine (14 mg, 0.12 mmol), 3 ml of DCM, and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiirnide hydrochloride (23 mg, 0.12 mmol). The reaction was stirred at room temperature for 16 hours at which time the reaction was quenched with 50 ml of 1 N HCl and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude was purified on a Combifiash (12 gram gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give ((S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l - hydroxyhex-2-en-l -y])cyclobutyl)methy])-N-(((S)-3-methoxypent-4-en-l- y l)sulfony l)-3 ',4,4',5 -tetrahy dro-2H,2'H-spiro [henzo [b] [1 ,4] oxazepine-3 , Γ- naphthalene]-7-carboxamide (31 mg, 0.046 mmol, 78% yield) as a thick yellow oil. STEP 5: (1SJ ^! R )'RJ ^, S,8'E;10^)-6-CHLORO-7 ^, -HYDROXY-] 0'-METHOXY- 3 ,4-DIHYDRG-2H, 15'H-SPIRQ [NAPHTHALENE- 1 , 22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE

To a 100 ml flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S _s E)-l- h} _' -droxyhex-2-en-l-yl)cyckjbuiyi)methyi)-N-(((S)-3-metho xypent-4-en- ! - yl)sulfonyl)-3',4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene] -7-carboxamide (from Step 4) (26 mg, 0.039 mmol) and DCM (25 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added titanium(iv) isopropoxide (9.1 μΐ, 0.031 mmol) and the reaction mixture was stirred at 45 °C for 1 hour at which time ((1,3-dimesityiimidazolidin- 2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (4.9 mg, 7.8 μιηοΐ) was added and the mixture was stirred to 45 °C for 16 hours. The reaction was then sparged with argon again for 15 minutes, (l,3-dimesityiimidazolidin-2- ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (4.9 mg, 7.8 μηιοΐ) was added again and the reaction was stirred at 80 °C for an additional 6 hours. The reaction was then filtered, concentrated and crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column;

Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give th title compound (2.5 mg, 4.2 μιηοΐ, 11% yield) as a white solid. ¾ NMR (400MHz, CDCh) δ 8.30 (br. s., 1H), 7.69 (d, ./ 8.4 Hz, I I I . 7.18 (dd, ./ 2.3. 8.4 Hz, 1 H),

7, 13 - 7.05 (m, 1 H), 7.01 - 6.88 (m, 2H), 5.92 - 5.81 (m, 1H), 5.86 (dd. ,/ 7. 15.6 Hz, IH), 5,75 (dd, ./ 6.8. 15.5 Hz, 1H), 4.30 - 4.23 (m, IH), 4.13 (q, .7=12.1 Hz, 2H), 3.95 - 3.83 (m, IH), 3.82 - 3.78 (m, IH), 3.60 (d, J=11.5 Hz, 3H), 3.47 - 3.23 (m, 2H), 3.12 (s, 3H), 2.86 - 2.65 (m, 2H), 2,55 - 2.37 (m, 2H), 2.36 - 2.23 (m, IH), 2.04 - 1.92 (m, 3H), 1.90 - 1.65 (m, 5H), 1.62 - 1.43 (m, IH). m/z (ESI, +ve ion) 601.0 (M+H) ⁺ . EXAMPLE 539. (lS,3'R,6 ^, R 7 ^, S,8 ^, E,12 ^, R)~6"CHLORO-7'~HYDROXY-12 ^, -((2R)" 2-HYDROXYPROPYL)-3 ₅ 4-DIIiYDRO-2H,15H-SPIRO[NAPIirHALE E- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8 ₅ 16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S,3 ^, R,6'R ₅ 7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22 ^! - | 2u jOX A | ! 3 jTI U A | Μ 4|ΠΙΛ/ΛΤΓ:ΤΙίΛ(ΎΠ.Ο! i 4.7.2.0 · ^, '. ί ) ^{| :} " ¹ | Pl - N i ^' AC<)S A [8,16,18,24]TETRAEN1-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

STEP 1 : (2R,4S)-2-((TERT-BUTYLDIPHENYLSILYL)OXY)-N,N-BIS(4- METHOXYBENZYL)OCT-7-ENE-4-SULFONAMIDE OR (2R,4R)-2-((TERT- BUTYLDIPHENYLSILYL)OXY)-N,N-BIS(4-METHOXYBENZYL)OCT-7- ENE-4-S

To a 100 ml flask was added [(2R,4R)-2-hydroxy-N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide and (2R,4S)-2 -hydroxy -N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide| (from Example 508, Step 1) (2.58 g, 5.76 mmol), DMF (40 ml), imidazole (785 mg, 11.5 mmol) and tert- butylchlorodiphenylsilane (2.25 ml, 8.65 mmol). The reaction was stirred at 65 °C for 16 hours at which time reaction was then quenched with 200 mi of saturated ammonium chloride and extracted with 600 ml of diethyl ether. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was first purified on a Combiflash (40g gold silica column), eluting with 10% to 30% EtOAc in heptanes. The racimic mixture (1 : 1 ) was then purified by preparator ' SCF chromatography (ChiralPak AD 250mm x 30mm column, Phenomenex, Torrance, CA; 16g/minute EtOH + (20mM Ammonia) + 64g/minute CO?. (20% co-solvent) on Thar 80 SFC; outlet pressure = 100 bar; temperature = 22 °C; wavelength = 220 nm; used 1.0 mL injections of 3647mg/41mL (89 mg/mL) sample solution of MeOH (35mL) and DCM (5mL); run time = 13 minutes & cycle time 10 minutes.) to provide

[(2R,4S)-2-((tert-butyldiphenylsilyl)oxy)-N,N-bis(4-me1hox} ⁷ benz}'l)oct-7-ene-4- sulfonarnide or (2R,4R)-2-((teri-butyldiphenyisilyl)oxy)-N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide] as the slower eluting isomer as a yellow liquid (TR = 2.34 minutes on analytical SFC; AD-H column; 15% EtOH in CO2).

STEP 2: (2R,4S)-2H(TERT-BUTYLDIPHENYLSlLYL)OXY)OCT-7-ENE~4- SULFON AMIDE OR (2R,4R)-2-((TERT-

BUTYLDIPHEN -7-ENE-4-SULFON AMIDE

To a 100 ml flask was added [(2R,4S)-2-((tert-butyldiphenylsilyl)oxy)-

N,N-bis(4-memoxybenzyl)oct-7-ene-4-sulfonarnide or (2R,4R)-2-((tert- butyldiphenylsilyl)oxy)-N,N-bis(4-memoxj ⁷ benzyl)oct-7-ene-4-sulfonarnide]

(from Step 1) (260 rag, 0.379 mmol), amsole (0.414 ml, 3,79 mraol), DCM (4 ml) and then TFA (2 ml). The reaction was stirred at 22 °C for 3 hours at which time the solvent was removed. The crude product was purified on a Combiflash (12g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give

[(2R,4S)-2-((tert iutyldiphenylsilyl)oxy)oct-7-ene-4-sulfonamide or (2R,4R)-2- ((tert-butyldiphenylsily])ox ')oct-7-ene-4-sulfonamide] (73.4 mg, 0.165 mmol, 44% yield) as a light yellow oil.

STEP 3 : (S)-N-(((2R,4S)-2-((TERT-BUTYLDIPHENYLSILYL)OXY)OCT-7- EN^-YL)SULFONYL)-6"-CIiLORO-5-(((lR,2R)-2 (S,E)-l -PIYDROXYHEX- 2-Ι ·Λ- Ι -Υ Ι .)(ΎΠ .ΟΒΙ . ΓΥ ί }V!i : i HY i .KV. i ·Ι - ΓΙ·: ΐ R AHY i ⁾ R ⁽ ?.l l.2 H- SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE OR (S)-N-(((2R,4R.)-2-((TERT-

BUTYLDIPHENYLSILYL)OXY)OCT-7-EN-4-YL)SULFONYL)-6'-CHLORO- 5-(((l R,2R)-2-((S,E)~ 1 -HYDROXYHEX-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] ~7~

CA

To a 100 nil flask was added (S)-6 ^! -chloro-5-(((lR ₅ 2R)-2-((S,E)-l - hydroxyhex-2~en-l-yl)cyclobut d)methyl)~3',4,4',5~tetrahydro-2H,2'H~ spiro[benzo[b][l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (from

Intermediate AA12A) (55 mg, 0.1 1 mmol), N,N-dimethylpyridin-4-amine (26 mg, 0.22 mmol), [(2R,4S)-2-((tert-bu1yldiphenylsilyl)oxy)oct-7-ene-4-sulfona mide or (2R,4R)-2-((tert-butyldiphenylsilyl)oxy)oct-7-ene-4-sulfonam ide] (from Step 2) (72 mg, 0.22 mmol) and N-(3-dimethylarrdnopropyl)-N'-ethylcarbodiimide hydrochloride (42 mg, 0.59 mmol). The reaction was stirred at room temperature for 16 hours at which time the solvent was removed and the crude product was purified on a Combifiash (12g gold silica column), eiuting with 2% - 10% EtOAc in heptanes + 0,2% AcOH, to give [(S)-N-(((2R,4S)-2-((tert- butyldiphenylsilyl)oxy)oct-7-m^

hydrox\'hex-2-en-l-yl)c 'clobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiroj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide or (S)-N- (((2R,4R)-2-((tert-butyldiphenylsilyl)ox oct-7-en-4-yl)sulfonyl)-6'-chloro-5- (((lR,2R)-2-((S,E)-l-hydroxyhex-2-em-l-yl)cyclobutyl)methyl) -3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxamide] (57 mg, 0.061 mmol, 56% yield) as a thick yellow oil.

STEP 4: (1 S,3'R,6'R,7'S ₅ 8T;12'S)~12 ^! -((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

| 2 ⁽ >X A| i ? I ! f Π Λ| ί i J l i^f AZ.Vf l: E RAC YCE C)l i J 7.2 ϋ ^{; ί'} .ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,12'R)-12'-((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-I-IYDROXY-3, 4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DL ZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8 ₅ 1 -15"-ONE 13', 13'-DIOXIDE

To a 100 ml flask was added I i S)-N-((( )--2 -{{Sort- butyldiphenyisiiy3)oxy)oct-7-en-4-yl)sulfony3)-6'-chioro-5-( ((lR,2R)-2-(( hydroxyhex-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetTahydro -2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide or (S)-N-

(((2R,4R)-2-((tert-butyldiphenylsilyl)ox\ oct-7-en-4-yl)sulfonyl)-6'-chloro-5- (((lR,2R)-2-((S,E)-l-hydroxy iex-2-en-l -yl)cyxlobutyl)methyl)-3',4,4',5- tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine-3,r-naphthalene]-7- carboxamide] (from Step 3) (57 mg, 0.061 mmol) and DCM (40 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda- Grubbs II (3.8 mg, 6.1 μη οΐ) and the mixture was stirred to 45 °C for 6 hours. The reaction mixture was filtered and concentrated. The crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give |i I S.3' R.6' R.7'S. X' I ·.. ! 2'S )- 12 ^" -{ { 2 R )- 2- ((tert-but\'l(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy -3,4-dihydro-2H,15'H- spiro[naphthalene-l,22'- |20jo\aj I |ihi«i| ! J4|dia/aicua > ciol I4.7 .i! ^; " ^{)1'i n} jpen!acosa|K.i6J8.2-sjieirae n]-15'-one 13 ^* ,13'-dioxide or (Ιβ^'Κ,ό'Κ,Τ'β,δΈ,^'Κ^Π'-^^^-ίίίβΛ- but'l(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxj ⁷ -3,4-dihydro-2H,15'H- spiro [naph thalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetrac ^

n]-15'-one 13',13'-dioxide] (10 mg, 0.012 mmol, 20% yield) as the faster eluting olefin isomer as a white solids.

STEP 5: (lS,:rR,6'R,7 ^! S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12 ^! -((2R)-2- HYDROXYlH OPYL)-3,4-Dim )RO-2H,15'H-SPlRO[NAPHraALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1 ^' .13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-2- HYDROXYPROPYL)-3.4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTHALENE-1.22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

To a 100 ml flask was added [(lS^'R^T'S^'E^^SJ-l^-^R^-^tert- buty (diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox\'-3,4-dihydro -2H,15'H- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracyc

n]-15 ^* -one 13',13'-dioxide or (lS^^ffR^'S^^^'R^ '-^RJ^-iitert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2H,15'H- spiro I naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazaietracycio[14,7.2,0-^0 ^l9 - ²⁴ ]pentacosa

n]-15'-one 13',13 ^! -dioxide] (from Step 4) (8.6 mg, 9,9 μτηοΐ) and TBAF (1 M in THF, 2.00 ml, 1.982 mmol). The reaction was stirred at 65 °C for 3.5 hours at which time the reaction was quenched with 50 ml of brine and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate and filtered. The solvent was removed by rotary evaporation, and the crude product was purified on a Combiflash (4 g gold silica column), eiuting with 50% to 90% EtOAc in heptanes + 0.2% AcOH), to give the title compound (2.6 mg, 4.1 μιηοΐ, 42% yield) as an off white solid, R NMR (400MHz, CDCh) δ 7.63 (d, J=8.6 Hz, 2H), 7.14 (dd,J=2.1, 8.5 Hz, ill).7.10 (d, J=2.2 Hz, IH), 7.00 - 6.93 (m, 1H), 6.93 - 6.87 (m, H), 5.76 (dd, ./ 3.8.15.7 Hz, 1H), 5.58 - 5.44 (m, IH), 4.43 - 4,30 (m, 1H), 4.26 - 4,14 (m, 3H), 3,98 - 3.89 (m, 2H), 3.80 - 3,62 (m, IH), 3,44 - 3.28 (m, IH), 3.25 - 3.05 (m, IH), 2.83 - 2.66 (m, 2H), 2.54 - 2.44 (m, 2H), 2.25 (d, J=14.1 Hz, 2H), 2.15 - 2.00 (m,lH), 1.94 - 1.40 (m, 9 H), 1.35 - 1.17 m, 5H). m/z (ESI, +ve ion) 629.0(M+H) ⁺ .

EXAMPLE 540. (lS,3 ^! R,6 ^, R,7'S,8Έ,lΓS,12'R)-6-CHLO O-7'-HYDROXY-12 ^, - ((2R)-2-METHOXYPROPYL)-ll'-MF^iYL-3,4-DIHYDRO-2H,I5'H- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ujOXA| 1 ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' YCi,.()l i 4.7.2,0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]ΤΕΤΡ _^ 4ΕΝ]-15'-ΟΝΕ 13 ^! ,13'-DIOXIDE OR

(lS,3¾,6'R,7^,8E,Il'S,12'S)-6-CHIi3RO-7'-HYDROXY-12'-((2 R)-2- METHOXYPROPYL)-ll'-METHYL-3,4~DiHYDRO-2H,15 ^, H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18 - 15'-ONE 13 13'-DIOXIDE

STEP 1: (2R,4R,5S)-2-METHOXY-5-METHYLOCT-7-ENE-4-SULFONAMIDE OR(2R,4S,5S)-2-METHOXY-5-METHYLOCT-7-ENE"4-SULFONAMlDE

To a 100 ml flask was added (|2R, 4S, 5S)-2-methoxy-N,N-bis(4- methoxybenzyl)-5-methyloct-7-ene-4-sulfonamide and (2R, 4R, 5S)-2-methoxy- N,N-bis(4-methoxybenzyl)-5-methyloct-7-ene-4-sulfonamide] (from Example 529 Step 2) (500 mg, 1.05 mmol), anisole (1.15 ml, 10.5 mmol), DCM (10 ml) and then TFA (4 ml). The reaction was stirred at 22 °C for 8 hours at which time the solvent was removed. The crude was purified on a Combiflash (12 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes) to give [(2R,4R,5S)- 2-methoxy-5-methyloct-7-ene-4-sulfonamide or (2R,4S,5S)-2-methoxy-5- methyloct-7-ene-4-sulfonamide] (127 mg, 0.540 mmol, 52% yield) as the slower eluting isomer, as a light yellow oil.

STEP 2: (S)-6'-CHLORO-5-(((l R,2R)-2-((l S ₅ 5S,6S,8R,E)-l-HYDROXY-8- METHOXY-5-METHYL-6-SULFAMOYLNON-2-EN-1- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO I BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lR,2R)-2-((I S,5S,6R,8R,E)-l -HYDROXY-8- METHOXY-5-METHYL-6-SULFAMOYLNON-2-EN-1 -

YL)CYCLOBUlYL)MEraYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

To a 100 ml flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxyhex-2-en-l-yl)cyclobut5'l)methyl)-3',4,4',5-tetrahydr o-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid (from

Intermediate AA12A) (27 mg, 0.051 mmol), [(2R,4R,5S)-2-methoxy-5-methyloct- 7-ene-4-sulfonamide or (2R,4S,5S)-2-methoxy-5-methyloct-7-ene-4-sulfonaraideJ (from Step 1) (42 mg, 0.18 mmol) and DCE (4 mL). The solution was sparged with argon for 15 minutes at which time Hoveyda-Grubbs 11 (3.2 mg, 5.1 μηιοΐ) was added as a 0.2 mL solution in DCE at room temperature. The mixture was stirred at room temperature for 16 hours. The solvent was removed from the filtrate and was directly purified on a Combiflash (12 gram gold silica column), eiuting with 50% - 90% EtOAc in heptanes + 0.2% AcOH, to give [(S)-6'-chloro- 5-(((lR,2R)-2-((lS,5S,6S,8R,E)-l-hydroxy-8-methoxy-5-me l-6-sulfamoylnon- 2-en-l-yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid or (S)-6'- chloro-5-((( lR,2R)-2-(( 1 S,5S,6R,8R,E)- 1 -hydroxj'-8-methoxy-5-methyl-6- sulfamoylnon-2-en-l-yl)c^ lobuty])methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid] (19 mg, 0.028 mmol, 56% yield) as white solids.

STEP 3: (lS,3 ^! R,6¾,7'S,8¾ll^,12^)~6~Cm

METHOXYPROPYL)-ll ^, -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSJTO At^MlDIAZATET ACYCLOtMJ^.O'^.O^^lPE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irS,12'R)-6-CHLORO-7'-HYDROXY-12 ^, -((2R)-2- METHOXYPROPYL)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|20jO.\,\| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί <Λ( ^' Υ(·|.ΟΙ i 4.7.2. · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj 5'-C)NE 13 ^! ,13 ^* -DIOXIDE

To a 25 ml flask containing [(S)-6'-chloro-5-(((lR,2R)-2- ((lS,5S,6S,8R _^ E)-l-hydroxy-8-memoxy-5-me1hyl-6-sulfamoylnon-2-en-l- yl)cyclobu1yl)methyl)-34,45-tetrahydro-2H,2'H-spiro[benzob][ l,4]oxazepine- 3, ^' l'-naphthalene]-7-carboxylic acid or (S)-6'-chloro-5-(((lR,2R)-2-

((lS,5S,6R,8R,E)-l-hydroxy-8"methoxy-5~methyl-6-sulfamoyl non-2-en~l- y 1 )cy cl ob uiy 1 )meih^

3,l'-naphthalene]-7-carboxylic acid] (from Step 2) (19 mg, 0.088 mmol) was added N,N-dimethylpyridin-4-amine (5.8 mg, 0.048 mmol) and 40 ml of DCM. The reaction mixture was cooled to 0 °C at which time N-(3- dimethylaminopropy])-N'-ethylcarbodiimide hydrochloride (11 rng, 0.056 mmol) was slowly added. The reaction was stirred at room temperature for 18 hour. The mixture was then quenched with 50 ml of IN HCl and extracted with 200 ml of EtOAc. The organic layer were dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude was purified on a Combiflash (4 gram gold silica column), during with 50% - 90% EtOAc in heptanes, to give the title compound (8.0 mg, 0.012 mmol, 43% yield) as a white solid. ¾ NMR

(500MHz, CDCb) δ 8.08 (br. s,, ill).7.70 (d, J=8.6 Hz, IH).7.19 (dd, 2.2.8.6 Hz, 1H), 7.10 (d, ./ 2.2 Hz, IH), 7.01 - 6.97 (m, 1H), 6.95 - 6.84 (m, 2H), 5.89 - 5.79 (m, IH), 5.77 - 5.71 19 (dd,■/ 7.6.15.4 Hz, 1H), 4.23 (dd, ./ 4.4.7.6 Hz, 1 IT), 4.19 (dd, ,/ 3.1.9.4 Hz, IH), 4.10 (s, 2H), 3,83 (d, ,/ ! ^(' ··.! Hz, 2H), 3.69 (d, J=14.4 Hz, IH), 3,39 (s, 3H), 3,25 (d, «7=14.2 Hz, IH), 3.09 - 3.00 (m, IH), 2.86 - 2.68 (m, 2H), 2.45 (ddd, J=5.0, 9.4, 14.7 Hz, 2H), 2.33 (t, J=8.8 Hz, IH), 2.21 - 1.95 (m, 6H), 1.92 - 1.71 (m, 3 H), 1.69 - 1.57 (m, 2H), 1.41 (t, ,/ 12.3 Hz, IH), 1,28 (d, ./ 5.9 Hz, 3H), 1.07 (d, 6.6 Hz, 311). m/z (EST, +ve ion) 657,0 ! YM!)

EXAMPLE 543. (1 S,3'R,6 ^* R,7'S,8'Z,12'S)-6-CHLORO-12'-((2R)-2- HYDROXYPROP YL)-7'-METHOXY-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[N APHTH ALENE- 1.22 ^' -

|2ujOXA| 1ΉΤί!1Α| Μ4|ΠίΑ/.ΥΠ:ΤΗΑ(Ύα.ί)Ι i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [ 8,16,18 ₅ 24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'Z,12'R)-6-CHLORO-12'-((2R.)-2-HYDROXYPROPYL)-7 ^f - METHOXY-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THL [1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13', 13*-DIOXIDE

STEP 1 : (2R,4S)-2-((TERT-BUTYLDIPHENYLSILYL)OXY)OCT-7-ENE-4- SULFONAMIDE OR (2R,4R)-2-((TERT~

BUTYLDIPHEN -7-ENE-4-SULFON AMIDE

To a 100 ml flask was added [(2R,4S)-2-((tert-bu1yldiphenylsilyi)oxy)- N,N-bis(4-methoxybenzyl)oct-7-ene-4-sulfonamide or (2R,4R)-2-((tert- butyldiphenylsilyl)oxy)-N,N-bis(4-me1hoxj ⁷ benzyl)oct-7-ene-4-sulfonamide] (from Example 508 Step 2) (565 mg, 0.824 mmol), anisole (0,90 ml, 8.2 mmol), DCM (4 ml) and then TFA (2 ml). The reaction was stirred at 22 °C for 3 hours at which time the solvent was removed. The crude product was purified on a Comhiflash (24 g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give [(2R,4S)-2-((tert-butyldiphenylsilyl)oxy)oct-7-ene-4- sulfonamide or (2R,4R)~2"((tert-but 4diphenylsiiyl)oxy)oct-7-ene-4-sulfonamide] (90.0 mg, 0.159 mmol, 19% yield) as a light yellow oil

STEP 2: (S)-NH((2R,4R)-2~((TERT-BUTYLDIPHENYLSrLYL)OXY)OCT-7- EN-4-YL)SULFONYL)-6 ^, -CHLORO-5-(((lR ₅ 2R)-2-((S.E)-l-HYDROXYHEX- 2 iN- I ^X)CYCLOBUTYL)METIWL)-3^4,4',5-TETRAHYDRO-2H,2'I-I- SPIRO[BENZO[B][l,4]OXAZEPINE-3, l'-NAPH ^' raALENE]-7- CARBOXAM1DE OR (S)-N-(((2R,4S)-2-((TERT-

BUTYLDIPHENYLSILYL)OXY)()CT-7-EN-4-YL)SULFONYL)-6'-CHLORO - 5-(((lR,2R)-2-((S,E)-l-FfYDROXYHEX-2-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TET AHYD O-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE~3, 1 '-NAPHTHALENE]-7-

To a 100 ml flask was added ( S>~ --chloro-5-({{ ! R .2R)-2-iiS.! ^; .)- i - hydroxyhex^-en-l-y^cyclobuty methy^-S'^^'^-tetrahydro^H^'H- spiro[benzo[b][l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (from

Intermediate AA12A) (150 mg, 0.294 mmol), N,N-dimethylpyridin-4-amine (71.9 mg, 0.588 mmol) and [(2R,4R)-2-((tert-bu1yldiphenylsilyl)oxy)oct-7-ene-4- sulfonamide or (2R,4S)-2-((tert-bu1yldiphenylsilyl)oxy)oct-7-ene-4-sulfonam ide] (from Step I ) (262 mg, 0.588 mmol) and then N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (1 13 mg, 0.588 mmol). The reaction was stirred at room temperature for 16 hours at which time the solvent was removed and the crude product was purified on a Combifiash (12 g gold silica column), eluting with 2% - 10% EtOAc in heptanes + 0.2% AcOH, to give [(S)-N-(((2R,4R)-2- ((tert-butyldiphenylsilyl)oxy)oct-7-en-4-yl)sulfonyl)-6 ^, -chloro-5-(((lR,2R)-2- ((S,E)-l-hydrox 'hex-2-en-l-yl)cydobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H - spiro[benzo[b] [ 1 ,4] oxazepine-3, ! '-naphthalene]-7-carboxamide or (S)-N- (((2R,4S)-2-((tert-bu1\'ldiphenylsilyl)oxy)oct-7-en-4-yl)sul fonyl)-6'-chloro-5- (((1 R,2R)-2-((S,E)- 1 -hydroxyhex-2-en- 1 -yl)cy clobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide carboxamide] (142 mg, 0.151 mmol, 52% yield) as a thick yellow oil. STEP 3: (l S,3'R,6'R,7'S,8'Z,12'R)-12'-((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE AND

(Ιβ^'Κ,ό'Κ,Τ'β,ΒΈ,ηΐ^-Π'-^Κί^-ίΟΓΕΚΤ-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* - pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DK)XIDE] OR

[(l S,3 ^, R,6 ^, R ₅ 7'S,8 ^, Z,12 ^, S)-12 ^, -((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7 ^* -HYDROXY-3 ₅ 4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16, 18 , 24] TETR AEN 1 - 15'-ONE 13", 13 -DIOXTDE AND

(lS,3 ^, R,6 ^, R,7 ^, S _s 8 ^, E _s 12 ^, S)-12 ^, -((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]QXA[13]TffiA[U4]DL^

[ -15'-ONE 13 VI 3'-DIGXlDE]

To a 100 ml flask was added [((S)-N-(((2R,4R)-2-((tert- butykliphenylsilyl)oxy)oct-7-en-4~yl)sulfonyl)-6'-chk o- hydroxyhex^-en-l-y^cyclobuty methy^-S'^^'^-tetrahydro^H^'H- spiro[benzo[b][l,4]oxazepine-3, l'-naphthalene]-7-carboxamide or (S)-N- (((2R,4S)-2-((tert-butyldiphenylsilyl)oxy)oct-7-en-4-yl)sulf onyl)-6'-chloro-5- (((l R,2R)-2-((S )-l½dro^hex-2-en-l-yl)cycl obut l)me^yl)-3 ^, ₅ 4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxamide carboxairiide] (from Step 2) (142 mg, 0.151 mmol% yield) and DCM (100 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda-Grubbs Π (19 mg, 0.030 mmoi) and the mixture was stirred at 45 °C for 6 hours. The reaction mixture was then filtered, concentrated and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give[[(l S,3'R,6'R,7'S,8 ^! Z, 12 ^! R)-12'- ((2R)-2-((tert-bu1yl(diphenyl)silyl)oxy)propyl)-6-chloro-7 ^, -hydroxy-3,4-dihydro- 2h, 15'h-spiro[naphthalene-l ,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ^{! 9} - ²⁴ ]pentacosa[ 8, 16, 18,24]tetrae n]-15'-one 13*, 13 '-dioxide and ί ^" 5 S. VR.t i< . T ^' S.H' i . i 2' P.. )- ; 2'-{ { 2 R )·-.?.--{ { tcrt- but 'l(diphenyl)silyl)oxy)prop} ⁷ l)-6-chloro-7'-hydroxj ⁷ -3,4-dihydro-2h,15'h- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetracyclo[^^

n]-15'-one 13', 13'-dioxide] or [(l S,3'R,6'R,7'S,8'Z, 12'S)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro [naphtha] ene- 1 ,22'- [20]oxa[ 13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16, 18,^ n |-15'-one 13', 13 '-dioxide and (l S,3'R,6'R,7'S,8'E, 12'S)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox>'-3,4 -dihydro-2h,1 5'h- spiro [naphthalene- 1 ,22'-

n]-15'-one 13', 13'-dioxidej j (68.3 mg, 0.079 mmol, 52.0 % yield) as a 9: 1 mixture of E to Z isomers, as a white solids.

STEP 4: (l S,3'R,6'R,7'S,8'Z, 12'S)-12'-((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'- METHOXY -3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s -

[20]OXA[13]THL\[1 ,14]DL ZATETRACYCLO[ 14.7.2.0^^0 ¹⁹ - ²⁴ ]I TACOSA [8 ₅ 16,18,24]TETRAEN]-15"-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R7^,8'ZJ.2'R)~12 ^! -((2R)-2-((TERT-

BUTYL(DlPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'- METHOXY -3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8 -15'-ONE 13 ',13 '-DIOXIDE

To a 100 ml flask was added [[(lS^'R-e'I^T'S^'Z^^RJ-n'-^^^-iitert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox'-3,4-dih ydro-2h,15'h- spiro [naphthalene- 1 ,22'- IKJ4jtctrao n]-15'-one 13',13'-dioxide and (lS,3'R,6'R,7'S,8'E,12'R)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro[naphthalene-l,22'- [2Q]oxa[13]thia[l,14]diazate^

n]-15'-one 13\13'-dioxide] or [(Ιβ^'Κ,όΊ ,Τβ,δ'Ζ,Ιϊβ^ΙΪ-^Κ^-ίίΙβιΐ- buty (diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox\'-3,4-dihydro -2h,15'h- spiro [naphthalene- 1 ,22'- [20joxa[13[thia[l,14[diazatetracycfo[½

n]~1.5'~one 13',13'-dioxide and (Ιβ^'Κ,ό'Κ,Τ'β,δΈ,Ιϊβ^Ι^-^Κ^-ίίΙεϊΐ- but'l(diphenyl)silyl)oxy propy )-6-cUoro-7'-hydroxy-3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- [2Q]oxa[13]thia[l,14]diaza ^^

n]-15'-one !3',13 ^! -dioxide]] (from Step 3) (50 mg, 0.058 mmol), THF (3 mL) and NaH (14 mg, 0.58 mmol). The reaction was stirred at room temperature for 15 minutes at which time Mel (0.018 ml, 0.29 mmol) was added. The reaction was stirred at room temperature for 3 hours and then the reaction was quenched with 100 ml of saturated ammonium chloride and extracted with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude was purified on a Combiflash (12 gram gold silica column), eluting with 10% to 50%» EtOAc in heptanes, to give

[(1 S,3'R,6' ,7'S,8'Z, 12'S)-I 2 ^, -((2R)-2-((tert-butyl(diphen l)silyl)oxy)propyl)-6- chloro-7'- methoxy -3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]tMa[l,14]diazatetrac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'-di oxide or (18,3Έ,6¾,7'8,8'Ζ, 12¾)-12'-((2 )-2-( 6Π- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'- methoxy -3,4-dihydro-2H,15'H- spiro [naphthalene- 1,22'-

[20joxa[13]thia[ l, 14]diazatetracy ^

n]-15'-one 13',13'-dioxide] (6.0 mg, 6,81 μηιοΐ, 12 % yield) as the slower eluting olefin isomer as a light yellow oil. STEP 5: (l S,3'R,6'R,7'S,8 ^! Z,12'S)-6~CHLORO-12 ^! ~((2R)-2-

HYDROXYPROPYL)-7'-METHOXY-3,4~DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[ 14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAE ]-15'-QNE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^! R,7'S,8'Z, 12'R)-6-CHLORO-12 ^! -((2R)-2-HYDROXYPROPYL)-7'- METHOXY-3,4-DIHYDRO-2H, 15 Ή- SPTRO [N ΑΡΗΤΉ ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE To a 100 ml flask was added [(1 S,3'R,6'R,7'S,8'Z, 12'S)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'- methoxy -3,4-dihydro-2H,15'H- spiro[naphthalene-l,22'-

[20]oxa[13]thia[ l, 14]diazatetracyclo[14.7.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 3',13'-dioxide or (l S,3'R,6'R,7'S,8'Z, 12'R)-12'-((2R)-2-((tert- but 'l(diphenyl)silyl)oxy)propyl)-6-chloro-7'- methoxy -3,4-dihydro-2H,15'H- spiro I naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazate1ra^

n]-15'-one 13',13'~dioxide] (6.0 nig, 6,9 μιηοί) and TBAF 1 M in THF (0.86 ml, 0.86 mmol). The reaction was stirred at room temperature for 16 hours at which time the reaction was quenched with 50 ml of brine and extracted with 200 ml of EtOAc, The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation and the crude was purified on a Combiflash (4 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give the title compound (2,9 rng, 4.5 μηιοΐ, 65% yield) as an off white solid. ^] H NMR (400MHz, CDCh) δ 8.92 (br. s„ ill).7,69 (d, ./ 8.6 Hz, 1H), 7.25 - 7.14 ira 2H), 7.09 (d, J=1.8 Hz, 1H), 7.02 - 6.92 (m, 2H), 5.78 - 5.63 (m, 1H), 5.39 (dd, J=8.0, 10.6 Hz, 1H), 4.18 - 4.06 (m, 3H), 4.02 - 3.93 (m, 2H), 3.83 - 3.61 (m, 2H), 3.35 (s, 3H), 3.32 - 3.23 (m, 2H), 2.86 - 2.71 (m, 2H), 2.58 - 2.35 (m, 4H), 2.33 - 2.20 (m, ill).2.09 - 1.98 (m, 3H), 1,97 - 1.79 (m, 6H), 1.77 - 1.67 (m, ill).1,51- 1.43 (m 111).1.34 (d, ./ 6.1 Hz, 311). m/z (ESI, +ve ion) 643.0 (M+H) ⁺ .

EXAMPLE 544. (lS,3 ^, R,6'R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)- 2-HYDROXYPROPYL)-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-

122'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-7'-HYDROXY-12'-((2R)- 2- HYDROXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTO ALENE-1 , 22'- |2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |Ρ!·Λ i ACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE i.T.l 3'-D10XlDE

STEP 1: [(lS,3'R,6'R,7'S,8'Z,12'R)-12'-((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DTHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 ^

[8, 16, 18,24]TETRAEN]-15'-ONE 13 I 3'-DIQXlDE AND

(lS,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E.12 ^, R)-12 ^, -((2R)-2-((TERT- BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-I-IYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE] OR

[(]S,3'R,6'R,7'S,8'Z,12 ^! S)-12'-((2R)-2-((TERT- BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή -S PIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSJTO Atl ^DIAZATETRACYCLOtMJ^ ^^O^^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND

(lS,3'R,6'R,7'S,8'E,12'S)-12'-((2R)-2-((TERT- BUTYL(DIPIlENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i.()l i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [ -15'-ONE 13', 13 ^* -DIOXIDE j

To a 100 ml flask was added i((S}-\-iii2R,IR)-2-iiieri- butyldiphenylsilyl)oxy)oct-7-en-^

hydrox'hex-2-en-l-y])c clobutyl)methy])-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxarnide or (S)-N- (((2R,4S)-2-((tert-butyldiphenylsilyl)oxy)oct-7-en-4-yl)sulf onyl)-6'-chloro-5- (((lR,2R)-2-((S,E)-l-hydroxyhex-2-em-l-yl)cyclobutyl)methyl) -3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide carboxamide] (from Example 543 Step 2) (64 mg, 0.069 mmol) and DCM (50 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda-Grubbs 11 (4.3 mg, 6.9 μπιοΐ) and the mixture was stirred to 45 °C for 6 hours. The reaction mixture was then filtered, concentrated and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give

[ [(l S,3'R,6'R,7'S,8'Z, 12'R)-12'-((2R)-2-((tei^^

chloro-7'-hydroxy-3,4-dihydro-2h, 15'h-spiro[naphthalene-.l ,22'- [20]oxa[13]thia[l, 14]diazatetra<^

nj-15'-one 13 ',13 '-dioxide and (l S,3'R,6'R,7'S,8'E,12'R)-12'-((2R)-2-((tert- butyl(diphenyl)silyi)oxy)propy

spiro [naphthalene- 1 ,22'-

n]-15'-one 13 ', 13 '-dioxide | or |;(l S,3'R,6'R,7'S,8'Z,12'S)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro[naphthalene-l,22'-

[20]oxa[13]tMa[l,14]cliazatetracy'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one ! 3', ! 3'-dioxide and (l S,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^* E ₅ 12 ^, S)-12 ^, -((2R)-2-((tert- buty (diphenyl)silyl)oxy)propyl)-6-chloro-7'-hy(kox\'-3,4-dihydro -2h,15'h- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetra^

n]-15'-one 13', 13'-dioxide]] (33 mg, 0.054 mmol, 38% yield) as a 3: 1 mixture of E to Z isomers, as a white solids.

STEP 2: ( lS,3 ^f R,6'R,7'S,8'E,i2'S)-6-CHLORO-7'-HYDROXY-l 2'-((2R)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-i ,22'- [20]OXA[13]THL\[1,14]DL\ZATETRACYCLO[14.7.2.0 ³ ^^0 ¹⁹ - ²⁴ ]PENTACOSA [8 ₅ 16, 18,24]TETRAEN]-15"-ONE 13', 13'-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7'-HYDROXY-12 ^, -((2R)-2-

HYDROXYPROPYL)-3,4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTHALENE-l ₅ 22'-

[2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J 6,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE

To a 100 ml flask was added [[(l S ₅ 3 ^, R,6 ^, R,7 ^, S,8 ^, Z,12 ^, R)-12 ^, -((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox '-3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- Hjaj teirae n]-15'-one 13', 13'-dioxide and (l S,3'R,6'R,7'S,8'E, 12'R)-12'-((2R)-2-((ten- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro [naphthalene- 1 ,22'-

n]-15'-one 13\13'-dioxide] or [(l S.S'R^'R.TS^^ l ^S^l ^-^R^-iitert- buty (diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox\'-3,4-dihydro -2h,15'h- spiro [naphthalene- 1 ,22'-

[20ioxa[13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ^3>6 .0 ^{! 9} ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-15 ^* -one 13 ', 13 '-dioxide and (l S,3'R,6'R,7'S,8'E, I 2'S)-12'-((2R)-2-((tert- but 'l(diphenyl)silyl)oxy propy )-6-cUoro-7'-hy(koxy-3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetracycio[14,7.2,0 -^0 ^l9 - ²⁴ ]pentacosa[

n]-15'-one 13',13'-dioxide]] (from Step 1) (20 mg, 0.023 mniol), and TBAF 1 M in

THF (2.1 ml, 2.1 mniol). The reaction was stirred at room temperature for 5 hours (No reaction observed by LCMS) at which time 1 ml of AcOH was added and the reaction was stirred at room temperature for an additional 16 hours (no reaction observed). The temperature of the reaction was then raised to 60 °C and the reaction was stirred for an additional 6 hours at which time the reaction was quenched with 50 ml of brine and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude product was purified on a Combiflash (4 g gold silica column), eluting with 50% to 90% EtOAc in heptanes + 0.2 % AcOH) to give the title compound (2.2 mg, 3.5 μηιοΐ, 15% yield) as an off white solid. ³ H NMR (400MHz, CDCb) 67.70 (d, ./ 8.4 Hz, 1H), 7.18 (dd, ./ 2.2.8.5 Hz, 1H), 7.09 (d, ./ 2.2 Hz, ill).6.99 - 6.87 (m, 3H), 5.96 - 5.80 (m, III).5.72 (dd, ./ 7.4.15.3 Hz, ill).4,36 - 4.22 (m, 2H), 4.18 - 4.02 (m, 3H), 3,70 (d, ,/ 14.1 Hz, 2H), 3.23 (d, ,/ 1 -I 3 Hz, I Hi.3.09 - 2.92 (m, ill). 2.82 - 2.69 (m, 2H), 2,49 - 2.19 (m, 111). 2.08 - 1.53 (m, 8 H), 1.46 - 1.37 (m, 1H), 1.34 (d, ./ 6.3 Hz, 3H). z (ESI, +ve ion) 629.0 (M+H) ⁺ .

EXAMPLE 546. (1 S,3'R,6 ^, R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12 ^! -((2S)- 2-HYDROXYPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- l. -

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8 ₅ 16,18,24]TETRAEN]-15"-ONE 13',13*-DK)XIDE OR

(lS,3'R,6 ^! R,7'S,8'E,12 ^! R)~6-CHLORO-7 ^! ~HYDROXY-12'-((2S)-2- HYDROXYPROPYL)"3,4-DIHYDRO-2H,15'H~SPIRO[NAl ⁵ HTHALENE-l,22 ^! ~ [20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.() ^3>, 0 ^!9 - ²⁴ ]PENTACOSA

[8, 16, 18 -15'-ONE 13", 13-DIOXIDE

STEP 1 : (2S,4S)-2-HYDROXY-N,N-BIS(4-METHOXYBENZYL)OCT- 4~S ULFO AMIDE AND (2S,4R)-2-HYDROXY-N,N-BIS(4- METHOXY -7-ENE-4-SULFONAMIDE

To a -78 °C solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l- sulfonamide (from Intermediate EE 19) (4.00 g, 10.3 mmol) in THF (40 mL) under argon was added n-butyllithium (2.5 M solution in liexane, 4.93 mL, 12.3 mmol) over 5 minutes. The mixture was stirred at -78 °C for 2 hours (solution toned red-pink) at which time (S)-(+)-l ,2-epoxypropane (Sigma-Aldtich, Milwaukee, Wi) (1 ,079 mL, 15.4 mmol) was added and stirred at 0 °C for 16 hours. The reaction was then quenched with 100 ml of saturated ammonium chloride and extracted with 300 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified on a Conibiflash (80g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give (2S,4S)-2-hydroxy-n,n-bis(4-methoxybenzyl)oct-7- ene-4-sulfonamide and (2S,4R)-2-hydroxy-n,n-bis(4-methoxybenzyl)oct-7-ene-4- sulfonamide] (3.88 g, 8.67 mmol, 84% yield) as a light yellow oil. STEP 2: (2S,4R)-2-((TERT-BUTYLDIPHENYLSn..YL)OXY)-N,N-BIS(4-

METHOXYBENZYL)OCT-7-ENE-4-SULFONAMIDE OR (2S,4S)-2-((TERT- BUTYLDIPHENYLSILYL)OXY)-N,N-BIS(4-METHOXYBENZYL)OCT-7- ENE-4-

To a 100 ml flask was added [(2S,4S)-2-hydroxy-n,n-bis(4- methoxybenzyl)oct~7-ene~4-sulfonaniide and (2S,4R)-2-hydroxy-n,n-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide] (from Step 1) (3.88 g, 8.67 mmol), DMF (60 ml), imidazole (1.18 g, 17.3 mmol) and tert-butylchlorodiphenylsilane (3.38 ml, 13.0 mmol). The reaction was stirred at 65 °C for 16 hours at which time reaction was then quenched with 200 ml of saturated ammonium chloride and extracted with 600 ml of diethyl ether. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was first purified on a Combiflash (80 g gold silica column), eluting with 10% to 30% EtOAc in heptanes. The racimic mixture (1 : 1) was then purified by preparatory SCF chromatography (ChiralPak AD 250mm x 30mm column, Phenomenex, Torrance, CA; 16g/minute EtOH + (20mM Ammonia) + 64g/minute CO2 (20% co-solvent) on Thar 80 SFC; outlet pressure = 1 00 bar; temperature = 22 °C: wavelength = 220 nm; used 1.0 mL injections of 3647mg/41mL (89 mg/mL) sample solution of MeOH (35mL) and DCM (5mL); run time = ^: 13 minutes & cycle time 10 minutes.) to provide [(2S,4R)-2-((tert- butyldiphenylsilyl)oxy)-N,N-bis(4-methoxybenz3'1)oct-7-ene-4 -sulfonamide or (2S,4S)-2-((tert-bu1yldiphenylsilyl)oxy)-N,N-bis(4-methoxybe nz\'l)oct-7-ene-4- sulfonamide] (2.10 g, 3.06 mmol, 44% yield) as the faster eluting isomer as a yellow liquid.

STEP 3 : (2S,4R)-2-((TERT-BUTYLDIPHE YLSILYL)OXY)OCT-7-ENE-4- SULFONAMIDE OR (2S,4S)-2-((TERT-BUTYLDIPI¾E YLSILYL)OXY)OCT- 7-ENE-4-SULFO

To a 100 ml flask was added [(2S,4R)-2-((tert-buryldiphenylsilyl)oxy)- N,N-bis(4-memoxybenzyl)oct-7-ene-4-sulfonamide or (2S,4S)-2-((tert- but cUphenylsil}d)ox -N,N-bis(4-methoxybenzyl)oct-7-ene-4-sulfonamide]

(from Step 2) (450 mg, 0.656 mmol), anisole (0.717 ml, 6.56 mmol), DCM (20 ml) and then TFA (5 ml). The reaction was stirred at 22 °C for 3 hours at which time the solvent was removed. The crude product was purified on a Combiflash (24g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give [(2S,4R)-2-((tert-butyldiphenylsiiyl)oxy)oct-7-ene-4-sulfona mide or (2S,4S)-2- ((tert-buryldiphenylsilyl)oxy)oct-7-ene-4-sulfonamide] (150 mg, 0.337 mmol, 51% yield) as a light yellow oil. STEP 4: (S)-N-(((2S,4R)-2-((TERT-BUTYLDIPHENYLSiLYL)OXY)OCT-7- EN-4-YL)SULFONYL)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXYHE X- 2-EN-l-YL)CYCLOBUTYL)METHYL)-3 ^, _s 4,4 ^, ,5-TETRAHYDRO-2H,2H- SPIR()[BENZO Bj[ l,4]()XAZEPINE-3,r-NAPHTHALENEl-7- CARBOXAMTDE OR (S)-N-(((2S,4S)-2-((TERT-

BUTYLDIPHENYLSrLYL)OXY)OCT-7-EN-4-YL)SULFONYL)-6'-CHLORO- 5-(((l R,2R)-2-((S,E)- 1 -HYDROXYHEX-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7-

To a 100 ml flask was added (S)-6 ^* -ch]oro-5-(((lR ₅ 2R)-2-((S,E)-l- hydrox 'hex-2-en-l -yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (from

Intermediate AA12A) (85 mg, 0.17 mmol), N,N-dimethylpyridin-4-amine (41 mg, 0.33 mmol) and [(2S,4R)-2-((tert-bu1yddiphenylsily])oxy)oct-7-ene-4-sulfona mide or (2S,4S)-2-((tert-butyldiphenylsilyl)oxy)oct-7-ene-4-suifonar nide] (from Step 3) (149 mg, 0.333 mmol) and then N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol). The reaction was stirred at room temperature for 16 hours at which time the solvent was removed and the crude product was purified on a Combiflash (12g gold silica column), eluting with 2% - 10% EtOAc in heptanes + 0.2% AcOH, to give [(S)-N-(((2S,4R)-2-((tert- butyldiphenylsilyl)oxy)oct-7-en-4-yl)sulfonyl)-6'-chloro-5-( ((lR,2R)-2-((S,E)-l- hy droxyhex-2-en- 1 -y l)cy clobut>'l)methy l)-3 ', ,4',5 -tetrahy dro-2H,2 ^! H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-N- (((2S,4S)-2-((tert-butyldiphenylsilyl)oxy)oct-7-en-4-yl)sulf onyl)-6'-chloro-5- (((l R,2R)-2-((S )-l½dro^hex-2-en-l-yl)cyclobut l)me^yl)-3 ^, ₅ 4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] ~7~ carboxamide] (100 mg, 0.107 mmol, 64% yield) as a thick yellow oil. Step 5; ( 1 S,3'R,6'R,7'S,8'E, 12'R)-12'-((2S)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3 ₅ 4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE] OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-12 ^, -((2S)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* - pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8 ₅ -15'-ONE 13',13'-DIOXIDE

To a 100 ml flask was added [(S)-N-(((2S,4R)-2-((tert- buiyldiphenyIsiiyl)oxy)oct-7-en-4-yl)si:ilfonyl)-6'-chloi -5-(((l R,2R)-2-((S,E)-l- hydrox 'hex-2-en-l -y])c dobutyl)methy])-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide or (S)-N- (((2S,4S)-2-((tert-butyldiphenylsilyl)ox ')oct-7-en-4-yl)sulfonyl)-6'-chloro-5- (((l R,2R)-2-((S,E)-l-hydroxyhex-2-en-l-y3)cyclobuiyl)methyi)-3', 4,4',5- tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,l '-naphthalene]-7- carboxamide] (from Step 4) (100 mg, 0.107 mmol) and DCM (40 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda-Grubbs II (13 mg, 0.021 mmol) and the mixture was stirred to 45 °C for 6 hours. The reaction mixture was then filtered, concentrated and the crude product was purified on a Combiflash (12 g gold silica column), eiuting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give [(l S,3'R,0 ^f R,7'S,8'E,12'R)~12 ^f -

((2S)-2-((tert-butyl(diphenyl^

2h, 15'h-spirofnaphthaleiie-l ,22'-

[20joxa[13]thia[ l, 14]diazatetracyc

n]-15 ^* -one 13', 13'-dioxide or (1 S,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, S)-12 ^, -((2S)-2-((tert- but 'l(diphenyl)silyl)ox propyl)-6-cUoro-7'-hydroxy-3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l ,14]<Iiazatetr^

nj-15'-one 13',13'-dioxide (29 mg, 0.034 mmol, 32% yield) as the faster eluting olefin isomer, as a white solids.

STEP 6: (1 S,3'R,6'R,7'S,8'E, 12 ^, S)-6-CHLORO-7'-HYDROXY-12'-((2S)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H ₅ 15Ή-SPIRO[NAPH^ΉALENE-l,22 ^, -

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAENl-15'-ONE 13', 13'-DTOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,12 ^! R)~6-CHLORO-7 ^! ~HYDROXY-12'-((2S)-2- HYDROXYPROPYL)"3,4-DIHYDRO-2H,15'H~SPIRO[NAl ⁵ HTHALENE-l,22 ^! ~ [20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN]~15'-ONE 13", 13 -DIOXIDE

To a 100 ml flask was added | (l S,3'R,6'R,7'S,8'E,12'R)-12 ^! -((2S)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox '-3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- I SJJj tctrao n]-15'-one 13 ', 13 '-dioxide] or (1 S,3'R,6'R,7'S,8'E,12'S)-12'-((2S)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro[naphthalene-l,22'-

[20]oxa[13]tiua[l,14]cUazatelTac lo[14;7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one ! 3',13'-dioxide] (from Step 5) (13 mg, 0.015 mmol) and TBAF (1 M in THF, 3.04 ml, 3.04 mmol). The reaction was stirred at 65 °C for 3.5 hours at which time the reaction was quenched with 50 ml of brine and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude product was purified on a Combiflash (4 g gold silica column), eluting with 50% to 90% EtOAc in heptanes) to give the title compound (6.0 mg, 9.5 μηιοΐ, 63% yield) as an off white solid, ^" Ή NMR (400MHz, CDCh) δ 8.45 (s, 1 H), 7.70 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.2, 8.5 Hz, 1H), 7.09 (d, J=2.2 Hz, lH), 6.95 - 6.88 (m, 3H), 5.96 - 5.85 (m, ill}.5.72 (dd, ./ 7.3.15.2 Hz, 111).4.37 (ddd, ,/ 2.4.6.1, 10.5 Hz, 2H), 4.24 (dd, ,/ 39.7.4 Hz, ill).4, 12 - 4.02 (m, 2H), 3.81 (d, ,/ 1 7 Hz, 1H), 3.71 (d, .7=14.3 Hz, 1H), 3,24 (d, J=14.3 Hz, ill).3,02 (dd, J=9A, 15,3 Hz, III).2.85 - 2.65 (m, 3H), 2.51 - 2.16 (m, 6H), 2.07 - 1.72 (m, 6 H), 1.71 - 1.59 (m, 2H), 1.40 (t, ./ 1 .9 Hz, 1H), 1.26 (d, ./ 6.! Hz, 3H). m/z (ESI, +ve ion) 628,9 (M+H) ⁺ .

EXAMPLE 547. (lS,3'R,6 ^! R,7 ^, S,8 ^, Z,12 ^, S)-6-CHLORO-7'-HYDROXY-12'-((2S)- 2-HYDROXYPROPYL)-3,4-DIHYDRO-2H,15 ^, H-SPIRO[NAPHTHALENE- 1,22'-

|2 ⁽ !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ iACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-DIQXiDE OR

(lS,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, Z.12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2S)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTOALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

[8,16.1 -15'-ONE 13',13'-DIOXIDE

STEP 1: (lS,:rR,6'R,7'S,8'Z,12'R)-12'-((2S)-2-((TERT- BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3 ₅ 4- DIHYDRO-2H, 15H-SPIRO[NAPHTHALENE-l ,22'-

|2 ⁽ !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί RAC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE i.T.i 3'-DIOXlDE] OR (l S,3 ^* R,6 ^, R ₅ 7 ^, S,8 ^, Z,12 ^, S)-12 ^, -((2S)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7 ^* -HYDROXY-3 ₅ 4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA

- 15'-ONE 13", 13 -DIOXIDE]

To a 100 ml flask was added [(S)-N-(((2S,4R)-2-((tert- butyldiphenylsilyl)ox oct-7-en-4-yl)sulfonyl)-6'-chloro-5-(((l R,2R)-2-((S,E)-l- hydrox\'hex-2-en-l-yl)c lobu1yl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro benzo b] l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-N-

(((2S,4S)-2-((tert-butyldiphenylsilyl)oxy)oct-7-en-4-yl)s ulfonyl)-6'-chloro-5- (((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l-yl)cyclobutyl)methyl) -3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxamide] (from Example 546, Step 4) (100 mg, 0. 107 mmol) and DCM (40 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda-Grubbs II (13 mg, 0.021 mmol) and the mixture was stirred to 45 °C for 6 hours. The reaction mixture was then filtered, concentrated and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give

[(l S,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, Z 2 ^, R)-12 ^, -((2S)-2-((tert-butyl(diphOTyl)silyl)oxy)propyl)-6- chloro-7'-hydroxy-3,4-dihydro-2h,15'h-spiro[naphthalene-l ,22'- [20]oxa[13]thia[i,14;|diazatetracyclo[14.7.2.0 ³ - ^f \0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae nj-15'-one 13',13'-dioxide] or (l S,3 ^, R,6 ^, R,7 ^, S.8 ^, Z ₅ 12 ^, S)-12 ^, -((2S)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox>'-3,4 -dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- [20joxaj 13]thia[ l, 14]diazateto^^ n]-15'-one 13',13'-dioxide] (29 mg, 0.034 mmol, 32% yield) as the slower eluting olefin isomer, as a white solids.

STEP 2: (l S ₅ 3 ^, R,6 ^, R,7'S,8 ^, Z,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2S)-2- IiYDR0XYPR0PYL) ,4-DIHYDR0-2H ₅ 15Ή-SPIR0[NAPHTHALENE-l,22 ^, - pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S,3'R,6'R,7'S,8'Z,!2 ⁱ R)-6-CHLORO-7 ⁱ -HYDROXY-12'-((2S)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'- | 2u jOXA| O ΙΊ ί Ι1Λ| I„ I 4 |Di A/.Yi ^' ! R AC YO.OI i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |Pl-N i ^' AC<)SA [ 8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

To a 100 ml flask was added [(l S,3'R,6 ^, R,7 ^, S ₅ 8 ^, Z ₅ 12 ^, R)-12 ^, -((2S)-2-((tert- but 'l(diphenyl)silyl)ox propyl)-6-chloro-7 ^, -hydroxy-3,4-dihydro-2h,15'h- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetracyclo[14.7.2.0 ³ ^

n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6'R,7 ^! S,8 ^, Z,12 ^, S)-12'-((2S)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l, 14]diazatetra<^

n]-15'-one 13',13'-dioxidej (from Step 1 ) (14 mg, 0.016 mmol) and TBAF (1 M in THF, 2.02 ml, 2.02 mmol). The reaction was stirred at 65 °C for 3 hours at which time the reaction was quenched with 50 ml of brine and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation and the crude product was purified on a

Combiflash (4 g gold silica column), eluting with 50% to 90% EtOAc in heptanes, to give the title compound [(l S,3'R,6'R,7'S,8'Z,12'S)-6-chloro-7'-hydroxy-12'- ((2S)-2-hydroxypropy3)-3,4-dihydro-2H,15'H (6.1 mg, 9.7 μιηοΐ, 60% yield) as an off white solid. 'H NMR (400MHz, CDCb) δ 9.94 (br, s., 1H), 7.68 (d, ./ 8.6 Hz, 1H), 7.32 (dd, .7=1.8, 8.2 Hz, IH), 7.18 (d, J=2.3 Hz, 1H), 7.13 - 7.05 (m, 2H),

6.94 (d, J=8.2 Hz, IH), 5.69 - 5.59 (m, 1H), 5.50 (dd, J=5.7, 11.2 Hz, IH), 4.48 (t, ./ 5.6 Hz, 1H), 4,41 - 4.29 (m, 1H), 4.13 - 4.02 (m, 2H), 4,00 - 3.90 (m, 1H), 3.68 (d, .7=15.1 Hz, 1H), 3,60 id. 14.1 Hz, ill).3,25 - 3.5 (m, 2H), 2.84 - 2.73 (m, 2H), 2.73 ·· 2.61 (m, ill).2.50 - 2.33 (m, 3H), 2.33 - 2.21 (m, III).2.21 - 2.12 (m, HI).2.06 - 1.77 {in.5H), 1.76 - 1.61 ins.4H), 1.48 (t, ./ I 1.5 Hz, ill).1.28 (d, ,/ 63 Hz, 3H). m/z (EST, +ve ion) 629.0 (M+H) ⁺ .

EXAMPLE 548. (1 S ₅ 3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-12 ^, -((2R)-2- HYDROXYPROP YL)-7'-METHOXY-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE- 1 ,22 ^! ~

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/Λ Π:ΤΗΛ(Ύα.ί)Ι i 4.7.2.0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,I2'R)-6-CHLORO-12'-((2R.)-2-HYDROXYPROPYL)-7 ^f - METHOXY-3,4-DIHYDRO-2H,15'H~SPIRO[NAPHTHALENE-l,22 ^! ~

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8 -15'-ONE 13',13'-DIOXIDE

Step 1 : (1 S,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, S)-12 ^, -((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'- METHOXY -3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 -DIOXIDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E _: ,12 ^, R)-12 ^, -((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'- METHOXY -3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ⁽ r- ^, \o ^l ' ^, -- ^,, |PHNT.\( S.A

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE

To a 100 ml flask was added [[(l S^'R.e'R.T'S^'Z ^R)-^'-^)^-^.!- but (diphenyl)silyl)oxy)prop}d)-6-chloro-7'-hydroxj ⁷ -3,4-dihydro-2h,15'h- spiro [naph thalene- 1 ,22'- 8.24i !eirac n]-15'-one 13', 13'-dioxide and (l S,3 ^, R.6'R,7 ^, S.8 ^, E.12 ^, R)-12 ^, -((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazateti^

n]-15'-one 13',13'-dioxidej or [(l S,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, Z.12 ^, S)-12 ^, -((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy'-3,4-di hydro-2h,15'h- spiro [naphthalene- 1 ,22'-

[20]oxa[13]tMa[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[ 8,16,18,24]tetrae n]-15 ^* -one 13 ', 13 '-dioxide and (l S,3'R,6'R,7 ^f S,8'E, I 2'S)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro [naphthalene- 1 ,22'- [20]oxa[ 13]mia[U4]cUazatetracyclo[14^

n]-15'-one 13',13'-dioxide]] (from Example 543, Step 3) (50 mg, 0.058 mmol), THF (3 mL) and NaH (14 mg, 0.58 mmol). The reaction was stirred at room temperature for 15 minutes at which time Mel (0.018 ml, 0.29 mmol) was added. The reaction was stirred at room temperature for 3 hours and then the reaction was quenched with 100 ml of saturated ammonium chloride and extracted with 400 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude was purified on a Combiflash (12 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give [(1 S,3'R,6'R,7'S,8'E, 12 ^* S)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'- methoxy -3,4-dihy dro-2H, 15Ή- spiro [naphtha] ene- 1 ,22'- [20] oxa i 3] ihi a[ I/I 4] ds

n]-15'-one 13 ^* ,13'-dioxide or (lS rR,6 ^, RJ^,8¾12'R)-12'-((2R)-2~((tert- bu1yl(diphenyl)silyl)oxy)propyl)-6-chloro-7'- methoxy -3,4-dihy dro-2H, 15Ή- spiro[naphthalene-l,22'- |20jo\aj I |ihi«i| i J4|dia/aicuac> ciol I4.7 .i! ^; " ^{)1'i n} jpen!acosa|H.i< 8.24jieirae n]-15'-one 13',13'-dioxide] (35 nig, 0.040 mmol, 70% yield) as the faster eluting olefin isomer as a light yellow oil.

STEP 2: (lS ₅ 3 ^! R,6'R,7'S,8'E,12'S)-6-CHLORO-12 ^, -((2R)-2- H YDRQX YPRQP YL)-7'-METHQXY-3 ,4-DIHYDRQ-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSJTO Atl ^DIAZATETRACYCLOtMJ^ '^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHL()R()-12'-((2R)-2-HYDROXYP ROPYL)-7'- METHOXY ^-DIHYORO^H SH-SPIROINAPHTHALENE-l^ ^* -

|2( !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN j-15'-QNE 13 VI 3'-D10XlDE

To a 100 ml flask was added [( iS,3 ^f R,6'R,7'S,8'E,12'S)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'- methoxy -3,4-dihy dro-2H, 15Ή- spiro [naphthalene- 1,22'-

[20]oxa[13]thia[l,14]diazatetracycio[14,7.2,0-V0 ^l9 - ²⁴ ]penta∞

n]-15'-one 13 ^* ,13'-dioxide or (lS,:rR,6 ^, R,7 ^! S,8T;i2'R)-12'-((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'- methoxy -3,4-dihy dro-2H, 15Ή- spiro[naphthalene-l,22'-

[20]oxa[13]mia[l,14]diazatetTacyclo[14.7.2.0 ³ ^0 ^]9 ' ²⁴ ]pentacosa[8,16,18,24]tetra^ n]-15'-one 13',13'-dioxide] (from Step 1) (38 mg, 0,044 mmol) and TBAF (1 M in THF, 3.27 ml, 3.27 μηιοΐ). The reaction was stirred at room temperature for 3 hours (No reaction observed by LCMS) at which time 0.2 ml of AcOH was added and the reaction was stirred at 65 °C for an additional 20 hours and then was quenched with 50 ml of brine and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sidfaie, filtered, the solvent was removed by rotary evaporation and the crude was purified on a Combifiash (12 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give the title compound (20 mg, 0.030 mmol, 70% yield) as an off white solid. ^! H NMR (400MHz, CDCb) δ 8.25 (s, IH), 7.70 (d, ,/ H4 Hz, 1H), 7.18 (dd, ,/ 2.2.8.5 Hz, IH), 7,09 (d, J=2.2 Hz, IH), 6.98 - 6.86 (m, 2H), 6.83 (s, ill).5.93 - 5.74 (m, IH), 5.55 (dd, ./ 8.8.15.3 Hz, IH), 4.40 - 4.28 (m, IH), 4.21 -4.11 (m, IH), 4.12 - 3.98 (m, 2H), 3.80 (d, ,/ 14 Hz, IH), 3.74 - 3.59 (m, 2H), 3.24 (s, Ml).3.23 - 3.16 (m, IH), 2.99 (dd, ,/ 102.15.3 Hz, H), 2.84 - 2,65 (m, 2H), 2.52 - 2.42 (m, H), 2.41 - 2.24 (m, 4H), 2.05 - 1.74 (m, 7H), 1.71 - 1.54 (m, 3H), 1.46 - 1.37 (m, IH), 1.34 (d,■/ 6.! Hz, 3H). m (ESI, +ve ion) 643.0 (M+H) ⁺ .

EXAMPLE 549. (lS,31 ,6'R,7 ^! S,8'E,12'S)-6-CHLORO-7 ^! "METHOXY-12'-((2R)- 2-METHOXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]TETRAE ]-15'-QNE 13',13'-D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,12'R)-6-CHLORO-7 ^! -METHOXY-12'-((2R)-2- METOOXYPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTOALENE-l,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA [8,16.18 '-ONE 13',13'-DIOXIDE

To a 100 ml flask was added [(lS,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-chloro-12 ^, -((2R)-

2-hydroxypropy3)-7'-methoxy-3,4-dihydro-2h,15'h-spiro| naphtha! ene-1,22'-

[20]oxa[13]thia|;i,14]diazatetracycio[!4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pen

n]-15'-one 13',13'~dioxide or (18,3Ί ,6¾,7 ^! 8,8Έ,12¾)-6-ΰΜθΓθ-12'-((21 )~2" hydroxypropyl)-7'-methoxy-3,4-cUhydro-2h,15 ^, h-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ^!9 ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'~dioxide] (from Example 548) (10 rag, 0.016 mrnoi), THF (2 mL) and NaH (3.8 mg, 0.16 mrnol). The reaction was stirred at room temperature for 15 minutes at which time Mel (0.020 mL, 0.32 mmoi) was added. The reaction was stirred at room temperature for 3 hours and then the reaction was quenched with 100 ml of saturated ammonium chloride and extracted with 400 ml of EtO Ac. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude was purified on a Combiflash (4 gram gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give the title compound (6.6 mg, 10 μιηοΐ, 63% yield) as a white film. 'Ή NMR

(500MHz, CDCb) δ 8.04 (s, 1H), 7.70 (d, =8.6 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, HI).7.10 (d, ,/ 2.0 Hz, 1H), 6.97 - 6.87 (m, 2H), 6.82 id../ 1.5 Hz, 1H), 5.94 - 5,70 (m, III).5.54 (dd, 88.15,2 Hz, 1H), 4.36 (dd, 4.9.8.3 Hz, 1H), 4.16 - 3,97 (m, 2H), 3.81 (d, .7=15.2 Hz, III).3.76 - 3.61 (m, 3H), 3,37 - 3.30 (m, 31!). 3.24 (s, 3H), 3.24-3.18 (m, 1H), 3.00 (dd,J=10.3, 15.2 Hz, 1H), 2.85 -2.66 (m, 2H), 2.46 - 2.41 (m, 1H), 2,39 - 2.24 (m, 3H), 2.07 - 1.75 (m, 9H), 1.69 - 1.62 (m, 2H), 1.39 (t, .7=12.8 Hz, 1H), 1.2.7 (d, J=5.9 Hz, 3H) m/z (ESI, +ve ion) 657.0 (M+H) ⁺ .

EXAMPLE 550, (lS,3'R,6'R,7 ^f S,8'Z,12'S)-6-CHLORO-7 ^f -HYDROXY-12'-((2R)- 2-HYDROXYPROPYL)-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, Z,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((2R)-2- HYDROXYPROPYL)-3.4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTHALENE-1.22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15 ^! -ONE 13', 13'-DIOXIDE

Step 1 : (1 S,3 ^, R,6 ^, R,7 ^, S,8 ^, Z,12 ^, S)-12 ^, -((2R)-2-((TERT-

BUTYL(DlPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- pOlOXAtl SJTO Atl ^DIAZATETRACYCLOtMJ^ '^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,12'R)-12 ^, -((2R)-2-((TERT-

BUTYL(DIPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1.22 -

2u jOX A | 1 ΙΊ ! ! 1 Λ | l . l 4 | D! A/.Vn -;i ^' R A( ^' YCI .()l i 4.7.2.0 ^• ^ 0 ^{| :, ! 1} | PH\,TAi S A

-15'-ONE 13',13'-DI0X1DE

To a 100 ml flask was added [(S)-N-(((2R,4S)-2-((tert- butyldiphenylsilyl)oxy)oct-7-en-4-yl)sulfonyl)-6'-chloro-5-( ((lR,2R)-2-((S,E)-l- hy droxyhex-2-en- 1 -y l)cy clobuty l)methy l)-3 ', ,4',5 -tetrahy dro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-N- (((2R,4R)-2-((tert-butv'ldiphenylsilyl)oxv')oct-7-en-4-yl)su lfonyl)-6'-chloro-5- (((lR,2R)-2-((S,E)-l½droxyhex-2-en-l -yl)cydobutyl)methyl)-3',4,4 ^, ,5- tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7- carboxamide] (from Example 539, Step 3) (57 nig, 0.061 mmol) and DCM (40 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda-Grubbs 11 (3.8 mg, 6.1 μηιοΐ) and the mixture was stirred to 45 °C for 6 hours. The reaction mixture was filtered, concentrated and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give [(1S,3 ^! R,6'R,7'S,8'Z, 12'S)-12'- ((2R)-2-((tert-bu1yl(diphenyl)silyl)oxy)propyl)-6-cMoro-7'-h ydroxy-3,4-dihydro- 2H, 15'H-spiro[naphthalene-l ,22'- [20] oxa i 3] ihi a[ I / 4] ds

n]-15'-one 13 ^* ,13'-dioxide or (^,Β'Κ,ό'Κ,Τ' ^β ,δ'Ζ,^'Κνΐ^-^Κ)^-^-!- butyl(diphenyl)silyl)oxy)propyl)-6-cWoro-7'-hydroxy-3,4-dihy dro-2H,15'H- spiro[naphthalene-l,22'- | 20 jo\aj I |ihi«i| i J 4|dia/aicu ac> ciol I 4.7 .i! ^; " ^{) 1 'i n} jpen!acosa| H. i 6J 8.24 jieirae n]-15'-one 13',13'-dioxide] (16 nig, 0.018 mmol, 30% yield) as the slower eluting olefin isomer as a white solids.

STEP 2: (J.S,3 ^! R,6'R,7'S,8'Z,12'S)-6-CHLORO-7 ^, -HYDRO.XY-12'-((2R)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTHALENE-l ₅ 22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN] S'~ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6'R,7'S,8'Z,12'R)-6-CHLORO-7'-HYDROXY-12'-((2R 2- HYDROXYIH OPYL)-3,4-DIHYDRO-2H,I5'H-SPlRO[NAPHraALENE-l,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

To a 100 ml flask was added [(l S,3'R,6 ^, R,7 ^, S,8 ^, Z,12 ^, S)-12 ^, -((2R)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydroxy-3,4-dih ydro-2H, 15'H- spiro [naphthalene- 1,22'-

[2Q]oxa[ 13]thia[l ,14]diazate^

n]-15'-one 13 ^* ,13'-di oxide or (l S^'R^^T'S^'Z. H'RJ-l^-^R)^-^!!- but (diphenyl)silyl)oxy)propyl)-6-chloro-7'-hy(kox\'-3,4-dihydro -2H, ^' 15'H- spiro [naphthalene- 1 ,22'- [20ioxa[13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ³ ^() ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-15'-one 13 ', 13 '-dioxide] (from Step 1) (14 mg, 16 μηιοΐ) and TBAF (1 M in THF, 2.02 ml, 2.02 mmol). The reaction was stirred at 65 °C for 3.5 hours at which time the reaction was quenched with 50 ml of brine and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The crude product was purified on a Combiflash (4 g gold silica column), eluting with 50% to 90% EtOAc in heptanes + 0.2% AcOH, to give the title compound (3.7 rag, 5.9 μηιο], 36% yield) as an off white solid. ^" Ή NMR (400MHz, MeOH) δ 7.75 id. «/=8.4 Hz, 1H), 7.8 - 7.70 (m, 1H), 7.27 ·· 7.06 (m, 3H), 7.03 - 6.90 (m, 2H), 5.73 - 5.50 (m, 2H), 4.63 (dd, ./ 2.5.9.0 Hz, ill .4.22 - 4.04 Or, 411).4.00 - 3.87 (m, 1H), 3.74 id../ 14.7 Hz, 1H), 3,49 - 3.36 (m, 1H), 3.30 - 3.16 (m, IH), 2,96 - 2.72 (m, 3H), 2,50 - 2.32 (m, IH), 2,32 - 1.78 (m, i!llj.1.65 (ddd, J=6,l, 8.7, 14.6 Hz, IH), 1.53 - 1.43 (m, IH), 1.27 (d, J=6.3 Hz, 4H). m/z (ESI, +ve ion) 629.0(M+H) ⁺ .

EXAMPLE 551. (1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7'-HYDROXY- 12'- ((2S)-2-HYDRQXYPRQPYL)-3,4-DIHYDRQ-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSJTO Atl ^DIAZATETRACYCLOtMJ^ '^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-12 ^! -((2S)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPTRO[NAPHTH ALENE-1 ,22'- |2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [8, 16, 18 -15'-ONE 13', 13'-D10XlDE

STEP 1: (2S,4R)-2-((TERT-BUTYLDIPHENYLSlLYL)OXY)-N,N-BIS(4-

METHOXYBENZYL)OCT-7-ENE-4-SULFONAMIDE OR (2S,4S)-2-((TERT-

BUTYLDIPHENYLSILYL)OXY)-N,N-BIS(4-METHOXYBENZYL)OCT-7-

ENE-4-SULFONAMIDE

To a 100 ml flask was added [(2S,4S )-2-hydroxy -n,n-bis(4- methoxybenzyl)oct-7-ene-4-sulfonarnide and (2S,4R)-2-hydroxy-n,n-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide] (from 546, Step 1) (3.88 g, 8.67 mmol), DMF (60 ml), imidazole (1.18 g, 17.3 mmol) and tert-butylchlorodiphenylsilane (3,38 ml, 13.0 mmol). The reaction was stirred at 65 °C for 16 hours at which time reaction was then quenched with 200 ml of saturated ammonium chloride and extracted with 600 ml of diethyl ether. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was first purified on a Combiflash (80 g gold silica column), eluting with 10% to 30% EtOAc in heptanes. Rf product = 0.19 eluting with 10% EtOAc in heptanes. The racimic mixture (1 : 1) was then purified by preparatory SCF chromatography (ChiralPak AD 250mm x 30mm column, Phenomenex, Torrance, CA; 16g/minute EtOH + (20mM Ammonia) + 64g/minute CO2 (20% co-solvent) on Thar 80 SFC; outlet pressure = 100 bar; temperature ^:=: 22 °C; wavelength ^:=: 220 nm; used 1.0 mL injections of 3647mg/41mL (89 mg/rriL) sample solution of MeOH (35nxL) and DCM (5mL); run time = 13 minutes & cycle time 10 minutes.) to provide [(2S,4R)-2~((tert-buty'ldiphenylsilyi)oxy)- ,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide or (2S,4S)-2-((tert- butyldiphenylsiiyl)oxy)-N,N-bis(4-methoxybenz>'l)oct-7-en e-4- sulfonamide](1761 mg, 2.57 mmol, 37% yield) as the slower eluting isomer as a yellow liquid (ΐκ. = 2.34 minutes on analytical SFC; AD-H column; 15% EtOH in

STEP 2: (2S,4R)-2-((TERT-B UTYLDIPHENYLSILYL)OXY)OCT-7-ENE-4- SULFONAMIDE OR (2S ₅ 4S)-2-((TERT-BUTYLDIPHENYLSILYL)OXY)OCT- 7-ENE-4-SULFO

To a 100 ml flask was added [(2S,4R)-2-((tert-butyldiphenylsilyl)oxy)- N,N-bis(4-memoxybenzyl)oct-7-ene-4-sulfonaniide or (2S,4S)-2-((iert~ bu1yldiphenylsilyl)oxy)-N,N-bis(4-methoxybenzyl)oct-7-ene-4- sulfonamide]

(from Step 1) (450 mg, 0.656 mmol), anisole (0.717 ml, 6.56 mmol), DCM (20 ml) and then TFA (5 ml). The reaction was stirred at 22 °C for 3 hours at which time the solvent was removed. The crude product was purified on a Combif!ash (24 g gold silica column), eiuting with 10% to 50% EtOAc in heptanes, to give [(2S,4R)-2-((tert-butyldiphenylsilyl)oxy)oct-7-ene-4-sulfona mide or (2S,4S)-2- ((tert-but 4diphenylsil}'1)oxy)oct-7-ene-4-sulfonamide] (137 mg, 0.307 mmol, 47% yield) as a light yellow oil.

STEP 3: (S)-N-(((2S,4R)-2-((TERT-BUTYLDIPHENrYLSILYL)OXY)OCT-7-

EN~4~YL)SULFONYL)-6' HLO

2-EN-l^L)CYCXOBUTYL)METm^L)"3^4,4',5~TETRAHYDRO-2H,2'H- SPTRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTH ALENEJ-7- CARBOXAMIDE OR (S)-N-(((2S,4S)-2-((TERT-

BUTYLDlPHENYLSILYL)OXY)OCT-7-EN^-YL)SULFONYL)-6'-CHLORO- 5-(((l R,2R)-2-((S,E)- 1 -HYDROXYHEX-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-3',4,4 ⁱ ,5-TETRAHYDRO-2FI,2'H- SPIRO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] - 7-

To a 100 ml flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S _s E)-l- hydroxyhex-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro -2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid (from

Intermediate AA12A) (50 mg, 0.098 mmol), N,N-dimethylpyridin-4-amine mg, 0.20 mrnol) and [(2S,4R)-2-((tert-butyldiphenylsilyl)oxy)oct-7-ene-4- sulfonamide or (2S,4S)-2-((tert-bu1yldiphenylsilyl)oxy)oct-7-ene-4-sulfonam ide] (from Step 2) (131 mg, 0.294 mrnol) and then N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (38 mg, 0.20 mrnol). The reaction was stirred at room temperature for 16 hours at which time the solvent was removed and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 2% - 10% EtOAc in heptanes + 0.2% AcOH, to give [(S)-N-(((2S,4R)-2- ((tert-butyldiphenylsilyl)ox oct-7-en-4-yl)sulfony])-6'-ch]oro-5-(((lR,2R)-2- ((S,E)-l-hydroxyhex-2-en-l-yl)cyclobut 'l)me l)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-N-

(((2S,4S)-2-((tert-butyldiphenylsilyl)oxy)oct-7-en-4-yl)s ulfonyl)-6'-chloro-5- (((lR,2R)-2-((S,E)-l½droxyhex-2-en-l -yl)cyclobutyl)methyl)-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxamide] (55 mg, 0.058 mrnol, 59% yield) as a thick yellow oil.

Step 4: (18,3¾,6¾,7'8,8Έ,12¾)~12'-((28)-2-((ΊΈ^Τ-

BLiTYL(DlPHENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3,4 - DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE] OR

(lS,3 ^, R,6'R,7'S,8'E,12'S)-12'-((2S)-2-((TERT-

BUTYL(DIPI-IENYL)SILYL)OXY)PROPYL)-6-CHLORO-7'-HYDROXY-3, 4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

| 2u jOXA| 1 ΉΤί !1Α| Μ 4 |ΠίΑ/.ΥΠ:ΤΗ Α(ΎΠ.ϋΙ i 4.7.2.U ' ".i ^{) 1} '" ¹ |Ρ1·Ν I ^' ACOSA [ 8, -15'-C)NE 13 ^! ,13 ^* -DIOXiDEj

To a 100 ml flask was added [(S)-N-(((2S,4R)-2-((tert- butylcUphenylsilyl)oxy)oct-7-en-4-yl)sidfonyl)-6'-chloro-5 ((lR ₅ 2R)-2 hydroxyhex-2-en-l-yl)cyclobut d)methyl)-3',4,4 5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphtha! ene]-7-carboxamide or (S)-N-

(((2S,4S)-2-((tert-butyldiphenylsilyl)oxy

(((lR,2R)-2-((S,E)-l½droxyhex-2-en-l -yl)cyclobu1yl)methyl)-3 ^, .4,4 ^, .5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxamide] (from Step 3) (55 mg, 0.59 mmol) and DCM (40 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda- Grubbs II (7.4 mg, 0.012 mmol) and the mixture was stirred to 45 °C for 6 hours. The reaction mixture was then filtered, concentrated and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40%) EtOAc in heptanes + 0.2% AcOH, to give |;(! S,3'R,6'R,7'S,8 ^f E,12 ^f R)-12'-((2S)-2- ((tert-butyl(diphenyl)silyl)oxy)propyl)-6-cMoro-7'-hydrox\'- 3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l ,14]diazatefra^

n]-15'-one ! 3',13'-dioxide] or (i S,3'R,6'R,7'S,8'E, i2'S)-!2'-((2S)-2-((tert- butyl(diphenyl)silyl)oxy)propyl)-6-chIoro-7'-hydroxy-3,4-dih ydro-2h,15'h- spiro[naphthalene-l,22'-

[20]oxa[13]thia[ l, 14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13',13'-dioxide] (14 mg, 0.016 mmol, 27% yield) as the faster eluting olefin isomer, as a white solids.

STEP5: (! S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12'-((2S)-2- HYDROXYPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAl ⁵ HTHALENE-l,22'- ^OlOXAtlSlTHIAt^MlDIAZATET ACYCLOI M.T^.O'^.O^^lPE TACOSA

[8J 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,i2'S)-6-CHLORO-7'-HYDROXY-12'-((2S)-2 - HYDROXYPROPYL)-3,4-DII-rORO-2H:,15'H-SPIRO|NAPHra:ALENE-l,22 '- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,i6, ! 8,24]TETRAEN]-15'-ONE 13',13'-DiOXIDE To a 100 ml flask was added [(l S^T^e'^T'S^'E^ ^RJ-l ^-^Si^-iitert- buTy (diphenyl)silyl)oxy)propyl)-6-chloro-7'-hydrox\'-3,4-dihydro -2h,15'h- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetracycfo[14.7^

n]-15 ^* -one 13 ^* , 13 '-dioxide] or (1 S,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, S)-12 ^, -((2S)-2-((tert- but 'l(diphenyl)silyl)ox ')propyl)-6-chloro-7'-hydroxy-3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- [20]oxa[13]mia[l ,14]diazate1ra^^

n]-15'-one 13',13 -dioxide] (from Step 4) (13 mg, 0.015 mmol) and TBAF (1 M in THF, 3.04 ml, 3.04 mmol). The reaction was stirred at 65 °C for 3 hours at which time the reaction was quenched with 50 ml of brine and extracted with 200 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the crude product was purified on a

Combiflash (4 g gold silica column), eiuting with 50% to 90% EtOAc in heptanes) to give the title compound (1.7 mg, 2.7 μιηοί, 18% yield) as an off white solid. ¾ NMR (400MHz, CDCh) δ 8.23 (br. s., IH), 7.65 (d, J=8.4 Hz, IH), 7,54 (d, J=8.4 Hz, IH), 7.16 (dd, J=2.3, 8.4 Hz, IH), 7.11 (d, ./ 2.2 Hz, IH), 7.00 - 6.82 (m, 2H), 5.74(dd, J=4.9, 15.8 Hz, IH), 5.66 - 5.46 (m, IH), 4.29 - 4.07 (m, 4H), 4.00 - 3,88 (m, 2H), 3.64 (d, ,/ 1 7 Hz, I H), 3.30 id. ./ 1 3 5 Hz, ! H), 3. 13 (d, 1 .7 Hz, IH), 2.78 - 2.73 (m, 2H), 2.65 - 2.47 (m, 2H), 2.26 (ddd, .7=5.8, 8,8, 14.6 Hz, 2H), 2.03 (s, 2H), 1.89 - 1.60 i ra 9H), 1.39 (d, ./ 7.6 Hz, IH), 1.28 (d, ./ 6. 1 Hz, 3H). m/z (EST, +ve ion) 628.9 { \i · H ) .

EXAMPLE 552. (lS,3'R,6 ^, R,7'S,8 ^, E,12'S)-6-CHLORO-7'-METHOXY-12'-((2S)- 2-METHOXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ¹⁹ ^ ⁴ ]PENTACOSA | 8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7 ⁱ -METHOXY-12'-((2S)-2- METHOXYPROPYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22 ^s - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18 '-ONE 13', 13'-DIOXIDE

To a 4 ml vial containing 2 rag of [(1 S,3'R,6'R,7'S,8'E,12'S)-6-chloro-7'- h}'droxy-12'-((2S)-2-hydroxypropyl)-3,4-dihydro- 1 ">"> ^< -

[20joxa 13]thia[l,14]diazatetracycfo[14J _^

n]-15'-one 13',13'-dioxide or (lS 'R ¾,7'S,8'E,12'R)-6~chloro-7 ^! ~lwdroxy-12'- ((2S)-2-hydroxypropyl)-3,4-dihydro-2H,15'H-spiro[naphthalene -l,22'- [20]oxa[13]thia[l,14]cUazatetracyc^

n]-15'-one 13',13'-dioxide] (from Example 546) was added 1 ml of DMF and NaT! (3.7 mg, 0.15 mmol). The reaction was stirred at room temperature for 15 minutes at which time Mel (4.8 μΐ, 0.076 mmol) was added and stirred for 2 hours. The reaction was then quenched with 10 ml of brine and extracted with 40 ml of

EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The crude product was purified on a

Combiflash (4g gold silica column), during with 50% to 90% EtOAc in heptanes, to give the title compound (2.0 mg, 3.0 μτηοί, 32% yield) as a white film. ^" Ή

NMR (400MHz, CDCh) δ 7.94 (s, 1H), 7.70 (d, ,7=8,4 Hz, 1H), 7.19 (dd, .7=2.3, 8.6 Hz, 1H), 7.10 (d, ./ 2.2 Hz, 1H), 6.97 - 6.80 (m, 3H), 5.98 - 5.78 (m, 1H), 5.53 (dd, ,/ 9.!.15,4 Hz, 1H), 4.46 (t, 94 Hz, III).4.09 id. J=l,6 Hz, 2H), 3.88 - 3,62 (m, 4H), 3.49 - 3.38 (m, 3H), 3.27 - 3,21 (m, 1H), 3.24 (s, 3H), 2.99 (dd, ./ 10,3.15.4 Hz, HI).2.86 ·· 2.66 (m, 2H), 2.52 - 2.41 (m, 1H), 2.40 - 2.19 (m, 4H), 2.04 - 1.61 (m, lOH), 1.46 - 1.35 (m, III).1.22 id. ,7=6.1 Hz, 3H). m/z (ESI, + ve ion) 657.0 (W W ⁾ .

EXAMPLE 553. (lS,3'R,6'R,7 ^, S,9'E,13'R)-6-CHLORO-13'-ETHYL-7 ^! - HYDROXY-3,4-DIHYDRO-2H, 16'H-SPlRO[NAPHTHALENE- 1 ,23'- [21 ]OXA[ 14]THIA[ 1 5]DIAZATETRACYCIX)[15 .2 -^0 ²⁰ ' ²⁵ ]HEXACOSA 9,17, 19,25] TETRAEN] - 16'-ONE 14', 14'-DIOXIDE

STEP 1 : (S)-6'-CHLORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)-5-(((lR,2R)-2-

((S)-l-HYDROXYBUT-3-EN"l-YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2¾-SPIRC)j BENZO[B] [ 1 ,4]OXAZEPINE-3, 1

NAPHTHALENE] -7-CARBOXAMIDE

To a 100 ml flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S)-l - hydroxybut-3-en-l-yl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (from

Intermediate AA13A) (72 mg, 0.15 mmol), N,N-dimethylpyridin-4-amine (37 mg, 0.30 mmol), (R)-hept-6-ene-3-sulfonamide (from Intermediate EE18)(79 mg, 0.45 mmol), DCM (5 ml) and then N-O-diniethylairanopi pylVN"- ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol). The reaction was stirred at room temperature for 16 hours at which time the solvent was removed and the crude product was purified on a Combiflash (12 g gold silica column), eluting with 2% - 10% EtOAc in heptanes, to give (S)-6'-chloro-N-((R)-hept-6-en-3- ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hy(koxv'but-3-en-l-yl)cvxlo but5d)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r -naphthalene]-7- carboxamide (90 mg, 0.14 mmol, 94% yield) as a white solid. STEP 2: ( 18,3¾ ¾,7'8,9Έ/13Έ)-6-€ΗΙ,ΟΚΟ-13'-ΕΤΗΥΙ.-7'-ΗΥΓ) ΚΟΧΥ-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! -

[21]OXA[14]THIA[l _s 15]DIAZATETRACYCLO[ 15 ,7.2.0 ³ \0 ²⁰ - ²⁵ ]HEXACQSAj 9,17, 19,25 ] TETRAEN j - 16'-ONE 14', 14'-DIOXIDE

To a 200 ml flask was added (S)-6'-chloro-N-((R)-hept-6-en-3- ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l -yl)cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxamide (from Step 1) (90 mg, 0.14 mniol) and DCM (100 ml). The mixture was stirred at room temperature and argon was through bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda-Grubbs TT (8.8 mg, 0.014 rnmol, as a 200 uL solution in DCM) and the mixture was stirred to 45 °C for 6 hours. The reaction mixture was concentrated and crude product was purified on a Combiflash (12 g gold silica column), eiuting with 1 0% - 40% EtOAc in heptanes + 0.2% AcOH, to give the title compound (33 mg, 0,054 rnmol, 38% yield) as a off white solid. Ή NMR (400MHz, CDCb) δ 9.33 (s, 1H), 7.72 (d, ./ 8.4 Hz, 1H), 7.32 (dd, ./ 2. 1 . 8.3 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.10 (d, ./ 2.0 Hz, IH), 6.97 (d, ./ X.2 Hz, I I I ). 5.54 - 5.45 i ns. 1H), 5.44 - 5 ,36 (m, I I I ). 4,26 - 4,02 (m, 2H), 3.97 - 3.89 (m, IH), 3, 84 - 3,58 (m, 3H), 3.34 - 3.1 1 (m, 2H), 2.84 - 2.74 (m, 2H), 2,72 - 2,62 (m, IH), 2.43 - 2.31 (m, IH), 2,29 - 2.10 (m, 4H), 2.06 - 1.88 (m, 6H), 1.85 - 1.69 (m, 3H), 1.68 - 1.42 (m, 3H), 1.15 (t, ./ 7 4 Hz, 3H), m/z (ESI, +ve son) 613.0 (M+H) ⁺ .

EXAMPLE 554. (1 S,3'R,6'R,7'S, 13'R)-6-CHLORO-l 3'-ETHYL-7'-HYDROXY- 3,4-DIHYDRO-2H,16'H-SPlRO[NAPHTHALENE-l,23'-

[2I]OXA[14]THiA[l ,15]DIAZATETRACYCLO[ 15.7,2.0 ^3> ^0 ²⁰ - ²⁵ ]HEXACOSA[ 17.19,25]TRIEN] -16'-ONE 14', 14 ^! ~D.10XIDE

A 100 ml flask was charged with ( lS,3 ^f R,6'R,7'S,9'E,13'R)-6-chloro- i3'- e1hyl-7'-hydrox\'-3,4-dihydro-2H,16'H-spiro[naphthalene-l,23 '- [21]oxa[14]thia[l,15]diazatetracyclo[15.7.2.0 ³ 0 ^M ' ^2S ]hexacosa[9,17,19,25]tetraen ]-16'-one 14',14'-dioxide (from Example 553) (30 mg, 0.050 mmol), 20 ml of EiOAc, and 11 mg of platinum(IV) oxide. The mixture was degassed by H ₂ three times at which time the reaction was stirred at room temperature under a hydrogen balloon for 3.0 hrs. The reaction was then filtered and the solvent was removed by rotary evaporation. The crude was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 10% to 90% MeCN in water, where both solvents contain 0.1% TFA, 45 minute method) to give the title compound (6.7 mg, 11 μιηοΐ, 22 % yield) as a clear film. Ή NMR (400MHz, CDCb) δ 9.99 (br, s., 1H), 7.67 (d, =8.4 Hz, ill). 7.41 (dd, J=1.8, 8.2 Hz, 1H), 7.32 (s, 1H), 7.17 (dd, ./ 2.2.8.5 Hz, ill).7.09 (d, ./ 2.2 Hz, 6.98 (d, ,/ 8.2 Hz, ill). 4.21- 4.11 (m, 2H), 3.70 id../ 5.1 Hz, 2H), 3.61 - 3.37 (m, 4H), 2,83 - 2.70 (m, 2H), 2.58 - 2.49 (m, IH), 2,33 - 2.22 (m, 1H), 2.22 - 2.12 (m, ill).2.01 - 1.70 (m, 9H), 1.66 - 1.51 (m, 4H), 1,49 - 1.43 (m, 4H), 1.35 ·· 1.25 (m, 2H), 1.19 - 1.06 (m, 3H). m/z (ESI, +ve ion) 615.0 ί M H ) .

EXAMPLE 555, (lS,3 ⁱ R,6'R,7'S,9'E,12'S,13'R)-6-CHLORO-7'-HYDROXY- i 2'.!3'-Di YiLT! iYi - .4-Γ)!ΗΥΡΗ()-2Ι 1.16'! !-SP!R()|\ APi Π H \i j ^' M -l 23'- [21]OXA[14]TH1A[1,15]DIAZATEII ACYCLO[15.7.2.0 ³ -^0 ²⁰ - ²⁵ ]HEXACOSA|; 9,17,19,25]TETRAENl-16'-ONE 14',14'-DTOXIDE OR

(1 S,3'R,6 ^! R,7'S,9'E, 12'S, 13'S)-6~CHLORO-7 ^! ~HYDROXY-12', 13 '-DIMETHYL- 3 ,4-DIHYDRG-2H, 16 ^! H-SPlRO [NAPHTHALENE- 1 ,23'- ^riOXAtl^THIAtl SlDIAZATET ACYCLOIlS.T^.O'^.O^lHEXACOSAI 9,17, 9,25 ]TETRAEN]- 6'-ONE 14",14-DIOXIDE

STEP 1 : (2R, 3S)-N,N-BIS(4-METH0XYBENZYL) -METHYLHEX-5-ENE-2- SULFO AMIDE OR (2S, 3S)- ,N-BIS(4-METHOXYBENZYL)"3- METHYLHEX-5-ENE-2-SULFONAMIDE

To a -78 °C solution of (S)-N,N-bis(4-methoxybenz 'l)-2-methylpent-4- ene-1 -sulfonamide (from Example 395, Step 3) (334 mg, 0.828 mmol) in THF (5 mL) under argon was added butyllithium (0.828 ml, 2.07 mmol) over 5 minutes (reaction turns bright pink). The mixture was stirred at -78 °C for 5 minutes at which time Mel (0.155 ml, 2.48 mmol) was added and stirred at 0 °C for 2 hours. The reaction was then quenched with 1 00 ml of saturated ammonium chloride and extracted with 300 ml of EtOAc. The organic layer was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation. The crude product was purified on a Combifiash (12 g gold silica column), eluting with 2% to 10% EtOAc in heptanes, to give | { 2R . 3S)-N,N-bis(4-methoxybenzyl)-3-methylhex-5- ene-2-sulfonamide and (2S, 3S)-N,N-bis(4-methox 'benzyl)-3-methylhex-5-ene-2- sulfonamide] (185 mg, 0.443 mmol, 534% yield) as a light yellow oils.

STEP 2: (2R, 3S)-3-METHYLHEX-5-ENE-2-SULFON AMIDE AND (2S, 3S)-3- METHYLHEX-5- -2-SULFONAM1DE

To a 100 ml flask was added [(2R, 3S)-N,N-bis(4-methoxybenzyl)-3- methylhex-5-ene-2-sulfonamide and (2S, 3S)-N,N-bis(4-methox>'benzyl)-3- methylhex-5~ene-2~sulfonamide ) |(from Step I)(l 85 mg, 0.443 mmol), anisole (0.484 ml, 4.43 mmol), DCM (8 ml) and then TFA (4 ml). The reaction was stirred at 22 °C for 6 hours at which time the sol vent was removed. The crude product was purified on a Combiflash (12g gold silica column), eluting with 10% to 50% EtOAc in heptanes, to give j (2R, 3S)-3-methylhex-5-ene-2-sulfonamide and (2S, 3S)-3-methylhex-5-ene-2-sulfonamide] (63 mg, 0.36 mmol, 80% yield) as a light yellow oil. Note: the desired peak off of Combiflash look very small compared to undesired peaks. Note: Use KMNO4 stain to visualize product after chromatography. STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT-3-EN-l- YL)CYCLOBUT L)METHYL)-N-(((2R,3S)-3-METHYLHEX-5-EN-2-

YL)SULFONYL)-3 ^f ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l -HYDROXYBUT- 3-EN-l ATL)CYCLOBUTYL)METOY^

YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2 ^! H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7-

CARBOX

To a 100 ml flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxybut-3-en-l -yl)cyclobutyl)me ])-3 ^, ,4 ₅ 4 ^, ,5-tetrahydro-2H ₅ 2H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (71 mg, 0. 15 mmol, Intermediate AA13A), [(2R, 3S)-3-methylhex-5-ene-2-sulfonamide and (2S, 3S)-3-methylhex-5-ene-2-sulfonamide] (57 mg, 0.32 mmol), N,N- dimethylpyridin-4-amine (36 mg, 0.30 mmol), 3 ml of DCM and then N-(3- dimethylaminopropyl)~N '~ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol). The reaction was stirred at room temperature for 16 hours at which time the reaction was quenched with 50 ml of 1 N HC1 and extracted with 200 ml of EtOAc, The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The crude product was purified on a Combiflash (12 g gold silica column), eiuting with 10% - 40% EtOAc in heptanes + 0.2% AcOH) to give [(S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l- yl)cyciobuty )raethyl)-N-(((2R,3S)-3-methyihex-5-en-2-y

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l-yl)cycl obutyl)methyl)- N-(((2S,3S)-3H'nethylhex-5-en-2-y])sulfbnyi)-3',4,4',5 etrahydro-2H,2

spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide] (63 mg, 0.098 mmol, 67% yield) as a thick yellow oil.

STEP 4: (18,3'Κ,6¾,7'8,9Έ,12'8, ΐ: )-6-€ΗΕΟΚΟ-7'-ΗΥΒΚΟΧΥ-12',13'- ΟΓΜΕΙΉΥΕ-3,4-ΟΙΗΥΟΚΟ-2Η,16Ή-8ΡΙΚΟ[ΝΑ� �ΗΊΉΑΕΕΝΕ-1 ,23'- [21]OXA[ 14]TH1A[1,15]DIAZATEII ACYCLO[15.7.2.0 ³ -^0 ²⁰ - ²⁵ ]HEXACOSA|; 9,I7, 19,2S]TETRAEN]- 16'-ONE 14', 14'-DIOXIDE OR

(1 S,3'R,6'R,7'S,9'E, 12'S, 13'S)-6-CHLORO-7'-HYDROXY- 12', 13 '-DIMETHYL- 3 ,4-DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 , 23'-

[21 iOXA|;i4]THIA|;i ,15]DIAZATETRACYCLO[ 15.7.2.() ³ > ^, 0 ²⁰ - ²⁵ ]HEXA(X)SA[ 9,17, 19,25]TETRAEN]-16'-ONE 14",14 -DIOXIDE

To a 200 ml flask was added [(S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxybut-3-en-l-yl)c lobut ' ^, l)methyl)-N-(((2R,3S)-3-rnethylhex-5-en-2- yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene] -7-carboxamide and (S)-6 ^, -cliioro-5-(((lR,2R)-2-((S)-l-hydroxybut- 3-en-l -yl)cyclobut 'l)methyl)-N-(((2S,3S)-3-methylhex-5-en-2-yl)sulfonyl)- 3 ^, ,4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine -3,l '-naphthalene |-7- carboxamide] (from Step 3) (63 mg, 0.098 mmol) and DCM (60 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda- Grubbs II (6.2 mg, 9.8 μιηοΐ) as a solution in DCM (0.2 ml) and the mixture was stirred at 45 °C for 6 hours. The reaction mixture was concentrated and crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give the title compound (15 mg, 0.024 mmol, 25% yield) as the slower eluting islomer, as an off white solids. ¾ MR (400MHz, CDCb) δ 8.41 (s, 1H), 7.72 (d, ,/ 8. Hz, ill).7.32 (d, ./ 2.0 Hz, III). 7,18 (dd, ./ 2.3.8.4 Hz, 111).7.09 id. ,/ 23 Hz, !H), 7.06 - 7.00 (m, ill).6.93 (d, ,7=8.2 Hz, IH), 5.65 (dd, J=5.9, 15.3 Hz, IH), 5.40 - 5.13 (m, 1H), 4.25 - 4.01 (m, 3H), 3.84 (d, J=15.8 Hz, 2H), 3.68 (d, J=14.1 Hz, IH), 3.24 - 3.04 (m, 2H), 2.86 - 2,61 (m, 2H), 2.44 - 2,38 (m, IH), 2.34 - 2,23 (m, H), 2.23 - 1,97 (m, 6H), 1.96 - 1.61 (m, 6H), 1.49 - 1,40 (m, IH), 1.45 (d, .7=7.2 Hz, 3H), 1.11 (d, ,7=7,0 Hz, 3H). m/z (ESI, +ve ion) 613.0 (M+H) ⁺ .

EXAMPLE 556, (1 S,3'R,6'R,7'S, 12'S, 3'R)-6-CHLORO-7'-HYDROXY-12', 13'- DlMETHYL-3,4-DlHYDRO-2H, 16'H-SPIRG [NAPHTHALENE- 1 ,23 '- [21 ]OXA[ 14 |THIA[ 1,15 jD AZ ATETRACYCLO| 15.7.2.0 ³ - ⁶ .0 ²⁰ - ²⁵ ]HEXACOS A[ 17,19,25 ]TRIEN]-16'-ONE 14',14'-DTOXIDE

OR(lS,3'R,6¾,7 ^, S,12'S,13¾)-6~CHLORO-7 ^! ~HYDROXY-12 3'-i31METHYL- 3 ,4-DIHYDRQ-2H, 16'H-SPIRO [NAPHTHALENE- 1 , 23'-

[21iOXA|;i4]THIA|;i,15]DIAZATETRACYCL )[15.7.2.() ^3>, 0 ²⁰ - ²⁵ ]HEXA(X)SA[ 17, 19,25]TRIEN]-16'-ONE 14', 14-DIOXIDE

A 100 ml flask was charged with j(lS,3'R,6'R,7'S,9 12 ^* S,13'R)-6-chloro- 7'-hy droxy- 12', 13'-dimethyl-3,4-dihydro-2H, 16'H-spiro| naphthalene- 1 ,23'- [21]oxa[14]thia[l,15]diazatetracycio[15.7.2.0^ ⁶ .0 ²⁰ - ²⁵ ]hexacosa[9,17,19,25]tetraen ]-16'-one 14',14'-dioxide or (18,3¾,6Έ,7'8,9Έ,12'8,13Έ)-6-ΰωοίΌ-7·½·άΓθχ� �- 12', 13'-dimethyl-3,4-dihydro-2H,l 6'H-spirofnaphthalene-l,23'- [21]oxa[14]thia[l,15]diazatetr^

]-16'-one 14',14'-dioxide] (from Example 555 ) (13 mg, 0.021 mmol), 10 ml of EtOAc, and platinum(iv) oxide (4.8 mg, 0.02! mmol). The mixture was degassed by H ₂ three times at which time the reaction was stirred at room temperature under a hydrogen balloon for 3.0 hrs. The reaction was then filtered and the solvent was removed by rotary evaporation. The crude product was purified on a Combiflash (4g gold silica column), eluting with 10% - 50% EtOAc in heptanes, to givethe title compound (8.7 mg, 0.014 mmol, 67% yield) as a white solid. ¾ NMR

(400MHz, CDCb) δ 8.49 (br. s., 1H), 7.62 (d, =8.6 Hz, 1H), 7.17 (d, J=2.0 Hz, i l l). 7.11 (dd, ,/ 2.3. 8.4 Hz, 1H), 7.05 - 6.93 (m, 2H), 6.87 (d, ./ 8.2 Hz, 1H), 4.04 (s, 2H), 3.95 (dq, ,/ 2 9 7.2 Hz, i l l ). 3,73 - 3.51 (m, 3H), 3.19 id. ,/ 14 5 Hz, 1H), 3.11 (dd, ,7=7,2, 15.3 Hz, 1H), 2,80 - 2.55 (m, 2H), 2.35 - 2. 17 (m, 2H), 2.06 ·· 1 ,89 (m, 3H), 1.88 - 1.59 (m, 5H), 1.39 (d, ./ 7.4 Hz, 3H), 1,39 - 1.30 (m, 6H), 1.28 - 1.20 (m, 3H), 0.95 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 615.0 ( +H) ⁺ .

EXAMPLE 557. (lS,3'R,6 ^! R,7'S,9 ^, E,12 ^, S,13 ^, S)-6-CHLORO-7 ^, -HYDROXY- 12', 13'"DlMETHYL-3,4-DlHYDRO-2H, 16'H-SPIRO[NAPHTHALE E-l ,23'- [21 ]OXA[ 14]THIA[ 1 , 15 ] DI AZ ATETR AC YCLO [ 15,7.2,0 - ⁶ .0 ²⁰ - ²⁵ ]HEXACOS A[ 9,17, 19,25] TETRAEN] - 16'-ONE 14', 14'-DIOXIDE OR

(lS,3'R,61 ,7 ^, S,9T,12^,13'R)-6-CHLORO-7'-HYDROXY-12 ^! ,13'-DIME ^r rHYL~ S^-DfflYDRO^H-l&H-SPIROINAPHTHALENE-l^S'- pilOXAfl ^TO Atl SlDIAZATETRACYCLOtlSJ^.O'^.O^'liiEXACOSAI 9,17,19,25]TETRAEN]-16'-QNE 14',14 ^! -D10X1DE

To a 200 ml flask was added [(S)-6'-chloro-5-(((l R,2R)-2-((S)-l- hydrox 'but-3-en-l-yl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5- en-2- lJsulfonylJ-S'^^'^-tetrahydro^H^'H-s iroltenzoltl l l^loxazepine-S,! '- naphthalene]-7-carboxamide and (1 'S)-6'-chloro-5-(((l R,2R)-2-((S)-l - hydroxybut~3-en-l~yl)cyclobutyl)m^

y l)sulfony i)-3 ',4,4',5 -tetrahy dro-2H,2'H-spiro [benzo [b] [ 1 ,4 ] oxazepine- 3 , Γ- naphthalene]-7-carboxamide] (Example 555, Step 3) (63 rng, 0.098 ramol ) and DCM (60 ml). The mixture was stirred at room temperature while argon was bubbled through the reaction mixture for 15 minutes. To the homogeneous solution was then added Hoveyda-Grubbs II (6.16 mg, 9.82 μηιοΐ) as a solution in DCM (0.2 ml) and the mixture was stirred at 45 °C for 6 hours. The reaction mixture was concentrated and crude product was purified on a Combiflash (12 g gold silica column), eluting with 10% - 40% EtOAc in heptanes + 0.2% AcOH, to give the title compound ( 1 5 mg, 0.024 mmol, 25%) yield as the faster eluting isomer as an off white solids, Ί 1 NMR (400MHz, CDCb) δ 8,81 (br. s . i l l ). 7.55 - 7.44 (m, 1H), 7.22 id. ./ 2.0 Hz, 1H), 6.99 (dt, ./ 2. 1 . 8.2 Hz, .21 i ). 6.90 (d, ./ 2.2 Hz, 1H), 6.77 (d, ./ 8.2 Hz, IH), 5.55 - 5.39 (m, IH), 5.38 - 5.24 (m, IH), 4.07 - 3,88 (m, 2H), 3.79 - 3.73 (m, IH), 3.56 - 3,30 (m, 3H), 3.22 - 3.04 (m, 2H), 2.66 - 2,52 (m, 2H), 2.44 (br, s., IH), 2.36 - 2.12 (m, 2H), 2.07 - 1.46 (m, 1 21 1 ). 1.33 (d, J=7.2 Hz, 3H), 0.95 - 0.85 (ni, 3H). m/z (ESI, +ve ion) 613.0 (M+H) ⁺ .

EXAMPLE 558. (lS,3'R,6 ^! R,7'S,8'E,12 ^! S)-6-CHLORO-7'-HYDROXY-12 ^, -(2- H YDROXY-2-METHYLPROP YL)-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-7'-HYDROXY-12'-(2-HYDROX Y-2- ME^Ή LPR0PYL) ₅ 4-DlHYDR0-2H,15Ή-SPIR0| APITmALENE-l ,22 ^, - | 20 jOX A| 1 31 1 1 11 Λ| 1 , N | PIA/.\ Π·. f ^' RAC YCf ,Oj Ν .7.2 0 ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8,I6,18,24]TETiLAE ]-15'-ONE 13', 13 '-DIOXIDE (ISOMER 1)

STEP 1: (S)-2 -HYDROXY -N,N-BIS(4-METHOXYBENZYL)~2~METHYLOCT~ 7..} ;M ;..4.SI ! J ON AV! H ! : AND AND (R)-2-HYDROXY-N,N-BIS(4- -2-METHYLOCT-7-ENE-4-SULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l-suifonamide (Tntermediate|EEI 9) (500 mg, 1.28 mmol) in THF (5 mL) was added n-BuLi (2.5 M solution in hexanes, 565 ,uL, 1.41 mmol) at -78 °C dropwise. After the reaction was stirred at -78 °C for 10 min, excess 1 ,2-epoxy-2-methylpropane was bubbled into the reaction at the same temp. The reaction was allowed to warm to ambient temperature and stirred for 2h. The reaction was quenched (saturated aqueous NH4CI), extracted {2 HlOAcs. and washed (brine). The combined organic layers were dried (NazSC ) and concentrated under reduced pressure. The residue was injected into a 24 g ISCO Gold column and purified by combi -flash, eluting with 15% to 30% EtOAc/hexanes to give the title compounds (411 mg, 0.890 mmol) as a colorless oil.

STEP 2: (S)-2-HYDROXY-2-METHYLOCT-7-ENE-4-SULFON AMIDE AND (R)-2-HYDROXY-2-METHYLOCT-7-ENE-4-SULFONAMIDE

To a solution of (S)-2-hydroxy-N,N-bis(4-methoxybenz l)-2-methyIoct-7- ene-4-sulfoiiamide and and (R)-2-hydroxy-N,N-bis(4-methoxybenzyl)-2- methyloct-7-ene-4-sulfonamide (Step 1) (322 mg, 0.698 mmol) in DCM (4.6 mL) was added anisole (758 ,u,L, 6.98 mmol) and TFA (1 .55 mL, 20.9 mmol) at ambient temperature. After the reaction mixture was stirred for 40 hours, the reaction was concentrated and the residue was injected into a 20 g ISCO Gold column and purified by combi-flash, eluting with 10% to 100% EtOAc /hexanes to give the tile compounds (96 mg, 0.43 mmol, 62% yield) as a colorless film.

STEP 3: (lS,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7'-HYDROXY-12 ^, -(2- HYDROXY-2-METHYLPROPYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE- 1 ,22 ^! - | 2u jOXA| 1 3 ΙΊ ! !1Λ| l . l 4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |P1-M ^' .\C<)SA

[ 8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE OR

(lS,3¾,6'R,7^,8 ^12'R)-6-CHLORO-7'-HYDROXY-12'-(2-HYDROXY-2- ME ^r rHYLPROPYL)-3,4-DlHYDRO-2H;i5'H-SPlRO[NAI ^J HTHALE E-l,22'- |;20]OXA[ 13 iTHIA[ l,14jDL4ZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAENl-15'-ONE 13', 13'-DTOXIDE (ISOMER 1 )

One of the title compounds (isomer 1) was prepared from (S)-6'-chloro-5- (((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l -yl)cyclobutyl)methyl)-3',4,4',5- tetrahydro-2H,2H-spiro[benzo[b][l ,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Intermediate AA12A) by a procedure analogous to that described in

Example 610, Steps 1 through 2, replacing (R)-hept-6-ene-3 -sulfonamide in Step

1 with (S)-2-hydroxy-2-methyloct-7-ene-4-sulfonamide and (R)-2 -hydroxy -2- methyloct-7-ene-4-sulfonamide (Example 558, Step 2). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to provide one of the title compounds as the faster eluting isomer as a white foam. Ή NMR (400 MHz, CDCb) δ ppm 8.21 (br. s, 1H), 7.70 (d, ./ 8.6 Hz, 1 H), 7.19 (dd,■/ 2.2. 8.5 Hz, 1 H), 7.09 (d, 2.2 Hz, 1 H), 6.96 - 6.88 (m, 3 H), 5.94 - 5.85 (m, 1 H), 5.72 (dd, J=7.6, 15.3 Hz, 1 H), 4.39 (m, 1 H), 4.24 (dd, ,7=3,8, 7.5 Hz, 1 H), 4.14 - 4.04 (m,

2 H), 3.80 (d, J= .9 Hz, 1 H), 3.71 (d, J=14.3 Hz, 1 H), 3.25 (d, J=I4.3 Hz, 1 H), 3.03 (dd, ./ 9 2. 15.3 Hz, 1 H), 2.84 - 2,70 (ra, 2 H), 2.55 - 2,27 (m, 5 H), 2.17 - 1.61 (m, 9 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.45 - 1.32 (m, 2 H); m/z (ESI, +ve ion) 643.2 (M+H) ⁺ . EXAMPLE 559. (1 S,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-r2'-(2- HYDROXY-2-METHYLPROPYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ 14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)~6"CHLORO-7 ^, ~HYDROXY-12 ^, -(2~HYDROXY-2-

METHYLPROPYL)-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPH^ΉALENE-1.22 ^, - [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE (ISOMER 2)

One of the title compounds (isomer 2) was obtained as the second (slower) eluting isomer from reversed phase preparatory HPLC purification in Example 558, Step 3. ³ H NMR (400 MHz, CDCb) δ ppm 9,70 (br. s, 1 H), 7.71 (d, ,7=8,4 Hz, 1 H), 7.36 (m, 1 H), 7.19 (dd, ./ .2.2. 8.4 Hz, 1 H), 7.09 (d, ./ 2.2 Hz, 1 H), 6.98 (d, ./ H.2 Hz, 1 H), 6.92 (m, 1 H), 5.73 - 5.62 (m, 1 H), 5.59 - 5.47 (m, 1 H), 4.59 (m, 1 H), 4.14 - 4.03 (m, 3 H), 3.96 (m, 1 H), 3,72 (d, ./ 14.5 Hz, 1 H), 3.25 (d, .7=14.1 Hz, 1 H), 3.11 (dd, .7=10.0, 14.7 Hz, 1 H), 2.84 - 2.69 (m, 3 H), 2.47 { in. 1 H), 2.33 (m, 2 H), 2.28 - 1.68 (m, 10 H), 1.42 (s, 3 H), 1.38 (s, 3 H), 1.49 - 1,27 (m, 2 H); m/z (ESI, +ve ion) 643.2 { V! H } EXAMPLE 560. METHYL 3-((lS,3'R,6'R,7'S,8'E,12'S)-6-CHLQRQ-7'-

H YDROXY- 12'-METHYL- 13 ^! , 13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DL4ZATETRACYCLO[14 .2X) ³ '^0 ¹⁹ - ²⁴ ]P

[8,16,18,24]TETRAEN]-12'-YL)PRQPANQATE OR METHYL 3- ((1 S,3'R,0'R, 7 ^* S,8'E, 12'R)-6-CHLORO-7'-HYDROXY- 12'-METHYL-13', 13'- DIOXIDO-lS'-OXO-S^-DlHYDRO^-SPmorNAPHTHALENE-l^^- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8, 16, 18,24]TETRAEN] - 12'- YL)P ROP ANO ATE (ISOMER 1 )

STEP 1 : (S)-l-(( ERT-BUTYLDIMETHYLSILYL)OXY)-N,N-BIS(4-

METHOXYBENZYL)OCT-7-ENE-4-SULFON AMIDE AND (R)- 1 -((TERT- BUTYLDIMETHYLSILYL)OXY)-N,N-BIS(4-METHOXYBENZYL)OCT-7- ENE-4-S ULFON AMIDE

To a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l -sulfonamide (Mermediate|EE 19) (3.00 g, 7.70 mmol) in THF (17.1 mL) was added n-BuLi (2.5 M solution in hexanes, 3.70 mL, 9.24 mmol) at -78 °C. After the reaction mixture was stirred for 5 mm, tert-butyl(3-iodopropoxy)dimethylsilane (6.94 g, 23.1 mmol) was addded at the same temperature. The reaction was stirred at -78 °C for 20 min and then allowed to warm to ambient temperature. After the reaction mixture was stirred at ambient temperature for 3h, the reaction was quenched (saturated aqueous NH4CI), extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 0% to 30% EtOAc/hexanes to give the title compounds (3.94 g, 7.01 mmol). STEP 2: (S)- 1 -((TERT-BUTYLDIMETHYLSILYL)OXY)-N,N-BIS(4-

METHOXYBENZYL)-4-METHYLOCT-7-ENE-4-SULFONAMIDE AND (R)- l-((TERT-BUTYLDIMETHYLSILYL)OXY)-N,N-BIS(4-

METHOXYBENZYL)-4-METOYLOCT-7-ENE-4-SULFON AMIDE

To a solution of (S)- 1 -((tert-butyldimethylsilyl)oxy)-N,N-bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide and (R)-l-((tert-butyldimethylsilyl)oxy)- N,N-bis(4-methoxybenz}'l)oct-7-ene-4-sulfonamide (Example 560, Step 1) (1.96 g, 3.49 mmol) in THF (12 ml.) was added n-BuLi (2.5 M solution in hexanes, 1.53 mL, 3.84 mmol) at -78 °C. After the reaction mixture was stirred at -78 °C for 3 min, iodomethane (0.65 mL, 11 mmol) was added. The resulting reaction was stirred for another 20 min at the same temperature, then allowed to warm to ambient temperature and stirred for 3 h. Then the reaction was quenched

(saturated aqueous NH ₄ C1), extracted (2 !· ^' ·() Ac), and washed (brine). The combined organic layers were dried (NaaSC ) and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 0% to 20% EtOAc/hexanes to give the title compounds (1.45 g, 2.52 mmol) as a colorless oil STEP 3: (S)-l -HYDR0XY-N,N-BIS(4~METH0XYBENZYL)-4-ME;THYL0CT- 7-ENE-4-S ULFON AMIDE AND (R)- 1 -HYDROXY -N,N-BIS(4-

METH0XYBENZYL)-4-METHYL()CT-7-ENE-4-SULF0NAMIDE

To a solution of (S)-l-((tert-but ddimethylsilyl)oxy)-N,N-bis(4- memoxybenzyl)-4-memyloct-7-ene-4-sulfonamide and (R)-l -((tert- but 'lcUme1hylsilyl)oxy)-N,N-bis(4-methoxybenzyl)-4-methyloct-7- ene-4- sulfonamide (Example 560, Step 2) (1.45 g, 2.52 mmol) in THF (12.6 mL) was added TBAF (1.0 M in THF, 6.29 mL, 6.29 mmol) at ambient temperature. After the reaction mixture was stirred for 24 h, the reaction was quenched (brine), extracted (2*EtOAc), and washed (I xbrme). The combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was injected into a 40 g ISCO Gold column and purified by combi-flash, eluting with 0% to 60% EtOAc/liexanes to give the title compounds (1.16 g, 2.51 mmol) as a colorless oil. STEP 4: (S)-4-(N,N-BIS(4-METHOXYBE ZYL)SULFAMOYL)-4- METHYLOCT-7-ENOIC ACID AND (R)-4-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-4-METHYLOCT-7-ENOIC ACID

To a solution of (S)-l -hydroxy -N,N-bis(4-methoxybenz\d)-4-methyloct-7- ene-4-sulfonamide and (R)-l -hydroxy -N,N-bis(4-methoxybenz>'l)-4-methyloct-7- ene-4-sulfoiiamide (Example 560, Step 3) (1.07 g, 2.32 mmol) in acetone (23 mL) were added KBr (0.028 g, 0.23 mmol), NaHCCb (5% w/w aqueous solution, 10,9 mL, 6,49 mmol), TEMPO (0,398 g, 2.55 mmol), and NaCIO (6% w/w aqueous solution, 3.17 mL, 2.55 mmol) at 0 °C and the resulting mixture was stirred at the same temp for 2 h. Then the reaction was concentrated under reduced pressure, diluted (EtOAc and ice-cold IN aqueous I ^' f ). extracted (2*EtOAc), and washed (brine). The combined organic layers were dried (NazSC ) and concentrated under reduced pressure. The residue was injected into a 12 g ISCO Gold column and purified by combi-flash, eluting with 20% to 100% EtOAc/hexanes to give the title compounds (880 nig, 1.85 mmol) as a colorless syrup.

STEP 5: (S)-METHYL 4-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-4- METHYLOCT-7-ENOATE AND (R)-METHYL 4-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-4-METHYLOCT-7-E OATE

To a solution of (S)-4-(N,N-bis(4-methoxybenzyl)sulfamo} ⁷ l)-4-methyloct- 7-enoic acid and (R)-4-(N,N-bis(4-methoxybenz>4)suifa,moyl)-4-metltyloct-7 - enoic acid (Example 560, Step 4) (880 mg, 1.85 mmol) in MeOH (6 ml.) was added thionyl chloride (0.27 mL, 3.7 mmol) at 0 °C dropwise. Then the reaction was allowed to warm to ambient temperature and stirred for 3 h. Then, the reaction was diluted (EtOAc and ice-cold water), extracted (2 EtOAc), and washed (saturated aqueous NaHCCb and brine). The combined organic layers were dried (Na ₂ S04) and concentrated under reduced pressure to provide a crude product, which was used for next step without any further purification.

STEP 6: (S)-METHYL 4-METHYL-4-SULFAMOYLOCT-7-ENOATE AND (R)-METHYL 4-METHYL-4-SULFAMOYLOCT-7-ENOATE

To a solution of (S)-methyl 4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4- methyloct-7-enoate and (R)-methyl 4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4- methyloct-7-enoate (Example 560, Step 5) (880 mg, 1.80 mmol) in DCM (12 ml.) was added anisole (1.95 mL, 18.0 mmol) and T ^' FA (4.01 ml,, 53.9 mmol) at ambient temperature. After the reaction was stirred for 16 h, the reaction was concentrated under reduced pressure. The residue was injected into a 24 g ISCO Gold column and purified by combi -flash, eluting with 0% to 20% MeOH

(containing 0.3% AcOH)/DCM to give the title compounds (132 mg, 0.529 mmol, 30%) as a colorless film.

STEP 7: METHYL 3-((lS,3 ^, R,6 ^, R,7 ^f S,8 ^, E,12 ^, S)-6-CHLORO-7 ^f -HYDROXY-12'- METHYL- 13 13 '-DIOX1DO - 15 '-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[ !4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-12'-YL)PRQPANQATE OR METHYL 3- ((1 S,3'R,6 ^! R,7 ^* S,8'E, 12'R)-6-CHLORO-7'-HYDROXY- 12'-METHYL-13', 13'- DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16, 18,24]TETRAEN] - 12'-YL)PROPANO ATE (ISOMER 1 )

One of the title compounds (isomer 1) was prepared from (S)-6'-chloro-5- (((lR,2R)-2-((S,E)-l- droxyhex-2-en-l-yl)cyclobutyl)methyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b | [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (Intermediate AA12A) by a procedure analogous to that described in

Example 610, Steps 1 through 2, replacing (R)~hept~6-ene~3 -sulfonamide in Step 1 with (S)-methyl 4-methyl-4-sulfamoyloct-7-enoate and (R)-methyl 4-methyl-4- sulfamoyloct-7-enoate (Example 560, Step 6). The crude product was pun i led by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μχη column;

Phenomenex, Torrance, CA; gradient elution of 50% to 80% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to provide one of the title compounds as the faster eiuting isomer as a white foam (isomer 1 ). ^! H NMR (400 MHz, CDCh) δ ppm 8.05 (br, s., 1 H), 7,73 - 7.67 (m, 1 H), 7, 19 (dd, ./ 2.2. 8.4 Hz, 1 H), 7.09 (d, ./ 2.2 Hz, 1 H), 7.01 (m, 1 H), 6.97 ·· 6.92 (m, 1 H), 6.78 (m, 1 H), 5.85 (m, 1 H), 5.64 (m, 1 H), 4.23 (m, 1 H), 4.15 - 4.08 (m, 1 H), 4.07 - 4.00 (m, 1 H), 3.79 - 3.68 (m, 2 H), 3.71 (s, 3 H), 3 ,30 (d, ./ 14.3 Hz, 1 H), 3.04 (dd, J=10.9, 15.2 Hz, 1 H), 2.85 - 2,69 (m, 2 H), 2.61 (m, 2 H), 2.47 (m, I H), 2.33 (m, 3 H), 2.25 - 1.88 (m, 6 H), 1.87 - 1.72 (m, 4 H), 1.71 - 1.61 (m, 1 H), 1.48 - 1.39 (m, 1 H) 1.45 (s, 3 H); m/z (ESI, +ve ion) 671.2 ( +H) ⁺ .

EXAMPLE 561. METHYL S-^l SJ'R^'RJ'S^' ^'S^e-CHLORO-?'- HYDROXY-^'-METHYL- VB'-DlOXlDO-l S'-OXO-S^-DlHYDRO^H- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2 ⁽ !ί>Χ Λ | i ? ! ! Π ! Λ | ί ! 4 | ί^! ΛΖΛ ί : ί AC YCT (>! i 4 7.2 ϋ ^; ".O ¹ " ^M | PL\ i ACOS A

[ 8, I6, 18,24]TETRAEN]-12'-YL)PRQPANQATE OR METHYL 3- ((1 S,3'R,6'R, 7 ^* S,8'E, 12'R)-6-CHLORO-7'-HYDROXY- 12'-METHYL-13', 13'- DIOXIDO- 15'-OXO-3,4-DTHYDRO-2H-SPIRO[NAPHTH ALENE- 1 ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8, 16, 18,24]TETRAEN j - 12'- YL)P ROP ANO ATE (ISOMER 2)

One of the title compounds (isomer 2) was obtained as the second (slower) eiuting isomer from reversed phase preparatoiy HPLC purification in Example 560, 'H NMR (400 MHz, CDCb) δ ppm 8.57 (br. s. , 1 H), 7.73 - 7.69 (m, 1 H i. 7.24 - 7.15 (ra, 1 H), 7.10 (m, 2 H), 6.98 - 6.92 (m, 1 H), 6.85 (m, 1 H), 5,92 (m, 1 Hi,.5.68 (m.1 H), 4.26 (m, 1 H), 4.15 - 4.09 ira 1 H), 4.08 - 4.01 (m, 1 H), 3.77 - 3.69 (m, 5 H), 3.29 (m, 1 H), 3.05 (del, J=10.4, 15.3 Hz, 1 H), 2.84 - 2.62 (m, 3 H), 2.56 - 2.15 (m, 7 H), 2.16 - 1.83 (m, 10 H), 1.70 - 1.60 (m, 1 H), 1.54 - 1.35 (m, 1 H), 1,50 is, 1 !!}: m/z (ESI, +ve ion) 671,2 (M+H) ⁺ .

EXAMPLE562. METHYL 3-((lS,3'R,6'R,7'S,8 ^! Z,12 ^! S)-6-CHLORO-7'- HYDROXY-I2'~METHYL-13',l 3-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-l,22'- |2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2,0 · ^, ) ^{|:, ! 1} |Pi-NT. SA [8,16,18,24iTETRAEN]-12'-YL)PROPANOATE OR METHYL 3- ((1 S,3'R,6'R,7'S,8'Z, 12'R)-6-CHLORO-7"-HYDROXY- 12'-METHYL~l 3', 13 ^* - D10XlDO-15 ^, -OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALE E-l,22'- |;20]OXA[13iTHIA[l,14jDL4ZATETRACYCLO|14.7.2,0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8,24]TETRAEN]-12'-YL)PR0PAN0ATE (ISOMER 1)

One of the title compounds (isomer 1) was obtained as the third (slower) elutmg isomer from reversed phase preparaiory HPLC purification in Example 560, 'HNMR (400 MHz, CDCb) 6 ppni 10,56 (br. s., 1 !!}.7.70 id. J=8,6 Hz, 1 H), 7.58 (dd,«/=1.6, 8,2 Hz, 1 H), 7,27 (m, 1 H), 7.17 (dd,J=2.2, 8.5 Hz, 1 H), 7.09 (d, ./ 2.2 Hz, 1 H), 6.96 (d, ./ H.2 Hz, I H), 5.78 - 5.68 (m, 1 H), 5.48 (dd, ./ 4.1.11.0 Hz, 1 H), 4.41 (m, 1 !!}.4.10 id.J ! 1.7 !!/.1 H), 4.00 (d,J=11.9Hz, 1 H), 3,77 (d, J=15.3 Hz, 1 H), 3.72 (s, 3 H), 3.56 !d.,/ 14,3 Hz, I H), 3,17 - 2,99 (ni, 2 H), 2.89 - 2.68 (m, 3 H), 2.64 - 2.41 (m, 4 H), 2.35 - 2.18 (m, 5 H), 2.16 - 2.00 (m, 3 H), 1.94 - 1.72 (m, 3 H), 1.70 - 1 .64 (m, 1 H), 1.55 - 1 .42 (m, 1 H), 1.50 (s, 3 H); m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 563. METHYL 3-((l S,3 ^, R,6'R,7'S,8'Z,12'R)-6-CHLORO-7'- HYDROXY- 12'-METHYL- 13', 13 ^* -DIOXIDO - 15'-OXO~3,4-DIHYDRO-2H- 8ΡΚΟ[ΝΑΡΗΊΉΑ1,ΕΝΕ-1,22'-

[20]OXA[ 13]THIA[ 1 , 14]DIAZATETRACYCLO[14.7.2.

0 ³ ' ⁶ .0 ¹⁹ⁱ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-12'-YL)PROPANOATE OR METHYL 3-((l S,3'R VR,7'S,8 ^! Z,12 ^! S)-6-CHLORO-7'-HYDROXY-12'- METHYL- 13 13 '-DIOXIDO - 15 '-OXO - 3,4-DIH YDRO-2H-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN] - 12'-YL)PROPANO ATE (ISOMER 2)

One of the title compounds (isomer 2) was obtained as the fourth (slowest) eluting isomer from reversed phase preparatory HPLC purification in Example 560. Ή NMR (400 MHz, CDCb) δ ppm 10.59 (s, 1 H), 7.70 (d, ./ 8 4 Hz, 1 H), 7.60 (dd, ./ 1.6. 8.4 Hz, 1 H), 7.32 id. ./ I . K Hz, 1 H), 7.16 (dd, ./ 2.2. 8.5 Hz, 1 H), 7.08 (d, ./ 2.2 Hz, I H), 6.96 i d. ./ 8.4 Hz, 1 ! ! }. 5.82 - 5.74 (m, 1 ! ! }. 5.50 (dd, «7=2.6, 11.1 Hz, 1 H), 4.41 (m, 1 H), 4,08 (d, J=1 1.9 Hz, 1 H), 3.97 (d, ,7=11,7 Hz, 1 H), 3.81 (d, ,7=15.5 Hz, 1 H), 3,71 (s, 3 H), 3.57 (d, ,7=14.1 Hz, 1 H), 3.11 - 2,99 (m, 2 H), 2.78 - 2,49 (m, 5 H), 2.40 - 2.31 (m, 2 H), 2.30 - 1.70 (m, 10 H), 1 .70 - 1.63 (ra, I H), 1.58 (s, 3 H), 1.53 - 1.38 (m, 211); m/z (ESI, +ve ion) 671.2 (M+H) ⁺ . EXAMPLE 564. (1 S,3 ^, R,6'R,7'S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((5- METHYL-l^^-OXADIAZOL^-^METHYL^S^-DIHYDRO-ZH S'H- SPIRO[N APHTHALENE-1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIMJ^.O'^.O^^lPE TACOSA [8J6,18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S _s 8¾12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, (5- ETHYL-l,3 _: ,4- OXADIAZOL-2-YL)METHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Ι..! |ί)!Λ/Λ! :ΓΗ.Λ( ^' .01117.2 ϋ ^; ".ϋ |ΡΗ\ i ACOSA [8,16,18,24]ΤΕΤ¾ΑΕΝ]-15'-ΟΝΕ 13 I 3 '-DIOXIDE (ISOMER 1)

STEP 1 : (R)-l -HYDROXY-N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-3 SULFONAMIDE AND (S)-I -HYDROXY -N,N-BIS(4- METHOXYBENZYL)HEPT-6-ENE-3-SULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l -sulfonamide (Intermediate|EE19) (2.55g, 6.55 mmol) in THF (26 mL) was added n-BuLi (2.5 M solution in hexanes, 2.88 mL, 7.20 mmol) at -78 °C dropwise. After the reaction mixture was stirred at -78 °C for 10 min, excess ethylene oxide was bubbled into the reaction. Then the reaction was stirred at the same temperature for 1 h, allowed to warm to ambient temperature, and stirred for 16 h. The reaction was quenched (saturated aqueous NKUCl), extracted {2 l ^: t{).\c). and washed (brine). The combined organic layers were dried (Na?,S04) and concentrated under reduced pressure. The residue was injected into a 120 g ISCO Gold column and purified by combi-flash, eluting with 30% to 60% EtOAc/hexanes to give the title compounds (1.80 g, 4.15 mmol) as a colorless oil.

STEP 2: (lS,3 ^f R,6'R,7 ^, S,8¾12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -((5-METHYL- l,3,4-OX )lAZOL-2-YL)METHYL)-3,4-DlHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147.2 ³ '« 0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8¾12'R)-6 HLORO-7'-HYDROXY-12'-((5-METl-iYL-l,3,4- OX ADIAZOL-2-YL)METHYL)-3 ,4~DTHYDRO~2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

| 2u jOXA| 1 3 ΙΊ ! !1Λ| Ι . Ι 4 |! !Λ/.νΓ!·Ί < Λ( ^' Υ(·|.ΟΙ i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |P1-M ^' .\C0SA

[ 8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE (ISOMER 1) One of the title compounds (isomer 1) was prepared by a procedure analogous to that described in Example 632, Steps 3 through 7, replacing 1- hydroxy-N,N-bis(4-methoxybenzy])oct-7-ene-4-sulfonarnide in Step 3 with (R)-l- hydroxy-N,N-bis(4-methoxybenzj .)hept-6-ene-3-sulfonamide and (S)-l-hydroxy- N,N-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide (Example 564, Step I). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μπι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds (isomer 1) as the faster eluting isomer as a white foam, ^] H NMR (400 MHz, CDCh) δ ppm 8,37 (br. s, I H), 7.71 (d, ./ 8 Hz, 1 H), 7.20 (dd, J=2.3, 8.7 Hz, 1 H), 7.1 1 (d, .7=2.2 Hz, 1 H), 7.02 - 6.92 (m, 3 H), 5.84 (m, I H), 5.77 - 5.70 (m, 1 H), 4.59 (m, 1 H), 4.28 - 4.23 (m, 1 H), 4.16 - 4.07 ( m. 2 I s ). 3.80 (d, 14 ! Hz, 1 H), 3,75 - 3.65 (m, 2 H), 3,40 (dd, ./ 7.4. 16.0 Hz, 1 H), 3.27 (d, .7=14.1 Hz, 1 H), 3.13 - 3.05 (m, 1 H), 2.85 - 2.73 (m, 2 H), 2.58 (s, 3 H), 2.41 (m, 3 H), 2.15 - 1.65 (m, 7 H), 1.45 (t, ./ I 1.4 Hz, 1 H), 1.28 (s, 3 H); m/z (ESI, +ve son ) 667.2 ( +H) ⁺ .

EXAMPLE 565. (IS^'R^'RJ'S^U^'Ri-e-CHLORO-T'-HYD OXY-^'- S-

MEmYL~l,3,4-OXADlAZOL-2-YL)METHYL)-3,4-DlHYDRO-2H,15'H-

SPTRO[NAPHTHALENE-l ,22'-

| 2( !ί>Χ Λ| i 3 ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,12 ^! S)-6-CHLORO-7'-HYDROXY-12'-((5-METHYL-l,3,4-

OXADTAZOL-2-YL)METHYL)-3,4-DmYDRO-2H,15'H-

SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, I 8,24]TETRAENl-15'-ONE 13', 13'-DTOXIDE (ISOMER 2)

One of the title compounds (isomer 2) was obtained as the second (slower) isomer from reversed phase preparaiory HPLC purification in Example

564, ' I I N .MR (400 MHz, CDCh) δ ppm 10.04 (br, s, 1 H), 7.74 - 7.68 (m, 1 H), 7.49 ^. . 7.43 i m. 1 H), 7.24 - 7.15 (m, 1 H), 7.10 (m, 2 H), 7.02 ·· 6.97 (m, 1 H), 5.73 (m, 1 H), 5.56 - 5.47 (m, 1 H), 4.48 (m, 1 H), 4.22 - 4.06 (m, 3 H), 3.89 (d, ./ 15.3 Hz, 1 H), 3.80 - 3.63 (m, 2 H), 3.34 - 3. 18 (m, 2 H), 3.14 (m, 1 H), 2.82 - 2.73 (m, 2 H), 2.56 (s, 3 H), 2.49 - 2,31 (m, 1 H), 2.23 (m, 3 H), 2.12 - 1.42 (m, 10 H). m/z (ESI, +ve ion) 667.2 (M+H) ⁺ . EXAMPLE 566.1 -METHYLETHYL ((1S,3'R,6'R,7'S,8'E,1 !'S.i.?. ^' R)-6- CHLORO-7'-H YDROXY - 11 '-METHYL- 13 ', 13 '-DIOXIDO - 15 '-OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN] - 12'-YL)ACETATE OR 1 -METHYLETHYL

((lS,3'R,6'R,7'S,8'E,irR,12'S)-6-CHLORO-7'-HYDROXY-ll'-ME THYL- 13^13 ^, -DT0Xro0-15 ^, -0X0 ₅ 4-DlHYDR0-2H-SPIR0[NAPH^ΉALENE-l,22 ^, - |20jOXA| I 311 HI Λ| I .. N |OI A/.\ Π·. ΓΗ. Λί Ύ ^' ί ^' ί.01 i -i.7.20 ^{:' i'} .0 ^li ' |Pi-:N i ACOSA

[8,16,18,24]TETRAEN]-12'-YL)ACETATE OR 1 -METHYLETHYL

((1 S,3'R,6'R,7'S,8'E, 11 'R, 12'R)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 13 13 ^, -DIOXIDO-15 ^, -OXO-3,4-DIHYDRO-2H-SPTRO| AP^m^ALE3SlE-l,22 ^, - pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8, 16, 18,24]TETRAEN j - 12'-YL)ACET ATE OR1 - METHYLETHYL

((lS,3'R,6 ^f R,7'S,8 .,!! ⁱ SJ2'S)-6-CHLORO-7'-HYDROXY-ir-MEmYL-

1 ^' . ! '-!)!OXH)0-1 '-OXO-3. !-!)!! !Y!)R -21 l-SPiROiX API 11 HA!.L\i ! .22'- |2uj XA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAEN]-12'-YL)ACETATE (ISOMER 1)

STEP 1 : (3R,4R)~!SOPRQPYL 3-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)-4-METHYLHEPT-6-ENOATE AND (3R,4S)-ISOPROPYL 3-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-4- METHYLHEPT-6-ENOATE AND (3S,4R)-ISOPROPYL 3-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-4-METFTYLHEPT-6-ENOATE AND (3S,4S)-iSGPROPYL 3-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-4- METHYLHEPT-6-ENOATE

The title compounds were prepared from (3R,4R)-3-(N,N-bis(4- methoxybenzyl)sulfamoyI)-4-methylhept-6-enoic acid and (3R,4S)-3-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-methylhept-6-enoic acidand (3S,4R)-3-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-methylhept-6-enoic acid and (3S,4S)-3-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-methylhept-6-enoic acid (Example 647, Steps 9) by a procedure analogous to that described in Example 647, Steps 10, replacing MeOH in Step 10 with 2-propanol. The crude product was used for next step without any further purification.

STEP 2: l -METHYLETHYL ((! S,3'R,6'R,7'S,8'E,1 l 'S, ! 2'R)-6-CHLORO-7'- HYDROXY- 1 1 '-METHYL- 13 ^! , 13'-DIOXIDO - 15'-OXO-3,4-DIHYDRO-2H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TETRAEN] - 12"- YL) ACETATE OR 1 -METHYLETHYL

((] 8,3¾ ν^7Έ,8Έ,11¾,12 )-6 ΗΕΟΚΰ-7 ^, -ΗΥΙ¾ΟΧΥ-] ] '-ΜΕΊΉΥΕ- 13 ', 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-12'-YL)ACETATE OR 1 -METHYLETHYL

((1 S,3'R,6'R,7'S,8'E, 11 'R, 12'R)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 13 ^, ,13 ^, -D10XIDO-15 ^, -OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TET AEN] - 12'-YL)ACETATE OR 1 -METHYLETHYL

((l S,3'R,6 ^! R,7'S,8 ^, E,l l ^, S,12'S)-6-CHLORO-7 ^, -HYDROXY-ir-METHYL- lS' S'-DIOXIDO-l S'-OXO-S^-DIHYDRO^H-SPIROINAPHTHALENE-l^^- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-12'-YL)ACETATE (ISOMER 1) One of the title compounds (isomer 1) was prepared from (S)-6'-chloro-5-

(((lR,2R)-2-((S,E)-l-hydroxyhex-2-eati-l-yl)cyclobutyl)me thyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid ( ntermediate AA12A) by a procedure analogous to that described in Example 61 1 , Steps 2 through 3, replacing (S)-2-(N,N-bis(4- methoxybenzyl)sulfamoyl)hex-5-en-l-yl carbamate in Step 2 with (3R,4R)~ isopropyi 3-(N,N-bis(4-methoxybenz 'l)sulfamoyl)-4-methylhept-6-enoate and (3R,4S)-isopropyl 3-(N,N-bis(4-methoxybenz>4)sulfa,moy )-4-methy]hept-6- enoate and (3S,4R)-isopropyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4- methylhept-6-enoate and (3S,4S)-isopropyl 3-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-methylhept-6-enoate (Example 566, Step 1). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μη column; Phenomenex, Torrance, CA; gradient elution of 50% to 80% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds (isomer 1 ) as the faster eluting isomer as a white foam, ³ H NMR (400 MHz, CDCh) δ ppm 8,01 (br, s., 1 H), 7.72 - 7,67 (m, 1 H), 7.18 (dd, ./ 2.2. 8.5 Hz, 1 H), 7.10 (d, ./ 2.2 Hz, 1 H), 7.01 (m, 1 H), 6.96 - 6.88 (m.2 Is).5.98 (m, 1 H), 5,73 (dd, J=7.6, 15.1 Hz, 1 H), 5.10 (quin, J=6.3 Hz, 1 H), 4,86 (m, 1 H), 4.26 (m, 1 H), 4.14 - 4.06 (m, 2 Hi.3.81 (d, .7=15,1 Hz, 1 H), 3.68 (d, =14.5 Hz, 1 H), 3.27 (d, J=14.3 Hz, 1 H), 3.02 (dd, =7.3, 16.7 Hz, 1 H), 2.83 - 2.71 Or, 2 H), 2.64 (dd, ./ 5.3.16.8 Hz, 1 H), 2.53 - 2.39 (m, 1 H), 2.38 - 2,27 (m, 2H), 2.12 - 1,74 (m, 9 H), 1.72- 1,64 (m, 1 H), 1.43 . 1 I Hz, 1 H), 1,30 (m, 6 H), 1.08 (d, .7=6.3 Hz, 3 H); m/z (ESI, +ve ion) 685.3 (M+H) ⁺ .

EXAMPLE 567.1 -METHYLETHYL ((1 S,3'R,6'R,7'S,8'E, 11 *S, 12'R)-6- CHLORO-7 ^! -HYDROXY-ir-METHYL-13V13'-DIOXrDO-15'-OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIl^T^.O'^.O^^lPE TACOSA [8,16,18,24]TETRAEN]-12'-YL)ACETATE OR 1 -METHYLETHYL

((lS,31 ,6 ^, R,7'S,8'E,irR,12'S)-6-CHLORO-7 ^, -HYDROXY-ll'-MEraYL- 13',13'-D10XIDO-15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALENE-l,2 2'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TETR AEN] - 12'-YL) ACET ATE OR 1 -METHYLETHYL

((18,3¾,6 ^! ί ,7'8,8Έ,11Ί ,12¾)-6-€ΗΕ010-7'-ΗΥΟί ΟΧΥ-1Γ-ΜΕΤΗΥί- 13^13 ^, -DIOXroO-15 ^, -OXO-3,4-DfflYDRO-2H-SPIRO| APHTHALENE-l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16, 18,24]TETRAEN] - 12'-YL)ACETATE OR1 -METHYLETHYL

((lS,3 ^! R,6 ^, R,7'S,8'E,irS,12'S)-6-CHLOR()-7'-HYDROXY-ir-METOYL- ^3^13 ^, -DTOXroO-15 ^, -OXO-3 ₅ 4-DlHYDRO-2H-SPIRO[NAPH^ΉALENE-l,22 ^, - [20]OXA[13]THIA[l,14]DL ZATETRACYCLO[14,7.2,0 ³ '^0 ¹⁹ - ²⁴ ]i¾^ ^{^^}

[8, 16, 18,24]TETRAEN] - 12'-YL)ACETATE (ISOMER 2)

One of the title compounds (isomer 2) was obtained as the second (slower) isomer from reversed phase preparatory HPLC purification in Example 566, Step 2. ¾ NMR (400 MHz, CDCb) δ ppm 9.75 (br. S, 1 H), 7,69 (d, J=8.6 Hz, 1 H), 7.22 - 7.15 (m, 1 H), 7.15 - 7.06 (m, 2 H), 6.99 - 6.91 (m, 1 H), 6.82 (m, 1 H), 5,94 (m, I H), 5.66 i dd. 5.6. 15.4 Hz, 1 H), 5.07 ( id. J 3. 12,5 Hz, 1 H), 4.33 (m, I H), 4.24 - 4.15 (m, 1 H), 4.09 (q, .7=12. 1 Hz, 2 H), 3,71 (m, 1 H), 3.56 (m, 1 H), 3.48 - 3.22 (m, 2 H), 3.14 (dd, J=5.9, 17.0 Hz, 1 H), 2.84 - 2.73 (m, 2 H), 2.73 - 2.57 (m, 2 H), 2.53 - 2.40 (m, 1 H), 2.35 (m, 9 H), 1.70 (qum, ./ 9,2 Hz, 1 H), 1 .58 - 1.41 (m, 1H), 1.31 - 1.23 (m, 6 H), 1.14 (d, J=7.0 Hz, 3 H); m/z (ESI, +ve ion) 685.3 (M+H) ⁺ .

EXAMPLE 568. 1 -METHYLETHYL (ilS,3'R,6'R,7'S,8'Z,irS,12 ^* R)-6- CHLORO-7'-HYDROXY-ir-METHYL-13',13'-DIOXIDO-15'-OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[l ,14]DIAZAraTRACYCLO[

8,16, 18,24]TETRAEN]-12'-YL)ACETATE OR I -METHYLETHYL

((l S,3 ^, R,6 ^, R,7 ^, S,8 ^, Z, l l ^, R,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-ir-METHYL- 13',13'"D10XIDO-15'-OXO-3,4-DlHYDRO-2H~SPIRO[NAPHTHALENE-l,2 2'~ [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ PENTACOSA[ 8,16, 18,24]TETRAEN] - 12'-YL)ACETATE OR 1 -METHYLETHYL

((1 S,3'R,6'R,7'S,8'Z, 11 'R, 12'R)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 13',13'-DIOXIDO-15'-()XO-3,4-DIHYDRO-2H-SPIRO|NAPHTHALENE-l, 22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ PENTACOSA[ 8, 16, 18,24] TETRAEN] - 12'-YL) ACETATE OR 1 -METHYLETHYL

((1 S,3'R,6'R,7'S,8'Z,1 l'S,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-l l'-METHYL- 13^13 ^, -DT0Xro0-15 ^, -0X0 ₅ 4-DlHYDR0-2H-SPIR0[NAPH^ΉALENE-l,22 ^, - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 ³ '^0 ¹⁹ ^ ⁴ PENTACOSA[ 8,16,18,24]TETiL E ]-12'-YL)ACETATE (ISOMER 1)

One of the title compounds (isomer 1 ) was obtained as the third (slower) eluting isomer from reversed phase preparatory HPLC purification in Example 566, Step 2. ¾ NMR (400 MHz, CDCb) δ ppm 9.56 (br. s, 1 H), 7.70 (d, ,/ H.6 Hz, I H), 7.35 - 7,28 (m, I H), 7. 1 8 (dd, ./ 2.3. 8.4 Hz, 1 H), 7. 12 - 7,06 < m. 2 H), 6.94 (d, ,7=8,2 Hz, 1 H), 5.81 - 5.70 (m, 1 H), 5.61 (dd, «/=5.3, 11.3 Hz, 1 H), 5,07 (td, J=6.3, 12.5 Hz, 1 H), 4.44 (m, 1 H), 4.19 - 4.03 (m, 3 H), 3.79 (d, J=15.1 Hz, 1 H), 3.64 (d, ,/ 14. 1 Hz, 1 H), 3.38 (dd, ,/ 4.5. 17.2 Hz, 1 H), 3.27 - 3.10 (m, 2 H), 3.04 (m, 1 H), 2,83 - 2,58 (m, 3 H), 2,48 - 1 ,63 (m, I I H), 1.45 (t ./ 1 2,6 Hz, 1 H), 1,30 - 1.24 (m, 6 H), 1,08 (d, ./ 6.7 Hz, 3 H); m/z (EST, +ve ion) 685,3 \\\-U) .

EXAMPLE 569.1-METHYLETHYL ((1S,3'R,6'R,7 ^* S,9'Z,1 l'S,12'R)-6- CHLORO-7-HYDROXY-l 1 ^f -METHYL-13',13'-DIOXIDO-!5'-OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [9, 16,18 ,24] TETRAEN] - 12"- YL) ACET ATE OR 1 -METHYLETHYL

((lS,3¾,6 ^! R,7^,9 ^! Z,irR,12'S)-6 HI RO-7 ^, -HYimOXY-ir-METHYL- 13 ', 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- [20iOXA|;i3]THIA|;i,14]DlAZATETRACYCL)[14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [9, 16,18,24] TETRAEN] - 12'- YL) ACETATE OR 1 -METHYLETHYL

((1 S,3'R,6'R,7'S,9'Z, 11 'R, 12'R)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 13',13'-D10XIDO-15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALENE-l,2 2'~ [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9, 16,18 ,24] TET AEN] - 12'-YL) ACET ATE OR 1 -METHYLETHYL

((lS,3'R,6'R,7'S,9'Z,ll'S,12'S)-6-CHLORO-7'-HYDROXY-ir-ME THYL- 13^13 ^, -DIOXroO-15 ^, -OXO-3,4-DfflYDRO-2H-SPIRO| APIίΓHALENE-l,22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [9, 16, 18,24]TETRAEN] - 12'-YL)ACETATE

One of the title compounds was obtained as the fourth (slower) eluting isomer from reversed phase preparatory HPLC purification in Example 566, Step 2. Ή N.MR (400 MHz, CDCb) δ ppm 10.07 (br, S, I H), 7.70 (d, ./ 8.4 Hz, 1 H), 7.48 (m, I H), 7.18 (dd, .7=2.2, 8,5 Hz, 1 H), 7.13 (m, 1 H), 7,09 (d, ./ 2.2 Hz, 1 H), 6.97 ! d. ,/ 8.4 Hz, 1 H), 5.78 - 5.70 (m, 1 H), 5.57 - 5.49 (m, 1 H), 5.10 (id. ,/ 6 2. 12,5 Hz, 1 I s ). 4.40 (m, 1 H), 4.24 (m, I H), 4.14 - 3,98 (m, 2 H), 3.85 i d. ,/ h i Hz, 1 H), 3,62 (d, ./ 14. 1 Hz, 1 H), 3.20 - 2,98 (m, 4 H), 2.89 - 2.72 (m, 3 H), 2.66 (m, 1 H), 2.29 - 2.17 (m, 2 H), 2.13 - 2.00 (m, 1 H), 1.99 - 1.86 (m, 4 H), 1.83 - 1.55 (m, 3 H), 1.50 - 1.36 (m, 1 H), 1.34 - 1.24 (m, 6 I I ). 11.08 id. ./ 6, 7 Hz, 3 H); m/z (EST, +ve ion) 685.3 (M+H) ⁺ .

EXAMPLE 570. 1 -METHYLETH YL ((1S,3'R,6'R,7 ^* S,8'Z, 1 l'S,12'R)-6- CHLORO-7' -I ^T DROXY-l l ^f -METHYL-13', 13'-DIOXIDO- ! 5'-OXO-3,4- DIHYDRO-2H-SPIRO[N APHTHALENE-1 ,22'-

[20]OXA[ 13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ PENTACOSA[

8, 16, 18,24 J TETRAEN] - 12'-YL) ACETATE OR 1 -METHYL ETHYL

((1 S,3'R,6'R,7'S,8'Z,11 'R ^SJ-e-CHLORO-T-HYDROXY-l 1 '-METHYL -

13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[l ,14]DIAZAraTRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ^ ⁴ PENTACOSA[ 8,16,18,24] TETRAEN] - 12'-YL) ACETATE OR -METHYLETHYL

((lS,3¾,6 ^! R,7^,8 ^! Z,irR,12'R)-6-CHLORO-7'-HYDROXY-ir-METHYL~ 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIH YDRO-2H-SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[l,14]DIAZAraTRACYCLO[147.2 ³ ' ^{6 19} ^ ⁴ PEj TACOSA[ 8,16,18,24]TETRAEN]-12'-YL)ACETATE OR 1 -METHYLETHYL

((lS,3 ^, R,6'R,7'S,8'Z,irS,12'S)-6-CHLORO-7'-HYDROXY-ir-METHYL- 13 ^, ,13 ^, -D10XIDO-15 ^, -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ₅ 22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ PENTACOSA[ 8,16, 18,24]TETRAEN] - 12*-YL) ACETATE (ISOMER 2)

One of the title compounds (isomer 2) was obtained as the fifth (slowest) eiuting isomer from reversed phase preparaiory HPLC purification in Example 566, Step 2. ¾ NMR (400 MHz, CDCh) δ ppm 10.58 (br. s., 1 H), 7.63 (d, ,/ 8 ⁽ > Hz, 1 H), 7.47 (m, 1 H), 7,15 (m, 1 H), 7,09 (dd, J=2.2, 8.5 Hz, 1 H), 7,01 (d, ./ 2.3 Hz, 1 !!}.6.89 (d, ./ 8.2 Hz, 1 H), 5.84 - 5.76 (m, 1 H), 5.50 (dd,■/ 6.3. 10.6 Hz, 1 III 5.01 (quisn, ,/ 6.3 Hz, I H), 4.32 (m, 1 H), 4.03 (d, !!,? Hz, 1 H), 3.96 (d, ,7=11,9 Hz, 1 H), 3.93 - 3.87 (m, 1 H), 3,71 (d, ./ 1 .3 Hz, 1 H), 3.60 - 3.46 (m, 1 H), 3.07 - 2.82 (m, 3 H), 2.73 - 2.63 (m, 2 H), 2.56 (dd, J=8.5, 16.7 Hz, 1 H), 2.45 - 2.32 (m, 1 H), 2.31 - 1.67 (m, 8 H), 1.64 - 1.54 (m, 2 H), 1.47 - 1.32 (m, 2 H), 1.23 -1.17 (m, 6 H), 1.08 (d, ./ 7 ίί Hz, 3 H); ra/z (ESI, +ve ion) 685.3 (M+H) ⁺ .

EXAMPLE 571. (1S,3'R,6'R,7'S,8 ^! E,1 rS,12'R)-6-CHL()RO-7'-HYDR()XY-ir- ΜΕΤΉΟΧΥ- 12'-(l-METHYLETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22 ^, -

[20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,I8,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(Ιβ,Β'Κ,ό'Κ,Τ'β,δΈ,ΙΙ'Κ,Ι^β^ό-ΟΗίΟΚΟ-� �-ΗΥΟΚΟΧΥ-ΙΙ'-ΜΕΤΗΟ Υ-Ι^- (l-METHYLETHYL)-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- ^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(IS^'R^'R 'S^'EJl'^n'Rj-e-CHLORO^'-HYDROXY-ll'-METHOXY-n'- (l-METOYLETHYL)-3,4-DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHOXY-12'-

(l-METHYLETHYL)-3,4-DniYDRO-2H,15'H-SPIRO|NAPHTHALENE-l,2 2'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE (ISOMER 1)

STEP 1 : N,N-BIS(4-METHOXYBENZYL)-2-METHYLPROPANE-l - SULFONAMIDE

To a solution of bis(4-memoxybenzyl)amine (Intermediate EE1 1) (3.35 g, 13.0 mmol) and TEA (6.34 ml, 45.6 mmol) in DCM2 (65 ml) was added isobutanesulfonvl chloride (1.70 mL, 13.0 mmol) dropwise over 5 minutes at 0 °C and the resulting cloudy mixture was stirred at the same temperature for 1 h. The reaction was then diluted (DCM) and washed (2* brine). The aqueous layer was back extracted once (EtOAc) and the combined organic layers were dried (MgSG- and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 1 0% to 40% EtOAc/hexanes to provide the product (2.00 g, 5.30 mmol, 41 %). STEP 2: (R)-METHYL 2-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-3- METHYLBUTANOATE AND (S)-METHYL 2-(N,N-BIS(4- METH -3-METHYLBUTANOATE

To a solution of N,N-bis(4-methoxybenzyl)-2-methylpropane-l- sulfonamide (Example 571 , Step 1) (1.93 g, 5.1 1 mmol) in THF (10 ml) was added n-BuLi (2.0 M solution in hexanes, 2.25 mL, 5.50 mmol) dropwise at -78 °C. After the reaction mixture wwas stirrerd at the same temperature for 5 min, chlorocarbonic acid methyl ester (0.593 ml, 7.67 mmol) was added and the resulting reaction mixture was stirred for another 20 min, and then allowed to warm to ambient temperature. The reaction mixture was quenched (saturated aqueous NFLCl, 10 mL) and extracted (EtzO, 2x30 mL). The combined organic layers were washed (brine, 10 mL. and, dried (MgSO- , concentrated under reduced pressure to give the crude material (2.22 g, 5. 1 1 mmol, 100%) as a colorless oil. The product was used in the next step without further purification.

STEP 3: (R)-l-PIYDROXY-N ₅ N-BIS(4-METHOXYBENZYL)-3- METHYLBUTANE-2-SULFONAMIDE AND (S)- 1 -HYDROXY-N,N-BIS(4- METH -3-METHYLBUTANE-2-SULFONAMIDE

To a solution of (R)-methyi 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- methylbutanoate and (S)-methyl 2-(N,N-bis(4-methoxybenz>'l)suifa,moyl)-3- methylbutanoate (Example 571, Step 2) (2.25 g, 5. 17 mmol) in THF (12 ml) was added lithium borohydride (0.225 g, 10.3 mmol) with very small amount of water at 0 °C. The reaction mixture was allowed to warm to ambient temperature a d stirred overnight. Then, the reaction mixture was quenched (0.5 N aqueous HC1, 50 mL) and extracted (EtOAc, 3 x 100 mL). The combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The crude product was injected into a 80 g 1SCO Gold column and purified by combi -flash, eluting with 20% to 80% EtOAc/hexanes to provide the produci (1.10 g, 2.70 mmol 52%>) as a colorless oil . STEP 4: (R)-N,N-BIS(4-METHOXYBENZYL)-3-METHYL-l-OXOBUTANE- 2-SULFON AMIDE AND (S)-N,N-BIS(4-METHOXYBENZYL)-3-METHYL-l- OXOB -2-SULFON AMIDE

To a solution of (R)-l-hydroxy-N,N-bis(4-methoxybenzyl)-3- methylbutane-2-sulfonamide and (S)-l-hydroxy-N,N-bis(4-methoxybenzyl)-3- methylbutane-2-sulfonamide (Example 571, Step 3) (1.10 g, 2.70 mmol) in DCM (10 ml.) was added Dess-Martin periodinane (2.29 g, 5.40 mmol) at ambient temperature. After the reaction was stirred for 12 h, the reaction mixture was diluted (saturated aqueous Na_S ₂ C solution, 15 mL) and extracted (Et?.0, 2x50 mL). The combined organic layers were washed (saturated aqueuos NaHCG:<x3 and brinex3), dried (MgS04), and concentrated under reduced pressure. The crude product was injected into a 40 g IS CO Gold column and purified by combi- flash, eluting with 10% to 40% EtOAc/hexanes to provide the product (1.00 g, 2.47 mmol, 91 %) as a colorless oil.

STEP 5 : [(3R,4S)-4-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-2- METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3S,4R)-4-HYDROXY-N,N- BIS(4-METOOXYBENZYL)-2-METHYLHEPT-6-ENE-3-SULFONAMIDE] AND [(3S,4S)-4-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-2- METHY LHEPT-6-E E- 3 - SU LFON AMIDE AND (3R,4R)-4-HYDROXY-N,N- BI S( -METHOXYBENZYL)-2-METHYLHEPT-6-ENE-3-S ULFONAMIDE] .

To a solution of (R)-N,N-bis(4-methoxybenzyl)-3-methyl-l-oxobutane-2- sulfonamide and (S)-N,N-bis(4-methoxybenz l)-3-methyl-l-oxobutane-2- sulfonamide (Example 571, Step 4) (1.00 g, 2.47 mmol) and allyl iodide (0.908 ml, 9.86 mmol) in DMF (25 ml) was added indium (1.13 g, 9.86 mmol). The reaction mixture was stirred at ambient temperature for 2days. The inorganic solid was filtered through celite to remove and the filter cake was rinsed (EtOAc). The filtrate was diluted (EtOAc, 200 mL) and washed (a mixture of water/saturated aqueous NaHCCb/brine, v/v/v = 2/1/1, 100 mL, water and brine). The organic layers were dried (Na ₂ S04) and concentrated under reduced pressure. The crude product was injected into a 40 g ISCO Gold column and purified by combi-flash, eiuting with 0% to 30% EtOAc/hexanes to provide one enantiomeric mixture (enantiomeric mixture i) (320 mg, 0,715 mmol, 29%, the faster eiuting enantiomeric mixtures) and the other enatiomeric mixture (enantiomeric mixture 2) (230 nig, 0.514 mmol, 21%, the slower eiuting enantiomeric mixtures) as a colorless oil . STEP 6: [(3R,4S)-4-METHOXY-N,N-BIS(4-METHOXYBENZYL)-2- METHY LHEPT-6-E E- 3 - SU LFON AMIDE AND (3S _s 4R)-4-METHOXY-N,N- BIS(4-METHOXYBENZYL)-2-METHYLHEPT-6-ENE-3-SULFONAMIDE] OR [(3S,4S)-4-METHOXY-N,N-BIS(4-METOOXYBENZYL)-2-

METHYLHEPT-6-ENE-3-SULFON AMIDE AND (3R,4R)-4-METHOXY-N,N- -METHOXYBENZYL)-2-METHYLHEPT-6-ENE-3-SULFONAMIDE].

To a solution of [(3R,4S)-4-hydroxy-N,N-bis(4-methoxybenzyl)-2- methylhept-6-ene-3-suIfonamide and (3S,4R)-4-hydroxy-N,N-bis(4- rnethoxybenz d)-2-methylhept~6~ene~3~sidfonamide] or [(3S,4S)-4-hydroxy-N,N- bis(4-memoxybenzyl)-2-memylhept-6-ene-3-sulfonamide and (3R,4R)-4- hydroxy -N,N-bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfonamide]

(enantiomeric mixture 1 in Example 571, Step 5) (242 mg, 0,541 mmol) and iodomethane (0.336 ml, 5.41 mmol) in THF (5.4 mL) was added r-BuOK (1 M solution in THF, 0.65 mL, 0.65 mmol) at 0 °C. The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched (brine), extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to provide crude products (250 mg, 0.542 mmol, 100%) as a colorless film, which were used in the next step without further purification.

STEP 7: | 3R,4S)-4-METHOXY-2-METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3S,4R)-4-METHOXY-2-METHYLHEPT-6-ENE-3-SULFON AMIDE] OR [(3S,4S)-4-METHOXY-2-METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3 -4-METHOXY-2-METHYLHEPT-6-ENE-3-SULFO AMIDE]

To a solution of [(3R,4S)-4-methoxy-N,N-bis(4-methoxybenzyl)-2- methylhept-6-ene-3 -sulfonamide and (3S,4R)-4-methoxy-N,N-bis(4- methoxybenzyl)-2-methylhept-6-ene- 3 -sulfonamide] or [(3S,4S)-4-methoxy-N,N- bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfonarnide and (3R,4R)-4- methoxy-N,N-bis(4-rnethoxybenz}'l)-2-rnethylhept-6-ene-3-sul fonamide|

(Example 571, Step 6) (250 mg, 0.542 mmol) in anisole (5.89 mJL, 54.2 mmol) was added 2,2,2-triiluoroacetic acid (4.02 mL, 54.2 mmol) at ambient temperature. After the reaction was stirred for 3 h, the reaction was heated to 50 °C for 22 h. Then reaction mixture was cooled to ambient temperature, concentrated under reduced pressure. The crude product was injected into a 4 g ISCO Gold column and purified by combi-flash, eluting with Q% to 20%

MeOH/DCM with 0.3% AcOH provided the products (97,4 mg, 0.440 mmol, 81 % yield) as a pale brown liquid.

STEP 8: [(S)-6'-chloro-5-(((lR ₅ 2R)-2-((l S,5R,6R,E)-1 -hydroxy-5-methoxy-7 methyl-6-sulfamoyloct-2-en-l-yl)cyclobutyl)me1hyl)-3',4,4',5 -tetrahydro-2H, spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (S)-6'~ chloro-5-((( 1 R,2R)-2-(( 1 S,5 S,6S,E 1 -hy droxy-5-methoxy-7-methyl-6- sdfamoyloct-2-en-l -yl)c lobutyl)methyl)-3 4,4 5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid] or [(S)-6'- chloro-5-(((lR,2R)-2-((l S,5S,6R,E)-l-hydrox '-5-methoxy-7-methyl-6- sulfamoyloct-2-en-l-yl)cvxlobul5d)methyl)-3',4,4',5-tetrahyd ro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid and (S)-6'- chloro -(« I R.2 R )-2-« 1

sulfamoyloct-2-en-l-yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'lic acid]

(S)-6'-chloro-5-(((lR,2R)-2-((S _s E)-l-hydroxyhex-2-en-l- yl)cyclobu1yl)methyl)-3 4,4 5-tetrahydro-2H,2'H-spiro[benzo b][ l,4]oxazepine- 3, -naphthalene]-7-carboxylic acid (Intermediate AA12A) (55.9 mg, 0.1 10 mmol) and [(3R,4S)-4-methoxy-2"methylhept-6~ene-3~sulfonamide and (3S,4R)- 4-methoxy-2-methylhept-6-ene-3 -sulfonamide] or | ^" (3S,4S)-4-methoxy-2- methylhept-6-ene-3-sulfonamide and (3R,4R)-4-methoxy-2-methylhept-6-ene-3- sulfonamide] (Example 571, Step 7) (97 mg, 0.438 mmol) were dissolved in DCE (1.2 mL) under Ar. The solution was sparged with Ar for 5 min and Hoveyda- Grubbs 2nd generation catalyst (14 mg, 0.022 mmol) was added at ambient temperature. The mixture was stirred at ambient temperature for 2.5 h while sparging the reaction with Ar (the clear green solution becomes increasingly darker). Then, after air was bubbling through the reaction for 10 min, the reaction was concentrated under reduced pressure, and directly absorbed to silica-gel. Purification of the residue by flash column chromatography (4 g S1O2, 20% to 100% EtO Ac/Hex with 0.3% AcOH) provided the products (72.5 mg, 0.110 mmol, 100%) as a off-white film. STEP 9: (1S,3'R,6'R,7'S,8'E,1 S,12'R)-6-CHLORO-7'-HYDROXY-i - METHOXY-12'-(l-METHYLETHYL)-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[l , 14]DiAZATETRACYCLO[14.7,2. 0 · ⁶ .0

1 ⁹ - ²⁴ ]PENTACOSA[8J 6,18,24iTETRAEN]-15 ^, -ONE 13',13'-DIOXIDE OR (1 S,3'R,0'R,7'S,8'E,1 rR, 12'S)-6-CHLORO-7'-HYDROXY~l 1 '-METHOXY-12'- ( ! -YU J lY! J . Π IV L )-3.4-i)U IY DRO-2J 1. 1 Ί I-SP!RO| \ ^' .\PI Π I Ι ΛΙ .ΓΝΙ - 1 22'- [20]OXA[13]TH1A[1,14]D1AZATETRACYCLO[14.7.2. 0 ³ '.0

i ⁹ ' ²⁴ iPENTACOSA|;8,16,18,24]TETRAENj-15'-ONE 13 ',13 '-DIOXIDE OR (lS^'R^^T'S^^ l l'^ 'R^e-CHLORO-T'-HYDROXY-l l'-METHOXY-n ^* - (l-MEraYLETHYL)-3,4-DmYDRO-2H,15H-SPIRO[NAPHTHALE E-l,22'- [20]OXA[ 13 |THIA[ l, 14jDIAZATETRACYCLO| 14.7.2. 0 ³ · ⁶ .0

1 ⁹ - ²⁴ ]PENTACOSA[8, I 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E, 1 1 'S.12'S)-6-CHLORO-7'-HYDROXY- 1 1 '-ΜΕΊΉΟΧΥ-12'- (l-METHYLETHYL)-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2. 0 ^{3 fj} . ⁽⁾

^{] 9} ' ²⁴ ]PENTACOS A[8, 16, 18,24] TETRAEN] - 15'-ONE 13', 13 '-DIOXIDE

(ISOMER 1)

To a solution of [(S)-6"-chloro-5-(((lR,2R)-2-((l S,5R,6R,E)-l -hydroxy-5- methoxy-7-methyl-6-sulfanioyloct-2-en-l-yl)cyclobut\'l)methy l)-3',4,4',5- tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carbox lic acid and (S)-6'-chl oro-5-((( 1 R,2R)-2-(( 1 S,5 S,6S,E)- 1 -hy drox '-5-methoxy-7- methyl-6-sulfamoyloct-2-en-l-yl)cyclobutyl)me1hyl)-3',4,4',5 -tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid] or [(S)-6'~ chloro-5-(((lR,2R)-2-((l S,5S,6R,E)-l-hydroxy-5-methoxj'-7-methyl-6- sulfamoyloct-2-en-l-yl)cyclobuty ^

spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid and (S)-6'- cWoro-5-(((lR,2R)-2-((l S,5R,6S,E)-l½droxy-5-methoxy-7-melhyl-6- sdfamoyloct-2-en-l -yl)c lobutyl)methyl)-3 4,4 5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , -naphthalene] -7-carboxy lie acid] (Example 571, Step 8) (72.5 mg, 0.110 mmol) in DCM (3.7 mL) was added EDC (63.1 mg, 0.329 mmol), DMAP (40.2 mg, 0.329 mmol), and triethylamine (45.8 μΐ, 0.329 mmol) at arabiant temperature. After the reaction was stirred for 18 h, the reaction was directly loaded into silica-gel and purification by flash column chromatography (4 g SiQ?„ 0% tol00% EA/hexanes) provided a crude product as a pale brown film. The crude product was purified by chiral SFC (AS-H 21 x250 mm column,

Phenomenex, Torrance, CA; using gradient elution of 18% - 50% EtOH (20 mM NEbyCCte) to provide one of the title compounds (isomer 1) as the third (slowest) eiuting isomer. ^j I I NMR (400 MHz, CDCb) δ ppm 7.72 (d,■/ K.4 Hz, I I I ). 7.58 (s, ! ! ! ). 7.43 (d, ,/ 8 2 Hz, I I I ). 7.18 (dd, ,/ 2 2. 8.5 Hz, i l l ). 7,09 id. ./ 2.2 Hz, IH), 6.93 (d, J=7.5 Hz, 1H), 5.77 - 5.58 (m, 2H), 5.08 (br. s., 1H), 4.21 - 4.02 (m, 3H), 3.97 - 3.85 (m, IH), 3.80 (m, I H), 3.73 - 3.60 (m, 1H), 3.40 (s, 3H), 3.28 (d, ./ 1 .3 Hz, IH), 3,22 - 3.05 (m, 2H), 2.86 - 2.70 (m, 2! I ). 2,68 - 2.50 (m, 2H), 2.48 - 2.23 (m, 2H), 2,20 - 2.10 (m, IH), 2.10 - 1.98 (m, 2H), 1 ,97 - 1.88 (m, IH), 1.83 (m, 2H), 1.76 - 1.57 (m, 2H), 1.48 (t, J=11.6 Hz, IH), 1.32 - 1.23 (d, J=7.0 Hz, 3H), 1.23 - 1.14 (d, ./ 7.i ⁾ Hz, 3H); m/z (ESI, +ve ion) 661.2 (M+Na) ⁺ .

EXAMPLE 572, (1S,3 ^! R,6'R,7'S,8'E, 1 rS,12'R)-6-CHLORO-7'-HYDROXY-ir- METHOXY-12'-(l-METHYLETIiYL)-3,4-DIHYDRO-2H, 15H- SPTRO[NAPHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1, 14]DL ZATETRACYCLO[14.7.2, 0 ^3/l .0

i9,2 ]PENTACOSA[8,16,18,24]TETRAEN]-15 ^! -ONE 13', 13 '-DIOXIDE OR (1 S,3'R,0'R,7'S,8'E,1 rR,12'S)-6-CHLORO-7'-HYDROXY~l 1 '-METHOXY-12'- (l-METflYLETHYL)-3,4-DIHYDRO-2H,15H-SPIRO|NAPHTHALENE-l,22'- [20]OXA[13]TH1A[1,14]D1AZATETRACYCLO[14.7.2. 0 ³ '.0

i^ ⁴ ;|PENTACOSA[8 ₅ 16.18,24]TETRAEN]-15'-ONE 13 ^* ,13'-DIOXIDE OR (lS ¾ )'R ^,8T I I'R;i2¾)-6-CHIX)RO-7 ^f iYDROXY-i r-METHOXY-12'- (l-METOYLETHYL)-3,4-DlHYDRO-2H 5'H-SPlRO[NAPHTHALENE"l,22'- [20]OXA[ 13]TfflA[l,14]DIAZATETRACYCLO[14.7.2. 0 ³ · ⁶ .0

1 ⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR (1 S,3'R,6 ^! R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-7'-HYDROXY- 1 1 '-METHOXY - 12'- (l-METHYLETHYL)-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2. 0 ^{3 fj} .()

3 ⁹ - ²⁴ ]PENTACOS A[8, 16, 18,24] TETRAEN] - 15 ^* -ONE 13', 13 '-DIOXIDE

(ISOMER 2)

One of the title compounds was prepared by a procedure analogous to that described in Example 571, Steps 6 through 9, replacing [(3R,4S)-4-hydroxy-N,N- bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfonarnide and (3S,4R)-4-hydroxy- N,N-bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfonarnide] or [(3R,4R)-4- hydroxy~N,N~bis(4-m.ethoxybenz 4)-2-methylhept-6~ene-3~sulfonamide and (3S,4S)-4-hydrox '-N,N-bis(4-methoxybenzyl)-2-methylhept-6-ene-3- sulfonamide] (enantiomeric mixtue 1 in Example 571, Step 5) with [(3R,4S)-4- hydroxy-N,N-bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfon amide and (3S,4R)-4-hydroxy-N,N-bis(4-methoxybenz\'l)-2-methylhept-6-e ne-3- sulfonamide] or [(3R,4R)-4-hydroxy-N,N-bis(4-methoxybenz>' ^, l)-2-methylhept-6- ene-3-sulfonamide and (3S,4S)-4-hydroxy-N,N-bis(4-methoxybenzyl)-2- methylhept-6-ene-3-sulfonamide] (enantiomeric mixture 2 in Example 571, Step 5). The crude product from silica-gel column chromatography was purified by chiral SFC (AD-H 21 ^250 mm column, Phenomenex, Torrance, CA; using 14 g/miii MeOH(neat) + 56 g/min CO?., 25% co-solvent at 70g/min, isocratic.) to provide one of the title compounds (isomer 2) as the faster eluting isomer as a white foam. ¾ NMR (400 MHz, CDCb) δ ppm 7.69 (d, J=8.4 Hz, 1 H), 7.61 (m, 1 H), 7.48 - 7.37 (m, 1 H), 7.15 (d, ./ 8.7 Hz, 1 H), 7.10 - 7.09 (m, 1 H), 6.93 (d, J=8.0 Hz, 1 H), 5.73 - 5.53 (m, 2 H), 5.25 (m, 1 H), 4.16 - 4.03 (m, 3 H), 3.88 - 3.77 (m, 1 H), 3.70 - 3.57 (m, 2 H), 3.43 (s, 3 H), 3.28 (d, .7=14.5 Hz, 1 H), 3.22 - 3.08 (m, 2 H), 2.83 - 2.62 (m, 3 H), 2.52 (m, 1 H), 2.37 - 2.11 (m, 3 H), 2.06 - 1.44 (m, 8 H), 1.17 id.■/ 7.0 Hz, 3 H), 1.1 1 (d, ./ 7.0 Hz, 3 H) : m /. (ESI, +ve ion) 661.2 (M+Na) ⁺ . EXAMPLE 573, ilS,3'R,6'R,7'S,8'E, l l'S,12'R)-6-CHLORO-7'-HYDROXY-ir- METHOXY-12'-(l-METHYLETHYL)-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13 |THIA[ l, 14]DIAZATETRACYCLO| 14.7.2. 0 · ⁶ .0

1 ⁹ - ²⁴ ]PENTACOSA[8J 6,18,24]TETRAEN]-15 ^! ~ONE 13 ',13 '-DIOXIDE OR (1S,3'R,6'R,7'S,8'E,1 l'R,12'S)-6-CHLORO-7'-HYDROXY-l r-METHOXY-12'- (l-METHYLETHYL)-3,4-DIHYDRO-2I-I,15'H-SPIRO[NAPHTI-iALENE-l ,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2. 0 ^; ".0

1 ⁹ - ²⁴ ]PENTAC0SA[8,16,18,24]TF;TRAEN]-15'-0NE 13',13'-DIOXIDE OR (lS,3 ^, R,6'R,7 ^! S,8'E,l l'R,12 ^, R)-6-CHLORO-7 ^! -HYDROXY-l l'-METHOXY-12'- (l -MEΉWLETHYL)-3,4-DIHYD O-2H, 15Ή-SPIRO[NAPI-ITOALENE-I,22'- [20]OXA[13]TOIA[1, 14]DL ZATETRACYCLO[14.7.2, 0 ^3/l .O ¹⁹ - ²⁴ ]PENTACOSA[8,16,! 8,24]TETRAEN]-15 ^f -ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6 ^! R,7'S,8'E, 1 1 'S.12'S)-6-CHLORO-7'-HYDROXY- 1 1 '-ΜΕΊΉΟΧΥ -12'- (l-METHYLETHYL)-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2. 0 ^{3 fj} . ⁽⁾

3 ⁹ - ²⁴ ]PENTACOS A[8, 16, 18,24] TETRAEN] - 15 ^* -ONE 13', 13 '-DIOXIDE

(ISOMER 3)

One of the title compounds (isomer 3) was obtained as the second (slower) eluting isomer from SFC puri fication in Example 572. M i NMR (400MHz,

CDCh) δ ppm 7.71 (d, J=8.6 Hz, 1 H), 7.65 (m, 1 H), 7.44 (m, 1 H), 7.18 (dd, ./ 2.2. 8.5 Hz, 1 I I ). 7.10 (d, ./ 2.2 Hz, 1 H), 6.93 (d, ,/ 8.2 Hz, 1 H), 5.79 - 5.68 (m, 1 H), 5,66 - 5.56 (m, 1 H), 5,24 (m, 1 H), 4.20 - 4,04 (m, 3 H), 3.74 (m, 1 H), 3,70 - 3.56 (m, 2 H), 3,43 (s, 3 H), 3.39 - 3. 15 (m, 3 H), 2.90 - 2.64 (m, 3 H), 2.60 - 2.39 (m, 1 H), 2.37 - 2.11 (m, 3 H), 2.07 - 1.47 (m, 8 H), 1.19 (d, J=7.2 Hz, 3 H), 1 .12 (d, ./ 7.2 Hz, 3 H); m-'z (ESI, +ve ion) 661.2 (M+Na) ⁺ .

EXAMPLE 574. (1S,3'R,6 ^! R,7'S,8'E,1 l ^, S ₅ 12 ^, R)-6-CHLORO-12'- (CYCLOPROPYLMETHYL)-7'-HYDROXY- 11 '-METHOXY-3,4-DIHYDRO- 2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DTOXIDE OR

(1 S,3'R,0'R,7'S,8'E,11 'R, 12'S)-6-CHLORO- 12'-(CYCLOPROPYLMETHYL)-7'- HYDROXY-H'-METHOXY-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,irR,12'R)-6-CHLORO-12'-(CYCLOPROPYLMETOYL)-7 '- HYDROXY-! l'-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1 ,22'- |2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥίΤΤΗΛ(ΎΠ.ϋΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS,3 ⁱ R,6'R,7 ^f S,8'E,Il'S,12'S)-6-CHI RO-12'-(CYCLOPROPYLMETHYL)-7'- HYDROXY - 11 '-METHQXY-3,4-DlHYDRQ-2H, 15 Ή- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-!5'-ONE 13',13'-DIOXIDE (ISOMER 1)

STEP 1: 2-CYCLOPROPYL-N,N-BIS(4- METHOXYBENZYL)ETHANESULFON AMIDE

To a solution of N,N-bis(4-methox 'benzyl)methanesulfonamide

(Intermediate EE12) (3.15g, 9.39 mmol) in THF (12 mL) was added n-BuLi (2.5 M solution in hexanes, 4.88 ml, 12.2 mmol) at -78 °C dropwise. After the reaction was stirred at the same temperature for 10 min, (bromomethyl)cyclopropane (3.64 ml, 37.6 mmol) was added into the reation for 30 minutes at the same temperature. Then, the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched (Saturated aqueous NH ₄ C1) and extracted

(2xEtOAc). The combined organic layers were washed (brine), dried (MgSO-i), and concentrated under reduced pressure. Purification of the residue by flash column chromatography (4 g Si0 ₂ , 0%» to30% EA/hexanes) provided the product (2,70 g, 6,93 mmol, 74%). STEP 2: (2R,3S)-l-CYCLOPROPYL-3-METHOXYHEX-5-ENE-2-

SULFONAMIDE AND (2S,3R)- 1 -CYCLOPROPYL-3-METHOXYHEX-5-ENE- 2-SULFONAMIDE AND (2R,3R)- 1 -CYCLOPROPYL-3-METHOXYHEX-5- ENE-2-S ULF ON AMIDE AND (2S,3 S)- 1 -CYCLOPROP YL -METHOXYHEX- -ENE-2-SULFONAM1DE

Title compounds were prepared as a mixture of four diastereomeors by a procedure analogous to that described in Example 571, Steps 2 through 7, replacing N, -bis(4-methoxybenz>'l)-2-methylpiOpane-l-sulfonaniide in Step 2 with 2-cyclopropyl-N,N-bis(4-methoxybenzyl)ethanesulfonamide (Example 574, Step 1 ). STEP 3: ( 1S,3'R,6'R,7'S,8'E,I l'S,l 2'R)~6-CHLORO-l 2'-

(CYCLOPROPYLMETHYL)-7'-HYDROXY-ir-METHOXY-3,4-DIHYDRO-

2H, 15'H"SPIRO| NAPHTHALENE-!, 22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI M.T^.O'^.O^^lPE TACOSA [8, 16,18,24]TETRAEN]~1 S'~0NE 13', 13 '-DIOXIDE OR

(IS^' ^'R 'S^'EJ l'^n'SVe-CHLORO-n'-CCYCLO OPYLMETHYL)"?'" HY DROXY - 11 '-METHQXY-3,4-DIHYDRQ-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

| 20 jO.\ A| 1 31 1 HI Λ| I . ! -i | PI Α/Λ Π·. ΓΗ. Λί ^' ΥΌ .01 i -1.7.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8,I6,18,24]TETiL EN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3¾,6 ^, R,7 ^, S.8 ^, E. l l ^, R,12 ^, R)-6-CHLORO-12 ^, -(CYCLOPROPYLMETHYL)-7'- HYDROXY-1 1 '-METHOXY-3,4-DIHYDRO-2H,l 5Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TOIA[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'S)-6~CHLORO-12'~(CYCLOPROPYLMETHYL)-7'- HYDROXY- 1 l'-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[.1 ,14]DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE (ISOMER 1)

One of the title compounds was prepared by a procedure analogous to that described in Example 571, Steps 8 and 9, replacing [(3R,4S)-4-methoxy-2- methylhept-6-ene-3-sulfonamide and (3S,4R)-4-methoxy-2-methylhept-6-ene-3- sulfonamide] or [(3S,4S)-4-methoxy-2-rnethylhept-6-ene-3-sulfonamide and

(3R,4R)-4-methoxy-2-methylhept-6-ene-3-sulfonamide] in Step 8 with (2R,3S)-1- cyclopropyl-3-methoxyhex-5-ene-2-sulfonamide and (2S,3R)-l-cyclopropyl-3- methoxyhex-5-ene-2-sulfonamide and (2R,3R)-l-cyclopropyl-3-methoxyhex-5- ene-2-sulfonamide and (2S,3S)-l-cyclopropyl-3-methoxyhex-5-ene-2- sulfonamide (Example 574, Step 2), The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column: Phenomenex, Torrance, CA; gradient elution of 50% to 75% MeCN in water, where both solvents contain 0,1 % TFA, 30 min method) to provide one of the title compounds (isomer 1) the faster eiuting isomer. ^! H NMR (400 MHz, CDCb) δ ppm 8.32 (br. s., 1 H), 7.70 (d,■/ 8.4 Hz, 1 H), 7.18 (dd, ./ 2.3. 8.4 Hz, 1 H), 7.10 id. ./ 2.2 Hz, 2 H), 7.00 - 6.90 (m, 2 H), 5.83 - 5.69 (m, 2 H), 4.25 - 4.16 (ra, 2 H), 4.16 - 4.09 (m, 2 H), 3,75 (m, 1 H), 3.67 (m, 2 H), 3.48 - 3.26 (m, 4 H), 3.20 (m, I H), 2.86 - 2.70 (m, 2 H), 2.60 - 2.30 (m, 4H), 2.20 (m, 1 H), 2.05 - 1.63 (m, 8 H), 1.58 - 1.38 (m, 1 H), 1.11 (rn, 1 H), 0.64 - 0.51 (rn, 2 H), 0.32 - 0.20 (rn, 1 H), 0.19 - 0.07 (m, 1 H); m/z (ESI, +ve ion) 655.2 (M+H) ⁺ .

EXAMPLE 575. (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-12'- (CYCLOPROPYLMETHYL)-7'-HYDROXY- 11 '-METHOXY-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6, I 8,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,11 'R, 12'S)-6-CHLORO- 12 ^, -(CYCLOPROPYLMETHYL)-7'- HYDROXY- 1 l'-METHOXY-3,4-DlHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irR,12'R)-6-CHLORO-12'-(CYCLOPROPYLMETOY L)-7'- HYDROXY-! 1 '~METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[13]TmA[l,14]DL ZATETRACYCLO[14.7.2.0^^0 ¹⁹ - ²⁴ ]i TACOSA [8,16,18,24]TETR _! 4ENl-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E, I l'S,I2'S)-6-CHI RO-12'-(CYCLOPROPYLMETHYL)-7'-

HYDROXY-l l'-METHOXY-3,4-DiHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13 iTHIA[l,14jDL4ZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^l9 ' ²⁴ ]PENTACOSA [8,I6,18,24]TETRAEN]-I5'-ONE 13',13'-DiOXIDE (ISOMER 2)

One of the title compounds (isomer 2) was obtained as the second (slower) isomer from the reversed phase preparatory HPLC purification in Example 574, Step 3. ¾ NMR (400MHz, CDC h ) δ ppm 7.84 (br. s,, 1 H), 7,78 - 7.68 (m, 1 H), 7.18 (dd, ./ .2.2. 8.5 Hz, 1 H), 7.09 (d, ./ .2.2 Hz, 1 H), 6.97 ·· 6.87 (m, 3 H), 5.91- 5.70 (m., 2 I I ). 4.37 (m, 1 H), 4.20 (m, 1 H), 4.17 - 4.01 (m, 2 H), 3.77 (m, 3 H), 3.34 - 2.97 (m, 5 H), 2.85 - 2.68 (m, 3 H), 2.48 -2.30 (m, 2 H), 2,09 - 1.6 ! (m, 10 H), 1,50 - 1.35 (m, 1 H), 1, 18 - 1.05 (m, 1 H), 0.61 (m, 2 H), 0.25 - 0.15 (m, 2 H): m/z (ESI, +ve ion) 655.2 (M+H) ⁺ .

EXAMPLE 576, METHYL ((lS,3 ^! R,6'R,7'S,8 ^, E,i rS, 12'R)-6~CHLORO-7 ^! - MEmOXY-l l'-METHYL- 'JS'-DlOXIDO-l S'-OXO-S^-DlHYDRO^H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l, 14]DIAZATETRACYCLO[14.7.2. 0 ⁱ '.0

¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-12'-YL)ACETATE OR METHYL ((lS,3'R,6 ^! R,7'S,8 ^, E,i rR,12'S)-6-CHLORO-7'-METHOXY-l l'-METHYL- 13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO|NAPHTHALENE-l,2 2'- [20] OX A [13] ΤΗΐ A [ 1 ,14] DI AZ ATETR A C YCLO [ 14.7.2. 0 ³ · ⁶ .0

1 ⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-12'-YL)ACETATE OR METHYL ((1 S,3'R,6'R,7'S,8'E,1 rR,12'R)-6-CHLORO-7'-METHOXY-l Γ-METHYL- 13 ', 13'-DTOXIDO - 15 '-OXO-3 ,4~DIHYDRO-2H-SPIRO [NAPHTHALENE- ! ,22'- [20]OXA[13]THIA[1, 14]DL ZATETRACYCLO[14.7.2, 0 ^3/l .O

1 ⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-12'-YL)ACETATE OR METHYL ((l S,3'R,6'R,7'S,8'E, i rS,12'S)-6-CHLORO-7'-METHOXY-l l'-METOYL- 13'J 3'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTOALENE-l ,22'- [20]OXA[13]THIA[l , 14]DiAZATETRACYCLO[14.7,2. 0 ^; ''.0

1 ⁹ - ²⁴ -12 ^, -YL)ACETATE

To a vigorously stirring solution of methyl ((1S,3'R,6'R,7'S,8'E,11'S,12'R)- 6-chloro-7'-hy droxy- 11 '-methy 1- 13 ', 13 '-di oxido- 15 '-oxo-3,4-dihy dro-2H- spiro[naphthalene-l,22'-[20]oxa[13]thia[l, 14]diazatetracyclo[14.7.2. 0 ^3,6 .0 ¹⁹ - ²⁴ ]pentacosa[8, 16, 18,24]tetraen] - 12'-yl)acetate or methyl

r-methyl-lS'JS'-dioxido- 15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2. 0 · ⁶ .0

1 ⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraen]-12'-yl)acetate or methyl

((1 S,3'R,6'R,7'S,8'EJ ! ⁱ R, 12'R)-6-chloro-7'-hydroxy-l l'-methyl-13', 13'-dioxido- 15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[ 1 3]thia[ 1 , 14] diazatetracy clo[ 14,7.2, 0 ³ - ⁶ .0

1 ⁹ ' ² ]pentacosa[ 8, 16, 18,24]tetraen] - 12'-yl)acetate or methyl

((l S,3'R,6'R;7'S,8Έ, l l 2'S)-6-chloro-7'-hydίΌxy-l l '-methyl 3^13'-dloxido- 15'-oxo-3 ,4-dihy dro-2H-spiro [naphtha! en e- 1 ,22'- [20]oxa[l 3]thia[l, 14]diazatetracyclo[14.7.2. 0 · ⁶ .0

¹⁹ - ²⁴ ]pentacosa| 8,16, 18,24]tetraen]-12'-yl)acetaie (Example 647) (22 mg, 0.033 mmol) and tetrafluoroboric acid (48% w/w % in water, 5.1 μΕ, 0.039 mmol) in DCM (0.66 mL) was added (trimethylsilyl)diazomethane (2.0 M solution in Et ₂ 0, 20 μί,, 0.039 mmol) at 0 °C. After the reaction was stirred at 0 °C for 1 h, the reaction was quenched (MeOH), diluted (cold water), extracted (2xEtOAc). The combined organic layers were washed (brine), dried (MgSOi), concentrated under reduced pressure. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μτη column; Phenomenex, Torrance, CA; gradient eluiion of 50% to 80% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to provide one of the title compounds as a white foam (8.1 mg, 0.012 mmol). ^; l ! NMR (400MHz, CDCb) δ ppm 7.99 (br. s., 1 H), 7.70 (d, ./ 8.6 Hz, 1 I I ). 7.19 (dd,■/ 2.2. 8.5 Hz, 1 H), 7.10 (d,■/ 2.3 Hz, 1 H), 6.95 - 6.88 (m, 3 H), 5.99 - 5.91 (rn, 1 H), 5,54 (dd, ./ 9.3. 15.2 Hz, 1 H), 4,95 (t, 6.4 Hz, 1 H), 4.10 (s, 2 H), 3.83 (d, .7=15, 1 Hz, 1 H), 3,78 (s, 3 H i. 3.74 - 3.67 (m, 2 H), 3.29 - 3.21 (m, 4 H), 3.15 - 2.96 (m, 2 H), 2.84 - 2.67 (m, 3 H), 2.52 - 2.42 (m, 1 H), 2.41 - 2.26 (ra, 1 H), 2.16 - 1.76 (m, 9 H), 1.74 - 1.60 (ra, 1 H), 1.40 (m, 1 H), 1.09 (d, .7=6, 1 Hz, 3 H); m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 581. (1 S,3'R,6'R,1 l'S.n'R -CHLORO-l l'.n'-DIMETHYL-?'- METHYLIDENE-3,4-DIHYDRO-2H,15'H-SPIRO|NAPHTHALENE-l,22'-

[20]OXA[ 13]TH1A[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13 ', 13 '-DIOXIDE

STEP 1: (lS,3 ^f R,6'R,ll'S,12'R)-6-CHLORO-il',12'-DiMETOYL-3,4- DIHYDRQ~2H,7'H, 15'H-SPIRO[NAPHTHALENE-l .22 ^" -

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i.()l i 4.7.2 U · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [16,18,24]TRIENE]-7',15'-DIQNE 13',13'-DIOXIDE

To a solution of (1S,3'R,0 ^! R,7'S,8'E,1 rS,12 ^! R)-6-chioro-7'-hydroxy- ir,12'-dimethyl-3,4-dihydro-2h,15'h-spiro|naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatefra<^

aen]-15'-one 13',13'-dioxide (1.20 g, 2.02 mmol. Example 719, Step 2) in EtOAc (50 mL) was added platinum (IV) oxide (92 g, 0.40 mmol, Aldrich) and the reaction was fitted with a Hz balloon and stirred vigorously for 15 h. The reaction mixtyre was filtered through Celite and concentrated to a yellow glaze. The yellow glaze was dissolved in dichloromethane (20 mL) and then Dess-Martin periodinane (0.95 g, 2.2 mmol, Aldrich) was added in four portions over 5 min at 0 °C. After the reaction was stirred at 0 °C for 15 min, the reaction was quenched with IN sodium thiosulfate solution at 0 °C (10 mL) and stirred vigorously at rt for 30 min. Then the reaction mixture was extracted (EtOAc). The separated organic layer was washed (brine), dried (Na?.S04), and concentrated under reduced pressure. The residue was purified by silica-gel chromnatography (0-25%

EtQAc/hexs, 0.1% AcOH) to provide (lS,3'R,6'R,irS,12'R)-6~chloro-l l',12'~ dimethyl-3,4-dihydro-2H,7'H, 15'H-spirofnaphthalene-l ,22'-

7',15 ^, -dione 13',13*-dioxide as an off-white solid (0.85 g, 70% yield), m/z (ESI, +ve ion) 599.2 {W W) .

STEP 2: (1S,3'R,6'R,1 l'S,12'R)-6-CHLORO-l l',12'~DlMETHYL-7'- METHYLIDENE-3,4-DIHYDRO-2H,151^SPIRO[NAPHTl-LALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 18,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE To a solution of (1S,3'R,6'R,1 rS,12'R)-6-chloro-l l',12'-dime l-3,4- dihydro-2H,7'H,15TI-spiiO|naphihaiene-l,22'-

[20]oxa[I3]1hia[l,I4]diazatetTacyclo[14J.2.0 ³ ^0 ^]9 ' ²⁴ ]pentacOsa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide (60 mg, 0.100 mmol) in THF (5.00 ml.) was added Tebbe reagent (285 mg, 1.00 mmol, Aldrich) at rt. After the reaction was stirred at rt for 30 min, the reaction was quenched with saturated sodium bicarbonate solution (10 ml.). Then the reaction mixture was extracted (Et ₂ 0). The separated organic layer was washed (brine), dried (Na ₂ S04), and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (5-30%

EtO Ac/heptanes with 0.1% AcOH) to give the title compound as an off-white solid (12 mg, 0.018 mmol, 18% yield). Ή NMR (400MHz, CD2CI2) δ 8,20 - 7.91 (m, 1H), 7.68 - 7.58 (m, IH), 7.16 - 6.95 (m, 2H), 6.89 - 6.73 (m, 3H), 4.83 - 4.55 (m, 2H), 4.09 - 3.93 (m, 3H), 3.74 - 3.49 (m, 2H), 3.23 - 3.04 (m, IH), 2.92 (dd, ./ 8.3.15.4 Hz, IH), 2.79 - 2,62 (m, 3H), 2.55 - 2,42 (m, IH), 2.05 - 1.68 (ra, 9H), 1.57 - 1.34 (m, 6H), 1.31 (d, J=7.2 Hz, 3H), 0.91 (d, .7=6.8 Hz, 3H). m/z (ESI, +ve ion) 597.2 { M · H ) .

EXAMPLE 597, (IS,3'R,6'R,7'S,9'E,1 l'S)-6-CHLORO-7',l l'~DIHYDROXY-3,4~ DIHYDRO-2H, 15 'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9, 16, 18,24]TETRAEN] - 15'-ONE ! 3 ^' .13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,9'E, 11 'R)-6-CHLORO-7', 1 l'-DIHYDROXY-3,4-DIHYDRO- 2H, 15'H-S PIRO | N APHTHAE ENE- 1 ,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[9, 16, 18,24]TETRAEN]-1 S'-ONE 13 ',13 '-DIOXIDE

To a solution of sodium ethoxide (18.4 ml, 49.3 mnioi) in EtOH (10 ml) was added benzyl mercaptan (5.82 ml, 49.3 mmol). potassium iodide (0.250 g, 1.51 mmol) and 2-chloro-l, l -dimethoxyethane (5,6! ml, 49.3 mmol). The reaction mixture was heated to reflux for 4h. The precipitate was filtered off, washed with ethanol. The filtrate was concentrated in vacuo, and purified by column chromatography on silica gel (20% EtOAc/hexanes) to afford benzyl (2,2- dimethoxyethyl suifane (9.00 g) as a slightly yellow oil.

The oil (6.00 g) was heated at 60 °C with 0.5 M aqueous H -SO t (30 mL) for 2h. The reaction mixture was neutralized with solid NaHCOs and extracted three times with 20 mL portions of DCM. The organic phase was dried over Na_S04 and concentrated to afford 2-(benzylthio)acetaldehyde (4.84 g) as a slightly yellow liquid. ¾ NMR (500 MHz, CDCb) δ 9.43 (1 H, t, J=3.3 Hz), 7.37-7.25 (5 H, m), 3.64 (2 H, s), 3.09 (2 H, d, J=3.4 Hz), STEP 2: (R)-l -(BENZYLTHIO)BUT-3-EN-2-OL ^N/) (S)-l - (BENZYLTHiO)BUT-3-EN-2-OL To a solution of 2-(benzylthio)acetaldehyde from Step 1 (4.78 g, 28.8 mmol) in THF ( 10 mL) at 0 °C was slowly added vinylmagnesium bromide, 0.7m solution in tetrahydrofuran (49,3 mL, 34.5 mmol). After stirring at 0 °C for 30 min, the reaction was quenched with saturated aqueous N i hil solution. The precipitated solids were dissolved with water and extracted with EtOAc. After drying and concentration, the residue was purified by column chromatography (20% EtOAc/hexanes) to give (R)-l -(benzylthio)but-3-en-2-ol and (S)-l- (benzylthio)but-3-en~2-ol (1.39g). ¾ NMR (500 MHz, CDCb) δ 7,30-7.25 (m, 3 I I I 7.24-7, 19 (m, 2 H), 5.82-5,74 (m, 1 H), 5.24 i d! . ,/ 1 7 1 . 1.3 Hz, 1 H), 5.1 ! (dt, ,/ 1 0 3. 1 ,2 Hz, I H), 4.13-4.07 (m, I H), 3.71 (s, 2 H), 2,61 (dd, ./ 1 3.7. 3.9 Hz, 1 H), 2.47 (dd, .7=13.7, 8.3 Hz, 1 H), 2.38 (br. s., 1 H).

STEP 3 : (R)-(( 1 -(BENZYLTHIO)BUT-3-EN-2-YL)OXY)(TERT- BUTYL)DIPHENYLSILANE ^IND (S)-((l -(BENZYLTHIO)BUT-3-EN-2- Y I . sOXY )f N K ! · !'>!. ! Y j . jDI Pi I ί Y I S! ! . AN I ·:

To a solution of (±)l -(benzylthio)but-3-en-2-ol from Step 2 (1.0 g, 5.15 mmol) in CH2.CI2 (25.7 ml) was added 2,6-lutidine (1 ,20 ml, 10.3 mmol), followed by tert-butyldiphenylsilyl triflate (2.40 g, 6.20 mmol). The reaction mixture was stirred at ambient temperature for 2h. The volume of the reaction was reduced to half by concentration under vacuum, and then the reaction mixture was loaded directly to a cartridge of silica gel and purified by column chromatography, (0- 20% EtOAc/hexanes, 40 g S1O2) to give (R)-((l -(benzylthio)but-3-en-2- l)oxy )(tert-b uty l)dipheny lsil ane and (S)-(( 1 -(benzyl thio)but-3 -en-2-y l)oxy )(tert- butylMiphenylsilane (2. 10 g). Ή NMR (500 MHz, CDCb) δ 7.72 - 7.67 (2 H, m), 7.67 - 7.62 (2 i !. m), 7.46 - 7.40 (2 I I. in). 7.37 (4 H, q, ./ 6.9 Hz), 7.26 - 7.17 (3 H, m), 7.17 - 7.11 (2 H, m), 5,87 (1 H, ddd, I 7. 1 . 10.6, 6.4 Hz), 5.09 - 5.01 (2 H, m), 4.24 (1 H, q, ,1=6.2 Hz), 3.52 - 3.42 (2 H, m), 2.60 - 2.52 (1 H, m), 2.52 - 2.45 (1 H, m), 1.09 - 1.05 (9 H, m).

STEP 4: (S)-2-((TERT-BUTYLDIPHEJ YLSILYL)OXY)BUT-3-ENE- 1- SULFON AMIDE AND (R)-2-((TERT-BUTYLDIPHENYLSILYL)OXY)BUT-3 - ENE-1 -SULFONAMIDE

To a mixture of (R)-((l-(benzylthio)but-3-en-2-yl)oxy)(tert- butyl)diphenylsilane and (S)-((l-(benzylmio)but-3-en-2-yl)oxy)(tert- butyl)dipheny lsil ane from Step 3 (2.10 g, 4.85 mmol) and iodosylbenzene (3.52 g, 16.0 mmol) in 300 ml of ether was added concentrated aqueous hydrogen chloride (35.6 mL, 427 mmol) gradually with vigorously Stirling. The resulting mixture was stirred for 3h and the lay ers was separated. The organic lay er was washed with water and dried over Na ₂ S04, concentrated under reduced pressure to give the crude sulfonylchloride product as a pale-yellow oil. The oil was dissolved in 100 mL of DCM, and this solution was slowly added to a stirring solution of aqueous NFbOH (23%) (67.5 mL, 485 mmol), chilled in an ice-water bath. After the addition, the mixture was stirred at ambient temperature for 0.5h. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2S€>4 and then concentrated under reduced pressure. The residue was purified by column chromatography, (0-70%

EtOAc/hexanes, 80g S1O2) to give (S)-2-((tert-butyldiphenylsilyl)oxy)but-3-ene- 1 -sulfonamide and (R)-2-((tert-butyldiphenylsilyl)oxy)but-3-ene- 1 -sulfonamide. ^] H NMR (500 MHz, CDCb) δ 7.74 - 7.69 (m, 2 H), 7.69 - 7.65 (m, 2 H), 7.50 - 7.44 (m, 2 H), 7.43 - 7.37 (m, 4 H), 5.92 (ddd, .7=17,2, 10.3, 7.2 Hz, 1 H), 5.06 (dt J=5.1, 1.0 Hz, I H), 5.03 (dt J=l 1.9, 1.0 Hz, 111).4.75 - 4.70 (ra, 111).4.43 (s, 2 H), 3.38 - 3.32 (m, 1 H).3.29 - 3.23 (m, 1 Hi.1.11 - 1.07 (m, 9 H).

The enantiomers were separated by SFC (OJ-H column with 22.5 g/min IPA (20

STEP 5: (S)-N-(((S)-2-((TERT-BUTYLDIPHE YLSILYL)OXY)BUT-3-EN-l - YL)SULFONYL)-6*-CHLORO-5 -(((1 R,2R)-2-(( S) - 1 -HYDROXYBUT-3 -EN- 1 - Y!.)i VC i OBL TYUYlh ! 11Y!.)-3'.4. .5- Π·. ! RAI !YI>RO-2l i.2'1 !- SPIRO[BENZO[B] [ ;i,4]OXAZEPINE-3, 1 '-NAPHTHALENE j-7- CARBOXAMIDE OR (S)-N-(((R)-2-((TERT-

BUTYLDIPHENYLSILYL)OXY)BUT-3-EN-l-YL)SULFON ^T L)-6'-CHLORO- 5-(((lR,2R)-2-((S)-l-HYDROXYBUT-; EN-l-YL CYCLOBUlY ^? L)METHYL - S'^^'j.TETRi^HYD O^H^'H-SPl OtBE ZOtBJIl^iOXAZEPlNE-S,!'- NAPHTHALENE] -7-C ARBOXAMIDE

N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (31.8 mg, 0.166 mmol) was added portionwise to a solution of (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l-hydroxybut-3-en-l-yl)cyclobutyl)me l)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (Intermediate AA13A) (50,0 mg, 0.104 mmol) and N,N-dimethylpyridin-4-amine (DMAP) (38,0 mg, 0.311 mmol) in CH2CI2 (2 ml) at 0 °C and stirred at 0 °C for 30 mm. (S)-2-((tert-butyldiphenylsilyl)oxy)but-3-ene-l -sulfonamide or (R)-2-((teri- butyldiphenylsilyl)oxy)but-3-ene- i -sulfonamide (first eluting enantiomer from chiral separation in Step 4, 96 mg, 0.246 mmol) was added and the reaction was stirred at 0 °C for 3h then at ambient temperature for 63h. The reaction mixture was loaded direcily to silica gel cartridge and purified by column chromatography (0-50% EtOAc/hexane, 12g S1O2) to provide (S)-N-(((S)-2-((tert- butyldiphenylsilyl)oxy)but-3-en-l-yl)sulfonyl)-6'-chloro-5-( ((lR,2R)-2-((S)-l- hydroxybut-3-en-l-yl)c clobutv'l)methyl)-3',4,4',5-tetrahydfo-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide or (S)-N-(((R)-2- ((tert-bu1yldiphenylsilyl)oxy)but-3-en-l-yl)sulfonyl)-6'-chl oro-5-(((lR,2R)-2-((S)- l-hydrox 'but-3-en-l-yl)cyclobu1yl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spirojbenzojb] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxamide.

STEP 6: (S)-6*-CHLORO-5-((( lR,2R)-2-((S)-l-HYDROXYBUT-3-EN-l - YL)CYCLOBUTYL)METHYL)-N-(((S)-2-HYDROXYBUT-3-EN- 1 - YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIR0[BENZ0|;B][ 1,4]0XAZEPINE-3,1'-NAPHTHALENE]-7- C ARBOXAMIDE OR (S )-6'-CHLORO-5 -((( 1 R,2R)-2-((R) - 1 -HYDROXYBUT- 3 -EN- 1 - YL)C YCLOBUTYL)METHYL)-N-(((S)-2-H YDROXYBUT-3 -EN - 1 - YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE

A solution of (S)-N-(((S)-2-((tert-butyldiphenylsilyl)oxy)but-3-en-l- yl)sulfonyl)-6 ^, -chloro-5-(((lR _s 2R)-2-((S)-l-hydroxybut-3-en-l- yl)cvxlobut5d)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxamide or (S)-N-(((R)-2-((tert- butyldiphenylsilyl)oxy)but-3-en-l-yl)sulfonyl)-6'-cMoro-5-(( (lR ₅ 2R)-2-((S hydrox 'but-3-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2' H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carboxamid e from Step 5(44 mg, 0.051 mmol) in THF (1.0 ml,) was treated with TBAF, LOM in THF (0.040 rriL, 0.15 mmol) and the resulting solution was stirred at ambient temperature for 80 h. The solution was absorbed onto a cartridge of S1O2 and purified by column chromatograph , to give (S)-6'-chloro-5-(((l R,2R)-2-((S)- 1 -hydroxy but-3-en- 1 - yl)cyclobut'l)methyl)-N-(((S)-2-hydroxybut-3-en-l-yl)sulfony ])-3',4,4 ^, ,5- tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine~3, -naphthalene]-7-carboxamide or (S)-6'-chloro-5-(((lR,2R)-2-((R)-l-hydrox'but-3-en-l-yl)cycl obu1yl)me1hyl)- N-(((S)-2½droxybut-3-en-l-yl)sdfonyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2H- spiro[benzo[b] [ 1 ,4] oxazepme-3, 1 '-naphthalene] -7-carboxamide (31 mg). MS (ESI) mJz = 637.1 [M+Naj L

STEP 7: (IS,3'R,6'R,7'S,9'E,1 l'S)-6-CHLORO-7',l l'-DTHYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DL ZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [9,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ⁱ R,7'S,9'E,Li'R)-6-CHLORO-7',ll'-DiHYDROXY-3,4-DIHYDRO-

2H, 15 Ή-S PIRO [N ΑΡΗΤΉ ALENE- 1.22'-

[20]QXA[13]THiA[U4]DiAZATET^^

[ 9, 16, 18,24 jTETRAEN j -15'-ONE 13', 13'-DIOXIDE

(S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l- y!)c^ciohusyi)nicihy!)-\-iiiS)-2-h>drox>!:Hi!- -en-i^n

tetraliydiO-2H,2'H-spiro|benzo|b][l,4]oxazepine-3,l'-naphtha iene]-7-carboxamide or (S)-6'-chloro-5-(((lR,2R)-2-((R)-l-hydroxybut-3-en-l-yl)c> ;'clobutyl)methyl)- N-(((S)-2½droxybut-3-en-l-yl)sdfonyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2H- spiro[benzo[b][L4]oxazepme-3,L~naphthalene]-7-carboxaniide from Step 6 (31 mg, 0,05 ! mrnol) was dissolved in degassed toiuene (26 mL), To this solution was added Hoveyda-Grubbs 2 ^nd Generation catalyst (3.0 mg, 4.8 μηιοΐ) at room temperature. The mixture was stirred at 110 °C under argon for 60 min. Air was bubbled through the reaction mixture for 10 min, then the solution was concentrated. The residue was purified by HPLC (5 to 95% MeCN/HbO with 0.1% TFA) to give a product containing an E-olefin. This material was further purified by column chromatography (0-5% MeOHDCM, 8g Sit ) to give one of the title compound (5.1 mg). ¾ NMR (500 MHz, CDCb) δ 10.14 (br. s., 1 H), 7.71 (d, J=8.3 Hz, 1 H), 7.41 (dd, ./ 8.3.1.7 Hz, 1 H), 7.18 (dd, =8.6, 2.2 Hz, 1 H), 7.10 (d, ./ 2.2 Hz, 1 H), 6.98 (d, ./ 8.3 Hz, 2 H), 5.88 (ddd, ./ 14.7.10.1, 4.0 Hz, I H), 5.65 (dd, ./ 15.2, 8.3 Hz, 1 H), 4.68 (d, 6.8 Hz, 1 H), 4.19-4.12 (ra, 2 H), 4.07 (dd, .7=15,2, 9.0 Hz, 1 H), 3.94 (d, .7=9,8 Hz, 1 H), 3.78 (dd, «7=15.3, 5,3 Hz, 1 H), 3.63 (d, ./ 14.2 Hz, 2 H), 3.38-3.22 (m, 2 H), 2.96 (br. s., 1 H), 2.87 (br. s., 1 H), 2.83-2.74 (m, 2 H), 2.52-2.43 (m, 1 H), 2.43-2.32 (m, 1 H), 2.22-2.11 (ra, 1 H), 2.05-2,00 (m, 2 H), 1.99-1,87 (m, 2 H), 1.87-1,71 (m, 3 H), 1.71-1,58 (m, 2 H), 1.52 (br. s., 1 H); MS (ESI) m!z = 587.1 | M 1! j .

EXAMPLE 598. (1 S,3'R,6'R,7'S,9'E,1 l'R)-6-CHLORO-7 ^f ,l l'-DIHYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - |2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2,0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [9,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13'-DIOXIDE OR

(lS,3¾,6'R,7^,9'E,!!'S)-6-CHLORO-7',i -DIHYDROXY-3,4-Dn-riT)RO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [9,16,!8,24]TETRAENl-15'-ONE 13',13'-D )XIDE

The title compound was synthesized following the same manner as Example 597 Step 5 - Step 7 with the second eluting enantiomer isolated from Step 4. ¾ N.V1R (500 MHz, CDCb) δ 10.16 (br. s., 1 H), 7.71 (d, J=8.6 Hz, 1 H), 7.43 (dd. ./ 8.3. 1.7 Hz, 1 H), 7.18 (dd, J=8.4, 2.3 Hz, 1 H), 7.10 (d, J=2A Hz, 1 H), 6.94 - 7.03 (m, 2 H), 5.80 - 5.9 ! (m, 1 H), 5,76 (dd, ./ ! 5.2, 2.0 Hz, 1 H), 4,62 (d, .7=8.3 Hz, 1 H), 4,27 (dd, J=15.7, 4.2 Hz, 1 H), 4.22 - 4.10 (m, 2 H), 3.92 (d, J=9.8 Hz, 1 H), 3.68 (dd, J=15.7, 3.9 Hz, 1 H), 3.66 - 3.52 (m, 2 H), 3.41 - 3.26 (m, 2 H), 3.01 (br. s., 2 H), 2.87 - 2.69 (m, 3 H), 2.55 - 2.38 (m, 2 H), 2.18 (q, 8.6 Hz, 1 H), 2.08 - 1.99 (m, 1 H), 1.98 - 1.87 (m, 2 H), 1.86 - 1.75 (m, 3 H), 1.73 - 1.63 (m, 1 H), 1.61 - 1.43 (m, 1 H); MS (ESI) m/z = 587.0 [M+H] ^l .

EXAMPLE 599. METHYL Ν-((18,3Έ,6 ^! ,7·8,8Έ,12¾)-6-(:ΗίΟΚΟ-12 ^! -

METOYL-13 ^f ,I3'-DIOXIDO-I5'-OXO-3,4-DIHYDRO-2H-

SPi ()i \ A FH i ! l. ! J \ ! :- 1 .22 -

[20]OXA[ 13]TH1A[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN j - 7'-YL)GL YCINATE-TRIFLUORO ACETIC ACID

STEP 1 : (S)-METHYL 5-((( 1 R,2R)-2-((E)-(((R)-TERT- BUTYLSULFINYL)IMINO)METHYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4',5"TETRAHYDRO-2H,2'H-

SPIRO I BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

CARBOXYLATE

To an oven-dried 100 ml round bottom flask was added (S)-methyl 6'- cWoro-5-(((lR,2R)-2-formylc clobu1yl)me l)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro|benzo|b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylaie (Intermediate

AAl lA, Step 20 A) (1.20 g, 2.64 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (961 mg, 7.93 mmol) and CuS0 ₄ (1.52 g, 15.9 mmol) followed by DCM (15 ml). The resulting mixture was stirred at ambient temperature for 66 h. The crude reaction mixture was filtered, concentrated and the residue purified by column chromatography (0 to 30% EtOAe/hexanes, 40g SiCte) to provide (S)-methyl 5- (((lR,2R)-2-((E)-(((R)-tert-but lsulflnyl)irnino)me l)cyclobu1yl)me1ilyl)-6 ^, - chloro-3',4,4',5-tetrahydro-2H,2'H-spiro| benzoj b] [ 1 ,4 joxazepine-3, Γ- naphthalene]-7-carboxylate as a white solid. MS (ESI) mlz = 579.3 [M+Na] ⁺

STEP 2: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)-l-((R)-l,l- DIMETHYLETHYLSULFINAMlDO)ALLYL)CYCLOBUTYL)METHYL)- 3 4,4 5-TETRAHYDRO-2H,2Ti-SPIR()|;BENZO| B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYL ATE

To a solution of (S)-methyl 5-(((lR,2R)-2-((E)-(((S)-tert- butylsulfinyl)inimo)memyl)cyclobutyl)m^

2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate from Step 1 (0.980 g, 1.76 mmol) in DCM (18 ml) at -10°C (cooled in an dry ice-acetone bath by controlling small amount of dr ' ice added every 5 min or so) was added vinylmagnesium bromide, 1.0 M in THF (2.1 mL, 2.1 mmol) dropwise. The reaction mixture was stirred at this temperature for lh. More vinylmagnesium bromide, l .OM in THF (2.0 mL, 2.0 mmol) was added and stirred for 30 min more before the reaction was quenched by addition of saturated aqueous NH4CI (50 ml). The solution was extracted with DCM (80 mL). The separated organic solution was dried over anhydrous Na2S€>4 and concentrated under reduced pressure. The residue was purified by column chromatography (0-60%

EtGAc/hexanes, 80g S1O2) to give (S)-methyl 6'-chioro-5-(((iR,2R)-2-((S)-i-((R)- 1 , 1 -dimethylethylsulfinamido)aliyl)cyxiobur}'i)methyl)~3',4,4', 5~tetraliy dro- 2H,2'H-spiro benzo b] [ l,4]oxazepine-3,r-naphthalene|-7-carboxylate. MS (ESI) mlz ^:zz: 585.2 [M+H] ⁺ . The other diastereomer was detected but not isolated.

STEP 3: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((S)-l-((R)-l ,1- DIMETHYLETHYLSULFINAMIDO)ALLYL)CYCLOBUTYL)METHYL)- 3\4,4',5-TETl AHYDRO-2H,2'H~SPIRO[BENZO[B][ l,4]OXAZEPINE-3,r- NAPHTHALENE j -7-C ARBOXYLIC ACID

(S)-methyl 6'-chloro-5-(((lR,2R)-2-((S)-l-((R)-l,l- dimethylemylsulfmamido)allyl)cj'clobut l)methyl)-3^4,4 5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late from Step 2 (493 mg, 0,842 mmol), 1M aqueous Li OH (4.2 mL, 4.2 mmol), THF (5 mL) and EtOH (5 mL) were mixed and stirred at 50 °C for 2h. After cooling to ambient temperature, the mixture was acidified by addition of saturaded aqueous NFLCi, and then extracied with EtOAc. The exiract was dried over MgS04, filtered and concentrated to yield (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-((R)-l,l- dime1hyleAylsulfinamido)allyl)cyclobutyl)m

spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carbox 'lic acid as a white solid. MS (ESI) m/z = 571,2 [M+H] ⁺ . STEP 4: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-((R)-l,l-

DIMETIlYLETHYLSULFINAMIDO)ALLYL)CYCLOBUTYL)METHYL)-N- ((R) 1EX-5-EN-2-YLSULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'FI- SPIRQ [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-N APHTHALENE] - 7- CARBOXAMIDE

(S)-6'-chloro-5-(((lR,2R)-2-((S)-l-((R)-l. l- dimethylethylsulfinamido)allyl)cyclo^

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid from Step 3 (480 mg, 0.840 mmol) was azeotroped with toluene. (R)-hex-5-ene-2- sulfonamide (Intermediate EE20) (330 mg, 2.02 mmol), DMAP (257 mg, 2.101 mmol), triethylamine (0.351 mL, 2.52 mmol), and N.l -((ethylimino)methylene)- N3,N3-dimethylpropane-l,3-diamine hydrochloride (322 mg, 1.68 mmol) (added at 0 °C) in DCM (20 mL) was stirred at ambient temperature for 17 h. The mixture was concentrated under reduced pressure and purified by column chromatography (0-10% V!eO! I DCM, 40g S1O2) to give (S)-6"-chloro-5- ((( 1 R,2R)-2-((S)~ 1 -((R)- 1 , 1 -dimethy lethy lsul .fmamido)ally l)cy clobuly l)methy 1)- N-((R)~hex-5-en-2-ylsdfonyl)-3^4,4^5 etrahydi -2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxamide. MS (ESI) mlz = 738 [M+Na] ⁺ .

STEP 5: (S)-l -((lR,2R)-2-(((S)-6'-CHLORO-7-(((R)-HEX-5-EN-2-

YLSULFONYL)CARBAMOYL)-3',4'"DIHYDRO-2H,2'H"

SPIRO I BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALEN j -5 (4H)- YL)METHYL)CYCLOBUTYL)PROP-2-EN- 1 - AMINIUM CHLORIDE

To a solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-((R)-l ,l- dimemylemylsulfinamido)allyl)cyclobutyl)methyl)-N-((R)-hex-5 -en-2- ylsulfonyl)-3 4,4^5-tetTahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,T- naphthalene]-7-carboxamide from Step 4 (700 mg, 0,977 mmol) in t-BuQH (10 niL) at ambient temperature, was added a solution of HC1 (4 M in 1,4-dioxane, 489 μί, 1.95 mmol), dropwise. The reaction mixture was stirred at for 30 min, then was concentrated under reduced pressure. Purification by column

chromatography gave (S)-l-((lR,2R)-2-(((S)-6 ^! -chloro-7~(((R)-hex-5~en-2- ylsulfonyl)carbamoyl)-3 ^, ,4'-dihydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, - naphthalenl-5(4H)-y )meihyl)cyclobuly])prop-2-en-l-aminiurn chloride. MS (ESI) mlz = 612.3 iM+Hf.

STEP 6: 2-(TRIMETHYLSILYL)ETHYL ((S)-l-((l R,2R)-2-(((S)-6'-CHLORO-

7 ((R)-IlEX-5-EN-2-YXSULFONYL)CARBAMOYL)-3',4'-DIHYDRO-2I-T,2 ^f H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 ^* -N APHTH ALEN] -5 (4H)~

YL)METHYL)CYCLOBUTYL)ALLYL)CARBAMATE

(S)-l -((1 R,2R)-2-(((S)-6'-chloro-7-(((R)-hex-5-en-2- ylsulfonyl)carbamoyl)-3 4'-dihydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalen]-5(4H)-yl)methyl)c}'clobutyl)prop-2-en-l-aminium chloride from Step 5 (240 mg, 0.392 mmol) in 1,4-dioxane (3.9 mL) was added l-[(2- ti methylsilyl)ethoxycarbonyloxyjpyrrolidin-2,5-dione (132 mg, 0.510 mmol), followed by triethylamine (0.164 mL, 1. 18 mmol). Trie mixture was stirred at ambient temperature for 20 minutes then was loaded into a silica gel cartridge and purified by column chromatography (0-30% EtOAc/ hexanes, 24g S1O2) to afford 2-(trimethylsily])ethyl ((S)-l -((lR,2R)-2-(((S)-6 ^* -chloro-7-(((R)-hex-5-en-2- ylsulfonyl)carbamoyl)-3V4 ^! -dihyd

naphthaienl-5(4H)-yl)methyl)cyclobut5 _' l)aliyl)carbamate. STEP 7: 2-(TRIMETHYLSILYL)ETHYL ((1 S,3 ^! R,6'R,7'S,8'E, 12'R)-6-

CHLORO- 12'-METHYL- 13', 13'-DI OXIDO- 15'-OX()-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

|;8,16, 18,24]TETRAENj-7'-YL)CARBAMATE

A solution of 2-(tnmethylsilyl)ethyl ((S)-l-((lR,2R)-2-(((S)-6'-chloro-7- (((R)-hex-5-en-2-ylsulfonyl)c^

spi ro [benzo [b] [ 1 ,4] oxazepine-3 , 1 ' -naphtha! en] -5 (4H)~

yl)methyl)cyclobutyl)allyl)carbamate from Step 6 (152 mg, 0.201 mmol) in 1,2- dichloroethane (70 mL) was sparged with argon for 10 min. To this solution was added Ti(OPr) ₄ (17 mg, 0.060 mmol), and the mixture was heated at 50°C for 15 min under and atmosphere of argon. Hoveyda-Grubbs 2 ^nd Generation catalyst (25 mg, 0.040 mmol) was added, and the reaction mixture was continued to heat at this temperature for 19h. The reaction mixture was cooled to ambient temperature and then air was bubbled through the reaction mixture for 5 min. The solution was concentrated and then the residue was purified by column chromatography (0%, to 60% (0.3%, AcOH/EtOAc)/hexanes, 24g SiC ), affording 2-(trimet ylsilyl)ethyl ((lS,3 ^, R,6 ^, R,TS,8 ^, E,12 ^, R)-6-chloro-12 ^, -methyl-13 ^, ,13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-L

[20joxa 13]thia[ l, 14]diazatetracycfo[^^

n]-7'-yl)carbamate. MS (ESI) mlz = 728,2 [M+H .

STEP 8: (18,3ΊΙ,61 ,7 ,8Έ,12¾ 7'-ΑΜ1 Ο-6"€ΉΕ01 0-12 ^! ~ΜΕΊΉΥΕ-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-D10X1DE TR1FLU ORO ACETATE

2-(trimethylsilyl)ethyl ((l S,:rR ₅ 6'R,7^,8T,J 2 ^! R)-6-chloro-12'-methyl- 13',13 ^, -dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[l ,14]cUazatetracyc^

n]-7'-yl)carbamate from Step 7 (S ! mg, 0,070 mraol) was dissolved into TFA (0.1 mL) and DCM (0.3 mL) and stirred at room temperature for for 2 h. The reaction mixture was loaded directly onto a cartridge of S1O2 and was purified by column chromatography (0-20% MeOH/DCM, 20g S1O2) to give (1 S,yR,6'R,TS,S'E,l2'R)-T- amino~6~chloro~12 ^! -methyl~3,4-dihydro-2H 15H-spiro[naphthalene-L

[20]oxa[13]thia[U4]diazatetra^

nj-15'-one 13',13'-dioxide trifluoroacetate. MS (ESI) miz = 584.3 M-CF ₃ C0 ₂ ] ⁺ .

STEP 9: METHYL N-((lS,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-12'-METHYL- 13 13'-DIOXIDO- 15 '-OXO-3 ,4~DIHYDRO-2H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TmA[ 14]DlAZATETRACYCLO[14.7.2.0^^0 ¹⁹ - ²⁴ ]PENTACOSA [ 8,16,18,24 jTETRAEN] -7'-YL)GLYCINATETRIFLUORO ACETIC ACID

(lS,3'R,61 ,7'S,8'E,12'R)-7 ^, -aiiiino-6-chloiO-12'-methyl-3,4-diliydro- 2H, 15'H-spiro[naphthalene-l ,22'- [20] oxa i 3] ihi a[ I / 4] ds

n]-15'-one 13',13'-dioxide trifluoroacetate (12 mg, 0.017 mmol), triethylamine (0.029 mL, 0.21 mmol) and methyl bromoacetate (0.020 mL, 2.1 mmol) were stirred in THF (0.2 mL) for 3 hours. Concentration of the reaction mixture was followed by purification by HPLC (5 to 95% V!eCN ! K) with 0.1% TFA) to give the mono-alkylated title product. ¾ NMR (500 MHz, CDCh) δ 7.67 (d, J=8.6 Hz, 1 H), 7.18 (dd, ./ 8.4. 2.1 Hz, 1 H), 7.09 (d, J==2.C) Hz, 1 H), 6.97 - 6.88 (in, 2 H), 6.75 (s, 1 H), 6,09 (ddd, ./ 14.5. 10.2, 3,7 Hz, 1 H), 5,72 (dd, ./ 15.2. 9.8 Hz, 1 H), 4.24 (t, J=9.5 Hz, 1 H), 4.14 - 4.07 (m, 1 H), 4,06 - 4.00 (m, 1 H), 3,87 (s, 3 H), 3.85 ·· 3.78 (m, 3 H), 3.77 - 3.66 (m, 2 H), 3.19 (d, ./ 1 -1.2 Hz, 1 H), 3.00 (dd, ./ 15.4. 10.5 Hz, 1 H), 2.85 - 2.73 (m, 2 H), 2.73 - 2.65 (m, 1 H), 2.51 - 2.36 (m, 3 H), 2.30 - 2. 18 (m, 2 I I ). 2,09 - 1.9 ! (m, 6 I I ). 1 ,85 - 1.68 (m, 4 H), 1.59 id, ,/ 6.X Hz, 3 H), 1.38 (t, J=12.7 Hz, 1 H); MS (ESI) mlz = 656.3 [M-CFsCOaj .

EXAMPLE 600. DIMETHYL 2,2 ^, -(((l S,3'R,6 ^! R,7'S,8'E,12 ^, R)--6--CHLORO-12 ^! -- METHYL-13',13'-DI()XIDO-15'-()XO-3,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί 1 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 ϋ ^; ",Ο ¹ " ^M |Ρ!·Λ i ACOSA

[8,16 _s 18 ₅ 24]TETRAEN]-7 ^, -YL)IMINO)DIACETATETRIFLUOROACETIC

ACID

This was prepared as outlined in Example 599. The title compound was isolated from the reaction mixture of Step 9. Ή NMR (500 MHz, CDCh) δ 7.83 (s, 1 H), 7.60 (d, ,7=8,8 Hz, 1 H), 7.09 (d, «/=8.6 Hz, 1 H), 7.01 (s, 1 H), 6.83 (d, J=8.6 Hz, 1 H), 6.81 - 6.76 (m, 1 H), 6.71 (s, 1 H), 5.74 (br. s., 1 H), 5.58 - 5.47 (m, 1 H), 4.17 (br. s., 1 I s ). 4.03 - 3.98 (m, 1 I s ). 3.98 - 3.92 (m, 1 I s ). 3.77 (d, J=15.4 Hz, 1 H ';.. 3.67 (s, 7 H), 3.66 - 3.57 (m, 6 H), 3,48 (br. s . 1 H), 3, 12 (d, ./ 14.7 Hz, 1 H i. 2.94 - 2.85 (m, 1 H), 2.77 - 2.64 (m, 2 H), 2.51 (br. s., 1 H), 2.27 (br. s., 3 H), 2.11 (d,■/ 14.2 Hz, 1 H), 1.94 id. ./ 14.7 Hz, 2 H), 1.88 (d, ,/ 7.8 Hz, 5 H), 1.50 (d, ,/ 6 8 Hz, 3 1.25 - 1.33 (m, 1 H).

EXAMPLE 601. 3 (1S,3 ^! R,6'R,7'S,8 ;,12¾)-6-CHL0R0-12'-METHYL-13',13 ^! ~ D10XlDO-15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALE E-l,22'- |;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN]-7'-YL)- 1 , 1 -DIMETHYLUREA TRIFLUOROACETATE

To a 2 mL vial was added hunig'sbase (12.86 μΐ, 0.074 mmol) and (18,31 ,6¾,7 ,8Έ,12¾)-6-οΜθΓθ-12'-Μ6 1-7'^ηΐίηο-3,4^ άΐΌ-2Η,15Ή- spiro I naphthalene- 1 ,22'- [20]oxa[13]thia[l ,14]diazate1racyclo[14.7.2 _^

n]-15'-one 13',13'-dioxide trifluoroacetate from Example 599, step 8 (4.3 mg, 7.4 μιηοΐ) in DCM (0.25 ml) at rt. The reaction mixture was stirred at ambient temperature for 5 rain, and then dimethylcarbamic chloride (7.9 mg, 0.074 mmol) was added. The reaction mixture was stirred for 21 h.The reaction mixture was diluted with MeOH, filtered and purified by HPLC (5% to 95% MeCN/HzO with 0.1% TFA) to give the title compound. ¾ NMR (500 MHz, CDCh) δ 8.04 (br. s„ 1 H), 7,68 (d, 7=8.6 Hz, 1 H), 7.18 (dd, .7=8.4, 2.3 Hz, 1 H), 7.09 (d, .7=2.2 Hz, 1 I I I 7.06 (s, 1 H), 6.93 - 6.90 (m, 1 H), 6.88 - 6.84 (m, 1 H), 5.82 - 5.72 (m, 1 H), 5.56 (dd, ./ 14.9. 7.6 Hz, 1 H), 4.38 (br. s., 1 I I ). 10 4.14 - 4.03 (m, 2 H), 3.93 (d, ,/ 1 2 5 Hz, 1 H), 3,69 (d, ./ 14.4 Hz, 1 H), 3.22 (d, .7= 14.4 Hz, 1 H), 2.98 (dd. ./ 15.3, 8.7 Hz, I H), 2.86 - 2,80 (m, 6 ! ! }. 2.79 - 2,70 (m, 2 H), 2.62 - 2,52 (m, 1 H i,. 2.51 - 2.39 (m, 1 H), 2.35 - 2.25 (m, 1 H i. 2.21 - 2.09 (m, 1 H i. 1.99 (d,

J=18.6 Hz, 4 H), 1.85 - 1.76 (m, 8 H), 1.55 (d, ./ 6.8 Hz, 3 H), 1.41 - 1.33 (m, 1 H); MS (ESI) miz ----- 654.8 [M+H] ⁺ .

EXAMPLE 602. (Ι β^'Κ,ό'Κ^'β,δΈ,^Ί^^'-ίΒΒ δ-ΜΕΙΉΥΕ-Ι^^- OXADIAZOL-3-YL)METHYL)AMINO)-6-CHLORO-12'-METHYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

| 2 ⁽ >X A| i ? I ! f Π Λ| ί i J l i^f AZ.Vf l: E RAC YCE C)l i J 7.2 0 ^{:' i'} .0 ^{l i} ' |Pi-:N i ACOSA

[8,16,18,24]TETiL E ]-1 '-ONE 13 3 '-DIOXIDE

To a 2 mL vial was added Ν,Ν-diisopropylethyl amine (5,38 μΐ, 0.031 mmol) and (l S,3¾,6'RJ^,8 ^ 12'R)-6-chloro-12'-meihyl-7'-a.mino-3,4-dihydro- 21 i.15 ^! H-spiro[naph.thalene- 1,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ^f \0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24] n]-15'-one ,13',13'-dioxide trifluoroacetate from Example 599, step 8 (6.0 mg, 1.0 μηιοΐ) in MeCN (0.34 ml) at ambient temperature. The reaction mixture was stirred for 5 mm, and then 3-(chloromethyl)-5-methyl-l,2,4-oxadiazole (4.1 mg, 0.031 mmol) was added. The reaction mixture was stirred at 70 °C for 16 h. The solution was diluted with MeOH, filtered and purified by HPLC (5% to 95%

MeCN/H ₂ 0 with 0.1% TF A) to give the dialkylated product. ¾ NMR (500 MHz, CDC! ;) 5 7.86 (s, 1 H), 7.69 (d, J=8.6 Hz, 1 H), 7.18 (dd, ./ 8.4. 2.3 Hz, 1 H), 7.09 id. ,/ 2.2 Hz, 1 H), 6.94 - 6.89 (m, 1 H), 6.87 - 6.82 (m, 1 H), 6.74 (d, 1 ,5 Hz, 1 H), 5.83 - 5,74 (m, 1 H), 5.63 (dd, .7=14.9, 8.8 Hz, 1 H), 4.23 - 4.15 (m, 1 III 4.12 - 3.92 (m, 6 !!}. 3.80 (d, J=15.9 Hz, 1 Is).3.7! (d, 13.7 Hz, 1 H), 3,43 (d, J=9.8 Hz, 1 H), 3.20 (d, ,/ 139 Hz, 1 H), 2,98 (dd, J=15.5, 10.4 Hz, 1 H), 2,85 - 2,73 (m, 2 H), 2.72 - 2.65 (m, 1 H), 2.63 (s, 6 H), 2.32 (t, J=8.2 Hz, 2 H), 2.21 (d,■/ 16.! Hz, 1 H), 2.07 - 1.89 (m, 5 H), 1.88 - 1.67 (m, 4H), 1.58 (d, .7=6.8 Hz, 3 !!}. 1.38 (t, 12.3 Hz, I H); MS (ESI) m/z ------ 775.8 j \1 · If | ^' .

EXAMPLE 603, (1S,3¾,6¾.,7¾,8T;12'R)-6-CHL0R0-12'-METHYL~7 ^! -((5- METHYL- 1 ,2,4-GXADI AZOL-3- YL)METHOXY)-3 ,4-DIHYDRG-2H, 15 Ή- SPIRO [NAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,I4]DIAZATETRACYCLO[!4.7.2,03- ⁶ .0 ^I9 - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1 ^' .13'-DIOXIDE

To a 2 mL vial was added sodium hydride, 60% dispersion in mineral oil (2.0 rng, 0.049 mmol) and (18,3¾,6Έ,7'8,8Έ,12Έ)-6-Λ1οΐΌ-7' ^^Γθχν-12'- methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

n]-15'-one 13',13'-dioxide (Example 404, Step I) (5.7 mg, 9.7 μτηοΐ) in THF (0.33 ml) at ambient temperature. The reaction mixture was stirred for 5 rain, and then 3-(chloromethyl)-5-methyl-l,2,4-oxadiazole (3,9 mg, 0.029 mmol) was added. The reaction mixture was stirred at ambient temperature for T7h. The reaction mixture was diluted with MeOH, filtered and purified by HPLC (5% to 95% MeCN/ftQ with 0, 1 % TFA) to give the title product, (2,6 mg, 39%), ^" Ή NMR (500 MHz, CDCh) δ 7.95 (s, IH), 7.70 (d, J=8.6 Hz, IH), 7.19 (dd, J=8.6, 2.2 Hz, 1H), 7.09 (d, ,7=2,2 Hz, IH), 6,92 (d, J=8.1 Hz, IH), 6,87 (dd, J=8.1, 2,0 Hz, IH), 6.80 id../ 1.7 !!/. IH), 5.88 (ddd,J=15.2, 9.3, 3.9 Hz, IH), 5.61 (dd,J=15.4, 9.0 Hz, 1 1 1 ). 4.57 (d, ,1=132 Hz, I I I ). 4.45 id. ,/ 1 3 2 Hz, ! H), 4.34-4.22 (m, ! ! ! ).

4.07 (q, ,7=12, 1 Hz, 2H), 3.93 (dd, .7=9,0, 3.4 Hz, IH), 3.83 (d, «7=14.9 Hz, 1H), 3.72 (d, ,7=14.4 Hz, IH), 3.22 (d, J=14.2 Hz, IH), 2.98 (dd, J=15.3, 10.4 Hz, IH), 2.85-2.70 (m, 2H), 2.63 (s, 3H), 2.60-2.51 (in, IH), 2.44-2.21 (m, 3H), 2.09-1.91 (4H, m), 1 .91-1.74 (3H, m), 1 ,70-1.62 (m, I H), 1.60 (d, .7=6.8 Hz, 3H), 1,39 (t, ,7=13,0 Hz, IH); MS (ESI) mlz [M+H] = 680.8,

EXAMPLE 604. (l S,3'R,6 ^, R,8 ^! E,12 ^! R)-6-CHLORO-12'-METHYL-3,4- DIHYDRO-2H,7'H, 15'H-SPIRO[NAPHTHALENE-l,22 ^! -

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAENE]-7', 15'-DIONE 13', 13'-Di OXIDE

A 2-dram vial was charged with (lS,3'R,6'R,7'S,8'E,12'R)-6-chIoiO-7'- hydrox '-12 ^, -methyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l, 14]diazatetracyd^^

n]-15'-one 13',13'-dioxide (Example 404, Step 1) (80 mg, 0.14 mmol) in DCM (2 mL) was added dess-martin periodinane (73 mg, 0.17 mmol) and NaHCCb (46 mg, 0.55 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was directly loaded onto a cartridge of S1O2, and then purified by column chromatography (0-10% MeOH/DCM, 4g S1O2) to give the title compound (65 mg). ^] H NMR (500 MHz, CDCb) δ 8.08 (s, 1 H), 7.75 (d, .7=8.6

Hz, 1 H), 7.32 (d, ,7=2,0 Hz, 1 H), 7.20 (dd, J=8.4, 2,3 Hz, 1 H), 7,08 (d, J=2.2 Hz, 1 H), 6.87 - 6.83 (m, 1 H), 6.81 - 6.76 (m, 1 H), 6.65 (ddd, ,7=15.8, 8.6, 7.2 Hz, 1 H), 5.95 (d, J=15.9 Hz, 1 H), 4.16 - 3.98 (m, 3 H), 3.92 - 3.79 (m, 2 H), 3.73 (q, J=9.5 Hz, 1 ! ! }. 3.25 (d, .7=14,4 Hz, ! H), 3.13 - 3.03 (m, ! H), 2.99 (dd, .7=15.4, 2.9 Hz, 1 H), 2.85 - 2,69 (m, 2 H), 2.43 - 2,31 (m, 1 H), 2.21 - 2,04 (m, 3 H), 2.03 - 1 ,96 ( in. 1 ! !}, 1 ,95 - 1 ,87 (m, 5 H), 1,60 i d. ./ 7. 1 Hz, 3 1 1 ). 1.40 { i. ./ 12.3 Hz, 1 H); MS (ESI) m/z = 583.2 [M+H] ⁺ ,

EXAMPLE 605. (1 S,3'R,6 ^! R,7'Z,9'S,12 ^! R)-6-CHLORO-9 ^! -HYDROXY-12'- METHYL - 7'-( I -PROPYN - 1 - YL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]Tffl A[l .MIDIAZATETRACYCLOIMJ^.O^^O'^IPENTACOSA [7,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'Z,9'R,12'R)-6-CHLORO-9'-HYDROXY-12 ^, -METHYL-7'-(l- PROPYN-1 -YL)-3,4-DIHYDRO-2H, 15 Ή-SPTRO [NAPHTHALENE- 1 ,22'- | 2 ⁽ >X A| i 1 ! f Π Λ| ί i J l i^f AZ.Vf l: E J^AC YCE C)l 1 4 7.2 ϋ ^{; ί'} .ϋ |ΡΗ\ i ACOSA 17.16, 18,24]TETRAEN]-15'-ONE 13', 13'-DK)XIDE

A 2-dram was charged with (l S,3'R,6 ^! R,8'E,12'R)-6-chloro-12 ^! -niethyl- 3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l ,22'- i;20]oxa[ 13]thia|;i ,14]diazatetracyclo[14.7.2,0 ³ - ^f \0 ¹⁹ - ²⁴ ]peniacosa[8,16, 18,24]tetrae ne]-7 ^* , 15'-dione 13', 13'-dioxide (Example 604) (20 mg, 0.034 ramol) and THF (0.69 ml). The reaction mixture was cooled to 0 °C and a solution of prop-l-yn-1- yl magnesium bromide (0.5 M in THF, 171 μΐ, 0.086 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with MeOH (0.2 ml.) & DCM (1 mL) and quenched with 0,04 mL of 4N HCi solution in dioxane. The mixture was loaded directly onto a silica gel cartridge and purified by column chromatography (0-50-100 % EtOAc/(0.3% v/v AcOH/hexanes), 4g S1O2). The desired fractions were pooled and then repunfied by HPi ( (5% to 95% MeCN/H ₂ 0 with 0.1% TFA) to give as the first elutmg compound, one of the title compounds. ^" 'H NMR (500 MHz, CD3OD) δ 7.73 (d, J=8.6 Hz, 1 H i. 7.17 (dd, ,7=8,6, 2.2 Hz, 1 H), 7.15 (d, ,7=1.5 Hz, 1 H), 7.10 (d, ./ 2.2 Hz, 1 H), 6.96 - 6.89 (m, 2 H), 5.48 (d, ./ 8.8 Hz, 1 H), 4.58 (td, J=8.6, 4.6 Hz, 1 I I ). 4.18 (d, ·/ 14.9 Hz, 1 H), 4.07 (s, 2 ! ! }. 3.89 - 3.80 (m, 1 H), 3.66 (d, ,/ 14 2 Hz, 1 H), 3.24 - 3.18 (m, 1 H), 3.12 (dd, ./ 1 5.0. 9.7 Hz, 1 H), 2,86 - 2,70 (m, 2 H), 2,70 - 2.62 (m, 1 H), 2,28 - 2.17 (m, 1 H), 2, 15 - 2.08 (m, 4 H), 2,00 - 1.82 (m, 8 H), 1 ,80 ·· 1,59 (m, 4 H), 1.51 - 1.40 (m, 4 H): MS (ESI) mlz = 623.2 | \! H i .

EXAMPLE 606. (1 S,3'R,6'R,7'Z,9'R, 12'R)-6-CHLORO-9'-HYDROXY~l 2'- METHYL-7'-(l -PROP YN- 1 - YL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.() ³ > ^, 0 ^{! 9} - ²⁴ ]PENTACOSA [7,16,18,24]TETRAEN]~15'~QNE 13 ',13 '-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! Z,9 ^! S,12'R)-6-CHLORO-9'-HYDROXY-12'-METHYL-7 ^, -(l- PROPYN-1 -YL)-3,4-DIHYDRO-2H, 15 Ή-SPIRO |NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[ 1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [7,16, 18,24]TETRAEN] - 15'-ONE 13', 13 '-DIOXIDE

This example was prepared as in Example 605 but the isolated compound was the second eiutmg isomer, ^! H NMR (500 Mi l/. CDCh) δ 7,98 (br. s,, 1 H), 7.72 (d, J=8.6 Hz, 1 H), 7. 19 (dd, .7=8.3, 2.2 Hz, 1 H), 7.10 (d, .7=2,0 Hz, 1 H), 7.06 - 7.00 (m, 1 H), 6,96 (d, J=8. I Hz, 1 H), 6.65 (s, 1 H), 5.67 (d, J=7.8 Hz, 1 H), 4.77 - 4,69 (m, 1 H), 4.14 - 4,08 (m, 1 H), 4.08 - 4,02 (m, 1 H), 3.90 - 3.80 (m, 1 H), 3,75 (d, ./ 14.2 Hz, 1 H), 3.68 (d, ./ 15.4 Hz, 1 H), 3.35 - 3.24 (m, 1 H), 3.16 (dd, J=15.5, 8.7 Hz, 1 H), 2.87 - 2.72 (m, 2 H), 2.71 - 2.57 (m, 2 H), 2.17 - 2.05 (m, 4 H), 2.04 - 1.92 (m, 4 H), 1.92 - 1 .77 (rn, 6 H), 1.61 - 1 .54 (d, ,/ 6 8 Hz, 3 H), 1.44 (t, ./ 1 3. ! Hz, 1 H); MS (ESI) mJz = 623.2 | VI · I I | EXAMPLE 609, (3R,6R,7R, 13R,23S)-6'-CHLORO- 13-METHYL~3',4'- ΟΠ 1 Y DRO-2 ! i. 1 61 !-SPi R()| 8.2 1 -ΟΙΟΧΛ- ! - Π ! .9 i - TR1AZAPENTACYCLO[15.7.2.1 ⁷ ' ¹⁰ .0 ³ ' ⁶ .0 ²⁰ - ²⁵ ]HEPTACOSA-9,17,19,25- TETRAENE-23 , 1 '-N APHTH ALEN j - 1 6-ONE 14, 14-DIOXIDE OR

(3R,6R,7S ₅ 13R,23S)-6 ^, -CHLORO- 13-METHYL-3 ^, ,4 ^, -DIHYDRO-2¾ 16H- SPIRO[8,21 -DIOXA- 14-THIA- 1,9, 15-

TRIAZAPENTACYCLO|;i 5.7.2. i ⁷ - ^u \0 ³ - ⁶ .0 ²⁰ - ²⁵ |HEPTACOSA-9, 17, 19,25- TETRAE -23 , 1 '-NAPHTHALEN] - 16-ONE 14, 14-DIOX1DE

STEP 1 : (R)-5-HYDROXY-N,N-BIS(4-METHOXYBENZYL)PENTANE-2- SULFONAMIDE

A solution of (R)-N,N-bis(4-methoxybenzyl)hex-5-ene-2 -sulfonamide

(200 mg, 0.496 mmol, Intermediate EE20, Step 1, second eluting enantiomer) in MeOH (20 mL) was cooled to -78°C. Ozone was bubbled though the reaction mixture until a blue color persisted in the solution (about 15 minutes). Nitrogen was bubbled through the reaction to remove the blue color before sodium borohydride (22.5 mg, 0.595 mmol) was added. The reaction mixture was stirred at ambient temperature under a positive argon pressure for 3 h. More sodium borohydride (50 mg) was added and stirring continued for another 2 h. The reaction was concentrated and the residue was absorbed onto Si0 ₂ then purified by flash chromatography, 0-30-100% EtOAc hexanes, to give (R)-5-hydroxy- N,N-bis(4-methoxybenzyl)pentane-2-sulfonamide (109 mg). ¾ NMR (500 MHz, CDCh) δ 7.22-7. 12 (m, 4H), 6,85 (d, J=8.8 Hz, 4H), 4.32 (d, .7=15.2 Hz, 2H), 4.21 (d, .7=15.2 Hz, 2H), 3,79 (s, 6H), 3,60 (t, .7=6.2 Hz, 2H), 3.01-2,88 (m, 1H), 2.43 (br. s, 1H), 2.01-1.95 (m, IH), 1.77-1.66 (m, 1H), 1.66-1.56 (m, lH), 1.56-1.46 (m, IH), 1.30 (d, ./ 6.8 Hz, 3H); C NMR (126 MHz, CDCh) δ 159.06, 129.83, 127.95, 113.83, 61.97, 58.90, 55, 13, 49.79, 29.33, 26.73, 13.84; MS (ESI) m!z = 430.1 [M+Na] ⁺ .

STEP 2: (R)-5-IODO-N,N-BIS(4-METHOXYBENZYL)PENTANE-2- SULFONAM1DE

Procedure adapted from J Org. Chern. 2002, 67, 772. To a solution of ( ?)- 5-hydroxy~AyV-bis(4~methoxybenzyl)pentane-2-sulfonamide from Step 1 (500 mg, 1.23 mmol) in THF (15 mL) was added imidazole (251 mg, 3.68 mmol), triphenylphosphine (644 mg, 2.45 mmol) and iodine (934 mg, 3.68 mmol) at 0 °C. The mixture was stirred for 24 h at ambient temperature. The solution was directly loaded onto a cartridge of S1O2 and was purified by column chromatography, 0- 30-100% EtOAc/hexanes, to give (R)-5-iodo-N,N-bis(4-methoxybenzyl)pentane- 2-suifonamide (270 mg). ^l H NMR (500 MHz, CDCh) δ 7.24-7.18 (m, 4H), 6.91- 6.85 (m, 4H), 4.35 (d, J=15.2 Hz, 2H), 4.25 (d, ,7=15.2 Hz, 2H), 3.83 (s, 6H), 3.13 (t, J=6.5 Hz, 2H), 2.80-2.89 (m, IH), 2.05-1 ,92 (m, 2H), 1.82-1 .72 (m, i l l ). 1.70- 1 ,62 (m, IH), 1.31 (d, J=6.8 Hz, 3H); MS (ESI) /z = 540.0 [M+Na] ⁺ . STEP 3: (R)-N,N-BIS(4-METHOXYBENZYL)-5-NITROPENTANE-2-

SULFONAMIDE Urea (219 rag, 3.65 mmol) was added to a stirring solution of (R)-5-iodo- N,N-bis(4-memoxybenzyl)pentane-2-sulfonairride from Step 2 (270 mg, 0.522 mmol) in DMSO (5 mL). After 5 minutes, sodium nitrite (252 mg, 3.65 mmol) was added to the mixture and stirring continued for 2 h. The reaction mixture was loaded to directly onto a cartridge of Si0 ₂ and was then purified by column chromatography, 0-100% EtOAc/hexanes, to give (R)-N,N-bis(4-methoxybenzyl)- 5-nitropentane-2-sulfonamide. MS (ESI) = 459.1 [M+Na] ⁺ .

STEP 4: (S)-METHYL 6'-CHLORO-5-(i(lR,2S)-2- VINYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAI-IYDRO-2H,2 ^f H- SPIRO[BENZO[B][l,4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE

A solution of methyltriphenylphosphonium bromide (2.91 g, 8.15 mmol) in THF (12 ml) was cooled to 0 °C. n-Butyllithium solution, 2.5m in hexanes (2.93 ml, 7.34 mmol) was added dropwise to the cooled solution. Following the addition the reaction mixture was for 10 min. This solution was slowly added to a cold (0 °C) solution of (S)-methyl 6'-chloro-5-(((lR,2R)-2- formylcyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4] oxazepine-3 , 1 '-naphthal ene] -7-carboxy late (370 mg, 0.815 mmol, Intermediate Intermediate AA11 A, STEP 20A) in THF (4 ml) until the yellow color persisted. After the addition was complete the mixture was stirred for 15 minutes. The reaction mixture was quenched by pouring the contents of the flask into ice-water (30 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (30 mL). The combined organic extracts were dried with anhydrous sodium sulfate, and then concentrated. The residue was purified by column chromatography, 10% EtOAc hexanes, 24g S1O2 to yield (S)- methyl 6'-chloro-5-(((lR,2S)-2-vinylc 'clobut 'l)methyl)-3',4,4 ^, ,5-tetrahydro- 2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylate (239 mg, 0.529 mmol). MS (ESI) m/z = 452.1 [M+H] ⁺ . STEP 5: (S)-METHYL 5-(((lR,2R)-2-((S)-3-(( )-3-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)BUTYL)-4,5-DIHYDROISOXAZOL-5- YL)CYCLOBUTYL)METHYL)-6'-CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H- SPiRO [BEN ZO [B] [ 1 ,4] OX AZEPINE-3 , Γ-Ν APHTH ALENE] - 7-C ARBOXY LATE AND (S)-METHYL 5-(((lR,2R)-2-((R)-3-((R)-3-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)BUTYL)-4,5-DIHYDROISOXAZOL-5- YL)CYCLOBUTYL)METHYL)-6'-CHLORO-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXYLATE

Procedure adapted from J. Org. Chem. 2002, 67, 772. A mixture of (S)-methyl 6'-chloro-5-(((l R,2S)-2-vmyIcyclobutyl)methyl)-3',4,4',5- tetrahydro-2H,2H-spiro[benzo[b][l ,4]oxazepine-3, r-naphthalene]-7-carboxylate from Step 4 (90 mg, 0.199 mmol), (R)-N,N-bis(4-methoxybenzyl)-5-nitropentane- 2-sulfonamide from Step 3(87 mg, 0.199 mmoi), 4-chiorophenyl isocyanate (183 mg, 1.20 mmol), and triethylamine (0.061 mL, 0.44 mmol) in benzene (1 mL) was refiuxed for ih. The reaction mixture was loaded directly into a solid cartridge of silica gel and purified by column chromatography, 0-20-50% EtQAc/hexanes, to give a mixture of the desired dihydroisoxazole diastereomers (109 mg), MS (ESI) mix ------ 870.3 [M+H] ⁺ . STEP 6: (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((S)-3-((R)-3-

SULFAMOYLBUTYL)-4,5-DIHYDROISOXAZOL-5- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETR^ HYDRO-2H,2 ^! H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE AND (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((R)-3-((R)-3- SULFAMOYLBUTYL)-4,5-DIHYDR01SOXAZOL-5-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _! 4HYDRO-2I-L2 ^, H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] ~7~

CARBOXYLATE

(S)-methy! 5-(((1 R2R)-2-((S)-3-((R)-3-(N,N-bis(4- methoxybenzyl)sulfamoyl)butyl)-4,5-di^

3' 4 4',5 elTahydro~2H,2'H-spiro[benzo[b][L4]oxazepine~3J '-oaphthaIe:oe]~7- and (S)-methyl 5-(((lR,2R)-2-((R)-3-((R)-3-(N,N-bis(4- methoxybenzy4)sulfamoyl)butyl)-4,5-dihydro^

3 ',4,4',5 -tetrahy dro-2H,2'H-spiro [benzofb] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxy late mixture from Step 5 (109 mg, 0.125 mmol) in anisole (684 μΐ, 6.26 mmol) and trifluoroacetic acid (482 μΐ, 6.26 mmol) was stirred at 40 °C for 22h. The reaction mixture was loaded directly into a cartridge of silica gel, and purified by column chromatography, 0-100% EtOAc/hexanes, 24g Si0 ₂ , to give (S)~methyl 6 -chloro-

5-(((lR,2R)-2-((S)-3-((R)-3-sulfamoylbu1yl)^ ₅ 5-dihydroisoxazol-5- yl)cyclobu1yl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o b][ l,4]oxazepine-

3,l'-naphthalene]-7-carboxylate and (S)-methyl 6'-chloro-5-(((l R,2R)-2-((R)-3-

((R)-3-sulfamoyibutyl)-4,5-d droisoxazol-5-yl)cyclobutyl)m^

tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate

(83.8 mg). MS (ESI) mlz ---- 630.2 | X I · I ! | STEP 7: (S)-6'-CHLORO-5-(((lR 2R)-2-((S)-3-((R)-3-SULFAMOYLBUTYL)- 4,5 >IHYDROISOXAZOL-5^T _J )CYCLOBUIY ,)METHYL)-;r,4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((R.)-3-((R)-3-SULFAMOYXBUTYL)-4,5-DTHY ^' DROTSOXAZOL-5- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPlRO[BENZO[B][L4]OXAZEPlNE-3,l ^, -NAPHTHALENE]-7-CARBOXYLIC ACID

(S)-raethyl 6"-chloro-5-((( lR,2R)-2-((S)-3-((R)-3-sulfamoylbut l)-4,5- dihydroisoxazol-5-yl)c clobuTy'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylate and (S)-methyl 6'- (*loro-5-(((lR,2R)-2-((R)-3-((R)-3-sulfamoylbutyl)-4 ₅ 5-dihydroisoxazol-5- yl)cyclobu1\d)metiiyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[ben zo[b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxylate from Step 6 (83.8 nig, 0.133 mmol) was stirred in a mixture of 1M aqueous LiOH (0.67 mL), THF (1.5 mL) and ethanol (1.5 mL) at 50 °C for 3 h. The pH of the mixture was adjusted to pH ^: = 5 by addition of I M aqueous HC1. The resulting solution was directly loaded into a cartridge of silica gel and purified by column chromatography, 0-10% MeQH/DCM, 12g S1O2, to give (S)-6 ^* -chloro-5-(((l R,2R)-2-((S)-3-((R)-3-sulfamoylbutyl)-4,5- dihydroisoxazol-5-yl)c\'c]obutyl)methyl)-3',4,4',5-tetTahydr o-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)-6'- cWoro-5-(((l R,2R)-2-((R)-3-((R)-3-sidfamo lbu1yl)-4,5-dmydroisoxazol- yl)c lobutyl)methyl)-3 4,4 5-tetrahydro-2H,2^spiro[benzo[b][l,4]oxazepine- 3,1 '-naphthalene] -7-carboxy lie acid (82 mg). Step 8: (3R,6R,7R, 13R,23S)-6'-CHLORO-13-NlETHYL-3 ^, ,4 ^, -DIHYDRO- 2Ή, 16H-SPIRO[8,21 -DIOXA- 14-THI A-l ,9, 15-

TMAZAPE TACYCLO[I57.2/l ⁷ - ^ll l0^^0 ²⁰ - ²⁵ ]HEPTACOSA-9,17,19,25- TETRAENE-23 , 1 '-NAPHTH ALEN] - 16-QNE 14,14-DIOXIDE OR

(3R,6R,7S,13R,23S)-6'-CHLORO-13-METHYL-3\4 ^, -DIHYDRO-2H, 16H- SPIRO[8, 21 -DIOXA- 14-ΊΉΙΑ- 1,9, 15-

TR1AZAPENTACYCLO[15.7.2.1 ⁷ ' ¹⁰ .0 ³ ' ⁶ .0 ²⁰ - ²⁵ ]HEPTACOSA-9,17,19,25- TETRAENE-23 , 1 '-NAPHTH ALEN] - 16-ONE 14, 14-DIOXIDE

N,N-dimethy]pyridin-4-amine (28 mg, 0.23 mmol) was added to a solution of (S)-6 ^, -chloro-5-(((lR,2R)-2-((S)-: ((R)-3-sulfamoylbutyl)-4 _^

5-yl)c 'clobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid and (S)-6 ^! - chloro-5-(((lR,2R)-2-((R)-3-((R)-3-sulta

yl)cyclobut\d)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[b enzo[b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxylic acid from Step 7 (82 mg, 0.13 mmoi, previously azeotroped with 5mL toluene) in CH2CI2 (67 ml) at 0 °C, N-(3- dimethylarninopropyl)-N'-ethylcarbodiiiTiide hydrochloride (51 mg, 0.27 mmol) was added and the mixture was stirred at ambient temperature for 17 h. The reaction mixture was concentrated, dissolved in MeCN, and then purified by

HPLC (10-95% ACN/water with 0.1% TFA) to give one of the title compounds. ¾ NMR (500 MHz, CDCb) δ 8.04 (br. s„ IH), 7,71 (d, .7=8.6 Hz, IH), 7.19 (dd, ./ K.6. 2.2 Hz, IH), 7.09 id. ./ 2.2 Hz, IH), 7.02 (s, IH), 6.97-6.86 (m, 2H), 4.60 (ddd, .7=11.5, 9.9, 6.7 Hz, IH), 4,39 (br. s . ! ! ! ). 4.15-4.09 (rn, IH), 4.08-4,02 (m, 2H), 3,73 (d, .7=14.4 Hz, IH), 3.22 (d, .7=14.4 Hz, IH), 3.14 (dd, .7=15,4, 7,6 Hz, IH), 2.84 - 2.74 (m, 3H), 2.74-2.63 (m, 2H), 2.58-2.41 (m, 2H), 2.33 - 2.23 (m, 1 H), 2.23-1.87 (m, 5H), 1.87-1 .77 (m, 2H), 1.77-1.69 (m, 1H), 1.64-1 .57 (m, 1H), 1.56 (d, ,7=7, 1 Hz, M i l 1.41 (t, ,/ 1 2 6 Hz, 1H); MS (ESI) m/z = 598.2 [M+H] ⁺ .

EXAMPLE 610. (l S,3 ^, R,6 ^, R,7 ^, S.8 ^, E.12 ^, R)-6-CHLORO-12 ^, -E^ΉYL-13 ^, ,13 ^, - DIOXIDO-lS'-OXO-S^-DlHYDRO-ZH-SPIROrNAPHTHALENE-l^^- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

[8, 16, 18,24] TETR AEN j - 7' - YL CARBAMATE

STEP 1 : (S)-6 ^* -CHLORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)-5-(((l R,2R)-2- ((S^-l-HYDROXYHEX^-EN-l-Y^CYCLOBUTY^METHYL^S'^^'.S- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE-3, 1 '- -7 -C ARB OXAMI D E

4-Dimethylaminopyridine (DMAP) (0.041 g, 0.33 mmol) was added to a solution of (S)-6'-chloro-5-((( 1 R,2R)-2-((S,E)- 1 -hydroxy hex-2-en- 1 - yl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,l '-naphthalene]-7-carboxylic acid (Intermediate AA12A) (0.100 g, 0.196 mmol triethylamine (0.082 mL, 0.59 mmol) and (R)-hept-6-ene-3-sulfonamide

(Intermediate EE2 ) (0,094 g, 0.53 mmol) in DC VI (1.0 ml.). Then EDC (0,075 g, 0.39 mmol) was added slowly in portions, and reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated. The residue was injected into a 12g ISCO Gold column and purified by combi -flash, eluting with 0% to 20% EtOAc (containing 0.3% AcOH)/hexanes to give (S)-6'- chloro- -((R)-hept-6-en~3"ylsulfonyi)-5-(((lR,2R)-2 (S,E)-l-hydroxyhex-2-en" l -} _' 1)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxarnide (0.080 g, 0.12 mmol).

STEP 2: (1 S^'R^'RJ'S^'E, 12'R)-6-CHLORO- 12 ^, -ETHYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, I 8,24]TETRAENl-15'-ONE 13', 13'-DTOXIDE

A 100 mL round bottom flask was charged with (S)-6'-chloro-N-((R)-hept- 6-en-3-ylsulfonyl)-5-(((l R,2R)-2-((S,E)-l -hy droxyhex-2-en-l - yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l,4]oxazepine- 3,1 '-naphthalene |-7-carboxamide (Example 610, Step 1 ) (0.080 g, 0.12 mmol) in AcOH (41 mL). it was stirred at ambient temperature under Ar bubbling through the reaction mixture for 15 rain. To the homogeneous solution was added

Hoveyda-Grubbs 2nd generation catalyst (0.015 g, 0.024 mmol). The mixture was stirred at ambient temperature under reduced pressui'e overnight and then air was bubbling through for 10 min. The reaction mixture was concentrated. The residue was injected into a 4 g ISCO Gold column and purified by combi-flash, eiuting with 20% to 40% EtOAc (containing 0.3%o AcOH)/hexanes to give the title compound (0.034 g, 0.057 mmol).

STEP 3 : ( 1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO- 12'-ETHYL- 13', 13'-DIOXlDO- 15'-OXO-3,4-DlHYDRO-2H-SPlRO[NAPHraALE E-l ,22'- [20]OXA[ 13]THIA[ 1 , 14]DIAZATETRACYCLO[ 14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-7'-YL CARBAMATE

To a solution of (l S,3 ^! R,6'R,7'S,8'E, 12'R)-6-chloro-12'-ethyl-7 ^! -hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1, 14] diazatetracy clo[l 4.7,2.0 ³ '.0 ¹⁹ · ²⁴ ]

pentacosa[8, 16, 18,24]tetraen]-15'-one 13', 13'-dioxide (Example 610, Step 2) (0.034 g, 0.057 mmol) in a mixture of CHCb/DMF (2 mL, v/v=l/l ) was added a solution of 2,2,2-trichloroacetyl isocyanate (0,021 g, 0.11 mmol) in chloroform (0.5 mL) at ambient temperature. After the mixture was stirred at ambient temperature for 1.5 h, MeOH (1 .0 mL) and water (0.5 mL) were added to the reaction mixture, followed by LiOH (10 mg). Then the reaction was stirred overnight. The reaction mixture was diluted with DCM, extracted (2xDCM), and washed (brine). The combined organic layers were dried (NazSC ) and concentrated under reduced pressure. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 70% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to provide the title compound as a white solid (0.015 g, 0,023 mmol). ¾ NMR (500 MHz, CDCb) δ ppra 7.97 (s, IH), 7,68 (d, «7=8.6 Hz, IH), 7.18 (dd, .7=2.3, 8,4 Hz, IH), 7.09 (d, J=2.2 Hz, IH), 7.07 - 7.03 (m, IH), 6.95 - 6.86 (ni, 2H), 5.84 - 5.70 (m, IH), 5.61 (dd, ,7=7.2, 15.3 Hz, I H), 5.13 (t, ./ 6.4 Hz, IH), 4.58 (br. s., 2H), 4.13 - 4.01 (m. M l ). 3.92 (dd, ./ 4.( 1,, 15.5 Hz, IH), 3.75 (d, .7=14.4 Hz, I H), 3.20 (d, .7=14,4 Hz, IH), 2.99 (dd, J=8.3, 15.4 Hz, IH), 2.80 - 2.73 (m, 2H), 2.67 - 2.54 (m, IH), 2.41 - 2.25 (m, 3H), 2, 12 - 1.75 (ra, 7H), 1 ,70 - 1.62 (m, I I I ). 1 .39 (t, .£=12.7 Hz, 1 1 1 ). 1 .24 - 1.17 (ra, 3H); m/z (ESI, +ve ion) 664,2 (M+Na) ⁺ .

EXAMPLE 61 1. ((18,3'Κ,6'Κ,7'8,8 ^! Ε, 12 ^! 8)-6-α-ΙίΟΜ)-7'-ΗΥΟΚΟΧΥ-13·,13'- DIOXIDO-lS'-OXO-S^-DlHYDRO-ffl-SPmorNAPHTHALENE-l^^- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16, 18,24]TETRAEN]-12'-YL)METHYL CARBAMATE

STEP 1 : (S)-2-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEX-5-EN-l-

YL CARBAMATE

A racemic mixture of (S)- 1 -hydroxy -N,N-bis(4-methoxybenzyl)hex-5- ene-2-sulfonamide and (R)- 1 -hydroxy -N,N-bis(4-methoxybenz l)hex-5-ene-2- sulfonamide (Example 434, Step 2) was purified by Thar 350 SFC (150 x50mm AD column; with 105 g/min MeOH +(20mM NH3) + 105 g/min CQ?„ Runtime = 20 min) to give a pure (S)- l-hydroxy-N,N-bis(4-methoxybenzyl)hex-5-ene-2- sulfonamide as the slower eluting isomer.

To a solution of (S)-i -hydroxy -N,N-bis(4-methoxybenzyl)hex-5-ene-2- sulfonamide (0.800 g, 1.91 mmol) in a mixture of CHCb/DMF (20 mL, v/v=l/l) was added a solution of 2,2,2-trichloroacetyl isocyanate (0.467 g, 2.48 mmol) in CHCh (3 mL) at ambient temperature. After the reaction was stirred for 0.5 h, MeOH (5 ml,), water (2 mL), and LiOH (100 mg) were added to the reaction mixture successively. The mixture was stirred at ambient temperature overnight. Then the reaction mixture was diluted (DCM), extracted {2 DC \S ). and washed (brine). The combined organic layers were dried (NazSC ) and concentrated under reduced pressure. The residue was injected into a 80g ISCO Gold column and purified by combi-flash, eluting with 30% to 45% EtOAc (containing 0.3%

AcOH)/hexanes to give (S)-2-(N,N-bis(4~methoxybenzyl)sulfamoyl)hex-5~en-i-yl carbamate (0.82 g, 1.8 mmoi).

STEP 2: (S)-2-SULFAMOYLHEX-5-EN-l-YL CARBAMATE

To a solution of (S)-2-(N,N-bis(4-methoxybenz\d)sulfajmoyl)hex-5-en-l-yl carbamate (0.820 g, 1.77 mmol) (Example 611, Step 1) in DCM (8.9 inL) was added anisole (0.96 mL, 8.9 mmol), followed by dropwise addition of TFA (3.2 mL, 43 mmol). After the reaction mixture was stirred at 40 °C overnight, the reaction mixture was concentrated. The residue was injected into a 40 g ISCO Gold column and purified by combi-flash, eluting with 30% to 60% EtOAc (containing 0.3% AcOH)/hexanes to give (S)-2-sulfamoylhex-5-en-l-yl carbamate (0.36 g, 1.6 mmol).

STEP 3: ((l S,3'R,6'R,7 ^, S,8'E,12'S)-6"CHLORO-7'~HYDROXY-13',13'- DIOXIDO-lS'-OXO-S^-DIHYDRO^H-SPIROtNAPHTHALE E-l ^^- | 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8,16,18,24] TETRAEN] - 12'- YL)METHYL CARBAMATE The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-

1 -hy droxyhex~2-en ~yl)cy clobuty l)m^

spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxyl ic acid (Intermediate AA12A) by a procedure analogous to that described in Example 610, Steps 1 through 2, replacing (R)-hept-6-ene-3-sulfonamide in Step 1 with (S)-2- sulfamoylhex-5-en- 1 -yl carbamate (Example 611, Step 2). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide the title compound as the faster elutmg isomer as a white foam. ¾ MMR (500 MHz,

CDCh) δ ppm 8.06 (s, 1H), 7.70 (d, J=8.6Hz, 1H), 7.19 (d, J=8.3 Hz, 1H),7.1() (d, 24 Hz, 111).6.96 - 6.90 (ra, 3H), 5,82 - 5.70 (m, 2H), 4.71 - 4.65 (ra, 2H), 4.37 (d, J=4.9 Hz, lH), 4.22 - 4.15 (m, 1H), 4.13 - 4.06 (m, 2H), 3.83 (d, J=14.9 Hz, 1H), 3.71 (d, ./ 14.2 Hz, ill).3.25 (d, J=14.4 Hz, 1H), 3.07 - 3.00 (m, 1H), 2,83 - 2.72 (ra, 2H), 2,44 (m, IH), 2.4! - 2.26 (m, 3H), 2.06 - 1,60 (m, 9H), 1.42 (m. I I I): m/z (ESI, +ve ion) 644.2 (M+H) ⁺ .

EXAMPLE 612. ((lS,3'R,6'R,7'S,8 ^! Z,12 ^! S)-6-CHLORO-7'-HYDROXY-13 ^, ,13 ^I - DIOXIDO- 15*-OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[N APHTHALENE- 1 ,22'- |20jOX.\| Ι3ΓΓ!Π.\| i.l4|5)! A .A ^' l ···Γ1 Λ(·Υ(·|.()| Ι4.7.2.ϋ ^; " 0 ¹ " ⁿ |PHNT.U ^' OS A[8,16,l 8,24 jTETRAEN] - 12'-YL)METHYL CARBAMATE

The title compound was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 611, Step 3. Ή NMR (500 MHz, CDCh) δ ppm 9.58 (br. s. ill).7.70 (d, J=8.6 Hz, 1H), 7.34 (d, ./ H.I Hz, ill .7.18 (dd, ./ 2.4.8.6 Hz, IH), 7.15 (m, 1H), 7.10 (d, ./ 2.2 Hz, ill .6.98 (d, 83 Hz, 111).5.63 (m, III).5.53 (dd, ./ 5.9.11.2 Hz, IH), 4.71 (dd, ,/ 5.6. 12.0 Hz, 1H), 4.56 (dd, .7=5,7, 11.9 Hz, IH), 4,45 (t, .7=5.9 Hz, IH), 4.14 (s, 2H), 4.02 - 3.96 (m, IH), 3.75 - 3.60 (m, 2H), 3.32 (m, 2H), 2.81 - 2.74 (m, 2H), 2.62 - 2,51 (m, 2H), 2.48 (m, IH), 2,31 - 2.23 (m, IH), 2.23 - 2.13 (m, IH), 2.04 - 1.58 (m, 8H), 1,53 (m, IH); m/z (ESI, +ve ion) 644.2 .

EXAMPLE 613.3-((lS,3 ^, R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-13 ^, ,13'- DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAENj-12 ^! -YL)PROPANENlTRILE OR 3- ((IS^TR i'R^'S^'E/^'R e-CHLORO^'-HYDROXY- ' S'-DIOXIDO-lS'- ()X()-3.4-0!l !Yf) ()-2i i-Ss'IR()| \AY'\ i l l !.\ί 4·.\!.-!.22'-

|2ίί!<)ΧΛ| Π !Ί I Ι1Λ| 1.14|! ΙΛ/.\ ^' Π: i ^' RACYCf.Oi i 4.7.2. · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24iTETRAEN]-12'-YL)PROPANENITRJLE (ISOMER 1)

STEP 1 : (S)-3-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEPT-6-EN-l - YL METHANESULFONATE AND (R)-3-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)HEPT-6-EN-l-YL

METHANESULFONATE

To a solution of (S)-l-hydroxy-N,N-bis(4-methoxybenzyl)hept-6-ene-3- sulfonamide and (R)-l -hydrox -N,N-bis(4-methox benzyl)hept-6-ene-3- sulfonamide (Example 564, Step 1) (50 mg, 0.1 1 mmol) and triethylamine (32 μί, 0.23 mmol) in THF (1 mL) was added methanesulfonyl chloride (13 μΐ,, 0.17 mmol) at 0 °C. The reaction was allowed to warm up to room temperature. After being stirred at room temperature for Ih, the reaction was quenched (sat.NHiCi), extracted (DCM) and washed (brine). The combined organic layers were dried ( a?.S04) and concentrated under reduced pressure to give the title compound (58 mg, 0.1 1 mmol).

STEP 2: (S 1 -CYANO-N,N-BlS(4-METHOXYBENZYL)HEPT-6-ENE-3- SULFONAMIDE AND (R)- 1 -CYANO-N,N-BIS(4-METHOXYBENZYL)HEPT- 6-ENE-3-SULFON AMIDE

To a solution of (S)-3-(n,n-bis(4-methoxybenzyl)sulfamoyl)hept-6-en-l-yl methanes uifonate and (R)-3-(n,n-bis(4-methoxybenzyi)sulfamoy l)hept-6-en- 1 -y 1 methanesuifonate (Example 613, Step 1 ) (58 mg, 0.11 mmol) in MeCN (1 mL) was added tetraethylammonium cyanide (89 mg, 0.57 mmol). After being stirred at 80 °C for 1 h, the reaction was quenched (sa NFUCl), extracted (DCM) and washed (brine). The combined organic layers were dried (Na S04) and concentrated under reduced pressure. The residue was injected into a 4 g ISCO Gold column and purified by combi-flash, eluting with 0%» to 40%

EtOAc/hexanes to give the title compound (50 mg, 0.11 mmol).

STEP 3: 3-((l S,3' ,6'R,7 ^! S,8'E,12'S)-6"CHLORO-7 ^! "HYDROXY-13 ^, , '- DIOXTDO-15'-OXO-3,4-DmYDRO-2H-SPIRO| SiAPHTHALENE-l ,22'- | 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN] - 12'- YL)PROP ANENITRILE OR 3~

((l S,3 ^, R,6 ^, R,7 ^, S.8 ^, E.12 ^, R)-6-CHLORO-7 ^, -HYDROXY-13 ^, ,13 ^, -DIOXIDO-15'- OXO-3,4-DIHYDRO-2H-SPmO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAENj-12 ^! -YL)PROPANENITRlLE (ISOMER 1)

One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)- 2-((S,E)-l-hyckoxyhex-2-en-l-yl)cyclobutyl)me ^

spiro[benzo[b] [1,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A) by a procedure analogous to that described in Example 61 1 , Steps 2 through 3, replacing (S)-2-(N,N-bis(4-methoxybenzyl)sulfamoyl)hex-5-en- 1 -yi carbamate in Step 2 with (S)-l-cyano-n,n-bis(4-memoxybenzyl)hept-6-ene-3- sulfonamide and (U)-l-cyano-n,n-bis(4-methoxybenzyl)hept-6-ene-3-sulfonamide (Example 6 3, Step 2). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient eiution of 45% to 70%» MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to provide one of the title compounds as the faster eluting isomer as a white foam. ¾ NMR (500 MHz, CDCb) δ ppm 8.08 (s, 1H), 7.70 (d, ./ 8.6 Hz, 1H), 7.19 (d, ./ 8.3 Hz, 1H), 7.13 - 7.06 (m, i l l ). 6.98 - 6.89 (m, 3H), 5,82 - 5.70 (m, 2H), 4.26 (t, 4 Hz, 11 1 ). 4.20 (m, ! ! ! }. 4.16 - 4,06 (m, 2H), 3.84 (m, 1 1 1 ). 3,72 (d, J=14.4 Hz, i l l ). 3,24 (d, J=14.4 Hz, 1H), 3.04 (dd, ./ 8.9. 15.3 Hz, 1 1 1 ). 2.90 - 2,72 (rn, 4H), 2.51 - 2,31 (m, 4H), 2.25 - 2.13 (ra, 2H), 2.06 - 1.67 {m. 9H), 1.41 (m, 1H); m/z (ESI, +ve ion) 624.2 .

EXAMPLE 614. 3-((l S,3 ^* R,6'R, 7'S,8'E, 12'R)-6-CHLORO-7'-HYDROXY- 13', 13'- DIOXIDO-15'-OXO-3,4-DiHYDRO-2H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[l J.4]DiAZATETRACYCL,O[14.7,2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16 ₅ 18,24]TETRAEN]-12 ^, -YL)PR0PANEN1TRILE OR 3- ((1 S,3'R,6 ^f R,7'S,8'EJ 2 ⁱ S)-6-CHLORO-7'-HYDROXY-13'J 3'-DIOXTDO-l 5 ^f - OXO-3,4~DiHYDRO-2H-SPIRO[NAPH ^" fflALENE-l ,22'- [20]OXA[13]TH1A[1J4]DL ZATETRACYCLO[14.7.2.0^^0 ¹⁹ - ²⁴ ]1 TACOSA

[ 8,16,18 ₅ 24|TETRAEN]-12 ^, -YL)PROPANENITRILE (ISOMER 2)

One of the title compounds was obtained as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 613 as a white foam. ^! H NMR (500 MHz, CDCb) δ ppm 9.70 (s, 1H), 7.72 (d, ./ 8.6 Hz, 1H), 7,44 (dd, ./ 2.0. 8,3 Hz, H), 7.19 (dd, ./ 2.3.. 8.4 Hz, I H i. 7. 10 (d, J=2.2 Hz, 1H), 7.07 ·· 6.96 (m, 2H), 5.79 - 5.67 (m, 1H), 5.57 (m, i l l ). 4.50 (t, ./ 6.0 Hz, IH), 4.18 - 4.08 (m, 2H), 3.88 (d, ./ 1 5.4 Hz, IH), 3.82 - 3.74 (m, IH), 3.69 (d, ./ 14.2 Hz, IH), 3.22 (d, ./ 1 .2 Hz, IH), 3.14 (ra, i l l ). 2.81 - 2.72 (m, 4H), 2,66 - 2,39 (m, 4H), 2.28 - 1.52 (m, i l l ! }. 1.52 - 1 ,42 (m, IH); m/z (ESI, +ve ion) 624,2 (M+H) ⁺ . EXAMPLE 615. (l S,3'R,6 ^, R,7 ^! S,8 ^, E, 12 ^, S)-6-CHLORO-7'-METHOXY-12 ^! ~(2- METHOXY-2-METHYLPROPYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

| 20 jOX A| I 31 1 HI Λ| I .. N | OI A/A Π·. ΓΗ. ΑίΎί ^' ί .ΟΙ i -i .7.2 0 ^{; i} '.U ^{l i,} |PH\ i ACOSA [8,I6,18,24]TETiLAE ]-15'-ONE 13 13'-D10X1DE OR

(lS,3'R,6 ^, R,7 ^, S.8 ^, E.12 ^, R)-6-CHLORO-7 ^, -METHOXY-12 ^, -(2-METHOXY-2- MEraYLPROPYL)-3,4-DIHYDRO-2H ₅ 15H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

To a solution of (l S^'R.e'R 'S.S'E ^SJ-e-chloro-T'-hydroxy-l ^^- hydroxy-2-methylpropyl)-3,4-dihydro-2H,15'H-spiro[naphthalen e-L22'-

[20|oxa 13jthia[ l 4jdiazatetrac cIo[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ i

pentacosa[8J 6,18,24]ietraen]-15'-one 13',13'-dioxide or ( ! S,3'R,6'R,7'S,8'E,12'R.)- 6-chloro-7'-hydroxy-l 2'-(2-hydrox\'-2-methylpropyl)-3,4-dihydro-2H,l 5Ή- spiro[naphthalene-l,22 ^, -[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 558) (10 mg, 0.016 mmol) in TOP (0.5 ml.) was added NaH (60% dispersion in mineral oil, 3.1 mg, 0.078 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 30 min, a solution of iodomethane (6.6 mg, 0.047 mmol) in THF (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h and then was quenched (water and 1 N aqueous HCl solution). The reaction mixture was diluted with EtOAc. The organics were extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S04) and concentrated under reduced pressure. The residue was injected into a 4 g ISCO Gold column and purified by combi -flash, eluting with 0% to 30% EtOAc (containing 0,3% AcOH) hexanes to give one of the title compounds (4.8 mg, 7.2 μηιοΐ). ^l H NMR (500 MHz, CDCh) δ ppm 7.80 (s, IH), 7.62 (d, J=8.6 Hz, IH), 7.11 (m, IH), 7.01 (d, ./ 2.4 Hz, IH), 6.86 - 6.81 (m, IH), 6.81 - 6.77 (m, IH), 6.71 (d, ./ 1 .7 Hz, IH), 5.83 (m, IH), 5.43 (dd, J=9.2, 15.3 Hz, IH), 4.41 (dd, ./ 3.7. 8.1 Hz, IH), 4,06 - 3,94 (m, 2H), 3.72 (d, ,7=14,9 Hz, IH), 3,64 (d, J=14.4 Hz, H), 3.60 (dd, J=3.8, 9.2 Hz, IH), 3.19 - 3.11 ( m. 41 1 ). 3.11 - 3.08 (s, 3H), 2.90 (dd, =10.3, 15.4 Hz, I H), 2.76 - 2,63 (m, 2H), 2.52 - 2,42 (m, I H), 2.42 - 2,34 On. 2H), 2.28 - 2, 1 I (m, 2H), 1.97 (in, H), 1.91 - 1.65 (m, 8H), 1.63 - 1.51 (m, 2H), 1.29 (s, 3H), 1, 18 (s, 3H); m/z (ESI, +ve ion) 671.2 { M l ! ) .

EXAMPLE 616. METHYL 3-((l S,3'R,6'R,7'S,8 ^! E,12 ^! S)-6-CHLORO-7'- HYDROXY-13',13'-D10XIDO-15'-OXO-3,4-DlHYDRO-2H"

SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-12'-YL)PROPANOATE OR METHYL 3- ((I S^'R^'R 'S^^^'R^e-CHLORO^'-HYDROXY- ' S'-DIOXIDO-lS'- OXO-3,4-DIHYDRO-2H-SPIRO| APHTHALENE- 1 ,22'- [20]OXA[13]THIA[l,i4]DIAZATETRACYCLO[14,7.2,0^ ⁶ .0 ¹⁹ - ²⁴ ]

[ 8,16,18,24 [TETRAEN] - 12'-YL)PROP ANO ATE

STEP 1 : (S)-l -HYDROXY -N,N-BIS(4-METHOXYBENZYL)OCT-7-ENE~4- SULFO AMIDE AND (R)-l -HYDROXY -N,N-BIS(4- METHOXYBENZYL)OCT-7-ENE-4-SULFONAMIDE

To a solution of (R)-l-((tert-bu1yldimethylsilyl)oxy)-N,N-bis(4- memoxybenzyl)oct-7-ene-4-sulfonamide and (S)-l -((tert-butyldimelhylsilyl)oxy)- N,N-bis(4-methoxybenzyl)oct-7-ene-4-sulfonamide (80 mg, 0.14 mmol)

(Example 560, Step 1) in THF (1 mL) was added TBAF (1 M solution in THF, 290 μΙ_, 0.290 mmol) at 0 °C. The reaction was allowed to warm up to ambient temperature. After the reaction mixture was stirred overnight, the reaction was quenched (saturated aqueous NH C!), extracted (DCM) and washed (brine). The combined organic layers were dried (Na?.S04) and concentrated under reduced pressure. The residue was injected into a 12 g ISCO Gold column and pun i led by combi-flash, eluting with 20% to 80% EtOAc/hexanes to give the title compound (51 mg, 0.1 1 mmol).

STEP 2: (S)-4-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)OCT-7-ENOIC ACID AND (R)-4-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)OCT-7- ENOIC ACID

To a solution of (S)-l -hydroxy -N,N-bis(4-methoxybenzyl)oct-7-ene-4- sulfonamide and (R)-l -hydroxy -N,N-bis(4-methoxybenzyl)oct-7-ene-4- sulfonamide (Example 616, Step 1) (125 mg, 0.279 mmol) in acetone (2,8 mL) were added KBr (3.3 mg, 0.028 mmol), 5% sodium bicarbonate in water (1.3 mL, 0.78 mmol), TEMPO (48 mg, 0,31 mmol), and 6% sodium hypochlorite in water (0.45 ml,, 0.36 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 3.5 h, the reaction was concentrated under reduced pressure, diluted (EtOAc and ice-cold 1 N aqueous HC1), extracted (2* EtOAc), and washed (brine). The combined organic layers were dried (Na_S0 ₄ ) and concentrated under reduced pressure. The residue was injected into a 12 g 1SCO Gold column and purified by combi-flash, eluting with 20% to 100%» EtOAc/hexanes to give the title compound (100 mg, 0.217 mmol). STEP 3: (S)-METHYL 4-(N,N-BlS(4-

METHOXYBENZYL)SULFAMOYL)OCT-7-ENOATE AND (R)-METHYL 4- (N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)OCT-7-ENOATE

To a solution of (S)-4-(N,N-bis(4-methoxybenzyl)sulfamoyl)oct-7-enoic acid and (R)~4~(N,N-bis(4-methoxybenz}'l)sulfan!oyl)oct-7-enoic acid (Example 616, Step 2) (439 mg, 0.951 mmol) in MeOH (3.17 mL) was added thionyl chloride (139 μΕ, 1.90 mmol) at 0 °C dropwise. Then the reaction was allowed to warm to ambient temperature. After the reaction mixture was stirred overnight, the reaction was diluted (EtOAc and ice-cold water), extracted (2xEtOAc), and washed (saturated aqueous NaHCCb and brine). The combined organic layers were dried (Na ₂ S04) and concentrated under reduced pressure to provide the title compound (452 mg, 0.950 mmol) which was used in the next step without further purification. STEP 4: METHYL 3-((lS,3 ^, R,6 ^, R ₅ 7 ^, S,8'E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY- 13 ^, ₅ 13 ^, -DIOXIDO-15 ^, -OXO-3 ₅ -DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^, - |2ujOXA| ! jTIUA| U4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,24iTETRAEN]-12'-YL)PROPANOATE OR METHYL 3- ((IS ¾ )'R 'S,8^12'R)-6-CHIimO-7' iYDROXY-13 i3 ⁱ -DIOXIDO-i5'- OXO-3,4 3IHYDRO-2H-SPiRO[NAPHTHAJ,ENE-l,22'-

[20]OXA[13]TfflA[l 4]DIAZATETlACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 12"-YL)PROPANO ATE One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)-

2-((S,EH-hydroxyhex-2-en-l-yl)cyxlo ^

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid (Intermediate AA12) by a procedure analogous to that described in Example 611, Steps 2 through 3, replacing (S)-2-(N,N-bis(4-methoxybenzyl)sulfamoyl)hex-5-en-l-yl carbamate in Step 2 with (S)-methyl 4-(N,N-bis(4-methoxybenzyl)sulfamoyl)oct- 7-enoate and (R)-methyl 4~(N,N~bis(4-m.ethoxybenzy'l)sulfamoyl)oct-7-enoate (Example 616, Steps 3). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 mill method) to provide one of the title compounds as the faster eluting isomer as a white foam. ¾ NMR (500 MHz, CDCb) δ ppm 8.03 (s, 1H), 7.70 (d, J=8.6 Hz, IH), 7.19 (dd, 2.2.8.6 Hz, 1H), 7.10 (d, ./ 2.2 Hz, 111).6.96 - 6,87 (m, 3H), 5.89 - 5.81 (m, H), 5.78 - 5,70 (m, IH), 4.24 (m, ill).4.20 - 4.14 (m, 111).4.14 - 4.06 (m, 2H), 3.83 (m, IH), 3.77 - 3.68 (m, 4H), 3.24 (d, ./ 44 Hz, IH), 3.02 (dd, ./ 9.4.15.3 Hz, !!!).2.87 - 2,70 (m, 4H), 2.51 - 2.40 (m, !!!). 2,39 - 2.21 (m, 5H), 2.06 - 1.93 (m, 3H), 1,91 - 1.74 (m, 3H), 1.72 - 1.57 (ra, IH), 1.43 - 1.38 (m, IH); m/z (ESI, +ve ion) 657,2 (M+H) ⁺ .

EXAMPLE 617. (1 S,3'R,6 ^f R,7'S,8'E,12'S)-6-CHLORO-12'-(2- HYDROXYETHYL)-7'-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE-1 ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8 ^, E,12 ^, R)~6"CHLORO-12 ^! "(2-HYDROXYETHYL)-7'- ΜΕΤΉΟΧΥ ,4-ΟΙΗΥϋΚΟ-2Η^ 5Ή-8ΡΙΚΟ| ΑΡΗΤΗΑίΕΝΕ-1,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 .0 ³ -* 0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', '-DIOXIDE

STEP 1 : (S)- 1 -HYDROXYHEPT-6-ENE-3-SULFON AMIDE AND (R)- 1 - HYDROXYHEPT-6-ENE-3-SULFON AMIDE

To a solution of (S)-l-hydroxy-N,N-bis(4-methoxybenz 'l)hept-6-ene-3- sulfonamide and (R)-l -hydroxy-N,N-bis(4-methoxybenzv'l)hept-6-ene-3- sulfonamide (Example 564, Step 1 ) (419 mg, 0,966 mmol) in DCM (6.4 mL) was added anisole (105 mg, 0.966 mmol) and 2,2,2-trifluoroacetic acid (110 mg, 0.966 mmol) at ambient temperature. After the reaction mixture was stirred at ambient temperature overnight, the reaction was heated at 40 °C for 5 h and the excess TFA was removed under reduced pressure. The residue was dissolved in THF/MeQHThQ (2.4 mL, v/v/v=l/l/l) and lithium hydroxide (231 mg, 9.66 mmol) was added at ambient temperature. After the reaction was stirred for 1 h, the reaction was quenched (saturated aqueous NH4CI), extracted (2><EtOAc), and washed (brine). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure. The residue was injected into a 40 g ISCO Gold column and purified by combi -flash, eluting with 0% to 20% MeOH/DCM to give the title compounds (55 nig, 0.29 nimoi)

STEP 2: (S)-l -((TERT-BUTYLDIPHENYLSILYL)OXY)HEPT-6-ENE-3- SULFONAMIDE AND (R)-l-((TERT-BUTYLDIPHENYLSILYL)OXY)HEPT- 6-ENE-3-SULFONAM1DE

To a solution of (S)-l-hydroxyhept-6-ene-3-sulfonamide and (R) ^' -l- hydroxyhept-6-ene-3-sulfonamide (Example 617, Step I ) (50 mg, 0.26 mmol) and imidazole (53 mg, 0.77 mmol) in DMF (1 ml.) was added tert- bulylchlorodiphenylsilane (0.10 mL, 0.38 mmol) at ambient temperature under Ar. After the reaction raxitue was stirred overnight, the reaction was quenched (saturated aqueous NH4CI), extracted (2><EtOAc), and washed (brine). The combined organic layers were dried (Na2.S04) and concentrated under reduced pressure. The residue was injected into a 12 g ISCO Gold column and purified by cornbi-flash, eluting with 0% to 40% EtOAc/hexane to give the title compounds (65 mg, 0.15 mmol).

STEP 3: (l S,3'R,6'R,7'S,8'E,12'S>6-CHLORO-7'-HYDROXY-12'-(2-(((2- METHYL-2-PROPANYL)(BIPHENYL)STLYL)OXY)ETITYL)-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,I6, 18,24]TETRAEN]-15'-ONE 13', 13'-D )XIDE OR

(lS,3'R,6 ^! R,7'S,8iV12¾)-6-CHLORO-7 ^! ~HYDROXY-12' 2~(((2-ME ^' raYL-2- PROPANYL)(DIPHENYL)SILYL)OXY)ETHYL)-3,4-DIHYDRO-2H,15H- SPTRO[NAPHTHALENE-l ,22'-

| 20 |() Λ| 1 31 1 HI Λ| I .. N | OI A/.\ Π·. ΓΗ. Αί ^' ΥΌ .01 i -i .7.2 ϋ ^; ".ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 VI 3'-DIOXIDE

One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)-

2-((S,E)-l-hydroxyhex-2-en-l -yl)cyxlob ^{^}

spiro[benzo[b][l,4]oxazeprae-3,l'-naphthalene]-7-carboxyl ic acid (Intermediate AA12A ) by a procedure analogous to that described in Example 610, Steps 1 through 2, replacing (R)-hept-6-ene-3-sulfonamide in Step 1 with (S)-l-((tert- butylcUphenylsilyl)oxy)hept-6-ene-3-sulfonamide and (R)-l -((tert- butyldiphenylsilyl)oxy)hept-6-ene-3-sulfonarnide (Example 617, Step 2). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to provide the title compound as the faster eluting isomer as a white foam.

STEP 4: (I S,3'R,6'R,7'S,8'E, 12'S)-6-CHLORO-7 ⁱ -METOOXY-i2'-(2-(((2-

METHYL-2-PROPANYL (pIPHENYL)SILYL)OXY)ETHYL)-3,4-DIHYDRO-

2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATET AC YCLO [ 14.7.2, 0 ^3>6 .0

¹⁹ · ²⁴ ]ΡΕΝΤ ACOS A[8, 16, 18,24]TETRAEN]-15 ^! ~ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,12'R)~6"CHLORO-7 ^, ~ME ^' raOXY-12'-(2~(((2"METHYL-2-

PR()PANYL)(DIPHENYL)SILYL)OXY)ETI-r ^;" L)-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14.7.2, 0 ^3>6 .0

1 ⁹ · ²⁴ ]ΡΕΝ ^' Ϊ ACOS A[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

To a solution of (IS ,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^* E, 12 ^, S)-6-chloro-7 ^, -hydroxy-12 ^, -(2-(((2- methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydro-2h, 15'H- spiro [naphthalene- 1 ,22'-

[20]oxa[13]thia[ l, 14]diazatetTacyclo[147.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13 ', 13 '-dioxide or (lS^'I^e'R^'S^'E^^R^e-chloro-T-hydroxy-l^^- (((2-methyl-2-propanyl)(diphenyl)silyl)oxy)ethyl)-3,4-dihydr o-2H,15'H- spiro I naphthalene- 1 ,22'-

[20]oxa[ 13]thia|;i ,14]diazaietracycio[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]p

n]-15'-one 13',13'-dioxide (Example 617, Step 3) (10 mg, 0.012 mmol) in THF (0.5 mL) was added NaH (60% dispersion in mineral oil, 2.3 mg, 0.059 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 30 min, a solution of iodomethane (2.2 μΕ, 0.035 mmol) in THF (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h and then was quenched (water and 1 N aqueous HCI solution). The reaction mixture was diluted (EtOAc). The organics were extracted (2xEtOAc), and washed (brine). The combined organic layers w¾re dried (NazSC ) and concentrated under reduced pressure to provide the crude title compound which was used in next step without further purification.

STEP 5: (lS,3 ^! R,6'R,7'S,8'E,12'S)-6-CHLORO-12'-(2-HYDROXYETHYL)-7'- ΜΕΤΉΟΧΥ ,4-ΟΙΗΥΏΚΟ-2Η^ 5Ή-8ΡΙΚΟ| ΑΡΗΤΗΑίΕΝΕ-1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR (lS,3 ^, R,6 ^, R ₅ 7 ^, S,8¾12 ^, R)-6-CHLORO-12 ^, -(2-HYDROXYETHYL)-7'- METHOXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- |2ujOXA| O p i II A| I„ I 4|Di A/.Yi ^' ! R AC YO.OI i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PHNTAi S A

[8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

To a solution of the crude product from Example 617, Step 4 in THF (1 mL) was added TBAF (1.0 M in THF, 0.58 mL, 0.58 mmol). After the reaction mixture was stirred at 37 °C for 5 h, the reaction was quenched (saturated auqeous NH ₄ C1), extracted (2 EtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S0 ) and concentrated under reduced pressure to provide a crude product. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as a white foam (3.0 nig, 4.8 μιηοΐ). Ή NMR (500 MHz, CDC ) δ ppm 7.94 (s, 1H), 7.70 (d, ,/ X.3 Hz, H), 7,19 (dd,J=2.2, 8.6 Hz, 1H), 7.10 id.,/ 2 Hz, 1H), 6.95 - 6.91 (m, IH), 6.91 - 6.88 (m, ill).6.84 (d, ./ 2.0 Hz, IH), 5.90 - 5.82 (m, Ml).5.55 (dd, J=9.0, 15.2 Hz, IH), 4.39 (m, IH), 4.14 - 4.02 (m, 3H), 3.97 - 3.87 (m, IH), 3.82 (d, ./ 15.2 Hz, IH), 3.72 (d, ,/ 142 Hz, IH), 3.66 (dd, ,/ 34.9.0 Hz, IH), 3,27 - 3.21 (m, 4H), 3.00 (dd, ,7=10,1, 15.3 Hz, IH), 2,85 - 2,71 (m, 2H), 2.50 - 2.41 (m, IH), 2,41

- 2,27 (m, 4H), 2.23 - 2.12 (m, IH), 2.10 - 1.93 (m, 4H), 1.90 - 1.54 (m, 5H), 1.45

- 1.34 (m, IH); m/z (ESI, +ve ion) 629.2 (M+H)+.

EXAMPLE 618.3-((lS,3 ^! R,6'R,7'S,8 ^, E,12 ^, S)-6-CHLORO-7'-HYDROXY-13 ^! ,13'- DIOXID()-15 ^, -()XO-3,4-DIHYDR()-2H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TETRAEN] - 12'-YL)-N,N-DIMETHYLPROP AN AMIDE OR 3 - ((Ιβ^^,ό'Ι,Τ'β,δΈ,ηΐ^-ό^ΉΕΟίΟ-Τ'-ΗΥΟίΙ ΟΧΥ- ', '-ΟΙΟΧΙΟΟ-^'- OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-12'-YL)-N,N-DIMETHYLPR0PANAM1DE

STEP 1 : 3-((lS,3'R,6'R,7 ^f S,8'E,I2'S)-6-CHLORO-7'-HYDROXY-13',13'- DIOXIDO-15'-OXO-3 -DIHYDRO-2H-SPiRO[NAPHTHALENE-l,22'- [20]OXA[13]TO1A[1 4]DIAZATET1ACYCLO[14.7.2.0 - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-12'-YL)PROPANOIC ACID OR 3- ((lS,3'R,6 ^f R,7'S,8'E,12'R)-6-CHLORO-7'-HYDROXY-13',13'-DIOXIDO-15 '- OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J -i2'-YL)PROPANOIC ACID

To a solution of methyl 3-(( iS,3'R,6'R,7'S,8'E, I2'S)-6-chloro-7'-hydroxy- 13713'~dioxdo~ 15'~oxo~34~dihy dro-2H-sp

Hjajteirae n]-12'-yl)propanoate or methyl 3-((lS,3'R,6'R,7'S,8'E,12'R)-6-chloro-7'-hydroxy- 13', 13'-dioxido-.l 5'-oxo-3,4-dihydro-2H-spiro| naphthalene- 1, 22'- [20]oxa[13]thia[l,14]diazatetracycto^

n]-12'-yl)propanoate (23 mg, 0.035 mmol) (Example 616) in a mixture of THF/water/MeOH (4 ml,, v/v/v = 2/1/1) was added LiOH (8.4 mg, 0.35 mmol). After the reaction mixture was stirred at ambient temperature for 2 h, the reaction mixture was acidified (1 N aqueous HCl solution), diluted (EtOAc), extracted (2* EtOAc). The combined organic layers were washed (brine), dried (NazSC ), and concentrated under reduced pressure to provide the crude title compound which was used in next step without further purification.

DIOXIDO-lS'-OXO-S^-DIHYDRO^H-SPIROI APHTHALENE-l ^^- [20]QXA[13]THIA[1,14]DL^

[8,16,18,24]TCTRAEN]-12'-YL)-N,N-DIMETHYLPROPANAMIDE OR 3- ((l S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7 ^! -HYDROXY-13',13'-DIOXIDO-15'- OXO-3,4-DIHYDRO-2H-SPmO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAEN]-12'-YL)-N,N-DIMETHYLPROPANAMIDE

To a solution of ; ((l S,3 ^! R,6¾,7'S,8¾ 12 ^, S)-6-chloro-7'-hydroxy-13V13'- dioxido- 15'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1 ,22'-

[20ioxa| 13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ^3>6 .0 ^{! 9} ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-12'-yl)propanoic acid or 3-(( lS,3 ^f R,6'R,7'S,8'E, 12'R)-6-chloro-7'-hydroxy- 13',13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[U4]cUazatetracyclo|^

n]-12'-yl)propanoic acid (0.020 g, 0.031 mmol) (Example 618, Step 1 ) in DMF (1.0 ml.) was added N-ethyl-N-isopropylpropan-2-araine (0.012 g, 0.093 mmol), hatu (0.018 g, 0.047 mmol), and dimethylamme (2.0 M solution in THF, 0.078 mL, 0.16 mmol). After the reaction mixture was stirred at ambient temperature for 5 h, the reaction mixture was diluted (MeOH) and purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as a white foam (0.016 g, 0,024 mmol). Ή NMR (500 MHz, CDCh) δ ppm 8.07 (s, IH), 7.72 (d, J=8.6 Hz, IH), 7.21 (m, IH), 7.11 (d, J=2.2 Hz, IH), 6.96 - 6.90 (m, 3H), 5.90 - 5.82 (m, IH), 5.78 - 5,71 (m, 1H), 4.26 (dd, J=4.2, 7,6 Hz, IH), 4.17 - 4,07 (m, 3H), 3.84 (d, .7=14,2 Hz, H), 3.73 (d, .7=14.2 Hz, IH), 3,26 (d, J=14.4 Hz, IH), 3.13 (s, 3H), 3.09 - 3.00 (m, 4H), 3.00 - 2.91 (m, IH), 2.86 - 2.68 (m, 3H), 2.49 - 2.44 (m, IH), 2.40 - 2.27 (m, 5H), 2.09 - 1.95 (m, 311).1.92 - 1.74 (m, 5H), 1.72 - 1 ,63 (m, IH), 1.42 (i, ./ ! 2.6 Hz, IH); m /, (ESI, +ve ion) 670.2 (M-!l) .

EXAMPLE 619. METHYL ((lS,3 ^! R,6'R,7'S,8'E,12'S)-6-CHL()RO-7'- HYDROXY-13', 13'-DIOXIDO-.l 5'-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-l,22'- |2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2,0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAEN]-12'-YL)ACETATE OR METHYL

((lS,3¾,6'R,7'S,8^I2'R)-6-CHIimO-7' iYDROXY-!3',13'-DIOXIDO-15'- OXO-3,4-DlHYDRO-2H-SPIRO[NAPH ^r fflALENE-l,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8,24]TETRAEN]-12'-YL)ACETATE (ISOMER 1)

STEP 1: (R)-METHYL 3-(N ₅ N-BIS(4- METHOXYBENZYL)SULFAMOYL)HEPT-6-ENOATE AND (S)-METHYL 3- (N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)HEPT-6-ENOATE

The title compounds were prepared from (S)- 1 -hydroxy -N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (R)- 1 -hydroxy -N, -bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide (Example 564, Step 1) by a procedure analogous to that described in Example 616, Steps 2 through 3.

STEP 2: METHYL ((lS,3 ^, R,6 ^, R,7'S,8 ^, E,12 ^, S)-6-CHLORO-7 ^! -HYDROXY- 13 ,13'-DTOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPIRO [NAPHTHALENE- 1 ,22'- | 20 jO.\ A| 1 31 1 HI Λ| I N | OI A/A Π·. I RAC VCi ()l i ·Ι 7.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN] - 12'-YL)ACETATE OR METHYL

((l S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-7 ^! -HYDROXY-13',13'-DIOXIDO-15'- OXO-3,4-DIHYDRO-2H-SPmO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16, 18,24]TETRAEN]-12'-YL)ACET ATE (ISOMER 1)

One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)- 2-((S,E)-l-hydroxyhex-2-en-l-yl)c^xlobut )methyl)-3^4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [1,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A) by a procedure analogous to that described in Example 61 1 , Steps 2 through 3, replacing (S)-2-(N,N-bis(4-methoxybenzy l)sulfamoyl)hex-5-en- 1 -yi carbamate in step 2 with (R)-methyl 3-(N,N-bis(4- methoxybenzyl)sulfamoyi)hept-6-enoate and (S)-methyl 3-(N,N-bis(4- methoxybenzyl)sulfamoyl)hept-6-enoate (Example 619, Steps 1). The cmde product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to provide one of the title compounds as the faster eluting isomer as a white foam. ¾ NMR (400 MHz, CDCb) δ ppm 8.30 (br. s., I I I ). 7.72 (d, ,/ 8.4 Hz, i l l ). 7.21 (dd,■/ 2.2. 8.5 Hz, 1 1 1 ). 7.12 (d, ,/ 2 2 Hz, i l l ). 6.99 - 6.91 (m. l ). 5.99 - 5.90 (m, ! ! ! }. 5.76 (dd, .7=7.6, 15.3 Hz, 1H), 4.68 (m, 1H), 4.29 (dd, ,/ -I i , 7.6 Hz, 1 1 1 ). 4, 16 - 4,07 (m, 2H), 3.86 - 3.77 (m, 4H), 3.73 (d, J=14.1 Hz, 1H), 3.31 - 3.22 (m, 2H), 3.08 (dd, 8.9.15.2 Hz, III).2.86 - 2.69 (m, 3H), 2.52 - 2.31 (m, Ml).2.22 - 2.12 (m, IH), 2.07 - 1.79 (m, 8H), 1,75 - 1.66 (m, ΓΗ), 1.44 (m, IH); m/z (ESI, +ve ion) 643.2 (M+H) ⁺ . EXAMPLE 620, METHYL ((lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-7'- HYDROXY - 1 '.13 '-DIOXIDO- 15 '-OXO-3,4-DIHYDRO-2H-

SP1RO [NAPHTHALENE- !.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TET AEN] - 12'-YL) ACET ATE OR METHYL

((lS,3'R,6 ^! R,7'S,8 ^, E,12 ^, S)-6-CHLORO-7'-HYDROXY-13',13 ^! "DIOXIDO-15 ^! " OXO-3.4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1.22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-12'-YL)ACETATE (ISOMER 2)

One of the title compounds was obtained as the second (slower) eluting isomer from the reverse phase preparatory HPLC purification in Example 619, Step 2 as a white foam. ¾ NMR (400 MHz, CDCh) δ ppm 7.72 (d, J=8.6 Hz, ill).7,42 (dd, ./ ! .6, 8.2 Hz, III).7.18 (dd, ,/ 2.2.8.4 Hz, ill).7,09 (d, J-2.0 Hz, IH), 7,04 - 6.96 (m, 2H), 5.75 - 5.64 (m, ill).5,59 - 5.43 (m, I Hi.4.55 (m, IH), 4.21 (m, IH), 4.18 - 4.04 (m, 2H), 3.90 (m, IH), 3.77 (s, 3H), 3.73 - 3.61 (m, IH), 3.34 - 3.18 (m, 2H), 3.13 (dd../ 8.6.15.3 Hz, IH), 2.84 - 2.66 (m, 4H), 2.41 - 1.78 (m, lOH), 1.78 - 1.58 (m, 2H), 1.54 - 1.35 (m, IH); m/z (EST, +ve ion) 643,2 (M+H) ⁺ . EXAMPLE 621.2-((lS,3'R,6 ^f R,7'S,8 iJ2 ^f S)-6-CHLORO-7'-HYDROXY-13'J3'- DiOXIDO-15 ^! ~OXD-3,4 ^IHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- |2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/Λ Π:ΤΗΛ(Ύα.ί)Ι i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [8,16,18,24]TETRAEN]-12'-YL)-N,N-DIMETHYLACETAMIDE OR 2- ((lS ¾ )'R 'S,8^12'R)-6-CHIimO-7' iYDROXY-13 i3 ⁱ -DIOXIDO- 5'- OXO-3,4 3mYDRO-2H-SPiRO[NAPHTHAJ,ENE-l,22'-

[20]OXA[13]TH1A[1 4]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,1 - 12'-YL)-N,N-DTMETHYLACET AMIDE

One of the title compounds was prepared from methyl

((lS,3¾,6 ^! R,7^,8T i2'S)-6-chloro-7'½droxy-13 13 ^! ~dioxido-15 ^! jxo-3,4^ dihydro-2H-spiro[naphthalene-l,22'-[20]oxa[13]thia[l,14]diaz atetracyclo[14.7.2. 0 ^: ".0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-12'-yl)acetate or methyl

((lS,3 ^! R,6¾,7^,8T i2 ^, R)-6-chloro-7'½drox}-13V13'-dioxido-15 ^! )xo-3,4 dihy dro-2H-spiro [naphthalene- 1 ,22'~

[20]oxa[13]thia[l,14]cUazatetracyc^

n]-12'-yl)acetate (isomer 1) (Example 619) by a procedure analogous to that described in Example 618, Steps 1 through 2. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column;

Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as a white foam. ¾ NMR (500 MHz, CDCb) δ ppm 8.22 (br. s., 1H), 7.63 (d, ,/ H. Hz, 1H), 7.11 (m, ill).7.02 (d, ./ 2.2 Hz, !!!).6.89 - 6.81 (m, 3H), 5.94 - 5.87 (ra, ill).5,64 (dd, ./ 7.K. 15.4 Hz, 111).4.65 (m, 1H), 4.19 (dd, 3.9. 7.6 Hz, 1H), 4.08 - 3.95 (m, 21 \) 3.71 (d, ./ 15.4 Hz, ill).3.62 id../ 14.4 Hz, 1H), 3.27 (dd, ,7=3.7, 16.4 Hz, IH), 3,18 (d, J=14.2 Hz, IH), 3.09 - 2.96 (m, 4H), 2.93 (s, 3H), 2.77 - 2.63 (m, 2H), 2.56 (dd, J=8.3, 16.4 Hz, IH), 2.40 - 2.20 (m, 3H), 2.20 - 2.08 (m, IH), 1.96 - 1.84 (m, 4H), 1.81 - 1.66 (m, 4H), 1.64 - 1.53 (m, IH), 1 ,35 (i, ./ 12.5 Hz, IH); m/z (ESI, +ve ion) 656.2 (M+H) ⁺ .

EXAMPLE 622.3 (18,3'Κ,6'Κ,7 ,8Έ,12Έ)-6-{:ΗΕ()ΚΟ-7'-ΜΕΤΗ()ΧΥ-13',13'- DIOXIDO-lS'-OXO-S^-DIHYDRO^H-SPIROI APHTHALENE-l^^- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA

[8,16,18,24]TETRAEN]-12'-YL)-N,N-DIMETHYLPROPANAMIDE OR 3- ((lS,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-CHLORO-7 ^! -METHOXY-13',13'-DIOXID()-15'- ΟΧΟ-3,4-ΟΙΗΥΟΚΟ-2Η-8ΡΙΚΟ[ΝΑΡΗΤΗΑ1ΕΝ� �-1,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA |8,16,18,24]TETRAENj-12'-YL)-N,N-DIMETHYLPROPANAMIDE

One of the title compounds was prepared from 3- ((18,3¾,6 ,7'8,8Έ,12 )-6-ΰωοΓθ-7 ^, -ΚνάΓθχν-13',13' 1ιοχκ1ο-15 ^! "θχο-3,4~ dihy dro-2H-spiro [naphthalene- 1 ,22'- [20 j oxa[ 13] thia[ 1,14] diazatetracy clo [ 14.7.2. 0 ³ · ⁶ .0 ¹⁹ ' ² ]pentacosa[8, 16, 18,24]tetraen]-12 ^, -yl)-N,N-dime lpropanamide or 3- ((IS^l ^'R 'S^'EJ^Ri-e-chloro-T'-hydroxy-lS^ '-dioxido-lS'-oxo-S^- dihy dro-2H-spiro [naphthal ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracycio[14,7.2,0 - ⁶ .0 ¹⁹ - ²⁴ ]

pentacosa[8, 16, 18,24]tetraen] - 12'-y l)propy 1 acid (Example 618) by a procedure analogous to that described in Example 617, Step 4. The cmde product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as a white foam. ¾ NMR (500 MHz, CDCh) δ ppm 7.93 (s, 1H), 7,70 (d, ./ 8.6 Hz, !!!).7.19 (dd, ,/ 2.2.8,6 Hz, IH), 7.14 - 7.05 (m, ill).6,94 - 6.90 (m, ill).6.90 - 6.86 (m, ills.6.82 (d, ./ i.7 Hz, Ml).5.86 - 5.78 (m, 1H), 5.53 (dd, ./ 9.2.15.3 Hz, IH), 4.19 (m, 1H), 4.14 - 4.02 (m, 2H), 3.81 (d, J=15.2 Hz, IH), 3.71 (d, ,/ 144 Hz, 1H), 3.68 - 3.60 (m, 1H), 3,28 - 3.21 (m, 4H), 3.10 (s, 3H), 3.04 - 2,95 (m, 4H), 2.88 - 2.72 (m, 4H), 2.49 - 2,26 (m, 7H), 2.08 - 1.92 (m, 4H), 1.87 - 1.59 (m, 3H), 1.39 (m, IH); m/z (ESI, +ve ion) 684.2 (M R) .

EXAMPLE 623, METHYL (iiS,3'R,6'R,7'S,8'E,12'S)-6-CHLORO-7'-(2- ETHOXY-2-OXOETHOXY)- 13', 13'-D10XIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 12'-YL)ACET ATE OR METHYL

((lS,3'R,6 ^! R,7'S,8 ^, E,12 ^, S)-6-CHLORO-7'-(2-ETHOXY-2-OXOETHOXY)- 13^13 ^, -DIOXroO-15 ^, -OXO-3,4-DfflYDRO-2H-SPIRO| APHTHALENE-l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PEOTACOSA

[8,16, 18,24]TETRAEN] - 12'-YL)ACETATE

To a solution of methyl (( l S,3 ^f R,6'R,7'S,8'E, 12'S)-6-chloro-7'-hydroxy- 13 3'-dioxido- 15'~oxo~3 4-dihydro-2H-spiro[naplithalene- l,22 ^! ~

n|-12'-yl)acetate or methyl ((18,3¾,6¾,7'8,8Έ, 12¾)-6-οωοΓθ-7 ^! ¾'άΓθχν-13·, 13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene- l ,22'- [20]oxa[ 13]thia[l, 14]diazatetra^

n j-12'-yl)acetate (isomer 1) (Example 619) (8.0 mg, 0.012 mmol) and rhodium (ii) acetate dimer (0.55 mg, 1 .2 μηιοΐ) in DCM (0.5 mL) was added ethyl diazoaceiate (0.01.5 ml,, 0.15 mmol) slowly. After the reaction mixture was stirred at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure and purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to provide one of the title compounds as a white foam (2.0 mg, 2.7 μιηοΐ). ¾ NMR (500 MHz, CDCI3) 6 ppm 8.03 (br. s. , IH), 7.69 (d, ,/ 8.6 Hz, 1 1 1 ). 7.19 (dd, 2 3. 8,4 Hz, 1H), 7.10 (d, .7=2,2 Hz, M i ). 6.95 - 6.91 (m, 1H), 6.91 - 6.87 (m, H), 6.81 (s, 1H), 5.94 ·· 5.86 (m, i l l ). 5.57 (dd, J=8.9, 15.3 Hz, IH), 4.78 (m, IH), 4.24 (q, ./ 74 Hz, 2H), 4.12 - 3.98 (m, 4H), 3.90 (dd, ./ 3. H. 8.9 Hz, IH), 3.83 - 3.80 i ns. IH), 3,78 ! s. i ). 3,75 - 3.66 (m, I H), 3.27 - 3.20 (m, 2H), 3,02 (dd, J=10.1 , 15.3 Hz, IH), 2,83 - 2.73 (m, 2H), 2.70 (dd, J=7.5, 16.5 Hz, IH), 2.65 - 2.58 (m, IH), 2.39 - 2.27 (m, 2H), 2.27 - 2.15 (m, IH), 2.06 - 2.02 (m, IH), 2.00 - 1.78 (m, 7H), 1 .75 - 1.66 (ra, IH), 1 ,44 - 1.38 (m, I H), 1 .32 (†, ,/ 7.2 Hz, 3H); nv ^' z (ESI, +ve ion) 729.2 (M+H) ⁺ . EXAMPLE 624. METHYL ((l S,3'R,6'R,7'S,8 ^, E, 12'S)-6-CHLORO-7'- METHOXY-13', 13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[144]DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ¹⁹ ^ ⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] - 12'-YL)ACETATE OR METHYL

((1 8,3¾,6¾,7'8,8Έ.,12Έ)-6-0-ίΙ^Ο-7'-ΜΕΤΗΟΧΎ-13', 13'-ΟΙΟΧΙΟΟ- 15'- OXO-3,4~DiHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 12'-YL)ACET ATE

To a vigorously stirred solution of methyl ((l S,3'R,6'R,7'S,8'E, 12'S)-6- chloro-7' iydroxy-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[iiaphth alene-

1 22'-

n]-12'-yl)acetate or methyl ((lS,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E ₅ 12 ^, R)-6-chloΓO-7 ^, -hydΓo -13 13 ^, - dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l ,14]diazate1ra<yc^^^

n]-12'-yl)acetate (isomer 1) (Example 619) (8,0 mg, 0.012 mmol) and fluoroboric acid (50 wt% solution in water, 1.6 μΐ,, 0.012 mmol) in DCM (0.5mL) was added (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 6.2 μΐ, 0.012 mmol) dropwise at 0 °C. After the reaction mixture was stirred at 0 °C for 1 h, another 0.5 equv. of (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 0.8 μL·, 0.006 mmol) was added to the reaction mixture. Then, the reaction mixture was stirred at 0 °C for lOmin, quenched (MeOH), and purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient eiution of 40% to 90% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to provide one of the title compounds as a white foam (I .5 mg, 2,3 .umol ). ¾ NMR (500MHz, (1X 1 ;) δ ppm Ή NMR (500 MHz, ( )3(Ί ) δ 8.00 (s, 1H), 7.74 - 7.67 (m, 1H), 7.22 - 7.15 (m, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.95 - 6.91 (m, 1H), 6.91 - 6.87 (m, ! ! ! ). 6.82 (d, J=1.7 Hz, I I I ). 5.98 - 5.86 (m, 1H), 5.54 (del.,/ H .15.3 Hz, ill).4,81 (m, !!!).4.14 - 4.02 (m, 2H), 3.83 - 3,66 (m, 6H), 3.32 - 3.19 (m, 5H), 3,00 Cdd ./ 10.1.15.3 Hz, 1H), 2.83 - 2.74 (m, 2H), 2,70 (dd, J=7.5, 16.5 Hz, IH), 2.52 - 2.40 (m, 1H), 2.39 - 2.19 (m, 3H), 2.07 - 1.74 (m, 8H), 1.71 - 1.64 {in. III).1.40 (!.-/ 12.7 Hz, III): m /. (ESI, +ve ion) 657.2 {M H}

EXAMPLE 625. (18,3 ^! ,6·Κ,7'8,8Έ,12'8)-12'-(2-(4-

BROMOPHENOXY)ETHYL)-6-CHLORO-7'-HYDROXY-3,4-DTHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'- |2ujOXA| 1ΉΤί!1Α| U4|DiA/.YiTTRAC ^' Ya.i)i i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE OR

(lS,3 ^, R ₅ 6*R,7 ^, S,8¾12 ^, R)-12 ^, -(2-(4-BROMOPHENOXY)ETHYL)-6-CHLORO-

7'-HYDRQXY-3,4-DIHYDRO-2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'- |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,I8,24]TETRAENl-15'-ONE 13',13'-D )XIDE

STEP 1: (S)-l-(4-BROMOPHENOXY)-N,N-BIS(4- METHOXYBENZYL)HEPT-6-ENE-3-SULFON AMIDE AND (R)- 1 -(4- BROMOPHENOXY)-N,N-BIS(4-METHOXYBENZYL)HEPT-6-ENE-3- SULFONAM1DE

To a solution of (S)-l-hydroxy-N,N-bis(4-methoxybenzyl)hept-6-ene-3- sulfonamide and (R)-l -hydroxy -N,N-bis(4-methoxybenz>'l)hept-6-ene-3- sulfonamide (Example 564, Step 1), (550 mg, 1.27 mmol) in toluene (8 mL) was added 4-bromophenol (219 mg, 1.27 mmol), tiiphenylphosphme (399 mg, 1.52 mmol), and di-tert-butyl azodicarboxvlate (351 mg, 1.52 mmol) successively at ambient temperature. After the reaction mixture was stirred for 24 h, the reaction solution was concentrated under reduced pressure. The residue was injected into a 24 g ISCO Gold column and purified by combi-flash, eluting with 10% to 40% EtOAc/hexanes to give the title compounds (450 mg, 0.765 mmol).

STEP 2: (lS,3 ^! R,6 ^, R,7 ^, S,8'E,12 ^, S)-12 ^, -(2-(4-BROMOPHENOXY)ETHYL)-6- CHLORO-7 ^! iYDROX ^r -3,4-Dim ^r DRO-2H,15 ^SPIRO|NAPI-m-IALENE- [20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14 .0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,12'R)~12 ^f -(2-(4-BROMOPHENOXY)ETHYL)-6-CHLORO- 7 ^, -HYDROXY-3,4-DIHYDRO-2H ₅ 15Ή-SPIRO[NAPHTHALENE-l,22 ^, - |2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE

One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)- 2-((S,E)-l-hydrox\'hex-2-en-l-yl)cyclobu1yl)me l)-3^4,4^5-tetrahydro-2H,2 ^, H- spiroj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate AA12A) by a procedure analogous to that described in Example 611, Steps 2 through 3, replacing (S)-2-( ,N-bis(4-methoxybenzyl)sulfamoyl)hex-5-en-l-yl carbamate in Step 2 with (S)-l-(4-bromophenoxy)-N,N-bis(4- methoxybenzyl)hept-6-ene-3-sulfonamide and (R)- 1 -(4-bromophenoxy)-N,N- bis(4-methoxybeiizyl)hept-6-ene-3-suifonamide (Example 625, Step 1). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as the faster eluting isomer as a white foam. ¾ NMR (500 MHz, CDCb) 6 ppm 8.02 (s, IH), 7.70 (d, ./ 8. Hz, i l l ). 7,40 id, J=8.0 Hz, 2H), 7.19 (dd, J=2,2, 8.3 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.96 - 6.87 (m, 3H), 6.87 - 6.80 (m, 2H), 5.83 (m, IH), 5.77 - 5.68 (m, 1H), 4.38 - 4.31 (m, IH), 4.30 - 4.20 { in. 3H), 4.16 - 4.05 i ns. 2H), 3.83 (d, ./ 14.7 Hz, ! ! ! ). 3.72 (d,■/ 14.4 Hz, I H), 3,24 (d, ./ 14.2 Hz, IH), 3.03 (dd, ./ 9.5. 15.2 Hz, IH), 2,83 - 2.72 (m, 2H), 2,62 (dd, «/=7.5, 15,5 Hz, IH), 2.49 - 2.40 (m, IH), 2.39 - 2.19 (m, 5H), 2.11 - 1.61 (m, 8H), 1.41 (t,■/ 12.8 Hz, i l l ): m/z (ESI, +ve ion) 771.0 (M+H) ⁺ .

EXAMPLE 626. 4-(3-((lS,3'R,6'R,7 ^! S,8'E,12'S)-6~CHLORO-7 ^! ~HYDROXY- lS^lS'-DIOXlDO-lS'-OXO-S^-DmYDRO^H-SPlROI APHTHALENE-l^^- ^OlOXAtlSlTHIAt^MlDIAZATET ACYCLOI MJ^.O'^.O'^JPE TACOSA [8, 16, 18,24] TETR AEN] - 12'-YL)PROP ANOYL)-N,N-DIMETHYL- 1 - PIPERAZINESULFONAMIDE OR 4-(3-((l S _s 3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO- 7 ^, -HYDROXY-13'.13'-DIOXIDO-15 ^, -OXO-3.4-DIHYDRO-2H- SPIRO[NAPHTH ALENE- 1 ,22'-

| 2( >X A| i ? I ! f Π Λ| ί i J l i^f AZ.Vf l: E RAC YCE C)l i J 7.2 0 ^{:' i'} .0 ^{l i} ' |Pl-:N i ACOSA [8,16,18,24] TETRAEN] - 12'-YL)PROPANOYL)-N,N-DIMETHYL- 1 - PIPERAZINESULFONAMIDE

One of the title compounds was prepared from 3- ((l S,3'R,6'R;7'S,8Έ,12 ^, S)-6-ch3oro-7 ^, -hydroxy-13', 13 ^! -dlo ίdo-15'-oxo-3,4- dihy dro-2H-spiro [naphthalen e- 1 ,22'- [20] oxa[ 13] thia[ 1 , 14] diazatetracy clo [ 14.7.2. 0 ³ · ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-12'-yl)propyl acid or 3- ((l S.3 ^, R,6 ^, R,7 ^, S,8Έ,12¾)-6-chloro-7 ^, ½dΓoxy-13 13 ^, -dioxido-15 ^, -oxo-3.4- dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[ 1 3]thia[ 1 , 14] diazatetracy clo[ 14, 7.2, 0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa[8,16,18,24]tetraen]-12'-yl)propyl acid (Example 618, Step 1) by a procedure analogous to that described in Example 618, Steps 2, replacing dimethylamine in Step 2 with N,N-dimethylpiperazine-.l -sulfonamide. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0. 1 % TFA, 30 min method) to provide one of the title compounds as a white foam. ¾ NMR (500 MHz, CDCb) δ ppm 8.50 (br. s, 1 H) 7.70 (d, ./ 8.3 ! Hz, 1 H) 7.18 (dd, ./ 8.44. 2.08 Hz, 1 H) 7.09 (d, ./ 1 .96 Hz, 1 H) 6,95 - 6.90 (m, 2 H) 6.88 (s, 1 H) 5.90 - 5,79 (m, 1 H) 5,70 (dd, 15.28. 7.21 Hz, 1 H) 4.23 (dd, «7=7.09, 4.16 Hz, 1 H) 4.15 - 4,04 (m, 3 H) 3,92 - 3.84 C m. 1 H) 3.79 (d, ./ 14.67 Hz, 1 H) 3.75 - 3.65 (m, 2 H) 3.63 - 3.51 (m, 2 H) 3,40 - 3.19 (m, 5 H) 3.07 - 2.92 (m, 2 H) 2,85 (s, 6 H) 2,81 - 2.70 (m, 2 I I ) 2.69 - 2.60 (m, 1 H) 2.47 - 2,23 (m, 6 H) 2.07 - 1.88 (m, 4 H) 1.88 - 1.71 (m, 6 H) 1.71 - 1.60 (m, I H) 1.47 - 1,35 (m, 1 H); m/z (ESI, +ve ion) 840,2 (M+Na) ⁺ .

EXAMPLE 627.2"((lS,3 ^, R,6'R,7 ^, S,8 ^! E,12 ^! S)-6~CHLORO-7 ^, -HYDROXY-13',13'- DIOXIDQ-15'-QX()-3,4-DIHYDRQ-2H-SPIRO[NAPHTHALENE--l,22'-

[20]OXA[13]Tffl A[l J^DIAZATETRACYCLOlMJ^.O^^O'^jPENTACOSA

[8,16,18,24] TETRAEN] - 12'- YL)-N-(3 -CHLOROPHENYL) ACET AMIDE OR 2- ((IS 'R^'R 'S^^^'R^e-CHLORO^'-HYDROXY- ' S'-DIOXIDO-lS'- OXO-3,4-DIHYDRO-2H-SPIRO| APHTHALENE- 1 ,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!.\ΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ iACOSA

[ 8, 16, 18,24] TETRAEN] - 12'- YL)-N-(3 -CHLOROPHENYL) ACET AMIDE

STEP 1: ((lS,3'R,6 ^, R,7'S,8'E,12'S)-6-CHLORO-7'-HYDROXY-13',13'-

DIOXIDO-lS'-OXO-S^-DIHYDRO^-SPIROINAPHTHALENE-l^^-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-12 ^! -YL)ACETIC ACID OR ((1 S,3'R,6 ^! R,7'S,8 ^! E,12 ^! R)~6- CHL()R()-7'-HYDROXY-13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2I-L SPIRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί !.\Ζ.\ ί : ί RAC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ iACOSA

[8,16,18,24] TETRAEN] - 12'-YL)ACETIC ACID

To a solution of methyl (( lS,3 ^f R,6'R,7'S,8'E,12'S)-6-chloro-7'-hydroxy- 13 ',13'~dioxido~ 15'~oxo~3,4~dihy dro-2H-spirojnaphthal ene- 1 ,22 ^! ~

[20]oxa[13]thia[l,14]diazatetracyc ^

4]ietraen|-12'-y3)acetate or methyl ((lS,3'R,6'R,7'S,8'E,12'R)-6-chloro-7 ^! -hydroxy- 13', 13'-dioxido-.l 5'-oxo-3,4-dihydro-2H-spiro| naphthalene- 1, 22'- [20]oxa[13]thia[l,14]diazatetra<yclo^^

n|-12'-yl)acetate (isomer 1) (330 mg, 0.51 mmol) (Example 619) in

THF/water/MeOH (4 mL, v/v/v ^; = 2/1/1) was added LiOH (61 mg, 2.6 mmol).

After the reaction mixture was stirred at ambient temperature for 2 h, the reaction mixture was acidified (i N aqueous HCl solution), diluted (EtOAc), and extracted (2* EtOAc). The combined organic layers were washed (brine), dried (NazSC ), and concentrated under reduced pressure to provide a crude product which was used in the next step without purification.

STEP 2: 2-((l S,3'R,6¾,7'S,8 ,12'S)-6-CHLORO-7'-HYDROXY-!3',13'- DiOXIDO-15 ^! ~OXO-3,4 ^IHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- |2ujOXA| O ΙΊ ί Ι1Λ| I„ I 4|ΠίΛ/.ΥΠΊ ^' ΗΛ(ΎΟ.ϋΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24iTETRAEN]-12'-YL)-N-(3-CHLOROPHENYL)ACETAMIDE OR 2- ((lS,3¾,6'R,7'S,8^I2'R)-6-CIIIimO-7' -iYDROXY-!3Vi3 ⁱ -DIOXIDO-15'- OXO-3,4 3IHYDRO-2H-SPiRO[NAPHTHAJ,ENE-i,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8,24]TETRAEN]-12'-YL)-N-(3-CI-iLOROPHENYL)ACETAMIDE To a solution of ((lS,3'R,6'R,7'S,8'E,12'S)-6-chloro-7'-hydroxy-13',13'- dioxido- 15'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1,22'-

n|-12*-yl)acetic acid or ((lS,3'R,6'RJ^,8 ^, EJ2'R)-6-chloro-7 ^! -hydi xy-13 ^, ,13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa{13]thia[l,14]diazatetra<yclo^

nj-12'-yl)acetic acid (Example 627, Step 1) (0.020 g, 0.032 mmol) and 3- chloroaniline (10 μΕ, 0.095 mmol) in pyridine (0.5 mL) was added EDC (0.018 g, 0.095 mmol). The reaction mixture was stirred at ambient temperature overnight and purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to provide one of the title compounds as a white foam (8.0 mg, 11 μηιοΐ). Ή MR (500 MHz, CDCh) δ ppm 8.38 (br. s., 1H), 8.03 - 7.93 (m, IH), 7.75 - 7.65 (m, 2H), 7.39 (d, ./ 7.8 Hz, ill).7.19 (dd, ./ 2.3.8.4 Hz, ill).7.13 - 7.09 (m, 2H), 7,02 - 6.88 (m, 3H), 5.84 (dd, ,7=7,6, 14.4 Hz, IH), 5,72 (dd, J=7.3, 15.2 Hz, 1H), 4.63 - 4.54 (m, 1H), 4.21 (dd, =4.2, 7.1 Hz, ill).4.16 - 4.03 (m, 2H), 3.79 (d, ./ 1-1.4 Hz, 1H), 3.70 (d, ./ 14.2 Hz, III).3.32 - 3.21 (m, 2H), 3.06 (dd, ./ 8.3.15.2 Hz, IH), 2.84 - 2,65 (m, 3H), 2.50 - 2,33 (m, 3H), 2.26 (dd, ./ 5.3.9.4 Hz, IH), 2.04 - 1.60 (m, 9H), 1.43 (t, .7=12.2 Hz, IH); m/z (ESI, +ve ion) 738.2 (M+H) ⁺ .

EXAMPLE 628.2-((lS,3'R,6'R,7'S,8 ^f E,12 ^f S)-6-CHLORO-7'-HYDROXY-13'J3'- DiOXIDO-15 ^! ~OXO-3,4 ^IHYDRO-2H-SPIROrNAPHTHALENE-l,22'- |2ujOXA| ! jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-N IAC<)SA

[ 8, 16, 18,24 jTETRAEN j -12'-YL)-N-(3-METHOXYPHE YL) ACET AMIDE OR 2-((l S,3'R,6'R,7'S,8'E, 12*R)-6-CHLORO-7'-HYDROXY- 13", 13-DIOXIDO-l 5 ^f - OXO-3,4 3IHYDRO-2H-SPiRO[NAPHTHAJ,ENE-l,22'-

[20]OXA[13]TOIA[1,14]DIAZATETI ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 12'-YL)-N-(3-METOOXYPHENYL) ACET AMIDE

One of the title compounds were prepared from ((1S,3'R,6'R,7'S,8'E,12'S)- 6-cMoro-7'-h} ⁷ droxy-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[nap hthalene-

[20]oxa[13]thia[l,14]diazatetra^^

n]-12'-yl)acetic acid or ((lS,3'R,6'R,7 ^! S,8'E,12'R)-6-chIoiO-7'-hydroxy-13',13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatefra<ycto^

n]-12'-yl)acetic acid (Example 627, Step 1) by a procedure analogous to that described in Example 627, Steps 2, replacing 3-chloroaniline with 3- methoxyaniline. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci85 um column; Phenomenex, Torrance, CA; gradient elution of 45% to 70%) MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to provide one of the title compounds as a white foam. ^l H NMR (500 MHz, CDCb) δ ppm 8,35 (br. s,, 1H), 7.84 (s, 1H), 7.70 (d, J=8,6 Hz, 1H), 7.26 - 7.21 (m, Ml).7.21 - 7.16 (m, 1H), 7.11 - 7.08 (m, Ml).7.07 - 7.02 (m, 1H), 7.00 - 6.88 (m, 3H), 6.70 (d, ,/ H.O Hz, 1H), 5.91 - 5.83 (m, 1H), 5.71 (dd, ,/ 7.3. 15,4 Hz, 1H), 4.66 - 4.59 (m, ill).4,21 (dd, ./ 4.2.7,3 Hz, ill).4.14 - 4.05 (m, 2H), 3,83 - 3.77 (m, 41! j.3.70 (d, .7=14,4 Hz, IH), 3.33 - 3,22 (m, 2H), 3.06 (dd, ./ 8,7.15.3 Hz, IH), 2.84 - 2.69 (m, 3H), 2.46 - 2.33 (m, 3H), 2.32 - 2.22 (m, IH), 2.03-1.72 (m, 8H), 1.70 - 1.59 (m, IH), 1.42 (m, IH); m/z (ESI, +ve ion) 734.2 \\\-U) . EXAMPLE 629.2-((lS,3'R,6'R,7'S,8 ^f EJ2 ^f S)-6-CHLORO-7'-HYDROXY-13',13'- DIOXIDO-15 ^! ~OXO-3,4 ^IHYDRO-2H-SPIRO[NAPH ^' mALENE-l,22'- |2ujOXA| !3jTIUA| U4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [8,16,18,24 jTETRAEN] - 12'-YL)-N-(5-METHOXY-2- METHYLPHENYL)ACET AMIDE OR 2-((l S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO- 7 ^, -HYDROXY-13^13 ^! 1iOXrDO-15 ^! ~OXO-3,4-DiHYDRO-2H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-12'-YL)-N-(5-METHOXY-2-

One of the title compounds was prepared from ((1S,3'R,6'R,7 ^! S,8'E,12' hloro-7'-h} ⁷ droxy-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[nap hthalen

122'-

[20]oxa[13]thia[l,14]diazatetra<ycto^

n]-12'-yl)acetic acid or ((lS,3'R,6'R,7'S,8'E,12'R)-6-chloro-7'-hydroxy-13 ^! ,13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro| ^" naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazate1r^

n]-12'-yl)acetic acid (Example 627, Step 1) by a procedure analogous to that described in Example 627, Steps 2, replacing 3-chloroaniline with 5-methoxy-2- methylaniline. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci85 um column; Phenomenex, Torrance, CA; gradient eiution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as a white foam. ¾ NMR (500 MHz, CDCb) δ ppm 8,27 (br. s . 111).7.70 (d, ,/ 86 Hz, ill).7.60 (s, !H), 7.57 - 7.51 (m, ill).7,19 (dd, J=2.2, 8.6 Hz, ill).7.10 (s, 1H), 7.09 (d, ,/ 7 ! Hz, 2H), 6.99 ·· 6.86 (ni, 3H), 6.67 (m, 1H), 5.92 - 5.81 (m, 1H), 5.73 (dd, ./ 7.6.15.4 Hz, 1H), 4.64 (in, IH), 4.22 (m, 1H), 4.14 - 4.05 (m, 2H), 3.83 - 3.77 (m, 4H), 3,70 (d, ./ ! 4.2 Hz, ill).3.33 (dd, ,/ 5.6.15.7 Hz, III).3.26 id. ,/ 14.4 Hz, IH), 3,06 (dd, J=8.8, 15.2 Hz, IH), 2.83 - 2.72 (m, 3H), 2,47 - 2.34 (m, 3H), 2.34 - 2.28 (m, IH), 2.26 (s, 3H), 2.05 - 1.72 (m, 8H), 1.70 ·· 1.64 (m, IH), 1.42 (t, ./ 1 .3 Hz, IH); ni / (ESI, +ve ion) 748.2 (M+H) ⁺ . EXAMPLE 630.2"((lS,3'R,6'R,7 ^, S,8 ^! E,12 ^! S)-6~CHLORO-7 ^, -HYDROXY-13 ^, ,13'- DIOXIDO-lS'-OXO-S^-DIHYDRO- H-SPIROINAPHTHALENE-l^^- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24] TETRAEN] - 12'- YL)-N-PHEN YL ACETAM1DE OR 2~

((IS 'R^'R 'S^^^'R^e-CHLORO^'-HYDROXY- ' S'-DIOXIDO-lS'- OXO-3,4-DIHYDRO-2H-SPIRO| APHTHALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i 3! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24] TETRAEN] - 12'-YL)-N-PHENYLACET AMIDE

One of the title compounds was prepared from ((1 S,3'R,6'R,7'S,8'E,12'S)- 6-chloro-7'-hydroxy-13 13'-dioxido~15 ^! ~oxo-3,4~dihydro-2H-spiro[naphthal^ 1 ,22'-[20] ox a! 13 ]thia[ 1,14] diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0

¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraen]-12'-yl)acetic acid or ((1S,3 ^! R,6'R,7'S,8'E,12'R 6-chloro-7'-hydroxy-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-s piro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracyc ^

n]-12'-yl)acetic acid (Example 627, Step 1) by a procedure analogous to that described in Example 627, Steps 2, replacing 3-chloroaniline with aniline. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as a white foam. 'H NMR (500 MHz, CDCb) δ ppm 8.32 (br. s., i l l ). 7,82 (s, i l l ). 7,72 (d, ./ 8.6 Hz, IH), 7.57 (d, .7=8. 1 Hz, 2H), 7.36 (t, J=7.8 Hz, 2H), 7.25 - 7.13 (m, 2H), 7.11 (d, J=2.0 Hz, 1H), 7.00 - 6.93 (m, 31 1 ). 5.93 - 5.84 (m, 1H), 5.74 (dd, ./ 7.5. 15.3 Hz, 1H), 4.64 (m, I I I ). 4.23 (dd, ./ 4.3. 7.2 Hz, I I I ). 4.17 - 4.06 (ra, 2H), 3,81 (d, ./ 14.7 Hz, i l l ). 3.72 id. .7=14.2 Hz, IH), 3.36 - 3.24 (m, 2H), 3,08 (dd, J=8.4, 15.0 Hz, IH), 2.85 - 2.72 (m, 3H), 2.48 - 2.36 (m, 3H), 2.36 - 2.20 (m, IH), 2.07 - 1.94 (m, 5H), 1.90 - 1.60 (m, 4H), 1 ,44 (t, ./ 12.3 Hz, IH); m/z (EST, +ve ion) 704.2 (Μ-ίΉ) ⁺ ,

EXAMPLE 631. 4-(((lS,3 ^, R,6 ^, R,7 ^, S,8'E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY- 13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO|NAPHTHALENE-l,2 2'- [20]OXA[13]THIA[1 , 14]DIAZATETRACYCLO[ 14.7.2. 0 ³ · ⁶ .0

1 ⁹ - ²⁴ ]PENTACOS A[ 8, 16, 18,24] TETRAEN j - 12'-YL)ACETYL)-N,N-

DIMETHYL- 1 -PIPERAZINESULFONAMIDE OR 4-(((l S,3TL6'R,7'S,8'E,12Ti 6-CHLORO-7'-HYDROXY- 13', 13'-DIOXIDO- 15"-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE- 1 ,22 ^! ~

[20]OXA[13]TH1A[1,14]D1AZATETRACYCLO[14.7.2. 0 ³ '.0

1 ⁹ ' ²⁴ ]PENTACOSA[8 ₅ 16.18,24]TETRAEN]-12 ^, -YL)ACETYL)-N,N- DIMETHYL- 1 -PIPERAZINESULFONAMIDE

One of the title compounds was prepared from ((1S,3'R,6'R,7'S,8'E,12'S)- 6-ch]oro-7'-hydroxy-13 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene- l,22'-[20]oxa[13]thia[l,14]dia.zatetracyclo[14,7.2.0 ³ · ⁶ .0

¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraen]-12 ^, -yl)acetic acid or ((18,3'^6¾,7 ^! 8,8Έ,12¾

6-chloro-7'-hydroxy-13',13'-dioxido-15'-oxo-3,4-dihydro-2 H-spiro[naphthalene-

1,22'~

IKJ4jtctrao n]-12'-yl)acetic acid (Example 627, Step 1) by a procedure analogous to that described in Example 627, Steps 2, replacing 3-chloroaniline with N,N- dimethylpiperazine-1 -sulfonamide. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as a white foam. ¾ NMR (500MHz, CDCb) δ ppm 8.22 (br. s., 1H), 7.70 (d, ./ 8.6 Hz, !!!).7.19 (m, III).7.10 (d, ./ 2.0 Hz, 1H), 6.97 - 6.92 (m, 2H), 6,90 (s.111).5,89 (m, Hi).5.72 (dil.J 73.15,2 Hz, !!!}.4.62 (m.111).4,29 (dd, ,/ 40.7.2 Hz, IH), 4,15 - 4,05 (m, 2H), 3.98 (m, H), 3.78 (m, 211).3,70 (d, J=UA Hz, IH), 3.63 - 3.53 (m, IH), 3.50 - 3.41 (m, 2H), 3.39 - 3.23 (m, 4H), 3.21 - 3.15 (m, IH), 3.07 (m, IH), 2.87 (s, 6H), 2.82 - 2,71 (m, 2H), 2.63 (dd, J=8.3, 15.7 Hz, IH), 2.46 - 2.23 (m, 4H), 2.06 - 1,91 (m, 5H), 1.89 - 1.71 (m, 3H), 1.70 - 1.63 (m, IH), 1.43 (t, ./ 12.5 Hz, IH); m/z (ESI, +ve ion) 804.2 (M R) EXAMPLE 632. (1 S,3'R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-l 2"-(2-(5- METHYL- L3,4-0XADIAZ0L-2-YL)ETHYL)-3,4-DIHYDR0-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7.2. 0 ^{3 FJ} .()

3 ⁹ - ²⁴ ]PENTACOS A[8,16,l 8,24]TETRAEN]-15 ^* -ONE 1 3', 13'~DIOXIDE OR

(1 S,31 ,6'R,7 ^! S,8'E, 12'R 6-CHL0R0-7'-HYDR0XY-12'-(2-(5-METHYL"1,3,4- OXADIAZOL-2-YL)ETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]TOIA[1 , 14]DL ZATETRACYCLO[ 14.7.2, 0 ^3/L .O

1 ⁹ - ² ]PENTACOSA[8,16,18,24]TETRAEN]-15 ^! ~ONE 13', 13 '-DIOXIDE

STEP 1 : (S)-l-((TERT-BUTYLDIMETHYLSILYL)OXY)-N,N-BIS(4- METHOXYBENZYL)OCT-7-ENE-4-SULFONAMIDE and (R)- ! -((TERT- BUTYLDIMETHYLSILYL)OXY)-N ₅ N-BIS(4-METHOXYBENZYL)OCT-7- ENE-4-SULFONAMIDE

To a solution of N,N-bis(4-methox 'benzyl)pent-4-ene-l -sulfonamide (Intermediate EE 19) (3.00 g, 7.70 mmol) in THF (17 mL) was added n-BuLi (2.5 M solution in hexanes, 3.70 mL, 9.24 mmol) at -78 °C. After the reaction mixture was stirred for 5 min, tert-butyl(3-iodopropoxy)dimethylsilane (6.94 g, 23.1 mmol) was added at the same temp. The reaction was stirred at -78 °C for 20 min and then allowed to warm to ambient temperature. The reaction was quenched (saturated aqueous NH ₄ C1 solution), extracted (2xEtOAc), and washed (brine).

The combined organic layers were dried (Na ₂ S04>, and concentrated under reduced pressure to provide a crude product. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 0% to 30%

EtOAc/hexanes to give the title compounds (3.94 g, 7.01 mmol) as a colorless liquid.

STEP 2: (S)-l -HYDROXY-N,N-BTS(4-METHOXYBE ZYL)OCT-7-ENE-4- SULFONAMIDE and (R)- 1 -HYDROXY-N,N-BIS(4- METHOXYBENZYL)OCT-7-ENE-4-SULFONAMlDE

To a solution of (S)-l-((tert-biiiyldimethylsily )oxy)~N,N~bis(4- methoxybenzyl)oct-7-ene-4-sulfonamide and (R)- 1 -((tert-butyldimethylsiiyl)oxy)- N,N-bis(4-methoxybenzyl)oct-7-ene-4-sulfonamide (Example 632, Step 1 ) (16.2 g, 28.8 mmol) in THF (30 mL) was added TBAF (1.0 M in THF, 57.7 ml,, 57.7 mmol) at 0 °C. After the reaction mixture was stirred at ambient temperature for 18 hours, the reaction was quenched (saturated aqueous NH ₄ C1 solution), extracted (2><EtOAc), and washed (brine). The combined organic layers were dried (N SOi) and concentrated under reduced pressure to provide a crude product. The residue was injected into a 220 g ISCO Gold column and purified by combi-flash, eluting with 30% to 50% EtOAc/hexanes to give the title compounds (12.9 g, 28,8 mmol) STEP 3: (S)-4-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)OCT-7-ENOIC ACID and (R)-4-(N,N-BIS(4-METHOXYBE ZYL)SULFAMOYL)OCT-7- ENOIC ACID

To a solution of (S)-l -hydroxy -N,N-bis(4-methoxybenzyl)oct-7-ene-4- sulfonamide and (R)-l -hydroxy-N,N-bis(4-raethoxybenzyl)oct-7-ene-4- sulfonamide (10.0 g, 22.3 mmol) (Example 632, Step 2), KBr (0.266 g, 2.23 mmol), 5% sodium bicarbonate in water (105 mL, 62.6 mmol) and TEMPO (3.84 g, 24.6 mmol) in acetone (112 mL) was added 6% sodium hypochlorite in water (30.5 mL, 24.6 mmol) at 0 °C and the resulting mixture was stirred vigorously at the same temp for 3.5 hours. The reaction was diluted (EtOAc and ice-cold IN aqueous HC1), extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S04> and concentrated under reduced pressure. The residue was injected into a 220 g ISCO Gold column and purified by combi-flash, eluting with 40% to 100% EtOAc/hexanes to give the title compounds (7.10 g, 15.4 mmol). STEP 4: (S)-l-(2-ACETYLHYDRAZlNYL)-N,N-BIS(4-METHOXYBENZYL)- 1-OXOOCT-7-ENE-4-SULFONAMIDE and (R)-l-(2-

ACETYLHYDRAZINYL)-N,N-BIS(4-METHOXYBENZYL)-l-OXOOCT-7- ENE-4-SULFON AMIDE

A solution of (S)-4-( ,N-bis(4-methoxybenz 'l)sulfamoyl)oct-7-enoic acid and (U)-4-(N,N-bis(4-methoxybenzyl)sulfamoyl)oct-7-enoic acid (0.80 g, 1.73 mmol) (Example 632, Step 3) and acetic hydrazide (0.260 g, 3.47 mmol) in DCM (5.8 ml,) was treated with EDC (0,997 g, 5.20 mmol), HOAt (0.708 g, 5.20 mmol) and TEA (0.725 mi_, 5.20 mmol) successively at 0 °C. ^r flien the reaction was allowed to warm to ambient temperature. After the reaction mixture was stirred overnight, the reaction was diluted (1 N aqueous HC1), extracted (2 ^χ EtOAc), and washed (1 ^χ brine, 1 ^χ saturated NaHCCb, and 1 ^χ brine). The combined organic layers were dried (Na ₂ S04) and concentrated under reduced pressure to provide a crude product, which was used in the next step without purification.

STEP 5 : (S)-N,N-BI S(4-METHOXYBENZYL 1 -(5-METHYL- 1,3,4- OXADIAZOL-5-YL)HEPT-6-ENE-3-SULFONAMIDE and (R)-N,N-BIS(4- ΜΕΤΗΟΧΥΒΕΝΖΥΕ)-1 5-ΜΓ^^.-1,3,4-ΟΧΑΓ)ΙΑΖΟΕ-5-ΥΕ)ΗΕΡΤ-6-ΕΝΕ - 3-SULFONA

A solution of (S)-l -(2-acetylhydrazinyl)-N,N-bis(4-methoxybenzyl)-l - oxooct-7-ene-4-sulfonaniide and (R)-l ~(2~acetylhy drazinyl)-N,N-bis(4- methoxybenzyl)-l-oxooct-7-ene-4-sulfonamide (0.730 g, 1.41 mmol) (Example 632, Step 4) and burgess reagent (1.34 g, 5.64 mmol) in THF (14 mL) was refluxed under N ₂ for 36 hours. Then the reaction was diluted (water), extracted (2 x DCM), and washed (1 ^χ brine). The combined organic layer were dried

(Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was injected into a 24 g 1SCO Gold column and purified by combi-flash, eiuting with 30% to 50% EtOAc/hexanes to give the title compounds (0.350 g, 0.701 mmol)

STEP 6: (S) -l-(5-METHYL-l,3,4-OXADIAZOL-2-YL)HEPT-6-ENE-3- SULFONAMIDE and (R) -l-(5-METHYL-l,3,4-OXADIAZOL-2-YL)HEPT-6- ENE-3 - SULFONAMIDE

To a solution of (S)-N,N-bis(4-methoxybenzyl)-l-(5-methyl-l,3,4- oxadiazol-5 -y l)hept-6-ene-3-sulfonamide and (R)- ,N-bis(4-methoxy benzyl)- 1 - (5-methyl-.l ,3,4-oxadiazol-5-yl)hept-6-ene-3-sulfonamide (0.350 g, 0.700 mmol) (Example 632, Step 5) in DCM (3.5 mL) was added anisole (0.75 mL, 7.0 mmol) and TFA (1.35 mL, 17.5 mmol) at room temperature. After the reaction mixture was stirred at 40 °C overnight, the excess TFA was removed under reduced pressure. The residue was injected into a 12 g TSCO Gold column and purified by combi-flash, eiuting with 0% to 10% MeOH/DCM (containing 0,3 % AcOH) to give the title compounds (0.140 g, 0.540 mmol)

STEP 7: (lS,3'R,6 ^, R,7 ^, S ₅ 8 ^, E ₅ 12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-(5-

METHYL-l,3,4-OXADIAZOL-2-YL)ETOYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-7'-HYDROXY-12'-(2-(5-MET HYL-l,3,4- OX ADIAZOL-2-YL)ETHYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i X A| 1311 HI Λ| I , N |OIA/.\ Π·. iRAi ^' Y ^' Ci, 01 i -1,7.20 ^; ".ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 VI 3'-DIOXIDE One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)-

2-((S,E)-l-hydroxyhex-2-en-l-yl)c^xlobut )methyl)-3^4,4^5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (Intermediate AA12) by a procedure analogous to that described in Example 610, Steps 1 through 2, replacing (R)-hept-6-ene-3-sulfonamide in Step 1 with (S) -!-(5- methyl-l,3,4-oxadiazol-2-yl)hept-6-ene-3-sulfonamide and (R) -l-(5-methyl- l,3,4-oxadiazol-2-yl)hept-6-ene-3-sulfonamide (Example 632, Step 6). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as the faster eluting isomer as a white foam. ^] H NMR (500 MHz, CDCb) δ ppm 8.11 (s, 1H), 7.70 (d, J=8.6 Hz, I I I).7.18 (dd, ,7=2,2, 8.6 Hz, I I I).7.13 - 7.05 (m, 1H), 6.96 - 6.84 (m, 3H), 5.75 - 5.64 (m, 2H), 4.25 - 4.21 (m, 1H), 4.21 - 4.15 (m, IH), 4.15 - 4.04 (m, 2H), 3.81 (d, ./ 14.4 Hz, 1H), 3.71 (d, ./ 1 .4 Hz, IH), 3,35 - 3.26 (m, III).3.26 - 3,17 (m, 2H), 3,02 (dd, J=9.4, 15,3 Hz, IH), 2.83 - 2.72 (m, 2H), 2,60 - 2,53 (m, 4H), 2.45 (m, IH), 2.42 - 2,24 (m, 4H), 2.08- 1.91 (m, 3H), 1.90 - 1.70 (m, 5H), 1.70 - 1.60 (m, IH), 1.40 (t, J=13.0 Hz, IH); m/z (ESI, +ve ion) 703.2 (M+Na) ⁺ .

EXAMPLE 633. (IS,3'R,6 ^, R,7'S,8'E,12'S)-12'-(4-BROMOBENZYL)-6- CHLORO^'-HYDROXY-S^-DIHYDRO^H S'H-SPIROINAPHTHALENE- 1,22'-

|20i() A| 1311 HI A| I„ 1 -I |ί)Ι.\/.νΠ: I RAC VCi, Ol i -1,7.20 ' ".O ¹ '" ¹ |P1-:N l ACOS A [8,16,18,24]TETRAEN1-15'-0NE 13 ^! ,13'-DIOXIDE OR

(lS,3 ^, R ₅ 6 ^, R,7 ^, S,8¾12 ^, R)-12*-(4-BROMOBENZYL)-6-CHLORO-7 ^, -HYDROXY- 3.4-f)!HYi)R -.?.l 1.1 i-SPlR()|\ API Π H AiJ ^: NI - 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

SIT;? 1 : (S)-l -(4-BROMOPHENYL)-N,N-BIS(4-METHOXYBENZYL)HEX-5- ENE-2-SULF ON AMIDE AND (R)- 1 -(4-BROMOPHENYL)-N,N-BIS(4- METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE

To a solution ofN,N-bis(4-metiioxybenzyl)pent-4-ene-l-sulfonamide (1.50 g, 3.85 mmol, Intermediate EE 19) at -78 °C in THF (10 mL) was added n- BuLi (2.5 M solution in hexanes, 1.5 mL, 3.9 mmoi). The reaction mixture was stirred at the same temperature for 15 minutes. Then a solution of l-bromo-4- (bromomethyl)benzene (1.92 g, 7.70 mmol) in THF (3.0 mL) was added and the reaction mixture was stirred at "78 ^" C for 1 h. The reaction was quenched (aqueous saturated NH ₄ C1), extracted (2 DC VI ). and washed (1 brine). The combined organic layers were dried (Na_S04) and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eiuting with 10% to 30% EtOAc/liexanes to give the title compounds (1.70 g, 3.04 mmol) STEP 2: (S)-l-(4-BROMOPHENYL)HEX~5-ENE-2-SULFONAMIDE AND (R)- 1 -(4-BROMOPHEN YL)HEX-5-E E-2-S ULFON AMIDE

To a solution of (S)-l-(4-bromophenyl)-N,N-bis(4-methox\'benzyl)hex-5- ene-2-sulfonamide and (R)-l -(4-bromophenyl)-N,N-bis(4-memoxybenzyl)hex-5- ene-2-sulfonamide (Example 633, Step 1) (1.70 g, 3.04 mmol) in DCM (8.0 mL) was added anisole (3.30 mL, 30.4 mmol) and TFA (11.7 mL, 152 mmol) at room temperature. After the reaction mixture was stirred over 2 days, the excess TFA was removed under reduced pressure. The residue was injected into a 40 g ISCO Gold column and purified by combi-flash, eluting with 10% to 40% EtOAc (containing 03 % AcOH)/hexanes to give the title compounds (0.75 g, 2.35 mmol).

STEP 3: (lS,3'R,6¾,7'S,8¾ 12'S)-12' 4-bromobenz )-6-chloro-7'-hydroxy-3,4- dihy dro~2H, 15 Ή-spiro [naphthalene- 1 ,22'-

[20]oxa[13]tMa[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[ 8,16,18,24]tetrae n]-15'-one 13', 13'-dioxide or (1 S,3'R,6'R,7'S,8'E,12'R)- ! 2'-(4-bromobenz>'l)-6- chloro-7'-hydroxy-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22 '-

n]-15'-one 13 ',13 '-dioxide One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)-

2-((S,E)-l-hydroxyhex-2-en-l-yl)c^xlobut )methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (Intermediate AA12) by a procedure analogous to that described in Example 610, Steps 1 through 2, replacing (R)-hept-6-ene-3-sulfonamide in Step 1 with (S)-l -(4- bromophenyl)hex-5-ene-2-sulfonamide and (R)~ 1 -(4-bromophenyl)hex-5-ene-2- sulfonamide (Example 633, Step 2). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep C -s 5 μ ^η ι column; Phenomenex, Torrance, C A; gradient elution of 50% to 80% MeCN in water, where both solvents contain 0.1% TFA, 30 mm method) to provide one of the title compounds as the faster eiuting isomer as a white foam. ¾ NMR (500 MHz, CDCta) δ ppm 8,20 (br. s . 1 H) 7.69 (d, ,/ 8 3 1 Hz, 1 H) 7.46 (d, ,7=8,07 Hz, 2 H) 7.24 - 7, 15 (m, 3 H) 7.09 (d, J=1.96 Hz, 1 H) 6.96 - 6.88 (m, 3 H) 5.72 (dt, ,7=15.16, 5.75 Hz, 1 H) 5.62 (dd, ,/ 1 5.4 ! . 7.34 Hz, 1 H) 4.41 - 4.28 (m, 1 H) 4.19 (dd, ./ 7.21 . 4.52 Hz, I H) 4.15 - 4.03 (m, 2 H) 3,78 i d. ./ 14.6? Hz, 1 H) 3,69 (d, ./ 14. 1 8 Hz, 1 H) 3.56 (dd, ,7=14,43, 4.89 Hz, 1 H) 3.25 (d, .7=14.43 Hz, 1 H) 3.1 1 ~ 2,95 (m, 2 H) 2.82 - 2.72 (m, 2 H) 2.57- 2.34 (m, 2 H) 2.30 - 2.17 (m, 1 H) 2.03 - 1.80 (m, 9 H) 1 ,78 - 1.61 (m, 2 H) 1 .43 (†, ,/ 12.59 Hz, I H) m/z (ESI, +ve ion ) 741.0 < M 1 ί > .

EXAMPLE 634. (IS,3'R,6'R,7'S,8'E,1 l'R,12'S)-6-CHLQRO-7'-HYDRQXY-l Γ- ME^WL-12'-(2-THIOPHENYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί 1 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 0 ' ".i ) ¹ '" ¹ |Ρ1·Ν i ^' ACOSA [ 8,16,18,24]TETRAEN1-15'-C)NE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 1 'S, 12'R)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12'-(2-

THIOPHENYLMETHYL)-3,4-DIHYDRO-2H,15H-SPIROP ^> «iAPHTHALENE-

1,22'- pOlOXAI lSlTHIAI l.MlDIAZATETRACYCLOiM.T^.O'^.O^^lPENTACOSA [8,I6, 18,24]TETRAENl-15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8 ^, E,i rR,12'R)-6-CHLORO-7'-HYDROXY-ir-METHYL-12'-(2- raiOPHENYLMETOYL)-3,4-DIHYDRO-2H,15'i-I-SPIRO| NAPHTHALENE-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 l'S, 12'S)-6-CHLORO-7'-H YDROXY- 11 '-METHYL- 12'-(2- THIOPHENYIAlEWIYL)-3,4-DII-IYDRO-2H, 15'H-SPIRO[NAPI-ITHALENE- 1,22'-

| 2ίί |0ΧΛ| O ΙΊ ί Ι1Λ| I„ I 4 |ΠίΛ/.ΥΠ Ί ^' Η Λ(ΎΟ.ΟΙ i 4.7.2 U · ^, '.ί ^{) | :} " ¹ |P1-M ^' .\C<)SA [ 8J 638,24]TETRAENj-15'-ONE 13',13'-DIOXIDE (ISOMER 1)

STEP I : (2R,3S)-N,N-BIS(4-METHOXYBENZYL)-3-METHYL-l - (THIOPHEN-2-YL)HEX-5-ENE-2-SULFON AMIDE AND (2R,3R)-N,N-BIS(4- METHOXYBENZYL)~3"METHYL-l~(TH10PHEN-2-YL)HEX~5~ENE-2-

SULFONAMIDE AND (2S ,3 S )-N,N-BI S(4-METHOXYBENZYL)-3 -METHYL- 1 -(THTOPHEN-2-YL)HEX-5-ENE-2-SULFONAMTDE AND (2S,3R)-N,N- BIS(4-METHOXYBENZYL)-3-MEraYL-l -(THIOPHEN-2-YL)HEX-5-ENE-2- SULFONAMIDE

To a solution of (R)-N,N-bis(4-methoxybenzv'l)-2-methylpent-4-ene-l- sulfonamide and (S)-N,N-bis(4-methoxybenz l)-2-methylpent-4-ene-.l - sulfonamide (1 ,07 g, 2.65 mmol) (Example 647, Step 7) in THF (6.5 mL) was added n-BuLi (2.5 M solution in hexanes, 1.06 mL, 2.65 mmol) at -78 °C. After the reaction was stirred at the same temperature for 20 min, a solution of 2- (chloromethyl)thiophene (0.703 g, 5.30 mmol) in THF (3.5 mL) was added and the resulting solution was stirred at -78 °C for 1 h. Then the reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched (saturated aqueous NFLCl), extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S04> and concentrated under reduced pressure. The residue was injected into a 40 g ISCO Gold column and purified by combi-flash, eluting with 0% to 20%» EtOAc (containing 0.3%

AcOH)/hexanes to give the title compounds (800 mg, 1 .60 mmol) as a pale yellow oil.

STEP 2: (2R,3S)-3-METHYL-l-(TOIOPHEN-2-YL)HEX-5-ENE-2- SULFONAMIDE AND (2R,3R)-3-METHYL- 1 -(TfflOPHEN-2-YL)HEX-5- ENE-2-SULF ON AMIDE AND (2S,3S)-3-METHYL-l-(THIOPHEN-2-YL)HEX- 5-ENE-2-SULFONAMIDE AND (2S,3R)-3-METHYL- 1 -(THIOPHEN-2- YL)HEX-5-ENE-2-SULFONAMlDE

To a solution of (2R,3S)-N,N-bis(4-methoxybenz>T)-3-methyl-l - (thiophen-2-yl)hex-5-ene-2-sulfonarnide and (2R,3R)-N,N-bis(4-methox>'benz 'l)- 3-memyl-l-(thiophen-2-yl)hex-5-ene-2-sulfonamide and (2S,3S)-N,N-bis(4- methoxybenz l)-3-methyl- 1 -(thiophen-2-yl)hex-5-ene-2-sulfonamide and (2S,3R)-N,N-bis(4-methoxybenzyl)-3-methyl-l-(thiophen-2-yl)h ex-5-ene-2- sulfonamide (0,680 g, 1.36 mmol) (Example 634, Step 1) in anisole (14.8 mL, 136 rnmol) was added TFA (10.1 mL, 136 mmol) at room temperature. After the reaction mixture was stirred overnight, the excess TFA was removed under reduced pressure. The residue was injected into a 12 g ISCO Gold column and purified by comhi-flash, dating with 0% to 20% MeOH/DCM (containing 0,3% AcOH) to give the title compounds (302 mg, 1.16 mmol).

STEP 3: (lS,3 ^! R,6¾,7'S,8T,,ll'R,12'S)-6-CHLORO-7 ^! -HYDROXY-ir- METHYL-12'-(2-raiOPHENYLMETHYL)"3,4-DIHYDRO-2H,15'H~

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7^,8¾irS,12'R)-6-CI-iLORO-7'4iYDROXY-ir-METI-IY L-12'-(2- THIOPHENYIAlF^iYL)-3,4~DfflYDRO~2H,15H-SP

1,22'~

|2ujOXA| O ΙΊ ί Ι1Λ| I„ I 4|ΠίΛ/Λ T! RAC YO OI i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE OR

(lS,3¾,6'R,7^,8TII'R,12¾)-6-CHIX)RO-7 ^f 1YDROXY-ir-METHYL 2'-(2- IHIOPHENYLMETHYL)~3,4-DIHYDRO-2H,15H-SPrRO[NAPHTHALENE~ 1,22'"

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0- ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,61,7 ^, S,8T,ll^,12'S)-6~CHLORO-7 ^, ~HYDROXY-ir-METHYL-12'-(2- THIOPHENYLMETFiYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE (ISOMER 1) One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)-

2-((S,E)-l-hydroxyhex-2-en-l-yl)c^xlobut )methyl)-3^4,4',5-tetrahydro-2H,2 ^, H- spiro|benzo|b][l,4]oxazepine-3, i'-naphihalene]-7-carboxylic acid (Intermediate AA12) by a procedure analogous to that described in Example 610, Steps 1 through 2, replacing (R)-hept-6-ene-3 -sulfonamide in Step 1 with (2R,3S)-3- methyl-l-(thiophen-2-yl)hex-5-ene-2-sulfonamide and (2R,3R)-3-methyl-l- (thiophen-2-y])hex-5-ene-2-sulfonamide and (2S,3S)-3-melhyl-l-(thiophen-2- yl)hex-5-ene-2-sulfonamide and (2S,3R)-3-methyl-l-(thiophen-2-yl)hex-5-ene-2- sulfonamide (Example 634, Step 2). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as the faster eluting isomer as a white foam. H NMR (500MHz, CDCb) δ ppm 7,63 (d, J=8.3 Hz, 1H), 7.15 - 7.07 (m, 2H), 7.06 - 7,00 (m, 1H), 6.96 - 6.85 (m, 4H), 6.79 - 6.66 (m, 1H), 6.20 - 5.42 (m, ill).4.16 (dd, ./ 3.1.7.9 Hz, 1H), 4.09 - 3.93 (m, 2H), 3.82 - 3.54 (m, 3H), 3.34 - 2.89 (m, 3H), 2.76 - 2.62 (m, 2H), 2.35 - 2.19 (m, 2H), 2.05 (m, 4H), 1,79 - 1.67 (m, 3H), 1.57 - 0.79 (m, 8H), , 0,04 - -0.04 (m. I I I): m/z (ESI, +ve ion) 681.2 (M+H) ⁺ .

EXAMPLE 635. (1S,3'R,6'R,7'S,8 ^! E,1 rRJ^'S^e-CHLORO^'-HYDROXY-H'- METHYL- 12 ^f -(2-TOIOPHENYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRQ [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TfflA[l,14]DIAZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6 ^! R,7'S,8'E, 11 'S, 12'R)-6-CHLORO-7*-HYDROXY-l 1 -METHYL- 12'-(2- TH10PHENYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 122'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TE,TRAEN]-15 ^! -ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E rR,12 ^! R)-6-CITLORO-7'-HYDROXY-ll'-METHYL-12'-(2- THIOPHENYLMETOYL)-3,4-DII-IYDRO-2H,15'H-SPIRO[NAPI-ITHALENE- 1.22'-

|2ίί!<)ΧΛ| 1 ΙΊ !!1Λ| l.l4|D!A/.Vn-;i ^' RA( ^' YCi..()l i 4.7.2.U ^' ".i ⁾¹ " ' ¹ |Ρ1·Ν I ^' ACOSA [8 ₅ 16, 18,24]TETRAEN]-15"-ONE 13', 13'-D )XIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 1 'S.12'S)~6-CHLQRQ~7'-HYDRQXY~ 1 I '-METHYL- 12'-(2- TH10PHENYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1 22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [8,1 -15'-ONE 13 ',13 '-DIOXIDE (ISOMER 2)

One of the title compounds was obtained as the second (slower) during isomer in the reversed phase preparatory HPLC purification of Example 634 Step 3 as a white foam. Ή NMR (500 MHz, CDCh) δ ppm 7.60 (d, ./ 8.3 ! Hz, 1 H) 6.81 - 7.09 (m, 8 H) 5.75 (m, 1 H) 5.54 (dd, ./ 1 .92. 5.38 Hz, 1 H) 4.37 (m, 1 H) 4.04 (m, 3 H) 3.67-3.56 (m, 2 H) 3.18 (br. s., 2 H) 2.82 - 2.60 (m, 2 H) 2.38-2.28 (m, 2 H) 1 .95-1.77 (m, 6 H) 1.61 -1 .49 (m, 7 H) 1. 15 - 1.01 (m, 3 H); m!z (ESI, +ve ion) 681.2 (M+H) ⁺ .

EXAMPLE 636. (1 S,3'R,6'R,7'S,8'E,1 S,12'R)-6-CHLORO-7'-HYDROXY-l 1 '- METHYL- 12'-(3-THIOPHENYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, R;i2 ^, S)-6-CHLORO-7'-HYDROXY-ir-METHYL-12'-(3- TIlIOPHENYLMETOYL)-3,4-DIHYDRO-2H,15'I-I-SPIRO| NAPHTHALENE- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R 7'S,8Έ;Γί'SJ2'S)-6-CHLORO-7 ⁱ -HYD OXY-ll'-METH X-12'-(3- THIOPHENYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~13'~ONE 13', 13 '-DIOXIDE OR

(IS^'R^'RJ'S^'EJl'^n'Rj-e-CHLORO^'-HYDROXY-ll'-METHYL- '-iS- THIOPHEN YLMETHYL)-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1,22'-

|20jO.\A| 1311 HI Λ| I . ! -i |PI A/A Π·. ΓΚΑίΎί ^' ί.01 i -1.7.20 ^;ί' .ϋ |ΡΗ\ iACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

One of the title compounds was prepared by a procedure analogous to that described in Example 634, Steps 1 through 3, replacing 2- (chloromethyl)thiophene in Step 1 with 3-(chloromethyl)thiophene. The crude product was injected into a 4g ISCO Gold column and purified by combi-flash, eluting with 20% to 60% EtOAc (containing 0.3% AcOH)/hexanes to give a mixture, which was further purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to provide one of the title compounds as the faster el uting isomer as a white foam. ¾ NMR (500MHz, CDCb) δ ppm 7.99 (br. s., ill).7.65 (d, J=8.3 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.22 - 7.12 (m, 4H), 7.12 - 7.08 (m, 1H), 6.94 - 6.89 (m, 1H), 6.89 - 6.84 (m, 1H), 5,53 - 5.35 (m, 2H), 4.43 - 4.37 (m, 1H), 4,29 - 4.19 (m, 2H), 4.07 (m, 111).3.88 (m, 1H), 3.77 (m, 1H), 3.55 (dd, J=4.9, 14.9 Hz, 1H), 3.32 (m, ill}.3.15 (dd, ./ 8.6.14.9 Hz, 2H), 2.79 - 2.72 (m, 211}.2.57 - 2.45 (m, 2H), 2.12 (m, ill).1.92 - 1 ,75 (m, 9H), 1.50 - 1.36 (m, ill).1.26 - 1.19 (m, 311): m/z (ESI, +ve ion) 681.2 (M+H) ⁺ .

EXAMPLE 637. (1S,3'R,6'R,7'S,8 ^! E,1 rS,12'R)-6-CHLORO-7'-HYDROXY-ir- ΜΕΤΉΟΧΥ- 12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3 ,4- DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(Ιβ,Β'Κ,ό'Κ,Τ'β,δΈ,ΙΙ'β, 'Κνό-ΟΗίΟΚΟ-Τ'-ΗΥϋΚΟΧΥ-ΙΙ'-ΜΕΤΗΟ Υ-Ι^- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 -DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 rR,12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHOXY-12'- ((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-Dn-rV ^r DRO-2H,15'H- SPIRO[N APHTHALENE- 1.22 ^' -

|2ίί!<)ΧΛ| 13ΙΊ Ι!1Λ| Ι.14|ΠΙΛ/.νΓΙ·Ί <Λ( ^' Υ(·|..ΟΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16, 18,24]TETRAEN]-15"-ONE 13', 13 ^* -DIOXIDE

OR(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,ll ^, R,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-ir-METHOXY- 12'-((2R)-TETRAHYDRO-2-FURAN YLMETHYL)- 3 ,4-DJH YDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8¾irS,12'S)-6-CHLOR()-7'-HYDROXY-ir-METHOXY -12'- ((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[N APHTHALENE- 1 ,22'- |2ujOXA| O ΙΊ ί Ι1Λ| I„ I 4|ΠίΛ/.ΥΠΊ ^' ΗΛ(ΎΟ.ϋΙ i 4.7.2 U · ^, '.ί) ^|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAEN]-15'-ONE 13',13 ^* -DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,ll'S,12'S)-6-CHI RO-7'-HY ^T DROXY-ll'-METFIOXY ^' -12 ⁱ - ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irR,12'R)-6-CHLORO-7'-HYDROXY-ll'-METHOX Y-12'- ((2S)-TETOAHYDRO-2-FURAISTYLMETHYL)-3,4-DIIiYDRO-2H,15H-

SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]TfflA[l,14]DIAZATEIIACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

0R(1S,3'R,6'R,7'S,8'E,1 rR,12'R)-6-CHLORO-7'-HYDROXY-l -ΜΕΤΗΟΧΥ- 12'-((2R)-TETRAHY DR0-2-FURAN YLMETHY L)-3 ,4-DIHYDRQ-2H, 15 Ή- SPIRO [ APHTHALENE- 1 ,22'- [20iOXA[13]THIA[l,14]DIAZATETRACYCL)[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE (ISOMER 1)

I486

STEP 1 : (R)-N,N-BIS(4- ETHOXYBENZYL)-2-(TETRAHYDROFURAN-2- YL)ETHANESULFONAMIDE AND (S)-N,N-BIS(4-METH()XYBENZYL)-2- (TETRAHYDROFURAN-2-YL)ETHANESULFON AMIDE

To a solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (6.00 g, 17.9 mmol) (Intermediate EE12) in THF (60 mL) was added n-BuLi (2.5 M in hexanes, 9.30 mL, 23.2 mmol) at -78 °C dropwise. After the reaction was stirred at -78 °C for 10 mm, 2-(bromomethyl)tetrahydrofuran (8.14 mL, 71.6 mmol) in THF (10 mL) was added into the reaction for 30 minutes at the same temp. Then the reaction was allowed to warm to ambient temperature and stirred over 2 days. The reaction was quenched (Saturated aqueous NH ₄ C1), extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (MgSO-O and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 0% to 50%

EtOAc/hexanes to give the title compounds (4.30 g, 10.2 mmol).

STEP 2: (S)-METHYL 2-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-3- ((R)-TET AHYDROFURAN-2-YL)PROPANOATE AMD (R)-METHYL 2- (N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-3-((S)-

TETRAHYDROFURAN-2-YL)PROPANOATE AND (S)-METHYL 2-(N,N- BIS(4-METHOXYBENZYL)SULFAMOYL)-3-((S)-TETRAHYDROFURAN-2- YL)PROPANOATE AND (R)-METHYL 2-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-3-((R)-TETRAHYDROFURAN-2- YL)PROPANOATE

To a solution of (R)-N,N-bis(4-methoxybenzyl)-2-(tetrahydrofuran-2- yl)ethanesuli namide and (S)-N,N-bis(4-methoxybenzyi)-2-(tetral'i drof uran-2- yl)ethanesulfonamide (Example 637, Step 1 ) (5.40 g, 12.8 mmol) in THF (64.4 mL) was added n-BuLi (2.5 M in hexanes, 6.18 mL, 15.5 mmol) at -78 °C. After the reaction was stirred for 5 min, chlorocarbonic acid methyl ester (1.99 mL, 25.7 mmol) was added and stirred for another 20 min, and then the reaction was allowed to warm to ambient temperature. After the reaction was stirred at ambient temperature for 2 h, the reaction was quenched (saturated aqueous NH 'i), extracted (2*EtOAc), and washed (brine). The combined organic layers were dried (MgSC ) and concentrated under reduced pressure.The products were used in the next step without further purification.

STEP 3: (S)-l -HYDROXY-N,N-BIS(4-METHOXYBENZYL)-3-((R)- TETRAHYDROFURAN-2-YL)PROPANE-2-SULFONAMlDE AND (R)-l -

HYDROXY-N,N-BIS(4-METHOXYBENZYL)-3-((S)-TETRAHYDROFURAN- 2-YL)PROPANE-2-SULFONAMIDE AND (S)-l-HYDROXY-N,N-BIS(4- METHOXYBENZYL)-3-((S)-TETRAHYDROFURAN-2-YL)PROPANE-2- SULFO AMIDE AND (R)-l -HYDROXY -N,N-BIS(4-METHOXYBENZYL)-3- ((R)-TETRAHYDROFURAN-2-YL)PROPANE-2-SULFONAMIDE

To a solution of (S)-methyl 2-(N,N-bis(4~methoxybenzyl)sulfamoyl)-3- ((R)-tetrahydrofuran-2-yl)propanoate and (R)-methyl 2-(N,N-bis(4- methoxybenz}4)sulfamoyl)-3-((S)-teirahydrofui"an-2-yl)propan oate and (S)-methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-((S)-tetrahydrofuran -2-yl)propanoate and (R)-methyl 2-(N,N-bis(4-memox 'benz\d)sulfamoyl)-3-((R)-tetrahydrofuran- 2-yl)propanoate (Example 637, Step 2) (6.15 g, 12.9 mmol) in THF (64 mL.) (with very small amount of water) was added lithium borohydride (0.842 g, 38.6 mmol) at 0 °C. The reaction mixture was allowed to warm to ambient temperature a d stirred overnight. The reaction was quenched (50 mL of 0.5 N aqueous HC1 solution), extracted (2 χ EtOAc), and washed (brine). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi -flash, eluting with 20% to50 % EtOAc/hexanes to give the title compounds (4.50 g, 10.0 mmol)

STEP 4: (S)-N ₅ N-BIS(4-METHOXYBENZYL)-l-OXO-3-((R)- TETRAHYDROFURAN-2-YL)PROPANE-2-SULFONAMIDE AND (R)-N,N- BIS(4-METHOXYBENZYL)-l-OXO-3-((S)-TETRAHYDROFURAN-2- YL)PROPANE-2-SULFO AMIDE AND (S)-N,N-BIS(4- METHOXYBENZYL)-l-OXO-3-((S)-TETRAHYDROFURAN-2- YL)PROPANE-2-SULFONAMIDE AND (R)-N,N-BIS(4- METHOXYBENZ YL)- 1 - OXO-3 - ((R)-TETRAHYDROFURAN-2- YL)PROPANE-2-SULFONAMIDE

To a solution of (S)- 1 -hydroxy -N,N-bi s(4-methoxybenz}'l)-3-((R)- tetrahydrofuran-2-yl)propane-2-sulfonamide and (R)-l -hydrox -N,N-bis(4- methoxybenzyl)-3-((S)-tetrahy drof uran-2-yl)propane-2-suU Onamide and (S)- 1 - hydroxy-N,N-bis(4-rnethoxybenzyl)-3-((S)-tetrahydrofuran-2-y l)propane-2- sulfonamide and (R)-l-hydroxy-N,N-bis(4-methoxybenzyi)-3-((R)- tetrahydrofuran-2-yl)propane-2-sulfonarnide (Example 637, Step 3) (4.50 g, 10.0 mmol) in DCM (50 mL) was added Dess-Martin periodinane (8.49 g, 20.0 mmol) at ambient temperature. After the reaction mixture was stirred for 12 hrs, the reaction was diluted (saturated aqueous Na2.S?.03 solution), extracted (2 I- ^' lO s. and washed (3 xsaturated aqueous NaHCOs and 1 xbrine). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was injected into a 120 g ISCO Gold column and purified by combi-flash, eluting with 10% to 40% EtOAc/hexanes to give the title compounds (2.36 g, 5.27 mmol) as cololess oil. STEP 5 : [(2R,3 S)-3-HYDROXY-N,N-BIS(4-METHOXYBENZYL)- 1 -((R)- TETRAH YDROF URA -2-Y L)HEX- 5 -ENE-2-SULFONAMlDE AND (2S ,3R)- 3-HYDROXY-N,N-B IS (4-METH OXYBENZYL) - 1 -((S)- TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMTDE] OR [(2R,3S)-

3-HYDROXY-N,N-BiS(4-METHOXYBENZYL)-l-((S)-

TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMIDE AND (2S,3R)- 3-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-l -((R)-

TETRAHYDR0FURAN-2-YL)HEX-5-F;NE-2-SULF0NAMIDE] OR [(2S,3S)- 3-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-l -((R)-

TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMH ⁾ E AND (2R,3R)-

3-HYDROXY-N,N-BIS(4-METOOXYBENZYL)-l-((S)-

TETRAHYDR0FURAN-2-YL)HEX-5-ENE-2-SULF0NAMIDE] OR [(2R,3R)- 3 -HYDROXY -N,N -BIS (4-METHOXYBENZ YL) - 1 -((S)- TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMIDEE AND (2S,3S)-3-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-l-((R)- TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMlDE] (RACEM1C MIXTURES 1 AND 2)

To a mixture of (S)-N,N-bis(4-methoxybenz l)-l-oxo-3-((R)- tetrahydrofuran-2-yl)propane-2-sulfonamide and (R)-N,N-bis(4-methoxybenzyl)- 1 -oxo-3-((S)-tetrahydfofuran-2-yl)propane-2-sulfonamide and (S)-N,N-bis(4- methoxybenzyl)-l-oxo-3-((S)-tetrahydrofuran-2-yl)propane-2-s ulfonarnide and (R)-N,N-bis(4-methoxy benzyl)- l-oxo-3-((R)-tetrahydrofuran-2-yl)propane-2- sulfonamide (Example 637, Step 4) (2.36 g, 5.27 mmol) and allyl iodide (1.94 mL, 21.1 mmol) in DMF (21 mL) was added indium (2.42 g, 21.1 mmol) at ambient temperature. After the reaction was stirred overnight, the reaction was diluted (EtOAc and saturated aqueous NaHCCb) and filtered through Celite to remove solid precipitates. Then the organic layer was separated from the filtrates, dried (MgS04), and concentrated under reduced pressure. The residue was injected into a 220 g ISCO Gold column and purified by combi-flash, uring with 20% to 30% EtOAc/hexanes to give one racemic mixture from the title compounds (0.840 g, 1.72 mmol) (racemic mixture 1) as the faster eluting products and another recemic mixture of the title compounds was obtained as the second (slower) eluting products (0.840 g, 1.72 mmol) (racemic mixture 2) STEP 6: [(2R,3S)-3-MYTHOXY-N,N-BIS(4-METHOXYBENZYL)-l -((R)-

TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMIDE AND (2S.3R)- 3 -MYTHQXY -N, -BIS (4-METHOXYBENZYL) - 1 - ((S)-

TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMIDE] OR [(2R.3S)- 3-MYTHOXY-N,N-BIS(4-METHOXYBENZYL)- 1 -((S)- TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMIDE AND (2S,3R)- 3-MYTHOXY-N,N-BIS(4-METHOXYBENZYL)-l-((R)-

TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFON AMIDE] OR | (2S,3S)- 3~MY ^r mOXY-N,N-BiS(4-ME ^' raOXYBENZYL)-l-((R)~

TETRAH YDROF URAN -2 - YL)HEX- 5 -ENE-2 - S ULFON AMIDE A D (2R.3R)- 3-MYTHOXY-N,N-BIS(4-METHOXYBENZYL)-l -((S)-

TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMTDE] OR [(2R,3R)- 3-ΜΎΤΗΟΧΎ-Ν,Ν-ΒΙ8(4-ΜΕΊΉΟΧΥΒΕΝΖΥ1,)-1 -((8)- TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMIDEE AND

(2S ₅ 3S)-3- MYTHOXY-N,N-BIS(4-METHOXYBENZYL)-l-((R)- TETRAH YDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMIDE]

To a solution of the racemic mixture 1 from Exampl e 637, Step 5 (840 mg, 1.72 mmol) and iodomethane (1.06 mL, 17.2 mmol) in THF (17 mL) was added t- BuO (1.0 M solution in THF, 1.89 mL, 1.89 mmol) at 0 °C. After the reaction mixture was stirred overnight at ambient temperature, the reaction was quenched (brine), extracted (EtOAc), and washed (brine). The combined organic layers were dried ( a ₂ S04) and concentrated under reduced pressure to provide a crude product which was used in next step without purification.

STEP 7 : [(2R, 3 S)-3 -MYTHOXY-((R)-TETRAHYDROFURAN-2-YL)HEX-5 - ENE-2-SULFON AMIDE AND (2S,3R)-3- MYTHOXY-(( S)- TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFONAMTDE] OR [(2R,3S)- 3-M ™0XY-((S)-TETRAHYDR0FURAN-2-YL)HEX~5-ENE-2- SULFONAMIDE AND (2S,3R)-3-MYTHOXY-((R)-TETRAHYDROFURAN-2- YL)HEX-5-ENE-2-SULFONAMIDE] OR [(2S,3S)-3-MYTHOXY-((R)- TETRAHYDROFURAN-2-YL)HEX-5-ENE-2-SULFON AMIDE AND (2R.3R)- 3 1YTH0XY-((S)-TETRAHYDR0FURAN-2-YL)HEX-5-ENE-2- SULFONAMIDE] OR |;(2R,3R)-3- YTHOXY-((S)-TETRAHYDROFURAN-2- YL)HEX-5-ENE-2-SULF0NAMIDEE AND (2S,3S)-3- MYTHOXY-((R)- TETRAHYDR0FURAN-2-YL)HEX-5~ENE-2-SULF0NAMIDE]

To a solution of the products from Example 637, Step 6 (864 nig, 1.72 mmol) in anisole (9.3 mL, 86 mmol) was added TFA (6.4 mL, 86 mmol) at ambient temperature. After the reaction was stirred over 2 days, the reaction was concentrated under reduced pressure. The residue was injected into a 12 g IS CO Gold column and purified by combi-flash, eluting with 20% to 70% EtOAc (containing 0.3% AcOH)/hexanes to give one racemic mixture of the title compounds (0.365 g, 1.38 mmol).

STEP 8: (Si-e'-CHLORO-S^^l R^^^-iil S R^R^I-l-HYDROXA^S-

METHOXY-6-SULFAMOYL-7-((S)-TETRAHYDROFURAN-2-YL)HEPT-2-

EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPlNE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHL()RO-5-(((lR,2R)-2-((lS,5S,6S,E)-l-HYDROXY-5- METHOXY-6-SULFAMOYL-7-((R)-TETRAHYDROFURAN-2-YL)HEPT-2- EN-l -YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2H,2H- SPIRO [BENZO [B ][ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID] OR [(S)-6'-CHLORO-5-(((l R,2R)-2-((l S,5R,6R,E)-l-HYDROXY-5- METHOXY-6-SULFAMOYL-7-((R)-TETRAHYDROFURAN-2-YL)HEPT-2- EN-I-YL)CYCLOBLIlTL)METHYL)-3',4,4',5-TETi ^: L' HYDRO-2H,2'H- SPIRO[BENZO[B] [ 1 ,4 jOXAZEPINE-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2R)-2-((l S,5S,6S,E)-l-HYDROXY-5- METHOXY-6-SULFAMOYL-7-((S)-TETRAHYDROFURAN-2-YL)HEPT-2- EN-l -YL)CYCIi3BUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'i-I- SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID] OR [(S)-6'-CHLORO-5-(((lR,2R)-2-((l S,5R,6S,E)-l-HYDROXY-5- METHOXY-6-SULFAMOYL-7-((S)-TETRAHYDROFURAN-2-YL)HEPT-2- EN-l-YL)CYCLOBUTYL)METHYT _J )-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2H-

SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)-2-((lS,5S,6R,E)-l-HYDROXY-5- METHOXY-6-SULFAMOYL-7-((R)-TETRAHYDROFURAN-2-YL)HEPT-2- EN-l -YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][ L4]OXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXYLIC ACID] OR |;(S)-6'-CHL()R()-5-(((l R,2R)-2-((l S,5S,6R,E)-l-HYDROXY-5- METOOXY-6-SULFAMOYT-7-((S)-TETRAHY ^T DRO

5-.\- i -Y I .)CVCLOBl 1 Y f >V!i ; ! I !Υ Ι .)-3'Α4'. ~ ΠΠ R,\i IY DRO-21 1.2 ! i- SPlRO[BENZO[B][L4]OXAZEPlNE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((l R,2R)-2-((l S,5R,6S,E)-l-HYDROXY-5- METHOXY-6-SULFAMOYL-7-((R)-TETRAHYDROFURAN-2-YL)HEPT-2- EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO j B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLI C ACID]

To a solution of (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l-hydroxyhex-2-en-l- y^cyclobut methy^-S'^^'^-tetrahydro^H^'H-s irotbenzotblt l^Joxazepi e- 3,l'-naphthalene]-7-carboxylic acid (200 mg, 0.392 mmol) (Intermediaie AA12) in DCM (4.5 ml.) was added the products from Example 637, Step 7 (361 mg, 1.37 mmol). The solution was sparged with Ar for 15 mm and Hoveyda-Grubbs 2nd generation catalyst (49 mg, 0.078 mmol) was added at ambient temperature. After the reaction mixtui'e was stirred at ambient temperature for 2.5 hours, air was bubbling through the reaction solution for 10 min. After the reaction was concentrated under reduced pressure, the residue was injected into a 12 g ISCO Gold column and purified by combi-flash, eluting with 20% to 100% EtOAc (containing 0.3% AcOH)/hexanes to give one of the title compounds as a dark brown oil.

STEP 9: (1 S,3'R,6'R,7'S,8'E,1 l 'S, 12'R)-6-CHLORO-7'-HYDROXY-l 1'- ΜΕΤΉΟΧΥ- 12'-((2S)- ETRAHYDRO-2-FURANYLMETHYL)-3 ,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO1A[1,14]DIAZATETI ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, I 8,24]TETRAENl-15'-ONE 13', 13'-DIOXIDE OR

(Ιβ,Β'Κ,ό'Κ,Τ'β,δΈ,Ι Ι'β, 'Κνό-ΟΗίΟΚΟ-Τ'-ΗΥϋΚΟΧΥ-Ι Ι '-ΜΕΤΗΟ Υ-Ι^- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETT ACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETTiAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 rR,12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHOXY-12'- ((2S)-TETRAHYDRO-2-FURAN^ LMETHYL)-3,4-DIHYDRO-2I-1, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

| 2u jOXA| 1 ΙΊ ! !1Λ| l . l 4 |! !A/.Vr!-;i ^' R A( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |Pl-N i ^' AC<)SA [ 8,16,18,24]TETR _! 4ENl-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 1 'R, 12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHOXY- ! 2'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ - ⁶ .0 ^l9 ' ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHOXY-12'- ((2S)-TET AHYD O-2-FURAN^LMETHYL)-3,4-DIHYDRO-2I-1, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PL\,T.\i SA [8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-CHLORO-7'-HYDROXY-l l'-METHOXY-12'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(Ιβ,Β'Κ,ό'Κ,Τ'β,δΈ^ΓΚ, 'Κ^ό-ΟΗίΟΚΟ-Τ'-ΗΥΟΚΟΧΥ-ΙΙ'-ΜΕΤΗΟΧΥ- Ι^- ((2S)-TETOAHYDRO-2-FURAISTYLMETHYL)-3.4-DIIiYDRO-2H ₅ 15H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R,7'S,8 .;ri¾,12'R)-6-CHl RO-7'-IWDROXY-ll'-METHOXY-12 ^f - ((2R)-1\ETRAHYDR0-2-FURANYLMF;THYL)-3 ₅ 4-DIHYDR0-2HV15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA[l,14]DIAZATETRACYCL)[14J.2X) ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE (ISOMER 1)

To a solution of the product from Example 637, Step 8 (310 mg, 0.441 mmol) in DCM (30 mL) was added EDC (380 mg, 1.98 rnmol), N,N- dimethylpyridin-4-amine (DMAP) (242 mg, 1.98 mmol), and triethylamine (0.276 mL, 1.98 mmol) successively at ambient temperature. After the reaction was stirred over 2 days, the reaction mixture was injected into a 4 g ISCO Gold column and purified by combi-f!ash, eluting with 0% to 100% EtOAc (containing 0.3% AcOH)/1exanes to give a mixture of two diasteromers as a pale brown film. The resulting mixture of two diastereoniers was furtlier purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 mm method) to provide one of the title compounds as the faster eluting isomer as a white foam. (60 mg, 0.088 mmol). ^" Ή NMR (500 MHz,

CDCb) δ ppra 8.12 (br, s., 1 H) 7.72 - 7,65 (m, 1 H) 7.23 - 7.13 (m, 2 H) 7.10 (d, ./ 2.20 Hz, 1 H) 6.97 - 6.84 {in.2 H) 5.75 (m, 2 H) 4.42 id../ 8. ⁽ ϊ7 Hz, 1 H) 4.22 (d, ./ 12.23 Hz, i H) 4.20 - 4,06 (m, 3 H) 3.73 (br, s., 2 H) 3.63 (br. s„ 2 H) 3,46 - 3.33 Cm.4 H) 2.84 - 2.70 (m, 2 H) 2.56 - 2.35 Cm.3 H) 2.35 - 2.22 (m, 2 H) 2.14 - 2.01 Cm.4 H) 1.98 - 1.76 (m, 7 H) 1.76 - 1.61 (m, 2 H) 1.55-1.43 (m, 2 H); rm/z (ESI, +ve ion) 685,2 (VI 11) ^' .

EXAMPLE 638. (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6~CHLORO-7 ^, -HYDROXY-l - METHOXY-12 ^, -((2S)-TETRAHYDRO-2-FURA]ST¥ ^r LMETHYL)-3 ₅ 4- DIHYDRO~2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|20i()XA| Γ. ΐΗ1Λ| Ι..! |ί)!Λ/.\ ! :ΓΗ.Λ( ^· ν ^' .()Ι 117.20 ' ".i) ¹ '" ¹ |Ρ1·Ν i ^' ACOSA

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO-7'-HYDROXY- 1 Γ-ΜΕΤΗΟΧΥ- 12'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,14]DIAZATCTRACYCLO|;i4.7.2.0 ³ '*0 ^l9 ^ ⁴ ]PE TACOSA

[8,16,I8,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, R,12 ^, S)-6-CHLORO-7'-HYD OXY-lr-MEΊΉOXY-12 ^, - ((2S)-TETOAHYDRO-2-FURANYLMETHYL)-3,4-DIIiYDRO-2H ₅ 15H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 rR,12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHOXY-12'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOIMJ^.O'^.O^^lPE TACOSA

[8,16,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,ll'S,12'S)-6-CHl RO-7'-HYDROXY-ll'-METHOXY-12'- ((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE OR

(1 S,3'R,0'R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHOXY-12'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R,7'S,8 .;ri¾,12'R)-6-CIlLORO-7' WDROXY-!l'-METHOXY-12 ^f - ((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE OR

(IS^'R^'R 'S^'EJl'^n'Rj-e-CHLORO^'-HYDROXY-ll'-METHOXY-n'- ((2R)-TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTI-I ALENE- 1 ,22'-

[20]QXA[13]THIA[U4]DL^

[8,I6,18,24]TETiL E ]-15'-ONE 13', 13 '-DIOXIDE (ISOMER 2)

One of the title compounds was prepared by a procedure analogous to that described in Example 637, Steps 6 through 9, replacing the racemic mixture 1 in Step 6 with the racemic mixture 2 from Example 637, Step 5. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Ci8 5 μηι column: Phenonienex, Torrance, CA; gradient elution of 45% to 75% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as the faster eluting isomer as a white foam. ^! H NMR (500 MHz, CDCb) δ ppm8.40 (br. s., 1 H) 7.74 - 7.66 (m, 1 H) 7.24 - 7.16(m, 2 H) 7.12 (d, J=1.96 Hz, 1 H) 7.00 - 6.88 (m, 2 H) 5.87 - 5.64 (m, 2 H) 4.25 (m, 1 H) 4.22 - 4.02 (m, 4 H) 3.86 - 3.57 (m, 4 H) 3.50 - 3.36 (m, 4 H) 2.87 - 2.69 (m, 2 H) 2,58 (m, 1 H) 2.44 - 2.26 (m, 4 H) 2.2 ! (m, 1 H) 2.17 - 1.78 (m, 1 1 H) 1 ,77 - 1.50 (m, 4 H); m/z (ESI, +ve ion) 685.2 (M+H) ⁺ .

EXAMPLE 639, (IS,3'R,6'R,7'S,8'E, 1 l'S.^'R^-CHLORO- '- (CYCLOBmTLMETHYL)-7 ^, -HYDROXY-l l ^, -METHOXY-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- pOlOXAI lSlTHIAIl.MlDIAZATETRACYCLOiM^^.O'^.O^^lPENTACOSA

[8,I6, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8 ^, E,l l ^, ,12 ^, S)-6-CHLORO-12'-(CYCLOBUΊΎLMEΊΉYL)-7 ^, - HYDROXY-l l '-METHQXY-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irS,12'S)-6-CHLOR()-12'-(CYCLOBUTYLMETHY L 7'- HYDROXY-! l'-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ⁱ⁹ ^ ⁴ |PENTACOSA [8J 6,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E, l l'R,12'R)-6-CHLORO-12'-(CYCLOBUTYLMETHYL)-7'- HYDROXY - 11 '-METHOXY-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13 [THIA[1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16,18,24]TETiL EN]-15'-ONE 13 ', 13 '-DIOXIDE (ISOMER 1)

One of the title compounds was prepared by a procedure analogous to that described in Example 574, Steps 1 through 3, replacing

(bromomethyl)cyclopropane in Step 1 with (bromomethyl)cyclobutane. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50 % to 85 % MeCN in water, where both solvents contain 0.1% TFA, 30 rain method) to provide one crude containing the faster eluting isomer. The crude was further purified by combi-flash (4 g ISCO Gold column), eluting with 10% to 60%

EtOAc (containing 0.3%» AcOH)/hexanes to give one of the title compounds. Ή NMR (500 MHz, CDC! : ) δ ppm 8.26 (br. s., 1 H) 7.70 (d, J=8.56 Hz, 1 H) 7.18 (dd, ./ 8.56. 2.20 Hz, 1 H) 7.14 - 7.02 (m, 2 H) 6.94 (s, 2 H) 5.78 (dd, ./ 1 5. 16. 6.60 Hz, 1 H) 5.65 (dt, J-13.94, 6.72 Hz, 1 H) 4.20 - 4.06 (m, 3 H) 3.95 (dd, ./ 7 34. 4, 16 Hz, 1 H) 3.77 (m, 1 H) 3,69 (m, I H) 3.52 (m, ! H) 3,41 - 3,34 i s, 3 H) 3.30 (d. J I 1.49 1 1/. 1 H) 3.12 (br. s., 1 H) 2.85 - 2.69 (m, 3 H) 2.58 - 2,48 (m, 1 H) 2.48 - 2.33 (m, 2 H) 2.33 - 2.22 (m, 2 H) 2.22 - 2.06 (m, 2 H) 2.03 - 1.80 (m, 8 H) 1.78 - 1.66 (m, 3 H) 1.50 - 1.39 (m, 2 H); m/z (ESI, +ve ion) 669.2 (M+H) ⁺ .

EXAMPLE 640. (1S,3'R,6 ^! R,7'S,8'E,1 l'S,12'R)-6-CHLQRQ-12'-

(CY CLOBUTYLMETHYL)-7'-HYDR()XY-l l'-METHOXY-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'-

|20!ΟΧΛ| ΐ: ΐ!!1Λ| Κ4 |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.20 ^:'i' .0 ^li ' |Pi-:N i ACOSA [8,16,18,24]TETiL E ]-15'-ONE BVB'-DIQXIDE OR

(lS,3¾,6 ^, R,7 ^, S.8Έ l ^, R,12 ^, S)-6-CHLORO-12 ^, -(CYCLOBUTYLMETHYL)-7 ^, - HYDROXY-11 '-METHOXY-3,4-DiHYDRO-2H,!5'H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1 4]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8 ₅ 16,18,24]TETRAEN]-15"-ONE 13',13 ^* -DK)XIDE OR

(1 S,3'R,6 ^! R,7'S,8'E, 11 'S, 12^)-6~CHLORO-12 ^! ~(CYCLOBUTYLMETHYL)-7'- HYDROXY- 11 '-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETR^\EN]-15'-ONE 13',13'-DIOXIDE OR

(lS.S'R.e'^T'S^^ll'R R^e-CHLORO-l^CYCLOBUTYLMETHYL)-?'- HYDROXY- 11 ^* -METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/Α Π:ΤΗΑ(Ύα.ΟΙ i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [8,16 8,24]TETRAENj-15'-ONE 13',13'-DIOXIDE (ISOMER 2)

One of the title compounds was obtained as the second (slower) eluting isomer from reversed phase preparatory HPLC in Example 639. Ή NMR (500 MHz, CDCb) δ ppm 8.15 (s, 1 H) 7.49 - 7.71 (m, 2 H) 7,08 (dd, J=8.56, 2.20 Hz, 1 H) 7.03 (d, ,7=2,20 Hz, 1 H) 6.92 - 6,77 (m, 2 H) 5.68 (dd, ./ 15.77.4,03 Hz, 1 H) 5.31 (br. s., 1 H) 4.23- 4.10 (m, 2 H) 4.02 (d, ./ 3.67 Hz, 1 H) 3.90 ·· 3.76 (m, 2 H) 3.70 (d, ./ 14.67 Hz, 1 H) 3.42 - 3.32 (m, 1 H) 3.30 (s, 3 H), 3.27 - 3.18 (m, 1 H)3.04 id../ 14.18 I !/. ! H) 2.80-2.61 (m, 3 H) 1.93 (m, 1 H) 2.50-2.34 (m, 3 H) 2.24 - 2,13 (m, 2 H) 2.13 - 1.98 (m, 3 H) 1.86 - 1,62 (m, 5 H) 1.62 - 1.39 (m, 4 H) 1.37 -1.26 (m, 2 H): m/z (ESI, +ve ion) 669.2 (M+H) ⁺ .

EXAMPLE 641. (1 S,3'R,6'R,7'S,8'EJ i'SJ 2'R)-6-CHLORO-7',l 1 '- DIMETHOXY -12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOtW.y^.O'^.O'^lPE TACOSA

[8,16,18,24]TE,TRAEN]-15 ^! -ONE 13', 13 -DIOXIDE OR

(lS,31 ,6'R,7^,8UirS,I2'R)-6-CHLORO-7 r-DIMETHOXY-12 ^, -((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[N APHTH ALENE- 1 ,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ' ".i) ¹ '" ¹ |Ρ1·Ν i ^' ACOSA

[8,16,18,24]TETRAENj-15'-ONE 13 ',13 '-DIOXIDE OR

(lS 'R,6'R,7 ^f S,8'E,ll'R,12 ⁱ S)-6-CHLORO-7',ll'-DIMETOOXY-12 ⁱ -((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- pOlOXAIlSlTHIAIl.MlDIAZATET ACYCLOiM.T^.O'^.O^^lPENTACOSA

[8,I6,18,24]TETRAEN]-15'-ONE 13' ₅ 13*-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,ll'R,12'S)-6-CHLORO-7',ll ^, -DIMEraOXY-12'-((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETR^\EN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irS,12'S)-6-CHLOR()-7',ir-DIMETHOXY-12'- ((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' AC<)SA [8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13 ^* -DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8¾ll ^, S ₅ 12 ^, S)-6-CIiLORO-7\ll ^, -DIMETHOXY-12 ^, -((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1.T.13'-DIOXIDE OR

(1 S,3'R,6'R, 7'S,8'E, 11 'R, 12 ^, R)-6-CHLORO-7 ^, _s 11 '-D1METHOXY- 12'-((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,1 l¾,12¾ -6-CHLORO-7*,l 1 '-DIMETHOXY-12'-((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIMJ^.O'^.O'^lPE TACOSA [8, 16, 18,24]TETRAENj~l 5'-ONE 13", 13-DIOXIDE

To a solution of product of Exampl e 637 in THF (0,5 mL) was added NaH (60% dispersion in mineral oil, 2.6 mg, 0.066 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 30 min, a solution of Mel (2.5 iiL, 0.039 mmol) in THF (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h. Then the reaction was quenched (water and 1 N aqueous HC1), extracted (EtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S04) and concentrated under reduced pressure to provide a crude product. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cie 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds (5.0 mg, 7.1 μηιοΐ) as a white foam. 'H NMR (400 MHz, CDCI3) δ ppm 8.18 (s, 1 H) 7,70 id. ./ 8.4 ! Hz, 1 H) 7.18 (dd, J=8.41, 2,35 Hz, 1 H) 7.10 (d, ./ 2.35 Hz, 1 H) 6.99 - 6.89 (m, 2 ! ! } 6.89 - 6.82 (m, 1 H) 5.85 - 5.69 (m, 1 I I ) 5.61 (dd, ,/ 15 36. 8.90 Hz, 1 H) 4,58 id. ./ 6.46 Hz, 1 1 1 } 4,40 - 4.26 (m, 1 H) 4.10 (s, 2 H) 3,86 - 3.64 (m, 5 H) 3.52 - 3,39 (m, 1 H) 3,39 - 3.33 (m, 3 H) 3.28 - 3.20 (m, 4 H) 3.01 (dd, J=15.26, 9.98 Hz, 1 H) 2.88 - 2.69 (m, 2 H) 2.54 - 2.40 (m, 3 H) 2.40 - 2.26 (m, 2 ! ! } 2.13 - 2.09 (m, 1 H) 2.07 - 1.81 (m, 9 ! ! } 1.75 - 1.60 (m, 1 H) 1,60 - 1 ,48 (m, I H) 1.40 (t, ./ ! 2.52 Hz, 1 H); m/z (ESI, +ve ion) 699.2 (M+H) ⁺ .

EXAMPLE 642, iiS,3'R,6'R,7'S,8'E,l l'S,12'R)-6-CHLORO-7',l 1'- DIMETHOXY-12'-((2S)-TETRAHYDRO-2-FURANYLMETHYL)-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAI lSlTHIAI^MlDIAZATETRACYCLOiM.T^.O'^.O^^lPENTACOSA

[8,16,18,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,l l ^, S,12'R)-6-CHLORO-7',l l ^, ~DIMETHOXY-12'-((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,i rR,12'S)-6-CHLORO-7',H'-DIMETHOXY-12'-((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-

[20iOXA[13]THIA[l,14]DIAZATETRACYCLO[14.7.2.() ³ - ⁶ ,0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAENi-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,l I'R,12'S)-6-CHLORO-7',i r-DrMETHOXY-12'-((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,61 7'S,8T,ll^,12'S)-6 mORO-7 -DlMETHOXY-12 ^! "((2S)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R,7'S,8 .;irSJ2^)-6-CHLORO-7',ll'-DIMETI-IOXY-12 ^f -((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[8,16,18,24]ΤΕΤ ΑΕΝ]-15'-ΟΝΕ 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'R, 12'R)-6-CHLQRQ-7', 1 Γ-DIMETHOXY- 12'-((2S)-

TETRAHYD O-2~FL ⁱ iL NYLMETHYL)-3,4-DIHYDRO-2H,I5'H- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[ 13]THIA[ 1, 14JDIAZ ATETRACYCLO

[14.7.2.0 ³ · ⁶ .0 ¹⁹ ' ²⁴ ] PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE OR (1S,3'R,6'R,7'S,8'E,1 l'R,12'R)"6"CHLORO-7',I I'-DIMETHOXY- 12'-((2R)-TETRAHYDR()-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- ! ,22' [20] OX A

I 1 Ι Η1Λ| I .. N |ΡΙΛ/Λ H RAi ^' VC ^' i.Ol 1-1.7.20'^ 0 ^|: ' ^!| |PH\,T.\i SA|8.!6. IS. 24]TETRAEN]-15'-ONE 13 ^* ,13'-DIOXIDE

To a solution of Example 638 (5 mg, 0.007 mmol) in THF (0.5 mL) was added NaH (60% dispersion in mineral oil, 1.4 nig, 0.036 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 30 min, a solution of Mel (1.4 ,uL, 0.022 mmol) in THF (0.5 mL) was added. The reaction mixture was stirred at ambient temperation for 2 h. Then the reaction was quenched (water and 1 N aqueous HCi), extracted (EtOAc), and washed (brine). The combined organic layers were dried (Na?.SC)4) and concentrated under reduced pressui'e to provide a crude product. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 85% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds. ¾ NMR (400 MHz, CDCb) δ ppm 8.07 (s, 1 H) 7.62 (d, ,7=8,41 Hz, 1 H) 7.10 (dd, .7=8,61 , 2.15 Hz, 1 H) 7,02 (d, J=1.96 Hz, 1 H) 6,91 - 6.81 (m, 2 H) 6.78 (s, 1 H) 5.70 - 5.57 (m, 1 H) 5.57 - 5.44 (m, 1 H) 4.33 (t, ./ 5.97 Hz, 1 H) 4.13 (quin, J=6.50 Hz, 1 H) 4.02 is. 2 H) 3,83 (q, ./ 7.30 Hz, 1 H) 3.78 - 3.55 (m, 4 H) 3.48 (t, ,/ 7 43 Hz, 1 I I ) 3.32 (s, 3 H) 3.23 - 3,09 (m, 4 H) 2.95 (dd, ./ 1 .26. 9,78 Hz, 1 H) 2.79 - 2.63 (m, 2 H) 2,49 (t, J=6.75 Hz, 2 H) 2.42 - 2.32 (m, 1 H) 2.32 - 2.17 (m, 3 H) 2.10- 2.00 (m, 1 H) 1.97-1.78 (m, 8 H) 1.66 - 1.51 (m, 2 H) 1.33 (t,■/ i 2.52 Hz, 1 H); m/z (ESI, +ve ion ) 699.2 (M+H) ⁺ .

EXAMPLE 643. (1S,3'R,6'R,7'S,8 ^! E,1 rS,12'R)-6-CHL()RO-7'-HYDR()XY-ir- ΜΕΤΉΟΧΥ- 12'-(2-METHYLPROPYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,1 rR,12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHOXY-12'- (2-METHYLPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-

[20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15 ^! -ONE 13', 13 -DIOXIDE OR

(lS,3 ^, ,6'R,7 ^! S,8Έ,l l'S,12'S)-6-CHLORO-7'-HYD OXY-l l'-METHOXY-12 ^, - (2-METHYLP ROP YL)-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO | NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l,i4]DL ZATETRACYCLO[14,7.2,0^^0 ¹⁹ - ²⁴ ]l^^^

[8,16,18,24]TETR _J! 4EN1-15'-0NE 13',13'-DIOXIDE OR

(lS,3¾,6'R,7^,8T I I'R,12¾)-6-CHIX)RO-7' rYDROXY-ir-METHOXY-12'- (2-METHYLPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18,24]ΊΈΤΚΑΕΝ]-15'-ΟΝΕ 13 I 3 '-DIOXIDE (ISOMER 1)

One of the title compounds was prepared by a procedure analogous to that described in Example 574, Steps I through 3, replacing

(bromomethyl)cyclopropane in Step 1 with l-bromo-2-methylpropane. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 50% to 75% MeCN in water, where both solvents contain 0.1% TEA, 30 min method) to provide one of the title compounds as the faster eluting isomer. ³ H NMR (400 MHz, CDCb) δ ppm 8, 15 is. I H) 7,70 id. ./ 8.61 Hz, 1 H) 7, 1 8 (dd, J==8.5I, 2.25 Hz, 1 H) 7.12 - 7,02 (m, 2 H) 6.97 - 6.92 (m, 2 H) 5.86 - 5,74 (m, 1 H) 5.74 - 5.62 (m, I H) 4,21 - 4.06 (m, 4 H) 3.80 (d, J=I5.26 Hz, 1 H) 3.70 (d, =14.48 Hz, 1 H) 3.54 (d, ./ 12.32 Hz, I H) 3,38 (s, 3 H) 3,29 (d, ./ ! 4.28 Hz, 1 H) 3.10 (br. s,, 1 H) 2.85 - 2.71 (m, 2 H) 2.58 - 2,33 (m, 3 H) 2.32 - 2.19 (m, I H) 2.19 - 2,06 (m, 2 H) 2.05 - 1.38 (m, 9 H) 1.08 - 0.93 (m, 6 H); m/z (ESI, +ve ion) 657.2 (M+H) ¹ .

EXAMPLE 644, iIS,3'R,6'R,7'S,8'E, l l'S,I2'R)-6-CHLORO-7'-HYDROXY-i r- ME ^r fflOXY-12'-(2-METHYLPROPYL)-3,4"DIHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE OR

(lS^'R-e'R-T'S^i l'^l^S^e-CHLORO-T-HYDROXY-ll'-METHOXY-l^-

(2-METHYLPROPYL)-3,4-DIHYDRO-2H,15'H-SPIR()[NAPHTHALENE- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6¾,7'S,8¾irS,12'S)-6-CHLORO-7'-HYDROXY-i -METHOXY-12'- (2-METHYLPROPYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(IS^'R^'R 'S^'EJl'^n'Rj-e-CHLORO^'-mOROXY-ll'-METHOXY-n'- (2-METHYLPROPYL)-3,4-DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE- 1,22'-

|2 ⁽ >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA [ -15'-ONE 13', 13 '-DIOXIDE (ISOMER 2)

One of the title compounds was obtained as the second (slower) eluting isomer from reversed phase preparatory HPLC in Example 643. Ή NMR (400 MHz, CDCb) δ ppm 8.17 (s, 1 H) 7.76 - 7.59 (m, 2 H) 7.19-7.13 (m, 1 H) 7.11 id. J=2.35 Hz, 1 H) 6.98 - 6.90 (m, 2 H) 5.78 (dd, ./ 1 .7"·.4.21 Hz, 1 H) 5.50 - 5.33 (m, 1 H) 4.30 - 4.19 (m, 2 H) 4.19 - 4.01 (m, 2 H) 3.97 - 3.87 (m, 1 H) 3.79 (d, ./ 13.69 Hz, 1 H) 3.47 (dd, ./ 10.96.2,93 Hz, 1 H) 3.44 - 3.26 (m, 4 II ) 3.12 (d, J=14.67 Hz, 1 H) 2.75 (br. s., 2 H) 2.59 - 2.44 (m, 3 H) 2.23 - 2.04 (m, 3 H) 1.87 - 1.57 Or, 8 H) 1.46 - 1.34 ins.1 H) 1.08 - 0.99 {in.6 H); m/z (ESI, +ve ion) 657,2 (V! Π) .

EXAMPLE 645. (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-l l'-METHOXY-7'- (2-(4-MORPHOLINYL)ETHOXY) - 12'-((2S )-TETRAHYDRO-2-

FURANYLMETHYL)-3 ,4-DIHYORO-2H, 15 'H-SPIRO [NAPHTHALENE- 1 ,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΑΖΑ ί : ί AC YC i (>! i 47.2 ' ".O ^1* " ¹ |PHNT. SA

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 l'S,I2'R)-6-CHLORO-l ! '-METHOXY-7'-(2-(4- MORPHOLINYL)ETHOXY)- 12'-((2R)-TETR AHYDRO-2-

FURANYLMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[N APHTHALENE-1 ,22'- POIOXAIISITHIAII.MIDIAZATETRACYCLOIT^T^.O'^.O^^IPENTACOSA

[8,I6,I8,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R,7'S,8 ^, E,ll ^, R,12'S)-6-CHLORO-ll'-METHOXY-7'-(2-(4- MORPHOLINYL)ETHOXY)-12 ^, -((2S)-TETRAHYDRO-2-

FURANYLMETHYL)-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 l'R,12'S)-6-CHLORO-l l'-METHOXY-7 ^, -(2-(4- MORPHOLINYL)ETHOXY)- 12'-((2R)-TETRAHYDRO-2-

FURANYLMETHYL)-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOIl^T^.O'^.O^^lPENTACOSA

[8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'S)-6-CHLORO- 11 '-METHOXY-7'-(2-(4- MORPHOLINYL)ETHOXY)-12'-((2S)-TETRAHYDRO-2-

FURANYLMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIR()[N APHTHALENE-1 ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'~DIOXIDE OR

(lS,3'R,6 ^, R;7 ^, S,8 ^, E,irS,12 ^! S)-6-CHLORO-ir-METHOXY-7 ^, -(2-(4- MORPHOLI YL)ETHOXY)-12'-((2R)-TETRAHYDRO-2- FURANYLMETHYL)-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TfflA[l ,14]DiAZATETRACYCLO[14;7 A ⁾³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S,3'R,6'R,7'S,8'E,ri'R,12'R)-6-CIfl..ORO-l l'-METHOXY-7'-(2-(4- MORPHOLINYL)ETHOXY)-12'-((2S)-TETRAHYDRO-2- FURi NYLMETHYL)-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE-l,22'- ^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI M.T^.O'^.O^^lPE TACOSA

[8, 16, 18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'R, 12'R)-6-CHLORO- 11 ^, -METHOXY-7'-(2-(4- MORPHOLIN YL)ETHOXY)- 12'-((2R)-TETRAHYDRO-2- FURANYLMETHYL)-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* - [20]OXA[13]THIA[1,14]DIAZATCTRACYCLO[14 ^^

[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

To a solution of the product in Example 637 in DMF (0,67 mL) was added NaH (60% dispersion in mineral oil, 5.8 mg, 0.15 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 15 min, 4-(2-bromoethyl)morpholine hydrobromide (20 mg, 0,073 mmol) was added. The reaction mixture was stirred at ambient temperation over 2 days. Then, the reaction was quenched (aqueous NKUCl), extracted (EtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S04) and concentrated under reduced pressure to provide a crude product. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA: gradient elution of 40% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 mm method) to provide one of the title compounds (8.0 mg, 10 μτηοΐ). ¾ NMR (500 MHz, CDCb) δ ppm 8.32 (br, s., ! H) 7.70 (d, ./ 8.56 Hz, 1 H) 7, 1 8 (d. ./ 8.56 Hz, 1 H) 7.14 - 7.08 (m, 1 H) 7.00 - 6.88 (m, 2 H) 6.82 (s, 1 H) 5.88 - 5.74 (m, 1 H) 5.60 (dd, ,/ 1 .79. 8.44 Hz, 1 H) 4.49 (d, ,/ 7 09 Hz, 1 H) 4.36 - 4.25 (m, 1 H) 4.16 - 3.99 (m, 5 H) 3,89 - 3.66 (m, 6 H) 3.61 (m, I H) 3.54 - 3,43 (m, 1 H) 3.43 - 3.33 C m. 4 H) 3,33 - 3.16 (m, 3 H) 3.05 - 2.90 (m, 3 H) 2,87 - 2.71 (m, 2 H) 2.58 - 2,27 (m, 5 H) 2.14 - 1 .45 (m, 13 H) 1.40 (t, ,/ 1 2 72 Hz, 2 H); ni (ESI, +ve ion) 798,2 (M+H) ⁺ .

EXAMPLE 646. (1 S,3 ^! R,6 ^* R,7'S,8'E,11 ^* S)-1 l'-BENZYL-6-CHLORO-7'- HYDROXY-3 ,4-DIHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1 ,21'- I I v !OX Al Ι 2 Ι 1 Η1 Λ| Ι .. ! 3 | ί)!Λ/ .\ Γ5·. ΓΗ.Λ(· ν(·ί .ΟΙ 13.7.2 0 '·".θ '"·· ^{! |} |TLiR .\( ^' OSA [ 8,15,17,23 ]TETRAENj-14'-C)NE 12',12'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 1 ^* R)- 11 '-BENZYL-6-CHLORO-7'-HYDROXY-3,4~ DIHYDRO-2H, 14'H-SPIRO[NAPHTHALENE-l ,21 ^* -

[19]OXA[ 12]TH1A[1,13]DL ZATEII ACYCLO[13.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]TETRACOSA [8,15, 17,23]TETRAEN]-14 ^! -ONE 12',12'-DIOXIDE

STEP : ( S)-N,N-BTS(4-METHOXYBENZYL)- 1 -PHENYLPENT-4-ENE-2- SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZ YL)~ 1 - PHENYLPENT-4-ENE-2-SULFON AMIDE

The title compound was prepared from N,N-bis(4-methoxybenzyl)but-3- ene-1 -sulfonamide (Intermediate EE16) by a procedure analogous to that described in Example 648, Step 1.

STEP 2: (1S,3'R,6'R,7'S,8'E,I I'S)-1 r-BENZYL-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 14'H-S PIRO [NAPHTHALENE- 1 ,21'-

[19] OX A [12] THI A [ I , 13 j DI AZ ATETR A C YCLO [ 13.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] TETR ACO S A

[8,15,17,23]TETRAEN]-14'-ONE 1 2'. l 2'- D10XIDi: OR

(1S,3 ^! R,6 ^* R,7'S,8'E,11 ^* R)-11 ^* -BENZYL-6-CHLORO-7'-HYDROXY-3,4- DTHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1,21 '-

[19]OXA[12]THIA[l,13]DIAZATETRACYCLO[13 ,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]TETRACOSA [8, 15, 17,23] TETRAEN ] - 14' -ONE 12', 12'-DIQXIDE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxyhex-2-en-l -yl)cyclobut>'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4 |oxazepine-3, -naphthalene]-7-carboxyiic acid (Intermediate AA12) by a procedure analogous to that described in Example 61 1 , Steps 2 and 3, replacing (S)-2-(N,N-bis(4~methoxybenz.yl)sulfamoyl)hex~5~en-l-yl carbamate in Step 2 with (S)-N,N-bis(4-me1hoxybenzyl)-l-phenylpent-4-ene-2-sulfonamid e and (R)-N,N-bis(4-methoxy benzyl)-! -phenylpent-4-ene-2-sulfonamide (Example 646, Steps 1), The crude product was purified by combi-f!ash (4 g ISCO Gold column), eluting with 20% to 60% EtOAc (containing 0.3% AcQH)/hexanes to give one of the title compounds as a white foam. ¾ NMR (500MHz, CDCb) δ ppm 8.21 (br, s., IH), 7.70 (d, J=8.6 Hz, ill).7.38 - 7.33 (m, 2H), 7.32 - 7.25 (m, 4H), 7.21 ·· 7.15 (m, ill).7.09 id../ .2.2 Hz, IH), 7.03 - 6.96 (m, IH), 6.71 (m, IH), 5.90 - 5.76 (m, 2H), 4.18 - 4.08 (m, 3H), 4.06 - 3.94 (m, IH), 3.74 - 3.62 (m, Ml).3,30 (d, J= 14.4 Hz, ill).3.23 - 3.12 (m, IH), 2.90 (dd, ./ 11.7, 13.4 Hz, IH), 2,84 - 2.71 (m, 2H), 2.63 - 2.44 (m, 3H), 2,43 - 2.32 (m, IH), 2.26 - 1.88 (m, 3H), 1.88 - 1.70 (m, 3H), 1.70 - 1.57 (m, IH), 1.45 (t, J=12.5 Hz, IH); m/z (ESI, +ve ion) 647.2 (M+H) ⁺ . EXAMPLE 647. METHYL ((lS,3'R,6'R,7'S,8'E,irS,12'R)-6-CHLORO-7'- HYDROXY- 11 '-METHYL- 13', 13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

[8, 16, 18,24]TETRAEN] - 12'-YL)ACET ATE OR METHYL

((1 S,3'R,6 ^f R,7'S,8'E,l 1 'R,12'S)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL-

I.T.1 '-!)!()XH)()-1 '-OXO-3. l-!)!! !Y!)R()-2i !-SPi Oi \Λ» 11 ΠΛί.!ΛΊ 1.22'- |2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAEN]-12'-YL)ACETATE OR METHYL

((1S,3'R,6'R,7'S,8'E,1 l'R,l 2'R)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL- i;r,13'-DIOXIDO-15'-OXO-:i4-DrHYDRO-2H-SPIRO[NAPH HALENE-l,22 ^! - [20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 12"-YL)ACET ATE OR METHYL

((lS,3'R,6'R,7'S,8'E,i S,12'S)-6-CHLORO-7'-HYDROXY-r -METHYL- 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIH YDRO-2H-SP1RO [NAPHTHALENE- 1 ,22'- [20iOXA|;i3]THIA|;i,14]DlAZATETRACYCL )[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] - 12-YL) ACETATE

STEP 1 : (R)-2-METHYLPENT-4-EN- 1 -OL AND (S)-2-METHYLPENT-4-EN- 1-OL

To a solution of (R)-2-methyl-4-pentenoic acid and (S)-2-methyl-4- pentenoic acid (22,8 mL, 200 mmol) in THF (300 mL) was added LiAlH.4 (1.0 M in THF, 200 mL, 200 mmol) at 0 °C dropwise and the resulting solution was allowed to warm to ambient temperature. After the reaction mixture was stirred at ambient temperature for 18 h, the reaction mixture was cooled to 0 °C and cautiously treated with water (7.6 mL), 15% aqueous solution of NaOH (7.6 mL), and water (22.8 mL) successively. After the resulting slurry was vigorously stirred for 1 h at ambient temperature, the suspension was filtered through C elite and the filter cake was washed with diethyl ether (2 ^χ 100 mL). The combined filterate were dried (Na ₂ S04) and concentrated under reduced pressure to provide crude title compounds as a colorless liquid which were directly engaged in the next step without further purification. STEP 2: (R)-2-METHYLPENT-4-EN- 1 - YL METHANESULFONATE AND (S)- 2-METHYLPENT-4-EN-1-YL METHANESULFONATE

To a solution of (R)-2-methylpent-4-en-l-ol and (S)-2-methylpent-4-en-l- ol (Example 647, Step 1) (18.8 g, 188 rnmol) and triethylamine (52.2 ml, 375 mmol) in EfcO (300 ml,) was added MsCl (16.0 ml,, 206 mmol) at -78 °C. After the reaction mixture was stirred for 20 mm at the same temperature, the reaction was allowed to warm to ambient temperature and stirred for 30 min. Then the mixture was diluted (water), extracted (2 ^χ Et ₂ 0), and washed (ice-cold 1 N aqueous HC1, water, saturated aqueous NaHCXK and water). The combined organic layers were dried (MgS04) and concentrated under reducd pressure to provide crude title compounds, which were used for next step without further purification.

STEP 3 2-((2-METHYLP ENT-4-EN- 1 -YL)THIO)P YRIMIDINE AND (S)-

2-((: f LPENT-4-EN- 1 -YL)THIO)P YRIMIDINE

To a solution of (R)-2-methylpent-4-en-l -yl methanes ulfonate and (S)-2- methylpent-4-en- 1 -yl methanesulfonate (Example 647, Step 2) (30.3 g, 170 mmol) and 2-mercapto-pyrimidine (28.6 g, 255 mmol) in EtOH (240 mL) was added EtONa (21% w/w solution in EtOH, 82.0 mL, 221 mmol) at ambient temperature and the resulting mixture was stirred at 60 °C for 17 h. The reaction mixture was concentrated under reduced pressure and the resulting pale yellow solid was suspended in EfeO (400 mL). After the suspension was stirred vigorously for 1 h. the slurry was filtered through Celite and the filter cake was washed (Et ₂ 0). The combined filtrates were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure to provide crude title compounds, which were directly engaged in the next step without further purification.

STEP 4: (R)-2-((2-METHYLPENT-4-EN-l-YL)SULFONYL)PYRJMIDrNE AND (S)-2-((2-METHYLPEOT-4-EN-l-YL)SULFONYL)PYRJ IDINE

To a solution of (R)-2-((2-methylpent-4-en-l -yl)thio)pyrimidine and (S)-2- ((2-methylpent-4-en-l -yl)thio)pyrimidine (Example 647, Step 3) (32.4 g, 167 mmol) in DCM (240 mL) was added 3-chloroperbenzoic acid (77% max, 78.0 g, 350 mmol) at 0 °C. The reaction was allowed to warm to ambient temperature and stirred for 1 h. The mixture was filtered through Celite and the filter cake was washed (DCM). The combined filtrates were washed (saturated aqueous NaHCCb and brine), dried (Na2SC>4), and concentrated under reduced pressure. The residue was injected into a 330 g ISCO Gold column and purified by combi -flash, eluting with 20% to 80% EtOAc/hexanes to give the title compounds (28.9 g, 128 mmol) as a colorless liquid.

STEP 5: SODIUM (R)-2-METFfYLPENT-4-ENE-l-SULFINATE AND

SODIUM (S)-2~METHYLPENT-4~ENE- 1 -SULFINATE

A solution of (R)-2-((2-methylpent-4-en-l-yl)sulfonyl)pyrimidine and (S)- 2-((2-methy]pent-4-en-l -y])sulfonyl)pyrimidine (Example 647, Step 4) (28.9 g, 128 mmol) in MeOH (430 mL) was treated with MeONa (25 wt. % solution in MeOH, 29.2 mL, 128 mmol) at ambient temperature and the resulting solution was stirred for 3 h. The reaction was concentrated under reduced pressure and the residue was triturated with EtzO. The slurry was filtered though filter paper and the filter cake was rinsed with hexanes to provide crude products (21.7 g, 128 mmol) as a pale yellow solid, which were used for next step without any further purification.

STEP 6: (R)-2-METHYLPENT-4-ENE- 1 -SULFONAMIDE AND (S)-2- METHYLPE T-4-ENE-l -SULFONAMIDE

To a solution of sodium (R)-2-methylpent-4-ene-l-sulfinate and sodium (S)-2-methylpent-4-ene-l -sulfinate (Example 647, Step 5) (21.7 g, 128 mmol) in water (51 1 mL) was added potassium acetate (12.5 g, 128 mmol) and hydroxylamine-o-sulfonic acid (28.9 g, 255 mmol) successively at ambient temperature. Then the reaction was heated to 50 °C for 2 h. The reaction mixture was cooled to ambient temperature and stirred overnight. The reaction was extracted (2 ^χ 15% iPA/DCM) and washed (brine). The combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure to provide the title compounds (19.5 g, 1 19 mmol) as colorless oil, which were used for next step without further purification.

STEP 7: (R)-N,N-BIS(4-METHOXYBENZYL)-2-METHYLPENT-4-ENE-.l - SULFONAMIDE AND (S)-N,N-BIS(4-METHOXYBENZYL)-2- METHYLPENT-4-ENE-l -SULFONAMIDE

To a solution of (R)-2-methylpent-4-ene-l -sulfonamide and (S)~2~ methylpent-4-ene-l -sulfonamide (Example 647, Step 6) (19.5 g, 1 19 mmol) in 2- butanone (600 mL) were added KI (1.98 g, 11.9 mmol), anhydrous K2CO3 (66.0 g, 478 mmol), and PMBC1 (40.5 mL, 299 mmol) successively and the resulting solution was stirred at 80 °C overnight. The reaction was cooled to ambient temperature and filtered through Celite to remove inorganic solids. The filter cake was washed with DCM and the combined filtrates were concentrated. The residue was injected into a 330 g ISCO Gold column and purified by combi -flash, eluting with 0% to 25% EtOAc/hexanes to give the title compounds (39.7 g, 98.0 mmol) as a colorless oil.

STEP 8: (3R,4R)-1 -HYDROXY-N,N-BIS(4-METHOXYBE ZYL)-4- METHYLHEPT-6-ENE-3-SULFON AMIDE AND (3S,4S)-l-HYDROXY-N,N- BIS(4-METHOXYBENZYL)-4-METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3R,4S)-l -HYDROXY-N,N-BIS(4-METHOXYBENZYL)-4-

METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3S,4R)-i-HYDROXY-N,N- BIS(4-METHOXYBENZYL)-4-METHYLHEPT-6-ENE-3-SULFONAMIDE

To a solution of (R)-N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-l- sulfoiiamide and (S)-N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-l - sulfonamide (Example 647, Step 7) (4.50 g, 11.1 mrnol) in THF (25 mL) was added n-BuLi (2.5 M solution in hexanes, 4.68 mL, 11.7 mmol) at -78 °C dropwise. After the reaction mixture was stirred at -78 °C for 25 min, excess ethylene oxide was bubbled into the reaction for 15 min at the same temp. The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched (sat. aqueous NH Cl), extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S04) and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 20% to 60% EtOAc/hexanes to provide the products (4.00 g, 8.94 mmol) (dr = 2:3) as a colorless oil.

STEP 9: (3R,4R)-3-(N,N-BIS(4-METHOXYBE ZYL)SULFAMOYL)-4- METHYLHEPT-6-ENOIC ACID AND (3S,4S)-3-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-4-METHYLHEPT-6-EN01C ACID AND (3R ₅ 4S)-3-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-4- METHYLHEPT-6-ENOIC ACID AND (3S,4R)-3-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-4-METHYLHEPT-6-ENOIC ACID

and

To a solution of (3R.4R)- 1 -hy droxy-Ν,Ν -bis(4-methoxy benz l)-4- methylhept-6-ene-3-sulfonamide and (3S,4S)-1 -hy droxy-N,N-bis(4- methoxybenz d)-4-methylhept~6~ene~3~sulfonamide and (3R,4S)-1 -hydroxy -N,N- bis(4-methoxybenzyl)-4-methy{hept-6-ene-3-sulfonamide and (3 S,4R)-1 -hydroxy - N,N-bi8(4-rnethoxybenz>4)-4-methylhepi-6-ene-3-sulfonanii de (Example 647, Step 8) (4.00 g, 8.94 mmol), KBr (0.106 g, 0,894 mmoi), NaHCGs (5% w/w in water, 42.0 mL, 25.0 mmol), TEMPO (1.54 g, 9.83 mmol) in acetone (89 mL) was added NaCIO (6°.:· w/w in water, 12.2 mL., 9.83 mmol) at 0 ° C and the resulting reaction was vigorously stirred at the same temp for Ih. The reaction was concentrated under reduced pressure (water bath <10 C°), diluted (EtOAc and ice- cold IN aqueous HC1), extracted (2 * EtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was injected into a 80 g ISCO Gold column and purified by combi-flash, eluting with 25% to 100% EtOAc/hexanes to provide the title compounds (1.90 g, 4.12 mmol) as a colorless syrup.

STEP 10: (3R,4R)-METHYL-3-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)-4-METHYLHEPT-6-EN01C ACID AND (38,48)-ΜΓ^^.-3-(Τ\ ^τ ,Ν-ΒΙ8(4-ΜΕΤΗΟΧΥΒΕΝΖΥΕ)8υΕΡΑΜΟΥ Ε)-4- METHYLHEPT-6-ENOIC ACID AND (3R,4S)-METHYL-3-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-4-METHYLHEPT-6-ENOIC ACID AND (3S,4R)-METHYL-3-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-4- METHYLHEPT-6-ENOIC ACID

To a solution of (3R,4R)-3-(N,N-bis(4-melhoxybenzyl)sulfanioyl)-4- methylhept-6-enoi c aci d and (3 S , S)-3-(N,N-bis(4-methoxybenzyl)siilfarnoyl)-4- methylhept-6-enoic acid and (3R,4S)-3-( ,N-bis(4-methoxybenzyl)sulfamoyl)-4- methylhept-6-enoic acid and (3S,4R)-3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4- methylhept-6-enoic acid (Example 647, Step 9) (595 mg, 1.29 mmoi) in MeOH (6.4 mL) was added SOCh (188 μΕ, 2.58 mmoi) at 0 °C dropwise. Then the reaction was allowed to warm to ambient temperature. The reaction was diluted (EtOAc and ice-cold water), extracted (2 EtOAc), and washed (saturated aqueous NaHCQs and brine). The combined organic layers were dried (Na2SC>4) and concentrated under reduced pressure to provide crude products, which were used for next step without any further purification.

STEP 11 : METHYL ((lS^'R^T'S^'E l'SamH-CHLORO-T-HYDROXY- 11 '-METHYL- 13', 13'-DIOXlDO- 15'-OXO-3,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]QXA[13]TffiA[U4]DL^

[8, 16, 18,24]TETRAEN] - 12'-YL)ACETATE OR METHYL

((l S,3'R,6'R,7'S,8¾,irR,12'S>6-CHL()R()-7'-HYDR()XY-l l'-METHYL-

13', 13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8, 16, 18,24]TETRAEN] - 12'-YL)ACET ATE OR METHYL

((1 S,3'R,6'R,7'S,8'E,11 ^, R ₅ 12'R)-6-CHLORO-7'-HYDROXY-l 1"-METHYL- 13^13 ^, -DIOXroO-15 ^, -OXO-3 ₅ -DfflYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^, - | 2u jOXA| 1 ΉΊ ! !1Λ| Ι . Ι 4 |! !Λ/.νΓ!·Ί < Λ( ^' Υ(·|.ΟΙ i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |P1-M ^' .\C<)SA [ 8,16,18,24 jTETRAEN] - 12'-YL)ACETATE OR METHYL

((1 S,3'R,6'R,7'S,8'E, 1 l'S, 12'S)-6-CHLORO-7"-HYDROXY- 1 1 '-METHYL - i;r,13' IOXIDO-15'-OXO-:L4-DrHYDRO-2H~SPIRO[NAPHTHALENE-l ,22 ^! ~ [20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 12"-YL)ACET ATE One of the title compounds was prepared from (S)-6'-chloro-5-(((lR,2R)- 2 (S,E)-l¾-droxyhex-2-en-l-yl)cyclobutyl)methyl)-3V4,4

spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxyl ic acid (Intermediate AA12A) by a procedure analogous to that described in Example 571 , Step 7 through 9, replacing (3R,4S)-4-methoxy-N,N-bis(4-methoxybenzyl)-2- methylhept-6-ene-3-sulfonamide and (3S,4R)-4-methoxy~N,N~bis(4- methoxybenz 'i)-2-methylhept-6~ene-3~sulfonamide] or [(3R,4R)-4-methox '-N,N- bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfonamide and (3 S,4S)-4- methoxy-N,N-bis(4~methoxybenz} _' )-2-methylhept-6-ene-3-sulfonamide in Step 7 with (3R,4R)~nietliyl-3~(N,N-bis(4-methoxybenz 'l)sulfamoyl)-4-methylhept-6- enoic acid and (3S,4S)-me1hyl-3-(N,N-bis(4-rnethoxybenzyl)sulfamoyl)-4- methylhept-6-enoic acid and (3R,4S)-methyl-3-(N,N-bis(4- methoxy benzy l)s ulfamoyl)-4-methy lhept-6-enoic aci d and (3 S ,4R)-methy S -3 - (N,N-bis(4-me1hoxybenzyl)sulfamoyl)-4-methylhept-6-enoic acid (Example 647, Step 10). The crude products were purified by reversed phase preparatory' HPLC (Gemini™ Prep Ci8 5 um column; Phenomenex, Torrance, CA; gradient elution of 45% to 70% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compound as the fastest eluting isomer as a white foam. ¾ NMR (500 MHz, CDCh) δ ppm 7.97 (br, s, 1 H), 7,70(d, J=8.4Hz, 1 ! ! }. 7.19 (dd, ,/ H. I . 2.20 Hz, 1 H), 7.10 (d, J=2.20 Hz, 1 H), 7.04 (d, ./ 1 5.4 ! Hz, 1 H), 6.98 - 6.87 (m, 2 H), 6.04 - 5.98 (m, ! H), 5.73 (dd, 15.04. 7,95 Hz, 1 H), 4.86 (br. s, 1 H), 4,25 (dd, ./ 6.72. 4.77 Hz, 1 H), 4. 15 - 4,04 (m, 2 H), 3.88 - 3.71 (m, 4 H), 3.71 - 3.58 (m, 1 H), 3.29 (d, J=14.67 Hz, 1 H), 3.07 (dd, J=16.87, 7.58 Hz, 1 H), 2.84 - 2.63 (m, 3 H), 2,52 - 2.39 (m, 1 H), 2,33 (t,■/ 8.80 Hz, 1 H), 2, 15 - 2.07 (ra, 2 H), 2,06 - 1.64 (m, 9 H), 1.44 (t, ,/ 1 2.72 Hz, 1 H), 1.09 (d, J=6.60 Hz, 3 H); m/z (ESI, +ve ion) 657.2 (M+H) ⁺ .

EXAMPLE 648, (1 S,3¾,6'R,7'S,8'E, I l 'S,12'R.)-12'-BENZYL-6-CHLORO-7'- HYDROXY- 1 1 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- l,22' 20]OXA|;i3]THlA[l,14]DIAZATETRi CYCLO[14.7.2.0 - ⁶ .0 ¹⁹ - ²⁴ ]

ΡΕΝΤΑ( 08Α 8,16,18,24]ΤΕΤΕ _^ ΑΕΝ |-15'-0ΝΕ 13',13'-DIOXIDE OR (18,3¾ Κ^'8,8Έ/ΓίΈ^2'8)-Γ2'-ΒΕΝΖΥΕ 3-α-ΪΙ.Ο Ο-7'-ΗΥΟΚΟΧΥ-11'- METHYL-S^-DIHYDRO-ffl^S^SPIROI APHTHALENE-l^^- |20jO.\A| ΠΙΊ I Ι1Λ| 1.14|Di Α/.ΥΠΊ ^' ΗΛ(ΎΟ.ϋΙ i 4.7.2 U · ^, '.ί ^)|: " ¹ 1

PENTACOSA[8,16,l 8,24]TETRAEN]-15'-ONE 13'.13'-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,I rR,12'S)-12'-BENZYL-6-CHLORO-7'-HYDROXY-l 1 ^* - METHYL~34-DIHYDRO-2H,]5'H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[13]TH1A[1 4]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16 ₅ 18,24]TETRAEN]-15'-ONE 13",13-DIOXIDE OR

(Ιβ^'Κ,ό'Κ,Τ'β,δΈ,ΙΙ'Κ,Ι^β^Ι^-ΒΕΝΖΥΕ -ό-ΟΗΕΟΚΟ-Τ'-ΗΥΟΚΟΧΥ-ΙΙ'- METHYL-3,4-D1HYDR0-2H;15'H-SP1R0[NAPHTHALE E-1,22'- [2()iOXA|13]THIA|;i 4]DIAZATETRACYCLO[14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]

PE -15'-ONE 13',13"-DIOXIDE (ISOMER !)

STEP I . (3R,4R)-N,N-BIS(4-METHOXYBENZYL)-3-METHYL- 1 - PHENYLHEX-5-ENE-2-SULFON AMIDE AND (3S,4S)-N,N-BIS(4- METHOXYBENZYL)-3-METHYL-l-PHENYLHEX-5-ENE-2- SULFONAMIDE AND (3S,4R)-N N-B1S(4-METH0XYBENZYL)-3~METHYL- 1 -PHENYLHEX-5-ENE-2-SULFONAMIDE AND (3R,4S)-N,N-BIS(4- METHOXYBENZYL)-3-METHYL-l -PHENYLHEX-5-ENE-2- SULFONAMIDE

To a solution of (R)-N,N-bis(4-methox benzyl)-2-methylpent-4-ene-l- sulfonaraide and (S)-N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene- 1 - sulfonamide (Example 647, Steps 7) (796 mg, 1.97 mmol) in THF (6.5 ml.) was added n-BuLi (2.5 M solution in hexanes, 0.79 mL, 1.97 mmol) at ^~ 78 °C. After the reaction was stirred at the same temperature for 15 min, a solution of benzyl bromide (0.468 ml,, 3.95 mmol) in THF (2.5 mL) was added and the resulting solution was stitrred -78 °C for 1 h. Then the reaction was allowed to warm to ambient temperature and stirred o vernight. The reaction was quenched (saturated aqueous NFLtCl), extracted (2 ^χ EtOAc), and washed (brine). The combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was injected into a 24 g IS CO Gold column and purified by combi-flash, eluting with 0% to 20% EtOAc / hexanes to provide the title compounds (859 mg, 1.74 mmol) as a colorless liquid.

STEP 2. (1S,3'R,6 ^! R,7'S,8'E, 1 l'S,12'R)-12'-BENZYL-6-CHLORO-7'- HYDROXY- 1 1 '-METHYL-3 ,4-DIHYDRO-2H, 15 'H-SPIRO [NAPHTH ALENE- L22' 20]OXA[i:^THIA[l,14]DIAZATETRACYCLO[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ] PENTAC0SA 8,16,18,24]TETRAEN j-15'-0NE 13',13'-DIOXIDE OR (18,3¾ Κ,7'8,8Έ/ΓίΈ^2'8)-Γ2'-ΒΕΝΖΥΕ 3-α-ΪΙ.Ο Ο-7'-ΗΥΟΚΟΧΥ-1 1 '- METHYL-S^-DIHYDRO-ffl^S^SPIROI APHTHALENE-l^^- | 2ϋ |0.\Λ| Ο ΙΊ ί Ι1Λ| I„ I 4 |ΠίΛ/.ΥΠ Ί ^' Η Λ(ΎΟ.ϋΙ i 4.7.2 U · ^, '.ί ^{) | :} " ¹ 1

PENTACOSA[8,16,l 8,24]TETRAEN]-15'-ONE 13'.13'-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E, 1 rR,12'S)-12'-BENZYL-6-CHLORO-7'-HYDROXY-l 1 ^* - METHYL~3 4-DIHYDRO-2H,] 5'H-SPIRO[NAPHTHALENE-l ,22 ^! - [20]OXA[13]TH1A[1 4]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13",13 -DIOXIDE OR

(Ιβ^'Κ,ό'Κ,Τ'β,δ'Ε,Ι Ι'Κ,Ι^β^Ι^-ΒΕΝΖΥΕ-ό-ΟΗΕΟΚΟ-Τ'-ΗΥΟΚΟ� �Υ-Ι Ι'- METHYL-3,4-DlHYDRO-2H;i5'H-SPlRO[NAPHTHALE E-l,22'- [20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]

PENTACOSA[8 ₅ 16,18,24]TETRAEN]-15'-ONE 13',13"-DIOXIDE (ISOMER !)

One of the title compounds was prepared from (S)-6'~chloro-5~(((lR,2R)~ 2-((S,E)-14tydroxyhex-2-en-l-yl)cyclobutyl)methyl)-3',4,4

spiro [benzo [b] [ 1 ,4] oxazepme-3 , Γ-naphthal ene] -7-carboxy lie acid (Intermediate AA12A) by a procedure analogous to that described in Example 571, Step 7 through 9, replacing (3R,4S)-4-methoxy-N,N-bis(4-methoxybenzv'l)-2- methylhept-6-ene-3-sulfonamide and (3S,4R)-4-methoxy-N,N-bis(4- methoxybenz 4)-2-methylhept~6~ene~3~sulfonamide] or [(3R,4R)-4-methoxy-N,N- bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfonarnide and (3 S,4S)-4- methoxy-N,N-bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfon amide in Step 7 with (3R,4R)~N,N~bis(4-methoxybenz} )-3-m.ethyl~l-phenylhex-5-ene-2- sulfonamide and (3S,4S)-N,N-bis(4-methoxybenzyl)-3-methyl-l-phenylhex-5- ene-2-sulfonamide and (3S,4R)-N,N-bis(4-methoxybenzyl)-3-methyl-l- phenylhex-5-ene-2-sulfonamide and (3R,4S)-N,N-bis(4-methoxybenz>'l)-3- methyl-l -phenylhex-5-ene-2-sulfonamide (Example 648, Step 1). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 80% MeCN in water, where both solvents contain 0. 1% TFA, 30 min method) to provide a mixture as the faster eluting peak, which was further purified by chiral Thar 80 SFC (IC 30 x 250 mm column, Phenomenex, Torrance, CA; using 40 g/min MeOH(20mM ammonia) + 40 g/min CO2, 50% co-solvent at 80g/miii, isocratic) to pro vide one of the title compounds as the faster eluting isomer. Ή NMR (400 MHz, CDCI3) δ ppm 7.59 (d, J=8.61 Hz, 1 H), 7.24 - 6.97 (m, 9 H), 6.87 - 6.74 (m, 1 H), 5.70 (m, 1 H), 5.60 - 5.39 (m, 1 H), 4.41 (m, 1 H), 4.06 (m, 3 H), 3.57 - 3.19 (m, 3 H), 2.95 (m, 1 H), 2,69 (m, 2 H), 2.37 - 2.28 (m, 2 H), 1.90 - 1,52 (m, 13 H), 1.17 - 1.04 (m, 3 H); m/z (ESI, +ve ion) 675.2 (M f i>

EXAMPLE 649. (18,3Έ,6'¾7Έ,8Έ,1 l'S,12'R)-12'-BENZYL-6-CHL()RO-7'- HYDROXY-11 '-METI-IYL-3,4-DIHYDRO-2H,15TI-SPIRO[NAPHTHALENE- L22' 20]OXA[i:^THIA[l,14]DIAZATETRACYCLO[14,7.2.0 ³ -^0 ¹⁹ - ²⁴ ] PENTACOSA8,16,18,24]TETRAENj-15'-ONE 13 ^! ,13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R ₅ 7 ^, S,8Έ,ll ^, R,12 ^, S)-12 ^, -BENZYL-6-CP^LORO-7 ^, -HYDRO Y-ll ^, - METHYL-3,4-DIHYDRO-2H,15^SPIRO|NAPHTHAL-ENE-l,22'- |2ίί|<)ΧΛ| ΠΙΊ Η1ΛΙ l.l4|! !A/.Vn:i ^' RA( ^' YCI.()l i 4.7.2.0 · ^, '.ί) ^|: " ¹ 1

PENTACOSA[8,16,l 8,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3¾,6'R,7^,8^Il'R,12^)-12 ⁱ -BENZYL-6-CHLORO-7'-I-IYDROXY-ir- METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- |;20]OXA[13iTHL4[l,14jDIAZATETRACYCLO|14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXTDE OR lS,3 ^, ,6 ^ί R,7 ,8Έ,llΈ,12'S)-12 ^, -BENZYL-6-CHLO O-7'-HYD OXY-lr METHYL-3,4-DlHYDRO-2H,I5'H-SPlRO[NAPHTHALE E-l,22'- [20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]

PENTACOSA[8,16,l 8,24]TETRAEN]-15'-ONE 13',13"-DIOXIDE (ISOMER 2)

One of the title compounds was obtained as the second (slower) eluting isomer from chiral SFC in Example 648. Ή NMR (500MHz, CDCb) δ ppm 8,55 (br. s., 1H), 7.74 - 7.64 (m, i l l ). 7.36 - 7.31 ί η ·. 4H), 7.26 - 7.23 (m, M l ). 7.21 - 7.14 (m, 2H), 7.09 id. ./ 2.2 Hz, 1H), 6.96 (d, ./ 8. ! Hz, 1H), 6.72 (m, 1H), 6.01 (m, 1H), 5.72 - 5.55 (m, 1H), 4.20 - 3.99 (m, 3H), 3,76 - 3.55 (m, 3H), 3.49 - 3,34 (m, I I I ). 3,06 (dd, ./ 7.6. 14.9 Hz, I I I). 2.84 - 2.68 (m, 2H), 2,63 (br. s,, IH), 2.50 (m, 11 1 ). 2.32 - 2.18 (m, 2H), 2.11 (s, 3H), 2.08 - 1.55 (m, 9H), 1.52 - 1.43 (m, H I ). 1.05 (d, ,/ 6.4 Hz, 1H); m (ESI, +ve ion) 675.2 (M+H) ⁺ .

EXAMPLE 650. (1S,3'R,6 ^! R,7'S,9'Z,1 l'S,12'R)-6-CHLORO-12'- (CYCLOPROPYLMETHYL)-7'-HYDROXY- 11 '-METHYL-3,4-DIHYDRO- 2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ¹⁹ ^ ⁴ ]PENTACOSA

[9,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,9'Z,1 rR, 12'S)-6 ;HI RO-r2'^CYCIi3PROPYLMETHYL)-7'- HYDROXY- 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTHALENE- 1,22'~

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥΠ:ΤΗΑ(ΎΠ.ΟΙ i 4.7.2 U · ^, '.ί) ^|: " ¹ |Pl-N i ^' AC<)SA [9,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE OR

(lS ¾ )'R ^,9'Z,ll'RJ2¾)-6-CHIX)RO-12'-(CYCLOPROPYLMEmYL)-7'- HYDROXY - 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- L22'"

[20]OXA[13]THIA[1 4]DIAZATETRACYCLO[14,7.2,0- ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9, 16, 18,24]TETRAEN] - 15'-ONE l.T.13 '-DIOXIDE OR

(lS,3'R,6 7 ^, S,9 ^, Z l^J2'S)-6 mORO-12 ^! ~(CYCLOI¾OPYLMETHYL)"7'- HYDROXY-11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[9, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

One of the title compounds was obtained as the second (slow er) eluting isomer from reversed phase preparatory HPLC in Example 380. ^" Ή NMR

(500MHz, CDCb) δ ppm 7.72 (d, J=8.3 Hz, IH), 7.31 - 7.25 (m, 1H), 7.23 - 7.15 ins. IH), 7. ! (i (d../ 2.2 Hz, 1H), 7.00 - 6.89 (m, 1H), 6.84 ins. IH), 6.11 (m, IH), 5.81 (m, 1H), 4.38 - 4,19 (m, 1H), 4.19 - 4.03 (m, 2H), 3.85 - 3,63 (m, 3H), 3.35 - 3.10 (m, 2H), 2.92 - 2,72 (m, 3H), 2.52 - 2.30 (m, 2H), 2.27 - 1,76 (m, 9H), 1.75 - 1.57 (m, 2H), 1.47 (m, III).1.20 - 1.04 ίη·.4H), 0.66 - 0.55 (m, 2H), 0.26 (m, 1H), 0.18-0.05 {in. III).

Example 651. (lS,3'R,6 ^, R,7'S,8 ^, E,12 ^, S)-6-CHLORO-12 ^f -((2R)-2-HYDROXY-3- ME ^r fflOXYPROPYL)-7'-MEraOXY-3,4~DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| i 1 ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ^; ".O ¹ " ^M |PH\ i ACOSA [8,16,18,24]TETiL4E ]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S.8 ^, E.12 ^, R)-6-CHLORO-12 ^, -((2R)-2-HYDROXY-3- METHOXYPROPYL)-7'-METHOXY-3 ,4-DIHYDRO-2H, 15 Ή-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THL4[1 4]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8 ₅ 16,18,24]TETRAEN]-15"-ONE 13',13'-DIOXIDE

STEP 1 : (S)-6'-CHLORO-5-(((l R,2R)-2-((S,E)-l -HYDROXY-6-

SULFAMOYLHEX-2-EN-l-YL)CYCLOBU L)METHYL)-3',4,4',5- TETRAH DRO-2H,2 ^! H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'- NAPHTHALENEl -7-C ARBOXYLIC ACID

To a 100 mL flask was added (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l - hy droxyhex-2-en- 1 -y l)cy clobuty l)me1hy l)-3 ', ,4',5 -tetrahy dro-2H,2 ^! H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (Intermediate AA12A; 500 mg, 0.980 mmol), pent-4-ene-l -sulfonamide (Intermediate EE 19; 878 mg, 5.88 mmol), and DCE (14 mL). The solution was sparged with argon for 15 min at which time Hoveyda-Grubbs 11 (61.4 mg, 0.098 mmol) was added as a 0.2 mL. solution in DCE at rt. The mixture was stirred at ft and sparged with argon (the vial was vented) for 2 h. The reaction mixture was then bubbled with air for 5 minutes and filtered to separate the insoluble sulfonamide homodimer. The crude product was purified on a Combiflash® (24g gold S1O2 column), eluting with 50% - 90% EtOAc in heptanes + 0.2% AcOH) to give (S)-6'-chloro- 5-(((lR,2R)-2-((S,E)-l-hydroxy-6-sulfanioylhex-2-en-l-yl)cyc lobutyl)methyl)- 3',4,4',5-tetrahydro-2h,2'h-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carbox lic acid (439 mg, 0.745 mmol, 76 % yield) as a white solid.

STEP 2: (1 S,3 ^! R,6'R,7 ^, S,8'E)-6-CHLORO-7 ^! -HYDROXY-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [N APHTH ALEN E- 1 ,22' - [20;|OXA[13]THIA[1 ,14]DIAZATCTRACYCLO[ 147.2 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

To a 1 L flask containing (S)-6'-chloro-5-(((lR,2R)-2-((S,E)- l-hydroxy-6- sidfamoylhex~2-en~l~yl)cyclobutyS^

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (from Step I , 439 mg, 0.745 mmol), which was previously dried by azeotroping twice with 10 mL of toluene, was added N,N-dimethylpyridin-4-amine (155 mg, 1 .27 mmol) and 400 ml, of DCM. The reaction mixture was cooled to 0 °C at which time N- (3-dimethylarninopropyl)-N'-ethylcarbodiimide hydrochloride (286 mg, 1.49 mmol) was slowly added. The reaction was then stirred at rt for 18 h. The mixture was quenched with 200 mL of IN HC1 and extracted with 600 mL of EtOAc. The organic layer was dried over anhydrous Na?.SQ4, filtered, and concentrated by rotary evaporation. The crude product was purified on a

Combiflash® (24g gold S1O2 column), eluting with 30% - 70% EtOAc in heptanes, to give (l S,3'R,6'R,7'S,8'E)-6-cliloro-7 ^, ~hydroxy-3,4~dihydro-2H, 15'H~ spiro I naphthalene- 1 ,22'- [20]oxa[ 13] thia[ l , 14]diazate1r^

n]-15'-one 13', 13 ^! ~dioxMe a white solid. ^! H NMR (500MHz, CD3OD) δ 7.75 (d, J=8.3 Hz, IH), 7.20 (dd, J=2.9, 7.6 Hz, IH), 7.12 (d, J=3.7 Hz, IH), 7.00 (dd, ./ 1 .7. 8.8 Hz, IH), 6.94 i d. ./ 8.3 Hz, IH), 6.88 (d, ,/ 2.2 Hz, I H), 5.95 - 5.86 (m, IH), 5,70 (dd, ./ 8. H. 15.9 Hz, I H), 4.25 - 4. 19 (ra, IH), 4.22 (dd, J=4.4, 8.6 Hz, IH), 4, 14 - 4.06 (m, 3H), 4.14 - 4.05 (m, 3H), 3, 84 (d, ./ 1 .2 Hz, IH), 3.68 i d . J=15.2 Hz, IH), 3.09 (dd, J=8.3, 15.9 Hz, IH), 2.87 - 2.74 (m, 2H), 2.45 - 2.30 (m, 3H), 2, 14 - 1.88 (m, 5H), 1 .86 - 1.69 (m, 4H). m/z (EST, +ve ion) 571.2 \ \\ - U ) . STEP:3 ( l S,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E)-6-CHLORO-7 ^, -METHOXY-3 ₅ 4-DIHYDRO-

2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ¹⁹ ^ ⁴ ]PENTACOSA [8 ₅ 16.18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

To a 100 mL flask was added (lS^T^T ^S.S^-e-chloro-T'^droxy- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazatetnK^

n]-15'-one ! 3'J 3'~dioxide (Step 2, 138 mg, 0.242 mmol), THF (10 ml.), and sodium hydride (29.0 mg, 1.208 mmol). The reaction was stirred at rt for 15 min at which time Mel (0.092 mL, 1.480 mmol) was added. The reaction was stirred at rt for 2 h at which time additional sodium hydride (58.0 mg, 2.42 mmol) and Mel (0.092 mL, 1.480 mmol) were added and the reaction was stirred at rt for an additional 16 h. The reaction was quenched with 100 mL of satd NL C! and extracted with 400 mL of EtOAc. The organic layer was dried over a?.S04, filtered, and the solvent was removed by rotary evaporation. The crude product was purified on a Combiflash® (12g gold SiC column), eluting with 10% to 50% EtOAc in heptanes, to give (1 S,3'R,6'R,7'S,8'E)-6-chioro-7'-methoxy-3,4-dihydiO- 2H, 15'H-spiro| naphthalene- 1 ,22 ^, - [20]oxa[13]thia[ l, 14]diazatetτacyclo[147.2 ³ · ⁶ .0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13', 13'-dioxide (120 mg, 0.205 mmol, 85 % yield) as an off white solid. ¾ NMR (400MHz, CDCb) δ 8.02 (s, 1H), 7.70 (d, J=8.6 Hz, i l l ). 7.19 (dd, ./ 2.2. 8.5 Hz, H i ). 7.10 (d, ./ 2.2 Hz, 1H), 6.97 - 6.87 (m, 2H), 6.84 (d, ,/ i . Hz, i l l ). 5.88 (ddd, ,7=5,2, 8.1, 15.1 Hz, ! ! ! ). 5.53 aid . ,/ 8. 7. 15,4 Hz, 1 H), 4.30 (ddd, J=4.8, 9.8, 15,0 Hz, I H i.. 4.15 - 3.98 (m, 2H), 3,84 - 3.69 (m, 2H), 3.67 (dd, .7=3.8, 8.7 Hz, 1H), 3.36 - 3.21 (m, 2H), 3.25 (s, 3H), 3.01 (dd, ,/ 10.3. 15.2 Hz, I I I ). 2,87 - 2.64 (m, 2H), 2.52 - 2.29 (m, 3H), 2,25 - 1.91 (m, 5H), 1 .88 - 1.75 (ra, 3H), 1.71 - 1.60 (m, 2H), 1.41 (t, «7=12.4 Hz, 1H). m/z (ESI, +ve ion) 585,0 (M+H) ⁺ . STEP 4: ( lS,3¾ R,7'S,8'E,12'S)-6-CHLORO-12'-((2R)-2-HYDROXY-3- METHOXYPROPYL)-7'-METHOXY-3,4-DIHYDRO-2H,15H- SPIRO[N APHTHALENE-1 ,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~15'~0NE 13', 13'-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'E,12'R 6-CHLORO-12'-((2R 2-HYDROXY-3- ME ^r fflOXYPROPYL)-7'-MEraOXY-3,4~DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

| 20 i()X A| ΐ : ΐ Η1 Λ| Κ, ! | ί)!Λ/Λ ! : ΓΗ.Λ( ^' Χ)Ι 1 17.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8,16,18,24] TETRAEN] - 15 '-ONE 13',13'-010ΧΓΟΕ

To a solution of (18,3¾,6¾,7'8,8 ^! Ε)-6-οΜθΓθ-7'-ιη6ΐ1ιοχν-3,4-(1ί1ιν(ΐ� �θ-2Η,15Ή- spiro[naphthalene-l,22 ^f -

[20]oxa[13]thia[l,14]diazatetracyclo[14;7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18 n]-15'-one 13',13'-dioxide (from Step 3, 42 mg, 0.072 mmol) in THF (2 mL) under Ar in -50 °C bath was added "BuLi (0.201 mL, 2.5 M in hexanes, 0.502 mmol, Sigma-Aldrich Chemical Company, Inc.). The solution was allowed to stir in the - 50 °C bath for 30 min. To the mixture was added (R)-(-)-glycidyl methyl ether (0.202 mL, 2.297 mmol, 97%, Sigma-Aldrich), the resultant mixture was allowed to warm with the bath to 0 °C over 45 min. To the reaction mixture was added saturated aqueous NH ₄ C1 (1.0 mL), the resulting mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 5 mL). The organic layers were combined. After removal of organic solvents under reduced pressure, the residue was re- dissolved in DMSO (2 mL) and subjected to reverse phase preparatory HPLC (Gemini™ Prep CI 8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 10% MeCN in water to 90% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA) to provide one of the title compounds as the first eluting fraction as a white foam, ^] H NMR (400 MHz, CDCh) δ 8.03 (s, 1H), 7.63 - 7,76 (m, IH), 7.19 (dd, «/=8.51, 2,05 Hz, 1H), 7.10 (s, I H i. 6.81 - 6.97 (m, 2H), 5.82 - 5.96 (m, 1H), 5.53 (dd, J=15.16, 9.10 Hz, IH), 4.49 (d, J=9.59 Hz, 1H), 4.25 - 4.37 (m, I H), 3.99 - 4.17 (m, 2H), 3.56 - 3.89 (m, 3H), 3.50 (dd, J=9.59, 3,52 Hz, I H), 3.33 - 3.46 (m, 4H), 3.1 8 - 3.33 (m, 3H), 2.90 - 3.08 (m, IH), 2.66 - 2,88 (m, 2H), 2.15 - 2.55 (m, 5H), 1.54 - 2, 12 (m, 10H), 1.20 - 1.47 (m, 3 H). m/z (ESI, +ve ion) 673.1 (M+H) ⁺ .

EXAMPLE 652. (1 S ₅ 3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-12 ^, -((2R)-2-HYDROXY-

3-METOOXYPROPYL)-7'-METOOXY-3,4-DTHYDRO-2H,15'H- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ⁱ⁴ ]PE TACOSA

[8, 16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E, 12 ^, R)-6-CHLORO-12 ^, -((2R)-2-HYDROXY-3-

ME ^r fflOXYPROPYL)-7'-MEraOXY-3,4~DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- i .22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in the synthesis of Example 651. ¾ NMR (400 MHz, CDCh) δ 8.06 (s., IH), 7.60 - 7.88 (m, IH), 7.14 - 7.26 (m, IH), 6.87 - 7.11 (m, 3H), 5.73 - 5.93 (m, IH), 5.46 (dd, ./ 1 5.65. 8.02 Hz, IH), 4.02 - 4.19 (m, 2H), 3.99 (d, 3.52 Hz, IH), 3.99-3, 87(ra, IH), 3.45 - 3.68 (m, 3H), 3,22 - 3.44 (m, 6H), 2.70 - 2.86 (m, 2H), 2,64 (s, IH), 2,46 (ni, IH), 2.25 -1.38 (m, 19 H). m/z (ESI, +ve ion) 673.1 { M i l ) EXAMPLE 653. (1 S,3'R,6'R,7'S,8'E,i rS, 12'S)-6-CHLORO-7'-HYDROXY-i r- METHYL- 12'-PHENYL-3 ,4-DIHYDRO-2H, 15 'H-SPIRO [NAPHTHALENE- 1 ">"><- ^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI M.T^.O'^.O'^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 -DIOXIDE OR

(IS^l^e'R 'S^'Ej rS/n^-e-CHLORO^'-HYD OXY-l l'-METHYL"^'- PHENYL-3,4-DIHYDRO-2H,15'H-SPIRO| NAPHTHALENE-L22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

STEP 1 : N,N-BIS(4-METHOXYBE ZYL)-l- PHENYLMETHANESULFONAMIDE B

The title compound was prepared from phenylmethanesulfonamide following a procediire similar to the one described for the synthesis of EEI2.

STEP 2: ( S,2S)-N,N-BIS(4-METHOXYBENZY )-2-METHYL-l - PHENYLPENT-4-ENE- 1 -SULFONAMIDE AND ( 1 R,2S)-N,N-BIS(4- METHOXYBENZ YL)-2-METHYL- 1 -PHENYLPENT-4-ENE- 1 -

SULFONAMIDE

To a -78 °C solution of N,N-bis(4-methoxybenzyl)-l- phenylmethanesulfonamide (1.47 g, 3.58 rnmol. Step 1) in THF (7.2 mL) under N? was added "BuLi (1.43 ml, 2.5 M in hexanes, 3.58 mmol) over 1.0 min. The mixture was allowed to stir in the -78 °C bath for 15 min. To the mixture was added (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (1.72 g, 7.15 mmol, prepared according to the procedure reported by Sigmaxi, M. S. el al. : J. Am. Chem. Soc, 2012, 134, 1 1408-11411) in one shot. After stirring in the bath for 2 min, the resulting mixture was removed from the cold bath and allowed to stir in ambient atmosphere for 40 min. The mixture was quenched with saturated aqueous NH4CI solution (10 ml,), diluted with water (10 mL) and extracted with EtOAc (3 x 18 mL). The organic layers were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column using 0-50% EtOAc/Hexanes as the eluent provided the title compound as a white solid.

STEP 3 : ( 1 S,2S)-2-METHYL- 1 -PHENYLPENT-4-ENE- 1 -SULFONAMIDE AND (1 R,2S)-2-METHYL- 1 -PHENYLPENT-4-ENE- 1 -SULFONAMIDE.

The title compounds were prepared as a mixture from (1 S,2S)-N,N-bis(4- methoxybenzyl)-2-methyl- 1 -phenylpent-4-ene- 1 -sulfonamide and ( 1R,2S)-N,N- bis(4-methoxybenzyl)-2-methyl-l-phenylpent-4-ene- 1 -sulfonamide (Step 2) following a procedure similar to the one described for the synthesis of EE17 (Step 2). STEP 4: (3S)-6 ^* -CHLORO-5-(((lR ₅ 2R)-2-((lS,2E,5S ₅ 6S)-l-HYDROXY-5- METHYL-6-PHENYL-6-SULFAMOYL-2-HEXEN-1- YL)CYCLOBUTYL)MEraYL)-3^4,4',5"TETRAHYDRO-2'H~SPIRO[L5" BENZOXAZEPINE-3,l'-NAPHTHALENE|-7-CARBOXYLI C ACID AND (3S)-6"-CIiLORO-5-(((lR,2R)-2 (l S,2E,5S,6R)-l-IiYDROXY-5-MET YX-6- PHENYL-6-SULFAMOYL-2-HEXEN-l-YL)CYCLOBUTYL)METHYL)- 3' ₅ 4 ₅ 4' ₅ 5.TETR HYDRO-2'H-SPIRO[L5-BENZOXAZEPINE~3;r- NAPHTHALENE] -7-C ARBOXYLIC ACID

A solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Intermediate AA1 1 A, 350 nig, 0.748 mmol) and (l S,2S)-2-methyl-l-phenylpent-4-ene-l- sulfonamide and (lR,2S)-2-methyl-l-phenylpent-4-ene-l-sulfonamide (Step 3, 384 mg, 1.60 mmol) in 1 ,2-dichloroethane (10.7 mL) was purged with Ar for 20 min at rt. To the mixture was added Hoveyda-Grubbs catalyst 2nd generation (47 mg, 0.075 mmol, Sigma- Aldrich Chemical Company, Inc.). ^' The mixture was purged with Ar for 5 mm, sealed under Ar balloon, and then placed into 47 °C bath. After stirring at 47 °C for 1.5 h, the mixture was cooled to rt, and purged with air for 5 min. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with Q-100% EtOAc/Hexanes (EtOAc contained 0.1% HOAc) provided the title compounds as white solid.

STEP 5: (1 S,3'R,6'R,7'S,8'E, 1 1 'S, 12 ^* S)-6-CHLORO-7 ^* -HYDROXY-l 1 '- METHYL- 12'-PHENYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTH ALENE- 1 ,22'-

| 20 |() Λ| I 31 1 HI Λ| I , N | ΟΙΛ/.\ Π·. E R.AC V C ^' E C)i 1 4 7.2 ϋ ^{; ί} '.ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13 3 '-DIOXIDE OR

(lS,3¾,6 ^! R;7^,8T,l l'S 2'R)-6-CHL()R()-7'-I-IYDR()XY-l l'-METHYL-12'- PHENYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

To a solution of (38)-6'-ο1ι1θΓθ-5-(((1Κ.2Κ)-2-((18,2Ε,58.68)-1½ώ· θ5-γ- 5-methyl-6-phenyl-6-sdfamoyl-2-hexen-l-yl)cyclobutyl)methyl) -3',4,4',5- tetrahydro-2'h-spiro[l ,5-benzoxazepine-3, -naphthalene]-7-carbox\'lic acid and (3S)-6 ^, -chloro-5 ((lR,2R)~2"((lS,2E,5S,6R)~l4iydroxy-5-methyl-6-pheny sulfamoyl-2-hexen-l -yl)cyxlobutyl)met^

benzoxazepme-3,.r-naphthalene]-7-carboxylic acid (280 rag, 0.412 mmol, Step 4) and 4-(dimethylamino)pyridine (151 mg, 1.237 mmol, ZZ - Alfa Aesar) in CHCb, was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (198 mg, 1.03 mmol, Thermo Fisher Scientific) at rt. The mixture was allowed to stir at rt for 72 h. After removal of organic sol vents under reduced pressure, the crude product was re-dissolved in DMF (5 mL) and subjected to reverse phase preparatory HPLC (Gemini™ Prep CI 8 10 μηι column; Phenomenex, Torrance, CA; gradient elution of 10% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) to provide one of the title compounds as the first eiuting fraction as a white foam. ¾ NMR (400 MHz, CDCI3) 6 8, 16 (m, i l l ). 7.71 (d, ,/ 7.24 Hz, H ! ). 7.36 - 7.61 (m, 41 ! }. 7.26 (m, I H i. 7.19 (m, 1 H)7.10 (m , IH), 6.95 (m 21 1 ). 6,07 (d, «7=6.65 Hz, IH), 5.76 (dd, ./ 15.06. 8.22 Hz, IH), 5.43 (m, 1H), 4.34 (m, IH), 4.11 (m, 2H), 3.87 (d, ./ 14.67 Hz, 1H), 3.73 id. ./ 1 .69 Hz, IH), 3.25 (d, J=14.09 Hz, IH), 2.96 - 3.12 (m, 1H), 2,66 - 2.88 (m, 2H), 2.26 - 2.55 (m, 3H), 1,57 - 2.15 (m, 10H), 1 .19 - 1.48 (ra, 2H), 1.05 (d, ./ 6. -1 Hz, 3H). m/z (ESI, +ve ion) 661.1 (M+H) ¹ .

EXAMPLE 654. (18,3Ί¾.,6¾,7 ^! 8,8Έ,1 rS,12'S)-6-CHLORO-7 ^, -HYDROXY-l Γ- METHYL- 12'-PHE YL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [N APHTH ALENE- 1,22'-

|20!()ΧΛ| ΐ: ΐ!!1Λ| Κ4 |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA [8,16,18,24]ΤΕΤ¾ΑΕΝ]-15'-ΟΝΕ 13',13'-DIQX1DE OR

(lS,3¾,6 ^! R;7^,8T l'S,12'R)-6-CHL()R()-7'-HYDR()XY-ll'-METHYL-12'- PHENYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in EXAMPLE 653, Step 5. ¾ NMR (400 MHz, CDCh) δ ^] H NMR (400 MHz, CDCh) δ 8.22 (br. s., 1H), 7,69 (d, ,/ 8.6! Hz, 1H), 7.5 ! - 7.62 (rn, 2H), 7.39 - 7.51 (m, 3H), 7.08 - 7.24 (m, 3H), 6.94 - 7.01 (m, ill).5.97 (m, 1H), 5.74 (dd, J=15.75, 4.99 Hz, 1H), 5.09 (m., 1H), 4.05 - 4.27 (m, 3H), 3.40 - 3.74 (m, 3H), 2.72 - 2.87 (m, 3H), 2.55 (br. s., 2H), 2.37 (br, s., 1H), 2.00-2.14 (m, 3H ), 1.69 - 1.99 (m, 7H), 1.61 (m, 2H), 0.93 - 1.14 (m, 3H), m/z (ESI, +ve ion) 661.1 (M+H) ⁺

EXAMPLE 655. (1 S,3'R,6 ^! R,7'S,8'E,12'R)-6~CHLORO-12 ^! ~ETHYL-17 ^! ~ FLUORO-7'-HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- [20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

STEP 1 : (S)-6 ^f -CHLORO-8-FLUORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)-5- (((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL) -

3^4,4^5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B]|;i ,410XAZEPINE-3,r- NAPHTHALENE] -7-C ARBOXAMIDE

The title compound was prepared from (S)-6'-chloro-8-fluoro-5-(((lR,2R)- 2-((S,E)-l½droxyhex-2-eOT-l -yl)<^

spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Intermediate AA16) and (R)-hept-6-ene-3-sulfonamide (Intermediate EE21) following a procedure similar to the one described in Step 2 for the synthesis of Example 660.

STEP 2: (1S,3'R,6'R,7'S,8'E,12'R)-6-CHL0R0-12'-E™YL-17'-FLU0R0-7'- HYDROXY-S^-DIHYDRO^lS'H-SPIROnSiAPHTHALENE-l^^- | 2u jOXA| Ι ί ΙΊ ΗΙΛΙ l . l 4 |! !A/A r!-;i ^' R A( ^' YCI.()l i 4.7.2.0 · ^, '.ί ^{) | :} " ¹ |P1-M ^' AC<)SA [ 8,16,18,24jTETRAENj-15'-()NE 13'.13'-DIOXIDE.

The title compound was prepared from (S)-6'-chloro-8-fluoro-N-((R)-hept- 6-en-3-ylsulfon l)-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l - yl)(yclobut\d)memyl)-3',4,4^5-tetrahydro-2H,2'H-spiro[benzo[ b][l ,4]oxazepine- 3,r-naphthalene]-7-carboxamide (Step 1) following a procedure similar to the one described in Step 3 for the synthesis of Example 660. Ή NMR (400 MHz, CDCb) δ 8.30 (d, .1 H 80 Hz, III).7.66 (d, .1 86! Hz, 111).7.18 (dd, J=8.51, 2.25 Hz, 1H), 7.09 (d, j 215 Hz, 1H), 6.99 (d, J 7.2·! Hz, 1H), 6.72 (d, J=11.54 Hz, III). 5.61 - 5.79 (m, 2H), 4.05 - 4.20 (m, 3H), 4.01 (d, j 4.-0 Hz, 1H), 3.77 - 3.88 (m, HI).3.57 - 3.68 {in. III).3.23 (d, J=14.48 Hz, Hi).2.99 (dd, J=15.16, 8.51 Hz, ill).2,69 - 2.85 (m, 2H), 2.42 - 2.55 (m, !!!).2,34 (d, J 11.93 Hz, 2H), 1.86 - 2,21 (m, 8H), 1.59 - 1.77 (m, 4H), 1.41 (t, j=12.52 Hz, 1H), 1.25 - 1.32 {m, H), 1.18-1.25 (m, 3 H). m/z (ESI, +ve ion) 617.0 {M il) .

EXAMPLE 656. (lS,3 ^! R,6 ^, R,7'S,8'E,irS,12'R)-6-CHLORO-ll'-METHYL-7'-(2- (4-MORPHOI N X)ETHOXY)-12'^2,2,2-TRIFLlJOROETHYL)-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALEN E- 1 ,22 ^s -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14J.2 ³ ' ^{6 19i4} ]PE TACOSA

[8,16,18,24]TETRAEN]~15'~ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,ll ^, S,12 ^, S)-6-CHLORO-ll ^, -METHYL-7 ^, -(2-(4-

MORl ⁵ HOLINYL)ETHOXY)-12 ^, -(2,2,2~TRIFLUOROETHYL)-3,4-DlHYDRO- 2H, 15'H-SPIRO[N APHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18 ,24] TETR AEN] - 15 ' -ONE 13', 13 ' -DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z, 11 'S, 1 ^-e-CHLORO- 11 '-METHYL-7'-(2-(4-

MORPHOLIK¥ ^r L)ETHOXY)-12'-(2.2,2-T LUOROETHYL)-3.4-DIHYDRO- 2H, 15'H-SPIROjNAPHTH ALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATEI1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z,1 l'S,l 2'S)-6-CHLORO-l l'-METHYL-7 ^* -(2-(4-

MORPHOL;1NYL ETHOXY)-12'-(2,2,2-TUIFLUOROETHYL)-3,4-DIHYDRO- 2H,15'H-SPIR0[NAPHTHALENE-1,22'-

[20iOXA|;i3]THLA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24] TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE

To a 0 °C flask charged with (lS ₅ 3 ^! R,6'R,7'S,8'E,l l'S,12'R)~6-chloro-7'- hydroxy-i r-methyl-12 ^, -(2,2,2 rifluoroethyl)-3,4-dihydiO-2H,15'H- spiro I naphthalene- 1,22'-

[20] oxa[ 13] thi a[ 1 ,14] di azatetracy do [ 14 ,7.2, 0 ³ · ⁶ .0 ^|9 · ²⁴ ] pen tacosa[8,16, 18,24]teirae n]-15 ^" -one 13',13'-dioxide or (lS ₅ 3 ^r R,6'R,7'S,8'E,l l'S,12 ^! S)-6-chloro-7 ^! -hydroxy- i -methyl-12'-(2,2,2-trifluoroethyl)-3,4-dihydro-2H,15 ^, H-spiro[naphthalene- 1 ,22'-| 20 j oxa[ 13]thiaj 1,14] diazatetracy clo

[14.7.2.0 ⁵ - ⁶ .0 ¹⁹ ' ² ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide or

trifluoroethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,2 2'- [20]oxa[13]thia[l ,14]diazatefr^

n]-15 ^" -one 13',13'-dioxide or (lS,3 ^r R,6'R,7'S,8'Z,l l'S,12 ^! S)-6-chloro-7 ^! -hydroxy- l l'-niethyl-12 ^, ~(2,2,24rifluoroethyl)~3,4-dihydiO-2H,15 ^, H-spiro[naphthalene- l,22'-| 2()]oxa[13]thia[l,14]diazatetracyclo[ 14.7.2.0 ³ ' ⁶ ,0 ⁱ⁹ - ²⁴ ]

pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (30 mg, 0.045 mmol, Example 663) and sodium hydride (18 mg, 60% dispersion in mineral oil 0.45 mmol, Strem Chemicals, Inc.) was added DMF (1.3 mL). This mixture was allowed to stir in the ice bath under N ₂ for 15 min, to the mixture was added 4-(2~ bromoethyl)morpholine hydrobromide (62 mg, 0.23 mmol, Acceia ChemBio Inc.). The mixture was allowed to stir at rt for 2.0 h. To the reaction mixture was added saturated aqueous NH4G solution (1.0 mL) and water (4 mL). The resulting mixture was extracted with EtOAc (3 x5 mL). The organic layers were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0- 100% EtOAc/Hexanes (EtOAc contained 0.1 % HO Ac) provided the title compound as a colorless film. ¾ NMR (400MHz, CDCb) δ 7.63 (d, J =8.6 Hz, i l l). 7.17 - 7.07 (m, 1H), 7.07 - 6.97 (m, 2H), 6.93 (s, 1H), 6.81 (d, j 8.0 Hz, I I I ). 5.82 - 5.70 (ra, i l l ). 5,48 (dd, J 8. 1. 15.6 Hz, ! 1 1 ). 4, 15 (br. s,, 11 1 ). 4.04 - 3.93 (111, 2H), 3,84 - 1.64 (m, 32H), 1.57 (td, j 8.8. 17.9 Hz, IH), 1.31 (t, J=i l ,4 Hz, 1H), 1.00 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 780.3 (M+H) ⁺ . EXAMPLE 657. (18,3Έ,6'Κ,7Έ,8Έ, 12¾)-6,17'-ΟΙ{:Ηί()ΚΟ-12'-ΕΉ-1ΥΕ-7'- HYDROXY-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

STEP 1 (S)-6'.8-DICHLORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)-5-

((( I R,2R)-2-((S ,E)- 1 -HYDROXYHEX-2-EN- 1 -YL)CYCLOBUTYL)METHYL)-

S'^^'j-TETR-^HYD O^H^'H-SPl OtBE ZOtBll I^iOXAZEPI E-S,!'-

NAPHTHALENEl-7-CARBOXAMIDE

The title compound was prepared from (S)-6',8-dichloro-5-(((lR,2R)-2- ((S,E)-l½droxyhex-2-en-l -yl)cyclobuty^^

spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Intermediate AA17) and (R)-hex-5-ene-3-sulfonamide (Intermediate EE21) following a procedure similar to the one described in Example 660, Step 1, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-60% EtOAc/Hexanes (EtOAc contained 0. 1% HO Ac) to provide the title compound as a white solid. STEP 2. (l S,3'R,6'R,7'S,8'E,12'R)-6,r7'-DlCHLORO-12'-ETHYL-7 ^! - HYDROXY-3,4-DIHYDRO-2H, 15 Ή-SPTRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was prepared from (S)-6',8-dichloro-N-((R)-hept-6-en- 3-y]sulfonyi)-5-(((IR,2R)-2-((S,E)-l-hydroxyhex-2-en-l -y])cyclo

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine-3, -naphthalene]-7- carboxamide (Step 1) following a procedure similar to the one described in Example 660, Step 3, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 10 μτη column; Phenomenex, Torrance, CA; gradient elution of 45% to 90% MeCN in water, where both solvents contain 0.1% TFA, 25 mill method) to provide the title compound as a white foam. *H NMR (400MHz, CDCb) δ 8.48 - 8.34 (s, I H ). 7.66 (d, ./ 8.6 Hz, i l l ). 7, 19 id. J=5.9 Hz, IH), 7,09 (br. s . 1H), 6.99 - 6.90 (m, IH), 6,83 (m, IH), 5.87 - 5.62 (m, 2H), 4.18 (d, ./ 4. ! Hz, IH), 4.16 - 3.96 (m, 3H), 3.84 - 3.62 (m, 2H), 3.25 (m, ill).3.01 (dd,J=9.4, 15.3 Hz, ill).2,90 - 21,26 (m, 19H), 1.25 - 1.13 (ra, 3H), m/z (ESI, +ve ion) 615.0 (M-H2O + H)

EXAMPLE 658. (lS,3'R,6 ^! R,7'S,8 ^! E,12 ^! S)-6-CHLORO-12'-((2S)-2-HYDROXY- 3-METHQXYPRQPYL)-7'-METHQXY-3,4-DIHYDRQ-2H,15 ^! H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13 ^" -DIQX1DE OR

(lS ₅ 3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -((2S)-2-HYDROXY-3- METHOXYPROPYL)-7'-METHOXY-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE-l,22 ^!

[20]OXA[13]™:A[l _s 14]DIAZATETRACYCLO[14J.2 ³ ' ^{6 19i4} ]PE]SlTACOSA

[8,16,18,24] TETR AEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compounds were prepared from (lS,3'R,6'R,7'S,8'E)-6-chloro-7'- methoxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1,22'- [20joxa|13]thia[l,14]diazatetracyclo^

n]-15'-one 13',13'~dioxide (Example 651, Step 3) following a procedure similar to the one described for the synthesis of Example 651, Step 4, except that (s)-(+)- giycidyl methyl ether (TCI - Tokyo Chemical Industry Co., Ltd.) was used in place of (R)-(-)-glycidyl methyl ether. The crude product was subjected to reverse phase preparatory HPLC (Gemini™ Prep CI 85 μπι column; Phenomenex,

Torrance, CA; gradient elution of 10% MeCN in water to 90% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA) to provide one of the title compounds as the first eluting fraction as a white foam. Ή NMR (400MHz, CDC] 3) δ 8.10 (br. s„ ill).7,70 id../ 8.6 Hz, !!!).7.22 - 7.15 (m, IH), 7.10 - 6.89 (m. -A I).6,82 (s, ill).5,86 (dd, J <>···.14.1 Hz, 1H), 5.53 (dd, ,/ 87. 15.4 Hz, IH), 4.41 (d, J=4.7 Hz, 1H), 4.20 - 4.01 (m, 4H), 3.86 - 3.60 (m, 4H), 3.56 - 3.48 (m, 2H), 3.42 (s, 3H), 3.24 (s, 3H), 3.45-1.26 (m, 19H). m/z (ESI, +ve ion) 673.0 (M+H) ⁺ .

EXAMPLE 659, (lS,3'R,6 ^, R,7 ^! S,8 ^, E,12 ^, S)-6-CHLORO-12'-((2S)-2-HYDROXY-

3-ΜΕ1ΉΟΧΥΡ10ΡΥΕ)-7'-ΜΕΊΉΟΧΥ-3,4"01ΗΥΟ ίΙΟ-2Η,15Ή-

SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 Yl 3 '-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,12'R)-6-CHLORO-12'-((2S)-2-HYDROXY-3- METHOXYPROPYL)-7'-METHOXY-3,4-DnTYDR()-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'

pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in the synthesis of Example 658. 'HNMR (400 MHz, CDCb) δ 7.63 - 7.75 (m, IH), 7.13 - 7,25 (m,

IH), 6.97 - 7.13 (m, 3H), 6.93 (d, J==8.()2 Hz, IH), 5.74 - 5.88 (m, IH), 5.43 (dd, ./ 15.36.7.73 Hz, !!!).4.22 (dd, ,/ 6.55.3,23 Hz, IH), 4.11 (m, 211).4,00 (m, IH), 3.44 - 3.66 (m, 5H), 3.41 (s, l).3.24 - 3.38 (m, 5H), 2.78 (m„ 2H), 2.31 - 2.59 (m, 3H), 2.12 - 2.31 (m, 4H), 1.73 - 2.12 (m, 5H), 1.61 - 1.73 (m, 2H), 1.48 - 1.26 (m, 3 !!}. m/z (ESI, +ve ion) 673,0 (M il) ^' , EXAMPLE 660. (1 S,3' ,6'R,7'S,8'E)-6-CHLO O-7'-HYDROXY-3,4

DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23'- [ 21 ] OXA[ 14] THIA[ 1 ,13 ,15 ] TRIAZ ATETRAC YCLO [ 15.7.2.0 ³ · ⁶ .0 ²⁰ · ²

S A[8, 17, 19,25]TETRAEN]-16'-ONE 14', 14'-DIOXIDE

A mixture of pent-4-en-l -amine (343 nig, 4.03 mmol, Sigma-Aldrich Chemical Company, Inc.) and sulfuric diamide (7.74 g, 81.0 mmol, Accela ChemBio Inc.) in 1 ,4-dioxane (7 mL) was refiuxed under N ₂ for 44 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (15 mL) and washed with water (4x 15 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc/Hexanes (EtOAc contained 0.1% HOAc) as the eluent provided the title compound as a colorless wax.

STEP 2: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(N-(PENT-4-EN-l-

YL)SULFAMOYL)-3',4,4 ^f ,5-TETRAI-r> JRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE.

To a solution of N-4-penten-l-ylsulfuric diamide (47 mg, 0.29 mmol, Step 1 ), (S)-6'-chloro-5-((( 1 R,2R)-2-((S)- 1 -h droxy ally I)cy clobutyl)methy 3)-3',4,4',5- tetrahydro-2h,2¾-spiro[benzo[b][ l,4]oxazepine-3,r-naphthalene]-7-caxbox lic acid (67 mg, 0.14 mmol, AA11 A), and 4-(dimethylamino)pyridine (17 mg, 0.14 mmol, Alfa Aesar) in dichloromethane (2.9 niL) under Ar was added

triethylamine (1 19 μΐ, 0.859 mmol, Sigma-Aldrich Chemical Company, Inc.) followed by l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol, Sigma-Aldrich Chemical Company, Inc.) at rt. The resulting mixture was allowed to stir at rt overnight. The reaction solution was directly purified by flash chromatography on ISCO Gold silica gel column using 0-1.00% EtOAc/Hexanes (EtOAc contained 0.1% HO Ac) as the eluent to provide the title compound as a white solid.

STEP 3: (IS^'R^'R 'S^'E^e-CHLORO-y-HYDROXY-S^-DIHYDRO- 2H, 16'H-SPIRO[NAPHTHALENE- 1 ,23'-

[21]OXA[14]TOIA[1,13,15]TRIAZATETRACYCLO[15.7.2.0 ³ ' ⁶ .0 ²⁰ ' ²⁵ ]HEXACO SA[8, 17, 19,25]TETRAEN]-16'-ONE 14', 14'-DIOXIDE

A solution of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox>'ally])cyclobutyl)methyl)-N-(N-(pent-4-en-l-yl)sul famoyl)-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide

(51 mg, 0.083 mmol, Step 2) in 1 ,2-dichloroethane (25 niL) was purged with Ar for 15 min. To the solution was added Hoveyda-Grubbs 2 ^nd generation catalyst (5.0 mg, 8.0 μιηοΐ, Sigma-Aldrich Chemical Company, Inc.) After the reaction solution was purged with Ar for 5 min, the resulting solution was allowed to stir at 55 °C under running Ar line for 4.0 h. The reaction solution was removed from the bath and allowed to cool to rt with air purge. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on 1SCO Gold silica gel column using 20-50% EtOAc/Hexanes (EtOAc contained 0.1 % HO Ac) as the eluent provided the title compound as a white foam. H NMR (400MHz, CDCb) δ 7.69 (d, 8.4 Hz, IH), 7.17 (dd, ./ 2 2. 8.5 Hz, IH), 7.12- 7.03 (m, 3H), 7.00 - 6.79 (m, 1H), 5.85 - 5.58 (m, 2H), 4.22 - 4.01 (m, 3H), 3.71 - 3.49 (m, 2H), 3.36 id. ./ 14.5 Hz, i l l ). 3.30 - 3.14 (m, 21 1 ). 2,86 - 2.70 (m, 2H), 2,64 (d, ,/ 5.7 Hz, IH), 2.56 - 2,28 (m, 2H), 2.21 - 1 .42 (m, 13H), 1.33 - 1.21 (m, 1H). m/z (ESI, +ve ion) 596.3 ( +H) ⁺ . EXAMPLE 661. { I S.3 ^' R.6'R.7'S.8 ^' H. ! ! ^' S. I 2'R )-6-CI !I .OKO-7'-: ! V DROX V- 1 ! METHYL-12'-(2,2,2-TRIFLUOROETHYL)-3,4-DIHYDR()-2H, 15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-QNE 13',13 ^" -DIQXIDE OR

(1 S,3'R,6'R,7'S,8'E, 1 l'S, 12'S)-6-CHLORO-7'-HYDROXY- 11 '-METHYL- 12'- (2,2,2-TRIFLUOROETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[N APHTHALENE- 1.22 ^' -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ -« 0 ¹⁹ ^ ⁴ ]PE rrACO

[ 8,16,18,24|TETRAENl-15'-ONE 13', 13'-DIOXIDE OR

(lS,3¾,6¾,7 ^! S,8'Z,i i'S,12¾)-6-CHLORO-7'-HYDROXY-l l'-METHYl,-12'- (2,2,2-TRIFLL ⁱ OROETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TETR AEN] - 15 ' -ONE 13 ', 13 ' -DIOXIDE OR

(lS,3'R,6'R,7'S,8 ^, Z,i S,12'S)-6-CHLORO-7'-HYDROXY-i -METHYL-12'- (2,2,2-TRIFLU()R()ETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[ 13]TOL [1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24] TETR AEN j - 15 ' -ONE 13 ', 13 ' -DIOXIDE

STEP 1 : 3,3,3-TRIFLUORO-N,N-BIS(4-METHOXYBENZYL)PROPA]SIE-l- SULFONAMIDE

The title compound was prepared from 3,3,3-trifluoropropane-l- sulfonamide (SynQuest Lab, Inc.) following a procedure similar to the one described for the synthesis of EE12.

STEP 2: {(3R,4S)~ 1,1, 1 -TRJFLUORO-N,N-BIS(4-METHOXYBENZYL)-4- METHYLHEPT-6-ENE-3-SULFO AMIDE AND ( S.4S )· i . i . I -TR I Ff . !., ^' < )R(>- N,N-BIS(4-METHOXYBENZYL)-4-METHYLHEPT-6-ENE-3- SULFONAMIDE

The title compounds were prepared from 3,3,3-trifluoro-N,N-bis(4- methoxybenzyl)propane-l -sulfonamide (Step 1) and (R)-pent-4-en-2-yl 4- methylbenzenesulfonate (prepared according to the procedure reported by Sigman, M. S, et al. ; J. Am. Chem. So . 2012, 134, 11408-11411 ) following a procedure similar to the one described in Step 2 for the synthesis of EXAMPLE 653. STEP 3: (3R4S)-l, l,l-TRJFLUORO-4-METHYLHEPT-6-ENE-3-

SULFQN AMIDE AND (3 S ,4S)~ 1 , 1 , 1 -TRIFLUORO-4-METH YLHEPT-6-E E- 3-SULFONAM1DE.

The title compounds were prepared from ((3R,4S)-l,l,l-trifluoro-N,N- bis(4-methoxybenz l)-4-methylhept-6-ene-3-sulfonarnide and (3S,4S)- 1 ,1, 1 - trifluoro~N,N~bis(4-m.ethoxybenz 4)-4-methylhept-6~ene-3~sulfonamide (Step 2) following a procedure similar to the one described for the synthesis of EE17 (Step 2).

STEP 4: ((S)-6'-CHLORO-5-(((lR ₅ 2R)-2-((S)-l- HYDROXY ALLYL)CYCLOBUTYL)METHYL)-N-(((3R,4S)- 1 ,1,1 - TMFLUORO-4"METHYLHEPT~6"EN-3-YL)SULFONYL)-3',4,4 ^! ,5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [ 1 ₅ 4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMIDE AND (S)-6'-CHLORO-5-(((l R,2R)-2- ((S)- 1 -HYDROXY ALL YL)CYCLOBUTYL)METHYL)-N-(((3S,4S)- 1 ,1,1- TRlFLUORO-4-METHYLHEPT-6-EN-3-YL)SULFONYL)-3',4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMIDE

The title compounds were prepared from (S)-6'-chloro-5-(((l.R,2R)-2-((S)- l~hydroxyallyl)cyclobu 4)m.ethyl)~3V,4V5-tetrahydro-2H,2 ^! H- spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (AA11A ) and (3R,4S)- 1,1,1 -trifluoro-4-methy lhept-6-ene-3 -sulfonamide and (3S,4S)- 1 , 1 , 1 - trifluoro-4-methylhept-6-ene-3-sulfonamide (Step 3) following a procedure similar to the one described in Step 2 for the synthesis of Example 660.

STEP 5: (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-7'-HYDROXY-H'- METHYL-12'-(2.2,2-TRIFLUOROETHYL)-3 ₅ 4-DIIiYDRO-2H,15H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.20 ' ".U ^1* " ¹ |PH\ i ACOSA

[8,16,18,24jTETRAENj-15'-ONE 13',13'-DIOXIDE OR

(lS,3¾,6'R,7^,8^Il'S,12'S)-6-CHI RO-7' iYDROXY-l!'-METI-IYL-12'- (2,2,2-TRIFLUOROETHYL)-3,4-DmYDRO-2H,15'H- SP1RO [NAPHTHALENE- 1 ,22'- pOlOXAIlSlTHIAIl.MlDIAZATETRACYCLOiM.T^.O'^.O^^lPE TACOSA [8 ₅ 16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(Ιβ^'Κ,ό'Κ,Τ'β,δ'Ζ,ΙΙ'β, 'Κνό-ΟΗΕΟΚΟ-Τ'-ΗΥϋΚΟΧΥ-ΙΓ-ΜΕΤΗΥΕ-Ι ^- (2,2,2-TRlFLUQRQETHYL)-3,4-DfflYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13 ^" -D10XIDE OR

(1 S,3'R,6'R,7'S,8'Z, 1 l'S, 12'S)-6-CHLORO-7'-H YDROXY- 11 '-METHYL- 12'- (2,2,2-TRIFLUOROETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22 ^! - [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TETRAEN]- 15 ' -ONE 13 ', 1 3 ' -DIOXIDE

The title compounds were prepared from ((S)-6'-chloro-5-(((lR,2R)-2- ((S)- 1 -hydroxy allyl)cyclobutyl)methyl)-N-(((3R,4S)- 1,1,1 -trifluoro-4-methylhept- 6-en-3-yl)sulfonyl)-3^4,4^5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3, - naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox\'allyl)c lobutyl)methyl)-N-(((3S,4S)-Ll,l-trifluoro-4-methylhept-6-en - 3-yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo b] [ l,4]oxazepine-3, - naphthalene]-7-carboxamide (Step 4) following a procedure similar to the one described in Step 3 for the synthesis of Example 660. Portion of the crude product was purified by reverse phase preparatory HPLC (Gemini™ Prep CI 8 10 μπι column; Phenomenex, Torrance, CA; gradient elution of 45% MeCN in water to 95% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) to provide one of the title compounds as the third eluting fraction as a white foam. ¾ NMR (4()0MHz, CDCh) δ 8.57 (br. s., 1 H), 7.80 - 7.61 (m, 1H), 7.18 (d, ./ 8.2 Hz, 2H), 7.10 (s, i l l ). 7.02 - 6.86 (m, 1 H), 6.84 - 6.63 < m. i l l ). 5,96 (d, i O.ii Hz, i l l ). 5,81 - 5.55 (m, 2H), 4.28 - 3.87 (m, 5H), 3,76 - 3.46 (m, 3H), 3.39 (m, 1H), 3.33 - 2.99 (m, 3H), 2.89 -1.46 (m, 14! ! }. 1.22 - 1.11 (m, 3H). m/z (ESI, +ve ion) 667.3 (M+H) ⁺ . EXAMPLE 662, (1 S,3'R,6'R,7'S,8'E, 1 'S,l 2'R)-6-CHLORO-7'-FIYDROXY-l 1 '- METHYI,-12'-(2,2,2-TRIFLUOROEraYL)-3,4-DlHYDRO-2H, 15'H- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13 iTHL4[ l,14jDIAZATETRACYCLO[14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6'R,7'S,8 ^, E,i S,12'S)-6-CHLORO-7'-HYDROXY-i -METHYL-12'- (2,2,2-TRIFLU()R()ETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13 ^" -DIOXIDE OR

(lS,3'R,6'R,7'S,8'Z,irS,12'R)-6-CHLORO-7'-mOROXY-l l '-METI-IYL-12'- (2 ₅ 2,2-TRIFLUOROETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| !3jTIUA| U4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PL\,T.\i SA

[8,16,18,24jTETRAENj-15'-ONE 13'.13'-DIOXIDE OR

(1S,3'R,6'R,7'S,8'Z,1 l'S,12'S)-6-CHLORO-7'-HA ^T DROXY-l l'-METHYL~12'~ (2,2,2-TRIFLUOROETHYL)-3,4-DIHYDRO-2H ₅ 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE

The title compound was obtained as a white foam as the fourth eluting isomer from the reversed phase preparatory HPLC separation in Example 661. 'H NMR (400MHz, CDCb) δ 10.31 - 10.01 (m, 1H), 7.77 - 7.66 (m, 1H), 7.53 - 7.42 (m, 1H), 7.18 (dd, ,/ 2.1.8.5 Hz, IH), 7,14 - 7.07 (m, 2H), 7.03 - 6.95 (m, IH), 5,82 - 5.68 (m, IH), 5.56 (d, ,7=9,6 Hz, IH), 4.41 (m, IH), 4.17 - 3.98 (m, 2H), 3.95 - 3.78 (m, 2H), 3.62 (d, J=13.9 Hz, IH), 3.19 - 2.96 (m, 4H), 2.95 - 1.36 (m, 17H), 1.16 - 1.06 ins.3H); mlz, (ESI, +ve ion) 667.2 ( +H) ⁺ .

EXAMPLE 663. iIS,3'R,6'R,7'S,8'E,l l ^, S ₅ 12'R)-6-CHLORO-7'-HYDROXY-l - METOYL-12'-(2,2,2-TRIFLUOROE;rHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE OR

(lS,3'R,61 ,7 ^, S,8T,l l^,12'S)-6~CHLORO-7 ^, ~HYDROXY-i r-METHYL-12'-

(2,2,2-TRIFLU()R()ETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'-QNE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z,1 rS, 12'R)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL-l 2'-

(2,2,2-TRlFLUOROETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l ₅ 22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI l^T^.O'^.O^^lPE TACOSA

[8J 6,18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(lS,3 ^, ,6'R,7 ^! S,8'Z,l l'S,12'S)-6-CHLORO-7'-HYD OXY-l l'-METHYL-12 ^, -

(2,2,2-TRIFLL ⁱ OROETHYL)-3,4-DlHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]QXA[13]THIA[l,14]DiAZATEm

[8, 16, 18,24] TETRAEN ] - 1 -ONL 13 . 1 3 ^" -DIOXIDE

Portion of th e crude product from Step 5 in the synthesis of Example 661 was purified by flash chromatography on ISCO Gold silica gel column with 0- 80%EtOAc/Hexanes (EtOAc contained 0.1 % HO Ac) to provide one of the title compounds (the third eluting fraction) as a white foam. ¾ NMR (400MHz, CDCb) δ 8.30 (br. s., 1H), 7.69 id. ./ 8.4 Hz, 1H), 7.18 (dd, J=2.2, 8.4 Hz, i l l ). 7.10 (d, ./ 2.2 Hz, 2H), 6.99 - 6.87 (m, 2H), 5.91 - 5.77 (m, ! ! ! ). 5.78 - 5.64 (m, 1H), 4,47 (m, 1H), 4.20 (br, s., 1H), 4.28 - 4,03 (m, 2H), 3.86 - 3.55 (m, 2H), 3.47 - 3.08 (m, 2H), 3.08 - 1.68 (m, 18H), 1.11 id . ./ 8 -1. 3H). m/z (ESI, +ve ion) 667.0 ( V! - H) .

EXAMPLE 664. (S)-6'-CHL()RO-5-(((lR,2R)-2-((S)-l-

HYDROXY ALLYL)CYCLOBUTYL)METHYL)-N-(N-((S)-PENT-4-EN-2-YL)- N-(PYRIDIN~2-YL;METHYL)SULFAMOYL)~3V1V4^5-TETRAHYDRO-2H,2'H~ SPIRO [BENZO [B ] [ 1 ,4] OXAZEPI Ε-3,Γ-Ν APHTHALENE] -7 - CARBOXAMIDE

A solution of triphenylphosphine (24.4 g, 93.0 mmol, Acros Organs cs), phthaiimide (8.54 g, 58.1 mmol, Alfa Aesar, A Johnson Matthey Company) and (R)-(-)-4-penten-2-ol (5.97 mL, 58.1 mmol, Sigma- Aldrich Chemical Company, Inc.) in THF (30 mL) under N2 was allowed to stir at 0 °C for 30 min. To the resulting milky mixture was slowly added diethyl azodicarboxylate (42.3 mL, 93.0 mmol, 40 wt.% solution in toluene). The resulting solution was allowed to warm with the bath to rt and stirred at rt for 4.5 h. After removal of organic solvents under reduced pressure, to the residue was added a mixture solvent of diethyl ether /Hexanes (2: 1 , 100 mL). The precipitate was filtered off through a pad of Celite® (diatomaceous earth) and rinsed with cold diethyl ether (2 ^χ 15 mL). The organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column using 0-40% EtOAc Hexanes as the eluent provided the title compound as a white solid.

STEP 2: (S)-PENT-4-EN-2- AMINE HYDROCHLORIDE A solution of (S)-2-(pent-4-en-2-yl)isoindoline-l,3-dione (12.0 g, 55.7 mmol, Step 1) and ethanoiamine (16.7 ml, 279 mmol, Sigma- Aidrich Chemicai Company, Inc.) in EtOH (22 ml) was allowed to stir under Ar with condenser in 40 °C oil bath overnight. The reaction flask was equipped with distill short path apparatus. Slow fraction distil lation of the solution in oil bath in an increasing temperature range of 85 °C to 120 °C provided the desired fractions (99.8 °C to 102 °C). The desired fractions were combined, placed into ice bath, and treated with HCl (10 mL, 4.0 N in 1 ,4-dioxane, Sigma- Aidrich Chemical Company, Inc.) under N ₂ . The resultant milky mixture was allowed to stir at rt for 20 min. After remo v al of organic sol v ents under reduced pressure, the residue was left under high vacuum for overnight to provide the title product as white solid.

STEP 3: (S)-PENT-4-E -2- AMINE

To a rt mixture of (S)-pent-4-en-2-amine hydrochloride (7.10 g, 58.4 mmol, Step 2) in water (15 mL) and diethyl ether (25 mL) was treated aqueous NaOH (6.0 N) to PH = 14. The organic layer was separated, and aqueous layer was back extracted with diethyl ether (3 x 15 mL). The organic layers were combined, washed with water (5 mL), brine (5 mL) and dried over MgSCk The solid was filtered off through a small pad of a CeliteCg ⁾ (diatomaceous earth) pad, the organic solution was placed into a flask equipped with distill short path apparatus. After distillation at 49 °C, the remaining residue was collected as a solution of the title product (56%) in diethyl ether.

STEP 4: (S)-N-(PYRIDIN-2-YLMETHYL)PENT-4-EN-2-AMINE

To a 0 °C solution of picolinaldehyde (135 mg, 1.26 mmol, Sigma- Aldrich Chemical Company, Inc.) and (S)-pent-4-en-2-amine (320 mg, 2.105 mmol, Step 3) in 1,2-dichloroethane (10 mL) was slowly added sodium cyanoborohydride (2.11 mL, 1.0 M in THF, 2.1 1 mmol, Sigma-Aldrich Chemical Company, Inc.). The mixture was allowed to warm with the ice bath to rt over 2.0 h. After stirring at rt for 1.0 h, the mixture was treated with saturated aqueous NHUCl (3 mL) and water (4 mL). The organic layer was separated, and the aqueous layer was back extracted with EtOAc (3 x 15 mL).The organic solutions were combined. After remo v al of organic sol v ents under reduced pressure, purification of the residue by- flash chromatography on ISCO Gold silica gel column using 0-10%

MeOH/dichloromethane (MeOH containing 1% NH QH) as the eluent provided the title compound as a white solid. STEP 5: N-((2S)-4-PENTEN-2-YL)-N-(2-PYRlDINYLMETHYL)SULFURIC DI AMIDE

The title compound was prepared from (S)-N-(pyridin-2-ylmethyl)pent-4- en-2-amine (Step 4) following a procedure simil ar to the one described for the synthesis of N-4-penten-l-ylsulfuric diamide as described in Step 1 for the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-90% EtO Ac/Hexanes to provide the title compound as a white solid.

STEP 6: (S)-6 ^! -CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(N-((S)-PENT-4-EN-2-YL) -

N-(PYRiDIN-2-YLMETOYI SULFAMOYL)-3',4,4',5-TETRAI-IYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE.

The title compound was prepared from N-((2S)-4-penten-2-yl)-N-(2- pyridinylmethyl)sulfuric diamide (Step 5) and (S)-6',8-dichloro-5-(((lR,2R)-2- ((S,E)-l-hydrox 'hex-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiroj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (67 mg, 0.143 mmol, AA11A), following a procedure similar to the one described for the synthesis of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxyallyl)cyclobutyl)m ethyl)- N-(N-(pent-4-en-] -yl)sulfamoyi)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide (Step 2 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-90% EtO Ac/Hexanes to provide the title compound as a white solid. ¾ N.V1R (400MHz, CD CI 3) δ 8.55 - 8.44 (m, i l l }. 7.74 id. ./ 8.6 Hz, 1H), 7.67 (dt, ./ 1 .7. 7.7 Hz, 1H), 7.55 (d,■/ 7.8 Hz, 1 1 1 ). 7.44 (dd, J=1.8, 8.4 Hz, i l l ). 7.31 (br. s., 1H), 7.23 - 7. 14 (m, 2H), 7.09 (d, J=2.0 Hz, 1H), 7.01 - 6.93 (m, 1H), 5.86 - 5.74 (m, 1H), 5,73 - 5.60 (m, 1H), 5.33 - 5.19 (m, 1 H), 5.11 (d, ./ 10.4 Hz, 1H), 5.00 - 4.88 (m, 2H), 4.88 - 4.70 (m, 2H), 4,23 - 4.04 (m, 3H), 3.94 - 3.80 (m, 1H), 3,73 - 3.62 (m, 1 H), 3.24 (d, 1 .3 Hz, 1 1 1 ). 3, 18 - 3,03 (m, 1H), 2.83 - 2.71 (m, 2H), 2,53-2.40 (m, 1H), 2.42 - 2.28 (m, 1H), 2.21 - 1.98 (m, 6H), 1.98 - 1.75 (m, 4H), 1.67 {tel. ./ 9.4. 19.0 Hz, 1H), 1 .61 - 1.50 (ra, i l l ). 1 ,49 - 1.39 (m, i l l ). 1 .14 id. ,/ 6, 7 Hz, 3H), m/z (ESI, +ve ion) 705.1 (M+H) ⁺ .

EXAMPLE 665. (lS,3'R,6 ^! R,7'S,8'E)-6-CHLORO-7'-HYDROXY-13 ^! -(2- METHOXYETHYL)-3,4"DIHYDRO-2H,16'H-SPIRO[NAPHTHALENE-I,23'- [21] GXA [ 14] THI A[ 1 , 13, 15 ] TRIAZ ATETRAC YCLO [15.7.2.0 ³ · ⁶ .0 ²⁰ · ²⁵ ]ΗΕΧΑ CO S A[8, 17, 19,25]TETRAEN]-1 o'-ONE 14', 14'~DIOXIDE

STEP 1 : N-(2-METHOXYETHYL)PE T-4-EN-l -AMINE

To a rt solution of pent-4-enylaniine (0.822 mL, 9.65 mmoi, J & W

PharmLab, LLC) in CH2G2 (20 mL) was added 2-bromoethyl methyl ether (0.908 mL, 9.65 mmol, Sigma-Aldrich Chemical Company, Inc.) followed by diisopropylethylamine (2,5 mL, Sigma-Aldrich Chemical Company, Inc.). The mixture was allowed to stir at rt for 20 h. To the mixture was added potassium carbonate (0.583 mL, 9.65 mmol, Sigma-Aldrich Chemical Company, Inc.) followed by acetonitrile (20 mL), the mixture was refluxed in a 70 °C bath overnight. The reaction vessel was removed from the bath and allowed to cool to rt. The solid was filtered off through a Celite® (diatomaceous earth) pad, and washed with acetonitrile (2x20 mL), The organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-100% MeOH in CH2CI2 (MeOH containing 0.1 % NHiOH) provided the title compound as a colorless syrup.

STEP 2: N-(2-METHOXYETHYL)-N-4-PENTEN- 1 -YLSULFURIC DIAMIDE

The title compound was prepared from N-(2-methoxyethyl)pent-4-en-l- amine (Step 1) following a procedure similar to the one described for the synthesis of N-4-penten-l-ylsulfuric diamide (Step 1 in Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc/Hexanes to provide the title compound as a white solid.

STEP 3: (S)-6'-CHLORO-5-(((l R,2R 2-((S l -

HYDROXYALLYL)CYCLOBUTYL)METIIYL)-N-(N-(2-METHOXYETOYL)- -(PE T-4-EN~l"YL)SULFAMOYL)-3 ^, ,4,4',5-TETR HYDRO-2H,2 ^, H- SPIRO BENZO[B] [1 ,4 jOXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE

The title compound was prepared from N-(2-methoxyethyl)-N-4-penten-l- ylsulfunc diamide (Step 2) and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyciobtit5 _' l)methyl)-3^4,4^5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'lic acid (AA11A ), following a procedure similar to the one described for the synthesis of (S)~6'~ cWoro-5-(((lR,2R)-2-((S)-l-hydrox>'allyl)cyclobut )methyl)-N-(N-(pent-4-en-l- yl)sulfamoyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene]-7-carboxamide (Step 2 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-70% EtOAc/Hexanes (EtOAc contained 0.1% HO Ac) to provide the title compound as a white solid. STEP 4: (lS,3 ^, R,6 ^, R,7'S ₅ 8 ^, E)-6-CHLORO-7 ^, -HYDROXY-13 ^, -(2- METHOXYETHYL)-3,4-DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l,23'- [21]OXA[14]THIA[1 _S 13 ₅ 15]TRIAZATETRACYCLO[15.7.2.0 ^J " ⁶ .0 ²⁰ ' ²⁵ ]HEXACO S A[8, 17, 19,25]TETRAEN]-16'-ONE 14', 14'-DK)XIDE The title compound was prepared from (S)-6'-chloro-5-(((TR,2R)-2-((S)-l- hydroxyallyl)cyclobutyl)methyl)-N-(N-(2-m

yl)sulfamoyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[berizo[b] [l,4]oxazepine-3,r- naphthalene|-7-carboxamide (Step 3), following a procedure similar to the one described in Step 3 for the synthesis of (l S,3'R,6'R,7'S,8'E)-6-ch]oro-7'-hydroxy- 3,4-dihydro-2H,16'H-spiro[naphthalene-l,23'-

aen]-16'-one 14', 14'-dioxide (Example 660), except that the crude product was purified by flash chromatography on IS CO Gold silica gel column using 0-70% EtOAc/Hexanes (EtOAc contained 0.1% HO Ac) to provide the title compound as a white solid. ¾ NMR (400MHz, CDCh) δ 9.36 (br. s., 1 H), 7.71 (d, ,/ H. Hz, i l l). 7.24 (dd, ,/ i .8. 8.2 Hz, 11 1 ). 7, 18 (dd, ./ 2.2. 8.4 Hz, I I I ). 7.10 id. ,/ 2 2 Hz, 1H), 7.02 - 6.92 (m, 2H), 5,92 - 5.62 (m, 2H), 4.25 - 4.01 (m, 4H), 3,78 - 3.22 (m, 13H), 3.00 - 1.58 (m, 15H), 1.52 (t, ./ i l .H Hz, IH). m/z (ESI, +ve ion) 644.0 { \ I · Π } . EXAMPLE 666, (2S)-1-((IS,3'R,6'R,7'S,8'E,1 l'S, 12'R)-6-CHLORO-7'-

HYDROXY- 1 1 '-METHYL- 13', 13'-DIOXIDO - 15'-OXO-3,4-DIHYDRO-2H- SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTfflA[ l,14jDL4ZATETRACYCLO| 14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-12'-YL)-3-METHOXY-2-PROPANYYL BENZOATE OR (2S)-l-((lS,3 ^, R,6'R,7 ^! S,8'E,l l'S,12'S)-6-CHLORO-7'-HYDROXY-l l'- METHYL - 13 ', 13 '-D S OXIDO- 15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-12 ^, -YL)-3-METHOXY-2-PROPANYYL BENZOATE

STEP 1 : (S)-N,N-BIS(4-METHOXY -2-METHYLPENT-4-ENE-l

SULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)methane sulfonamide (9. 10 g,

27.1 mmol, EE 12) in THF (78 ml) under N?. in a -78 °C bath was added "BuLi

solution (1 1.9 ml, 2.5 M in hexanes, 29.8 mmol, Sigma- Aldrich Chemical

Company, Inc.). The mixture was allowed to stir in the cold bath for 25 min. To

the mixture was added a solution of (R)-pent-4-en-2-yl 4-methylbenzenesulfonate

(9.78 g, 40.7 mmol) (prepared according to the procedure reported by Sigman, M.

S. et al. ; J. Am. Che r, Soc , 2012, 134, 11408-1141 1 ) in THF (12 mL). The

mixture was allowed to stir in the ice bath for 30 min, removed from ice bath, and allowed to stir at rt for 72 h. To the mixture was added 1.0 aqueous HC1 ( 5 mL), the resulting mixture was diluted with water (12 mL) and extracted with EtOAc (2 x 18 mL). After removal of organic solvents under reduced pressure, purification

of the residue by flash chromatography on ISCO Gold silica gel column with 0- 25-60% EtOAc/Hexanes provided the title compound as a white solid.

STEP 2: (2R,4R,5S)-2-HYDROXY-l-METI-iOXY-N,N-BIS(4-METHOXYBENZYL)-5- METHYLOCT-7-ENE-4-SULFONAMIDE AND (2R,4S,5S)-2-HYDROXY-l-METHOXY- N,N-BlS(4-METHO -5-METHYLOCT-7-ENE-4-SULFONAMlDE

To a solution of (S)-N,N-bis(4-methoxy benzyl )-2-methylpent-4-ene-.l - sulfonamide (1 ,25 g, 3. 10 mmol, Step 1) in THF (10,33 ml) under N ₂ in -78 °C bath was added "BuLi (1.43 ml, 2.5 M in hexanes, 3.56 mmol, Sigma-Aldrich Chemical Company, Inc.) drop wise. The mixture was allowed to stir in the bath for 35 min. To the mixture was added (R)-(-)-glycidyl methyl ether (0.819 ml, 9,29 mmol, Sigma-Aldrich Chemical Company, Inc.) in one shot. The resulting solution was allowed to warm with the ice bath to rt and left to stir at rt overnight. The reaction mixture was quenched with saturated aqueous NH ₄ C1 ( 5 mL), diluted with water (12 mL) and extracted w ith EtOAc (2 ^χ 15 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-100% EtOAc Hexanes (EtOAc contained 0.1 % HO Ac) provided the title compounds as a white solid.

STEP 3: (2R,4R,5S)-4-(N,N-BIS(4-METOOXYBENZYL)SULFAMOYL)-l - METHOXY-5-METHYLOCT-7-EN-2-YL BENZOATE AND (2R,4S,5S)-4- ( .N-BIS(4-METHOXYBENZYL)SULFA OYL)-l-METHOXY-5- METHYLOCT-7-EN-2-YL BENZOATE

To a 0 °C solution of (2R,4R,5S)-2-hydroxy-l-methoxy-N,N-bis(4- methoxybenzy l)-5-methy 1 oct-7-ene-4-sulfonamide and (2R,4S ,5 S)-2-h droxy- 1 - methoxy-N,N-bis(4~methoxybenz} _' )-5-methyloct-7-ene-4-sulfonamide (670 mg, 1.36 mmol, Step 2) and 4-(dimethylamino)pyridine (200 mg, 1.64 mmol, Sigma- Aldnch Chemical Company, Inc.) in CHCb (13 mL) under N2 in ice bath was added triethylamine, anhydrous (0.569 mL, 4.09 mmol, Sigma-Aldrich Chemical Company, Inc.) followed by benzoyl chloride (0.237 mL, 2.04 mmol, Sigma- Aldrich Chemical Company, Inc.). The mixture was allowed to warm with ice bath to rt and to left to stir at rt overnight. The mixture was quenched with saturated aqueous NaHCCb (3 mL), diluted with water (2 mL) and extracted with dichloromethane (3x 5 mL). After removal of organic sol vents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-80% EtOAc/Hexanes (EtOAc contained 0.1% HO Ac) provided the title compounds as a syrup.

STEP 4: (2R,4R,5S)-l-METHOXY-5-METHYL-4~SULFAMOYLOCT-7-EN-2- YL BENZOATE AND (2R,4S,5S)-l-ME ^r fflOXY-5-METHYL-4- SULFAMOYLOCT-7-EN-2-YL BENZOATE

The title compound was prepared from ((2R,4R,5S)-4-(N,N-bis(4- methoxybenzyl)suliamoyl)-l-methoxy-5-methyioct-7-en-2-yi benzoate and (2R,4S,5S)-4-( ,N-bis(4-me1hoxybenz\d)sulfamoyl)-l-methoxy-5-me1h^^ en-2-yl benzoate (Step 3) following a procedure similar to the one described for the synthesis of EE17 (Step 2). STEP 5: (2S,4R,5S)-4-(N-((S)-6'-CHLORO-5-(((l R,2R)-2-((S)-l-

HYDROXY ALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,r~NAPHTHALEN]-7- YLCARBONYL)SULFAMOYL)-l-METHOXY-5-METHYLOCT-7-EN-2-YL BENZOATE AND (2S ₅ 4S,5S)-4-(N-((S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXY ALLYL)CYCLOBU L)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPIRQ[BENZQ[B] [ 1 ,4] QXAZEPLNE-3, Γ-Ν APHTHALEN] -7- YLCARBONYL)SULFAMOYL)-l-METHOXY-5- ETHYLOCT-7-EN-2-YL BENZOATE

The title compound was prepared from (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyall l)c clobutyl)methyl)-3',4,4',5-tetrahydfo-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (AA1 1 A) and (2R,4R,5S)-l~methoxy-5-methyl-4-sulfamoyloct-7-en-2-yl benzoate and

(2R,4S,5S)-l-methox '-5-rnethyl-4-sulfamoyloct-7-en-2-yl benzoate (Step 4) following a procediire similar to the one described in Exampe 660, Step 2, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0- 100% EtO Ac/Hexanes (EtOAc contained 0.1 % HO Ac) to provide the title compounds as a white solid.

STEP 6. (2S)-1-((1S,3'R,6 ^! R,7'S,8'E, 1 l ^, S,12 ^, R)-6-CHLORO-7'-HYDROXY-l Γ-

METOYL-13VI3'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-

SP1RO [NAPHTHALENE- 1 ,22'- |;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8,16, 18,24]TETRAEN]-12'-YL)-3-METHOXY-2-PROPANYYL BENZOATE OR (2S)-1-((1S,3'R,6'R,7 ^! S,8'E, 1 l ^, S,12'S)-6-CHLORO-7 ^, -HYDROXY-l 1 '- METHYL - 13 13 '-DIOXIDO - 15 '-OXO - 3,4-DIH YDRO-2H- SPIRO[NAPHTHALENE-1.22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETl AEN]-12 ^, ~YL)-3-METHOXY-2"PROPANYYL BENZOATE

The title compound was prepared from (2S,4R,5S)-4-(N-((S)-6'-chloro-5- (((l R,2R)-2-((S)-l-hydroxyallyl)c lobutyl)me l)-3',4,4',5-tetfahydro-2H,2'H- spiro|benzo|b] [l,4]oxazepine-3, i ⁱ Hiaphihalen]-7-ylcarbonyl)sulfa,moyl)- l- methoxy-5-methyloct-7-en-2~yl benzoate and (2S,4S,5S)~4~(N~((S)-6'-chloro~5~ (((1 R,2R)~2-((S)~1 iydroxyally^^

spiro[benzo[b] [ 1 ,4]oxazepine-3 , Γ-naphthalen] -7-ylcarbonyl)sulfamoyl)- 1 - methoxy-5-methyloct-7-en-2-yl benzoate (Step 5) following a procedure similar to the one described in Example 660, Step 3, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 810 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 90% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to provide one of the title compounds as the faster eluting isomer as a white foam. ^! H NMR

(400MHz, CDCh) δ 8.12 (d, .7=7.2 Hz, 2H), 7,67 (d, ./ 8.6 Hz, IH), 7,64 - 7.56 (m, 111).7.52 - 7.45 (m, 2H), 7.22 - 7.13 (m, 2H), 7.13 - 7.06 (m, IH), 6.94 - 6.86 (m, 2H), 6.82 (s, IH), 5.82 - 5.70 (m, IH), 5.65 - 5.49 (m, 2H), 4.39 (d, ./ 8.2 Hz, IH), 4,20 - 3.96 (m, 2H), 3.90 - 3,80 (m, IH), 3,80 - 3.56 (m, 4H), 3.51 - 3,35 (m, 3H), 3.31 - 3.11 (m, I Hi.2.97 (dd, .7=9,3, 14.6 Hz, IH), 2,88 - 2.71 (m, 2H), 2.52 - 1.19 Cm.17H), 1.09 ·· 1.02 (d, ./ 8.2 Hz, 3H). m/z (ESI, +ve ion) 776.9 (M R) .

EXAMPLE 667 (1S,3'R,6 ^! ,7'S,8 ^! E,1 rS)-6-CHLORO-7'-HYD OXY-ir- METHYL- 12'-(2-PYRIDINYLMETHYL)-3,4-DIHYDRO-2H, 15 Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

|2 ⁽ i )XAj 13ΓΠ U2.!4|TRiAXATLTR,\(-Yi ^' LO| I4.7.2.ii ^; ".0 ^! " ^I! !N ! AC OSA[8,16,l 8,24]TETRAEN]-1 -ON I .13',13'-DIOXIDE OR

(lS,3¾,6¾.,7 ^! S,8'Z,ll'S)-6-CHLORQ-7 ^! -H^^

PYRlDlNYLMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1,22'-

[20]OXA[i;T^«A[l,12,14]TRIAZATETRACYCLO[14,7.2.0 ³ ' ⁶ ,0 ⁱ⁹ - ² ]PENTAC OS A[8, 16, 18.24jTLTRAL\|-i 5 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compounds were prepared from (S)-6'-chloro-5-(((TR,2R)-2-((S)- l -hydroxydlyl)cyclobut 'l)me1hyl)-N-(N-((S)-pent-4-en-2-yl)-N-(pyridin-2- ylmethyl)sulfamoyl)-3',4,4',5-tetrahydro-2H,2 ^, H-spiro[berizo[b] [l ,4]oxazepine- 3,1 '-naphthalene I -7-carboxamide (Example 664) following a procedure similar to Step 3 in the synthesis of Example 660, except that HO Ac (1 0.0 eq. ) was added as a co-solvent and the reaction was prolonged to 96 h to completion. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep C I 8 10 μτη column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1 % TEA, 35 min method) to provide one of the title compounds as the first eluting isomer as a white foam. 'H N .M R (400MHz, CDCb) δ 8,72 (d, J 5.5 Hz, i l l ). 8,39 (t, .1 7 5 Hz, I I I ). 8.26 - 8, 1 8 (m, IH), 7.83 - 7.75 (m, IH), 7.74 - 7,65 (m, IH), 7.18 (dd, J 2.2. 8.5 Hz, IH), 7.10 (d, J=2.2 Hz, IH), 7.00 - 6.85 (m, 3H), 5.92 - 5.66 (m, 3H), 5.21 (d, j ! v.2 Hz, IH), 4.39 - 4.26 (m, 2H), 4.16 - 4.06 (s, 2H), 3.83 (d, j 1 4.7 Hz, IH), 3.75 - 3.66 (d, j 1 4 5 Hz, I H), 3. 19 (d, j 1 .3 Hz, I H), 3.03 (dd, .! 8.8. 15.5 Hz, IH), 2.86 - 2.69 (m, 2H), 2,66 - 2.49 (m, 2H), 2.41 - 2. 13 (m, 3H), 2, 1 1 - 1.58 (m, 8H), 1.46 - 1.36 (m, IH), 1.17 - 1.08 (m, 3H). m/z (ESI, +ve ion) 677.0 (M+H) ⁺ ; EXAMPLE 668. (lS,3'R,6'R,7'S,8 ^! E,i rS)-6-CHLORO-7'-HYDROXY-l l'- METHYL- 12'-(2-PYRIDINYLMETHYL)-3 ,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHΊΉALENE-l,22 ^, -

[20]OXA[ 13]THlA[l, 12, 14]TRlAZATETiLACYCLO[ 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTAC OSA[8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13' -DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z, 11 *S)-6-CHLORO-7*-HYDROXY- 1 1 '-METHYL- 12'-(2- PYRIDiNYLMETHYL)-3,4-DIHYDRO-2H, 15 ^! H-SPIRO[NAPH ^" fflALENE- 1 ,22'-

[20]OXA[13]TOIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ² ]PENTAC OS A[8, 16, 18,24]TETRAEN] -15 ' -ONE i .V. I .V -DIOXIDE

The title compound was obtained as a white foam as the second e!irting isomer from the reversed phase preparatory HPLC separation in EXAMPLE 667. ¾ NMR (400MHz, CDCh) δ 8.43 (d. J=3.9 Hz, 1 H), 7.81 - 7.66 (m, 21 1 ). 7.61 id. j H i Hz, IH), 7.26 - 7, 16 (m, 2H), 7.08 (dd, J 2.0. 11.0 Hz, 2H), 7.03 - 6.96 (ra, 1H), 6.94 - 6.86 (m, i l l ). 6,56 (dd, J 7.7. 15.2 Hz, IH), 5.97 (d, j=15.6 Hz, i l l ). 5.26 (d, J=16.2 Hz, IH), 4.54 (d, J=17.2 Hz, IH), 4.32 -0.82 (m, 29H); 677.0 { \ I · Π }

EXAMPLE 669, il S,3'R,6'R,7'S,8'E, l l'S,12'R)-6-CHLORO-7'-(2- METHOXYETHOXY)-i r-METHYL-12' 2,2,2-TRJFLUOROETHYL)~3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16, 18 ,24] TETRAEN]- 15 ' -ONE 13 ', 13 ' -DIOXIDE OR

(1 S,3'R,6 ^! R,7'S,8 ^, E, 11 'S, 12'S)-6-CHLORO-7'-(2-METHOXYETHOXY)- 11 '-

METHYL-12'-(2,2,2-TRIFLUOROETHYL)-3,4-DIHYDR()-2H, 15TL

SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z,1 l'S,l 2 ^, R)-6-CHLORO-7 ^, -(2-METHOXYETHOXY)-l 1

METH L-12'-(2,2,2-TRIFLUOROETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TETRAEN]- 15 ' -ONE 13 ', 1 3 ' -DIOXIDE OR

(1 S,3'R,0 ^! R,7'S,8'Z, 11 'S, 12'S)-6-CHLORO-7'-(2-METHOXYETHOXY)- 11 '- METHYL-12'-(2,2.2-TRIFLUOROETHYL)-3,4-DIHYDRO-2H.15H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8, 16, 18,24] TETRAEN ] - 15 ' -ONE 13 13 ' -DIOXIDE

To a solution of (1S,3'R,0'R,7 ^* S,8'E, 1 l'S,12'R)-6-chfoiO-7'-hydroxy-l l ^! - methy 1 - 12'-(2,2,2-trifluoroethy l)-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'- I KJ4j tctrao n]-15'-one 13',13'-dioxide or (1S,3'R,6'R,7'S,8'E,1 l 'S, 12'S)-6-chloro-7'-hydroxy- 1 r-meihyi- 12'-(2,2,2-trifiuoroeihyl^^^

1 ,22'-[20] oxa[l 3]thia[ 1 , 14] diazatetracy clo

[14.7.2.0 - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15 ^" -one 13 ',13' -dioxide or

(lS.3'R,6 ^, R,7 ^, S,8 ^, Z,l l ^, S,12 ^, R)-6-chloro-7 ^, ½ciroxy-l l ^, -methyl-12 ^, -(2^2- trifluoroethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l ,22'- H^ij teirae n]-15'-one 13',13'-dioxide or (1S,3'R,6'R,7'S,8'Z,1 l 'S, 12'S)-6-chloro-7'-hydroxy- 1 r-methyl-12'-(2,2,2-trifluoroethyl)-3,4-dihydro-2H,15^spiro[ naph1halene-

1,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (32 mg, 0.048 mmol. Example 663) in DMF (2 mL) under N ₂ was added sodium hydride (19 mg, 60% dispersion in mineral oil, 0.480 mmol, Strem Chemicals, Inc.) at 0 °C. The mixture was allowed to stir in the ice bath for 15 min, followed by addition of 2-bromoethyl methyl ether (0.023 mL, 0.24 mmol, 96%, stablized with sodium carbonate, Sigma- Aldrich Chemical Company, Inc.). The resulting mixture was removed from the ice bath and continued to stir at rt for overnight. The reaction mixture was quenched with saturated aqueous NH4CI solution (3 mL), diluted with water (3 mL) and extracted with EtOAc (3 x5 mL). The organic layers were combined, washed with water (2 x 5 mL), brine and dried over MgSCk After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 40-100% EtOAc/Hexanes (EtOAc containing 0.1 % HO Ac) provided the title compound as a white solid. Ή NMR (400MHz, CDCh) δ 8.21 (br. s., 1H), 7.69 (d, J=8.6 Hz, 1H), 7.18 (dd, J=2.2, 8.6 Hz, 1H), 7.10 (d, j 2.0 Hz, 1 H), 6.99 - 6.87 (m, 3H), 5.77 (m, lH), 5.58 (m, 1 H), 4.55 (t, j 4.7 Hz, i l l ). 4.17 - 4,06 (m, 2H), 3.88 - 3.76 (m, 2H), 3.74 - 3,66 (m, IH), 3.60 - 3,40 (m, 4H), 3.29-1.40 (m 22H), 1.16 - 1.05 (m, 3H). m/z (ESI, +ve ion) 725,2 (M+H) ⁺ .

EXAMPLE 670. (1 S,3'R,6'R,7'S,8 ^! E, 1 l ^! S,12'R)-6-CHLORO-7'-(2- METHOXYETHOXY)-! r-METHYL-12'~PHENYL-3,4-DIHYDRO-2H,15'H- SPiRQ[NAPHTHAI.ENE~l,22'- [20]OXA[ 13]TOIA[1,14]DL ZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 ^* S, 12 ^, S)-6-CHLORO-7'-(2-METHOXYETHOXY)-l 1 '- METHYL- 12'-PHENYL-3 ,4-DIHYDRQ-2H, 15 Ή-SPIRQ [NAPHTHALENE- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8,16, 18 ,24] TETRAEN]- 15 ' -ONE 13 ', 1 3 ' -DIOXIDE

The title compounds were prepared from 2-bromoethyl methyl ether (96%, stabilized with sodium carbonate, Sigma-Aldrich Chemical Company, Inc.) and the crude product obtained from Step 5 in the synthesis of

(lS,3¾,6¾,7¾,8¾,l l'S,12¾.)-6-chloro^

dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

[20]oxa[ 13]thia[l ,14]diazatetracyclo[14.7.2,0 ³ - ^f \0 ^l9 - ²⁴ ]peniacosa[8,16, 18 n]-15 ^" -one 13',13'-dioxide and (l S,3'R,6'R,7'S,8 ^! E,irS,12'S)-6-chloro-7'- hydiOxy-i r-methyi-12'-phenyI-3,4~dihydro-2H,15'H~spiiO[naphthalene-l, 22'- [20ioxa[13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ³ ^() ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-15'-one 1.3',13'-dioxide (Example 653), following a procedure similar to the one described for the synthesis of Example 669, except that the crude product after removal of organic solvents was re-dissolved in DMF (3 mL) and subjected to reverse phase preparatory HPLC (Gemini™ Prep CI 8 10 μηι column;

Phenomenex, Torrance, CA; gradient elution of 10% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0, 1% TFA) for purification to provide one of the title compounds as the first eluting fraction as a white foam. ^] H NMR (400 MHz, CDCb) δ 8.14 (s, l i s ). 7.71 (d, J 8.4 j Hz, 11 1 ). 7,48 - 7.58 (m, 2H), 7.39 - 7.47 (m, 3H), 7, 19 (dd, J 8. 1. 2.25 Hz, i l l ). 7, 10 (d, J=2.15 Hz, 1H), 6.85 - 6.99 (m, 3H), 5.93 - 6.08 (m, 1H), 5.59 (dd, J=15.26, 9.00 Hz, 1 H), 5.44 (d, j 4. ! ! Hz, Hi), 4.02 - 4.19 (m, 2H), 3.79 - 3.95 (m, 2H), 3.73 (d, J==13,89 Hz, i l l ). 3.46 - 3.67 (ra, 4H), 3,37 - 3.44 (m, 3H), 3.23 id. j 14.28 Hz, 1H), 3.00 (m, 1H), 2.74-2.83 (m, 2H), 2.47 - 2.61 (m, 1H), 2.13 - 2.46 (m, 2H), 1.91 - 2.13 (m, 4H), 1.83 (m, 3H), 1 .63 (m, IH), 1.21 - 1.48 (m, 2H), 1.01 (d, J=6,85 Hz, 3 H). m/z (ESI, +ve ion) 719.1 (M+H) ⁺ .

EXAMPLE 671. (1 S,3'R,6'R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2- METHOXYETHOXY)- 11 '-METHYL-12'-PHENYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-QNE 13',13 ^" -DIQXIDE OR

(lS,3 ^! R,6 ^, R,7^,8¾irS,12'S)-6-CHL()R()-7'-(2-METHOXYETI- )XY)-ir- METIT L-12'-PHENYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-

1 ">"> ^< -

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCL )[ 14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24] TETR AEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was obtained as a white foam as the second e!irting isomer from the reversed phase preparatorv' HPLC separation in Example 670. ^[ H NMR (400 MHz, CDCb) δ ^! H NMR (400 MHz, CDCb) δ 8.08 (br. s., 1H), 7.70 (d, J=8.41 Hz, IH), 7.52 - 7.61 (m, 2H), 7.38 - 7.50 (m, 3H), 7. 16 - 7.25 (m, 2H), 7.10 (d, j=2. 15 Hz, 1H), 7.00 (d, J 8.22 1 1/. IH), 6.74 (m, 1H), 6.11 (m, IH), 5.54 (dd, J=I5.65, 7.83 Hz, IH), 4.96 (br. s., IH), 4.03 - 4.20 (m, 2H), 3.71 - 3.84 (m, 2H), 3.59 - 3.70 (m, 2H), 3.51 - 3.59 (m, 2H), 3.41 - 3.51 (m, 2H), 3.38 (s, 3H), 2,97 (m, IH), 2.73 - 2.86 (m, 2H), 2.45 - 2,64 (m, 2H), 2.33 (m, I H), 1.63 - 2.15 (m, 9H), 1.50 C m. IH), 0.97 (d, j 6.85 Hz, 3 H). m/z (ESI, +ve ion) 719.1 (M+H) ⁺ . EXAMPLE 672, (lS,3'R,6 ^, R,7'S,8'E,irS,12'R)-6-CHLORO-7'-HYDROXY-12'- ((2S)-2-HYDROXY-3-METHOXYPROPYL)-H'-METHYL-3,4-DIHYDRO-

2H, 15'H"SPIRO| NAPHTHALENE-!, 22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOIM.T^.O'^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]-!5'-ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8 ^, E,irS,12'S)-6-CHLORO-7'-HYDROXY-12'-((2S)-2- HYDROXY-3-METHOXYPROPYL)-ir-METHYL~3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( >X A| i ? I ! f !! \| ί i J |i^f \Z \ f 1: E RAC YCE C)l i J 7.20 ^{:' i'} .0 ^li ' |Pi-:N i ACOSA |8.i .i8.24! rL!RAi:Ni- 15 -ONi: 13',13'-DIOXIDE

STEP 1: (2SH-((1S,3'R,6'R,7'S,8'EJ l ^, S,12'R)-6-CHLORO-7 ^, -HYDROXY-l Γ- METOYL-13VI3'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO1A[1,14]DIAZATEIIACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8 ₅ 16.18,24]TETRAEN]-12'-YL)-3-METHOXY-2-PROPANYYL BENZOATE AND (2S)-l-((iS,3'R,6'R,7'S,8'E,l l'S , 12'S)-6-CHLORO-7'-HYDROXY- 11 '- METHYL- 13',] 3 '-DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-l ₅ 22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.( ^)3> ^0 ^!9 - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-12'-YL)-3-METHOXY-2-PROPANYYL BENZOATE

The title compounds were prepared as a mixture following the procedure described in Step 6 for the synthesis of Example 666, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc/Hexanes (EtOAc contained 0.1% HO Ac) to provide the title compounds as a mixture as a white solid, m/z (ESI, +ve ion) 777.3 (M+H) .

STEP 2. (1S,3'R,6¾ ^! S,8T,11'SJ^'Ri-e-CHLORO-y'-HYDROXY-^'-^S)^ HYDROXY-3-METHOXYPROPYL)-! 1 '~METHYL-3,4-DIHYDRO-2H,I5'H- SPIRO[NAPHTHALENE- 1 ,22'- | 2ujOXA| O ΙΊ ί Ι1Λ| I„ I 4|DI A/ATETR ACYC ^' f .Oj i 4.7.2.U ' ".i ^{) 1} '" ¹ |Ρ1·Ν I ^' ACOS A

[8,16,18,24jTETRAENj-15'-ONE 13',13'-DIOXIDE OR

(lS^'R^'R.T'S^ i rsa^SK-CHLORO-T-HYDROXY-iy-^S)^- HYDROXY-3-METHOXYPROPYL)-l l'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE

A mixture of crude {2 }- ! -{{ I S.3 ^' R.6' .7'S.8'H. ! 2'S}-6-chIoro-7'-meihoNv- 13',13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spifo[naphthalene-l,22'- [20]oxa[I 3]thia[l,I4]diazatetTacyclo[147.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-12'-yl)-3-methoxy-2-propanyyl benzoate or (2S)-1-((1S,3'R,6 ^! R,7'S,8 ^! E,12'R)~ 6-chloro-7'-methoxy-13',13'-dioxido-15'-oxo-3,4-d^

1,22'-

[20]oxa[ 13]thia|;i , 14]diazatetracycio[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pen

n]-12'-yl)-3-methoxy-2-propanyyl benzoate (Step 1) (32 mg, 0.041 mmol) and lithium hydroxide monohydrate (69.2 mg, 1.65 mmol, Sigma- Aidnch Chemical Company, Inc.) in THF/MeOH/water (3 : 1 : ! .3 mL) was allowed to stir in a 55 °C bath for 1.5 h. The reaction mixture was removed from the bath and allowed to stir at rt for overnight. The organic solvents were removed under reduced pressure. The resultant mixture was treated with AcOH (0.1 mL), diluted with water (3 mL), and extracted with 30% 'PrOH/chloroform (3x6 mL). The organic solutions were combined. After removal of organic solvents under reduced pressure, the crude product was re-dissolved in DMF (1 mL) and subjected to reverse phase preparatory HPLC (Gemini™ Prep CI 810 μχ column;

Phenomenex, Torrance, CA; gradient elution of 10% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) for purification to provide one of the title compounds as the first eluting fraction as a white foam. 'Π NMR (400MHz, CDCb) δ 8.19 (br, s., III).7.69 (d, j 86 Hz, IH), 7.18 (dd, J=2.1, 8.5 Hz, lit).7.10 (s, III).7.00 - 6.87 (m, 3H), 5.89 (d, J=9.0 Hz, ill).5.72 (dd, j 7.4.14.7 Hz, Hi).4.54 (d, j 10.2 Hz, 1H), 4.40 (br. s., III). 4.27 (br. s., ill).4.09 is.2H), 3.81 id..1 157 Hz, IH).3.69 (d, j 143 Hz, III). 3.51 (m, IH), 3.42 (m, 4H), 3,24 (d, J=14.3 Hz, ill).3,09 - 2.95 (m, III).2.88 - 1.17 (m, 19H), 1.05 (d, j 6.5 Hz, 3H). m/z (ESI, +ve ion) 673,3 (M+H) ⁺ .

EXAMPLE 673. (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-7'-HYDROXY-12 ^! "

((2S)-2-HYDROXY-3-METHOXYPROPYL)-ir-METHYL-3,4-DIHYDRO- 2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-QNE 13',13'-DIOXIDE OR

(lS,3'R,6 ⁱ R,7'S,8'E,ri'SJ2'S)-6-CHLORO-7'-HYDROXY-I2'-((2S)-2-

HYDROXY-3-METHOXYPROPYL)-ir-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]TIlIA[l,14]DIAZATETRACYCLO[14.7.2.() ^3>, 0 ^!9 - ²⁴ ]PENTACOSA

[8,16,18,24] TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 672, Step 2, ^l H NMR (400MHz, CDCb) δ 8.19 (br. s., ill).7.78 - 7,59 (m, Hi).7.18 id. J 6.8 Hz, IH), 7.09 (s., 1H), 7.03 - 6.84 (m, 3H), 5.84 - 5.61 (m, I Hi.5.60- 5.54 (m, IH), 4.61 - 4.31 (m, 1H), 4.23 (d, j 18.2 Hz, III).4.17 - 3.97 (m, 3H), 4.00 - 3.61 (ra, 4H), 3.61 - 1.21 (m, 24H), 1.20 - 0.98 (ra, 3H). m/z (EST, +ve ion) 673.3 (M+H) ⁺ .

EXAMPLE 674. (1 S,3 ^, R,6 ^! R,7'S,8 ^! E,12 ^! S)-6-CHLORO-7'-HYDROXY-12'- PHENYL-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE"l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ^3>, 0 ^!9 - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12'-PHENYL"3,4-

DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18 ,24] TETR AEN] - 15 ' -ONE 13', 13 ' -DIOXIDE

STEP 1 : ((S)-N,N-BIS(4-METOOXYBENZYL)-l-PHENYLPENT-4-ENE-l- SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)- 1 - -4-ENE- 1 -SULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)-l-phenylmethanesulfonamide (3.00 g, 7.29 mmol, prepared in Step! in the synthesis of Example 653) in THF (36.5 mL) under N? in bath was added sodium bis(tnmethyisilyl)amide(8.02 mL, 1.0 M solution in THF, 8.02 mmol, Sigma- Aldrich Chemical Company, Inc.) at - 78 °C. After stirring in -78 °C bath for 10 min, to the solution was added 4- bromobut-l-ene (0.757 mL, 7.29 mmol, Sigma-Aldrich Chemical Company, Inc). The resulting mixture was removed from the bath and was allowed to warm to rt over 1.0 h. Additional sodium bis(trimethylsiiyl)amide(8.02 mL, 1.0 M solution in THF, 8.02 mmol, Sigma-Aldrich Chemical Company, Inc.) was added, and the solution was allowed to stir at rt for 1.5 h. The solution was quenched with saturated aqueous NH ₄ C1 (10 mL), diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The organic layers were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash

chromatography on ISCO Gold silica gel column with 0-70% EtOAc/Hexanes provided the title compound as a white solid.

STEP 2: (S)-l-PHENYLPENT-4-ENE-l-SULFONAMIDE AND (R)-l - PHENYLPENT-4-ENE- 1 -SULFONAMIDE

The title compounds were prepared as a mixture two isomers from ((S)- N,N-bis(4-methoxybeiizyl)-l -phenylpent-4-ene-l -sulfonamide and (R)-N,N-bis(4- methoxybenzyl)-l-phenylpent-4-ene-l -sulfonamide (Step 1) following a procedure similar to the one described for the synthesis of EE17 (Step 2).

STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBOTYL)METHYL)-N-(((S)-l-PHElSIYLPENT-4- EN-l-YL)SULFONYL)-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARBOXAMIDE AND (S)-6'-CHLORO-5 -(((1 R,2R)-2-((S) - 1 - HYDROXY ALLYL)CYCLOBUTYL)METHYL)-N-(((R)-l-PHENYLPENT-4- EN-l-YL)SULFONYL)-3',4,4',5-TETRAI-riT)RO-2H,2'H- SPIRO[BENZO[B][l 4]OXAZEPINE-3,l'-NAPH ^' raALENE]-7- CARBOXAMIDE

The title compounds were prepared as a mixture of two isomers from (S)- 1 -pheny lpent-4-ene- 1 -sulfonamide and (R)- 1 -pheny lpent-4-ene- 1 -sulfonamide (Step 2), and (S)-6'-ch3oro-5-(((lR,2R)-2-((S)-l-hydroxyaI3yl)c cIobutyl)meth l)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphtha]ene]-7- carboxylic acid (AA11A), following a procedure similar to the one described in Step 2 for the synthesis of Example 660, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-60% EtQAc/Hexanes (EtOAc contained 0.1% HO Ac) to provide the title compound as a white solid, m/z (ESI, +ve ion) 675.2 (M R)

STEP 4: (lS,3 ^, R,6'R,7 ^, S,8'E,12'S)-6-CHLORO-7 ^, -HYDROXY-12'-PHENYL-3,4- DIHYDRO-2H, 15H-SPIRO[NAPHTHALENE-l ,22'-

|2( !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ^; ".O ¹ " ^M |PH\ i ACOSA |S.i6.iH.24! r!: ! R.\i:Ni- 15 -ONi: 13',13'-DI0X1DE OR (18,3¾,6'Κ,7'8,8Έ,12'Κ)-6-0-ίΙ.ΟΚΟ-7'-ΗΥΟ ΟΧΎ-12'-ΡΗΕΝΥΙ.-3,4- DIHYDRO-2H, 15 Ή- SPIRO [Ν ΑΡΗΤΗ ALENE- 1 ,22 ^! -

|2ίί|0ΧΛ| 1ΉΤί!1Λ| Ι.Ι4|ΠίΑ/ΛΠ.ΤΗΑ(Ύα.ί)Ι i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,241 TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE The title compound was prepared from (S)-6'-chloro-5-(((l.R,2R)-2-((S)-l- hydrox'allyl)cyclobutyl)methyl)-N-(((S)-l-phenylpent-4-en-l- yl)sulfonyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r -naphthalene]-7- carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)c lobutd)methyl)-N-(((R)-l-phenylpent-4-en-l-yl)sulfonyl)- 3 l,4 ^! ,5-tetrahydro-2H,2 ^! H-spiro[benzo[b][l,4]oxazepine~3,i'-naphthalene]-7- carboxamide (Step 3) following a procedure similar to the one described in Step 3 for the synthesis of Example 660, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep C I 85 μιη column;

Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to pro vide one of one of the title compounds as the first eluting isomer as a white foam. ^l H NMR

(400MHz, CDCh) δ 8.25 (br. s„ ill).7,77 - 7.62 (m, 211 ).7.62 - 7.52 (m, 2H), 7.52 - 7.39 (m, 3H), 7.23 - 7.14 (m, 2H), 7.11 (d, i=2.2 Hz, 1H), 6.99 - 6.91 (m, Hi), 5.71 (dd, j 4.2.15.9 Hz, III).5.62 - 5.48 (m, 1H), 5.19 (d, J=10.8 Hz, 1H),4.31 - 4.20 (m, 2H), 4,18 - 4.03 (m, ill).3.96 (br. s„ ill).3,87 - 3.75 (m,

IH), 3.40 - 3.28 (m, 1H), 3.15 (d, J=16.2 Hz, 1H), 2.76 (br. s., 2H), 2.65 - 2.51 (m, 2H), 2.51 - 2.39 (m, IH), 2.38 - 1.22 (m, 12H). m/z (ESI, +ve ion) 647.0 i\i H) .

EXAMPLE 675. (1 S,3'R,6 ^f R,7'S,8 ⁱ E,12 ⁱ S)-6-CHLORO-7'-HYDROXY-12'- PHi-.\YI.-. -l-l)li IYDRO-2! 1.1 ^' i i-Ss'IR()| N AIM ΓΠ J ·.%!.-'·.22'- |2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [8,16,18,24|TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(lS,3¾,6'R,7^,8^I2'R)-6-CHLORO-7'-HYDROXY-!2'-PHENYL-3,4 - DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 674, Step 4. Ή N.V1R (400MHz, CDCh) δ 8.15 - 8.00 (m, 1H), 7.72 (d, j 8.0 Hz, 1H), 7.54 (d, J=14.9 Hz, 2H), 7.42 (d, J=19.4 Hz, 3H), 7.25 - 7.00 ins. 3H), 6.94 (d, j 6.3 Hz, 2H), 5.90 (d, J=10.8 Hz, 1H), 5.75-5.70 (m, 1H), 5,45 - 5.26 (m, 1H), 4.32-3.97 (m, 3H), 3,93 - 3.62 (m, 2H), 3.31 - 3.14 (m, i l l ). 2,99-1.22 (m, 18H); m/z (ESI, +ve ion) 647.0 (M+H) ⁺ .

EXAMPLE 676. (1S,3'R,6'R,7 ^* S,8'E,1 l'R,12'R)-6-CHLORO-l 1'-

CYCLOPROPYL-7'-HYDROXY-12'-METHYL-3,4-DII-IYDRO-2H,15'H-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]TH1A[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,1 l'S,l 2'R)-6-CHLORO-l l'-CYCLOPROPYL-7'-HYDROXY- '-METHYL-S^-DIHYDRO^H S^SPIROINAPHTHALE E-l^^- [20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14J.2 ³ ' ^{6 19i4} ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS.S'R^'^T'S^'E rR.l^S^e-CHLORO-l l'-CYCLOPROPYL-T'-HYDROXY- 12'-METHYL-3 ,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13 iTHIA[l,14jDIAZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, I 8,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,l l ^, S,12'S)-6-CHLORO-i r-CYCLOPROPYL-7'-HYDROXY- 12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO|NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8,16, 18 ,24] TETRAEN]- 15 ' -ONE 13 ', 13 ' -DIOXIDE

STEP 1 : (R)-2-CYCLOPROPYL-N,N-BIS(4-METHOXYBENZYL)PENT-4- ENE-1 -SULFONAMIDE AND (S)-2-CYCLOPROPYL-N,N- METHOXYBENZYL)PENT-4-ENE- 1 -SULFONAMIDE

The title compounds were prepared from (R)-2-cyclopropylpent-4-ene-l- sulfonamide and (S)-2-cyclopropylpent-4-ene- l -sulfonamide (prepared in Step 8 for the synthesis of Example 690) following a procedure similar to the one described for the synthesis of EE 12, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-60%

EtOAc/Hexanes to provide the title compounds as a mixture of two isomers.

ΙΊΈΡ 2: (2S,3R)-3-CYCLOPROPYL-N,N-BIS(4-METHOXYBENZYL)HEX-5- ENE-2-SULFON AMIDE AND (2R,3R)-3-CYCLOPROPYL-N,N-BlS(4- METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE AND (2S,3S)-3- CYCLOPROPYL-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2- SULFONAMIDE AND (2R,3S)-3-CYCLOPROPYL-N ₅ N-BIS(4- METHQXYBENZYL)HEX-5-ENE-2-SULFQNAMrDE

The title compounds were prepared from (R)-2-cyclopropyl-N,N-bis(4' methoxy benzyl)pent-4-ene-l -sulfonamide and (S)-2-cyclopropyl-N,N-bis(4- methoxybenzyl)pent-4-ene-l -sulfonamide (Step 1 ) following a procedure similar to the one described for the synthesis of EE 17 (Step 1), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-30% EtOAc/Hexanes to provide the title compounds as a mixture of four isomers, m/z (ESI, +ve ion) 444.1 (M+H) ⁺ .

STEP 3: (2S,3R)-3-CYCLOPROPYLHEX-5-ENE-2-SULFONAMIDE AND (2R,3R)-3-CYCLOPROPYLHEX-5-ENE-2-SULFONAMIDE AND (2S,3S)-3- CYCLOPROPYLHEX-5-ENE-2-SULFONAMIDE AND (2R,3S)-3- CYCLOPROPYLHEX-5-ENE-2-SULFONAMIDE

The title compounds were prepared from (2S,3R)-3-cyclopropyl-N,N- bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide and (2R,3R)-3-cyclopropyl-N,N- bis(4-methoxybenzyi)hex-5-ene-2-sulfonamide and (2S,3S)-3-cyclopropyl-N,N- bis(4-methoxybenzyl)hex-5-ene-2-sulfonamide and (2R,3S)-3-cyclopropyl-N,N- bis(4-me1hoxybenzyl)hex-5-ene-2-sulfonarnide (Step 2) following a procedure similar to the one described for the synthesis of EE 17 (Step 2), except that the crude product was purified by flash chromatography on IS CO Gold silica gel column using 0- 100% EtOAc/Hexanes (EtOAc contained 0, 1 % HO Ac) to provide the title compounds as a mixture.

STEP 4: (S)-6 ^! "CHLORO-5~(((lR,2R)~2"((lS,5S,6S,E)-5-CYCLOPROPYL-l- HYDROXY-6-SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 2 I-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, 1 "- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((lS,5S,6R,E)-5-CYCLOPROPYL-l-HYDROXY-6-SULFAMOYLHEPT-2- EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6 ^, -CHLORO-5-(((lR,2R)-2-((l S,5R,6S,E)-5-CYCLOPROPYL- 1 -HYDROXY -6-SULFAMO YLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H 2 I-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, 1 "- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-((( 1 R,2R)- 2-((lS,5R,6R,E)-5-CYCLOPROPYL-l-HYDROXY-6-SULFAMOYLHEPT-2- EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO[BENZO|B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXYLIC ACID

The title compounds were prepared as a mixture from (S)-6'-chloro-5- (((lR,2R)-2-((S)-l-hydroxyaltyl)cyclobutyl)meihyl)

spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxyl ic acid (AAllA) and (2S,3R)-3-cyclopropylhex-5-ene-2-sulfonamide and (2R,3R)-3-cyclopropylhex-5- ene-2-sulfonarnide and (2S,3S)-3-cyclopropylhex-5-ene-2-sulfonamide and

(2R,3S)-3-cyclopropylhex-5-ene-2-sulfonamide (Step 3) following a procedure similar to the one described in Step 4 for the synthesis of Example 653. STEP 5: (1S,3'R,6'R,7'S,8'E,1 l'R,12'R)-6-CHL()R()-ir-CYCLOPROPYL-12'- METOYL-13VI3'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPi ()i\AFHill.\!J \i:-1.22-

[20]OXA[13]TH1A[1 4]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8,16,18,24]TETRAEN]-7'-YL ACETATE AND (1S,3'R,6'R,7'S,8'E,1 l'R,12'S)- 6-CHLORO- 11 '-C YCLOPROPYL- 12'-METHYL- 13' , 13 '-DIOXIDO - 1 -OXO- 3,4-DIHYDRO-2H-SPlRO[NAPHTHALENE-l,22'- [ 20] OXA[ 1 ΓΠ 1 , 14]DI AZATETRACYCLO [14 .2.0 ³ -^0 ^{i 9} - ²⁴ ]PENTACOSA[8, 16, 18,241TETRAEN]-7'-YL ACETATE AND (1 S,3'R,0'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO- 1 1 '-CYCLOPROPYL-12 ^! ~METHYL- 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- [2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]-7'-YL ACETATE AND (1 S,3'R,6'R,7'S,8'E,1 l 'S, 12'S)-6- CHLORO- 11 '-CYCLOPROPYL-12'-METHYL- 13', 13'-DIOXIDO- 15'-QXQ-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20] OXA[ 13]THI A[ 1 , 14] DI AZ ATETR AC YCLO

[14 .21 ⁾³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[8/ );i 8 ₅ 24]TCTRAEN]-7'-YL ACETATE

The title compounds were prepared from (S)-6'-chloro-5-(((l.R,2R)-2- ((1 S,5S,6S,E)-5-cyclopropyl-l -hydroxy -6-sulfamoylhept-2-en-l - yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l,4]oxazepine- 3, -naphthalene|-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2- ((l S,5s,6R,E)-5-c^ lopropyl-l-hydroxy-6-sulfamoylhept-2-en-l - yl)cyclobut\d)methyl)-3',4,4^5-tetrahydro-2H,2'H-spiro[benzo [b][l ,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2- ((1 S,5R,6S,E)-5-cyclopropyl- i-hydroxy-6-sulfarnoylhept-2-en-l- yl)c> lobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2- ((l S,5R,6R,E)-5-cyclopropyl-l-hydroxy-6-sulfamoylhept-2-en-l- yl)c lobutyl)methyl)-34,45-tetrahydro-2H,2^spiro[benzo[b][l,4]oxa zepine- 3, -naphthalene]-7-carboxylic acid (Step 4) following a procedure similar to the one described for the synthesis of Example 690, Step 10, except that the crude product was purified by reversed phase preparatory HPLC (Gemini® 10 μη NX- CI 8110 A column; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to provide the title compounds as a mixture.

STEP 6: (IS,3'R,6'R,7'S,8'E,1 l'R,12'R)~6~CHLORO~l 1 '-CYCLOPROPYL-7'- HYDROXY-]2'-METHYL-3,4 3IHYDRO-2H,15'H-SPlRO[NAPHTHALENE- 1,22'-

|;20]()XA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8 ^, E,irS,12'R)-6-CHLORO-ir-CYCLOPROPYL~7 ^! ~HYDROXY- 12 ^, -ME^ΉYL-3,4-DIHYDRO-2H 5Ή-SPIRO| APH HALENE-l,22 ^, - [20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7,2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24] TETRAEN] -15' -ONE 13 ' , 13 ' -DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,irR,12 ^! S)-6-CHLORO-ll'-CYCLOPROPYL-7'-HYDROXY- 12'-METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE - 1 ,22'- |20jOXA| I 311 HI Λ| I .. N |PI A/A Π·. E R. AC VC ^' E C)i i J 7.20 ^; ".O ¹ " ^M |PH\ i ACOS A |8.i .i8.24! r!: ! R.\i:Ni- 15 -ONi: 13',13'-DI0X1DE OR

(lS,3'R,6 ^! R,7 ^, S,8'E,ll'S,12'S)-6-CHL0R0-ir-CYCL0PR0PYL-7'-HYDR0XY- 12'-METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA

[8, 16, 18,24] TETRAEN ] - 15 ' -ONE 13 ', 13 ' -DIOXIDE The title compounds were prepared from (lS,3'R,6'R,7'S,8'E,irR,12'R)-6- chloro-1 r-cyclopropyl-12'-methyl-13',13'-dioxido-15'-oxo-3,4-dihydro -2H- spiro [naphthalene- 1 ,22'- Hjaitetrae n]-7'-yi acetate and (1S,3'R,6'R,7'S,8'E,1 l'R,12 ^! S)-6-chioro-l l'-cyclopropyl-12'- methyl- 13', 13'-dioxido- 15'-oxo-3 ,4-dihy dro-2H-spiro [naphthalene- 1 ,22'- [20] oxa i 3] ihi a[ I /I 4] ds

n]-7'-yl acetate and (1 S,3'R,6'R,7 ^! S,8'EJ l 'S;i2¾)-6-chloro-i r-cyciopropyl-12 ^! ~ niethyl-13 ^, J3'-dioxido-15'-oxo-3,4-dihydro-2H"Spiro[naphthalene-l ,22'- [20]oxa|;i 3]thia[U4]diazatetra^

n]-7 ^* -yl acetate and (1 S,3'R,6'R,7'S,8'E, 11'SJ 2'S)-6-chloro-l 1 '-cyclopropyl-12'- methyl-13^13 ^, -dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-L22'- [20]oxa[13]thia[l,14]diazatetracydo[M _^

n]-7'-yl acetate (Step 5) following a procedure similar to the one described for the synthesis of Example 683, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 90% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to provide one of the title compounds as the second eluting fraction as a white foam. ¾ MR (400MHz, CDCb) δ 8.01 (br. s., 1H), 7.71 - 7.51 (m, 2H), 7.16 - 7.05 (m, 2H), 7.03-6.99 (m, 1H), 6.94 - 6.80 (m, 1H), 5.79 (dd, .1 !-! 3. 15.6 Hz, i l l ). 5,43 (dd, j 7.9. 15.6 Hz, i l l ). 4,44 (d, j 7 6 Hz, 1H), 4.15 - 3.76 (m, 4H), 3.76 - 3.52 (m, 3H), 3.30 - 0.95 (m, 19H), 0.80 (d, j 4.9 Hz, 1H), 0.65 (d, J=16.0 Hz, 1H), 0.48 - 0.35 (m, 1H), 0.19-0.08 { in. I I I ). 0.08 - -0.01 (m, i l l ), m/z (ESI, +ve ion) 607.0 (M-H ₂ ()+H) ⁺ .

EXAMPLE 677, (1 S,3'R,6'R,7'S,8'E, 1 1 'R, 12'R)-6-CHLORO- 1 1 '-

C YCLOPROPYL-7'-HYDROXY- 12'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO[14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1S,3'R,6 ^! R,7'S,8 ^, E,1 l'S,12'R)-6-CHLORO-l l'-CYCLOPROPYL-7 ^! -HYDROXY- 12 ^, -ME^ΉYL-3,4-DIHYDRO-2H 5Ή-SPIRO| APH HALENE-l,22 ^, - [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8,16, 8,24] TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE OR

(lS,3 ^, R,6'R,7 ^! S,8'E,l l'R,12 ^, S)-6-CHLORO-l l ^, -CYCLOPROPYL-7'-HYDROXY- 12 ^, -ME™YL-3,4-DIHYDR0-2H,15'H-SPIR()[NAPHTHALENE-1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,ll ^, S,12'S)-6"CHLORO-ir-CYCLOPROPYL-7'-HYDROXY- 12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO|NAPHTHALENE-l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was obtained as a white foam as the fourth eluting isomer from the reversed phase preparatory HPLC separation in Example 676, Step 6. ^f H N.MR (400MHz, CDCh) δ 7,76 - 7.61 (m, 2H), 7.18 (dd, .! .1 .6,7 Hz, 1H), 7.10 (s, I Hi.7.04 - 6.86 (m, 2H), 5,82 - 5.61 (m, ill).5.56 - 5.34 (m, ill). 4.26 - 4.04 (m, 2H), 4.02 - 2.90 (m, 7H), 2.86 - 2.67 (m, 2H), 2.66 - 1.04 (m, 16H), 0.94 - 0.74 (m, 2H), 0.64 - 0.17 (m, 2H), 0.15-0.03 (m, 1H). m/z (ESI, +ve ion) 607.0 ( V!-! 1-0 · ! !} ^' . EXAMPLE 678, (1S,3 ^! R,6'R,7 ^! S,8'E,1 l'R,12 ^! R)-6-CHLORO-l 1'-

CYCLOPROPYL-7 ^! -HYDROXY-12 ^, -METHYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TET AEN] - 15 ' -ONE 13', 13 ' -DIOXIDE OR

(18,3¾,6 ^! ΐν7'8,8Έ,1 l'S,12'R)-6-CHLORO-l l'-CYCLOPROPYL-7 ^! -HYDROXY- 12'-METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE - 1 ,22'- |20jO.\A| 1311 HI Λ| I ..1 -1 |PI A/A Π·. iRACVCi.01 i -1.7.20 ^{; i'} .U ^li, |PH\ iACOSA |S.i .iH.24i r!: ! R.\i:Ni- 15 -ONi: 13',13'-DIOXIDE OR

(lS,3 ^, R,6'R,7 ^, S.8 ^, E.ll ^, R,12 ^, S)-6-CHLORO-ll ^, -CYCLOPROPYL-7 ^, -HYDROXY- 12'-METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,11 ^* S, 12'S)-6-CHLORO-l 1 '-CYCLOPROPYL-7'-HYDROXY- '-METHYL-S^-DIHYDRO^H S^SPIROINAPHTHALENE-l^^-

2ujOXA| O I ^' l l II A| I . I 4|Di A/.Yi ^' ! R AC YO.OI i 4.7.2.U ^' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA 8,16,18,241 TETRAENI -15' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was obtained as a white foam as the fifth eluting isomer from the reversed phase preparatory HPLC separation in Example 676. ^ι Ή N.V1R (400MHz, CDCh) δ 7.95 (d, J=8.4 Hz, ill).7.71 (d, j 8.6 Hz, 1H), 7.28- 7.16(m, 2H), 7.10 (s, 1H), 7.03 - 6.92 (m, 1H), 6.19 - 5.92 (m, 1H), 5.54 - 5.37 (m, 1H), 4.27 - 3.99 (m, 3H), 3.99 - 3.61 (m, 3H), 3,46 - 3.15 (m, 2H), 2.92 -1.18 (m, 1 H).1,57 (d, J 8.-1 Hz, 31!}.0,97 - 0,82 (m, 1H), 0.81-0.73(m, 1H), 0.52 (dd, j 4.5.9.2 Hz, ill).0.31 - 0.13 (m, 1H), 0.11-0.01 (m, 1H). m/z (ESI, +ve ion) 607.0 (\!··ί ! )·!!} . EXAMPLE 679. (1 S,3'R,6'R,7'S,8'E, 1 I'S, 12'R)-6-CHLORO-l 2'-((2S)-2- HYDROXY-3-METHOXYPROPYL)-7'-METHOXY-i -METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA [8,16,18,24]TETRAEN]~15'~ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S _s 8 ^, E _s ll ^, S,12 ^, S)-6-CHLORO-12 ^, -((2S)-2-HYDROXY-3- METHOXYPROPYL)-7'-METHOXY-ir-METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[N APHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Ι..! |ί)!Λ/Λ! :ΓΗ.Λ( ^' .01117.20 ^;ί '.ϋ |ΡΗ\ i ACOSA |8.i .i8.24! rL!R.\i:Ni- 15 -ONi: 13',13'-DIOXIDE

STEP 1: (2S)-l-((lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,ll ^, S,12 ^, R)-6-CHLORO-7 ^, -METHOXY-ll ^, - METHYL- 13', 13 '-DIOXIDO - 15 '-QXQ-3 ^-DIHYDRQ^H- SPIROINAPHTHALENE-l^'- ^OJOXAt jmiAn/MiDIAZATETRACYCT _^ ^

[8,16,18,24]TETRAEN]-12'-YL)-3-METHOXY-2-PROPANYL BENZOATE AND (2S)-1-((1 S,3'R,6'R,7'S,8'E,1 rS,12'S)-6-CHLORO-7'-METHOXY-i - METHYL-13',13'-DIOXIDO-.15'-OXO-3,4-DIHYDRO-2H- SP1RO [NAPHTHALENE- 1 ,22'- ;20]OXA[13]IHIA[L14]DlAZATETiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA 8,16,18,24]TETRAEN]-12'-YL)-3-METHOXY-2-PROPANYL BENZOATE

The title compounds were prepared from (2S)-1- ((lS,3 ^, R ₅ 6 ^* R,7 ^, S,8¾ll ^, S ₅ 12 ^, R)-6-chloro-7 ^, ½droxy-ll ^, -metiiyl-13\13 ^, -dio^ 15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

n]-12'-yl)-3-methoxy-2-propanyl benzoate and (2S)-1-

((1 S,3'R,6 ^f R,7'S,8'E,i i'S ,12 ^, S)-6-chloro-7'-hydroxy-l 1 '-methyl- 13" ,13-dioxido-

15 ^! -oxo-3,4~dihydro~2H~spiro[naphthalene-l,22'- i8.24jteirae n]-12'-yl)-3-methoxy-2-propanyl benzoate (prepared in Step 1 for the synthesis of Example 672) following a procedure similar to the one described for the synthesis of Example 669 using methyl iodide instead of 2-bromoethyl methyl ether.

STEP 2: (1S,3'R,6'R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-12 ^, -((2S)-2-HYDROXY-3- METl- )XYPROPYL)-7'-METHOXY-ir-METHYL-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2θ!() Λ| I 311 HI Λ| I 14 j Of A A ΓΓ. ΓΗ. ΛίΎί ^' ί.01 i -1.7.2 ' ".O ^1* " ¹ |PHNT.\C0SA [8,16,18,24jTETRAEN]-15'-ONE 13'.13'-DIOXIDE OR

(lS,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E,ll'S ₅ 12 ^, S)-6-CHLORO-12 ^, -((2S)-2-HYDROXY-3- METHOXYPROPYL)-7'-METOOXY-ir-METHYL-3 l-DIHYDRO-2HJ5 ^! H- SP1RO [NAPHTHALENE- 1,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14 .2 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8,16,18 ,24] TETR AEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was prepared from (2S)-1- ((lS,3'R,6 ^! R,7'S,8 ^, E,ll'S,12'R)-6-chioiO-7'-methoxy-ir-methyl-13',13'-dio xido- 15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracyclo[M^

n]-12'-yl)-3-methoxy-2-propanyl benzoate and (2S)-1-

15'-oxo-3 ,4-dihy dro-2H-spiro [naphtha! en e- 1 ,22'-

n]-12'-yl)-3-methoxy-2-propanyl benzoate (Step 1) following a procedure similar to the one described for the synthesis of Example 672 (Step 2), except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 10 μηι column; Phenomenex, Torrance, CA; gradient elution of 45% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as the second eluting fraction as a white foam. ¾ NMR (400MHz, CDCh) δ 7.77 (br. s., i l l ). 7.73 - 7.64 (m, 1H), 7.22 - 7.15 (m, 1H), 7.13 - 6.97 (m, 2H), 6.96 - 6.83 (m, 2H), 6.01 - 5.86 (m, 1H), 5.50 (dd, J 9.1 , 15.0 Hz, 11 1 ). 4,61 id. J=9.4 Hz, i l l ). 4,37 (br. s . i l l ). 4.21 - 4.02 (m, 3H), 3.90 - 3.60 (m, 4H), 3,55 - 3.22 (m, 2H), 3.41 (s, 3H), 3.20 (s, 3H), 2.88 - 1.09 (ni, 18! ! ). 1.03 (d, j 5.2 Hz, 3H). m/z (ESI, +ve ion) 687.1 (M+H) ¹ .

EXAMPLE 680. (18,3'Κ,6'Κ,7'8)-6-( ΗΕΟΚΟ-7·-ΗΥϋΜ)ΧΥ-3,4-ΟΙΗΥϋΜ)- 2Η,9Ή, 15'H-SPI O[NAPHTO ALENE-1 ,22'-

[20]OXA[13]THIA[1 ,10, 14]T1UAZATETOACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTAC

QSA[16,18,24]TRIENE]-9',15'-DiQNE 13',13'-DIOXiDE OR (lS,3'R,6'R,7'R)-6-

CHL()R()-7'-HYDR()XY-3,4-DIHYDRO-2H,9'H,15'H-

SPTRO[NAPHTH ALENE- 1 ,22'-

[20] OXA[ 13]THIA[ 1, 10,14] TRI AZ ATETRAC YCLO [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ - ²⁴ ]PENTAC OSA[ 16, 18,24]TRJENE]-9',15'-DIONE 13',13'-DIOXIDE

To a solution of racernic trans cyclobutane-l ,2-dica.rboxyHc acid (20.2 g,

140 mmol, Atlantic Research Chemicals Ltd) in THF (699 ml) in a 2 L round flask under running N ₂ line was added borane-THF complex (1.0 M, 559 ml, 559 mmol, Sigma- Aldrich Chemical Company, Inc.) drop wise via additional funnel over 65 min at 0 °C. The resulting mixture was allowed to stir in the ice bath for 15 min, removed from ice bath and left to stir at rt for 36 h. The reaction flask was placed into 0 °C ice bath, to the solution under running N ₂ line was slowly added ice (-300 g) over 45 min, vigorous gas formation was observed. The mixture was allowed to stir in ice bath for 2.0 h till gas formation ceased. The organic solvent and most of the water was removed under reduced pressure. To the residue was added 10% aqueous NaOH solution (200 niL), the mixture was allowed to stir at rt for 1.0 h. The resulting mixture was extracted with 30% 'PrOH/chloroform (3 x200 mL). The organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 50% to 100% of solvent A in hexanes (solvent A is 1 :3:6 MeOH/EtOAe/hexanes) as eluent provided the title compounds as colorless syrup (14.76 g, 91%).

STEP 2: ((lR,2R)-2-(HYDROXYMETHYL)CYCLOBUTYL)METHYL

BENZOATE H

To a suspension of sodium hydride (4.76 g, 119 mmol, 60% dispersed in mineral oil, Sigma-Aldrich Chemical Company, Inc.) in THF (298 ml) under running N2 line in ice bath was added a solution of a mixture of (1R,2R)- cyclobutane-1 ,2-diyldimethanol and (1 S,2S)-cy clobutane- 1 ,2-diyldimethanol

(13.8 g, 119 mmol, Step 1) in THF (100 mL) drop wise over 40 min. The resulting mixture was allowed to warm to rt over 30 min, heated in 50 °C oil bath for 2.5 h, then cooled to rt and allowed to stir at rt overnight. Large amount of precipitate was formed. The suspension was cooled to -50 °C, to the mixture was slowly added a solution of benzoyl chloride (16.7 g, 119 mmol, Sigma-Aldrich Chemical Company, Inc.) in 50 mL THF over 30 min. The mixture was allowed to warm with the bath to rt, and was allowed to stir at rt for 3 h. To the mixture under running N2 line was slowly added saturated aqueous NH4CI (100 mL), and water (100 mL). The resulting mixture was extracted with EtOAc (3 150 mL). The organic layers were collected and combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 15-80% EtOAc/Hexanes as eiuent provided the desired product as a mixture (19.7 g, 75%). LCMS (ES) [M + l ] ⁺ m/z 221. This mixture product was dissolved in MeOH (164 mg/mL) and was purified by SFC (Method: 250 ^χ 30 mm Chiralpak AD-H column, 2 in series w/ total length 500 mm, w/ 140 mL/min of 10% Ethanoi (20 mM NIL,)/ 90% CO2. Outlet pressure 100 bar; Temp. 20 °C; Wavelength 226 mm). The title compound was obtained as the second eluting stereoisomer (with retention time of 3.5-4.0 min) as a colorless syrup, m (ESI, +ve ion) 221.0 (M+H) ⁺ . STEP 3. (( 1 R,2R)-2-FORMYLC YCLOBUTYL)METHYL BENZOATE

To a solution of ((lR,2R)-2-(hydroxymethyl)cyclobutyl)methyl benzoate (3,32 g, 15.1 rnrnol , Step 2) in CH2Q2 (30 mL) under N ₂ was added

(diacetoxyiodo)benzene (5.34 g, 16.6 mmol, Acros Organics) followed by 2,2,6,6- tetramethylpiperidinooxy (0.118 g, 0.754 mmol, Lancaster Synthesis Ltd.) at 0 °C. The mixture was allowed to warm to rt and left stirring at rt. TLC (66%

EtO Ac/Hexanes) was used to monitor the reaction to completion (in 4 h). The reaction mixture was concentrated under reduced pressure, and the residue was purified flash chromatograph on ISCO Gold silica gel column using 20-45% EtOAc Hexanes as eluent to provide the title compound as colorless syrup (2.98 g, 91%). ¾ NMR (400MHz, CDCb) δ 9.77 (d, J=l ,37 Hz, IH), 8.13 - 7.92 (m, 2H), 7.66 - 7.52 (m, IH), 7.52 - 7.39 (m, 2H), 4.52 - 4.27 (m, 2H), 3.26 - 2.97 (m, 2H), 2,30 - 2.03 (m, 3H), 2.01 - 1.89 (m, 1 H).

STEP 4. ((1 R ₅ 2R)-2-((R)-3-(TERT-BUTOXY)- 1 -HYDROXY-3- OXOPROPYL)CYCLOBUTYL)METHYL BENZOATE AND ((1 R,2R)~2~((S)~ 3 -(TERT-BUTOXY)- 1 -HYDROXY-3 - OXOP

To a solution of ((l R,2R)-2-formylcydobutyi)methyl benzoate (1.40 g, 6.41 mmol, Step 3) in THF (80 mL) in ice bath under N2 was added drop wise of 2-tert-butoxy-2-oxoethylzine chloride (12.8 mL, 0.5 M in diethyl ether, 6.41 mmol, Rieke Metals, Inc.). The mixture was allowed to warm to rt with ice bath, and left stirring at rt for 14 h. To the rt solution was added additional 2-tert- butoxy-2-oxoethylzinc chloride (12.8 mL, 0.5 M in diethyl ether, 6.41 mmol, Rieke Metals, Inc) over 3 min. The mixture was allowed to stir at rt for additional 2,5 h, and was quenched with saturated aqueous NH4CI (50 mL), diluted with water (60 mL). The organic layer was separated, and the aqueous layer was back extracted with EtOAc (3 *35 mL). The organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 10-70%

EtOAc/Hexanes as eluent provided the title compounds as a mixture.

STEP 5. (R)-3 -(( 1 R,2R)-2-((BENZOYLOXY)METHYL)CY CLOBUTYL)-3 - HYDROXYPROPANOIC ACID AND (S)-3-((lR,2R)-2- ((BE ZOYLOXY)METHYL)CYCLOBUTYL)-3-HYDROXYPROPANOIC ACID

A mixture of ((l R,2R)-2-((R)-3-(tert-butoxy)-l-hydroxy-3- oxopropyl)cyclobutyl)methyl benzoate and ((lR,2R)-2-((S)-3-(tert-butoxy)-l- hydroxy-3-oxopropyl)cyclobutyl)methyl benzoate (1.66 g, 4.96 mmol, Step 4) in CH2CI2 (5.29 mL) and trif!uoroacetic acid (1.32 ml, Acros Organics) was allowed to stir at for 5.0 h, Additional triffuoroacetic acid (1.32 ml, Acros Organics) was added and the resulting mixture was allowed to stir at rt for 1.5 h. After removal of organic solvents under reduced pressure, the residue was re-dissolved in 30% 'PrOH/chloroform, washed with saturated aqueous NH4CI solution (4 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 100% EtOAc to provide the title compounds.

STEP 6. ((1 R,2R)-2-((R)-3-((2-(BENZYLTHTO)ETHYL)AMINO)-l - HYDROXY-3-OXOPROPYL)CYCLOBUTYL)METHYL BENZOATE AND ((lR,2R)-2-((S)-3-((2-(BENZYLTHIO)ETHYL)AMIN O) - 1 -HYDROXY-3 - OXOPROPYL)CYCLOBUTYL)METHYL BENZOATE

To a solution of (R)-3-((lR,2R)-2-((benzoyloxy)methyl)cyclobu1yl)-3- hydroxypropanoic acid and (S)-3-(( lR,2R)-2-((benzoyloxy )methyl)cyclobutyl)-3- hydroxypropanoic acid (166 nig, 0.596 mmol, Step 5) in CHCb (10 mL) and hunig's base (0.467 mL, 2.68 mmol, Sigma- Aldrich Chemical Company, Inc.) at rt under N ₂ was added 4-(dimethylamino)pyridine (87.0 mg, 0.716 mmol, Sigma- Aldrich Chemical Company, inc.), s-benzylcysteamine hydrochloride (365 mg, 1.79 mmol, Sigma- Aldrich Chemical Company, Inc.) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (343 mg, 1.79 mmol, Advanced ChemTech) in sequence. The mixture was allowed to stir at rt ovemighi. The mixture was quenched with saturated aqueous NH C! solution (2 mL), and extracted with CH2CI2 (3 8 mL). Organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 0-80% EtOAc (EtO Ac contained 0.1% HO Ac) to provide the title compounds.

STEP 7. ((lR,2R)-2-((R)-l 1,1 l-DIMETHYL-6-OXO-l,10,10-TRIPHENYL-9- OXA-2-THIA-5-AZA-10-SILADODECAN-8-YL)CYCLOBUTYL)METHYL BENZOATE AND (( ! R,2R.)~2~((S)~ 11,1 1 -DIMETHYL-6-OXO- 1 , 10, 10- TRIPHENYL-9-OXA-2- ^' raiA-5-AZA- 10-SILADODEC AN-8-

To a 0 °C solution of ((lR,2R)-2-((R)-3-((2-(benzylthio)ethyl)a.mino)- i- hydroxy-3-oxopropyl)cyclobutyl)methyl benzoate and ίί I R :R )-2-ii S )-3-ii 2- (benz> thio)ethyl)aniino)-l-hydroxy-3-oxopropyl)cyclobut5 _' l)methy benzoate (0.600 g, 1.40 mmol. Step 6) in CH2CI2 (14 mL) was added 2,6-dimethylpyridine (0,326 ml, 2.81 mrnol, Sigma-Aldrich Chemical Company, Inc.) followed by (1, 1- dimethylethyl)diphenylsilyl trifluoromethanesulfonate (0.981 g, 2.53 mmol, TCI America). The mixture was allowed to warm with the ice bath to rt and to stir at rt for 2.5 h. The reaction solution was quenched with saturated aqueous NaHCCb solution (3 mL), diluted with water (5 mL), and extracted with 30%

'PrOH/chloroform (3x8 mL). The organic solutions were combined, washed with water (3 mL) and brine (3 mL). After remo val of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 0-50% EtOAc provided the titled products as two fractions each containing one of the title compounds. Combined both fractions to provide the title compounds as a mixture.

STEP 8. ((1 R,2R)-2-((R)- 1 -((TERT-BUTYLDIPHENYLSTLYL)OXY)-3-OXO- 3-((2-SUL;FAMOYLETHYL)AMiNO)PROPYL)C;YCLOBUWL

BENZOATE AND ( ( I R.2 R ) ^■■ ?. - ( ( S )·· HOT ^' RT - BUTYLDIPHENYLSILYL)OXY)-3-OXO-3-((2- SULFAMOYLETHYL) AMINO )PROPYL)CYCLOBUTYL)METHYL

A mixture of ((l R,2R)-2-((R)-l l,l l -dimethyl-6-oxo-l,10,10-triphenyl-9- oxa-2-thia-5-aza- 10-siladodecan-8-yl)cy clobutyl)methy 1 benzoate and (( I R,2R)-2- ((S)- 11,11 -dimethyl -6-oxo-l , 10,10~triphenyl-9~oxa-2-thia-5~aza- 10-siladodecan- 8-yl)cyclobut l)methyl benzoate (227 mg, 0.341 mmol, Step 7) and iodosobenzene (300 mg, 1.36 mmol, TCI America) in CH2CI2 (22 mL) was allowed to stir at rt for 8 min. To the mixture was added HC1 (37%, 2.45 mL, Sigma-Aldrich Chemical Company, Inc.) drop wise over 4 min. After stirring at rt for 20 min, the mixture was added drop wise into a cold solution of ammonium hydroxide (221.3 mL, 28%, Sigma-Aldrich Chemical Company, inc.) in ice bath over 12 min. The resulting mixture was allowed to stir in the ice bath for 40 min, diluted with water (10 mL) and 30% 'PrOH/chloroform (12mL), and was let settled at rt overnight. The organic layer was collected and the aqueous layer was back extracted with 30% 'PrOH/chloroform (2x 8 mL). The organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on SCO Gold silica gel column using 0- 80- 100% EtOAc provided the title compounds as a mixture.

STEP 9. (R)-; ((TERT-BUTYIJ3iPHENYLSILYL)OXY)-3-((l R,2R)~2- (HYDROXYMETHYL)CYCLOBUTYL)-N-(2- SULFAM()YLETHYL)PROPANAMIDE AND (S)-3-((TERT- BUTYLDIPHENYLSILYL)OXY)-3-((lR,2R)-2- (HYDROXYMETHYL)CYCLOBUTYL)-N-(2- S

To a mixture of (( lR,2R)-2-((R)-l-((tert-butyldiphenylsilyl)oxj -3-oxo-3-

((2-suliarnoyleihyl)a,mir!o)propyl)cyclobuty )methyl benzoate and ((lR,2R)-2- ((S)- l-((tert-butyldiphenylsilyl)oxy)-3-oxo-3-((2- sulfamoylemyl)arruno)propl)cyclobutyl)methyl benzoate (220 nig, 0.353 mmol, Step 8) in methanol (3.5 mL) was added sodium methylate (0.663 mL, 30%, Acros Organics). The mixture was allowed to stir at rt for 2.5 h and treated with water (6 mL). After removal of methanol solvent under reduced pressure, the resultant mixture was extracted with 30% 'PrOH/chloroform (2 ^χ 8 mL). The organic fractions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 0-10% MeOH/CHzCh to provide the title compounds as a mixture. STEP 10. (R)-3-((TERT-BUTYLDTPHENYLSILYL)OXY)-3-((l R,2R)-2- FORMYLCYCLOBUTYL)-N-(2-SULFAMOYLETHYL)PROPANAMIDE AND (S)-3-((TERT-BUTYLDIPHENYLSILYL)OXY)-3-((lR,2R)-2- F -N-(2-SULFA OYLETHYL)PROP AN AMIDE

The title compounds were prepared as a mixture from (R)-3-((tert- butyldiphenylsilyl)oxy)-3-((lR,2R)-2-(hydrox

sulfamoy lethy l)propanamide and (S)-3 -((tert-but ldipheny isily l)oxy )- 3 -(( 1 R,2R)- 2-(hydrox methyl)cyclobutyl)-N-(2-sidfamo lethyl)propanamide (Step 9), following a procedure similar to the one described above for the synthesis of ((lR,2R)-2-formylcyclobutyl)meihyl benzoate (Step 3), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-10% MeOH/CFfcCh to provide the title compounds as a white solid.

STEP 11. (S)-METHYL 5-(((l R,2R)-2-((S)-l -((TERT-

BUTYLDIPHENYLSILYL)OXY)-3-OXO-3-((2- SULFAMOYLETHYL)AMINO)PROPYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

CARBOXYLATE AND (S)-METHYL 5-(((lR,2R)-2-((R)-l-((TERT-

BUTYLDIPHENYLSlLYL)OXY)-3-OXO-3-((2- SULFAM()YLETHYL)AMIN())PROPYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

To a rt solution of (S)-methyl 6'-chloro-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene] -7-carboxyl ate (62.3 mg, 0.174 mmol, Intermediate AAl l A, STEP 12A), (R)-3-((tert-but 'ldiphenylsilyl)oxy)-3- ((l R,2R)-2-formylcyclobutyl)-N-(2-sulfamoyle1hyl)propanafnide and (S)-3-((tert- b uty Idipheny lsily l)oxy )-3 -(( 1 R,2R)-2-formy 1 cy clob uty l)-N-( 2- sulfamoylethyl)propanamide (45.0 mg, 0.087 mmol, Step 10) in CH2CI2 (1161 μΐ) was added acetic acid (0.38 mL, Sigma- Aldrich Chemical Company, Inc.). The mixture was allowed to stir at rt for 6 min, to the solution was added a solution of sodium cyanoborohydride (26 μΐ, 1.0 N in THF, 0.026 mmol, Sigma- Aldrich Chemical Company, Inc.) in THF (2.0 mL) drop wise over 1.0 h. The mixture was allowed to stir at rt for 1.0, treated with saturated aqueous NaHCOs (3 mL), diluted with water (3 mL), and extracted with CH2CI2 (3 x5 mL). The organic layers were combined, washed with water (3 mL) and brine (2 mL), and dried over MgS0 ₄ . After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-80% EtOAc/Hexanes (EtOAc contained 0.1 % HO Ac) provided the title compounds as a white solid.

STEP 12. (S)-5-(((lR,2R)-2-((S)-l-((TERT-BUTYLDlPHENYLSILYL)OXY)-3- OXO-3-((2- SULFAMOYLETHYL)AMINO)PROPYL)CYCLOBUTYL)METHYL)-6'-

CHLORO-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID AND ((S)-5-(((] R,2R)-2-((R)-l-((TERT- BUTYLDlPHENYLSILYL)OXY)-3-OXO-3-((2-

SULFAMOYLETHYL)AMINO)PROPYL)CYCLOBUTTL)METHYL)-6'- CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACI

To a rt mixture of (S)-methyl 5-(((lR,2R)-2-((S)-l-((tert- buty ldipheny lsilyl)oxy)-3-oxo-3-((2-

8uli½rioylethyi)amino)propyi)cyc]obutyl)methyl)-6'-chlor o

2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-ca rboxylate and (S)- metfayl 5-(((lR,2R)-2-((R)-l-((tert-butyldiphenylsilyl)oxy)-3-oxo-3- ((2- sulfamoylethyl)airiino)propyl)cyclobutyl)methyl)-6'-chloro-3 ',4,4',5

2H,2'H-spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naph thalene] -7-carbox late (105 mg, 0.122 mmol, Step 11) in 1,4-dioxane (0.4 mL) and MeOH (0.100 mL) was added 0.5 M aqueous lithium hydroxide solution (0.978 mL, 0.489 mmol, Sigma- Aldrich Chemical Company, Inc.). After stirring at rt for 40 min, to the mixture was added 4 M aqueous lithium hydroxide solution (0.15 mL). The resulting mixture was allowed to stir at rt overnight. The reaction mixture was treated with 6.0 N HC1 to PH = ^: 4.0. After removal of water and organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 0-10% MeQH/GHhCb. provided the title compounds as a mixture.

STEP 13. (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXY-3-OXO-3-((2- SULFAMOYLETHYL) AMINO )PROPYL)CYCLOBUTYL)METHYL)-3',4,4',5-

TETRAHYDRO-2H,2 ^! H-SPIRO[BENZO[B][l,4]OXAZEPiNE-3, l '- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO~5-(((lR,2R)- 2-((R)- 1 -HYDROXY-3-OXO-3-((2-

SULFAMOYLETHYL)AMINO)PROPYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDR0-2H,2'H-SPIR0|;BENZ0[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID

To a rt mixture of i S )-^-{({ I R .2 )-2-{( S)- s -(( ierl~but> ldiphen> isi Iy! )ox> )- 3-oxo-3-((2-sulfamoylethyl)amino)propyl)cyclobutyl)methyl)-6 '-chloro-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro| benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid and ((S)-5-((( lR,2R)-2-((R)-l -((tert-butyldiphenylsilyl)oxy)-3-oxo-3-((2- sulfamoylethyl)amino)propyl)cyclobut )methyl)-6'-chloro-3',4,4',5-te1rahyd 2H,2'H-spiro[benzo[b] [L4]oxazepine-3,r-naphthalene]-7-carboxylic acid (105 mg, 0.122 mmol. Step 11) in CH2CI2 (0.4 mL) was added tetrabutylammonium fluoride (0.71 mL, 1.0 M in THF, 0.71 mmol, Sigma- Aldrich Chemical Company, Inc.) followed by water (0.1 mL). The mixture was allowed to stir at rt overnight, treated with water (3 mL), and extracted with 30%) 'PrOH/chloroform (3 * 4 mL). The organic fractions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatograph on ISCO Gold silica gel column using 0-10% MeOH/CtfcCb provided the title compounds as a mixture.

STEP 14. (lS,3'R,6'R,7 ^f S)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H,9'H,15'H-SPIRO[NAPHTHALENE-l ,22'-

[20]OXA[13]TOL [ l,10,14]I¾lAZATETiL CYCLO[ 14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ ]PENTAC OSA[16, i8,24]TRIENE]-9', 15'-DIONE 13', 13'-DIOXIDE AND (1 S,3'R,6'R,7'R)- 6-CHLORO-7 ^! -HYDROXY-3,4-DIHYDRO-2H,9'H,15 ^! H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,10,14]TRTAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PE TAC OSAI 16, 18,24]TRIENE]-9', 15'-DIONE I .?.13'-DIOXIDE

The title compounds were prepared from (2S,3R)-3-cyclopropylhex-5-ene- 2-sulfonamide, and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hyclroxy-3-oxo-3-((2- sulfamoylethyi)amino)propyi)cydob^

spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid and (S)-6'- chloro-5-(((lR,2R)-2-((R)-l-hydroxy-3-oxo-3-((2- sulfamoylethyl)amino)propyl)cyclobutyl)methyl)-3',4,4',5-tet rah^

spiro [benzo [b] [1,4] oxazepine-3 , l.'-naphthal ene] -7-carboxy li c aci d (S ep 13 ) following a procedure similar to the one described for the synthesis of EXAMPLE 653, Step 4, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 810 μτη column; Phenomenex, Torrance, CA; gradient elution of 45% MeCN in water to 70% MeCN in water over a 45 min period, where both solvents contain 0,1% TFA) to provide one of the title compounds as the first eiuting isomer as a white foam. ^l ll NMR (400MHz,

CDCI3) 617.76-7,65 (m, 2H), 7.56 (s, 111).7.18 (d, J=9.0 Hz, 2H), 7.11 -7.08 (rn, 21 \ ).7.07 - 6.98 (m, ill).6,19 (br. s, ill).4.23-4.08 (m, 3H), 3,98 -0.89 (m, 22H). m/z (ESI, +ve ion) 588.1 {W W) .

EXAMPLE 681. (lS,3'R,6'R,7'S)-6-CHLOR()-7 ^, -HYDROXY-3,4-DIHYDRO- 2H,9TI, 15'H-SP1R0[NAPHTHALENE-1,22'-

[20]OXA[13]THIA[1^0,14]TRIAZATETOACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC

OSA[16,18,24]TRIENE]-9',15'-DIONE 13',13'-DI0X1DE OR (lS,3'R,6'R,7'R)-6-

CHL()R()-7'-HYDR()XY-3,4-DIHYDRO-2H,9'H,15'H-

SPTRO[NAPHTH ALENE- ! ,22'- [20] OXA[ 13]THIA[ 1,10,14] TRI AZ ATETRAC YCLO [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]ΡΕΝΤ AC

OSA[16,18,24]TRJENE]-9 ^! ,15'-DIONE 13',13'-DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 680, Step 14. 'HNMR (400MHz, CDCh) δ 10.10 - 9.56 (m, ill).7.74 (d, J 8.2 Hz, 111).7,52 id. J 7.6 Hz, IH), 7.23 - 7.15 (m, 2H), 7.10 (s., IH), 7.05 - 6.97 (m, I Hi.5.86 (d, j 10.4 Hz, 1H), 4.68-4.63 (m, IH), 4.58-4.53 (m, ill .4.25 - 4.05 (m, Ml).3.92 (d, .1 15 1 Hz, IH), 3.71 (d, .1 133 Hz, IH), 3.52 id..! 1 .5 Hz, IH), 3.31 (d, J=14.5 Hz, H), 3.25 - 3,06 (m, 2H), 2.78-1.32 (m, 15H). m/z (ESI, +ve ion) 588.1 (M+H) ⁺ . EXAMPLE 682. (lS,3'R,61V7'S,8T,12^>6-CHLORQ-I2H2-HYDRQXY-2- P OPANYL)-7'-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-l 2 ^f -(2-HYDROXY-2-PROPANYL)-7 ^f - ME^ΉOXY-3,4-DIHYDRO-2H ₅ 15Ή-SPIRO[NAPHTHALENE-l,22 ^, - [20]OXA[13]raj:A[l _s 14]DIAZATETRACYCLO[14J.2 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24] TETR AEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

To a solution of diisopropyl amine (240 μΐ, 1.71 mmol, Sigma- Aldrich Chemical Company, Inc.) in THF (6.0 ml.) under N? was added "BuLi (0.68 mL, 2.5 M in hexanes, 1.71 mmol, Sigma-Aidnch Chemical Company, Inc.) dropwise over 2 min at -78 °C. The mixture was moved into a 0 °C ice hath and left stirring in the bath for 8 min. This freshly made lithium diisopropylamide solution was then placed into -40 °C bath for a temporary storage. To a -78 °C solution of (l S,3¾,6'R,7^,8¾)-6-ehloro-7'-methox

1 ,22420] oxa[ 1 IT] thiap , 14 ^

[8,16, 18,24]tetraen]-l 5'-one 13',13'-dioxide (Example 651 , Step 3) (25 mg, 0.043 mmol) in THF (1.0 mL) under Ar was added Ν,Ν,Ν',Ν'- tetramethylethylenediamine, redistilled (26 μΐ, 0. 17 mmol, Sigma- Aldrich Chemical Company, Inc.) After stirring at -78 °C for 5 min, to this solution was added the freshly made lithium diisopropylamide solution as above (1.60 mL, 0.428 mmol). The resultant mixture was allowed to stir at -78 °C for 10 min, and then warmed to - 10°C over 40 min. To the - 10°C solution was added anhydrous acetone (dried over sieves, 1.0 mL, Sigma-Aldrich Chemical Company, Inc.) in one shot. The resulting solution was removed from the bath and left stirring at ambient atmosphere for 10 min before being quenched with saturated aqueous NH4CI (1 .0 mL). The mixture was diluted with water (2 mL) and extracted with EtOAc (3 x 5 mL). Organic layers were combined and dried over MgSC After remo v al of organic sol v ents under reduced pressure, the crude product was subjected to reverse phase preparatory HPLC (Gemini™ Prep C I 8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 55% MeCN in water to 90% MeCM in water over a 20 min period, where both solvents contain 0.1% TFA) to provide the title compound as a white foam. ^] H NMR (400MHz, CDCh) δ 8.28 (br, s., I I I ). 7.69 - 7.57 (m. 1 1 1 ). 7, 10 (dd, J 2.2. 8.5 Hz, IH), 7.01 (d, J 2.2 Hz, IH), 6,90 - 6.80 (m, 2H), 6.74 (s, 1H), 5.82 - 5.62 (m, IH), 5,45 (dd, J=8.1 , 15.4 Hz, I H), 4.35 - 4.25 (m, IH), 4.08 - 3.92 (m, 2H), 3.76 - 3.53 (m, 3H), 3.26 - 3.07 (m, 4H), 2,93 (dd, J '.>. ?. 15.2 Hz, IH), 2,78 - 2.60 (m, 2H), 2.47 - 2.26 (m. l ). 2.26 - 1.51 (m, 12), 1.45 (s, 3H), 1.34 (s, 3H), m/z (ESI, +ve ion) 643.0 (M+H) ⁺ . EXAMPLE 683. (1 S,3'R,6'R,7'S,8'E,1 l.'R)-6-CHLORO-l 1 '-CYCLOPROPYL-7'- HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- | 2u jOXA| 1 ΉΤί !1Λ| Μ 4 |ΠίΑ/Α Π:ΤΗ Α(Ύα.ί)Ι i 4.7.2.U ' ".i ^{) 1} '" ¹ |Ρ1·Ν I ^' ACOSA [ 8,16,18,24jTETRAENj-15'-ONE 13', 13'-DIOXIDE OR

(IS ,3'R,6'R,7'S,8'E, 1 l ^* S)-6-CHLORO-l 1 '-CYCLOPROPYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18 ,24] TETR AE ] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

To a rt solution of (I S^'R^'R^'S^'Ej rSj-e-chloi -ir-cyclopropyl-

13', 13'-dioxido-l 5'-oxo-3,4-dihydro-2H-spiro| naphthalene- l , 22'-

n]-7'-yl acetate and (l S,3'R,6 ^, R,7'S,8 ^, E,i rR)-6-chloro-i r-cyclopropyl-13',13 ^* - dioxido-15'-oxo-3,4-dihydro-2H-spiro| ^" naphthalene-l,22'- [20]oxa[13]thia[l ,14]diazatefra<^

n]-7'-yl acetate (35 mg, 0.054 mmol, Example 690) in anhydrous MeOH (2 mL) was added 5.4 M sodium methoxide in methanol (60 μί, 0.32 mmol, Acros). The mixture was allowed to stir at rt for 35 min. To the mixture was added HC1 (0.1 mL, 4.0 N) and water (0.2 mL). The resulting solution was subjected to reversed phase preparatory HPLC (Gemini™ Prep CI 8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% to 95% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to provide one of the title compounds as the first eiuting isomer as a white foam. ¾ NMR (400MHz, CDCb) δ 8.37 (br. s . H i ). 7.70 (d, J 8.4 Hz, IH), 7.18 (dd, J 2.0. 8.6 Hz, H i ). 7.10 (s, H i ). 7.02 - 6.90 (m, 2H), 6.84 (s, IH), 5.95 - 5,82 (m, 1H), 5.74 (dd, 1=7.9, 15.6 Hz, 1H), 4.35 (dd, j 9.8. 15.7 Hz, IH), 4.26 (dd, 1=3.5, 8.0 Hz, 1H), 4.15 - 4.02 (m, 2H), 3.83 - 3.64 (ra, 2H), 3,46 (dd, J 3.7. 15.8 Hz, 1H), 3,23 (d, J 14.5 Hz, IH), 3,06 (dd, J=9,7, 14.8 Hz, IH), 2.87 - 2,66 (m, 2H), 2.53 - 2.29 (m, 3H), 2.29 - 1,39 (m, 11H), 0.79 (d, j=5.1 Hz, IH), 0.64 - 0.51 (m, 2H), 0.31 (d, j 9.6 Hz, IH), 0.25 - 0.16 (m, IH). m/z (ESI, +ve urn ) 611.1 (M+H) ⁺ . EXAMPLE 684, (IS,3'R,6'R,7'S,8'E, 1 l'R)-6-CHLORO-l l'-CYCLOPROPYL-7'- HYDROXY-3,4 3IHYDRO-2H,15H~SPIRO[NAPHTHALENE-l,22 ^! -

[20]OXA[ 13]THLA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(l S,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,ll ^, S)-6-CHLORO-i r-CYCLOPROPYL-7 ^, -HYDROXY-3 ₅ 4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

20]OXA[13]THIA|;i,14]DL ZATETRACYCLO[14.7.2.0 ³ - ⁶ .() ^!9 - ²⁴ ]PENTACOSA 8, 16,18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 683. ¹ 1 1 NMR (400MHz, CDC] 3) δ 8.55 (br. s„ IH), 7,68 i d. j 8.4 Hz, IH), 7,22 - 7,08 (m, 3H), 7.06 - 7.00 (m, IH), 6,99 - 6.89 (m, IH), 5.94 - 5.78 (m, IH), 5,78 - 5.67 (m, IH), 4.22 - 4.05 (m, 3H), 4.00 - 3.63 (m, 3H), 3.63 - 3.35 (m, 3H), 2.77-1.19 (m, 16H), 0,96 - 0.85 (m, I H), 0.65 - 0.50 (m, 2H), 0,36-0.32 (m, IH), 0.23 - 0.10 (m, IH); m/z (ESI, +ve ion) 61 1.1 ( M l ! )

EXAMPLE 685, (1 S,3 ^! R,6'R,7 ^! S,8'E, 1 l'S)-6-CHLORO-l l '-ETHYL-T- H YDROXY-3 ,4-DIHYDRO-2H, 15 Ή-S PIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[ 1, I 2,14]TRTAZATETRACYCLO[ 14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]

PENT AC OS A[8, 16, 18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE OR

(1S,3'R,6'R,7 ^, S,8 ^, E,1 l'R)-6-CHLORO-l l ^! -ETHYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ² ]PENTAC OS A[8, 16, 18,24]TETRAEN] -15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compounds were prepared from 5-hexen-3-ol (MP Biomedicals, Inc.) following a procedure similar to the one described for the synthesis of (S)-2- (pent-4-en-2-yl)isoindoline-l ,3-dione (Step 1 for the synthesis of Example 664), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-40% EtOAc/Hexanes (EtOAc containing 0.1% HO Ac) to provide the title compound as white solid.

STEP 2: (S)-HEX-5-EN-3-AMTNE AND (R)-HEX-5-EN-3-AMINE

A mixture of (S)-2-(hex-5-en-3-yl)isoindoline-l,3-dione and (R)-2-(hex-5- en-3-yl)isoindoline-l,3-dione (11.2 g, 48.8 mmol, Step 1) in ethanolamine (29.3 ml, 488 mmol, Sigma-Aldrich Chemical Company, Inc.) under reflux condenser was allowed to stir for 3.0 h at 78 °C, for 66 h at 45 °C, and then for 3.0 h at 110 °C. The reaction flask was equipped with distill short path apparatus, and slow fractional distillation of the solution in oil bath at 120 °C provided the title compounds (70-90 °C) which were directly carried to the next step.

STEP 3: N-((3S)-5-HEXEN-3-YL)SULFURIC DIAMIDE AND N-((3R)-5- HEXEN-3-YL)SU

The title compounds were prepared from (S)-hex-5-en-3-amine and (R)- hex-5-en-3-amine (Step 2) following a procedure similar to the one described for the synthesis of N-4-penten-l-ylsulfuric diamide (Step 1 in the synthesis of Example 660), except that the crude product was purified by flash

chromatography on I SCO Gold silica gel column using 0-100%) EtOAc/Hexanes to provide the title compounds as a white solid.

STEP 4: (S)-6'-CHLORO-N-(N-((R)-HEX-5-EN-3-YL)SULFAMOYL)-5- (((lR.2R)-2-((S)-l-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3' ₅ 4.4 ^, ,5-

TETRAHYDRO-2I-i,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE-3, I '- NAPHTHALENE] -7 -C ARB OXAMIDE AND (S)-6 ^! -CHLORO-N-(N-((S)-HEX- 5-EN-3-YL)SULFAMOYL)-5-(((lR,2R)-2-((S)-l-

FIYDROXYAIJ^ .)CYCLOBUWL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

The title compounds were prepared from N-((3S)-5-hexen-3-yl)sulfuric diamide and N-((3R)-5-hexen-3-yl)sulfuric diamide (Step 2) and (S)-6'-chloro- (((1 R,2R)~2-((S)~1 iydroxyally^^

spiro [benzo [b] [ 1 ,4] oxazepme-3 , -naphtha! ene] -7-carboxy lie acid (A A 11 A), following a procedure similar to the one described for the synthesis of (S)-6'- chloro-5-(((lR,2R)-2-((S)-l-hydroxyallyl)cyclobut 'l)methyl)-N-(N-(pent-4-en-l- yl)sdfamoyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, I '- naphthal ene] -7-carboxamide (Step 2 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc Hexanes (EtOAc contained 0.1% HO Ac) to provide the title compounds as a white solid.

STEP 5: ((1 S,3'R,6'R,7'S,8'E,1 l 'S)-6-CHLORO-l . l'-ETHYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,12, !4]™AZATETRACYCLO[14.7.2,0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOS A[8, 16, 18,24]TETRAEN j- 15 ' -ONE 13 ' , 13 ' -DIOXIDE AND (1 S,3'R,6'R,7'S,8'E,1 l ^* R)-6-CHLORO-l 1 ^F ~ETHYL~7'~HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'-

| 2u jOXA| 1 3 ΓΗ ! !Λ| U 2J 4 | T!U AXATiTRACYCLOI 14.7.2.0 * '\0 ^{) Μ M} |PLNTAi ^' OS A[ 8, 16, 18,24] TETRAEN j - 15 ' -ONE 1 ^" . 13 ^" -DIOXIDE

The title compounds were prepared from (S)-6'-chloro-N-(N-((R)-hex-5- en-3-y l)sulfamoyl)-5-((( 1 R,2R)-2-((S)- 1 -hydroxy ally l)cy clobuty l)methy !)-

3',4,4',5-tetrahydro-2H,2'H-spiro| benzo| b]| l,4 |oxazepine-3,r-iiaphthalene]-7- carboxamide and (S)-6'-chlor o-N-(N-((S)-hex-5-en-3-yl)sulfamoy l)-5-(((l R,2R)- 2-((S)-l -hydroxy allyl)c>'clobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [ 1 ,4] oxazepme-3, 1 '-naphthalene] -7-carboxamide (Step 3), following a procedure similar to the one described for the synthesis of

(lS,3'R,6'R,7 ^, S,8'E)-6-chIoro-7'-hydroxy-3,4-dihydi -2H, 16TI-spiro|naphtha3ene- 1,23'-

[2I]oxa[14]thia[L13,15]triazatetracyclo[15.7.2.0 ³ -^0 ²⁰ - ²⁵ ]hexacosa[8,17,l¾ aen]-16'-one 14',14'-dioxide (EXAMPLE 660, Step 3), except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep C ! 8 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 20 min method) to provide one of the title compounds as the first eluting isomer as a white foaniTI NMR (400MHz, CDCb) δ 7.69 - 7.63 (m, 1H), 7.15 (dd, j 2.2.8.5 Hz, 1H), 7.09 (d, .! 2.2 Hz, IH), 7.00 - 6.86 (m, 3H), 5.93 (br. s., IH), 5.87 - 5.64 (m, 2H), 4.71- 4.55 (m, 2H), 4.05 (br, s., 1H), 3.83 - 3.71 (m, 1H), 3.59 - 3.09 (m, 3H), 2.84 - 2.70 (m, 2H), 2.59 - 2.49 (m, 1H), 2.47 - 2.28 (m, 2H), 1.97 - 1.43 (m, 13H), 1.05 - 0,80 (m, 3H); iv, /. (ESI, +ve ion) 600.1 (M il) .

EXAMPLE 686. (1 S,3'R,6 ^f R,7'S,8'E,i rS)-6-CHLORO-i r-ETOYL-7'- HYDROXY-: 4 31HYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20iOXA|;i3]TOIA|;i,12,14]TRIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOS A[8, 16, 18,24]TETRAE ] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE OR

(1S,3'R,6'R,7 ^! S,8'E,1 l'R)-6-CHLORO-l r-ETHYL-7*-HYDROXY-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]ΟΧΑ[13]ΤΗΙΑ[1,12,14]ΤΜΑ^^

OSA[8,16 ₅ 18,24]TETRAE ]-15'-ONE 13',13'-DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 685, Step 5. ^l H NMR (400 Mi!/. CDCb) δ 8.70 (br. s., IH), 7.69 (d, J=8,6 Hz, IH),

7.18 (dd, J=2.3, 8.4 Hz, IH), 7.09 (d, J=2.2 Hz, IH), 6.95 - 6.86 (m, 2H), 6.84 (s, IH), 5.94 - 5.80 (m, IH), 5.73 (d, j 8.2 Hz, 2H), 4.27 (br. s., IH), 4.11 - 4.02 (m, 3H), 3.83 - 3.66 (m, 2H), 3,52 (br. s,, IH), 3.20 (d, .! 14.3 Hz, !!!).3.00 (dd, j 9,6.15.3 Hz, IH), 2,86 - 2.69 (m, 2H), 2.55 - 2.36 (m, 2H), 2,30 - 1.32 (m, 12H), 1.16-0.80 (m, 3H). m/z (ESI, +ve ion) 600.0 (M R) . EAMPLE 687. (I S,3'R,6'R,7'S,8'E, 1 l ^, S)-6-CHLORO-7'-HYDROXY-12'-((2R)-2-

HYDROXY-: METHOXYPROi )-i r~METHYL-3 ₅ 4-DrHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [2()iOXA|;i3]TOIA|;i 2 4]TRIAZATETRACYCLO|;i4.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTAC OS A .[8, 16, 18,24]TETRAEN]-15 ^" -ONE 13 ' , 13 ' -DIOXIDE

STEP 1 : (R)-l -METHOXY-3-((S)-PENT-4-EN-2-YL A INO)PROPAN-2-OL

To (S)-pent-4-en-2-amine (0.916 g, 6.02 mmol, 56% in diethyl ether, prepared in Step 3 for the synthesis of Example 664) was added (R)-(-)-glycidyl methyl ether, 97% (0.531 mL, 6.02 mmol) followed by water (2 mL) at rt. The flask was sealed and allowed to stir vigorously at rt for 24 h. The mixture as diluted with water (8 mL) and extracted with diethyl ether (5 x 8 mL). The organic layers were combined, dried over NazSO*. The solid was filtered off through a small pad of Celite® (diatomaceous earth). Removal of organic solvents provided the title compound as a crude colorless syrup.

STEP 2: (S)-N-((R)-2-((TERT-BUTYLDIMETHYLSlLYL)OXY)-3-

METHOXYPROPYL)PENT-4-EN-2 -AMINE

To a mixture of (R)-l-methoxy-3-((S)-pent-4-en-2-ylamino)propan-2-ol (0.957 g, 2.76 mmol, Step 1), imidazole (0.547 ml, 8.29 mmol) and tert-butyl- chlorodimethylsilan (1.25 g, 8.29 mmol) was added DMF (9.2 ml) at rt. The mixture was allowed to stir at rt for 72 h, treated with water (25 mL) and extracted with EtOAc (3x 15 mL). The organic layers were combined and washed with water (3x 15 mL). Removal of organic solvents under reduced pressure provided the crude title compound.

STEP 3: N-((2R)-2 (DIMETOYL(2-METHYL-2-PROPANYL)SiLYL)OXY)-3- METHOXYPROPYL)-N-((2S)-4 )SULFURIC DIAMIDE

The title compound was prepared from (S)-N-((R)-2-((tert- butj _' 'ldimethylsilyl)oxy)-3-methoxypropyl)pent-4-en~2-aiiii iie (Step 2) following a procedure similar to the one described for the synthesis of N-4-penten-l-ylsulfuric diamide (Step 1 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0- 100% EtOAc/Hexanes (EtOAc containing 0.1% HO Ac) to provide the title compound as a white solid. STEP 4: (S)-N-(N-((R)-2 (TERT-BUTYLDIMETHYLSILYL)OXY)-3-

METHOXYPROPYL)-N-((S)-PENT-4-EN-2-YL)SULFAMOYL)-6'-CHLORO - 5-(((lR,2R)-2-((S)-l-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3 ^, _: ,4 ₅ 4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALENE] -7 -C ARB OXAM1DE

The title compounds were prepared as a mixture from N-((2R)-2- ((dimethyl(2-methyl-2-propanyl)silyl)oxy)-3-methoxypropyl)-N -((2S)-4-penten- 2-yl)sulfuric diamide (Step 3) and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)c lobut 'l)rnethyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , -naphtha! ene] -7-carboxy lie acid (A A i 1 A ), following a procedure similar to the one described for the synthesis of (S)-6'- chloro-5-(((lR,2R)-2-((S)-l-hydroxyallyl)cyclobutyl)methyl)- N-(N-(pent-4-en-l- yl)sulfamoyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4 ]oxazepine-3,r- naphthalene]-7-carboxamide (Step 2 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc Hexanes (EtOAc contained 0.1% HO Ac) to provide the title compound as a white solid.

STEP 5: (1 S,3'R,6'R,7'S,8'E, 1 l 'S)-6-CHLORO-12 ^f -((2R)-2-((DIMETHYL(2- METHYL-2-PROPANYL)SILYL)OXY)-3-METHOXYPROPYL)-7'- HYDROXY - 11 '-METHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]TOIA[ 1, 12,14]TTUAZATETRACYCLO[147.2.0~3,6~.0~19,24~]P

ENT ACOS A[8, 16, 18,24]TETRAEN] - 15 '-ONE 13 ' , i 3 '-DIOXIDE

The title compound was prepared from (S)-N-(N-((R)-2-((tert- but ldimeth lsil l)oxy)-3-methox propyl)-N-((S)-pent-4-en-2-yl)sulfamoyl)-6 ^, - chloro-5-(((lR 2R)-2-((S)-l-hydroxyaliy )cyclobutyl)methy])

2H,2'H-spiro[benzo[b][l,4]oxazepine~3,r-naphthalene]-7-ca rboxamide (Step 4), following a procedure similar to the one described for the synthesis of

(lS,3'R,6'R,7^,8T,)-6-chloro-7 ^! -hydroxy-3,4-dihydro-2H,16'H-spii [naphthalene- 1,23'-

[21]oxa[14]thia[ l,13,15]triazatetracycio[15.7.2.0 ³ ^ 0 ²⁰ - ²⁵ ]hexacosa[8,17,19,25]tetr aen]-16'-one 14',14'-dioxide (Example 660, Step 3), except that the crude product was purified by reversed phase preparatory HPLC (Gemini® 10 μτη NX-C18 110 A column; gradient elution of 50% to 95% MeCN in water, where both solvents contain 0. 1 % TFA, 20 min method) to provide the title compound as a white foam.

STEP 6: (1 S,3'R,6'R,7'S,8'E,1 l 'S)-6~CHLORO-7 ^! ~HYDROXY-12'-((2R)~2- HYDROXY-3-METHOXYPROPYL)-ir-METHYL~3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]TOIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTAC OSA[8,16,18,24]TETRAEN]-15'-ONE 13 ^" ,13 '-DIOXIDE

To a flask containing (l S^'^e'R.T'S^'E.l l'SJ-e-chloro-n'-^R)^- ((dimethyl(2-methyl-2-propanyl)silyl)ox> -3-methoxypropyl)-7'-hydroxy-ir^ methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[L12,14]triazatetracyclo[14.7.2.0~3,6~.0~1 9,24~]pentacosa[8,16, 18,24]tetraen]-15'-one 13\13'-di oxide (37 mg, 0.047 mmol, Step 5) was added tetrahutyl ammonium fluoride(0.469 mL, 1.0 N in THF, 0.469 mmol, Sigma- Aldrich Chemical Company, Inc.) at rt. The solution was stirred at rt for 24 h. After removal of organic solvents under reduced pressure, purification of the residue by reversed phase preparatory HPLC (Gemini™ Prep CI 8 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 45% to 90% MeCN in water, where both solvents contain 0.1% TFA, 20 rain method) provided the title compound as a white foam. ¾ NMR (40()MHz, CDCh) δ 8.76 (br. s., 1H), 7.74 - 7.65 (m, 1H), 7.24 - 7, 13 (m, 2H), 7.08 (d, J 2.2 Hz, 1H), 6.98 - 6.86 (m, 2H), 5.77 - 5.51 (m, 2H), 4,50 - 4.36 (m, I I I ). 4.21 - 3.96 (m, 3H), 3,92 (t, J=5,6 Hz, 1H), 3.86 - 3.63 (m, 3H), 3.59 - 3.46 (m, 3H), 3.43 - 3.40 (m, 4H), 3.25 (d, J=14.3 Hz, 1H), 3.06 (dd, J=5.9, 15.5 Hz, 1H), 2.83 - 2.70 (m, 2H), 2.59 - 2.35 (m, 3H), 2.22 - 1.38 (m, 9H), 1 .34 (d, J 6 7 Hz, 3H), 1 .30 - 1.23 (ra, lH). m/z (EST, +ve ion) 674.3 (M+H) ⁺ .

EXAMPLE 688. (lS^'^e'^T'S^U^'R^lT-DlCHLORO-l '-ETHYL-T- METHOXY-3,4-DIHYDRO-2H,15'H-SPIR()[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24] TETRAEN ] - 15'-ONE 13 ', 13' -DIOXIDE

The title compound was prepared from (1S,3'R,6'R,7'S,8'E,12'R)-6,17'- dichloro-12'-ethyl-7'-hydroxy-3,4-dihydro-2H, 15H-spirofnaphthalene-l,22'^

n]-15'-one 13', 13' -dioxide (Example 657) following a procedure similar to the one described for the synthesis of Example 669 using methyl iodide instead of 2- bromoethyl methyl ether, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 85 μπι column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to provide the title compound as a white film. 'II NMR (4()0MHz, CDC!:) δ 7.65 (d, ./ 8.4 Hz, !!!).7.19 (dd, ,/ 2.!. 8,5 Hz, 1H), 7.09 (s, !H), 7.01 - 6,97 (m, 1H), 6.95 - 6.91 (m, 1H), 5.87 - 5,74 (m, IH), 5.55 (dd, ./ 8.8.15.5 Hz, 1H), 4.19-1.20 (ni, 35H). m/z (ESI, +ve ion) 615.0 i\f-Mei)il H)

EXAMPLE 689. (lS,3 ^! R,6 ^, R,7'S,8'E,irS,12'R)-6-CHLORO-7'-METHOXY-ll'- METHYL- 12'-(2,2,2-TRTFLUOROETHYL)-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THLA|;i,14]DIAZATETRACYCL)[14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~15'~ONE 13',13'-DIOXIDE OR

(lS,3¾,6¾.,7¾,8¾li'S,i2^)-6-CHimO-7 ^, -METOOXY-ll'-METOYL-12 ^! - (2,2,2-TRIFLL ⁱ OROETHYL)-3,4-DlHYDRO-2H,15'H- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |8.i6.i8.24! rL ! R.\i:Ni- 15 -ONi: 13',13'-DI0X1DE OR

(lS,3'R,6'R,7 ^, S,8'Z,ll'S,12'R)-6-CHLORO-7'-METOOXY-ir-METHYL-12'- (2,2,2-TRiFLUOROETHYL)-3,4-DIHYDRO-2H,i5'H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'Z,11*S, 12 ^, S)-6-CHLORO-7'-METHOXY-l 1 '-METHYL- 12"- (2,2,2-TRlFLUOROETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ "*0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24] TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was prepared from lS,3'R,6'R,7'S,8'E,H'S,12'R)-6- chloro-7'-hy drox - 11 '-methyl- 12'-(2,2,2-trifluoroethy l)-3 ,4-dihy dro-2H, 15 Ή- spiro [naphtha] ene- 1 ,22'-

[20]oxa[13]thia[l, 14]diazatetra<y^

n]-15'-one 13',13'-dioxide and (lS,3'R,6'R,7'S,8'E,l l'S,12'Sy6-ehloro-7 ^* - hy droxy- 11 '-methyl- 12'-(2,2,2-trifluoroeth l)-3,4-dihydro-2H, 15Ή- spiro [naph thai ene- 1,22'- [20] ox a[ 13 ] thiaf 1 , 14 ] di azatetracy cl o

[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'~one 13 ^" , 13 '-dioxide and (lS,3'R,6'R 7'S,8'Z,l l'S,12'R)-6-chioro-7'-hydroxy-i r-metliyl-12'-(2,2,2- trifluoroethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l, 14]diazatetra<yclo^

n]-15'-one 13',13'-dioxide and (lS,3'R,6'R,7'S,8'Z,l l'S,12'Sy6-ehloro-7 ^* - hydroxy- 11 '-methyl- 12'-(2,2,2-trifluoroeth l)-3,4-dihydro-2H, 15Ή- spiro [naph thai ene- 1 ,22'- 8.24i !eirac n]-15'-one 13',13'-dioxide (Example 663) following a procedure similar to the one described for the synthesis of Example 669 using methyl iodide instead of 2- bromoeihyi methyl ether, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 10 μηι column: Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0,1% TFA, 30 min method) to provide one of the title compounds as the second elutmg isomer as a white foam H NMR (400MHz, CDCb) δ 8.13 (s, Hi).7.69 (d, j 8.6 Hz, IH), 7.18 (d, j 8.4 Hz, ill).7.10 (s, 1H), 6.99 - 6.86 (m, 2H), 5.85 - 5.74 (m. 111).5,55 (dd, j 9.0.15.7 Hz, ill).4.58 (d, J 5.3 Hz, IH), 4,10 (m, 2H), 3.81 (d, J 14.9 Hz, IH), 3.76 - 3.64 (m, 2H), 3.31 -3,18 (s, 3H), 3.27-1.23 (m, 18H), 1.12 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 681.0 (W W) .

EXAMPLE 690. (1 S,3'R,6'R,7'S,8'E,1 l*S)-6-CHLORO-l l'-CYCLOPROPYL- 13 ^, ₅ 13 ^, -DIOXIDO-15 ^, -OXO-3 ₅ -DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^, -

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL ACETATE AND (1 S,3'R,6'R,7'S,8'E,1 l'R)-6- CHLORO- 11 '-CYCLOP RQPYL- 13 13 '-DIOXIDO- 15 '-OXO-3,4 -DIHYDRO- 2H-SP1R0[NAPHTHALENE-1,22'- |;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2,0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-7'-YL ACETATE

STEP 1: BENZYL 2-CYCLOPROPYLACET ATE

To a mixture of granular potassium iodide (19.9 g, 120 mmol, ZZ -INACTIVE - Mallinckrodt GmbH), potassium carbonate powder (41.5 g, 300 mmol, Fluka Chemie GmbH), and cyclopropylacetic acid (9.28 mL, 100 mmol, Alfa Aesar, Avocado, Lancaster) in DMF (100 mL) was added benzyl bromide (30.5 mL, 250 mmol, Sigma- Aldrich Chemical Company, Inc.) at rt. The mixtiire was allowed to stir at 90 °C under condenser and N ₂ for overnight. The reaction mixture was cooled to rt, the solid was filtered off on a pad of C elite® (diatomaceous earth) and washed with EtOAc (3 x20 mL). The combined organic solution was diluted with EtO Ac (400 mL) and washed with water (4x200 mL) and brine (45 mL), and dried over MgS0 ₄ . After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-40% EtOAc/Hexanes provided the title compound as a as a dark brown oil.

STEP 2: (R)-BENZYL 2-CYCLOPROPYLPENT-4-ENOATE AND (S)- BENZYL 2-CYCLOPROPYLPENT-4-ENOATE

To a solution of diisopropylamine (18.1 mL, 129 mmol, redistilled, 99,95%, Sigma-A!drich Chemical Company, Inc.) in THF (100 mL) at -78 °C under N ₂ was added "BuLi (51.7 mL, 2.5 M solution in hexanes, 129 mmol,

Sigma-Aldrich Chemical Company, Inc.) over 10 min. The mixture was allowed to stir in the cold bath for 20 min, then removed from the ice bath. After stirring at ambient atmosphere for 20 min, this freshly made lithium diisopropylamide solution was replaced into the -50 °C bath for temporary storage. To a solution of benzyl 2-cyclopropylacetate (16.200 g, 85 mmol, Step 1 ) in THF (170 mi) under N ₂ in -78 °C bath was added ally! bromide(7.37 ml, 85 mmol, reagentplus, Sigma- Aldrich Chemical Company, Inc.) followed by slow addition of the freshly made lithium diisopropylamide solution (124 ml, 0.758 M, 94 mmol) over 15 min. The mixture was stirred at -78 °C for 30 min, and then was removed from the bath and allowed to stir at ambient temperature for 45 min. The reaction mixture was poured into saturated aqueous NITiCl (.150 mL), diluted with water (150 mL) and extracted with EtOAc (3 x200 mL). The organic solutions were combined. After remo v al of organic sol v ents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-50%

EtOAc/Hexanes provided the title compounds as as mixture, m/z (ESI, +ve ion) 231.1 (M+H) ⁺ .

STEP 3: (R)-2-CYCLOPROPYLPENT-4-EN-l-OL AND (S)-2- C YCLOPROP YLPENT-4-EN- 1 -01.

To a solution of (R)-benzyl 2-cyclopropylpent-4-enoate and (S)-benzyl 2- cyclopropylpent-4-enoate (1 1.2 g, 48.6 mmol, Step 2) in THF (200 mL) under N2 in 0 °C ice bath was slowly added lithium aluminum hydride (56.0 mL, 1.0 M in THF, 56.0 mmol, Sigma-Aldrich Chemical Company, Inc.) via syringe over 10 min. The mixture was allowed to stir in the ice bath for 3.0 h. To the mixture was slowly added EtOAc (45 mL), the solution was removed from ice bath followed by addition of saturated aqueous NH4CI (80 mL). The resulting mixture was treated with 60 mL of 1.0 N aqueous solution of citric acid (Sigma- Aldrich Chemical Company, Inc.), diluted with water (150 mL). The organic layer was separated and the aqueous layer was back extracted with EtOAc (3 x200 mL). The organic layers were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-60% EtOAc Hexanes provided the title compounds as a mixture. STEP4: (R)-2-C YCLOPROPYLPENT-4-EN- 1 - YL METHANESULFONATE AND (S)-2-CYCLOPROPYLPENT-4-EN-l-YL METHANESULFONATE

To a solution of (R)-2-cyclopropylpent-4-en-l-ol and (S)-2- cyclopropylpent-4-en-l-ol (7.00 g, 55.5 mmol, Step 3) in dichloromethane (80 mL) in 0 °C ice bath under 2 was added triethylamine (9.26 mL, 66.6 mmol, Sigma-Aldrich Chemical Company, Inc.) followed by methanesulfonyl chloride (5.15 mL, 66.6 mmol, Sigma-Aldrich Chemical Company, inc.). The resulting milky mixture was allowed to stir in the ice bath for 3.0 h. To the cloudy mixture was added cold water (50 mL). The organic layer was separated and the aqueous layer was back extracted with dichloromethane (3x40 mL). The organic layers were combined, washed subsequently with water (40 mL), brine (40 mL), and dried over MgSC . Removal of organic solvents under reduced pressure provided the crude titled compounds as a mixture, which was immediately used without further purifi cation.

STEP 5 : (R)-2-((2-C YCLOPROPYLPENT-4-EN- 1 -YL)THIO)PYRIMIDINE AND (S)-2-((2-C YCLOPROPYLPENT-4-EN- 1 -YL)TfflO)P YRIMIDINE

To a solution of (R)-2-cyclopropylpent-4-en-l-yl methanesulfonate and (S)-2-cyclopropylpent-4-en-l-yl metha esulfonate (10.0 g, 49.0 mmol, Step 4) and 2-mercapto-pyrimidine (6.59 g, 58.7 mmol, Sigma-Aldrich Chemical Company, Inc) in DMF (98 ml) was added potassium carbonate anhydrous (8.11 g, 58.7 mmol, Fluka Chernie GmbH). The mixture was allowed to stir at 70 °C for 2.5 h, cooled to rt and poured in water (400 mL), extracted with EtOAc (3 x ^' 100 mL). The combined organic layer was washed subsequently with water (4 ^χ 80 mL), brine (30 mL), and dried over MgSCk After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-70% EtOAc/Hexanes provided the title compounds as a mixture.

STEP 6: (R)-2-((2-CYCLOPROPYLPENT-4-EN-l-

YL)SULFONYL)PYRIMIDF E AND (S)-2-((2-CYCLOPROPYLPENT-4-EN-l - YL)SULFONYL)PYRIMIDINE

The title compounds were prepared from (R)-2-((2-cyclopropylpent-4-en- l-yl)thio)pyrimidine and (S)-2-((2-cyclopropylpent-4-en-l-yl)thio)pyrimidine (Step 5) following a procedure similar to the one described for the synthesis of 2- (((2r,3s)-3-methylhex-5-en-2-yl)sulfonyl)pyrimidine (Step 4 in the synthesis of EE22), except that the crude products was purified by flash chromatography on ISCO Gold silica gel column using 0-70% EtOAc/Hexanes provided the title compounds as a solid mixture, m'z (ESI, +ve ion) 253.1 (M+H) ⁺ .

STEP 7: SODIUM (R)-2-CYCLOPROPYLPENT-4-ENE-l-SULFINATE AND SODIUM (S)-2-CYCLOPROP YLPENT-4-ΕΝΈ- 1-SULFlNATE

The title compounds was prepared from (R)-2-((2-cyclopropylpent-4-en-l - yl)sulfonyl)pyrimidine and (S)-2-((2-cyclopropylpent-4-en-l - yl)sulfonyl)pyrimidine (Step 6) following a procedure similar to the one described for the synthesis of sodium (2r,3s)-3-methymex-5-ene-2-sulfinate (Step 5 in the synthesis of EE22). The crude product mixture was directly used without further purification. STEP 8: (R)-2-CYCLOPROPYLPENT-4-ENE-l -SULFONAMIDE AND (S)-2- CY CLOPROPYLPENT-4-ENE- 1 -SULFONAMIDE

The title compound was prepared as a mixture from sodium (R)-2- cyclopropylpent-4-ene- .l -sulfmate and sodium (S)-2-cyclopropylpent-4-ene-l - sulfinate (Step 7) following a procedure similar to the one described in Step 6 for the synthesis of (2R,3S)-3-methylhex-5-ene-2-sulfonamide EE22.

STEP 9: (S)-6'-CHLORO-5-(((lR,2R)-2-((l S,5S ₅ E)-5-CYCLOPROPYL-l - HYDROXY-6-SULFAMOYLHEX-2-EN-l -YL)CYCLOBUTYL)METHYL)-

3 ^f ,4,4',5-TETRAHYDRO-2H 2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 "- NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-((( 1 R,2R)- 2-((l S, 5R,E)-5-CYCLOPROPYL-l -HYDROXY-6-S ULFAMOYLHEX-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-3',4,4 ⁱ ,5-TETRAHYDRO-2H,2 ^f H-

SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID

The title compounds were prepared as a mixture from (S)-6'-chloro-5-

(((l R,2R)-2-((S)~l-hydroxyallyl)^

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (AA11A) and (R)-2-c clopropy lpent-4-ene- 1 -sulfonamide and (S)-2-cy clopropylpent-4-ene- 1 - sulfonamide (Step 8) following a procedure similar to the one described in Example 653, Step 4,

STEP 10: (l S _^ TR^'R^'S^'EJ l'Sj-e-CHLORO-ir-CYCLOPROPYL- S'- DIOXID()-15 ^, -()XO-3,4-DIHYDR()-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-7'-YL ACETATE AND (1 S,3 ^! R,6'R,7'S,8'E,1 l'R)-6- CHLORO-ir-CYCLOPROPYL- ^ '-DIOXIDO-lS'-OXO-S^-DIHYDRO- 2H-SPIRO[NAPHTHALENE-1.22'-

[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[ 14.7,2.0 ³ - ⁶ .0 ^{! 9} - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] -7'-YL ACETATE To a flask containing (S)-6'-chloro-5-(((lR,2R)-2-((l S ₅ 5S,E)-5- cyciopropyl- -hy droxy-6-sulfamoylhex-2-en- 1 -y l)cyclobutyl)methy l)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxyli c acid and (S)-6'-chloro-5-(((lR,2R)-2-((l S,5R,E)-5-cyclopropyl-l-hydroxy-6- sulfamoylhex-2-en-l-yl)cyclobut\'l)methyl)-3',4,4',5-ten'ahy dro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (101 mg, 0.161 mmol, Step 9), 4-(dimethylamino)pyridine (58.8 mg, 0.482 mmol, ZZ - Alfa Aesar) and l-(3-dimethylarriinopropyl)-3-ethylcarbodiimide hydrochloride (92.0 mg, 0.482 mmol, Thermo Fisher Scientific) was added CHCb.(40 mL) at rt. The mixture was allowed to stir at rt for 24 h. After removal of organic solvents under reduced pressure, the residue was re-dissolved in HO Ac (4.0 mL) and left at rt for overnight. The mixture was subjected to reverse phase preparatory HPLC (Gemini™ Prep CI 8 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 45% MeCN in water to 95% MeCN in water over a 25 min period, where both solvents contain 0.1% TFA) to provide the titled compounds as a 1 : 1 mixture of two isomers. ^] H NMR (400MHz, CDCh) δ 8.24 - 8.03 (m, 1H), 7.78 - 7.62 (m, 1H), 7.18 (dd, j 2,3.8,4 Hz, 1H), 7,10 (s, 1H), 7,04 - 6,82 (m, 3H), 6.03 - 5.88 (m, III).5,72 - 5.54 (m, ill).5.36 - 5.22 (m, ill).4,43 (dd, J=10,0, 15.6 Hz, 0.5H), 4.18 - 3.98 (m, 2H), 3.96 - 3.54 (m, 3H), 3.48 - 2.89 (m, 3.5H), 2.89 - 2.68 (m, 2H), 2.57 - 1.20 (m, 14.5H), 0.93 - 0.72 (m, 1.5H), 0.66 - 0.44 (m, 2H), 0.39 - 0,06 (m, 2H). m/z (ESI, +ve ion) 653.0 ( M II) .

EXAMPLE 691, (lS,3'R,6 ^, R,7 ^! S,8'E)-6~CHLORO-7'-HYDROXY-l l'-((2R)~ TETRAHYDRO-2-FURANYLMETHYL)-3 _s 4-DlHYDRO-2H,14'H- SPIRO j NAPHTHALENE- Ι.2Γ- [19]OXA[12]THIA[l,ll,13]TOAZATETRACYCLO[13J.2.0 ³ '«0 ¹⁸ ' ²³ jTETRAC OSAj 8. ! 5.17.23 jTLTRAHN |- i i'-ONL 12',12'-DIOXIDE AND

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-ir-((2S)-TETRAHYDRO-2- FURANYLMETHYL)-3 ,4-DIHYDRO-2H, 14"H-SPIRO[N APHTHALENE- 1,21 '- I i9|OX,\| Ι2ΓΠΠ.\| i.l 1.1 1 i sAZA f 1: 1 R.\CV( 0| !3.7,2,0 ^; ".0 ^is;; | Π·.1 R.\C OSA [8,15,r7,23]TETRAEN]-14'-ONE 12',12'-DIOXIDE

STEP 1 : (R)-N-((TETRAHYDROFURAN-2-YL)METHYL)PROP-2-EN- 1 - AMINE AND (S)-N-((TETRAHYDROFURAN-2-YL)METHYL)PROP-2-EN-l - AMINE

The title compounds were prepared as a mixture from tetrahydro-furan-2- carbaldehyde (J & W PharmLab, LLC) and allylamine (Sigma- Aldrich Chemical Company, Inc.) following a procedure similar to the one described for the procedure in Example 664, Step 4.

STEP 2: N-2-PROPEN- 1 -YL-N-((2R)-TETRAHYDRO-2- FURANYLMETHYL)SULFURIC DIAM1DE AND N-2-PROPEN-l-YL-N- ((2S)-TETRAHYDRO-2-FURANYLMETHYL)SULFURIC DIAMIDE

The title compounds were prepared as a mixture from (R)-N- ((tetrahydrofuran-2-yl)methyl)prop-2-en-l -amine and (S)-N-((tetrahydrofuran-2- yl)methy l)prop-2-en- 1 -amine

(Step 1 ) iollovving a procedure similar to the one described for the synthesis of N- 4-penten-l-ylsulfuric diamide (Step 1 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc/Hexanes to provide the title compounds as a white solid mixture.

STEP 3 : (S)-N-(N- ALLYL-N-(((R)-TETR AHYDROFURAN-2-

YL)METHYL)SULFAMOYL)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5-TETRAHYDRO-

2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7-

CARBOXAMIDE and (S)-N~(N-ALLYL-N-(((S)-TETRAHYDROFURAN-2-

YL)METHYL)SULFAMOYL)-6'-CHL()RO-5-(((lR,2R)-2-((S)-l-

FIYDROXYAIJ^T.)C^ T _J OBUWL)METHYT _J )-3',4,4',5-TETRAHY ^' DRO-

2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3, l'-NAPHTHALENE]-7-

CARBOXAMIDE

The title compounds were prepared as a mixture from N-2-propen-l-yl-N- ((2R)-tetrahydro-2-furanylmethy])sulfuric di amide and N-2-propen-l -yl-N-((2S)- tetrahydro-2-furanylmethyl)sulfuric diamide (Step 2) and (S)-6'-chloro-5- (((lR,2R)-2^(S)-14iydroxyallyl)cyclobuty^^

spiroj benzoj bj [ L4|oxazepine-3, -naphthalene]-7-carboxyiic acid (AA11A), following a procedure similar to the one described in Step 2 for the synthesis of Example 660, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-70% EtOAc/Hexanes (EtOAc contained 0.1 % HO Ac) to provide the title compounds as a white solid.

STEP 4: (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-l l'-((2R)- TETRAHYDRO-2-FURANYLMETHYL)-3,4-DIHYDRO-2H,14'H- SPTRO[NAPHTH ALENE- 1 ,21 '-

[19]OXA[12]THIA[1, 1 1 ,13]TRIAZATETRACYCLO[13.7.2.0 ^J - ⁶ .0 ¹⁸ ' ²³ ]TETRAC

OS A[ 8,15, 17,23 jTETRAENj- 14'-ONE 1 , 12'-DIOXIDE AND

(lS,3¾,6'R,7 ^f S,8'E)-6-CHLORO-7'-I-IYDROXY-l l'-((2S)-TETRAI-IYDRO-2-

FURANYLMETHYL)-3,4-DIHYDRO-2H, 14'H-SPIRO[NAPHTHALENE-l,2r- [19]OXA[ 12]THlA[ l,l l,13]TRlAZATEm CYCLO[13 .2.0 ³ -^0 ¹⁸ - ²³ ]TEm C OSA [8,15,r7,23]TETRAEN]-14'-ONE 12' ₅ 12'-DIOXIDE

The title compounds were prepared from (S)-N-(N-allyl-N-(((R)- tetrahydrofuran-2-yl)methyl)sulfaiTioyl)-6'-chloro-5-(((lR,2 R)-2-((S)-l- hydroxyallyl)cyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-N-(N- allyl-N-(((S)-teirahydrofijran-2-y1)meihyl)sulfamoyl)-6 ^! -chloro-5-(((l

((S)-l-hydrox\'allyl)cyclobutyl)methyl)-3^4,4^5-tetrahydr o-2H,2'H- spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7-carboxamide (Step 3), following a procedure similar to the one described in Step 3 for the synthesis of Example 660, except that the reaction was prolonged to 24 h, and the crude products were purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 10 μηι column; Phenornenex, Torrance, CA; gradient eiution of 45% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide the title compounds as a 1 : 1 mixture as a white foam. ^] H NMR (400MHz, CDCI3) δ 9,87 (br. s. , 0.5H), 8.83 (br. s., 0.5H), 7.70 - 7.56 (m, !H), 7.1 1 (td, j 2.3. 8.5 Hz, IH), 7.06 - 6.91 (m, 2H), 6.89 - 6.73 (m, 2H), 6.17 - 6.01 (m, 0.5H), 5.94 - 5.64 (m, 1.5H), 4.40 (dd, J=4.6, 15.9 Hz, 0.5H), 4.35 - 4.26 (m,

0.5H), 4.20 (d, j 1 5.7 Hz, 0.5H), 4.15 - 4.03 (m, 1.5H), 3.96 - 3.20 (m, 7H), 3.09 - 3.02 (m, ! H), 2.78 - 2,64 (m, 2H), 2.40 - 2.25 (m, ! H), 2.05 - 1.27 (m, 17H); (ESI, +ve ion) 642,3 ( VI H ) .

EXAMPLE 692. (l S,3 ^, R,6 ^, R,7'S,8'E,12'S)"6-CHLORO-7'-HYDROXY-12'~(2" PYmDIN iX)-3,4-DIHYDR()-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[ !4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA | 8. i 6. i 8.24i rE ! R.\i :N i- 1 5 -ONi : 13 ',13'-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'E, 12'R)-6-CHLORO-7 ^! -HYDROXY-12'-(2-PYRIDINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22 ^* -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

STEP 1 : N,N-BIS(4-METHOXYBENZYL)- 1 -(P YRIDIN

YL)METHANESULFONAMIDE

The title compound was prepared from pyridin-2-ylmethanesulfonamide

(Princeton Bio) following a procedure similar to the one described for the synthesis of EE 12. STEP 2: (S)-N,N-BIS(4-METHOXYBENZYL)-l-(PYRIDl ~2-YL)PENT-4- ENE -SULFONAMIDE AND (R)-N ₅ N-BIS(4-METHOXYBENZYL)-l- (PYRIDIN-2-YL)PENT-4-ENE- 1 - SULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)-l-(pyridin-2- yl)methanesulfonamide (390 mg, 0.945 mmol, Step 1 ) and 4-bromo-l -butane (0.288 ml,, 2.84 mmol. Matrix Scientific) in THF (8.0 mL) under Ar was added LiHMDS (0.993 mL, 1.0 M in THF, 0.993 mmol, Sigma- Aklnch Chemical Company, Inc.) over 2 min at -78 °C. The resulting mixture was stirred in the -78 °C bath for 10 min, and then removed from the bath and was allowed to stir at ambient atmosphere for 4 h. The resulting mixture was quenched with saturated aqueous NEUCl (5 mL), diluted with water (10 mL) and extracted with EtOAc (14 mL x 3). The organic layers were combined, washed with water (5 mL), brine (3 mL), and dried over MgS0 ₄ . After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column using 0-100 % EtOAc/Hexanes as eluent provided the title compounds as a colorless syrup.

STEP 3: (S)-l -(PYRIDIN-2-YL)PENT-4-ENE-l -SULFONAMIDE AND (R)-l- (PYRIDIN-2-YL)PENT-4-ENE- 1 - S ULFON AMIDE

The title compounds were prepared as a mixture from a mixture of (S)- N,N-bis(4-methoxybenzyl)-l -(pyridin-2-yl)pent-4-ene-l-sulfonamide and (R)- N,N-bis(4-methoxy benzyl)- 1 -(pyridin-2-yl)pent-4-ene- 1 -sulfonamide (Step 2) following a procedure similar to the one described in Step 2 for the synthesis of EE17.

STEP 4: (S)-6'-CHLORO-5-(((l R,2R 2-((S l -

HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(((S)- l-(PYRiDIN-2- YL)PENT~4"EN-l-YL)SULFONYL)~3 ^! ,4,4',5-TETRAHYDRO-2H,2'H" SPIRO| BENZO[B]|;L4iOXAZEPINE-3, l'-NAPHTHALENE]-7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-(((R)-l-(PYRIDIN-2- YL)PENT-4-EN-l-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIR()[BENZO Bj[ l,4]()XAZEPINE-3,r-NAPHTHALENEl-7- CARBOXAMTDE

The title compounds were prepared as a mixture from (S)-6'-chloro-5- (((lR,2R)-2-((S)-l-hydroxyallyl)cyclobutyl)meihyl)-3

spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (AAl lA) and a mixture of (S)-l-(pyridin-2-yl)pent-4-ene-l-sulfonamide and (R)- 1 -(pyridin-2- yl)pent-4-ene- 1 -sulfonamide (Step 3), following a procedure similar to the one described in Step 2 for the synthesis of Example 660, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc Hexanes to provide the title compounds as a mixture.

STEP 5: (lS ₅ 3 ^! R )¾J'S,8T, i2^)-6-CHLORO-7'-HYDROXY-] 2'-(2- PYRIDI YL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [N APHTHALEN E- 1 ,22'- ^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI M.T^.O'^.O'^lPE TACOSA

[8,16, 18,24] TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE AND

(lS,3 ^, R,6'R,7 ^! S,8'E,12'R)-6-CHLORO-7'-HYDROXY-12'-(2-PYRlDiNYL)-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TET AEN] - 15 ' -ONE 13 ', 1 3 ' -DIOXIDE

The title compound was prepared from (S(S)-6'-chioro-5-(((lR,2R)-2-((S)- 1 -hydroxy ally l)cy clobutyl)methy 1)-N-(((S)- 1 -(pyridin-2-yl)pent-4-en-l - yl)sulfonyl)-3',4,4 ⁱ ,5-tetrahydro-2H,2 ⁱ I-I-spiro[benzo[b] [l ,4]oxazepine-3,r- naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxy ally l)cy clobutyl)methyl)-N-(((R)- 1 -(pyridin-2-yl)pent-4-en- 1 - yl)sulfonyl)-3',4,4^5-tetrahydro-2H,2'H-spiro benzo b] [ l,4]oxazepine-3,r- naphthalene]-7-carboxamide (Step 4) following a procedure similar to the one described in Step 3 for the synthesis of Example 660, except that Ti(O ^s Pr)4 (3.0 eq., Sigma- Aldnch Chemical Company, Inc.) was added to the reaction solution immediately before the Hoveyda-Grubbs Catalyst (2nd generation). The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 10 um column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to provide one of the title compounds as the first eluting isomer as a white foam. Ή NMR (400MHz, CDCb) δ 8.78 (br. s., 1H), 7.89 (t, j 7.6 Hz, 1H), 7.74-7.69 (m, 2H), 7.50 - 7.41 (m, I I I ). 7.20 (dd, j 2.2. 8.5 Hz, 1 1 1 }. 7.10 (d, j 2.2 Hz, 1H), 7,00 - 6.93 (m, 3H), 5.99 - 5.87 (m, IH), 5,81 - 5.60 (m, 2H), 4.32 (br. s., IH), 4,21 - 4.04 (m, 2H), 3.98 - 3.86 (m, i l l ). 3,73 (d, J=14.5 Hz, I H ). 3,28-3.22 (m, IH), 3.03 (dd, J=7.6, 7.6 Hz, IH), 2.88-1.22 (m, 17H). m/z (ESI, +ve ion) 648.0 i M H ) . EXAMPLE 693. (1 S,3 ^, R,6'R,7'S,8'E,12'S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2- PYR!MN Yl.)- .4-1)11 IYORO-21 I. ! Ί f-SP!RO|\ ^' .\PI ill i AiJ-Ni -l .22'- [20]OXA[13]raj:A[l _s 14]DIAZATETRACYCLO[14J.2 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]~15'~ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-PYRIDINYL)-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l 4jDIAZATETRACYCLO|14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,18 ,24] TETRAEN]- 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title cornpound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 692, Step 5. ^" Ή NMR (400MHz, CDCb) δ 8.83-8.75 (ni, ill).7.98 - 7.83 (m, 1H), 7.79 - 7.62 (ni, 2H), 7.54 - 7.39 (m, 1H), 7.24 - 7.06 (m, 3H), 7.04 - 6.91 (m, 211), 5.96 - 5.83 (m, 1H), 5,80 - 5.43 (m, 2H), 4.37 - 4.21 (m, 2H), 4,19 - 4.07 (m, 2H), 4.03 - 3.84 (m, 2H), 3,78 - 3.66 (m, 1H), 3.50 - 1.32 (m, Γ7Η), m/z (ESI, +ve ion) 648.0 { M f i

EXAMPLE 694. (lS,3 ^, R,6 ^, R,7'S,8'E)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(l,3- OXAZOL-2-YLMETHYL)-3,4-DIIiYDRO-2H,15^SPIRO[NAPIiraALEj E-

1,22'-

[20]OXA[13]THIA[1,12,14]TRIAZATETRACYCLO[14.7.2.0 ^J - ⁶ .0 ¹⁹ - ²⁴ ]PENTAC OS A[8, 16, 18 ,241 TETRAEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

STEP 1: N-(OXAZOL-2-YLMETHY ^' :L)BUT-3 -EN- 1 - AMINE

To a solution of 3-buten-l-amine (5.71 ml, 61.8 mmol, Alfa Aesar, A

Johnson Matthey Company) and oxazole-2-carbaldehyde (2.00 ml, 20.6 mmol, J & W PharmLab, LLC) in dichloromethane (20 mL) in ice bath was added sodium cyanoborohydride (14.4 ml, 1.0 N in THF, 14.4 mmol, Sigma-Aldrich Chemical Company, Inc.) in three portions over 20 min at 0 °C. The resulting solution was allowed to stir in the ice bath for 1.0 h. To the mixture was added NaBHiOAc (6.36 g, 20.0 mmol, Sigma-Aldrich Chemical Company, Inc.). The reaction solution was removed from the ice bath, and allowed to stir at ambient temperature for 1 h. The reaction mixture was treated with aqueous NaOH (2.0 N, 10 ml.) and water (25 mL), and was extracted with dichloromethane (3x20 mL). The organic layers were combined, washed with aqueous HC1 (3>< 10 mL). The aqueous layers were combined, basified with aqueous NaOH (2.0 N) to PH=14, and extracted with 30% 'PrOH//chloroform (3x25 mL). The 'PrOHZ/chloroform solutions were combined and washed with brine (8 mL). After removal of organic solvents under reduced pressure, the residue was left under high vacuum to provide the crude title compound, which was used without further purification.

STEP 2: N-3-BUTEN-l-YL-N-(l ₅ 3-OXAZOL-2-YLMETHYL)SULFU IC

DI AMIDE The title compound was prepared from (N-(oxazol-2-ylmethyl)but-3-en-l- amine (Step 1) following a procedure similar to the one described for the synthesis of N-4-penten-l-ylsulfuii (Step 1 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-100% EtOAc/Hexanes to provide the title compound as a white solid.

STEP 3: (S)-N-(N-(BUT-3-EN-l-YL)-N-(OXAZOL-2-

YLMETHYL)SULFAMOYL)-6 ^! -CHLORO-5-(((lR,2R)-2~((S)-l- HYDROXY ALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2Η,2Ή-8ΡΚ()|;ΒΕΝΖΟ[Β| [ 1,4]ΟΧΑΖΕΡΙΝΕ-3,1·-ΝΑΡΗΤΗΑΕΕΝΕ]-7- CARBOXAMTDE

The title compounds was prepared from N-3-buten-l-yl-N-(l ,3-oxazol-2- ylmethyl)sulfuric diamide (Step 2) and (S)-6 ^, ~chloro-5 ^» (((lR,2R) ^» 2 ^» ((S)-l- hydroxyallyl)c clobutyl)methyl)-3',4,4',5-tetrahydfo-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (AAl 1 A ), following a procedure similar to the one described for the synthesis of (S)-6'- cWoro-5-(((lR,2R)-2-((S)-l-hydroxyallyl)cyclobu1yl)me l)-N-( ]-(pent-4-en-l- yl)sulfamoyl)-3',4,4',5-tetrahydro-2H,2H-spiro benzo b] l,4]oxazepine-3, - naphthalene]-7-carboxamide (Step 2 in the synthesis of Example 660), except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-80% EtOAc/Hexanes (EtOAc contained 0.1% HO Ac) to provide the title compounds as a white solid. STEP 4: ( S,3 ^f R,6'R,7'S,8'E)-6-CHLORO-7'-HYDROXY-12'-(l ,3-OXAZOL-2- YLlVIETHY^-S^-DIHYDRO^H S^SPIROI APHTHALENE-l^^- | 2u jOXA| 1 3 ΓΗ ! !Α| U 2J 4 | T!U AXATiTRACYCLOI 14.7.2.0 * '\0 ^{) Μ} ^ΡίίΝΤΑί ^' OS Α[ 8, 16, 18 ,24] TETRAEN | - 15 ' -ONE 1 ^" . 13 ^" -DIOXIDE The title compounds were prepared from (S)-N-(N-(but-3-en-l-yl)-N-

(oxazol-2-ylmethyl)sulfamoyl)-6'-chloro-5-(((lR,2R)-2-((S )-l- hydroxyallyl)cyciobtm _' l)methyl)-3^4,4',5-tetrahydro-2H,2'H- spiroj benzoj b][ 1,4 ]oxazepine-3, -naphthalene]-7-carboxamide (Step 3), following a procedure similar to the one described in Step 3 in the synthesis of Example 660, except that Ti(0 ¹ Pr) ₄ (2.0 eq.) was added immediately before the Hoveyda-Grubbs catalyst (2nd generation), and the reaction was prolonged to 72 h. The crude product was purified by reversed phase preparatory HPLC

(Gemini™ Prep C18 10 μη column; Phenomenex, Torrance, CA; gradient elution of 45% to 90% MeCN in water, where both solvents contain 0. 1% TFA, 30 min method) to provide the title compound as a white foam. ¾ NMR (4()()MHz,

CDCI3) 6 8,87 (br. s„ IH), 7.76 - 7.65 (m, 2H), 7.18 (dd, j 2 3. 8,6 Hz, IH), 7.14

- 7,07 (m, 2H), 7.02 - 6.89 (m, H I 5.94 - 5,81 (m, IH), 5.79 - 5.67 (m, IH), 5.42

- 5.27 (m, 1H), 4.71 (d, j 1 7.4 Hz, i l l ). 4.25 - 4.19 (m, IH), 4.17 - 4.04 (m, 2H), 3.84 (d, .1 15. ! Hz, IH), 3.77 - 3.64 (m, 2H), 3.33 - 3.21 (m, 2H), 3.20 - 3.08 (m, IH), 2,84 - 2.72 (m, 2H), 2.70 (s, ! H), 2.55 - 2.19(m, 4H), 2.01 - 1.60 (m, 5H), 1.65-1.56 (m, 2H), 1.46 (t, J=11.9 Hz, IH). m/z (ESI, +ve ion) 653.0 ( M R ) .

EXAMPLE 695. (1 S,3'R,6'R,7'S,12'R)-5-CHLOR()-12'-ETHYL-7'-HYDROXY- 2,3 -D1HYDRO - 15 TI-SPIRO[INDENE- 1 ,22'-

| 2( !ί>Χ Λ| i 3 ! ! Π! Λ| ί 1 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 0 ^; ".O ¹ " ^M |PH\ i ACOSA

[ 16,18,24]TR1EN]-15'-0NE 13',13'-DI0X1DE OR (18,3¾,6'ίΙ,7'8,12 ^! 8)-5- CHLORO-12 ^! -ETHYL-7'-HYDROXY-2,3-DIHYDRO-15'H-SPIRO[INDENE- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 18,24] TRIEN] - 15 '-ONE 13', 13 ' -DIOXIDE

A flask containing a mixture of (lS,3'R,6'R,7'S,8'E,12'S)-5-chloro-12'~ ethyl-7'-hydroxy-2,3-dihydro-15H-spiro[indene-l,22'- [20]oxa[13]thia[l,14]diazatetracy^^

AEN]-15'-one 13',13'-dioxide or (lS,3 ^, R,6'R,7'S,8'E,12'R)-5-chloro-12'-ethyi-7'- hydroxy-2,3-dihydro-15'H-spiro[indene-l,22'-

n]-15'-one 13 ',13' -dioxide (10 nig, 0.017 mmol, Example 699) and PtO?. (1.0 mg) in EtOAc (5 mL) was purged with H?. balloon for 10 min. The mixture was allowed to stir at rt under H ₂ for 3.5 h. The flask was then purged with air for 2 min, and the solid was filtered off through a small pad of a C elite® (diatomaceous earth), and washed with EtOAc (2 x4 mL). The organic solutions were combined. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on ISCO Gold silica gel column with 0-50% EtOAc/Hexanes (EtOAc contained 0.1% HO Ac) provided the title compound as a film. ^! !I NMR (400MHz, CDCb) δ 9.84 (br, s., 1H), 7.37 (d, .1 HO Hz, 1H), 7.33 (br, s., ill).7.23 - 7.16 (m, 3H), 6,99 - 6.91 (m, ill).4.37 - 4.06 (m, 3H), 3,75 - 3.37 (m, 4H), 3.19 (d, J=14.1 Hz, IH), 3.00 - 2.88 (m, 2H), 2.46 (br. s, 1H), 2.33 - 2,04 (m, 4H), 2.01 - 1.22 (m, 14), 1.16 - 1.10 (m, 3H). m/z (ESI, +ve ion) 587.2 (W W)

EXAMPLE 696. (1 S,3 ^, R,6 ^! R,7'S,8 ^! E,12 ^! S)-6-CHLORO-7'-HYDROXY-12 ^, -(2- HYDROXY-2-PROPANYL)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA |H.16.1Η.2 ΓΠ: .\!:N |- 15 -ONEi 13',13'-DIOX!DE OR

(lS,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E.12 ^, R)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-HYDROXY-2- PROP ANYL)-3,4-DIHYDRO-2H, 15*H-SPIRO[N APHTHALENE- 1 ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8, 16, 18,24] TETR AEN ] - 15 ' -ONE 13 13 ' -DIOXIDE

STEP 1 : (S)-2-HYDROXY-N,N-BIS(4-METHOXYBENZYL)-2- METHY LHEPT-6-E E- 3 - SU LFON AMIDE AND { R · -2 ·ί !YDROXY -\.\- BIS(4-METHOXYBENZYL)-2-METHYLHEPT-6-ENE-3-SULFONAMIDE

To a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-l -sulfonamide (445 mg, 1.142 mmol, EE19) in THF (5.7 ml) under Ar was added "BuLi (594 μΙ, 1.49 mmol, 2.5 M in hexanes, Sigma- Aldrich Chemical Company, Inc.) drop wise over 2 rain at -78 °C. The resulting mixture was stirred in the -78 °C bath for 30 min, followed by addition of anhydrous acetone (0.5 mL, Sigma- Aldrich Chemical Company, Inc.). The reaction flask was removed from the bath and was allowed to stir at ambient atmosphere for 25 min. The reaction mixture was quenched with saturated aqueous NH4CI (2 mL), diluted with water (10 mL) and extracted with EtOAc (3x12 mL). The organic layers were combined, washed with water (6 mL), brine (3 raL), and dried over MgSCH. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-20-30% EtOAc/Hexanes as eluent provided the title compounds as a colorless syrup. STEP 2: (S)-2-IiYDROXY-2-METHYLHEPT-6-ENE-3-SULFONAMIDE AND (R)-2 -HYDROXY -2-METHYLHEPT-6-ENE-3-SULFON AMIDE

The title compound was prepared as a mixture from (S)~2~hydroxy-N,N- bis(4-methoxybeiizyl)-2-methylhept-6-ene-3-sulfonamide and (R)-2-hydroxy- N,N-bis(4-methoxybenzyl)-2-methylhept-6-ene-3-sulfonamide (Step 1) following a procedure similar to the one described in Step 2 for the synthesis of EE17.

STEP 3: (S)-6 ^! -CHLORO-N-(((S)-2-HYDROXY-2-METHYLHEX-5-EN-3- YL)SULFONYL)-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2 I-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTI-TALENE]-7- CARBOXAMIDE OR (S)-6'-CHLORO-N-(((R)-2-HYDROXY-2- METHYLHEX-5-EN-3-YL)SULFONYL)-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO- 2H,2TT-SPIRO[BENZO[B] [ I,410XAZEPINE-3,l '-NAPHTHALENE]-7- CARBOXAMIDE.

The title compounds were prepared as a mixture from (S)-6'-chloro-5-

(((l R,2R)-2-((S)~l-hydroxyallyl)cyc^

spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxyl ic acid (AA11A) and a mixture oi S)-2-hydroxy-N,N-bis(4-methoxybenzyi)-2-methylhept-6-ene-3- sulfonamide and (R)-2-hydroxy-N,N-bis(4-methoxybenzyl)-2-methylhept-6-ene- 3 -sulfonamide (Step 2), following a procedure similar to the one described in Step 2 for the synthesis of Example 660.

STEP 4: (lS,3 ^, R,6'R,7'S,8'E,12'S)-6-CHLORO-7 ^! -HYDROXY-12'-(2-

HYDROXY-2~PROPANYL)~3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]raJA[l,14]DIAZATETR^

[8, 16, 18,24] TETRAEN] - ! 5 ' -ONE 13 ' , 13 ' -DIOXIDE AND

(lS,3¾,6¾_,7¾,8T;i2'R)-6-CHLORO-7 ^, -HYDROXY-12'-(2-HYDROXY-2-

PROPANYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'- |;20]OXA[ 13 iTHIA[ l,14jDL4ZATETRACYCLO| 14 .2 ³ - ^f \0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8, 16, 18 ,24] TET AEN] - 15 ' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was prepared from a mixture of (S)-6'-chloro-N-(((S)- 2-hydroxy-2-methylhex-5-en-3-yl)sulfonyl)-5-(((lR,2R)-2-((S) -l- hydroxyall l)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, l '-naphthalene]-7-carboxamide and (S)-6'-chloro-

N-(((R)-2~hydroxy-2-m.ethylhex

hydroxyallyl)cyclobtm _' l)methyl)-3^4,4',5-tetrahydro-2H,2'H- spiroj benzoj b][ 1,4 ]oxazepine-3, -naphthalene]-7-carboxamide(Step 3), following a procedure similar to the one described in Step 3 for the synthesis of Example 660, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CIS 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 55% MeCN in water to 80% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA) to provide one of the title compounds as the first eluting isomer as a white foam H N.V1R (400MHz, CDC ): ¾ MR (400MHz, CDCh) δ 8.64 (br. s., i l l ). 7.70 (d, j 8.4 Hz, 1H), 7.18 (dd, j 2.0. 8.4 Hz, IH), 7.10-7.08 (ra, 2H), 7,02 - 6,88 (m, 2H), 5.71 - 5.54 (rn, 2H), 4,10 (dt, j 5.2.12.1 Hz, 3H), 3,87 - 3.69 (m, 21!).3.24 (d, j 14 ! Hz, IH), 3.04 (dd, J 6.3. 15.5 Hz, IH), 2.85 - 2.69 (m, 2H), 2.58 - 1.60 (m, Γ7Η), 1.55 (s, 3H), 1.42 (s, 3H); (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 697, (1 S,3'R,6' ,7'S,8'E, 12 ^, S)-6-CHLORO-7'-HYDROXY-12'-(2- HYDROXY-2-PROP ANYL)-3 ,4-DIHYDRQ-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l 4]DIAZATETRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ^l9 - ²⁴ ]PENTACOSA

[8,16,I8,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7'-HYDROXY-12 ^, -(2-HYDROXY-2- PROP ANYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSJTO Atl ^DIAZATETRACYCLOtMJ^.O'^.O'^lPE TACOSA

[8,16,18,24] TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 696, Step 4. ^" Ή NMR (400MHz, CDCb) δ 8.19 Cor. s., IH), 7.58 (d, j 8.4 Hz, IH), 7.33 (br. s., IH), 7.16 - 7.06 (m, IH), 7.02 (s, IH), 6.96 - 6.82 (m, 2H),5.69 (dd, j 5.3.15.8 Hz, IH), 5,48 id. j 6,! Hz, IH), 4, 18 - 4,01 (m, 2H), 3.98 - 3.82 (m, 21 \) 3.80 - 3,66 (rn, IH), 3.64 - 3.10 (m, 3H), 2.72-2,65(m, 2H), 2,54 - 1.52 (m, 16H), 1.47 (s, 3H), 1.39 (s, 3H). m/z (ESI, +ve ion) 629.2 (M+H) ⁺ . EXAMPLE 698. (18,3¾,6'Κ,7'8,8Έ,!2'Κ)-5-€ΗΙΧ) Ο-7'-ΗΥΟ ΟΧΎ-12'- νΠ.ΙΉΥί -2.:^ί)iHYί)! )-!.^ 1-SP!KOil^!)i·:Nί·-! . 2'- |2iί!<)XΛ| 1ΉΤί!1Α| Μ4|ΠίΑ/Α Π:ΤΗΑ(Ύα.ί)Ι i 4.7.2.0 ^• ^0 ^{|:, ! 1} [PHNTACOSA [8,16,18,241 TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE

STEP 1 : (S)-5 ^! -CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)-5-(((lR,2R)-2- ((S)-l-HYDROXYALLYL)CYCLOBUTYL)METHYL)-2',3 ^, ₅ 4,5- TETRAHYDRO-2H-SPTRO [BENZO [B] [1,4] OX AZEPINE-3 , 1 '-TNDENE] -7- CARBOXAMIDE

The title compound was prepared from (S)-5'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobutyl)methyl)-2',3',4,5-tetrahydro-2H- spiro[benzo[b][l,4]oxazepine-3,l'-indene|-7-carbox lic acid (AA20) and (R)- pent-4-ene-2-sulfonamide (EE17), following a procedure similar to the one described in Step 2 for the synthesis of Example 660, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-20% EtOAcHexanes (EtOAc containing 0.3% HO Ac) to provide the title compound as white solid.

STEP 2: (ISJ' ^' J'S^ n' S-CHLO O^'-HYDROXY- '- METHYL-2,3-DIHYDRO-15TI-SPIRO[INDENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE

The title compound was prepared from (S)-5'-chloro-N-((R)-hex-5-en-2- ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hydroxy

tetrahydro-2H-spiro[benzo[b][l,4]oxazepine-3, -indene]-7-carboxamide (Step 1), following a procedure similar to the one described in Step 3 for the synthesis of Example 660, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 810 μηι column; Phenomenex, Torrance, CA; gradient elution of 50% MeCN in water to 80% MeCN in water over 40 min period, where both solvents contain 0.1% TFA) to provide the title compound as a white foam. ¾ NMR (400MHz, CDCb) δ 8.08 (s, Hi).7.48 - 7.41 (m, 1H), 7.25 - 7,17 (m, 2H), 7.00 - 6.91 (m, 3H), 5.89 - 5,77 (m, IH), 5.76 - 5.66 (m, H), 4.29 - 4.14 (m, 4H), 3.85 (d, J 13.7 Hz, IH), 3.67 - 3.55 (m, I Hi.3.15 - 2.87 (m, 4H), 2.49 - 2.40 (m, IH), 2.40 - 2.28 (m, 2H), 2.19 (ddd, J=3.1, 7.8, 13.1 Hz, 2H), 2.04 - 1.91 (m, !!!).1.91 - 1.61 (m, 7H), 1.56 id. j 5.4 Hz, 3H); (ESI, +ve ion) 571.2 (WW) .

EXAMPLE 699. (1 S,3 ^, R,6 ^! R,7'S,8'E,12'S)-5-CHI,ORO-12'-ETHYL-7'- HYDROXY-2,3-DIHYDRO-15'H-SPIRO[INDENE-I,22'- [20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-5-CHLORO-12 ^, -ETHYL-7 ^, -HYDROXY-2 ₅ 3- DIHYDRO- 15 Ή-SPIRO [INDENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ - ^f \0 ^l9 ' ²⁴ ]PENT.ACOSA [8,16,18 ,24] TET AEN] - 15 ' -ONE 13', 13 ' -DIOXIDE

STEP 1 : (S)-5'-CHLORO-N-((S)-HEPT-6-EN-3-YLSULFO YL)-5-((( lR ₅ 2R)-2-

((S)-l-HYDROXYALLYL)CYCLOBUTYL)METHYL)-2 ^, ,3V4 ₅ 5- TETRAHYDRO-2H-SPIRO[BE ZO[B] [l,4]OXAZEPINE-3,r-INDENE]-7- CARBOXAMIDEAND (S)-5 ^! -CHLORO-N-((R)-HEPT-6-EN-3- YLSULFONYL)-5-(((lR,2R)-2-((S)-l -

HYDROXYALLYL)CYCLOBUTYL)METHYL)-2',3',4,5-TETRAHYDRO-2H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPlNE-3 , 1 '-INDENE] -7-C ARBOXAMIDE

The title compounds were prepared from (S)-5'-chloro-5-(((lR,2R)-2-((S)-

1 -hydroxy allyl)c lobut 'l)methyl)-2 ^, ,3',4,5-tetrahydro-2H- spiro[benzo[b] [l,4]oxazepine-3,l'-indene]-7-carboxylic acid (AA20) and a mixture of (R)-hex-5-ene-3-sulfonamide and (S)-hex-5-ene-3-sulfonamide (EE21 : EE212 =1 : 1), following a procedure similar to the one described in Step 2 for the synthesis of Example 660, except that the crude product was purified by flash chromatography on ISCO Gold silica gel column using 0-40% EtOAc/Hexanes (EtOAc containing 0.3% HO Ac) to provide the title compounds as a mixture.

STEP 2: (l S,3'RXVR,7 ^, S,8 ^! E,12 ^! S)-5-CHLORO-12'-ETHYL-7 ^, -HYDROXY- 2,3 -D1HYDRO - 15 'H-SPIRO[INDENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[K

| S. i . i H.24i r!: ! R .\i :N i- 1 5 -ONi : 13 ',13'-DI0X1DE OR (1 S,3'R,6'R,7'S,8'E, 12'R)-5-CHLORO-l 2'-ETHYL-7'-HYDROXY-2,3- D\\ lYDRO- 1 1 l-SIMRO| l\ DI.Ni ^' - i .22 -

|2ujOXA| O ΙΊ ί II A| I„ I 4|Di Α/.ΥΠΊ!<Λ(ΎΟ.ΟΙ i 4.7.2 U · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16,18,241 TETR AEN] -15' -ONE 13 ' , 13 ' -DIOXIDE The title compounds were prepared from a mixture of (S)-5'-chloro-N-

((S)-hept-6-en-3-ylsulfonyl)-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobur'l)methyI)-2',3',4,5-tetrahydro-2H- spiroj benzoj b][ 1,4 ]oxazepine-3,l'-indene]-7-carboxamide and (S)-5'-chloro-N-

((R)-hept-6-en-3-ylsulfonyl)-5-(((IR,2R)-2-((S)-l- h}'droxyallyl)cyciobu )m.ethyl)~2 ^! ,;T,4,5-tetrahydro-2H- spiro[benzo[b][l,4]oxazepine-3, -indene]-7-carboxamide (Step 1), following a procedure similar to the one described in Step 3 for the synthesis of Example 660, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 85 μιη. column; Phenomenex, Torrance, CA; gradient elution of 55% MeCN m water to 80% MeCN in water over a 20 min period, where both solvents contain 0.1 % TFA) to provide one of the title compounds as the first eluting isomer as a white foam. ¾ NMR (400MHz, (1X1;) δ 8,25 (br. s,, 1H), 7.44 (d, j 7.8 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.09 - 6.88 (m, 3H), 5.97 - 5.78 (m, Hi), 5.78 - 5.64 (m, III).4.36 - 4.14 ins.3H), 4.06 (br. s., Hi).3.83 (d, j 15.! Hz, ill).3.61 id, J 14.! Hz, ill).3,21 - 2,85 (m, 411).2.54 - 2,30 (ra, 311).2,30 - 1,52 (m, 12H), 1.35 - 1.13 (m, 3H); (ESI, +ve ion) 585.1 (M+H) ¹ .

EXAMPLE 700. (1 S 'R^'R 'S^^^'S^S-CHLO O-n'-E HYL-?'- HYDROXY-2,3-DIHYDRO-15'H-SPIRO[INDENE-I,22'- |20i()XA| Γ, ΐΗΙΛΐ Ι,,! |ί)!Λ/Λ! :ΓΚΛ(Α ^' , 01117.20 ^:'i' .0 ^li ' |Pl-:N i ACOSA |8.i6.i8.24! rL ! R.\i:Ni- 15 -ONi: 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, S.8 ^, E.12 ^, R)-5-CHLORO-12 ^, -ETHYL-7 ^, -HYDROXY-2 ₅ 3- DIHYDRO- 15 Ή-SPIRO [INDENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8,16,18 ,24] TETRAEN]- 15 ' -ONE 13', 13 ' -DIOXIDE

The title compound was obtained as a white foam as the second eluting isomer from the reversed phase preparatory HPLC separation in Example 699, Step 2. Ή N.MR (400MHz, CDCb) δ 8,26 (br. s . 111).7.67 (br, s., IH), 7.36 (d, .1 HO Hz, IH), 7,25 - 7.15 (m, 3H), 7.04 - 6.87 (m, 2H), 5,67 (dd, J=4.3, 15.7 Hz, IH), 5.47 (dd, J 7.3.14.6 Hz, IH), 4.37 - 4.16 (m, 3H), 4.10 (d, J 16.2 Hz, IH), 3.93 (d, j 15.1 Hz, 2H), 3.74 (d, j 14.5 Hz, IH), 3.46 - 3.35 (m, IH), 3.12 (d, j 15.1 Hz, 1 IT), 3.01 - 2.88 (m. Mi).2,67 - 1.36 (m, 1 ill).1 ,22 (dd, j 6.4.6.4 I !/..3H). m/z (ESI, +ve ion) 585.2 (M+H) ^H" .

EXAMPLE 701. (lS,3'R,6 ^! R,7 ^, S,8'E,12'R)-6-CHLORO-12'-ETHYL-17 ^! - FLU0R()-7 ^, -ME™0XY-3,4-DIHYDR0-2H,15TI-SPIR()[NAPHTHALENE- l. -

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15 ' -ONE 13 13 ' -DIOXIDE

The title compound was prepared from (lS,3'R,6'R,7'S,8'E,12'R)-6-chloro- 12 ^, -e%i-17-fluoro-7'-hydroxy-3,4-d% [20]oxa[13]thia[l ,14]diazatefra^

4]tetraen]-15'-one !3',13'-dioxide (EXAMPLE 656) following a procedure similar to the one described for the synthesis of Example 669 using methyl iodide instead of bromorihyl methyl ether, except that the crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep C I 8 5 μιη column;

Phenomenex, Torrance, CA; gradient elution of 45% to 95% MeCN in water, where both solvents contain 0.1% TFA, 25 min method) to provide the title compound as a white foam ¾ NMR (400MHz, CDCb) δ 8.21 (d, ,/ 7 0 Hz, H), 7.66 (d, 1=8.6 Hz, 1H), 7.18 (dd, J=2.3, 8,4 Hz, IH), 7.10 (d, J=2.2 Hz, IH), 6,88 - 6.79 (m, 1H), 6.72 (d, J=l 1.5 Hz, IH), 5.80 (ddd, J=5.0, 8.0, 15.2 Hz, IH), 5.53 (dd, ./ 8. . 15.3 Hz, IH), 4.19 - 4.03 i ns. 3H), 3.79 (d, ./ 1 5. ! Hz, IH), 3.70 - 3.55 (m, 2H), 3.30 - 3. 17 (m, 4H), 2,97 (dd, ./ ! 0.2, 15.3 Hz, IH), 2.87 - 2.68 (ra, 3H), 2,61 - 1.56 (m, 13H), 1.47 - 1.36 (m, IH), 1,27 (s, IH), 1,23 (dd, 1=8.3, 8,3 Hz, 3H). m/z (ESI, +ve ion) 631.2 (M S I ) . EXAMPLE 702. (1 S 'R^'R 'S^^^'S^e-CHLORO-n'-iiRi-HYDROX l^- THIAZOL-2-YL)METHYL)-7'-METOOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]raj:A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ -« 0 ¹⁹ ^ ⁴ ]PE rrACOSA [ 8,16,18,24jTETRAENj-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^f S,8 ^, E,12 ^, S)-6-CHLORO-12 ^, -((S)-HYDROXY(l,3- FnAZOL-2- YL)METHYL)-7'-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18 ,24] TETRAEN]- 15 ' -ONE 13 ', 13 ' -DIOXIDE OR

(lS,3 ^, R,6 ^, R,7 ^, S,8i 2 ^, R)-6-CHLORO-12 ^, -((R)-HYDROXY(l,3-THIAZOL-2-

YL)METHYL)-7'-METHOXY-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1,22'-

[20]OXA[13]TH1A[1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-l 2'-((S)-HYDROXY(l,3-THIAZOL-2- YL)METHYL)-7'-METHOXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| !3jTIUA| I 4|niA/ATI:TRA( ^' YCl.Oj i 4.7.2.0 ^• ^0 ^{|:, ! 1} IPHNTACOS A

[8,16,18,241 TETR AEN j -15' -ONE 13 ' , 13 ' -DIOXIDE

To a -78 °C solution of (18,3'¾6Έ,7'8,8Έ)-6-ο1ι1οΐΌ-7'-ΐΏβ4οχν-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- i;20]oxa[13]thia|;i,14]diazatetracyclo|14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ ]pentacosa

[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 651, Step 3) (25 mg, 0.043 mmol) in THF (2.0 mL) was added lithium diisopropylamide (0.17 ml, 0.26 M, 0.043 mmol, fresh solution prepared following a procedure similar to the one described in the synthesis of Example 682). The solutiuon was allowed to stir at - 78 °C to -30 °C for 30 min, to the mixture was added 2-thiazolecarboxyladehyde (48 mg, 0.43 mmol, Sigma- Aldrich Chemical Company, Inc.). The resulting solution was allowed to warm to rt over 20 min, and stirred at rt for 30 min. The reaction mixture was then quenched with saturated aqueous NH ₄ C1 (0.2 mL), diluted with water (3 mL) and extracted with EtOAc (3 x4 mL). The organic layers were combined. After remo val of organic sol vents under reduced pressure, the residue was subjected to reverse phase preparatory HPLC (Gemini™ Prep CI 8 5 μίη column; Phenomenex, Torrance, CA; gradient elution of 10% MeCN in water to 90% MeCN in water over a 20 min period, where both solvents contain 0.1% TFA) to provide one of the title compounds as a white foam. Ή NMR (400MHz, CDCb) δ 8.70 (hr. s., I I I ). 7.81 (d, ,/ 3.3 Hz, 1H), 7.72 - 7.64 (m, 1H), 7,44 - 7.38 (m, 1 ! ! }. 7.23 - 7. 13 (m, 2H), 7, 10 (d, ./ 2.2 Hz, ! ! ! ). 7.04 - 6.91 (rn, 2H), 6.01 (d, J=1.2 Hz, 1H), 5.88 - 5.75 (m, 1H), 5.49 (dd, ./ 7.2. 15.1 Hz, lH), 4.33 (d, J=7.0 Hz, lH), 4.20 - 4.04 (m, 2H), 3.69 - 3.23 (m, 5H), 3.36 (s, 3H), 2.89 - i ,27(rn, 17H). m/z (ESI, +ve ion) 666.3 ( V!-VleO! ! H ) and 720.3 (M+Na) ⁺ .

EXAMPLE 703. (1 S,3'R,6'R,7'S,8'E,1 l'R)-6-CHLORO-7 ^f -HYDROXY-l ! '- lW;NYL-3,4 3IHYDRO-2H,15 ^! H-SPrRO[NAPHTHALENE-l ,22'- [20]OXA[13]THIA[1 ,14]

DIAZATETRAC TLO[14,7.2.0 -^0 ¹⁹ - ²⁴ ]PENTACOSA[8, I 6,18,24]TETRAEN]- 15'-ONE 13',13'-DI0X1DE OR (l S,3'R,6'R,7'S,8 ^! E,i rS)-6~CHLORO-7'- HYDROXY-i r-PHENYL"3,4-DIHYDRO-2H,15'H~SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA|; 13 ]THI A 1,14]

DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15 ^! -ONE i 3', 13'-D10XIDE

STEP1 : (R)-ETHYL 2-PHENYLPENT-4-ENOATE AND (S)-ETHYL 2- PHENYLPENT-4-Ε

To a solution of 2- phenylacetic acid ethyl ester (11 .7 ml, 73.1 rnmol) in THF (146 ml) at ~78°C was added ally! bromide (6.32 ml, 73.1 mmol), followed by sodium bis(trimethylsilyl)amide, 0.6 M in toluene (122 ml, 73.1 mmol) over 5 min. The mixture was removed from ice bath and allowed to warm up to ambient temperature. After another 30 min, the mixture was poured into saturated ammonium chloride aqueous solution, diluted with water and extracted with EtOAc (3x). The combined organic solution was concentrated, and residue was purified by chromatography on silica gel eluting with 0% to 50% EtOAc in hexane to provide the title compounds (13.65g, 91%). m/z (ESI, +ve ion) 205.1 (M+H) ⁺ .

-PHENYLPENT-4-EN- ! -01, AND (S)-2-PHENYLPENT-4-EN- -

To a solution of (R)-ethyl 2-phenylpent-4-enoate and (S)-ethyl 2- phenylpent-4-enoate (13.65 g, 66.8 mmol) in Et?.0 (200 mL) at 0°C was added lithium aluminum hydride, 1.0 M solution in tetrahydrofuran (75 mL, 75 mmol) via a syringe over 15 min. The reaction mixture was stirred at this temperature for 2h. The reaction was monitored by TLC (EtOAc/Hexanes: 1/3). To the reaction mixture at 0°C was added 2.85 mL of water, 2.85 mL of 15% sodium hydroxide aqueous solution and 8.25 mL of water in order. The mixtui'e was stirred at room temperature for 40 min, and solid was filtered off. The filtrate was concentrated. and residue was purified by chromatography on silica gel eluting with 0% to 50% EtOAc in hexane to provide the title compounds (9.24g, 85%). ^! H NMR (400 MHz, CDCh) δ 7.40 - 7.33 (m, 2 H), 7.28 - 7.22 (m, 3 H), 5.81 - 5.69 (m, 1 H), 5, 12 - 4.94 (m, 2 H), 3,84 - 3.72 (m, 2 H), 3.01 - 2.85 (m, 1 H), 2,57 - 2.37 (m, 2 H). STEP 3: (R)-2~((2-PHENYLPENT-4-EN-i-YL)TH10)PYRIMIDlNE AND (S)-2- ((2-PHENYLPENT-4-EN- 1 - YL)TH10)P YRIMID1NE

To a solution of (R)-2-phenylpent-4-en-l-ol and (S)-2-phenylpent-4-en-l- ol (9.24 g, 57.0 mmol) in DCM (100 ml) at 0°C under N ₂ was added

triethylamine (9.51 ml, 68.3 mmol), followed by methanesulfonyl chloride (5.29 ml, 68.3 mmol) dropwsie. The mixture became white milky during the addition of methanesulfonyl chloride. The mixture was left stirring at 0°C for Ih. To the cloudy mixture was added water and the mixture was extracted with DCM

(3xl 00mL). The organic layers were combined, and washed with water, dried over magnesium sulfate. The solvent was removed under reduced pressure. To a solution of the residue obtained above (13.70 g, 57.0 mmol) in DMF (150 ml) was added 2-mercapto-pyrimidine (8.43 g, 75.2 mmol) and potassium carbonate (4.54 ml, 75.2 mmol). The mixture was heated at 70°C for 2h, and then cooled to room temperature. The reaction mixture was poured in water, extracted with EtOAc (3x200 mL). The combined organic layer was washed with water and brine and concentrated. The crude product was purified by chromatography on silica gel eluting with 0% to 50% EtOAc in hexane to provide the title compounds (13.87g, 95%). m/z (ESI, +ve ion) 257.0 (M+H) ⁺ .

STEP 4: (R)-2-((2-PHENYLPENT-4-EN-I -YL)SULFONYL)PYRIMIDINE AND (S)-2-((2-PHENYL;PENT-4-EN-l~YL SULFONYL)PYRrMIDrNE

To a solution of (R)-2-((2-phenylpent-4-en-l-yl)thio)pyrirnidine and (S)-2- ((2-phenylpent-4-en-l -yl)thio)pyrimidine (2.16 g, 8.43 mmol) in DCM (40.0 ml) and DMF (2.0 ml) at 0°C was added 3-chloroperbenzoic acid (4.62 g, 20.66 mmol) in one portion. The resulting mixture was stirred at 0°C for 5 min and at room temperature for 16h, and then heated at 50°C for 4h. The mixture was poured into a mixture of ice and saturated sodium bicarbonate aqueous solution. The layers were separaied. The aqueous layer was extracted with DCM (3x). The combined organic solution was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 0% to 100% EtOAc in hexane to provide the title compounds (2,02 g, 83%), m/z (ESI, +ve ion) 289,0 (M+H) ⁺ . STEP 5 : (R)-2-PHENYLPENT-4-ENE- 1 -SULFONAMIDE AND (S)-2- PHENYLPENT-4-ENE- 1 -SULFONAMIDE

(R)-2-((2-phenylpent-4-en- 1 -yl)sulfonyl)pyrimidine and (S)-2-((2- phenylpent-4-en-l-yl)sulfonyl)pyrimidine (2.02 g, 7.01 mmol) in MeOH (40 mL) was heated at 35°C until the solution became clear. To this solution was added sodium methoxide, 25 wt % solution in methanol (1.561 mL, 7.01 mmol) via a syringe slowly. The resulting mixture was stirred at room temperature for 30 min. The solvent was removed and residue was dried on high vacuum for 20 min. To the residue obtained was added water (40,0 ml .}, followed by sodium acetate trihydrate, granular (1.32 mL, 14.0 mmol) and amidoperoxymonosulfuric acid (1.58 g, 14.0 mmol) at room temperature. The resulting clear solution was stirred at 75 °C in a preheated oil bath for 30 min. then cooled to room temperature, hasified using ice-cold saturated sodium carbonate, and extracted with 20% i- PrOH/DCM (3x). The combined orgamcs were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 20% to 80% EtOAc in hexane to provide the title compounds (0.92 g, 58.3%). m/z (ESI, +ve ion) 226.0 (M+H) ⁺ .

STEP 6: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((lS,5S,E)-l -HYDROXY-5-PHENYL- 6-SULFAMOYLHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)-

2-((IS,5R,E)-l -HYDROXY ^T -5-PHENYL-6-SULFAMOYLHEX-2-EN-l - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H-

SPIRO| BENZO[B]|;i,4iOXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID

A mixture of (S)-6'-chloro-5-(((l R,2R)-2-((S)-l- hydroxyallyl)cyclobtm _' l)methyl)-3',4,4',5-tetrahydro-2H,2'H

spiroj benzoj b] [ 1,4 |oxazepine-3, -naphthaIene]-7-carboxyli (127 mg, 0.271 mmol. Intermediate AA11A) and (R)-2-phenylpent-4-ene-l- sulfonamide and (S)-2-phenylpent-4-ene- 1 -sulfonamide (183 mg, 0.814 mmol) in 1,2-dichloroethane (4.0 ml) was purged with argon for 10 mm. To this solution was added Hoveyda-Grubbs catalyst (2nd generation) (17.01 mg, 0.027 mmol) in 1 mL of DCE slowly. The reaction mixture was stirred under argon balloon at room temperature for 16h. The mixture was subjected to column for purification by chromatography on silica gel eluting with 20% to 80% EtOAc (containing 0.3% AcOH ) in hexane to provide the title compounds (0.115 g, 63.7%). m/z (ESI, +ve ion) 665.2 (M+H) ⁺ .

STEP 7: (1S,3'R,6'R,7'S,8'E,1 l'R)-6-CHLQRO-7'-HYDRQXY-ll ^* -PHENYL-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THTA[1 ,14] ί)!Λ/Λ ΓΚΓΚΛ(Ύ(·ΓΟί 117.20· ^: '.0 ^|; ' !Ρ1·Ν l ^' A( ^' <)SA|8. i . j 8.2-1 ΓΠΠ ^' ΚΛΗΝ |- 15'-ONE 13',13'-DIOXIDE OR (IS^R^' 'S^'E rSH-CHLORQ-?'- HYDROXY-ri'-PHENYL-3,4-DIHYDRO-2H,15Ti-SPIRO[NAPHTHALENE- 1.22'-! 201 OXA[ 13] ^' fflIA[ 1 , 14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TET AEN]- 15'-ONE 13', 13 '-DIOXIDE To a solution of (S)-6'-chloro-5-(((lR,2R)-2-((lS,5S,E)-l-hydroxy-5- phenyl-6-sulfamoylhex-2-en-l-yl)cyclobut^ )methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [1,4] oxazepine-3 , 1. '-naphthal ene] -7-carboxy li c aci d and (S)-6'- cWoro-5-(((lR,2R)-2-((lS,5R,E)-l-hydroxy-5-phenyl-6-sulfamoy lhex-2- yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l,4]oxazepine- 3, -naphthalene] -7-carboxy lie acid (115 mg, 0.173 mmol) in DCM (50 ml) at 0°C was added 4-(dimethylamino) pyridine (63.4 mg, 0.519 mmol), followed by l-(3- dimethylarninopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.519 mmol) in 3 mL of DCM. The reaction mixture was stirred at this temperature for 20 mm, and then warmed up to room temperature and stirred for 3h. The solvent was removed and residue was purified by chromatography on silica gel eluting with 20% to 100% EtOAc (containing 0.3% AcOH) in hexane to give the product with desired mass, and further purified by reversed phase preparatory' HPLC

(Gemini™ Prep C18 5μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide the first eluting isomer as a white solid as one of the title compounds. ¾ NMR (400 MHz, CDCb) δ 8.59 (br s, 1 H), 7.73 (d, J=8.61 Hz, 1 H), 7.38 - 7.31 (m, 2 H), 7.28 - 7.25 (m, 1 H), 7.23 - 7.15 (m, 3 H), 7.11 (d, ./ 2 15 Hz, 1 H), 7,04 - 6.95 (m, 3 H), 6,06 - 5.96 (m, 1 H), 5,70 (dd. ./ 15.26. 7,83 Hz, 1 H), 4.56 (dd, J=15.45, 5.67 Hz, 1 H), 4.28 (d, J=5.28 Hz, 1 H), 4.19 - 4.07 (m, 2 H), 3.86 - 3.70 (m, 2 H), 3.63 (dd, J=15.55, 7.34 Hz, 1 H), 3.29 (d, ./ 14.28 Hz, 1 I I ). 3.12 (d, J=16.04 Hz, 2 H), 2.84 - 2.75 (m, 2 H), 2.47 (dd, ./ 14.57, 5.77 Hz, 4 H), 2.04 (d, J=9.39 Hz, 3 1 1 ). 1.88 - 1.63 (m, 5 H), 1 .46 (t, J=12.72 Hz, 1 H). m/z (ESI, +ve ion) 646.9 (M+H) ⁺ .

EXAMPLE 704, (I S,3'R,6'R,7'S,8'E, 1 l'S)-6-CHLORO-7'-HYDROXY-l V- PHE YL-3,4 ^IHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[1,14]

DIAZA^ΈTRACYCLO[14.7.2.0 ^3■ 0 ^{, 9} ' ^M ;|PE TACOSA[8 ₅ 16.18,24]TETRAEN]- 15 -ONE 13', 13 '-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E, 1 l'R)-6-CHLORO-7'- HYDROXY-i -PHENYL-3,4-DIHYDRO-2H,15'H-SPlRO[NAPHTHALENE- l,22'- 20jOXA[ 131THIA[l,14|

DIAZATETRACYCLO[14,7.2.0 - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8, I 6,! 8,24]TETRAEN]- 15'-ONE 13 ',13 '-DIOXIDE

The other title compound as a white solid was obtained as the later eluting isomer from the reversed phase preparatory HPLC separation in Example 703, Step 7. ¾ NMR (400 MHz, CDCh) δ 8.54 (br s, 1 H), 7.68 (d, J=8.41 Hz, 1 H), 7.38 - 7.32 (m, 2 H), 7.29 - 7.25 (m, 2 H), 7.24 - 7.16 (m, 3 H), 7.12 (d, ./ 2.15 Hz, 1 H), 7.04 - 6.95 (m, 2 H), 5.80 (d, ,/ 430 Hz, 2 H), 4,36 (d, ./ 14.48 Hz, 1 H), 4.30 - 4.20 (m, 2 H), 4.05 (br s, 1 H), 3,69 (dd, ./ 15.26.8.02 Hz, 2 H), 3,42 (d, J=13.50 Hz, 1 H), 3,27 (d, J=15.45 Hz, 1 H), 2.99 (br s, 1 H), 2.78 (br s, 2 H), 2.64 - 2,30 (ra, 5 H), 2.08 - 1.67 (ra, 8 H), 1.52 (br s, 1 H). mz (ESI, +ve ion) 646.9 (M+H) ⁺ .

EXAMPLE 705. (1 S,3'R,6'R,7'S, 11 'R)-6-CHLORO-7'-HYDROXY- 11 '-

PHENYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]

DL ZATETRACYCLO[14.7.2,0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ |PENTACOSA|;i6,18,24]TRIEN]-15 ^! - ONE 13", 13-DIOXIDE OR (I S,3'R,6'R,7'S, 11 'S)-6-CHLORO-7'-HYDROXY- ir ^> HF;NYL~3,4 >IHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20] OXA[ 13]THI A[ 1,14]

DIAZATETRACYCLO|14.7.2.0 ³ - ^f \0 ¹⁹ - ²⁴ ]PENTACOSA[16,18,24]TRJEN]-15'- ', 13 '-DIOXIDE

A mixture of the first eluting isomer from Example 703, Step 7

[(1 S,3 ^! R,6'R,7 ^! S,8'E, 11 'R)-6~c oro~7'~hydroxy-l 1 '-phenyl-3,4-dihydro-2H, 15Ή- spiro|naphthalene-l,22'~[20]oxa|13]thia[l,14]diazatetracyclo [14.7.2,0 ³ ^0 ⁱ⁹ ' ²⁴ ] pentacosa[8, 16, 18,24 jtetraen]-! 5'-one ! 3',13'-dioxide or

(1 S,3'R,6 ^! R,7'S,8'E, 11 'S)-6-chloro-7'-hydroxy- 11 '-phenyi-3,4-dihydro-2H, 15Ή- spiro [naph thalene- 1 ,22'- [20] oxa[ 13] thia[ 1 , 14]

diazatetracyclo[14 .2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13 - dioxide] (4.9 nig, 7.57 μηιοΐ,) and platinum (iv) oxide (0.344 nig, 1.514 μιηοΐ) in EtOAc (6.0 mL) was stirred under hydrogen balloon at room temperature for lh. The solid catalyst was filtered off through syringe filter, and filtrate was concentrated. The crude product was purified by reversed phase preparatory

HPLC (Gemini™ Prep CI 8 5μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide one of the title compounds as a white solid. ¾ NMR (400 MHz, DMSO-i/.,} δ 7.70 (d,■/ K.6 ! Hz, 1 H), 7.34 - 7.26 (m, 3 H), 7.25 -

7.18 (rn, 4 I s ). 7.12 - 7.08 (rn, 1 I s ). 7.03 (m, 1 H), 6,97 (d, ./ 8.02 Hz, 1 H), 4, 12 - 4.00 (m, 3 H), 3.92 (d, ./ 14.48 Hz, 1 H), 3.71 - 3.61 (m, 2 H), 3.55 (d, J=9.39 Hz, 1 ! ! }. 3.44 - 3.33 (m, 1 ! ! }. 3.26 (d, ,/ 14.48 Hz, 1 H), 3.12 (dd, ./ 1 .26. 9.39 Hz, 1 H), 2,98 - 2,90 (m, 1 H), 2.85 - 2,67 (m, 3 H), 2.56 - 2,47 (ra, 1 H), 2.35 - 2.21 (m, 2 H), 2,09 - 1.98 (m, 2 H), 1.97 - 1.82 (m, 4 H), 1.75 - 1.66 (m, 2 H), 1,45 - 1.23 (m, 5 H). m/z (ESI, +ve ion) 648.8 (M+H) ⁺ .

EXAMPLE 706. (1 S,3'R,6'R,7'S,9'E, 1 'S)-6-CHLORO-7'-HYDROXY-l 1'- (HYDROXYMETHYL^S^-DIHYDRO-ffl S^SPIROI APHTHALl-nslE- 1,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[9,16,18,24] TETR AEN] - 15 '-ONE 13Y13'~DIOXIDE OR

(1S,3'R,6'R,7'S,9'E,1 l'R)-6-CHLORO-7'-HYDROXY-l Γ- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'

[20]QXA[13]THIA[1,14]DLAZ^^

[9,16,18,24]TETRAEN]-15'-ONE 13',13 ^* -DIOXIDE OR

(1S,3'R,6'R,7'S,9'Z, I l 'R)-6-CHLORO-7'-HYDROXY-l ! '-

(HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[ 13 ]TH1 A[ 1,14] DIAZ ATETRAC YCLO

|;i4.7,2.0 ³ -^() ^{i 9} - ²⁴ lPENTACOSA|;9,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE OR (1 S,3'R,6'R,7'S,9'Z, 1 l'S)-6-CHLORO-7 ^f -HYDROXY-ri'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15^SPIRO[ APHTHALENE- 1 ,22'-[20] OXA[ 13]THIA[ 1,14]

DIAZATE RACYCLO 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA[9J 6,18,24iTETRAEN] 15 ^* -ONE 13',13'-DTOXIDE

STEP 1 : (Z)-4-((TERT-BUTYLDIPHENYLSILYL)OXY)BUT-2-EN-l -OL

To a suspension of sodium hydride, 60% dispersion in mineral oil (0.478 mL, 22.70 mmol) in 20 mL of THF under nitrogen at room temperature was added a solution of cis-2-butene-l,4-diol (2.0 mL, 22.70 mmol) in 80 mL of THF slowly. The mixture was stirred at 50 °C for Ih, and then cooled to room temperature. To the cloudy mixture was added a solution of tert-butylchlorodiphenylsilane (5.90 mL, 22.70 mmol) in 20 mL of THF. The resulting mixture was stirred at room temperature for 16 h, and then 80 mL of saturated ammonium chloride aqueous and 100 mL of EtOAc were added. The mixture was stirred for 10 min and layers were separated. The aqueous layer was extracted with EtOAc (2x80 mL). The combined EtOAc solution was dried over sodium sulfate, filtered and

concentrated to provide the crude product. The crude product was purified by chromatography on silica gel eluting with 0% to 40% EtOAc in hexane to provide the title compound (5.78 g, 78%). M i NMR (500 MHz, CDCh) δ 7.79 - 7.66 (m, 4 H), 7.50 - 7.35 (m, 6 H), 5.83 - 5.60 (m, 2 H), 4.37 - 4.24 (m, 2 H), 4.10 - 3.96 (m, 2 H), 1 , 16 - 1.04 (m, 9 H).

STEP 2: (Z)-11 1-DIBUTYL-2 ₅ 2-DI ETHYL-3,3-DIPHENYL-4,9-DIOXA-3- SILA- 1 1 - STANNAPENTADEC-6-ENE

To a suspension of sodium hydride, 60% dispersion in mineral oil (1.303 g, 32.6 mmol) in THF (40 mL) at room temperature was added a solution of (Z)- 4-((tert-butyldiphenylsilyl)oxy)but-2-en-l -ol (10.64 g, 32,6 mmol) in THF (50 mL) dropwise. After the reaction mixture was stirred for 5 min,

tributyl(iodomethyl)stannane (7.02 g, 16.29 mmol, prepared according to the reference: Synthetic Communication, 24(8), 1117-1 120, 1994) in THF (40 mL) was added, followed by HMPA (40mL).The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by addition of water (300 mL) and brine (84 ml). The layers were separated, and then the aqueous layer was extracted with ether (3x 200 mL). The combined organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was absorbed into 80g of silica gel and dried, and then purified by chromatography on silica gel eluting with 0% to 5% EtOAc in hexane to provide the title compound (1.26 g, 12.4%). ¾ NMR (400 MHz, CDCb) δ 7.77 - 7.70 (m, 4 H), 7.47 ·· 7.40 (m, 6 H), 5.83 - 5.75 (m, 1 H), 5.62 - 5.53 (m, 1 H), 4.33 - 4.29 (m, 2 H), 3.81 (dd, ,/ 6.26. 0.78 Hz, 2 H), 3.68 - 3.61 (m, 2 H), 1.58 - 1.47 (m, 6 H), 1.38 - 1.27 (m, 6 H), 1.12 - 1.08 (m, 9 H), 0.96 - 0.88 (m, 15 H). STEP 3: (S)-2-(((TERT-BU LDIPHENYLSILYL)OXY)METHYL)BUT-3- EN-l -OL AND (R)-2-(((TERT-

BUTYLD1PHENYLSILYL)0XY)METHYL)BUT- 3 -EN- 1 - OL

To a solution of (Z)-l l ,l l-dibut l-2,2-dimethyl-3,3-diphenyl-4,9-dioxa-3-sila-l 1 - stannapentadec-6-ene (1.26 g, 2.01 mraol) in THF (70 mL) at -78°C was added butyllithium, 1.6 M in hexanes (3.76 mL, 6.02 mmoi) slowly. The reaction mixture was stirred at -78°C for lh, before being quenched with water (30 mL). The layers were separated and aqueous layer was extracted with ether (3x 80 mL). The combined organic solutions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with DCM to provide the title compounds (0.277 g, 40,5%). ¾ NMR (400 MHz, CDCb) δ 7.78 - 7.69 (m, 4 H), 7.52 - 7.40 (m, 6 H), 5.84 - 5.65 (m, 1 H), 5.24 - 5.11 (m, 2 H), 3.92 - 3.74 (m, 4 H), 2.68 - 2.54 (m, 1 H), 1.17 - 1.08 (m, 9 H).

STEP 4: (R)-((2-((BENZYLTHIO)METHYL)BUT-3-EN-l-YL)OXY)(TERT- BUTYL) DIPHENYLSILANE AND (S)-((2"((BENZYLTH10)METHYL)BUT- 3-EN - 1 - YL)OXY) (TERT-BUTYL)DIPHENYLSILANE

A mixture of (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)but-3-en-l-ol and (R)-2-(((tert-bu1yldiphenylsilyl)oxy)methyl)but-3-en-l-ol (0.277 g, 0.813 mmol), (mercaptomethyl)benzene (0.105 nil, 0.895 mmol) and cyanomethylenetri-n- butylphosphorane (0.353 ml, 1.464 mmol) in toluene (2.96 ml) was heated at 90°C for 3h. The reaction mixture was cooled to room temperature, and diluted with EtOAc, washed with saturated ammonium chloride aqueous solution and brine, dried over sodmm sulfate, concentrated. The crude product was absorbed into lOg of silica gel and dried, and then purified by chromatography on silica gel eluting with 0% to 30% EtOAc in hexane to provide the title compounds (0.229 g, 63%). ³ H NMR (400 MHz, CDCb) δ 7.75 - 7.70 (m, 4 H), 7.52 - 7.42 (m, 6 H), 7,35 - 7.26 (m, 5 H), 5.82 (ddd, J=17.07, 10.51, 7.83 Hz, 1 H), 5.20 - 5.11 (m, 2 H), 3.81 - 3.66 (m, 4 H), 2.86 - 2.79 (m, 1 H), 2.60 - 2.46 (m, 2 H), 1.14 - 1.09 (m, 9 H). m/z (ESI, + ve ion) 469.1 (M+Na) ⁺ .

STEP 5: (R)-2-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)BUT-3- ENE-1 -SULFONAMIDE AND (S)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)BUT-3-ENE-l -SULFONAMIDE

To a mixture of (R)-((2-((benzylthio)methy])but-3-en-l-yl)oxy)(tert- butyl)diphenylsilane and (S)-((2-((benz lthio)methyl)but-3-en- 1 -yl)oxy)(tert- butyl)diphenylsilane (0.229 g, 0.513 mmol) and iodosylbenzene (0.372 g, 1.692 mmol) in 50 mL of ether was added hydrogen chloride (3.76 ml, 45.1 mmol) gradually with vigorously stirring. The resulting mixture was stirred for 2h. The reaction mixture was settled and layers were separated. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried on high vacuum for lh. The solution of residue in 5 ml, of DCM was added slowly into a solution of ammonium hydroxide, 28% (7.13 ml, 51.3 mmol) at 0°C. The resulting mixture was stirred at room iemperature for 2h, and then settled. The layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by

chromatography on silica gel eluting with 0% to 60% EtOAc in hexane to provide the title compounds (0. 138 g, 66.7%), m/z (ESI, +ve ion) 426.1 (M+Na) ⁺ .

STEP 6: (3S)-6'-CHLORO-5-(((lR,2R)-2-((l S)-l-HYDROXY-3-BUTEN-l-YL) CYCLOBUTYL)METHYL)-N-(((2R)-2-((((2-METHYL-2-PROPANYL)

(DIPHENYL)SII X)OXY)METHYL)-3-BUTEN-l -YL)SULFONYL)-3',4,4',5- TETRAHYDRO-2'H-SPIRO[l,5-BENZOXAZEPINE-3, -NAPHTHALENE]-7- CARBOXAMIDE AND (3S)-6 ^! ~CHLORO-5~(((lR,2R)~2"((lS)-l-HYDROXY-3- BUTEN-l-YL)CYCLOBUTYL)METHYL)-N-(((2S)-2-((((2-METHYL-2- PROP AN YL) (DIPHENYL)SILYL)OXY)METHYL)-3 -BUTEN- 1 - YQSULFONY^-S'^^'^-TETRAHYDRO^'H-SPIROtl^- BENZOXAZEPINE-3,1 '-NAPHTHALENE] -7-CARBOXAMIDE

A mixture of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l - yl)cyclobut\d)methyl)-3',4,4^5-tetrahydro-2H,2'H-spiro[benzo [b][l ,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (0.080 g, 0.166 rnmol, Intermediate AA13A), (R)-2-(((tert-butyldiphenylsilyl)ox )methyl)but-3-ene- 1 -sulfonamide and (S)-2- (((tert-but 4diphenylsil}'1)oxy)meihyl)but-3-ene~l-suifonamide (0.134 g, 0.332 rnmol), N,N-dimethylpyridin-4-amine (0.061 g, 0.498 rnmol) and l- ((ethylimino)methylene)-N3,N3-dimethylpropane-l ,3-diamine hydrochloride (0,064 g, 0.332 rnmol) in 5 niL of DCE was stirred at room temperature forl 6h. The solvent was removed under reduced pressure, and residue was purified by chromatography on silica gel eluting with 0% to 50%» EtOAc (containing 0.2% AcOH) in hexane to provide the title compounds (0.168 g. 1 17%). m/z (EST, +ve ion) 867.2 (M+H) ⁺ .

STEP 7: (S)-6'-CHLORO-5-((( 1 R,2R)-2-((S)- 1 -HYDROXYBUT-3-EN- 1 -

YL)CYCLOBUTYL)MF iYL)-N ((R)-2-(HYDROXYMETHYL)BUT-3-EN- 1-ΥΕ)8υΐΤΌΝΥΙ,)-3',4,4',5-ΊΈΤ¾ΑΗΥΟΚΟ-2Η, 2Ή- SPIRO BENZO[B] [1 ,4 T.OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT- 3-EN-l-YL)CYCLOBUTYL)METHYL)-N-(((S)-2- (HYDROXYMETHYL)BUT-3-EN-l-YL)SULFO YL)-3',4,4',5- TETRAHYDR0-2H,2'H-SPIR0|;BENZ0[B] [ 1 ₅ 4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMIDE

A solution of (3S)-6'-chloro-5-(((lR,2R)-2-((l S)-l-liydroxy-3-buten-l- yl)c 'clobutyl)methyl)-N-(((2R)-2-((((2-methyl-2- propany])(diphenyl)silyl)oxy)m^^

2H-spiro[l,5-benzoxazepine-3, -naphthalene]-7-carboxarnide and (3S)~6 ^! ~chloro~ 5-(((l R,2R)-2-((l

methyl-2-propanyl)(diphenyl)silyl)oxy)methyl)-3-buten-l-y l)sulfonyl)-3',4,4',5- tetrahydro-2H-spiro[l,5-benzoxazepine-3,r-naphthdene]-7-carb oxaim (0, 168 g, 0.194 mmol) in 1 mL of THF was treated with tetra-n-butylammonium fluoride, IM solution in THF (3.87 ml, 3.87 mmol). The reaction mixture was stirred at room temperature for 24h. The solvent was removed under reduced pressure and residue was purified by chromatography on silica gel eluting with 0% to 10% MeOH in DCM to provide the title compounds (0.088 g, 72.2%). m/z (ESI, +ve ion) 629.2.1 (M+H) ⁺ .

STEP 8: (1S,3 ^! R,6'R,7'S,9'E, I S)-6-CHLORO-7'-HYDROXY-H'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[ 13]THIA[ 1 , 14]

DIAZATETRACYCLO[14J.2.0 ³ ' ⁶ 0 ¹⁹ - ² ]PEOTACOSA[9,16,18,24]TETRAEN]- 15'-ONE 13',13'-DIOXIDE OR (l S,3 ^, R,6'R,7'S,9'E,i rR)-6-CHLORO-7'- HYDROXY- 11 '-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15 Ή-

SPIRO[NAPH ^' raALENE-l ,22 ^! ~[20]OXA

[ 13]THIA[1,14]DIAZATETI ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA[9,I6,18, 24|TETRAEN;|-15 ^, -0NE 13',13'-DIOXIDE OR (l S,3'R,6'R,7'S,9 ^! Z, i rR)-6-

CHLORO-7"-HYDROXY-l 1 ^f -(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H- SPI O [ APHTHALENE- 1 ,22'- [20] OXA

[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA[9,16,18, 24]TETRAEN]-15'-ONE 13',I3'-DIQX1DE OR (l S,3'R,6'R,7'S,9'Z,l l'S)-6- CHLORO-7'-HYDROXY-l 1 '-(HYDRQXYMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA

1 1 1 1 1 11 Λ| I .. i i | OIA/.\ H . ΓΚΛί ^' ΥΌ .ΟΙ N .7.2 0 '^ 0 ^{| :} ' ^PH\,T.\i SA| . ! 6. I S. 24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

A solution of (S)-6 ^* ~chl oro~5~(((l R,2R)~2~((S)~ 1 -hydroxy but-3-en- 1 - yl)cyclobulyl)methyl)-N-(((R)-2-(hydroxymethyl)but-3-en-l-yl )sulfonyl)-

3',4,4',5-tetrahydro-2H,2H-spiro[henzo[h] [ 1 ,4 joxazepme-3, 1 '-naphthalene j -7- carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l -hydroxy but-3-en-l - yl)cyciobuU4)methyl)-N-(((S)-2-(hydroxymethyl)but-3-en-l-y

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide (0.088 g, 0.140 mmol) in toluene (200 mL) was subjected to three cycles of evacuation/back-filling with nitrogen. To this solution was added a solution of Hove da-Grubbs catalyst (2nd generation) (0.018 g, 0.028 mmol) in 1 mL of Toluene at room temperature. The reaction mixture was stirred at 106 °C under nitrogen for 4h. Air was blown into mixture for deactivating the catalyst. The reaction was cooled to room temperature and concentrated. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep C 18 5μιη column: Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 mill method) to provide the first eluting isomer as one of the title compounds. ^! H NMR (400 MHz, CDCb) δ 7.73 (d, ./ 8.61 Hz, 1 1 1 ). 7.41 (dd, ,/ H 41 , 1 ,96 Hz, 1 H), 7. 1 9 (dd, ,/ 8.61 . 2, 15 Hz, 1 H), 7.10 (d, J=2.35 Hz, 1 H), 7.02 - 6.95 (m, 1 H), 6.93 (s, 1 H), 5.75 (ddd, ./ 14.67. 10.86, 3.23 Hz, 1 H), 5.41 (dd, ./ 14.77. 10.07 Hz, 1 H), 4.18 - 4.07 (m,

2 H), 4.01 - 3.86 (m, 2 H), 3.66 (d, ,/ 14.28 Hz, 2 H), 3.61 - 3.48 (rn, 3 H), 3.30 (d, .7=14.48 Hz, 1 H), 3.23 - 2,99 (m, 3 H), 2.81 - 2,74 (m, 2 H), 2.46 - 2,34 (m, 2 H), 2.19 - 1.76 (m, 6 H), 1.66 - 1.47(m, 4 H), 1.35 - 1.27 (m, 2 H). m/z (ESI, +ve ion) 601.2 ( +H) ⁺ . EXAMPLE 707. (1 S,3'R,6 ^! R,7'S,9'E,1 l'R)-6-CHLORO-7 ^f -HYDROXY-l Γ- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALElSIE- l,22'-[2()]OXA

[ 13]THI A[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14, 7.2, 0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]ΡΕΝΤ ACOS A[ 9, 16,18, 24]TETRAENj-15'-ONE 13',13'-D10XIDE OR (18,3Ί,6¾,7'8,9Έ,1Γ8)-6- CHL()R()-7' -IYDR()XY r-(HYDR()XYMETHYL)-3,4-DIHYDRO-2H,15'i-I- SPIRO [ APHTHALENE- 1 ,22'- [20] OXA

[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ' ²⁴ ]PENTACOSA[9,16,18, 24]TETRAEN]-15'-ONE 13 ^! ,13'-DIQX1DE OR (lS,3'R,6'R,7'S,9'Z,irR)-6-

CHLORO-7'-HYDROXY-l 1 '-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA

I 1 11111 Λ| I .. i 1 |OI.\/.\ H . f ^' RACY( ^' f ,Oj N.7.20'^ 0 ^|: ' ^PHNTAi SA|9.!6.18. 24]TETRAEN]-15'-ONE 13 ^* ,13'-DIOXIDE OR (lS,3 ^! R,6'R,7'S,9'Z,ll'S)-6- CHLORO-7'-HYDROXY- 11 '-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15Ή-

SPIRO[NAPHTHALENE-1,22 ^! -[20]OXA

[13]TH1A[1,14]DIAZATEIIACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA[9,16,18, 24 jTETRAEN]-15 ^* -ONE 13',13'-DIOXIDE

A second title compoimd as a white solid was obtained as the later eluting isomer from the reversed phase preparatory HPLC separation in Example 706, Step 8. ^j ll NMR (400 MHz, CDCh) δ 7.73 (d, ,/ H.4I Hz, 1 H), 7.41 (dd, ./ 8.3!. 2,05 Hz, 1 III 7.19 (dd, J=8.61 , 2.35 Hz, 111).7.10 {O.J 235 Hz, 1 H), 7,00 (d, J=8.22 Hz, 1 H), 6.94 - 6.90 (m, 1 H), 5.76 (ddd, ,/ 1 -I 62.10,71, 4.01 Hz, 1 H), 5.41 (dd, J=15.16, 10.66 Hz, 1 H), 4.16-4.11 (m, 2 H), 4.00 - 3.87 (m, 3 H), 3.66 (d,■/ I4.2H Hz, 2 !!}.3,57 - 3,52 (m, 3 H), 3.30 (d,■/ 14.48 Hz, 1 H), 3.24 - 2.99 (m, 3 H), 2,81 - 2.75 (m, 2 H), 2.44 - 2.36 (m, 2 H), 2.16 - 2.08 (m, 2 H), 2,05 - 1.67 (m, 7 H), 1.52 - 1.27 (m, 2 H). m/z (ESI, +ve ion) 601.2 (M+H) ⁺ .

EXAMPLE 708. (lS,3'R,6'R,7'S,i rS)-6-CHLORO-7'-HYDROXY-l l'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- L22'-[20]QXA[13]THIA

[L14]DIAZATETiL CYCLO[ 14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTACOSA[16,18,24jTRIEN]- 15 -ONE 13', 13 '-DIOXIDE OR (IS,3'R,6'R,7'S, 1 l'R)-6-CHLORO-7'- HYDROXY- 1 1 '-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA

[ 13]THIA[ 1, 14]DIAZATETRACYCLO[14.7.2.0 ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[ 16, 18,24 JTRIENJ- 15'-ONE 13', 13'-DIOXIDE

A mixture of the first eluting isomer from Example 706, Step 8

[(1 S,3'R,6'R,7'S,9'E,1 l'S)-6-chloro-7'-hydroxy-l l'-(hydroxymethyl)-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-[20]oxa[ 13] thi a[ 1 , 14] diazatetracy clo

[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa[9, 16,18,24]tetraen]-15 ^! -one 13',13'-dioxide or (1 S,3'R,6'R,7'S,9'E, 1 1 'R)-6-chloro-7'-hydrox -l 1 '-(hydroxymethy l)-3,4-dihydro- 2H, ! 5'H-spiro[naphthalene-l ,22'-[20]oxa[ 13]thia[ 1 , 14] diazatetracy clo

[ 1 , 7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[9, 16, 18,24] tetraen] - 15 '-one 13 ', 13 '-dioxi de or (lS,3'R,6'R,7'S,9'Z,l l'R)-6-chloro-7'-hydro

2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[ 13]thia[l , 14]dia.zatetracycio[14,7.2,0 - ⁶ .0 ¹⁹ - ²⁴ ]

pentacosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide or (1 S,3'R,6'R,7'S,9'Z,1 l 'S)~ 6-cMoro-7'-hydroxy-n'-(hydroxymethyl)-3,4-dihydro-2H,15'H- spiro[naphthalene- 1 ,22'-[20] oxa[ 13]thia[ 1 , 14] diazatetracy o

[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]peiitacosa[9,16,18,24]tetraen]-15'~one 13 ^! ,I3'-dioxide] (4.0 mg, 6.65 μτηοί) and platinum (iv) oxide (0.30 mg, 1.33 μηιοΐ) in ethyl acetate (2.0 mL.) was stirred under hydrogen balloon at room temperature for 2h. The solid catalyst was filtered off through a syringe filter, and filtrate was concentrated. The crude product was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 5μιη column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide one of the title compounds. 'H NMR (500 MHz, CDCh) δ 9.15 (br s, 1 H), 7.71 i d. ./ 8. 1 Hz, 1 1 1 ). 7.23 - 7.13 (ra, 3 1 1 ). 7.11 (d, J=1.96 Hz, 1 H), 6,99 - 6.92 (m, 1 H), 4.17 - 4.07 (m, 2 H), 3.88 (dd, J=15.28, 5.01 Hz, 1 H), 3.82 - 3.71 (m, 3 H), 3.70 - 3.63 (m, 2 H), 3.55 - 3.45 (m, 1 H), 3.26 (d, ./ 14.43 Hz, 1 H), 3.14 (br s, 1 H), 2.83 - 2.75 (m, 2 H), 2.41 - 2.34 (m, 2 H), 2,30 - 2.16 (m, 1 H), 2.13 - 1.78 (m, 7 H), 1.73 - 1.32 (m, 9 H). m/z (ESI, +ve ion) 603.2 (M+H) ⁺ .

EXAMPLE 709. (lS ₅ 3 ^, R,6 ^, R,7 ^, S,9 ^, Z,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12'-

(HYDROXYMETTTYL)-3,4-DIHYDRO-2H,16'H-SPIRO[NAPHTHALENE- l,23'-[21 ]OXA

I 1 -1 1 1 H I A | I i 5 | OI .\/.\ H . Πί ΛίΎί ^' ί , Ol ! 5, 7.2 Ο ' ".ϋ ' ^{π !} |H HXAC OS.\| . I 7. 1 9.2 5]TETRAEN]-16'-ONE 14',14'-DIOXIDE AND (Ιβ^^,όΊ ,Τ'β^'Ζ,ηΐ^-ό" CHLORO-7 ⁱ 1YDROXY-12'-(HYDROXYMETI-IYL)-3,4-DIHYDRO-2H,16 ⁱ H- SPIRO [NAPHTHALENE- 1 ,23 ^! - [21 ] OX A

[14]THL [1,15]DT ZATET1 ACYCLO[15.7.2.0 ³ -^0 ²⁰ - ²⁵ ]HEXACOSA[9,17,19,2 5 JTETRAEN] - 16'-ONE 14', 14'-DIOXIDE

STEP 1 : 2- ALLYLPROP ANE- 1 ,3 -DIOL

A solution of diethyl allylmalonate (7.93 ml, 40 mmol) in 40 mL of THF was added dropwise to a stirred solution of lithium aluminum hydride, 1.0 M solution in THF (100 ml, 100 mmol) in THF (250 mL) at 0°C over 30 min. The ice bath was removed, and reaction mixture was stirred at room temperature for 4h.The reaction mixture was cooled to 0°C To this mixture wewr added the 3.8 mL of water, 3.8 mL. of 15% sodium hydroxide aqueous solution, and 1 1 mL of water in order. The reaction mixture was stiired at room temperature for 10 min, and filtered through celite. The filtrate was concentrated, and residue was purified by chromatography on silica gel eluting with 30% to 90% EtOAc in hexane to provide the title compound (4.43 g, 95%). Ή NMR (400 MHz, CDCh) δ 5.84 - 5,62 (m, 1H), 5.09 - 4.89 (m, 2H), 4.14 - 4,08 (m, 2H), 3.70 - 3.61 (m, 2H), 3.54 (dd, ./ 7.2-1. 10.76 Hz, 2H), 2.04 - 1.95 (m, 2H), 1.81 - 1.68 (m, 1H). STEP 2: (R)-2-(((TERT-BUTYLDIPHENYLSILYL)OXY)METFIYL)PENT-4- EN-! -GL AND (S)-2-(((TERT-

BUTYLDlPHENYLSILYL)OXY)METHYL)PENT-4-EN-l-OL

To a suspension of sodium hydride, 60% dispersion in mineral oil (0.589 g, 14.7 mmol) in 15 mL of THF under nitrogen at room temperature was added a solution of 2-allylpropane-l,3-diol (1.71 g, 14.7 mmol) in 45 mL of THF slowly. The mixture was stirred at 50 °C for lh, and then cooled to room temperature. To the cloudy mixture was added a solution of tert-butylchlorodiphenylsilane (3.83 mL, 14.72 mmol) in 30 mL of THF. The resulting mixture was stirred at room temperature for 16h, and then 50 mL of saturated ammonium chloride aqueous and 100 mL of EtOAc were added. The mixture was stirred for 10 min and layers separated. The aqueous layer was extracted with EtOAc (2x100 mL); combined EtOAc solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel eluting with 0% to 50% EtOAc in hexane to provide the title compounds (4.99 g, 84%). ¾ NMR (400 MHz, CDC] 3) δ 7.79 - 7.71 (m, 4 H), 7.55 - 7.38 (m, 6 H), 5.79 (ddt, ,/ 1 7 12. 10,07, 7.04, 7.04 Hz, 1 H), 5.13 - 4.96 (m, 2 H i. 3.92 - 3.67 (m, 4 H), 2.62 (br s, 1 H), 2.14 (t, J=7.04 Hz, 2 H), 1.94 (quint, ./ 6.83. 6.83, 6.83, 6.83, 4.33, 4.33 Hz, 1 H), 1.15 is. 9 H).

STEP 3 : (S)-((2-((BENZYLTHIO)METHYL)PENT-4-EN- 1 -YL)OXY)(TERT- BUTYL)DIPHE YLSILANE AND (R)-((2-((BENZYLTHIO)METHYL)PENT- 4-EN-l-YL)OXY)(TERT-BUTYL)DIPHENYLSILANE

A mixture of (R)-2-(((tert-butyldiphenylsilyl)ox ^, )rnethyl)pent-4-en-l-ol and (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en-l-ol (4,39 g, 12.4 mmol), benzylmercaptan (1.60 mL, 13.6 mmol) and cyanomethylenetri-n- butylphosphorane (5.38 mL, 22.3 mmol) in toluene (45 mL) heated at 90°C for 3h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with saturated ammonium chloride aqueous solution and brine, dried over sodium sulfate, filtered and concentrated. The crude product was absorbed into 80g of silica gel and dried, and then purified by chromatography on silica gel eluting with 0% to 30% EtOAc in hexane to provide the title compounds (4,91 g, 86%). Ή NMR (400 MHz, CDCb) δ 7.76 - 7.72 (m, 4 H), 7.53 - 7.43 (m, 6 H), 7.39 ·· 7.33 (m, 4 H), 7.32 - 7.26 (m, i H), 5.80 - 5.68 (m, i H), 5.1 1 - 5.01 (m, 2 H), 3.79 - 3.67 (m, 4 H), 2.73 - 2.66 (m, 1 H), 2,55 (dd, ./ 12 9 j . 6.26 Hz, 1 H), 2.32 - 2.26 (m, 2 ! ! }. ! .91 - I 80 (m, 1 ! ! }. ! .16 - 1. 1 1 (m, 9 H).

STEP 4: (S)-2-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4- ENE-1 -SULFONAMIDE AND (R)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-ENE-l -SULFONAMIDE

To a mixture of (S)-((2-((benz}dthio)methyl)pent-4-en-l -yl)oxy)(tert- butyl)diphenylsilane and (R)-((2-((benzyltbio)methyl)pent-4-en- 1 -yl)oxy)(tert- butyl)diphenylsilane (2.46 g, 5.34 mmol) and iodosylbenzene (3.88 g, 17.6 mmol) in ether (300 mL) was added concentrated hydrchlonc acid (39.2 mL, 470 mmol) gradually with vigorous stirring. The resulting mixture was stirred for 2h. The reaction mixture was settled and layers separated. The organic layer was washed with water and dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried on high vacuum for ih. The solution of residue in 5 mL of DCM was added slowly into a solution of ammonium hydroxide, 28% N3¾ (74.3 mL, 534 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2h and settled. The layers were separated. The aqueous layer was extracted with DCM (3x), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by

chromatography on silica gel eluting with 0% to 60%» EtOAc in hexane to provide the title compounds (1.04 g, 46.5%). ^] H NMR (400 MHz, CDCb) δ 7.75 - 7.61 (m, 4 H), 7.53 - 7.37 (m, 6 H), 5.80 - 5.60 (m, 1 H), 5.14 - 5.01 (m, 2 H), 4.62 (s, 2 H), 3.88 - 3.65 (m, 2 H), 3.34 (dd, J=14.38, 6.36 Hz, 1 H), 3.12 (dd, J=14.48, 5.28 Hz, 1 H), 2.42 - 2.16 (m, 3 H), 1.15 - 1.02 (m, 9 H). STEP 5 : (S)-6'-CHLORO-5-((( 1 R,2R)-2-((S)- 1 -HYDROXYBUT-3-EN- 1 -

YL)CYCLOBUTYL)METHYL)-N-(((R)-2-(HYDROXYMETHYL)PENT-4-EN- 1 -YL) SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l -HYDROXYBUT- 3-EN-l -YL)CYCLOBUTYL)METHYL)-N-(((S)-2-

(m ^r DROXYMETHYL)PENT-4-EN-l -YL)SULFONYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '- N APHTH ALENE] -7 -C ARB OXAMIDE

A mixture of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l - yl)c> lobu1yl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l ,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (0.070 g, 0.145 mmol, Intermediate AA13A), (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-ene-l -sulfonamide and (R)-2- (((tert-butyldiphenylsilyl)oxy)methyl)pent-4-ene-1 -sulfonamide (0.121 g, 0.29 mmol), 4-(dimethylamino)pyridine (0.053 g, 0.436 mmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.056 g, 0.29 mmol) in 5 mL of DCE was stirred at room temperature for 16h. The reaction mixture was directly loaded on column (5g silica gel) for purification by chromatography on silica gel eluting with 0% to 50% EtOAc (containing 0.2% AcOH) in hexane to provide the precursor of the title compound. The precursor of the title compound was treated with tetrabutylammonium fluoride, 1.0 M in THF (6.41 mL, 6.41 mmol) in 2 mL of THF was stirred at room temperature for 4.5 days. The solvent was removed under reduced pressure and residue was purified by chromatography on silica gel eluting with 0% to 10% MeOH in DCM to provide the title compounds (0,055 g, 59%). m/z (ESI, +ve ion) 643.2 ( VI - 1 1 ) ^' . STEP 6: (l S,3'R,6'R,7'S,9'Z,12'S)-6-CHL()R()-7'-HYDROXY-12'-

(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 16Ή-8ΡΚΟ [NAPHTHALENE- L23'-[21 ] OXA| 14]THIA[ 1 , 15]

DLAZ ATETRAC Y C LO [ 15.7.2.0 ³ · ⁶ .0 ²⁰ - ²⁵ ]HEXACOS A[9, 17,19,25]TETRAEN] - 16'-ONE 14',14'-DI()XIDE AND (l S,3 ^, R,6'R,7'S,9'Z,12'R)-6-CHLORO-7'- HYDROXY-12'-(HYDROXYMETHYL)~3,4-DIHYDRO-2H,16 ^! H- SPIRO [NAPHTHALENE- 1 ,23 ' - [21 ] OXA[ 14] THIA[l /15]DIAZATETRACYCIi3[ 157.2^y ³ '^0 ²⁰ - ²⁵ ]HEXACOSA[9J 7,19 25]TE TRAEN]-16'-ONE 14V14'-DIOXIDE

A solution of (S)-6'-chl or o-5-(((l R,2R)-2-((S)-l-hy droxybut-3-en-l - yl)cyclobu d)methyl)-N-(((R)-2-(hydroxyme1hyl)pent-4-en-l-yl)sulfonyl)- 3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-na phthalene]-7- carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l -hydroxy

yl)cyclobuty )methyl)-N-(((S)~2-(hydroxy

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7- carboxamide (0.055 g, 0.086 mmol) in toluene (130 mL) was subjected to three cy cles of evacuation''back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs catalyst (2nd generation) (10.7 mg, 0.017 mmol) in 1 mL of toluene at room temperature. The reaction mixture was stirred at 106 °C under nitrogen for 4h. Air was blown into mixture for 5 min. The reaction mixture was cooled to room temperature, and then concentrated. The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 5μπι column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TEA, 30 min method) to provide the first eluting component as the Z olefin compounds. ¾ NMR (400 MHz, CDCb) δ 7.73 (d, ./ 8.4 ! Hz, 1 H), 7.38 (dd, ./ 8.3 1. 1.66 Hz, 1 H), 7.29 - 7.26 (m, 1 H), 7, 1 8 (dd, ./ 8.4 j . 2. 15 Hz, I H), 7.09 (d, ./ 2. 15 Hz, 1 H), 6.96 (d, ./ 8 41 Hz, 1 H), 5.58 - 5.44 (m, 2 H), 4.13 - 4.07 (m, 2 H), 3.88 (d, .7=15,45 Hz, 1 H), 3,80 - 3.46 (m, 6 H), 3.20 - 3.06 (m, 2 H), 2.80 - 2.73 (m, 2 H), 2.50 (d, J=10.37 Hz, 3 H), 2.40 - 2.29 (m, 2 H), 2.14 - 1.76 (m, 9 H), 1.70 - 1.39 (m, 4 H). m/z (ESI, +ve ion) 615.1 (M+H) ⁺ .

EXAMPLE 710. (l S,3'R,6' ,7'S,9 ^! E, 12 ^! S)-6-CHLORO-7'-HYDROXY-12 (HYDROXYMETHYL)~3,4-DTHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1,23'-[21]ΟΧΑ[14]

THLA[l,15]DlAZATElllACYCLO[ 15.7.2.0 ³ - ⁶ .0 ²⁰ - ²⁵ ]HEX/\COSA[9,r7,19,25]TE TRAEN]-16'-ONE 14',14'-DIOXIDE AND (1 S,3¾,6TL7'S,9'E,12'R 6- CHLORO-7'-HYDROXY-12'-(HYDROXYMETHYL)-3 ₅ 4-DlHYDRO-2H,16H-

SPIRO [NAPHTHALENE- 1 ,23 '- [21 ] OXA[ 1 ]

THlA[l,15]DIAZATETRACYCLO[157.2.0 ³ -^0 ^2a25 ]HEXACOSA[9,17,19,25]TE -16'-ONE 14', 14'-DIOXIDE

The E olefin title compounds were obtained as a white solid as the later eluting component from the reversed phase preparatory HPLC separation in

Example 709, Step 6. Ή NMR (400 MHz, CDCb) 67.72 (d, ./ 8.4! Hz, 1 H), 7.61 (dd, ./ 8. 1.2.05 Hz, 1 H), 7.24 (d, ./ 2.15 Hz, 1 H), 7.18 (dd, ./ K.4f.2.35 Hz, 1 H), 7.09 (d, ,/ 235 Hz, 1 H), 7,02 - 6.93 (m, 1 H), 5,52 - 5.44 (m, 1 H), 5,28 (t, J=\ 1.74 Hz, 1 H), 4.17 - 4.04 (m, 2 H), 3.95 - 3.85 (m, 2 H), 3.69 - 3.51 (m, 5 H), 3.09 (d, ./ 13.89 Hz, 1 H), 3.01 (dd, ,/ 15.65.8.02 Hz, 1 H), 2.84 - 2.71 (m, 3 III 2.18 - 2.00 (m, 5 !!}.1.93 - 1.51 (m, 9 !!}.1.49 - 1.30 (m, 3 H). m/z (ESI, +ve ion) 615.1 (M+H) ⁺ .

EXAMPLE 711. (lS^'R^'R^'S^'S^e-CHLORO-T-HYDROXY-l?- {HYDROXYYIHTJ ΙΥΙ. Μ-ΟΠ 1YDRO-2} i.1 'i !-SF!R( ⁾ i\ AF! I Π 1AU \T.~

1,23'"[21]ΟΧΑ[14]ΊΉ1Α[1,15]

DIAZATETRACYCLO[15.7.2.0 ³ ' ⁶ .0 ²⁰ ' ²⁵ ]HEXACOSA[17,19,25]TRIEN]-16'- ONE 14*,14'-DIOXIDE AND (1 S,3'R,6'R,7'S,12 ⁱ R)-6-CHLORO-7 ^f -HYDROXY- 12 ^ί -(HYD OXYMEΊΉYL -3,4 ^1ΉYDRO-2H,16Ή-SPI O[NAPHTHALENE- 1 ,23'-[21 ] OXA[ 14]THIA[ 1,15]

DIAZATETRACYCLO|15.7.2.0 ³ - ⁶ .0 ²⁰ - ²⁵ ]HEXACOSA|;i7,19,25iTRIENj-16'- ONE 14', 1 '-DIOXIDE

A mixture of the compounds from Example 709, Step 6

[(I S,3¾,6'R,7'S,9'Z, 12'S)-6-chloro-7' iydroxy

2H,16'H-spiro[naphthalene-l,23'-[21]oxa[14]thia[l,15]

diazatetracyclo[15:7.2A ⁾³ '^0 ²⁰ - ²⁵ ]hexacosa[9, 17J 9,251tetraenl-16'-one 14',14'- dsoxide and (1 S,3'R,6'R,7'S ,9'Z, 12 ^, R)-6-chloro-7 ^* -hydroxy-l 2'-(hydroxymethyl)- 3 4-dihydro-2H/16H-spiro[naphthalene-l,23' 21]oxa[] 4]thia[l,15]

diazatetracyclo [ 15.7.2.0 ³ ' ⁶ .0 ²⁰ ' ²⁵ ]hexacosa[9,17;i9,25]tetraeii|-16'-one 14',14'~ dioxide (4mg, 6.5 μηιοΐ,) and platinum(IV) oxide (0.15 mg, 0.65 μηιοΐ) in ethyl acetate (2.5 mL) was stirred under hydrogen balloon at room temperature for 2 h. The solid catalyst was filtered off through a syringe filter, and filtrate was concentrated. The crude product was purified by reversed phase preparatory

HPLC (Gemini ^1M Prep CI 8 5μιη column; Phenomenex, Torrance, CA; gradient eiution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide the title compounds. Ή NMR (400 MHz, CDCh) δ 10.40 (br s, l i ! ). 7.72 (d, ./ 8.6 i Hz, i l l ). 7,54 - 7.46 (m, I I I ). 7.35 (br s, i l l ). 7.18 (dd, ./ 1 .96. 8.61 Hz, 1H), 7.10 (s, 1H), 6.99 (d, ./ H. I Hz, M l ). 4.14 (s, 2H), 3.77 (dd, ./ 3.62. 10.86 Hz, 2H), 3.74 - 3.58 (m, 4H), 3.55 - 3.45 (m, 3H), 3,24 (d, ./ 1 5.06 Hz, 11 1 ). 2,82 - 2.73 (m, 2H), 2.45 - 2.27 (m. l ). 2, 1 1 - 1.84 (m, 6H), 1.81 - 1.57 (m, 5H), 1.54 - 1.32 (m, 6H). m/z (ESI, +ve ion) 617.2 (M+H) ⁺ . EXAMPLE 712. (1 S,3 ^! R,6 ^, R,7'S,12'S)-6-CHL()RO-7'-HYDR()XY-12'-

(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPlRO[NAPHTHALENE- 1.22'-! 201 OXA[ 13]THI A[ 1 , 14] DIAZ A TETR A C YCLO [14.72.0 ^; ".0 ¹⁹ ' ²⁴ ]PENTACOS A[ 16, 18,24]TRIEN] - 15"- ONE 13',13'-DIOXIDE OR (1S,3 ^! R,6'R,7'S,12'R)-6-CHLORO-7'-HYDROXY- 12 ^! "(HYDROXYMETHYL)-3,4~DIHYDRO-2H,15'H"SPIRO[NAPHTHALENE - l,22'-[20jOXA[131THIA[l,14

DIAZATETRACYCLO[14,7.2.0 ^3/l .0 ¹⁹ - ² ]PENTACOSA[16,I8,24]TRIEN]-!5'- O ' _S 13'-DI0X1DE

STEP 1 : (S)-l -((TERT-BUTYLDIMETHYLSTLYL)OXY)PENT-4-EN- AND (R)-i -((ThRT-BLTYLDlYli-.11 IYl.SU.Yf .)OXY )P!.\ 1 -4-HV2-

To a solution of (tert-butylcUmemylsilyloxy)acetaldehyde (5.46 mL, 28.7 mmol) in THF (100 mL) at 0°C was added allylmagnesium bromide, 1.0 M solution in diethyl ether (143 mL, 143 mmol) dropwise over Ih. The reaction was stirred at room temperature for 2h. The reaction was cooled to 0°C and was quenched with saturaied ammonium chloride (80 mL). The mixture was extracted with EtOAc (3x 100 mL). The combined organic solution was washed with brine, dried over sodium sulfate and filtered, concentrated. The crude product was purified by chromatography on silica gel eluting with 0% to 60% EtOAc in hexane to provide the title compounds (3,70 g, 59.7%). ¾ NMR (400 MHz, CDCh) δ 5.92 - 5.77 (m, 1 H), 5.17 - 5.05 (m, 2 H), 3.71 (qd, J=6.52, 3.72 Hz, 1 H), 3.66 - 3.60 (m, 1 H), 3.50 - 3.41 (m, 1 H), 2.27 - 2.21 (m, 2 H), 0.95 - 0.87 (m, 9 H), 0.10 - 0.03 (m, 6 H). STEP 2: (S)-((2-(BENZYLTHIO)PENT-4-EN- 1 -YL)OXY)(TERT- BUTYL)D1METHYLSILANE AND (R)-((2-(BENZYLTHIO)PENT-4-EN-l - YL)OXY)(TE -BUTYL)DIMETHYLSILANE

A mixture of (S)-l-((tert-biiiyldimethylsiiyl)oxy)pent-4~en-2-ol and (R)-l- ((tert-butyldimethylsilyl)oxy)pent-4-en-2-ol (1.03 g, 4.76 mmol),

phenylmethanethiol (5.58 mL, 4,76 mmol) and 2- (tributylphosphoranylidene)acetonitrile (2.50 mL, 9.51 mmol) in toluene (2.0 ml.) was heated at 110°C for 5h. The reaction mixture was cooled to room

temperature, and diluted with EtOAc, washed with saturated ammonium chloride and brine, dried over sodium sulfate, and filtered, concentrated. The crude product was absorbed into 30g of silica gel and dried, and then purified by

chromatography on silica gel eluting with 0% to 20% EtOAc in hexane to provide the title compounds (0.498 g, 32.5%). ^l H NMR (400 MHz, CDCh) δ 7.35 - 7. 14 (m, 5 H), 5,84 - 5.64 (m, 1 H), 5,07 - 4.95 (m, 2 H), 3,77 - 3.50 (m, 4 H), 2.69 - 2.15 (m, 3 H), 0.89 ·· 0.80 (m, 9 H), 0.07 ·· 0.04 (m, 6 H). STEP 3: (S)-l -((TERT-BUTYLDIMETHYLSTLYL)OXY)PENT-4-ENE-2-

SULFONAMIDE AND (R)- 1 -((TERT-BUTYLDIMETHYLSILYL)OXY)PENT- 4-EN E-2-S LI LF ON AMIDE

To a mixture of (S)-((2-(benzylthio)pent-4-en-l -y])ox ')(tert- butyl)dimethylsilane and { )-( ( 2-{ ben/y 1 ihi o }pen! - -I -en- 1 -v I )o\ )( teri- butyl)dimethylsilane (0.300 g, 0.93 mmol) and iodosylbenzene (0.675 g, 3.07 mmol) in diethyl ether (80 mL) was added hydrochloric acid (6.82 mL, 82 mmol) gradually with vigorously stirring. The resulting mixture was stirred for Ih. The reaction mixture was settled and layers separated. The organic layer was washed with water and dried over sodium sulfate, concentrated under reduced pressure and dried in vacuo for Ih. The residue obtained above was dissolved in 5 mL of DCM and added slowly into a solution of ammonium hydroxide (12.9 mL, 93 mmol) at 0°C. The resulting mixture was stirred at 0°C to room temperature for 2h. The lay ers were separated. The aqueous layer was extracted with DCM (3x), and the combined organic solution was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 0% to 60% EtOAc in hexane to provide the title compounds (0.1 14 g, 43.9%). m/z (ESI, +ve ion) 280.2 i \ \ M y .

STEP 4: (S)- -(((S)-l-((TERT-BUTYLDlMETHYLSlLYL)OXY)PENT-4-EN- 2-YL)SULFONYL)-6'-CHLORO-5-(((l R,2R)-2-((S)-l -HYDROXYBUT-3-EN- l -YL)CYCLOBUTYL)METI-IYL)-3',4,4',5-TETRAI-iYDRO-2I-I,2'H- SP1RO [BENZO [B] [1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE AND (S)-N-(((R)-1 -((TERT-

BUTYLDIMETHYLSILYL)OXY)PENT-4-E -2-YL)SULFONYL)-6'-

CHLORO-5-(((l R,2R)-2-((S)-l-HYDROXYBUT-3-EN- l - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETiLAHYDRO-2H,2 ^, H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMTDE

A mixture of (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l- yl)cyclobutyl) methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine- 3, 1 ^f -naphthalenej~7~carboxyiic acid (0.060 g, 0. 124 mmol, intermediate AA13A), (S)-l-((tert-butyldimethylsilyl) oxy)pent-4-ene-2-sulfonamide and (R)-l -((tert- buty ⁷ ldimethylsilyl)oxy)pent-4-ene-2-sulfonamide (0.052 g, 0.187 mmol), N,N- dimethy3pyridm-4-amine (0.046 g, 0.373 mmol) and Nl-((ethylimino)methylene)- N3,N3-dimethylpropane-l ,3-diamine hydrochloride (0.048 g, 0.249 mmol) in 3 mL of DCE was stirred at room temperature for 16h. The solvent was removed under reduced pressure, and residue was purified by chromatography on silica gel eluting with 0% to 50% EtOAc (containing 0.2% AcOH) in hexane to provide the title compounds (0.081 g. 88%). m/z (ESI, +ve ion) 743.3 (M+H) ⁺ . STEP 5: (1S,3 ^, R,6'R,7'S,9'Z,12'S)-6-CHL0R0-12 ^! -(((DIMETHYL(2-ME™YL- 2-PROPANYL)Sn^T _J )OXY)METHYL)-7'-HYDROXY-3,4-DIHYDRO- 2H,15'H-SPIRO[NAPHTHALENE-l,22'- [ 20 |OXA[ 13]THIA[ 1 , 14]DI AZ ATETRAC YCLO

[ 14,7.2.0 ³ ' .0 ¹⁹ ' ² ]PENTACOSA[9, 16,1 8,24]TETRAEN]-15'-ONE 13', 13'- DIOXIDE AND ( 1 S,3'R,6'R,7 ^! S,9'Z, 12'R)-6-CHLORO- 12'-(((DIMETHYL(2~ METHYL-2-PROPANYL) SILYL)OXY)METHYL)-7'-HYDROXY-3,4- DIHYDRO-2H, ! 5 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

| 2θ !() Λ| I 31 1 Η1 Λ| I J -I | ί)Ι.\/.νΠ : i RACVCi .Ol i -1.7.2 0 ^{:' i'} .0 ^{l i} ' |Pi-:N l ACOSA [9, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXlDE AND

(1S,3¾,6 ^! R,7 ^, S,9'E,12'S)-6-CHL0R0-12 ^, -(((DIME™YL(2-METOYL-2-

PROPANYL)SILYL)OXY)METOYL)-7'-I-IYDROXY-3,4-DIHYDRO-2H, 15'H- SPIR0[NAPHTHALENE- 1 ,22'-[20] OXA[l 3]THI A[ 1 , 14] DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[9,16, 18,24]TETRAEN; 15'-ONE 13' ₅ 13'-DIOXJDE AND (l S,3'R VR,7'S,9 ^! E,12 ^! R)-6-CHLORO-12'- (((DlMETHYL(2-METHYL~2"PROPANYL)SlLYL)OXY)METHYL)-7'- HYDROXY-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[1 3]THIA[1 , 14]DIAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

PENTACOS A[9, 16,18,24] TETRAEN ] - 15 '-ONE 13', 13 '-DIOXIDE

A solution of (S)-N-(((S)-1 -((tert-butyldimethyisilyl)ox>')pent-4-en-2- yl)sulfonyl)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en- l-

3,r-naphthalene]-7-carboxamide and (S)-N-(((R)-1 -((tert- butyldimethylsilyl)oxy)pent-4-en-2-yl ^

hydrox 'but-3-en-l-yl)c 'clobutyl)methyl)-3',4,4',5-tetfahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxaraide (0.081 g, 0.109 mmol) in toluene (150 mL) was subjected to three cycles of evacuation/backfilling with mtrogen. To the homogeneous solution was added a solution of Hove da-Grubbs catalyst (2nd generation) (0.014 g, 0.022 mmol) in 1 mL of toluene at room temperature. The reaction mixture was stirred at 106 °C under nitrogen for 2h. The reaction mixture was cooled to room temperature, and air was blown into mixture for 5 min. The mixture was concentrated and the residue was purified by chromatography on silica gel eluting with 0% to 45% EtOAc in hexane to provide the title compounds (0.067g, 85.9%). m/z (ESI, +ve ion) 715.3 (M+H) ⁺ .

STEP 6: (1 S,3'R,6'R,7'S,9'Z,12 ^! S)-6-CHLORO-7 ^! -HYDROXY-12'- (HYDROXYMETHYL)-3,4-DlHYDRO-2H,15'H-SPlROiNAPHTHALENE- 1,22' j 20]OXA[ 13]THIA[l,14j DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[9,16,18,24]TETRAENj- 15'-ONE 13' ₅ 13'-DIOXIDE AND (lS,3'R,6'R,7'S,9'Z,12'R)-6-CHLORQ-7'- HYDROXY- 12'-(HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TOL1A[1,14]DIAZATETRACYCLO[147 .0 ³ -*0 ¹⁹ ^ ⁴ ]PEOTACOSA

[9, 16, 18,24]TETRAEN] - 1 S'-ONE 13', 13'-D10XIDE AND

(lS,3'R,6'R,7'S,9'E,12'S)-6-CHLORO-7'-HYDR()XY-12 ^! - (HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SP1R0[NAPHTHALENE- 1,22'- |2ujOXA| 13 ΙΊ I II \| I J 4|Di A/A ΠΊ ^' ΗΛίΎΟ.ϋΙ 14.7.2.0'^ 0 ^{|:, !|} |PH\,T.\i SA

[9,16,18,24]TETRAENj-15'-C)NE 13',13'-DIOXIDE AND

( 1 S,3'R,6'R,7'S,9'E, 12'R)-6-CHLORO-7'-HYDROXY- 12'-

(HYDROXYMETHYL)-3,4-DlHYDRO-2H,15'H-SPlROiNAPHTHALENE-

1 ,22'-[20] OXA|; 13 ]THIA[ 1 , 14JDIAZATETRACYCLO

[14.7.2.0 ³ -^0 ⁱ⁹ - ²⁴ ]PENTACOSA[9,16,18,241TETRAEN]-15'-ONE 13',13'-

DIOXIDE

A mixture of (lS,3'R,6 ^! R,7'S,9'Z,12'S)-6-chloro-12'-(((diiTiethyl(2-meihyl- 2-propanyl)silyl)oxy)methyl)-7'-hydroxy-3,4-dihy

1,22'-

[20]oxa[13]thia[l,14]cUazatetra^

n]-15'-one 13\13'-dioxide and (lS,3'R,6'R,7'S,9'Z,12'R)~0~chloro~12'- (((dimethyl(2-me1hyl-2-propanyl)silyl)oxy)me^

2H,15'H-spiro[naphthalene-l,22'-

[20joxajl3]thia[l,

n]-15'-one 3 ',13 '-dioxide and (lS,3'R,6'R,7'S,9'E,12'S)-6-chloro-12'- (((dimethyl(2-me1hyl-2-propanyl)silyl)ox\ nethyl)-7 ^, -hydroxy-3,4-dihydro- 2H, 15'H-spiro[naphthalene-l ,22'- \ 20 \ \ \ I 3 |t ia| i . i 4 |dia/aielracveioj 14.7.2 ίί ^; U ^{! ; ,} !| cnia osa| . i Ί 8.24! !eu ;ie n]-15'-one 13',13 ^! -dioxMe and (l S,3'R,6 ^! R,7'S,9'E,12'R)-6~chloro-12'- (((dimethyl(2-methyl-2-propanyl)silyl)oxy)methyl)-7'-hydrox '-3,4-cUhydro^ 2H, 15'H-spiroj naphthalene- 1,22'- [20]oxa[13]thia[ l, 14]diazate1ra^

n]-15'-one 13',13'-dioxide from Step 5 (0.027 g, 0.038 mmol) and

tetrabutylammonium fluoride, 1.0 M in THF (0.075 ml, 0.075 mmol) in 2 mL of THF was stirred at room temperature for 48h. The solvent was removed and residue was dissolved in 8 mL of DCM and washed with water. The solvent was removed and residue was purified by reversed phase preparatory HPLC

(Gemini ^1M Prep C18 5μτη column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide the title compounds, m/z (ESI, +ve ion) 601.2 (M+H) ⁺ . STEP 7: (l S,3'R,6'R,7 ^! S,12'S)-6-CHLORO-7 ^! ~HYDROXY-12'-

(HYDROXYMETHYL)-3,4-DlHYDRO-2H,15'H-SPlROiNAPHTHALENE- 1 ,22'-[20] OXA|; 1 i l l II A| 1 , 14] DIAZ A

TETRACYCLO[! 4.7.2,0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[16J 8,24]TRiEN]-I5'-ONE 13',13'-DIGX1DE OR (l S,3'R,6'R,7'S,12 ^! R)-6-CHLORO-7'-HYDROXY-12'~ (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22 20] OXA[ 13]THIA [1,14] DIAZ A

TETRACYCLO[14.7.2.0 ⁵ ' ⁶ .0 ¹⁹ ' ² ]PENTACOSA[16,18,24]TRIEN]-15'-ONE 13',13'-D10XIDE A mixture of (lS,3'R,6'R,7 ^f S,9'Z, I 2'S)-6-chloro-7'-hydroxy-12'-

(hydroxymethyl)-3,4-dihydro-2H,15'H-spiro[naphtiialene-l, 22'

[20|oxa[13jthia[ l, 14jdiazatetracyclo 114.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentac-osa[9, 16, 18,24]tetraen]-l 5'-one 13', ! 3'-dioxide and

(1 S,3'R,6'R,7'S,9'Z, 12 ^, R)-6-chloro-7 ^, -hydroxy-12 ^, -(hydroxymethyl)-3,4-dihydro- 2H,15'H-spiro[naphthalene-l,22'-[20]oxa[13]thia

i;i,141diazatetracyc3o| 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[9,16,18,24]tetraen]-15'-one l S^lS'-dio ide and il S^'R^'R.T'S^ ^S^e-chloro-y'-hydrox - '- (hydroxymethyl)-3,4-dihydro-2H,15'H-spiro[naphtiialene-l,22' - [20]oxa[13]thia[ l ,14]diazatetracyclo[14.7.2.O ^'i ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa

[9,16,18,24jietraenj-15'-one 13 ',13 '-dioxide and (lS,3'R,6'R,7 ^* S,9'E, 12'R)-6- chloro-7'-hydroxy-l 2'-(hydroxymethyl)-3,4-dihydro-2H, 15 Ή-spiro [naphtha! ene- l,22'-[20]oxa[13]thia[l ,14] diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]

pentacosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide from Step 6 (4.2 mg, 6.99 μηιοΐ) and platinum (iv) oxide (0.3 7 mg, 1 .40 μηιοΐ) in ethyl acetate (0.5 mL) was stirred under hydrogen balloon at room temperature for lh. The solid catalyst was filtered off through syringe filter, and filtrate was concentrated and the residue was purified by reversed phase preparatory HPLC (Gemini™ Prep CI 8 5μηι column; Phenoraenex, Toirance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide the first eluting isomer as one of the title compounds. ¾ NMR (500 MHz, CDCb) δ 7,69 (d, J=8.56 Hz, 1 H), 7.24 - 7.14 (m, 3 H), 7.09 (d, .7=2,20 Hz, 1 H), 7.00 - 6.90 (m, 1 H), 4.25 ·· 4.16 (m, 1 H), 4.16 ·· 4.04 (m, 4 H), 3.82 ·· 3.62 (m, 3 H), 3.62 - 3.57 (m, 1 H), 3.53 (dd, J=15.16, 6.11 Hz, 1 H), 3.27 {d. -/ 14.43 Hz, 1 H), 3.24 - 3. 14 (ra, 1 H), 2,85 - 2.70 (ra, 3 H), 2.49 - 2.38 (ra, 1 H), 2.26 - 2.13 (ra, 1 H), 2.06 ·· 1.87 (m, 2 H), 1.87 - 1.76 (ni, 2 H), 1.75 - 1.58 (ni, 4 H), 1.57 - 1.41 (m, 5 H), 1.40 - 1.30 (m, 3 H). m'z (ESI, +ve ion) 603.2 I 1 1 > ^" .

EXAMPLE 713, (1 S,3 ^, R,6 ^! R,7'S,12 ^! R)-6-CHLORO-7 ^! -HYDROXY-12'-

(HYDROXYMETHYL)-3,4-DlHYDRO-2H,15'H-SPlROiNAPHTHALENE-

1,22'-[20]OXA[13]

THIA[l ,14]DIAZATETRACYCIi3[ 14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[16, 18,241TR 1EN]-15'-0NE 13' _s 13'-DIOXIDE OR (l S,3'R,6 ^! R,7 ^, S,12 ^, S)-6-CHLORO-7'- HYDROXY-12'-(HYDRQXYMETHYL)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20] OX A [13]

THI A[ 1 , 14] DLAZ ATETRAC YCLA3 [ ^ ^

IEN]-15'-ONE 13',13'-D10X1DE

The second elutmg isomer obtained from the reversed phase preparatory HPLC separation in Example 712, Step 7 is another of the title compounds. ^! H N.MR (500 MHz, CDCb) δ 7.71 id. J=8.56 Hz, 1 H), 7.45 (d, ,/ 1 .96 Hz, I H), 7,30 (dd, 7=8.19, 2.08 Hz, 1 H), 7.18 (dd, .7=8.44, 2.32 Hz, 1 H), 7.10 (d, .7=2,20 Hz, 1 H), 6.97 (d, J=8.31 Hz, 1 H), 4.54 (quin, J=6.17 Hz, 1 H), 4.17 - 4.08 (m, 4 H), 3.89 (dd, J=15.16, 5.87 Hz, 2 H), 3.66 - 3.57 (m, 3 H), 3.22 (d, ./ 14.43 Hz, 1 H), 3.16 - 3.08 (m, 1 H), 2.80 - 2.74 (m, 2 H), 2.34 - 2.24 (m, 1 H), 2.04 - 1.96 (m, 2 H), 1.95 - 1.88 (m, 2 H), 1.87 - 1.78 (m, 5 H), 1.69 - 1.61 (m, 5 H), 1.49 - 1.39 (m, 4 H). m/z (ESI, + ve ion) 603.2 (M+H) ⁺ .

EXAMPLE 714. (18,3'Κ,6 ^! ί ,7'8,8Έ,11'8,12'ίΙ)-6 ΗΕΟΚΟ-7',1 Γ~

DIMETHOXY- 12'-METHYL-3.4-DIHYDRO-2H ₅ 15Ή- SPIRO[NAPHTHALENE-1,22"-[20]OXA[13]THTA

[l,14]DlAZATETiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TACOSA[8,16,18,24]TETR AEN]-15'-ONE 13', 13'-DI()XIDE OR (lS,3 ^, R,6'R,7'S,8'E,i rS,12'S)-6-CHLORO- 7,11 '-DIMETHOXY- 12'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPH ^' raALENE-l,22 ^! -[20]OXA[13]TfflA

16,18,24]TETR AENj-15'-ONE 13',13'-DIOXIDE OR (18,3'¾6¾,7'8,8Έ,11 ¾,12¾)-6- CHLORO-7,1 1 '-DIMETHOXY- 12'-METHYL-3,4-DIHYDRO-2H,l 5Ή- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[13]THIA

[l,14]DlAZATEm CYCLO[14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTACOSA[8,16,18,24]TETR AEN]-15'-ONE 13',I 3'-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E,1 l'R,l 2'S)-6- CHLORO-7',i r-DIMETHOXY-12'-METHYL-3,4-DmYDRO-2H,15'H- SPIRO [N APHTHALENE- 1 ,22' - [ 20] OXA[ 13 ] THI A[ 1,14] DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN; 15'-ONE 13', 13'-DIOXIDE

STEP 1 : ( )-METHYL 2-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)PROPANOATE AND (S)-METHYL 2- (N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)PROPA]SIOATE

To a mixture of bis(4-methoxybeiizyl)amine (8.96 g, 34.8 mmol,

Intermediate EE1 1 ), 4-(dimethylamino) pyridine (0.327 g, 2.68 mmol) and triethyl amine (11.2 mL, 80 mmol) in DCM (100 mL) at 0°C was added methyl 2- (chlorosulfonyl)propanoate (5 g, 26.8 mmol) slowly over 30 min. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was diluted with 300 mL of DCM and 100 mL of 0.5 N hydrochloric acid aqueous solutions. The layers were separated, and the aqueous layer was extracted with EtOAc (2x100 mL). The combined organic solution was dried over sodium sulfate, filtered, concentrated. The crude product was purified by chromatography on silica gel eluting with 0% to 70% EtOAc in hexane to provide the title compounds (9, 14 g, 84%). m/z (ESI, +ve ion) 430.1 (M+Na) ⁴ . STEP 2: (R)-l -HYDROXY-N,N-BIS(4-METHOXYBENZYL)PROP ANE-2- SULFONAMIDE AND (S)- 1 -HYDROXY-N.N-BIS (4- METHOXYBENZ YL)PROP AN E-2-S L ⁵ LF ON AMIDE

To a solution of (R)-methyl 2-(N,N-his(4- methoxybenzyl)sulfa,moyl)propanoate and (S)-methyl 2-(N,N-bis(4- memoxybenzyl)sulfamoyl)propanoate (4.57 g, 11.2 mmol) in THF (25 ml) at 0°C was added lithium borohydride (0.734 ml, 22.4 mmol) with a few drops of water. The reaction mixture was stirred at 0°C to room temperature for 16h. The reaction mixture was diluted with 50 mL of 0.5 N hydrochloric acid aqueous solution and 100 mL of EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x80 mL). The combined organic solution was dried over sodium sulfate, filtered, concentrated. The crude product was used in the next step without further purification, m/z (ESI, +ve ion) 402.1 (M+Na) ⁺ .

STEP 3: (R)-N,N-BIS(4-METHOXYBENZYL)-l-OXOPROPANE-2- SULFONAMIDE AND (S)-N,N-BIS(4-METHOXYBENZYL)-l - OXOPROPANE-2-SULFONAMIDE

To a solution of (R)-l-hydroxy-N,N-bis(4-memoxybenzyl)propane-2- sulfonamide and (S)-l -hydroxy -N,N-bis(4-methoxybenzyl)propane-2- sulfonamide (4,26 g, 11.2 mmol) in DCM (1 12 mL) was added dess-martin periodinane (7. 14 g, 16.8 mmol) slowly. The reaction mixture was stirred at room temperature for 3h. The reaction mixture was loaded in a column for purification by chromatography on silica gel eluting with 20% to 60% EtOAc in hexane to provide the title compounds (2.85 g, 67.3%), ³ H NMR (400 MHz, CDCh) δ 9.83 - 9.70 (m, 1 l i s. 7.22 ·· 7.18 (m, 4 H), 6.92 ·· 6.88 (m, 4 H), 4.33 (d, J=1.96 Hz, 4 H), 4.30 - 4.21 (m, 1 I I ). 3.84 (s, 6 H), 1.50 (d, ./ 6. K5 Hz, 3 H).

STEP 4: (2R,3S)-3-HYDROXY-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE- 2-SULFON AMIDE AND (2S,3S)-3-HYDROXY-N,N-BIS(4-

METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE AND (2R,3R)-3- HYDROXY-N,N-BIS(4-METHOXYBENZYL)HEX-5-ENE-2-SULFONAMIDE

AND (2S,: R)-:^HYDROXY-N,N-BiS(4-METHOXYBENZYL)HEX-5-ENE-2- SULFONAMIDE

To a mixture of (R)-N,N-bis(4-methoxybenzyl)-l-oxopropane-2- sulfonamide and (S)-N,N-bis(4-methoxybenzyl)- 1 -oxopropane-2-sulfonamide

(2,85 g, 7.55 mmol) and ally! iodide (2.78 ml, 30.2 mmol) in DMF (76 ml) was added indium (0.475 mL, 30.2 mmol). The reaction mixture was stirred at room temperature for l h. The solid was filtered off, and filtrate was diluted with EtOA (200 mL) and washed with a 100 mL of mixture of water/saturated sodium bicarbonate/brine (2: 1 : 1), water and brine, dried over sodium sulfate, filtered, concentrated. The crude product was purified by chromatography on silica gel eluting with 0%-60% EtOAc in hexane to provide the title compounds (2,54 g, 80%). ¾ NMR (400 MHz, CDCh) δ 7,24 - 7.14 (m, 4 H), 6.91 - 6,82 (m, 4 H), 5.97 - 5.55 (m, 1 H), 5.21 - 5.05 (m, 2 H), 4.50 - 4.09 (m, 5 H), 3.84 - 3.78 (m, 6 H), 3.15 - 2.89 (m, 2 H), 2.58 - 1.99 (m, 2 H), 1.31 - 1.21 (m, 3 H). STEP 5: (2R,3S)-3-HYDROXYHEX~5-ENE-2-SULFONAMIDE AND (2S,3S)-3 H YDROXYHEX- 5 -ENE-2 - SULF ON AMIDE AN D (2R,3R)-3-HYDROXYHEX- 5-ENE-2-SULFON AMIDE AND (2S,3R)-3-HYDROXYHEX-5-ENE-2- SULFONAMIDE

To a mixture of (2R,3S)-3-hydroxy-N,N-bis(4-methoxybenz l)hex-5-ene- 2-sulfonamide and (2S,3S)-3-hydroxy-N,N-bis(4-methoxybenzyl)hex-5-ene-2- sulfonamide and (2R R)-3-hydroxy~N,N-bis(4-methoxybenz}'l)hex-5-ene-2- sulfoiiamide and (2S,3R)-3-hydroxy-N,N-bis(4-methoxybenzyl)hex-5-ene-2- sulfonamide (2.54 g, 6.05 mmol) and anisole (6.58 mL, 60,5 mraol) in DCM (30.3 mL) was added trifluoroacetic acid (18 ml, 242 mmol) slowly. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and saturated sodium bicarbonate solution. The layers were separated. The aqueous layer was extracted with IPA/DCM (1 :3) (2x70 mL). The organic solution was dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 10% to 100% EtOAc in hexane to provide the title compounds (0.818 g, 75%). m/z (ESI, +ve ion) 202.1 (M+Na) ⁺ .

STEP 6: (2R,3S)-3-((TERT-BUTYLDIMETOYLSILYL)OXY)HEX-5-ENE-2- SULFONAMIDE AND (2S,3S)-3-((TERT-

BUTYLDIMETHYLSILYL)OXY)HEX-5-ENE-2-SULFONAMIDE AND (2R,3 R)-3 - ((TERT-BUTYLDIMETHYL S ILYL)OXY)HEX-5 -ENE-2- SULFONAMIDE AND (2S,3R)-3-((TERT-

BUTYLDIMETHYLSILYL)OXY)HEX-5-ENE-2-SULFONAMIDE

To a solution of (2R,3S)-3-hydroxyhex-5-ene-2-sulfonamide and (2S,3S)- 3 hydroxyhex-5-ene-2-sulfonamide and (2R,3R)-3-hydroxyhex-5-ene-2- sulfonamide and (2S,3R)-3-hydroxyhex-5-ene-2-sulfonamide (302 mg, 1.68 mmol) in DCM (12.0 ml.) was added tert-butylchlorodimethylsilane (279 mg, 1.85 mmol), followed by imidazole (0.167 mL, 2.53 mmol). ^' The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and residue was diluted with IN hydrogen chloride (1 mL) and water (10 mL), extracted with Et ₂ 0 ( 2 x20 mL). ^' The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude title products. The mixture was used in the next step without further purification, m/z (ESI, +ve ion) 294.1 (M+H) ⁺ . STEP 7: (S)-6'-CHLORO-5-(((l R,2R)-2-((S,E)-l -HYDROXYHEX-2-EN- 1 -

YL)CYCLOBUTYL)MF iYL)-N-(((2R,3S)-3-HYDROXYHEX-5-EN-2-

YL)SULFONYL)~3V4,4',5-TETRAHYDRO-2H,2'H-

SP1RO [BENZO | B | [ 1 ,4] 0.\ AZHPI\ l-:-3 , Γ -NAPHTHALENE] -7-

CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN- 1 -YL)CYCLOBUTYL)METHYL)-N-(((2S,3 S )-3 -

HYDROXYHEX-5-EN-2~YL)SULFONYL)-:r,4,4V5-TE ^' TRAHYDRO-2H,2'H- SPIRO [BENZO [B] [1,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMTDE AND (S)-6'-CHLORO-5-(((l R,2R)-2-((S,E)-l- HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-N-(((2R,3R)-3- HYDROXYHEX~5"EN-2-YL)SL ⁱ LFONYL)~3 ^! ,4,4',5-TETl AHYDRO-2H,2'H" SPIRO [BENZO [B j [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l- HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL) -N-(((2S,3R)-3- HYDROXYHEX-5-EN-2-YL)SULFONYL)-3',4,4',5-TETR _J ' HYDRO-2H,2'H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

A mixture of (rS)-6'-chloro-5-(((lR,2R)-2-((E)-l-hydroxyhex-2-en-l- yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (150 mg, 0.294 mmol, Intermediate AA12A), (2R,3S)-3-((tert-butyldimethylsilyl)oxy)hex-5-ene-2-sulfonam ide and (2S,3S)-3- ((tert-butyldimethylsilyl)oxy)hex-5-ene-2-sulfonamide and (2R,3R)-3-((tert- butyldimethylsilyl)oxy)hex-5-ene-2-sulfonamide and (2S,3R)-3-((tert- butyldimethylsilyl)oxy)hex-5-ene-2-sulfonamide (129 mg, 0.441 mmol), 4- (dimethyl amino) pyridine (108 mg, 0.882 mmol) and l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (113 mg, 0.588 mmol) in 4 mL of DCM was stirred at room temperature for 16 h (It was observed that the TBS group was lost during the period of reaction). The solvent was removed under reduced pressure, and residue was purified by chromatography on silica gel eluting with 0% to 60% EtOAc (containing 0.15% AcOH ) in hexane to provide the title compounds (0.1 15 g, 58.3%). m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

STEP 8: (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-7',l r-DlHYDROXY-12'- METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]

DL/ ZATCTRACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TCTRAEN]- 15'-ONE 13',13'-DIOXIDE AND (l S,3'R,6 ^, R,7'S,8 ^, E,l l ^, S,12'S)-6-CHLORO- 7 ^* ,1 1 '-DIHYDROXY-I2'-METHYL-3,4-DIHYDRO-2H,l 5Ή- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3]THI A[ 1 , 14]

DIAZATETRACYCLO[14.7.2.0 ^3>6 .0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15 -ONE I3', 13'-DIOXIDE AND (IS,3'R,6'R,7'S,8'E,1 l'R, l 2'R)-6-CHLORO- 7, 11 '-D1HYDROXY- 1 2'-METHYL~3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[1 , 14]

DIAZATCTRACYCLO[14;7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA[8,16, 18,24]TETRAEN;|- 15'-ONE 13 ^* , 13'-DIOXIDE AND (l S,3¾,6¾,7^,8 l l¾, 12'S)-0-CHLQRQ- 7,1 1 '-DIHYDROXY-12'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3]THI A[ 1 , 14]

DIAZATETRACYCLO[14 .2.0 ³ .« 0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15 -ONE 13 ^* , 13'-DIOXIDE

A solution of (S)-6'-chloro-5-(((l R,2R)-2-((S,E)- 1 -hy droxyhex-2-en- 1 - yi)cyclobutyl)methyi)-N-(((2R,3S)-3-hydrox>¾ex-5-en-2-yl )sulfonyl)-3',4,4 ^, ,5- tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-6 ^, -chloro-5-(((l R,2R)-2-((S,E)-l-hydroxyhex-2-en-l- yl)cyclobutyl)me l)-N-(((2S ₅ 3S)-3½droxyhex-5-en-2-yl)sidfon ])-3 ^* ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l- yl)c lobut5d)methyl)-N-(((2R,3R)-3-hydroxyhex-5-en-2-yl)sulfonyl) -3',4,4',5- ietrahydro-2H,2H-spiro[benzo[b |[l ,4]oxazepine-3,r-naphthalene]-7-carboxaniide and (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l - yl)cyclobu1yl)methyl)-N-(((2S,3R)-3-hydroxv'hex-5-en-2-yl)su lfonyl)-3',4,4',5- tetTahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,T-naphthalen e]-7-carboxarriide (115 mg, 0.171 mmol) in AcOH (20 ml.) was blowed with argon for 10 mm, and Hoveyda-Grubbs catalyst (2nd generation) (53.7 mg, 0.086 mmol) was added. The reaction mixture was stirred under reduced pressure at 60°C for 3h. The solvent was removed under reduced pressure, residue was purified by chromatography on silica gel eluting with 40% to 100% EtOAc (containing 0.3 % AcOH ) in hexane to provide the title compounds (0.025 g, 24.5%). m/z (ESI, +ve ion) 601.2

(M+H) ⁺ .

STEP 9: (1S,3'R,6'R,7'S,8 1 rS,12'R)-6-CHLORO-7',l l'-DIMETHOXY-12'- METHYL-3,4-DlHYDRO-2H, 15'H-SPTRO [N ΑΡΗΤΉ ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ jPENTACOSA[8,16,18,24]TETRAEN]-

15-ONE 13',13'-DI0XIDE OR (lS,3 ^f R,6'R,7'S,8'E,irS,12'S)-6-CI-ILORO-7',1 Γ-

DIMETHOXY - 12'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-1,22 ^! ~[20]OXA[13]TH1A[1,14]

DIAZATE RACYCLO 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA[8J6,18,24iTETRAEN]-

15 ^* -ONE 13',I3'-DIOXIDE OR (1 S,3'R,6'R,7'S,8'E,11 'R,12'R.)~6~CHI,0R0~7',11'-

DIMETHOXY- 12'-METHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO I NAPHTHALENE- 1 ,22'-[20] OXA[ 13] THI A[ 1 , 14 j

DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj-

15'-ONE 13', 13'-DIOXIDE OR (1 S,3 ^! R,6'R,7'S,8'E, 11 ¾, 12'S)-6-CHLORO-7', 11 ^* -

DIMETHOXY- 12'-ΜΕΊΉΥί-3,4-ϋΙΗΥϋ10-2Η, 15Ή-

SPIRO[NAPHTHALENE-1.22'-[20]OXA[13]THIA[1,14]

DIAZATETRACYCLO[14,7.2.0 ^3/ \0 ¹⁹ - ² ]PENTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13 ^! ,13'-DI0X1DE

To armxture of (!S,3'R,6'R,7'S,8'E,ll'S,!2'R)-6-chloro-7',l l'-dihydroxy- 12'-methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[ 13 ]thia[ 1,14] diazatetracy clo[ 14.7.2 ⁾ ·".0 ¹⁹ · ²⁴ ]

pentacosajS, 16,18, 24]tetraen]-15'-one 13',13'-dioxide and

(lS,3'R ₅ 6 ^, R,7 ^, S,8¾ll ^, S ₅ 12 ^, S)-6-c loro-7\ll ^, -dihydroxy-12 ^, -methyl-3^^

21 i.15 ^! H-spiro[naphthalene- 1,22'- [20]oxa[13]tMa[l,14]cfcazatelTacyclo[14/7.2.0^

n]-15'-one !3',13'-dioxide and (1S,3'R,6'R,7'S,8'E,I I'R,12'R)-6-chloro-7',l l'- dihydroxy~12 ^! -methyl-3,4-dihydro-2H,15H-spiro[naphthalene-l,22 ^! - [20]oxa[ 13 ]thia[ 1,14] diazatetracy clo[ 14.7.2 ⁾ ·".0 ¹⁹ · ²⁴ ] pentacosa[8, 16, 18,24 ]tetraen]-l 5'-one 13 ', 3 '-dioxide and

(1 S,3'R,6'R,7'S,8'E, 11 'R, 12'S)-6-chloro-7', 11

2H,15'H-spiro[naphthalene-l,22'- [20]oxa|;i3]thia[l,14]diazatetr^

n]-15'-one 13',13'-dioxide from Step 8 (20.1 mg, 0.033 mmol) and methyl iodide (20.8 μΐ, 0.334 mmol) in THF (1 mL) was added sodium hydride, 60% dispersion in mineral oil (21.1 μΐ, 1.00 mmol) portionwise. The reaction mixture was stirred at room temperature for Ih. The reaction was quenched with water, mixture was subjected to purification by reversed phase preparatory HPLC (Gemini™ Prep CI 85μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide the first eiuting isomer as one of the title compounds as a white solid. ^! H NMR (400 MHz, CDCh) δ 8.11 (s, IH), 7.72 (d, ,/ H.22 Hz, IH), 7.20 (d, ./ 8.41 Hz, IH), 7.12 (s, H), 7.01- 6.91 (m, 2H), 6.85 is. H), 5.72 - 5,59 (m, 2H), 4.37 (d, .7=6.85 Hz, IH), 4.12 (s, 2H), 3.91 - 3.71 (m, Ml).3,66 (br s, IH), 3.55 - 3.35 (m, 4H), 3.31 - 3.20 (m, 3H), 3.09 - 2.97 (m, IH), 2.87 - 2.74 (m, 2H), 2.63 - 2.25 (m, 4H), 2.19- 1.94 (m, 3H), 1.92 - 1.67 (m, 3H), 1.63 (d, ./ 7.24 Hz, 3H), 1.50 - 1.31 (m, 2H). m/z (ESI, +ve ion) 629,2 (M+H) ⁺ . EXAMPLE 715. (1S,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-CHLORQ-7',l V- DIMETHOXY- 12'-METHYL-3,4-DIHYDRO-2H ₅ 15Ή- SPIRQ [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOL [1,14]DL ZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |;8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE _()R

(lS,3'R,6'R,7'S,8'E,ri'R,12'R)-6-CFn. RO-7',ll'-DIMETOOXY-12'-METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALE E-l,22'-

^OlOXAtlSlTHIAtl ^DIAZATCTRACYCLOIM.T^.O'^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(1S,3¾,6'R,7¾,8¾,1 l'R,12 ^f S)-6-CHLORO-7 -DIMETHOXY-12'-METHYL- 3 ,4-DlH YDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

|;2 ]OXA[13iTHIA[l,14jDL4ZATETRACYCLO[14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO-7 ^* , 1 -DIMETHOXY -12'-METHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[2()iOXA|;i3]THIA|;i ,14]DlAZATETRACYCLO[ 147.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE

The second elutmg isomer obtained as a white solid from the reversed phase preparatoiy HPLC separation in Example 714, Step 9 is another of the title compounds. ¾ NMR (400 MHz, CDCh) δ 7.71-7,63 (m, IH), 7.18 (dt, ./ 2.64. 5.62 Hz, IH), 7.12 - 7.00 (m, 2H), 6.98 - 6.85 (m, 2H), 5.77 (br s, IH), 5.54 (dd, ./ 7.34. 15.36 Hz, IH), 4.26 - 4.19 (m, IH), 4.16 - 4.03 (m, 2H), 3.93 (d, ./ 14.48 Hz, IH), 3,88 - 3,83 (m, IH), 3.78 - 3.65 (m, 2H), 3.58 - 3,44 (m, 3H), 3.44 - 3.34 (m, 3H), 3.34 - 3.23 (m, 3H), 2,93 (br s, IH), 2.78 (m, 2H), 2.74 - 2,70 (m, IH), 2.62 (d, J=7.43 Hz, IH), 2.46 - 2.33 (m, 2H), 2.26 - 1.56 (m, 5 H), 1.62 - 1.53 (m, 3H), 1.53 - 1.43 (m, 2H). m!z (ESI, +ve ion) 629.2 { \ I · Π } .

EXAMPLE 716. (18,3¾,6'ί ,7'8,8Έ,11Ί ,12¾)-6-€Ηί01 0-7',11'-

DIMETHOXY- 12'-METHYL-3 ₅ 4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-1,22 ^* -[20]OXA[13]THIA[1 ,14]

DIAZATETRACYCLO[14J.2.0 ³ -^0 ¹⁹ ' ² ]PEOTACOSA[8,16,18,24]TETRAEN]-

15'-ONE 13',I3'-DI0X1DE OR (l S,3'R,6'R,7'S,8'E,i rR,I2'S 6-CHLORO-7',l l'-

DIMETHOXY- 12'-METHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]THIA[ 1,14]

DIAZATE RACYCLO[14 .2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-

15'-ONE I3',13'-D10XIDE OR (1 S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLORO-

7',1 -DIMETHOXY-12'-METHYL-3,4-DIHYDRO-2H, I 5'H-

SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3]THI A[ 1 , 14] DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAENj- 15'-ONE 13', 13'-DIOXIDE OR (1 S,3'R,6'R,7'S,8 ^! E, 11 "S.12'S)-6-CHLORO-7', I Γ- DIMETHOXY- 12'-METHYL-3,4-DIHYDRO-2H ₅ 15Ή- SPIRO[NAPHTHALENE-1.22'-[20]OXA[13]THIA[1,14]

DIAZATETRACYCLO[14 .2 ^3/ \0 ¹⁹ - ² ]PENTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13 ^! ,13'-DI0X1DE

The third eluting isomer obtained as a white solid from the reversed phase preparaioiy HPLC separation in Example 714, Step 9 is another of the title compounds. ¾ NMR (400 MHz, CDCh) δ 7.72 (d, .7=8.41 Hz, IH), 7.25 (br s, 1H), 7.19 (dd, ./ 2.45.8.31 Hz, ill).7.10 (s, Ml).6.96 (d, J=8.22 Hz, IH), 6.77 (d, J=1.96 Hz, IH), 5.78 (dd, ./ 5.09.10.17 Hz, IH), 5.51 (t, ./ 10.17 Hz, IH), 4.24 (t, 7.04 Hz, IH), 4 14 - 4,04 (m, 2H), 3.88 - 3.73 (m, 3H), 3.43 - 3,32 (m, 2H), 3.31 - 3.22 (m, 3H), 3.22 - 3.14 (m, 3H), 2.91 (br s, IH), 2.79 (d, J=5.48 Hz, 2H), 2.75 - 2.69 (m, IH), 2.57 - 2.47 (m, IH), 2.41 - 2.27 (m, 3H), 2.23 - 1.64 (m, 5H), 1.62 - 1.52 (m, 4H), 1,49 - 1.27 (m, 2H). m/z (ESI, +ve ion) 629.2 i\\ U) . EXAMPLE 717. (lS,3'R,6 ^! R,7'S,8'E,irR,12'S)-6-CHL0R0-7',ir~

DIMETHOXY- 12'-METHYL-3.4-DIHYDRO-2H ₅ 15Ή- SPIRO [NAPHTHALENE- ! ,22'-[20] OXA[ 13]THTA| 1 , ! 4]

ί)!Λ/Λ ΓΜΚΛ(Ύ(·ί.Οί ! 17.20 · ^: '.Π ^|; ' !Ρ1·Ν i ^' , ^' <)SA|8. i . 8.2-1 ΓΠΠ ^' ΚΛΗΝ |- 15'-ONE 13',13'-DI0XIDE OR (lS,3'R,6'R,7'S,8 ^, E,ll ^, S,12'R)-6-CHL0R0- 7, 11 '-DIMETHOXY- 12'-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22 ^! -[20]OXA[l 3]THIA[1 , 14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13',13'-DIOXIDE OR ( 1 S,3'R,6'R,7'S,8'E, 11 'S, 12'S)-6-CHLORO-7', IV- DIMETHOXY- 12 ^* -METOYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'-[20]OXA[l 3]TffiA[ , 14]

DL/ ZATETRACYCLO[14;7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13 ^* ,13'-DIOXIDE OR (1 S,3'R,6'R ,7'S,8 ^* E,1. l 'R,12'R)-6-CHLORO- 7\l l ^, -DIMETHOXY-12'-METOYL-3,4-DIHYDRO-2H, 15H- SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[l 3]THI A[ 1 , 14]

DIAZATETRACYCLO[14 .2.0 ³ .« 0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAE j- 15 -ONE 13 ^* , 13'-DIOXIDE

The fourth eluiing isomer obtained as a white solid from the reversed phase preparatory HPLC separation in Example 714, Step 9 is another of the title compounds. ^] H NMR (500 MHz, CDCh) δ 8.34 - 8.06 (m, 1H), 7.72 (d, ./ 8.56 Hz, i l l ). 7,41 (dd, ./ 2.08. 8.19 Hz, 1H), 7.23 - 7. 4 (m, I H), 7. 10 (d, ./ 2.20 Hz, I I I). 7.00 id. ./ 8.3 1 Hz, lH), 6.96 - 6.88 (m, 1H), 6.02 ·· 5.91 (m, lH), 5.51 (dd, ./ 5.62. 10.76 Hz, 1H), 5.38 - 5.33 (m, 1H), 4.37 (m, 1 H), 4.17 - 4.05 (m, 3H), 3.89 - 3.84 (ra, IH), 3,83 - 3.70 (m, 2H), 3.46 - 3.33 (ra, 3H), 3.32 - 3.16 (m, 4H), 2.94 (dd, ,/ 8 44. 15,04 Hz, H), 2.82 - 2,70 (m, 3H), 2.57 - 2.49 (m, H), 2.32 - 1.85 (m, 4H), 1.78 - 1.57 (m, 2H), 1.56 - 1.51 (m, 3H), 1.49 ·· 1.29 (m, M l ), m'z (ESI, +ve ion) 629.2 (M+H) ⁺ .

EXAMPLE 718. (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-l l'-HYDROXY-7'- METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA[ 13]THIA[ 1,14]

DIAZATE RACYCLO[14.7.2.0 ³ '* 0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24] TETRAEN]- 15 ^! "ONE 13',13'-D10XIDE OR (1 S,3 ^! R,6'R,7'S,8'E,1 l ^, S,12 ^, S>6-CHLORO-ir- HYDROXY-7 ^, -METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'~

|20|() Λ| ΠΙ Η1Λ| I .. i ! |PI.\/.\ Π·. ΓΗ. ΛίΎί ^' ί.01 i -i.7.2 ί ^f \ ' ^* ' ¹ j

PENTAC OS A[8, 16, 18,24] TETRAE ] - 15 '-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,ll'R,12'R)-6-CHLORO-ll'-HYDROXY-7'-ME TI- )XY-12'- METHYL-3,4-DlHYDRO-2H, 15'H-SPTRO [N APHTH ALENE- 1 ,22'- [20]OXA[13]THIA[1,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ . () ⁱ⁹ - ²⁴ jPENTACOSA[8,16,18,24]TETRAENj- 15-ONE 13 ^* ,13'-DIOXIDE OR (1S,3'R,6'R,7'S,8'E,1 l'R,l 2'S)-6-CHLORO-l V- HYDROXY-7'-METHOXY-12'-METHYL-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-1,22'-[20]OXA[13]TH1A[1,14]

DIAZATETRACYCLO|14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |8,16,18,24]TETRAENj- 15 ^* -ONE 13',13'-DIOXIDE

STEP 1 : (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l -METHOXYHEX-2-EN- 1 -

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO|BENZO[B;||;i,4|OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOX YLIC

ACID

To a suspension of sodium hydride, 60% dispersion in mineral oil (6.2 μΐ, 0.294 mmol) in 0.5 mL of THF was added a solution of (S)-6'-chloro-5-(((lR,2R)- 2-((S,E)-l -hydroxyhex-2-en-l-yl)cyclobutyl)me1hyl)-3 4,4^5-tetTahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (50 mg, 0.098 mrnol, Intermediate AA12A) in 2 mL of THF slowly. The reaction mixture was stirred at room temperature for 40 min, and then methyl iodide (12.18 μΐ, 0.196 mrnol) was added. The mixture was stirred for 3h. The reaction was quenched with saturated ammonium chl oride aqueous solution, and then 30 ml, of EtOAc was added. The organic layer was separated, and dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel eluting with 0% to 60% EtOAc in hexane to provide the title product (47.3 mg, 92%). m/z (ESI, +ve ion) 524.2 (M+H) ^H \

STEP 2: (S)-6'-CHLORO-N-(((2R,3S)-3-HYDROXYHEX-5-EN-2-

YL)SULFONYL)-5-(((lR,2R)-2-((S,E)-l-METHOXYHEX-2-EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPTRO[BENZO[B][l ₅ 4]OXAZEPTNE-3,l '-NAPHTHALENE]-7-

CARBOXAMIDE AND (S)-6'-CHL0R0-N-(((2S,3S) -HYDR0XYHEX-5-EN- 2-YL)S ULFONYL)-5-(((l R,2R)-2-((S,E)- 1 -METHOXYHEX-2-EN- 1 - YL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2H,2 ^, H- SPIRO [BENZO [B j[l,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6 ^! ~CHLORO-N-(((2R,3R.)-3-HYDROXYHEX-5- EN-2-YL)SULFONYL)-5-(((lR,2R)-2-((S,E)-l-METHOXYHEX-2-EN-l- YL)CYTIX)BUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,l ^* -NAPHTHALENE]-7- CARBOXAM1DE AND (S)-6'-CHLORO-N-(((2S,3R)-3-HYDROXYHEX-5-EN- 2-YL)SULFONYL)-5-(((l R,2R)-2-((S,E)- 1 -METHOXYHEX-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

To a mixture of (S)-6'-chloro-5-(((lR,2R)-2-((S,E)-l-methox\'hex-2-en-l- yl)cyclobu1yl)methyl)-3 4,4^5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine- 3, -naphthalene]-7-carboxylic acid (82 mg, 0.156 mmol), (2R,3S)-3-hydroxyhex- 5-ene~2-sulfonamide and (2S,3S)~3 hydroxyhex-5-ene-2-sulfonamide and (2R,3R)-3-hydroxyhex-5-ene-2-sulfonamide and (2S,3R)-3-hydroxyhex-5-ene-2- sulfonamide (33.7 mg, 0.188 mmol. Example 720, Step 5) in DCM (6 mL) at 0°C was added N,N-dimethylpyridin-4-amine (57.3 mg, 0.469 mmol), followed by Nl-((ethyHrnino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (90 nig, 0.469 mmol) in 2 mi of DCM dropwise. The ice-bath was removed and reaction mixture was stirred at room temperature for 5h. The solvent was removed under reduced pressure, and crude product was purified by chromatography on silica gel eiuting with 0% to 80%EtOAc (containing 0.3% AcOH) in hexane to provide the title compounds (73.2mg, 68.3%). xalz (ESI, +ve ion) 685.3 (M+H) ⁺ .

STEP 3: (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-l l'-HYDROXY-7'-

METOOXY-12'-METHYL-3,4-DfflYDR()-2i-I,15 ^! H-SPIRO[NAPHTHALENE-

1,22'- |20jOXA| I 311 Η1Λ| I J ! |OI.\/.\ Π·. ΓΗ. ΛίΎί ^' ί. Ol i -i.7.2 ίΓ".ϋ ^1: ' |ΡΗ\ i ACOSA [8,16,18,24]TETiL E ]-15'-ONE 13',13'-D10X1DE OR

(lS,3¾,6 ^! R,7^,8T,ll'S,12'S)-6-CI-ILORO-ir-HYDROXY-7'-MEra:OXY-1 2'- METOYL-3,4-DIHYDRO-2I-I,15'H-SPiRO[NAPHTOALENE-l,22'- [20]OXA[13]THIA[l,14]DiAZATETRACYCLO[14.7,2.0 ³ -^0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16,18,24]TETP^AEN j-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E,1 l*R,12*R)-6-CHLORO-l l'-HYDROXY-7"-METHOXY-l 2'- METHYL-3.4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THI A[l , 14] DI AZ ATETRA CYCLO[14J.2 ³ -^0 ¹⁹ " ^M ]PENTACOSA[8,16 ₅ 18,24]TETRAEN]-15'-ONE

13',13'~DIOXiDE OR (1 S,3'R,6'R,7'S,8'E,1 l'S,12'S)-6-CHLORO-l 1 '- HYDROXY-7'-METHOXY-12'-ME ^r rHYL~3,4-DIHYDRO-2H,15 ^! H- S PIRO [NAPHTHALENE- 1 ,22' - [ 20] OX A [ 13]THIA[ 1 , 14]DIAZA

TETRACYCLO[14J.2.0 ⁵ '« 0 ¹⁹ ' ² ]PENTACOSA[8,16,18,24]TETRAE ]-15'- ONE 13',13'-DI0X1DE

A solution of (S)-6'-chloro-N-(((2R,3S)-3-hydroxyhex-5-en-2-y])sulfonyl)- 5-(((lR,2R)-2-((S,E)-l -methox\'hex-2-en-l-yl)cv'clobutyl)rne1hyl)-3',4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide and (S)-6'-chloro-N-(((2S,3S)-3-hydroxyhex-5-en-2-yl)sulfonyl)-5 -(((lR,2R)-2-

((S,E)-l-methoxyhex-2-en~l -y])cyctobu^

spiro[benzo[b] [1,4] oxazepine-3, Γ -naphtha! ene]-7-earhoxamide and (S)-6'-chioro- -(((2R,3R)-3-hydroxyhex-5-en-2-yl)sulfonyl)-5-(((lR,2R)-2-(( S,E)-l- methoxyhex-2-en-i-yl)cyclobutyl)rnethyl)-3',4,4',5-tetrahydr o-2I-I,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxamide and (S)~6'~chl oro- N-(((2S,3R)-3-hydroxyhex-5-en-2-yl)sulfonyl)-5-(((lR,2R)-2-( (S,E)-l- methoxyhex-2-en-l -yl)cyclobutyl)methyl)-3',4,4',5-tetraliydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide from Step 2 (73.2 mg, 0.107 mmol) in 1 ,2-dichloroethane (12,0 mL) was sparged with argon for 10 min. To this solution was added tetraisopropoxytitanium (9.1 mg, 0.032 mmol), and the mixture was heated at 40°C for Ih with stirring under argon balloon. (1,3- dimesit}4imidazolidin-2-ylidene)(2-isopropoxybenzj'lidene)ru thenium(^ chloride (13.4 mg, 0.021 mmol) in 1 mL of DCE was added slowly, and mixture was heated at 55°C 1 h while 0.2 eq of catalyst in 1 ml of DCE was added dropwise. The reaction mixture was stiired at 50°C for 16 h. The reaction mixture was cooled to room temperature and bubbled with air for 5 min, and concentrated. The residue was purified by chromatography on silica gel eiuting with 0% to 80%EtOAc (containing 0.3% AcOH) in hexane to provide the crude product. Further purification by reversed phase preparatory HPLC (Gemini™ Prep CI 8

5μτη column; Phenomenex, Torrance, CA; gradient elution of 40% to 90% MeCN in water, where both solvents contained 0.1% TFA, 30 min method) to provide the first eluting isomer as one of the title compounds as a white solid. 'Ή NMR (500 MHz, CDCh) δ 8.00-8.16 (m, 1H), 7.70 (d, J=8.31 Hz, 1H), 7.24 - 7.15 (m, HI).7.10 (d, ,/ 1.47 Hz, !!!).6.96 - 6.85 (m, 2H), 6.77 (s, 1H), 5.70 - 5.63 (m, I I I).5.61 - 5.53 (m, III).4.46 (q, 7.34 Hz, IH), 4.12 - 4,02 (m, 2H), 3.86 - 3.69 (m, 2H), 3.62 (dd, ./ 3.42.8.56 Hz, IH), 3.30 - 3.18 (m, 3H), 2.99 (dd, ./ 10. 1. 15.16 Hz, IH), 2.84 - 2.71 (m, 2H), 2.51 - 2.41 (m, 2H), 2.36 - 2.22 (m, 2H), 2.05 - 1,93 (m, 3H), 1.83 - 1.78 (dd, ,/ 954.18,34 Hz, 3H), 1.77 - 1,64 (m, 2 H), 1.63 - 1.58 is 3H), 1.42 - 1,27 (m, 3H). m . (ESI, +ve ion) 615.2 (M+H) ⁺ .

EXAMPLE 719. (1S,3'R,6'R,7'S,8 ^! E,1 rS ₅ 12'R)-6-CHLORO-7'-(2- METHOXYETHOXY)- 11 ^f ,I2'-DIMETOYL-3,4-DIHYDRO-2H,l 5Ή- SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]

THIA[l,14]DlAZATEm CYCLO[14.7.2.0 ³ - ⁶ ,0 ⁱ⁹ - ²⁴ jPENTACOSA[8,16,18,24]T ETR AEN 1 -15' -ONE- 13', 13'-DIOXIDE

STEP 1: (S)-6'-CHLORO-5-(((lR,2R.)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL) ETHYL)-N-(((2R,3S)-3-

METHYLHEX-5-EN-2-YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H - SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , Γ -NAPHTHALENE] -7- CARBOXAMIDE

4-dimethylaminopyridine (DMAP) (3.42 g, 28.0 mmol) was added to a solution of (S)-6 ^, -(^oro-5^((lR,2R)-2-((S)-l½droxyallyl)cyclobu1yl)meth yl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid (Intermediate AA11A; 7.7 g, 16.4 mmol) and (2R,3S)-3- methylhex-5-ene-2-sulfonamide (Intermediate EE22; 5.83 g, 32.9 mmol ) in DCM (411 ml) cooled to 0 °C. EDC hydrochloride (6.31 g, 32.9 mmol) was then added slowly portionwise. The mixture was stirred while allowing to reach ambient temperature overnight. The mixture was then washed with I N HCl and brine and the aqueous layer was back-extracted with EtOAc. The combined organics were dried over MgS04, filtered and concentrated. The yellow oily residue was loaded onto a 220 g ISCO Gold column and purified eluting with 0 % to 20 % EtOAc (containing 0.3 % AcOH)/heptanes, to provide (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyclobutyl)methyl)-N-(((2R,3S)-3-methylhex-5-en -2-yl)sulfonyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3, 1 '-naphthalene j-7- carboxamide (7.89 g, 12.6 mmol, 76 % yield, 88% pure).

STEP 2. (1S,3'R,6'R,7'S,8'E,1 rS,12 ^f R)-6-CHLORO-7'-HYDROXY-l V,W- DIMETHYL-3,4-DIHYDRQ-2H, 15 Ή- SPIRO [N APHTH ALEN E- 1 ,22'- [20]OXA[13]THIA[1 ,14]

DIAZATETRACYCLO[14J.2.0 ³ -^0 ¹⁹ ' ² ]PEOTACOSA[8,16,18,24]TETRAEN]- 15'-ONE 13 ',13 '-DIOXIDE

To a 20L reactor blanketed in argon was charged 14 L of 1,2- dichioroethane (1,2-DCE). (S)-6'-chloro-5-(((lR.2R)-2-((S)-l- hydroxyallyl)c lobu d)methyl)-N-(((2R,3S)-3-me1hylhex-5-en-2-yl)sulfonyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7- carboxamide (18.75 g, 29.9 mmol) was added as a solution in 400 mL 1,2-DCE followed by a 400 mL rmse. The reactor was sealed and purged with argon. (l,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzyliden e)ruthenium(VI) chloride (' ^" Grubbs-Hoveyda 11", 1.87 g, 2.99 mmol) was added as a solution in 150 mL of 1,2 DCE followed by a 50 mL rinse. The reactor was heated to 60 °C over 1 h with an argon sweep of the headspace and held at temperature for 9 h. The reaction was quenched by the addition of 2-(2-(vinyloxy)ethoxy)ethanol (1.50 g, 11.4 mmol), cooled to ambient temperature, and concentrated to ~ 200 mL volume by rotary evaporation. The reaction was transferred to a 1 L round- bottomed flask and diluted to 500 mL volume with 1 ,2-DCE. The reaction was treated with 52 g of Silicycle Si-Thiol (SiliCycle Inc., Quebec City, Quebec CANADA Cat# R51030B) with stirring for 9 h at 40°C, filtered and rinsed with 2 x 65 mL dichloromethane. The solution was passed through a Whatman GF/F filter cup (GE Healthcare Bio-Sciences Pittsburgh, PA, USA) to afford a transparent y ellow solution. The reaction was concentrated to afford a crude product mass of 27.4 g. The residue was slurried in 250 mL isopropyl acetate and evaporated to dryness three times. The reaction was suspended in 270 mL isopropyl acetate, heated to dissolution, allowed to cool to ambient temperature and stirred for 18 h. The solids were filtered and washed with 65 mL isopropyl acetate. The solid was air-dried for 30 minutes then placed under high vacuum for 3 hours to afford 12.6 g of (lS,3 ^! R,6'R,7'S,8'E,i rS,12'R)-6-chloro-7'-hydroxy- 1 Γ , 12'-dimethyl-3,4-dihy dro-2H, 15 'H-spiro[naphthalene- 1 ,22'- [20ioxa| 13jthia[ l, 14jdiazatetracyclo[14.7.2.0 ³ > ⁶ .0 ^{! 9} ' ²⁴ i pentacosa

[8,16,18,24]ietraen]-15'-one 13 ',13 '-dioxide ( 91.7% weight purity). ³ H NMR (500 MHz, CD2CI2) δ 8.06 (s, 1 H), 7.71 (d, J=8.56 Hz, 1 H), 7.17 (dd, J=8.44, 2,32 Hz, 1 H), 7.09 (d, ./ 2.20 Hz, 1 H), 6.91 (s, 3 H), 5.81 (ddd, ./ 14.92. 7.82, 4.16 Hz, 1 H), 5.71 (dd, ,/ 1541.8.3! Hz, 1 H), 4.16 - 4.26 (rn, 2 Is).3.83 (d,

14.43 Hz, 1 H), 3.69 (d, ,7=14,43 Hz, 1 H), 3,25 (d, «7=14.43 Hz, 1 H), 3.04 (dd, ./ 15.28.9.66 Hz, 1 H), 2.68 - 2.84 (m, 2 H), 2.41 (app qd, J=9.80, 3.70 Hz, 1 H), 2.25 - 2.34 (m, 1 H), 1.93 -2.00 (m, 5 H), 1.74 - 2.11 (m, 9 H), 1.62- 1.73 (m, 1 H), 1.43 (d, ,/ 7.W Hz, 3 H) 1.35 - 1.42 (rn, 1 H) 1.03 id. J=6.60 Hz, 3 !!}. MS (ESI, +ve ion) m/z 599.2 (M+H) ^H" .

STEP 3: (1S,3'R,6'R,7'S,8'E,1 l'S,12 ^, R)-6-CHLORO-7 ^, -(2- METHOXY ETHOXY)- 1 Γ , 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO|NAPHTHALENE-1,22'-|;20]OXA[13|THIA

[l,14]DIAZATETRACYCLO[14.7.2.0 ³ -^0 ⁱ⁹ - ²⁴ ]PENTACOSA[8,16,18,24]TETR AEN]-15'-ONE-13', 13'-DIOXIDE

To a solution of (lS,3'R,6 ^f R,7 ^, S,8 ^, E,irS,12 ^, R)-6-chloro-7 ^, -hydrox>'- 1 Γ , 12'-dimetliyl-3,4-dihy dro-2H, 15 'H-spiro[naphthalene- 1 ,22'- [ 20 ] ox aj 13 j thia[ 1 , 14 j di azatetrac cl o

[ 14,7.2.0 ³ ' ⁶ ,0 ⁱ⁹ - ²⁴ lpentacosa[8,! 6,18,241tetraenl-15'-or!e 13*,13'-dioxide (Example 719, Step 2; 100 mg, 0.167 mmol) in DMF (3.34 ml.) cooled to 0 °C was added sodium hydride, 60% dispersion in mineral oil (66.8 mg, 1.67 mmol). The reaction mixture was stirred at 0 °C for 15 rain, and then 2-bromoethyl methyl ether (Alfa Aesar, 0.078 mL, 0,834 mmol) was added. The reaction mixture was stirred at ambient temperature. After 48 h, the mixture was quenched with aq. NH ₄ C1 and diluted with water, then extracted with EtOAc. The organic layer was dried over MgS04 and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eiuting with 10-40 % EtOAc (containing 0,3% AcOH)/heptanes to provide the title compound (61 mg, 0,093 mmol, 55.6% yield), ^l H NMR (500MHz, CD2CI2) δ 8.02 (s, III).7.70 (d, j 8.6 Hz, 111).7.17 (dd, .! 2.2.8.6 Hz, III).7.09 id. j 2.2 Hz, 1H), 6.91 (s, 2H), 6.86 (s, 1H), 5.79 (ddd, 1=3.3, 9.6, 15,2 Hz, 1H), 5.54 (dd, j 9.8.14.4 Hz, ill).4.26 (ddd, J=1.0, 7.3, 14.4 Hz, 1H), 4.12 - 4.04 (m, 2H), 3.82 (d, j 15.2 Hz, III).3.75 (dd, j 3.3.9.2 Hz, !!!).3.69 (d, j 14.7 Hz, 1H), 3.53 - 3.49 (m, IH), 3.48 - 3,41 (m, 2H), 3.39 - 3.34 (m, IH), 3.32 (s, 3H), 3.25 (d, J=14.2 Hz, IH), 3.02 (dd, j 103.15,4 Hz, IH), 2.83 - 2,70 (m, 2H), 2.49 - 2.41 (rn, 111).2.36 - 2.28 (m, IH), 2.21 - 2.13 (m, IH), 2.13 - 2.07 (m, IH), 2.05 (d, j 13.7 Hz, !!!).1.99 - 1.91 (m, 3H), 1.89 - 1.77 (m, Ml).1.71 - 1.59 (m, IH), 1 ,44 (d, J 7.3 Hz, 3H), 1.39 (t, j 1 .1 Hz, 111).1.02 (d, .! 6.8 Hz, 3H). MS (EST, +ve ion) m/z 657.1 (M+H) ⁺ .

EXAMPLE 720. (1 S,3'R,6 ^f R,7'S,8'E,l i'SJ 2'R)-6-CHLORO-l l',12'-DIMETHYL- 7 ^! ~(2-(4-MORPHOIJNYL)ETHOXY)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24] TETRAEN]-15'-ONE-13', 13'-DIOXIDE

To a solution of (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)-6-chfoiO-7'-hydroxy- i ,12'-dimethyl-3,4-dihydro-2H,15'H -spiro[naphthalene-l,22'- [20]oxa[ 13 jthiaj 1 , 14] diazatetracy clo

|;i4.7.2.0- ^f () ^!9 ' ²⁴ lpentacosa[8,16,18,241tetraenl-15'-one 13',13'-dioxide (Example 719, Step 2; 20 mg, 0,033 mraol) in DMF (0,668 mL) cooled to 0 °C was added sodium hydride, 60% dispersion in mineral oil (13.4 mg, 0.334 mmol). The reaction mixture was stirred at 0 °C for 15 min, and then 4-(2- bromoethyl)morpholine hydrobrornide (Combi-Blocks inc.; 45.9 mg, 0.167 mraol) was added. The reaction mixture was stirred at ambient temperature overnight then it was quenched with aq. NH ₄ C1 and diluted with water, then extracted with EtOAc (3x8 mL). The combined organic layer was dried over MgSC>4 and concentrated. The crude oily yellow residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-40-60 % EtOAc (containing 0.3% AcOH)/ eptanes; nothing eluted; the column was then flushed with 100% EtOAc to provide the title compound (17.5 mg, 0.025 mniol, 73,6 % yield). Ή NMR (500MHz, CD2CI2) δ 7.71 (d, J=8.6 Hz, ill).7.17 (dd, j 2.2.8.6 Hz, IH), 7,09 id., j 2.0 Hz, I I I).6,93 (dd, J=1.5, 8.1 Hz, IH), 6,90 (d, J=8.1 Hz, IH), 6,87 (s, IH), 5,80 (ddd, J=3,2, 9.5, 14.9 Hz, IH), 5.53 (dd, J=9.0, 15,2 Hz, IH), 4.23 (q, j 7.0 Hz, IH), 4.11 - 4.05 ins.3H), 3.82 (d, j 15.2 Hz, IH), 3,74 (dd, J 3.2.9.0 Hz, IH), 3.72 - 3.66 (rn, SH), 3,58 - 3,50 (m, IH), 3.42 - 3,36 (m, IH), 3.25 (d, J 1 .4 Hz, IH), 3.03 (dd, J iO.l.15.3 Hz, IH), 2.84 - 2.70 (m, 2H), 2.59 - 2.50 (m, 6H), 2.47 - 2.39 (m, IH), 2.33 (qiun, j 9.0 Hz, IH), 2,21 - 2,13 (m, IH), 2.12 - 2.05 (m, 2H), 2.00 - 1,90 (rn, 3H), 1.89 - 1.75 (m, 3H), 1.72 - 1,61 (m, !!!). 1.44 (d, J 7.1 Hz, l).1,42 - 1.35 (rn, IH), 1.02 (d, j 8 Hz, 3H). MS (ESI, +ve ion) m/z 712.1 {M l!)

EXAMPLE 72 . (1 S,3 ^! R,6'R,7'S,8'E, 11 'S, 12'R)-6-CHLORO-l 1 ', 12'- DIMETHYL-7'-(3-(4-MORI ⁾ HOLl YL)PROPOXY)-3,4-DlHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20] OX A [13] ΤΗΐ A [ 1 ,14] DI AZ ATETR A C YCLO [ 4.7.2, 0 ³¹⁶ .0 ^{! 9,24} ] PENT ACO S A [8, 16, 18,24] TETRAEN] - 15'-ONE- 13', 13'-DIOXlDE

STEP I.4-(3-IODOPROPYL)MORPHOLINE

A solution of 4-(3-cWoropropyl)morpholine hydrochloride (Aldrich; 124 mg, 0,62 mrnol) and sodium iodide (a.c,s. reagent; 0,025 mL, 0.62 mrnoi) in DMF (3.1 mL) was heated to 60 °C for 3 h. The reaction mixture was carried on to the next step as is,

STEP 2. (1 S,3'R,6'R,7 ^! S,8'E, 1 l'S,12'R)~6~CHLORO~l r,12'-DIMETHYL-7'-(3-(4- MORPHOLINYL)PROPOXY)-3,4-DIHYDRO-2H, 15Ή-

SP! RO I NAPHTHALENE- 1 ,22'-

[20]OXA[ T3]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14.7.2.0 ³ 0 ¹⁹ ^ ⁴ ]PENTACOS A

[8,16,18,24] TETRAEN]-15'-ONE-13', 13'-D10XIDE

To a solution of (18,3¾,6¾,7'8,8Έ,1 Γ8,12¾)-6-οωοΓθ-7 ^! ¾'άΓθχν- 1 1 ',12'-dimethyl-3,4-dihydro-2H,15'H -spirofnaphthalene-1 ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo

[14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]peiitacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 719, Step 2; 12 mg, 0.020 mmol) in DMF (0.734 ml.) at ambient temperature was added sodium hydride, 60% dispersion in mineral oil (8.01 mg, 0.20 mmol). The reaction mixture was stirred at 0 °C for 15 min, and then 4-(3- iodopropyi)morpholine (25.5 mg, 0.100 mmol) (reagent assumed to be a 0.2M solution in DMF) was added. The reaction mixture was stirred at 70 °C overnight. LC/MS analysis of the reaction mixture showed complete conversion. The mixture was quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (4 4 mL). The combined organic layer was dried over MgS0 ₄ and concentrated. The crude oily residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-50 % EtOAc (containing 0.3% AcOH)/heptanes to provide the title compound (12 mg, 0.017 mmol, 82% yield). 'f t NMR (500MHz, CD2CI2) δ 7.71 (d, J 8.6 Hz, IH), 7.17 (dd, J=2,2, 8.6 Hz, IH), 7.09 (d, J=1.7 Hz, 1H), 6.91 (s, 2H), 6.87 (s, 1H), 5.77 (ddd, J=2.9, 9.3, 14.9 Hz, IH), 5.53 (dd, J=8.8, 14.7 Hz, IH), 4.25 (q, J=7.4 Hz, H I ). 4.10 - 4.07 { in. 2H), 3.82 (d, J=14.9 Hz, I H), 3.75 - 3.66 (m, 71 1 ). 3.46 - 3.39 (m, IH), 3.31 - 3.25 (m, i l l ). 3,25 (d, J 14.2 Hz, IH), 3.02 (dd, .1 i n 3. 15.4 Hz, IH), 2,83 - 2.70 (m, 2H), 2.55 - 2.38 (m, 7H), 2,37 - 2.28 (m, i l l ). 2.21 - 2.08 (m, 2H), 1.99 - 1.90 (m, 2! I ). 1.89 - 1.75 (m, 3H), 1.75 - 1.61 (m, 4H), 1.44 (d, j 7.3 Hz, 3H), 1 .40 (t, J 13.0 Hz, i l l ). 1 ,03 id. J 6.8 Hz, 3H). MS (ESI, +ve ion) m/z 726.1 (M+H) ⁺ .

EXAMPLE 722, (1 S,3'R,6'R,7'S,8'E,1 i'SJ 2'R)-6-CHLORO-l 1 \12'-DIMETHYL- 7 ^f -(2-(TETRAHYDRO-2H-PYRAN-4-YL)ETHOXY)-3,4-DIHYDRO-2H,1 5'H- SPIRO [NAPHTHALENE- 1 ,22'- [ 20 |OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO

[14,7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA[8, 16,18,24]TETRAEN]-15'-ONE-13', 13'- DIOXIDE

To a solution of (1S,3'R,6'R,7'S,8'E, 1 i'S,12'R)-6-chloro-7'-h} droxy- 11 ', 12'-dimethyl-3,4-dihy dro-2H, 15 Ή -spiro[naphthalene-l ,22'- [20]oxa[ 13 jthiaj 1 ,14] di azatetracy do

[14.7,2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,1 8,24]tetraen]-15'-one 13',13'-dioxide (Example 719, Step 2; 20 nig, 0.033 mmol) in DMF (0.668 mL) cooled to 0 °C was added sodium hydride (60% dispersion in mineral oil; 13.4 mg, 0.334 mmol). The reactio mixture was stirred at 0 °C for 15 min, and then 4-(2-bromoethyl)- tetrahydropyran (Maybridge Chemical Co., Ltd: 0.032 mL, 0.167 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The mixture was then quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3 x 8 mL). The combined organic layer was dried over MgS04 and concentrated. The crude oily residue was loaded onto a silica gel cartridge and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-30-40-50 % EtOAc (containing 0.3% AcOH)/heptanes to provide the title compound (20.7 mg, 0.029 mmol, 87% yield). ^] H NMR

(500MHz, CD2CI2) δ 8.18 (br s, 1H), 7.71 (d, j 8.6 Hz, I I I ). 7.17 (dd, j 2.2. 8.6 Hz, 111).7.09 (d, .! 2.2 Hz, 1H), 6.91 (s, 2H), 6.86 (s, !!!).5.77 (ddd, J 3.4.9.5, 15.2 Hz, IH), 5.52 (dd, J 9.0.15.2 Hz, IH), 4.30 - 4.23 (m, H), 4.10 - 4,06 (m, 2H), 3.91 ·· 3.85 (m, 2H), 3.82 id. J=15.2 Hz, ill).3.73 - 3.63 (m, 2H), 3.42 (td, j 6.7.9.3 Hz, IH), 3.34 (qt, .1 2.2.11.7 Hz, 211).3.29 - 3.24 (m, IH), 3.25 id. .! 14.2 Hz, III).3.02 (dd, J 10.1, 15.3 Hz, III).2.84 - 2.70 (m, 21 \) 2.45 - 2,38 (m, III).2.32 (qum, J 9.0 Hz, ill).2,20 - 2,01 (m, 3H), 2.01 - 1.90 (m, 3H), 1,89 - 1.75 (m, 3H), 1.72 - 1.63 (m, IH), 1.62 - 1.52 (m, 4H), 1.44 (d, J=7.3 Hz, 3H), 1.47 - 1.41 (ra, 3H), 1.42 - 1.36 (m, IH), 1.02 (d, J .8 Hz, 3H). MS (EST, +ve ion) m/z 711.1 (VI· 11)

EXAMPLE 723. (1 S,3'R,6'R,7'S,8'E,1 'SJ 2'R)-6-CHLORO-l l',12'-DIMETHYL-

7 ^! ~(2-(1 ⁱ lPERIDl YL)ETHOXY)-3,4-DIHYDRO-2H,15'H-

SPIRO[N APHTHALENE-1 ,22'~

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ^3> ^0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24] TCTRAEN]-15'-ONE,-13', 13'-DI0X1DE

To a solution of (1S,3'R,6'R,7'S,8'E, I rS,12'R.)~6~chloro~7'~hydroxy-

11 ', 12'-dimethyl-3,4-dihydro-2H, 15Ή -spiro[naphthalene-l ,22'- [20]oxa[ 13 jthiaj 1 , 14] diazatetracy clo

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24|tetraen]-15'-one 13',13'-dioxide (Example 719, Step 2; 20 mg, 0.033 mmol) in DMF (0.668 mL) at ambient temperature was added sodium hydride (60% dispersion in mineral oil: 13.35 mg, 0.334 mmol). The reaction mixture was stirred at ambient temperature for 15 min, and then l-(2- chloroethyl)piperidine monohydrochloride (Sigma- Aldrich Corporation; 30.7 mg, 0,167 mmol) was added followed by sodium iodide (a.c.s. reagent; 25 mg, 0.167 mmol). The reaction mixture was stirred at ambient temperature for 30 min then heated to 70 °C for 3.5 h. The mixture was then cooled to ambient temperature, quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (4x4 mL). The combined organic layer was dried over MgSC).* and concentrated. The crude oily residue was purified by chromatography through aRedi-Sep pre- packed silica gel column (4 g), eiuting with 10-50 % EtOAc (containing 0.3% AcOH)/heptanes (nothing eluted) then with 100% EtOAc (nothing eiuted) then 100% EtOAc/EtOH (3:1 ) to provide the title compound (16 mg, 0.023 mmol, 67,5% yield). ^: l 1 N.MR (500MHz, CD2CI2) δ 7,65 (d, J 8.6 Hz, ill), 7,08 (dd, j 2.2.8.6 Hz, ill).7,02 (d, J 8.6 Hz, ill), 6,99 (d. j 2.2 Hz, ill).6,87 is. ill). 6.74 (d, j=8.1 Hz, 1H), 6.06 - 5.99 (m, H), 5.40 (dd, J=8,6, 15.4 Hz, IH), 3,97 - 3.90 Cm.2H), 3.82 (d, j 6.6 Hz, ill).3.76 ·· 3.67 (m, 2H), 3.66 (d, J=14.9 Hz, IH), 3.59 (d, j 14.4 Hz, ill).3.55 - 3.46 (m, IH), 3.15 (d, j 14.2 Hz, !!!).2.93 - 2,80 (m, 5H), 2.73 - 2.60 (m, 2H), 2.39 - 2,25 (m, 2H), 2.03 (br s, 3H), 1.96 - 1.86 (m, 3H), 1.85 - 1.78 (m, 2H), 1,78 - 1.72 (m, IH), 1.68 (br s, 6H), 1,57 (quin, J=9.3 Hz, IH), 1.49 - 1.37 (m, 2H), 1.28 (d, J=6.8 Hz, 3H), 1.32 - 1.23 (m, IH), 0.90 (d, j 6.! Hz, 3H). MS (ESI, +ve ion) m/z 710.1 (M+H) ⁺ .

EXAMPLE 724. (1 S,3 ^! R,6 ^* R,7'S,8'Z,1 l'S,12'R)-6-CHLORO-l l',12'-DIMETHYL- 7 ^f -(2-(4-MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l ,22 ^! -

|2ujOXA| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί·ΗΛ(·Υ(·ί..ΟΙ i4.7.2,U' ^, '.i ^{)|:, !|} |Pl-N I ^' ACOSA [8,16,18,24] TETR AEN] - 15 '-ONE 13 ^* ,13'-DIOXIDE

STEP 1. (lS,3'R,6 ^! R,7 ^, S,8'Z,ll'S,12'R)-6-CHLORO-7'-HYDROXY-ir,12'- DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OX A 113]THI A[ 1 , 14] DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16, 18,24]TETRAEN; 15'-ONE 13', 13'-DIOXIDE

A 1000 mL RB flask was charged with (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox 'allyl)c^ lobut5d)memyl)-N-(((2R,3S)-3-methylhex-5-en-2-yl)sulfonyl)- 3\4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [I ,4]oxazepine-3, -naphtha]ene]-7- carboxamide (Example 719, Step 1; 710 mg, 1.13 mmol) and DCM (569 mL). The solution was sparged with argon for 15 min, then Hoveyda-Grubbs II (70.9 mg, 0.113 mmol) (solid) was added.

The mixture was stirred at 45 °C for 5 h. The reaction mixture was then sparged with air for 20 minutes while cooling to ambient temperature, then it was concentrated under reduced pressure. The crude oil was absorbed onto a plug of silica gel and purified through a 220 g ISCO Gold column, eluting with 10-20 (15 minutes)-50 % EtOAc (containing 0.3% AcOH) in heptanes over 36 minutes to provide (l S,3 ^! R,6 ^, R,7^,8'Z,i rS,12'R)-6-chloro-7'-hydrox -11 ^12'-dimethyI-3,4- dihy dro-2H, 15 'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]

pentaeosa[8,16,18,24 jtetraenj-15'-one 13 ',13 '-dioxide as the first eluting minor isomer followed by (l S,3 ^, R,6 ^, R,7 ^, S ₅ 8Έ ₅ l l ^, S,^ 2 ^, R)-6-chloΓO-7 ^, -h dΓoxy-11 12 ^, - dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[ 13 ]thia[ 1,14] diazatetracy cio[ 14.7.2. ir".0 ¹⁹ · ²⁴ ]

pentacosa 8,16,18,24]tetraen]-15'-one 13', 13'-dioxide (Example 719, Step 2) as the second eluting and major isomer. The semipure material thus obtained was loaded onto a silica gel column and purified eluting with 5% acetone in DCM to provide the title compound. ¾ NMR (500MHz, CD2CT2) δ 8.83 (br s, 1H), 7.71 (d, J 8.3 Hz, IH), 7.17 (dd, J 2.3. 8.4 Hz, IH), 7.11 (dd, J=1.6, 8.2 Hz, 1H), 7.09 (d, J=2.2 Hz, IH), 7.02 (s, 1H), 6.93 (d, J=8.1 Hz, IH), 5.82 - 5.75 (m, IH), 5.67 (dd, .1 65.11.4 Hz, IH), 4.43 (s, 1H), 4.12 - 4,05 (m, 2H), 3.85 - 3.76 (m, 2H), 3.67 (d, j 14.·! Hz, 1H), 3.25 (d, J 1 .4 Hz, IH), 3,28 - 3.19 (m, I Hi.2.83 - 2,65 (m, 3H), 2.38 - 2.23 (m, 2H), 2.19 - 2.11 (m, 2H), 2.10 - 1.99 (m, 3H), 1.97 - 1.87 {in.2H), 1.87 - 1.80 ins. IH), 1.79 - 1.70 {in.2H), 1.47 (d, j 7,3 Hz, 3H), 1.47 - 1,40 (m, lis). 1.06 (d, J 6.6 Hz, Ml). MS (EST, +ve ion) m/z 599.1 i\\ \l) .

STEP 2: (lS,3 ^, R,6'R,7'S,8'Z,irS,12'R)-6-CHLOR()-l l ^, ,12 ^, -DIMETHYL-7 ^, -(2-(4- MORPHOLIWL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'- |2ujOXA| 13ΙΊ !!1Λ| l.i4|! !A/.Vn-;i ^' RACYCi,.()l i4.7.2.U' ^, '.i ^{)|:, !|} |Pl-N I ^' ACOSA [8,16,18,24 ITETRAEN] - 15'-ONE 13 ', 13 '-DIOXIDE

The title compound was synthesized from (1S,3*R,6'R,7'S,8'Z,1 l'S,12'R)- 6-chloro-7'-hydrox -l ,12'-dimethyl-3,4-dihydro-2H,15'H-spiro| ^" naphthalene- 1 ,22'-[20] oxa[l 3]thia[ 1 , 14]

diazatetracyclo[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]peiitacosa|;8,16,18,24]tetraen]-15'~one 13',13'- dioxide (Example 724, Step 1; 33 mg; 0.055 mmol) following the procedure described for Example 7. Purification of the crude material via column

chromatography eluting with 3:1 EtOAc/EtOH provided

(lS,3'R,6 ^, R,7 ^, S,8 ^, Z,ll ^, S,12 ^! R)-6-chloiO-ll',12 ^! ~dimethyl"7'-(2-(4- morpholinyl)ethoxy)-3,4-dihydro-2H, 15'H-spiro|naphthalene-l ,22'- [20]oxa[ 13]thia[ 1,14] diazatetracy clo-

[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraeii]-15'-one 13 ',13 '-dioxide (21.6 mg, 0.03 mmol, 55.1%). 'H NMR (400MHz, CD2CI2) δ 7.68 (d, j 8,4 Hz, IH), 7.21 (br s, IH), 7.15 (d, j 76 Hz, IH), 7.10 (dd, 1=2.2, 8,4 Hz, ill).7.06 (d, j 2.2 Hz, IH), 6.72 (d, j 8.2 Hz, IH), 5.80 - 5.70 (m, IH), 5.44 (t, J-10,2 Hz, IH), 4.28 - 4.21 (rn, IH), 4,01 (dd, j 121.19,4 Hz, 2H), 3,78 - 3,70 (m, 2H), 3.72 (d, J 1 .9 Hz, IH), 3.66 (t, J=4.4 Hz, 4H), 3,59 (ddd, j 2,7.5.3, 7.8 Hz, IH), 3.48 - 3.41 (m, IH), 3.42 (d, J=14.5 Hz, IH), 3.23 (dd, J=9.5, 14.8 Hz, IH), 3.15 - 3.06 (m, IH), 2.90 - 2.80 (m, IH), 2.79 - 2.70 (m, 2H), 2.68 - 2.57 (m, 4H), 2.46 - 2.31 (m, 2H), 2,13 (s, 3H), 2,08 - 2.00 (m, IH), 1.88 (br s, 3H), 1,84 - 1.67 (m, 3H), 1.49 - 1.38 (m. 11 1 ). 1 ,32 (d, J 7.0 Hz, 3H), 1 ,01 id. j 6.3 Hz, 3H), MS (ESI, + ve ion) m/z 712.1 (M+H) ⁺ .

EXAMPLE 726. Ν-(2-(((Ι 8,3'Κ,6'Κ,7'8,8Έ, 1 1 '8, 12Έ)-6-αΐΕΟΚΟ-1 1 ', 12'- DIMETHYL- 13', 13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]

THIA[ 1 4]DIAZATET¾ACYCLO[14.7.2.0 ³ -^0 ¹⁹ " ²⁴ ]PENTACOSA[8,16, 18,24 TETRAENE]-7'-YL)0XY)ETHYL)4-METHYL;BENZENESULF0NAMIDE

To a solution of (l S,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,l l ^, S,12 ^, R)-6-chloro-7 ^, -hydroxy- 11 ', 12'-dimethyl-3,4-dihydro-2H, 15Ή -spiro[naphthalene-l ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy cio [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 719, Step 2; 21 mg, 0.035 mmol) in DMSO (0.35 mL) at ambient temperature was added N~ tosylaziridine (Sigma Aldrich; 6.9 mg, 0.035 mmol). After stirring at ambient temperature for 5 min, potassium t-butoxide (sublimed, 99.99% trace metals basis; Sigma Aldrich; 19.7 mg, 0.175 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The mixture was then quenched and diluted with water, then extracted with EtOAc (4 x 5 mL). The organic layer was dried over MgS04 and concentrated. The crude oily residue was loaded onto a silica gel cartridge and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-50% % EtOAc (containing 0.3%

AcOH)/heptanes to provide the title compound (17.2 mg, 0.022 mmol, 61.6%). ¾ NMR (400MHz, CD2CI2) δ 8.17 (s, 1H), 7.77 (d, j K.4 Hz, 2H), 7.73 (d, j 9,2 Hz, 1H), 7.40 id. J 7.8 Hz, 2H), 7.21 (dd, J 2.3. 8.4 Hz, 1H), 7.14 id. J 2.2 Hz, H I ). 6.95 (s, 2H), 6.88 (s, IH), 5.78 (ddd, j 3.7. 9.2, 15.1 Hz, i l l ). 5.49 (dd. J=8.7, 15.0 Hz, 111).4,73 (t, .1 60 Hz, 1H), 4,31 - 4,21 (m, ill).4.15 - 4.11 (m, 2H), 3.81 (d, J=14.3 Hz, 1H), 3.73 (d, J=14.5 Hz, 1H), 3.68 (dd, j 3.3,, 9.2 Hz, 1H), 3.45 (ddd, j 4.3.6,2, 10.0 Hz, 1H), 3,29 (d, j 1-1,5 Hz, 1H), 3.32 ·· 3,24 (m, 1H), 3.14 - 3.01 (m, 3H), 2.91 - 2,74 (m, 2H), 2.47 (s, 3H), 2.43 - 2.27 (m, 2H), 2,09 (d, J 10,2 Hz, 3H), 1,99 (dd, .1 49.9.8 Hz, 3H), 1,94 - 1,85 (m, 111).1.85 - 1,77 (m, 2H), 1.75 - 1.66 (m, IH), 1.48 (d, j 70 Hz, 3H), 1.47 - 1.40 (m, 1H), 1.07 (d, J 6.8 Hz, 3H). MS (ESI, +ve ion) m/z 796,0 (M+H) ⁺ .

EXAMPLE 727. (1S,3'R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-l l',12'-DIMETHYL- 7 ^, -(2-(3-OXO-4-MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H,15 ^, H- SPTRO[NAPHTHALENE-l,22'-

|20j ⁽ .)XA| I 311 HI A| I , i -I [01 A/A Π·. ΓΚΑίΎί ^' ί, 01 i -1.7.20·".ϋ ^{|:, !|} |ΡΗ\ l ACOSA [8,16,18,24] TETRAEN]-15'-QNE-13 ^! , 13'-D10XIDE

To a solution of (lS,3¾,6¾,7'S,813,irS,12'R) -7'-(2-bromoethoxy)-6- chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15 'H-spiro [naphthalene-! ,22'- [20]oxa[.l 3]thia[ 1,14]diazatetracyclo-

[14.7.2.0 ⁵ ' ⁶ .0 ¹⁹ ' ² ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 14; 12 mg, 0.017 mmol) and morpholin-3-one (Sigma Aldrich; 8.59 mg, 0.085 mmol) m DMF (0,34 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 6.80 mg, 0.170 mmol). The reaction mixture was stirred at ambient temperature for 1 h then it was quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3 x 3 mL). The organic layer was dried over MgS€>4 and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-50% % EtOAc (containing 0,3% AcOH)/heptanes then with 100% EtOAc to provide the desired product contaminated by unreacied morpholinone. This material was repunfied eluting with 5-20% acetone in DCM; then with 20- 00 % EtOAc in DCM to provide the title compound (9.2 mg, 0.013 mmol, 74.5%). ¾ NMR (400MHz, CD2CI2) δ 8.28 (br s, IH), 7.71 (d, J 8.4 Hz, 1H), 7.17 (dd, J 2.3. 8.6 Hz, IH), 7.09 (d, j 2.3 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.85 (s, 1H), 5.81 (ddd, J=3.3, 9.6, 15.1 Hz, 1H), 5.52 (dd, j 94. 15.2 Hz, 1H), 4.30 - 4.22 (m, 1H), 4.12 - 4.06 (m, 4H), 3,83 (t, .1 5 3 Hz, 2H), 3.81 (d, j 14. 7 Hz, 11 1 ). 3.77 (dd, .! 3. 1 . 9,2 Hz, i l l ). 3,69 (d, J i -! .3 Hz, IH), 3.58 - 3,52 (m, 2H), 3.47 - 3.38 (m, 4H), 3.25 (d, J=14, l Hz, IH), 3.03 (dd, j 10. i . 15.4 Hz, IH), 2.85 - 2.69 (m, 2H), 2.47 - 2.38 (m, IH), 2.38 - 2.26 (m, IH), 2.22 - 2.10 (m, I H), 2.10 - 2.01 (m, 2H), 2.00 - 1.90 (m, 3H), 1 .90 - 1.75 (ra, 3H), 1 ,73 - 1.63 (m, I H), 1 .44 id. j 7.2 Hz, 3H), 1 .43 - 1.34 (ra, IH), 1.02 (d, J 6 8 Hz, 3H). MS (ESI, +ve ion) m/z 726.1 (M+H) ⁴ .

EXAMPLE 728.(1 S,3'R,6'R,7'S,8'E, 1 1'S, 12'R)-6-CHLORO- 11 ', 12 -DIMETHYL- 7'-(2-(2-OXO-l -PIPERIDINYL)ETHOXY)-3,4-DJHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20] OX A [13] ΤΗΐ A [ 1 ,14] DI AZ ATETR A C YCLO [ 14.7 , 2, 0 ³¹⁶ .0 ^{! 9,24} ] PENT ACO S A [8, 16, 1 8,24] TETRAEN] - 15'-ONE- 13', 1 3'-DIOXlDE

To a solution of (lS,3'R,6'R,7 ^f S,8'E, l l 'S,I2'R.) -7 ^* -(2-bromoethoxy)-6- chloro-11 ', 12'-dimethyl-3,4~dihydro-2H, 15 'H-spiro[naphthalene-l ,22'- [20]oxa[ 13 jthiaj 1 ,14] diazatetracy clo-

[14.7.2.0 ³ -^0 ^{i 9} - ²⁴ ]pentacosa[8,16,1 8,24]tetraen]-15'-one 13',13'-dioxide (Example 14, 21 mg, 0.030 mmol) and delta-valerolactam (Sigma; 14.7 mg, 0.149 mmol) in DMF (0.595 1T1L) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 1 1.89 mg, 0.297 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The mixture was then quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3x5 mL). The organic layer was dried over MgS(>4 and concentrated. The crude material was purified by

chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0-10-50-100 % EtQ Ac/heptanes to provide the title compound (9 mg, 0.012 mmol, 41.8% yield). ¾ MR (400MHz, CD2CI2) δ 8.47 (br s, IH).7.71 (d, J=8.4 Hz, li!).7,17 (dd, j 23.8.4 Hz, IH), 7,09 id. J 2.3 Hz, IH), 6.94 (dd, j 18.8.0 Hz, IH), 6.90 id. j 8.0 Hz, IH), 6.86 (d, j 1.6 Hz, IH), 5.80 (ddd, j 3.3.9.6, 15.1 Hz, IH), 5.52 (dd, J 8.9.15.0 Hz, IH), 4.25 (q, J 6.8 Hz, 111).4,12 - 4.04 (m, 2H), 3,82 (d, J 14.9 Hz, IH), 3,76 (dd, j 32.9.1 Hz, IH), 3,69 (d, J=14,3 Hz, IH), 3.54 - 3.43 (m, 2H), 3.42 - 3.30 (m, 4H), 3.25 (d, J=14.3 Hz, IH), 3.02 (dd, j 10.0.15.3 Hz, !!!).2.84 - 2,68 (m, 2H), 2.48 - 2.38 (m, IH), 2.37 - 2.26 (m, 3H), 2,23 - 2.12 (m, IH), 2,11 - 2.01 (m, 2H), 2,01 - 1.89 (m, 3H), 1,88 - 1.78 (m, 3H), 1.79 - 1.73 (m, ill).1,72 - 1.63 (m, IH), 1.44 (d, .! 70 Hz, 3H), 1.43 - 1.34 (m, IH), 1.02 (d, j 6.8 Hz, 3H). MS (ESI, +ve ion) m/z 724.3 {W W) .

EXAMPLE 729, (iS,3'R,6'R,7'S,8'E,i l'S,12'R)-6-CHLORO-l 1 ', 12'-DIMETHYL- 7 ^, -(2-(2-OXO-l,3-OXAZOLIDIN-3-YL)ETHOXY)-3,4-DIHYDRO-2H _s 15 ^, H- SPIRO j NAPHTHALENE- 1 ,22'- |20j(.)XA| ΠΙ HI A| I , i ! |OIA/.\ Π·. ΓΚΑίΎί ^' ί, Ol i -1.7.20 ^;i '.U ^li, |PL\ iACOSA [8,16,18,24] TETRAEN]-15'-ONE-13 ^! , 13'-D10XIDE

To a solution of (1S,3 ^! R,6'R,7 ^! S,8'E,1 l'S,i2'R) -7'-(2-bromoethoxy)-6- chloro-11 ', 12'-dimethyi-3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[ 13 jthiaj 1,14] diazatetracy cio-

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-one 13 ^f ,13'-dioxide (Example 14, 2 ! mg, 0.030 mmol) and 2-oxazolidone (Sigma; 13 mg, 0,149 mrnoi) in DMF (0.595 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 11.9 mg, 0.297 mmol). The reaction mixture was stirred at ambient temperature and after 3.5 h the mixture was quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3x5 mL). The organic layer was dried over MgS€>4 and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0-10-50-100 %

EtO Ac/heptanes to provide 16.5 mg of desired product contaminated by a large amount of oxazolidone. This material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 5-15 % acetone in DCM, to provide the title compound (6.4 mg, 0.090 mmol, 30.2 % yield). ^l

NMR (500MHz, CD2CI2) δ 8.16 (br s, ill).7,71 (d, J 8.6 Hz, IH), 7,17 (dd, .! 2.2.8,6 Hz, ill).7.09 (d, .1 22 Hz, III).6.95 - 6.89 (ra, 2H), 6,85 (s, ill).5,81 (ddd, J 3.2.9.8, 1.5.1 Hz, III).5.53 (ddd, J 1.2.9.3, 15.2 Hz, H), 4.27 (t, j 8 ! Hz, 2H), 4.29 - 4.22 (m, IH), 4.12 - 4.06 (m, 2H), 3.83 (d, j 15.4 Hz, IH), 3.78 (dd, j 3.3.9.2 Hz, IH), 3.69 id. j 14.2 Hz, IH), 3.61 (dt, j 2.3.8.0 Hz, 2H), 3.54 (ddd, J=2.9, 6,6, 13.9 Hz, IH), 3,39 (ddd, J 2,4.3.7, 9.5 Hz, 211).3.31 (ddd, J=2.9, 5.9, 13.9 Hz, IH), 3.25 (d, i= A Hz, IH), 3.03 (dd, J=10.3, 15.4 Hz, IH), 2.83 - 2.70 (m, 2H), 2.47 - 2.38 (m, IH), 2.33 (quin, J=9.1 Hz, IH), 2.22 - 2.14 (m, IH), 2.12 - 2.01 (m, 2H), 2,00 - 1.90 (m, 3H), 1.89 - 1.74 (m, 3H), 1.72 - 1.63 (m, ill).1.45 (d, j 7.3 Hz, 3H), 1.43 - 1.35 (m, IH), 1,02 (d, j 6,8 Hz, 3H), MS (ESI, +ve ion) m/z 712.0 (M+H) ^H" .

EXAMPLE 730, (1S,3 ^! R,6'R,7'S,8'E,1 rS,12'R)-6-CHLORO-l 1 ', 12'-DIMETHYL- 7'-(2-(2-OXO- 1 -PYRROLlDINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO j NAPHTHALENE- 1 ,22'-

|20j ⁽ .)XA| 1311 HI A| I , i 1 |OIA/.\ Π·. ΓΚΑίΎί ^' ί, Ol i -1.7.20 ^;i' .U ^li, |PH\ iACOSA [8,16,18,24] TETRAEN]-15'-ONE-13', 13'-D10XIDE

To a solution of (1S,3¾,6'R,7'S,8'E, 1 rS,12'R.) -7 ^* -(2-bromoethoxy)-6- chloro-11 ', 12'-dimethyl-3,4~dihydro-2H, 15 'H-spiro[naphthalene-l ,22'- [20]oxa[ 13 jthiaj 1 , 14] diazatetracy cio-

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 14, 24 mg, 0,034 mrnol) and 2-pyrrolidinone (Sigma Aldrich; 0.013 ml., 0.17 mmol) in DMF (0.68 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 13.6 mg, 0.340 mmol). The reaction mixture was stirred at ambient temperature and after 3.5 h it was quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3 x 5 mL). The combined organic layer was dried over MgS(>4 and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0-10-50-100 % EtOAc/heptanes to provide the title compound (9.8 mg, 0.014 mmol, 40.6 % yield). ¾ MR (500MHz, CD2CI2) δ 8.53 (br s, 1H), 7.71 (d, J=8,6 Hz, H), 7.16 (dd, J=2.2, 8.6 Hz, 1 1 ! }. 7.09 (d, J=2.2 Hz, H), 6.94 (dd, j 1.7. 8.1 Hz, IH), 6.90 (d, J 7.8 Hz, IH), 6.86 (d, i i .5 Hz, IH), 5.80 (ddd, j 3.3. 9.7, 15.1 Hz, IH), 5.52 (dd, J=8.9, 15.0 Hz, IH), 4.28 - 4.22 (m, I H), 4.11 - 4,05 (m, 2H), 3.82 (d, J 1 .2 Hz, IH), 3.76 (dd, J 3.3. 9.2 Hz, IH), 3.69 (d, J=14.4 Hz, IH), 3.51 - 3.45 (m, IH), 3.44 - 3.40 (m, 2H), 3.40 - 3.29 (m, 3H),

3.25 (d, j 14.2 Hz, IH), 3.03 (dd, j 10.3. 15.4 Hz, IH), 2.84 - 2.70 (m, 2H), 2.46 - 2,38 (m, ! ! i ). 2.37 - 2.30 (m, IH), 2.29 (t, .! 8. 1 Hz, 2H), 2.21 - 2.13 (rn, H), 2.12 - 2.02 (m, IH), 1,97 (dd, j 7.5. 15.3 Hz, 2H), 2,01 - 1.90 (m, 2H), 1.89 - 1.74 (m, 3H), 1.72 - 1.55 (m, 3H), 1.44 (d, j 7. 1 Hz, 3H), 1.43 - 1.34 (m, IH), 1.02 (d, j 6.H Hz, 3H). MS (ESI, +ve ion) m/z 710.0 (M+H) ⁺ .

EXAMPLE 731. (1 S,3'R,6'R,7'S,8 ^! E, 1 l ^! S,12'R)-6-CHL()RO-l r, 12'-DIMETHYL- 7'-(2-(2-OXO-l -AZETEDrNYL)ETHOXY)-3,4-DII-IYDRO-2H, 15'H- SPTRO[NAPHTHALENE-l,22'-

|20|() Λ| ΠΙ 1 Η1Λ| I , i i |OI.\/.\ Π·. ΓΗ. Λί Ύί ^' ί, ί >l i -1.7.20 ^; ".ϋ ^1: ' |ΡΗ\ i ACOSA

[8,16,18,24] TETRAEN]-15'-QNE-13 ^! , 13'-D10XIDE

To a solution of (lS,3 ^! R,6 ^* R,7'S,8'E,irS,12'R) -7'-(2-bromoethoxy)-6- chloro-1 ,12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[ 1,14] diazatetracy clo- [14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraen]-15 ^! -one 13',13'-dioxide (Example 14, 21 rng, 0.030 rnmol) and 2-azetidinone (Sigma Aldrich; 10.6 rng, 0.149 rnmol) in DMF (0.595 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 11.9 mg, 0.297 rnmol). The reaction mixture was stirred at ambient temperature. LC/MS analysis showed the desired mass but very low conversion after 1.5 h and still partial conversion after 12 h. More base and reagent were then added and the temperature was increased to 40 °C. After 24 h the reaction mixture was quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3 x 5 ml,). The combined organic layer was dried over MgSC and concentrated. The crude material was purified by chromatography through a Redi-Sep pre- packed silica gel column (4 g), eluting with 0-10-50-100 % EtO Ac/heptanes to provide the title compound (3,4 mg, 90% purity). Ή NMR (500MHz, CD2CI2) δ 8.21 (br s, III .7.71 id. j H. Hz, II!}.7.17 (dd, j 2.2.8.6 Hz, 1H), 7.09 id. j 2.2 Hz, ill).6.95 - 6,88 (m, 2H), 6.86 (s, III).5.8! (ddd, J 3.3.9.7, 15,1 Hz, 1H), 5.53 (dd, J=10.0, 14,9 Hz, I Hi.4.29 - 4.21 (m, ill).4.11 - 4.04 (m, 2H), 3.83 (d, j 15.2 Hz, III).3.77 (dd, j 3.4.9.0 Hz, 111).3.69 (d, j 14.4 Hz, ill).3,49 (ddd, J 4.5.6.4, 9,8 Hz, ill).3.39 - 3.33 (m, 111 ).3,32 - 3.28 (m, III}.3.25 (d, J 14.2 Hz, Us).3.27 - 3.21 (m, 3H), 3.03 (dd, .1 103.15,4 Hz, 1H), 2.86 (t, J 4,0 Hz, 1H), 2.82 (d, j 5.9 Hz, 1H), 2.80 - 2.70 (m, 2H), 2.47 - 2.39 (m, 1H), 2.33 (quisn, J v.Oi!/. ill).2.22 - 2.13 (m, 1H), 2.13 - 2.02 (m, 2H), 2.00 - 1.89 (m, 3H), 1.89 - 1.75 (m, 3H), 1,72 - 1.63 (m, ill).1.44 (d, j 7 i Hz, 31!).1.43 - 1.36 (m, ill).1.02 (d, j 6.8 Hz, 3H). MS (ESI, +ve ion) m/z 696.3 (M il) . EXAMPLE 732. N-(2-(((l S,3'R,6'R,7'S,8 ^! E,1 l ^! S,12'R)-6-CHLORO-l l',12 ^! - DIMETHYL-13', 13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'- [20] OX A [13]

THIA[L14]DIAZATETRACYCLO[14.7.2,0 ³ -^0 ¹⁹ - ²⁴ ]1 TACOSA[8,16,18,24] TETRAEN]-7'-YL)OXY)ETHYL)ACET AMIDE

To a solution of (1S,3 ^! R,6'R,7'S,8'E,1 l'S,12'R) -7'-(2-bronioethoxy)-6- chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l ,14]diazaietracydo

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15 ^! -one 13 ^f ,13'-dioxide (Example 14, 17.5 mg, 0.025 mmol) and acetaniide (Sigma: 6.32 μΐ, 0.124 mmol) in DMF (0.496 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 9.91 mg, 0.248 mmol). The reaction mixture was stirred at ambient temperature. After 3 h the reaction mixture was quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3x5 mL). The cornbined organic layer was dried over MgSC and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0-10-50-100 % EtO Ac/heptanes to provide the title compound (7.9 mg, 0.012 mmol, 46,6 % yield), ¾ NMR (500MHz, CD2CI2) δ 8.31 (s, 1H), 7.71 (d, j 86 Hz, ill .7.17 (dd, j 2.3.8.4 Hz, 1H), 7.09 (d, j 2.2 Hz, 1H), 6.93 (dd, j 1.7.8.1 Hz, ill).6,91 id. J 8.! Hz, 1H), 6.86 id..1 i 5 Hz, 1H), 5.80 (ddd, .! 3.3.9,7, 15,1 Hz, 1H), 5.75 (br s, ill).5,54 (ddd, j !,?..9.3, 15.2 Hz, 1H), 4.29 - 4.22 (m, ill).4.12 - 4.05 (m, 2! I ).3,83 (d, J 15.2 Hz, ill).3,77 (dd, .1 3.3.9.2 Hz, 111). 3.69 (d, j 14.2 Hz, 1H), 3.47 - 3.42 (m, 1H), 3.39 - 3,33 (m, 1H), 3.33 - 3.27 (m, 2H), 3.25 (d, j 14.4 Hz, 1H), 3.04 (dd, J=10.1, 15.3 Hz, 1H), 2.83 - 2.70 (m, 2H), 2.44 (ddd, j 2.9.9.8, 18.3 Hz, 1H), 2.34 (quia j 9,0 Hz, 1H), 2.21 - 2.13 (in, 1H), 2,12 - 2.02 (m, 2H), 2.01 - 1.94 (m, 3H), 1,93 (s, 3H), 1,89 - 1.77 (m, 3H), 1,72 - 1.63 (m, III).1.44 (d, j 7 ! Hz, 3H), 1.43 - 1.37 (m, 1H), 1.02 (d, j 6.8 Hz, 3H). MS (ESI, +ve ion) m/z 684.3 (M+H) ⁺ .

EXAMPLE 733. (lS,3 ^, R,6 ^! R,7'S,8 ^! E,ll'S,12'R)-7'-(2-(4-ACETYL-l- PIPERAZlNYL)ETHOXY)-6-CHLORO-11^12'-DI ETHYL-3,4-DIHYDRO- 2H, 15 Ή - SPIRO |N APHTHAE ENE- 1,22'- [20]OXA[13]THTA| ! ,14 jDIAZATETRACYCLO

[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PE TACOSA[8,16,18,24]TETRAEN]"15'-ONE"13', 13'- DIOXIDE

To a solution of (1S,3'R,6'R,7'S,8'E,H'SJ2'R) -7*-(2-bromoethoxy)-6- chloro-11 ',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20joxaj 13]thia[l,14]diazatetracycIo

[14.7.2.0 ³ ' .0 ¹⁹ ' ² ]pentacosa[8,16,18,24]tetraen]-15"-one 13',13'-dioxide (Example 14, 30 mg, 0.042 mmol) and 1 -acetylpiperazine (Alfa Aesar; 27.2 mg, 0.212 mmol) in DMSO (0.850 mL) was heated to 50 °C. After 45 min the mixture was cooled to ambient temperature, quenched and diluted with water, then extracted with EtOAc (3 x 3 mL). The combined organic layer was dried over MgS0 ₄ and concentrated. The crude material was purified by chromatography through a Redi- Sep pre-packed silica gel column (4 g), eluting with 0-20-50-100 % EtO Ac/heptanes then with 100 % 3:1 EtOAc/EtOH to provide sernipure raaterial. This material was repurified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-50-80 % (3:1 EtOAc/EtOH)/heptanes to provide the title compound (13.7 mg, 0.018 mmol, 42,8 % yield). Ή NMR

(500MHz, CD2CI2) δ 7.71 id..1 83 Hz, 1H), 7.17 (dd, J 2.2.8,6 Hz, IH), 7.09 id. j 2.2 Hz, IH), 6.91 (s, 2H), 6.86 (s, Hi).5.79 (ddd, j 3.4.9.5, 14.9 Hz, 1H), 5.53 (dd, J 9.7.14.3 Hz, Hi).4.25 (br s, IH), 4.11 - 4.05 (m, 2H), 3,82 (d, J 15.2 Hz, IH), 3,74 (dd, J 2.9.9.0 Hz, IH), 3.69 (d, j 14.2 Hz, ill).3,56 - 3.52 (m, 2H), 3.50 (td, J=5.9, 10.0 Hz, 1H), 3.44 - 3.41 (m, 2H), 3.37 (td, J=6.1, 10.0 Hz, IH), 3.25 (d, j 14.2 Hz, IH), 3.03 (dd, j iU.i.15.3 Hz, IH), 2.84 - 2,70 (m, 2H), 2.52 (t, J==5.9 Hz, 2H), 2.48 - 2,44 (m, 2H), 2.41 (t, j : 1 Hz, 2H), 2.44 - 2.38 (ra, IH), 2.37 - 2.29 (m, IH), 2.16 (d, J=11.7 Hz, IH), 2.13 - 2.03 (m, 2H), 2.02 (s, 3H), 2.01 - 1.90 (m, 3H), 1.90 - 1.75 (m, 3H), 1.71 - 1.62 (m, ill).1.44 (d, J=7.1 Hz, Ml).1,43 - 1.35 (m, IH), 1.03 (d, J 68 Hz, 3H). MS (ESI, +ve ion) 'z 753,1 {M l!)

EXAMPLE 734, iIS,3'R,6'R,7'S,8'E,l l'S,I2'R)-6-CHLORO-l ! ',12'-DIMETHYL- 7 ^, -(2 4-METHYLSULFONYL)-l-PIPERAZINYL)ETHOXY)-3,4-DIHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14]DI AZ ATETRAC YCLO

[M ^.O^^O^^lPENTACOSAtS^^lS^lTETRAE l-lS'-ONE-lS', 13'- DIOXIDE

To a solution of (1S,3 ^, R,6 ^, R,7 ^, S,8 ^, E _S 11 ^, S,12 ^, R) -7'-(2-bromoethoxy)-6- chloro-i ,12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20] oxa[ 131 thi a[ 1 , 14] diazatetracy clo

[14 .21 ⁾³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]ietraen]-15 ^! -one 13 ^f ,13'-dioxide (Example 14, 30 mg, 0.042 mmol) and 1 -(methanesulfonyl)piperazine (Accela ChemBio Inc.; .34.9 mg, 0.212 mmol) in DMSO (0.850 mL) was heated to 50 °C. After 4.5 h the mixture was cooled to ambient temperature, quenched and diluted with water, then extracted with EtOAc (4 x 3 mL). The combined organic layer was dried over MgSO-t and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0-10-50-100 % EtO Ac/heptanes to provide most of the desired product. The column was then flushed with 100% 3: 1 EtOAc/EtOH to provide the rest of the desired product. This semipure material thus obtained was repurified through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-60 % (3: 1

EtOAc/EtOH)/heptanes to provide the title compound (22.1 mg, 0.028 mmol, 65.9 % yield: 97% purity). ¾ NMR (500MHz, CD2CI2) δ 7.62 (d, J=8.6 Hz, IH), 7.08 (dd, J 2.2.. 8.6 Hz, 1H), 7.01 (d, 3=2:2 Hz, IH), 6.88 (d, j 8. 1 Hz, i l l ). 6,83 - 6.76 (m, 2H), 5.73 (ddd, J=3.5, 9.2, 15.1 Hz, 1H), 5.45 (dd, J=8.9, 15.3 Hz, 1H), 4.16 - 4.07 (m, 1H), 4.01 - 3.97 (m, 2H), 3.73 (d, j 1 5.2 Hz, IH), 3.69 (dd, .1 3.2. 9.0 Hz, 1 1 1 ). 3.61 (d, .! 14.2 Hz, 1H), 3.43 (td, j 5 4. 10.5 Hz, i l l ). 3,29 (id, j 5 6. 10.3 Hz, IH), 3.18 (d, J=14.2 Hz, IH), 3.15 - 3.09 (m, 5H), 2.94 (dd, J=10.1, 15.3 Hz, IH), 2.66 (s, 3H), 2.75 - 2.61 (m, 2H), 2.55 - 2,48 (m, 5H), 2.33 (ddd, j 3.2. 10,0, 18.3 Hz, i l l ). 2.29 - 2,21 (m, IH), 2.12 - 2,00 (m, 2H), 2.00 - 1,92 (m, 2H), 1 ,91 - 1.81 (m, 2H), 1.80 - 1.65 (m, 3H), 1,63 - 1.54 (m, IH), 1.34 (d, J 7.3 Hz, 3H), 1.34 - 1.27 (m, IH), 0.94 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) nv'z 789.1 i M H ) .

EXAMPLE 735. N-(2-(((l S,3 ^! R,6'R,7'S,8'E,1 l'S,12'R)-6-CHLGRO-l l',12'- DIMETHYL- 13", 13 ^* -DIOXIDO- 15'-OXO-3,4-DTHYDRO-2H- SPIRO[NAPHTHALENE-1 ,22 ^! -[20]OXA[13]

THlA[l,14]DIAZATETRi CYCLO[14.7.2.0 ³ -^0 ¹⁹ ^ ⁴ ]PE TACOSA[8,16,18,24]T ETRAEN]-7'-YL)OXY)ETHYL)METHANESULFONAMIDE

1 /j

To a solution of (18,3¾,6Έ,7'8,8Έ,1Γ8,12Έ.) -7 ^* -(2-bromoethoxy)-6- chloro-11 V12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[ 1,14] diazatetracy clo

[ 14.7.2.0 ³ ' .0 ¹⁹ ' ² ]pentacosa[8,16,18,24]tetraen]-15 ^, -one 13 ^* , 13'-dioxide (Example 14, 30 mg, 0.042 mmol) and methanes ulfonamide (Matrix Scientific; 0.015 nil... 0.212 mmol) in DMF (0.850 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 16.99 mg, 0.425 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then quenched with aq. NH ₄ C1 and diluted with water, then extracted with EtOAc (3 x 5 mL). The combined organic layer was dried over MgSO* and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0-10-50-100 % EtO Ac/heptanes to provide the desired product contaminated by unreacted methanesulfonamide. The semipure material was taken up in DCM and washed twice with water, dried and concentrated. The material was repurified as above to provide the title compound (12.2 mg, 0.017 mmol, 39.9% yield, 92% purity). ¾ NMR (500MHz, ClM ^' ) δ 8.28 (br s, ill}. 7.70 (d, J=8.6 Hz, 1H), 7.17 (dd, J 2.3.8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.93 (dd, J=1.7, 8.1 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.89 (d, 1=1.5 Hz, 1H), 5.81 (ddd, j 3.5.9.4, 15.2 Hz, ill .5.54 (dd, j H.9.15.3 Hz, ill).4.51 (t, j 5.7 Hz, 1H), 4.23 (q. J 7.3 Hz, ill).4.1 I - 4,05 (m, 211).3.82 (d, .! 15.2 Hz, 1H), 3.77 (dd, J 3.7.8,8 Hz, I Hi.3.69 (d, j l-i. l Hz, 1H), 3.53 (ddd, J 4.0.6.3, 10.0 Hz, 1H), 3.36 (ddd, j 3.H.6.0, 9.8 Hz, ill .3.25 id. j 14.2 Hz, 1H), 3.26 - 3.17 (m, 2H), 3.04 (dd, .! !O O.15.4 Hz, ill).2.94 (s, 3H), 2.84 - 2.70 (m, 2H), 2,46 (ddd, j 3.7. 9.3, 18.6 Hz, 1H), 2.39 - 2.30 (m, 111).2,20 - 2,02 (m, 3H), 2.01 - 1.90 (m, 3H), 1.89 - 1.75 (m, 3H), 1.72 - 1.63 (m, 1H), 1.44 (d, j 7.1 Hz, 3H), 1.42 - 1.36 (m, 1H), 1.02 (d, .1 6.8 Hz, 3H). MS (ESI, +ve ion) m/z 720.0 (Yl-H)\ EXAMPLE 736. ETHYL (2-(((l S,3'R,6'R,7'S,8'E,l l'S,12'R)-6-CHLORO-l l',12'- DIMETHYL- 13', 13'-DIOXIDQ-15'-QXO-3,4-DIHYDRQ-2H- SPIRO [ APHTHALENE- 1 ,22'- [20] OXA[ 13]

TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]T ETRAEN]-7'-YL)OXY)ETHYL)CARBAMATE

To a solution of (1S,3'R,6'R,7'S,8 ^* E,11 ^* S,12'R) -7'-(2-bromoethoxy)-6- chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15 Ή-sprro j naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1, 14]diazatetracy clo

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15 ^, -one 13',13'-dioxide (Example 14, 31 mg, 0.044 mmol) and urethane (0.020 mL, 0.220 mmol) in DMF (0.850 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil; 17.56 mg, 0.439 mmol). The reaction mixture was stirred at ambient temperature (no reaction after 15 min at 0 °C). After stirring overnight (still partial and sluggish reaction) the mixture was quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3 5 mL). The combined organic layer was washed once with water, dried over MgS(>4 and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0-20-40-100 % EtO Ac/heptanes to provide semi pure desired product. This material was repunfied as above to obtain the title compound (7.3 mg, 0.010 mmol, 23.3%, 94% pure). ^! H NMR (500MHz, Acetone- 6) δ 10.39 (br s, 1H),

7,75 (d, 8.3 Hz, ! ! ! ). 7.22 (dd, ,/ 2.3. 8,4 Hz, ! H), 7. 15 (dd, J 2.0. 8. 1 Hz, 1H), 7.13 (d, ./ 2,4 Hz, 1H), 6.95 (d, ./ 1 .7 Hz, 1H), 6.90 (d, ./ 8 ! Hz, 1H), 5.99 (br s, i l l). 5.87 (ddd, ./ 3.2. 9.3, 14.7 Hz, ! ! ! ). 5.59 (dd, ,/ 9.4. 14.5 Hz, 1H), 4.26 (q, ./ 7.2 Hz, i l l ). 4.13 - 4.07 (m, 2H), 4.06 - 3.99 (m, 2H), 3,86 (d, ,/ 1 5.4 Hz, H i ). 3.81 idd. ,/ 3 2. 9.0 Hz, i l l ). 3,70 id. ./ 14.2 Hz, IH), 3.46 (id, ./ 5.9. 9.7 Hz, 1H), 3.34 (d, .7=14,2 Hz, H), 3,34 { id. J=5,7, 9.8 Hz, IH), 3,28 - 3, 17 (m, 2H), 3.15 (dd, ./ 10,3. 15.4 Hz, IH), 2.87 - 2.70 (m, 2H), 2.51 (ddd, ./ 2.7. 9.5, 16.9 Hz, IH), 2.34 (qum, ./ K.6 Hz, IH), 2.29 - 2.21 i ns. IH), 2.19 - 2.08 { in. 2H), 1.99 - 1 .89 (m, 3H), 1.86 - 1.71 (m, 4H), 1.50 - 1 .42 (m, H), 1.40 (d, ./ 7. 1 Hz, 3H), 1.18 (t, ./ 7. ! Hz, 3H), 0.99 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 714.3

(M+H) ⁺ .

EXAMPLE 737. tert-BUTYL 4-(2-(((l S,3'R,6 ^! R,7'S,8 ^, E,l l ^, S,12'R)-6-CHLORO- 1 l',12'-DIMETHYL-l 3 3'-DIOXIDO-15 ^, -OXO ,4-DIHYDRO-2H- SP1R0[NAPHTHALENE-1 ,22'-

| 2θ !() Λ| I 31 1 Η1 Λ| I„ i ! | OI.\/.\ Π·. ΓΗ.ΛίΎί ^' ί ,ΟΙ i -I .7.2 0- 3.6 - .0 · 1 9.2 -1 · |I ^' \T ACOSA[8, 16, 18,24]TETRAEN]-7'-YL)OXY)ETHYL)-l - PIPERIDINECARBOXYLATE

To a solution of (1S,3 ^! R,6'R,7'S,8'E, 1 l'S,12'R)-6-chloro-7 ^! ~h} droxy- 11 ', 12'-dimethyl-3,4-dihy dro-2H, 15 'H-spiro[naphthalene- 1 ,22'- [20]oxa[13 jthiaj 1 ,14]diazatetracyclo

[14.7,2.0 ³ -^0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]ietraen]-15 ^! -one 13 ^f ,13'-dioxide (Example 719, Step 2; 30 mg, 0.050 mmol) in DMF (1.0 mL) cooled to 0 °C was added sodium hydride (60% dispersion in mineral oil; 20 mg, 0.50 mmol). The reaction mixture was stirred at 0 °C for 15 min, and then N-boc-4-(2-bromo-ethyl)- piperidiiie (Astatech, Inc.: 73.2 mg, 0.250 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 d. The mixture was then quenched with aq NH ₄ C1 and diluted with water, then extracted with EtOAc (3 x 8 mL). The combined organic layer was dried over MgS0 ₄ and concentrated. The crude oily residue was purified by chromatography through a Redi-Sep prepacked silica gel column (4 g), eiuting with 10-50-100 % EtO Ac/heptanes to provide the desired material contaminated by a large amount of alkylating reagent. The semipure material was re uri fled eiuting with 0-5-10% Acetone in DCM to provide the pure title compound (6.7 mg, 0.0083 mmol, 16.5% yield), ¾ NMR (500MHz, CD2CI2) δ 8.16 (br s. !i!).7.71 (d../ 8.6 Hz, !!!).7.17 (dd, ,/ 2.2.8.6 Hz, 111).7.09 (d, ,/ 24 Hz, ill).6.94 - 6.89 (m, 2! I ).6,86 (s, 111).5,77 (ddd, J=3.2, 9.6, 15,1 Hz, I Hi,, 5.51 (ddd, ,7=1,0, 8.8, 14.9 Hz, 1H), 4.29 - 4.23 (m, 1H), 4.11 - 4.06 (m, 2H), 4.05 - 3.98 (m, 2H), 3.82 (d, J=15.2 Hz, lH), 3.70 (dd, J=3.2, 9.0 Hz, 1H), 3.69 (d, ./ 14.9 Hz, ill .3.42 (id../ 6,6.9.3 Hz, ill).3.26 (id, ./ 6.6. 9,3 Hz, IH), 3.25 id../ 14.2 H/. ill).3.02 (dd../ 10.1.15.3 Hz, ill).2.83 - 2.71 (m, 2H), 2.71 - 2.59 (m, 2H), 2.41 (ddd, J=3.2, 10.0, 18.3 Hz, IH), 2.36 - 2.28 (m, 1H), 2.21 - 2.13 (m, IH), 2.12 - 2.01 (m, 2H), 2.00 - 1.90 (m, 3H), 1.88 - 1.74 (m, 3H), 1.71 - 1.58 (m, 5H), 1.54 - 1.47 (m, IH), 1.45 (d, ./ 7 ! Hz, 3H), 1.42 (s, 9H), 1.41 - 1.36 (m, IH), 1.11 - 1.04 (m, 2H), 1.02 (d, .7=6,8 Hz, 3H), MS (ESI, +ve ion) m/z 810.4 (M+H) ⁺ .

EXAMPLE 738. ETHYL (((1S,3'R,6 ^! R,7'S,8'E,1 rS,12 ^! S)-6-CHLORO-l l',12'- DIMETHYL-13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'- [ 20] OXA[ 13 ]

^' ΠΠΛΙ i.!4if)!A/.\iin R.\CVCLO| UJ^ O^^O ¹ ' ^' |Ρ}Λ 1Λ(Ό8Α|8.Ι .ί8,,24|ϊ ETRAEN]-7'-YL)OXY)ACETATE

STEP 1 : (2R,3S)-N ^T -BIS(4-METEIOXYBENZYL)-3-METHYLHEX-5-ENE-2- SULFONAMIDE AND (2S,3S)-N,N-BIS(4-METHOXYBENZYL)-3- METHYLHEX-5-ENE-2-SULFONAM1DE

The title compounds were synthesized from N,N-bis(4- methoxybenzyi)ethanesulfonamide (Intermediate EE13; 1 148 mg, 3.29 mmol) and (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (prepared according to the procedure by Sigman, VI. S. et al. ; J. Am. ( ^' he . Soc , 2012, 734(28), 11408-

1 141 1 ; 1579 mg, 6,57 mmol) following the procedure described for Example 26, Step 1. (2R,3S)-N,N-bis(4-methoxybenz l)-3-methylhex-5-ene-2-sulfonamide and (2S,3S)-N,N-bis(4-methoxybenz> )-3-methyihex-5~eiie-2-sulfonamide were obtained as a 2.4 : 1 mixture (539 mg, 1 .29 mmol, 39.3% yield).

STEP 2: (2R,3S)-3-METHYLHEX-5-ENE-2-SULFONAMIDE AND (2S,3S)-3- METHYLHEX-5-ENE-2-SULFON AMIDE

The title compounds were synthesized from (2R,3S)-N,N-bis(4- methoxybenzyl)-3-methymex-5-ene-2-sulfonamide and (2S,3S)-N,N-bis(4- methoxybenzyl)-3~meth}'lhex-5-ene-2-sulfonamide (539 mg; 1.29

mmol) following the procedure described for Example 26, Step 2. (2R,3S)-3- methylhex-5-ene-2-sulfonamide and (2S,3S)-3-methylhex-5-ene-2-sulfonamide were obtained as a 2.3 : 1 mixture (203 mg, 1 .15 mmol, 89% yield).

1 / j / STEP 3: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-((lS,5S,6R,E)-l-HYDROXY-5- METHYL-6-SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)-

3' _; 4 ₅ 4' ₅ 5-TETRAHYDRO-2H,2'H"SPIRO[BENZO[B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((l S,5S,6S,E)- 1 -HYDROXY-5-METHYL-6-SULFAMOYLHEPT-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPlNE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

The title compounds were synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S,E)-l-hydroxyhex-2-en-l -yl)cyclobutyl)methyl ^

spiroj benzoj b] [l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (Intermediate AA12A; 75 mg, 0.147 mmol) and a 2.3: 1 mixture of (2R,3S)-3-methylhex-5-ene- 2-sulfonamide and (2S,3S)-3-methylhex-5-ene-2-sulfonamide (153 mg, 0.863 mmol) following the procedure described for Example 26, Step 3. The mixture of (S)-6'-duoro-5-(((lR,2R)-2-(il S,5S,6R,E)-l-hydiOxy-5-methyl-6-su3famoylhept- 2-OT-l -yl)cyclobutyl)methy])-3 ^, ,4,4 ^, ,5-tetrah dro-2H ₅ 2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid and (S)-6'- chloro-5-(((lR,2R)-2-((lS,5S,6S,E)-l-hydroxy-5-niethyl-6-sul famoyihept-2-en-l- yl)c lobutyl)methyl)-3 4,4 5-tetrahydro-2H,2^spiro[benzo[b] [ l,4]oxazepine- 3,1 '-naphthalene] -7-carboxy lie acid (73 mg, 0.118 mmol, 80 % yield) was carried on to the next step.

STEP 4. (1S,3'R,6'R,7'S,8'E, I l 'S, 12'S)-6-CHLORO-7'-HY ^T DROXY ^T -l l ',12'- DIMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[ 1 , 14JDIAZ A TET ACYCLO[!4 /2 -^0 ¹ - ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN]-15'- ONE 13' ₅ 13'-DIOXIDE

The title compound was synthesized from (S)-6'-chloro-5-(((l R,2R)-2-

((iS,5S,6R,E)-i-hydroxy~5~methy

yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2- ((1 S,5S,6S,E)- 1 -hy droxy-5-meftyl-6-sulfamoy lhept-2-en- 1 - yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l,4]oxazepine- 3, -naphthalene|-7-carbox lic acid (73 mg, 0.118 mmol) following the procedure described for Example 164, Step 6. The crude material was purified by chromatography through a 12 g ISCO gold column, eluting with 10-40-50 % EtOAc (containing 0.3% AcOH) in hexanes over 24 min, to provide

(lS,3'R,6'R,7^,8T,ll^,12^)-6-chloro-7 ^, -hydroxy-ll 12'-dimethyl-3,4-dihydro- 2H, 15'H-spiro[naphthalene-l ,22'~[20]oxa[i 3]

thia[l,14]diazatetracyclo[14.7.2.0 ' ^f \0 ¹⁹ ' ² ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide as the first eluting minor isomer. This material was repurified via reverse-phase HPLC eluting with 50-70 % acetonitrile (containing 0.1 % TFA) in water (containing 0.1 % TFA) to provide the title compound (5.8 mg, 00097 mmol, 8.2% yield, 90% purity). H NMR (400MHz, CD2CI2) δ 8.21 (s, 1H), 7.71 (d, ./ 8.4 Hz, ill).7,18 (dd, J=2.3, 8.4 Hz, 111).7.14 (dd, ,/ 2 I.8.1 Hz, ill).7,09 (d, J=2.3 Hz, IH), 6,95 (d, ./ 8.2 Hz, IH), 6.69 (br s, ill).6.10 - 5,99 (m, ill).

5.67 (dd, J=6A, 15.4 Hz, IH), 4,20 - 4.14 (m, IH), 4.11 (d.J 12.1 Hz, IH), 4.06 (d,■/ i i.9 Hz, IH), 3.84 - 3.74 (m, IH), 3.76 id../ 15.5 Hz, IH), 3.65 (d, ./ 14.7

Hz, IH), 3,44 id../ 14.7 Hz, 111).3,33 - 3.20 (m, IH), 2.86 - 2.70 (m, 2H), 2,60 - 2,48 (m, 2H), 2.31 - 2.20 (m, 2H), 2,08 - 1,98 (m, 2H), 1.97 - 1.80 (m, 4H), 1,79 -

1.68 (m, IH), 1.67 - 1.49 (m, 2H), 1,46 (d, ./ 7.2 Hz, 3H), 1.42 (br s, IH), 1.08 (d, ./ 7.0 Hz, Ml). MS (ESI, +ve ion) m/z 599.1 (M il) .

STEP 5: ETHYL (((lS,3'R,6 ^! R,7'S,8 ^, E,ll ^, S,12'S)-6"CHLORO-ir,12'- DIMETHYL-13',13'-DIOXIDO-15'-OX()-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-1,22'-[20]OXA[13]THTA

[1,14]DIAZ ATETRAC YCLO[ 14.7.2, 0 ³ · ⁶ .0 ¹⁹ - ²⁴ ]PENTACOS A[8, 16, 18,24]TETR AEN]-7'-YL)OXY)ACETATE

To a solution of (1S,3¾,6'R,7 ^! S,8'E,1 l'S,12'S)-6-chloro-7'-hydroxy- 1 Γ, 12'-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene-l ,22'- [20|oxa[13jthia[l,14jdiazatetrac clo[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ i

pentacosa[8,16,18,24]tetraen]-15'-one 13',I3'-dioxide (Example 738, Step 4; 21 mg, 0.035 mmol) in DCM (701 μΐ) at ambient temperature was added rhodium (II) acetate dimer (Sigma Aldrich; 0.387 mg, 0.876 μιηοΐ), followed by the dropwise addition of ethyl diazoacetate (Sigma Aldrich; 7.98 μΐ, 0.077 mmol). The reaction mixture was stirred at ambient temperature for 24 h adding more reagent as needed to drive the reaction. The reaction mixture was then directly injected onto a Redi-Sep pre-packed silica gel column (4 g), and purified eluting with 0 % to 30 % EtOAci containing 0.3% AcOH) in heptanes, to provide ethyl ίίί 1 S.3 ^' R.6'R.7'S.KT.

oxo-3 ,4-dihydro-2H-spiro [naphthalene- 1,22'- [20] oxa[ 13 ] thi a[ 1 , 14] di azaieto^

n]-7'-yl)oxy)acetate (9.4 mg, 0.014 mmol, 39.1% yield, 90% purity). ¾ NMR (400MHz, CD2CI2) 68.09 (br s, ill).7.71 (d, ./ 8.6 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.17 (d, ./ 8.4 Hz, 1H), 7.09 (d, ./ 2.3 Hz, III).6.96 (d, ./ 8.2 Hz, 1H), 6.64 (s, Hi).6.13 - 6.02 (rn, 1H), 5.51 (dd, J=9.0, 15.7 Hz, 1H), 4.15 (dq, ,/ 2.2.7,1 Hz, 2H), 4.11 - 4,03 (m, 2H), 4.04 (d, ,/ 164 Hz, ill).3.95 (d, .7=16,6 Hz, 1H), 3.86 (dd, ./ 3.6.8.5 Hz, ill).3.82 - 3.77 (m, Hi).3.77 (d, ./ 14.9 Hz, 1H), 3.68 (d, ./ 15.7 Hz, 111).3,42 id../ 1 .3 Hz, 111).3,22 (dd, ./ 10.9.15.2 Hz, 111).2.87 - 2,70 (m, 2H), 2.66 - 2.48 (rn, 2H), 2.40 (ddd, .7=3.7, 8.6, 17.0 Hz, 1H), 2.29 - 2.18 (m, I! is.2.09 - 1.98 (m, 3H), 1.97 - 1.81 (m, 4H), 1.73 (td, ./ 8,7.17.4 Hz, 1H), 1.47 id../ 72 !!/ 3H), 1.41 id../ 12.! Hz, 1H), 1.24 (t, J=6.8 Hz, 3H), 1.07

(d, J=7.0 Hz, 3H). MS (ESI, +ve ion) /z 685.1 (M+H) ⁺ .

EXAMPLE 739. (((lS,3'R,6'R,7'S,8 ^! E,irS,12'S)-6-CHLORO-ll',12'- DIMETHYL -13', 13 ^* -DIOXIDO- 15 ^* -OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE- 1 ,22420] OXA[13]THIA

[l,14]DIAZATETiL CYCLO[14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTACOSA[8,16,18,24]TETR AEN]-7'-YL)OXY)ACETIC ACID

A vial was charged with ethyl (((Ι8,3Έ,6Έ,7'8,8Έ,1 l'S,12'S)-6-ch!oro- 11 V12'-dimethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[n aphthalene-l,22'- [20joxa[13]thia[l,14]

diazateiracyclo[14.7.2.0 ³ ^ 0 ^Ϊ9 · ² ^

(Example 738; 7.7 mg, 0.011 mmol), THF (150 μ!). MeOH (75 μΐ) and 1 N LiOH (79 μΐ, 0.079 mmol). The mixture was stirred at ambient temperature for 45 min then it was quenched with 1 N HC1 (157 μΐ, 0.157 mmol), diluted with brine and extracted with EtOAc. The combined organics were dried over MgSOi and concentrated. The crude material was purified by chromatography through a Redi- Sep pre-packed silica gel column (4 g), eluting with 15 % to 50 % EtOAc (containing 0.3% AcOH) in heptanes to provide (((1S,3'R,6'R,7'S,8'E,1 l'S,12'S)- 6-chloro- 11 ', 12 ^* -dimethy 1- 13', 13'-dioxido- 15 ^* -oxo-3,4-dihy dro-2H- spiro [naphthalene- 1 ,22'- [20] oxa

I ! jihiaj ! . i4 jdia/.atelrac> c!oj 14.7.2.0 ^; '·.ί) ⁵ " ⁿ |penUiCO a! 8.16. ! H.24iieiraen|-7 ^' ~ yl)oxy)acetic acid (5.5 mg, 0.0084 mmol, 74.5 % yield). ^! H NMR (500MHz, CD2CI2) δ 8.91 (br s, 1H), 7.73 (d, ./ 8. Hz, 1H), 7.23 (dd, ./ i.B.8.2 Hz, 1H), 7.20 (dd, ./ 2.3.8.4 Hz, III).7.12 (d, ./ 2.2 Hz, 1H), 6.97 (d, ./ 8.3 Hz, III .6.77 (br s, IH), 6.28 - 6.18 (m, IH), 5.53 (dd, 9.2.15.5 Hz, IH), 4,12 - 4.08 (m, 2H), 4.06 (d, ,7=17,1 Hz, H), 3.98 (d, .7=17,1 Hz, IH), 4.01 - 3,92 (m, IH), 3.90 - 3.85 (m, 2H), 3.80 (d, ./ 14,4 Hz, IH), 3.43 (d, ./ 14.7 Hz, IH), 3.22 (dd, J=10.8, 14.4 Hz, IH), 2.83 - 2.71 (m, 2H), 2.64 - 2.56 (m, IH), 2.52 (ddd, ./ 3.9.8.8, 17.9 Hz, IH), 2.24 -2.16 (m, 1H),2.11 -2.01 (m, 2H), 1,99- 1.93 {in.2!!}.1.90 (dt, =5.0, 8.9 Hz, 4H), 1.76 (td, J=9.1, 18.6 Hz, IH), 1.50 (d, ./ 7.) Hz, 3H), 1.49 - 1.42 (m, IH), 1.08 (d, ./ 7.! Hz, 3H). MS (ESI, +ve ion) m/z 657.0 ( +H) ⁺ .

EXAMPLE 740. (1S,3'R,6'R,7'S,8'E,1 l'S,12'R)~6-CHLQRQ~12'-ETHYL~7'~(2~ METHOXYETHOXY)- 11 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8, 16, 18,24] TETRAEN] - 15 '-ONE- 13 ', 13 '-DIOXIDE

STEP I : (3R,4S)-N,N-BIS(4-ME HOXYBENZYL)-4-METHYLHEPT-6-ENE- 3 -SULFO AMIDE AND (3S,4S)-N,N-BIS(4-METHOXYBENZYL)-4- -6-ENE-3-SULFONAMIDE

The title compounds were synthesized from N,N-bis(4- methoxybenzyl)propane-l -sulfonamide (Intermediate EE14; 1512 mg, 4.16 mmol) and (R)-pent-4-en-2-yl 4-methylbenzenesulfonate (prepared according to the procedure by Sigman, M. S. etai.;J. Am. Chem. Soc, 2012, 134(2%), 11408- 11411; 2.0 g, 8.32 mmol) following the procedure described for example 26, step 1 . (3R,4S)-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfon amide and (3S,4S)-N,N-bis(4-methoxybenzyl)-4-methylhept-6-ene-3-sulfon amide were obtained as an inseparable mixture (335 mg, 0.776 mmol, 18.7 % yield)

STEP 2: (3R,4S)-4-METHYLHEPT-6-ENE-3-SULFONAMIDE AND (3S,4S)-4- METHYLHEPT-6-ENE-3-SULFON AMIDE

The title compounds were synthesized from (3R,4S)-N,N-bis(4- methoxybenzyl)-4-methylhept-6-ene-3 -sulfonamide and (3S,4S)-N,N-bis(4- methoxybenzyl)-4-methylhept-6-ene-3-sulfonamide (335 mg, 0.776

mmol) following the procedure described for Example 26, Step 2. (3R,4S)- 4- methylhept-6-ene-3-sulfonamide and (3S,4S)-4-methylhept-6-ene-3-sulfonamide were obtained as an inseparable mixture (67.6 mg, 0.35 mmol, 45.5% yield).

STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((l S ₅ 5S,6R,E)-l -HYDROXY-5-

METHYL-6-S ULFAMOYLOCT-2-EN- 1 -YL)CYCLOBUTYL)METHYL)-

S'^^' -TETRAHYDRO^.H^TI-SPIROIBENZOtBJ j l ^lOXAZEPINE-S,!'-

NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)-

2-((l S,5S,6S,E)-l-HYDROXY-5-METHYL-6-SULFAMOYLOCT-2-EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC

ACID

The title compounds were synthesized from (S)-6'-chloro-5-(((l R,2R)-2- ((S,E)-l-hydroxyhex-2-en-l-yO^

spiro [benzo [b] [1,4] oxazepme-3 , -naphthalene] - 7-carboxy lie acid (Intermediate AA12A; 40 mg, 0.078 mmol) and a mixture of (3R,4S)- 4-methylhept-6-ene-3- sulfonamide and (3S,4S)-4-methylhept-6-ene-3-sulfonamide (67,6 mg, 0,35 mmol) following the procedure described for Example 164, Step 5. The mixture ο£ (8)-6'-ο1ι1θΓθ-5-(((1Κ,2Κ)-2-((18,58 ₅ 6Κ,Ε)-1

sdfamoyloct-2-en-l -yl)c -lobutyl)rnethyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro [benzo [b] [ 1 ,4] oxazepme-3 , Γ -naphthalene] -7-carboxy lie acid and (S)~6 ^! - chloro-5-(((lR,2R)-2-((lS,5S,6S,E)-l-hydroxy-5-methyl-6-sulf amoyloct-2-en-l-

3, l '-naphthalene]-7-carboxylic acid (46 mg, 0,073 mmol, 92 % yield) was carried on to the next step. STEP 4, (1 S,3'R,6'R,7'S,8'E, 11 ^* S, 12'R)-6-CHLORO- 12'-ETHYL-7'-HYDROXY- ir-METHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]D1AZA

TETR,4CYCLO[ 14,7.2.() ³ - ⁶ ,0 ^{i 9} - ²⁴ jPENTACOSA[8,16,18,24]TETRAEN]-15'- ONE 13 ^f ,13'-DiOXIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((l S,5S,6R,E)~l-hydroxy-5-methyi-6-sulfamoyloct-2~en-l-yl)cyclo b^

3',4,4',5-tetraliydro-2H,2'H-spiro[benzo[bl [l,4]oxazepme-3,l '-naphthalene j-7- carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((l S,5S,6S,E)-1 -hydroxy -5- methy 1-6-s ul famoy 1 oct-2-en- 1 -y l)cy clobuty l)methy l)-3 ',4,4',5 -tetrahy dro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (63 mg, 0.100 mmol) following the procedure described for Example 164, Step 6. The crude material was purified by chromatography through a 12 g ISCO gold column, eluting with 10-40-50 % EtOAc (containing 0.3% AcOH) in hexanes over 24 min, to provide (I S^l^e'R ^^UirS/l^ Ve-chioro-n'-ethyl-T'- ydroxy-ir- methyl-3,4-dihydro-2H,15'H-spifo[naphthalene-l,22'- [20]oxa[13]thia[ l, 14]diazatetTacyclo[147.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13',13'-dioxide as the second eluting major isomer. This material was repurified by chromatography through a 12 g ISCO gold column, eluting with 0- 10 % acetone in DCM to provide the title compound (20 mg, 0.033 mmol, 32.7% yield). ¾ NMR (400MHz, CD2CI2) δ 8.33 (br s, H), 7.71 (d, .7=8.4 Hz, IH), 7.17 (dd, .1=23, 8.4 Hz, IH), 7.09 (d, J=2.3 Hz, IH), 6.96 - 6.88 (m, 3H), 5.86 (ddd, ,1=3.9, 9.0, 15.1 Hz, IH), 5.71 (dd, ./ 8.2. 15.1 Hz, I H), 4.22 (dd, J=3.9, 8.2 Hz, IH), 4,09 - 4.08 (m, 2H), 3.98 (ddd, ./ ! 2. 3.7, 8.8 Hz, IH), 3.82 (d, 1 7 Hz, IH), 3.69 (d, J=14.3 Hz, IH), 3.25 (d, ./ 1 .3 Hz, IH), 3.04 (dd, J=9.5, 15.4 Hz, I H), 2.85 - 2.69 (m, 2! I ). 2.41 (ddd, ./ 3.7. 9.8, 18.4 Hz, IH), 2.35 - 2.24 (m, IH), 2,21 - 2. 1 1 (ra, IH), 2, 10 - 2.03 (m, 2H), 1 .99 - 1.90 (ra, 3H), 1,90 - 1.74 (m, 5H), 1 .67 (qum, J=9.5 Hz, 2H), 1.45 - 1.34 (m, H), 1.27 (t, ,/ 7 4 Hz, 3H), 1.02 (d, ./ 6.8 Hz, 3H). MS (ESI, +ve ion) m/z 613.0 { M l ! ) .

STEP 5: (1 S,3'R,6'R,7'S,8'E,1 l 'S, 12'R)-6-CHLORO-12'-ETHYL-7'-(2- METHOXYETHOXY)- 1 1 '-METHYL-3,4-DIHYDRO-2H, 15Ή- SP1RO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THIA

[l ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ -^0 ^{i 9} - ²⁴ ]PENTACOSA[8, 16, 18,24]TETR ΑΕΝ]-15'-ΟΝΕ-13', 13'-DIOXIDE To a solution of (1 S,3'R,6'R,7'S,8'E, 1 l'S,12'R)-6-chfoiO-12 ^* -ethyl-7'- hydroxy-1 l '-methyl-3,4-dihydro-2H,15'H-spiro[naphtha]ene-l,22'- [20]oxa[ 13]thia[ 1, 14] diazatetracy o

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24|tetraen]-15'-one 13', 13 '-dioxide (10 mg, 0.016 mmol) in THF cooled to 0 °C was added sodium hydride (60% dispersion in mineral oil; 6.52 mg, 0.163 mmol). The reaction mixture was stirred at 0 °C for 15 min, and then 2-bromoethyl methyl ether (Alfa Aesar; 7.7 μΐ, 0.082 mmol) was added. The reaction mixture was stirred at ambient temperature for several hours adding more reagents in small portions. Minimal reaction was observed and the reaction seemed to stall at about 50% conversion after 5 days. The mixture was then quenched with aq NH CI and diluted with EtOAc. The organic layer was separated, dried over MgS04 and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 10-40 % EtOAc (containing 0.3% AcOH) in heptanes to provide

(1 S,3'R,6 ^! R,7'S,8'E, 11 'S, 12'R)-6-chloro- 12'-ethyl-7'-(2-methoxyethoxy)-l Γ- methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [ 20] oxa[ 13 ]thia

[l,14]diazatetracyclo[14.7.2.0 ³ - ^, 0 ^!9 - ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-one-13 13'-dioxide (1.8 mg, 0.0027 mmol, 16.4% yield), ^" Ή NMR (500MHz, CD2CI2) δ 8.08 (s, 111).7.71 (d, ./ 8.6 Hz, lH), 7.17 (dd, ./ .2.4.8.6 Hz, 1H), 7.09 (d, ./ 2.2 Hz, ill).6.91 (d, ./ 0.7 Hz, 2H), 6.87 (s, 1H), 5.82 (ddd, ,/ 3.4.9.4, 15.3 Hz, 1H), 5.54 (dd, ,/ 94.15.8 Hz, ill).4,1 I - 4,05 (m, 211).4.00 (dd, ,/ 28.9.4 Hz, ill). 3.82 (d, ,7=14,9 Hz, IH), 3.78 (dd, .7=3,2, 9.0 Hz, IH), 3.69 (d, «7=14.4 Hz, 1H), 3.53 (ddd, J=3.4, 5.4, 9.3 Hz, IH), 3.45 (dt,■/ 3.7.5.0 Hz, 2H), 3.38 (ddd, ./ 3.4. 5.9, 9.5 Hz, IH), 3.32 (s, 311).3.25 (d, ./ 14.4 Hz, IH), 3.02 (dd, ./ 10.3.15.4 Hz, IH), 2,84 - 2.70 (m, 21!}.2.45 (ddd, ,7=3,7, 10.0, 19.1 Hz, IH), 2.37 - 2.29 (m, IH), 2.29 - 2.19 (m, IH), 2.13 - 2.08 (ni, IH), 2.08 - 2.01 (m, 2H), 2.00 - 1.89 (ni, 3H), 1.89 - 1.77 (m, 4H), 1.66 (quin, ./ 8.6 Hz, IH), 1.44 - 1.35 (ni. IH), 1.28 (t, ./ 7.3 Hz, l ⁾ .1.02 (d, ,/ 6,8 Hz, 311). MS (EST, +ve ion) m/z 671.1 (M+H) ⁺ ; 693.1 (M+Na) ⁺ .

EXAMPLE 741. METHYL (((lS,3'R,6'R,7'S,8'E,irR)-6-CHLORO-ir-ETHYL- 13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTOALENE-l,2 2 ^f - [20]OXA[13]THIA

|;i,141DIA ATETR,4CYCLO[14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTACOSA[8,16,18,24]TETR AEN]- 7*-YL) OXY) ACETATE

STEP 1 : (S)-2-ETHYL-N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-l-

SULFONAMIDE AND (R)- 2-ETHYL-N,N-BIS(4-METHOXYBENZYL)PENT- 4-ENE-l -SULFONAMIDE

The title compound was synthesized from N,N-bis(4-methoxybenzyl) methanesulfonamide (intermediate EE12; 1.10 g, 3.28 mmol) and hex-5-en-3-yl 4- methylbenzenesulfonate (prepared according to the procedure by Sigman, M. S. et al. ; J. Am. Che r, Soc , 2012, 1 J 28), 11408-1 141 1 ; 1.50 g, 5,90 mmol) according to the procedure described for Intermediate 38, Step 1. (S)-2-ethyl-N,N- bis(4-methoxybenzyl)pent-4-ene-l -sulfonamide and (R)-2-ethyl-N,N-bis(4- memoxybenzyl)pent-4-ene-l -sulfonamide were obtained as a racemic mixture (435 mg, 1.04 mmol, 31.8% yield).

STEP 2: (S)-2-ETHYLPENT-4-ENE-l -SULFO AMIDE AND (R)- 2- ETHYLPENT-4-ENE- 1 -SULFONAMIDE

The title compound was synthesized from a racemic mixture of (S)~2~ ethyl-N,N-bis(4-methox>'benz\'l)pent-4-ene-l -sulfonamide and (R)-2-ethyl-N,N- bis(4-methoxybenzyl)pent-4-ene-l -sulfonamide (435 mg, 1.04 mmol) according to the procedure described for Example 26, Step 2, (S)-2-ethylpent-4-ene-l- sulfonamide and (R)-2-ethylpent-4-ene-l -sulfonamide were obtained as a racemic mixture (149 mg, 0.84 mmol, 81% yield).

STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((l S,5S,E)-l~HYDROXY-5- (SULFAMOYLMETHYL)HEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H,2'H-SPIR()[BENZO B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-((ilR,2R)- 2-((lS,5R,E)-l -HYDROXY-5-(SULFAMOYLMETHYL)HEPT-2-EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H- SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l '-NAPHTHALENE]-7-CARBOXYLIC ACID

The title compounds were synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S,E)-l-hydrox\'hex-2-en-l-yl)c lobutyl)methyl)-3^4,4^5-tetrahydro-2H,2 ^, H- spirojbenzojb] [ 1 ,4] oxazepine-3, 1 '-naphthalene]-7-carboxylic acid (I termediate AA12A; 80 mg, 0.157 mmol) and a mixture of (S)-2-ethylpent-4-ene-l- sulfonamide and (R)-2-ethylpent-4-ene-l -sulfonamide (149 mg, 0.84 mmol) following the procedure described for Example 164, Step 5. Purification of the crude material eluting with a gradient of 0-20-50-100% EtOAc in heptanes followed by a gradient of 20-50% EtOAc (containing 0.3% AcOH) in heptanes provided an inseparable mixture of (S)-6'-chloro-5-(((lR,2R)-2-((lS,5S,E)-l- hydroxy -5-(sulfaraoylmethyl)hept-2-en- 1 -yl)cyclobutyl)methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((lS,5R,E)-l-hydroxy-5- (sulfamoylmethyl)hept-2-en-l-yl)cyclobutyl)methyl)-3',4,4',5 -tetrahy

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid (75 rng, 0.122 mmol, 77% yield).

STEP 4. ! S,3'R,6'R,7'S,8'E,1 l ^* R)-6-CHLORO-l l'-ETHYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 12 -

[20]OXA[13]THIA[1,14]DIAZA

TETRACYCLO(14J.2.0 ³ ' ⁶ .0 ⁱ⁹ ^ ⁴ jPENrrACOSA[8,16,18,24]TETRAEN]-15'-

ONE 13 ^f ,13'-DiOXIDE

The title compound was synthesized from (S)-6'-chloro-5-(((l ,2R)-2- ((1 S,5S,E)-1 -hydroxy-5-(sulfamoylmethyl)hept-2-en-l -yl)cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3, 1 '-naphthalene j-7- carboxylic acid and (S)-6'-chloro-5-(((l R,2R)-2-((l S,5R,E)-l-hydroxy-5- (sulfamoylmethyl)hept-2-en-l-yl)cyclobu1\ )methyl)-3',4,4',5-terxahydro-2H spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (75 mg, 0.122 mmol) following the procedure described for Example 164, Step 6. The crude material was purified by chromatography through a 12 g ISCO gold column, elutmg with 10-30-50 % EtOAc (containing 0.3% AcOH) in hexanes over 24 min, to provide (1 S,3 ^! R,6'R,7'S,8'E,1 l'R)-6-chloro-l l '-e l-7'-hydroxy-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-[20]oxa[ 13]thia[ 1,14]

diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8, 16,18,24]tetraen]-15 ^! -one 13 ^f ,13'- dioxide as the first eluting isomer (20.4 mg, 0.034 mmol, 28.0% yield). ¾ NMR (400MHz, CD2CI2) δ 8.45 (br s, 11 1 ). 7,67 (d. J=8.6 Hz, ! ! ! ). 7.44 (br s, I I I ). 7.15 (dd, .7=2.3, 8.4 Hz, IH), 7.10 (d, «/=2.3 Hz, 1H), 6.96 (dd, ,/ 1 8. 8.0 Hz, IH), 6.91 (d, J=8.0 Hz, IH), 5.71 (dd, J=4.7, 15.7 Hz, IH), 5.66 - 5.55 (m, IH), 4.24 - 4.13 { in. 2H), 3.96 (br s, IH), 3.92 id. ./ 1 5.7 Hz, IH), 3.79 (br s, I H), 3.64 (d, ./ 13.3 Hz, IH), 3,42 i d. ./ 1 .5 Hz, 11 1 ). 3,30 - 3.11 (m, 2H), 2,79 - 2.71 (m, 21 1 ). 2,56 - 2.41 (m, 2H), 2.29 (dd, J=5.5, 13.9 Hz, IH), 1.91 ·· 1.75 C m. 7H), 1.75 - 1.63 (m, 4H), 1.45 (dt,■/ 7. . 14.3 Hz, 2H), 0.92 (t, ./ 7.3 Hz, 3H). MS (ESI, +ve ion ) m/z 599.0 (M+H) ⁺ . STEP 5: METHYL (((lS,3'R,6 ^, R,7'S,8 ^, E,i r )-6~CHLORO-ir-ETHYL-13',13'- DI()XIDO-15 ^! -OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1 ,14]DTAZA

TETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ^19!2 ]PENTACOSA[8,16,18,24jTETRAEN]- T- YL)OXY) ACETATE

To a solution of (1S,3'R,6'R,7 ^! S,8'E, 1 l ^* R)-6-chloro-l l'-ethyl-^'-hydroxy- 3,4-dihydro-2H,15'H-spiro[naphthalene-L22'-

[ 20 joxa 13 jthia[ 1 , 14 j diazatetracy clo[ 14.7.2.0 ³ · ⁶ . () ^{! 9 24} ]

pentac-osa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 765; 18 nig, 0.030 mmol) in THF (0.60 mL) cooled to 0 °C was added sodium hydride (60% dispersion in mineral oil; 6 mg, 0.150 mmol). The reaction mixture was stirred at 0 °C for 30 min, and then methyl bromoacetate (Alfa Aesar; 8.33 μΐ, 0.090 mmol) was added. The reaction mixture was stirred at ambient temperature for 6 h (more NaH was added to drive the reaction to near completion) and then was quenched with sat. NH4CI, extracted with EtOAc, dried over MgS04 and concentrated The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0 % to 30 % EtOAc (containing 0.3% AcOH) in heptanes, to provide methyl (((l S,3'R,6'R,7'S,8'E,i rR)-6-chioro-i r-ethyl- 13 ^f , 13'-dioxido-l 5'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14.7 ,2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa| 8,16,18,24jtetraenj- 7'-yl)oxy)acetate (5.0 mg, 0.0075 mmol, 24.8% yseld). ^! H N.YiR (400MHz, CD2CI2) δ 8.27 (br s, IH), 7.70 (d, ,/ 8. Hz, III).7.16 (dd, .7=2.2, 8.4 Hz, IH), 7.09 id../ 2.3 Hz, ill).7.00 - 6.96 (m, IH), 6.91 (d, J=8.0 Hz, IH), 6.91 - 6.87 (m, IH), 5.88 (ddd, =4.3, 8.0, 15.5 Hz, IH), 5.52 (dd, ./ 7.8.15.8 Hz, IH), 4.13 id../ 16.6 Hz, IH), 4.13 - 4.04 {in.3H), 3.99 (d, ./ 16.4 Hz, H), 3,85 (dd, ./ 3.5.7.6 Hz, IH), 3.72 (s, 3H), 3.64 (d, ./ 145 Hz, IH), 3.59 - 3.52 Cm.2H), 3.37 (d, ./ 14.7 Hz, ill).3.27 (br s, IH), 2.83 - 2.68 Cm.2H), 2.46 (br s, 2H), 2.32 - 2.16 (m ₅ 2H), 2.13 - 2.04 (m, IH), 2.02 - 1.95 (m, IH), 1.95 - 1.84 Cm.3H), 1.83 - 1,74 (m, 3H), 1.70 {dd../ 90.18,4 Hz, H), 1.61 - 1,42 (m, 2H), 0.96 (t, .7=7.3 Hz, 3H). MS (ESI, +ve ion) m/z 671.0 (M+H) ⁺ .

EXAMPLE 742. (18,3¾,6'Κ,7'8,9Έ,12'Κ)-6-(ΗΕΟΚΟ-7·-ΗΥϋΜ)ΧΥ- 12'- METOYL-3,4-DIHYDRO-2I-I,15'H-SPiRO|NAPHTOALENE-I,22'- [20]OXA[ 13]THI A[ 1 , 14] DIAZ A

TETR^\CYCLO[147.2.0 -^0 ¹⁹ - ²⁴ ]PE TACOSA 9,16,18,24jTETRAENi-15'- ONE 13', 13-DIOXIDE

STEP 1: (S)-6 ^! "CHLORO-5"(((lR,2R)"2-((S)-l-HYDROXYBUT-3-EN-l- YL)CYCLOBUTYL)METHYL)-N-((R)-PENT-4-EN-2-YLSULFONYL)-

3 ^f ,4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7 -C ARB OXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l-hydroxybut-3-en-l-yl)cyclobut>d)me l)-3^4,4^5-tetrahydro-2H,2H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (intermediate AA13A; 166 mg, 0.344 mmol) and (R)-pent-4-ene-2-sulfonamide (intermediate EEl 7; 87 mg, 0.585 mmol) following the procediire described for Example 719, Step 2, Step 1. Purifi cation of the crude material provided (S)-6'-chloro-5- (((lR,2R)-2-((S)-l-hydroxybut-3-en-l-yl)c clobu1yl)methyl)-N-((R)-pent-4-en-2- ylsulfonyl)-3 4,4 5-tetTahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene] -7-carboxamide (134 mg, 0.219 mmol, 63.5% yield).

STEP 2. (1 S,3'R,6'R,7 ^* S,9'E, 12'R)-6-CHLORO-7'-HYDROXY-l 2'-METHYL-

3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[ 13]THI A[ 1 , 14]DI AZATETRAC YCLO

[14.7.2.0 - ^f () ^!9 - ²⁴ lPENTACOSA|;9,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE

A 500 mL round bottom flask was charged with (S)-6'-chloro-5-(((lR,2R)- 2-((S)-l -hydroxybut-3-en-l-yl)cyclobutyl)methyl)-N-((R)-pent-4-en-2- ylsulfonyl)-3',4,4\5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]ox azepine-3,r- naphthalene] -7-carboxamide (134 mg, 0.219 mmol) in toluene (146.00 mL). It was stirred at ambient temperature for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (27.4 mg, 0.044 mmol) in toluene (8 mL) at ambient temperature. The mixture was stirred at 106 °C under nitrogen for 80 min. Air was blown through the solution for 10 mm to deactivate the catalyst, and then the mixture was concentrated. The crude dark oil was absorbed onto a plug of silica gel and purified by chromatography through a 24 g ISCO column, eiuting with 10 % to 20 % to 40% EtOAc (containing 0.3% AcOH) in hexanes over 90 min. The material thus obtained was further purified by reverse phase HPLC to provide

(lS,3'R,6'R,7^,9T,12'R)-6-chloro-7 ^, -hydroxy-12'-methyl-3,4-dihydro-2H, 15TL spiro [naphthalene- 1 ,22'-[20 ] oxa[ 13 ]thia[ 1 , 14] diazateiracy clo

[14 .21 ⁾³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[9,16,18,24]ieiraen]-15 ^! -one 13 ^! ,13'~dioxide as the first during and minor isomer. ^! H NMR (500MHz, CDCb) δ 10.00 (br s, 1H), 7.71 (d, ./ K.6 Hz, ill).7.44 (d, ./ 8.3 Hz, ill .7.18 (dd, ./ 2.1.8.4 Hz, 1H), 7.10 (d, ,/ i 7 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 5,63 - 5,52 (m, 2H), 4.17 - 4.12 (m, 2H), 4.07 (ddd, ·/ 5.1.7.1, 12.2 Hz, 1H), 3.90 - 3.84 (m, ill).3.62 (d, ./ 14.2 Hz, IH), 3.58 (br s, III .3.35 id../ 14.2 Hz, IH), 3.33 - 3.24 (m, III).3.09 - 2.94 (m, ill). 2,83 - 2.73 (ns.2H), 2,59 (dd, ./ 2.6.13.8 Hz, 211).2.50 (td, ./ 9.7.14.1 Hz, 2H), 2.41 - 2.29 (m, 2H), 2,17 - 2.11 (m, IH), 2.02 (d, ,7=7,6 Hz, H), 1.98 - 1,87 (m, 2H), 1.79 (t, ./ 8,1 Hz, 3H), 1.72-1.61 (m, IH), 1.56 (d, ./ 7.1 Hz, 3H). MS (ESI, +ve ion) mz 585.1 (M+H) ⁺ .

EXAMPLE 743. (1 S,3'R,6 ^, R,7 ^, S,9 ^, Z,12 ^, R)~6"CHLORO-7 ^! ~HYDROXY-12 ^, - METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]

DIAZATE RACYCLO[14.7.2.0 ³ '* 0 ³⁹ - ²⁴ ]PENTACOSA[9,16,18,24]TETRAEN]- 15'-QNE 13', 13 '-DIOXIDE

The title compound was synthesized as described for Example 742, Step 2. (lS,3¾,6'R,7 ^! S,9¾,12¾)-6-chloro-7'-hydroxy

spiro[naphthalene-l,22'-[20]oxa[.13]thia[l,.14]diazatetra cyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[9,16,18,24]tetraen]-15'-one 13',13'~dioxide was obtained as the second during and major isomer. ¾ NMR (500MHz, CDCh) δ 10.76 (br s, IH), 7.60 (d, ./ K.3 Hz, IH), 7.50 (d, ./ 7.8 Hz, IH), 7.45 - 7.36 (m, IH), 7.15 (dd, ./ 2.2.8.6 Hz, ill).7.10 (d, ./ 2.2 Hz, IH), 6,99 (d, ,/ 8.3 Hz, IH), 5.67 (br s, IH), 5.39 (br s, 1H),4.31 id../ 1 i / !!/. IH), 4.14 (d, ,7=11.7 Hz, H), 4.06 - 3.97 (m, IH), 3.77 (br s, IH), 3.61 (br s, IH), 3.45 - 3.35 (m, IH), 3.08 (d, ./ 1-1.9 Hz, IH), 3.04 - 2,87 ( m. 3H), 2.76 (t, J=6.0 Hz, 2H), 2.68 - 2,48 (m, 2H), 2.35 (d, ,/ 6 8 Hz, 2H), 1.94 - 1.84 (m, 2H), 1,83 - 1.67 (m, 5H), 1.62 (d, ,7=7, 1 Hz, 3H), 1.57 - 1,45 (m, 2H). MS (ESI, +ve ion) m/z 585.1 (M+H) ⁴ .

EXAMPLE 744. (IS^'R^'R 'S^^^'Sj-e-CHLORO^'-HYDROXY-n'- METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO |NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1 ,14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ² ]PENTACOSA[9,16,18,24]TETRAENj- 15'-ONE 13',13'-DI()XIDE

STEP 1 : (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT-3-EN ^' -l YL)CYCLOBUTYL)METHYL)-N-((S)-PENT-4-EN-2-YLSULFONYL)-

3',4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][ l,410XAZEPINE- APHTH ALEM ΕΊ -7 -C ARB OXAMIDE

The title compound was synthesized from (S)-6'~chloro~5~(((l R,2R)~2~ ((S)-l-hydrox 'but-3-en-l-yl)c 'clobutyl)me1hyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiroj benzoj bj [l,4|oxazepine-3, -naphthalene]-7-carboxylic acid (intermediate AA13A; 15 mg, 0.031 mmol) and (S)-pent-4-ene-2-sulfonamide (intermediate EE172; 5.6 mg, 0.037 mmol) following the procedure described for Example 719, Step 2, Step 1. Purification of the crude material provided (S)-6'-chloro-5- (((lR,2R)-2-((S)-l-hydroxybut-3-en-l-yl)cyclobutyl)me l)-N-((S)-pmt-4-en- ylsulfonyl)-3^4,4^5-te1rahydro-2H,2 ^, H-spiro[benzo[b] [L4]oxazepine-3, - naphthalene]-7-carboxamide (19 mg, 0.031 mmol).

STEP 2. (lS,3'R,6'R,7¾,9 ^, Z,12 ^, S)-6-CHLORO-7 ^f -HYDROXY-12 ^, -METHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO

[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[9/16;i 8 ₅ 24]TETRAEN]-15'-ONE 13',13'~ DIOXIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l-hydroxybut-3-en-l-yl)cyclobut\'l)methyl)-N-((S)-pent- 4-en-2-ylsulfonyl)- 3 ^, ,4,4',5-tetrahydro-2H,2 ^, H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7- carboxamide (42.5 mg, 0.067 mmol) following the procedure described for Example 742, Step 2. Purification by chromatography through a 24 g ISCO column, eluting with 10 % to 20 % to 40% EtOAc (containing 0.3% AcOH) in hexanes over 90 min. followed by a second purification through a 12 g ISCO column, eluting with 0 % to 30% EtOAc (containing 0.3% AcOH) in hexanes provided (l S,3 ,6'R,7'S,9'Z,12^)-6-chIoro-7'½droxy-12'~niethyl-3,4-dihydro - 2H, 15'H-spiroj naphthalene- 1,22'- [20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ 0 ¹⁹ - ²⁴ ]

pentaeosa[9,16, 18,24 jtetraenj-15'-one I3',13'-dioxide as the first eluting isomer (13.4 mg, 0.023 mmol 34.3% yield). ^! H NMR (400MHz, CD2CI2) δ 10.31 (br s, I H), 7.65 (d, J=8.6 Hz, IH), 7.42 (dd, ./ 2.0. 8.4 Hz, IH), 7.37 (br s, IH), 7.15 (dd, .7=2.3, 8.6 Hz, IH), 7.10 (d, «/=2.2 Hz, IH), 6.98 (d, J=8,4 Hz, IH), 5.72 (dt, ./ 4.8. 10.7 Hz, IH), 5.44 (td, J=5.5, 10.6 Hz, IH), 4.27 (d, ./ I l l Hz, IH), 4.14 (d, J=11.9 Hz, I H), 3.69 - 3.54 (m, 21 1 ). 3.53 - 3.41 (m, 2H), 3.27 (br s, 2H), 2.75 (t, J=6.1 Hz, 3H), 2.71 - 2.58 (m, IH), 2.46 (br s, IH), 2,34 - 2.18 (m, 2H), 2.13 (br s, IH), 1.97 - 1.86 (ni, 3H), 1.85 - 1.74 (m, 4H), 1.67 (d, ./ 6. Hz, IH), 1.59 (d, ./ 7.0 Hz, 3H), 1.55 - 1.45 (m, I H). MS (ESI, +ve ion) m/z 585.1 (M+H) ⁺ . EXAMPLE 745. (lS,3'R,6 ^! R,7'S,9Έ,12 ^! S)-6-CHLORO-7'-HYDROXY-12 ^, - METHYL-3,4-DlHYDRO-2H;i5'H-SPlRO[NAPHraALE E-l,22'- [20]ΟΧΑ[13]ΤΉΙΑ[1,14]

DIAZATETRACYCLO[14,7.2.0 ^3/ \0 ¹⁹ - ² ]PENTACOSA[9,16,18,24]TETRAEN] 15'-ONE 13 I 3 '-DIOXIDE

The title compound was synthesized as described for Example 744, Step 2,

(lS,3'R,6 ,7 ^, S,9T,12 ^, S)-6-chloro-7 ^, -hydroxy-12'-methyl"3,4-dihydro-2H,l^ spiro[naphthalene-l,22 ^, H;20]oxa[13]thia|;i,14]diazaietracyclo 14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ] pentacosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide was obtained as the second eluting isomer (13.2 mg, 0.023 mmol 34.3% yield). 'HNMR (400MHz, CD2CI2) 59.92 (br s, IH), 7.67 (d, ,/ 8.6 Hz, IH), 7.49 (dd,■/ 2.2.8.4 Hz, IH), 7.15 (dd, ./ 2.3.8.4 Hz, IH), 7.10 (d, ,/ 23 Hz, IH), 6.98 (d, J=8.2 Hz, IH), 5,67 (ddd, ./ 4.7,, 8.8, 14,5 Hz, IH), 5.59 - 5.48 (m, IH), 4,26 (d, ./ I 1,7 Hz, IH), 4.13 id. J=11.9Hz, IH), 3.83 {id../ 4.9.6.7 Hz, IH), 3.76 - 3.65 (m, IH), 3.55 ·· 3.41 (m, 2H), 2.80 - 2.72 (m, 3H), 2.72 - 2.64 (m, IH), 2.52 - 2.38 (m, 3H), 2.31 (ddd, ,/ 48.8.4, 13.8 Hz, l).2.14 (td, ./ 6.3.13.9 Hz, ill).1.97 - 1.87 (m, 3H), 1.87 - 1.70 (m, 4H), 1.61 (d, J=7.0 Hz, 3H), 1.55 - 1.43 (m, 2H). MS (ESI, +ve ion) m/z 585.1 (M+H) ⁺ .

EXAMPLE 746. (lS^R-ffR^S^l^R e-CHLORO-l^-ETHYL-?'- HYDROXY-3,4-DIHYDRO-2H, 15'H-SP1R0[NAPHTHALENE-1,22'-

[ 20 |OXA[ 1 ΓΠ 1 , 14JDI AZA

TETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ jPENTACOSA[9,16,18,24]TETRAE ]-15'- ONE 13V13'-DIOXIDE

STEP 1 : (S)-6'-CHLORO-N-((R)-HEX-5-EN-3-YLSULFONYL)-5-(((lR,2R)-2- ((S)-l-HYDROXYBUT-3-EN-l -YL)CYCLOBU L)METHYL)- 3 ^f ,4,4',5~ TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3, 1 ^* - APHTHALENE] -7 -C ARB OXAM1DE

The title compound was synthesized from (S)-6'-chloro-5-(((l R,2R)-2-

((S)-l-hydroxybut-3-en-l-yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiro[benzo[b] l,4]oxazepine-3,r-naphthalene|-7-carboxylic acid (intermediate AA13A; 140 mg, 0.290 mmol) and (R)-hex-5-ene-3-sulfonamide (intermediate EE18; 85 mg, 0,523 mmol) following the procedure described for Example 719, Step 2, Step 1. Purification of the crude material provided (S)-6'-chloro-N-((R)- hex-5-en-3-ylsulfonyl)-5-(((lR,2R)-2-((S)-l -hydroxy but-3-en-l - yl)cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine- 3, -naphthalene]-7-carboxamide (150 mg, 0.239 mmol, 82 % yield). STEP 2. (1 S,3'R,6'R,7'S ^'E _^ ^' i-e-CHLO O-^'-ETH X^'-HY ^' D OXY ^' -S^- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]TH1A[ 1 , 14]DI AZA

TETRACYCLO|;l4.7.2.0 ^3■ ^0 ¹ - ²⁴ ]PENTACOSA[9,16,18,24]TET AEN]-15 ^, - ONE 13',13'-DIOXIDE The title compound was synthesized from (S)-6'-chloro-N-((R)-hex-5-en- 3-ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l-yl)cycl obutyl)methyl)-

3',4,4',5~tetraliydro-2H,2'H~spiro[benzo[bl[l,4]oxazepme- 3,l '-naphthalene j-7- carboxamide (150 mg, 0.239 mmol) following the procedure described for Example 742, Step 2. The crude material was subjected to a first purification by chromatography through a 24 g ISCO column, eluting with 10 % to 20 % to 40% EtOAc (containing 0.3% AcOH) in hexanes over 90 inin. The material thus obtained was further purified by reverse phase HPLC eluting with a gradient of 50-70-100% MeCN (containing 0.1% TFA) in water (containing 0.1% TFA) to provide (lS,3Ί ,6 ^, ,7'S,9Έ,12 ^, R)-6-chloro-12'-ethyl-7 ^! lydlΌ y-3,4-dlhydro- 2H,15'H-spiro[naphthalene-l,22'- 20]oxa[13]thia l,14] diazatetracyclo

[ 14,7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[9,16 ₅ 18,24]tetraen]-15"-one 13',13'-dioxide as the first eluting isomer. R NMR (500MHz, CD2CI2) δ 9.99 (br s, 1H), 7.71 (d, J=8.6 Hz, ill).7.36 (dd, ,/ 1.8.8.4 Hz, 1H), 7.16 (dd, ./ 2.4.8.6 Hz, III).7.09 (d, ,/ 2.2 Hz, ill).7.01 (br s, ill).6,97 id../ 8.3 Hz, 1H), 5.63 - 5.52 (m, 21 \) 4.19 (d, ./ 12.0 Hz, 1H), 4.12 (d, ,/ 120 Hz, ill).3.89 - 3.82 (m, 2H), 3,61 (d, J=14.4 Hz, IH), 3.58 - 3.50 (m, IH), 3.36 (d, J=13.9 Hz, IH), 3.02 - 2.91 (m, 1H), 2.84 - 2.69 (m, 2H), 2.62 - 2.56 (m, IH), 2.55 - 2.47 (m, IH), 2.41 - 2.26 (m, 2H), 2.21 - 2.09 (m. Ml).2,02 - 1.92 (m, 2H), 1.91 - 1,81 (m, 3H), 1,77 (t, ./ 8.3 Hz, 2H), 1,74 - 1.63 (m, 2H), 1.54 (t J=l 1.1 Hz, IH), 1.12 (t, J=7.5 Hz, 3H). MS (ESI, +ve ion) m/z 599.2 (M+H) ⁺ .

EXAMPLE 747. (lS,3¾,6'R,7'S,9 ^, Z,12 ^, S)-6-CHLORO-12'-ETHYL-7 ^! - HYDROXY-3,4-DIHYDRO-2H, 15'H-SP1R0[NAPHTHALENE-1,22'- [ 20 |OXA[ 1 ΓΠ 1 , 14JDI AZA

TETRACYCLO[14,7.2.0 ³ -^0 ⁱ⁹ - ²⁴ ]PENTACOSA[9,16,18,24]TETRAEN]-I5'- ONE 13V13'-DIOXIDE

STEP 1 : (S)-6 ^f -CHLORO-N-((R)-HEX-5-EN-3-YLSULFONYL)-5-(((lR,2R)-2- iiS )- I -i !Y DROXYBt ί · 3· !·:\ · I - Y ! . ·( ^' Y ( ^' \ OR I I Y f . )M I Ti IYI . )- 3Ά4'.

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOX AMIDE AND (S)-6"-CHLORO-N-((S)-HEX-5- EN-3-YLSULFONYL)-5-(((l R,2R)~2-((S)~ 1 -HYDROXYB UT-3 -EN - 1 - YL)CYCLOBUTYL)METHYL)- 3 ^! ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [1 ,4] OXAZEPTNE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE

The title compounds were synthesized from (S)-6'-chloi -5-(((lR,2R)-2-

((S)-l-hydroxybut-3-en-l-yl)cyclobut}4)me d)-3 ,4^5-tetrahydro-2H,2T^ spiro[benzo[b] [l,4]oxazepine-3, ^' l'-naphthalene]-7-carboxylic acid (intermediate AA13A; 224 nig, 0.465 mmol) and a racemic mixture of (R)-hex-5-ene-3- sulfonamide (intermediate EE 18) and (S)-hex-5-ene-3-sulfonamide (intermediate EE182) (167 mg, 1.02 mmol) following the procedure described for Example 1, Step 1. Purification of the crude material provided a mixture of (S)-6'-chloro-N- ((R)-hex-5-en-3-ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hydroxybut- 3-en-l- yl)cycIobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine- 3,r-naphthalene]-7-carboxamide and (S)-6'-chloro-N-((S)-hex-5-en-3-ylsulfonyl)- 5-(((lR,2R)-2-((S)-l-hydrox 'but-3-en-l-yl)cyclobutyl) methyl)- 3',4,4',5- tetTahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalen e]-7-carboxaraide

(235 mg, 0.375 mmol, 81% yield).

STEP 2. (lS,3 ^, R ₅ 6 ^, R,7 ^, S.9 ^, Z.12 ^, S)-6-CHLORO-12 ^, -ETHYL-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO

[14.7.2.0 - ⁶ .0 ^!9 - ²⁴ 1PENTACOSA[9,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE The title compound was synthesized from a mixture of (S)-6'-chloro-N-

((R)-hex-5-en-3-ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hydroxyb ut-3-en-l- yl)cyclobu d)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxa zepine- 3,r-naphthalene]-7-carboxamide and (S)-6'-chloro-N-((R)-hex-5-en-3- ylsulfonyl)-5-(((lR,2R)-2-((S)-l-hydroxybut-3-en-l-yl)cyclob utyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ I ,4]oxazepine-3, 1 '-naphthalene]-7- carboxamide (235 mg, 0.375 mmol) following the procedure described for Example 45, Step 2. The crade material was subjected to purification by chromatography through a 24 g ISCO column, eluting with 10 % to 20 % to 40% EtOAc (containing 0.3% AcOH) in hexanes over 60 min. to provide

(1 S,3 ^! R,6'R,7'S,9'Z, 12*S)-6-chloro- 12'-ethy -7'-hydroxy-3,4-dihydro-2H,l 5Ή- spiro [naphthalene- 1 ,22'- iioxaj I3|t ia| i. i4|dia/aielracveloj 14.7.20 ^;i '.0 ^|1!;, ipcniacosa|v 16. |8.24|!οί!;ιο n]-15'-one 13',13'-dioxide as the first eluting isomer. Ί1 NMR (400MHz, CD2CI2) δ 10.25 (br. s, 1H), 7.66 (d, J=8.4 Hz, ills.7.41 (dd, ./ 2.0.8.4 Hz, lH), 7.36 (br s, 1H), 7.15 (dd,■/ 2.2.8.5 Hz, 1H), 7.10 (d, ./ 2.3 Hz, ill).6.98 (d, ./ 8.4 Hz, ill).5,73 - 5.63 (m, ill).5.50 - 5.40 (m. 111).4,27 (d, ,/ ! 1.7 Hz, !!!).4.14 (d, ,/ 11 Hz, if!).3.65 (br s, 2H), 3,55 (br s, 1H), 3.52 - 3.43 (m, IH), 3.26 (br s, ill).3.20 - 3.10 (m. III).2.76 (t, ./ 6.2 Hz, 2H), 2.64 (br s, 3H), 2.49 (ttd, ./ 3.7. 7.5, 18.2 Hz, 2H), 2.23 (br s, 2H), 1.96 - 1,86 (m, 3H), 1.85 - 1.73 (m, 4H), 1.72 - 1.60 (m, 3H), 1.09 (t, ,7=7,4 Hz, 3H). MS (ESI, +ve ion) m/z 599.2 (M+H) ⁺ , EXAMPLE 748. (lS,3'R,6 ^, R,TS,9 ^, E,12 ^, S)-6-CHLORO-12 ^, -ETHYL-7'-

HYDROXY-3,4-DIHYDRO-2H ₅ 15Ή-SPIRO[NAPHTHALENE-l,22 ^, -

[20]OXA[13]THIA[1,14]DIAZA

TETR _! 4CYCLO[14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTACOSA[9,16,18,24]TETRAEN

ONE 13',13'-DTOXIDE

The title compound was synthesized as described for Example 747, Step 2, (lS,3¾,6'R,7^,9^I2'S)-6-chloro-12'-ethyl-7'½drox}'-3,4-dih ydro-2H,15'H- spirojnaphthal ene- 1 ,22 ^! -

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9,16,18,24]tetrae n]-15'-one 13',13'-dioxide was obtained as the second eluting isomer. ¾ NMR (400MHz, CD2CI2) δ 9.90 (br s, ill).7,67 (d, J=8.6 Hz, 1H), 7.48 (dd, «/=2.2, 8,4 Hz, 1H), 7.24 (br s, 1H), 7.15 (dd,■/ 2.3.8.4 Hz, lH), 7.09 (d, ./ 2.3 Hz, 1H), 6.98 (d, ./ 8.4 Hz, !!!).5.64 (ddd, ,/ 4.3.8.6, 14.7 Hz, 1H), 5.60 - 5.49 (m, 1H), 4.24 (d, ./ ! 1.5 Hz, 1H), 4.12 (d, 11.9 Hz, Hi).4.17 - 4.05 (rn, !!!}.3.86 - 3,77 (m, ill).3.58 - 3.36 (m, 3H), 2,82 - 2.67 (m, 3H), 2.50 - 2.36 (m, 3H), 2,35 - 2.22 (m, 2H), 2.18 - 2.07 (m, 2H), 1.97 - 1.87 (m, 3H), 1.86 - 1.71 (m, 4H), 1.66 - 1.55 (m, 2H), 1.54 - 1.44 (m, 1H), 1.09 (t,■/ 7.5 Hz, 3H). MS (ESI, +ve ion) m/z 599.2

\\\-U) .

EXAMPLE 749. (1 S,3'R,6'R,7'R, 12'R)-6-CHLORO-7'-HYDROXY-l 2'- METHYL~3,4~DIHYDRO~2IL 15'H-SPTRO [N APHTH ALENE- ! ,22'- [20]OXA[ 13]THI A[ 1 , 14] DIAZ A

TETRACYCLO[14.7.2.0 ³ " ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[16,18,24]TRIEN]-15 ^, -ONE

13 ^, ,13'-DIOXIDEOR(lS,3 ^! R,6 ^, R,7'R,12'S 6-CHLORO-7'-HYDROXY-12'- METHYL-3.4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]ΤΉΙ A[ 1 , 14]DI AZ ATETRAC YCLO

[14 .21 ⁾³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[16J.8,24]mrEN]-15'-ONE 13 I 3 '-DIOXIDE

STEP 1 : (S)-6'-CHLORO-5-(((lR,2R)-2-((R)-l-HYDROXYBUT-3-EN-l- YL)CYCLOBU L)METHYL)-N-((R)-PENT-4-EN-2-YLSULFONYL)- 3 ',4 ,4', 5 -TETRAHYDRO-2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 ^* - NAPHTHALENE ] -7 -C ARB OX AMI D E AND (S)-6'-CHLORO-5-(((l R,2R)-2- ((R)-l-HYDROXYBUT-3-EN-l -YL)CYCLOBUTYL)METHYL)-N-((S)-PENT- 4-EN-2-YLSULFONYL)-3',4,4' ₅ 5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B j [ 1 ,4] OXAZEPlNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((R^I -hydroxybut-S-en-l-y cj lobuty methylJ-S'^^'^-tetrahydro^H^'H- spiro [benzo [b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid (Intermediate AA13B: 160 mg, 0.332 mmol) and a racemic mixture of (R)-pent-4-ene-2- sulfonamide (intermediate EE 17) and (S)-pent-4-ene-2-sulfonamide (intermediate EE 172) following the procedure described for Example 1, Step I , Purification of the crude material provided a mixture of (S)-6'-chloro-5-(((lR,2R)-2-((R)-l- hydroxv'but-3-en-l-yl)cyclobutyl)methyl)-N-((R)-pent-4-en-2- ylsulfonyl)-

3',4,4',5-tetrahydro-2H,2'H-spiro| benzo | b] [l , 4]oxazepine-3,l '-naphtha! ene]-7- caxboxamide and (S)-6'-chloro-5-(((IR,2R)-2-((R)-l-hydroxybut-3-en-I - yl)c> lobu1yl)methyl)-N-((S)-pent-4-en-2-ylsulfonyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxamide (130 mg, 0.212 m oi, 63.9% yield).

STEP 2. (1 S,3'R,6'R,7'R, 9'E ₅ 12'R)-6-CHLORO-7'-HYDROXY-12 ^! -ME ^' raYL-

3,4"01ΗΥΟίΙΟ-2Η,15Ή-8ΡΙ1 0[ΝΑΡΗΤΗΑΕΕΝΕ-1,22'-

[20]OXA[ 13]THIA[ 1 , 14]DI AZ ATETRAC YCLO

[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[9/16;i 8 ₅ 24]TETRAEN]-15'-ONE 13',13'~ DIOXIDE AND (1 S,3'R,6'R,7'R, 9'Z,I2'R)-6-CHLQRQ-7'-HYDRQXY-12'- METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO |NAPHTHALENE- 1 ,22'- [20]OXA[13]THTA| 1 ,14 jDIAZATETRACYCLO

[14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[9,16,18,24]TETRAEN]"15'"ONE Β',Β'- DIOXIDE OR (1 S,3'R,6'R,7 ^* R, 9'E,12'S)-0-CHLOR()-7'-HYDROXY-12'- METHYL-3.4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[B]THIA[1,14]DIAZATETRACYCLO

[14.7.2.0 ³ · ⁶ .0 ^ί9 · ²⁴ ]ΡΕΝΤΑ€Ο8Α[9,16,18,24]ΊΈΊ^ ΕΝ]-Ι5'-ΟΝΕ Β',Β'- DIOXIDE AND (1S,3'R,6'R,7'R, 9 ^, Z,12 ^, S)-6-CHLORO-7'-HYDROXY-12'- METHYL~3,4~DIHYDRO~2H, 15'H-SPIRO [N APHTH ALENE- 1 ,22'- [20]OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO

[14.7.2.0 - ⁶ .0 ^!9 - ²⁴ 1PENTACOSA[9,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXTDE

The title compounds were synthesized from a mixture of (S)-6'~chloro-5" (((1 R,2R)-2-((R) -hydroxybut-3^

ylsulfonyl)-3 4,4 5-tetTahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r- naphthalene] -7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((R)-l-hydrox>'but- 3-en-l-yl)c^xlobut'l)methyl)-N-((S)-pent-4-en-2-ylsulfonyl)- 3',4,4 ^, ,5-tetrahydro- 2H,2'H-spiro[benzo[b] j 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide (130 mg, 0,212 mmol) following the procedure described for Example 748, Step 2.

Purification of the crude material provided a mixture of (1S,3'R,6'R,7'R,

9 ^, E,12 ^, R)-6-ch3oro-7'-hydroxy-12'-methyl-3,4-dihydro-2H,15 ^! H- spiro [naphthalene- 1 ,22'-[20] oxa[ 13 ]thia[ 1 , 14] diaza

and(lS,3'R,6 7 ^, R,9'Z,12 l)-6-chioro-7'-hydroxy-12 ^! -niethyi-3,4-dihydi - 2H, ! 5'H-spiro[naphthalene- 1 ,22'- [20]oxa[l 3]thia[l, 14]diazatetracyclo[14.7,2.0 ³ · ⁶ 0 ¹⁹ · ²⁴ ]

pentaeosa[9,16,18,24]tetraen]-15'-one 13*,13'-dioxide or (1S,3'R,6'R;7'R,9'E,12'S)- 6-cMoro-7'-hydroxy-12 ^, -memyl-3,4-dihydro-2H,15 ^, H-spiro|naphthalene-l,22'- [20] oxa[ 131 thi a[ 1 , 14] di aza

tetracyclo[14;7,2A) ³ - ⁶ i) ¹⁹ - ²⁴ ]pentacosa[9 ₅ 16/18,24]tetraen]-15'-on 13',13'-dioxide aiid(lS,3'R,6'R;7 ^, R,9'Z 2'S)-6-chloro-7'-hydroxy-12'-methyl-3,4-dihy

2H, ! 5'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]1hia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]

pentacosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide as the first eluting component (52.4 mg, 0.090 mmol, 42.2% yield). Further elution provided a mixture of (1 S,3'R,6'R,7'R,9'EJ 2 ^f R)-6-chloro-7'-hydroxy-i2'-methyl-3,4-dihydro- 2H,15'H-spiro[naphthalene-l,22'-[20]oxa[13]thia

[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ^!9 ' ²⁴ ]pentacosa[9,16,18,24]tetraen]-15'-oiie 13',13'-dioxide and (lS,3'R,6 ^, R,7'R,9'Z,12'R)-6-chloro-7'-hydiOxy-12'-methyl-3,4- dihy dro-2H, 15'H-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracycio[14.7.2.0 - ⁶ .0 ¹⁹ - ²⁴ ] pentacosa[9,16,18,24] tetraen]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'R,9'E,12'S)-6-chloro-7'-hydroxy- 12'-meihyl~3,4-dihy dro-2H, 15'H-spiro[naphtha] ene- 1 ,22'- [20] oxa[ 13]thia[ 1 , 14] diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[9, 16,18,24]tetraen]-15'-one 13',13'- dioxide and (1 S _s 3 ^, R,6 ^, R,7 ^, R,9 ^, Z,12 ^, S)-6-chloro-7 ^, -hydroxy-12 ^, -methyl-3,4- dihy dro-2H, 15'H-spiro[naphthalene- l,22'-[20]oxa[ 13 jthiaj 1 , 14 jdiaza

ietracycio[14 .2 ³ ' ⁶ .0 ¹⁹ - ² ]peniacosa [9J 6, i 8,24]ietraen]-15'-one ! 3',13'-dioxide as the second eluting component (53.9 mg, 0.092 mmol, 43.4% yield).

STEP 3. (1 S,3'R,6¾,7'RJ 2'R)-6 ;HI RO-7' iYDROXY-12'-METI-iYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^s - [20]OXA[ 13]THI A[l , 14]DIAZ ATETRAC YCLO

[ 14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSAil6,18,24]TRlEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'R, 12'S)-6-CHLORO-7'-HYDROXY-12'-METHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |;20]()XA[ 13 |THIA[ l,14jDIAZATETRACYCLO

[14.7.2.0 ³ -^0 ^{i 9} - ²⁴ ]PENTACOSA[16,18,24]TRIEN]-15'-ONE 13',13'-DTOXIDE

The title compound was synthesized from a mixture of

(l S,3'R,6 ^, R ₅ 7 ^, R,9¾, 12 ^, R)-6-chloro-7 ^, ½droxy-12 ^, -me l-3,4-dihydro-2H ₅ 15 ^, H- spiro [naphthalene- 1 ,22'- [20] oxa[ 13] thia

[ l,14]diazatetracyclo[ 14.7.2,() ³ ' ⁶ .0 ^!9 ' ²⁴ ]pentacosa[9,16,18,24]tetraen] 5'-one

13', 13'-dioxide and il S^^R ^^l ^RJ-e-c loro^^drox -i y-meth l-S^- dihy dro-2H, 15'H-spiro [naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ] pentacosa[9,16,18,24] tetraen]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'R,9 ^, E,12 ^, S)-6-chloro-7 ^, -hydroxy- 12'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphtha] ene- 1 ,22'-[20] oxa[ ! 3]thia[ 1 , 4] diazatetracyclo[14,7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ] pentacosa[9, 16,18,24]tetraen]-15'-one 13',13'- dioxide and (1 S _s 3 ^, R,6 ^, R _s 7 ^, R ₅ 9 ^, Z,12 ^, S)-6-chloro-7 ^, -hydroxy-12 ^, -methyl-3,4- dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'-[20]oxa[ 13 jthiaj 1,14]

diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ^39>24 ]pentacosa [9, 16, 18,24]tetraen] - 15'-one 13', 13 ^s - dioxide (Step 2, first eluting component: 26 mg, 0.044 mmol) following the procedure described for Example 84 providing (18,3¾,6¾,7¾,12Έ)-6-αίι1θΓθ-7'- hydroxy - 12'-methyl-3,4-dihy dro-2H, 15'H-spiro| naphthalene- 1 ,22'-[20 j oxaj 13 ]thia I ! J4jdia/aic!rae>c!oj 14.72 O ^;i' .ii ^{li, i} |pen[acosa i s . ! .2 |tricn i- ! '-ΟΠΟ 13',13'- dioxide or (I S,3'R,6 ^, R,7 ^, R,12 ^, S)-6-cMoro-7 ^, ½droxy-12 ^, -methyl-3 _s 4-dihydro- 2H,15'H-spiro[naphthalene-l,22 ^, - 20]oxa[13]thia l,14]diazatetracj ⁷ clo

5 [147.2^ ³ -« 0 ¹⁹ ' ²⁴ ]pentacosa[16,18 ₅ 24]trien]-15'-one 13',13'-dioxide. (23 mg, 0,039 mniol, 88% yield). ¾ NMR (400MHz, CD2CI2) δ 9.25 (br s, 1H), 7.73 (d, =8.6 Hz, III).7.35 (d l.■/ 2.2.8.2 Hz, 1H), 7.17 (dd, ./ 2.3.8.6 Hz, 1H), 7.13 (d,■/ 2.2 Hz, 111).7.09 (d, ,/ 23 Hz, ill).6.97 (d, J=8.2 Hz, IH), 4.15 - 4,07 (m, 2H), 3.97 - 3,88 (m, IH), 3.76 (d, .7=15.7 Hz, IH), 3.72 (br s, IH), 3.68 (d, J=15.1 Hz, ill).0 3.28 (d, J=13.9 Hz, IH), 3.21 (dd, J=8.0, 15.7 Hz, IH), 2.85 - 2.71 (m, 2H), 2.44 (quia ./ 7.8 Hz, IH), 2.39 - 2.27 Or, 2H), 2,13 - 2.01 (m, IH), 1.98 - 1.88 (m. Ml).1,87 - 1.78 (m, 2H), 1.77 - 1.58 (m, 5H), 1,52 (br s, 2H), 1.50 (d, ./ 70 Hz, 3H), 1.48 - 1.39 (m, 3H). MS (ESI, +ve ion) m/z 587.2 (M+H) ¹ . 5 EXAMPLE 750. (18,3'Κ,6Έ,7'Κ,12'8)-6-α-ΙΙ.Ο Ο-7'-ΗΥΓ)ΚΟΧΥ-ί2'- METHYL-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A| 1,14]

DIAZATETRACYCLO[14.7.2.0 ³ - ^f \0 ¹⁹ - ²⁴ ]PENTA(X)SA[16,18,24]TRJEN]-15'- ONE 13', 13 '-DIOXIDE OR (1 S,3'R,6'R,7'R, 12'R)-6-CHLORO-7"-HYDROXY-0 12'-METHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22 ^! - [20]OXA[ 13 ]THIA[ 1, 14JDIAZA

TETRACYCLO[14.7.2,0-^0 ¹ - ²⁴ ]PENTACOSA[16,18,24]TRIEN]-I5'-ONE 13V13'-DIOXIDE

The title compound was synthesized from a mixture of

(lS,3 ^, R,6'R,7 ^, R,9¾,12 ^, R)-6-chloro7 ^, ½droxy-12 ^, -me l-3,4-dihydro-2H,15 ^, H- spiro [naphthalene- 1 ,22'- [20] oxa[ 13] thia[l ,14]diazatetracyclo[147.2 '^0 ¹⁹ - ²⁴ ]pentacosa[9,16,18,24]tetraen]-15'-one 13V13'~dk>xide and (lS,:m,6'R,7'R,9'Z,12'R ^

dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [2()ioxa| 13jthia[ l, 14jdiazateiracycIo[14J.2X) ³ ^0 ^!9 ' ²⁴ i peniacosa

[9, 16,18,24]tetraen]-15'-one 13 ', 13 '-dioxide or (l S,3'R,6'R,7'R,9'E, 12'S)-6-chloro- 7'-hy droxy- 12'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]

diazatetracy clo[ 14,7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9, 6, 18,24]tetraen]-15"-one 13',13'- dioxide and (1 S,3'R,6'R,7'R,9'Z,12'S)-6-chloro-7'-hydroxy-12'-methyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

[2()ioxa| 13jthia[ l, 14jdiazatetracycIo[14J.2X) ³ - ⁶ .0 ^!9 ' ²⁴ |pentacosa

[9, 16,18,24]tetraen]-15'-one 13 ', 13 '-dioxide (Example 749, Step 2, the second eluting component; 26 mg, 0.044 mmol) following the procedure described for Example 84 providing (l S,3 ^, R,6 ^, R,7'R,12'S)-6-chloro-7'-hydroxy-12 ^, -methyl-3,4- dihydro~2iL 15H~spirojnaphthalene~l,22'-

15'-one 13',13 ^* -dioxide or (lS,3'R,6'R,7'R,12'R)-6-chloro-7'-hydiOxy-12'-methyl- 3,4-dihydro-2H, 15'H-spiro|naphthalene-l ,22'-

[20]oxa[13]thia[ l, 14]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa [16,18,24]trien]- 15'-one 13',13'-dioxide. (24.5 mg, 0.042 mmol, 94% yield). ¾ NMR (400MHz, CD2CI2) δ 8.14 (br s, Hi), 7.73 (d, J==8.4 Hz, H i ). 7.35 (d, J=2.0 Hz, 1H), 7.17 (dd, ./ 2.3. 8.6 Hz, 1H), 7.09 (d, ./ 2.2 Hz, 11 1 ). 6.96 (dd, ,/ 2 2. 8.0 Hz, i l l ). 6.92 (d, J=8.0 Hz, 1H), 4.10 (s, 2H), 4,08 - 4.02 (m, 1H), 3.97 (d, .7=15,7 Hz, IH), 3.68 (d, J=13.7 Hz, IH), 3.55 - 3.48 (m, IH), 3.21 (d, J=14.3 Hz, IH), 3.04 (dd, J=8.2, 15.5 Hz, IH), 2.84 - 2.68 (m, 2H), 2.51 - 2.37 (m, 2H), 2.04 - 1.88 (m, 4H), 1.88 - 1 ,74 (m, 3H), 1.66 - 1 .56 (rn, 3H), 1.53 (br s, 3H), 1.48 (d, J=7.0 Hz, 3H), 1.45 - 1.31 (rn, 4H). MS (ESI, +ve ion) mJz 587.2 (M+H) ⁺ .

EXAMPLE 751. (1 S,3'R,6'R, 12'R)-6-CHLORO-12'-METHYL-3,4-DIHYDRO- 2H,7'H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

20]OXA[ 13]THI A[l , 14]DIAZ ATETRAC YCLO [14 .2.0 ³ -^0 ^{i 9} - ²⁴ ]PENTACOSA|;i 6/i8,24]TRIEN]-7^15 ^f -DIONE 13',13'- DIOXIDE OR (l S,3'R,6'R,12'S)-6-CHLORO-12'-METHYL-3,4-DIHYDRO- 2Η,7Ή, 15'H-SP1R0[NAPHTHALENE-1 ,22'- [ 20 |OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO

[ 14,7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOS A[ 16, 18,24]TRIEN]-7' ₅ 15 ^* -DIONE 13', 13 ^* - DIOXIDE

A flask charged with dimethyl sulfoxide (0.044 mL, 0.622 mrnol) in CH2CI2 (0.777 mL) was cooled to -78 °C. Oxalyl chloride, (2.0 M solution in dichloromethane; 0.155 mL, 0.311 mrnol) was then added dropwise and the resulting mixture was stirred at -78 °C for 30 min. A solution of

(lS,31 ,6 ^, R,7¾,12'R 6~chloro-7 ^! ~hydroxy-12'-methyi-3,4 lihydro-2H,15'H~ spiro I naphthalene- 1 ,22'-

15'-one 13',13 ^* -dioxide or (lS,3 ^, R,6'R,7 ^, R,12 ^, S)-6-chloro-7 ^, -hydroxy-12 ^, -met-iyl- 3,4-dihydro-2H, 15'H-spiro|naphthalene-l ,22'- [20]oxa[13]thia[ l, 14]diazatetracyclo [14,7.2,0 ^3/l .0 ¹⁹ - ² ]per!tacosa[16, 18,24]irien]- 15 -one 13', 13'-dioxide (Example 749; 36.5 mg, 0.062 mmol) in CH2CI2 (~ 0.3 mL) was then added dropwise and the mixture was stirred at -78 °C for 30 min. Triethylamine (0.173 mL, 1.243 mmol) was then added dropwise and the mixture was stirred at -78 °C for 10 min then all owed to reach ambient temperature. After 20 min. the mixture was quenched by the addition of water (1 mL) and extracted with EtOAc (added IN HCl and brine to the aqueous layer) and the organic phase was dried over MgSC¼ and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 0 % to 45 % EtOAc (containing 0.3% AcOH)/hexanes, to provide (1 S,3'R,6'R,I2'R)-6-chloro- 12'~meihyl-3,4-dihydro-2H,7'H, 15Ή- spiro [naphthalene- 1 ,22'- [20]oxa[13]lhia[U4]diazate1xacyclo^

7',15'-dione 13',13'-dioxide or (lS,3'R,6'R,12 ^! S)-6-chIoro-12'-niethyI-3,4-dihydro- 2H,7'H,15'H~spiro [naphthalene-1,22'-

[20]oxa[l 3]thia[l, 14]diazatetra yclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa [16,18,24]trien]- 7',15'-dione 13', 13 '-dioxide (21 mg, 0.036 mmol, 57.7% yield). ^l NMR

(400MHz, CD ₂ C] ₂ ) δ 8.27 (br s, 111).7,72 (d, J=8.4 Hz, !!!).7.18 (dd, ,/ 2.4.8,5 Hz, 1H), 7.10 (d, ,/ 23 Hz, 1H), 7.01 - 6.97 (m, 2H), 6,93 id.../ 8.6 Hz, 1H), 4.15 - 4.04 (m, 2H), 3.94 - 3.87 (m, 1H), 3.83 (dd, J=4.7, 15.7 Hz, IH), 3.74 (d, J=14.5 Hz, ill .3.27 id../ 14.5 Hz, IH), 3.15 (dd, ./ 7M 15.5 Hz, IH), 3.10 (dd, ./ 9,0. 18,2 Hz, IH), 2,88 - 2,69 (m, l).2.44 - 2.24 (m, 2H), 2.10 (dd, J=8,6, 17.6 Hz, IH), 2.05 - 1.96 (m, 3H), 1.96 - 1.86 (m, 2H), 1.85 - 1.74 (m, 3H), 1.68 - 1.57 (m, 2H), 1.56 - 1.50 ins.2H), 1.48 (d, ,/ 7.0 Hz, 311).1.45 - 1.39 (m, IH). MS (ESI, + ve ion) m/z 585.2 (Μ-ίΉ) ⁺ ,

EXAMPLE 752. (lS,3 ^, R,6 ^, R,7 ^, S,12 ^, S)-6-CHLORO-7'-HYDROXY-12 ^, -(l-

METHYLETHYL)-3,4-DIHYDR0-2H,15'H-SPIR()|;NAPHTHALENE-1,22 '- [20]OXA[13]ΤΗΐΑ[1 ,14]DIAZA

TETRACYCLO[14.7.2.0 ³ " ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA[16,18,24]TRIEN]-15 ^, -ONE

13',13'-DIOXIDE OR (1 S,3'R,6 ^, R,7'S,12 ^, R)-6-CHLORO-7'-HYDROXY-12'-(l- METHYLETHYL)-3,4-DIIWDRO-2il,!5'H-SPIRO[NAPHTI-IALENE-l,22 ^f - [20]OXA[ 13]THI A[ 1 , 14JDIAZA

TETiL CYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]l TACOSA[16,18,24]TiIEN]-15'-O E 13',13'-DIOXIDE

STEP i : N,N-BIS(4-METHOXYBENZYL)-2-METHYLPROPANE-.l -

SULFONAMIDE

To a solution of bis(4-methoxybenzyl)amine (Intermediate EE11 ; 1.550 g, 6.02 mmol) and triethylamine (2.93 ml, 21.08 mmol) in CH2CI2 (30.1 ml) cooled to 0 °C was added isobutanesulfonyl chloride (Sigma Aldrich; 0.786 ml, 6.02 mmol) dropwise over 5 minutes. The cloudy mixture was stirred at 0 °C for 1 h. TLC (50% EtOAc in hexanes) showed complete loss of both starting material and formation of a new product (LC/MS analysis was consistent with the desired product). The mixture was then diluted with CH2CI2 and washed twice with brine. The aqueous phase was back extracted once with EtOAc and the combined organics were then dried o ver MgS04 and concentrated. The crude orange oil was purified by chromatography through a column (40 g), eluting with a gradient of 0 % to 20 % to 60 % EtOAc in hexane, to provide N,N-bis(4-methoxybenzyl)-2- methylpropane-1 -sulfonamide (1.563 g, 4.14 mmol, 68.7 % yield) as a white solid.

STEP 2: (S)-N,N-BIS(4-METHOXYBENZYL)-2-METHYLHEX-5-E E-3- SULFONAMIDE AND (R)-N,N-BIS(4-METHOXYBENZYL)-2- METHYLHEX-5 -ENE-3 -SULFONAMIDE

N,N-bis(4-methoxybenzy])-2-methylpropane-l -sulfonamide (1560 mg, 4.13 mmol) was azeotroped in PhMe under vacuum for 2 h, then, under Ar, THF was added and the solution was cooled to -78 ° C. Butyllithium solution (2.5 M in hexanes; 1.984 mL, 4.96 mmol) was then added and the mixture was stirred at -78 ° C for 60 min. In a separate flask, a solution of ally 1 iodide (0.761 mL, 8.26 mmol) in THF (8 mL) was cooled to -78 °C. To this solution was added the light red anion solution slowly. After 30 min. the mixture was quenched with sat. NH4CI, allowed to reach ambient temperatui'e and extracted with EtOAc, dried over MgS04 and concentrated. The orange crude oil was purified on a 40 g ISCO GOLD column eluting with a gradient of 5-10% EtOAc in hexanes to provide an inseparable mixture of (S)-N,N-bis(4-methoxybenz l)-2-methylhex-5-ene-3- sulfonamide and (R)-N,N-bis(4-methoxybenzyl)-2-methylhex-5-ene-3- sulfonamide (1.26 g, 3.02 mmol, 73.0 % yield).

STEP 3: (S)-2-METHYLHEX-5-ENE-3-SULFONAMIDE AND (R)-2- METHYLHEX-5-ENE-3-SULFON AMIDE

The title compounds were synthesized from (S)-N,N-bis(4- methoxybenzyl)-2-me1hylhex-5-ene-3-sulfonamide and (R)-N,N-bis(4- methoxybenzyl)-2-methylhex-5-ene-3-sulfonamide (630 mg, 1.51 mmol) following the procedure described for Example 58, Step 2 providing (S)-2- methylhex-5-ene-3-sulfonamide and (R)-2-methylhex-5-ene-3-sulfonamide (236 mg, 1.33 mmol, 88% yield).

STEP 4: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT-3-EN-l- YL)CYCLOBUTYL)METHYL)-N-(((R)-2-METHYLHEX-5-EN-3-

YL)SULFONYL)-3 ^f ,4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE AND (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT-

3-EN-l-YL)CYCLOBUTYL)METHYL)-N-(((S)-2-METHYLHEX-5-EN-3-

YL)SULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO B j [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l-hy<_roxybut-3-en-l-yl)cydob^

spirojbenzojb] [ 1 ,4] oxazepine-3, 1 '-naphthalene]-7-carboxylic acid (Intermediate AA13 A; 107 mg, 0,222 mmol) and a racemic mixture of (S)-2-methylhex-5-ene- 3-sulfonamide and (R)-2-methylhex-5-ene-3-sulfonamide (136 mg, 0.767 mmol) following the procedure described for Example 1, Step 1. Purification of the crude material provided a mixture of (S)-6'-chloro-5-(((l.R,2R)-2-((S)-l-hydroxybut-3- en-l-yl)c lobutyl)methyl)-N-(((U)-2-methylhex-5-en-3-yl)sulfonyl)-3 ^, ,4,4 ^, ,5- tetrahydro-2H,2H-spiro benzo b][ l,4]oxazepine-3,r-naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((l R,2R)-2-((S)-1 iydroxybut-3-en- i-yl)cyclobuiy]) N-(((S)-2-methyihex-5-en-3-yl)sulfonyl)-3 ^f ,4,4',5-tetrahydro-2H,2 ^f H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxamide (29 mg, 0.045 mmol, 20.4 % yield).

STEP 5. (l S,3 ^, R,6'R,7 ^, S,9E,12'R 6-CHLORO-7'-HYDROXY-12'-(l- METHYLETHYL)-3,4-DIHYDRO-2H, 15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THI A[ 1 , 14]DI AZ A

TETRACYCLO[14.7.2,0 ³ -^0 ¹⁹ - ²⁴ ]I TACOSA[9,16,18,24]TETRAEN]-15'- ONE 13',13'"DIOXIDE AND ((l S,3'R,6 ^! R,7'S,9Z,12'R)"6-CHLORO-7 ^! "

HYDROXY- 12'-( 1 -METHYLETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO [ APHTHALENE- 1 ,22'- [20] OXA[ 13]

THLA[i;i4]DIAZATETRACYCLO[14 .2X) ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[9,16,18,24]T ETRAEN]-15'-ONE 13',13 ^! ~D10X1DE OR (lS^'R^'R 'S^lTS^-CHLORO- 7'-HYDROXY- 12'-( 1 -METHYLETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-1,22"-[20]OXA[13]

TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ ' ²⁴ jPENTACOSA[9,16,18,24]T ETRAENj-15'-ONE 13 ^! ,13'-DIOXIDE AND (lS,3'R,0'R,7'S,9Z,12'S)-6- CHLORO-7'-HYDROXY- 12 ^* -(1 -METHYLETHYL)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-1 ,22 ^! ~[20]OXA[13]

THIA[l/14]DIAZATET]^ACYCLO[147.2 ³ -^0 ¹⁹ ^ ⁴ ]PE TACOSA[9;i6,18,24]T ETRAEN] - 1 S'-ONE 13', 13'-DIOXIDE

The title compounds were synthesized from a mixture of ((S)-6'~chloro-5" (((l R,2R)-2-((S)-l-hydroxyhut-3-en-l-yl)cyclobulyl)methyl)-N-((( R)-2- methylhex-5-en-3-yl)su]fonyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepme-3 , Γ-naphthal ene] -7-carboxamide and (S)-6'-chl oro- 5-(((lR,2R)-2-((S)-l-hydrox 'but-3-en-l-yl)cyclobutyl)methyl)-N-(((S)-2- methylhex-5-en-3-yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxamide (29 mg, 0.045 mmol) following the procedure described for Example 742, Step 2. Purification of the crude material provided a mixture of (lS,3'R,6'R,7'S,9E, 12'R)-6-chloro-7'- hydro y-12 ^, -(l-meth leth l)-3,4-dihydro-2H,15Ή-s iro[naph1halene-.l,22 ^, -

[9,16,18,24]tetraen]-15'-one 13U3'-dioxide and (lS,3'R,0'R.7'S,9Z,12'R)-6- choro-7'-hydrox -12'-(l-me le l)-3,4-dihydΓO-2H,15Ή-s ifo[na hthalene- l,22'-[20]oxa[l 3]thiaj 1.14]diaza

tetracyclo[14.7.2.0 ' ⁶ .0 ⁱ⁹ - ^2,, ]pentacosa[9,16,18,24]tetraenj-15'-one 13',13'-dioxide or (lS,3 ^, R,6'R7'S,9E 2'S)-6-chIoro-7 ^! -hydroxy-12'-(l-met ylethyl)-3,4-d 2H, 15'H-spiro[naphthalene- 1 ,22'-

[9,16,18,24]tetraen]-15'-one 13U3'-dioxide and (lS^'R.e'R.rS^Z ^SVe- chloro-7'-hydroxy-12Hl-methylethyl^

l,22'-[20]oxa[l 3]thia| 1.14]diaza

ietracydo[14.7.2,0 ³ ^0 ¹⁹ ' ² ' ⁱ ]pentacosa[9/16J8,24]teiraen]-15'-one 13',13'-dioxide as the first eluting component (12 mg, 0.020 mmol, 43.3 % yield). Further elution provided a mixture of 18,3¾,6¾,7'8,9Ε,12¾)-6-ο1ι1θΓθ-7'-1> ΐΓθχ}'-12'-(1- methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]lhia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa

[9,16,18,24jtetraenj-15'-one 13 3 ^! -dioxide and ((lS,3'R,0'R.7'S,9Z,12 ^! R)-6- chloro-7'-hydroxy-12 l-methylethy

l,22'-[20]oxa[13]thia[l .14]diaza

tetrac clotMJ^.O'^O'-^l entacosaigje S^itetraenl-lS'-one 13',13 ^! -dioxide or (lS,3¾,6¾,7'S,9E,12'S)-6-chiorc 7'¾lro^^^

2H, 15'H-spiro[naphthalene- 1 ,22'~

[20]oxa[13]lhia[l 4]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa

[9,16,18,24;|tetraen ^' |-15'-one 13',13'-dioxide and (lS,3'R,0'R.7'S,9Z,12 ^! S)-6- chloro-7'-hydroxy-12'-(l-methylethy^

L22'-[20]oxa[]3]thia[lJ4]

(Uazatetracyclo[14J.2I ⁾³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[9,16,18,24]tetraen]-15'-one 13',13'- dioxide as the second eluting component (14 mg, 0.023 mmol, 50.5 % yield). STEP 6. (18,3¾,6'Κ,7'8,12'8)-6-α-ίΙ.Ο Ο-7'-ΗΥΒΚΟΧΥ-12'-(1-

METHYLEΊΉYL 3,4 ^1ΉYDRO-2H, L Ή-SPIRO[NAl HALENE,-l,22 ^ί -

[20]OXA[13]TH1A[1,14]D1AZA

TETR,4CYCLO[ 14.7.2.0 ³ - ⁶ .0 ^l9 - ²⁴ jPENTACOSA[16,18,24jTRlEN]-15'-ONE 13 ^* , 13'-DIOXIDE OR (lS ⁱ R,6'R,7'S, 12'R)-6-CHLORO-7'-HYDROXY-r2'-(l- METHYLETHYL)-3,4-DlHYDRO-2H,15 ^, H-SPlRO[NAPHTHALENE~L22'- [20]OXA[ 13]Tffl A[ 1 , 14JDIAZ A

TETRACYTLO[14 /2 -^0 ¹ - ²⁴ ]PENTACOSA[16J 8,24]TRiEN]-15'-ONE 13V13'-DIOXIDE

The title compound was synthesized from a mixture of

(lS,3 ^, R,6 ^, R,7 ^, S,9E 2 ^, R)-6-(^oro-7 ^, ½drox>'-12 ^, -(l-me lelhyl)-3 _s 4-d (iro- 2H, 15'H-spiro| naphthalene- 1,22'- [20]oxa[13]ftia[l, 14]diazatefra<yd

n]-15'-one 13',13'-dioxide and (18,3¾,6¾,7'8,9Ζ,12ΊΙ)-6-οΜθΓθ-7'^ ^Γθχν-12 ^! "

(l-methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,2 2'-

[20] oxa[ 131 thi a[ 1 , 14] diazatetracy clo

[14 .21 ⁾³ - ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa[9,16,18,24]tetraen]-15 ^! ~one 13 ^f ,13'-dioxide or

(lS,3¾,6 ^, R,7'S,9E,12'S)-6-cMoro-7 ^, ½droxy-12 ^, l-methylethyi)-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14;7,2.0 ³ - ⁶ i) ^{! 9} ' ²⁴ ]pentacosa

[9,16,18,24]tetraen]-15 ^* -one 13 I 3 '-dioxide and (lS,3 ^* R,6'R,7 ^! S,9Z,12'S)-6- cMoro-7'-hydroxy-12'-(l-methylethyl)-3,4-dihydro-2H,15'H-spi ro[naphthalene- 1.22'-! 201 oxa[ 13 ] thia[ 1 , 14]diaza

tetracyclo[14.7,2.0 ³ - ⁶ .0 ^{! 9} -¾ 13', i3'-dioxide (Step 5, first eluting component; 12 mg, 0.020 mmol) following the procedure described for Example 84 providing (l S,3'R,6'R,7'S,12'S)-6-chloro-7'-hydroxy- 12'-(l-methylethyl)-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[U4]diazatetnK^

15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,12'R)-6-chloro-7'-hydi xy-12'-(l - methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- 120 ! xiij I |thia| U 4 |di«/a tetracv oi 14.7 2.ϋ ^{; ί} '.0 ^{'' n} j pen!aco a| i J 8.24 | inen i- 15'-one 13',13'-dioxide (7.8 mg, 0.013 mmol, 64.8 % yield). ¾ NMR (400MHz, CD2CI2) δ 9.12 (br s, IH), 7.68 (d, ./ 8.4 Hz, 1H), 7.22 (s, 1H), 7.16 (app. dd, ,/ 2 4. 8.5 Hz, 2H), 7,09 (d, ./ 2.3 Hz, IH), 6.94 (d, ,/ 8.2 Hz, IH), 4.18 - 4.09 (ra, 2H), 3.75 - 3.67 (m, 2H), 3.61 (d, J=14.3 Hz, IH), 3.35 (d, J=13.7 Hz, IH), 3.34 - 3.26 (m, IH), 2.82 - 2.72 (m, 2H), 2.65 (did, ./ 3.6. 6.9, 13.9 Hz, IH), 2.43 - 2.32 (m, 2H), 1 ,98 - 1.89 (m, 3H), 1 .89 - 1.68 (m, 5H), 1 ,63 - 1.50 (m, 6H), 1 .47 - 1.32 (m, 4H), 1.13 (d, J=7.0 Hz, 3H), 1.09 (d, .7=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 615.2 (M+H) ⁺ .

EXAMPLE 753, (1 S,3'R,6 ^f R,7'S,12'R)-6-CHLORO-7 ^f -HYDROXY-12'-(l- METHYLETHYL)~3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE~l,22'- [20]OXA[ 13 |THIA[ 1, 14JDIAZA

TETRACYTLO[! 4.7.2,0-^0 ¹ - ²⁴ ]PENTACOSA[16,18,24]TRIEN]-I5'-ONE

13V13'-DIOXIDE OR (1 S,3'R,6 ^! R,7'S,12 ^! S)-6~CHLORO-7'-HYDROXY -12'-(1- METHYLETHYL)-3,4-DIHYDRO -2H,15H-SPIRO[NAPHTHALENE-l,22'- [ 20] OXA[ 1 ΓΠ 1 , 14]DI AZ ATETRAC YCLO

[ 14,7.2.0 ³ - ⁶ ,0 ¹⁹ - ²⁴ 1PENTACOSA[16, 18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was synthesized from a mixture of

(lS^^e'R.T'S^^n^-e-chloro-T'-hydro y- '-il-melhyle^ -S^-djhydro- 2H, 15 ^! H-spiro[naphthalene- 1,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetra^

n]-15'-one 13',13'-dioxide and (lS,3'R,6'R,7'S,9Z,12'R)-6-chloiO-7'-hydroxy-12'-

(l -methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14.7.2, 0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] pentacosa[9, 16, 18,24]tetraen]-l 5'-one 13 ',13 '-dioxide or (1 S,3'R,6'R,7'S,9E, I 2'S)-

6~chloro-7'-hydroxy-12'-(l~meih}'lethyl)~3,4-di

l,22'-[20]oxa[13]1hia

[ l,14]diazateiracyclo[ 14J.2 ) ³ ' ^{6 !9} ' ²⁴ ]pentacosa[9J 6,18,24]tetraen]-15'-one 13 ^* , 13'-dioxide and (l S,3'R,6 ^f R,7'S,9ZJ 2 ^f S)-6-chloro-7'-hydroxy-12'-(l- methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]peniacosa

[9,16, .18,24]tetraen]-.15'-one 13',13'-dioxide (Example 752, Step 5, the second eluting component; 14 mg, 0.023 mmol) following the procedure described for Example 84 providing (l S,3 ^, R,6 ^, R,7 ^, S,12'R)~6"Chloro-7' iydroxy-12'-(l- methylethy l)-3,4-dihydro-2H, 15'H-spiro|naphthalene-l ,22'- [20]oxa[13]thia[ l, 14]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa [16,18,24]trien]- 15'-one 13',13'-dioxide or (lS,3'R,6 ^, R,7'S,12 ^, S)-6-chloro-7 ^, -hydroxy-12'-(l- methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[ 3] thia[ 1 , i 4] diazatetracy clo [ 14.7 2.0 ^; ".0 ¹⁹ ' ²⁴ ]pentacosa[ 16, 1 8,24]trien]- 15'-one 13',13'-dioxide (8.5 mg, 0,014 mmol, 60.5 % yield). ¾ NMR (400MHz, CD2CI2) δ 9.67 - 9.31 (m, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.26 (dd, J=2.0, 8.2 Hz, 1H), 7.17 (dd, ./ 2.3. 8.4 Hz, I I I ). 7.09 (d, ,/ 2.2 Hz, 1H), 7.00 (s, 1H), 6.95 (d, ,/ H 2 Hz, 1 H), 4.13 - 4.03 (m, 2H), 3,79 (d, ,/ 1 5.3 Hz, IH), 3.73 - 3.69 (m, 1H), 3.66 (d, J=14.5 Hz, IH), 3.64 - 3.60 (m, IH), 3.25 (d, ./ 14.3 Hz, IH), 3.15 (dd, ./ 8. 1 . 15.4 Hz, I H), 2.84 - 2.71 (m, 21 I L 2.65 (did. ./ 4.0. 6.9, 13.9 Hz, IH), 2.31 - 2, 15 (m, 2H), 2.05 - 1 .95 (m, 2H), 1.94 - 1.88 (m, 3H), 1.87 - 1 .75 (m, 3H), 1.67 (dd, .7=8.2, 16.4 Hz, 2H), 1 ,59 (dd, J=9.4, 19.0 Hz, 2H), 1.54 - 1.36 (m, 5H), 1 , 15 (d, ./ 7.i ⁾ Hz, 3H), 1.10 (d, J=6.8 Hz, 3H). MS (ESI, +ve ion) m/z 615.3 (M+H) ⁺ .

EXAMPLE 754, (1 S,3'R,6'R,7'R, 12 ^, S)-6-CHLORO-7'-HYDROXY-12'-(l - METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]TH1A[ 1 , 14JDIAZ A

TETRACYCLO|;i4.7.2.0 ³ -^0 ^19>24 ]PENTACOSA[16J 8,24]TRiEN]-15'-ONE 13V13'-DIOXIDE OR (l S,;rR,6 ^! R,7'R, 12 ^, R)-6-CHLORO-7'-H DROXY-12'-(l- METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1 , 14]DI AZ A

TETRACYCLO[14 .2I ⁾³ -^0 ¹⁹ - ²⁴ ]1 TACOSA[16J 8,24]TRIEN]-15'-ONE 13',13'-DIQX1DE

STEP 1 : S)-6 ^* -CHLORO-5-(((lR,2R)-2-((R)-l -HYDROXYBUT-3-E -l -YL)

CYCLOBUTYL)METHYL)-N-(((R)-2-METHYLHEX-5-EN-3-

YL)SULFONYL)-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H.2 ^, H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , Γ -NAPHTHALENE] - 7-

CARBOXAMIDE AND (S)-6 ^! ~CHLORO-5-(((l R,2R)-2~((R)-l-

HYDROXYBUT-3-EN-l-YL)CYCLOBUTYL)MEraYL)-N-(((S)-2-

METHYLHEX-5-E -3-YL)SULFONYL)-3 4,4^5-TCmAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-

CARBOXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2-

((R)-l-hydroxybut-3-en-l-yl)cyclobutyl)methyl)-3',4,4',5- tetrahydro-2H,2'H- spiro[benzo[b] [l,4] oxazepine-3,r-naphthaIene]-7-carboxyiic acid (Intermediate AA13B; 100 mg, 0.207 mmol) and a racemic mixture of (S)-2-methylhex-5-ene- 3-sulfonamide and (R)-2-methylhex-5-ene-3 -sulfonamide (Example 752, Step 3; 99 mg, 0.560 mmol) following the procedure described for Example 719, Step 2, Step 1 . Purification of the crude material provided a mixture of (S)-6'-chloro-5- (((l R,2R)-2-((R)-l½droxybut-3-en-l -yl)cyclobutyl)methy])-N-(((R)-2- methylhex-5-en-3-yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide and (S)-6'-chloro- 5-((( 1 R,2R)-2-((R)- 1 -hydroxy but-3-en- 1 -yl)cy clobuty l)methyl)-N-(((S)-2- me1hylhex-5-en-3-yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2'H-sp iro[benzo[bl[l ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide (78 mg, 0, 122 mmol, 58.6 % yield).

STEP 2. (18,3¾,6'Κ,7' ,9Ε,12¾)-6-α-ΙΕΟ Ο-7'-ΗΥΟΚΟΧΥ-12'-(1 - METHYLETHYL)-3 ,4~D1HYDRQ~2H, 15 ^* H-SPIRO[N APHTHALENE- 1 ,22 ^s - [20] OXA[ 13 ] THI A[ 1 , 14] DIAZ A

TETRACYCLO[14J.2.0 ³ ' ⁶ .0 ⁱ⁹ ^ ⁴ jPENTrACOSA[9,16,18,24]TETRAEN]-15'- ONE 13 ^f ,I3'-DTOXIDE AND (1S,3'R,6'R,7'R,9Z,12'R)~6~CHL0R0~7'~

HYDROXY - 12'-( 1 -METH YLETHYL)-3 ,4-DIHYDRO-2H, 15Ή- SPI RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[ 1,14]DIAZATETRACYCLO[14.7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9,16, 18,24] TETR AEN] - 15 '-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ^, R,7 ^, R,9E _s 12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(l-METHYLETHYL)- S^-DIHYDRO^H.lS'H-SPIROINAPHTHALENE-l^^-

[20] OX A [13] THI A [ ! ,14] DI AZ ATETR A C YCLO [ 14.7.2, 0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] PENT ACO S A [9, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-D10XIDE AND

(lS,3'R,6'R,7'R,9Z,12'S)-6-CHLOR()-7'-HYDROXY-12'-(l-METHYLE THYL)- 3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE-! ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO [14.7,2.0 ³ · ⁶ 0 ¹⁹ · ²⁴ ]

PENTACOS A[9, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compounds were synthesized from a mixture of ((S)-6'-chloro-5- ((( 1 R,2R)-2-((R)- 1 -hy droxy but-3 - en- 1 -y l)cy clobuty l)methy l)-N-(((R)-2- methylhex-5-en-3-yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxamide and (S)-6'-chloro-

5- (((l R,2R)-2-((R)- 1 -hy droxy but-3-en- 1 -yl)c>'clobutyl)methyl)-N-(((S)-2- methylhex-5-en-3-yl)sulfonyl)-3',4,4',5-tetTahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxamide (78 mg, 0.122 mmol) following the procedure described for Example 742, Step 2. Purification of the crude material provided an E/Z mixture of isomers: (1S,3'R,6'R,7'R,9E,12'R)-

6- chloro-7'-hydroxy-l 2'-(l -methylethyl)-3,4-dihydro-2H, 15'H-spiro[naphthalene- L22'-[20]oxa[13]thia[l ,14]diazatetrac\'clo[14.7.2.0 - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa

[9 ₅ 16.18,24]tetraen]-15'-one 13 ^! J 3'-dioxide and ((lS,3 ^! R,6'R,7'R,9ZJ 2'R)-6- chloro-7'-hy droxy- 12'-(l-methylethyl)-3,4-dihydro-2H, 15'H-spiro[naphthalene- l,22'-[20]oxa[13]thia[l _: , 14]diaza

tetracycloI .T^.O^^ O^lpentacosa^l^lS^ltetraenl-lS'-one 13 ',13 '-dioxide or (l S,3'R,6 ^, R,7 ^, R,9E,12^)-6-chloro-7 ^, -hydrox5'-12 ^, -(l-methyIe i)-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa

[9,16, 18,24]tetraen]-15'-one 13 ',13 '-dioxide and (lS,3'R,6'R,7'R,9Z,12'S)-6- chloro-7'-hy droxy- 12'-(l-methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene- 1 ,22'-[20] oxa[ 13] thia[ 1 , 14] diazatetracyclo[14 .2 ³ 0 ¹⁹ ^ 13 ^* ,13'- dioxide as the first eluting component (30,7 mg, 0.050 mmol, 41.2 % yield). Further elution provided another E/Z mixture of isomers:

(lS,3'R,6'R,7'R,9E,12'R)-6-chforo-7'-hydroxy-12^

2H, 15'H-spiro[naphthalene- 1 ,22'-[20] oxa[ 13]thia[ 1,14] diazatetracy cl o

[14.7.2.0 ^,6 .0 ^l9 ' ²⁴ ]pentacosa [9,16,18,24]tetraen]-15'-one 13',13'-dioxide and (lS,3'R,6'R,7'R,9Z,12'R)-6-dilorQ-7'-hydroxy-12^^

2H, 15'H-spiro[naphthalene- 1 ,22'- [20] oxa[ 13] thi a[ 1 , 14] diaza

tetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide or (lS,3 ,6'R,7 l,9E,12^)-6-chloro-7 ^, ½droxy-12'-(l-methyiethyl)-3,4-dihydro- 2H, 15 Ή -spiro [naphthal ene- 1 , 22'- [20 ] oxaj 13 ]

ihia[l, 14]diazatetracyclo[14.7,2.0 ³ ' ⁶ .0 ³⁹ - ²⁴ ]pentacosa [9,16,18,24]tetraen]-I 5'-one 13',13'-dioxide and (lS,3'R,6 ^! R,7'R,9Z,12'S)-6-chloro-7'-hydroxy-12 ^* -(l- methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l ,14]diaza tetrac clo[ 14.7,2.0 ^3>6 .0 ^{Ϊ 9} ' ²⁴ ]

pentacosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide as the second eluting component (29.2 mg, 0.048 mmol, 39.1 % yield).

STEP 3. (1 S,3'R,6'R,7'R, 12'S)-6-CHLORO-7"-HYDROXY- 12'-(l - METHYLETHYL)-3,4-DlHYDRO-2H,15'H-SPlRO[NAPHTHALENE-l,22'- [20]OXA[ 13 |THIA[ 1, 14JDIAZA

TETRACYTLO[! 4.7.2,0 ³ -^0 ^19>24 ]PENTACOSA[16,18,24]TRiEN]-15'-ONE 1 y, 13'-DIOXIDE OR (1 S,3'R,6 ^! R,7'R, 12'R)-6-CHLORO-7'-HYDROXY- 12'-( 1 - METHYLETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'- [ 20 |OXA[ 13]THI A[ 1 ,14 |DIAZA

TETRACYCLO[14.7.2.0 ³ - ⁶ ,0 ^{i 9} - ²⁴ ]PENTACOSA[16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE

The title compound was synthesized from the first eluting component of example 754 step 2: (30.7 mg, 0.050 mmoi),a mixture of

(lS,3'R,6'R,7'R,9E,12'R)-6-diloro-7'-hydroxy-12 ^, -(l -methylethy3)-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'- [20] oxa[ 13] thi a[ 1 , 14] diazatetracy clo

[14 .21 ⁾³ -^0 ¹⁹ ' ²⁴ ]pentacosa[9, 16,18,24]ieiraen]-15 ^! ~one 13 ^s , 13 '-dioxide and (lS,3'R,6 ^, R 7'R,9Z,12'R)-6-chioro-7'½droxy-12 ^! -(l-methylethyl)-3,4-dihydro- 2H, 15'H-spiroj naphthalene- 1,22'- [20]oxa[ 13 ]thia[ 1 , 14] diazatetracy cioj 14.7, 2.0 ³ · ⁶ 0 ¹⁹ · ²⁴ ]

pentaeosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide or (1S,3'R,6 ^* R,7'R,9E,12'S)- 6-chloro-7'-hydroxy-12'-(l-inethylethyl)-3,4-dihydro-2H,15'H -spiro[naphthalene- l ,22'-[20]oxa[13]

tMa[l ,14]diazatetrac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[9,16,18,24]tetraen]-15'-one 13',13'-dioxide and (lS,3'R,6'R,7'R,9Z,12 ^* S)-6-chloro-7 ^* -hydroxy-12'-(l- methylethy l)-3,4-dihydro-2H, 15'H-spiro|naphthalene-l ,22'- [20]oxa[13]thia[ l, 14]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa

[9,16,18,24]tetraen]-15'-one 13', 13 '-dioxide following the procedure described for Example 84 providing (l S,3 ^, R,6'R,7'R,12'S)-6-chloro-7'-hydroxy-12 ^, -(l- methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-[20 ]oxa[13] thia[l ,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa [16, 18,24]trien]-15'-one

13',13'-dioxide or (1 S,3'R,6'R,7'R, 12'R)-6-chloro-7'-hydroxy-12'-(l -methylethyl)-

3 ,4-dihydro-2H, 15 Ή-spiro | naphthalene- 1 , 22'-

[20]oxa[ ! 3]thia[ l, 14]diazatetracyclo [14.7.2.0 ^3>6 .0 ¹⁹ - ²⁴ ]pentacosa [16, 18,24]trien]- 15'-one 13',13'-dioxide (26.4 mg, 0.043 mmol, 86 % yield). ¾ NMR (400MHz,

CD2CI2) δ 9.55 (br s, 1H), 7.72 (d,■/ H.4 Hz, H i ). 7.33 (dd, ./ 2. 1 . 8.3 Hz, i l l .

7.17 (dd, ,/ 2 3. 8.4 Hz, i l l ). 7,08 (app. t, ./ 2.6 Hz, 2H), 6.95 (d, ,/ 8 2 Hz, I I I ).

4.10 - 4.01 (m, 2H), 3,78 (d, J=15.3 Hz, 1H), 3.68 (d, «7=13.5 Hz, 1H), 3.71 - 3.62

(ni, 11 1 ). 3.56 - 3.50 (m, 1H), 3.22 (d, J=14.3 Hz, 1H), 3.13 (dd, ./ 7.2. 15.5 Hz, 1H), 2.84 - 2.68 { in. 2H), 2.50 (qd, ,/ 6.7. 13.5 Hz, i l l ). 2.43 - 2.30 { in. 2H), 2.10

- 1 .96 (rn, 2H), 1.95 - 1 ,75 (m, 6H), 1.73 - 1 .48 (m, 6H), 1.47 - 1.36 (m, 3H), 1.20

(d, .7=6.8 Hz, 3H), 1.10 (d, J=6,8 Hz, 3H). MS (ESI, +ve ion) m/z 615.2 (M+H) ⁺ .

EXAMPLE 755. ilS,3 ⁱ R,6'R,7'R,12'R)-6-CHLORO-7 ⁱ -HYDROXY-12'-(l- METHYLETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]D1AZA TETRACYCLO[14 /2 -^0 ¹ - ²⁴ ]PENTACOSA[16J8,24]TRiEN]-15'-ONE 13Vi3'-DIOXIDEOR(lS,3¾ VR7'R,12'S)-6-CHLORO-7'-HYDROXY-12 ^! -(l- METHYLETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [ 20]OXA[ 1 ΓΠ 1 ,14]DIAZA

TETRACYCLO[14.7.2.0 ³ ' ⁶ ,0 ⁱ⁹ ' ² ]PENTACOSA[16,18,24]TRIEN]-15'-ONE 13',13'-D10XIDE

The title corapoimd was synthesized from the second eluting coraponent of

Example 754, Step 2, (29.2 mg, 0.048 mmol), a mixture of

ilS,3*R,6'R,7 ^! R,9E,12'R)-0-ehioro-7'-hydiOxy

2H,15'H-spiro[naphthalene-l,22'-[20]oxa[13]thia[l,14]

diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[9,16,18,24]tetraen]-15'-one 13',13'- dioxide and (lS,3 l,61 ;7'R,9Z,121l)-6-chioiO-7'-hydroxy-12'~(l"methylethyl)" 3,4-dihydro-2H,15'H-spiro|naphthalene-l,22'- [20]oxa[ I 3 ]thia[ 1 , 14] diazatetracy clo[ 14.72.<r' 0 ^{! 9<24} ] pentacosa

[9 ₅ 16,18,24]tetraen]-15'-one l.T. I . -dioxide or { i S.3'R.iYR.7'R..9H.. ! 2'SK>-chioro- 7'-hy droxy- 12'-(l -methylethyl)-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]

diazatetracy clo[ 14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[9, 16, 18,24]tetraen]-l 5'-one 13', 13'- dioxideand (lS,3 l,61 ,7'R,9Z,12^)-6~chloro-7 ^! iydiOxy-12'-(l-methyletiiyi)- 3 ,4-dihydro-2H, 15 Ή-spiro | naphthalene- 1 ,22'- [20]oxa[ 13 ]thia[ 1 , I 4] diazatetracy clo[ 14.72.<r' 0 ^{] 9<24} ] pentacosa

[9,16,18,24]tetraen]-15'-one 13', 13 '-dioxide following the procedure described for Example 29 providing (lS,3*R,6'R,7 ^! R,12'R)-6-chioro-7 ^! -hydiOxy-12'-(l- methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- U |di !/aielracveioj 14.7.20 ^{; !'} .0 ^1;i 'Mpcniacosa 116.18.24|irieni- 15'-one 13',13'-dioxide or (iS,:rR,6'R,7'R,i2'S)-6-chloro-7'-hydroxy-12'-(l- methylethyl)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- 120 ! xiij i:?|thia| I.I4|di;i/a tetracv oi 14.72.0 ^;ί ',0 ^{!'' n} jpen!aco a| i ,.i8.24|irieni- 15 ^! -one 13' l3'-dioxide (26.3 mg, 0.043 mmol, 90 % yield). H NMR (400MHz, CD2CI2) δ 7.72 (d,■/ K.6 Hz, 1H), 7.33 (d, ,/ 1.8 Hz, 1H), 7.17 (dd, ./ 2.3.8.4 Hz, 1H), 7,09 (d, ,/ 2.3 Hz, Hi).6.96 (dd, 22.8,4 Hz, IH), 6.90 (d, ./ 8.2 Hz, ill). 4.14.4.03 (m, 2H), 3.94 - 3.84 (m, 2H), 3.69 (d, J=14.5 Hz, 1H), 3.24 (d, J=14.1 Hz, ill).3.28 - 3.20 (m, ill .3.04 (dd, ./ 6.1.15.5 Hz, Hi).2.83 - 2,68 (m, 2H), 2,63 (dtd, ./ 2.6.7,0, 14.0 Hz, ill).2.57 - 2,40 (m, 2H), 2.06 - 2,02 (m, IH), 1.95 - 1,78 (m, 5H), 1.76 - 1.69 (m, IH), 1.68 - 1,59 (m, 3H), 1.57 - 1.46 (m, IH), 1.44 ·· 1,34 (m, 311).1.31 (dd, J=5.7, 10.2 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H), 1.13 (d, ./ 7.0 Hz, 3H). MS (ESI, +ve ion) m/z 615.3 ! M l!)

EXAMPLE 756. (1S,3'R,6 ^! R,7'S,10 ^, E,12 ^, R)"6"CHLORO-12'"ETHYL~7 ^, ~

HYDROXY-3.4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THI A[ 1 , ! 4]DI AZ A

TETOACYCLO[14 .2 ³ '^0 ^19ί4 ]PENTACOSA[10,16 ₅ 18,24]TETRAEN]-15 ^, -

ONE 13',13'"D10X1DE

STEP 1. (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYPENT-4-EN-.l-YL)CYCLOBUTYL)METHYL)-3',4,4V

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,l

NAPHTHALENE] -7-CARBOXYLATE

To a solution of (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2- formylcyclobu1\'l)methyl)-3',4,4',5-tetrariydro-2H,2'H- spiro [benzo [b j [1,4] oxazepme-3 , -naphthalene] -7-carboxy late (Intermediate

AA11 A, step 20B; 200 mg, 0.403 mmol) in THF (4 mL) under Ar, cooled to -78 °C was added 3-butenylmagnesium bromide, (Sigma Aldrich; 0.5 M solution in tetrahydrofuran; 0.806 mL, 0.403 mmol). More reagent was added to drive the reaction as needed. The mixture was then quenched with sat. NH ₄ C1, allowed to reach ambient temperature and extracted with EtOAc, dried over MgS04 and concentrated. The crude material was absorbed onto a plug of sil ica gel and purified by chromatography (12 g 1SCO gold; 5-15% EtOAc in hexanes) to provide (S)-tert-butyl 6'-chloro-5-((( 1 R,2R)-2-((S)- 1 -hydroxypent-4-en- 1 - yl)cyclobut d)methyl)-3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine- 3,r-naphthalene]-7-carboxylate (55 mg, 0.10 mmol, 24.7% yield) as the first eiuting and minor isomer.

STEP 2. (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYPE T-4-EN-l -YL)

CYCLOBUTYL)METHYL)-3 ^f ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

To a solution of (S)-tert-butyl 6'-chloro-5-(((l R,2R)-2-((S)-l -hydroxypent- 4-en-l-yl)cyc]obutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (Example 756, step 1, 55 mg, 0.10 mmol) in CH2CI2 (0.8 mL) at ambient temperature, TFA (0.2 mL) was added and the mixture was stirred at ambient temperature for 3 h. The mixture was then diluted with EtOAc, washed once with sat. NaHCCb, dried over MgSG , filtered and concentrated. The crude (S)-6'-chloro-5-(((l R,2R)-2-((S)-l- hydroxypent-4-en ~yl)cyclobtm _' l)methyl)-3^4,4^54etrahydro-2H,2'H- spiro[benzo[b] [l,4] oxazepine-3,r-naphthalene]-7-carboxylic acid thus obtained was used without further purification.

STEP 3. N,N-BIS(4- ETHOXYBENZYL)PROP-2-ENE-l-SULFONAMIDE

The title compound was synthesized from N,N-bis(4- methoxybenzyl)amine (Intermediate EE11; 2.5 g, 8.54 mmol) and 2-propene-l- sulfonyl chloride (Matrix Scientific; 1 g, 7.11 mmol) following the procedure described for Intermediate EE13. Purification of the crude material provided N, bis(4-methoxybenzyl)prop-2-ene-l -sulfonamide (1.15 g, 3. 18 mmol, 44.7 % yield).

STEP 4. (R)-N,N-BI S(4-METHOXYB ENZYL)PENT- 1 -ENE-3 -

SULFONAMIDE AND (S)-N,N-BiS(4-METHOXYBENZYL)PENT-l-ENE-3- SULFONAMIDE

The title compounds were synthesized from N,N-bis(4- methoxybenzyi)prop-2-ene- 1 -sulfonamide (Example 756, step 3, 265 mg, 0.733 mmol) following the procedure decribed for Intermediate EE18, Step 1. (R)-N,N- bis(4-methoxybenzyl)pent-l -ene-3-sulfonamide and (S)-N,N-bis(4- methoxybenzyl)pent-l-ene-3 -sulfonamide (161 mg, 0,413 mmol, 56.4% yield) were obtained as a racemic mixture.

STEP 5. (R)-PENT- 1 -ENE-3-SULFONAMIDE AND (S)-PENT-l -ENE-3- SULFONAMIDE

The title compounds were synthesized from (R)-N,N-bis(4- methoxybenzyl)pent-l -ene-3-sulfonamide and (S)-N,N-bis(4- methoxybenzyl)pent-l-ene-3 -sulfonamide (Example 756, step 4, 160 mg, 0.411 mmol) following the procedure decribed for Intermediate EE 17, Step 2. (R)-pent- l-ene-3-sulfonamide and (S)-pent-l -ene-3-sulfonamide (52 mg, 0.348 mmol, 85% yield) were obtained as a racemic mixture.

STEP 6. (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYPE T-4-EN-l -

YL)CYCLOBUTYL)METHYL)-N-((R)-PENT- 1 -EN-3-YLSULFONYL)- 3' _; 4 ₅ 4' ₅ 5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r- NAPHTHALENE ] -7 -C ARB OX AMI D E AND (S)-6'-CHLORO-5-(((l R,2R)-2- ((S )- 1 -HYDROXY? ENT-4-EN- 1 -YL)CYCLOBUTYL)METHYL)-N-((S)-

PENT-l-EN-3-YLSULTONYL)-:r,4,4^5-TETRAHYDRO-2H,2 ^! H- SP1RO [BENZO I B | [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2-

((S)~l-h}'droxypent-4-en -}/j^

spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (Example 756, Step 2; 49 mg, 0.099 mmol) and a racemic mixture of (R)-pent-l-ene-3- sulfonamide and (S)-pent-l -ene-3-sulfonamide (Example 756, Step 5; 52 mg, 0,348 mmol) following the procedure described for Example 1, Step 1.

Purification of the crude material provided a mixture of (S)-6'-chloro-5-(((lR,2R)-

2- ((S)-l -hydroxypent-4-en-l -yl)cyclobutyl)methyl)-N-((R)-pent-l-en-3- ylsulfonyl)-3',4,4',5~tetrahydro~2H,2'H-spiro [benzo[b][l ,4]oxazepine-3, - naphthalene] -7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxypent- 4-en-l -yl)cyclobut> )methyl)-N-((S)-pent-l-en-3-ylsulfonyl)-3',4,4',5-tetrahy(lr o- 2H,2'H-spiro[benzo[b] [1 ,4]oxazepine-3, r-naphthalene]-7-carboxamide (47 mg, 0,075 mmol, 76 % yield), STEP 7, (1 S,3'R,6'R,7'S, 10Έ, 12'R)-6-CHLORO-l 2'-ETHYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! - [20] OXA[ 13]THI A[l , 14]DIAZ ATETRAC YCLO

[ 14.7.2.0 ³ ' ⁶ .0 ⁱ ' ² ]PENTACOSAil0,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE

The title compound was synthesized from a mixture of (S)-6'-chloro-5- (((1 R,2R)-2-((S)-l -hydroxypent-4-en-l -yl)cyclobutyl)methyl)-N-((R)-pent-l-en-

3- ylsulfonyl)-3',4,4 5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r- naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxypent- 4-en-l -yl)cyclobut> )methyl)-N-((S)-pent-l-en-3-ylsulfonyl)-3',4,4 ^, ,5-tetrahydro- 2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, -naphthalene]-7-carboxamide (Example 756, step 6, 47 mg, 0.075 mmol) following the procedure described for Example 742, Step 2. The crude material was subjected to a first purification by

chromatography through a 12 g ISCO column, eluting with 10 % to 20 % to 50% EtOAc (containing 0.3% AcOH) in hexanes over 25 min. to provide the title compound (contaminated by unknown impurities) as the first eluting component. Purification of this material via reverse-phase HPLC provided (lS,3 ^, R,6'R,7 ^, S,10¾,12¾)-6-cMoro-12 ^, -e l-7 ^, -hydroxy-3,4-dihydro-2H,15'H- spiro [naphthalene- 1 ,22'-[20] oxa[l 3 ]thia[ 1,14]

diazatetracyclo|;i4.7.2.0 ³ - ⁶ .() ^{i 9} ' ²⁴ |pentacosa [10,16,18,24]tetraen]-15 ^! -one 13',13'- dioxide (2,2 mg, 0.004 mmol), ^! H NM (400MHz, CD2CI2) 6 9,88 is. i l l ). 7,72 id. ./ 8.6 Hz, IH), 7.39 (dd, ./ 2.2. 8.4 Hz, i l l ). 7.18 - 7.14 (m, 2H), 7.09 id. ./ 2.2 Hz, IH), 6.96 (d, ,/ 8.4 Hz, I H), 6.07 (ddd, =5.2, 10.5, 15.4 Hz, IH), 5.37 (ddd, 1 .4. 8.0, 15.5 Hz, IH), 4.17 - 4.05 (m, 2! I ). 3,83 (ddd, ./ 4.5. 8.2, 11 ,7 Hz, IH), 3.75 (d, .7=15,5 Hz, IH), 3.64 (d, .7=13.9 Hz, IH), 3,65 - 3.58 (m, IH), 3.23 (d, .7=14.3 Hz, IH), 3.15 (dd, J=8.5, 15.6 Hz, IH), 2.81 - 2.71 (m, 2H), 2.52 - 2.44 (m, 2H), 2.40 (br s, IH), 2.37 - 2.25 (m, 2H), 2.18 - 2.06 (m, 2H), 2.05 - 1.96 (m, 2H), 1 ,93 - 1.64 (m, 6H), 1.47 - 1 ,39 (m, 2H), 1 ,03 (t, ./ 7.4 Hz, 3H). MS (ESI, +ve ion) m/z 599.2 (M+H) ⁺ . EXAMPLE 757. (lS,3'R,6 ^, R,7 ^, S,10¾,12 ^, S)-6-CHLORO-12 ^, -ETHYL-T- ΗΥΟΚΟΧΥ-: 4 3ΓΗΎΟΚΟ-2Η,15'Η-8ΡΙΚΟ[ΝΑΡΗΤΗΑΕΕΝΕ-1,2 2'- [20]OXA[13]THIA[1,14]DIAZA

TETR,ACYCLO[ 14.7.2.0 ³ - ⁶ .0 ^{i 9} - ²⁴ jPENTACOSA[10,16,18,24]TETRAEN]-15'- ONE 13',13'-DK)XIDE

The title compound was synthesized as described for Example 756, Step 7. The crude material was subjected to a first purification by chromatography through a 12 g ISCO column, eluting with 10 % to 20 % to 50% EtOAc

(containing 0.3% AcOH) in hexanes over 25 min. to provide the title compound (contaminated by unknown impurities) as the second eluting component.

Purification of this material via reverse-phase HPLC provided

(lS,31 ,6 ^, R,7 ,10Έ,12 ^, S)-6-chlolΌ-12'-ethyl·7'-hydroxy-3,4-dlhydro-2H,15Ή - spiro[naphthalene-l,22'-[20]oxa[13]thia[l, 14]diazatetrac clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ] pentacosa[10,16, 18,24]tetraen]-15'-one 13',13'-dioxide (1.9 mg, 0,003 mmol). ¾ NMR (400MHz, CD2CI2) δ 10.03 (s, IH), 7.73 (d, =8.4 Hz, 1H), 7.41 (dd, J=2. l, 8.3 Hz, 1H), 7.19 - 7.15 (in, 2H), 7.09 (d,■/ 2.3 Hz, i l l ). 6.96 (d, J=8.2 Hz, 1H), 6.1 8 (ddd, J=5.8, 9.8, 15,7 Hz, 1 H), 5.69 (dd, ,/ 8.0. 16.2 Hz, i l l ). 4, 13 - 4.06 (m, 2H), 4.01 (ddd, J=4.1, 8.2, 11.7 Hz, 1H), 3.87 (d, J=15.3 Hz, IH), 3.65 (d, J=14.5 Hz, I H), 3.48 (t, ./ 8.9 Hz, 1H), 3.13 (d,■/ 14 ! Hz, I I I ). 3.04 (dd, ./ H.2. 15.5 Hz, IH), 2.82 - 2.68 (m, 2H), 2,50 (dd, ./ 5.( 13.6 Hz, IH), 2.29 (ddd, ,/ 3.8. 7,4, 13.4 Hz, IH), 2.21 - 2.14 (m, IH), 2.12 - 2,04 (m, 2H), 2,04 - 1.97 (m, 2H), 1.92 (ddd, J=7.4, 11.0, 13.3 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.73 (td, J=4.5, 15.0 Hz, IH), 1.68 - 1.59 { in. 2H), 1.49 - 1.41 i ns. 3H), 1.05 (i, ./ 7.3 Hz, 3H). MS (ESI, +ve ion) m/z 599.2 (M+H) ⁺ .

EXAMPLE 758. (1 S,3'R,6 ^! R,7'S,8 ^! E,1 rR)-6-CHLORO-7'-HYDROXY-l 1'- METOYL-3,4-DIHYDRO-2H,14'H-SPIRO[NAPHTOALENE-l,21 '- [19]OXA[12]TfflA[l,13]

DI AZATETRACYCLO [ 13.7.2.0 ³ · ⁶ .0 ¹ - ^2J ]TETRACOS A[ 8, 15, 17,23]TETRAEN] - 14'-ONE 12M2'-DIOXIDE

STEP 1. (S)-6 ^, -CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL) METHYL)-N-((R)-PENT-4-EN-2-

YLSULFONYL)-3',4,4',5-TETRAHYDRO-2H,2 ^! H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPI Ε-3,Γ-Ν APHTH ALENE] -7 -

CARBOXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l½droxyallyl)cyclobu1yl)me l)-3 4,4 ^, ,5-tetrahydro-2H.2H- spiro[benzo[b][l,4]oxazeprae-3,l'-naphthalene]-7-carboxylic acid (Intermediate AA11 A; 165 mg, 0.353 mmol) and (R)-pent-4-ene-2-sulfonamide (Intermediate EE17; 79 nig, 0.529 mmol) following the procedure described for Example 719, Step 2, Step 1. Purification of the crude material pro vided (S)-6'-chloro-5- (((l R,2R)-2-((S)-l-bydroxyallyl)(y^

ylsulfonyl)-3',4,4',5~tetrahydro-2H,2'H"SpiiO[benzo[b] [l,41oxazepine-3, ~ naphthalene] -7 -carboxamide (44 mg, 0.073 mmol, 20.8 % yield).

STEP 2. (1 S,3'R,6 ^! R,7'S,8'E, 11 *R)-6-CHLORO-7'-HYDROXY-l 1 '-METHYL- 3 ,4-DlH YDRQ-2H, 14'H-SPIRO [NAPHTHALENE- 1,21'- [19]OXA[ 12|THIA[ l,13]DIAZATETRACYCLO

[13.7.2.0 ³ -^0 ¹⁸ ' ²³ ]TETRACOSA[8,15,r7,23]TETRAEN]-14'-ONE 12',12'- DIOXIDE

A 100 mL round bottom flask was charged with (S)-6'-chloro-5-(((lR,2R)- 2-((S)-l-hydroxyallyl)cyclobut 'l)methyl)-N-((R)-pent-4-en-2-ylsulfonyl)-

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine- 3,r-naphthalene]-7- carboxamide (44 mg, 0.073 mmol) in DCM (24.5 mL). The solution was subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added Hoveyda-Grubbs II (9.2 mg, 0.015 mmol) as a solution in 3 mL DCM at ambient temperature. The mixture was heated to reflux under nitrogen for 7 h. The mixture was then sparged with air for 10 min to deactivate the catalyst, and then it was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi- Sep pre-packed silica gel column (12 g), eluting with a gradient of 10-55% EtOAc (containing 0.3% HOAc) in hexanes to provide the title compound. This material was repurified by column (4 g ISCO gold eluting with a gradient of 15- 55% EtOAc (containing 0.3% AcOH) in hexanes) to provide partial separation of the impurities. The clean fractions were combined and concentrated to afford (1 S,3'R,6'R,7 ^! S,8'E, 1 1 'R)-6-chloro-7'~hydroxy-l 1 '-methyi-3,4-dihydro-2H, 14Ή- spiro [naphthalene- 1 ,2 Γ- [ 19] oxa[ 12] thia[ 1,13]

diazatetracyclo[13,7.2.0 ³ ^ Q 12', 12'- dioxide (10 mg, 0.018 mmol, 23.8 % yield). ³ H NMR (500MHz, MeO! \~ ) δ 7.72 (d, =8.6 Hz, 1H), 7.16 (dd, J=2.2, 8.6 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.03 (dd, ,/ 2.O. 8.3 Hz, 1H), 6.92 (d, ./ 8. 1 Hz, I I I . 6.88 id. J=2.0 Hz, IH), 5.95 (id, ,/ 6 2. 15,3 Hz, i l l ). 5.77 (dd, ./ 6.8. 15.4 Hz, ! ! ! ). 4.08 (s, 2H), 4.06 - 4.01 (m, IH), 3.86 - 3.77 (m, IH), 3.68 (dd, J=3.4, 15.2 Hz, IH), 3.67 (d, J=14.4 Hz, 1H), 3.38 (d, ,/ 14.4 Hz, IH), 3.22 (dd, J=9.4, 15.3 Hz, IH), 2.86 - 2.71 (m, 2H), 2,70 - 2,53 (m, 3H), 2.41 (dq, ./ 4.5. 9.0 Hz, i l l ). 2.08 (d, i 3 7 Hz, IH), 2,02 - 1.96 (m, IH), 1 ,95 - 1.88 (m, 2H), 1.87 - 1.79 (m, 2H), 1 ,69 (quin, .7=9,4 Hz, IH), 1.51 (d, ,1=7.1 Hz, 3H), 1.50 - 1.45 (m, IH). MS (ESI, +ve ion) m/z 571.2 (M+H) ⁺ .

EXAMPLE 759. (1 S,3'R,6'R,7'S,8'E,1 l'S)-6-CHLORO-7'-HYDROXY-l Γ- METHYL-3,4-DIHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1 ,21'- [19]0XA[12]TH1A[1,13]

DIAZ A TETR A C YCLO [ 13.7.2.0 ³ · ⁶ .0 ³⁸ ' ²³ ]TETRACOSA[8,l 5, 17,23]TETRAEN] - 14 ^! -ONE 12', 12'-DIOXJDE

STEP 1. (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l -

HYDR0XYAL;LYL)CYCL0BU L) METHYL)-N-((S)-PENT-4-EN-2- YLSULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

The title compound was synthesized from (S)-6'~chloro~5~(((l R,2R)~2~ ((S)-l-hydroxyallyl)c lobutyl)methyl)-3^4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiroj benzoj bj [ L4 |oxazepine-3, -naphthaIene]-7-carboxyiic acid (Intermediate AA11A; 77 mg, 0, 165 mmol) and (S)-pent-4-ene-2-sulfonamide (Intermediate EE172; 70 mg, 0.469 mmol) following the procedure described for Example 719, Step 2, Step 1. Purification of the crude material provided (S)-6'-chloro-5- (((lR,2R)-2-((S)-l½droxyallyl)<yclobutyl)me ])-N-((S)^ent-4-en-2- ylsulfonyl)-3',4,4 ^! ,5 etrah}'dro-2H,2'H-spiro[benzo[b] [l,4]oxazepine~3, - naphthalene]-7-carboxamide (74 mg, 0.124 mmol, 75 % yield).

STEP 2. ( 1 S ,3 'R,6'R,7 ^! S, 8Έ, 1 1 'S)-6-CHLORO-7 ^f -HYDROXY- 11 '-METHYL- 3 ,4-DIHYDRO-2H, 14'H-SPIRO [NAPHTHALENE - 1 ,21 '- [ 19 ]OXA[ 12JTHI A[ 1 , 13]DI AZ ATETRAC YCLO

[ 13,7.2.0 ³ - ⁶ ,0 ¹⁸ - ²³ 1TETRACOSA[8, 15,17,23]TETRAEN]-14'-ONE 12', 12'- DIOXIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l-hydroxyallyl)cyclobut}4)methyl)-N-((S)-pent- te1rahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalen e]-7-carboxamide (Example 759, step 1, 74 mg, 0.124 mmol) following the procedure described for Example 758, Step 2. The crude material was absorbed onto a plug of siiica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10-55% EtOAc (containing 0.3% HOAc) in hexanes to provide a mixture of compounds. This material was repurified by reverse phase HPLC providing (lS^'R^'R^'S^'E^rS -chloro-T'-hydroxy-l 1'- methyl-3,4-dihydro-2H,14'H-spiro[naphthalene-l,2 -

[19ioxa|12jthia[l,13jdiazatetracyclo[13.7.2.0 ³ - ⁶ .0 ^!8 ' ²³ i

tetracosa[ 8,15, 17,23] tetraen] - 14'-one 12', 12'-dioxi de as th e first eluting maj or component (6.8 mg, 0.012 mmol, 9.6 % yield). ¾ NMR (400MHz, CD2CI2) δ 8.22 (br s, 1H), 7.71 id../ 8.4 Hz, III).7.21 (dd, ,/ 2.!.8.3 Hz, 1H), 7.17 (dd, ./ 2.3.8.4 Hz, 111).7.09 (d, ,/ 22 Hz, 1H), 6.96 (d, J=8.2 Hz, ill).6,75 is. ill). 5.89 - 5.85 (m, ill).5,82 (dd, J=4.9, 15.6 Hz, 1H), 4.14 - 4.07 (m, 3H), 3,91 - 3.78 (m, 1H), 3.71 (d, J=14.5 Hz, Ml).3.70 - 3.60 (m, 1H), 3.33 (d, J=14.5 Hz, 1H), 3.19 (dd, ./ 7.6.15.7 Hz, III).2,85 - 2.70 (m, 2H), 2.66 - 2.52 (m, 3H), 2,44

- 2.33 (m, 1H), 2.05 - 1,96 (m, 2H), 1.96 - 1.88 (m, 2H), 1.86 - 1,80 (m, 1H), 1.79

- 1.73 (m, 1H), 1.72 - 1.56 (m, 2H), 1.53 (d, J=7.2 Hz, 3H), 1.49 - 1.40 (m, 1H). MS (ESI, +ve ion) m/z 571.2 (M il) ^' .

EXAMPLE 760. (1S,3 ^! R,6'R,1 l'S)-6-CHLORO-ir-METHYL-3,4-DlHYDRO- 2Η,7Ή, 14'H-SPlRO[NAPHTHALENE-l ,21 '- [ 19]OXA[ 12]THI A[ 1 , 13]DI AZ ATETRAC YCLO

[13,7.2.0 ³ - ⁶ ,0 ¹⁸ - ²³ ]TETRACOSA[15,17,23]TRIEN]-7',14'-DIONE 12',12 ^f - DIOXIDE

The title compound was isolated as a side product of Example 759, Step 2. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10-55% EtOAc (containing 0.3% HOAc) in hexanes to provide a mixture of compounds. This material was repurified by reverse phase HPLC providing (1 S,3 ^! R,6'R, 11 'S)-6-chloro- 11 '-methyl~3,4-dihydro-2H,7 ^! , 14Ή- spiro [naph thalene- 1,21'-

[19]oxa[12]thia[l,13]diazatetracyclo[13.7.2.0 ³ - ⁶ .0 ¹⁸ ' ²³ ]tetracosa [15,17,23]triene]- 7',14'-dione 12',12'-di oxide as the second eluting minor component (3.4 nig, 0.006 mmol, 4.8 % yield). ¾ NMR (5()0MHz, CD2CI2) δ 8.88 (br s, IH), 7.72 (d, ,/ 8.3 Hz, H), 7,29 (dd, ./ 2. , 8.2 Hz, IH), 7. 7 (dd, J=2.3, 8,4 Hz, IH), 7.09 (d, ./ 2.4 Hz, IH), 6.96 (d, J=8.3 Hz, IH), 6.90 (d, J=2.0 Hz, IH), 4.15 (d, J=12.5 Hz, IH), 4.09 (d, ,/ 12.0 Hz, IH), 4.04 (d, ./ 15.4 Hz, IH), 3.74 (td, ./ 3.7.7.3 Hz, IH), 3.69 (d, ,/ 144 Hz, H), 3.23 (dd, 8.8.15.7 Hz, IH), 3,18 (d, ./ 14.4 Hz, IH), 2.91 - 2.84 (m, IH), 2,75 - 2.69 (m, IH), 2.83 - 2.68 (m, 2H), 2,66 - 2.56 (m, IH), 2.52 - 2.43 (m, IH), 2.36 - 2.24 (m, IH), 2.13 - 2.00 (m, 4H), 1.97 - 1.89 (m, 2H), 1.86 - 1.66 (m, 4H), 1.50 (d, ,/ 7.3 Hz, 3H), 1.48 - 1.41 (m, !!!). MS (ESI, +ve ion) m/z 571.2 (M+H) ⁺ .

EXAMPLE 761. (18,3'Κ,6'Κ,7·8,11¾)-6-α-ΙΕΟΚΟ-7'-ΗΥΒΚΟΧΥ-1 1'- METHYL-3,4-DIHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1 ,21'- [19]OXA[12]THIA[l,13]DIAZA

TETiL4CYCLO[13.7.2.0 ³ -^0 ¹⁸ - ²³ ]TETRACOSA[15,17,23]TiIEN]-14'-O E 12',12'-DIOXIDE

The title compound was synthesized from (1S,3'R,6'R,7'S,8'E,1 l'R)-6- chloro-7'-hydroxy-ll'-me1hyl-3,4-dihydro-2H,14H-spiro[naphth alene-l,2 - [ 19] ox a[ 12] thia[ 1 , 13 ] di azatetracy cl o

[13.7.2.0 ⁵ - ⁶ .0 ¹⁸ ' ²³ ]tetracosa[8,15,17,23]tetraen]-14'-one 2',I2'-dioxide (7,7 mg, 0.013 mmol, Example 758) following the procedure described for Example 84 providing (1S,3'R,6'R,7'S,1 l'R)-6-chloro-7'-hydroxy-l l'-methyl-3,4-dihydro- 2H, 14'H-spiro[naphthalene- 1 ,21 '-

I i ioMii I2|ih:a| 1.1 |dia/:Ue!rac> cic^l ! .7.2 O' ".θ ^ικ ' ^: i!ciracosal Ι . i 7.23 ricn 1~ 14'-one 12',12'-dioxide (4.9 mg, 0,0009 mmol, 63.4% yield). 'H NMR (400MHz, CD2CI2) δ 8.83 (br s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.17 (dd, J=2,3, 8.4 Hz, IH), 7.13 - 7.05 (m, 3H), 6.92 (d, ./ 8.0 Hz, IH), 4.12 (s, 2H), 3.78 (d, ./ I ' I Hz, IH), 3.75 - 3.67 (m, 2H), 3.63 (d, ,/ 14.3 Hz, IH), 3.35 - 3.27 (m, IH), 3.28 (d, ,/ 14.3 Hz, IH), 2,84 - 2,68 (m, 21 1 ). 2.37 - 2.24 (m, 2H), 2.06 - 1 ,98 (m, 2H), 1.99 - 1 .85 (m, 3H), 1.85 - 1.76 (m, IH), 1.76 - 1.61 (m, 3H), 1.59 - 1.50 (m, 4H), 1.48 (d, ./ 7.0 Hz, 3H), 1.44 - 1.32 { in. 2H). MS (ESI, +ve ion ) m/z 573.1 ! M ! ! ) .

EXAMPLE 762. (1 S,3¾,6¾,7 ^! S,8'E,1 l'R)-6-CHLORO-7'-HYDROXY-l Γ- ETHYL-3,4-DIHYDRO-2H,14'H-SPlRO[NAPHTHALENE-l,2 - [ 19]OXA[ 12JTHI A[ 1 , 13]DI AZ A

TETRACYCLO[13.7.2.0 ⁵ ' ⁶ .0 ¹⁸ - ²³ jTETRACOSA[8,15,17,23]TETRAEN]-14'- ONE 12',12'-DIOXIDE

STEP 1. (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2R)-2-((l S,5R,E)-l- HYDROXY-5-SULFAMOYLHEPT-2-EN-l-YL)CYCLOBUTYL)METHYL)- ;r,4,4V5-TETRAHY ^T DRO-2H,2TI-SPIRO[BENZO[B][ I,410XAZEPINE-3,r- N APHTH ALENE] -7 -C ARB OXYL ATE

A 50 mL RB flask was charged with (S)-tert-butyl 6'-chloro-5-(((l R,2R)-

2-((S ₅ E)-l½droxyhex-2-en-l-yl)cydobu1yl)me l)-3^4 ₅ 4 5 etrahydro-2H,2 ^, H- spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naphthalen e] -7-carboxy 1 ate (Intermedi ate AA12B, Step IB, first eiuting isomer; 184 mg, 0,325 mmol) and (S)-hex-5-ene-3- sulfonamide (Intermediate EE18; 318 nig, 1.95 mmol) and DCM (4,6 niL) and the resulting solution was sparged with Ar. To the homogeneous solution was added Hoveyda-Grubbs Π (20.36 mg, 0.032 mmol) as a solution in 2 mL DCM at ambient temperature. The mixture was stirred under Ar at ambient temperature (venting the flask and adding solvent as needed) overnight. The reaction mixture was directly injected into a 24 g ISCO Gold column, and purified eiuting with a gradient of 0-20-100% EtOAc in hexanes over 20 mm to give (S)-tert-butyl 6'- chloro-5-(((lR,2R)-2-((l S,5R,E)-1 -hydroxy-5-sulfanioylhept-2-en-l -

3, l '-naphthalene]-7-carbox late (80 mg, 0.121 mmol, 37.3% yield).

STEP 2. (S)-6'-CHLORO-5-(((lR,2R)-2-((lS,5R,E)-l-HYDROXY-5- SULFAMOYLHEPT-2-EN- 1 -YL)CY CLOBUTYL)METHYL)-3',4,4',

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID

To a solution of (S)-tert-butyl 6'-chloro-^-i i i I R.2 K }-2-(( I S .^R.l - l -

2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (80 mg, 0.121 mmol) in CH2CI2 (1.94 mL) at ambient temperature, TFA (0.486 mL) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was then diluted with EtOAc, washed once with sat. NaHC0 ₃ , dried over MgSC , filtered and concentrated to give a brown foam. The crude material was used without further purification.

STEP 3. (1S,3'R,6'R,7 ^! S,8'E,1 l'R)-6-CHLORO-7'-HYDROXY-l l'-ETHYL-3,4- DIHYDRO-2H, 14'H-S PIRO [N APHTH ALENE- 1 ,2V- [ 19]OXA[l 2]THTA| 1 , 13 jDIAZATETRACYCLO

[I; 7.2.0 ³ -^0 ¹⁸ - ²³ ]TETRACOSA[8,15,17,23]TET1 AEN]"14'-ONE 12',12'- DIOXIDE

N,N-dimethylpyridin-4-amine (25.1 mg, 0.206 mmol) was added to a solution of (S)-6 ^! "cWoro-5-(((lR,2R)-2 (lS,5R,E)-l~hydroxy-5-siJfamoylhept-2~ en- 1 -y l)c clobuty l)methy l)-3 ',4,4',5-tetrahy dro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3,l'-naphthalene]-7-carboxylic acid (Example 762, step 2, 73 mg, 0.121 mmol) (previously azeotroped with 2.5 mL toluene for 1 h) in CH2C 2 (60.5 ml.) at 0 °C. N-(3-dimethylajminopropyl)-N'-ethylcarbodiimide hydrochloride (46.4 mg, 0.242 mmol) was then added portion-wise slowly and the mixture was stirred while allowing to reach ambient temperature for 22 h. The mixture was then washed with IN HC3 and brine, the aqueous layer was back extracted with EtOAc and the combined organs cs were dried over anhydrous magnesium sulfate, then concentrated. The crude material was purified by chromatography through a ISCO gold column 24 g, eluting with a gradient of 10 % to 55 % EtOAc (containing 0.3% AcOH) in hexanes, to provide the title compound. This material was repurified by reverse phase HPLC to provide (lS,3 ^, R,6 ^, R,7 ^, S,8Έ,l l ^, R)-6-chloro-7 ^f -hydroxy-l l ^, -ethyί-3, -dihydro-2H,14Ή- spiro[naphthdene-l,21'-[19]oxa[ 12]mia[l ,13]cUazatetracyclo [13.7.2.0 ³ · ⁶ .0 ¹⁸ · ²³ ] tetracosa[8,15,17,23]tetraen]-14'-one 12',12'-dioxide (21 mg, 0.036 mmol , 29,7% yield). ¾ NMR (400MHz, CD2CI2) δ 8.21 (s, i l l ). 7.70 (d, ,/ 8 6 Hz, I H i. 7.17 (dd, J=2.4, 8.5 Hz, IH), 7.09 (d, J=2.3 Hz, IH), 7.02 (dd, J=2.3, 8.6 Hz, 1H), 6.93 (d, ./ 8.2 Hz, 11 1 . 6.91 id. =2.0 Hz, 1H), 5.80 - 5.76 (m, 2H), 4.17 - 4.06 (m, 2H), 4.01 - 3.96 (m. 1 1 1 ). 3,73 - 3.62 (m, 3H), 3.34 (d, .7=14,5 Hz, H), 3.22 (dd, ./ 6.7. 15.5 Hz, IH), 2.86 - 2.70 (m, 2H), 2.67 - 2.45 (m, 4H), 2.27 - 2.15 (m, IH), 2.04 - 1.96 (m, 2H), 1.94 - 1.86 (m, 2H), 1.86 - 1.76 (m, 2H), 1.76 - 1.62 (m, 3H), 1.52- 1.43 (ra, 1H), 1.13 (\. 7.4 H/.3H). MS (ESI, +ve ion) m/z 585.1 ( M If) .

EXAMPLE 763. (1S,3'R,6'R,7 ^! S,8'E,1 l'R)-6-CHLORO-l r-ETHYL-7'-

METHOXY-3,4-DIHYDRO-2I-L14'H-SPIRO|NAPHTI-IALENE-l,2r- [ ;i9]OXA[l 2]THIA[1 ,13]DIAZA

TETRACYCLO[13.7.2.0 ³ -^0 ¹⁸ -]TETRACOSA[8;i5,17,23]TETiLAE ]-14'- ONE 12',12 ^* -DIOXIDE

The title compound was synthesized from (1 S^'R^'RJ'S^'E, 1 l'R)-6- chloro-7'-hy droxy- 11 '-ethyl-3,4-dihy dro-2H, 14'H-spiro [naphthalene- 1,2 Γ- [19joxaj 2]thia[l,13]diazatetrac clo

[13.7.2.0 ³ - ⁶ .0 ¹⁸ ' ²³ ]tetracosa[8,l 5,17,23]tetraen]-14'-one 12',12"-dioxide (6 mg, 0.0102 mmol, Example 762) following the procedure described for Example 735 providing (lS,3 ^, R,6'R,7'S,8 ^! E,i R)-6-chloro-ir-ethyi-7'-methoxy-3,4-dih dro- 2H, 14'H-spiro[naphthalene- 1 ,21 '-

[8,I5,17,23]tetraen]-14'-one 12',12'-dioxide (4.7 mg, 0.008 mmol, 76% yield). ¾ NMR (400MHz, X!eOI I-c/V} δ 7.72 (d, ,/ H.4 Hz, 1H), 7.15 (d, ./ 8.4 Hz, IH), 7,10 (s, IH), 7,04 (br s, IH), 6.96 (br s, IH), 6.88 (d, ./ 7.8 Hz, IH), 6,01 - 5.85 (m, IH), 5.58 (dd, ,7=8,5, 15.2 Hz, IH), 4,06 (s, 2H), 3,71 (dd, J=2.9, 14.7 Hz, IH), 3.65 (d, ./ 14.5 Hz, IH), 3.60 (dd, ./ 3.9.8.0 Hz, !!!).3.48 (br s, IH), 3.36 (d, ./ 15.! Hz, IH), 3,22 is.3H), 3,17 (dd, ./ 11.2.15.3 Hz, !!!).2.87 - 2.74 (m, 2H), 2.73 - 2.53 (m, 3H), 2,49 - 2.37 (m, I Hi.2.18 (br s, IH), 2,12 - 2.04 (m, IH), 2.01 - 1.84 (m, 3H), 1.84 - 1.65 (m, 4H), 1.54 - 1.43 (m, ill).1.11 (t, ./ 6.9 Hz, Ml). MS (ESI, +ve son) m/z 599.0 !M !!) . EXAMPLE 764. (((IS,3TL6'R,7'S,8'E,1 l'R)-6-CHLORO-l i'-ETHYL-12',l 2'- D! OXIDO - 1 -0X0- ,4-D!HYDRQ~2H~SPi RQ [NAPHTHALENE- 1 ,2 V~

[19]OXA[12]THIA[l,13]

DIAZATETRACYCLO| 13.7.2 ³ -^0 ¹⁸ - ²³ ]TETRA(X)SA[8,15,17,23 |TETRAEN] 7'-YL)OXY)ACETIC ACID

solution of (1 S,3'R,6 ^! R,7'S,8'E, 11 'R)-6-chloro-l 1 '-ethyl-7'-methoxy 3 ,4-dihy dro-2H, 14'H-spiro [naphthalene- 1 ,2 Γ-

[19]oxa[ 12]thia[l 3]diazatetracyclo| 13.7.2.0 ³ - ⁶ .0 ^l8 - ²³ ]tetracosa

[8,15, 17,23]tetraen]-14'-one 12',12'-dioxide (9.3 mg, 0.016 mmol, Example 762) in DCM (318 μΐ) at ambient temperature was added rhodium (II) acetate dimer (Sigma Aldrich; 0.176 mg, 0.397 μηιοΐ), followed by the dropwise addition of ethyl diazoacetate (Sigma Aldrich; 3.62 μΐ, 0.035 mmol). The reaction mixture was stirred at ambient temperature for 4 h adding more diazoacetate reagent as needed to drive the reaction to near completion. The reaction mixture was then directly injected onto a Redi-Sep pre-packed silica gel column (4 g), and purified eluting with 0 % to 35 % EtOAc (containing 0.3% AcOH) in heptanes. The material isolated was repurified eluting with 15-35% EtOAc (containing 0.3%

AcOH) in heptanes. The intermediate ester was taken up in THF/MeOH (2: 1) and treated with 10 eq of IN LiOH at ambient temperature for 1 h. The mixture was then quenched with IN HCl, diluted with brine, extracted with EtOAc, dried over MgS04, filtered and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with 20 % to 50 % EtOAc (containing 0.3% AcOH) in heptane, to provide (((l S,3¾,6 ^ί R,7 ,8Έ,l rR)-6-chloro-l l '-eίhyS-12 12'-diOxido-14 ^, -oxo-: 4- dihy dro-2H-spiro [naphthalene- 1 ,2 Γ- [ 19 j oxa[ 12] thia [V13]diazaietracyclo[ 13.7.2,Q ³ ^ 0

yl)oxy)acetic acid (1.0 mg, 1.56 μηιοΐ, 9.78 % yield). 'H NMR (400MHz, CD2CI2) δ 7.69 (d, J=8.6 Hz, IH), 7.17 (dd, J=2.3, 8.6 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.06 (d, ,/ 8.4 Hz, IH), 6.93 (d, .7=8.2 Hz, I I I ). 6.77 (br s, i l l ). 5.79 (br s, IH), 5,67 (dd, J=8.0, 15.8 Hz, I H), 4.11 (s, 2H), 4.02 id. ,/ ! 5 8 Hz, I H), 3.94 (d, ./ 1 .2 Hz, IH), 3.78 (t, J=5.9 Hz, IH), 3.74 - 3.68 (m, i l l ). 3.66 (d, J=14.9 Hz, IH), 3.60 (br s, IH), 3.33 (d, ./ 14.3 Hz, IH), 3.23 (dd, ,/ 7.H. 15.1 Hz, I H), 2,84 - 2.71 (m, 2H), 2.66 (br s, 2H), 2.62 - 2.47 (m, 2H), 2,06 - 1.95 (m, 2H), 1.94 - 1.85 (m, 2H), 1.78 (dd, ./ 9.7. 19.5 Hz, 3H), 1.69 (dd, ./ 9,1. 18,2 Hz, 2H), 1.54 - 1.45 (m, IH), 1.12 (ΐ, J=7.4 Hz, 3H). MS (ESI, +ve ion) m/z 643.0 ί M H ) .

EXAMPLE 765, (1 S,3'R,6'R,7'S,9'E,1 l'R)-6-CHLORO-7'-HYDROXY-l Γ-

ME ^r rHYL~3,4-DIHYDRO-2H,14'H-SPlRO[NAPHTHALENE"l,21'- [ 19]OXA[ 12 |THIA[ 1, 13 JDIAZA

TETRACYCLO[! 3.7.2,0-^0 ^1S>23 ]TETRACOSA[9J 5,17,23]TETRAEN]-14'- ONE 12',12 ^! -DIOXIDE OR (1 S,3 ^! R,6'R,7'S,9'E, 1 l'S)-6-CHLORO-7'- HYDROXY-H'-METHYL-3,4~DIHYDRO-2H,14'H"SPIRO[ APHTHALENE- 1 ,21 19 j OX A[ 12]THIA[ 1 , 13 ]DI AZ A

TETRACYCLO[13.7.2.0 ⁵ ' ⁶ .0 ¹⁸ - ²³ jTETRACOSA[9,15,17,23]TETRAEN]-14'- ONE 12 ^! ,12'-D10X1DE

STEP 1. (R)-N,N-BIS(4-METHOXYBENZYL)BUT-3-ENE-2-SULFONAMIDE AND (S)-N ₅ N-BIS(4-METHOXYBENZYL)BUT-3-ENE-2-SULFONAMIDE

The title compounds were synthesized from N,N-bis(4- methoxybenzyl)prop-2-ene-l -sulfonamide (Example 756, Step 3; 230 mg, 0.636 mmol) following the procedure decribed for Intermediate EE 18, Step 1. (R)-N,N- bis(4-methoxybenzyl)but-3-ene-2-sulfonamide and (S)-N,N-bis(4- methoxybenzyl)but-3-ene-2-sulfonamide (131 mg, 0.349 mmol, 54.8% yield) were obtained as a racemic mixture.

STEP 2. (R)-BUT-3-ENE-2-SULFONAMIDE AND (S)-BUT-3-ENE

SULFONAMIDE

The title compounds were synthesized from (R)-N,N-bis(4- methoxybenzyl)but-3-ene-2-sulfonamide and (S)-N,N-bis(4-methoxybenzyi)but- 3-ene-2-suifonamide (131 mg, 0.349 mmol) following the procedure decribed for Intermediate EE17, step 2. (R)-but-3-ene-2-sulfonamide and (S)-but-3-ene-2- sulfonamide (32.4 mg, 0.240 mmol , 68.7% yield) were obtained as a racemic mixture.

STEP 3. (S)-N-((R)-BUT-3-EN-2-YLSULFONYL)-6 ^, -CHLORO-5-(((l R,2R)- ((S)- 1 -HYDROXYBUT-3-EN- 1 -YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAH YDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3, 1 '- NAPHTHALENE ] -7 -C ARB OX AMI D E AND (S)-N-((S)-BUT-3-EN-2- YLSULFONYL)-6'-CHLORO-5-(((l R,2R)-2-((S)-l -HYDROXYBUT-3-EN-l YL)CYCIX)BUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-SPIRO

[BENZO[B][l,4]OXAZEPl E-3J ^! -NAPHTHALENE]~7-CARBOXAMrDE

The title compound were synthesized from (S)-6'-chloro-5-(((lR,2R)-2~ ((S)-1 iydroxybut-3-en -yl)cyclobut}4)me 4)-3 ,4^54etrahydro-2Ii,21^ spiro[benzo[b][l,4] oxazepine-3,l'-naphthalene]-7-carboxylic acid (Intermediate AA13A; 73 nig, 0.151 mmol) and a mixture of (R)-but-3-ene-2-sulfonamide and (S)-but-3-ene-2-sulfonamide (Example 765, step 2, 32 mg, 0.237 mmol) following the procedure described for Example 719, Step 2, Step 1. Purification of the crude material provided (S)-N-((R)-but-3-en-2-ylsulfonyl)-6'-chloro-5-(((lR,2R)-2-(( S)- l-hydroxj'but-S-en-l-y c clobuly methy -S'^^'^-tetrahydro^H^'H- spiroj benzoj b] [ 1,4 ]oxazepine-3, 1 '-naphthalene]-7-carboxamide and (S)-N-((S)- but-3-en-2-ylsidfonyl)-6'-(^oro-5-(((lR,2R)-2 (S)-l½droxybut-3-en-l- yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l,4] oxazepine- 3,1 '-naphthalene I -7-carboxamide (68 mg, 0.113 mmol, 74.9 % yield, 85% purity). STEP 4. (1S,3'R,6'R,7'S,9'E,1 rR)-6-CHLORO-7'-HYDROXY-l l'-METHYL- 3 ,4-DIH YDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1,21'- [ 19]OXA[l 2]THTA| 1 , 13 jDIAZATETRACYCLO

[13.7.2.0 ³ -^0 ¹⁸ - ²³ ]TETRACOSA[9,15,17,23]TET1 AEN]-14'-ONE 12',12'- DIOXIDE OR (1S,3'R,6'R,7'S,9'E,1 l'S 6-CHLOR()-7'-HYDROXY-H'- METHYL-3.4-DIHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1 ,21'- [19]OXA[12]THIA[l,13]DIAZATETRACYCLO

[ 13.7.2.0 ³ - ⁶ .0 ⁱ⁸ - ²³ ]TETRACOSA[9,15,r7,23]TETR EN]-I4'-ONE 12',12'~ DIOXIDE The title compound was synthesized from a mixture of (S)-N-((R)-but-3- en-2-ylsulfonyl)-6'-chloro-5-(((l R,2R)-2-((S)- 1 -hydroxy but-3-en- 1 - yl)cv'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[ben zo[b] | l ,4|oxazepine- 3, 1 '-naphthalene j-7-carboxamide and (S)-N-((S)-but-3-en-2-ylsulfonyl)-6'-chloro- 5 ((lR,2R)-2-((S)-l-hydrox} but-: en-l-yl)cyclobut 'l) methyl)-3 ^* ,4,4 ^, ,5- tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxarnide (Example 765, step 3, 68 mg, 0.113 mmol, 85% purity) following the procedure described for Example 45, Step 2. The crude material was purified by silica gel chromatography on a 12 g IS CO Gold column eluting with a gradient of 10-20- 50% EtOAc (containing 0.3% AcOH) in hexanes over 22 min. to provide an inseparable mixture of isomers. This material was repurified by reverse phase HPLC providing (1 S,3 ^! R,6'R,7'S,9'E, 11 'R)-6-chloro-7'-hydroxy- 1 1 '-methyl-3,4- dihy dro-2H, 14'H-spiro [naphthalene- 1 ,2 Γ- [ 19] oxa[ 12]thia[ 1 , 13 ] diazatetracy cio [13.7.2.0 ³ - ⁶ .0 ^{i S} - ²³ ] tetracosa[9, 15, ! 7,23]tetraen]-14'-one ! 2', 12'-dioxide or (lS,3'R,6 ^f R,7'S,9UirS)-6-chloro-7^

spiro [naphthalene- 1 ,2 Γ- [ 19] oxa[ 12] thia[ 1,13]

diazatetracyclo|;i3.7.2.0 ³ ' ⁶ .() ^{i S} - ²³ |tetracosa [9,15, 17,23 jtetraen]-14'-one 12',12'- dioxide as the first eluting isomer (1.3 mg, 0.0023 mmol, 2 % yield). Ή NMR (400MHz, CD2CI2) δ 8.49 (br s, IH), 7.71 (d, J=8.4 Hz, IH), 7.27 (dd, J=2.2, 8.2 Hz, I H), 7.18 (dd, J=2.4, 8.5 Hz, IH), 7.09 id. 2.3 Hz, IH), 7.03 (s, IH), 6.96 (d, ./ 8.2 Hz, IH), 5,74 (ddd, ./ 4.9. I 0.il 15,4 Hz, I H), 5.49 (dd, J=8,9, 15.6 Hz, IH), 4.32 (qd, ,7=6,8, 9.0 Hz, IH), 4, 18 - 4.09 (m, 2H), 3.72 (dd, ,7=8,0, 15.1 Hz, IH), 3.69 (d, J=15.1 Hz, IH), 3.64 - 3.58 (m, IH), 3.34 (d, J=14.5 Hz, IH), 3.23 (dd, ./ 2.2. 15.3 Hz, IH), 2.85 - 2.69 (m, 2H), 2.58 - 2.45 (m, 2H), 2.42 - 2.32 (m, IH), 2,05 - 2.00 (m, IH), 2.00 - 1.93 (m, 2H), 1 ,93 - 1.85 (m, IH), 1 .85 - 1.78 (m, IH), 1 ,71 - 1.64 (m, 2H), 1.57 (d, .7=7.2 Hz, 3H), 1.52 - 1.40 (m, 3H). MS (ESI, +ve ion) m/z 571.1 ( +H) ⁺ . EXAMPLE 766. (l S,3¾,6¾,7 ^! S,9'E,i l'R)-6-CHLORO-7'-HYDROXY-l Γ- ETHYL-3,4-DlHYDRO-2H,14 ^, H-SPlRO[NAPHTHALENE-l,2I'- [ 19]OXA[ 12]THI A[ 1 , 13 ]DT AZ A

TETRACYCLOtn.y^.O^.O^^lTETRACOSA^lS^T^SlTETRAENl-W- ONE 12',12'"D10X1DE OR (1 S,3'R,6'R,7'S,9'E,1 rS)-6-CHLORO-7'- HYDROXY-1 1 '-ETHYL-3 ₅ 4-DIHYDRO-2H,l 4'H-SPIROj NAPHTHALENE- 1 ,21 '-[ 19] OXA[ 12]THIA [1,13]DIAZA

TETRACYCLOtlSJ.ZO^.O^^lTETRACOSA^lS T^SlTETRAENl-W- ONE 12',12 ^* -DIOXIDE

STEP 1. (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-HYDROXYBUT-3-EN-l- YL)CYCLOBUTYL)METHYL)-N-((R)-PENT-l -EN-3-YLSULFONYL)-

3',4,4',5 -TETRAHYDRO-2H,2TI-SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-

NAPHTHALENE] -7-C ARBOXAMIDE AND (S)-6 ^! ~CHL0R0-5~(((1 R,2R)~2-

((S)-l-HYDROXYBUT-3-EN ^L)CYCLOBUTYL)METHYL)~N-((S)-PENT~ l-EN-3-YLSULFONYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3,l ^* -NAPHTHALENE]-7-

C ARBOXAMIDE

The title compound were synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-14iy<lroxybut-3-en-l-yl)cydobuty^^

spiro[benzo[b] [l,4] oxazepine-3,r-naphthalene]-7-carboxylic acid (Intermediate AA13A; 239 nig, 0.496 mmol) and a racemic mixture of (R)-pent-l-ene-3- sulfonamide and (S)-pent-l-ene-3-sulfonamide (Example 756, Step 5; 127 mg. 0.851 rnmol) following the procedure described for Example 719, Siep 2, Step 1. Purification of the crude material provided (S)-6'-chloro-5-(((lR,2R)-2-((S)-l - hy droxybut-3-en- 1 -yl)cyclobutyl)methyl)-N-((R)-pent- 1 -en-3-ylsulfonyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3, 1 '-naphthalene j-7- carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l -hydroxy but-3-en-l - yl)cyxlobuiyl)methyl)~N^^

spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxamide (214 nig, 0.349 rnmol, 70,4 % yield), STEP 2. (1 S,3'R,0'R,7'S,9'E,1 rR)-6-CHLORO-7'-HYDROXY-l l'-ETHYL-3,4- DIHYDRO-2H, 14'H-S PIRO [N APHTH ALENE- 1 ,2V-

[ 19]OXA[l 2]THTA| 1 , ! 3 jDIAZATETRACYCLO

[I; 7.2.0 ³ -^0 ¹⁸ - ²³ ]TETRACOSA[9,15,17,23]TET1 AEN]"14'-ONE 12',12'- DIOXIDE OR (1S,3'R,6 ^! R,7'S,9'E, 1 l'S)-6-CHLORO-7'-HYDROXY-i r-ETHYL- 3 ,4-DTHYDRO-2H, 14'H-SPIRO [NAPHTHALENE- 1 ,21'- [19]OXA[12]THIA[l,13]DIAZATETRACYCLO

[ 13.7.2.0 ³ -^0 ⁱ⁸ - ²³ ]TETRACOSA[9,15,r7,23]TETR _J ' EN]-14'-ONE 12',12'~ DIOXIDE The title compound was synthesized from a mixture of (S)-6'~chloro~5~

((( 1 R,2R)-2-((S) - 1 -hydroxy but-3 -en- 1 -y l)cy clobuty l)methy l)-N-((R)-pent- 1 - en-3 - ylsulfonyl)-3',4,4 5-tetTahydro-2H,2H-spiro[benzo[b] [l,4]oxazepine-3,T- naphthalene]-7-carboxamide and (S)-6'-chloro-5-(((lR,2R)-2-((S)-l-hydroxybut- 3-en-l-yl)c^xlobut 'l)methyl)-N-((S)-pent-l-en-3-ylsulfonyl)-3',4,4',5-tetrahyd ro- 2H,2'H-spiro[benzo[b 11 1 A\ oxazepine-3, 1 '-naphthalene] -7-carboxamide (Example 766, step 1 , 214 mg, 0.349 rnmol) following the procedure described for Example 742, Step 2. The crude material was purified by silica gel chromatography on a 40 g 1SCO Gold column eluting with a gradient of 10-50% EtOAc (containing 0.3% AcOH) in hexanes over 30 min. to provide an inseparable mixture of isomers. This material was repunfied by reverse phase HPLC providing

(lS,3'R,6'R,7'S,9 ^* E,i rR)-6-chloro-7'-hydroxy-l l'-ethyl-3,4-dihydro-2H,14'H- spiro [naph thalene- 1,21'-

[19]oxa[12]thia[],13]diazatetracydo[13.7.2.0 ³ - ⁶ .0 ¹⁸ ' ²³ ]tetracosa

[9,15,17,23]tetraen]-14'-one 12',12'-dioxide or (lS,3Ί ,6' ,7'S,9Έ,ll'S)-6-chiOlΌ- 7 ^! -hydroxy Γ-ethyi-3,4-dihy^^

[19]oxa[12]thia[l,13]diazatetTacyclo [13.7.2.0 ^3>6 .0 ¹⁸ · ²³ ] tetracosa

[9,15,17,23]tetraen]-14'-one 12',12'-dioxide as the first eluting and major isomer (13.3 mg, 0.023 mmol, 6.5 % yield). ^! H NMR (400MHz, CD2CI2) δ 8.68 (br s, ill).7.71 (d, J=8.4 Hz, ill).7.27 (dd, ./ 2.!.8.3 Hz, Hi).7.18 (dd, 23.8,4 Hz, 1H), 7.09 (d, .7=2,2 Hz, IH), 7.03 (s, IH), 6.96 (d, J=8.2 Hz, IH), 5,76 (ddd, J=5.2, 10.0, 15.4 Hz, IH), 5.43 {dd../ 9.8.15.8 Hz, IH), 4.17 - 4.09 (m, 2H), 4.11 - 4.06 (m, IH), 3.76 (dd, ./ 9.3.15.7 Hz, IH), 3.69 (d, ./ 14.7 Hz, IH), 3.63 (ddd, ./ 22.5.7, 8.5 Hz, IH), 3.33 (d, 14.7 Hz, IH), 3.20 (dd, 34.15,7 Hz, IH), 2.85 - 2.69 (m, 2H), 2.63 - 2.44 (m, 2H), 2.43 - 2.33 (m, IH), 2.23 (qdd, J=3.9, 7.4, 13.3 Hz, IH), 2.09 - 2.02 (m, IH), 2.01 - 1.90 (m, 3H), 1.90 - 1.85 (m, IH), 1.86 - 1.78 (ra, 2H), 1,70 - 1.60 (m, 2H), 1.58 - 1.48 (ra, IH), 1,47 - 1.39 (m, IH), 1.01 (t, ./ 7 -1 Hz, 3H). MS (ESI, +ve ion) m/z 585.1 (M+H) ⁺ .

EXAMPLE 767. (1 S,3 ^! R,6'R,7'S,9'E,1 l'S)-6-CHLORO-7'-HYDROXY-l Γ-

ETOYL-3,4-DIHYDRO-2H,14'H-SPIRO[NAPHTI-IALENE-l,21 '- [19]OXA[ 12]THIA[ 1 , 13 ]DIAZ A

TETRACYCLO|;i3.7.2.0 -^0 ¹⁸ - ²³ ]TETRACOSA 9,15,17,23]TETR _j! AENi-14'- ONE 12'J2'-DIOXIDE OR (IS,3'R,6'R,7'S,9'E,1 l'^-e-CHLORO^*- ί iYOROXY- i I '-!.!! !Yi -3.4-f)!l !Yi)R()-2l 1. i Γ! !-SPlROj \,\F! 111 lA!J N! - 1,21'~[ 19] OXA[ 12]THIA[ 1 , 13]DIAZA

TETR,4CYCLO[13.7.2.0 ³ - ⁶ .0 ^l8 - ²³ jTETRACOSA[9,15,17,23]TETRAEN]-14'- ONE 12',I2'-DIOXIDE

The second eluting and minor isomer from the purifications described in Example 766, step 2 was contaminated by 18% olefin isomer. This material was further purified by SFC (Column: Chiralpak OD-H, 2.1 x 25 cm; Mobile phase: 35% Methanol/ 65% CO?,; Flow rate: 50 mL/min; SFC Outlet pressure: 100 bar; Temp. = 23 C; Wavelength: 260 nm; Sample dissolved to 2.6 mg/mL in 6: 1

Methanol:DCM; introduced 0.15 mL of sample solution, or 0.4 mg crude sample in each preparative injection) to provide the pure title compound (5.5 mg, 0.0094 mmol, 2.7 % yield). ¾ NMR (400MHz, CD2CI2) δ 8.58 (br s, 1 H), 7.67 (d, J=8.6 Hz, i l l ). 7.27 (br s, 2H), 7. 16 (dd, .7=2.3, 8.6 Hz, U i ). 7.09 (d, .7=2.3 Hz, I I I ). 6.92 (d, ./ 8.2 Hz, i l l ). 5.81 ·· 5.69 (m, 1H), 5.42 (dd, ./ 9.7. 15.2 Hz, IH), 4.16 (br s, 3H), 3.67 (br s, IH), 3.61 - 3.35 (m, 4H), 2,82 - 2.69 (m, 2H), 2.67 - 2.56 (m, I H), 2.43 - 2.30 (m, IH), 2,28 - 2.10 (m, 4H), 1 .95 - 1.84 (m, 2H), 1 , 83 - 1.65 (m, 6H), 1.46 - 1.35 (m, IH), 1.02 (t, ./ 7.4 Hz, 3H). MS (ESI, +ve ion) m/z 585. 1 I 1 1 > ^" .

EXAMPLE 768. (l S,3 ^, R,6 ^, R,7 ^, S, l l ^, R)-6-CHLORO-H ^, -ETHYL-7 ^, -HYDROXY-

3 ,4-DIHYDRQ-2H, 14 ^! H-SPlRO [NAPHTHALENE - 1 ,21 '- [ 19 jOXA[ 12JTHI A[ 1 , 13]DI AZ A

TETRACYCTA3[13.7.2.0 ³ '^0 ^{i 8} ' ²³ ]TETRACOSA[15,17,23]TRIEN]- 14'-ONE 12', 12'-D10XIDE OR (18,3Ί ,6¾,7'8,1 l'S)-6-CHLORO-l l '-ETHYL-?'- HYDROXY-3,4-DIHYDRO-2H,14'H-SPIR()[NAPHTHALENE-l,2r- [ 19]OXA[ 12]THI A[ 1 , 13 ]DT AZ ATETRAC YCLO

[13.7.2.0 ³ -^0 ¹⁸ ' ²³ ]TETRACOSA[L5, 17,23]mrEN]-14'-ONE 12',12'-DI0X1DE

The title compound was synthesized from (1 S,3'R,6'R,7'S,9'E, 1 l 'R)-6- chloro-7'-hydroxy- 11 '-ethyl-3,4-dihy dro-2H, 14'H-spiro[naphthalene- 1,21 '- [ 19]oxa[ 12]thia[ 1 , 13] diazatetracy clo [13 .2.0 ³ -^0 ^iS - ']teiracosa[9,15,17,23]tetraen]-14'-one 12',12'~di oxide or

(1 S,3'R,6'R,7'S,9'E, 1 rS)-6-cMoro-7'-hydroxy- 11 *-ethyl-3,4-dihydiO-2H, 14Ή- spiro [naphthalene- 1,21'- [19]oxa[12]thia[U3]diazatetra^

]-14'-one 12',.12'-dioxide (Example 766; 11 nig, 0.0 9 mmol) following the procedure described for Example 84 providing (lS,3'R,6'R,7'S,H'R)-6-chloro-H'- ethyl-7'-hydroxy-3,4-dihydro-2H,14'H-spiro[naphthalene-l,21' - [19]oxa[12]thia|;i,13]dia.zatetracycio[13,7.2,0 - ⁶ .0 ¹⁸ - ²³ ] tetracosa[15,17,23]trien]- 14 ^f -one 12',12'-dioxide or (1S,3'R,6'R,7 ^! S,1 l'S)-6-chloro-l l'-ethyl~7'~hydroxy-3,4~ dihy dro-2H, 14'H-spiro [naphthalene- 1 ,2 Γ- 119] oxa[ 12] thia[ 1,13] diazatetracy clo [13.7.2.0 ³ ' ⁶ .0 ⁱ⁸ - ²³ ]tetracosa|15,17,23]trien]-14'-one 12',12'-dioxide (3.5 mg, 0.006 mmol, 31.7 % yield). ¾ NMR (400MHz, CD2CI2) δ 9,60 is, IH), 7,72 id, ,/ 8.6 Hz, IH), 7,35 (dd, .7=2.1, 8.3 Hz, IH), 7.16 (dd, J=2.4, 8.5 Hz, IH), 7.12 (d, .7=1.8 Hz, IH), 7.09 (d, ./ 2.2 Hz, IH), 6.97 (d, ./ 8.2 Hz, IH), 4.11 (s, 2H), 3.90 - 3.84 (m. 111).3,82 (d, ./ 1 .5 Hz, IH), 3.63 (d, ,/ 14.1 Hz, IH), 3.58 - 3.50 (m, H),

3.18 (d, ,7=14,1 Hz, H), 3.11 (dd, .7=7,7, 15.4 Hz, IH), 2,84 - 2.69 (m, 2H), 2.30 - 2.08 (m, 4H), 2,05 - 1.94 (m, 4H), 1.93 - 1.86 (m, 2H), 1.85 - 1.74 (m, 3H), 1.70 - 1.56 (m, Ml).1.50 - 1.39 (m, 3H), 1.12 (t, ,7=7.4 Hz, 3H). MS (ESI, \e ion) m/z 587,2 (M+H) ⁺ .

EXAMPLE 769. (lS,3'R,6'R,7'S,8 ^! E)-6-CHL()R()-7'-HYDR()XY-l l',l Γ- DIMETHYL-3,4-DIHYDRO-2H 4H-SPIRO[NAPHTHALENE-l,21'-

[19]OXA[12]THIA[l,13]DIAZA

TETiLACYCLO[13.7.2.0 -^0 ¹⁸ - ²³ ]TETRACOSA[8,15,17,23]TETR/\EN]-14'- ONE 12',12'-DIOXIDE

STEP 1. (S)-TERT-BUTYL 6'-CHLORO-5-(((l R,2R)-2-((S ₅ E)-l -HYDROXY-5- METHYL-5-SULFAMOYLHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-

3' _; 4 ₅ 4' ₅ 5-TETRAHYDRO-2H,2'H"SPIRO[BENZO[B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE

The title compound was synthesized from (S)-tert-butyl 6'~chloro~5~ (((lR,2R)~2 (S )-1 iydroxyhex-2"en -yl)cyclobut 4)methyl)"3^4,4',5~ tetrahydro-2H,2'H-spiro[benzo[b ^" ||T,4] oxazepine-3J '-naphihaiene]-7-carboxyiaie (Intermediate AA12B, step IB, first eluting isomer; 171 mg, 0.302 rnmol) and 2- methylpent-4-ene-2-sulfonamide (Example 781, Step 2, 99 mg, 0.604 mmol) following the procedure described for Example 762, step 1. The reaction mixture was directly injected into a 24 g ISCO Gold column, and purified eluting with a gradient of 0-20-80 % EtOAc in hexanes over 18 min to give (S)-tert-butyl 6'- chloro-5-(((lR,2R)-2-((S,E)-l-hydroxy-5-methyl-5-sulfamoylhe x-2-en-l-

3, l '-naphthalene]-7-carboxylate (39 mg, 0.059 mmol, 19.6 % yield).

STEP 2. (S)-6'-CHI,ORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-5-METHYI,-5- SULFAMOYLHEX-2-EN-l-YL)CYCLOBUT ^;" L)METHYL)-3',4,4 ^! ,5- TETRAHYDRO-2H,2TI-SPIRO[BENZO[B][l,4]OXAZEPINE-3, l '- NAPHTHALENE] -7-CARBOXYLIC ACID

The title compound was synthesized from (S)-tert-butyl 6'-chioro-5~ (((lR,2R)-2-((S,E)-l-hydroxy-5-methyl-5-sulfarnoylhex-2-en-l - yl)cyclobu d)methyl)-3 4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine- 3,r-naphthalene]-7-carboxylate (Example 769, step 1, 39 mg, 0.059 mmol) following the procedure described for Example 762 Step 2. The crude material was used without further purification. STEP 3. (lS,31 ,6'R,7 ^! S,8'E)-6-CHLORO-7 ^, -HYDROXY-i r,i r-DlME ^' raYL- 3 ,4-DIH YDRG-2H, 14'H-SPIRO [NAPHTHALENE- 1,21'- [ 19]OXA[l 2]THTA| ! , 13 jDIAZATETRACYCLO

[13 .2.0 ³ ' ^{6 18} ^ ³ ]TETRACOSA[8,15,17,23]TETRAEN]-14'-ONE 12',12'- DIOXIDE

The title compound was synthesized from (S)-6'-chloro-5-(((l ,2R)-2- ((S,E)-l-hydroxy-5-methyl-5-sulfamoylhex-2-en-l-yl)cyclobuty l)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro | ^" benzo| ^" b] |T,4]oxazepine-3,l'-naphthalene]-7- carboxylic acid (Example 769, step 2, 35 mg, 0.058 mmol) following the procedure described for Example 762, Step 3. The crude material was purified by silica gel chromatography through a 12 g ISCO gold column eiuting with a gradient of 10-45-60% EtOAc (containing 0.3 % AcOH) in hexanes to provide (lS,3'R,6 ^! R,7'S,8'E)-6-chloro-7'-hydro

spiro [naphthalene- 1 ,2 Γ - [ 19] oxa[ 12] thia[ 1 , 13 ] diaza

tetracycio[13.7.2.0 ³ - ⁶ .0 ¹⁸ - ²³ ]tetracosa[8,15,17,23jtetraenj-14'-one 12', 12'-dioxide (6,8 mg, 0.012 mg, 20 % yield). 'H NMR (400MHz, CD2CI2) δ 8.38 (br s, 1H), 7,71 (d, J=8.4 Hz, 1H), 7.23 - 7.17 (m, 1H), 7. 17 (dd, .7=2.3, 8.4 Hz, 1H), 7.09 (d, ./ 2,3 Hz, IH), 6.94 (d, ./ 8.2 Hz, 1H), 6.74 (br s, 1H), 6.15 (td, ./ 5.7. 15.8 Hz, IH), 5.93 - 5.82 (m, 1H), 4,18 (t,J=4.8 Hz, 1H), 4.12 - 4.05 (m, 2H), 3.71 (d, J=14.7 Hz, IH), 3,66 (d, J=13.7 Hz, IH), 3.36 (d, .7=14.5 Hz, 1H), 3.20 (dd, J=9.5, 15.4 Hz, IH), 2.86 - 2.72 (m, 2H), 2.67 (dt, ./ .·,.!.8.6 Hz, ill).2.60 (br s, 2H), 2.35 (dd, ./ 4.5.8.8 Hz, IH), 2.06 - 1.97 ins.3H), 1.97 - 1.91 {in. IH), 1.89 - 1,78 (m, 3H), 1.68 {id../ 9.4.19.2 Hz, 2H), 1.56 (br s, 3H), 1.53 (s, 3H). MS (ESI, +ve ion) m/z 585.1 (M+H) ^H \

EXAMPLE 770. (lS,3'R,6'R,7 ^f S)-6-CHLORO-7'-HYDROXY-ir,ll'- DIMETHYL-3,4-DIHYDRO-2H, 14'H-SP!RO[N APHTHALENE-1 ,21 '- [19] OXA[ 12]THI A[ 1 , 13]DI AZ A

TETR,ACYCLO[13.7.2.0 ³ - ⁶ .0 ^l8 - ²³ jTETRACOSA[15,17,23jTRlEN]-14'-ONE 12 ^* ,12'-DIOXIDE

The title compound was synthesized from (lS,3'R,6'R,7'S,8'E)-6-chioro-7 ^! - hydroxy-1 l i -dimethyl-3,4-dihydro-2H,14'H-spiro[naphthalene-l,2r- [19]oxa[12]thia[l,13] diaza

tetracycio[13.7.2.0- ⁶ .0 ¹⁸ ' ²³ ]tetracosa[8,15,17,23]tetraenhl4'-one 12',12'-dioxide (Example 769; 5 mg, 0.0086 mmol) following the procedure described for

Example 84 providing (lS,3'R,6'R,7'S)-6-chloro-7'-hydroxy-l 1 ,i -dimethyl-3,4- dihy dro-2H, 14'H-spiro [naphthalene- 1 ,2 Γ- [ 19] oxa[ 12]

thia[l,13]diazatetracyclo[13.7.2.0 ³ -^0^^

12 ^* , 12'-dioxide (3.2 mg, 0.0054 mmol, 63,8 % yield). ¾ NMR (500MHz, CD2CI2) δ 10.20 (br s, ill).7.71 (d, .7=8,6 Hz, IH), 7.47 (dd, ./ 2.1.8.4 Hz, IH), 7.28 (d, ./ 1.7 Hz, IH), 7.15 (dd, J=2.3, 8.4 Hz, IH), 7.09 (d, ./ 2 A Hz, IH), 6.95 (d, ./ 8.3 Hz, IH), 4.10 - 4.05 (m, 2H), 3.94 - 3.85 (m, IH), 3.81 (d, .7=15.4 Hz, IH), 3.58 (d, .7=14,2 Hz, IH), 3.15 (d, .7=14,4 Hz, IH), 3.08 (dd, ./ 8.2.15.0 Hz, IH), 2.82 - 2.70 (m, 3H), 2,62 (br s, IH), 2.27 (qum, J=8.3 Hz, IH), 2.11 - 2.07 (m, 1 H), 2.04 - 1.97 (m, 2H), 1.96 - 1.85 (m, 3H), 1.82 - 1.74 (m, 3H), 1 ,70 - 1.

5H), 1.51 (s, 31 ! ). 1.48 (s, 3H). MS (ESI, +ve ion) m/z 587, 1 i V! H )

EXAMPLE 771. (l S ₅ 3 ^, R,6 ^, R,7 ^, S,9 ^, E)-6-CHLORO-7 ^, -HYDROXY-3 ₅ 4- DIHYDRO-2H, 14H-SPIRO[NAPHTHALENE-l ,21 ^* - [ 19]OXA[ 12]THI A[ 1 , 13]DI AZ ATETRAC YCLO

[13.7.2.0 - ⁶ .0 ^!8 - ²³ 1TETRACOSA 9,15,17,23]TETRAEN]-14'-ONE 12',12'- DIOXIDE

STEP 1. PROP-2-E E-1 -SULFONAMIDE

The title compound was synthesized from N,N-bis(4-methoxybenzyl)prop- 2-ene-l -sulfonamide (Example 756, Step 3; 265 mg, 0.733 mmol) following the procedure decribed for Intermediate EE17, Step 2 providing prop-2-ene-l- sulfonamide (35 mg, 0.289 mmol, 39.4 % yield).

STEP 2. (S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYBUT-3-EN-l-YL)CYCLOBUT X)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [1,4]ΟΧΑΖΕΡΓΝΕ-3,Γ- N APHTHALENE1 -7-C ARBOXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S)-l½droxybut-3-en-l -yl)(^clobutyl)me l)-3^4,4^54etrahydro-2H,2H- spiro[benzo[b] [l,4] oxazepine-3, r~naphthalene]-7-carboxylic acid (Intermediate AA13A; 49 mg, 0.102 mmol) and prop-2-ene- 1 -sulfonamide (Example 771, step

1, 35 mg, 0.289 mmol) following the procedure described for Example 719, Step

2, Step 1. Purification of the crude material provided (S)-N-(allylsulfonyl)-6'- chloro-5-((( 1 R,2R)-2-((S)- 1 -hydroxy but-3-en- 1 -yl)cy clobutyl)methyl)-3',4,4',5~ tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide (50 mg, 0.085 mmol, 84 % yield).

STEP 4. (1 S,3'R,6'R,7'S,9 ^, E)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 14TI-SPIROI NAPHTHALENE- 1,21'- [ 19]OXA[l 2]THIA| 1 , 13 jDIAZATETRACYCLO

[13.7.2.0 ³ - ⁶ .0 ¹⁸ - ²³ ]TETRACOSA[9,15,17,23]TET1 AEN]-14'-ONE 12',12'- DIOXIDE OR (1 S,3 ^, R,6 ^, R,7 ^, R,9 ^, E)-6-CHLORO-7 ^, -HYDROXY-3 ₅ 4-DIHYDRO- 2H, 14'H-SPIRO [NAPHTHALENE- 1 ,21'-

[19]OXA[12]THIA[1, 13]DL ZATETRACYCLO[13.7.2,0^ ⁶ .0 ¹⁸ - ²³ ]

TETiL CQSA[9,15,17,23]TETRAEN]-14'-QNE 12',12'-DI0X1DE

The title compound was synthesized from (S)-N-(allylsulfonyl)-6'-chloro- 5 -((( 1 R,2R)-2-((S)- 1 -hydroxy but-3-en- 1 -y i)cy clobuty l)methy i)-3 ^* ,4,4', 5 - tetrahy dro-2H,2'H-spiro| benzoj bj[ 1,4] oxazepine-3, l'-naphthalene]-7- carboxarnide (Example 771, step 3, 50 mg, 0.085 mmol) following the procedure described for Example 742, Step 2. The crude material was purified by silica gel chromatography on a 12 g IS CO Gold column eluting with a gradient of 10-20- 50% EtOAc (containing 0.3% AcOH) in hexanes over 18 min to provide (l S,3'R,6¾,7'S,9^M)-chk)ro-7'½droxy~3,4^

l,21'-[19]oxa[12]thia[l, 13] diazatetracyclo[13.7.2.0 ³ ' ⁶ .0 ¹⁸ ' ²³ ] tetracosa

[9,15,17,23]tetraen]-14'-one 12',12'-dioxide (5.8 mg, 0.0010 mmol, 12.2% yield). ^] H NMR (400MHz, CD2CI2) δ 7.69 (d, ./ 8.4 Hz, i l l . 7.19 - 7.15 (m, IH), 7.14 (br s, 1 H), 7.12 (br s, i l l ). 7,09 (d, ./ 2.2 Hz, l i s ). 6.93 (d, ,/ 8 2 Hz, I I I). 5.79 (td, ·/ 6.7. 15.7 Hz, IH), 5.59 (td, J=7.3, 15.0 Hz, 1H), 4.19 (dd, J=8.0, 14.3 Hz, 1H), 4.13 (s, 2H), 4.11 - 4.04 (m, IH), 3.62 (br s, 3H), 3.37 (br s, 2H), 2.83 - 2.69 (m, 2H), 2,60 (quin, J=8.9 Hz, H), 2.47 - 2,35 (m, ! ! ! ). 2.28 (ddd, ,/ 5.2. 8,6, 14.0 Hz, IH), 2.18 - 2.10 (m, IH), 1.98 - 1.74 (m, 6H), 1 ,67 (quin, .7=10.6 Hz, IH), 1.56 ·· 1.48 (ni, IH), 1.46 (dd, J=10.0, 20.0 Hz, IH). MS (ESI, +ve ion) m/z 557.2 (M+H) ⁺ .

EXAMPLE 772. (18,3¾,6Ί ,7'8,8Έ,1 l'R)~6"CHLORO-7 ^! ~HYDROXY-l Γ- (METHOXY METHYL)-3,4-DIHYDRO-2H,14'H-SPIR()|NAPHTHALENE- 1 ,21 ^* -[ 19] OXA[ 12]THIA[ 1,13]

DIAZATETRACYCLO[l 3.7.2.0 ³ · ⁶ .0 ³⁸ - ²³ ]TETRACOSA[8,15, 17,23] TETRAEN] - 14 ^! -QNE 12',12'-D10XIDE OR (18,3¾,6'ί ,7'8,8Έ,1 l'S)-6-CHLORO-7'- HYDROXY- 1 1 '-(METHOXY METHYL)-3,4-DIHYDRO-2H, 14Ή- SPIRO [NAPHTHALENE- ! ,21 '-[ 19] OXA[ 12]ΤΗΐ.Α[ 1 , ! 3]

DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ - ²³ ]TETRACOSA[8,15,17,23]TETRAEN]- 14'-ONE 12',12'-DI()XIDE

STEP 1. (R)-METHYL 2-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)PENT-4-ENO.ATE AND (S)-METHYL (N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)PENT-4-ENOATE

,N-bis(4-methoxy benz l)but-3 -ene- 1 -sulfonamide (Intermediate EE 16; 740 mg, 1.971 mmol) was azeotroped in PhMe under vacuum for 2 h, then, under Ar, THF was added and the solution was cooled to -78 ° C. Butyllithium solution (2.5 M in hexanes; 0.946 ml,, 2.37 mmol) was then added and the mixture was stirred at -78 ° C for 60 min. In a separate flask, a solution of methyl

chloroformate (Sigma Aldrich; 0.305 mL, 3.94 mmol) in THF (4 mL) was cooled to -78 °C. To this solution was added the anion solution slowly. After 0 min the mixture was quenched with sat. H4C1, allowed to reach ambient temperature and extracted with EtOAc, dried over MgS0 ₄ and concentrated. The crude mixture of (R)-methyl 2-(N,N-bis(4-methoxy benzyl)sulfamoyl)pent-4-enoate and (S)-methyl 2-(N,N-bis(4~methoxybenzyl)sulfamoyl)pent-4-enoate (¾ NMR showed a significant amount of unreacted starting material) was used without further purification.

STEP 2. (R)- 1 -HYDROXY-N,N-BlS(4-METHOXYBENZYL)PENT-4-ENE-2- SULFONAMIDE AND (S)-l-HYDROXY-N,N-BIS(4- METHOXYBENZYL)PENT-4-ENE-2-SULFON AMIDE

To a 50 mL round-bottomed flask charged with a mixture of (R)-methyl 2- ( ,N-bis(4-methoxybenzyl)sulfamoyl)pent-4-enoate and (S)-methyl 2-(N,N-bis(4- methoxy benzyl) sulfamoyl)pent-4-enoate (Example 772, step 1, 854 mg, 1.97 mmol) in THF (9.85 mL) at ambient temperature was added lithium borohydride (2.0 M solution in tetrahydrofuran; 1.97 mL, 3.94 mmol) and a few drops of MeOH. The mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with IN HC1, diluted with NH ₄ C1 and extracted with EtOAc. The organic phase was dried over MgSCH, filtered and concentrated. The crude material was purified by chromatography through a 24 g ISCO Gold column, eiuting with a gradient of 15 % to 60 % EtOAc in hexane, to provide a mixture of (R)-l -hydroxy -N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide and (S)~l~hydroxy-N,N-bis(4-meihoxybenz3'l)pent-4-ene-2-sulfonam ide (415 mg, 1.02 mmol, 52.0 % yield for the two steps).

STEP 3. (R)- 1 -METHOXY-N,N-BIS(4-METHOXYBENZYL)PENT-4-ENE-2- SULFO AMIDE AND (S)-l-METHOXY-N,N-BlS(4- METHOXYBENZYL)PENT-4-ENE-2-SULFONAMIDE

To a 50 mL round-bottomed flask was added a mixture of (R)- [-hydroxy - N,N-bis(4-memoxybenzyl)pent-4-ene-2-sulfonamide and (S)-l -hydroxy -N,N- bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide (Example 772, step 2, 415 mg, 1.02 mmol) and iodomethane (1.27 mL, 20.5 mmol) in THF (6.82 mL) and the mixture was cooled to - 78 °C. Potassium tert-butoxide (1.0 M solution in tetrahydrofuran; 1.003 mL, 1.003 mmol) was added dropwise via a syringe slowly. The mixture was stirred for 1 hr then it was allowed to warm to ambient temperature. The mixture was then quenched with sat NH4G and extracted with EtOAc. The organic phase was dried, filtered and concentrated. The crude material was purified by chromatography through a 24 g ISCO Gold column, eiuting with a gradient of 10% to 40% EtOAc in hexane, to provide (R)-l- methoxy-N,N-bis(4-methoxybenz 1)pent-4-ene-2-sulfonairade and (S)-l - methoxy-N,N-bis(4-methoxybenz l)pent-4-ene-2-sulfonamide (371 mg, 0, 884 mmol, 86 % yield). STEP 4. (R)- 1 -METHOXYPENT-4-ENE-2-SULFONAMIDE AND (S)-l- METHOXYPENT-4-ENE-2-SULFON AMIDE

To a solution of (R)-l -methoxy -N,N-bis(4-methoxy benzy l)pent-4-ene-2- sulfonamide and (S)- 1 -methoxy -N,N-bis(4-methoxy benzy l)pent-4-ene-2- sulfonamide (371 mg, 0.884 mmol) and anisole (0.961 mL, 8.84 mmol) in CH2CT2 (4.4 mL) at ambient temperature was added trifluoroacetic acid (2.63 mL, 35.4 mmol) slowly. After stirring for 5 h (TLC 30% EtO Ac/hex showed complete loss of starting material) the mixture was concentrated. The residue was diluted with EtOAc, washed with sat. NaHCCb, back extracted with EtOAc, dried over MgS0 ₄ and concentrated. The crude material was purified via chromatography through a 24 g ISCO gold column eluting with a gradient of 0-50% EtOAc in hexanes to provide (R)-l -methoxy pent-4-ene-2-sulfonamide and (S)-l -methoxy pent-4-ene-2- sulfonamide (139 mg, 0.776 mmol, 88 % yield).

STEP 5. (S)-METHYL 6'-CHLORO-5-(((lR,2R)-2-((l S,5R,E)-l-HYDROXY-6- METHOXY-5-SULFAMOYLHEX-2-EN-l -YL)CYCLOBUTYL)METFFYL)- 3 ⁱ ,4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE~3, 1 '- NAPHTHALENE] -7 -C ARB OXYL ATE AND (S)-METHYL 6'-CHLORO-5- (((1 R,2R)-2-((l S, 5 S,E)- 1 -HYDROXY-6-METHOXY-5-SULF AMOYLHEX-2- EN-l-YL)CYCLOBUTYL)METHYL)-3' ₅ 4.4 ^, ,5-TETRAHYDRO-2H,2H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , Γ -NAPHTHALENE] - 7- CARBOXYLATE

The title compound was synthesized from (S)-methyl 6'-chloro-5- (((lR,2R)-2-((S,E)-l-hydroxyhex-2-en-l -yl)cyclobutyl)me l)-3',4,4 ^, ,5- tetrahydro-2H,2'H-spiro[benzo[b][l,4] oxazepine-3,r~naphthalene]-7-carboxylaie (Intermediate AA12A, Step 1A: 100 mg, 0.191 mmol) and a mixture of (R)-l- methoxypent-4-ene-2-sulfonamide and (S)- 1 -methoxypent-4-ene-2-sulfonamide (Example 772, Step 4; 137 mg, 0.763 mmol) following the procedure described for Example 762, Step 1. The reaction mixture was directly injected into a 12 g 1SCO Gold column, and purified eluting with a gradient of 10-20-50-100 % EtOAc in hexanes over 16 min to give (S)-methyl 6'-chloro-5-(((l R,2R)-2- ((i S,5R,E)-l -hydroxy-6-meihoxy-5-sulfamoylhex-2-en~l-yl) cyclobut>'l)m.ethyl)~ 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carbox late and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((lS,5S,E)-l-hydroxy-6- methoxy-5-sulfamoylhex-2-en-.l -yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro[benzo[b] [l,4] oxazepine-3,1 '-naphthalene] -7-carboxylate (52 mg, 0.082 mmol, 43.0 % yield). STEP 6. (S)-6'-CHLORO-5-(((lR,2R)-2-((lS,5R,E)-l-HYDROXY-6-

METHOXY-5-SULFAMOYLHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)- 3 ^, ,4,4',5-TETRAHYDR()-2H,2TI-SPIRO[BENZ()[B]|;i ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID AND (S)-6'-CHLORO-5-(((lR,2R)- 2-((l S,5S,E)- 1 -HYDROXY-6-METHOXY-5-SULFAMOYLHEX-2-EN- 1 - YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7 - C ARB OXYLI C ACID

A B flask was charged with (S)-methyl 6'-chloro-5-(((lR,2R)-2- ((l S,5R,E)-l -hydroxy-6-methoxy-5-sulfamoylhex-2-en-l-yl)cyclobu1yl)methy l)- 3\4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7- carboxylate and (S)-methyl 6'-chloro-5-(((lR,2R)-2-((lS,5S,E)-l -hydroxy-6- methoxy-5-sulfamoylhex-2-en-l-yl)cyclobutyl)methyl)-3',4,4', 5-tetrahydro- 2H,2 ^, H-spiro| ^' benzo| ^' b] [ l,4]oxazepine-3,r-naphthalene|-7-carboxylate (Example 772, step 5, 52 mg, 0.082 mmol) , THF (1.1 mL), MeOH (0.548 mL) and 1 N LiOH (0.575 mL, 0.575 mmol). The mixture was stirred at ambient temperature for 50 min. then at 50 °C for 1.5 h, then again at ambient temperature overnight then again at 50 °C for 2 h. The mixture was then quenched with 1 N HC1 (1.15 mL, 1.15 mmol), diluted with brine (20 mL), then extracted with EtOAc (2 x 15 mL). The combined organics were dried (MgS0 ₄ ) and concentrated. The crude mixture of (S)-6'-chloro-5-(((lR,2R)-2-((l S,5R,E)-l -hydroxy-6-methoxy-5- sulfamoylhex-2-en-l-yl) cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid and (S)~6 ^! ~ cMoro-5-(((lR,2R)-2-((l S,5S,E)-l-hydrox>'-6-methoxy-5-sulfamoylhex-2-en-l- yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b] [ 1 ,4] oxazepine- 3,r-naphthalene]-7-carboxylic acid was taken on to the next step without further purification.

STEP 7. (1 S,3'R,6'R,7'S,8'E,irR)-6-CHLORO-7'-HYDROXY-i - (METHOXYMETHYL)-3,4-DIHYDRO-2H, 14'H-SPIRO[NAPHTHALENE- 1,21 19] OXA[ 12]THI A[ 1 , 13]DIAZA

TETR,4CYCLO[ 13.7.2.() ³ -^0 ^{i 8} - ²³ ]TETRACOSA[8, 15, 17,23]TETRAEN]-14'- ONE 12',12'-DIOXIDE OR (1S,3 ^! R,6'R,7'S,8'E, 1 l ^, S)-6-CHLORO-7'- HYDROXY - 11 '-(METHOXY METHYL)-3 ,4-DIHYDRO-2H, 14Ή- SPI O [ APHTHALENE- 1 ,21 '-[ 1 9] OXA[ 12] THI A[ 1 , 13]

DI AZATETRACYCLO [ 13.7.2.0 ³ · ⁶ .0 ³⁸ - ²³ ]TETRACOSA[8,15, 17,23] TETRAEN] - 14'-ONE 12', 12'-D10XIDE The title compound was synthesized from a mixture of (S)-6'-chloro-5-

(((lR,2R)-2-((l S,5R,E)-l -hydrox\'-6-methoxy-5-sulfamoylhex-2-en-l- yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine- 3,l '-naphthalene]-7-carboxylic acid and (S)-6'-chloro-5-(((l R,2R)-2-((l S,5S,E)- 1 - hydroxy-6-methoxy-5-sulfamoylhex-2-en-l-yl)cyclobutyl) methyl)-3',4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b j [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxy lie acid (Example 772, step 6, 50.8 mg, 0.082 mmol) following the procedure described for Example 74, Step 3. The crude material was purified by

chromatography through a ISCO gold column 12 g, eluting with a gradient of 10- 40-50 % EtOAc (containing 0.3% AcOH) in hexanes over 20 min, to provide the inseparable mixture of the two epimers. This material was repunfied via reverse- phase HPLC eluting with a gradient of 45-60% MeCN (containing 0.1 % TFA) in water (containing 0.1 % TFA) over 39 min. to provide (1 S,3'R,6'R,7'S,8'E, 1 1'R)- 6-chloro-7'-hydroxy-l 1 '-(methoxymethyl)-3,4-dihydro-2H, 14Ή- spiro[naphthalene- l ,21 '-[ 19]oxa[12]thia[ .l , 13]

diazatetracyclo[13.7.2.0 ³ -^0 ¹⁸ - ²³ ]tetracosa[8, 15, 17,23]tetraen]-14 ^! -oiie 12',12'- dioxide or (1 S,3'R,6'R,7'S,8'E,1 rS)-6-chloro-7'-hydroxy-l l '-(methoxymethyl)- 3 ,4-dihy dro-2H, 14'H-spiro [naphthal ene- 1,2 ! '- [19]oxa[12]thia[l , 13]diazatetracyclo[i 3,7.2,0 ³ ' ⁶ .0 ^ls - ²³ ] tetracosa

[8, 15, 17,23]tetraen]-14'-one 12', 12'-dioxide as the first eluting and major isomer (7.1 mg, 0.012 mmol, 14.4% yield). ^! H NMR (400MHz, CD2CI2) δ 8.35 (br s,

IH), 7,71 (d, ,/ 8.6 Hz, IH), 7. 18 (dt, ./ 2.2. 8.0 Hz, 2H), 7.09 (d, ./ 2,3 Hz, IH), 6,95 (d, ./ 8.2 Hz, IH), 6.73 (br s, i l l ). 5.92 (td, .7=5,9, 15, 8 Hz, IH), 5.84 (dd, ./ 5.3. 15.3 Hz, I H), 4.14 - 4.07 (m, 3H), 3.93 - 3.81 (m, 3H), 3.71 (d, ./ 14.9 Hz, 1 IT), 3.66 (dd, ,/ 4 , 7. 15.3 Hz, IH), 3,40 (s, 3H), 3,33 (d, ./ 14.5 Hz, IH), 3.1 6 (dd, .7=8.1, 15.6 Hz, IH), 2, 89 - 2.67 (m, 41 ! ). 2.59 (dt, .7=4.9, 8,3 Hz, IH), 2,38 (dq, ./ 5.8. 8.6 Hz, IH), 2.04 (br s, IH), 1.98 - 1.88 (m, 3H), 1.87 - 1.80 (m, IH), 1 .81 - 1.72 (ra, 1H), 1,70 - 1.61 (m, 2H), 1 .48 - 1.40 (ra, 1H). MS (ESI, +ve ion) m/z 601.3 i VI H ) EXAMPLE 773. (lS,3'R,6 ^! R,7'S,8'E,irS)-6-CHLORO-7'-HYDROXY-ir- (METHOXYMETHYL)-3,4-DIHYDRO-2H, 14 ^* H-SPIRO | APHTHALENE- l,21'~[19]OXA

[ 12]TH1A[1,13]DIAZATET1 ACYCLO[13.7.2.0 ³ -^0 ¹⁸ - ²³ ]TETRACOSA[8,15,17, 23 jTETRAENj-14 ^* -ONE 12',12'-DIOXIDE OR (1 S,3'R,6'R,7'S,8 ^* E,I . l'R)-6- CHLORO-7-HYDROXY- 1 1 '-(METHOXYMETHYL)-3,4-DIHYDRO-2H, 14Ή- SPIRO [NAPHTHALENE- 1 ,21 ^* -

[19]OXA[ 12]TH1A[1,13]DIAZATEII ACYCLO[13.7.2.0 ³ -^0 ¹⁸ - ² ^TETRACOSA [8,15, 17,23]TETRAEN]-14'-ONE 12',12'-DK)XIDE

The title compound (5.7 mg, 0.0095 mmol, 11.6% yield) was obtained as the second eluting and minor isomer from the purification described in Example 772 step 7. ^l H NMR (400MHz, CD2CI2) δ 7.70 (d, ,7=8,6 Hz, IH), 7. 17 (dd, .7=2.3, 8.4 Hz, 1H), 7.09 (d, J=2.3 Hz, IH), 7.07 (dd, ./ 2.0. 8.0 Hz, 1H), 6.95 (d, J=2.0 Hz, i l l). 6.93 (d, ./ 8.2 Hz, IH), 5.88 - 5.81 (m, IH), 5.79 (dd,■/ 4.3. 15.5 Hz, 1H), 4.11 (s, 2H), 4.03 - 3.98 (m, IH), 3,95 - 3.87 (m, 2H), 3.86 - 3.81 (m, IH), 3,66 id ./ 14.7 Hz, IH), 3.64 (dd, ./ 5,4. 15.4 Hz, IH), 3.38 (s, 3H), 3.37 - 3.33 (m, i l l ). 3.25 (dd, ./ 7. L 15.3 Hz, I H), 2.84 - 2.66 (m, 4H), 2.62 - 2.43 (m, 3H), 2.02 - 1 ,96 (m, IH), 1.94 - 1 .81 (m, 3H), 1.77 - 1,60 (m, 3H), 1.48 (t, J=10.3 Hz, IH). MS (ESI, +ve ion) m/z 601.3 (M+H) ⁺ .

EXAMPLE 774, (1 S,3'R,6'R,7'S,8'E,1 l'R)-6-CHLORO-7 ^, -HYDROXY-l Γ- (METHOXYMETHYL)- 11 '-METHYL-3 ,4-DIH YDRO-2H, 14Ή- SP1RO [NAPHTHALENE- Ι . Γ- [19]OXA[12]THIA[1,I3]DIAZATETRACYCLO[!3.7.2,0- ⁶ .0 ^IS ' ²³ ]TETRACOSA [8,15,17,23]TETRAEN] - 14'-ONE 12 ^' .12'-DIOXIDE OR

(lS,3'R,6'R,7'S,8 ^, E,i S)-6-CHLORO-7 ^, -HYDROXY-i - (METHOXYMETHYL)-ll'-METHYL-3,4-DIHYDRO-2H,14'H-SPIRO

[NAPHTHALENE- 1,21'-

I Ι·· ⁾ |ΟΧΛ| Ι2ΓΓ!Π.\| Ι.Ι3|5)!Λ . Λ ^' 1 ···Γ1 Λ(·Υ(·|.( ⁾ | j3.7.2.0 ^;! '.O ^{ls ,;} |

TETRACOSA8, 15,17,23 ]TETRAEN]-14'-ONE 12',12'-DIOXIDE

STEP 1. (R)-METHYL 2-(N,N-BIS(4-METHOXYBENZYL)SULFAMOYL)-2- METHYLPENT-4-ENOATE AND (S)-METHYL 2-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)-2-METHYLPENT-4-ENOATE

The title compounds were synthesized from (S)-N,N-bis(4- me1hoxyben2yl)pent-4-ene-2-sulfonamide (Intermediate EE17, Step 1, first eluting isomer; 515 rng, 1.322 ramol) following the procedure described for Example 772, Step 1. The crude mixture of (R)-methyl 2-(N,N~bis(4- methoxybenzyl)sulfamoyl)-2-methylpent-4-enoate and (S)-methyl 2-(N,N-bis(4- methoxy benzyl)sulfamoyl)-2-methylpent-4-enoate was taken on to the next step without purification. STEP 2. (R)-l -HYDROXY-N,N-BIS(4-METHOXYBENZYL)-2- METHYLPENT-4-ENE-2-SULFONAMIDE AND (S)- 1 -H YDROX Y-N ,N- BlS(4-METHOXYBENZYL)-2-METHYLPENT-4-ENE-2-SULFONAMIDE

The title compounds were synthesized from the crude mixture of (R)- methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-methylpent-4-enoate and (S)- methyl 2-(N,N-bis(4-niethoxybenzj'l)sulfamoyl)~2-methylpent-4-enoat e (Example 774, step I, 592 nig, 1.32 mmol) following the procedure described for Example 772, Step 2. Purification of the crude material by chromatography through a 24 g ISCO Gold column, eluting with a gradient of 20% to 60% EtOAc in hexane provided a mixture of (R)-l -hydroxy -N,N-bis(4-methoxybenzyl)-2-methylpent-4- ene-2-sulfonamide and (S)-l-hydroxy-N,N-bis(4-methoxybenzyl)-2-methylpent- 4-ene-2-suifonamide (292 mg, 0.696 mmol, 52.6% yield for the two steps).

STEP 3. (R)-l-METHOXY-N,N-BlS(4-METHOXYBENZYL)-2- METHYLPENT-4-ENE-2-SULFONAMIDE AND (S)- 1 -METHOXY-N,N-

BIS(4-METOOXYBENZYL)-2-METHYLPENT-4-ENE-2-SULFONAMTDE

The title compounds were synthesized from a mixture of (R)- l-hydroxy- N,N-bis(4-methoxyberizyl)-2-methylpent-4-ene-2-sulfonamide and (S)-l - hydroxy -N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-2-sulfonamide (Example 774, step 2, 292 rag, 0.696 mmol) following the procedure described for Example 772, Step 3. The crude mixture of (R)-l -hydroxy -N,N-bis(4-methoxy benzyl)-2- methylpent-4-ene-2-sulfonamide and (S)- 1 -hy cLroxy-N,N-bis(4-methoxybenzyl)- 2-methylpent-4-ene-2-sulfonamide was used without purification.

STEP 4. (R)~ 1 -METHOXY -2-METHYLPENT-4-ENE-2-S ULFON AMIDE AND (S)-l-METHOXY-2-METHYLPENT-4-ENE-2-SULFONAMIDE

The title compounds were synthesized from a mixture of (R)~l -hydroxy - N,N-bis(4-methoxy berizyl)-2-methylpent-4-ene-2-sulfonamide and (S)-l - hydroxy -N,N-bis(4-methoxybenzyl)-2-methylpent-4-ene-2-sulfonamide (Example 774, step 3, 302 mg, 0.697 mmol) following the procedure described for Example 772, Step 4. Purification of the crude material by chromatography through a 24 g ISCO Gold column, eluting with a gradient of 0% to 50% EtOAc in hexane provided (R)-l-methoxy-2-methylpent-4-ene-2-sulfonamide and (S)-l-methoxy- 2-methylpent-4-ene-2-sulfonamide (76 mg, 0.393 mmol, 56.5 % yield for the two steps).

STEP 5. (S)-6 ^* -CHLORO-5 -(((1 R,2R)-2-(( 1 S ,5R,E)~ 1 ~HYDROXY-6- ETHOXY-5-METHYL-5-SULFAMOYLHEX-2-EN-1- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B J [l ,4]OXAZEPINE-3, ! '-NAPHTHALENE]-7-C ARBOXYLIC ACID AND (S)-6 ^, -CHLORO-5-(((lR,2R)-2-((lS,5S,E)-l -HYDROXY-6- METHOXY-5-METHYL-5-SULFAMOYLHEX-2-EN-1- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

The title compound was synthesized from (S)-6'-chloro-5-(((l R,2R)-2-

((S,E)-l-hydroxyhex-2-m-l -yl)cyciobu^^^

spiro[benzo[b] [l,4] oxazepine-3, -naphthalene]-7-carboxylic acid (Intermediate AA12A; 50 mg, 0.098 mmol) and a mixture of (R)-l -methoxy-2-methylpent-4- ene-2-sulfonami de and (S)- 1 -methoxy-2-methy lpent-4-ene-2-sulfonamide (Example 774, Step 4; 76 mg, 0.393 mmol) following the procedure described for Example 762, Step 1 but using 1,2-DCE as solvent. The reaction mixture was directly injected into a 12 g ISCO Gold column, and purified eluting with a gradient of 10-20-50-100 % EtOAc in hexanes over 16 min to provide partial purifcation of (S)-6'-chloro-5-(((lR,2R)-2-((lS,5R,E)-l-hydroxy-6-methoxy-5 - methyl-5-sulfamoylhex-2-en-l-yl)cyclobutyl) methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l '-naphthalene]-7-carboxylic acid and (S)-6'- cWoro-5-(((lR,2R)-2-((lS,5S,E)-l-hydroxy-6-methoxy-5-methyl- 5-sulfam 2-en-l-yl)cyclobut )methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[bl[l,4] oxazepine-3, I '-naphthalene]-7-carboxylic acid. This mixture was used without further purifcation.

STEP 6. (l S,3'R,6'R,7'S,8'E,i rR)-6-CHLORO-7'-HYDROXY-ir- (METHOXYMETHYL)- 1 1 '-METHYL-3,4-DlHYDRO-2H, 14Ή- SPIRO[NAPHTHALENE-l ,21 '-[ 19] OXA[ i 2]THI A[ 1 ,13]

DI AZATETRACYCLO [ 13.7.2.0 ³ · ⁶ .0 ¹⁸ - ²³ ]TETRACOS A[ 8,15, 17,23 jTETRAEN] - 14 ^* -ONE 12',i2'-DIOXIDE OR (1S,3'R,6'R,7'S,8'E, 1 l'S)-6-CHLORO-7'- HYDROXY-1 1 '-(METHOXY METHYL)-! 1 '-Ν Π ^' ! i IYI .- 4-ί)Π IY DKO- 2H, 14'H-SPIRO[NAPHTHALENE- 1 ,21 '- [19]OXA[ 12]THIA[1, 13]DIAZATETRACYCLO[13.7.2,0 - ⁶ .0 ^IS ' ²³ ]TET ACOSA [8, 15, 17,23] TETRAEN] - 14'-ONE 12', 12'-DIQXIDE

The title compound was synthesized from a mixture of (S)-6'-chloro-5- (((lR,2R)-2-((lS,5R,E)-l -hydroxy~6~methoxy-5^

yl)cyclobu1\d)methyl)-3',4,4',5-tetrariydro-2H,2'H-spiro[ benzo[b] [l ,4]oxazepine- 3,r ^» naphthaleiie]-7~carboxylic acid and (S)-6'-chloro-5-(((lR,2R)-2-((l S,5S,E)-l- hydroxy-6-methoxy-5-raethyl-5-sulfamoylhex-2-en-l-yl)c> lobutyl)me1hyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7- carboxylic acid (Example 774, step 5, 56 nig, 0.088 nimoi) following the procedure described for Example 762, Step 3. The crude material was purified by chromatography ihrough a ISCO gold column 12 g, eluting with a gradient of 10- 40-50 % EtOAc (containing 0.3% AcOH) in hexanes over 24 min, to provide the inseparable mixture of the two epimers. This material was repurified via reverse- phase HPLC eluting with a gradient of 45-60% MeCN (containing 0.1 % TFA) in water (containing 0.1 % TFA) over 36 min. to provide the first eluting and minor isomer (1S,3'R,6 ^! R,7'S,8'E,1 rR)-6-chloro-7'-hydroxy-l r-(methoxy methyl)-! Γ- methy 1-3 ,4-dihy dro-2H, 14'H-spiro | naphthalene- 1 ,2 Γ- [ 19 j oxaj 12]thia

[ l, 13]diazatetracyclo[13.7.2,0 ³ ' ⁶ .0 ^{! 8} - ^?3 ] tetracosa[8,15, 17,23]tetraen]-14'-one 12',12'-dioxide or (lS,3'R,6 ^, R,7 ^, S,8 ^! E,l l ^! S)-6-chloro-7 ^! -hydiOxy-ir-

(methoxymethyl)-l Γ -methyl-3 ,4-dihy dro-2H,14'H-spiro[naphthalene-l,21'- [19]oxa[ 12]thia[l , 13]diazaietracydo i 1 3.7 2.0 ^; ".0 ^{i K} " j

tetracosa[8,15, 17,23]tetraen]-14'-one 12',12'-dioxide (4.1 mg, 0.0067 mmol, 7,5 % yield). ¾ NMR (500MHz, MeO -d4) δ 7.73 (d, J=8.6 Hz, IH), 7.17 (dd, J=2.2, 8.6 Hz, IH), 7.12 (dd, ./ 2. 1. 8.2 Hz, IH), 7.10 (d, ./ 2.2 Hz, I H), 6.93 (d, ./ K. I Hz, IH), 6,90 i d. ./ 1 .7 Hz, IH), 6,20 (td, ./ 6.3. 15.2 Hz, IH), 5.81 (dd, ,/ 7.9, 15,3 Hz, IH), 4.21 (dd, .7=4,3, 7.7 Hz, IH), 4,06 (s, 2H), 3.86 (d, «7=13.7 Hz, IH), 3.72 (d, ,7=14.2 Hz, IH), 3.66 (q, J=10.0 Hz, 2H), 3.40 (d, ./ 14.4 Hz, IH), 3.37 (s, 3H), 3.09 (dd, J= \ 1.2, 15.2 Hz, IH), 2,87 (dd, J=6.4, 16.9 Hz, I H), 2,83 - 2.72 (m, 21 0. 2,53 (dd, ./ 6.7. 17.0 Hz, 2H), 2.36 (dq, J=4,3, 9.3 Hz, IH), 2,09 (d, ./ 13.4!!/.111).1,99 - 1.88 (m, 3!!}.1.82 (dt,J=5.1, 9,2 Hz, 2H), 1.76 - 1,67 (m, IH).1.54 (s, 3H), 1.48 - 1,40 (m, ill). MS (ESI, +ve ion) mJz 615.1 i.YI H) . EXAMPLE 775. (lS,3'R,6 ^! R,7'S,8'E,irS)-6-CHLORO-7'-HYDROXY-ir- (METHOXY METHYL)-! 1 '-METHYL-3 ,4-DIH YD RO-2H, 14Ή- SPIRO[NAPHTHALENE-l,21'-

[19]OXA[12]TH1A[1,13]DL ZATETRACYCLO[13.7.2.0^^0 ¹⁸ - ²³ ]TETRACOSA [8,15,17,23] TETRAEN]- 14'-ONE 12 ^* ,12'-DIOXIDE OR

(1S,3'R,6'R,7'S,8'E,1 l'R)-6-CHLORO-7'-HYDRiXW-l Γ-

(METHOXYMETHYL)- 11 '-METHYL-3 ,4-DIH YDRG-2H, 14Ή-

SP1RO [NAPHTHALENE- 1,21 19] OXA[ 12]THI A[ 1,13] DIAZ ATETRAC YCLO

[13.7.2.0 ³ - ⁶ .0 ^iS - ²³ lTETRACOSA];8,15,17,23]TETRAEN]-14'-ONE 12',12'-

DIOXIDE

The title compound (4,8 mg, 0.0078 mmol, 8.8 % yield) was obtained as the second eluting and major isomer from the purification described in Example 774 step 6. ^! ll NMR (500MHz, eOH -,·/·/) δ 773 (d, J=8.6 Hz, IH), 7.17 (dd, «/=2.4, 8.6 Hz, IH), 7.11 - 7.08 (m, .21 i).6.92 (d,■/ 8. I Hz, ill).6.89 (br s, IH), 6.24 (td, ,/ 64.15,6 Hz, ill), 5.77 (dd, ./ 6.8. 15.4 Hz, ill).4.18 (dd, ,/ 4,2.5,9 Hz, IH), 4.06 (s, 211).3,77 (d, J=9.8 Hz, IH), 3.77 - 3.70 (m, 2H), 3.70 (d, J=9.5 Hz, ill). 3.41 (d,J=14.7Hz, IH), 3.31 (s, 3H), 3.13 (dd, J=l l. L 15.3 Hz, IH), 2.87-2.75 (m, 211).2.71 (dd, ./ 6.L 17.9 Hz, IH), 2.65 (dd, ./ 6,6.16.9 Hz, IH), 2.62 - 2.54 (m, IH), 2,34 (qd, ./ 4.4.8.8 Hz, IH), 2.09 id../ 134 Hz, IH), 1.99 - 1.89 (m, 3H), 1.89 - 1,79 (m, 211).1,73 (quin, .7=9.2 Hz, ill).1,49 (s, 3H), 1,47 - 1.40 (m, IH). MS (ESI, +ve ion) m/z 615.1 (M+H) ⁴ . EXAMPLE 776. (lS,3'R,6' ,7'S,8'E)-6-CHLORO-7'-HYD OXY-3,4-

DIHYDRO-2H, 14'H-SPIRO[NAPHTHALENE-l,2r-

119]OXA[ 1 2 ΓΙ Ι1Λ| 1 .13]DIAZ ATETRAC YCLO

[ 13.7.2.0 ³ - ⁶ .0 ⁱ⁸ - ²³ ]TETRACOSA[8, 15J 7,231TETRAEN]-14'-ONE 12',12 ^! - DIOXIDE AND (!S,3'R,6'R,7'S,8'Z)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 14'H-SPIRO [ APHTHALENE- 1,21'- [19]OXA[12]TO1A[1 3]DIAZATET1 ACYCLO[13.7.2.0 ³ - ⁶ .0 ¹⁸ - ²³ ]

TETRACOS A[8, 15,17,23] TETRAEN] - 14'-ONE 12" , 12 -DIOXIDE

STEP 1. (S)-6'-CHLORO-5-(((lR,2R)-2-((S,E)-l-HYDROXY-5- SULFAMOYLPENT-2-EN- 1 -YL)CY CLOBUTYL)METHYL)-3',4,4',

TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, -

N APHTH ALENE] -7-CARBOXYLIC ACID

A vial was charged with (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-((S,E)-l- hydroxyhex-2-en-l -yl)c clobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxaz.epine-3 , 1 '-naphthaien e] -7-carboxyl ate (Intermedi ate AA12B, Step IB, first eluting isomer; 42 mg, 0.074 mmol), but-3-ene-l - sulfonamide (Intermediate EE15: 60.2 mg, 0.445 mmol) and DCM (1 mL). The solution was sparged with argon then Hoveyda-Grubbs II (4.65 mg, 7.42 μίηοί) was added as a solution in 0.5 ml, DCM at ambient temperature. The mixture was stirred under Ar (venting the via] and adding solvent as needed) at ambient tenperature. Aafter 2h more catalyst solution was added and the mixture wasstirred for 1 additional hour. The reaction mixture was directly injected into a 12 g ISCO Gold column, and purified eluting with a gradient of 0-20-100 % EtOAc in hexanes over 20 min to give the intemediate ester. This material (24 rag contaminated with unreacted sulfonamide) was taken up in 1.2 mL of DCM and treated with 0.15 mL TFA at ambient temperature for 5 h, then the mixture was diluted with EtOAc, washed once with NaHCCb, dried and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with 10 to 50 to 100% EtOAc in hexane, to provide (S)-6'-chloro-5-(((l R,2R)-2-((S,E)-l-hydroxy-5-sulfamoylpent-2-en-l- yl)cyclobutyl) rnethyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine- 3,r-naphthalene]-7-carboxylic acid (9.2 mg, 0.016 mmol, 21.6 % yield). STEP 2. (lS,3'R,6 ^, R,7'S,8 ^, E)-6-CHLORO-7 ^, -HYDROXY-3,4-DIHYDRO- 2H, 14'H-SPIRO[NAPHTHALENE- 1 ,21 '- [ 19]OXA[ 12 ]THI A[ 1,13 ]DI AZ ATETRAC YCLO

[13.7.2.0 ³ -^0 ^!8 ^]TETRACOSA[8,15,17,23]TETRAEN]-14'-ONE 12',12'- DIOXIDE AND (lS,3'R,6'R,7 ^! S,8'Z)-6-CHLORO-7'-HYDROXY-3,4~

DIHYDRQ-2H,14'H-SPIR() [NAPHTHALENE- 1 ,21 '-

[19] OX A [12] ΤΗΐ A [ 1 ,13 ] DI AZ ATETR A C YCLO [ 3.7 , 2, 0 ^{3 >6} .0 ^{! 8,23} ]

TETRACOSA[8,15J 7,23]TETRAEN]-14'-ONE 12 ^! ,12'-DIOXIDE

The title compounds were synthesized from (S)-6'-chloro-5-(((lR,2R)-2- ((S,E)-l-hydroxy-5-sulfaraoylpent-2-en-l-yl)c> lobutyl)methyl)-3^4,4^5- tetrahydro-2H,2'H-spiro [benzo[b] [l ,4]oxazepine~3, -naphthalene]-7-carboxylic acid (Example 776, step 1, 9.2 mg, 0.016 mmol) following the procedure described for Example 762, Step 3. The crude material was purified by chromatography through a ISCO gold column 4 g, eluting with a gradient of 10-55 % EtOAc (containing 0.3% AcOH) in hexanes, to provide the title compounds as a 5.4 : 1 mixture of olefin isomers (E:Z respectively; 4.5 mg, 0.008 mmol, 50.5 % yield). Analytical data for the major isomer (18,3Έ,6Ί ,7Έ,8Έ)~6~άι1οί·ο~7'~ hy droxy-3,4-dihy dro-2H, 14'H-spiro[naphthalene- 1 ,21 '-

[19]oxa[12]thia[l,13]diazatetracycio[13.7.2^

]-14'-one 12',12'-dioxide. '!! NMR (400MHz, CD2CI2) δ 8.46 - 8.11 (m, IH), 7.70 (d, 8.6 Hz, 111).7.17 (dd, ,/ 23.8.4 Hz, ill).7,12 - 7,07 (m, 2H), 6.94 (d, ./ 8,2 Hz, IH), 6.89 (d, .1=1.6 Hz, 1H), 5.80 (dd, J=4.3, 15.5 Hz, 1H), 5.72 (td, ./ 6.1.15.6 Hz, 1H), 4.14 - 4.08 (m, 2H), 3.97 (t, ,/ 5.2 Hz, 1H), 3.75 - 3.57 (m, ■ill).3.33 (d, J=14.3 Hz, !!!}.3.21 (dd, ./ 6.7.15.5 Hz, 1H), 2.85 - 2.7! (m, 2H), 2.70 - 2.62 (m, 2H), 2,61 - 2.54 (m, III).2.51 - 2.42 (m, IH), 2,04 - 1.97 (m, 1H), 1.96 - 1.88 (m, 3H), 1.87 - 1.79 (m, IH), 1.75 - 1.60 (m, 3H), 1.51 - 1.41 (m, IH). MS (ESI, +ve ion) m/z 557.2 (M+H) ⁺ .

EXAMPLE 777. (1S,3'R,6 ^! R,7'S,8'E,1 l'S,12'R)-6-CHLORO-7'-(2-((2,4- DIMETHOXY BENZYL)AMINO)ETHOXY)-11^12'-DIMETHYL-3,4- DIHYDRO-2H,15TI-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DLAZATCTRACYCLO[14.7.2,0 ³ '^0 ¹⁹ - ²⁴ ]

PENTACOSA[8,16,18,24]TETR/\EN]-15'-ONE-13', 13'~D10X1DE

To a solution of (1S,3 ^! R,6'R,7'S,8'E,1 l'S,12'R.) -7'-(2-bromoethoxy)-6- chloro-11 ', 12'-dimethyl-3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

[20]oxa[ 13 jthiaj 1,14] diazatetracy cio

[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 14, 15 mg, 0.021 mmol) and 2,4-dimethoxybenzylamine (Sigma Aldrich; 3,83 μΐ, 0.025 mmol) in THF (0.425 mL) at 0 °C was added triethylamine (8.86 μΐ, 0.064 mmol). The reaction mixture was stirred at 0 °C for 1 h (no reaction); then at ambient temperature overnight; no reaction, DMSO was then added (0.4 mL) followed by more reagent and base and the mixture was heated to 50 °C for 5 h. The mixture was the quenched and diluted with water, then extracted with EtOAc (3x3 mL). The organic layer was dried over MgS0 ₄ and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a gradient of 50-100 % EtOAc in heptanes (nothing eluted); The column was then flushed with 100 % 3: 1 EtOAc/'EtOH to provide the title compound but contaminated This material was further purified via Reverse- Phase HPLC providing (1 S,3'R,6'R,7'S,8'E, 1 l'S,l 2 ^, R)-6-chloro-7'-(2-((2,4- dimethoxybenzyl)amino)ethoxy)~ 11 ', 12'-dimethy 1 -3,4-dihy dro-2H, 15'H-spiro [naphthalene- i ,22'-[20] oxa[ 13]thia[ 1 , 14] diazatetracy clo

[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa| 8,16,18,24] tetraen|-15'-one-13', 13'-dioxide

(trifluoroacetic acid salt; 10.6 mg, 0.013 mmol, 63% yield, 95% purity), ¾NMR (500MHz, CD2CI2) δ 8.49 - 8.35 (m, 1H), 8.26 (br s, 111).7.70 (d, ./ 8.6 Hz, lH), 7.19 (br s, 1H), 7.17 (dd, ./ 2.4.8.6 Hz, 111).7.09 (d, ./ 2.2 Hz, 1H), 6.95 - 6.89 (m, 2H), 6,81 (s.111).6,54 - 6.50 (m, 2H), 5.83 (ddd, ,/ 27.9.8, 14.9 Hz, 1H), 5.48 (dd, J=9,2, 15.0 Hz, 111).4,28 - 4,21 (m, 1H), 4.19 (br s, 2H), 4,07 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.83 - 3.79 (ni, Ml).3.77 (br s, 1H), 3.68 (d, ./ 1 .4 Hz, 1H), 3.63 (br s, 111).3.47 (br s, 1H), 3.24 id../ 14.4 Hz, 1H), 3.13 (d, ./ 18.K Hz, 2H), 3,00 (dd, ./ iO.i.15.3 Hz, 111).2.84 - 2.70 (ra, 211).2,45 - 2,37 (m, 111).2.37 - 2.28 (m, 1H), 2.18 - 2.10 (m, 1H), 2.09 - 2.01 (m, 2H), 2.00 - 1.90 (m, 3H), 1.89 - 1.73 (m, 3H), 1.72 - 1.64 (m, 1H), 1.43 id../ 7.1 Hz, 3H), 1.41 - 1.35 (m, 111). 1.00 (d, ./ 6,8 Hz, 31!) MS (ESI, +ve ion) m/z 792.1 {M il)

EXAMPLE 778. (iS,3 ⁱ R,6'R,7'S)-10ACETYL-6-CHLORO-7 ⁱ -HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

[20] OXA[ 13] THI Aj 1,10,14] TRIAZATETRACYCLO

I 14.7.2.0 ^; ^;! ^{i,: n} iFi;N ^' rA(-()SA| Ι6.ΐΗ.24Γ!·ΚΠ:Ν|· !5 ^: ·{)Νί:·!3 ^: .13'-DIOXIDE OR(lS,3'R,6¾,7 ^, R)-i0'ACETYL-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 15'H-SPlRO[NAPHTHALENE- 1 ,22'- [20] OXA[ 13] ΤΉΤΑ[ 1 , 10, 14] TRTAZ ATETRAC YCLO

[14 .21) ³ -^0 ¹⁹ ' ²⁴ ]PF;NTACOSA[16J.8,24]TMEN]-15'-ONE-13' ₅ B'-DIOXIDE

STEP 1 : BIS(2,4-DIMETHQXYBENZYL)AMINE

MeC 3ΜΦ

OMe OMe

2,4-dimethoxybenzaldehyde (Sigma Aldrich; 1.1 g, 6.61 mmol) was dissolved in 20 mL THE at ambient temperature. To the solution was added 2,4- dimethoxybenzylamine (Sigma Aldrich; 1.5 mL, 9.98 mmol) followed by sodium triacetoxyborohydride (Sigma Aldrich; 1.7 g; 8.4 mmol) and the mixture (increasingly cloudy) was stirred at ambient temperature overnight. ^' The mixture was then diluted with sat. NaHCCb and extracted with EtOAc, dried over MgS04 and concentrated. The residue was purified by chromatography on 40 g ISCO column eluting with a gradient of 0 to 100% EtOAc to deliver bis(2,4- dimethoxybenzyl)amine (2.08 g, 6.55 mmol, 99% yield, 96% purity)

STEP 2: N,N-BIS(2,4-DIMETHOXYBE ZYL)ETHENESULFONAMIDE

To a solution of bis(2,4-dimethoxybenzyl)amine ( Example 778, step 1, 1 .500 g, 4,73 mmol) and triethylamine (2.301 ml, 16.54 mmol) in CH2CI2 (23.63 ml) cooled to 0 °C was added 2-chloroethanesulfonyl chloride (0.494 ml, 4.73 mmol) dropwise over 5 minutes. The yellow mixture was stirred at 0 °C for 1 h. TLC (50% EtO Ac/hex anes) showed complete loss of both starting materials and formation of a new product. The mixture was then diluted with CH2CI2 and washed twice with brine, then dried over MgS0 ₄ and concentrated. The crude orange oil was purified by chromatography through a column (24 g), eluting with a gradient of 0 % to 20 % to 60 % to 100% EtO Ac in hexane, to provide N,N- bis(2,4-dimethoxybenzyl)ethenesulfonamide (1.162 g, 2.85 mmol, 60.3 % yield)

STEP 3: 2-AMINO-N,N-BIS(2,4- DIMETHOXYBENZYL)ETHANESULFONAMIDE

To a solution of N,N-bis(2,4-dimethoxybenzyl)ethenesulfonarnide

(Example 778, step 2, 260 mg, 0.638 mmol) in MeOH (2.55 mL), was added triethylamine (0.097 mL, 0.702 mmol) followed by ammonia (7 N solution in methanol; 1.823 mL, 12.76 mmol). The mixture was heated to 60 °C overnight. The solvent was then removed under reduced pressure and the residue was dried under high vacuum. The crude material was purified via column chromatography eluting with a gradient of 0 to 100% CH2CI2 (containing 10% MeOH and 0.2% EtsN) in hexanes to provide 2-amino-N,N-bis(2,4- dimethoxybenz>'l)ethanesulfonamide (60 mg, 0, 141 mmol, 22.15 % yield) STEP 4: (S)-6 ^* -CHLORO-5-(((lR,2R)-2-

{ RY PROXY YI H 1 I 1 Υ ! . )ίΎ( ί OBL TY UY! i -: 1 1 1 Y ! . )-.V.4. .5- Π ·. ! R AI !Y DRO-

2H,2'H"SPIRO[BENZO[B][ l,4]OXAZEPINE-3,l'- APHTHALENE] -7- CARBOXYLIC ACID

A vial was charged with (S)-methyl 6'-chloro-5-(((lR,2R)-2- (hydroxymethyl)cyelobutyl) methyl)-3',4,4',5-tetrahydro-2H,2H- spiro [benzo | b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Intermediate

AA1A, Step 19 A; 300 mg, 0.658 mmol) , THF (8.77 mL), MeOH (4.39 mL) and 1 N LiOH (4.61 mL, 4.61 mmol). The mixture was stirred at 60 °C for ! h then it was quenched with 1 N HC1 (9.21 mL, 9.21 mmol), diluted with brine (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried (MgS04) and concentrated. The crude (S)-6'-chloro-5-(((lR,2R)-2-

spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid was used without further purification. STEP 5: (S)-6'-CHLORO-5-((( lR,2R)-2-FORMYLCYCLOBLTYL)METHYL)-

3 ^f ,4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3 , 1 '- NAPHTHALENE] -7 -C ARB OXYLIC ACID

A 100 mL round-bottom flask was charged with (S)-6'-chloro-5-(((lR,2R)- 2-(hydrox methyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid (Example 778, step 4, 290 mg, 0.656 mmol) and DCM (3.28 mL). To the solution, cooled to 0 °C was added Dess-Martin periodinane (417 mg, 0.984 mmol). The mixture was stirred while allowing to reach ambient temperature for 1 h then it was diluted with EtOAc (30 mL), washed with 1 N sodium thiosulfate (1 x 30 mL) and brine (1 X 30 mL). The aqueous layer was back extracted with EtOAc (lx 15 mL) and the combined organics were dried over MgS€>4 and concentrated. The crude red foam was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0 % to 40 % EtOAc in hexane, to provide (S)-6 ^! ~chloro-5-(((lR,2R)-2-formylcyclobutyl)methyl)-3V4,4', 5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (20 ! mg, 0.457 mmol, 69.6 % yield). STEP 6: (S)-5-(((lR,2R)-2-ACRYLOYLCYCLOBUTYL)METHYL)-6'-

CHLORO-S'^^^S-TETRAHYDRO^H^'H-

SPIRO[BENZO[B][l,4]OXAZEPINE-: r-NAPHTHALENE]-7-CARBOXYLIC ACID

To a solution of (S)-6'-chloro-5-(((l R,2R)-2-formylcyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid (Example 778, step 5, 164 mg, 0.373 mmol) in tetrahydrofuran (1.86 mL) under an argon atmosphere at 0 °C was added vinylmagnesium bromide (1.0 M solution in tetrahydrofuran; 0.634 mL, 0.634 mmol) dropwise, via syringe. After 0.5 h the mixture was quenched with saturated aqueous ammonium chloride, diluted with brine and extracted with EtOAc. The organic phase was dried over MgS04 and concentrated. The crude material was taken up in 3 mL CH2CI2 and treated directly with Dess-Martm periodinane (237 mg, 0.559 mmol) at 0 °C for 1.5 h then diluted with EtOAc, washed with saturated sodium thiosulfate and brine (once each). The aqueous layer was back-extracted once with EtOAc and the combined organics were dried over MgS04 and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a gradient of 0 % to 50 % EtOAc in hexane, to provide (S)-5-((( ^' lR,2R)-2-aciyloylcyclobutyl)methyl)-6'-chloro-3',4,4', 5- tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (73 mg, 0.157 mmol, 42.0 % yield for the three steps).

STEP 7: (S)-5-(((lR,2R)-2-(3-((2-(N,N-BIS(2,4- DIMETHOXYBENZYL)SULFAMOYL)

ETHYL)AMINO)PROPANOYL)CYCLOBUTYL)METHYL)-6'-CHLORO- ;r,4,4',5-TETRAHYDRO-2H,2TI-SPIRO[BENZO[B][ l,410XAZEPINE-3,l '- NAPHTHALENE]-7-CARBOXYLIC ACID AND (S)-5-(((lR,2R)-2-(3-((2- (N (2,4-DIMETHOXYBENZYL)

SULFAM()YL)ETHYL)AMIN())PROPANOYL)CYCL()BUTYL)METHYL)-6'- CHLORO~3^4,4^5-TETRAHYDRO~2H,2'H~

SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYL IC ACID

To a solution of (S)-5-(((lR,2R)-2-acryloy Icy clobutyl)methyl)-6'-chloro-

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7- carboxylic acid (Example 778, Step 6; 63 nig, 0.135 mmol) and 2-amino-N,N- bis(2,4-dimethoxybenzyl) ethanesulfonamide (Example 778 Step 3; 60 mg, 0.141 mmol) in CH2CI2 (2.7 mL) at ambient temperature was added N,N- diisopropylethylamine (0.071 mL, 0.406 mmol) dropwise, via syringe. After 3 h the mixture was concentrated in vacuo and the crude material was purified via reverse-phase HPLC (34 min.; 2 injections) to provide an inseparable mixture of (S)-5-(((lR,2R)-2-(3-((2-(N,N-bis(2,4- dimethox 'benz}d)sulfamoyl)ethyl)amino)propanoyl) cyclobutyl)methyl)-6'- chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-3, - naphthaleiie]-7-carboxyiic acid and (S)-5-(((lR,2R)-2-(3-((2-(N(2,4- dimethoxy benzyl) sulfamoyl)ethyl)amino)propanoyl)cyclobutv'l) methyl)-6'- chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '- naphthalene] -7-carboxylic acid (53 mg, 0.60 mmol). This material was used without further purification.

STEP 8: (S)-6'-CHLORO-5-(((lR,2R)-2-(3-(N-(2- S ULF AMO YLETHYL) ACETAMIDO)

PROPAN()YL)CYCLOBUTYL)METHYL)-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO[B] [1 ,4]OXAZEPTNE-3, .1 '-N APHTH ALENE] - 7 -C ARB OXYLIC

ACID

To a solution of (S)-5-(((l R,2R)-2-(3-((2-(N,N-BIS(2,4- dimethoxybenzyl)sulfamoyl) ethyl)amino)propanoyl)(yciobutyl)methyl)-6'- chloro-3',4,4',5-tetrahydro-2H,2'H-spiro [benzo[b] [l,4]oxazepine-3,l'- naphthalenej-7-carhoxyiic acid and (S)-5-(((l R,2R)-2-(3-((2-(N(2,4- dime1hoxybenzyl)sidfamoyl)ethyl)ammo)pro^

3',4,4',5~tetraliydro-2H,2'H~spiro[benzo[bl [l,4]oxazepine-3,l '-naphthalene j-7- carboxylic acid (Example 778, step 7, 53 mg, 0.060 mmol) in CH2CI2 (1.19 mL) at ambient temperature was added triethylamine (0.029 raL, 0.208 mmol) followed by acetic anhydride (6.18 μΐ, 0.065 mmol) and the mixture was stirred at ambient temperature for 30 mm. The mixture was then diluted with EtOAc and washed with NaHCOs. The aqueous phase was back extracted with EtOAc and the combined organics were dried over MgSCM and concentrated. The crude material was taken up in CH2CI2 (1.5 mL) and thioanisole (0.070 mL, 0.595 mmol) was added followed by the dropwise addition of trifluoroacetic acid (0.5 mL, 6.73 mmol). After stirring for 30 min (bright blue color developed) LC/MS analysis showed complete conversion to the desired product. The mixture was then diluted with EtOAc, washed with sat. NaHCC , dried over MgS04 and concentrated. The crude material was purified via reverse-phase HPLC to provide (S)-6'-chloro-5- ((( 1 R,2R)-2-(3-(N-(2-s dfmnoy leth^

3 ^f ,4,4 ^f ,5-teirahydro-2H,2'i-I-spiro| benzo | b] [ .1 ,4 joxazepine-3,1 '-naphtha! ene]-7- carboxylic acid (26.8 mg, 0.042 mmol, 71.2% yield).

STEP 9: (l S ₅ 3 ^, R,6 ^, R,7 ^, S)-10'ACETYL-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[13]THIA[ 1 , 10, 14] TRIAZ ATETRAC YCLO

[14.7.2.0 - ⁶ .0 ^!9 - ²⁴ lPENTACOSA[16,18,24|TRIENj-15'-ONE-13', 13'-DIOXIDE OR (1 S,3'R,6'R,7'R)-10'ACETYL-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'- [20] OXA[ 13] THI Aj 1,10,14] TRIAZATETRACYCLO

[ 14.7.2.0 ³ ' ⁶ .0 ^ί9 · ²⁴ ]ΡΕΝΤΑ(Χ)8Α[ 16, 18,24]ΤΜΕΝ|-15 ^, -ΟΝΈ-13·, 13'-DI()XIDE (S)-6'-chloro-5-(((lR,2R)-2-(3-(N-(2- su3famoylethyl)acetamido)pi panoyl)cyc3obutyi) methyi)-3',4,4 ^! ,5-tetrahydro- 2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,l '-naphthalene]-7-carboxylic acid (Example 778, step 8, 26.8 mg, 0.042 mmol) was placed into a 100 mL round bottom flask and CH2CI2 (84.8 mL) was added folowed by N,N-dimethylpyridin- 4-amine (7.77 mg, 0.064 mmol). The mixture was cooled to 0 °C and N-(3- dimethylaminopropy])-N'-ethylcarbodiimide hydrochloride (16.25 mg, 0.085 mmol) was added slowly portion-wise and the mixture was stirred while allowing to reach ambient temperature overnight, then it was concentrated. The crude material was purified by chi maiography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a gradient of 0 % to 100 % EtOAc (containing 0.3% AcOH) in hexanes, to provide the desired intermediate ketone (13 mg). This material was dissolved in 1 .5 MeOH and to the cold solution (0 °C) was added sodium borohydrate (1.604 mg, 0.042 mmol) in one portion. LC/MS analysis after 10 min. showed complete conversion to the expected mixture of diastereomers. The mixture was quenched at 0 °C with sat. NH4CI and extracted with EtOAc (4 x 10 ml.), dried over MgS04 and concentrated. The crude material was purified via reverse-phase HPLC to provide the title compounds as a 5: 1 mixture of

diastereomers. This material was repunfied by SFC to provide (1S,3'R,6'R,7'S)- 10'acetyl-6-chloro-7'-hydroxy-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1 , 10, 14] tnazatetracy clo[ 14.7.2.0 ³ · ⁶ 0 ¹⁹ · ²⁴ ]

pentacosa[16,18,24]trien]-15 ^* -one-13',13 ^! -dioxide or (I S,3'R,6'R,7 ^! R)-10'acetyi-6- chloro-7'-hydroxy -3,4-dihy dro-2H, 15TI-spiroj naphthalene- 1,22'- [20] oxa[ I 3 ] thi a[ 1,10, 14] tri azatetracy cl 0

[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]tnen]-15 ^! -one-13',13'-dioxide (0.9 mg, 0.001 mmol). ^! H NMR (400MHz, MeO -d ) 0 7.75 (d, J=8.8 Hz, I I I ). 7.28 (s, I I I ). 7.21 - 7. 12 (ra, 2H), 7 10 (s. IH), 6,87 (d, J=7.6 Hz, 1H), 4.14 - 4.10 (m, 1H), 4.10 - 4,02 (m, 2H), 3.94 - 3.83 (m, 2H), 3.71 (d, .7=14.1 Hz, IH), 3,67 - 3,63 (m, IH), 3.59 (br s, i l l ). 3.53 - 3.46 (m, 2H), 3.39 (d, J=13.3 Hz, 2H), 3.16 - 3.10 (m, IH), 2.87 - 2.71 (m, 3H), 2.51 (br s, IH), 2.13 (s, 3H), 2.09 - 2.03 (m, IH), 2.01 - 1.82 (m, 4H), 1 .79 - 1.64 (m, 3H), 1.62 - 1.50 (m, I H), 1 .50 - 1.41 (m, IH). MS (ESI, +ve ion) m/z 616.1 (M+H) ⁺ .

EXAMPLE 779. (3'R,6'R,7S, 22S)-6'-CHLORO-7-HYDROXY-3',4'~DIHYDRO~ 2Ή, 15H-SPIRO[i 0,20-DIOXA- 13 -THI A- 1,14-

DL/ ZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA-16,18,24-TRlE E-22, 1 '-NAPHTHALENJ-l 5-ONE- 13, 13-DIOXIDE OR (3 ^* R,6'R,7R, 22S)-6 ^! -

CHLORO-7-HYDROXY-3',4'-DIHYDRO-2'H, 15H-SPIRO[ 10,20-DIOXA- 13- TfflA- 1 , 14-DI AZ ATETRAC YC LO [ 14.7.2, 0 ³ · ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOS A- 16, 18,24- TRIENE-22, 1 ' ·ΧΛΡί ΓΠ lAS .i iN i- Ι 5·ΟΝί :· 1 . 13-DIOXIDE

STEP 1 : ((lR,2S)-2-((E)-PENT-l-E -l -YL)CYCLOBUTYL)METHYL

ACETATE

A solution of (butyl)triphenylphosphonium bromide (30.5 g, 76 mmol) in THF (271 ml) was cooled to 0 °C. Butyllithium solution (2.5 M in hexanes; 29.2 ml, 73.0 mmol) was added dropwise and the resulting mixture was stirred at 0 °C for 12 min. ( iR,2S)-2-formylcyclobulyl) methyl acetate (Intermediate AA1 1 A, Step 16: 5.30 g, 33.9 mmol) was added and the mixture was stirred for 60 min. TEC (1 :2 EtOAc / hexane) showed complete disapperance of the starting material. The reaction mixture was added to stirred ice-water (60 mL), the organic phase was separated and the aqueous was extracted with EtOAc (200 mL). The combined organics were dried over MgSCX^ and concentrated to give a red oil.

The crude material was purified by silica gel chromatography eiuting with a gradient of 0-50% EtOAc in heptanes to give ((l R,2S)-2-((E)-pent-l-en-l - yl)cyclobu1yl)methyl acetate (4.66 g, 23.8 mmol, 70% yield).

STEP 2: (lR,2S)-2-((E)-PENT-l-EN-l- YL)CYCLOBUTANECARB ALDEHYDE

Lithium hydroxide (1 N, aq.; 53.5 mL, 53.5 mmol) was added to a solution of ((l R,2S)-2-((E)-pent-l-en-l-yl)c clobutyl)methyl acetate (Example 779, step 1, 3.5 g, 17.8 mmol) in MeOH (100 mL) at ambient temperature. The reaction was warmed to 45 °C and left overnight. The mixture was then cooled and most of the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with IN HC1 and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was redissolved in DCM (40 mL), sodium bicarbonate (7.49 g, 89 mmol) was added and the mixture was stirred vigorously and cooled to 0 °C. Dess-Martin periodinaiie (9.08 g, 21.4 mmol) was added in 10 portions over 20 min. The mixture was warmed to ambient temperature and stirred for an additional 4 h, quenched with IN sodium thiosuifate and IN sodium bicarbonate (1 : 1, 50 mL:50 ml.) and then stirred vigorously for 2 h. The layers were separated and the orgamcs were dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in hexanes and filtered through celite to remove remaining light yellow solids. This material was used without further purification. STEP 3. : (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((E)-PENT-l-EN-l -YL)

CYCLOBUTYL)METHYL)~3V4,4V5-TETRAHYDRO-2H,2'H-SPIRO

[BENZO [B] [ 1 ,4] OXAZEP1N E-3, 1 '-NAPHTHALENE] - 7- C ARBOXYL ATE

(lS,2R)-2-((E)-pent-l-en-l -yl)cyclobutanecarbaldehyde (Example 779, step 2, 213 mg, 1.397 mmol) was added to a solution of (S)-methyl 6'-chloro- 3',4,4',5-tetrahy dro-2H,2'Hspiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7- carboxylate (Intermediate AA11A, Step 11 , 250 mg, 0.699 mmol) in DCM (3.88 mL) and AcOH (1.94 mL). The mixture was stirred at 0 °C for 10 min. then sodium cyanoborohydride (88 mg, 1.40 mmol) was added slowly portion wise during 40 min and maintained at 0 °C for 1 h. The mixture was then poured slowly into sat. Na ₂ C0 ₃ solution (50ml) at 0 °C and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous magnesium sulfate. filtered and concentrated. The crude material was purified by column

chromatography on a 24 g column eluting with a gradient of 0 to 10 to 20 % EtOAc in heptane) to provide (S)-methyl 6'~chloro-5"(((lR,2S)-2-((E)-pent-l-en~ l-yl)c 'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (294 mg, 0,595 mmol, 85% yield).

STEP 4: (S)-6'-CHLORO-5-(((lR,2S)-2-((E)-PENT-l -EN-l- YL)CYCLOBUlTL)MEraYL)-3',4,4',5~TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7 - C ARB OXYLI C ACID

A solution of (S)-methyl 6'-chloro-5-(((lR,2S)-2-((E)-pent-l-en-l- yl)cyclobutyl)methyl) -3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine- 3, l '-naphthalene]-7-carboxylate (Example 779, step 3, 294 mg, 0,595 mmol) in THF (7.9 mL) and MeOH (3.97 mL) was treated with 1 N LiOH (4.17 mL, 4.17 mmol) at 50 °C for 1 h then at 60 °C for 3.5 h. The mixture was then cooled to ambient temperature, quenched with 1 N HCl (8.33 mL, 8.33 mmol), diluted with brine (50 mL), then extracted with EtOAc (3 x 30 mL), The combined organics were dried (MgS0 ₄ ) and concentrated to give a white foam. The crude (S)-6'- chloro-5-(((lR,2S)-2-((E)-pent-l-en-l-yl)cyclobutyl)me1hyl)- 3',4,4',5-tetrahydro- 2H,2*H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 -naphthalene] -7-carboxylic acid (268 mg, 0.558 mmol) was used without further purification.

STEP 5: (S)-N-((2-(ALLYLOXY)ETOYL)SULFONYL)-6'-CHL()RO-5- (((1 R,2S)-2-((E)-PENT-l-EN-l -YL)CYCLOBUWL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4] OX AZEPINE-3, 1 '- NAPHTHALENE] -7 -C ARB OXAMIDE

The title compound was synthesized from (S)-6'-chloro-5-(((l R,2S)-2- ((E)-pent-l -en-l-yl)cyckjbutyi)methyl)-3',4,4 5-tetrahydro-2Il,2'H- spiro[benzo[b] [l,4]oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (Example 779, step 4, 170 mg, 0.354 mmol) and 2-(allyloxy)ethaiiesulfonamide (Example 817, Step 3, 398 mg, 2,41 mmol) following the procedure described for Example 1 , Step 1. Purification of the crude material provided (S)-N-((2- (allyloxy)ethyl)sulfonyl)-6 ^, -chloro-5-(((lR,2S)-2-((E)-pent-l-en-l-

3,l ^f -naphthalene]-7-carboxamide (50 mg, 0.080 mmol, 22.5% yield).

STEP 6: (3'R,6'R,7E, 22S)-6'-CHLORO-3 ^, ,4 ^, -DIHYDRO-2 ^, H,15H-SPIRO[ 10,20- DIOXA-13-ΤΉΤΑ-1 ,14-DIAZATETRACYCLO[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]PENTACOS A- 7-16,18,24-TETRAENE-22, Γ-ΝΑΡΗΤΗΑΕΕΝ]-15-ΟΝΈ-13, 13-DIOXIDE

The title compound was synthesized from (S)-N-((2- (dlyloxj e hyl)sulfonyl)-6'-chloro-5-(((l R,2S)-2-((E)-pent-l-en-l- yl)c 'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro [benzo[b] [l ,4]oxazepin 3, -naphthalene]-7-carboxamide (Example 779, step 5, 50 mg, 0.080 mmol) following the procedure described for Example 742, Step 2. Purification of the crude material provided (3'R,6'R,7E, 22S)-6 ^, -chloro-3 ^, ₅ 4'-dihydro-2H,15H- spiro[10,20-dioxa-13-thia-l,14-d^^

16,18,24-tetraene-22, r-naphthalen]-15-one-13, 13-dioxide (27 nig, 0.048 mmol, 60.8% yield).

STEP 7. (3'R VR,7S, 22S)-6'-CHLORO-7-HYDROXY-3',4'-DIHYDRO-2'H,15H- SP1RO [ 10,20-DIOXA- 13 -THIA- 1,14-

DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA-16,18,24-TRIENE-22, 1 '-NAPHTH ALEN] - 15 -ONE- 13, 13-DIOXIDE OR (3'R,6'R,7R, 22S)-6'- CHLQRQ-7-HYDRQXY-3',4'-DlHYDRQ-2'H, 15H-SPIRO[ 10,20-DIOXA- 13- THIA- 1 , 14-DIAZ ATETRAC YCLO [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ - ²⁴ ]PENTACOS A- 16, 18,24- TRIENE-22, 1 ' -N APHTH ALEN] - 15 -ONE- 13, 13 -DIOXIDE

A solution of (3'R,6 ^! R,7E, 22S)-6'-chloro-3',4'-dihy dro-2'i-1, 1 SHspiro[10,20-dioxa-13-1hia-l,14-diaza^

16, 18,24-tetraene-22, r-naphthalen]-15-one-13, 13-dioxide (Example 779, step 6, 27 mg, 0.048 mmol) in THF (2.2 mL) under Ar was cooled to 0 °C and treated with borane tetrahydrofuran complex (1.0 M in tetrahydrofuran; 0.291 mL, 0.291 mmol). After 1 h N-methylmorpholine oxide (75 rng, 0.640 mmol) was added in one portion and the mixture was stirred while allowing to reach ambient temperature. After 24 h the mixture was diluted with water and brine and extracted with EtOAc and the combined organics were dried over MgS04 and concentrated. The crude material contains a mixture of regioisomers at the 7 and 8 position each of which is a mixture of R/S isomers at the respective new sterocenter. The regioisomers were separated via reverse-phase HPLC to obtain a 3,8 : 1 mixture of epirners (3'R,6'R,7S, 22S)-6'-chloro-7-hydroxy-3',4'-dihydro- 2Ή, 15H-spiro[ 10,20-dioxa- 13 -thia- 1 , 14- diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa-16,18,24-triene-22, -naphthalenj-15- one-13, 13-dioxide and (3'R,6'R,7R, 22S)-6'-chloro-7-hydroxy~3',4'-dihydro- 2Ή, 15H-spiro[ 10,20-dioxa- 13 -thia- 1 , 14- diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa-16,18,24-triene-22, l'-naphthalen]-15- one-13, 13-dioxide as the second eluting component. This fraction was repunfied by SFC to remove the minor epimer. (Sample preparation: 4.0 mg/2 mL (2.0 mg/mL) sample solution in MeOH. Preparative Purification: Column: Chiralpak OJ-H, 21 X 250 mm, 5 μηι; Mobile Phase A: CO2; Mobile Phase B: MeOH (20 mM NFb); Composition: 40% B; Flow Rate: 50 mL/rnin; Loading: 0.5 mL of sample solution prepared as above (1.0 mg/injection); Detection: UV @ 244 nm: Total Elution Time: 6.2 min; Instrument: Thar 80 SFC) The 7-hydroxy regioisomer, (3'R,6'R,7S, 22S)-6 ^, -chloro-7-hydroxy-3 ^, ,4'-dihydro-2H,15H- spiro[10,20-dioxa-13-thia-l,14-diazatetracyclo[14.7.2.0 ^3,6 .0 ¹⁹ ' ²⁴ ]pentacosa- 16,I8,24-triene-22, l'-naphthalen]-15-one-13, 13-dioxide or (3'R,6'R,7R, 22S)-6'- chloro-7-hydroxy-3',4'-dihy dro-2'H, 15H-spiro[ 10,20-dioxa- 13-thia- 1 ,14- diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa-16, I 8,24-triene-22, l '-naphthalen]-I 5- one-13, 13-dioxide (1.9 mg, 0.003 mmoL 6.8% yield) was isolated as the first eluting and major epimer. ¾ NMR (4()()MHz, CD2CI2) δ 7.73 (d, ./ K.4 FIz, I I I ). 7.27 ( dd . ,/ 2 I . 8.3 Hz, i l l ). 7, 18 is, i l l ). 7, 17 (dd, J=2.2, 8.8 FIz, 11 1 ). 7.08 (d, J=2.2 Hz, IH), 6.94 (d, «7=8.2 Hz, 1H), 4.13 - 4.09 (m, IH), 4.07 (s, 2H), 4.05 - 3.94 (m, 2H), 3.82 (dt, J=2.3, 11.1 Hz, 2H), 3.71 (d, J=14.1 Hz, IH), 3.64 - 3.56 (m, 2H), 3.40 (td, ,/ 2.7. 15.3 FIz, IH), 3.19 (d, ./ 14.3 Hz, IH), 3.01 (dd, ./ 8. 1. 15,4 Hz, I H), 2.82 - 2,72 (m, 2H), 2.20 - 1.86 (m, 6H), 1.85 - 1.76 (m, IH), 1.69 - 1.36 (m, 6H). MS (ESI, +ve ion) m/z 575.0 (M+H) ⁺ .

EXAMPLE 780. (3R,6R,8S, 22S)-6'-CHLORO-8-HYDROXY-3",4 ^, -DIHYDRO- 2Ή, 15H-SPIRO[ 10,20-DIOXA- 13-THIA- 1,14-

DL/ ZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA-16,18,24-TRlE E-22, 1 '-NAPHTHALEN]-15-ONE- 13, 13-DIOXIDE OR (3R,6R,8R, 22S)-6'-

CHLORO-8-HYDROXY-3 ^f ,4'-DIHYDRO-2'H, 15H-SPIRO[ 10,20-DIOXA- 13- THIA- 1 , 14-DI AZ ATETRAC YC LO [ 14.7.2, 0 ³ · ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOS A- 16, 18,24- TRIENE-22, 1'-ΝΑΡΗΉ-ΙΑίΕΝ]-15-ΟΝΕ-13, 13-DIOXIDE

From the purification described in Example 779, step 7, the initial reverse phase separation gave the 8-hydroxy epimers with (3R,6R,8S, 22S)-6'-chloro-8- h droxy-3 ^, ,4'-dihydro-2 ^, H, 15H-SPIRO[ 10,20-dioxa- 13-lhia-l , 14- diazatetracycloE14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]pentacosa-16,18,24-triene-22, -naphthalen]-15- one-13, 13-dioxide and (3R,6R,8R, 22S)-6 ^, -chIoro-8-hydroxy-3 ^, ,4'-dihydro- 2 ^* H,15H-spiro[l 0,20-dioxa-13-thia-l ,14-

(Uazatetra(ycio[14 .2.0 ³ ' ⁶ .0 ³⁹ ' ²⁴ ]pentacosa-16,18,24-triene-22, r~naphthalenj-15- one-13, 13-dioxide as the first eluting component as a 7.5: 1 mixture of epimers. This fraction was further purified by SFC (Sample preparation: 4.0 mg/3 mL (1.3 mg/mL) sample solution in MeOH:DCM (2: 1). Preparative Purification: Column: Chiralpak IC, 21 X 250 mm, 5 ην. Mobile Phase A: CO2; Mobile Phase B: MeOH(20 mM NH3); Composition: 35% B; Flow Rate: 50 mL/min; Loading: 0.5 mL of sample solution prepared as above (0.7 rag/injection); Detection: UV @ 244 nm; Total Elution Time: 27.4 min; Instrument: Thar 80 SFC) to provide the first eluting and major isomer as (3R,6R,8S, 22S)-6'-chloro-8-hydroxy-3',4'- dihydro-2'H,15H-spiro| 10,20-dioxa-13 hia-l,14-diazatetracyclo

[14.7.2. Ο^.Ο ¹⁹ · ²⁴ ] pen tacosa- 16,18,24-tri ene-22, l'-naphthalen]-15-one-13, 13- dioxide or (3 ,6R,8R, 22S)-6 ^! -chloro-84iydroxy-3',4'-dihydro-2 ^! H,15H- spiro[ 10,2 ⁽⁾ -dioxa-13-thia-l,14-diazatetracyc3o [ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa-

16, 18,24-triene-22, l.'-naphthalen]-15-one-13, 13-dioxide (2.2 rng, 0.004 rnmol , 7.9% yield). Ή NMR (400MHz, CD ₂ C3 ₂ ) δ 7,72 (d, J=8.6 Hz, IH), 7.23 (d, .7=7.4 Hz, 1H), 7.17 (d, J=8.6 Hz, IH), 7.08 (s, IH), 7.04 (br s, 1H), 6.94 (d, J=8.0 Hz, Ι Π). 4.12 - 4.01 (m, 2H), 3.98 - 3.81 (m, 4H), 3.74 (d, ./ 14.7 Hz, IH), 3.69 - 3.56 (m. 11 1 ). 3,56 - 3.43 (m, 2H), 3.41 - 3.31 (m, i l l ). 3,22 (d, ,/ 14.3 Hz, i l l ). 3.27 - 3.13 (m, IH), 2.84 - 2,68 (m, 2H), 2.37 - 2.24 (m, IH), 2.16 (br s, 2H), 2.10 - 1.99 (m, 3H), 1.90 (br s, 2H), 1.83 (br s, IH), 1.75 - 1.67 (m, IH), 1.54 - 1.43 (m, 3! i s, MS (ESI, +ve ion) m/z 575.0 ( M I f ) . EXAMPLE 781. (1 S,3'R,6'R,7'S,11 ¾,13¾)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! - [21 ] OXA[ 14]THI A[ 1,15] DI AZ APENTAC YCLO

[ 15.7.2.0 ³ ' ⁶ .0 ^Η · ^ί3 .0 ²⁰ · ²⁵ ]ΗΕΧΑεθ8Α[17,19,25]ΤΚΙΕ ]-16'-ΟΝΕ 14 ^* ,14'- DIOXIDE or (1 S,3'R,6'R,7'S,1 1 'S,13'S)-6-CHLORO-7'-HYDROXY-3,4- D1HYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 '- [21 ] OXA[ 14]THI A[ 1 , 15 ]DI AZ APENTAC YCLO

[15.7.2.0 ³ -^0 ^{i i} - ¹ l0 ²⁰ ' ²⁵ HEXACOSA[I7, I 9,25]TRIEN]-16'-ONE 14',14'-DIOXTDE

To a solution of Example 793 (1.8 mg, 3.1 μηιοΐ) in MeOH (10 ml.) was added rhodium, 5 wt. % on carbon (0.5 μΐ, 3 μηιοΐ). The reaction mixture was subjected to three cycles of evacuation/back-filling with hydrogen and stirred at r.t. overnight under hydrogen balloon. After the catalyst was filtered off the filtrate was concentrated and the residue was purified by reverse phase

preparatory HPLC (Gemini™ Prep Cis 5μπι column: Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give 0.51 mg of the title compound as a white solid. ¾ NMR (500MHz, CD3CN) δ 7.70 (d, J=8.6 Hz, 1H), 7,47 (s. 11 1 ). 7, 1 8 (dd, ./ 2.3. 8.4 Hz, 11 1 ). 7.14 (s, 11 1 ). 7.03 (dd, ,/ 2 0. 8.1 Hz, 1H), 6,89 (d, «/=8.1 Hz, 1H), 4.20 - 4.10 (m, 2H), 3.67 - 3,52 (m, 3H), 3.51 - 3.41 (m, 3H), 2.78 - 2.73 (m, 2H), 2.69 (td, J=4.2, 8.4 Hz, 2H), 2.50 - 1.03 (m, 15H), 0.94 - 0.82 (m, 4H). 585.2 m/z (ESI, +ve ion).

EXAMPLE 783. (1 S ₅ 3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -ETHYL-7 ^, -(3-

OXETANYLOXY)-3,4 1fflYDRO-2H, 15H-SPIRO[NAPHTHALENE-L22'- [20] OXA[ 13]THI A| 1,14] DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA[8,16,18,24]TETRAEN; 15'-ONE 13', 13'-DIOXIDE

Sodium hydride, 60% dispersion in mineral oil (1.7 fiL, 0.083 mmol) was added to a solution of Example 422, Step 1 (10.0 mg, 0.017 mmol) in 1.0 mL of THF at 0 °C. The reaction mixture was stirred at 0°C for 30 min and then 3- bromooxetane (22 μΕ, 0.27 mmol) was added. The reaction mixture was stirred at r.t. for 3 days and then queched with aq NH4CI solution. It was added 1 N HC1 solution (1 mL) and EtOAc (40 mL). The organic layer was seperated and concentrated. The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 20% to 90% MeCN in water, where both solvents contain 0.1% TFA, 40 min method) to provide the title compound (1.4 nig, 2.14 μηιοΐ) as a white foam. ^] H N.MR (400MHz, CD3CN) δ 9.40 (br s, ill).7,73 (d, ./ 8.4 Hz, !!!).7.24 -7.18 (m, ill).7.17 - 7.13 (m, ill).7,00 - 6.95 (m, III).6.92 - 6.87 (m, ill).6,82 - 6.77 (m, 1H), 5.85 - 5.75 (ni, ill).5.61 - 5.52 (m, 1H), 4.12-3.91 ( m, 3H), 3.84 - 3.76 (m, 2H), 3.74 - 3.68 (m, III).3.55 (dd, ./ 2.9 11.5 Hz, ill).3.45 - 3.37 (m, 1H), 3.29 - 3.23 (ra, IH), 3,13 - 2.98 (m, 1H), 2,83 - 2.70 (ra, 3H), 2,53 - 2.48 (m, 2H), 1.82 - 1.71 (m, 8H), 1,59 - 1.54 (m, III).1.48 - 1.38 (m, 3H), 1,34 - 1.26 (m, 2H), 1.16 (s, 4H), 0.93 - 0.84 (m, Ml). MS (ESI) m/z 655.2 [M + H] ⁺ .

EXAMPLE 784. (lS,3 ^, R,6 ^, R,7 ^, S ₅ 8 ^, E.10 ^, R,12 ^, R)-6-CHLORO-7 ^, -HYDROXY-3.4- DIHYDRO-2H, 16TI-SPIRO [NAPHTHALENE- 1 ,23 ^* -

[2i]OXA[14]THIA[l,15]DiAZAPENTACYCLO [15.7.2.0 ³ - ⁶ .0 ^!0 - ¹² .0 ²⁰ ' ²⁵ ]HEXACOSA[8, 17,19,25]TETRAEN]-16'-ONE 14', 14'- DIOXIDE or (1 S,3 ^! R,6'R,7'S,8'E, 10'S, 12'S)-6-CHLORO-7'-HYDROXY-3,4~ DIHYDRO-2H _s 16H-SPIRO[NAPHTHALENE-l,23'- [ 21 ]OXA[ 14JTHI A[ 1 , 15]DI AZ APE TAC YCLO

[157.2 j ³ - ^f \0 ^10J 0 ²⁰ - ² ^HEXACOSA[8,17, 19,251TETRAEN]-16'-ONE 14', 14'- DIOXIDE

Step 1 : (Z)-4-((TERT-BUTYLDIPHENYLSILYL)OXY)BUT-2-EN-l-OL

To a solution of 6 y-2~butene~l,4~diol (5.0 ml,, 57 mmol) and N,N- diisopropylethylamine (11.9 mL, 68 mmol) in DCM (114 mL) was added tert- butyldiphenylsilyl chloride (14.8 mL, 56.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then at r.t. for 16 h. The reaction was quenched by sat. NH4CI solution (10 mL) at 0 °C and extracted with ethyl acetate (120 mL). The organic phase was washed with NH4CI solution (40 mL), NaHCCb solution (40 mL), brine (10 mL) and dried over anhydrous MgSOi. After concentration the residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 50 % EtOAc /hexane to provide the title compound (12.0 g, 36.8 mmol, 65 % yield).

Step 2: ((l S,2R)-2-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLOPROPYL) METHANOL and ((1 R,2S)-2~(((TERT-BUTYLDIPHENYLSILYL)OXY) METHYL)CYCLOPROPYL)METHANOL

To a solution of diethylzinc, 1.0 M solution in hexanes, (29.4 mL, 29.4 mmol) in DCM (49 mL) was added dropwise diiodomethane (4.74 mL, 58.8 mmol) at -10 °C. After 15 min of stirring, a white precipitate was formed and a solution of (4R,5R)-(-)-2,2-dimethyl-alpha,alpha,alpha',alpha'-tetraphen yl-l,3- dioxolane-4, 5 -dimethaolato [ 1 ,2-bis(dimethoxy )ethane j titanium(IV)di chloride (0,527 g, 0.735 mmol) and molecular sieves 4A ( 1.3 g) in DCM (8 mL) were added by cannula at -10 °C. The solution was stirred at that temperature for 5 min and a solution of (Z)-4-((tert-butyldiphenylsilyl)oxy)but-2-en-l-ol (Example 784, Step 1 ) (8.0 g, 24.5 mmol) in DCM (49 mL) was added at -10 °C . The resulting mixture was allowed to warm to 0 °C for 2 h with light exclusion. The reaction was quenched with 1 N HCl solution at -40 °C and extracted with DCM (2x60 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous MgSCn. After concentration the residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 50 % EtOAc /hexane to provide the title compound (5.72 g, 16.8 mmol, 69 % yield). Step 3 : (1 S,2R)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)CYCLO PROPANE

CARBALDEHYDE and (lR,2S)-2-(((TERT-BUTYLDIPHENYLSILYL)OXY) METHYL)CYCLOPROPANECARB ALDEHYDE

To a white slurry solution of (diacetoxyiodo)benzene (1.04 g, 3.2 mmol) and ((lS,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl )me1hanol

(Example 784, Step 2) (1.0 g, 2.9 mmol) in DCM (9.8 mL) was added 2,2,6,6- tetramethylpiperidinooxy (0.023 g, 0.147 mmol) in one portion and it was stirred at r.t. for 2 h (The mixture became a homogeneous, bright pale orange solution). The reaction mixture was diluted with DCM (60 mL) and washed with sodium bicarbonate solution (30 mL), brine (30 mL) and dried over anhydrous MgSC . It was concentrated to provide the title compound, which was used without further purification.

Step 4 : TERT-B UTYLD1PHEN YL((( 1 R,2R)-2-((E)-PROP - 1-EN-l- YL)CYCLOPROPYL) METHOXY)SILANE and TERT- BUTYLDIPHENYL((( 1 S,2S)-2-((E)-PROP-l -EN-1- YL)CYCLOPROPYL)METHOXY)SILANE

To a solution of (ethyi)triphenylethyiphosphonium bromide (1.4 g, 3.76 mmol) m THF (15 mL) was slowly added n-butyllithium, 2.5 M solution in hexanes (1.3 mL, 3.2 mmol) at -78 °C (dry ice bath). The reaction mixture was stirred at -78 °C for 1 h, forming an orange solution. (lS,2R)-2-(((tert- Butyldiphenyisiiyl)oxy)methyl)cyclopropanecarbaldehyde (Example 784, Step 3) (0.98 g, 2.89 mmol) in THF (4 mL) was added at -78 °C. The temperature of the bath was slowly warmed up to r.t.. The reaction was quenched by sat. NH4CI solution (20 mL), extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSOi. After concentration the residue was loaded on a 24g ISCO Gold column and eluted with 0 % to 30 % EtOAc /hexane to provide the title compound (0.40 g, 1.14 mmol, 39 % yield). Step 5: ((lR,2R)-2-((E)-PROP-l-E -l-YL)CYCLOPROPYL)METHANOL and ((l S,2S)-2-((E)-PROP-l-EN-l -YL)CYCLOPROPYL)METHANOL

To a solution of tert-butyldiphenyl(((l R,2R)-2-((E)-prop-l -en-l- yl)cyclopropyl)methoxy)silane (Example 784, Step 4) (2.0 g, 5.7 mmol) in THF (28 mL) was added tetrabutylammonium fluoride solution, 1.0 M in THF (5.7 mL, 5.7 mmol). The resulting mixture was stirred at r.t. for 18 h. After concentration the residue was loaded on a 24g ISCO Gold column and eluted with 0 % to 50 % EtOAc /hexane to provide the title compound (0.62 g, 5.5 mmol, 98 % yield).

Step 6: 2-((((lR,2R)-2-((E)-PROP-l-EN-l-

YL)CYCLOPROPYL)METHYL)THIO) PYRIMIDINE and 2-((((lS,2S)- PROP- 1 -EN- 1 - YL)C YCLOPROPYL)METHYL)THIO) PYRIMIDINE

(E)-Diethyl diazene-l,2-dicarboxylate (DEAD), 40% w/w in toluene (0.78 mL, 4.3 mmol) was added dropwise to a solution of tributylphosphine (1 .2 mL, 4.85 mmol) in THF (19 mL) at 0 °C. After it was stirred at r.t. for 10 min, ((lR,2R)-2-((E)-prop-l-en-l-yl) cyclopropyl)methanol (Example 784, Step 5) (0.32g, 2.85 mmol) was added dropwise to the phosphine/DEAD complex via syringe as the neat liquid. After the resulting ROiW)EAD Bu3P mixture was aged at 0 °C for 20 mm, pyrimidine-2-thiol (0.640 g, 5.71 mmol) was added in small portions. The reaction mixture was stirr at r.t, for 4 h. Hexane (40 ml.) was added to the reaction mixture and it was stirred at r.t. for 15 min. The solid was removed by filtration and the filtrate was concentrated. The residue was loaded on a 12g ISCO Gold column and eluted with 0 % to 15 % EtOAc /hexane to provide the title compound (0.35g, 1.7 mmol, 60 % yield).

Step 7: 2-((((lR,2R)-2-((E)-PROP-l-EN-l-

YL)CYCLOPROPYL)METHYL)SULFONYL)PYRIMIDINE and 2-((((lS,2S)- 2-((E)-PROP-l-EN-l- YL)C YCLOPROPYL)METHYL)S ULF ON Y L)P Y RIMIDINE

To a solution of 2-((((IR,2R)-2-((E)-prop-l -en-l- yl)cyclopropyl)methyl)tnio)pyrimidine (Example 784, Step 6) (0.40 g, 1.9 mmol) in DCM (9.6 mL) was added 3-chlorobenzoperoxoic acid (0.863 g, 3.85 mmol) in three portions at 0 °C during a perion of 15 min and then it was stirred at r.t. for 3 h. The reaction was then poured into ice and saturated sodium carbonate solution and extracted with DCM. The combined organics were concentrated to provide the crude title compound (0.45g, 1.9 mmol, 98 % yield), which was used without futher purification.

Step 8: SODIUM ((lR,2R)-2-((E)-PROP-l -EN-l-YL)

CYCLOPROPYL)METHANESULFINATE and SODIUM ((iS,2S)- PROP- 1 -EN- 1 - YL )CYCLOPROPYL)METHANESULFIN ATE

To a stirred solution of 2-((((lR,2R)-2-((E)-prop-l-en-.l - clopropyl)methyl) sulfonyl)pyrimidine (Example 784, Step 7) (0.45g, 1.9 mmol) in MeOH (19 mL) was added sodium methoxide (0.43 ml., 1 .9 mmol). After the mixture was stirred at r.t. for 1.5 h, it was concentrated and EteO was added to the mixture. The solid was collected by filtration and purified by washing with cold Et?.0 to provide the title compound, which was used without futher purification.

Step 9: ((lR,2R)-2-((E)-PROP-l-EN-l-

YL)C YCLOPROPYL)METHANESULFONAMIDE and ((1 S,2S)-2-((E)-PROP- 1 -EN- 1 -YL)CYCLOPROPYL)METHANESULFONAMIDE

A solution of sodium ((lR,2R)-2-((E)-prop-l-en-l - yl)cyclopropyl)methanesulfinate (Example 784, Step 8) (0.35g, 1.9 mmol) in water (13 mL) was treated with sodium acetate (0.236 g, 2.88 mmol) and hydroxy lamine-o-sulfonic acid (0.266 g, 2.11 mmol). The reaction was stirred at 50°C for 0.5 h and at r.t. for 1.5 h. Then the reaction was cooled to 0°C, basified with NaOH solution. It was extracted with DCM (2x70 mL) and the combined organic phases were washed with brine and dried over anhydrous MgSi After concentration the residue was loaded on a 12g TSCO Gold column and eluted with 0 % to 75 % EtOAc /hexane to provide the title compound (0.022g, 0.126 mmol).

Step 10: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYOROXYALLYL)CYCLOBUTYL) METHYL)-N-((((lR,2R)-2-((E)-PROP-l- EN- 1 -YL)CYCLOPROPYL)METHYL) SULFONYL)-3',4,4',5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALE E]-7- CARBOXAMIDE and (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXYALLYL)CYCLOBUTYL)METHYL)-N-((((lS ₅ 2S)-2-((E)-PROP-l - EN ~YL)CYCLOPROPYL)METOYL)SUL

2H,2'H~SP1RG[BENZ0[B] [1,4] OXAZEPESfE-3, Γ -NAPHTHALENE] -7- CARBOXAMIDE

4-Pyrrolidinopyridine (19 mg, 0.13 mmol) was added (S)-6'-chloro-5- (((l R,2R)-2-((S)-l-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tet rahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carboxylic acid (Example 784, Step 9) (65 mg, 0.139 mmol) and DIE A (0,088 niL, 0.505 mmol) in DC VI (1.3 ml). Then N-(3-dimethylaminopropyl)-N ^, -ethylcarbodiimide hydrochloride (121 mg, 0.631 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C to r.t. overnight. The reaction mixture was concentrated and the residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 40 % EtOAc

(containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (58 mg, 0.093 mmol, 74 % yield)

Step 11 : (1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-CHLORO-7'-HYDROXY-3 ₅ 4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! - [21 ] OXA[ 14]THI A[ 1 , 15]DI AZ APENTAC YCLO

[ 15.7.2.0 ³ ' ⁶ .0 ¹⁰ · ¹² .0 ²⁰ · ²⁵ ]ΗΕΧΑΟΟ8Α[8,17,19,25]ΤΕΤΚΑΕΝ]-16·-ΟΝ� � 14',14'- DIOXIDE or (1 S,3'R,6'R,7'S,8Ti 10'S, 12'S)-6-CHLORO-7 ^! -HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 '- [21 ]OXA[ 14 |THIA[ 1, 15 [DIAZ APENTACYCLO

[15.7.2.0 ³ - ⁶ .0 ⁱ⁰ - ¹² .0 ²⁰ ' ²⁵ ]HEXACOSA[8, 17,19,25]TETRAEN]-16'-ONE 14', 14'- DIOXIDE

A 100 ml_ round bottom flask was charged with (S)-6'~chloro-5-(((lR,2R)- 2-((S)-l½droxyailyl)cyclobiityl)me l)-N-((((lR,2R)-2-((E)-prop-l-en-l- yl)cyciopropyl)methyl) sulfonyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxamide (Example 784, Step 10) (72 mg, 0.115 mmol) and Hoveyda-Grabbs II (25 mg, 0.040 mmol) and DCE (58 mL). The reaction mixture was subjected to three cycles of

evacuation/back-filling with nitrogen and heated at 60 °C for about 6 h under nitrogen . SiliaMetS (0.2 g, 0.62mmol/g) was added and stirred at r.t. for 30 min. The scavenger was filtrated off and the filtrate was concentrated. The residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 50 % EtOAc

(containing 0.3 % AcQH)/hexane (containing 0.3 % AcOH) to provide the title compound (1.3 mg, 2.2 μηιοΐ) as the second (slower) eluting isomer. Ή NMR (400MHz, CD ₃ CN) δ 7.76 - 7.71 (m, IH), 7.42 (d, J=2.0 Hz, 111).7,25 - 7.19 (m, IH).7.13 (s, I Hi.7.04 - 6.98 (m, ill).6,92 - 6.85 (m, 21!).5.60 (dd, ,7=5,2, 15.6 Hz, IH), 5.39 - 5.29 (m, IH), 4.11 - 4.02 (m, 2H), 4.01 - 3.97 (m, IH), 3.94 - 3.83 (m, 2H), 3.78 - 3.71 (m, 2H), 3.69 - 3.57 (m, 2H), 3.50 - 3.42 (m, 3H), 3.22 (d, ./ 14 \ Hz, 2H), 2.98 (dd, J=4.6, 15.0 Hz, 2H), 2,83 - 2.70 (m, 3H), 2,55 - 1.53 (m, 2H), 1.44 - 1.37 (ni, 2H), 0.97 (dt, J=4.8, 8.9 Hz, IH), 0.92 - 0.82 (m, 2H), 0.34-0.24 ins. IH). m/z (ESI, +ve ion) 583.2 I 11 > ^" . EXAMPLE 785. (lS,3'R,6'R,7 ^, S,8 ^! E,10 ^! R,12 ^, R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1,23- [21 ]OXA[ 14]THIA[1 , 15]DIAZ APENTACYCLO

[15.7.2.0 ³ ' ⁶ .0 ⁱ⁰ - ⁱ² .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETRAENj-16 ^! -ONE 14', 14'- DI()XIDEor(lS,3'R,6'R,7'S,8 ^, E,10'S,12'S)-6-CHLORO-7' IYDROXY-3,4- DmYDRO-2H,16'H-SPIRO[NAPHTHALENE-l,23'- [21 ] OXA[ 14]THI A[ 1 , 15 ]DIAZ APENTACYCLO

[15.7.2.0 -^0 ^!0 - ¹² .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,251TETRAEN]-16 ^, -ONE 14',14'- DIOXIDE

The title compound (2. Img, 3.60 μι οΐ) was obtained as the first (faster) eluting isomer from Example 784 step 11, as a white solid. Ή NMR (400MHz, CD3CN) δ 9.48 (br s. His.7.76 - 7.71 (m, lH), 7.45 - 7.39 (m, ills.7.24 ·· 7.20 (m, 1H), 7.15 (s, 1H), 7.07 - 7.01 (m, 1H), 6.95 - 6.88 (m, 1H), 5.94 (dd, ./ 7.8. 15.1 Hz, IH), 5.62 - 5,49 (m, 1H), 4.23 - 4.15 (m, IH), 4.11 - 4.05 (m, 2H), 3.79 - 3.57 (m, 4H), 3.21 (d, J=I3.9 Hz, 1H), 3.10 - 3.00 (m, IH), 2.83 - 2.72 (m, 2H), 2,49 - 1.62 (m, 711).1.43 (d, ./ i( ⁾ .4 Hz, Ml).1.11 (dd, ./ 4.7.9.0 Hz, IH), 0.95 - 0.83 (rn, 2H), 0.27 - 0,20 (m, IH). m/z (ESI, +ve ion) 583.2 ( M II) .

EXAMPLE 786. iIS,3'R,6'R,7 ^f S,8'E,l l'RJ3'R)-6-CHLORO-7'-(2- VU.n !OXY!. Π K)XY)-3.4-DiRYORO-2i 1.16'! !-SPlRO!WFi Π I l.\!J N! -l 23- [21]OXA[14]THIA[l,15]

DIAZAPENTACYCLO|;i5.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹³ .0 ²⁰ " ²⁵ ]HEXACOSA[8 ₅ 17,19,25]TETRA

EN]-16'-ONE 14',14 ^! ~DIOXIDEor (lS,3'R,6'R,7'S,8 ^! E,irS,13'S)-6-CHLORO-7'- (2-METHOXYETHOXY)-3,4-DIHYDRO-2H,16 ^, H-SPIRO[NAPHTHALEN ^' E- l,23'-[21]OXA|;i4]THIA|l,15]DIAZA

PENTACYTLO[15.7.2,0-^0 ^n>l 0 ²⁰ - ²⁵ ]HEXACOSA[8,17J9,25]TEm

ONE 14',14'-DIOXIDE

NaH (2.5 mg, 0.063 mmol) was added to a solution of Example 793 (7,3 mg, 0.013 mmol) in THF (1.0 mL) at 0"C (ice bath) and it was stirred at this temperature for 30 min. Then l-bromo-2-methox ethane (3.5 μΐ, 0.038 mmol) was added slowly and it was stirred at r.t, overnight. The reaction mixture was quenched with water (15 mL) and acidified with IN HC1 solution to pH 1-2. It was extracted with EtOAc (30 mL) and the organic phase was washed with brine, dried over anhydrous MgSCH and concentrated. The residue was purified by reverse phase preparatory HPLC (Gemini™ Prep Cis 5μτη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (2.1 mg, 1.8 μτηοΐ, 26 % yield) as a white solid. ^l H NMR (500MHz, CDsCN) δ 9.39 (br s, IH), 7.74 (d, ./ 8.6 Hz, i l l ). 7,23 - 7.19 (m, 2H), 7.17 - 7. 14 (ni, 11 1 ). 7.08 (dd, ./ 2.0. 8.1 Hz, IH), 6.92 - 6.88 (m, i l l ). 5.57 (td, ./ 6.2. 15.6 Hz, IH), 5.44 (dd, ./ 6.5. 15.8 Hz, ! ! ! ). 4.19 - 4.07 (m, 2H), 3.66 (d, ./ 14.2 Hz, IH), 3,54 (dd, ./ 6.7. 15.0 Hz, I H), 3.43 - 3.33 (ra, 4H), 3,23 - 3.20 (m, 3H), 3.19

- 3.14 (m, 2H), 2.82 - 2,73 (m, 4H), 2.72 - 2.67 (rn, 2H), 2.62 - 2,52 (m, 2H), 2.07

- 2.01 (m, 2H), 1.91 - 1.87 (m, 2H), 1.82 - 1.77 (m, IH), 1.74 - 1.51 (m, 5H), 1.45 (td, ./ 5.0. 9.5 Hz, IH), 1.05 (ddd, ./ 5.4. 6.7, 8.5 Hz, IH). m/z (ESI, +ve ion)

641 .2 (M+H) ⁺ .

EXAMPLE 787. (lS,3¾,6'R,7'S,10'S,12'R)~6~CHLORO-7 ^! ~HYDROXY-3,4-

DIHYDRO-2H,16H-SPIRO[NAPHTHALENE-l,23'

[ 21 ]OXA[ 14JTHI A[ 1 , 15]DI AZAPE TAC YCLO

[ 15,7.2.0 ³ - ⁶ ,0 ^{10J 2} .0 ²⁰ - ²⁵ ]HEXACOSA[17,19,25]TRIEN]-16 ^* -ONE 14 ^f ,14'-

DIOXIDE and (1 S,3 ^! R,6'R,7'S, 10'R, 12 ^, S)-6-CHLORO-7'-HYDROXY-3,4-

DIHYDRO-2H, 16 ^* H-SPIRO[NAPHTH ALENE-1 ,23'-

[21 ]OXA[ 14]THIA[ 1 , ! 5 ]DI AZAPENTAC YCLO

[15.7.2.0 ³ ' ⁶ .0 ^!0 - ¹² .0 ²⁰ ' ²⁵ ]HEXACOSA[17,19,25]TRTEN]-16 ^f -ONE 14',14'- DIOXIDE

Step 1 : (1 S,3 ^! R,6 ^, R,7'S,8'E,10'R,12'R)-6-CHL()RO-7'-HYDROXY-3,4- DIHYDRO~2H, ! όΉ-SPIRO [NAPHTHALENE- 1,23 - [21 ]OXA[ 14]THIA[1 , 15JDIAZ APENTACYCLO

[15.7.2.0 ³ ' ⁶ .0 ⁱ⁰ ' ⁱ² .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETRAENj-16 ^! -ONE 14', 14'- DIOXIDE find (1 S,3'R,6 ^f R,7'S,8Ti,l 0'S,12'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! - [21 ] OXA[ 14]THI A[ 1 , 15]DI AZ APENTAC YCLO

[ 15.7.2.0 ³ ' ⁶ .0 ⁱ⁰ - ⁱ² .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETRAENj-16'-ONE 14',14'- DIOXIDE

A 100 mL round bottom flask was charged with (S)-6'-chloro-5-(((lR,2R)- 2-((S)-l-hydroxyallyl)cyclobutyl)methyl)-N-((((lR,2R)-2-((E) -prop-l-en-l- yl)cyciopropyl)inethyl) sulfonyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxamide (Example 784, Step 10) (20, 1 mg, 0.032 mmol) and Hoveyda-Grubbs II (16 mg, 0.026 mmol) and DCE (16.1 mL). The reaction mixture was subjected to three cycles of evacuation/back-filling with nitrogen and stirred at 60 °C for 6 h under nitrogen. SiliaMetS (0.2 g, 0.62mmol/g) was added and stirred at r.t. for 30 min. The scavenger was filtrated off and the filtrate was concentrated. The residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 60 % EtOAc

(containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compounds (5.5 mg, 9.4 μιηοΐ, 29 % yield).

Step 2: (lS,3'R,6 ^! R,7'S,10 ^! S,12'R)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 16H-SPIRO[N APHTH ALENE- 1 ,23'-

[21 ]OXA[ 14]THI A[ 1 , 15 ]DI AZ APENT AC YCLO

[15.7.2.0 ³ ' ⁶ .0 ⁱ⁰ ' ⁱ² .0 ²⁰ - ²⁵ ]HEXACOSA[17,19,25]TRTEN]-16 ^f -ONE 14',14'-

DIOXIDE and (lS,3 ^, R,6 ^, R ₅ 7 ^, S,10 ^, R,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-3,4-

DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 ^* - [21]OXA[14]TfflA[l , 15]DIAZAPENTACYCLO [15.7.2.0 ³ - ⁶ .0 ¹⁰ ' ¹² .0 ²⁰ ' ²⁵ ]HEXACOSA[ 17, 19,25]TRIEN]~16'~ONE 14 ^* ,14'- DIOXIDE

To a solution of (Example 787, Step 1) (20.2 mg, 0.034 mmol) in MeOH (17 mL) was added rhodium (3.6 mg, 1.7 μηιοΐ) (5 wt. % on carbon). The reaction mixture was subjected to three cycles of evacuation/back-filling with hydrogen and stirred at r.t. under hydrogen overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 60 % EtOAc (containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compounds (0.98 mg, 1.7 μηιοΐ 10% yield), ^" Ή NMR (500MHz, CDsCN) δ 7.72 (d,■/ 8.6 Hz, I I I ). 7.20 (dd, ./ 2.4. 8.3 Hz, I I I . 7.15 (d, ./ 2.4 Hz, i l l ). 7,05 - 7.02 (m, 11 1 ). 6.92 (d, ./ 8.3 Hz, 2H), 4. 17 - 4,07 (m, 2H), 3.84 - 3.78 (m, i l l ). 3,66 - 3.51 (m, 2H), 3.40 - 3.35 (m, i l l ). 2,99 (br s, 3H), 2.81 - 2.73 (m, 2H), 2.65 - 2.60 (m, 1H), 2.36 - 0.88 (m, 1 81 1 ). m/z (ESI, +ve ion) 585.2 (M+H) ⁺ . EXAMPLE 791. (3R,6R,7S,8E, I 2R,22S)-2 ⁱ -CHLORO-7-HYDROXY-12- METHYL-7 ^! ,8'-DIHYDRO-6'H, 15H-SPIRO[20-OXA- 13-TfflA- 1 , 14- Dl AZATETRAC Y CLO [14.7.2.0 ³ ^ 0 ¹⁹ - ²⁴ ]PENTACOSA-8,16,18,24- TETRAENE-22,5'-QUINOLIN|-15-ONE 13,13-DIOXIDE

Step 1 : (S)-5-(((lR,2R)-2-((S,E)-l-((TERT- BUTYLDlMETHYLSILYL)OXY)HEX-2-EN- 1 - YL)CYCLOBUT L)METHYL)-2'-CHLORO-N-((R)-HEX-5-EN-2-

YLSULFONYL)-4,5,7',8'-TETRAHYDRO-2H,6'H-

SPIRO[BENZO[B][L4]OXAZEPrNE-3,5'-QLTNOI NE]-7-CARBOXAMiDE

N,N-Dimethylpyridin-4-amine (DMAP) (23 mg, 0.19 mmol) was added to a solution of (S)-5-(((l R,2R)-2~((S,E)- 1 -((tert-butyldimethy lsily l)oxy)hex-2-en- 1 - yl)cyclobutyl)methyl)-2 ^, -chloro-4,5,7 ^, ,8'-tetrahydro-2H,6 ^, H- spiro benzo b] l,4]oxazepine-3,5'-quinoline|-7-carboxylic acid (Example 798, Step 15) (60 rng, 0.096 mmol), (R)-hex-5-ene-2-sulfonamide (55 mg, 0.34 mmol) and DIEA (0.067 mL, 0.3844 mmol) in DCM (3.0 mi .). Then \ -( .·,- dimethylamino propy3)-N'-ethyicarbodiimide hydrochloride (147 mg, 0.768 mmol) was added and it was stirred at r.t. overnight. After concentration the residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 20 %

EtOAc (containing 0.3 % AcQH)/hexaiie (containing 0.3 % AcOH) to provide the title compound (67 mg, 0.087 mmol, 91 % yield).

Step 2: (S)-2'-CHLORO-N-((R)-HEX-5-EN-2-YLSULFONYL)-5-(((lR,2R)-2- ((S,E)-l-HYDROXYHEX-2-EN-l-YL)CYCLOBUTYL)METHYL)-4,5,7 ^, ,8'- TETiL HYDRO-2H,6'H-SPIRO[BENZO[B][l,4]OXAZEPiNE"3,5'- QUINOLINEJ-7-CARBOXAMIDE

To a solution of (S)-5-(((lR,2R)-2-((S,E)-l-((tert- but 'ldimethylsilyl)oxy)hex-2-en-l-yl)cyclobu1\'l)methyl)-2'-chl oro-N-((R)-hex-5- en-2-ylsdfonyl)-4,5,7\8'-tetrahydro-2H,6'H-spiro[benzo[b] [l ,4]oxazepine-3,5'- quinoline]-7-carboxamide (Example 791, Step 1) (67 mg, 0,087 mmol) in DCM (2.0 mL) was added tetrabutylammonium fluoride, 1.0 M solution in

tetrahydrofuran (0.057 mL, 0.217 mmol) and small amount of molecuier sieve 4A. The mixture was stirred at 55 °C for 40 h. It was concentrated and the residue was purified by reverse phase preparatory HPLC (Gemini™ Prep Cis 5 ₍ um column; Phenomenex, Torrance, CA; MeCN in water with 0. 1% TFA, gradient elution) to give the title compound (56 mg, 0.085 mmol, 98% yield).

Step 3: (3R,6R,7S,8E, 12R,22S)-2 ^! -CHLORO-7-HYDROXY-12-METHYL-7',8'- DIHYDRO-6H.15H-SPIRO[20-OXA-13-THIA-1 ,14-

DI AZATETRACYCLO[ 14.7,2.0 ³ · ⁶ .0 ³ » ] PENTACOSA-8, 16, 18,24- TETRAENE-22,5'-QUINOLrN]-15-ONE 13,13-DIOXiDE

A 50 mL round bottom flask was charged with (S)~2'~ehloro~N-((R)~hex-5- en-2-ylsulfonyl)-5-(((l R,2R)-2-((S,E 1 -hydroxyhex-2-en- 1 - yl)cv'clobutyl)mefhyl)-4,5,7',8'-tetrahydro-2H,6'H-spiro| benzoj b] 11 ,4]oxazepine- 3,5'-quinoline]-7-carboxamide (Example 791 , Step 2) (56 mg, 0.085 mmol) and Hoveyda-Grubbs II (21 mg, 0.034 mmol) and AcOH (43 mL). The mixture was stirred at r.t. for 36 h under vacuum. SiliaMet DMT (0.5 g, 0.62mmol/g) was added to the reaction mixture and it was stirred at r.t. for 30 min. After concentration the residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 60 % EtOAc (containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (20 mg, 0.034 mmol, 40 % yield). ¾ NMR

(500MHz, CD¾CN) δ 8.09 - 8,05 (m, 1H), 7.26 - 7.20 (m, IH), 7.02 - 6,97 (m, 1 1 1). 6.92 - 6.88 (m, I I I ). 6.87 - 6.84 (m, i l l ). 5.74 - 5.66 (m, IH), 5.50 - 5.46 (m, IH), 4.48 - 4.43 (m, IH), 4.10 - 4.02 (m, 3H), 3.80 (d, ./ 14.9 Hz, IH), 3.66 - 3.61 (m, IH), 3,31 - 3.25 (m, 3H), 3.05 (dd, J=10.1 , 15.3 Hz, IH), 2,96 (dd, ./ 3. 1 . 6.5 Hz, IH), 2.90 - 2.76 (m, 2H), 2,38 - 1 ,61 (m, 10H), 1.55 - 1.48 (m, 2H), 1.46 - 1.42 C m. 3H). m/z (ESI, +ve ion) 586.2 (M+H) ⁺ . EXAMPLE 793. (1 S,3'R,0'R,7'S,8'E, 1 !'R,13'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! - [21 ] OXA[ 14]THI A[ 1,15] DI AZ APENTAC YCLO

[ 15.7.2.0 ³ · ⁶ .0 ^Η · ^ί3 .0 ²⁰ · ²⁵ ]ΗΕΧΑεθ8Α[8,17,19,25]ΤΕΤΚΑΕΝ]-16'-ΟΝΕ 14',14'- DIOXIDE or (I S,3'R,6'R,7'S,8'EJ l 'S,13'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 '- [21 ] OXA[ 14]THI A[ 1 , 15 ]DI AZ APENTAC YCLO

[15.7.2.0 ³ · ⁶ .0 ^{! !} - ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8, 17,19,25]TETRAEN]-16'-ONE 14', 14'- DIOXIDE or (1 S,3 ^! R,6'R,7'S,8'E, 11 *S, 13 ^! R)-6-CHLORO-7 ^! ~HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[ APHTHALENE-1 ,23'- [ 21 |OXA[ 14JTHI A[ 1 , 151 DI AZ AP ENT AC YCLO

[15J.2.0 ³ " ⁶ .0 ¹¹ ' ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8,17,19,25]TETRAENj-16'-ONE 14',14'- DIOXIDE or (1S,3'R,6'R,7'S,8'E,1 l ^, R,13 ^, S)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 16H-SPIRO[NAPHTH ALENE-1 ,23'- [21 ]OXA[ 14]THIA[ 1 , 15 ]DIAZ APENTAC YCLO

[15.7.2.0 ³ ' ⁶ .0 ^!! ' ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8,17,19,25]TETRAEN]-16 ^f -ONE 14', 14'- DIOXIDE

Step 1 : 2- ALL YL- 1 , 1 -DIBROMOC Y CLOPROP ANE

To a solution of 1,4-pentadiene (7.6 mL, 73 mmol), bromoform (7.1 mL, 81 mmol) and benzenemethanaminiurn N,N,N-triethyl chloride (1.67 g, 7.3 mmol) in DCM (60 mL) and pentane (60 mL) was slowly added sodium hydroxide (29.4 g, 734 mmol) solution in water (29.1 mL) at 0 °C. The ice bath was removed after the addition. The reactiom mixture was stirred at r.t. overnight. The solid was filtered off and the the filtrated was extracted with ether (80 ml). The organic phase was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed and disstilled under reduced prerssure to give the tiltle compounds, 2-allyl-l, .l -dibromocyclopropane (7.1g, 29.6 mmol) as an oil (bp 50- 55 °C / 3-5mmHg). Step 2: l-ALLYL-2-BROMOCY CLOPROP ANE

To 2-allyl-L l -dibromocyclopropane (Example 793, Step I ) (2.6g, 10.8 mmol) (containing 15 % of bromoform) was added tributylstannane (2.96 mL, 10.8 mmol) at 0 °C during 40 min. The resulting mixture was stirred at r.t. over night. The reaction was monitored by NMR. Additional tributylstannane (1.0 mL) was addedand it was stirred at r.t. until bromoform was completely consumed. The reaction mixture was directely disstilled under reduced pressure (b.p. 38- 42°C/7-8mmHg) to give the title product as an oil (0.5 g, 3.10 mmol). Step 3: l,2-DI(PYRJMIDIN-2-YL)DISULFANE

To a solution of 2-mercapto-pyrimidine (2.0 g, 18 mmol) in acetonitril (80 mL) and water (16 mL) was added iodine (0.459 mL, 8.92 mmol). The resulting mixture was stirred at r.t. for 1 h. After concentration water was added and it was extracted with DCM (3x120 mL). The combined organic phase was washed with 30 mL of sodium thiosulfate (1 M), brine and dried over anhydrous MgS0 ₄ . It was concentrated and the crude product was used for further reactions. Step : 2-((2-ALLYLCYCLOPROPYL)THIO)PYRIMIDINE

Magnesium (0.206 g, 8.47 mmol), which was washed with 0.1 N HC1 (1 mL), MeOH (10 x 2 mL), ether (10 mL) and dried under vaccum, in TOP (5.0 mL) was actived with a small amount of iodine and 1,2-dibromoethane (0.024 mL, 0.282 mmol) by sonication for 35 mm. To this suspension was added one fifth amount of l-allyl-2-bromocyclopropane (Example 793, Step 2) (1.0 g, 6.21 mmol) in THF (5.0 mL) at 50 °C during a period of 0.5 h. After the reaction occured, the rest of l-allyl-2-bromocyclopropane was added dropwise at 20-30°C and then it was stirred at r.t. for 1.5 h. The formed (2-allylcyclopropyl)magnesium bromide reagent was named Grignard A.

To a solution of 1 ,2-di(pyrimidin-2-yl)disulfane (Example 793, Step 3) (1.49 g, 6.71 mmol) in THF (10.0 mL) was slowly added (2-allylc clopropyl)magnesium bromide (Grignard A) (1.13 g, 6.1 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 12 mm and then at r.t. for 1 h. The reaction was quenched by sat. H4CI (10 mL). Water (20 mL) was added and it was extracted with ethyl acetate (3x40 mL), washed with brine, dried over anhydrous MgS0 ₄ and concentrated. The residue was loaded on a 4g TSCO Gold column and eluted with 0 % to 10 % EtOAc/hexane to provide the title compound.

Step 5 : 2-((2-ALLYLCYCLOPROPYL)SULFONYL)PYRIMIDINE

To a solution of 2-i(2-allylcyclopropyi)thio)pyrimidme (Example 793,

Step 4) (2.05g, 10.7 mmol) in DCM (53 mL) was added 3-chloroperoxybenzoic acid, 77% max. (5.02 g, 22.39 mmol) in three portions at 0 °C during a period of about 15 min. The ice bath was then removed and the mixture was stirred at r.t. for 0.5 h. The reaction was then poured into ice and saturated sodium bicarbonate aqueous solution and extracted with DCM. The organic phase was washed with brine, dried over anhydrous MgS04 and concentrated. The residue was loaded on a 40g ISCO Gold column and eluted with 0 % to 70 % EtOAc/hexane to provide the title compound (1.26 g, 52.7 % yield).

Step 6: SODIUM 2-ALLYLCYCLOPROPANE- 1 -SULFINATE

To a stirred solution of 2-((2-allylcyclopropyl)sulfony])pyrimidine

(Example 793, Step 5) (0.8g, 3.57 mmol) in MeOH (36 mL) was added sodium methoxide (0.82 ml, 3.6 mmol). The reaction was stirred at r.t. for 1.5 h. It was concentrated and then Et ₂ 0 was added. The precipitate was collected by filtration and the solid was washed with cold EtiO and dried under vacuum to give the title product which was used without futher purification in the next step.

Step 7: 2-ALLYLCYCLOPROPANE- 1 -SULFONAMIDE A solution of sodium 2-allylcyclopropane-l-sulfinate (Example 793, Step 6) (0.59 g, 3.5 mmol) in water (23 ml.) was treated with sodium acetate (0.432 g, 5.26 mmol) and hydroxylamine-o-sulfonic acid (0.529 g, 4.21 mmol). The mixture was stirred at 50°C for 0.5 h and at r.t. for 1.5 h and then cooled to 0°C. It was basified with aqueous NaOH solution and extracted with EtOAc and then DCM. The organic phase was washed with brine, dried over anhydrous MgSC and concentrated. The residue was loaded on a 12g ISCO Gold column and eluted with 0 % to 75 % EtOAchexane to provide the title compound (0.56g, 3.47 mmol, 99% yield), Step 8: (S)-N-(((lR,2R)-2-ALLYLCYCLOPROPYL)SULFONYL)-6'-CHLORO- 5-(((lR,2R)-2-((S)-l-HYDROXYALLYL)CYCLOBUTYL)METHYL)-3' _: ,4 ₅ 4 ^, ,5- TETRAHYDR0-2H,2'H-SPIR0 BENZ0[B] [ 1 ₅ 4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMIDE and (S)-N-(((l S,2S)-2- ALLYLCYCLOPROPYL)SULFONYL)-6'-CHLORO-5-(((lR,2R)-2-((S)-l- HYDROXY ALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2!!.2 ^' !!-SP!R()|B!;\/()iB|| i.4K)X.\/l:l ^> INI 3. ! ^' -ΝΛΡ1 ΓΠ ΙΛ1.ΓΛΙ· |-7- CARBOXAMIDE and (S)-N-(((lS,2R)-2-

ALLYLCYCLOPROPYL)SULFONYL)-6'-CHLORO-5-(((lR,2R)-2-((S)-l - HYDROXYALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2FI,2 -SPIRO[BENZO[B][l,410XAZEPINE-3,r-NAPHTHALENE]-7- CARBOXAMIDE and (S)-N-(((lR,2S)-2-

ALLYLCYCL0PR0PYL)SULF0NYL)-6'-CHL0R0-5-(((lR,2R)-2-((S)-l - FYDR0XYALLYL)CYCL0BU L)METHYL)-3',4,4',5-TETRAHYDR0- 2H,2H-SPIR0[BENZ0[B][l,4]0XAZEPINE-3,r-NAPHTHALENE]-7- CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (52.2 nig, 0.427 mmol) was added to a solution of (S)-6 ^! -chloro-5-(((lR,2R)-2-((S)-l-hydroxyallyl)cyclobuty

3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylic acid (Intermediate AA1 1) (100 mg, 0.214 mmol), 2- allylcyclopropane-l-sulfonamide (Example 793, Step 7) and DIEA (0.149 ml, 0.855 mmol) in DCM (4.3 mL). Then N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (328 mg, 1.71 mmol) was added slowly. After the reaction mixture was stirred at r.t. overnight the reaction mixture was concentrated and the residue was loaded on a 12g ISCO Gold column and eluted with 0 % to 20 % EtOAc (containing 0.3% HO Ac) / hexane (containing 0.3% HO Ac) to provide the title compound (1 12 mg, 0.183 mmol, 86 % yield).

Step 9: (1S,3'R,6'R,7'S,8 ^! E, 1 rR,13 ^, R)-6-CHLORO-7'-HYDROXY-3,4-

DIHYDRO-2H, 16H-SPIRO[N APHTH ALENE-1 ,23'- [21]0XA[14]TH1A[1 , 15]DIAZAPENTAC YCLO

[ 15.7.2.0 ³ -^0 ^{i i} - ^l l0 ²⁰ - ²⁵ ]HEXACOSA|;8,17, 19,25]TETRAENj-16'-ONE 14', 14'-

DIOXIDE or (1 S,3'R,6'R,7'S,8'E,1 l 'S, 13'S)-6-CHLORO-7'-HYDROXY~3,4-

DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1.23'-

[21 ] OXA[ 14]THI A[ 1 , 15 ]DI AZ APENT AC YCLO

[15.7.2.0 ³ · ⁶ .0 ^{! !} ' ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8, 17,19,25]TETRAEN]-16'-ONE 14', 14'-

DIOXIDE or Cl S^'R.e'R.TS.S'E.i rS.lS'R^-CHLORO-T'-HYDROXY-S^-

DIHYDRO-2H,16'H-SPIRO[NAPHTHALENE-l,23 ^! -

[ 21 |OXA[ 14JTHI A[ 1 , 15]DI AZAPE TAC YCLO

[lSJ.lO^^O^^ O^lHEXACOSAtS.nj^SlTCTRAENj-ie'-ONE 14',14'~ DIOXIDE or (1 S,3'R,6'R,7'S,8 ^! E,1 rR,13'S)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTH ALENE-1, 23'- [21 ]OXA[ 14]THI A[ 1 , 15 ]DI AZ APENT ACYCLO

[15.7.2.0 ³ ' ⁶ .0 ^{! !} ' ¹³ .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETRAE ]-16 ^f -ONE 14', 14'- DIOXIDE

A 500 mL round bottom flask was charged with (S)-N-(((R)-2- ailylcyciopropyl) sulfonyl)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox 'allyl)cyclobu1yl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxamide (Example 793, Step 8) (1 12 mg, 0.183 mmol), Hoveyda-Grubbs II (46 mg, 0.073 mmol) and AcOH (200 mL). The mixture was stirred at r.t. for about 36 h under house vacumm. Then SiliaMet DMT (1.0 g, 0.62 mmol/g) was added to the reaction mixture and stirred at r.t. for 30 mill. The reaction mixture was concentrated and the residue was loaded on a 12g ISCO Gold column and eluted with 0 % to 40 % EtOAc (containing 0.3% HO Ac) / hexane (containing 0.3% HO Ac) to provide a mixture of stereoisomers (59.1 mg, 0.101 mmol, 55 % yield). The mixture of stereoisomers was pun i led by HPLC with chirai column (OJ) eluting with i-PrOH / hexane. The title compound (20. 1 mg) was obtained as the first (faster) eluting isomer as a white solid ¹ ! ! NMR (500MHz, CD ₃ CN) δ 7.70 (d, .7=8.6 Hz, IH), 7.41 (br s, IH), 7.21 - 7.09 (m, 3H), 6.82 (br s, IH), 5.65 - 5.57 (m, IH), 5.55 - 5.47 (m, IH), 4.15 - 4.01 (m, 2H), 3.75 - 3.68 (m, I H), 3.55 (br s, IH), 3.44 (br s, 2H), 2,81 - 2.71 (m, 2H), 2,59 (d, .7=11.2 Hz, 2H), 2.50 - 2.43 (m, IH), 2.23 - 0.79 (m, 1 ! ! ). m/z (ESI, +ve ion) 583.2 { M · H ) .

EXAMPLE 794. (lS,3'R,6 ^, R,7 ^! S,8'E,i rR,13 ^, R)"6-CHLORO-7'"HYDROXY-3,4- DIHYDRO-2H, 16 ^* H-SPIRO[NAPHTH ALENE-1 ,23'- [21 ]OXA[ 14]THI A[ 1 , 15 ]DT AZ APENT ACYCLO

[15.7.2.0 ³ -^0 ^{i i} - ¹ l0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETl AEN]~16 ^! "ONE 14',14'- DIOXIDE or (1 S,3'R,6'R,7'S,8 ^* E,1 rS, 13'S)-6-CHLORO-7' iYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 ^* - [2i]OXA[14]THIA[l,15]DiA APENTACYCLO

[15.7.2.0 ³ -^0 ¹¹ - ¹³ .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETR _J ' EN]-16 ^, -ONE 14',14'- DIOXIDE or (lS,3 ^, R,6'R,7'S,8'E,i rS,13'R)-6-CHLOR()-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1,23 - [21 ]OXA[ 14]THIA[1 , 15]DIAZ APENTACYCLO

[15.7.2.0 ³ ' ⁶ .0 ⁱⁱ ' ⁱ³ .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETRAENj-16 ^! -ONE 14', 14'- DIOXIDE or (1 S,3'R,6'R,7'S,8'E,1 l'R,13 ^, S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H,16'H-SPIRO[NAPHTHALENE-l ,23'- [21]OXA[14]THIA[l ,15]DIAZ APENTACYCLO

[15 .2.0 -^0 ^{! !} - ¹ 0 ²⁰ - ²⁵ ]HEXACOSA[8, 17,19,251TETRAEN]-16 ^, -ONE 14', 14'- DIOXIDE

The title compound (3.7 mg) was obtained as the fourth (last) eluting isomer from Example 793 as a white solid, ^" Ή NMR (500MHz, CD3OD) δ 7.74 (d, J=8.6 Hz, IH), 7.45 - 7.35 (m, 2H), 7.18 - 7. 15 (m, IH), 7.13 - 7, 12 (m, 1H), 6.87 (d, ./ 8. ! Hz, IH), 5.80 - 5.73 (m, IH), 5.57 - 5.49 (m, IH), 4.27 - 4.22 (m, IH), 4, 14 (d, ,/ 12.0 Hz, i l l ). 3.74 - 3.67 (m, H), 3,63 - 3,56 (m, 2H), 3.55 - 3.50 (m, i l l ). 3.23 - 3. 10 (m, 2H), 2,90 - 2.76 (m, 3H), 2.70 - 2.54 (m, 3H), 2, 15 - 2.08 (m, IH), 1.99 (s, IH), 1.94 - 1.87 (m, 2H), 1.86 - 1.70 (m, 3H), 1.59 - 1.50 (m, IH), 1.31 - 1.23 (in, 3H). m!z (ESI, +ve ion) 583.2 { \ I · Π } . EXAMPLE 795. (IS,3'R,6'R,7'S,8'E,1 l'R,13'R)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! - [21 ] OXA[ 14]THI A[ 1 , 15]DI AZ APE T AC YCLO

[ 15.7.2.0 ³ · ⁶ .0 ^Η · ^ί3 .0 ²⁰ · ²⁵ ]ΗΕΧΑεθ8Α[8,17,19,25]ΤΕΤΚΑΕΝ]-16'-ΟΝΕ 14',14'- DIOXIDE or (I S,3'R,6'R,7'S,8'EJ l 'S,13'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 '- [21 ] OXA[ 14]THI A[ 1 , 15 ]DI AZ APENT AC YCLO

[15.7.2.0 ³ · ⁶ .0 ^{! !} ' ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8, 17,19,25]TETRAEN]-16'-ONE 14', 14'- DIOXIDE or (1 S,3 ^! R,6'R,7'S,8'E, 11 ^* S, 13 ^! R)-6-CHLORO-7 ^! ~HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[N APHTHALENE-1 ,23'- [ 21 |OXA[ 14JTHI A[ 1 , 15]DI AZAPENTAC YCLO

[15.7.2.0 ³ " ⁶ .0 ¹¹ ' ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8,17,19,25]TETRAENj-16'-ONE 14',14'- DIOXIDE or (1S,3'R,6'R,7'S,8'E,1 rR ₅ 13 ^, S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16 ^* H-SPIRO[NAPHTH ALENE-1 ,23'- [21 ]OXA[ 14]THI A[ 1 , 15 ]DI AZAPENTAC YCLO

[15.7.2.0 ³ '^0 ^!! ' ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8,17,19,25]TETrRAEN]-16 ^f -ONE 14', 14'- DIOXIDE

The title compound (3.5 nig) was obtained as the third eluting isomer from Example 793 as a white solid. ³ H NMR (500MHz, CD3OD) δ 7.77 - 7.73 (m, 1H), 7.29 - 7.26 (ra, 1H), 7,25 - 7.20 (m, 1H), 7.19 - 7.15 (ra, 1H), 7,11 - 7.08 (m, 1H), 6.83 - 6.78 (m, ill).5,70 - 5.64 (m, III).5.52 - 5.46 (m, IH), 4,07 - 3.98 (m, 311). 3.72 - 3.66 (m, Ml).3.39 (d, J=14.4 Hz, IH).3.12 (del, J=10.3, 15.2 Hz, IH), 3.04 (d,■/ 5.4 Hz, IH), 2.85 - 2.70 (m, 3H), 2.66 - 2.57 (m, IH), 2.44 - 2.37 (m, IH), 2,35 - 2.27 (m, 1 H), 2.16 - 2.10 (m, IH), 2,03 - 1.83 (m, 5H), 1.81 - 1.72 (ra, IH), 1.47 - 1.39 (m, IH), 1.35 - 1.27 (m, 2H), 1.26 - 1.17 (m, 2H). z (ESI, +ve ion) 583.2 (M+H) ⁺ .

EXAMPLE 796. (1 S,3 ^! R,6'R,7'S,8'E,1 rR,13 ^! R)-6-CHLORO-7'-HYDROXY-3,4-

DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1,23- [21 ]OXA[14]THIA[l , 15JDIAZ APENTACYCLO

[15.7.2.0 ³ - ⁶ .0 ⁱⁱ - ^l3 .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,25]TETRAENj-16'-ONE 14',14'-

DIOXIDE or (lS,3'R,6'R,7'S,8Ti,l l'S,13'S)-6-CHLORO-7'-HYDROXY~3,4-

DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 '-

[21 ] OXA[ 14]THI A[ 1 , 15 ]DIAZ APENTACYCLO

[15.7.2.0 -^0 ^!! - ¹³ .0 ²⁰ - ²⁵ ]HEXACOSA[8,17,19,251TETRAEN]-16 ^, -ONE 14',14'-

DIOXIDEor(lS,3 ^f R,6'R,7'S,8'E,irS,13 ⁱ R)-6-CHLORO-7'-HYDROXY-3,4-

DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^s -

[21 ] OXA[ 14]THI A[ 1 , 15 jDIAZ APENTACYCLO

[15.7.2.0 ³ ' ⁶ .0"· ¹ .0 ²⁰ · ²⁵ ]ΗΕΧΑϋΟ8Α[8,17,19,25]ΤΕΤ ΑΕΝ]-16'-ΟΝΕ 14',14'- DIOXIDE or (1 S,3'R,6'R,7'S,8 ^! E,1 rR,13'S)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 '- [21 ]OXA[ 14 |THIA[ 1,15 jDIAZ APENTACYCLO

[15.7.2.0 ³ · ⁶ .0 ^{! !} - ¹³ .0 ²⁰ ' ²⁵ ]HEXACOSA[8, 17,19,25]TETRAEN]-16'-ONE 14', 14'- DIOXIDE

The title compound (12.1 mg) was obtained as the second eluting isomer from Example 793 as a white solid. Ή NMR (500MHz, CD ₃ ()D) δ 7.74 (d, ,/ H.6 Hz, H), 7,48 (br s, IH), 7.40 (d, J=7.3 Hz, I H), 7.16 (dd, ,/ 2 4. 8.6 Hz, IH), 7.13 - 7.10 (m, IH), 6.84 (d, ,7=8, 1 Hz, H), 5.70 - 5,62 (m, IH), 5.56 - 5.48 (m, IH), 4.23 (d, ./ 12.0 Hz, IH), 4.08 (d, ./ I 1 .7 Hz, IH), 3.60 (d, J=11.0 Hz, 3H), 3.46 - 3,39 i ns. IH), 3,26 - 3.17 (m, I H), 2.90 - 2,74 (ra, 4H), 2,68 - 2.60 (m, 2H), 2.18 - 2.09 (m, IH), 2,04 - 1.98 (m, IH), 1.91 (br s, 4H), 1 ,73 - 1 ,64 (m, IH), 1.61 - 1.53 (m, IH), 1.48 - 1.43 (m, IH), 1.42 - 1.29 (m, 3H), 0.97 - 0.88 (m, IH). m/z (ESI, +ve ion) 583.2 (M+H) ⁺ .

EXAMPLE 798. (3R,6R,7S,8E, 12R,22S)-2'-CHL()RO-12-ETHYL-7- HYDROXY-7',8'-DIHYDRO-6'H, 15H-SPIRO[20-OXA - 13-THI A- 1 , 14- DL ZATF;TRACYCLO[14,7.2,0 ^3/i .0 ¹⁹ - ²⁴ ] PENTACOS A~8, 6, 18,24- TETRAENE-22,5'-QUINOLIN]-15-ONE 13,13-DIOXIDE

Step 1 : 2-CHLORO-5,6,7,8-TETRAHYDROQUI OLI E-5-CARBALDEHYDE

To a stirred suspension of (memoxymethyl)triphenylphosphonium chloride (17.0 g, 49.6 mmol)) in THF (41 mL) was added slowly a solution of potassium 2- methylpropan-2-olate (41 mL, 41 mmol) at 0°C via cannula under nitrogen. The resulting cherry -red solution was stirred at 0 °C for 1 h. A solution of 2-chloro- 7,8-dihydroquinolin-5(6H)-one (3.00 g, 16.5 mmol) in THF (10.0 mL) was added dropwaise. The reaction mixture was stirred at r.t. for 1 h. The reaction quenched with water (5 mL). It was concentrated at 35 °C to about 40 mL, then aqueous 30% H2SO4O5 mL) was added at r.t. and it was stirred at 50 °C for 16 h. The reaction mixture was gradually poured into saturated sodium carbonate solution (70 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2x30 mL). The combined organic phases were washed with brine and dried over anhydrous MgS0 ₄ . After concentration the residue was loaded on a 80g ISCO Gold column and eluted with 0 % to 90 % EtOAc /hexane to provide the title compound (3.0 g, 15.3mmol , 93% yield).

Step 2: 2 ^f -CHLORO-7',8'-DIHYDRO-6'H-SPIRO[[ l,3]DIOXANE-5,5'- QUINOLINJ-4-OL

To a reaction mixture of 2-chloro-5,6,7,8-tetrahydroquinoline-5-carbaldehyde

(Example 798, Step 1) (3.0 g, 15.3 mmol) and formaldehyde (34.2 mL, 460 mmol) in DCM (77 mL) and MeOH (77 mL) was added sodium

hydrogencarbonate (0.644 g, 7.67 mmol) in one portion. The resulting mixture was stirred at r.t. for 1 h. It was concentrated and extracted with ethyl acetate (100 mL). The organic phase was washed with brine and dried over anhydrous , It was concentrated to provide the title compound (3.90g, 15.3 mmol, 99 % as a yellow oil which was used without further purification.

Step 3: '-CHLORO-T'^'-DIHYDRO-e'H-SPIROj l l^ jDIOXA E-S '- QUINOLINj-4-ONE

To a solution of 2'-chloro-7',8'"dihydro-6'H-spiro[[l,3]dioxane-5,5 ^, ~ quinolin]-4-ol (Example 798, Step 2) (3.80 g, 14.8 mmol) in DCM (74 mL) was added Dess-Martin periodinane (9.45 g, 22.3 mmol) portionwise at 0 °C. After it was stirred for 10 minutes, the cooling bath was removed. The mixture was stirred at r.t. for 1 h and then extracted with EtOAc. The organics were washed with 1 N sodium thiosulfate solution, saturated sodium bicarbonate solution, brine and dried over anhydrous MgSC . After concentration the residue was loaded on a 80g ISCO Gold column and eluted with 0 % to 30 % EtOAc /hexane to provide the title compound (1.5 g, 5.91 mmol, 40 % yield).

Step 4; 2-CHLORO-5-(HYDROXYMETHYL)-5,6,7,8- TETRAHYDROQUINOLINE-5-CARBOXYLIC ACID

To a solution of 2'-chloro-7',8'-dihydro-6'H-spiro[[l ,3 jdioxane-5,5'~ quinolin]-4-one (Example 798, Step 3) (1.50 g, 5.91 mmol) in THF (26 mL) and MeOH (13 mL) was added sodium hydroxide (23.6 mL, 47.3 mmol). The mixture was stirred at r.t. for 1 h. It was concentrated, acidified with 2N hydrochloric acid solution to pH = 5 and extracted with EtOAc (80 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate. It was concentrated to afford the title compound (1.42g, 5,88 mmol, 99 % yield) as a pale yellow oil, which was used without further purification.

Step 5: METHYL 2-CHLQRQ-5-(HYDROXYMETHYL)-5,6,7,8- TETRAHYDRO QUINOLINE-5-CARBOXYLATE

To a solution of 2-chloro-5-(hydroxyniethyl)-5,6,7,8~tetrahydroquinoline- 5-carboxylic acid (Example 798, Step 4) (1.4 g, 5.8 mmol) in MeOH (58 mL) and benzene (58 mL) was added slowly (trimethylsilyl)diazomethane, 2.0 M in diethyl ether (3.2 mL, 6.4 mmol). The reaction mixture was stirred at r.t. for 1 h. The reaction was quenched by addition of acetic acid (0.2 mL). After concentration the residue was loaded on a 40g ISCO Gold column and eluted with 0 % to 90 % EtOAc /hexane to provide the title compound (1.48 g, 5.79 mmol, 100% yield).

Step 6: METHYL 2-CHLORO-5-((4-(METHOXYCARBONYL)-2- NITROPHENOXY) METHYL)-5,6,7,8-TETRAHYDROQUINOLINE-5- CARBOXYLATE

To a solution of methyl 2-chloro-5~(hydroxymethyl)-5, 6,7,8- tetrahydroquiiioliiie-5~carboxyiate (Example 798, Step 5) (1.78 g, 7.0 mmol) in THF (26 mL) was added lithium bis(trimethylsilyl)amide (8.0 mL, 8.0 mmol). After the resulting mixture was stirred at r.t. for 20 min, methyl 4~fiuoro-3~ nitrobenzoate (1 ,66 g, 8.35 rnmol) in THF (13 mL) was added. The resulting orange mixture was stirred at r.t. for 30 min. It was quenched with saturated ammonmm chloride solution and extracted with EtOAc. The organics were washed with brine, dried (MgSC ) and concentrated. The residue was loaded on a 40g ISCO Gold column and el u ted with 0 % to 90 % EtOAc /hexane to provide the title compound (3.05 g, 7.0 rnmol, 100 % yield).

Step 7: METHYL 5-((2-AMINO-4-

(METHOXYCARBONYL)PHENOXY)METHYL)-2-CHLORO-5,6,7,8- TETRAHYDROQUINOLINE-5-CARBOXYLATE

A 100 mL flask was charged with methyl 2-chioro-5~((4- (methoxycarbonyl)-2-nitrophenoxj ^ethyl)-5,6,7,8-tetrahydroquinoline-5- carboxylate (Example 798, Step 6) (3.2g, 7.4 rnmol). Acetic Acid (56 mL) and iron powder (4.11 g, 74 mmol). The mixture was stirred at 70 °C for 2.5 h. The reaction mixture was cooled to room temperature and filtered through celite and washed with EtOAc (100 mL). The filtrate was diluted with EtOAc (100 mL), washed with saturated aqueous sodium carbonate solution, brine and dried with over anliydrous sodium sulfate. It was concentrated to afford the title compound (3.0g, 7.4 mmol, 100 % yield), which was used without further purification. Step 8: (Z)-METHYL 2'-CHLORO-7',8 ^, -DIHYDRO-2H,6 ^! H-SPIRO[BENZ() [B] [I ,4] OXAZEPINE-3,5'-QUINOLlNE]-7-CARBOXYLATE

A 500 mL pear flask was charged withmethyl 5-((2-amino-4- (me1hoxycarbonyl)phenoxy)methyl)-2-chloro-5,6,7,8-tetrahydro quinoline-5- carboxylate (Example 798 , Step 7) (2.98 g, 7.36 mmol) and THE (74 mL) and it was cooled to -78 °C under nitrogen. To the cold solution was added dropwise lithium aluminum hydride, 2.0 M in THE (5.52 mL, 1 1.0 mmol). The resulting pale yellow solution was stirred for 10 minutes at -78 °C. It was quenched carefully with MeOH (5.5 mL) (vigorous gas evolution) at the same temperature. The mixture was diluted with EtOAc (120 mL) and stirred over saturated aqueous Rochelle salt (50 mL) for 5 minutes. The organics were washed with brine and dried with over anhydrous sodium sulfate. It was concentrated to afford the title compound (2.63g, 7.4 mmol, 100% yield) as a pale yellow oil, which was used without further purification.

Step 9: (S)-METHYL 2'-CHLORO-4,5,7',8'-TETRAHYDRO-2H,6'H- SPIRO[BENZO [B] [ 1 ,4] OXAZEPINE-3,5'-QUINOLINE] -7-C ARBOXYLATE

To a solution of (Z)-methyl 2'-chloro-7',8'-dihydro-2H,6'H- spiroj benzoj b] [ 1,4 ]oxazepine-3,5'-quinoline|-7-carboxylate (Example 798 , Step 8) (2.63 g, 7.37 mmol) and acetic acid (1.3 mL, 22 mmol) in DCE (6.1 mL) was added sodium triacetoxyborohydride (2.79 g, 14.7 mmol) at r.t. The resulting mixture was stirred at r..t overnight. Ethyl acetate (150 mL) was added and it was washed with sodium bicarbonate solution (2x40 mL), brine (40 mL), dried over Na ₂ S04 and concentrated. The residue was loaded on a 40g ISCO Gold column and el u ted with 0 % to 85 % EtOAc /hexane to give a racemic product which \\ separated by chiral preparative HPLC (chiral column : OD ; eluted with 10% i~ PrOH/hexane) to provide the title compound as the second eluting isomer (1.2 g 3.3 mmol, 45 % yield).

Step 10: ((lR,2R)-2-((S,E)-l-HYDROXYHEX-2-EN-l-

YL)CYCLOBUTYL)METHYL BENZOATE

A dr ' flask charged with dry hexane (14 mL) under nitrogen atmosphere was cooled to 0 °C (ice bath). Cyclohexene (2.8 mL, 27 mmol) was added and the mixture was stirred for 3 min. Then borane dimethyl sulfide complex (1.30 mL, 13.7 mmol) was added and it was stirred for 14 min. The reaction mixture was observed as a white suspension. To the white suspension was added n-propyl acetylene (1.36 mL, 13.7 mmol). The ice bath was removed and the reaction mixture was stirred at r.t. for 15 min. The mixture was cooled at -78 °C (dry ice bath) and diethylzmc, 1.0 M solution in heptane (13.7 mL, 13.7 mmol) was added. The cooling was switched to an ice bath (0 °C) and stirrd for 6 min (The solution became dark-grey). The solution was moved back to -78 °C bath. This solution was called solution A.

To a mixture of (( lR,2R)-2-formylcy cl obutyl)methyl benzoate (Intermediate

AA17, STEP 8) (1.00 g, 4.58 mmol), (2S)-3-exo-(morpholino)isoborneal (0.219 g, 0.916 mmol) in hexane (7.0 mL) and toluene (2.0 mL) at 0 °C was added 16 mL. of solution A via syringe. After stirring at 0 °C for 3 min, the reaction was quenched with saturated NH Cl solution (15 mL), diluted with water (20 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ S04 and concentrated. The residue was loaded on a 80g ISCO Gold column and eluted with 0 % to 20 % EtOAc /hexane to give the title compound (0.56 g, 1.95 mmol, 43% yield). Step 1 1 : ίί I R.2R }-2-ii SJ ^: )- i -ii 1 f - ^' RT-Bl . 1 Y f . DI .YU i lYLS! LY UOXY )! f i: X-2- EN - 1 -YL)CYCLOBUTYL)METHYL BENZOATE

To a solution of ((l R,2R)-2-((S,E)-14iy<_roxyhex-2-en-l- yl)cyclobutyl)methyl benzoate (Example 798 , Step 10) (500 mg, 1.73 mrnol) in DCM (12 ml.) 0 °C (ice bath) under N ₂ was added 2,6-dimethylpyridine (0.80 mL, 6.9 mrnol) and followed by tert-butyldimethylsilyl trifluoromethanesulfonate (0.80 mL, 3.5 mrnol). The mixture was stirred at 0 °C to r.t. overnight. The reaction was quenched with saturated NaHCCh solution, diluted with water and extracted with ethyl acetate. The organic phase was washed with citric acid (1.0 M, 2x20 mL.), NaHCCb solution, brine and dried over MgS04 and concentrated. The residue was loaded on a 24g ISCO Gold column and eluted with 0 % to 20 % EtOAc hexane to give the title compound (0.56 g, 1.4 mrnol, 80% yield). Step 12: ((1 R,2R)-2-((S,E)- 1 -((TERT-BUTYLDIMETHYLSILYL)OXY)HEX-2- EN-1 -YL)CY CLOBUTYL)METHANOL

To a solution of ((l R,2R)-2-((S ₅ E)-l-((tert-birtyldimet ylsilyl)oxy)hex-2- en-l -y])cyclobutyl)methyl benzoate (Example 798, Step 11) (0.56 g, 1.4 mmol) in MeOH (5 mL) was added sodium methoxide (1.6 mL, 6.9 mmol). After stirring at r.t. for 2 h, the solution was treated with saturated NHCOs solution, diluted with water, and extracted with EtOAc (3x30 mL). The organic phase was washed with brine, dried over MgSCU and concentrated to give the title compound (0.40 g, 1 .34 mmol, 96 % yield).

Step 13: (lR,2R)-2-((S,E)-l-((TERT-BUTYLDIMETHYLSILYL)OXY)HEX-2- EN- 1 - YL)C YCLOBUTANEC ARB ALDEHYDE

A solution of Dess Martin periodinane (0.852 g, 2.01 mmol) in DCM (2.5 niL) was added over 10 min to a solution of ((lR,2R)-2-((S,E)-l -((tert- bu1yldimethylsilyl)ox>')hex-2-en-l-yl)cyclobutyl)methanol (Example 798, Step 12) (0.4 g, 1.34 mmol) in DCM (2.5 niL). Water (0.024 mL, 1.34 mmol) in DCM (5 ml.) was added dropwise over 5 min. The reaction was quenched with 20 mL of Dess-Martin Extractor (1 : 1 mixture of sat. NaHCO, solution /10% a?.S2Q3 solution). The mixture was stirred at r.t. for 15 min. The organic phase was washed with brine, dried over MgSC and concentrated to afford the title compound (0.40g, 1.34 mmol, 100 % yield), which was used without futher purification.

Step 14: (S)-METHYL 5-(((lR,2R)-2-((S,E)-l-((TERT-

BUTYLDIMETHYLSILYL)OXY) HEX-2-EN-1-

Y )CYCLOBUTYL)METHYL)-2'-CHLORO-4,5,7 ^! ,8 ^, -TETRAHYDRO-2H,6'H- SPTRO[BENZO [B] [ 1 ,4] OXAZEPlNE-3,5'-QUINOLINE] -7-C ARBOXYLATE

A 10 mL of flask was charged with (S)-methyi 2'-ehioro-4,5,7',8'- tetrahydro-2H,6'H-spiro[benzo[b] [l,4]oxazepine-3,5'-quinoline]-7-carboxylate

(Example 798 , step 9) (101 mg, 0.281 mmol) and (l R,2R)~2-((S,E)~l ~((tert- butyldimelhylsilyl)oxy)hex-2-en-l-yl)cyclobutane carbaldehyde (Example 798 , Step 13) (83 mg, 0.28 mmol) in DCM (2.8 mL). The reaction mixture was stirred at r.t. for 10 min and then sodium triacetoxyborohydride (179 mg, 0.844 mmol) was added. The mixture was stirred at r.t. for 20 min. Ethyl acetate (80 mL) was added. The mixture was washed with sodium bicarbonate solution (30 mL), brine (20 mL), dried over anhydrous MgS(>4 and concentrated. The residue was loaded on a 4g ISCO Gold column and eluted with 0 % to 80 % EtOAc /hexane to give the title compound (150 mg, 0.235 mmol, 84 % yield).

Step 15: (S)-5-(((lR,2R)-2-((S,E)-l-((TERT- BUTYLDIMETHYLSlLYL)OXY)HEX-2-EN-l

YL)CYCIX)BUTYL)METHYL)-2'-CHLORO-4,5,7',8 ^f -TETRAHYDRO-2H,6'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,5'-QUrNOLINE]-7-CARBOXYLIC ACID

Lithium hydroxide solution (1.4 mL, 4.7 mmol) was added to a solution of (S)-melhyl 5-(((lR,2R)-2-((S,E)-l-((tert-butyldime1hylsilyi)oxy)hex-2-e n-l- yl)c 'clobutyl)methyl)-2'-chloro-4,5,7 ^, ,8 ^, -tetrahydro-2H,6 ^, H- spiro[benzo[b][l,4]oxazepine-3,5'-qiiinoiine]-7-carbox>'l ate (Example 798, Step 14) (150 nig, 0.235 mmol) in MeOH (1.0 mL) and THF (2.0 mL). The resulting mixture was stirred at 40 °C for 24 h. The mixture was diluted with ethyl acetate (20 mL), washed with brine (pH~4, 10 mL), dried over anhydrous MgSC and concentrated to provide the title compound (130 mg, 0.208 mmol, 89 % yield).

Step 16: (S)-5-(((lR,2R)-2-((S,E)-l-((TERT- BUTYLDIMETHYLSILYL)OXY)HEX-2-EN-l-

YL)CYCLOBUTYL)METOYL)-2'-CHLORO-N-((R)-HEPT-6-EN-3- YLSUL,FONYL)-4,5,7',8'-TETRAHYDRO-2H,6 ^! H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 5 '-QUINOLINE] -7-CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (23 mg, 0.19 mmol) was added to a solution of Example 798 , Step 15, (R)-hept-6-ene-3-sulfonamide (EE202) (59.5 mg, 0,336 mmol) and DIEA (0.067 mL, 0,384 mmol) in DCM (3 mL). Then N-(3- dimethylaminopropy -N'-ethylcarbodiimide hydrochloride (147 mg, 0.768 mmol) was added. After the reaction mixture was stirred at r.t. overnight it was concentrated. The residue was loaded on a 12g ISCO Gold column and eluted with 0 % to 20 % EtOAc (containing 0.3% HO Ac) / hexane (containing 0.3% HO Ac) to provide the title compound (40 mg, 0.051 mmol, 53 % yield).

Step 17: (S)-2'-CHLORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)-5-(((lR,2R)-2- ((S )-l-HYDROXYHEX-2-EN-l-YL)CYCLOBUTTL)METOYL)-4,5 ^, ,8'-

TETRAHYDRO-2H,6'H-SPiRO[BENZO[B][l ,4]OXAZEPrNE-3,5'- QUINOLINE]-7-CARBOXAMIDE

To a solution of (S)-5-(((l R,2R)-2-((S,E)-l -((tert- butyldimethylsilyl)oxy)hex-2-en-l-yl)cyclobutyl)me1hyl)-2'-c hloro-N-((R)-hept- 6-en-3-ylsulfonyl)-4,5,7',8 ^, -tetrahydro-2H,6'H-spiro[benzo[b] [l,4]oxazepine-3,5'- quinoline|-7-carboxamide (Example 798, Step 16) (40 mg, 0.051 mmol) in DCM (2.0 niL) was added ietrabutvlarnmonium fluoride, 1.0 M solution in THF (0.033 mL, 0.127 mmol) and small amount of 4A molecular sieve.The mixture was stirred at 55 °C for 36 h. It was concentrated and the residue was purified by- reverse phase preparatory HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (34 mg, 0.051 mmol, 99 % yield).

Step 18: (3R,6R,7S,8E,12R,22S)-2'-CHLORO-12-ETHYL-7-HYDROXY-7',8'- DIHYDRO-6'H, 1 5H-SP1RO [20-GXA- 13 -ΤΉΙΑ- 1, 14- DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ] PENT ACQS A-8, 16, 18,24- TETRAENE-22,5'-QUINQLINj-15-ONE 13,13-DIOXIDE

A 50 mL round bottom flask was charged with (S)-2'-chloro-N-((R)-hept- 6-en-3-ylsulf<Miyl)-5-(((lR,2R)-2-((S,E)-l-hydroxyhex-2-e n-l- yl)cyclobu1yl)methyl)-4,5,7 8'-tetrahydro-2H,6'H-spiro[benzo[b] [ l,4]oxazepine- 3,5'-quinoline]-7-carboxamide (Example 798, Siep 17) (34 mg, 0.051 mmol) and Hoveyda-Grubbs Π (13 mg, 0.020 mmol) and AcOH (25 ml). The mixture was stirred at r.t for about 36 h under louse vacumm. SiliaMet DMT (0.25 g,

0.62mmol/g) was added to the reaction mixture and it was stirred at r.t. for 30 min. It was concentrated and the residue was loaded on a 4g ISCO Gold column and eluted with 0% to 60 % EtOAc (containing 0.3% HO Ac) / hexane (containing 0.3% HO Ac) to provide the title compound (12 mg, 0.020 mmol, 39 % yield). ¾ NMR (500MHz, CD ₃ CN) δ 8.07 (d, ,/ 8.3 Hz, 111).7.22 (d, ,/ 83 Hz, ill).7.01 - 6.97 (m, 1H), 6.91 - 6,88 (m, 1H), 6.87 - 6.84 (m, 1H), 5.75 - 5,69 (m, 1H), 5.68 - 5.63 (m, 1H), 4.11 - 4.01 (m, 3H), 3.96 - 3.89 (m, 1H), 3.80 (d, ./ 14.7 Hz, Ml). 3.63 (d, ./ 14.4 Hz, 1H), 3.28 (d, ,/ 14.4 Hz, 1H), 3.05 (dd, J=10.0, 15.4 Hz, 1H), 2,91 - 2.84 (m, 1H), 2,84 - 2.75 (m, IH), 2,60 - 2.54 (m, 1H), 2,42 - 1.87 (ra, lOH), 1.84 - 1.67 (m, 5H), 1.47 - 1.39 (m, Ml).1.13 (t, ./ 7.6 Hz, 3H). m/z (ESI, +ve ion) 600.2 (VI H) . EXAMPLE 801. (lS,3 ^! R,6 ^, R,7'S,8'E,10'R,12'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1,23-

|2! !OXAI Ι4Ι Η1Λ| IJ5|i)!A/.\PHN ΓΛίΎΠ.ΟΙ ! 5.7.20 ^{; !'} .0 ^{1π 1} '.( ^),u !hXAC 08Α[8,17,19,25]ΤΕΊΈΑΕΝ]-16'-ΟΝΕ 14',14'-DIOXIDE or

(lS,3'R,6 ^! R,7 ^, S,8'E,l()'S,12'R)-6-CHL()R()-7'-HYDROXY-3,4-DIHYDRO- 2H, 16'H-SPIROjNAPHTHALENE- 1 ,23'-

[2i]OXA[14]THlA[l,15]DIAZAPENTACYCLO[15.7.2.0 ³ -^0 ¹⁰ - ¹² .0 ^{2 25} ]HEXAC OSA[8,17,19,25]TETRAEN]-16'-ONE 14',14'-DIOXIDE

The title compound (1.3 mg) was obtained as a single isomer (second eluting peak) from the reverse phase preparative HPLC in Example 802 as a white solid, "H NMR (500MHz, CDCb) δ 7.76 - 7.67 (m, IH), 7,57 - 7.45 (m, I H), 7.23

- 7, 16 (m, 2H), 7.12 - 7.07 i ra IH), 7.02 - 6,94 (m, IH), 5.83 - 5.65 (m, IH), 5.63

- 5,39 (m, IH), 4.15 (s, 2H), 3.88 - 3.72 (m, IH), 3.68 - 3,53 (m, IH), 3.48 - 3.32 (m, IH), 3.27 - 3.06 (m, IH), 2.82 - 2.69 (m, 2H), 2.35 - 2.21 (m, 2H), 2.16 - 0.65 (m, 16H). m/z. (ESI, + ve ion) 583.2 ( W W ) .

EXAMPLE 802. (1 S,3'R,6¾,7'S,8 ^! E, 10 ^! R, 12'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H _s 16H-SPIRO[NAPHTHALENE-l,23'-

OSA[8, 17,19,25]TETRAEN]-16'-ONE 14',14'-DIOXIDE or

(lS,3 ^, R,6 ^, R,7 ^, S,8¾10 ^, S 2 ^, R)-6-CHLORO-7 ^, -HYDROXY-3,4-DIHYDRO- 2H, 16'H-SP1R0[NAPHTHALENE- 1 ,23'- pi lOXAtMlTfflAIl. l SlDIAZAPENTACYCLOIl

OS A[8, 17, 19,25] TETRAEN] - 16'-ONE 14', 14'-DIOXIDE

Step 1 : ((lR,2S)-2-((E)-PROP-l -EN-l-YL)CYCLOPROPYL)METHANOL and ((l S ₅ 2R)-2-((E)-PROP-l-EN-l-YL)CYCLOPROPYL)METHANOL

To a solution of diethylzinc (1.0 M solution in hexane, 33.6 mL, 33.6 mmol) in DCM (61 mL) was added dropwise diiodomethane (5.4 mL, 67 mmol) at -10 °C. After 15 min of stirring, a white precipitate was formed and a solution of (4R,5R)-(-)-2,2-dimethyl-a, a, a', a'-tetraphenyl-l,3-dioxolane-4,5- dimethaolato[l,2-bis(dimethoxy)ethane] titanium(IV)di chloride (1.09 g, 1.52 mmol) m DCM (8.0 mL) was added by cannula at -10 °C. The solution was stirred at the same temperature for 5 min and a solution of (2E,4E)-hexa-2,4-dien- l-ol (3.0 g, 30.6 mmol) in DCM (61 ml.) was added at -10 °C. The resulting mixture was allowed to warm to 0 °C for 2 h with light exclusion. The reaction was quenched with 1 .0 N HC1 solution at -40 °C. The mixture was extracted with DCM (2x30 mL) and the combined organic layers were washed with brine (20 mL), dried over anhydrous MgS04 and concentrated. The residue was loaded to a 40g ISCO Gold column and eluted with 0 % to 90 % EtOAc/hexane to provide the title compound (2.2 g, 64% yield).

Step 2: 2-((((lR,2S)-2-((E)-PROP-l-EN-l-

YL)CYCLOPROPYL)METHYL)THIO)PYRIMIDINE and 2-((((l S,2R)-2-((E)- PROP - 1 -EN- 1 - YL)C YCLOPROPYL)METHYL)THIO)PYRIMIDINE

An oven-dried 25 mL flask was charged with triphenylphosphine (1.122 g, 4.28 mmol) in toluene (12 mL) under an atmosphere of nitrogen and then charged with (E)-diisopropyl diazene-l,2-dicarboxylate (0.84 ml, 4.3 mmol) in toluene (1 mL) at 0 °C. It was added dropwise (E)-(2-(prop-l-en-l-yl)cyclopropyl)methanol (Example 802, Step 1; 0.4g, 3.57 mmol) and stirred at 0°C for 20 min. Then a solution of 2-mercapto-pyrimidine (0.480 g, 4.28 mmol) in THF (10 mL) was added slowly and it was stirred at rt for 5 h. It was concentrated and the residue was loaded to a 40g ISCO Gold column and eluted with 0 % to 90 %

EtOAc/hexane to provide the title compound (0.29 g, 1.41 mmol, 39 % yield).

Step 3: 2-((((lR,2S)-2-((E)-PROP-l-EN-l-

YL)CYCLOPR()PYL)METHYL)SULFONYL)PYRIMIDINE and 2-((((l S.2R)- 2-((E)-PROP-l -EN-l-

YL)CYCLOPROPYL)METHYL)SULFONYL)PYRIMIDrNE

To a solution of (E)-2-(((2-(prop-l-en-l- yl)cyclopropyl)methyl)thio)pyrimidine (Example 802, Step 2; 0.63 g, 3.05 mmol) in DCM (15 mL) was added 3-chlorobenzoperoxoic acid (1.437 g, 6.41 mmol) in three portions at 0 °C during a period of 15 min. The ice bath was then removed and the mixture was stirred at rt for 3 h. The reaction was then poured into ice and saturated sodium bicarbonate solution. It was extracted with DCM (3x30 niL)) and the combined organic phases were washed with brine (10 mL), dried over anhydrous MgS(>4 and concentrated. The residue was loaded to a 80g ISCO Gold column and eluted with 0 % to 70 % EtOAc/hexane to provide the title compound (0.043g, 0.180 mmol, 6 % yield).

Step 4: SODIUM ((lR,2S)-2-((E)-PROP-l-EN-l-

YL)CYCLOPROPYL)METHANESULFINATE and SODIUM ((l S,2R)-2-((E)- PROP- 1 -EN- 1 - YL)C YCLOPROPYL)METHANESULFIN ATE

o and O

To a stirred solution of (E)-2-(((2-(prop-l -en-l - yl)cyclopropyl)methyl)sulfonyl)-pyrimidine (Example 802, Step 3; 43 mg, 0.18 mmol) in MeOH (1 .8 mL) was added sodium meth oxide (41.3 μΐ, 0. 180 mmol). After the reaction was stirred at rt for 1.5 h it was concentrated evaporated and Et20 was added. The solid was collected with filtration and purified by washing with cold Et?.0 to give the title compound, which was used without further purification.

Step 5 : ((lR,2S)-2-((E)-PROP-l -EN-l -

YL)CYCLOPROPYL)METHANESULFONAMlDE and ((1 S,2R)-

1 -EN- 1 -YL)CYCLOPROPYL)METHANESULFONAMIDE

O and O

A solution of sodium (E)-(2-(prop-l-en-l -yl)cyclopropyl)methanesulfinate

(Example 802, Step 4; 33 nig, 0.18 mmol) in water (1.2 mL) was treated with sodium acetate (22 mg, 0.27 mmol) and hydroxylamine-0-sulfonic acid (27 mg, 0.22 mmol). The reaction was stirred at 50°C for 0.5 h and stirred at rt for 1 .5 h. Then it was cooled to 0°C, basified with NaOH solution and extracted with DCM (2x40 mL). The combined organic phases were dried over anhydrous MgSOs and concentrated. The residue was loaded to a 12g IS CO Gold column and eluted with 0 % to 75 % EtOAc/hexane to provide the title compound (30 mg, 0.17 mmol, 95 % yield).

Step 6: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXY ALL YL)C YCLOB UTYL)METHYL)-N-(((( 1 R,2S)-2-((E)-PROP - 1 - EN-l -YL)CYCLOPROPYL)METHYL)SLT.FONYL)-3^4,4' ₅ 5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3 ₅ l ^* -NAPHTHALENE]-7- CARBOXAMIDE and (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBL ⁱ TYL)METHYL)- -((((lS,2R)~2"((E)-PROP-l- EN-l-YL)CYCLOPROPYL)METHYL)SULFONYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE

4-Pyrrolidinopyridine (22 mg, 0.15 mmol) was adde(S)-6'-chloro-5-

(((l R,2R)-2-((S)~l-hydroxyallyl)cyc ^

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxyli c acid (Intermediate AA11 A; 70 mg, 0.15 mmol). Example 802, Step 5 (30 mg, 1.7 mmol) and DIEA (0, 104 mL, 0.598 mmol) in DCM (1.3 ml). Then N-(3-dimethylaminopropy])-N'- ethylcarbodiimide hydrochloride (143 mg, 0.748 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C overnight. After concentration the residue was loaded to a 12g ISCO Gold column and eluted with 0 % to 75 % EtOAc (0.3%HOAc) / hexane (0.3%HOAc) to provide the title compound (35 mg, 0.056 mmol, 37 % yield). Step 7: (1 S,3'R,6 ^f R,7'S,8'E,10'R, 12'S)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! -

[21]OXA[14]THIA[l _s 15]DIAZAPENTACYCLO[15.7.2.0 ³ \0 ¹⁰ - ¹² .G ²⁰ - ²⁵ ]HEXAC OSA[8, 17,19,25jTETRAENj-16'-()NE 14'.14'-DIOXIDE or

(lS,3¾,6'R ^,8^10'S/12¾)-6-CHLORO-7'-I-IYDROXY-3,4-r)II-IYDRO- 2H, 16'H-SPIRO[NAPHTHALENE- 1.2 '-

OS A[8, 17, 19,25 JTETRAEN] - 16'-ONE 14', '-DIOXIDE

A 100 mL round bottom flask was charged with (TS)-6'~chloro~5~ (((1 R,2R)-2-((S)~ 1 -hydroxy ally l)cy clobur>'l)methyl)~N-(((2~((E)-prop- 1 -en- 1 - yl)cyciopropyl)methyl)suifonyl)-3',4,4',5-tetraliydro-2H,2'H - spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxamide (Example 802, Step 6; 35 mg, 0.056 mmol) and Hoveyda-Gmbbs II (12 mg, 0.020 mmol) and DCE (28 mL). The reaction mixture was subjected to three cycles of

evacuation/back-filling with nitrogen and heated at 60 °C for about 6 h under nitrogen. Then di(ethylene glycol) vinyl ether (3 mg, 0.022 mmol) was added and stirred at rt for 30 min. The reaction mixture was concentrated and the residue was loaded to a 12g ISCO Gold column and eluted with 0 % to 60 % EtOAc

(0.3%HOAc) / hexane (0.3%HOAc) to provide the title compound (3.9 mg, 6.7 μιηοΐ, 12 % yield) as a single isomer (first eluting peak) as a white solid. Ή NMR (500MHz, CD3CN) δ 11.50 (s, 1H), 7.77 - 7.71 (m, 1H), 7.56 - 7.53 (m, 1H), 7.48

- 7.43 (m, 1 1 1 ). 7.21 - 7.17 (m, 1H), 7.15 - 7.12 (m, 1 1 1 ). 6.98 - 6.94 (m, 1 1 1 }. 5.60

- 5,54 (m, 1H), 5.24 - 5.18 (m, 1 H), 4.56 - 4,49 (m, 1H), 4.16 - 4.08 (m, 2H), 3.95

- 3,90 (m, 1H), 3.88 - 3.77 (m, 2H), 3.64 - 3,59 (m, 1H), 3.20 - 3.08 (m, 3H), 2.81 - 2.72 (m, 2H), 2.22 - 2.15 (m, 2H), 2.05 - 1.97 (m, 3H), 1.85 (br. s., 2H), 1.77 -

1.67 (m, 2H), 1.53 - 1.46 (m, 1 1 1 }. 1.40 - 1.34 (m, 1 1 1 ). 1.18 - 1.10 (m, i l l }. 0.87 - 0.82 (m, IH), 0.79 - 0.73 (m, IB) miz (ESI, +ve ion) 583.2 ( M I f ) .

EXAMPLE 803, (1 S,3'R,6'R,7 ^! S,8'E, 11 'R, 13 ^! R)-6-CHLORO-7'-METHOXY-3,4- D1HYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 '- | 2 i j()XA| 14 jTI I IA| I J 5 |I>I .A/API^TACY( ^' L<>j 1 .7.2.U ^; ".O ^{1 u ;} .Ο - !HXAC OS A[8, 17, 19,25 JTETRAEN] - 16'-ONE 14', 14'-DIOXIDE or

(18 ¾,6 ^! Κ7 ,8Έ^Γ8 ₅ 13'8)-6-€ΗΕΟΚΟ-7 ^ί 1ΈΊΉΟΧΎ-3,4-Ι31ΗΥΟΚΟ- 2H, 16'H"SPIRO| NAPHTHALENE- 1 ,23'-

[lllOXAtMjTOIAtiaSlDIAZAPENTACYCLOilS ^-O^^O^^l^^jHEXAC OSA[8,17,19 ₅ 25]TETRAEN]-16'-ONE 14',14'-DiOXIDE

Sodium hydride (60% dispersion in mineral oil; 2.1 mg, 0.051 mmol) was added to a solution of Example 793 (6.0 mg, 10.3 μηιοΐ) in THF (1.0 mL) at 0°C and it was stirred at the same temperature for 30 min. Then iodomethane (1.9 μΐ,, 0.031 mmol) was added and then the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with methanol (1 mL) and acidified with IN HC1 solution to pH 1 -2. it was extracted with EtOAc (30 mL) and the organic phase was washed with brine, dried over anhydrous MgSQ and concentrated. The residue was purified by reverse phase preparatory HPLC (Gemini™ Prep CJS 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient eiution) to give the title compound (4.7 mg, 7.9 μηιοΐ, 77 % yield) as a white solid. ^" T-INM (500MHz, D-CS) δ 9.37 - 9.31 (m, 1H), 7.71 (d, 8.3 Hz, ill). 7.21 - 7.18 (m, ill).7,17 - 7.13 (m, 21!).7.08 - 7.04 (m, IH), 6,92 - 6.88 (m, 1H), 5.68 - 5.60 (m, Ml).5.44 - 5.37 (m, IH), 4.17 - 4.05 (m, 2H), 3.64 - 3.59 (m, IH), 3.54 - 3.47 (m, IH), 3.42 - 3.34 (m, 2H), 3.28 - 3.23 (m, IH), 3.04 (s, 3H), 2.80 - 2,74 (m, 3H), 2.73 - 2.69 (m, 2H), 2.59 - 2,55 (m, IH), 2.52 - 2.48 (m, IH), 2.07 - 2,01 (m, IH), 1.88 (m, 8H), 1.42 (td, .7=5.0, 9,7 Hz, H), 1.05 - 1.00 (m, IH). m /. (ESI, +ve ion) 597.2 (M+H) ⁺ . EXAMPLE 804. (1 S,3'R,6 ^f R,7'S,8'E, 1 *S, 1 3 ^, S)-6-CHLORO-7'-METHOXY-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^! -

[21]OXA[14]THL\[ia5]DL\ZAPENTACYCLO[ 15.7.2.0^ ⁶ .0 ¹¹ - ¹³ .0 ²⁰ - ²⁵ ]HEXAC OSA[8, 17, 19,25jTETRAEN]-16'-ONE 14', 14'-DI()XIDE or

(I S ,3'R,6'R,7'S,8'E, 1 l 'RJ 3 ^f R)-6-CHLORO-7'-METOOXY-3,4-DTHYDRO- 2H, 16'H-SPIRO[NAPHTHALENE- 1 ,23'-

[2I]OXA[14]THlA[ l , 15]DIAZAPENTACYCLO[15.7.2.0 ³ -^0 ¹¹ - ¹ l0 ^{2 25} ]IlEXAC OS A[8, 17, 19,25 JTETRAEN] - 16'-ONE 14', ! 4'~Di OXIDE

Sodium hydride (60% dispersion in mineral oil; 2.3 mg, 0.057 mmol) was added to a solution of Example 796 (6.6 mg, 0.0 ! 1 mmol) in THF ( 1.0 mL) at 0°C and it was stirred at the same temperature for 30 min. Then iodomethane (2.1 uL,, 0.034 mmol) was added and then the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with methanol (1 mL) and acidified with IN HC1 solution to pH 1 -2. It was extracted with EtOAc (30 mL) and the organic phase was washed with brine, dried over anhydrous MgS04 and concentrated. The residue was purified by reverse phase preparatory HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1 % TFA, gradient elution) to give the title compound (6.3 mg, 10.6 μηιοΐ, 93 % yield) as a white solid. Ή NMR (500MHz, CD3CN) δ 9.46 - 9,32 (m, 1H), 7.74 - 7.68 (m, 1 H),

7,22 - 7.17 (m, I I I ). 7.16 - 7.09 (m, 2H), 7,03 - 6.99 (m, I I I ). 6.93 - 6.89 (m, i l l ). 5.66 - 5.58 (m, 1H), 5.51 - 5.43 (m, M l ). 4.16 - 4.06 (m, 2H), 3.66 - 3.61 (m, M l ). 3.57 - 3.51 (m, 1H), 3.37 - 3.31 (m, 2H), 3.30 - 3.26 (m, 1H), 3.04 (s, 3H), 3.02 - 2.97 (m, 1H), 2, 78 - 2,74 (m, 2H), 2.52 - 2.50 (m, 1H), 2,08 - 2,02 (m, IH), 1 .90 - 1.84 (m, 3H), 1.8.1 - 1 ,75 (m, 2H), 1.67 - 1.61 (m, 2H), 1.60 - 1 ,50 (m, 2H), 1.39 - 1.35 ( m. H), 1.22 id. ./ 3.7 ! ! . 11 1 ). 1 , 18 - 1.13 (m, i l l ), m/z (ESI, +ve ion) 597.2 (M+H) ⁺ .

EXAMPLE 805. (1 S,3'R,6 ^* R,7'S,8'E,1 l'S,13'S)-6-CHLGRO-7'-(2- METHOXYETHOXY)-3 ₅ 4-DlHYDRO-2H,l 6'H-SPIRO[NAPHTHALENE-1 ,23'- pilOXAtl^THIAt^lS!DIAZAPE TACYCLOIlS-T^-O^^O ^! ^^^^lHEXAC OSA| 8,17,19,25]TETRAEN]-16'-ONE 14',14'-DIGXIDE or

(l S,3'R,6¾,7'S,8 ,l l¾, i;rR)-6-CIfl..ORO-7'-(2-METHOXYETHOXY)-3,4- DIHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-l ,23 ^s -

[21]OXA[ 14]THIA[1 , 15]DIAZAPENTACYCLO[ 15.7.2.0

OSA[8, 17,19,25]TETRAEN]-16'-ONE 14', 14'-DIOXIDE

Sodium hydride (60% dispersion in mineral oil; 2.4 mg, 0.060 mmol) was added to a solution of Example 796 (7 mg, 0.012 mmol) in THF (1.0 ml.) at 0°C and it was stirred at this temperature for 30 mm. Then l-bromo-2-methoxy ethane (3.38 μί, 0.036 mmol) was added slowly and it was stirred at rt overnight. The reaction mixture was quenched with water (15 mL) and acidified with IN HQ solution to pH 1-2. It was extracted with EtOAc (30 mL) and the organic phase was washed with brine, dried over anhydrous MgS€>4 and concentrated. The residue was purified by reverse phase preparatory HPLC (Gemini™ Prep Cis 5iim column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (1.2 mg, 1.8 μιηοΐ, 16 % yield) as a white solid. Ή N .MR (500MHz, CD3OD) δ 7,77 - 7.73 (m, 11 1 ). 7.20 - 7. 1 1 (ra, 4H), 6.97 - 6.92 (m, IH), 5.72 - 5.64 (m, M l ). 5.56 - 5.50 (m, IH), 4.22 - 4.16 (m, M l ). 4.14 - 4.10 (m, IH), 3.68 (d, ./ 14.7 Hz, IH), 3.64 - 3.57 (m, IH), 3.51 (dd, ./ 4.4. 8.1 Hz, 1H), 3.47 - 3.42 (m, !H).3.41 - 3,23 (m, 8H), 3.05 (id, ./ 4.3.8.4 Hz, 111). 2.87 - 2.75 (m, 3H), 2,65 - 2.53 (m, 2H), 2.14 - 2.08 (m, ill).2,03 - 1.97 (m, III). 1.94 - 1.88 (m, 2H), 1.86 - 1.79 (m, 1H), 1.72 - 1.65 (m, 2H), 1.64 - 1.54 (m, 2H), 1.51 - 1.43 (m, 2H), 1.22- 1.18 (m, 1H). m/z (ESI, +ve ion) 641.2 { M · Π } ,

EXAMPLE 807. (1S,3R,6R, 7S.9'Z)-7'-HYDROXY-3,4-DTHYDRO-2H, 5'H- SPIRO[NAPHTHALENE-l ,22'-[20] OXA[ 1 11 HI Λ

[^MlDIAZATETRACYCLOtM.T^.O^^O^^lPENTACOSAI^l^lS^lTETR AEN]-15'-ONE 13 ^* ,13'-DIOXIDE

A mixture of (1S,3'R,6'R, Z'S.P'^-e-chloro-T'-hydroxy-S^-dihydro- 2H, 15 Ή-spiroj naphthalene- 1 , 22'- [20joxa 13]thia[l,14]diazatetracycfo[14.7

n]-15'-one 13',13'-dioxide (Example 834; 0,009 g, 0.016 mmol), 2-(di-tert- butylphosphino)biphenyl (0.94 mg, 3.15 μιηοΐ), palladium (II) acetate (0,3 mg, 1.5 μηιοΐ) and sodium formate (1.1 mg, 0.032 mmol) in MeOH (0.8 mL) was degassed by It was stirred at 72°C for 16 h. The reaction mixture was filtered to get rid of the solid and the filtrate was concentrated. The residue was purified by reverse phase preparatory HPLC (Gemini™ Prep Cis 5μιη column;

Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give 3.6 mg of the title compound as a film. ¾ NMR (400 MHz, CD2CI2) δ 10.88-10.21 (m, 1H), 7.73-7.61 (m, Ml).7,45-7.27 (m, 2H), 7.23-7.05 (m, 3H), 6.99 id. ,/ 8.4 i Hz, ! H), 5.63-5,51 (m, 1H), 5.48-5.37 (m, ! ! ! }. 4.36-4,27 (m, H i ). 4.23-4. 15 (m, i l l ). 3,91 -3.81 i ra IH), 3.73 (br. s., IH), 3,64 id. ./ 13.89 1 !/. I I I ). 3.50 (d, J=13,69 Hz, IH), 3.32-3, 12 (m, 2H), 2.78 (t, J=6.16 Hz, 2H), 2.62 (m, 2H), 2.37-2.15 (m, 3H), 1.91-1.50 Or, ! ! ! ! }. m/z (ESI, +ve ion) 537.2 (M+H) ⁺ .

EXAMPLE 808. (1S,3'R, 6'R 7¾ iO'£)-6-CHLORO-7'-HYDROXY-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [ 10, 16, 18,24] TETR AEN] - 15'-ONE 13', 13'-DIOXIDE

A 500 mL round bottom flask was charged with (1S, 3'R, 6'II 7'S, 9'Z)-6- chloro-7'-hydroxy-3,4-dihydro-2H, 15 'H-spiro[naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14, 7.2, 0 ³ · ⁶ .0 ¹⁹ · ²⁴ ]

pentacosa 9,16,18,24]tetraen]-15'-one 13', 13'-dioxide (Example 834; 0.142 g, 0.249 mmol) in toluene (210 mL). It was stirred at ambient temperature for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs 11 (0.042 g, 0.050 mmol) in toluene (10 mL). After the mixture was stirred at 106 °C under nitrogen for 60 min it was concentrated. The residue was loaded to a 120 g ISCO Gold column and eluted with 0 % to 20 % EtOAc (containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH). The third peak was collected and purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/'min C0 ₂ on a Thar 80 SFC. Outlet pressure 100 bar: Temp. 20 °C: Wavelength 220 nm) to give the title compound (6.3 mg) as a white solid. ^! H NMR (400 MHz, CD2CI2) δ 7.72 (d, ./ 8.4 ! Hz, IH), 7.42- 7.36 (m, IH), 7.22-7.14 (m, 2H), 7.11-7.07 (ra, 1H), 6,98-6.93 (m, 1 H), 6.16 (ddd

5. 1 8. 10.03, 15.50 Hz, i l l ). 5.65-5.53 (rn, IH), 4, 16-4.04 (m, 2H), 3.95-3.87 (m, IH), 3.87-3.79 (m, IH), 3.67-3.60 (m, IH), 3.52 (t, J=8.31 Hz, IH), 3.15 (d, ./ 14.28 Hz, I H), 3.06 (dd, ./ H. I . 15.36 Hz, IH), 2.80-2.72 (m, 2H), 2.44-2.52 (m, IH), 2.25 (quin, ./ 8.85 Hz, IH), 2.13-2.04 (rn, 2H), 2.03-1 ,95 (m, 2H), 1 .94- 1.26 (rn, 9H). m/z (ESI, +ve ion) 571.0 (M+HV\

EXAMPLE 815. (3R, 6S, 2S)-6'-CHLORO-3 ',4'-DIHYDRO-2'H, 15H- SPIRO [ 10,20-DIOXA- 13 -ΊΊ Π Λ- 1,14-

DIAZATETRACYCLO[14,7.2.0 ^3/1 .0 ¹⁹ - ² ]PENTACOSA-I6, 18,24-TRIENE- N APHTHALEN ] - 15 -ONE 13,13-DIOXIDE

A 50 mL flask was charged with Example 826 (0.012 g, 0.022 mmol), EtOAc (21.5 mL) and platinum (IV) oxide (4,89 mg, 0.022 mmol) was added. The mixture was degassed by and was stirred at ambient temperature under hydrogen for 40 min. It was filtered through syringe filter to remove catalyst. The filtrate was concentrated and the residue was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/min C0 ₂ on a Thar 80 SFC. Outlet pressure 100 bar; Temp. 20 °C; Wavelength 220 nm) to give the title compound (2.6 mg, second eluting peak) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.20-8,06 (m, IH), 7.72 (m, IH), 7.20-7.15 (m, IH), 7.14-7.07 (m, 2H), 6.96 (s, i l l ). 6.82 (m, IH), 4, 12-4,08 (m, 2H), 3.90-3.84 (m, 2H), 3,84-3.79 (m, IH), 3.74-3.61 (m, 3H), 3.50-3.42 (m, IH), 3.39-3.33 (m, IH), 3.26 (d, J=14.28 Hz, 1 1 1 ). 3.21-3.12 (ra, i l l ). 2,81 -2.72 (m, 2H), 2,24-2.08 (m, 2H), 2,07-1.36 (m, 12H). m/z (ESI, +ve ion) 559. 1 (M+H) ⁺ .

EXAMPLE 816. (3R, 6S. 2S)-5'-CHLORO-2',3 ^, -DIHYDRO-l 5H-SPIRO[l 0,20- DIOXA-I3-TOIA-1, 14-DIAZATETRACYCLO[14,7.2,0 ^3/1 .0 ¹⁹ - ²⁴ ]PENTACOSA- 16, 18,24-TRIENE-22, Γ-INDENJ-I 5-O E 13, 13-DIOXIDE

A 50 mL flask was charged with Example 817 (0.043 g, 0.079 mmol),

EtOAc (26 mL). Platinum (IV) oxide (0.0.18 g, 0.079 mmol) was added and the mixture was degassed by It was stirred at ambient temperature under hydrogen for 65 min. It was filtered through syringe filter to remove catalyst. The filtrate was concentrated and the residue was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/min CO2 on a Thar 80 SFC. Outlet pressure 100 bar; Temp. 20 °C; Wavelength 220 nm). The title compound (17 mg) was obtained as a single isomer (second eluting peak) as a white solid. Ή NMR (400 MHz, CD2CI2) δ 7.49-7.45 (m, IH), 7,36-7.34 (m, 1H), 7.29-7.25 (m, i l l ). 7,22-7.20 (m, I H i.. 7.20-7, 16 (m, IH), 6.90-6.86 (m, 1H), 4.21- 4.09 C m. 2! i s. 3.96 (td, ./ 6.53. 10.42 Hz, IH), 3.89-3.82 (m, IH), 3.71 (dd,

./ 2.93. 15.06 Hz, 1 1 1). 3.61-3.51 (m, 2H), 3.48-3.32 (m, 4H), 3.21-3.15 (m, 2H), 3,01 (q. ./ 7.3·; ! 1 1/. 4H), 2.96-2.87 (m, IH), 2.35-2,25 (m, ! ! ! ). 2.23-2, 15 (m, IH), 2.05-1.94 (m, IH), 1.93-1.80 (m, 3H), 1.68-1.55 (m, IH), 1.53-1.26 (m, 2H). m/z (ESI, +ve ion) 545.0 (M+H) ⁺ .

EXAMPLE 817. (3R, 6S, 7£ ^' ,22S 5 ^! -CHLORO-2',3'-DIHYDRO-15H- SPIRO [ 10,20-DIOXA- 13 -ΊΉΙΑ- 1,14- DIAZATETRACYCLO[14J.2.0 ³ '^0 ³⁹ ' ²⁴ ]PENTACOSA-7,16,18,24-TETRAENE- 22,1' -INDEN] - 15 -ONE 13,13 -DIOXIDE

Step 1 : 3-(2-BROMOETHOXY)PROP-l-ENE

Br

Perbromomethane (19.48 g, 58.7 mmol) was added to a solution of 2-

(allyloxy)ethanol (5.0g, 49.0 mmol) in DCM (190 mL). The resulting solution was cooled to 0 °C and triphenylphosphine (15.41 g, 58.7 mmol) was added. It was stirred at 0 °C to ambient temperature for 3 h. After concentration, the residue was loaded to a 80g ISCO Gold column and eluted with 0 % to 15 % EtOAc/DCM to provide 4.14 g of the title compound as colorless oil. ¾ MR (400MHz, DMSO- db) δ 5.89 (tdd, ./ 5.3. 10.5, 17.3 Hz, 1H), 5.29 (qd,■/ 1 .8. 17.2 Hz, 1H), 5.21 - 5.11 (m, 1H), 4.01 (td, ./ ! 5. 5.3 Hz, 2H), 3,75 - 3.67 (m, 2H), 3.65 - 3.58 (ra.

2H). Step 2: SODIUM 2-(ALLYLOXY)ETHANESULFONATE

A mixture of 3-(2-bromoethoxy)prop-l-ene (Example 817, Step 1 : 4.14g, 25.09 mmol) and sodium sulfite (3.48 g, 27.6 mmol) in water (20 mL) was stirred at 1 10°C for 4 h. After concentration, the residue was added acetone (10 rnL) and stirred for a minute. The title compound (5.24 g) was collected as a white solid by filtration, ^] H NMR (400MHz, DMSO-a ) δ 5,86 (tdd, J=5.4, 10.5, 17.2 Hz, IH), 5.23 (qd, ,/ i 8. 17.2 Hz, IH), 5, 17 - 5,06 (m, IH), 3.90 (td, ./ 1 .6. 5,5 Hz, 2H), 3.67 - 3.51 (m, 2H), 2.75 - 2.63 (m, 2H). Step 3; 2-(ALLYLOXY)ETHANESULFON AMIDE

A mixture of sodium 2~(allyloxy)ethanesulfonate (Example 817, Step 2; 3.87 g, 20.57 mmol) and phosphorus oxychloride (54.6 mL, 596 inmol) was stirred at 130°C for 4.6 h. It was concentrated by rotavapor. To the residue was added CH3CN (32 mL) and stirred for I min. The mixture was filtered to remove the precipitate. NH (30% aq.) (30 mL) was added slowly to the filtrate at 0°C and it was stirred for 0.6 h. The reaction mixture was diluted with EtOAc (470 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 40g ISCO Gold column and eluted with 0 % to 15 % EtOAc/hexane to provide 1.19 g of the title compound as a colorless oil. ¾ NMR (400 MHz, DMSO-ifc) δ 6.72-6.91 (m, 2H), 5.81-5.95 (m, IH), 5.27 (qd, ./ 1 .74.

17,29 Hz, I H), 5.22-5,34 (m, IH), 5.10-5.21 (m, IH), 3.97 (td, ,/ i 47. 5,48 Hz, 2H), 3,67-3.80 (m, 2H), 3.19-3,28 (m, 2H).

Step 4: ((l R,2R)-2-(((TETRAHYDRO-2H-PYRAN-2- YL)OXY)METHYL)CYCLOBUTYL) METHANOL

To a stirred solution of (lR,2R)-cyclobutane-l,2-diyldimethanol (1.5 g, 12.9 mmol) in dichloromethane (1.10 g, 12.9 mmol) at 23°C was added 3,4- dihydro-2H-pyran (0.543 g, 6.46 mmol), followed by pyridine 4- methylbenzenesuifonate (0,325 g, 1.29 mmol). It was stirred at rt for 24 h. The mixture was concentrated to afford the title compound.

Step 5: (lR,2R)-2-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)cyclobutanecarbaldehyde

To a white slurry solution of iodobenzene diacetate (5.40 g, 16.8 mmol) and ((1 S,2S)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclobutyl)me thanol (from Step 4, 2.80 g, 14.0 mmol) in DCM (7.0 ml) was added 2,2,6,6- Tetramethyl-l -piperidinyloxy, free radical, 2,2,6,6-Tetramethylpiperidine 1 -oxyl (Tempo, 0, 109 g, 0.699 mmol) in one portion at rt and then the mixture was vented to atmosphere and stirred at rt for 1.3 h. It was concentrated and the residue was loaded to a 80g ISCO Gold column and eluted with 0 % to 10 % EtOAc/hexane to provide the title compound (0,806 g) as an oil

Step 6 : 2-(((lR,2S)-2-((E)-PENT-l-EN-l-

YL)CYCLOBUTYL)METHOXY -2H-PYRAN

A solution of (butyl)triphenylphosphonium bromide (4.83 g, 12.1 mmol) in THF (50 ml) was cooled to 0 °C. n-Butyllithium solution (2,5 M, in hexane, 5,33 ml, 13.3 mmol) was added dropwise and it was stirred at 0 °C for 22 rain. (lS,2S)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methy (Step 5, 0.800 g, 4.04 mmol) was added and it was stirred at 0 °C for 60 rnin. The reaction mixture was added to a stin-ed saturated NaHCC^ solution (20 ml). The organic phase was separated and the aqueous was extracted with EtOAc (200 ml). The combined organics were dried (MgSO/ _j. ) and concentrated. It was concentrated and the residue was loaded to a 24g ISCO Gold column and eluted with 0 % to 5 % EtOAc/hexane to provide the title compound (0.498 g) as a colorless oil.

Step 7: ((1 R,2S)-2^;(E)-PENT-l-EN-!-YL)CYCLOBUTYL)METHANOL

4-Methylbenzenesulfonic acid (0.071 g, 0. 11 mmol) was added to a solution of 2-(((l S,2R)-2-((E)-pent-l-en-l-yl)cyclobut5 _' ^, l)rnethoxy)tetrahydro-2H- pyran (Step 6, 0.490 g, 2.056 mmol) in MeOH (29.4 ml). It was stirred at it for 2 h. It was added saturated Na^CO^ solution (2 mL) and then concentrated. The residue was extracted with EtOAc (150 ml). The combined organics were dried over anhydrous sodium sulfate and filtered through a short plug of silica gel. The filtrate was concentrated to give the title compound, (0.268 g) as colorless oil.

Step 8: (1 R,2S)-2-((E)-pent- 1 -en-1 -yl)cyclobutanecarbaldeh de

To a white slurry solution of iodobenzene diacetate (0.581 g, 1.80 mmol) and ((l S,2R)-2-((E)-pent-l-en-l-yl)cyclobutyl)methanol (Step 7, 0.265 g, 1.72 mmol) in DCM (0.86 ml) was added 2,2,6,6-Tetramethyl-l -piperidinyloxy, free radical, 2,2,6,6-Tetramethyipiperidine 1-oxyl (Tempo) (0.013 g, 0.086 mmol) in one portion. It was stirred at rt for 2 h. The mixture became a homogeneous, bright pale orange (1.6 M solution in DCM) and was used without work up.

Step 9: (S)-METHYL 5'-CHLORO-5-(((l R,2S)-2-((E)-PENT-l-EN-l- YL)CYCLOBUTYL)METHYL)-2',3',4,5-TETRAHYDRO-2H-

SPIRO| BENZO[B]n ,4|OXAZEPINE-3, l'-INDENE]-7-CARBOXYLATE

A screw-cap vial was charged with (S)-methyl 5'-chloro-2',3',4,5- tetTahydro-2H-spiro[benzo[b] [.l ,4]oxazepine-3, -indene]-7-carboxylate (0.160 g, 0.465 mmol), ( S,2R)-2-((E)~pent~l~en-l-yl)cyclobutanecarbaldehyde (Step 8, 0.320 ml, 0.512 mmol) and acetic acid (0.53 ml, 9.3 mmol) in DCM (7.8 mi). The mixture was stirred at it for 10 rain. Sodium triacetoxyhydroborate (0.296 g, 1.39 mmol) was added in portions and the reaction was maintained at rt for 18 h. The reaction mixture was extracted with EtOAc (140 ml). The organic phase was washed with Na ₂ C0 ₃ solution and brine, dried over anhydrous sodium sulfate. It was concentrated and the residue was loaded to a 4g ISCO Gold column and eluted with 0 % to 10 % EtOAc/hexane to provide the title compound (0.177 g) as a film.

Step 10: (S)-A- (2 AIXYLOXY)ETHYL)SULFONYL)-5'-CHLORO-5- (((ii¾2^-2 | ¾-PENT-l-EN-l-YL)CYCLOBUTYL)METHYL)-2',3',4,5-

TETTlAHYDRO-2H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,r-INDENE]-7- CARBOXAMIDE

N-(3-Dimemylammopropyl)-N'-emylcarbodiimide hydrochloride (EDC; 0.097 g, 0,506 mmol) was added to a solution of (S)-5'~c ]om~5~(((lS,2R)-2-((E)~ pent-l-en-l-yl)cyclobut 'l)methyl)-2',3',4,5-tetrahydro-2H- spiro[benzo[b] [l,4]oxazepine-3, l'-indene|-7-carbox lic acid (Step 9; 0.1 18 g, 0.253 mmol) and 2-(allyloxy)ethanesulfonamide (Example 817, Step 3; 0.059 g, 0,354 mmol) in DCM (10 mL). Then N,N-dimemylpyiiam-4-amine (DMAP) (0.062 g, 0.506 mmol) was added and it was stirred at ambient temperature for 15 h. The solution was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μτη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give 85 mg of the title compound as a film, m/z (EST, +ve ion) 6.13.1 (M+H) ⁺ . Step 11: (3R, 6S, 7E,22S)-5 ^, -CHLORO-2 ^, ,3 ^, -DIHYDRO-15H-SPIRO[10,20-

DIOXA-13-THIA-1 4-DIAZATCmACYCLO|;i4 .2.0 ³ '« 0 ^l9 - ²⁴ ]PENTACOSA- 7,16, 18,24-TETRAENE-22, 1 '-INDEN] - 15-ONE 13,13-DIOXIDE

A 500 mL three-necked round bottom flask was charged with (5)-N-((2- (aliyloxy)ethyl) sulfonyl)-5'-chloro-5-(((75;2R)-2-((/2;)-pent-l-en-l - yl)c lobu1yl)methyl)-2\3',4,5-tetrahydro-2H-spiro[benzo[b][l ,4]oxazepine-3, - indene]-7-carboxamide (Example 817, Step 10: 0.085 g, 0.139 mmol) in toluene (300 mL). It was stirred at ambient temperature for 10 rain to dissolve the solid

starting material and then subjected to three cycles of evacuation/back-filling with

nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs

II (0.017 g, 0.028 mmol) in toluene (5 mL). After the mixture was stirred at 107°C

under nitrogen for I h air was blown for 10 rain to deactivate the catalyst, and

then concentrated. The residue was purified by reverse phase preparative HPLC

(Gemini™ Prep 5μηι column; Phenomenex, Torrance, CA: MeCN in water

with 0.1% TFA, gradient elution) to give 57 mg of the title compound as a white

solid. Ή N.V1R (400 MHz, CD2CI2) δ 8.32-8.12 (m, ill).7.44-7.36 (m, 1H), 7.22

(s, 3H), 7.02-6.94 (m, 1H), 6.92-6.80 (m, 1H), 6.00-5.86 (m, 1H), 5.67-5.49 (m,

1H), 4.30-4,22 (m, 1H), 4.15 (m, 1H), 3.86-3.99 (m, 4H), 3,85-3.38 (m, 3H), 3.25

(dd, .7=7.43, 15.45 Hz, ill).3,20-3.10 (m, ill).3.01-2.89 (m, 2H), 2.65-2.47 (m,

1H), 2.39-1.05 (m, 8H). m/z (ESI, +ve ion) 543. EXAMPLE 818, ί /.V, 3 % 6'i?)-6-CHLORO-3,4-DIHYDRO-2H, 14Ή- SP1RO [NAPHTHALENE- 1 ,21 '-[ 19] OXA[ 12] ! !!!AI 1,13]

DIAZATETRACYCL()[13.7,2.() ^3>6 .() ^iS ' ² iTETRACOSA|;i5,17,23]TRIEN]-14 ^! - ONE 12",12'-DIOXIDE

A 50 ml, flask was charged with (1S,3'R,6'S, 7'£ ^' )-6-chloro-3,4~dihydro-2H,14 ^r H~spiro [naphmalene-l,2r[19]oxa[12]tma[l,13]diazatetracyclo[13.7.2.0 ³ ' ⁶ .0 ¹⁸ ' ²³ ]tetracosa[7,15,17,23] tetraenj-14 ^! -one 12',12'-dioxide (Example 829; 0.0046 g, 8.50 μιηοΐ), EtOAc (8.50 mL). It was added platinum (TV) oxide (1.93 mg, 8.5 μπιοΐ) and the mixture was degassed by After it was stirred at ambient temperature under hydrogen for 54 min it was filtered through syringe filter to remove catalyst. The filtrate was concentrated to give 4.4 mg of the title compound as a white solid. 'HNMR (400 MHz, CD2CI2) δ 8.05 (br, s., IH), 7.76-7.67 (m, IH), 7.21-7.14 ( IH), 7.10 (dd, .7=2.25, 4.99 Hz, IH), 7,06-6.87 (m, 3H), 4.13-4,10 (m, IH), 3.91-3.60 (m, 4 3.30-2.98 On.3H), 2.80-2.69 (m, 2H), 2.25-2.10 (m, IH), 2.06-0.85 (m, 1711). m/z (ESI, +v ion) 543.0 !Y! Π) .

EXAMPLE 823. (15, i ¾ 6¾-3,4-DIHYDRO-2H,14'H-- SPTRO [NAPHTHALENE- 1,21'- I i jOX A| I 211 Η1Λ| I , ! 3 |OI.\/.\ Π·. f ^' RACYCf ,Oj 13,7.2 ^; ",ϋ ^{1κ ,:} | Th 1 RACOSA

[15,17,23] TR1EN] - 14'-ONE 12', 12'-DIOXIDE

Under nitrogen atmosphere, 10% palladium on carbon (8 mg, 7.95 μηιοΐ) was added to a solution of Example 829 (0.0043 g, 8 μηιοΐ) in MeOH (8 mL).

Then it was stirred at ambient temperature under ¾ for 90 rnin. The mixture was filtered through syringe filter to provide the title compound (3.6 mg) as a white

solid. Ή N.V1R (400 MHz, CD2CI2) δ 8.08-8.00 (m, IH), 7.78-7.73 (m, IH), 7.20- 7.08 (m, 3H), 6.98 (s, IH), 6.94-6,90 (m, 2H), 4.18-4.12 (m, 2H), 3,93-3.81 (m,

2H), 3.80-3,72 (m, 2H), 3.65 (br. s., IH), 3.22 (d, ,7=14,48 Hz, IH), 3.19-3.07 (m,

2H), 2.78 (dd, ./ 5.77.9.49 Hz, 2H), 2.24-2.14 (m, IH), 2.08-1.09 (m, 15H). m/z

(ESI, +ve ion) 509.1 (VI 11) ^' . EXAMPLE 824, i.iV, 6R, .¾)-3 ^' ,i-!)!HY!)R()-2'i!,, 15H-SP!RO[l 0,20-DIOXA- 13-TfflA-l,14-DIAZATETRACYCLO[14.7.2.0 ³ . ⁶ . ^0i9>24 |PENTACOSA-16,18,24- TRIENE-22, 1 ' -N APHTH ALEN] - 15-ONE 13,13-DTOXIDE

Under nitrogen atmosphere, 10% palladium on carbon (6 mg, 5.4 μιηοΐ) was added to a solution of (Example 826; 0.003 g, 5.4 μιηοΐ) in MeOH (5 mL). Then it was stirred at ambient temperature under ¾ for 3 h. It was filtered through syringe filter to afford the title compound (2,6 mg) as a white solid. ¹ H NMR (400 MHz, CD2CI2) δ 8.14-8.10 (m, 1H), 7.76-7.72 (m, IH), 7.22-7.15 (m, 2H), 7.12 ! d. 7 1 1 .35 Hz, 2H), 6.97-6.94 (m, 1H), 6.84-6.79 (m, IH), 4.14-4.10 (m, 3H), 3.90-3.84 (m, 3H), 3,79-3.75 (m, I H), 3.68-3.63 (m, 3H), 3.48-3.45 (m, IH), 3,38-3.34 (m, IH), 3.29 (d, .7=14,09 Hz, 2H), 3.23-3, 17 (m, IH), 2.79 (d, 7=4.50 Hz, 2H), 2.21-1.25 (m, 1 i l l ), m/z (ESI, +ve ion) 525.2 (M+H) ⁺ .

EXAMPLE 825. (1S,3'R, 6'S: 7'£ ^' )-6-CHLORQ-3,4~DLHYDRQ~2H,13'H~

SPIRO[NAPHTHALENE- 1.20 ^' -

[ lSlOXAtl l lTHIAt^ lDIAZATET ACYCLOI ^J^.O'^.O^lTRICOSAI^l

4,16,22]TETRAEN]-13'-ONE Γ , 1 1 '-DIOXIDE

Step 1 : (S)-METHYL 6'-CHLORO-5-(((lR,2S)-2-((E)-PENT-l -EN-l- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR _j! 4HYDRO-2H,2 ^, H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

A screw-cap vial was charged with (S)-methyl 6'-chloro-3 ^! ,4,4',5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (Intermediate AA11A, Step 12A; 0.190 g, 0.53 mmol), (l S,2R)-2-((E)-pent-l-en- l -yl)cyclobutanecarbaldehyde (Example 817, Step 5; 0.43 ml, 0.69 mmol) and acetic acid (0.61 ml, 10.6 mmol) in DCM (8.8 ml). After the mixture was stirred at rt for 14 min, sodium triacetoxyhydroborate (0.563 g, 2,65 mmol) was added in portions and the reaction was maintained at rt for 15 h. The reaction mixture was extracted with EtOAc (140 ml,). The organic phase was washed with Na ₂ C03 solution and brine, dried over anhydrous sodium sulfate. It was concentrated and the residue was loaded to a 4g ISCO Gold column and eluted with 0 % to 10 % EtOAc/hexane to provide the title compound (0.12 g) as a film. Step 2. (S)-6'-CHLORO-5-(((lR,2S)-2-((E)-PENT-l -EN-l-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C A BOXYLIC

ACID

Lithium hydroxide solution (1.0 M aqueous solution, 2.4 ml, 2.4 mmol) was added to a solution of (S)-methyl 6'-chloro-5-(((l S,2R)-2-((E)-pent-l-en-l- yl)c lobutyl)memyl)-3 4,4 5-tetrahydro-2H,2'H-spiro[benzo[b][ l,4]oxazepine- 3,l'-naphthalene]-7-carboxylate (Step 1, 0.1 18 g, 0.239 mmol) in THF (4.8 ml) and MeOH (2.4 ml), it was stirred at 50 °C for 12 h. It was concentrated, acidified with 1 N HCl and solid product was formed. It was filtered to collect the title compound (0.115 g) as a white solid.

Step 3 : (.V)-.V-( Hl l -3-i ^' \- i -YLSULFONYL)-6'-CHLORO-5-(((7R, 2^-2-ίγ£)- PENT-l-EN"l-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETR HYDRO- 2H,2!-i-SPIRO[BENZO[B][ I ,4]OXAZEPINE-3, l'-NAPFITFIALENE]-7- CARBOXAMIDE

N-(3-Dimethylaminopfopyl)-N'-ethylcarbodiimide hydrochloride (EDC; 0,016 g, 0.083 mmol) was added to a solution of (S)-6'-chloro-5-(((/_¾ 2/?)-2-((E)- pent-l-en-l-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2' H- spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (Step 2: 0.020 g, 0.042 mmol) and but-3-ene-l -sulfonamide (EE15; 0.011 g, 0.083 mmol) in DCM (1.7 ml,). Then N,N-dimethylpyndm~4-amine (DMAP) (10 mg, 0.083 mmol) was added and it was stirred at ambient temperature overnight. The mixture was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5μηι column; Phenornenex, Torrance, CA; MeCN in water with 0.1 % TFA, gradient elution) to give the title compound (24 mg) as a film, m/z (EST, +ve ion) 597.2 (M+H) ⁺ .

Step 4 : (1S, 3'R 6'S, 7'£)-6-CHLORO-3,4-DIHYDRO-2H,13H- SPIRO INAPHTHALENE- 1 ,20'- [18]OXA[l l]THIA[l,12]DIAZATETRACYCLO[.12.7.2.0 ³ ' .0 ^l7 ' ²² ]TRTCOSA[7,l 4,16,22]TETRAEN]-13'-ONE 1 Γ-DIOXIDE

A 500 mL three-necked round bottom flask was charged with (,S -N-(but-

yl)cyclobu1\d)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[b enzo[b] [l ,4]oxazepine- 3,r-naphthalene]-7-carboxamide (Step 3; 0.024 g, 0.040 mmol) in toluene (134 mL). It was stirred at ambient temperature for 0 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (5 mg, 8 μηιοΐ) in toluene (5 mL). After the mixture was stirred at 107 °C under nitrogen for 1 h, air was blown for 10 min to deactivate the catalyst and then concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep 5μηι column; Phenomenex, Torrance, CA: MeCN in water with 0.1 % TFA, gradient elution) to give the title compound (10.7 mg) as a white solid. 'H NMR (400 MHz, CD2CI2) δ 8.16-8.04 (m, 1H), 7.79-7.63 (m, IH), 7.29- 7.14 (m, 2H), 7.13-7.07 (m, IH), 7.02-6.94 (m, 1H), 6.76-6.68 (m, I H), 5.89-5.78 (m, IH), 5,45-5.35 (m, I H), 4.24-4. 14 (m, 2H), 4.03 (d, ,/ i 2 32 Hz, IH), 3.54 (s, 4H), 3.36 (s, IH), 2.81-2,39 (m, 6H), 2.02-1.16 (m, 8H), m/z (ESI, +ve ion) 527.2 (M+H) ⁺ .

EXAMPLE 826, (3S, 6R, 7£ _> 22 _i S -6 ^, -CHLORO-3 ^, ,4 ^! -DIHYDRO-2 ^! HJ 5H- SP1RO [ 10,20-DIOXA- 13 -ΊΉΙΑ- 1,14-

DIAZATETRACYCLO[14.7.2.0 ³ '^ ⁰⁾⁹ ' ²⁴ ]PENTACOSA-7,16,18,24-TETRAENE- 22,I'-NAPHTHALEN]- 15-ONE 13, 13-DIOXIDE

Step 1 : (Λ .ν-{{2-{ΛΙ.ΙΛ .ΟΧΥ)Ι·. Π m )St U 0\ΥΜ~6'~Π Π.ϋΚϋ- ίί Hi 2SJ- 2-f†E)-PENT-l-EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHY DRO- 21 S.211-SPI OI i-NZ<)| B!| i .4j()XA/iiPIXi 3. Γ-ΝΛΡ! ΠΉΑ!.ΗΝ!:|·7· CARBOXAMTDE

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC; 0.056 g, 0,292 mmol) was added to a solution of { . V ) - ' - c h ! o r o - - ( ( { / S. /?)-2-((E)- pent-l-en-l-yl)cycIobutyI)methyl)-3',4,4',5-tetraliydro-2H,2 'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (Example 825, Step 2; 0,070 g, 0.146 mmol) and 2-(allyloxy)ethanesulfonamide (Example 817, Step 3; 0,043 g, 0.262 mmol) m DCM (7 ml.). Then N,N-dimethylpyridin-4- amine (DMAP) (0.036 g, 0.292 mmol) was added and it was stirred at rt overnight. The mixture was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (34 mg) as a film, m/z (ESI, +ve ion) 627.2 (M+H) ⁺ .

Step 2: (¾<5/t7E,22S)-6'-CHLORO-3 ^, ,4 ^, -DIHYDRO-2H.15H-SPIRO[ 10,20-

DIOXA-13-TH -1,14-DIAZATETRACYCLO[14,7.2,0 ³ '^ ⁰¹⁹ - ²⁴ ]PENTACOSA- 7,16,18,24-TETRAENE-22, 1 '-N APHTHALEN] - 15-ONE 13 , 13 -DIOXIDE A 500 mL three-necked round bottom flask was charged with (<S)~N-((2-

(allyloxy)ethyl) sulfony -o'-chloro-S-iii/S 2R-2-^E)-pent-l-en-l - y cyclobut methy^-S'^^'.S-tetrahydro- H^'H-spirotbenzotbJtl^Joxazepine- 3,l'-naphthalene]-7-carboxamide (Example 826, Step 1 ; 0,034 g, 0.054 rnmol) in toluene (180 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (7 mg, 1 1 μηχ)]) in toluene (5 mL), After the mixture was stirred at 107 °C under nitrogen for 1 h, air was blown for 10 min to deactivate the catalyst. The mixture was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μτη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (22 mg) as a white solid, ¾ NMR (400 MHz, CD2CI2) δ 8.17-8.10 (m, 1 H), 7.75-7.70 (m, 1H), 7,20-7.09 (m, 3H), 6.96 (s, 1 H), 6.79-6,70 (m, 1H), 6.03-5.94 (m, 1H), 5.70-5.59 (m, i l l ). 4.22-4.12 (m, H i ). 4.11-4.07 (m, 1H), 3.98-3.88 C m. 3H), 3.85- 3.64 (m, 4H), 3.22 (d, ./ 14.28 Hz, I I I ). 3.18-3.00 (m, 2H), 2.81 -2.73 (m, 2H), 2,63-2.50 (m, I I I ). 2.36-2.24 (m, \ 2.22-1 .18 (m, 9H). m/z (ESI, +ve ion) 557.2 (M+H) ⁺ .

EXAMPLE 827. (3S, 6R, 225> 6'-CHL()R()-3^4 ^! -DIHYDRO-2TI, 15H- SPTRO[ 10,20-DIOXA- 13-THIA- 1,14-

DIAZATETRACYCLOIM ^-O^^^^^lPENTACOSA-l^lS^-TRIENE^,!'- N APHTHALEN] -15 -ONE 13,13-DIOXIDE

A 50 mL flask was charged with Example 826 (0.0038 g, 6,82 p,mol), EtOAc (7 mL) and platinum (IV) oxide (1.6 mg, 6.82 μηιοΐ). After the mixture was degassed by N2 it was stirred at rt under hydrogen for 44 min. It was filtered through syrmge filter to remove catalyst. The filtrate was concentrated to give the title compound (3.8 rng) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.16- 8.10 (m, Mi).7.75-7,68 (m, 1H), 7.19-7.07 (m, Ml).6,97-6.92 (m, III).6.87-6.80 (m, IH), 4.13-4.08 (m, 2H), 3.88-3.84 (m, 2H), 3.72-3.65 (m, 2H), 3.50-3.43 (m, HI).3.39-3.32 (m, IH), 3.26 (d, ./ 14.28 Hz, 1H), 3.17 (dd, ./ 7.04.15.65 Hz, IH), 2,80-2.73 (m, 2H), 2.24-1.76 (m, 6H), 1.71 1,40 (m, 8H). ni , (ESI, +ve ion) 559,1 (M+H) ⁺ .

EXAMPLE 829. (IS, 3 'R, 6 'S, 7'i. ^' )-6-CHLORO-3,4-DIHYDRO-2H, 14Ή- SPIRO[NAPHTHALENE-l,21'-

[19iOXA|;i2]THIA|;i,13]DIAZATETRACYCLO[13.7.2.0 ³ - ⁶ .0 ^!8 - ²³ ]TETRACOSA

[7, 15, 17,23 ] TETR AEN 1 - 14'-ONE 12', 12-DIOXIDE

Step 1 ; (5)-6'-CHLORO-5-(((7R,25)-2-((E)-PENT-l -EN-1- YL)CYCLOBUTYL)METHYL)-N-(PENT-4-EN-l-YLSULFONYL)-

TETRAHYDRO-2H,2'H-SPIRO[BENZO|Bj|l,4]()XAZEPINE-3,r- N APHTH ALENE1 -7 -C ARB OXAMIDE

N-(3-Dimethylarninopropyl)-N'-ethylcarbodiimide hydrochloride (EDC; 0.016 g, 0,083 mmol) was added to a solution of (,S)-6 ^, -ch]oro-5-(((7S' _> 2R)-2-((E)- pent-l-en-l-yl)cyclobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 825, Step 2; 0,020 g, 0.042 mmo1)and pent-4-ene-l -sulfonamide (EE192; 0.012 g,

0,083 mmol) in DCM (1.7 mL). Then N,N-dimeihylpyridm-4-amme (DMAP) (10 mg, 0.083 mmol) was added and it was stirred at rt for 22 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Ci8 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0, 1 % TFA, gradient elution) to give the title compound (20 mg) as a film, m/z (ESI, +ve ion) 61 1 .2 (M+H) ⁺ .

Step 2 : {1S 'R 6'S, 7'£)-6-CHLORO-3,4-DIHYDRO-2H,14H- SPIRO [NAPHTHALENE- 1,21"-

[lQlOXAt^lTHIAtl SlDIAZATETRACYCLOIlS.T^.O'^.O^^'lTETRACOSA

[7,15, 17,23]TETRAEN] -14'-ONE 12', 12'-DIOXIDE

A 500 mL three-necked round bottom flask was charged with (5)-6'- cMoro-S- ii^ iJ^- ^' ^-pent-l -en-l-y cyclobut lJrnethy -N-ipen -en-l- y lsu]fonyl)-3',4,4',5-tetTahydro-2H,2'H-spiro[benzo[b] [1 ,4]oxazepine-3, 1 '- naphthalene] -7-carboxamide (Example 829, Step 1; 0.020 g, 0.033 mmol) in toluene (110 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (4.10 mg, 6.54 μηιοΐ) in toluene (5 mL). After the mixture was stirred at 107 °C under nitrogen for 56 mm it was concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5um column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (10.7 mg) as a white solid. ^y ll NMR (400 MHz, CD2CI2) δ 7.99 (br. s., 1H), 7.72 (d, .7=8,61 Hz, H), 7.17 (td, ,/ 227.8,56 Hz, H), 7.12-7,08 (m, 1H), 7.04-6.96 (m, IH), 6.95-6.90 (m, IH), 6.75 (br. s., IH), 5.61-5.51 (m, 2H), 4.12- 4.07 (m, 2H), 3.81-3.66 (m, 3H), 3.49-3.31 (m, 111).3.23-3.03 (m, 2H), 2.81-2.67 (m, 3H), 2,24-2.12 (m, l).2,09-1.98 (m, ill) 1.23 (s, 5H). m/z (ESI, +ve ion) 541,1 ί\Ί 11) . EXAMPLE 830. (iS ^, ₎ 3¾;6¾)-6-CHLORO-3 ₅ 4-DIHYDRO-2H,13 ^, H-

SPIRO[NAPHTH ALENE- 1 ,20'-

I IH!OXAI i 1111 II A| I .. ! 2|P!.\/.\ Π·. f ^' RACYCf ,Oj i -1,7.20 ' 'V' ^1* " ¹ |TRii ^' OSA| 14. 16,22]TRIEN]-13'-ONE 1 l',l 1 '-DIOXIDE

A 50 mL flask was charged with Example 825 (0.003 ! g, 5.88 μιηοί), EtOAc (6 mL) and platinum (IV) oxide (1.3 mg, 5.88 μηιοΐ). The mixture was degassed by N2 and it was stirred at rt under hydrogen for 1 h. The mixture was filtered through syringe filter to remove catalyst and the filtrate was concentrated to give the title compound (3.1 mg) as a white solid. ^l R NMR (400 MHz, CD2CI2) δ 7.76-7.69 (m, IH), 7.21-7.06 (m, 3H), 7.02-6.84 (m, 2H), 4.08 (d, ./ 7.24 Hz, 2Ii), 3.73-3.60 (m, 3H), 3.50 (d, ./ 12.32 Hz, IH), 3.39-3.32 (m, IH), 3.27 (d, J=14.08 Hz, IH), 2.76 (br. s., 2H), 2.33-2,21 (m, IH), 2.14-1.22 (ra, 15H). m/z (ESI, +ve ion) 529, 1 ( il) . EXAMPLE 831. (IS, 3 R, 6R, 7R, 10 ¾ 11 ¾ 6-CHLORO- 10'-METHYL~3,4- DIHYDRO-2H, 17 'H-SPIRO[N APHTHALENE- 1.24'-

[8/12,22]TllOXA[15]THIA[L16]DlAZAl ⁵ ENTACYCLO[16 .2 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACQSA[18,2C),26]TRIENj-17'-ONE 15',15'-DI()XIDE OR

(!S,3'R,6'R7'R,10'R,irS}-6-C-ll&M)A0 ^< -M Ti^

|8.!2.22|TR!()XAj Ι5|ΠΠΛ| ! J 6iD! Α/ΑΡΗΝΤΑίΎΠ.Ο| 167.2.1 ^{1 i} .(i ^; '\(K ^{l :} "|

OCTACOSAjl 8,2Q,26]TRIEN]-I7'~ONE 15', IS'-DIOXIDE OR

(IS, 3 .6'R, 7'S. lO'R, 11 ¾)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRO[NAPHTHALENE-l ₅ 24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIE ]-17'-ONE I5',15'-DIOXIDE OR

(IS, 3 R, 6'R, 7'S, 10'S.ll ¾)-6-CHLORO - 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SP1RO [NAPHTHALENE- 1 ,24'- 1.12.22 ITRIOXA] I5|T! \\\\ 1. i 6ii)! A/APL\ ^' l A( ^' V( ^' 1.0| 16.72.Γ".0 ^! " 0 ^''! '| OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7 ^' S, 10 'S, 11 '5)-6-CHLORO - 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8J2,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16,7.2.1 ⁷ . ³³ ,0 ³ ' ⁶ .0 ²¹ · ²⁶ ] QCTACQSA[18,20,26]TRIEN]-17'-QNE 15 ',15 '-DIOXIDE OR

(IS, 3'R 6'R 7'S, 10'R 11 'R)-6-CHLORO-10'-METHYL-3,4-DIHYDRO-2H.17Ή- SPTRO[N APHTHALENE- 1 ,24'-

[8 ₅ 12,22]TMOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ]

OCTACOS A[ 18,20,26]TRIEN]-I7'-ONE 15', 15'-DIOXIDE OR

(IS, 3 , 6'R, 7'R, 10'S, 11 !R)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THLA[1,16]DIAZAPENTACYCLO[16,7.2.1 ⁷ - ¹¹ ,0 ³ ^.0 ²¹ - ²⁶ ] OCTACOSA[18,2Q,26jTRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3'R, 6'R, 7'S JO'S, 117¾-6-CHLORO- 10'-METOYL-3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE-l ,24'- 18.12.221 ^' t ^' RIOXAj Ι5| ^' Π Ι!Λ| 1.IGjDlA/APKYl Λί ^' Υί 16.72.Γ".0 ^! " 0 ^''! '| OCTACOSA[18,20,26]TRIEN]-r7'-ONE 15',15'-DI0X1DE

Step 1 : (S)-Methyl 6' hloTO-5-(((lR,2R)-2-((2R,4S,5R)-4-hydTOTiy-5- methyltetrahydro-2H-pyran-2-y])c dobutyl)methyl)-34,45-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxy late or (S)-methyl 6'- chloro-5-(((Hi 2R)-2-((2R 4S, 5i?)-4-hy droxy-5-methyl tetrahy dro-2H-pyran-2- yl)cyclobu d)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxa zepine- 3,l'-naphthalene]-7-carboxylate or (S)-methyl 6'-chloro-5-(((H?,2i?, ⁾ -2- ((2S, 4S, 55)-4-hydroxy-5-methyltetrahy dro-2H-pyran-2-yl)cyclobut\'l)methyl)- 3',4,4',5 etraliydro-2H,2'H-spiro[benzo[bl [l,4]oxazepine-3, -naphthalene]-7- carboxylate or (S)-methyi 6'-cMoro-5-(((ii^2i? 2-^2-?,4i?,5 _i S)-4-hydrox -5- methyltetrahydro-2H-pyran-2-yl)cyclobuty^

spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylate or (S)-methyl 6'- chloro-5-(((H?, 2R)-2-((2S, 4R, 55)-4-hydroxy-5-methyltetrahydro-2H-pyran-2- yl)cyclobutyl)nieihyl)-3^4,4^54.etrahydro-2H,2'Hspiro[benzo | bi ] 1.4|oxa/epine- 3, -naphthalene]-7-carboxylate or (S)-methyl G-c\Aoro-5-(((lR,2R)-2- ( (2R, 4R, 5i?)-4-hy droxy-5-methyltetrahy dro-2H-pyran-2-yl)cy clobutyl)methyl)- 3^4,4',5-tetrahydfo-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxylate or (S)-methyl 6'-chloro-5-(((lR,2R)-2-((2R,4R,5R)-4-hydroxy-5- methyltetrahydro-2H-pyran-2-yl)cyclobutyl) methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo | b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late

TFA (5.1 mL) was added slowly to a solution of (5)-methyl 6'-chloro-5- ((( lR.2R)-2-fom^ c clobut^ methyl) 4,4^5-tetΓahydΓO-2H,2Ή- spiro| benzo b]| 1.4]oxazepine-3 ₅ -naphthalene]-7"Carboxylate (intermediate A Al l A, STEP 20A: 0.417g, 0.919 mmol) and 2-methyl-3-buten-l-ol (0.123 mL, 1.19 mmol) in DCM ( 10 mL) which was degassed with N ₂ It was stirred at rt for

22 min. The reaction mixture was added slowly to Na2C03 (aq) solution (40ml) and MeOH (20 mL). After it was stirred at rt for 15 min, the mixture was exiracied with EtOAc (3x130 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Ci8 5μιη column; Phenomenex, Torrance, CA MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (32 mg, second eiuting peak) as a white solid, m/z (ESI, +ve ion) 540.1 (M+H) ⁺ .

Step 2; N,N-BIS(4-METHOXYBENZYL)ETHENESULFON AMIDE

2-Chlofoethanesulfonyl chloride (0.645 mL, 6.13 mmol) was added dropwise to a solution of bis(4-methoxybenzyl)amine (EE1 1 ; 1.435 g, 5.58 mmol) and triethylamine (2.71 mL, 19,5 mmol) in DCM (20.7 mL) at 0°C (ice bath). It was stirred at 0°C for 28 mm. EtOAc (200 mL.) and water (10 mL) were added. The organic phase was washed with brine (3 mL), dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 80g ISCO Gold column and eiuted with 0 % to 30 % EtOAc/liexane to provide the title compound (1.68 grams) as a white solid, m/z (ESI, +ve ion) 370.0 (M+Na) ⁺ . Step 3 : (S)-6'-CHLORO-5-(((iit2iy-2-(T2¾ 45:JR)-5-METHYL-4-(2- S UL F AMO YLETHOXY )TETRAFfYDRO-2H-P YRAN-2-

YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAI-IYDRO-2I-L2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((Hi 2R)-2-((2R 4S, 5i?)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CY ^T CLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '- APHTHALENE] -7-C ARBOXYLIC

ACID OR (S)-6'-CHL()RO-5-(((i7?.2R)-2-((2S, 4S, J.S 5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID OR (S)-6'-CHLORO-5-(((H?, 2R)-2-((2S, 45 ^' ,5A ^, )-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCL0BUTYL)METHYL)-3',4,4',5-TETRAHYDR0-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (^-6'-CHLORO-5-(((li? ₎ 2i^-2-(T2i?, i? ₎ 55)-5-]VIETHYL-4-(2- S ULF AMOYLETHOXY JfETRAH YDRO-2H-P YRAN -2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID OR (S)-6'-CHLORO-5-(((Hi 2R)-2-((2S. 4R, 55)-5-METHYL-4-(2-

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR (S)-6'-CHLORO-5-(((7R, 2R)-2-((2R, 4R, JR)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)C^XLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H ₅ 2 'H-

SPlRO[BENZO[B] [ l ,4]OXAZEPlNE-3,l '-NAPHTHALENE]-7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((/i?.2R)-2-((2S, 4R, 5^)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO[B] [ L4]()XAZEPINE-3,r-NAPHTHALENE]-7-CARBOXYLIC ACID

1923

Sodium hydride (60% dispersion in mineral oil; 6.2 mg, 0.30 mmoi) was added to a solution of (/ ¾)-methyi 6'-chloro-5-(((i/?,2 ?j-2-f 2i?, 5)-4-hydroxy-5- methyltetrahydro-2H-pyran-2-yl)cyclobutyl)memyl)-3 4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (Example 831, Step 1 ; 0.016 g, 0.030 mmol) in THF (0.8 mL), which was cooled by ice bath. After it was stirred at rt for 8 min N,N-bis(4-methoxybenzyl)elhenesulfonamide (Example 831, Step 2; 0.019 g, 0.053 mmol) in THF (1.5 mL) was added. It was stirred at rl for 60 min. Water (2 mL) and EtOAc (120 mL) were added. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μπι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (7.8 mg).

Hydrolysis I: The residue was dissolved in THF (3 mL), MeOH (6 mL) and 1 M LiOH solution (6 mL) and the mixture was stirred at 50°C for 3.5 h. It was concentrated, acidified with IN HC1 solution to pH 2-4, extracted with EtOAc (100 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate and concentrated.

Hydrolysis II: The residue was dissolved in 1 :3 TFA/DCM (5 mL) and stirred at rt for 3 days. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5iim column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (5 mg) as a white solid, m/z (ESI, +ve ion) 633.1 (M+H) ⁺ . Step 4: (IS, 3^,6Ti7 <ii9¾;77¾ 6-CHLORO-10'-ME ^r rHYL~3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'-

[8,12,22]TTUOXA[15]TmA[l ₅ 16]DTAZAPE TACYCLO[16.7.2.1 ⁷ ' .0 ³ ' ⁶ .0 ²¹ - ²⁶ ]

OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS, 3 R, 6R, 7'R, 10R, 11 ¾)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO INAPHTHALENE- 1.24'-

1.12.221 ^' t ^' RIOXAj 1 | ^' Π UA| 5. i is i f )! A API : I .\( ^' V( ^' 1.()| 16.72.Γ ^Μ .ί! ^; " '| OCTACOS A[ 18,20,26]TRIEN] - 17'-ONE 15', 15'-DIOXIDE OR

(IS, 3 , 6R, 7'S 10 11 ¾)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]TfflA[l,16]DLAZAPENTACYCLO[16,7.2.1 ⁷ - ³ ^0 ³ ' ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TR1EN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS, 3 R, 6R, 7'S, 10 ^! S 11 ¾>6-CHLORO - 10'-METHYL-3 ,4-DIHYDRO-2H, 17 Ή - SPTRO[N APHTH ALENE- ! ,24'-

[8,12,22]TMOXA[15]THIA[1,16]DIAZAPENTACYCLO[16.7.2.1 ⁷ - ¹¹ .0 ^J ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[18,20,26]TRIE ]-17'-ONE 15',15'-DIOXIDE OR

( IS, 3 R, 6 R, 7 ' 10 'S 11 '5)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 II- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THL [l,16]DLAZAPENTACYCLO[16.7.2.i ⁷ - ¹¹ .0^ ⁶ .0 ²¹ - ²⁶ ] OCTAC()SA[18,20,261TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3R, 6R, 7'S, !OR, 11 ?)~6~CHLORO~ 10'-NlETHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TRIOXA[15]THIA|;i,161DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .( ⁾²¹ · ²⁶ ] OCTACOSA[18,20,26]TRIE ]-17'-ONE 15',I5'-DIOXIDE OR

(IS, 3 , 6R, 7R, 10 'S, 11 'i?)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

|;8,12,22jTRK)XA[15jTHIA[l,16]DIAZAPENTACYCL()|;i6.7.2.1 ⁷ - ¹ ^() ³ > ^, 0 ^2! - ²⁶ ] OCTACOSAjl 8,2Q,26]TRIEN]-17'~ONE 15', 15'-DIOXIDE OR

(IS, 3 R, 6'R, 7'S.10% 11 'R)-6-CHLORO- 10'-ΜΕΤΉ YL~3,4-DIHYDRO-2H, 17Ή-

SPIRO [NAPHTHALENE- 1 ,24'-

I H, ! .22 jl IOXA! i 511 IIA| I. Ι6|[)ΙΛΖΛΡΐ;ΧΤΛ(Ύ(Ί.<}| 16.7.2. ! ^{' ! !} .0 ^; ".ϋ· ^Ι ·| OCTACOSA[18,20,26]TRIEN]-1 T-ONE 15',15'-DIOXIDE

N,N-Dimethylpyridin-4-amine (DMAP) (0.012 g, 0.095 mmol) was added to a solution of (i ¾)-6'-chloro-5-(((ii?, 2R)-2-((2 ¥S)-5-me1hyl-4-(2- sulfamoylethoxy)te1rahydro-2H-pyran-2-yl)c> lobu1yl)methyl)-3',4,4',5- ΐ6ΐτ3Η '(ΐΓθ-2Η,2Ή-3ρίΓθ^6ηζο[¾[1,4]οχαζθρί ^η 6-3, -ηαρ1ιίΓΐ3ΐβη6]-7-θ3Γ5οχν1ίο acid (Example 831, Step 3: 0.005g, 7.90 μηιοί ) m DCM (22 mL) at 0°C. Then N 1 -((ethy limino)methylene)-N3 ,N3 -dimeih lpropane- 1,3-d amine hydrochloride (EDC; 0.014 g, 0.071 mmol) was added slowly in portions and it was stirred at 0°C to rt for 19 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column: Phenomenex,

Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (3.4 mg) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.32- 8,26 (m, lis).7.72 (d, ,/ H I Hz, ill).7.24-7.15 (m, 2H), 7,11-7.07 (m, ill).7.00 (s, Ui).6.62-6.57 (m, IH), 4.13-4,08 (m, 2H), 3.98-3.85 (m, 2H), 3,78-3.63 (m, 5H), 3.59 (d, J=2.74 Hz, IH), 3.53-3.46 (m, 2H), 3.27 (d, J=14.48 Hz, IH), 3.18 idd../ 9.78.15.45 Hz, IH), 2.83-2.74 (m, 2H), 2.48-2.38 (m, IH), 2.29-2.20 (m, 1 IT), 2.12-1.63 (m, 9H), 1.61-1.52 (m, IH), 1.42 !!.,/ 1262!!/. IH), 0.87 id. J=7.04 Hz, 3H). m/z (ESI, +ve ion) 615.0 (M f i> EXAMPLE 832, (IS, 3 'R, 6'i?)-6-CHLORO-3,4-DIHYDRO-2H,7'H, 15Ή- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]THIA[1,14]DL ZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |;i6,18,24|TRIENE|-7',15'-DI()NE 13',13'-DI()XIDE

STEP 1 : (IS,3'R,6'R, 7'5)-6-CHLORO-7'-HYDROXY-3 ₅ 4-DlHYDRO- 2H, 15 'HSPIRO [NAPHTHALENE- Ι.22'|20|()ΧΛ| I 311 i l!Aj I . I -1 |ΟΙΛΖΛ ^' Π· ^' ϋΛ(Ύ( .()11 ·17.2.(ί" ^' '.!? ^ι " ''jPI- ^' N ^" Λ( ^' OSA[16,18,24jTRIEN]-15'-GNE 13 ^* ,13'-DIGXIDE

A mixture of(lS 6 7 9'E)~6-cMoro-7- ydroxy-3 -& ydro~

2H, 15 Ή-spiroInaphthalene- ,22'-

[20]oxa[13]thia[i;i4]diazatetracycio[14 .2,0-^0 ^l9 - ²⁴ ]pentacos

nj-15'-one 13',13'-dioxide (Example 846; 0,112 g, 0.196 mmol) and platinum 0V) oxide (0.045 g, 0.196 mmol) in EtOAc (33 mL) was stirred under H ₂ at rt for 3 h. It was filtered through synnge filter to remove solid catalyst and the solution was concentrated to provide title compound (112 mg) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.93 (m, 1H), 7.71 (m, III).7.15 (m, 3H), 7.09 id../ 2.35 Hz, 1H), 6.95 (ra, 1H), 4.10 (m, 2H), 3.78-3.62 (m, 4H), 3.46-3,34 (m, IH), 3.26 (d, J=14.28 Hz, IH), 3.16 (dd, ./ 9.00,, 15.26 Hz, IH), 2.82-2.71 (m, 2H), 2.45-2,33 (ni, IH), 2.26-2.16 (m, IH), 2.08-1.16 (m, 17!! ). m/z (ESI, +ve ion) 573.2 { M · Π } , STEP 2: (/X- '?,6¾)-6-CHLORO-3,4-DIHYDRO-2H,7'H,15TI- SPIRO[NAPHTHALENE- 1.22-

|20jO.\,\| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PHNT.\COSA [16J8,24]TRIENE]-7',15'-DIONE 13',13'-DIGXIDE

A flask charged dimethyl sulfoxide (0,019 mL, 0.27 mmol) and DCM (0.7 mL) was cooled to -78 °C. Oxalyl chloride (2.0 M solution in DCM, 0.070 mL, 0.141 mmol) was added dropwise and the reaction was stirred for 16 rain. A solution of th e product (from Step 1; 0.031 g, 0.054 mmol) in DCM (0.5 mi.) was added dropwise and the reaction was stirred at -78°C for 25 min. Triethylamine (0.068 mL, 0.49 mmol) was added dropwise and it was stirred at rt for 1 h. The reaction mixture was quenched with water (2 mL), extracted with EtOAc (130 mL). The organic phase was washed with IN HCl solution (2x3 mL), brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN inwater with 0.1% TFA, gradient elution) to provide the title compound (9 mg) as a white solid. ^] H NMR (400 MHz, CD2CI2) δ 7.75-7.68 (m, 1H), 7.20-7.15 (m, 1H), 7.14-7.08 (m, 2H), 6,98-6.92 (m, 1H), 6.90-6,85 (m, 1H), 4.14-4.05 (m, 2H), 3.83-3.70 (m, 2H), 3.66-3.47 (m, 3H), 3.28 (d 14.28 Hz, ill .3.20 (dd, ./ 8.41.15.45 Hz, 3.14-3.07 (m, 1H), 3.02-2.91 (m, !!!). 2,83-2.73 (m, 3H), 2.58-2.36 (m, 2H), 2.17-1.67 (m, 8H), 1.64-1,40 (m, 4H). m/z (ESI, +ve ion) 571,1 (M+H) ⁺ .

EXAMPLE 833. (1S,3'H6'R 7¾9¾-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1,23-

[21]OXA[14]THIA[l,i5]DLAZATCTRACYCLO[L5,7.2,0^^0 ²⁰ - ²⁵ ]HEXACOSA[ 9,17,19,25 ]TETRAE ]-16'-ONE 14',14'-DIOXIDE OR (1S 'R,6'R, 7¾P'Z)-6- CHLORO-7'-HYDROX ^r -3,4-Dn-r\ ^r DRO-2H,16'H-SPIRO| siAPHTOALENE- 1,23'- [21]OXA[14]THLA[1,15]DIAZATET1 ACYCLO[15.7.2.0 ³ - ⁶ .0 ²⁰ - ²⁵ ]HEXACOSA [9,17,19,25] TETR AEN j - 16'-ONE 14',14'-DIOXIDE

Step 1 : (i 6'-CHLORO-5-(((iR, 2iy-2-^- l -HYDROXYBUT-3-EN-l-

YL)CYCIX)BUTYL)METHYL)-N-(PENT-4-EN-l -YLSULFONYL)-3',4 TETRAH YDRO-2H,2'H-SPIRO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , V~

APHTHALENE] -7 -C ARB OXAM1DE

N-(3-Dirnethylarninopropyl)-N ^! ~ethylcarbodiiniide hydrochloride (EDC; 0.036 g, 0.19 mmol) was added to a solution of (S)-6'-chloro-5-(((H2,2R)-2-((S)-l- hydroxybut-3-en-l-yl)cyclobutyl) methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazeprae-3, l'-naphthalene]-7-carboxylic acid (Intermediate AA13A; 0.045 g, 0.093 mmol) and pent-4-ene- 1 -sulfonamide (EE192; 0.098 g, 0.654 mmol) in DCM (6.2 mL). Then N,N-dimethylpyridin-4-amine (DMAP) (0.023 g, 0.19 mmol) was added and it was stirred at rt for 15 h. After it was concentrated, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TF A, gradient elution) to provide the title compound (22 mg) as a film, m/z (ESI, +ve ion) 613.0 (M+H) ⁺ . Step 2 : (!S 'R,, 6 ^! R, 7¾ 9¾)-6-CHLORO-7"-HYDROXY-3,4-DIHYDRO- 2H. 16'H-SPIRO[N APHTHALENE- 1 .23'-

[21]OXA[14]TH1A[1J 5]DL ZATETRACYCLO[15.7.2.0^ ⁶ .0 ²⁰ - ²⁵ ]HEXACOSA| 9,17,19,25 ]TETRAENj-16'-ONE 14',14'-DIOXIDE OR (lS 'R, 6'R, 7 9'Z)-6- CHLORO-7"-HYDROXY-3,4-DlHYDRO-2H, 16'H-SPIRO[NAPHTHALENE-

L23'-

[21]OXA[14]TfflA[l,15]DIAZATETRACYCLO[15.7.2.0 ³ - ⁶ .0 ²⁰ⁱ⁵ ]HEXACOSA [9, 17, 19,25]TETRAEN]-16"-ONE 14', 14 ^* -DIOXIDE

A 250 mL round bottom flask was charged with ( / ¾)~6'~chloro~S~ {{(IR, 2R)-2~(l -hydroxy but-3-en- 1 -yl)cy clobutyl)methyl)-N-(pent-4-en- 1 - ylsulfonyl)-3',4,4 ^, ,5-tetrahydro-2H,2 ^, H-spiro[benzo [b][ l,4]oxazepine-3,l'- naphthalene] -7-carboxamide (Example 833, Step 1; 0.022 g, 0.036 mmol) in toluene (90 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (4.5 mg, 7.2 μιτιοΐ) in toluene (5 mL). After the mixture was stirred at 106 °C under nitrogen for 73 min, air was blown for 10 min to deactivate the catalyst, and then concentrated. The residue was purified by reverse phase preparative HPLC (Gemini ^1M Prep C is 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution). The title compound (2.1 mg) was obtained as a single isomer (second eluting peak) as a white solid. Ή NMR (400 MHz, CD2CI2) δ 9.54 (br, s., 1H), 7.73-7.67 (m, 1H), 7.32-7.28 (m, 1H), 7.27-7,23 (m, 1H), 7.20- 7, 15 (m, 1H), 7.12-7.07 (m, IH), 6.98-6,93 (m, i l l ). 5.64-5.55 (m. I I I ). 5,53-5.44 (m, IH), 4,21 -4.09 (m, 2H), 3.72-3.53 (m, 4H), 3,35-3.29 (m, IH), 2.80-2,74 (m, 2H), 2.71-2.64 (m, IH), 2.55-1.42 (m, 18H). m/z (ESI, +ve ion) 585.0 ( +H) ⁺ .

EXAMPLE 834. (1S 'R, 6'R, 7¾02)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 16TI-SPIRO[NAPHTHALENE-l ,23 ^* - pilOXAtl^THIAtl SlDIAZATETRACYCLOIlS.T^.O^^O^JHEXACOSAI

9,17, 19,25]TETRAEN]-16'-ONE 14',14'-DIOXIDE OR (1S, 3'H 6'R 7¾Ρ'£)-6- CHLORO-7'-HYDROXY-3,4-DIHYDRO-2H,16'H-SPIRO[NAPHTOALENE- 1,23'- [21]OXA[14]THL\[1,15]DLAZATETRACYCLO[15.7.2,0^ ⁶ .0 ²⁰ - ²⁵ ]HEXACOSA| 9,17,19,25 jTETRAEN] -16'-ONE 14',14'-DIOXIDE

The title compound (5.0 mg) was obtained as a single isomer (first eluting peak) from the reverse phase preparative HPLC in Example 833 as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 9.29-9.22 (m, IH), 7.76-7.69 (m, IH), 7.37-7.33 i ns. IH), 7.26-7.22 (m, IH), 7.19-7.14 (m, IH), 7.11-7.07 (m, IH), 6.95 i d. 8.22 Hz, 1 1 1 ). 5.60-5.42 (ra, 2H), 4, 18-4.09 (m, 21 1 ). 3.85-3.73 (m, 2H), 3,65 (d, J=14.48 Hz, IH), 3,61 -3.55 (m, IH), 3.47 (td, .7=7.19, 14,57 Hz, IH), 3.28-3.16 (m, 2H), 2.80-2.72 (m, 2H), 2.41-2.34 (m, IH), 2.15 (s, 16H). m/z (ESI, +ve ion) 585.0 ( \! I I ) .

EXAMPLE 835. (1S,3'R, 6'R 7¾)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 16'H-SPIRO[N APHTH ALENE- 1 ,23'| 21 j OX A[ 14]

THI A[ 1 , 15]DTAZATETR ACYCLO[ 15.7.2.0 ³ - ⁶ .0 ²⁰ ' ²⁵ ]HEXACOS A[ 17,19,25]TRI EN] - 16'-ONE 14 ^! , 14'-DIOXIDE

A mixture of (IS, 3 R.6 % 7'S 9 '£)-6-chloro-7'-hydroxy-3,4-dihydro- 2H,16'H-spiro[naphthalene-l,23'-

[21]oxa[14]thia[l,15]cUazatetrac lo|;i5 .2.0 ³ ' ^f \0 ⁰ - ²⁵ ]hexacosa[9,17,19,25]tetraen| -16'-one 14',14'-dioxide (Example 833; 0.0021 g, 3.6 μηιοΐ) and platinum (IV) oxide (0.8 mg, 3.6 μηιοΐ) in EtOAc (1.4 mL) was stirred under H ₂ at rt for 2 h. It was filtered through syringe filter to remove solid catalyst and the filtrate was concentrated to provide the title compound (1.8 mg) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 7.75-7.68 (m, 1H), 7.38-7.28 (m, 2H), 7.21-7.14 (m, 1H), 7.12-7.07 (m, 1H), 7.00-6.92 (m, 1H), 4.16-4.09 (m, 2H), 3.81-3.73 (m, 1H), 3.65 (d, ./ 13.5·;·· Hz, 211).3.58-3,48 (m, 211).3.28 (d, ,/ 1448 Hz, III).2,81-2.72 (m, 2H), 2.47-2.38 (m, IH), 2.11-0.75 (m, 21H). m/z (ESI, +ve ion) 587.0 ( +H) ⁺ .

EXAMPLE 836, (1S,3'R,6R, 7¾77'5)-6-CHLORO-3 ₅ 4-DIHYDRO-2H,17'H-

[8,12,22]TMOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2.i ⁷ - ¹ ^0^ ⁶ .0 ¹ - ²⁶ ]O CTACOSA[18,20,26]TRIEN1-17'-ONE 15',15'-DIOXIDE OR

(IS, 3 R, 6'R, 7'S, 11 'R)-6-CHLORO-3,4-DIHYDRO-2H, 17 Ή- SPIRO[NAPHTHALENE-l,24'-

[e ^lTRIOXAIlSlTHIAtl DIAZAPENTACYCLOIie^^.l'^'.O^.O^^OC

TACOSA[18,20,26]TRIEN]-17'-ONE 1S',15'-DT0XIDE OR

(IS, 3 % 6% 7'S 11 'R)-6-CHLORO-3,4-DIHYDRO-2H, 17 Ή- SP1RO [NAPHTHALENE- 1 ,24'-

|;8,12,22jTRIOXA[15jTHIA[l,16]DIAZAPENTACYCL()|;i6.7.2.1 ⁷ - ¹ ^() ³ > ^, 0 ^! - ²⁶ ]O CTACOS A[l 8,20,26]TRIEN] - 17'-ONE 15', 15'-DIOXIDE OR (IS, 3'R, 6'S, 7'S, 11 S)-6-CHLORO-3,4-DIHYDRO-2H,l 7Ή- SPIRO[NAPHTHALENE- 1 ,24 ^! ~

[8,12 _S 22]TR10XA[15]THIA[1,16]D1AZAPENTACYCL0[16.7.

),26]TRIEN]-17'-ONE 15',15'-DIOXIDE

Step 1 : (S)-METHYL e-C\^OKO-5-(((lR,2R)-2-((2R, 4R)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ⁱ ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5- (((7i¾2i?^-2-(†25 i)-4-HYDROXYTETRAHYDRO-2H-PYRA -2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7-

C ARB OXYL ATE OR (5)-METHYL &~CRLORO~5~(((ni2R)--2-{(2R, 4S)~4~ HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ⁱ ,4,4',5-TETRAHYDRO-2H 2Ti-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5- (((III 2R)-2-((2S, 45)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCI BUTYL)METOYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^, H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE

A mixture of (S)-methyl 6'-chloro-5-(((Hi, 2ii)-2- formylcv'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiroj benzoj b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (Intermediate

AAl lA, STEP 20A; 0.243 g, 0,535 mmol), 3-buten-l -ol (0.541 ml, 0,696 mmol) in TFA (4.5 mL) and DCM (9 mL) was degassed with N ₂ and stirred at rt for 30 min. It was quenched with NaHC0 ₃ solution to pH >7 and extracted with EtO Ac

(60 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated. To the residue was added saturated Na ₂ C0 ₃ solution ( 1 mL), MeOH

(2 mL) and THF (2 mL). After it was stirred at rt for 30 min it was neutralized with 1 N HCl solution to pH 7 and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 24g ISCO Gold column and eluted with 0 % to 50 % EtOAc/hexane to provide the title compound (210 mg) as a white solid, m/z (ESI, +ve ton) 526.1 ( VI i ! ) .

Step 2: (5)-6'-CHLORO-5-(((H¾2R -2-^2R, ^R)-4-(2-

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBU L)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (Sy&~CHLORO'5~(((lR2Rj--2-{{2S, 4R)~4~(2~

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MF -IYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (5)-6 ^, -CHLORO-5-(((7R,2R)-2-((2R _> 45)-4-(2- SULF AMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID OR (S 6'-CHLORO-5-(((iA ⁵ , 2R)-2-((2S, 4S)-4-(2-

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)C^XI,OBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

Sodium hydride (60% dispersion in mineral oil; 18 mg, 0.84 mmol) was added to a solution of (<S)-methyl 6'-chloro-5-(((iR, 2R)-2-((2S, 4R)-4- h} _' -droxytetrah} _' -dro-2H-pyran-2-yl)cyclobutyl) methyl)-3',4,4',5-tetrahydro- 2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r-naphtiialene]-7-carb oxylate (Example 836, Step 1 ; 0.1 13g, 0.215 mmol) in THF (9 mL), which was cooled to 0 °C. After it was stirred at rt for 10 min, N,N-bis(4-methoxybenzyl) ethenesulfonairade (Example 831, Step 2; 0.112 g, 0.322 mmol) in THF (2.5 mL) was added and it was stirred at rt for 20 h. Water (2 mL) and EtOAc (130 mL) were added. The organic phase was washed with brine and dried over anhydrous sodium sulfate and concentrated to provide a residue.

Hydrolysis I: The residue was dissolved in THF (7 mL), MeOH (7 mL) and 1 M LiOH solution (5 mL) and stirred at 50°C for 1.6 h. It was concentrated, acidified with 1 N HC1 solution to pH 2-4, extracted with EtOAc (90 ml,). The organic phase was washed with brine and dried over anhydrous sodium sulfate. It was concentrated to give a residue.

Hydrolysis II: The residue was dissolved in 1:3 TFA/DCM (4 mL) and stirred at rt for 20 h. After concentration, the residue was loaded to a 12g ISCO Gold column and eluted with 0 % to 15 % EtOAc (containing 0.3 % AcOH)DCM (containing 0.3 % AcOH) to provide the title compound (110 mg) as a film, m/z (ESI, +ve ion) 619.1 (M+H .

Step 3 : (IS, 3 'R, 6'R 7'S, 11 ¾)-6-CHLORO-3,4-DIHYDRO-2H, 17 Ή- SPTRO[NAPHTH ALENE- 1 ,24'-

|8.i2.22|TRIOXAj i |ΤΠΙΛ| i . ! 6iDiA/APh\ Α( Π ,()| 16.72.1 ^{" 1 l} .0 ^{i !} 'J)' ^' ··|() CTACOSAjl 8,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

(IS 'R, 6'R, 7'S, 11 'R)-6-CHLORO-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-[8, 12,22]TRIOXA[l 5JTHLA

[LlDlAZAl TACYCLOtie ^.l ^' ^^O^^O^^OCTACOSAtlS^O^blTRIE ]- 17'-ONE 15', 15'-DIOXIDE OR (IS, 3 6'S 7'S 11 'R)-6-CHLORO-3,4- DIHYDRO-2H, 17 'H-SPIRO[N APHTHALENE- 1 ,24'-

[8,I2,22]IIlOXA[15]IHIA[l,16]DIAZAl TACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ - ⁶ .0 ¹ - ²⁶ ]O CTACOSAjl 8,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

( V,3¾6¾7¾ //S -6-CHLORO-3,4-DIIIYDRO-2H,17T-I- SPiR( ⁾ i\AFHillA!J\i:-l.2f-

|8.!2.22|i ^' R!()XAi Ι5|ΠΠΑ| ! . ί 6iO! A/AFIiNTAC^ ^' CI.OI 16,7.2.1 ^{' 1 i} .u ^; ".O ^l CTACOSA[18,20,26]TRIEN1-17'-ONE 15',15'-DIOXIDE N,N-Dimethyipyridiii-4-amine (DMAP) (0.150 g, 1.23 mmol) was added to a solution of (S)-6'-chl oro-5 -(((//?„ 2R)-2 -((2S,4R)-4-(2- sulfanio} _' 1ethoxy)ietrah} _' -dro-2H-pyran-2-yl)cyclobutyl) methyl)-3',4,4',5- tetrahy dro-2H,2 'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalene] ~7carboxy li c acid (Example 836, Step 2; 0.095 g, 0.153 mmol) in DCM (200 mL) at 0°C. Then N 1 -((ethy limino)rnethyl ene)-N3 ,N3 -dimeihy lpropane- 1,3-d amine hydrochloride (EDC; 0.147 g, 0.767 mmol) was added slowly in portions and it was stirred at

0 C to rt for 3 days. After it was concentrated, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elusion ) to give the title compound (1.5 mg, third eluting peak) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.22-8.15 (m, I H), 7.76-7.69 (m, 1H), 7.26-7.21 (m, 1 H), 7.20-7.15 (m, 1 H), 7.05-7.1 1 (m, IH), 7.01 -6.94 (m, 1H), 6.57-6,50 (m, 1H), 4.11-4.08 (rn, 2H), 3.87 (br. s., IH), 3.83-3,77 (m, 21 1 ). 3.76-3.68 (rn, 3H), 3,59-3.51 (m, 2H), 3.18 (d, J=14.28 Hz, IH), 3.12 (dd, J=8.90, 15.55 Hz, IH), 2.81-2.72 (m, 2H), 2.43- 2.35 (m, IH), 2.16-2.09 (m, IH), 2.08-1.52 (m, 13H), 1.45-1.37 (m, IH). m/z (ESI, +ve ion) 601 , 1 ( VI 1 1 ) ,

EXAMPLE 837. (1S,3 ^! R, 6'R, 7'S, 11 ¾)-6-CHLORO-3,4-DIHYDRO-2H, 17 Ή- SPTRO[NAPHTH ALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DI0X1DE OR

(IS, 3 'R, 6'R, 7% 11 ?)-6-CHLORO-3,4-DIHYDRO-2H ₅ 17 Ή- SPIRO[NAPHTHALENE-l,24"-[8, 12,22]TTUOXA[15]TTnA[l ₅ lDIAZA

PENTACYCLOtiej.Z l'^^O'^^^^lOCTACOSAtlS^O^eiTRIENl-n'-ONE 15',15'-DIOXIDE OR (1S, 3'R, 6'S, 7¾ ii '/?)-6-CHLORO-3,4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[l 8,20,26] TRlEN]-17'-ONE 15',15'-D10XIDE OR

(1S 'R, 6'S, 7'S, / / ¾>6-CHLORO-3,4-DIHYDRO-2H,17T-I- SPIRO [NAPHTHALENE- 1 , 24'- [8,12,22]TRIOXA[15]THL [1,16]DLAZAPENTACYCLO[16,7.2. 1 ⁷ - ¹¹ .0^ ⁶ .0 ²¹ - ²⁶ ] OCTAC()SA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE

The title compound (11.1 mg) was obtained as a single isomer (first eluting pealv) from the reverse phase preparative HPLC in Example 836 as a white solid. Ή NMR (400 MHz, CD2CI2) δ 8.30-8.13 (m, 1H), 7,71 (m, IH), 7.17 (m, IH), 7,07 (m, 21 1 ). 6.96 (m, IH), 6.82 (m, i l l ). 4.1 1 (m, IH), 4.06-3.94 (m, 3H), 3.86 (ddd, J=3.42, 8.02, 11.44 Hz, IH), 3.81-3.68 (m, 4H), 3.54-3.44 (m, IH), 3.35-3.20 i ns. 4H), 2.78 (d, J=5.09 Hz, 2H), 2.25-2.03 (m, 5H), 1.98-1.82 (m, M l ). 1 .77-1.63 (m, 2H), 1.59-1.20 (m, 4H). m/z (ESI, +ve ion) 601.1 (M+H) ⁺ .

EXAMPLE 838. (1S 'R, 6'R, 7¾ ii ¾>6-CHLORO-3,4-DIHYDRO-2H,17'H- SPIRO [NAPHTHALENE- 1 ,24'- [8, 12,22]TRJOXA [ 15]

THIA[ 1 , 16]DIAZAPENTACYCLO[l 6.7.2, 1 ⁷ - ^s 0 ³ · ⁶ 0 ²³ · ²⁶ ] OCTACOS A[ 18,20,26] TRlEN]-17'-ONE 15', 15 '-DIOXIDE OR (lS,3'R, 6'R, 7'S, H 'R)-6-CViLORO-3,4- DIHYDRO-2H, 17'H-SPIRO[NAPHTHALENE-l,24'-

[8,I2,22]TRI0XA[15]THIA[ 1J DIAZAPENTACYCL0[16.7.2. Γ· ^η .0 ³ ' ⁶ ,0 ²¹ · ²⁶ ]Ο€ TACOS A[ 18,20,26]TRIEN] -17-ONE 15', 1 S'-DIOXIDE OR

(IS, 3 'R, 6'S, 7'S, / / K)-6-CHLORO-3 ₅ 4-DIHYDRO-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 , 24'-

[8,12,22]TRIOXA[15]THL [1,16]DIAZAPENTACYCLO[16,7.2. 1 ⁷ - ³ ^0 ³ '^0 ²¹ - ²⁶ ] OCTACOSAj l 8,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

(IS, 3'R, 6'S: 7¾ II ¾ 6-CHLORO-3,4~DiHYDRQ~2H J 7Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[ 8,12,22]TRIOXA[ 15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ . ⁽⁾²¹ · ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', I 5'-DIOXIDE

The title compound (12.1 mg) was obtained as a single isomer (second eluting peak) from the reverse phase preparative HPLC in Example 836 as a white solid. Ή NMR (400 MHz, CD2CI2) δ 8.25-8.18 (m, 1H), 7.71 (m, I II), 7.19 (m, 1H), 7,09 (m, IH), 7.02 (m, 1H), 6.95 (ra, 1H), 6,82 (m, 1H), 4.20-4.03 (m, 3H), 4,03-3.94 (m, M l ). 3.84-3.62 (m, 3H), 3.57-3.36 (m, 3H), 3.34-3,20 (m, IH), 3.19- 2.87 (m, 3H), 2.81-2.70 C m. 2H), 2.42-1.71 (m, 9H), 1.69-1.58 (m, IH), 1.47-1.37 i ns. IH), 1.33 (dd, J==5.()9, 10.76 Hz, IH). m/z (ESI, +ve ion) 601.1 (M+H) ⁺ .

EXAMPLE 840. (IS, 3 'R, 6 % 7 9'R, 10 '5)-6-CHL()RO-7',9', 10'-TRIHYDROXY- 3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [16,18,24]TRIE ]-15'-ONE 13',13'-DIOXIDE AND (1S,.3'R,6'R.7'S,9'SJ0'R)-6- C! U ORG-?'.'/.10'-TRU !Y!)R()XY-3. i-DU iYDRO-21 ! . i 5 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THLA|;i 4]DIAZATETRACYCL)[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'~DiOXIDE

A solution of osmium (VIII) oxide (2.5% solution in ter t-BuO , 0.46 mL, 0.037 mmol) was added to a solution of (1S,3'R.6'R, 7¾',9'2)-6-chloro-7'-hydiOxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

|20jox«ij I3|t ia| U4|dia/aielracveioj 14.7.20 ^;i '.0 ^pi ipcniacosa|v.i6.18.24| tetraen]-15'-one 13',13'~dioxide (Example 807; 0.105 g, 0.184 mmol) in acetone (8.4 mL) and THF (8.4 mL). Then 4-methylmorpholine N-oxide (0.058 g, 0.496 mmol) in water (0.08 mL) was added and the mixture was degassed with nitrogen and stin-ed at rt for 2 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (5.2 mg) as a white solid. \H NMR (400 MHz, CD2CI2) δ 7,70 (t, ./ 7.43 Hz, III).7.17 (hr. s., 2H), 7.09 (br. s., 1H), 6.95 (d, ./ 8.22 Hz, III .6.81- 6.91 (m, 1H), 4.31 (br. s., 1H), 4.15-4.06 (m, 2H), 3.98-3.82 (m, 2H), 3.79-3.20 (m, 6H), 2.77 (br. s,, 3H), 2.34-1.34 (m, 13H), m/z (ESI, +ve ion) 605.2 (M+H) ⁺ .

EXAMPLE 841. (1S 'R,6'R, 7¾iO¾77¾>6-CHLORO-10'-METHYL-3,4- DIHYDRO-2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8, 12,22]TRIOXA[l 5]THIA[1, 16JDIAZAPENTACY CLO [16 .2/i ⁷ - ¹ 0 ³ -^0 ^2! - ²⁶ ]OCTACOSA[18,20,261TRIEN]-17'-ONE 15', 15'-DIOXIDE OR (1S, 3'R, 6'R. 7'R, 10'R, 11 ¾)-6-CHLORO-10 ^f -METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALEN E- ί .24'·

[ 8,12,22]TRIOXA[ 15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE I5', 15'-DIOXIDE OR

(IS, 3 'R, 6'R, 7'S, 10'R, 11 ¾')- 6-CHLQRQ- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SP1RO [NAPHTHALENE- 1.24'-

[8/12,22]TRIOXA[15]TIflA[ lJ 61DIAZAPENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ^3> ^0 ^2! - ²⁶ ] OCTACOS A[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 'R, 6 'R, 7'S.10 % 11 S)-6-CHLORO- 10 -METHYL-3 ,4-DiHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8J 2,22]TRIOXA[15]THIA[l ,I6]DIAZAPENTACYCLO[ 16,7.2. 1 ⁷ · ³ ^0 ³ ' ⁶ .0 ²¹ · ²⁶ ]

QCTACQSA[18,20,26]TRIEN]-17'-QNE 15 ',15 '-DIOXIDE OR

(IS, 3 6 % 7 'S, 10 ' 11 ¾> 6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA [18,20,26]TRIEN]-17'-ONE I5',15'-DIOXIDE OR

(IS 'R, 6'R, 7'S 10'R, 11 'R)-6-CHLORO- 1 ()'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]THL [1,16]DIAZAPENTACYCLO[16,7.2. 1 ⁷ - ¹¹ .0 ³ ^.0 ²¹ - ²⁶ ] OCTAC()SA[18,2Q,26jTRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3'R, 6'R, 7'R, 10'SJ 1 ' ?)-6-CHLORO-10'-METOYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,I2,22]II lOXA[15]IHIA[l,16]DlAZAl ⁵ ENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR

(ISJ'R, 6'R, 7'S, 10'S, 11 'i?)-6-CHLORO- 0'-METOYL-3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THL [l,I6]DIAZAPENTACYCLO[16.7.2. i ⁷ - ¹¹ .() ³ - ⁶ .0 ^2! - ²⁶ ] OCTACOSA [18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE

Step 1 : (5)-METHYL 6'-CHLORO-5-(((7i¾2iR!)-2-((2R, 45; ^j R)-4-HYDROXY-5- METHYLTETRAHYDRO-2H-PYRAN-2-YL)CY CLOBUTYL)METHYL)-

NAPHTHALENE] -7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((IR, 2R)-2-((2R, 4S, 5i?)-4-HYDROXY-5-METHYLTETRAHYDRO-2H-

PYRAN-2-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H - SPIRO [BENZO [B ] [ 1 ,4] QXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((//¾ 2R)-2-((2S, 4S,.5S}-4- HYDROXY-5-METOYLTETRAHYDRO-2H-PYRAN-2- YL CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6'-C LORO-5-(((lR,2Ii)-2-((2R, 4R, 5S)-4- HYDROXY-5-METHYL TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6' m RQ-5-(((JR.2R)-2-((2S, 4R,5S)-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][ l,4]OXAZEPINE-3J'-NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'~CHLORO-5~(((l 2R)-2-{(2R, 4R,5R)-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENEJ-7-

CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-((( 1R.2R)-2-((2R, 4R, 5R)~4~ HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

TFA (5.1 mL) was added slowly to a solution of (<S)-methyl 6 ^f -chloro-5- (((/i?,2i?)-2-formylc\ lobutyl)methyl)-3^4,4\5-tetrahydro-2H,2'H- spiro [benzo | b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Intermediate AA11A, STEP 20A; 0.417g, 0.919 mmol) and 2-methyl-3-buten-l-ol (0.123 mL, 1.19 mmol) in DCM (10 mL) which was degassed with N ₂ It was stirred at rt for

22 min. The reaction mixture was added slowly to NaaCCb (aq) solution (40 mL) and MeOH (20 mL). After it was stirred at rt for 15 min, the mixture was extracted with EtOAc (3x130 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Ci8 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution). The title compound (60 mg) was obtained as a single isomer (first eluting peak), m/z (ESI, +ve ion) 540.1 { \ I · Π } .

Step 2; (¾)-6'-CHLORO-5-(((/R, 2R)-2-((2R, 4S,5R)-5-MF;mYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (^-6 ^, -CFiLORO-5-(((li? ₎ 2i^-2 2i? ₎ ^ ₎ 5i?)-5-]VIETHYL-4-(2- S ULF AMO YLETHOXY)TETRAH YDRO-2H-P YRAN -2- YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-T,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (5)-6'-CHLORO-5-(((7i?,2i?j--2 5; 4S;.55)-5-MEraYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTFIALENE]-7-CARBOXYLIC ACID

OR (5)-6'-CHlA3RO-5-(ii/i?,2i?;-2- ^' 25^ _l S 5i?)-5-MF^m _J -4-(2-

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (5)-6'-CHLORO-5-(((7R, 2R)-2-((2R, 4R, 55)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3,! ^* -NAPHTHALENE]-7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((7R, 2^- -^2S;4R, JS)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR (5)-6'-CHLORO-5-(((H?, 2R)-2-((2R, 4115R)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-L2 ^, H-

SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((H 2R)-2-((2R, 4R JR)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4 ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

Sodium hydride (60% dispersion in mineral oil; 12 mg, 0.55 mmol) was added to a solution of (i ¾ niethyi 6'-c loTO-5-(({lR,2R)-2-((2R, 4S)-4-hydTOxy-5- methyltetrahydro-2H-pyran-2-yl)cyclobutyl)me&^

spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox date (Example 841, Step 1 ; 0.030 g, 0.030 mmol) in THF (1.6 mL), which was cooled by ice bath. After it was stirred at rt for 24 min N,N-bis(4-methoxybenz l)ethenesulfonamide

(Example 831 , Step 2; 0.039 g, 0.1 1 1 mmol) in THF (2 mL) was added. It was stirred at rt for 60 min. Water (2 mL) and EtOAc (120 mL) were added. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to pro vide the title compound (15 mg). Hydrolysis I: The residue was dissolved in THF (3 mL), MeOH (6 mL) and 1 M Li OH (6 mL) and the mixture was stirred at 50°C for 3 h. It was concentrated, acidified with IN HC1 solution to pH 2-4, extracted with EtOAc (100 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate and concentrated.

Hydrolysis II: The residue was dissolved in 1 :3 TFA/DCM (5 mL) and stirred at rt for 18 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μτη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (8 mg) as a white solid, m/z (ESI, +ve ion) 633.1 (M+H) ⁺ .

Step 3 : (IS, 3 % 6 R, 7'R, JO'S, 11 ¾> 6-CHLQRQ- 10'-METHYL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'-

[8, 12,22]TTUOXA[15]TTnA[l ₅ 16]DTAZAPENTACYCLO[16.7.2. 1 ⁷ ' .0 ³ ' ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ', 15 '-DIOXIDE OR

(IS, 3 R, 6'R, 7R, 10'R 11 ¾)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1,24'-

[8,I2,22]TRIOXA[ I 5]TIflA[l,161DIAZAPENTACYCLO[16.7.2.

OCTACOSA [18,20,26]TRIEN]-17 ^! -ONE I5',15'-DIQXIDE OR

(IS, 3 R, 6R, 7'S 10'R 11 ¾> 6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THIA[1,16]DIAZAPENTACYCLO[16,7.2. 1 ⁷ - ³ ^0 ³ ' ⁶ .0 ²¹ - ²⁶ ]

OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS, 3 , 6'R, 7'S, 10 ' 11 ¾)-6-CHLORO - 10'-METHYL-3 ,4-DIHYDRO-2H, 17 Ή- SPTRO[N APHTH ALENE- 1 ,24'-

[8 2,22]TMOXA[15]THIA[1,16]DIAZAPENTACYCLO[16.7.2.1 ⁷ - ¹¹ .0 ^J ' ⁶ .0 ²¹ ' ²⁶ ]

OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR

( IS, 3 R, 6 R, 7 ' 10 'S 11 ¾> 6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 II-

SPIRO[NAPHTHALENE-l,24'- [8,12,22]TMOXA[15]THLA[ l,16]DIA APENTACYCLO[16.7.2. i ⁷ - ¹¹ .0 ³ ^.0 ²¹ - ²⁶ ] OCTACOSA [18,20,26]TRIEN]-r7'-ONE 15',15'-DIOXIDE OR (IS, 3'R, 6'R, 7'S.10'R,117?)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE- 1 ,24 ^! ~

[8/12,22]TllOXA[15]THIA[L16]DlAZAl ⁵ ENTACYCLO[16 .2 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TR1EN]-17'-ONE 15',15'-DIOXIDE OR

(IS, 3 'R, 6'R, 7'R, lO'S 1 / 'R)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, ! .7Ή-

|8.!2.22|TR!i)X,\j Ι5|ΠΠΛ| U 6iD! Α/ΑΡΗΝΤΑίΎΠ.Ο| 167.2.1 ^{1 i} .(i ^; '\(K ^{l :} "| OCTACOSAjl 8,2Q,26]TRIEN]-I7'~ONE 15', IS'-DIOXIDE OR

(IS, 3 'R.6'R, 7'S.10'S, 11 'R)-6-CHLORO- 10'-ΜΕΤΉ YL~3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCTACOSA [18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

N,N-Dimethylpyridin-4-amine (DMAP) (0.026 g, 0.215 mmol) was added to a solution of (1 ¾)-6'-chloro-5-(((ii?, 2R)-2-((2R, 5)-5-me1hyl-4-(2- sulfamoylethoxy)te1rahydro-2H-pyran-2-yl)c>'clobu1yl)meth yl)-3',4,4',5- te1rahydro-2H,2 ^, H-spiro[benzo[b][L4]oxazepine-3,r-naphthalene]-7-carbo x\'lic acid (Example 841, Step 2: 0.008g, 13 μηιοΐ) m DCM (32 mL) at 0°C. Then Nl- ((ethylirnino)methylene)-N3,N3-dimethylpropane-l,3-diamine h drochloride (EDC) (0.027 g, 0.139 mmol) was added slowly in portions and it was stirred at 0°C to rt for 17 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column: Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (5.5 mg) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.22 (s, ill).7,72 (d, ,/ 8.6! Hz, !!!).7.18 (dd, ,/ 2.35.8,41 Hz, 1H), 7,09 (d, ./ 2.35 Hz, IH), 7,06-7.02 (m, I Hi.6.98-6,89 (m, 1H), 6.82 (d, .7=1,96 Hz, 1H), 4.13-3.99 (m, 5H), 3.89-3.77 (m, 3H), 3.75-3.65 (m, 2H), 3.44 (d, J=11.54 Hz, IH), 3.23-3.11 (m, 3H), 3.06 (t, ./ i 1.44 Hz, IH), 2.80-2.72 (m, 111).2.36-2.2 (m, 2H), 2.10-2.02 (m, 2H), 1.98-1.89 (m, 2H), 1.88-1.77 (m, 3H), 1,71-1.59 (m, IH), 1.58-1.48 (m, IH), 1.41 (t, .7=12.81 Hz, IH), 0.88-0.84 (m, 3H), m/z (ESI, +ve ion) 615.0

(M+H) ⁺ . EXAMPLE 843. (1S,3'R,6'R, 7'R)-6-CHLORO-7'-HYDROXY-3,4-DIHYDRO- 2H, 15 Ή-SPIRO j NAPHTH ALE E- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA I 16.18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

A mixture of (i.S;3%i'?,7¾9'ii)-6-chloro-7'-hydroxy-3,4-dihydro-

2H, 15 'H-spiro[naphthalene- 1.22'- [20]oxa[13]thia[U4]diazatetracyclo^

tetraen]-15'-one 13',13'-dioxide (Example 844; 0.248 g, 0.434 mmol) and platinum (IV) oxide (0.099 g, 0.434 mmol) in EtOAc (140 mL) was stirred under ¾ at rt for 1 h. The mixture was filiered through syringe filter to remove solid catalyst. The filtrate was concentrated to provide the title compound (5 mg) as a white solid. ^" Ή NMR (400 MHz, CD2CI2) δ 8,54 (m, Hi).7.77-7.69 (m, IH), 7.28 (m, I Hi.7.17 (m, IH), 7,12-7.05 (m, 211).6.94 (m, 1H), 4.14-4,06 (m, 2H), 3.96-3.88 (ni, 111).3.86-3.76 (m, IH), 3.73-3.66 (m, III).3.64-3.56 (m, lH), 3.41-3.31 (m, 1H), 3.27-3.18 (m, IH), 3.14-3.04 (m, Hi), 2.83-2,71 (m, 2H), 2.52-2.31 (m, 2H), 2,07-1.2! (m, 15H), 0.94-0.81 (m, 2H). m/z (ESI, +ve ion) 573.2 {\i · H) .

EXAMPLE 844. (1S,3'R,6'R 77?,i? i)-6-CHLORO-7'-HYDROXY-3,4- DII-FtDRO-2H, 15 'H-SPIRO[N APHTHALENE- 1,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".O ¹ " ^M |Ρ!·Λ i ACOSA

[9, 16, 18,24]TETRAEN] -15'-ONE 13', 13'-DIOXIDE

Step 1 ; (5)-METHYL 6'-CHLORO-5-((( / ?, 2R)-2-((R)- 1 -HYDROXYBUT-3-EN- l-YL)CYCLO BUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPlRO[BENZO[B] [l,4] ()XA/i !\ i 3. Γ-ΝΑΡΙ Π ! Λ! .1 ^" N 1 · ^" [ - 7- CARBOXYLATE

To a mixture of ally! iodide (0,81 mL, 8.8 mmol), indium powder (140 mg,

8.8 mmol) in DMF (41 mL) was added (7 ¾>methyl 6'-chloro-5-((2- forraylcyciobut>4)raethyl)-3',4,4 ^f ,5-teirahydro-2H,2'i-I- spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (intermediate AA11A, Step 20A; 1.00 g, 2.2 mmol) in DMF (15 mL). It was stirred at rt for 15 min. The reaction was diluted with water (30 mL) and EtOAc (300 mL). The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 0g ISCO Gold column and eluted with 0 % to 5 % EtOAc/hexane to provide the title compound (304 mg) as a white solid, m/z (EST, +ve ion) 496,0 (M+H) ⁺ .

Step 2: (5)-6'-CHLORO-5-(((lR,2R)-2-((R)-l-HYDROXYBUT- YL)CYCLOBUTYL)METHYL)-3' ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2 SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

A mixture of lithium hydroxide (1.0 M aqueous solution, 6.45 mL, 6.45 mmoi) and (7 'S)-methyl 6'-chloro-5-((2-((i?)-l -hydroxybut-3-en-l- yl)c>'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[ benzo[b] [l,4]oxazepine- 3,l'-naphthalene]-7-carboxylate (Example 844, Step 1 ; 0.32 g, 0.645 mmol) in MeOH (6.5 mL) and THF (6.5 mL) was stirred at 50°C for 3 h. The reaction mixture was concentrated and the residue was acidified with IN HCl solution to pH 2-3. It was extracted with EtOAc (200 mL), washed with brine (3 mL), dried over anhydrous sodium sulfate and concentrated to provide the title compound (31 1 mg) as a white solid, m/z (ESI, +ve ion) 482.1 (M+H) ⁺ .

Step 3: (S)-N-(BUT-3-EN-l -YLSULFONYL)-6'-CHLORO-5-(((7R,2R)-2-^)-l -

HYDROXYBUT-3-EN-I-YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO [BENZO [B ] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '- N APHTH ALENE1 -7 -C ARB OXAMIDE

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC; 0.247 g, 1.29 mmol) was added to a solution of (i ¾)-6'-chloro-5~((2~((i?)- l - hydroxybut-3-en-l-yl)cyclobutyl) methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [ l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 844, Step 2 ; 0.31 lg, 0.645 mmol) and but-3-ene-l -sulfonamide (EE1 5; 0.480 g, 3.55 mmol) in DCM (34 ml,). Then N,N-dimethylpyridin-4-amine (DMAP) (0. 150 g, 1.226 mmol) was added and it was stirred at rt overnight. After concentration the residue was loaded to a 24 g ISCO Gold column and eluted with 0 % to 20 % EtOAc (containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (303 mg) as a white solid, m/z (ESI, +ve ion) 599.2 ( M R )

Step 4; (!S 'R, 6 ^! R, 7 ^, A ^, , 9'i:)-6-CI-ILORO-7'-HYDROX ^,i t -3,4-DII-IYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[ 1 ,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [9, 16, I 8,24]TETRAENl-15'-ONE 13', 13 '-DIOXIDE

A 500 mL three-necked round bottom flask was charged with (5)-N-(but- 3-en-l-ylsdfonyl)-6 ^, -chloro-5^((l/t 2S>2-^R)-l -hydroxybut-3-en-l - yl)c lobutyl)methyl)-3\4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-

3, i '-naphthalene]-7-carboxamide (Example 844, Step 3 ; 0.020 g, 0.033 mmol) in toluene ( 100 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (4.18 mg, 6.68 μηιοΐ) in toluene (5 mL) at ambient temperature. The mixture was stirred at 106°C under nitrogen for 1 h. Air was blown for 10 min to deactivate the catalyst and then it was concentrated. The residue was purified by reverse phase preparative HPLC (Gemini ^lM Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (8.4 mg, second peak) as a white solid. ^l H NMR. (400 MHz, CD2CI2) δ 9.96 (br. s., IH), 7.75 (d, J=8.61 Hz, IH), 7.52 (br. s., IH), 7.15-7.38 (m, 2H),

7.09 (d../ 2.35 Hz, IH), 6.98 (br. s., IH), 5.73-5.63 ins. IH), 5.54-5.45 (m, IH),

4.10 (ddd,J=5.09, 13.01, 15.55 Hz, 3H), 3.92-3.61 (ra, 211).3,42-3.28 (m, IH), 3,25-2.98 (m, 2H), 2.80-2.63 (m, 4H), 2.61-2.51 (m, 2H), 2.33 (t, ,/ 822 Hz, ill). 2.24-1.23 (m, 11H). m/z (ESI, +ve ion) 571.1 { M · H ) .

EXAMPLE 845. (1S,3R, 6'R, 7 ?)-6-CHLORO-7'-HYDROXY-3,4~DIHYDRO- 2H, 15 'H-SPIRO[NAPHTHALENE- 1,22*-

[20]OXA[13]raj:A[l _s 14]DIAZATET ACYCLO[14J.2 ³ ' ^{6 19i4} ]PE TACOSA

[9, 16, 18,24]TETRAEN]-15'-ONE 13", 13-DIOXIDE

The title compound (4.5 nig) was obtained as a single isomer (first eiuting peak) from the reverse phase preparative HPLC in Example 844 as a white solid. ³ H NMR (400 MHz, CD2CI2) δ 9.48-9.39 (m, IH), 7.77-7,71 (m, IH), 7.50-7.44 (m, IH), 7.21-7.15 (m, IH), 7.13-7.08 (m, 2H), 7.02-6.97 (m, IH), 5.68-5.58 (m, IH), 5.56-5.47 (m, IH), 4.19-4.08 (m, 2H), 3.96 iddd../ 2.15.6.06, 15.06 Hz, IH), 3.87 (d../ 1 .45 Hz, IH), 3.81 i.id.. 4.0!.8.71 Hz, 111).3,70 id . I I4.2H Hz, IH), 3.33-3.23 (m, 2H), 3,18 (dd, J=8.51, 15.55 Hz, IH), 2.81-2.74 (m, 2H), 2.72-2.67 (m, IH), 2.63-2.53 (m, 2H), 2.50-2.37 (m, 2H), 2.30 (m, IH), 2.05 (m, IH), 1.98-1.81 im.h 4111.79-1.68 (m, 2H), 149-1.38 (m, IH). m . (ESI, +ve ion) 571,1 (M+H) ⁺ . EXAMPLE 846. (IS, 3 'R, 6 % 7'S.9 'E)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRQ-2H, 15 Ή-SPIROj NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI M.T^.O'^.O^^lPE TACOSA [9J 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

Step 1 : ( 'S)-N-(BUT-3-EN-l-YLSULFONYL)-6 ^, -CHLORO-5-(((7R,2R)-2-(l- HYT)ROXYBUT-3-EN-I-YL)CYCLOBUTYX)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '- N APHTH ALENE] -7 -C ARB OXAMIDE

N,N-dimethylpyridin-4-amine (DMAP) (0.830 g, 6.80 mraol) was added to a solution of (β)~6' Μοτο~5 -{{{! 2R)-2-((S)~ 1 -hydroxy but-3-en- 1 - yl)cyclobutyl)methyl)-3^4,4',5-tetrahydro-2H,2'H-spiro[benzo [b] [l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (Intermediate AA13A; 1 .82 g, 3.78 mmol) and but-3-ene-l -sulfonamide (1.873 g, 13.86 mmol) in DCM (140 mL) which was cooled to 0°C. Then EDC (1.303 g, 6.80 mmol) was added portion by portion and it was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (400 mL), washed with IN HQ solution (2x5 ml.), brine (3 raL), and dried over anhydrous sodium sulfate, concentrated. The residue was loaded to a 80g ISCO Gold column and eluted with 0 % to 15 % EtOAc (containing 0.3 %

AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (2.09 g) as a white solid, m/z (ESI, +ve ion) 599.0 ( V! I I ) .

Step 2: (i^ 5¾ d^ ¾ 97i>6-CHL()R()-7'-HYDROXY-3,4-DIHYDRO- 2H, 15 'H-SPIRO[N APHTHALENE- 1,22'- [20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[ 14.7.2.0 ³ · ⁶ .0 ^ί9 · ²⁴ ]ΡΕΝΤΑ€Ο8Α[9,16, 18,24]ΊΈΊ^ ΕΝ]-15'-Ο Ε ', '- DIOXIDE

A 1L round bottom flask was charged with (i '5)-N-(but-3-en-l- ylsulfonyl)-6'-chloro-5-(((iii,2ii)-2-(l-hydroxybut-3-en-l-y l)cyclobutyl)niethyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro [benzojb] [ 1 ,4]oxazepine-3, 1 '-naphthalene]-7- carboxamide (Example 846, Step 1; 1.02 g, 1.70 mmol) in toluene (587 mL). It was stirred at rt for 10 mm to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (0.213 g, 0.340 mmol) in toluene (20 mL). After the mixture was stirred at 106 °C under nitrogen for 75 min air was blown for 10 min to deactivate the catalyst, and then concentrated. The residue was loaded to a 330g ISCO Gold column and eluted with 0 % to 2.5 % EtOAc (containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to give the title compound (0.27 g, second eluting peak) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 9.96 (br. s., 1H), 7.78-7.65 (m, 1 H), 7.37 (dd, ./ i .96. 8.22 Hz, I I I ). 7.16 (dd, J=2.35, 8,61 Hz, 1 H), 7.10 (d, J=2.15 Hz, IH), 7.04 (br. s., IH), 6.98(m, 1H), 5.66-5,47 (m, 2H), 4.23-4.09 (m, 2H), 3,98 (ddd, ./ 5. 1 8. 10.56, 15.55 Hz, IH), 3.86 (dd, J=3.81, 9.49 Hz, IH), 3.64-3.49 (m, 2H), 3.38 (id, ./ 4.74. 15.36 Hz, 2H), 2.92 (br. s., IH), 2.81 (br. s., IH), 2.79-2.73 (m, 2H), 2,73-2.63 (m, I H), 2.52 (d, 1 2, 72 Hz, H), 2,40-2,25 (m, 2H), 2.18 (d, J=8,22 Hz, IH), 2.01-1,52 (m, 8H). rn/z (ESI, +ve ion) 571.0 (M+H) ⁺ .

EXAMPLE 850. (3R 6R 7S, 1 IR, /2Z,2- 5)-6'-CHLORO-l l-HYDROXY-3',4'- DIHYDRO-2'H, 17H-SPIRQ [8,22-DIQXA- 15-THIA- 1 , 16-

DIAZAPENTACYCLOj 16.7.2, 1 ⁷ ' ^{! !} .0 · ⁶ .0 ²¹ · ²⁶ J OCTACOSA-12, 18,20,26- TETR AENE-24, 1 '-N APHTHALEN] - 17-ONE 15,15-DIOXIDE OR

(3R.6R. 7R.11R 72Z,245)-6'-CHLORO-l l-HYDROXY-3',4'-DIHYDRO-2 ^, H,17H- SP1R0[8,22-DI0XA- 15-THIA- 1,16- DI AZAPENTACYCLO[ 16.7,2.1 ⁷ · ¹¹ .0 ³ ' ⁶ , 0 ²ⁱ · ²⁶ ] OCTACOS A- 12, 18,20,26- TETRAENE-24, 1 '-N APHTHALEN] - 17-ONE 15, 15-DIOXIDE OR

(3R, 6R, 7S, IIS, 72Z,24S)-6 ^! -CHLORO-l l-HYDROXY-S'^'-DIHYDRO^'H, ! 7H- SPIRO [ 8,22-DIOXA- 15 -THI A- 1 , 16-DI AZ APENTAC YCLO

[ 16,7.2, l ⁷ - ³ ^ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA-12,18,20,26-TETRAENE-24,r- APHTHALE ] - 17 -ONE 15,15-DIOXIDE OR (3R 6R, Z/< iiS i2Z245)-6'-

CHLORO-l l-HYDROXY-3',4 ^, -DIHYDRO-2'H,17H-SPIRO[8,22-DIOXA-15- THI A- 1 , 16-DT AZAPENTACYCLO[ 1 7.2. 1 ^{" ; ;} 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 12, 18,20,26-TETRAENE-24, 1 ^* -N APHTHALEN] - 17-ONE 15,15-DIOXIDE

Step 1 : (S)-METHYL 6'-CHLOR.O-5-(((lR,2B -2-((2S, 4R>4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL) METHYL)- 3Vlv4^5-TETUAHYDRO-2H,2¾-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENEJ-7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((/R,2R -2-i /?,4iR)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2-YL) CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [l ,4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7-

CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((lR,2 )-2-((2S, 4S) - HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ⁱ ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [I ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5- (((IR, 2R)-2-((2Ii 45)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] QXAZEPLNE-3 , 1 '-NAPHTHALENE] -7- C ARB OXYL ATE

TFA (6 mL) was added slowly to a solution of (5)~methyl 6'-chloro-5-

spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Intermediate AA1 1 A, Step 20A; 0.412 g, 0.9 ! mmol) and 3-buteti-l-ol (0, 10 mL, 1.18 mmol) in DCM (12 mL), which was degassed with N ₂ After it was stirred at rt for 35 min, the reaction mixture was added slowly to Na ₂ C0 ₃ (aq) solution (50 mL) and MeOH (15 mL). It was stirred at rt for 1.5 h and then extracted with EtOAc (3x90 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 24g ISCO Gold column and eiuted with 0 % to 30 % EtOAc/hexane, to provide a mixture, which was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/misn MeOH (0.2%DEA) + 60 g/min CO2 on a Thar 80 SFC. Outlet pressure 100 bar; Temp. 20 °C;

Wavelength 220 nm). The title compound (102 mg) was obtained as a single isomer (second eluting peak), m/z (ESI, +ve ion) 526. 1 (M+H) ⁺ .

Step 2: (<S')-METHYL 6'-CHLORO-5-(((7i i?i" fS)-4-OXOTETl AHYDRO- 2H-PYRAN-2-YL)CYCLOBUT L)METHYL)-3'.4,4 ^, ,5-TET AHYDRO- 2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL ff-CHLORO-S-^/R,^^-^^- OXOTETRAHYDRO-2H-PYRAN-2^'L)CYCLOBUTYL METHYL)-3 ^! ,4,4 ^! ,5- TETRAH YDRO-2H,2'H-SPIRO [BENZO[B] [ 1 ,4] OXAZEPINE-3 ,Γ-

NAPHTHALENEj-7-CARBOXYLATE

A 100 mL flask charged dimethyl sulfoxide (0.041 mL, 0.58 mmol) and DCM (2.8 mL) was cooled to -78°C. OxaM chloride (2.0 M solution in DCM, 0.15 mL, 0.29 mmol) was added dropwise and the reaction mixture was stirred for 10 min. (5)-Methyl 6'-chloro-5-(((7i?,2i?)-2-((2 ₎ S', 4i?)-4-hydroxytetrahydro-2H- pyran-2-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 850, Step

1 ; 0.102 g, 0.194 mmol) in DCM (2.8 mL) was added in one portion to above solution. After it was stirred at -78°C for 17 min, triethylamine (0.135 mL, 0.97 mmol) was added and it was stirred at -78°C to it overnight. It was quenched with water (3 mL), extracted with (140 mL). The organic phase was washed with 1 N HCi solution, brine, dried over anhydrous sodium sulfate. It was filtered through silica gel and concentrated to provide the title compound (100 mg) as a white solid, m/z (ESI, +ve ion) 524.1 ( M l ! ) .

Step 3: (S)-METHYL 6' HLORO-5-(((Hi2/ i-2 S ¹ , 4 ?)-4-I-riO OXY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3Vlv4^5-TCTRAHYDRO-2H,2¾-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE OR (5)-METHYL 6'-CHLQRQ-5-

((( 1R, 2R)-2-((2R, 4R)-4-HYDROXY-4-VlNYLTETR AHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2 'HSPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 -NAPHTHALENE] -7 - CARBOXYLATE OR (5)-METHYL 6'-CnLORO-5-((( R2R)~2- (2S S)~4~ HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (5)-METHYL &~CRLORO~5~(((lR2R)--2-{(2R,4S)~4~ HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [ l,4]QXAZEPI E-3, 1 '-NAPHTHALENE j-7- CARBOXYLATE

Vinylmagnesium chloride (1.6 M solution in THF; 0.58 mL, 0.93 mmol) was added dropwise to a solution of 0S)-methyl 6'-chloro-5-(((/i?,2i? -2Y S>4- oxotetrahydro-2H-pyran-2-yl)cyciobuiyi)rnethyl)-3 ^f ,4,4',5-teirahydro-2H,2Ti- spiro [benzo [b] [ 1 ,4] oxazepme-3 , Γ -naphtha! ene] -7-carboxy late (Example 850, Step 2; 0.097 g, 0.185 mmol) in THF (6 mL) at 0°C. It was stirred at 0°C for 5 mm. It was quenched with NT^Cl solution and extracted with EtOAc (180 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. filtered through short plug of silica gel. After concentration, the title compound was obtained (102 nig) as an oil. m/z (ESI, +ve ion) 552.1 { Yi H ) .

Step 4: (S)-6'-CHLORO-5-(((/R, 2R)-2-((2S, 4R)-4-HYDROXY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- S'^^'^-TETRAHYDRO^^'H-SPIROpENZOPltl^lOXAZEPINE-a,!'- APHTH ALENE J -7 -C ARB OXYL1C ACID OR (5)-6'-CHLORO-5-(((iii,2i^-2-

( ? _J ^?)-4 WDROXY-4A^rNYT-,TETRAT-rYDRO-2H-PYRAN-2-

YL CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7- C ARBOXYLIC ACID OR (S 6'-CHLORO-5-(((iA ⁵ , 2R)-2-((2S, 45)-4-HYDROXY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- T A4'.5-TI ^: .TRAI I YDRO-21 Ι.2Ί l-SIMIU)| Βί \ΥΟ| B j| Ι.4|ΟΧΛ/Ι·.Ρ!\ϊ·.- .1 NAPHTHALENE] -7-CARBOXYLlC ACID OR (S)-6'-CHLORO-5-(((Hi 2R 2- ((2R, ^5 -4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUlTL)METHYL 3',4,4 ^, ,5~TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

Lithium hydroxide (1.0 M aqueous solution, 5.43 mL, 5.43 mmol) was added to a solution of (/ ¾)-methyl 6'-chloro-5-(((iii2i? 2-^2S)-4-hydroxy-4- vinyltetrahydro-2H-pyran-2-yl)cyclobul5 _' ^, l)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 850, Step 3; 0, 100 g, 0.18 mmol) in THF (12 mL) and MeOH (6 mL). It was stirred at 50 °C for 60 min. It was concentrated, acidified with 1 N HC1 solution to pH 2-4, extracted with EtOAc (160 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini ^lM Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1 % TEA, gradient elution). The title compound (33 mg) was obtained as a single isomer (first eluting peak) as a white solid, m/z (ESI, +ve ion) 538, 1 (M+H) ¹ .

Step 5; 4R)-4- HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRQj BENZO [B] [1 ,4 jOXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE OR (5)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7R, 2RJ-2- ((2R, 4R)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARB OX AMIDE OR (S)-N ALLYLSULFONYL)-6'-CHLORO-5-(((lR,2R)-2- ((2S,4R)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l '-NAPHTHALENE]-7-

CARBOXAMIDE OR ( ₁ S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7i?, 2-¾ ⁾ -2- ^, ,S 4 -IYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7~

CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (9.54 mg, 0.078 mmol) was added to a solution of (5)-6'-chloro-5-(((lR,2R)-2-((2S,4R)-4-hydrox>'-4- vinyltetrahydro-2H-pyran-2-yl)cyclobutyl) methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3,l'-naphthalene]-7-carboxylic acid (Example 850, Step 4; 0.014 g, 0,026 mmol) in DCM (0.9 mL) at 0°C. Then Nl- ((ethylimino)methylene)-N3,N3-cUmethylpropane-l,3-diamine hydrochloride (EDC) (10.5 mg, 0.055 mmol) was added slowly in portions and it was stirred at

0°C to rt for 16 h. Then it was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini ^lM Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (l lmg) as a white solid, m/z (ESI, +ve ion) 641.1 ί M i l )

Step 6: (3R 6R, 7S 1R, 12Z,24S)-6'-CHLORO-l l-HYDROXY-3',4'-DIHYDRO- 2Ή, ! .7H-SPIRO[8,22-DIOXA-l 5-THIA-l ,16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ ' ⁿ .0 ³ - ⁶ .0 ²ⁱ ' ²⁶ ] OCTACOSA-12, 18,20,26- TETRAENE-24, 1 '-NAPHTH ALEN] - 17-ONE 15,15-DIOX1DE OR

(3R, 6R, 7R, liR, 12Z,24S)~6'~CHLORO-l l-HYDROXY-3",4'-DIHYDRO-2'H,l 7H- SPIRO[8,22-DIOXA- 15-ΊΉΙΑ- 1 , 16- DI AZAPENTACYCLOP 6.7,2. ⁷ · ¹¹ .0 ³ ' ⁶ . Q ²ⁱ · ²⁶ ] OCTACOS A - 12, 18,20,26- TETRAENE-24, 1 '-NAPHTH ALEN] - 17-ONE 15, 15-DlOXIDE OR

(3R 6R 7S, IIS, i2Z,24S)-6'-CHLORO-l l-HYDROXY-3',4'-DlHYDRO-2'H,l 7H- SPIRO [ 8,22-DIOXA- 15 -THI A- 1 , 16-DI AZ APENTAC YCLO

[ 16,7.2. 1 ⁷ - ^{3 3} ,0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA-12,18,20,26-TETRAENE-24,l'- APHTH ALEN] - 17 -ONE 15,15-DIOXIDE OR (3R, 6R, 7R, llS, 12Z,24S)-&- CHLORO-l l-HYDROXY-3'.4 ^, -DIHYDRO-2'H ₅ 17H-SPIRO[8,22-DIOXA-15- THI A- 1 , 16-DT AZAPENTACYCLO[ 1 7.2. 1 ^{" ; ;} 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 12, 18,20,26-TETRAENE-24, 1 '-NAPHTHALEN] - 17-ONE 15,15-DIOXIDE

A 2.50 mL round bottom flask was charged with ( _; S ^' )-N-(allylsulfonyl)-6'- chloro-5-(((/i?, 2R)-2-((2S, 4i?)-4-hydr oxy-4-vinyltetrahy dr o-2H-py ran-2- yl)cyclobut 'l)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine-

3, -naphthalene]-7~carboxamide (Example 850, Step 5; 0.011 g, 0.017 mmol) in toluene (36 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (2.2 mg, 3.4 μηιοΐ) in toluene (3 mL). The mixture was stirred at 106 °C under nitrogen for 1 h. Then it was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Ci8 5um column; Phenomenex,

Torrance, CA; MeCN in water with 0.1% TFA, gradient elution). The title compound (1.1 mg) was obtained as a single isomer (second eluting peak). ^" Ή NMR (500 MHz, ClhC ) δ 8, 1 1 (m, IH), 7.69 (m, I H i. 7.17 (m, IH), 7,09 (m, 2H), 6.92 (m, 2H), 6.10 (dd, J=1.96, 11.98 Hz, IH), 5.84 (dd, ./ 1 .2.59. 15.53 Hz, IH), 5.53-5.45 (m, 2H), 4.13-4.01 (m, 2H), 3.94-3.80 (m, 3H), 3.73 id. 13.94 Hz, H), 3,46 (dt, ,/ 3.9 j . 1 1.86 Hz, H), 3,20-3,05 (m, 3H), 2.82-2.72 (ra, 2H), 2, 17-1.99 (m, 6H), 1.96-1 ,34 (m, 9H). m/z (ESI, +ve ion) 613.0 (M+H) ⁺ . EXAMPLE 851. (3R/)R S, 1 lS _ 2E 4S)-6'-CHLQRO-l l-HYDRQXY-3'A'- DIHYDRO-2'H, 17H-SPIRO [ 8,22-DIOX A- 15 -ΤΉΙΑ- 1 , 16- DIAZAPENTACYCLO [16,7.2, 1 ⁷ - ¹¹ 0 ³ - ⁶ ,0 ^2L26 ]OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-NAPHTH ALEN] - 17-ONE 15,15-DIOXIDE OR

(3R.6R, 7R, 1 IS 2E.2- ,S)-6'-CHLORO-l l-HYDROXY-3',4'-DIHYDRO-2'H, 17H- SPIRO[8,22-DIOXA- 15-THIA- 1 , 16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ ' ⁿ 0 ³ - ⁶ .0 ²¹ ' ²⁶ ]OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-NAPHTH ALEN j - 17-ONE 15, 15-DIOXIDE OR

(3R, 6R, 7R, HR, 12E, .?. _f '.S)-6 ^' -C! II .ORO- 1 1 -HYDROXY-3',4'-DIHYDRO- 2Ή, 17H-SP.1R0[8,22-DI0XA-15-THIA- 1 , 16- DIAZAPENTACYCLO[16.7,2.1 ⁷ - ^{! !} 0 ³ - ⁶ .0 ⁱ - ²⁶ ]OCTACOSA-12, 18,20,26- TETR AENE-24, 1 '-NAPHTH ALEN] - 17-ONE 15,15-DIOXIDE OR

(3R.6R. 7S, 1IR 2E, .?-/.Y}-6'-Ci H .ORO- i l-HYDROXY-3',4'-DIHYDRO-2'H, 17H- SP1R0[8,22-DI0XA- 15-THIA- 1,16-

DIAZAPENTACYCL [16.7.2.1 ⁷ > ^{! l} 0 ³ -^0 ²ⁱ > ⁶ ]OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-N APHTH ALEN] - 17-ONE 15, ! 5-DIOXIDE

The title compound (4.6 mg) was obtained as a single isomer (first eiuting peak) from the reverse phase preparative HPLC in Example 850. ¾ NMR (500 MHz, CD2CI2) δ 8.28 (br. s. , IH), 7.65 id . «7=8.56 Hz, IH), 7.15 (dd, .7=2.32, 8,44 Hz, IH), 7.10 (d, ,7=2.20 Hz, IH), 7.01 (dd, ,7=1.71, 8.07 Hz, IH), 6.92-6.97 (m, IH), 6.85 (s, IH), 6.31 (d, ./ 1 5.4 ! Hz, ! ! ! ). 5.94 (ddd, ./ 6. ! ! . 8.93, 15.28 Hz, IH), 4,35-4.27 (m, I H), 4,24-4, 13 (m, 2H), 4.12-4.07 (rn, IH), 3,95-3,89 (m, IH), 3,60 (d, ./ 14. 1 8 Hz, IH), 3,35-3.49 (rn, 4H), 3.28 (dd, .7=3,91, 10.76 Hz, IH), 2.79-2.70 (m, 2H), 2.43 id. ./ 3.9 ! Hz, IH), 2.00-1.54 (m, 12H), 1.44 (br. s., IH), 1.39-1.33 (m, IH). m/z (ESI, +ve ion) 613.0 { \ I · Π } .

EXAMPLE 853. (1S,3'R, 6'R 7'i?,SK)-6-CHLORO-7',8'-DlHYDROXY-3,4- DIHYDRO-2H, 15 'H-SPIRO[N APHTH ALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE OR (1S, 3'R 6'H 7'S,8'S)-6- CHLORO-7',8'-DIHYDROXY-3,4-DIHYDR()-2H, 15'H- SPIRO [NAPHTHALENE- ,22'-

[20]OXA[13]TOIA[1 ,14]D.1AZATETRACYCLO[14.7,2.0

3,6 ₀ i9,24 |p _ENX ACOSA [16,18,24] TR1EN]-15'-0NE 13',13'-D10XIDE

A solution of osmium(VIII) oxide (2.5% solution in tert- uOH, 0.18 mL, 0.014 ramol) was added to a solution of (1S, 3'R, 6'S, 7'£)-6-chloro-3,4-dihydro- 2H, 15 'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]tMa[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[7,16,18,24]tetrae n]-15'-one 13', 13'-dioxide (Example 858; 0.040 g, 0.072 mmol) in acetone (3.3 mL) and THF (3.3 mL). Then 4-methylmorpholine N-oxide (0.020 g, 0.173 mmol) was added and the mixture was degassed with nitrogen. It was stirred at rt for 2.5 h and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini ^IM Prep C is 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1 % TFA, gradient elution). The title compound (4.1 mg) was obtained as a single isomer (first eluting peak) as a white solid. ^l H NMR (400 MHz, CD2CI2) δ 8.53 (br. s. , 1H), 7.69 (m, i l l ). 7.18 (dd, J=2,25, 8.51 Hz, 1H), 7.09 C m. 2H), 7.02-6.89 (m, 2H), 4.16-4.04 (m, 2H), 3.85-3.69 (m, 2H), 3.67-3.48 (m, 2H), 3.44-3.30 (m, 2H), 3.22-3.09 (m, 2H), 2.84-2.73 (m, 2H), 2.59 (m, 1H), 2,39 (m, H i ). 2.18-1 .28 (m, 1 ! ! } m/z (ESI, +ve ion) 589, 1 (M+H) ⁺ .

EXAMPLE 857. (lS,3'R, 6'R, 7'R,8'R)-6-CHLORO-T,S'-O YOROXY-3,4-

DIHYDRO-2H, 15 Ή-SPIROj NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAt^MlDIAZATET ACYCLOI M.T^.O'^.O^^lPE TACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3 6'R, 7'S,8'S)-6- CHLORO-7',8 ^! -DiHYDROXY-3,4-DIHYDRO-2H, 15'H- SPIRO [NAPHTHALENE- 1 ,22'-

|20jOXA| I 311 HI Λ| I .. N |PI A/A Π·. f ^' RACYCf .Oj N.7.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA

[16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE

The title compound was obtained as a single isomer (second elutmg peak) from the reverse phase perparative HPLC in Example 853. Ή NMR (400 MHz, CD2CI2) δ 7.74 (m, 1H), 7.33-7.43 (m, 1H), 7.19 (m, 1H), 7.10 (d, ,7=4,50 Hz, 111).7.00-6.88 (m, 2H), 4.16-4.04 (m, 2H), 3.97-3.78 (m, 2H), 3.75-3.67 (m, ill). 3.65-3.51 (m, 2H), 3.51-2.97 (m, 5H), 2.78 (br. s., 2H), 2.39-1.16 (m, 14H)). 'z (ESI, +ve ion) 589.1 ( M If) .

EXAMPLE 858. (1S 'R,6'S, 7' )-6-CHLORO-3,4-DIHYDRO-2H,15'H- SPIRO[NAPHTHALENE-l,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[7, 16, 18,24]TETRAEN]-1 S'-ONE 13', 13 '-DIOXIDE

Step I; (5)-METHYL 6'-CHLORO-5-i((/¾2S)-2- VINYlXYCLOBUlTL)MEraYL)-3',4,4',5-lT;TRAHYDRO-2H,2'H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-

CARBOXYLATE

A solution of methyltriphenylphosphonium bromide (1.02 g, 2.86 mmol) in THF (5.7 ml.) was cooled to 0°C. w-Butyl lithium solution (2.5 M in hexane, 1.03 mL, 2.58 mmol) was added dropwise and it was stirred at 0 °C for 9 min. The resulting Wittig reagent (yellow solution) was added to a solution of (5)-methyl 6'~ cWoro-5-(((i^ 2i?)-2-formylc\xlobutyl)methyl)-3^4,4^5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox date (Intermediate ΑΑΓ1Α, Step 20 A; 0.130 g, 0.286 mmol) in THF (1.2 mL) until the yellow color persisted. After it was stirred at 0°C for 5 min, the reaction mixture was added to a stirred ice-water (3 mL). The organic phase was separated and the aqueous was extracted with EtOAc (120 mL). The combined organic phase was washed with brine, dried anhydrous sodium sulfate. After concentration the residue was loaded to a 4g ISCO Gold column and eluted with 0% to 10% EtOAc/hexane to provide the title compound (92 mg) as a white solid, m/z (ESI, +ve ion) 452.1 (M+H) ⁺ .

Step 2: (S)-6'-CHLORO-5-(((lR,2S)-2-VI rYLCYCLOBLTYL)METHYL)-

3',4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO [B] [l ,4]OXAZEPINE-3,l ^* - N APHTHALENE] -7-C ARBOXYLIC ACID

Lithium hydroxide (IM aqueous solution; 1.9 mL, 1.9 mniol) was added to a solution of (<S)-methyl 6'-chloro-5-(((H?,25')-2-vinylcyclobutyl)methyl)-3 ^, ,4,4 ^, ,5- tetrahy dro-2H,2'H-spiro[benzo[b j j 1 ,4] oxazepine-3, 1 '-naphthalene |-7-carboxy late (Example 858, Step 1 ; 0,087 g, 0. 192 mmol) in TOF (4 mL) and MeOH (2 mL). It was stirred at 50°C for 4 h. After concentration, it was acidified with 1 N HC1 solution to pH 2-3, extracted with EtOAc (80 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. The solution was concentrated to give the title compound (84 mg) as a white solid, m/z (ESI, +ve ion) 438.2 (M+H) ⁺ .

Step 3 ; (5)-6'-CHLORO-N-(HEX-5-EN- 1 ~YLSULFONYL)-5-((( 1R, 25)-2- VINYLCYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO[B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOX AMIDE

N,N-Dinietliyipyridin-4-amine (DMAP) (0.030 g, 0.247 mmol) was added to a solution of (A 6'-chIoro-5-(((7i?, 25 -2-vmyIc clobutyl)methyl)-3',4,4',5- tetrahydro-2H,2'H-spiro[benzo[b] [ l,4] oxazepine-3, r-naphthalene]-7-carboxylic acid (Example 858, Step 2; 0.060 g, 0.137 mmol) and hex-5-ene-l -sulfonamide (EE25; 0.1 12 g, 0.685 mmol) in DCM (5 mL) at 0°C (ice bath), Then N~(3~ dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (0,047 g, 0.25 mmol) was added portion by portion slowly and it was stirred at rt for 16 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (72 mg) as a white solid, m/z (ESI, +ve ton) 583,3 ί VI H )

Step 4: (1S,3'R,6'S.7'£)-6-CHLORO-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22' -[20] OXA[ 13]THIA[1 , 14]

ί)!Λ/Λ ΓΚΓΚΛ(Ύ(·ί,Οί !·!,?.20· ^: '.0 ^|; ' ^PHNTAC ^' OSA| 7. i 6J 8.2-1 iTI RALN 15'-ONE 13',13'-DI()XIDE

A 250 mL round bottom flask was charged with (yS)-6'-chloro-N-(hex-5- en-l-ylsulfonyl)-5-(((H?,2S)-2-vinylcyclobuty^^

2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxamide (Example 858, Step 3; 0.072 g, 0,123 mrnoi) in toluene (137 mL), It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (0.015 g, 0.025 mmol) in toluene (3 mL). The mixture was stirred at 106°C under nitrogen for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cm 5μηι column; Phenomenex, Torrance, C A; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (55 mg) as a white solid, ¾ NMR (500 MHz, CD2CI2) δ 8.05 (m, IH), 7.72 (m, ill).7.17 (m, 1H), 7.09 (m, 1H), 6.99-6.91 (m, 2H), 6.79 (m, 1H), 5.71 (dd../ 6.24.15.53 Hz, IH), 5.48-5.39 (m, 1H), 4.13-4.04 (m, 2H), 3,83-3.69 (m, 2H), 3.64 (ddd, ./ 6,48.9.23, 15.10 Hz, IH), 3,47-3.36 (m, IH), 3.24 (d, .7=14, 18 Hz, IH), 3.08 (dd, .7=9.54, 15.41 Hz, IH), 2,83-2.70 (m, 3H), 2.57-2.49 (m, IH), 2.29 (quin, ./ 8.93 Hz, IH), 2.17-1.48 (m, 12H), 1.43 (t, ./ 1235 Hz, IH), m/z (ESI, +ve ion) 555,2 i M My. EXAMPLE 859. (i5' ₍ 3^d¾ i2¾?)-6-CHLORO-12 ^, -ETHYL-7 ^, -METHYLIDENE- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI M.T^.O'^.O^^lPE TACOSA [16,18,24]TRIEN]-15'-ONE 13', '-DTOXTDE

A solution of methyltriphenylphosphonium bromide (2.4 g, 6.8 rnmol) in THF (20 mL) was cooled to 0°C. n-Butyl lithium solution (2.5 M in hexane; 2.5 mL, 6.16 rnmol) was added dropwise and it was stirred at ( ⁾ °C for 10 min. The resulting Wittig reagent (yellow solution) was added dropwise to a solution of (1S,3'R, 6'R, 72y?)-6-chloro-12 ^* -ethyl ,4-dihydro-2H,7¾15^spiro[naph1ha]ene- 1,22'- [20]oxa[13]mia[l ,14]diazate1r^

7 ^! ,15'-dione 13 I 3 '-dioxide (Example 886; 0,410 g, 0.684 rnmol) in THF (8 mL) at 0°C until the yellow color persisted. After it was stirred at 0 °C for 12 min, the reaction mixture was added to a stirred ice-water (4 mL). It was acidified with IN HC1 solution to pH 2-4. The organic phase was separated and the aqueous phase was extracted with EtOAc (200 mL). The organic phase was washed with brine, dried anhydrous sodium sulfate. After concentration the residue was loaded to a 40g ISCO Gold column and eluted with 0% to 10% EtOAc (containing 0.3 % AcOH) hexane (containing 0.3 % AcOH) to provide the title compound (2.59 mg) as a white solid, ^] \ \ NMR (400 MHz, CD2CI2) δ 8.09 (m, lH), 7.73 (m, IH), 7.19 (m, IH), 7.09 (m, IH), 6.97 (m, IH), 6.88 (m, 2H), 4.75-4.64 (m, 2H), 4.14-4.04 (m, 2H), 3.87 (rn, H), 3.82-3,69 (m, 2H), 3.27 { O. J 1 08 Hz, IH), 3.05 (dd, ./ 7.04. 15.45 Hz, ! ! ! ). 2.88-2.71 (m, 3H), 2.61 -2,51 (m, H i ). 2.14-1.25 (rn, 1 8! ! }. 1.19-1. 1 1 (rn, 3H). m/z (ESI, +ve ion) 597.1 (M+H) ⁺ .

EXAMPLE 861 , (3R.6R, 7S 2R.22S)-6 ^* -CHLORO-7-HYDROXY-l 2-METHYL- 3 ',4 ^! -DIHYDRO-2 ^! H, 15H-SPIRO [ 1 0,20-DIOXA- 13-ΤΉΙΑ- 1 , 14- DI AZ ATETRAC Y C LO [14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ jPENTACOS A-l 6, 18,24-TRIENE-22, 1 N APHTH ALEN ] - 15 -ONE 13, 3-DIOXIDE OR (iR, <a^, ZS: 72/¾22Λ)-6 ^, - CHLORO-7-HYDROXY-12-MF;THYL-3V^-DiHYDRO-2 ^! H,15H-SPIRO[10,20- DIOXA-13-TfflA-l,14-DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA- 16, 18,24-TRIENE-22, 1 '-NAPHTHALEN] - 15-ONE 13, 13-DI OXIDE

Step 1 : BI S (4-METHOXYBENZYL) AMINE

A solution of 4-methoxybenzaldehyde (10.7 mL, 88 mmol) and 4- methoxybenzylairane (4.5 g, 137 mmol) in DCM (105 mL) and AcOH (21 mL) was stirred at rt for 15 min. Then it was cooled to 0°C, and was added slowly sodmm cyanoborohydride (2.8 g, 44 mmol). It was stirred at 0 °C to rt for 1 h. The reaction mixture was added slowly to NaOH solution, neutralized to pH ^:=: 8-10 and exiracted with EtOAc (2x200 raL). The organic phase was washed with brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 330g ISCO Gold column and eluted with 0% to 20% EtOAc/DCM to provide the title compound (6.0 g) as a white solid, m/z (ESI, +ve ion) 258.2 ^{ \i · H )

Step 2: N.N-BIS(4-METHOXYBENZYL)PROP-l -ENE-2-SULFONAMIDE

Prop-l-en-2-ylmagnesium bromide (0.5 M in THF; 20 mL, 10 mmol) was added dropwise to a solution of sulfuryi di chloride (1.2 mL, 15 mmol) in hexane (20 mL) at 0°C. It was allowed to rt and stirred for 1 h. To this mixture was added DCM (20 mi.) and it was cooled in ice bath. Triethylamine (5.6 mi,, 40 mmol) was added slowly, followed by addition dropwise of N,N-bis(4- methoxybenzyl)prop-l-ene-2-sulfonamide (Example 861, Step 1 ; 1.27 g, 3.51 mmol) in DCM (35 raL). It was stirred at 0°C for 20 min. The reaction mixture was poured slowly into ice water (20 g), and extracted with EtOAc (340 mL). The organic phase was washed with 1 HCl solution (20 mL), NaHC03 solution (10 mL), brine (4 mL), and dried over anhydrous sodium sulfate. After concentration the residue was loaded to a 120g ISCO Gold column and eluted with 0% to 15% EtOAc hexane to provide the title compound (1.27 g) as a pale yellow solid, m/z (ESI, +ve ion) 361.2 (M+H) ⁺ . Step 3: (SJ-TERT-EUTYL 6'-CHLORO-5-(((/i?,2i^-2-†S -l-((4-

METHOXYBENZ YL)OXY)B UT-3-E - 1 - YL)C YCLOB UTYL) METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [I ,4]OXAZEPINE-3,r- NAPHTHALENE] ~7-C ARBOXYLATE

At 0 °C, sodium hydride (60% dispersion in mineral oil; 43 mg, 2.1 mmol) was added to a solution of (S)-ter(-hutyl 6'-chioro-5-(((Hi 2R)-2~((S)~1~ hydroxy but-3-en-l-yl)cyclobutyl) methyl)-3 ^, ,4,4',5-tetrahydro-2H,2'H- spiro I benzo | b j [ 1 ,4] oxazepine-3 , Γ-naphthal ene ] -7-carboxy late (Intermediate AA13A, Step IB; 0,82 g, 1.52 mmol) in DMF (6.6 mL). It was stirred at 0°C for 26 min. Then 4-methoxybenzyl chloride (1.48 g, 9.45 mmol) and potassium iodide (0.142 g, 0.85 mmol) was added and it was stirred at 0°C to rt for 3 days. The reaction mixture was poured into water (10 mL), and diluted with EtOAc (300 ml,). After separation. The organic phase was washed with IN HC1 solution, NaHCC solution, and brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 80g ISCO Gold column and eluted with 0% to 7% EtOAc/hexane to provide the title compound (24 ! mg) as a film, m/z (ESI, +ve ion) 658.3 (M+H) ⁺ .

Step 4: (S) - TER F-BIJT YL 6"-CHLORO-5-(((/R,2R -2-(†S)-l-((4-

YU . Π JXY I .NZV 5 )()XY }- -()X()PR()PY i }( Y( i .()Bl ^' TY U.YU i \Yi .)

3' _; 4' ₅ 5.TETl AHYDRO-2H,2 ^" H"SPIRO[BENZO[B] [l,4]OXAZEPINE-3,l

NAPHTHALENE] -7-CARBOXYLATE

Sodium periodate (0,910 g, 4.25 mmol) was added to a solution of (S)-tert- butyl 6'-chloro-5-(((7i?,2i^-2-(†S)-l-((4-methoxybenzyl)oxy)but- 3-en-l- y^cyclobut methy^-S'^^'.S-tetrahydro- H^'H-spirotbenzotbJ tl^Joxazepine- 3, -naphthalene|-7-carboxylate (Example 861, Step 3; 0.80 g, 1.2 mmol) in THF

(8.7 mL), acetone (8.7 mL) and water (2.9 mL) at 0°C. It was added osmium tetroxide (2.5 wt % solution in 2-methyl-2-propanol: 0.71 mL, 0.073 mmol) and was stirred at 0 °C to it for 21 h. The reaction mixture was diluted with EtOAc (300 mL) and the organic phase was washed with 1 N sodium thiosulfate solution (3 mL), brine (3 mL) and dried over anhydrous sodium sulfate. After

concentration, the title compound was obtained, which was used for next reaction without purification, m/z (ESI, +ve ion) 660.3 (M+H) ⁺ . Step 5: (SJ-TERT-BUTYL 6'-CHLORO-5 ((iii2i^-2-(T5)-3-HYDROXY-l-((4- METHOXYBENZYL)OXY)PROPYL) CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , !

NAPHTHALENE] -7-CARBOXYLATE

Sodium borohydride (10 mg, 2.9 mmol) was added portion by portion slowly to a solution of (S)-tert-hutyl 6'-chloro-5-(((H?,2i^-2-(7S)-l-((4- me1hoxybenzyl)ox\')-3-oxopropyl)cyclobu1yl)methyl)-3',4,4',5 -tetrahydro- 2H,2'H-spiro[benzo[b][l ,4]oxazepine-3,l'-naphthalene]-7-carboxylate (Example

861 , Step 4; 0.480 g, 0.727 mmol) in MeOH (14 ml.) at 0°C and it was stirred at

0°C for 10 min. Water (5 mL) was added and it was concentrated to remove the MeOH. Then it was extracted with EtOAc (220 mL), the organic phase was washed Na2CO3 solution (1 mL), brine (1 mL), and dried over anhydrous sodium sulfate. After concentration the residue was loaded to a 80g ISCO Gold column and eluted with 0% to 20% EtOAc/hexane to provide the title compound (290 mg) as a white solid, m/z (ESI, +ve ion) 662.2 { \ I · Π }

Step 6: (SJ-TERT-BUIYL (V-C! jj .ORO- iii /A ^J .2Rj~2- i(S)- 1 ·{{ ·

METHOXYBENZYL)OXY)-N,N-BIS(4- ETHOXYBENZYL)-3-((R)-2- SULFAMOYLPROPOXY)PROPYL)CYCLOBUTYL)METOYL)-3',4,4',5- TETRAHYDRO-2H,2 Ή-SPIRO [BENZO [B] [ 1 ,4]OXAZEPINE-3, 1 ^* - NAPHTHALENE] -7-CARBOXYLATE AND (5)-TERT-BUTYL 6'-CHLORO- 5-(((lR 2R)-2-((S)-\ -((4-METHOXYBENZYL)OXY)-N,N-BIS(4- METHOXYBENZYL)-3 -((S)~2~

SULFAMOYLPROPOXY)PROPYL)CYCLOBUTYL)MEraYL)-3',4,4',5" TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [l,4| OXAZEPINE-3,1'- NAPHTHALENE] -7-CARBOXYLATE

A solution of (S)-ter t-bu yl 6'-chloro-5-(((H?,2i? 2-(†S)-3-hydroxy-l-((4- me1hoxybenz}d)oxy)propyl)cyclobutyl)me1hyl)-3 4,4^5-tetTahydro-2H,2'H- spiro[benzo[b] [l,4] oxazepine-3, -naphthalene]-7-carboxylate (Example 861, Step 5; 0.287 g, 0.433 mmol) in THF (8.7 mL.) was cooled with ice bath. Sodium hydride (57-63% oil dispersion, 16 rng, 0.74 mmol) was added and it was stirred at cooling for 19 min, to which a solution of N,N-bis(4-methoxybenzyl)prop-l - ene-2-sulfoiiamide (Example 861, Step 2; 0.28 g, 0.78 mmol) in THF (6 mL) was added. It was stirred at rt for 19 h. The reaction mixtui'e was poured into water (2 mL) and extracted with EtOAc (1 0 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA: MeCN in water with 0.1% TFA, gradient elution). The HPLC fraction was concentrated at rt, then neuteaiized with NaHCC)3 solution to pH 7, extracted with EtOAc(15() mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate and concentrated to provide the title compound (57 mg) as a mixture of two isomers. Step 7 : (S)-6'-CHLORO-5-(((7R, 2R)-2-((S}- 1 -HYDROXY-3~((i?)-2- SULFAMOYLPROPOXY)PROPYL)CYCLOBUTYL)MEraYL)-3',4,4',5" TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [l ,4 jOXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((H?, 2RJ-2- ((S 1 -HYDROXY-;, -Ci.V)~2~

SULFAMOYLPROPOXY)PROPYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3, r- NAPHTHALENE] -7-CARBOXYLIC ACID

(S)~Tert- utyl e'-cMoro-S-Cii ^ ^^-f^-l-^-metttoxybenz Oox )-- N,N-bis(4-methoxy-benzyl)-3-((i?)-2- sulfamoylpropoxy)propyl)c clobutv'l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox date (Example 861, Step 6; 0.055 g, 0.054 mmol) was added to a mixed solvent TFA (4 mL) and DCM (12 niL). It was stirred at rt for 16 h. After concentration, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (33 mg) as a white solid, m/z (ESI, +ve ion) 607.3 (M+H) ⁺ . Step 8: (3R 6R. 7S, /2i?,225)-6 ^f -CHLORO-7-HYD OXY-12-MEmYL-3',4'- DIHYDRO-2'H, 15H-SPIRO [ 10,20-DIOXA- 13 -THIA- 1 , 14- DIAZATETRACYCLO[14;7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA~16,18,24-TRlE E-22,r- N APHTHALEN] -15 -ONE 13, 13-DIOXIDE OR (3R, 6R, 7S, 12R, 22R)-S- CHLORO-7-HYDROXY- l 2-METHYL-3',4 ^, -DIHYDRO-2 ^, H ₅ 15H-SPIRO[l 0,20- DIOXA-13-TfflA-l, 14-DIAZATETRACYCLO[ 14.7.2.0 - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA- 16, 18,24-TRIENE-22, 1 '-NAPHTHALENJ-15-ONE 13, 13-DIOXIDE

4-Dimethylaminopyridine (DMAP) (0.073 g, 0.598 mmol) was added to a solution of (i 'S)-6'-chloro-5-(((7 2R)-2-((lS)- 1 -hydroxy-3-(2- sulfamoylpropoxy)propyl)cyclobutyl)metiiyl)-3',4,4',5-tetrah ydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 861 , Step 7; 0.033 g, 0.054 mmol) in DCM (100 mL). It was cooled by ice bath. EDC

(0.063 g, 0.326 mmol) was added and it was stirred at 0°C to rt for 3 days. It was concentrated and the residue was purified by SFC (Method: 250 x 21.2 mm 1C-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/rain CO2 on a Thar 80 SFC. Outlei pressure 100 bar; Temp. 20 °C; Wavelengih 220 nm). The title compoimd was obtained as a single isomer (2.4 nig, first eluting peak) as a white solid. ^! H N .V1 R (500 MHz, CD2CI2) δ 7.71 (m, i l l s. 7.30 (m, 1 1 1 ). 7.19-7.04 (m, 3H), 6.95 (m, 1H), 4.19 (m, 1 H), 4.1 1 (m, 1H), 3.95 (br. s., 1H), 3.87-3.72 (m, 3H), 3.65- 3.48 (m, 3H), 3.37 (d, J=16.87 Hz, 2H), 2,99-2.87 (m, 2.83-2.69 (m, 2H), 2.16-2.06 (m, 1 1 1 ). 2.01-1.48 (m, 1 1H), 1.45- 1.38 (m, 3H). m/z (ESI, +ve ion) 589.2 ( \! I I ) . EXAMPLE 862. {311 11 7 ?, i2S',225)-6'-CHLORO-7-HYDROXY-12-METHYL- 3 ^! ,4 '-DIHYDRO-2'H, 15H-SPIRO [ 10,20-DIOXA- 13-THIA- 1 , 14- DIAZATETRACYCLO[14;7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA~16,18,24-TRlE E-22,r- NAPHTHALEN] - 15-ONE 13,13-DIOXIDE OR (3R, 6R, 7S, 12S, 22S -&- CHLORO-7-HYDROXY-l 2-METHYL-3',4'-DIHYDRO-2'H,15H-SPIRO[l 0,20- DIOXA-13-THIA-1, 14-DIAZATOTRACYCLO[14 .2.0 -^0 ¹⁹ ' ²⁴ ]PENTACOSA- 16, 18,24-TRIENE-22, 1 '-NAPHTHALENJ-l 5-ONE 13, 13-DIOXIDE

The title compound (4.2 nig) was obtained as a single isomer (second eluting pealv) from the reverse phase preparative HPLC in Example 861. ¾ NMR (500 MHz, CD ₂ C] ₂ ) δ 7.72 (d, 7.83 Hz, 1H), 7.43 (d, ./ 7.09 Hz, 1H), 7, 17 (br. s., 2H), 7.09 (br. s. , IH), 6,92-6.99 (m, I H i,. 4.07-4, 14 (m, 3H), 3.89 (br, s,, 2H), 3.83-3.75 (m, 3H), 3.70-3.58 (m, 3H), 3.26-3.07 (m, 2H), 2.76 (br. s., 3H), 2.41 (br. s„ 11 1 ). 2, 1 1 -1.08 (m, 13H). m/z (ESI, +ve ion) 589.2 (M+H) ⁺ .

EXAMPLE 863. (3R, 6R, 7R, 1 IE, 225 6'-CHLQRQ-7-HYDRQXY-3 ^! ,4'- DIHYDRO-2'H,15H-SPIRO[9,20-DIOXA-13-THIA-1,14-

DI AZATETRACYCLO[ 14.7.2.0 ³ ' ⁶ .0 ¹⁹ · ²⁴ ]ΡΕΝΤ ACOSA-1 1, 16,! 8,24- TETRAENE-22, 1 '-NAPHTH ALEN] -15-ONE 13,13-DIOXIDE OR (SR,.6R, 7S, 1 IE, 225)-6 ^f -CHLORO-7-HYD OXY-3',4'-DIHYD O-2'H, 1

SPIRO [9,20-DIOXA- 13-THIA- 1 , 14-

DL ZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA~11,16,18,24- TETRAENE-22,l'-NAPHTHALEN]-15-ONE 13,13-DIOXIDE

Step 1: (SJ-TERT-BUTYL 6'-CHLORO-5-(((ii? _; 2S 2-

\ !NV!.( V( i ()!¾!. !Ύ!.}\Π·. Π 1 Υ!.)-3'.4.·Γ.5- Π·.1 R.\HYi)R()-2l 1.2 i !-

SP1RO [BENZO [B] [ 1 ,4] OXAZEP1NE-3, 1 '-NAPHTHALENE] -7-

CARBOXYLATE

«-Butyl lithium (2.5 M solution in hexane; 2.0 mL, 4.94 mmol) was added to a solution of methyltriphenylphosphonium bromide (2.02 g, 5.64 mmol) in THF (25 mL) at 0 °C, which was degassed by nitrogen. The reaction mixture was stirred at 0 °C for 10 min, becoming a yellow solution. The resulting solution (0.9 mL is enough) was added dropwise to a solution of (5)-tert-butyl 6'-chloro-5- (((i/i2^)-2 omiylcyclobut> )methyl)-3^4,4 ^, ,5 etraliyd

spiro[benzo[b][l,4]oxazepine-3,l'-naphthalene]-7-carboxyl ate (Intermediate AA11A, Step 20B; 0.700 g, 1.41 mmol) in THF (23.5 ml.) at 0 °C, which was degassed until the yellow color persisted. It was poured slowly to ice water (15 mL), extracted with EtOAc (200 mL). The organic phase was washed with brine (2 mL) and dried over anhydrous sodmm sulfate and concentrated. The residue was loaded to a 80g ISCO Gold column and eluted with 0% to 3% EtOAc/hexane to provide the title compound (617 mg) as a white solid, m/z (ESI, +ve ion) 494.2 ( M i l ) .

Step 2; (SJ-TERT-BUTYL 6'-CHLORO-5-(((i ?,2 ?j-2-f(K)-l ,2- DIHYDROXYETHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2H,2'H-SPlRO[BENZO[B][l,4]OXAZEPlNE-3,r~NAPHTHALENE]~7" CARBOXYLATE OR (S)-TERT-BUTYL e^CHLORO-SHii/ i^ ii^- ^)-!^- DIHYDROXYETOYL)CYCLOBU L)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2 ^" H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE

4-Methylmorpholine N-oxide (0.294 g, 2.51 mmol) was added to a solution of (S)-tert-buty\ 6'-chloro-5-(((/i?,2<S)-2-vinylcyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4] oxazepine-3, l'-naphthalene]-7- carbox late (Example 863, Step 1 ; 0.540 g, 1.09 mmol) in acetone (27 mL), THF (27 mL) and water (0.2 mL). After the reaction mixture was degassed with nitrogen, osmium tetroxide, (2.5 wt % solution in 2-methyl-2-propanol (1. 1 mL, 0.11 mmol) was added dropwise and it was stirred at rt for 2.5 h. A solution of sodium thiosulfate (1.0 M aqueous solution, 3 mL) was added and stirred at rt for 20 rain. It was concentrated extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 220 g ISCO Gold column and eluted with 0% to 10% EtOAc/DCM. The title compound (288 mg) was obtained as a single isomer (first eluting peak), m/z (ESI, +ve ion) 528.1 (M+H) ⁺ . Step 3 : (SJ-TERT-EUTYL 5 ~(((1R 2R)-2-((R)-2-(ALLYLOXY)- 1 -

HYDROXYETim CYCLOBUTYL)METHYL)-6'-CHLORO-3',4,4 ^f ,5- TETRAHYDRO-2H,2 Ή-SPIRO [BENZO [B] [ 1 ,4]OXAZEPINE~3, 1 ^* - NAPHTHALENE] -7-CARBQXYLATE OR (S)-TERT-BUTYL 5-(((ϋ<2^ ·2- ^-2-(ALLYLOXY)-lHYDROXYETHYL)CYCLOBUTYL)METHYL)-6 ^f - CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][l ,4]

OXAZEPiNE~3, ~NAPHTHALENE]-7~CARBOXYLATE

Sodium hydride (60% dispersion in mineral oil; 22 mg, 1.06 mmol) was added to a solution of (S)-tert-butyl 6 ^! ~chloro~5~(((ii?,2ft)-2~((i?)-l,2~

dihydroxyethyl)cyclobutyl)me1hyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiroj benzoj bj [ l,4 |oxazepine-3, -naphthalene]-7-carboxylate (Example 863, Step 2; 0.28 g, 0.53 mmol) in DMF (15.6 mL). It was stirred at 0°C for 20 rain. AIM iodide (0.068 mL, 0.742 mmol) in DMF (0.8mL) was added and it was stirred at 0°C to rt for 19 h. It was quenched with water (2 mL) and extracted with EtOAc (200 mL). The organic phase was washed with brine, and dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 40g ISCO Gold column and eluted with 0% to 20% EtOAc/hexane to provide the title compound (115 mg) as a film, m/z (ESI, +ve ion) 568.3 (M+H) ⁺ . Step 4: (S)-6'-CHLORO-5-(((7R, 2^ 2-ffK)-l-HYDROXY-2-(((£)-3- SULFAMOYLALLYL)OXY)ETHYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [l ,4 jOXAZEPFNE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((lR,2R)-2- ((S 1 -HYDRO Y- 2-(((E)-3 -

8υίΡΑΜΟΥίΑΕΕΥΕ)ΟΧΥ)ΕΊΉΥί)εΥ€ ΟΒυΊΥΧ)ΜΕΊΉΥί)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID

A flask was charged with (S)-tert-butyl 54i(JR,2R}-2-{{R)-2-(&lly\oxy)-} - hydrox ethyl) cyclobuty'l)methyl)-6'-chloro-3V4,4',5~tetrahydro~2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 863, Step 3; 0,025 g, 0.044 ramol) and N,N-bis(4-methoxybenz>'l)eihenesiilfonamide (Example 831 , Step 2; 0.138 g, 0.396 mmol) in 1,2-Dichloroethane (1.5 mL). It was stirred at rt for 10 mm to dissolve the solid starting material and then degassed with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (7.5 mg, 8.8 μι ^η οΐ) in dichloroethane (0.5 mL) and it was stirred at 60 °C for 80 mm. It was concentrated, dissolved in 1 :3 TF A/DCM (0.4 mL) and stirred at rt for 19 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini ^lM Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (35 mg) as a film, m/z (ESI, +ve ion) 591.1 (M+H) ⁺ .

Step 5 : (3R 6R, 7R, 1 IE, 22Δ> 6'-CHL()RO-7-H YDR()XY-3^4 ^* -DIH YDRO- 2Ή, 15H-SPIRO [9,20-DIOXA- 13 -THI A - 1 ,14-

DL ZATETRACYCLO[14,7.2.0 ³ '^0 ¹⁹ - ²⁴ ]PENTACOSA-11, 16,18,24- TETRAENE-22, -NAPHTHALEN]-l 5-QNE 13,13-DIOXIDE OR

(3R, 6R, 7S, HE, 225 6 ^* -CHLORO-7-HYDROXY-3^4'-DIHYDRO-2'H, 15H- SPTRO[9,20-DIOXA- 13-THTA- 1,14-

DiAZATETRACYCLO[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA-l 1,16,18,24- TETRAENE-22, 1 '-NAPHTHALEN] -15-ONE 13,13-DIOXIDE

4-Dimethylaminopyridine (DMAP) (0.062 g, 0.51 mmol) was added to a solution of (S)-6'-chloro-5-(((H?, 2R)~2~((R)- 1 -hydroxy-2-(((E)-3- sulfamoylallyl)ox\ ethyl)cyclobut 'l)me1hyl)-3^4,4^5-tetrahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (Example 863, Step 4; 0.030 g, 0.051 mmol) in DCM (102 mL), which was cooled by ice bath. EDC (0.068 g, 0.355 mmol) was added slowly and it was stirred at 0°C to rt for 22 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (13.5 mg) as a white solid. Ή NMR (400 MHz, CD2CI2) δ 8.58-8.45 (m, IH), 7,69 (m, IH), 7.17 (m, 2H), 7.09 id. J=2.35 Hz, ill).6,98 (m, Hi).6.9! (m, ill).6.73 (d,

J=15.06 Hz, III).4,45 id. J=18.39 Hz, 4.16-4.05 ira 3H), 3.82-3,68 (m, 2H), 3.62 (d, J=13,89 Hz, 1H), 3.44 (m, ill).3.34 Cm. lH), 3.24 (m, 1H), 3.13 (dd, ./ N.SO.14.67 Hz, 1H), 2.71-2.81 (m, 2H), 2.44-2.33 (m, 2H), 2.29-1.55 (m, 9H), 1 ,52- 1.42 (m, 1 H). m/z (ESI, + ve ion) 573, 1 i \\ U) .

EXAMPLE 865. (S)-6'-CHLORO-5-(((7R,25)-2-(2-

HYDROXYETHYL)CYCLOBUTYL)METHYL)-N-(METHYLSULFONYL)- 3',4,4',5-TETRAHYDRO-2H,2 ^" H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3,l '- NAPHTHALENE j -7 -C ARB OXAMI D E

Step 1 : {.S ^' i-VILT! !YI.6'-CHLORO-5-(((iA ⁵ , /i- f2 -2-

METHOXYVTNYT.)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

CARBOXYLATE

A solution of bromo(methoxymethyl)triphenylphosphorane (3.37 g, 8.70 mmol) in THF (22 mL) was cooled to 0 °C. /2-Butyl lithium (2.5 M solution in hexane; 2.78 mL, 6.96 mmol) was added dropwise and it was stirred at 0 °C for 17 min, which was yellow solution. This solution was added slowly to a solution of (5)-methyi 6'-chloro-5-(((/#2i?)-2-fon^

2H,2 ^, H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carb oxylate

(Intermediate AA1 1A, Step 20A; 0.395 g, 0.87 mmol) in THF (5 mL) until the yellow color persisted and it was stirred at 0 °C for 5 min. The reaction mixrure was poured slowly to ice-water (15 ml,). It was extracted with EtOAc (200 mL) and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 4g IS CO Gold column and eluted with 0% to 10% EtOAc/hexane to provide the title compound (74 mg) as a white solid, m z (ESI, +ve ion) 482.3 (M+H) ⁴ .

Step 2: (S)-METHYL 6'-CHLORO-5-(((H?, 25)-2-(2-

OXOETHYL)CYCLOBUTYL)METHYL)-3',4,4', 5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE

1 N HC1 solution (0.5 ml.) was added to a solution of a mixture of (S)- methyl 6'-chloro-5-(((ii¾ 2i?)-2-((E)-2-me1hox\'vinyl)cyclobut 'l)methyl)-3',4,4 ^, ,5- tetrahydro-2H,2'H-spiro[benzo [b] [l,4]oxazepine-3,r-naphmalene]-7-carboxylate

(Example 865, Step 1 ; 0.034 g, 0.071 mmol) in acetone (1.8 mL.). It was stirred at it for 18 h. After it was concentrated, the residue was neutralized with NaHC0 ₃ solution and extracted with EtOAc (80 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to provide the title compound (33 mg) as a white solid, m/z (ESI, +ve ion) 468.2 (M+H) ¹ . Step 3: (S)-METHYL 6'-CHLORO-5-(((7R, 25 -2-(2-

HYDROXYETHYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2H,2 ^" H-SPIRO[BENZO[B][l,4]OXAZEPINE-3;r-NAPHTHALENE]-7- CARBOXYLATE

Sodium borohydrate (powder, reagent grade 98%; 6.8 mg, 0.194 mmol) was added to a solution of (S)-methyl 6'-chloro-5-(((/i?,2S)-2-(2- oxoethyl)c>'clobu1yl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (Example 865, Step 2; 0.013 g, 0.028 mmol) in MeOH (0.9 mL). It was stirred at rt for 30 min. After concentration the residue was diluted with EtOAc (60 mL). The organic phase was washed w ith \r CO solution and brine, dried over anhydrous sodium sulfate. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title product (23 mg) as a white solid, m/z (ESI, +ve ion) 470.1 ( M i ! ) .

Step 4: (S)~6'~CHLORO-5~(((]R,2S)-2-(2-

HYDROXYEIHYL)CYCLOBUTYL)METHYL)~3',4,4',5-TETl AHYDRO- 2H,2Ti-SPIRO[BENZO[B][ I ,4]OXAZEPINE-3, l'-NAPI-ITHALENE]-7- CARBOXYLIC ACID

Lithium hydroxide (1 M aqueous solution, 0.5 mL, 0.5 mmol) was added to a solution of (<S')-methyl 6'-chioro-5-(((iii2S>2-(2- hydroxyethyl)cyclobutyl)methyl)-3',4,4',5-tetfahydro-2H,2'H- spiro[benzo[b][l,4]oxazeprae-3,l'-naphthalene]-7-carboxylate (Exaraple 865, Step 3; 0,023 g, 0.049 mmol) in THE (1 mL) and MeOH (0.5 mL). After it was stirred at 50 °C for 2.6 h, it was concentrated, acidified with 1 N HCl solution to pH 2-3, diluted with EtOAc (80 mL), washed with brine, and dried over anhydrous sodium sulfate. The solution was concentrated to provide the title compound (22 mg) as a white solid, m/z (ESI, +ve ion) 456.3 (M+H) .

Step 5; (5)-6'-CHLORO-5-(((7R,25)-2-(2-

! ί V D R ί ) X Y ί · T Π Y I . K C I . ϋ B 1 1 V L).\H ! HY I . )-\-i Ml . Π i V LS l 1 ! ( ⁾ \Y! .}- 4.4 ·· ^· iΊ Π·RΛ! !Y DRO-21 L2 ^" ! ! -SPi R()| BHNZOI B l 1 1 ,4] OXAZEPINE-3,1 '- NAPHTHALENE! -7 -C ARB OXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (5.8 mg, 0.047 mmol) was added to a solution of (<S -6'-chloro-5-(((7/?,25)-2-(2-hydrox 'e1hyl)cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'Hspiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carbox lic acid (Example 865, Step 4; 0.012 g, 0.026 mmol) and

methanesulfonamide (0.013 g, 0, 132 mmol) in DCM ( ! mL) at 0°C (ice bath). Then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (9 mg, 0,047 mmol) was added portion by portion slowly and it was stirred at rt for 20 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep C J S 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient eiution) to give the title product (55 nig) as a white solid. Ή NMR (400 MHz, CD2CI2) δ 9.89-9.74 (m, IH), 7.73 (m, I H), 7,35-7.25 (m, 2H), 7.18 (ra, IH), 6,95 (m, IH), 4.11 (m, 2H), 3.90 (d, ,/ 14.87 Hz, 2H), 3,69 id,, «7=14.09 Hz, 2H), 3.37 (m, 3H), 3.31 (d, ,7=14,28 Hz, IH), 3.09 (dd, J=8.90, 14.97 Hz, 4H), 2.84-2.73 (m, 2H), 2.48-2.37 (m, IH), 2.18-1.50 (m, 8H), 1.44 (t, J=11.93 Hz, IH). m/z (ESI, +ve ion) 533.2 (M+H) ⁺ .

EXAMPLE 866. (3R 6R, 75',2i _i S)-6'-CHLORO-7-HYDROXY-3',4'-DlHYDRO- 2Ή, 14H-S PIRO [9, 19-DI OXA- 12-THI A- 1 , 13 -

DIAZATETRACYCLO[ 13 ,7.2,0 - ⁶ .0 ¹⁸ - ²³ ]TETRACOSA- 15, 17,23-TRIENE-21 , 1 ^* - N APHTHALEN] - 14-ONE 12,12-DIOX.!DE OR (3R 6R, ^' Ή .? ί )-(^{Ί \ > ORO-l- HYDROXY-3',4'-DIHYDRO-2'H,14H-SPIRO[9,19-DIOXA-12-THIA-l,13- DIAZATETRACYCL()[13.7.2.() ³ >^() ^{i S} ' ²³ |TETRACOSA-15,17,23-TRIENE-21, l'- N APHTHALEN] - 14-ONE 12,12-DIOXIDE

Step l : (Λ)- //· Κ7 ^' -ΙΪΙ.ΊΎ Ι . 6-CHLORO-5-(((lR,2Ii)-2-((R)-l,2- DIHYDROXYETOYL)CYCLO-BUTYL)METOYL)-3',4,4',5-TETRAHYDRO- 2Η,2Ή-8Ρ¾0|;ΒΕΝΖΟ[Β| [ 1,4]ΟΧΑΖΕΡΙΝΕ-3,1·-ΝΑΡΉ-ΙΑίΕΝΕ]-7- C ARBOXYL ATE OR (5)-TERT-BUTYL 6'-CHLORO-5-(((iR, 2R)-2-((S)- 1 ,2- DIHYDROXYETHY^CYCLOBUTY^METHYLVS'^^'^-TETRAHYDRO- 2H 2!-i-SPIRO[BENZO[B] [I ,4]OXAZEPINE-3,r-NAPI-ITHALENE]-7- CARBOXYLATE

The title compound (289 mg) was obtained as a single isomer (second elutmg peak) from the reverse phase preparative HPLC in Example 863, Step 2. m/z (ESI, +ve ion) 528.1 { \ I · Π } Step 2: (S)-6'-CHLORO-5-(((lR, 2R)-2-((S)A -HYDROXY-2-(2-

SULFA OYLETHOXY)ETHYL)CYCLOBUT L) METHYL)-3 ^, ,4,4',5-

TETRAHYDRO-2H,2'H-SPIRO [BENZO | B] [ 1 ,4] OXAZEPINE-3 , Γ- NAPHTHALENE]~7-C ARBOXYLIC ACID OR (»S)-6'-CHLORO-5(((H?, 2RJ-2- ( (R)-l -HYDROXY -2-(2-SULFAMOYLETHOXY)ETHYL)

CYCLOBUTYL)METl-iYL)-3',4,4',5-TETRAJiYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

To a solution of (S)-tert-butyl 6'-chioro-5-(((i/i2^>-2-ff¾)-l,2- dihydroxye 4)cyclobut}4)methyl)-3',4,4',5-teirahydro-2I-i,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late (Example 866, Step 1 ; 0.020 g, 0,038 mmol) in THF (0.95 mL) at 0°C was added sodium hydride (57- 63% oil dispersion; 2.8 nig, 0.133 mmol) and it was stirred at 0°C for 19 mm, and N,N-bis(4-methoxybenzyl)ethenesulfonamide (Example 831, Step 2; 0.020 g, 0.057 mmol) in THF (0.5 mL) was added. After it was stirred at 0°C to rt for 2.7 h, the mixture was concentrated and added 4-methylanisole (100 nig) and cooled by ice bath. 1 :3 TFA/DCM (3 mL) was added and it was stirred at 0°C to rt for 19 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini ^IM Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1 % TF A, gradient eluti on) to give the title product (9 mg) as a film, m/z (ESI, +ve ion) 579. 1 ( W W ) .

Step 3: (3R, 6¾ 7S', 2iS)-6 ^, -CHLORO-7-HYDROXY-3 ^, ,4 ^, -DIHYDRO-2U14H- SPIRO[9, 19-DIOXA - 12-THIA- 1 , 13- DIAZATETRACYCLO[13.7.2.0 ³ ' ⁶ .0 ¹⁸ ' ²³ ]TETRACOSA-15,17,23-TRIENE-21,r- APHTHALEN] - 14-ONE 12,12-DIOXIDE OR (3R, 6R, 7R,2 S)-6'-CHLORO-7-

HYDROXY-3',4'-DIHYDRO-2'H,14H-SPIRO[9, 19-DIOXA-12-THIA-l, 13- DIAZATETRA CYCLO[13,7.2.0 ³ - ⁶ .0 ^1S - ²³ ]TETRACOSA-I5, I 7,23-TRIENE- 21, 1' -N APHTH ALEN ] - 14-ONE 12,12-DIOX1DE

4-Dimethyiaminopyridine (DMAP) (0.019 g, 0.155 mmol) was added to a solution of (5)-6'-chloro-5-(((H?,2R -2-^S)-l -hydroxy-2-(2- sulfamoylemoxy)e l)cA ]obuty])methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, r-naphthalene]-7-carboxylic acid (Example 866, Step 2; 0.009 g, 0,016 mraol) in DCM (31 rnL) which was cooled by ice bath.

EDC (0.021 g, 0, 109 mmol) was added slowly and it was stirred at 0°C to rt overnight. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0, 1% TFA, gradient elution) to give the title product (3.8 mg) as a film. 'HNMR (400 MHz, CD2CI2) δ 7.73 ins. IH), 7.26 (m, ill).7.18 (m, 1H), 7,13 (m, IH), 7.09 (m, IH), 6.97 (ra, 1H), 4,70 (m, IH), 4.12 (m, 2H), 4.07 (m, IH), 3,99-3,77 (m, 3H), 3.49-3.37 (m, 2H), 3,35-3.16 (m, 31!).3.06 (dd, ./ 6.1 .15.55 Hz, IH), 2.82-2.74 (m, 2H), 2.64 (dd, J=7.53, 16.73 Hz, IH), 2.46 (br. s., IH), 2.18-1.53 (m, 8H), 1.47-1.37 (m, IH). m/z (ESI, +ve ion) 561.2 {M il}

EXAMPLE 867. (lS 6'S,8'S 6-C LORO-S'-HYDROXY-3,4-OJHYDRO- 2H, 15'H-SPIRO[NAPHTHALENE-1,22'- 201 OXA[ 13]

THL [1,14]DIAZATETRACYCLO[14,7.2.0 ³ - ⁶ ,0 ¹⁹ ' ²⁴ ]

PENTACOSA[16,18,24]TRIEN]-I5'-O E 13',13'-DIOXIDE OR (1S,3'R6'S,8'R)- 6-CHLORO-8 ^! -HYDROXY-3,4-DIHYDRO-2H, 15 Ή- SPI RO [ N APHTH ALENE- 1,22'-[20]OXA[13]

TfflA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ ' ²⁴ ]PENTACOSA[16,18,24]TR IEN]-15'-ONE 13',13'-DIOXIDE

A mixture of (IS, 3 % 6'S, 8 % 9 'E)-6-chloro-8'-hy droxy-3,4-dihy dro- 2H,15'H-spiro [naphthalene- l,22'[20]oxa[13]thia[l,14]diazaietracyclo[14,7.2,0 ³ -^0 ¹⁹ - ²⁴ ]pentacosa[9,16,I8 etraen]-15'-one 13',13'-dioxide (Example 884: 0,004 g, 7.00 μηιοΐ) and platinum (IV) oxide (1.6 mg, 7.0 μτηοί) in EtOAc (7 mL) was stirred under ¾ at rt for 46 min. It was filtered through syringe filter to remove solid catalyst. The filtrate was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title product (2 mg) as a white solid. ¾ NMR (500 MHz, CD2CI2) δ 8.26 (br. s., IH), 7.73 (m, ! ! ! ). 7.18 (dd,■/ 2.20. 8.56 Hz, IH), 7.09 (d, ,/ 2.45 Hz, IH), 7.0 ! (m, 2H), 6.93 (ra, IH), 4,09 (m, 2H), 3.86-3.69 (m, il l ). 3,46-3.35 (m, 2H), 3.23 (d, .7=14, 18 Hz, IH), 3. 12-3,04 (m, IH), 3.02-2.90 (m, IH), 2.81-2.71 (m, 3H), 2.67-1.25 (m, 16H). m/z (ESI, +ve ion) 573,2 (M+H) ⁺ .

EXAMPLE 870. (3R 6R 7R,22-S ¹ )-6 ^, -CHLORO-7-HYDROXY-3 ^, ,4 ^, -DIHYDRO- 2Ή, 15H-SPIRO [9,20-DIOXA- 13-ΤΉΙΑ-1 , 14-

DIAZATETRACYCLOIM-T^-O^^O^^lPENTACOSA-l^lS^-TRIENE^l'- N APHTHALEN] -15 -ONE 13,13-DIOXIDE OR (3R, 6R, 7S,22S & -CHLQRO-7- HYDROXY-3',4'-DIHYDRO-2'H, 15H-SPIRO j 9,20-DIOXA- 13-THI A- 1 , 14- DIAZATET A-CYCLO[14.7.2.0 ³ '6 0 ¹⁹ ^ ]PENTACOSA-16,18,24-T ffiNE- 22, Γ-ΝΑΡΗΤΗ ALEN] - 15-ONE 13, 13-DIOXIDE

Platinum (IV) oxide (0,24 mg, 1.05 μιηοΐ) was added to a solution of Example 863 (0.003 g, 5.2 μηιοΐ) in EtOAc (1 mL). It was stirred under H ₂ atmosphere for 2 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Ci8 5um column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title product (2,2 mg) as a film. Ή NMR (500 MHz, CD2CI2) δ 7.67 (m, 1H), 7.44 (br. s„ IH), 7.33 (br. s,, 1H), 7.15 (dd, J=2.20, 8,56 Hz, IH), 7.09 (d, .7=2.20 Hz, IH), 6.96 (d, J=8.07 Hz, IH), 4.26-4.13 (m, 2H), 3.84 (m, IH), 3.80-3.64- (m, M l ). 3.55 (br. s., 3H), 3.42-3.35 (m, IH), 3.28 (dd, ./ 2.45. 9.54 Hz, I H), 2.80- 2,71 (m, 2H), 2.41-1 .20 (m, 1 ! ! } m/z (ESI, +ve ion) 575, 1 (M+H) ⁺ .

EXAMPLE 872. (IS, 3 % 6'R 8 % 12 'R)-6-CHLORO- 12'-ETHYL-7'- METHYLIDENE-3,4-DIHYDRO-2H,15Ti-SPIRO|NAPHTHALENE-l ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-D10XlDE

At 0°C, μ-οΚ1θΓθ[(1ί(θ} ⁷ ο1ορ6ηία-2,4-άίθη-1-}'1)]άίΓη6^1(μ- methylene)titaniumaluminum (Tebbe's reagent, 0.5 M solution in toluene; ! .9 mL, 0.97 mmol) was added to a solution of Example 915 (0.058 g, 0.097 mmol) in THF (2.4 mL). It was stirred at 0°C for 10 min. It was poured into ice water (lOmL), acidified with I N HC1 solution to pH 2-4, extracted with EtOAc (2x110 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. After concentration the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μπι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title product (19 mg) as a white solid. ^! H NMR (500 MHz, CD2CI2) δ 7.99-8.05 (m, IH), 7.73 (m, IH), 7.27 (m, IH), 7, 19 (m, IH), 7.11 (m, IH), 6.83 (ra, IH), 6,79 (m, IH), 5.96 (m, I H), 5.87-5.79 (m, IH), 4,74 (s, IH), 4,67 (s, IH), 4, 11-4.01 (m, 2H), 3.94-3,86 (m, 2H), 3.73 (d,J=14,18Hz, IH), 3.27 id../ 14.18!!./ IH), 3.11 (m, IH), 3,03 (dd,

4.77.15.53 Hz, IH), 2.84-2.73 (m, 2H), 2.25-2,15 (m, IH), 2.12-1.49 (m, 13H), 1.39 (t ./ 1.2.96 Hz, IH), 1.24-1.14 (m, 3H). m/z (ESI, +ve ion) 595.1 {M l!)

EXAMPLE 876, (IS, 3 R, 6'R, 7'R, 9'R, II 'i?)-6-CHLORO-9'-METHYL-3,4- D1HYDRO-2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

1.12.221 ^' t ^' RIOXAj Ι5| ^' Π Ι!Λ| 5.1 ίί)ΙΛΖΛΡΙ: I Λ(ΎΠ.()| 16.72.Γ".0 ^! " 0 ^''! '| OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7'R, 9 'S, 11 'R)-6-CHLORO-9'-METHYL-3 ,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THIA[l,i6]DIA APENTACYCIi3[16,7.2,l ⁷ - ³ ^0 ³ ' ⁶ .0 ²¹ - ² ^

QCTACQSA[18,20,26]TRIEN]-17'-QNE 15 ',15 '-DIOXIDE OR

(IS, 3 R, 6'R, 7'S, 9 R, 11 'R)-6-CHLORO-9'-METHYL-3 ,4-DIHYDRO-2H, 17 Ή- SPTRO[NAPHTH ALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOS A[ 18,20,26]TRIEN]- 17'-ONE 15', 15'-DIOXIDE OR

(IS 'R 6'R, 7'S9'S 11 'R)-6-CHLORO-9'-METHYL-3,4-DIHYDRO-2H.17Ή- SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]THIA[1,16]DIAZAPENTACYCLO[16,7.2.1 ⁷ - ¹ ^0^ ⁶ .0 ²¹ - ²⁶ ] OCTAC()SA[18,2Q,26jTRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6'R 7' 9 R, 11 '5)-6-CHLORO-9'-METOYL-3,4-DiHYDRO-2H, 17Ή- SPIRO[N APHTHALENE- 1 ,24'-

[8,12,22]TllOXA[15]THIA[l,16]DlAZAl ⁵ ENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ² ^ OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

( IS, 3'R 6R,7'S 9'S 11 '^-e-CHLO O-g'-METOYL-S^-DIHYDRO^ILnT-i- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2.i ⁷ - ¹ ^() ³ - ⁶ .0 ^2! - ²⁶ ] OCTACOSAjl 8,2Q,26]TRIEN]-I7'~ONE 15',15'-DIOXIDE OR

(IS, 3 R, 6'R, 7'S, 9 R, 11 ¾)-6-CHLORO-9 ^* -METH YL-3 ,4-DIHY DRO-2H, 17Ή- SPIRO[N APHTHALENE-1 ,24'- |8.i2.22|TRiOXA] Ι5| ^' Π Ι!Λ| 1.IGjDlA/APK.Yl Λί ^' Υί 1.0| 16.72.Γ".0 ^! " 0 ^''! '| OCTACOS A[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 'R, 6 'R, 7'R, 9 'S, 11 ¾)-6-CHLQRQ-9'-METH YL-3 ,4-DIHY DRQ-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 ,24'- [δ,Ι^ΙΤΊυθΧΑΙΙΰΙΤΉΙΑίΙ,ΙόΙΟΙΑΖΑΡ Ε^ΑΟΥΟίΟίΙό.Τ^.Ι ⁷ - ¹¹ ^ ³ · ⁶ .^ ¹ · ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

Step 1 : (iS)-METHYL

METOYLTETRA-HYDRO-2I-I-PYRAN-2-YL)CYCLOBUTYL)METI-IYL)- 3^4 ₅ 4^5-TETUAHYDRO-2H,2¾-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE OR { Λ ^' )-Μ ΓΝ IY I . 6'-CHLORO-5- (((/¾ 2R)-2-((2S,.4S, 5S)-4-HYDROXY-6-METHYLTETRA-HYDRO-2H- PYRAN-2-YL)CYCLOBUTYL)ME ^r THYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (,S> METHYL 6'-CHLORO-5-(((7A ⁵ , 2R)-2-((2R, 4S, <JR)-4- HYDROXY-6-METHYLTETRA-HYDRO-2H-PYRAN-2- YL)CYCL0BU1YL)METHYL)-3V4 1',5-TETRAHYDR0-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR -METHYL 6'~CHLORO-5-(((lR R)-2-{(2R, 4S, 6S)~4~ HYDROXY-6-METHYLTETRA-HYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3 ^, _: ,4 ₅ 4 ^, _s 5-TETRAHYDRO-2H ₅ 2'H- SPIRO| BENZO[B] |;L4 iOXAZEPINE-3, l '-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6' J1L0R0-5-(((1R, 2R)-2-((2R 4R 6R)-4- HYDROXY-6-METHYLTETRA-HYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL (V-C! Π .ΟΚΟ- -ίί ί // .2R)-2-((2S, 4R, 6S')-4- HYDROXY-6-METHYLTETRA-HYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [l ,4]OXAZEPINE-3, l '-NAPHTHALENE]-7-

CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((/R, 2R)~2-((2R, 4S, 6R)-4-

2,001 HYDROXY-6-METHYLTETRA-fTYDRO-2H-PYRAN-2-YL)CYCXOBUTYL)

METHYL)-3' ₅ 4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6'-C LORO-5-(((lR,2Ii)-2-((2R, 4R, 6S)-4- HYDROXY-6-METHYLTETRA-HYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE

A mixture of (S)-methyl 6'-chloro-5 -(((!R, 2R)-2-

spiroj benzoj b] [ 1 ,4] oxazepiiie-3, 1 '-naphthalene] -7-carboxylate (Intermediate AA11A, Step 20A; 0.190 g, 0.419 mmol) and 4-penten-2-ol (0.047 mL, 0.54 mmol) in TFA (1.7 mL) and DCM (3.5 mL) was degassed with N ₂ and stirred at rt for 1 h. It was quenched with NaHCG ₃ solution and extracted with EtOAc (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 12g IS CO Gold column and eluted with 0% to 10% (EtOAc/hexane) to provide the title (124 mg) as a film. The film was stirred with saturated Na ₂ C0 ₃ solution (lmL)/MeOH (2 mL) and THF (2mL) at rt for 50 min. It was extracted with EtOAc (100 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 4g ISCO Gold column and eluted with 0% to 40%

(EtOAc/hexane) to provide the title compound (86 mg) as a white solid, m/z (ESI, +ve ion) 540.1 { Y! H } Step 2: (S)-6'-CHLORO-5-(((/R, 2R)-2-((2S, 4R, fiR)-6-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B][ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLI C ACID OR (S)-6'-CHLORO-5-(((/R, 2R)-2-((2R, 4S) 6 ^' 5)-6-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-((( R,2R -2-^2R, 4R, 6i? 6-METHYL-4-(2- S ULF AMOYLETHOXY ^' )TETRAH YDRO-2H-P YRAN -2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((7R, 2R)-2-((2R, 4S, <5i?)-6-METHYL-4-(2- SULF AMOYLETHOXY) TETRAHYDRO-2H-PYRAN-2- YL)CY ^T CLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (5)-6'-CHLORO-5-(((H¾,2R; -2-^25; 4R, 65)-6-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-L2 ^, H- SPi Oi Bi ^; N/C)l P || i .4 K>X AZ!- Pi \ ! -3.1 '-N M ! i 1 L\l J Xi : i~7~C \RB( ⁾ XY E ACID OR (S 6'-CHLQRG-5-(((lR,2R)-2-((2Il 4S, <5S)-6-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (,S 6'-CHLORO-5-((f A ⁵ , 2R)-2-((2R, 4R 6S)-6-METHYL-4-(2- SULF AMOYLETHOXY) TETRAHYDRO-2H-PYRAN-2- YL)C^XLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H ₅ 2'H- SPlRO[BENZO[B][l,4]OXAZEPlNE-3,l'-NAPHTHALENE]-7-C ARBOXYLIC ACID OR (S)-G-CHLORO-5-{{{lR,2R)-2-((2S, 4S, <JR)-6-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

At 0 °C, sodium hydride (60% dispersion in mineral oil; 14 mg, 0,650 mmol) was added to a solution of (1 ¾)-methy 1 6'-chloro-5 -(((Hi, 2R) -2-((2S, i?)-4- hydrox\'-6-methyl-tetrahydro-2H-pyran-2-yl)cyclobutyl)methyl )-3',4,4 ^, ,5- tetrahydro-2H,2'H-spiro[benzo[b] [l,4] oxazepine-3,l'-naphthalene]-7-carboxylate

( Step 1; 0,090 g, 0.167 mmol) in THF (6 mL). It was stirred at rl for 10 min.

Then N,N-bis(4-methoxybenzyl)-ethenesulfonamide (Example 876, Step 1, 0.075 g, 0.217 mmol) in THF (2.5 mL) was added. It was stirred at rt for 19 h. The reaction was quenched with water (2 mL) and extracted with EtOAc (120 mL).

The organic phase was washed with brine and dried over anhydrous sodium sulfate. After it was concentrated, the residue was purified by re verse phase preparative HPLC (Gemini™ Prep Cis 5μτη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient eiution) to provide an intermediate (120 mg) as a white solid.

Hydrolysis I: The white solid was dissolved in THF (4 mL), MeOH (4 mL) and 1

M LiOH solution (3 mL) and stirred at 43°C for 16 h. It was concentrated, acidified with IN HCl to pH 2-4, extracted with EtOAc (110 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate. It was concentrated to give a residue.

Hydrolysis II: The residue was dissolved in 1:2 TF/VDCM (5 iriL) and stirred at rtovernight. It was concentrated and the residue was loaded to a 12g ISCO Gold column and eluted with 0% to 50% (EtOAc(0.3% HOAc)/hexane), to provide the title compound (35 mg) as a film, m'z (ESI, +ve ion) 633.1 (M+H) ⁺ .

Step 3 : (IS, 3 R, 6% 7'R, 9'R, 11 K)-6-CHLORO-9'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'- 18.12.221 ^' t ^' RIOXAj Ι5ΓΠ ΠΛ| ! .IGiD!A/APHNl ,\CVC1.0| 16.72.Γ".0 ^! " 0 ^''! '| OCTACOSA[18,20,26]TRiEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 'R, 7R, 9 'S, 11 K)-6-CHLORO-9'-METHYL-3 ,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TTUOXA[15]TmA[l ₅ 16]DTAZAPE TACYCLO[16.7.2.1 ⁷ ' .0 ³ ' ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS, 3 , 6R, 7'S, 9 , 11 'R)-6-CHLORO-9'-METHYL-3 ,4-DlHYDRO-2H, 17 Ή- SPIRO INAPHTHALENE- i.24'-

[8,12,22]TRIOXA[I5]TIflA[l,161DLAZAPENTACYCLO[16.7.2.

OCTACOS A[ 18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR

(1S3R, 6R, 7'S9'S 11 'R)-6-CHLORO-9'-METHYL-3,4-DIHYDRO-2H.17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THL [1,16]DIAZAPENTACYCLO[16,7.2.1 ⁷ - ¹ ^0^ ⁶ .0 ²¹ - ²⁶ ]

QCTACQSA[18,20,26]TRIEN]-17'-QNE 15 ',15 '-DIOXIDE OR

(IS, 3 R, 6R, 7'S, 9 R, 11 '5)-6-CHLORO-9'-METHYL-3,4-DiHYDRO-2H, 17Ή- SPIRO[N APHTHALENE- 1 ,24'-

[8,I2,22]TllOXA[15]THIA[l,16]DlAZAl ⁵ ENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ]

OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

( IS, 3R, 6R,7'S 9'S 11 '^-e-CHLO O-g'-METOYL-S^-DIHYDRO^HJ?!-!-

SPIRQ[NAPHTHAI.ENE~1,24'- [8,12,22]TMOXA[15]THIA[l,I6]DIAZAPENTACYCLO[16.7.2.i ⁷ - ¹¹ .0 ³ - ⁶ .0 ^2! - ²⁶ ] OCTACOSAjl 8,2Q,26]TRIEN]-I7'~ONE 15 ',15 '-DIOXIDE OR

2,007 (IS, 3 R, 6'R, 7'S, 9 R, J 1 '5)-6-CHLORO-9'-METOYL-3,4-DiHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE- 1 ,24 ^! ~

[8/12,22]Tl lOXA[15]THIA[L16]DlAZAl ⁵ ENTACYCLO[ 16 .2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

( IS, 3 'R, 6% 7R, 9 Έ, 11 ¾)-6-CHLORO-9'-METHYL-3 ,4-DIHYDRO~2H, 17 Ή- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THlA[ i;i6]DIAZAPENTACYCLO[16 .2. i ⁷ - ¹ ^() ³ - ^{6 2!} - ²⁶ ] OCTACOSAj l 8,2Q,26]TRIEN]-I7'~ONE 15',15'-DIOXIDE N,N-dimethylpyridin-4-amine (DMAP) (0.061 g, 0.497 mmol) was added to a solution of (1 ¾)-6'-chloro-5-(((ii?, 2R)-2-((2S, R)-6-me1hyl-4-(2- sulfamoylethoxy)te1rahydro-2H-pyran-2-yl)c> lobu1yl)methyl)-3',4,4',5- te1rahydro-2H,2 ^, H-spiro[benzo[b][L4]oxazepine-3, -naphthalene]-7-carboxylic acid (Example 876, Step 2; 0.035 g, 0.055 mmol) in DCM (50 mL) at 0°C, Then Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-di hydrochloride (EDC; 0.053 g, 0.276 mmol) was added slowly in portions and it was stirred at

0°C to rt overnight. After it was concentrated, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5um column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (4.5 mg) a white solid. ^! H NMR (500 MHz, CD2CI2) δ 8.34-8.24 (m, 1H), 7,71 (s, 1H), 7, 18 (m, IH), 7.08 (m, 2H), 6.97 (s, 1H), 6.83 (m, IH), 4.14-3.97 (m, 3H), 3.85 (ddd, J=3.30, 8.19, 11.49 Hz, IH), 3.80-3.64 (m, 4H), 3.55-3.45 (m, IH), 3.40-3.33 (m, IH), 3.32-3.21 (m, 3H), 2.87-2.70 (m, 2H), 2.25- 1.58 (m, I l l s). 1.49-1.38 (m, H), 1.18 i d. ./ 6. i I Hz, 3H), 1, 15-1.06 (m, 2H). m/z (ESI, +ve ion) 615.0 (M+H) ⁺ ,

EXAMPLE 877. (1S,3'R6'R8%9'R, /i'A -e-CHLORO-^'-ETHYL-S'^'- DIHYDROXY-7'-METHYLIDENE-3,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE- 1 ,22 ^! - [20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ⁱ⁴ ]PE TACOSA [16, 18,24] TRTEN] - 15 '-ONE 13', 13 '-DIOXIDE OR ( IS, 3 % 6% 8 % 9 12 R)-6- €ΗΕΟΚΟ-12'-Γ^^.-8^9'-ΟΙΗΥΟ ΟΧΥ-7'-ΜΕΉ-ΪΥΠΟΕΝΕ-3,4-ΟΙΗΥΟ Ο- 2H.15 'H-SPIRO[NAPHTHALENE- 1,22'-

|2ίί|0ΧΛ| 1ΉΤί!1Λ| Μ4|ΠίΛ/Α Π:ΤΗΛ(Ύα.ί)Ι i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [ 16,18,24] TRS EN] -15 '-ONE 13',13'-DIOXIDE OR (lS R6R8R,9R,12Ry6- CHI RO-12'-F^iYX-89'-DIHYDROXY-7'-METI-IYLIDENE-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATEIIACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [16,18,24]TRIEN]-15'-ONE !3',13'-DTOXIDE OR {IS, 3% 6 8%9'S i2'/?)-6- CHLORO~12'-ETHYL-8',9'-DlHYDROXY-7'-METHYLIDENE-3,4-DlHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALEN E-1,22'-

[20]OXA|;i3]THIA|;i,14]DlAZATETRACYCLO[14J.2X) ³ - ⁶ .() ^!9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE

The title compound (1.8 mg) was obtained as a single isomer (second eluting peak) from the reverse phase preparative HPLC in Example 873 as a white solid. Ή N.V1R (500 MHz, CD3OD) δ 7.77 (m, 1H), 7.25 (m, IH), 7.18 (m, 1H), 7.11 (m, 2H), 6.81 (m, IH), 5.16 is, IH), 5.08 (s, IH), 4.10-3.99 (m, 2H), 3.86 (d, J=7.58 Hz, 111).3,77 (dd, ./ 4.2H. 15.28 Hz, 111).3.71-3.63 (ra, 2H), 3,62-3.59 (m, III).3,56-3.51 (m, I Hi.3.46 (m, IH), 3,38 (m, IH), 3.17 (m, III).2.91-2,73 (m, 3H), 2.68 (br. s., IH), 2.21-1.77 (m, 9H), 1,75-1.63 (m, 2H), 1.51-1.33 (m, 3H), 1.11 (i, ./ 6.85 Hz, 3H). m/z (ESI, +ve ion) 629.2 !YS iS} .

EXAMPLE 878. (1S,3R,6R, 7¾ii¾)-6-CHLORO-3,4-DIHYDRO-2H,17'H- SPlRO[NAPHTHALENE-l,24 ^, -[8,12,22]TRIOXA[15]

THI A[ 1 , 16] DI AZAPENTACYCLO [ 16.7.2.1 ^7>!! .0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A[ 18,20,26] TRIEN]-17'-ONE 15',15'-DIOXIDE OR (1S,3R,6R, 7¾ '?)-6-CHLORO-3,4- DIHYDRO-2H, 17 Ή-SPIROj NAPHTHALENE- 1 ,24'-

[8,12,22]TRi:OXA[15]THIA|;i,lDIAZAPENTACYCLO[ 16,7.2. l ⁷ - ^!i .0 - ⁶ .() ²¹ - ²⁶ ]OC TACOSA[18,20,26]TRIEN]-17'-ONE 1S',15'-DI0XTDE OR

(IS, 3 R, 6'S, 7'S 11 'R)-6-CHLORO-3,4-DIHYDRO-2H, 17 Ή- SP1RO [NAPHTHALENE- 1 ,24'- 1 .12.22 ITRIOXA] Ι5| ^' Π I!A| 1.iGjDlA/APK.Yl Λί ^' ΥΠ.Ο| 16.72.Γ".0 ^! " 0 ^''!' | OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3%6'S, 7'S, 11 ¾')-6-CHLORO-3,4-DIHYDRO-2H,17 ^" H- SPIRO [NAPHTHALENE- 1 ,24'-

[S^^lTTUOXAtlSlTHIAtUieiDTAZAPENTACYCLOtiej.Zl ⁷ - ¹¹ ^ ³ ' ⁶ .^ ¹ - ²⁶ ] QCTACQSA[18,20,26]TRIEN]-17'-QNE 15 ',15 '-DIOXIDE

Step 1 : (S)-METHYL 6'-CHLORO-5-(((IR, 2R)-2-((2R,4R)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- S'^^'^-TETRAHYDRO-ffl^'H-SPIROtBENZOIBK l^lOXAZEPINE-S,! '- NAPHTHALENE]-7-CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-

(((/i?,2i? 2 S _; 4/?)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO BENZO[B] [1 ,4 jOXAZEPINE-3, 1 '-NAPHTHALENE]-7-

CARBOXYLATE OR fS)-METHYL 6' ;HLORO-5-(((/A ^, .2i? 2Y i?, 4' ₁ S)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3' _; 4' ₅ 5.TETl AHYDRO-2H,2 ^" H"SPIRO[BENZO[B] [l,4]OXAZEPINE-3;r- NAPHTHALENE] -7-CARBOXYL ATE OR (5 METHYL 6'-CHLORO-5- ((( IR, 2R) -2-((2S, 4S)-4-HYDROXYTETRAH YDRO-2H-P YRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO BENZO[B] [1 ,4 jOXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE

A mixture of (S)-methyl 6 ^! -chIoro-5-(((/i?, 2i?)-2- form} _' 1cyclobutyl)meihyl)-3^4,4^5 .etrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7 -carboxy 1 ate (Intermediate AA11A, Step 20A: 0.243 g, 0.535 mmol), 3-buten-l-ol (54 mg, 0.7 mmol) in TFA (4.5 mL) and DCM (9 mL) was degassed with N ₂ and stirred at rt for 30 min. It was quenched with NaHC0 ₃ solution to pH >7 and extracted with EtOAc (60 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated. To the residue was added saturated Na ₂ C0 ₃ solution (1 mL), MeOH (2 mL) and THF (2 mL). After it was stirred at rt for 30 min it was neutralized with IN HCI solution to pH 7 and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 24g ISCO Gold column and eluted with 0 % to 50 % EtOAc/hexane to provide the title compound (210 nig) as a white solid, rn/z (ESI, +ve ion) 526. 1 (M+H) \

Step 2: {S &-C iLORO-5-{(OR,2R)-2-((2R, 4R)-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID OR (5)-6'-CHLORO-5-((( IR, 2R)-2-((2S, 4R)-4-(2-

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIR()[BENZO I B j [ 1 ,4 ] OXAZEPINE-3, 1 '-NAPHTHALENEJ-7-C ARBOXYLIC

ACID OR (S)-6'-CliLORO-5-(((lR, 2R)-2-((2R 4S)-4-(2-

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPTRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l '-NAPHTHALENE]-7-CARBOXYLIC

S ULF AMO YLETHOXY)TETRAH YDRO-2H-P YRAN -2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

Sodium hydride (60% dispersion in mineral oil; 14 mg, 0.341 mmol) was added to a solution of (5)-methyl 6'-ch\oro-5-(((lR 2R)-2-((2R, 4R)-4- hydroxytetrahydro-2H-pyran-2-yl)cyclobu1yl) methyl)-3',4,4',5-tetrahydro- 2H,2 ^, H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carb ox>'late (Example 878, Step 1 ; 0.046 g, 0.087 mmol) in THF (2.5 mL), which was cooled to 0°C. After it was stirred at rt for 15 min, N,N-bis(4-methoxybenzyl)e1henesulfonamide (Example 831, Step 2; 0.052 g, 0.15 mmol) in THF (1.4 mL) was added. It was stirred at rt for 2 h. The reaction mixture was quenched with water (2 mL) and extracted with EtOAc (120 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate. It was concentrated and the residue was loaded to a 12g ISCO Gold column and eluted with 0%, to 10% (EtOAc/DCM) to provide the addition product (40 mg). The addition product was dissolved in TOF (5 mL), MeOH (5 mL) and 1M LiQH solution (3 mL) and stirred at 50 °C for 2 h. It was concentrated, acidified with 1 N HC1 solution to pH 2-4, extracted with EtOAc (1 10 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate. It was concentrated to give a residue.The residue was dissolved in 1 :3 TFA/DCM (4 mL) and stirred at rt for 19 h. It was concentrated and the residue was loaded to a 4g ISCO Gold column and eluted with 0% to 20% 30 min (EtOAc(0.2% HOAc)/DCM) to provide the title compound (11.5 mg) as a film, m/z (ESI, +ve ion) 619.1 (M+H) ⁺ . Step 3 : (IS, 3 % 6 % 7'S.11 ¾)-6-CHLORO-3,4-DIHYDRO-2H, 17 Ή- SPIRO[NAPHTHALENE-l ,24'-[8, 12,22]TRIOXA[ 15]

THIA[ 1,16] DI AZ APENT AC YCLO [ 16.7.2.1 ^l .0 ³ · ⁶ . () ²ⁱ · ²⁶ ] OCTACOS A[ 18,20,26] TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR (1S,3'R, 6'R, 7'S, / / 'i?)~6~CHI,ORO~3,4- DIHYDRO-2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-[8, 12,22]TRIOXA

[15]THJA[l,lDL ZAPEOTACYCLO[16.7.2.1 ⁷ ' ^ll .0 ^3>6 .0 ²ⁱ - ²⁶ ]OCTACOSA[18,20,2 6]TRIEN]-17'-ONE 15'J 5 ^* -DIOXIDE OR (1S, 3'H 6'S, 7'S, ii 'i?)-6-CHLORO-3,4- DIHYDRO-2H, 17 'H-SPIRO[NAPHTHALENE- 1 ,24'-

[8, 12,22]II lOXA[15]IHLA[L16]DIAZAPENTAC^CLO[ 16.7.2.1 ⁷ - ¹ ^0 ³ - ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR

( V _J 3¾ 6¾ 7¾ / / ',S -6-CHLORO-3,4-DIirYDRO-2H,17T-I- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THL [l,16]DIAZAPENTACYCLO[16.7.2. i ⁷ - ¹¹ .0 ³ - ⁶ .0 ^2! - ²⁶ ] OCTAC()SA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE N,N-Dimethyipyridiii-4-amine (DMAP) (0.018 g, 0.15 mmol) was added to a solution of (5 -6'-chl oro-5 -(((//?„ 2R)-2-((2R, 4R)-4-(2~ sulfanio} _' 1ethoxy)ietrah} _' -dro-2H-pyran-2-yl)cyclobutyl) methyl)-3',4,4',5-

acid (Example 878, Step 2; 0.0115 g, 0.019 mmol) in DCM (26 niL) at 0°C. Then N 1 -((ethy limino)methyl ene)-N3 ,N3 -dimeihy lpropane- 1,3-d amine hydrochloride (EDC) (0.019 g, 0.10 mmol) was added slowly in portions and it was stirred at

0°C to rt for 22 h. It was diluted with EtOAc (100 ml,), washed with 1 N HC1 (2x1 mL), brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 4g IS CO Gold column and eluted with 0% to 7%

(EtOAc(0.2% HOAc)/DCM) to provide the title compound (7.2 mg) as a white solid, ^" Ή NMR (400 MHz, CD2CI2) δ 8.13 (br. s . H i ). 7.70 (d, ,/ H 4 I Hz, I I I ). 7.17 (dd, J=2.35, 8.41 Hz, 1H), 7.10 (m, 2H), 6.96 (m, 1H), 6.71 (s, 1H), 4.09 (s, 2H), 4.04-3.95 (m, 2H), 3.85 (d, ./ 5.48 Hz, 1H), 3.81 (m, IH), 3.73-3.66 (m, 2H), 3,64-3.59 (m, IH), 3.58-3,49 (m, 3H), 3.32-3.17 (m, 2H), 2.81-2,73 (m, 2H), 2.42- 2.31 (m, IH), 2.04 (d, J=5,67 Hz, IH), 1.99-1 ,24 (m, 12H). m/z (ESI, +ve ion) 601.1 ( Vl - i l) .

EXAMPLE 881. (IS, 3 R.6 'S, 8 ¾)-6-CHLORO-8'-HYDROXY-3,4-DMYDRO- 2H, 15 Ή-SPIRO [NAPHTHALEN E- 1 ,22'- [20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.0 ^3>6 ,0 ^{! 9} - ²⁴ ]

PENTACOS A[ 16, 18,24]TRIEN] - 15'-ONE 13', 13'-DIOXJDE OR (IS.3 % 6' 8 'R)~ 6-CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'-[20] OXA|; 13 ]THIA 1, 14]

DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ¹⁹ - ^M ]PEOTACOSA[ 1 6, 18,24]™EN]- 15"- ONE 13', 13 -DIOXIDE

A mixture of (IS, 3 % 6'S, 8 'R, 9 'E)-6-chloro-8'-hydroxy-3,4-dihydro- 2H, 15 Ή-spiroj naphthalene- 1 , 22'- |lhi.i| i J4|dia.aioirae>cioj I4.7.2. ⁽ i ".0 ^| jpeniacoha|v.l6.i8.24| tetraen]-15'-one 13',I3'-dioxide (Example 883; 0.002 g, 3.5 μπιοΐ) and platinum (IV) oxide (0.79 mg, 3.5 μηιοΐ) in EtOAc (1.7 mL) was stirred under H ₂ at rt for 1 h. It was filtered through syringe filter to remove solid catalyst and the filtrate was concentrated to provide the title compound (1.9 mg) as a white solid. ^! H NMR (400 MHz, CD30D) δ 7.78 (d, J=8.41 Hz, 1H), 7.37 (br. s., 1H), 7.20 (dd, =2.35, 8.41 Hz, 2H), 7.12 (d, ./ 2.1 Hz, 1H), 6.86 (m, 1H), 5.69 (br. s., 1H), 4.17-3.43 (m, 6H), 3.19-3.13 (m, 2H), 2.87-2.74 (m, 3H), 2.38 (br. s„ 2H), 2,31-2.20 (m, IH), 2.11 (d, ,7=13.11 Hz, 2H), 2.04-1.89 (m, 5H), 1.88-1,16 (m, 8H). wz (ESI, +ve ion) 573.2 (M+H) ⁺ . EXAMPLE 882. (1S,3'R,6'R, 7%8'E, /2'i?)-6-CHLQRQ~12 ^! -ETHYL~7'~

HYDR0XY-3 _S 4-D1HYDR0-2H, 15 'H-SPIRO[NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOIMJ^.O'^.O'^HPENTACOS A[8, 16, 18,24]TETRAE ]-15 ^* -ONE 13', 13'-DIOXIDE

Step 1 : (Sy TERT- UTYL 6 ^! -CHLORO-5-(((/i?,2i? 2 f7x ⁵ )-l- HYDROXYAIJ^ .)CYCIOBUWl METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPIRO[BENZO[B][l,4]OXAZEPI E-3,r-NAPHTHALENE]-7- CARBOXYLATE OH

Vinylmagnesium chloride solution (1.4 mL, 2.23 mmol) was added dropwase to a solution of (<S)-tert-butyl 6'-chloro-5-(((/i?,2i?j-2- formylcyclobut5 _' l)methyl)-3',4,4',5--tetrahydro-2H,2 ^, H- spiro I benzo j b j [ 1 ,4] oxazepine-3 , Γ-naphthal ene ] -7-carboxy late (Intermediate AA1 1A, Step 20B;.754 g, 1.52 mmol) in THF ( 19 mL) which was cooled with ice bath. It was stirred at 0°C for 10 min. The reaction mixture was quenched with NH4CI solution and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 220g ISCO Gold column and eluted with 0% to 10% (EtOAc/hexane). The second peak was the title compound (270 mg) as a white solid, m/z (ESI, +ve ion) 524.2 ( VI i ! ) . Step 2: (S)-6'-Ci1LORO-5-(((lR,2R)-2-((R)-\ -

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO- 2H.2'H-SPIRO[BENZO[B]|;i,4]OXAZEPI E-3,r-NAPHTHALENE]-7-

CARBOXYLIC ACID

Lithium hydroxide (I .0 M aqueous solution; 6.4 mL, 6.4 mmol) was added to a solution of (S)-tert-hui ] 6'-chloro-5-(((7R, 2R -2-^S)-l - hydroxyallyl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 882, Step 1 ; 0,306 g, 0.584 mmol) in THF (13 mL) and MeOH (6.5 mL). It was stirred at 77 °C for 4,5 h. The reaction mixture was concentrated, acidified with IN HC1 solution to pH 2-3 and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (273 mg) as a white solid, m/z (ESI, +ve ion) 468.2 (M+H) ⁺ .

Step 3: (S)-6'-CHLORO-N-((R)-HEPT-6-EN-3-YLSULF01SrYL)-5-(((7R,2R;-2 - ■fK)- 1 -HYDROXY ALL YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2 Ή-SPIRO [BENZO [B] [ 1 ,4]OXAZEPINE-3, 1 ^* - N APHTH ALENE1 -7 -C ARB OXAMIDE

4-Dimethylaminopyridine (DMAP) (0.340 g, 2.78 mmol) was added to a solution of (A -6'-chloro-5-(((H^,2i?^-2-f 2?)-l-hydrox\'allyl)cyclobutyl)methyl)- 3',4,4',5-tetrahydro-2H,2'H-spiro| ^" benzo| ^" b]|T,4]oxazepine-3, -naphthalene]-7- carbox iic acid (Example 882, Step 2; 0.1 86 g, 0.397 mmol) and (jR)-hept-6-ene- 3-sulfonamide (EE21 ; 0, 137 g, 0.775 mmol) in DCM (8 mL). It was cooled with ice bath. Then EDC (0.229 g, 1.19 mmol) was added portion by portion and it was stirred at 0°C to rt for 20 h. It was diluted with DCM (180 mL) and washed with IN HC1 (3 mL) and brine (lmL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 40 g ISCO Gold column and eluted with 0% to 25% (EtOAc(0.2% HOAcj/hexane) to provide the title compound (107 mg) as a white solid, m/z (ESI, +ve ion) 627, 1 { Yl · H ) ^'

Step 4: (/5 ¾ d7¾ 7'R,e'EJ2'R)-6-CHLORO-12'-ETHYL-7 ^, -HYDROXY-3 ₅ 4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

A solution of (»S -6'-chloro-N-((i?)-hept-6-en-3-ylsulfonyl)-5-(((H?, 2R)-2- ((R)-\ -hydroxy ally 1) cyclobut 'l)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [1,4] oxazepine-3, 1 '-naphthalene] -7-carboxamide (Example 882, Step 3; 0, 107 g, 0.171 rnmol) in 1 ,2-dichloroethane (122 mL) was degassed with Ν ^! 2· A solution of Hoveyda-Hoveyda-Grubbs II (0.021 g, 0.034 mmol) in 1 ,2- dichloroethane (5 mL) was added and the mixture was stirred at 45°C for 4 h. After conce tration, the residue was loaded to a 40g ISCO Gold column and eluted with 0% to 30% (EtOAc(0.2% HOAc)/hexane) to provide the title

compound (78 mg) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.77 (m, 1H), 7.42 (m, 1H), 7.20 (m, IH), 7.11 (m, 2H), 6.94 (m, 1H), 5.54-5.48 (m, 2H), 4.11 (m, 2H), 3,94 (dd, ./ 5.67. 15.45 Hz, H i ). 3.79 (m, 1 H), 3.71 (ra, 21 1 ). 3,05 (dd, ./ 6.06. 15.26 Hz, 1H), 2.87-2.77 (m, 2H), 2.61-2,47 (m, 2H), 2.42-2.33 (m, IH), 2.15-2.03 (m, 5H), 1.99-1.83 (m, 5H), 1.81-1.73 (m, 2H), 1.72-1.64 (m, 1H), 1.52- 1 ,43 (m, IH), 1.18 (t, ./ 7.53 Hz, M l ), m/z (ESI, +ve son) 599.1 (M+H) ⁺ .

EXAMPLE 883. (IS, 3 % 6'S, 8 'S, 9 'Z)-6-CHLORO-8'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [N APHTH ALENE- 1 ,22'[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[l 4.7.2.0 ³ · ⁶ .0 ^{Ϊ 9} · ²⁴ ] PENT AC OS A[9, 16, 18,24] TETRAEN] - 15 '-ONE 13' , 13 '-DIOXIDE OR

(IS, 3 % 6 'S, 8 'R.9 ' )-6-CHLQRQ-8'-HYDRQXY-3,4-DIHYDRQ-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtl SJTO Atl ^DIAZATEmACYCLOtMJ^ ^^O^^lPE TACOSA

[9, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

Step 1 : (i 6'-CHLORO-5-(((iR,2^-2-^S)-2-HYDROXYBUT-3-EN-l -

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((7i¾26 2-i K)-2-HYDROXYBUT-3-EN-l -

YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-N APHTHALENE] -7-C ARBOXYLIC ACID

The title compound (16.7 nig) was obtained as a single isomer (first eiuting pealv) from the reverse phase preparative HPLC in Example 884, Step 3 a white solid, rn/z (ESI, +ve ion) 482. 1 (M+H) \ Step 2: (S)-N-(BUT-3-EN-l-YLSULF01 ^

HYDROXYBUT-:^EN-l -YL)CYCLOBUTYL)METHYL)-3' ₅ 4,4',5- TETRAH YDRO-2H,2'H-SPIRO [BENZO[B] [ 1 ,4] OXAZEPINE-3 ,Γ- NAPHTHALENEj-7-CARBOXAMIDE OR (5)-N-(BUT-3-EN-l- YLSULFONYL)-6'-CHLORO-5-(((H?, 2S)-2-( f»)-2-HYDROXYBUT-3-EN-l - YL)CYCLOBUTYL)METHYL)-3',4,4 ^! ,5-TE,TRAHYDRO-2H ₅ 2'H~

SP1R0[BENZ0 [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (10.7 mg, 0.087 mmol) was added to a solution of (5)-6'-chloro-5-(((i/i25 -2-f†5)-2-hydroxybut-3-en-l- yl)cyclobu1yl)methyl)-3^4,4^5-tetrahydfo-2H,2'H-spiro[benzo[ b] [l,4]oxazepine- 3,l'-naphthalene]-7-carboxylic acid (Example 883, Step 1; 0.014 g, 0.029 mmol) and but-3-ene-l-sulfonamide (EE15; 0.018 g, 0.131 mmol) in DCM (1.1 mL) at

0°C. Then N-(3-dimethyiaminopropyi)-N'-ethyicarbodiiniide hydrochloride (EDC; 0.011 g, 0.058 mmol) was added portion by portion and it was stirred at rt for 18 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Ci8 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (6.5 mg) as a white solid, m/z (ESI, +ve ion) 599.2 (M+H) ⁺ . Step 3 ; ( IS.3 'R, 6 ^! S 8 ¾ 9 'Z)-6-CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE-

1,22'[20]OXA|;13]TH1A[1,14]DIAZATETR CYCLO[14.7.2.0 - ⁶ .0 ¹⁹ - ² ] PENTAC0SA[9,16,18,24]TETRAEN]~1S'~0NE 13",13 -DIOXIDE OR

(IS, 3 'R, 6'S: 8 % 9 '2r)-6-CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [9J 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

A 250 mL round bottom flask was charged with (5)-N-(but-3-en-l- y lsulfonyl)-6'-chloro-5-(((H?, 2S)-2 -((S)-2- y droxybut-3-en-l - yl)c lobutyl)methyl)-3\4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine- 3, -naphthalene]-7-carboxamide (Example 883, Step 2; 8,0 mg, 0.013 mmol) in toluene (44 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (1.7 mg, 2.6 μηιοΐ) in toluene. The mixture was stirred at 106 °C under nitrogen for 1 h and then concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep C is 5μτη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (4.2 mg, second during peak) as a white solid. ^" Ή NMR (500 MHz, CD2CI2) δ 9, 1 8 (br, s,, 1H), 7.73 (m, I H i. 7.25 (d, .7=7,34 Hz, 1H), 7, 18 (dd, .7=2.08, 8.44 Hz, i l l ). 7.09 (d, J=2.20 Hz, lH), 7.05 (br. s., M l ). 6.98 (m, 1H), 5.68-5.56 (m, 2H), 4.74- 4.66 (m, 1H), 4.10 (s, 2H), 3.98 (d, ./ 15.4 ! Hz, I I I ). 3.90-3.82 (m, 2H), 3.77 (d, J=13.94 Hz, i l l ). 3.42-3.35 (m, 2H), 3,32-3.23 (m, 1 H), 2.84-2,72 (m, M l ). 2.49- 2.40 (m, 2H), 2.39-2.30 (m, 1H), 2.26-2.17 (m, 2H), 2.12-2.06 (m, 2H), 2.00-1.93 (m, IH), 1.92-1.75 (m, 3H), 1.59-1.49 (m, 2H), 1.41 U. ./ 1 3.33 Hz, i l l ), m/z (ESI, +ve ion) 571 .3 ( \ 1 H i . EXAMPLE 884. (IS, 3 'R, 6 'S, 8 % 9 '£>6~CHLQRQ~8'~HYDRQXY-3,4- DIHYDRQ-2H, 15 Ή-SPIRQj NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI M.T^.O'^.O^^lPE TACOSA

[9,16,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H,15'H~SPIRO[NAPHTHALENE- L22'"

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [9, 16, 18,24]TETRAEN] - 15 '-ONE 13', 13 '-DIOXIDE

Step 1 : (5 METHYL 6'-CHL()RO-5-(((7i?,2^-2-irii)-2- METHOXYVINYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPrRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7- C ARB OXYL ATE

A solution of chloro(methoxymethyl)triphenylphosphorane (0.227 g, 0.661 mmol) in THF (5.5 mL) was cooled to 0 °C. N-Butyl lithium solution (2.5 M in hexane; 0.25 mL, 0.63 mmol) was added dropwise and it was stirred at 0 °C for 7 min. (S)-methyl

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepme-3, 1 '-naphthalene] -7-carboxylate (Intermediate AAl 1 A, Step 20 A; 0.075 g, 0.165 mrnol) in THF (2 mL) was added in one portion and it was stirred at 0 °C for 8 min. The reaction mixture was poured slowly to ice-water (5 mL) and extracted with EtOAc (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 12 g TSCO Gold column and eluted with 0% to 10% (EtOAc/hexane) to provide the title compound (120 mg) as a white solid, m/z (ESI, +ve ion) 482.1 (M+H) ⁺ .

Step 2: (S)-6'-CHLORO-5-(((7R, 2S)-2~(2~

OXOEmYL)CYCLOBUTYL)METHYL)"3',4,4',5-TEm' HYDRO-2H,2 ^, H-

SPIR()[BENZO Bj[ L4]()XAZEPINE-3,r-NAPHTHALENEl-7-CARBOXYLIC ACID

A mixture of (5)-methyl 6'-chloro-5-(((H?,2i?)-2-((E)-2- methoxyvinylJcj'clobut methylJ-S'^^'^-tetrahydro^H^'H- spiro|benzo[b] [l,4]oxazepine-3,r-naphihalene]-7-carboxylate (Example 884, Step 1 ; 0.120 g, 0.249 mrnol) and lithium hydroxide (1.0 M aqueous solution, 2 mL, 2 mrnol) in MeOH (1 mL) and THF (1.5 mL) was stirred at rt for 3 days. It was concentrated and was added 1 N HC1 solution (6 mL) and acetone (20 mL) and stirred at rt for 27 h. It was concentrated at rt and the residue was extracted with EtOAc (120 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to provide the title compound (109 mg) as a white solid, m/z (ESI, +ve ion) 454.1 ( V! I I ) . Step 3: (S)-6'-CHLORO-5-(((H?, 2.¾-2-^R)-2-HYDROXYBUT-3-EN-l- YL CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S 6'-CHLORO-5-(((iA ⁵ , ^-2-^S)-2-HYDROXYBUT-3-EN- 1 - YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

At 0°C, vinylmagnesium chloride (1.6 M solution in THF; 0.25 mL, 0.40 mmol) was added dropwise to a solution of (5')-6'-chloro-5-iii /i?,25)-2-(2- oxoethyl)cyclobuU4)methyl)-3' _: ,4,4 ^! ,5-ietrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylic acid (Example 884, Step 2; 0.060 g, 0.132 mmol) in THF (2.2 mL.), which was cooled to 0°C. It was stirred at rt for 0.5 h. The reaction mixture was poured into ice-water, acidified with IN HC1 solution to pH 2-3, extracted with EtOAc (130 mL). The organic phase was washed with brine (1 mL), dried over anhydrous sodium sulfate, filtered through silica gel and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Ci8 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution). The title compound (14 mg) was obtained as a single isomer (second eluting peak) as a white solid, m/z (ESI, +ve ion) 482, 1 i V! H )

Step 4: (¾-N-(BUT-3-EN-I-YLSUIJONYL:)-6'-CHLORO-5-(((iA ^, , 2S -2 fK)-2- HYDROXYBUT-:^E -l -YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAH YDRO-2H,2'H-SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '- NAPHTHALENE] -7-CARBOX AMIDE OR (5)-N-(BUT-3-EN- 1 - YLSULFONYL)-6'-CHLORO-5-(((/ii2^-2-^5)-2-HYDROXYBUT-3-EN-l- YL)CYCLO-BUTYL)MEraYL)-3',4,4',5"TETRAHYDRO-2H,2'H- SPIRO [BENZO B j [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMTDE

N,N-Dimethylpyridin-4-amine (DMAP) (9.12 mg, 0.075 mmol) was added to a solution of (S)-6'-chloro-5-(((H?, 25)-2-f† ^' i?)-2-hydroxybut-3-en-l - y cyclobut methy^-S'^^'.S-tetrahydro- H^'H-spirotbenzotbJ tl^Joxazepine- 3,l '-naphthalene]-7-carboxylic acid (Example 884, Step 3; 0.012 g, 0.025 mmol) and but-3-ene-l -sulfonamide (EE15; 0,015 g, 0.112 mmol) in DC VI (0.9 ml .) at 0°C (ice bath). Then N-(3-dimethylaminopfopyl)-N ^, -ethylcarbodiimide hydrochloride (EDC; 9 mg, 0.05 mmol) was added portion by portion slowly and it was stirred at rt for 18 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini ^lM Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0, 1 % TFA, gradient elution) to provide the title compound (8 mg) as a white solid, m/z (ESI, +ve ion) 599.2 (M+H) ⁺ .

Step 5 ; ( IS.3 % 6% 8 9 ¾)-6-CHLORO-8'-HYDROXY-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTAC()SA [9, 16, 18,24]TETRAEN] - 15'-ONE 13 ', 13 '-DIOXIDE OR (IS, 3 'R, 6'S, 8 'S, 9 Έ)-6~ C! U .O O-8 -ί iY i)ROXV - .4-i)!| !Y ORO-2i 1. i !-SPi Oi Ws 1 1 1 1Λ! .! \ [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[9, 16, 18,24]TETRAEN] - 15'-ONE l .T. 13 '-DIOXIDE

A 250 mL round bottom flask was charged with (jS -N-(but-3-en-l- ylsidfonyl)-6'-chloro-5-(((7/¾25 2-( K)-2½droxybut-3-en-l- yl)cyclobu1\d)methyl)-3',4,4V ^< >-tetrahydro-2H,2'H-spiro[benzo[b] [l ,4]oxazepine- 3,r-naphthalene]-7-carboxamide (Example 884, Step 4; 0.008 g, 0.013 mmol) in toluene (33 mL). It was stirred at ft for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda- Hoveyda-Grubbs II (1.7 mg, 2.7 μηιοΐ) in toluene (3 mL). The mixture was stirred at 106 °C under nitrogen for 53 min. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0. 1% TFA, gradient elution) to provide the title compound (2, 1 mg) as a white solid. ^! H NMR (500 MHz, CD2CI2) δ 8.09 (m, IH), 7.73 (m, i l l ). 7.19 (m, 2H), 7.09 (m, IH), 6.96 (m, IH), 6.81 (m, IH), 5.79 (dd, J=7.58, 15.41 Hz, IH), 5.66-5.57 (m, IH), 4.21-4.15 (m, I H), 4.12-4.06 (m, 2H), 3.87 (ddd, ./ 3.30. 10.58, 15,47 Hz, IH), 3.78 (dd,

... 4.28. 15.53 Hz, IH), 3.73 (d, .7=14. 18 Hz, IH), 3.58 (ddd, «7=2.93, 6,97, 15.53 Hz, IH), 3.24 (d, ,7=14.43 Hz, IH), 3.04 (dd, ,7=6.48, 15.53 Hz, IH), 2.82-2.73 (m, 2H), 2.72-2.57 (m, 2H), 2.34-2.20 (m, 2H), 2.07-1.34 (m, 10H). m/z (ESI, +ve ion) 571.3 (M+H) ⁺ .

EXAMPLE 885. (IS, 3 ΊΙ 6'R 8 % 12 'R)-6-CHLORO - 12'-ETHYL-3,4-DIH YDRO- 2H, 7Ή, 15 'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAENE]-7', 1 S'-DIONE 13', 13'-D10XIDE

Step 1 : (1S 'R, 6'R, 7¾5'Z, i2'R)-6-CHLORO-12 ^, -ETHYL-7 ^, -HYDROXY-3 ₅ 4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]TO1A[1,14]DIAZATEII ACYCLO[14.7.2.0 - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

| 8,16, 18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(IS, 3'R, 6R, 7'S,8'E, i2' ?)-6-CHLORO-12'-ETHYL-7'-HYDROXY-3,4-

DIHYDRO-2H, 15 'H-SPIRO[NAPHTHALENE- 1 ,22'-

[20]QXA[13]THiA[l,14]DL ZATET^^

[8, 16, 18,24]TETRAEN]-1 S'-ONE 13", 13 -DIOXIDE

The title compounds were prepared by the same procedure described in Example 422, Step 1. The title compounds contained both trans- (1007) and cis- isomers. m/z (ESI, +ve ion) 599.1 (M+H) ⁺ .

Step 2 : (IS, 3 'R 6 , 8 12 'R)-6-CHLORO - 12'-ETH YL-3 ,4-DIHYDRO- 2H,7'H, 15'H-SPTRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[ 1 , 14]DIAZATETRACYCLO[ 14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAENE]-7', 15'-DIONE 13', 13'-D10XIDE

A 100 mL flask charged dimethyl sulfoxide (0.181 mL, 2.56 mmol) and DCM (5 mL) was cooled to -78 °C. Oxalyl chloride (2.0 M solution in DCM, 0.68 mL, 1.36 mmol) was added dropwise and the reaction mixture was stirred for 17 min. The resulting solution was added to a mixture of Example 885, Step 1 (0.511 g, 0.853 mmol) in DCM (8.5 mL) (not homogenous solution), which was cooled to -78°C. After it was stirred at -78°C for 56 min, triethylamme (0.5 mL, 3.4 mmol) was added dropwise and it was stirred at -78°C for 1 h. It was quenched with water (30 mL) and extracted with EtOAc (200 mL). The organic phase was washed with 1 N HCl solution (6 mL), brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution). The title compound (4.6 mg) was obtained as a single isomer (first eluting peak) as a white solid. ^] H NMR (400 MHz, CD2CI2) δ 9.45 (s, IH), 7.72 (d, ,7=8,41 Hz, 1H), 7.32 (dd, .7=2.15, 8.22 Hz, i l l ). 7,22 (d, J=2.15 Hz, 1 1 1 ). 7.17 (dd, J=2.35, 8.61 Hz, 1H), 7.10 (d, ,7=2.15 Hz, 1H), 6.95 (d, ./ K.4 I Hz, I I I ). 6.46 (td, J=8.31 , 11.15 Hz, I I I ). 6.25 (d, J= 11.15 Hz, 1H), 4. 19- 4,08 (m, 2H), 3.70 (dd, 77. 14,77 Hz, 2H), 3.38-3,23 (m, M l ). 3.02 (q, J=9.59 Hz, 1H), 2,95-2.73 (m, 5H), 2.36-2.26 (m, M l ). 2.19 (d, J=9.39 Hz, IH), 2.08-1.65 (m, 9H), 1.56-1.48 (m, IH), 1.10 (t, ,7=7.43 Hz, 3H). m/z (ESI, +ve ion) 597.1 ( W W ) . EXAMPLE 886. (IS) 3 R, 6'R, 12 '/¾)-6-CHLORO- 12'-ETHYL-3 ,4-DIHYDRO- 2Η,7Ή, 15 Ή- SPIRQ [NAPHTHALENE- 1.22 ^" -

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PL\,TAi S A

-7',15'-DIQNE 13',13'-DIGXIDE

Step 1 : (1 S 'R,6 ^! R7^,8T i2 ^! R)~6-CHLORO-12'-ETHYL-7 ^! ~HYDROXY-3 ₅ 4- DIHYDRQ-2H, 15 Ή- SPIRO [N APHTH ALENE - 1 ,22'- [20]OXA[13]THIA[1 ;i4]DIAZATETRACYCLO[14.7,2.0 ^3>6 .0 ^!9 - ²⁴ ]PENTACOSA [8, 16, 18 , 24] TETRAEN] - 15'~ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 719, Steps 1 and 2 using (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox'ally])cyclobutyl)methyl)-3 ^, ,4,4',5-tetrahydro-2H,2 ^, H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylic acid (Intermediate AAllA) and (R)-hept-6-ene-3 -sulfonamide (Intermediate EE21), and the desired product, (1 S,3'R,6'R,7'S,8'E, 1.2*R)-6-chloro-l 2'-ethy]-7'-hydroxy~3,4~dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]tliia[l,14]diazatetracycio[14.7.2.0- ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,I6,18,24]tetrae n]-15'-one 13',13'-dioxide was obtained (first eluting major peak) as a white solid from the reverse-phase preparative HPLC.

Step 2: {IS, 3 R, 6 'R, 7 'S, 12 'i?)-6-CHLORO-12*-ETHYL-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- \ ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example Example 925, Step 1 , using (l S,3'R,6'R,7'S,8'E,12'R)-6-chloro-12'- ethyl-7 ^, -hydroxy-3,4-dihydro-2H,15 ^, H-spiro[naphthalene-l,22'- [2Q]oxa[ 13]thia 1 , 14] di azateto^

n]-15'-one 13', 13'-di oxide (from Step 2).

Step 3: (1S R 6R, /2'A ⁵ )-6-CHLORO-12 ^, -ETHYL-3,4-DIHYDRO-2H,7'i-I, 15'H- SPIRO [NAPHTHALENE- 1 ,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [16,18,24]TRIENE]-7',15'-DIONE 13',13'-DIOXIDE

A 200 mL flask charged DMSO (1.7 mL, 25 mmol) and DCM (20 mL) was cooled to -78 °C. Oxalyl chloride (2.0 M solution in DCM; 6.6 mL, 13 mmol) was added dropwise slowly and the resulting mixture was stirred at to -78 °C for 15 min. The mixture was called solution (I). {1S.3 R.6 R, Ζ 'Δ' /^ '^Ι-δ^^ΙθΓθ-Π'- ethyl~7'~hydroxy-3,4~dihydro^

[20]oxa[13]thia[U4]diazatetra^^

15'-one 13',13'-dioxide (from Step 2, 0.79 g, 1.3 mmol) in DCM (20 mL) (not homogenous solution) was added dropwise to the above solution (I). After it was stirred at -78°C for 1 h, triethylamine (5 mL, 35 mmol) was added dropwise and it was stirred at -78°C for 1 h. The reaction was quenched with water (30 mL), extracted with EtOAc (400 mL). The organic phase was washed with 1 N HC1 solution (2x13 mL), brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 80g ISCO Gold column and eluted with 0 % to 15 % EtOAc (containing 0.3 % AcOHV'DCM (containing 0.3 % AcOH) to provide the title compound (372 mg) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8,27 (m, 1H), 7.73 (m, IH), 7.18 (m, IH), 7.10 (m, 1H), 6.99 (m, 2H), 6.92 (m, IH), 4.16- 4,05 (m, 2H), 3.86-3.66 (m, 3H), 3.29 id../ 14.48 Hz, IH), 3,22-3.11 (m, 2H),

2,85-2.72 (m, 3H), 2.41-2.31 (m, IH), 2.31-2.19 (m, IH), 2.16-2,06 (m, 2H), 2.05- 1.71 (m, 9H), 1.64-1.56 (m, IH), 1.50-1.34 (m, 4H), 1.14 (t, ./ 7.53 Hz, 3H). m/z (ESI, +ve ion) 599.1 ( +H) ⁺ .

EXAMPLE 891. (1S,3R,6R, 7Xii >6-CHLQRQ-7',10'-DlHYDRQXY-3,4- DIHYDRO-2H, 15 Ή-SPIROj NAPHTHALENE- 1 ,22'-

[20]OXA[13]Tffl A[l J^DIAZATETRACYCLOlMJ^.O^^O'^jPENTACOSA

[16,18,24]TRIEN]-15'-QNE 13',13'-DI0X1DE OR (1S,3'R6'R 7'S,10'R)-6- CHLORO-7',10 ^! -DIHYDRQXY-3,4-DIHYDRO-2H,15'H- SP1R0[NAPHTHALENE-1,22'-

|2( >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.20 ^' ".O ¹ '" ¹ |Pi-:N i ACOSA

[16,18,24] TRIEN]-15'-ONE 13',13 ^! -D10X1DE OR iiS.S'R YR.7'S,9'S)~6~ CHLORO-7',9'-DIHYDROXY-3,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE-1,22'-[20]OXA[13]THIA[1,14]DIAZATETRACYCLO

[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA|;i6,18,24]TRIEN]-15'-ONE 13', 13 '-DIOXIDE OR (1S R, 6R, 7¾P ?)-6-CHLORO-7',9'-DIHYDROXY-3,4-DIHYDRO- 2H, 15 'H-SPIRO[N APHTHALENE- 1 ,22'-

|2( >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 ^' ".O ¹ '" ¹ |PH\ i ACOSA

[16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE

A solution of (IS.3'R, 6'R, /'5,9 i)-6 hloro-7'-hydrox5 ^? -3,4-dihydro- 2H, 1 5 'H-spiro| naphthalene- 1 ,22'- [20]oxa[13]thia[l, 14]diazatetra^

tetraen]-15'-one 13 ',13 '-dioxide (Example 846) in THF (4.3 mL) under N ₂ was cooled to 0°C and treated with borane THF complex (1.0 M solution in THF; 0.64 mL, 0.64 mmol). It was stirred at 0°C for 2.5 h. Then N-methylmorpholine oxide (0.263 g, 2.243 mmol) was added in one portion and the mixture was stirred while allowing to reach rt for 30 min. After it was concentrated the residue was stirred in MeOH (35 mL) at 70°C overnight. It was diluted with water, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/min CO:? on a Thar 80 SFC. Outlet pressure 100 bar; Temp. 20°C; Wavelength 220 nm) to give the titlt compound (7.8 mg, first eluting peak) as a white solid. Ή NMR (400 MHz, CDCb) δ 7.70 (m, IH), 7.18 (m, 1H), 7.12- 7,00 (m, 2H), 6.97-6.82 (m, 2H), 4.17-3,99 (m, 4H), 3.79-3.63 (m, 2H), 3,45-3.26 (m, 1H), 3.25-3.14 (m, I I I ). 3.11-2.99 (m, IH), 2.85-2.70 (m, 2H), 2.27 (br. s., IH), 2.13-0.99 (m, 16H). m/z (ESI, +ve ion) 589.2 { \ I · Π } . EXAMPLE 892. (1S,3'R,6'R, 7'S / 0¾ -6-CHLORO-7*,l Q'-DIHYDROXY-3,4- DIHYDRO-2H, 15 'H-SPIRO[N APHTHALENE- 1 ,22'-

|2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [16,18,24]TRIENj-15'-ONE 13',13'-DIOXIDE OR (lS3'R,6'R7'Si()'R)-6- CHLORO-7", 10'-DIHYDROXY-3,4-DIHYDRO-2H, 15 Ή-

SPIRQ[NAI¾THAi.ENE~l,22'-

[20]OXA[13]TH1A[1 4]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[16,18,24]TRIE ]-15'-ONE 3', 13'-DIOXIDE OR (IS, 3 % 6'R, 7'S, 9'S)-6-

CHLORO-7',9'-DIHYDROXY-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR {lS,3'R,6'R7'S,.9'K)-6-

CHLORO-7',9'-DIHYDROXY-3,4~DlHYDRO-2H,15 ^, H-

SP1RO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[16, 18,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE

The title compound (7.4 mg) was obtained as a single isomer (second eluting peak) from the reverse phase preparati ve HPLC in Example 891 as a white solid, ^" Ή NMR (400 MHz, CDCb) δ 9,06 (br, s. 111).7.70 (m, IH), 7.17 (m, 2H), 7.13 (s, ill).7.09 (d, ,7=2,15 Hz, I Hi,.6.94 (m, IH), 4,13-4.02 (m, 2H), 3.96-3.87 (m, 2H), 3.80-3.65 (m, 3H), 3.633.56 (m, IH), 3.25 (d, ./ 14.28 Hz, IH), 3.18- 3.09 (m, IH), 2.83-2.74 (m, 2H), 2.44-2.32 (m, 2H), 2.07-0.99 (m, 16H). m/z (ESI, +ve ion) 589, 1 (VI 11) ,

EXAMPLE 893. (IS, 3 ΊΙ 6'R 7'S, /0'_3)-6-CHLORO-7', 1 Q'-DIHYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIROfN APHTHALENE- 1 ,22'- |20i X A| I 311 HI Λ| I„!-! |P!.\/.\ Th f ^' RACYCf ,Oj N.7.2 ϋ ^;ί' .ϋ |ΡΗ\ iACOSA [16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE OR (1S,3'R6'R 7'S.10R)~6~ CHLORO-7',10'-DIHYDROXY -3,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22"- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R6'R 7'S,9'S)-6- CHLORO-7',9'-DIHYDROXY-3,4-DTHYDRO-2H, 15 Ή- SPIRO[N APHTHALENE- 1.22 ^' -

|2ujOXA| 13ΙΊ Η1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C0SA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S,9'R)-6- CHLORO-7',9'-DIHYDROXY-3,4-DIHYDRO-2H, 15 Ή- SPi ()i\AFHillA!J \i:-l,22-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [16, 8,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound (7,5 mg) was obtained as a single isomer (third e!uting peak) from the reverse phase preparative HPLC in Example 891. ¾ MR (400 MHz, CDCb) δ 7,70 id. ./ 8.41 Hz, IH), 7.18 (d, J==6.26 Hz, 2H), 7.12-7.04 (m, 2H), 6.96 (d, J=8.22 Hz, IH), 4.35-4,26 (m, IH), 4.16-4.07 (m, 2H), 3,84-3.60 (m, 5H), 3.30 (d, =14.28 Hz, IH), 3.21 (br. s., IH), 2,83-2.73 (m, 2H), 2.54 (br. s., IH), 2.24 (br. s., 2H), 2.04-1.02 (m, 13H). m/z (ESI, +ve ion) 589.1 ! M ! ! ) .

EXAMPLE 894, (IS, 3 % 6'R, 7'S, 70'S)-6-CHLORO-7',l 0'-DIHYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[16,18,24]TRIEN]-15 ^* -ONE 13 ',13 '-DIOXIDE OR (1S R,6R ^! S.10'R)~6~ CHLORO-7',10'-DIHYDROXY-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (1S,3'R6'R 7'S,9'S)~6~ CHL()RO-7',9'-DIHYDROXY-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2θ!() Λ| I 311 HI Λ| I .. ! -i |OI.\/.\ Π·. E R.AC VC ^' E C)i i J 7.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA

[16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE OR (1S,3R,6'R 7'S.9R)-6- CHLORO-7',9'-DIHYDROXY-3,4-DIHYDRO-2H.15 Ή- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound (7.7 mg) was obtained as a single isomer (fourth eluting peak) from the reverse phase preparative HPLC in Example 891. ¾ NMR (400 MHz, CDCb) 67.68 (d, ./ 8.6! Hz, IH), 7.35 (d, ./ 8. Hz, ill).7.25 (br. s . IH), 7.17 (d, ,/ 86! Hz, IH), 7.09 (s, IH), 6.94 id. ,/ 822 Hz, IH), 4.25 (ra.

2,038 ill).4.18-3.98 ( in. l).3.85-3.51 (m, 6H), 3.30 (d,J=15.06 Hz, ill).3.20 id. J=13.30 Hz, 2H), 2,77 (br. s .3H), 2.39-2.18 (m, Ml).2,10-1.13 (m, 9H). m/z (ESI, +ve ion) 589.1 (M il) . EXAMPLE 895 , ( IS, 3 R, 6R, 7'R, IO'S, 1 / ¾> 6-CHLORO- 10'-METHYL-3 ,4- DIHYDRO-2H, 17 'H-SPIRO[NAPHTHALENE- 1 ,24'-

[8,12,22]TMOXA[15]THlA[l,16]DIAZAPENTACYCLO[16,7.2.i ⁷ - ¹ ^() ³ - ⁶ .0 ^2! - ²⁶ ]

OCTACOSA[l 8,2Q,26]TRTEN]-17'~ONE 15',1S'~DI0XIDE OR

(IS, 3'R, 6'R, 7R, 10'R, 11 S)-6-CHLORO-10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SP!ROiNAF!!!HA!JiM:- 1.24··.

[8,12,22]TRi:OXA[15]THIA|;i,161DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE I5',15'-DIOXIDE OR

(IS, 3 'R, 6'R, 7'S 10'R 11 ¾')- 6-CHLQRQ- 10'-METHYL-3,4-DlHYDRQ-2H, 17 Ή- SP1RO [NAPHTHALENE- 1 ,24'- 1 .12.22 ITR!OXA] Ι5| ^' Π Ι!Λ| 1. i 6iD! A/APLYl A( ^' V( ^' 1.0| 16.72.Γ".0 ^! " 0 ^''! '| OCTACOS A[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7'S.10 % 11 S)-6-CHLORO- 10-METHYL-3 ,4-DlHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8J2,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16,7.2.1 ⁷ · ³ ^0 ³ ' ⁶ .0 ²¹ · ²⁶ ] OCTACOSA[18,20,26]TR1EN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7 'S 10 ' 11 ¾> 6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPTRO[NAPHTH ALENE- 1 ,24'-

[8 ₅ 12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ]

OCTACOS A[ 18,20,26]TRIEN]- 17'-ONE 15', 15'-DIOXIDE OR

(IS, 3'R, 6'R, 7'S 10'R 11 'R)-6-CHLORO- 1 ()'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THL [1,16]DIAZAPENTACYCLO[16,7.2.1 ⁷ - ¹¹ ,0 ³ ^.0 ²¹ - ²⁶ ] OCTAC()SA[18,2Q,26jTRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3'R, 6'R, 7'R, 10 ¾ 11 '?)-6-CHLORO-10'-METOYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,I2,22]IIlOXA[15]IHIA[l,16]DlAZAl ⁵ ENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSAjl 8,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

(IS, 3 R, 6'R, 7'S.10% 11 'R)-6-CHLORO- 10'-ΜΕΤΉ YL~3,4-DIHYDRO-2H, 17Ή-

SPIRO [NAPHTHALENE- 1 ,24'-

I H, ! .22 jl IOXA! i 511 IIA| 1.1 Α|[)ΙΛΖ.\Ρΐ;ΧΤΛ(Ύ(Ί.0| !A.7.2. ! ^{' ! !} .0 ^; ".ϋ· ^ι '| OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

Step 1: (<S)-METHYL e'-CHLORO-S-^fi ^-^ /i^J^^-HYDROXY-S" METHYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBU L)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [I ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (<S)-METHYL 6'-CHLORO-5- (((1 2R) -2-((2R, 4S.5R)-4-HYDROXY-5-METHYL TETRAHYDRO-2H- PYRAN-2-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

C ARB OXYL ATE OR (<S)-METHYL &~Cm.O ~5~(i{lR2R)-2-{(2S, 4S,5S -4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBU L)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- C ARBOXYL ATE OR (S)-METHYL Λ ^' -Π U .ORO-5-((( //i.2R)-2~((2R, 4R, J^-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4' ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL G-CHLOR.O-5-{{{lR,2R)-2-((2S, 4R,5S)-4- HYDROXY-5-METHYL TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUlYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '- APHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/R,2/^2-((2R, 4R,5R)-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (5)-METHYL 6'-a-lLORO-5-(((lR.2RJ-2-((2R, 4R R 4~ HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBlJTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO[B][ l,4]()XAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE

TFA (5.1 mL) was added slowly to a solution of (<S)-methyl 6 ^f -chloro-5- (((H?,2i?)-2-formylcyclobutyl)methyl)-3^

spiro [benzo | b] [1,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Intermediate AA11A, Step 20A; 0.417g, 0.919 mmol) and 2-methyl-3-buten-l-ol (0.123 ml, 1.19 mmol) in DCM ( 10 mL) which was degassed with N ₂ It was stirred at rt for

22 min. The reaction mixture was added slowly to Na2C03 solution (40 mL) and MeOH (20 mL). After it was stirred at rt for 15 mm, the mixture was extracted with EtOAc (3x130 ml.). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1 % TFA, gradient elution) to provide the title compound (24 nig, second eluting peak) as a white solid, m/z (ESI, +ve ion) 540.1 ( M R )

Step 2; (5)-6'-CHLORO-5-(((7R, 2R)-2-((2R, 4S. JR)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO I BENZO [B] [1 ,4 ] OXAZEPINE-3, 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR 5)-6'-CHLORO-5 - ((( 11 2R) -2-((2R, 4S, 5R)-5 -METHYL-4-(2- S ULF AMO YLETHOXY)TETRAH YDRO-2H-P YRAN -2-

YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR (S)-6'-CHLORO-5-(((/R, 2R} -2-i(2S.4S, 55)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR ( _i S)-6'-CHLORO-5-(((/i?,2i? 2-^2S _; 4S;5i?)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B | [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR (S)-6'-CHLORO-5-(((H?, 2R)-2-((2R, 4R, 5S)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCI,OBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B | [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((7i¾ 2R)-2-((2S, 4R, JS)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3V^ l',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ][ 1,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID OR (S)-6'-CHLORO-5-(((H?, 2R)-2-((2R, 4R, JK)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR i.V}-6'-( i n .( ⁾ R()-^ -iV7 /,'V 2R)-2-((2R, 4R JR)-5-METHYL-4-(2- S ULF AMO YLETHOXY)TETRAH YDRO-2H-P YRAN -2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID

Sodium hydride (60% dispersion in mineral oil; 6.24 mg, 0 2% mmol) was added to a solution of (i ¾ methyl 6'-c loTO-5-(({lR,2R)-2-((2R, 4S)-4-hydTOxy-5- methyltetrahydro-2H-pyran-2-yl)cyclobutyl)m

spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox date (Example 895, Step 1 ; 0.024 g, 0.044 mmol) in THF (1.3 ml,), which was cooled by ice bath. After it was stirred at rt for 8 min N,N-bis(4-methoxybenzyl)ethenesulfonamide (Example 831, Step 2, 0.029 g, 0.084 mmol) in THF ( ! mL) was added. It was stirred at it for 2 h. Water (2 mL) and EtOAc (120 ml.) were added. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5um column; Phenonienex, Torrance, CA; MeCM in water with 0.1% TFA, gradient elution) to provide the title compound (7 mg).

2,045 Hydrolysis I: The residue was dissolved in THF (4 mL), MeOH (4 mL) and 1 M

LiOH solution (3 mL) and the mixture was stirred at 50°C for 2.5 h. It was concentrated, acidified with 1 N HCl solution to pH 2-4, extracted with EtOAc (80 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate and concentrated.

Hydrolysis II: The residue was dissolved in 1 :3 TFA/DCM (4 ml.) and stirred at rt for 20 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (5 mg) as a white solid, m/z (ESI, +ve ion) 633.1 ( \ 1 · 1 1 :· .

Step 3 : (IS, 3 R, 6R, 7'R, lO'S, 11 ¾)-6-CHLORO-l 0'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

|;8, 12,22jTRIOXA[ 15 jTH:iA[ l ,16]DIAZAPENTACYCL()|;i6.7.2.1 ⁷ - ¹ ^0 ^3> ^0 ^2! - ² ^ OCTACOS A[18,20,26]TRiEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 , 7R, 1 OR, 11 ¾)-6-CHLORO - 10'-METHYL-3,4-DIHYDRQ-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8, 12,22]TTUOXA[ 15]THIA[l ₅ 16]DTAZAPENTACYCLO[ 16.7.2. 1 ⁷ ' .0 ³ ' ⁶ .0 ²¹ - ²⁶ ]

OCTACOSA[18,20,26]TRIEN]-17'-QNE 15 ', 15 '-DIOXIDE OR

(IS, 3 , 6'R, 7'S 10 , 11 ¾ 6-CHLORO- 1 ()'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 .2 -

[8 ₅ 12,22]TRIOXA[ 15]THIA[l ,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOS A[ 18,20,26]TRIEN] - 17'-ONE 15', 15'-DIOXIDE OR

(1S 3R, 6R, 7'S lO'S, 11 ¾)-6-CHLORO-l()'-METHYL-3,4-DIHYDRO-2H, l 7Ή- SPIRO [NAPHTHALENE- 1 ,24'- ^! " | OCTACOSA[18,20 ₅ 26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7 'S / 0 'S, 11 '5)-6-CHLORO - 10'-METHYL-3,4-DIHYDRO-2H, 1 7 Ή- SPIRO[N APHTHALENE- 1 ,24'- [8, 12,22]II lOXA[ 15]IHIA[ l ,16]DlAZAl ⁵ ENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ^2e OCTACOSA[ 18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR (IS, 3'R, 6'R, 7'S.10'R, 11 ?)~6~CHLORO~ 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8/12,22]TllOXA[15]THIA[L16]DlAZAl ⁵ ENTACYCLO[16 .2 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

(IS, 3 'R, 6'R, 7'R, lO'S 1 / 'R)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, ! .7Ή- 8ΡΠ ( ⁾ !\ΛΡΗΠ1Λ!.ί·\Ί·:-Ι.2·Γ-

|8.!2.22|TR!()XAj Ι5|ΠΠΑ| ! . ί 6iD! Α/ΛΡΗΝΤΛίΎΠ.ΟΙ 167.2.1 ^{1 i} .(i ^; '\(K ^{l :} "| OCTACOSAjl 8,20,26]TRIE ]-17'-ONE 15',15'-DIOXIDE OR

(IS, 3 'R.6'R, 7'S.10'S, 11 'R)-6-CHLORO- 10'-METH YL~3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ . ⁽⁾²¹ · ²⁶ ] OCTACOSA[l 8,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE

N,N-Dimethylpyridin-4-amine (DMAP) (0.014 g, 0.118 mmol) was added to a solution of (1 ¾)-6'-chloro-5-(((ii?, 2R)-2-((2S, ^)-5-me1hyl-4-(2- sulfamoylethoxy)tetrahydro-2H-pyran-2-yl)c>'clobutyl)meth yl)-3',4,4',5- tetrahydro-2H,2'H-spiro[benzo[b][L4]oxazepine-3,r-naphthalen e]-7-carbox\'lic acid (Example 895, Step 2; 0.005 g, 7.9 μηιοΐ) in DCM (32 mL) at 0°C. Then Nl- ((ethylimino)methylene)-N3,N3-dimethy]propane-l,3-diarnine hydrochloride (EDC; 0.018 g, 0.095 mmol) was added slowly in portions and it was stirred at

0°C to rt for 23 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5um column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (2.7 mg) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.76 (d, ./ 8. 1 Hz, 1H), 7,20 (dd, ./ 2.05.8.31 Hz, 2H), 7.12 (d, ./ 215 Hz, 1H), 7.07 (d, J=\ .96 Hz, III).6,96 (d, ./ 8.22 Hz, 1H), 4.09-4.15 (m, 2H), 3.96-4,08 (m, 2H), 3.83 (dd, J=2.84, 7.92 Hz, 1H), 3.65-3.80 (m, 4H), 3.57 (br. s., ills.3.43 (dd, ./ 4.50.11.15 Hz, lH), 3.22-3.29 (m, !!!).3.11-3.21 (m, 2H), 2.76-2.87 (m, 2H), 2,68 (s, 1H), 2,45-2.53 (m, 1H), 2.17-2.24 (m, 1H), 1.30-2.11 (m, 9H), 0.89-0,96 (m, ΓΗ), 0.84 (d, ,7=6,85 Hz, 3H). m/z (ESI, +ve ion) 615.0 (M+H) ⁺ . EXAMPLE 898. (1S,3R, 6R, 7 ^, ^)-6-CHLORO-7'-(HYDROXYMETHYL)-3,4- DIHYDRO-2H, 15 Ή-SPIROj NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[16,18,24]TRIEN]-15'-QNE 13',13'-DI0X1DE OR (1S, 3'R 6'R 7'5)-6-CHLORO- 7'-(HYDROXYMETHYL)-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1 ,22'[20]OXA[13]THIA[1 ,14]DIAZATETRACYCLO[l 4.7.2.0 ³ 0 ^{, 9} - ²⁴ ]PENTAC QSA[16,18,24]TRiEN]-15'-ONE 1 '. 1 '-l)!()XH)i- ^'

A solution of (IS, 3 R, 67?)-6-cMoro-7'-methylidene-3,4-dihydro-2H, 15Ή- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l,14]<Hazatetracy^

15'-one 13',13'-dioxide (Example 904; 0.G18g, 0.031 mmol) in THF (1.5 mL) was cooled with ice hath. 9-BBN (0.5 M solution in tetrahydrofuran, 1.2 mL, 0.62 mmol) was added dropwise. After it was stirred at rt for 1 h, MeOH (10 mL) and trimethylamine N-oxide (0.208 g, 1.86 mmol) were added in one portion and the mixture was stirred at rt for 2 h. Then it was concentrated. The residue was stirred in MeOH (30 mL) at 68¾ for 20 h. It was diluted with water and extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column: Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution), ) to provide the title compound (6.2 m, second eluting peak) as a white solid. *H NMR (400 MHz, CD2CI2) δ 7.77 (m, IH), 7.19 (m, 2! I ). 7.13 (m, I H), 7.04 (m, I H), 6.97 (m, IH), 4,44 (m, IH), 4.17-4.04 (m, 2H), 4,00-3,82 (m, 2H), 3.81-3.69 (m, 2H), 3,63 (br. s . IH), 3.19-3.05 (m, IH), 2,90-2.74 (m, 2H), 2.65-2,48 (m, IH), 2.39 (d, J=5.48 Hz, IH), 2.25-2.18 (m, IH), 2.12 (d, J=12.72 Hz, IH), 2.06- 1.26 (m, 1 7! ! ). m/z (ESI, +ve ion) 587.1 (M+H)-

EXAMPLE 900. (3R, 6R,, 7R, IIS,24S)-6'-CHLORO-\ 1 -HYDROXY-3',4'- DIHYDRO-2'H, 17H-SPIRO[8,22-DIOXA-15-THIA-l, 16- DI AZAPENTACYCLO [ 16.7,2.1 ^' · " .0 ^; '·.0 ²¹ · ²⁶ ] OCTACOS A- 18,20,26-TRIENE- 24,l '-NAPHTHALENj-17-ONE 15,15-DIOXIDE OR (3R, 6R, 7S lR, 24S)-&- CHLORO- 1 1 -HYDROXY-3^4'~DIHYDRO-2'H, 17H-SPTRO[8,22-DIOXA- 15- THIA- 1 , 16-DIAZAPENTACYCLO[l 6.7.2.1 ⁷ · ^π .0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCTACOSA- 18,20,26- TRIENE-24, Γ-NAPHTHALEN] - 17-ONE 15, 15-DIOXIDE OR

(3R, 6R, 7R, liR, 24S)-6'-CHLORO- 1 1 -HYDROXY-3',4'-DIHYDRO-2'H, 17H- SPIRO[8,22-DIOXA- 15-ΊΉΙΑ- 1 , 16-

DIAZAPENTACYCLO[[16.7.2.1 ⁷ ' ¹¹ .0 ³ - ⁶ .0 ²¹ ' ²⁶ ]OCTACOSA-18,20,26-TRIENE- 24,l '-NAPHTHALEN|-17-ONE 15,15-DIOXIDE OR (3R, 6R, 7S 1S,24S)-G- CHLORO- 1 1 -HYDROXY-3',4'-DIHYDRO-2'H, 17H-SPTRO[8,22-DIOXA- 15- THIA- 1 , 16-DIAZAPENTACYCLO[l 6.7.2.1 ⁷ · ^π .0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCTACOSA- 18,20,26- TRIENE-24, Γ-ΝΑΡΗΤΗ ALEN] - 17-ONE 15,15-DIOXIDE

Step 1 : (S)-METHYL 6'-CHLORO-5-(((H2, 2R)-2-((2S, 4.S )~4~

HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- S'^^'^-TETRAHYDRO-ffl^'H-SPIROpENZOPl tl^lOXAZEPINE-a,! '- NAPHTHALENE]-7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((//?, 2/^-2-†2^, ^i?)-4-HYDROXYTETRAHYDRO-2I-I-PYRAN-2- YL)CYCLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 45)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- S'^^'^-TETRAHYDRO-ffl^'H-SPIROpENZOPl tl^lOXAZEPINE-a,! '- N APHTHALENE] -7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- 4R)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE

TFA (6 mL) was added slowly to a solution of (&)-methyl 6'-chloro-5- (((/R,2R)-2-formyl cyclobutyl)methyl)-3',4,4',5-tetraltydro-2H,2T-I- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Intermediate

AA11A, Step 20A, 0.412 g, 0.908 mmol) and 3-buten-l-ol (0.10 ml, 1.18 mmol) in DCM (12 mL) which was degassed with N2 It was stirred at rt for 35 mm. The reaction mixture was added slowly to Na2C03 (aq) solution (50 mL) and MeOH (15 mL). After the mixture was stirred at rt for 83 min, it was extracted with EtOAc (3x90 mL). The combined organic phases were dried over anliydrous sodium sulfate and concentrated. The residue was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/'mm CO2 on a Thar 80 SFC. Outlet pressure 100 bar; Temp. 20 °C; Wavelength 220 nm) to provide the title compound (128 mg, first eluting isomer) as a white solid, m/z (ESI, +ve ion) 526. 1 (M+H) ⁺ . Step 2: (S)-METHYL 6'-€ΗίΟΚΟ-5-(((7Λ, 2Λ -^-4-ΟΧΟΤΈΤΚΑΙ1ΥΟΚΟ- 2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2H,2 ^" H-SPIR0[BENZ0[B] [ l ,4]0XAZEPINE-3;r-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((iR, 2R -2-^K)-4- OXOTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUWI METHYL)-3',4,4',5- TETRAHYDRO-2H,2 Ή-SPIRO [BENZO [B] [ 1 ,4]OXAZEPINE~3, 1 *- NAPHTHALENE] -7-CARBOXYLATE

A 50 ml, flask was charged with dimethyl sulfoxide (0.051 mL, 0.724 mmol) and DCM (3.5 mL) was cooled to -78 °C. Oxalyl chloride (2.0 M solution in DCM, 0.18 mL, 0.36 mmol) was added dropwise slowly and the reaction stirred for 15 min. (S)-Methyl (y'-cUo -5 (( !R, 2R)-2-((2R S)-4- yd^

pyran-2-}d)cyclohutyl)meth}d)-:r,4,4V5-tetrahydro-2H,2 ^' H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Example 900, Step 1 , 0.127 g, 0.241 mmol) in DCM (3.5 mL) was added in one portion to above solution. It was stirred at -78°C for 20 min. Then triethylamine (0.17 mL, 1.2 mmol) was added and it was stirred at -78°C to rt for 2 h. It was quenched with water (3 mL) and extracted with EtOAc (130 mL). The organic phase was washed with 1 N HC1 solution (2 mL), brine and dried over anhydrous sodium sulfate. It was filtered through silica gel to provide the title compound (126 mg) as a white solid, in / (EST, +ve ion) 524, 1 ! YM ! ) Step 3 : (5)-METHYL 6'-CHLORO-5-(((H2, 2R)-2~((2S, 4S)-4-HYDRQXY-4- VINYLTCTRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((7i¾2i?^-2-(†25 i)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MEra:YL)-3',4,4',5-TETRAHYDRO-2H,2'I-i- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] ~7~

C ARB OXYL ATE OR (<S)-METHYL 6'-CHLORO-5-(((Hi 2R)-2-((2R, 4S)-4- HYDROXY -4- VINYLTETRAHYDRO -2H-P YRAN -2 - YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H ₅ 2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((iR, 2R)-2-((2R, 4R)-4- HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] - 7- C ARB OXYL ATE

Vinylmagnesium chloride (1.6 M solution in tetrahydrofuran, 0.50 mL, 0.79 rnmol) was added dropwise to a solution of (S)-methyl 6'-chloro-5-(((/i?,2i?)- 2-( ft)-4-oxotetrahydro-2H-pyran-2-yl)cyd^

2H,2'H-spiro[benzo[b][l ,4]oxazepine-3, -naphthalene]-7-carboxylate (Example 900, Step 2, 0, 126 g, 0.240 ramol) in THF (8 mL) at 0°C, It was stirred at 0°C for 20 min. It was quenched with NH4CI solution and extracted with EtOAc (180 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered through short plug of silica gel and concentrated to gi v e the title compound (133 mg) as an oil. mlz (ESI, +ve ion) 552. 1 (M+H) ⁺ .

Step 4: (5)-6'-CHLORO-5-(((H¾, 2R)-2-((2S, 4S)-4-HYDROXY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL) METHYL)- : ,4,4 5-TETRAHYD O-2H,2Ί-I-SPIRO[BENZO[B] [ l,4]O AZEPINE-3,l ^f - NAPHTHALENE] -7-C ARBOXYLIC ACID OR (<S')-6 ^, -CHLORO-5-(((H? ₎ 2RJ-2- ^2-S R)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (SY6'-CHLORO-5-(((lR2R)-2-((2R 4S)-4-HYDROXY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBLTTYL)METHYL)-

3 ',4,4',5 -TETRAHYDRO -2H,2 Ή-SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 ^* - NAPHTHALENE] -7-C ARBOXYLIC ACID OR (5^-6 ^, -CHLORO-5-(((iR,2R -2- ^2/t 4R)-4-HYDROXY-4-VINYLTETRAIiYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, 1 -NAPHTHALENE] -7-C ARBOXYLIC ACID

Lithium hydroxide (1.0 M aqueous solution, 7.2 mL, 7.2 mmol) was added to a solution of (1 ¾)~methyl

vinyltetrahydro-2H-pyran-2-yl)cyclobutyl)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [ l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 900, Step 3, 0, 133 g, 0.241 mmol) in THF (16 mL) and MeOH (8 mL). It was stirred at 50°C for 3 h. The reaction mixture was concentrated, acidified with IN HC1 solution to pH 2-4, extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep C is 5}im column; Phenomenex, Torrance, CA; MeCN in water with 0. 1 % TFA, gradient elution) to provide the title compound (50 mg, second elutmg isomer) as a white solid, m/z (ESI, +ve ion) 538. 1 (M+H)\

Step 5 ; PROP-2-ENE-1 -SULFONAMIDE

To a solution of ammonia (0.5 M solution in THF, 100 mL, 49.8 mmol) under N ₂ was added 2-propene-l -sulfonyl chloride (2.0 mL, 14.2 mmol, Matrix Scientific). The mixture became cloudy upon addition, and was left stirring at rt for 4 h. To the mixture was added water, 1.0 N HC1 and it was extracted with EtOAc. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 40g ISCO Gold column and eiuted with 0 % to 100 % EtOAc/hexane to provide the title compound (669 mg) as a colorless solid. ^! H NMR (400MHz, CDCb) δ 6.05 - 5.89 (m, lH), 5.57 - 5.41 (m, 2H), 4.99 - 4.78 (m, 2H), 3.89 - 3,79 (m, 2H).

Step 6: (5 N-(ALLYLSULFONYL)-6 ^, -CHLORO-5-(((7R,2 y-2-CC2S', 4S)-4- HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4 ^! ,5-TETRAHYDRO-2H ₅ 2'H~

SP1RO [BENZO [B] [ 1 ,4] OXAZEP1NE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE OR (S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7R, 2R 2- f 2^, ¥i?)-4-HYDROXY-4-VrNYLTETRAHYDRO-2H-PYRAN-2- YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR0[BENZ0|;B][ 1,4]0XAZEPINE-3,1'-NAPHTHALENE|-7- CARBOXAMTDE OR (5)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7i¾ 2R)-2- ( (2S, 4i?)-4-H YDROXY-4 - VIN YLTETRAHYDRO-2H-P YRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO [BENZO [B] [1 ,4]OXAZEPTNE-3, 1 '-NAPHTH ALENEj-7-

CARBOXAMIDE OR (S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7R, 2RJ-2- ^2R R)-4-HYDROXY-4-VI]SIYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2H,2'I-i- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (0.016 g, 0.13 mmol) was added to a solution of (S &-chloro-5-(((lR, 2R)-2-((2R, 45 -4-hydroxy-4-vinyltetrahydro- 2H-pyran-2-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H - spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 900, Step 4; 0.023 g, 0.043 mmol) and prop-2-ene-l -sulfonamide (Example 900, Step

5; 0.020g, 0.167 mmol) in DCM (1.4 mL) at 0°C. Then Ni- ((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (EDC) (0.017 g, 0.090 mmol) was added in portions and it was stirred at 0°C to rt for 3 days. Then it was concentrated. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0. 1 % TFA, gradient elution) to provide the title compound (5.2 mg) as a white solid, m/z (ESI, +ve ion) 641.1 ⁽ M R )

Step 7: (3R 6R.7R IS, /2£,24S)-6'-CHLORO-l l -HYDROXY-3',4"-DIHYDRO- 2 Ή, 17H-SPIRO [8,22-DIOXA- 15-ΊΉΙΑ- 1 , 16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ - ^{! !} .0 - ⁶ .0 ²¹ - ²⁶ ] OCTACOSA- 18,20,26-TRIENE- 24, 1 '-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3R 6 7S 1R 2E, 24S)~ 6'-CHLORO- 11 -HYDROXY-3',4'~DIHYDRO~2'H,l 7H-SPIRO[8,22-DIOXA- 15- THIA- 1 , 16-DlAZAPENTACYCLOi 16.7.2.1 ⁷ · ^π .0 ^3>6 .0 ²¹ · ²⁶ ] OCTACOSA- 18,20,26- TRIENE-24, Γ-NAPHTHALEN] - 17-ONE 15, 15-DIOXIDE OR

(3R, 6R, 7R, 11R, 12E, .?. _f '.S 6 ^' -C! II .ORO- 1 1 -I-IYDROXY-3',4'~DII YDRO- 2Ή, 17H-SPiRO[8,22-DIOXA-l 5-THIA- 1 , 16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ - ^{! !} .0 - ⁶ .0 ²¹ - ²⁶ ] OCTACOSA- 18,20,26-TRlENE- 24,r-NAPHTHALEN]-17-ONE 15, 15-DIOXIDE OR (3R 6R, 7S) US /2£24,S)-6'- CHLORO-l l-HYDROXY-3',4'-DIHYDRO-2'H,17H-SPIRO[8,22-DIOXA-15- ΊΉΙΑ- 1 , 16-DI AZAPENTACYCLOj; 16.7.2.1 ^7Λ K 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCTACOS A- 18,20,26-TRI ENE-24, 1 '-N APHTHALEN] - 17-ONE 15,15 -DIOXIDE

A 250 niL round bottom flask was charged with (5)-N-(allylsulfonyl)~6'~ cMoro-5-(((lR2R)-2-((2S, 4R)-4-hydroxy-4-Yim

yl)cyclobu1yl)methyl)-3^4,4^5-tetrahydfo-2H,2'H-spiro[ben zo[b] [l,4]oxazepine- 3,l'-naphthalene]-7-carboxamide (Example 900, Step 6, 5.2 mg, 8.1 μίηοΐ) in toluene (17 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/¾ack-filling with nitrogen. To the homogeneous solution was added a solution of Hove da-Grubbs II (1 mg, 1.6 μη οΐ) in toluene (3 ml,). The mixture was stirred at 106°C under nitrogen for 1 h. Then it was concentrated. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep C is 5μιη column: Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (3 mg) as a w hile solid, m/z (ESI, +ve ion) 613.0 i .V! · ! !} ^· . Step 8 : ( JR, 6R, 7R, 1 IS, 24S)-6'-CHLORO- 11 -HYDRQXY~3',4'-DiHYDRO- 2Ή, 17H-SPIRO[8,22-DIOXA-l 5-THIA- 1,16-

DIAZAPENTACYCLO| 16.7.2.1 ⁷ - ^{! !} .0 - ⁶ .0 ²¹ - ²⁶ ] OCTACOSA-18,20,26-TRIENE- 24, l '-NAPHTHALEN]- 17-ONE 15,15-DIOXIDE OR (3R, 6R, 7S lR 24S)-6'~ CHLORO-l l-HYDROXY-3 ^, ,4 ^, -DIHYDRO-2'H,17H-SPIRO[8,22-DIOXA-15- THIA- 1 , 16-DlAZAPENTACYCLOi 16.7.2.1 ⁷ · ^{! !} .0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- TRIENE-24,r-NAPHTHALEN]-l 7-ONE 15,15-DIOXIDE OR

(3R, 6R, 7R, ll 24S &-CHLORO-l l-HYDROXY-3' ₅ 4'-DIHYDRO-2'H,17H- SPIRO[8,22-DIOXA- 15-THIA- 1,16-

DIAZAPENTACYCLOI116.7.2.1 ⁷ - ^{! !} .0 - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA-18,20,26-TRIENE- 24, l '-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3jR, 6jR, 7S IS,24S)-6'- CHLORO-l l-HYDROXY-3 ^, ,4 ^, -DIHYDRO-2'H,17H-SPIRO[8,22-DIOXA-15- THIA- 1 , 16-DlAZAPENTACYCLOi 16.7.2.1 ^{7>! !} .0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- TRIENE-24,r-NAPHTHALEN]-l 7-ONE 15,15-DIOXIDE

Platinum (IV) oxide (1.1 mg, 4.9 μηιοΐ) was added to a solution of

(3R.6R R.JJS 2E 4S)-6'-ch\oroAl~hyd^

(Uoxa-15-lMa-l,16-diazapentac'clo[16J.2 ⁷ ' ⁱⁱ .0 ³ ' ⁶ .() ^2l ' ^% ]octacosa-18,20,26- triene-24,l'-naphthalen]-17-one 15,15-dioxide (Example 900, Step 7, 0.003 g, 5 μηιοΐ) in EtOAc (5 mL). It was stirred under H ₂ for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA: MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (1.2 mg) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.15 (m, IH), 7.71 id../ 8. 1 Hz, IH), 7.19 (m, IH), 7.07- 7,12 (m, IH), 6.96 (m, 2H), 6.86 (ra, IH), 4,63-4,52 (m, IH), 4.13-4.06 (ra, 2H), 3,89-3.78 (m, 3H), 3.75-3.66 (m, 2H), 3.31 (ddd, ./ 6.26.11.98, 14,82 Hz, ill). 3.22 (d, ./ 14.28 Hz, IH), 3.00 (dd, ./ 9.68.14.97 Hz, IH), 2.81-2.71 (m, 2H), 2.43 (br. s., 2H), 2.06 (d, J=13.50 Hz, i l l ). 2,00-1.19 (m, 16H). m/z. (ESI, + ve ion) 615.0 (M+H) ⁺ .

EXAMPLE 901. (3R, 6R, 7R, 11S, 24S)-G-CHL0R0-1 l-HYDROXY-3',4'- DIHYDRO-2'H,17H-SPIRO[8 ₅ 22-DIOXA-l 5-THIA-l ,16-

DIAZAPENTACYCLO

24,r-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3R 6R 7S, 1 IR, 24S)-6'- CHLORO-l l -HYDROXY-3',4'-DIHYDRO-2 ^, H,I7H-SPIRO[8,22-DIOXA-15- ΊΉΙΑ- 1 , 16-DIAZAPENTACYCLO[ 16.7.2.1 ⁷ - ^{"! 1} , 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- TRIENE-24, -N APHTHALEN] - 17-ONE 15, 15-DIOXIDE OR

(3R, 6R, 7R, 1 IR 24S)-6'-CHLORO - 11 -H YDROXY-3 ',4'-DIH YDRO-2'H, 17H- SPIRO[8,22-DIOXA~ 15-THIA- 1 , 16-

DIAZAPENTACYCLOIie.T^. l'^^O'^.O^'^lOCTACOSA-l S^O^e-TRIENE-

24,l'-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3R 6R 7S 1S,24S)-G- CHLORO-11 -HYDROXY-3',4'-DIHYDRO-2 ^, H,I7H-SPIRO[8,22-DIOXA-15- ΊΉΙΑ- 1 , 16-DIAZAPENTACYCLO[l 6.7.2.1 ⁷ - ^{"! 1} , 0 ³ ' ⁶ .0 ²¹ · ²⁶ ] OCTACOS A- 18,20,26-TRlENE-24, 1 '-N APHTHALEN] - 17-ONE 15,15 -DIOXIDE

Step 1 : (S)-6'-CHLORO-5-(((/R, 2R)-2-((2S, ,S 4-HYDROXY-4-

VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METT L)- S'^^'^-TETRAHYDRO^^'H-SPIROpENZOPltl^lOXAZEPINE-a,!'- APHTH ALENE] -7 -C ARB OXYLIC ACID OR (S)-6'-CHLORO-5-(((7R,2R;-2-

^2S;4i?)-4-HYDROXY-4-VINYLTETRAHYDR()-2H-PYRAN-2- YL)CYCLOBU L)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO 5-(((lR,2R)-2-((2R 4S 4-HYDROXY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ^' .4. ^. Γ.5-ΊΤ. ΓΚΛΙ iVDRO-2! f.2 ^' 1 l-Si'IRO| ί ^; Ν/0| B|| U | OXAZEPINE-3, Γ- N APHTH ALENE] -7 -C ARB OXYLIC ACID OR (5)-6'-CHLORO-5-(((iR,2R-2- ^2i?,4/?)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYR _! 4N-2-YL)

CY ^T CLOBUTYL)METOYL)-3 ^f ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

Lithium hydroxide (1.0 M aqueous solution, 7.2 mL, 7.2 mmol) was added to a solution of (/ ¾ -methyl 6'-ch\oTO-5-(((lR,2R)-2-((2R)-4- ydroxy-4- vinyltetrahydro-2H-pyran-2-yl)cyclobutyl)metfy^

spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Example 900, Step 3; 0.133 g, 0.241 mmol) in THF (16 mL) and MeOH (8 mL). It was stirred at 50°C for 3 h. The reaction mixture was concentrated, acidified with IN HC1 solution to pH 2-4, extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (29 mg, first eluting peak) as a white solid, m/z (ESI, +ve ion) 538, 1 (M+H) ⁺

Step 2: (S N-(ALLYLSOL¥ONYL 6' l-lLORO^(((lR,2Rj-2-((2S, 45)-4- HYDROXY-4-VINYLTET AHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXAMIDE OR (5)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((H¾, 2R}-2~ CC2S; 4R)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4' ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE OR (5)-N-(ALLYLSULFONYL)-6'-CHLORO-5-((( R, 2/^-2- f 25', i?)-4-HYDROXY-4-V]NYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRQ [BENZO [B] [ l,4]QXAZEPINE-3, 1 '-NAPHTHALENE j-7-

C ARB OX AMID E OR (S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7R, 2Rj-2- f ^' f ^, 4 ^)-4 TYD OX ^τ -4 ^r INYI ETRAI-Γt DRO-2ϊ-ΐ-PY AN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPlNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXAMIDE

N,N-dimethylpyridin-4-amine (DMAP) (5,7 mg, 0.047 mmol) was added to a solution of (S)-6'-c \oro-5-(((lR,2R)-2-((2R,4S) - ydroxy-4-v^ 2H-pyran-2-yl)(¾'clobutyl)methyl)-3',4,4',5-tetrahydro-2H,2 'H- spiro [benzo [b] [ 1 ,4] oxazepme-3 , -naphtha! ene] -7-carboxy lie acid (Example 901 ,

Step 1 ; 0.023 g, 0.043 mmol) and prop-2-ene-l -sulfonamide (Example 900, Step

5; 0.013 g, 0.11 mmol) m DCM (0.6 nil . ) at 0°C. Then Nl- ((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine h drochloride (EDC; 6.3 mg, 0.033mmol) was added in portions and it was stirred at 0°C to rt for 3 days. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep C J S 5μιη column; Phenomenex, Torrance, CA: MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (3.1 mg) as a white solid, m/z (ESI, +ve ion) 641.1 (M+H) ⁺ .

Step 3 : (3R 6R. 7R.1 IS, 12E, 24S)-6'-CHLORO- 11 -HYDROXY-3',4'-DIHYDRO- 2 Ή, 17H-SP1RO [8,22-DIOXA- 15-ΊΉΙΑ- 1,16-

DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^η .0 ^3>6 .0 ²¹ · ²⁶ j OCTACOS A- 18,20,26-TRIENE- 24,l'-NAPHTHALEN]-! 7-ONE 1 5, 15-DIOXIDE OR (3R 6R 7S, I W, 12E,24S)- 6 ^, -CHLORO-l l-HYDROXY-3 ^, ,4 ^* -DIHYDRO-2'H,17H-SPIRO[8,22-DIOXA-15- ΊΉ1Α- 1 , 16-DIAZAPENTACYCLO[ 16.7.2.1 \ 0 ³ · ⁶ . () ²ⁱ · ²⁶ ] OCTACOS A- 18,20,26- TRIENE-24, 1 ' -N APHTH ALEN] - 17-ONE 15, 15-DIOXIDE OR

(3R.6R. 7R.11R /2£ ^' , 245)-6 ^! -CHLORO-l l-HYDROXY-3',4'-DIHYDRO- 2 Ή, 17H-SP1RO [8,22-DIOXA- 15-THIA- 1,16-

DIAZAPENTACYCLO[ 16.7.2.1 ⁷ .».0 ^3>6 .0 ²¹ · ²⁶ j OCTACOS A- 18,20,26-TRIENE- 24, Γ-Ν APHTH ALEN] - 17-ONE 1 5, 15 -DIOXIDE OR (3R 6R 7S, US 12E,24S)~G~ CHLORO-l l-HYDROXY-3',4'-DIHYDRO-2'H,17H-SPIRO[8,22-DIOXA-15- ΊΉ1Α- 1 , 16-DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ¹ K 0 ³ · ⁶ . () ²ⁱ · ²⁶ ] OCTACOS A- 18,20,26- TRIENE-24, 1 '-NAPHTH ALEN]-!.7-ONE 15, 15-DIOXIDE

A 250 mL round bottom flask was charged with (5)-N-(allylsulfonyl)-6'- chioro-5-(((Hi 2R)~2~((2S, R)-4-hydroxy-4-vinyltetrahydro-2H-pyran-2- y cyclobut methy^-S'^^'.S-tetrahydro- H^'H-spirotbenzotbJ tl^Joxazepine-

3 ,1 '-naphthalene j-7-carboxamide (Example 901, Step 2; 3.1 mg, 4.8 μηιοΐ) in toluene (17 mL). it was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (1 mg, 1.6 μηιοΐ) in toluene (3 mL). The mixture was stirred at 106 °C under nitrogen for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1 % TFA, gradient elution) to provide the title compound (3 mg) as a white solid, m/z (ESI, +ve ion) 613.0 (M+H) ⁺ .

Step 4; (3R, 6R, 7R, 1 IS, 24S -6 ^* -CHLORO- 1 1 -HYDROXY-3\4'-DIHYDRO- 2 1 1.17H-SPIRO [8,22-DI OXA- 15-ΊΉΙΑ- 1 , 16- DL ZAPENTACYCLO[16.7.2.1 ⁷ ^0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA-18,20,26-T1 1ENE- 24,r-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3R 6R 7S, / 1R, 24S)-6'- CHLORO-n -HYDROXY-3',4 ^, -DIHYDRO-2'H ₅ 17H-SPIRO[8 ₅ 22-DIOXA-15- THI A- 1 , 16-DT AZAPE TACYCLO[ 1 7.2.1 ^{" ss} 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- TRIENE-24,T-NAPHTHAL-EN]-17-ONE 15,15-DIOXlDE OR

(3R, 6R, 7R, 245 6'-CHLQRQ-l l-HYDRQXY-3',4'-DIHYDRQ-2'H,17H- SPIRO [ 8,22-D IOXA- 15-THIA- 1 , 16- DIAZAPENTACYCLO[16.7.2.1 ⁷ - ⁿ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ]OCTACOSA-18,20,26-TRIENE- 24, Γ-NAPHTHALEN] - 17-ONE 15,15-DlOXIDE OR (3R6R 7S,llS,24S)-6'- CHLORO-ll-HYDROXY-3 ^, ,4 ^, -DIHYDRO-2'H ₅ 17H-SPIRO[8,22-DIOXA-15- THI A- 1 , 16-DT AZAPE TACYCLO[ 1 7.2. f ^;; 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- TRIENE-24, T-NAPHTHAL-EN]-17-ONE 15, 15-DIOXlDE

Platinum (IV) oxide (1.1 mg, 4.83μιηο1) was added to a solution of (3R.6R.7R.JJS,12E,24S)-6'-ch\oroAl~hyd^

dioxa-15-thia-l,16-diazapentacyclo-16.7.2.1 ⁷ ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ]octacosa-18,20,26- triene-24,l'-naphthalen]-17-one 15,15-dioxide (Example 901, Step 3; 0.003 g, 5 μηιοΐ) in EtOAc (5 mL). It was stirred under H ₂ for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (1.3 mg) as a white solid. ¾ NMR (400 MHz, CD ·(·!·■} δ 8.24 (s, 1H), 7.72 (d, ./ 8.4! Hz, 1H), 7.18 (dd, ./ 2.35. 8,41 Hz, 1H), 7.08 (ra, 2H), 6,96 (m, ill).6.61 (d, J=l .96 Hz, 111).4.07 (m, 2H), 3,88 (m, 1H), 3.84-3.75 (m, 2H), 3.57-3,45 (m, 2H), 3.41 id.,/ 121 Hz, ill). 3.27 (d, J=14.08 Hz, IH), 3.11 (dd, J=10.17, 15.65 Hz, 1H), 2.83-2.73 (m, 2H), 2,42 (m, IH), 2.33-2.20 (m, 2H), 2.18-1.20 (m, 17H). m/z (ESI, +ve ion) 615.0 (WW) .

EXAMPLE 904, (IS, 3 % 6'i?)-6-CHLORO-7'-METOYLIDENE-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DL ZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

At 0°C, bis cyclopentadieny -^i-cliloroidimethylaluminum)- _, !!- niethylenetitaniurn, (Tebbe's reagent, 0.5 M solution in toluene, 10.5 mL, 5.25 mmol) was added to a solution of (IS. 'R, 6 ^" ?)-6-chloro-3,4-dihydro-2H,7 ^f H, 15'h- spiro[naphthalene-l,22'-[20]oxa[13]thia[l ,14]

diazaietracyclo[ 14.7.2.() ³ '^0 ¹⁹ - ²⁴ ]pentacosa|;i 6,18,24|inene]-7',15'-dione 13',13'- dioxide (Example 832, 0.150 g, 0.263 mmol) in THF (10.5 mL). It was stirred at 0°C for 5 min. The reaction mixture was poured into ice water (30 mL), acidified with 1 N HCl solution to pH 3-5, extracted with EtOAc (3x70 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 4g ISCO Gold column and eluted with 0 % to 15 % EtOAc (containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (123 mg) as a white solid. ^] H NMR (400 MHz, CD2CI2) δ 8.05 (m, IH), 7.72 (m, 1H), 7.17 (m, IH), 7.09 (m, IH), 6,93 (m, 2H), 6.83 (m, IH), 4.79 (s, IH), 4.73 (d, J=1.56 Hz, i l l ). 4, 15-4.06 (m, 2H), 3.97-3.87 (ni, IH), 3.78-3.69 (m, 2H), 3.35-3.23 (m, 2H), 3.06 (dd, J=8.02, 15.45 Hz, IH), 2.84-2.74 (m, 3H), 2.60-2.50 (m, IH), 2.08-1.38 (m, 14H). m/z (ESI, +ve ion) 569,0 ( V! 1 1) ,

EXAMPLE 905. (IS 'R, i5'i?,9'ii)-6-CHLORO-3,4-DIHYDRO-2H,7 ^! H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

| 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [9, 16, 18,24]TETIL E E] -7', 15'-DIONE 13', 13'-D10XIDE

A flask charged dimethyl sulfoxide (0.10 mL, 1.42 mmol) and DCM (2 mL) was cooled to -78°C. Oxaiyl chloride (2.0 M solution in DCM, 0.36 mL, 0.71 mmol) was added dropwise and the reaction was stirred for 30 min. A solution of (IS, 3'R, 0'#//¾9'£>6-chto

l,22'-[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]

pentac-osa[9,16,18,24]tetraen]-15'-one-13',13 ^, -dioxide (Example 846, 0.058 g, 0.102 mmol) in DCM (1.2 mL) was added dropwise and the reaction was stirred at -78 °C for 1 h. Tnethylamine (0.35 mL, 2.5 mmol) was added dropwise and it was stirred at rt for 1 h. The reaction mixture was quenched with water (2 mL) and 1 N HQ solution (3 mL), extracted with EtOAc (130 mL). It was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 4g ISCO Gold column and eiuted with 0 % to 35 % EtOAc (containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (16 mg) as a white solid. Ή NMR (400 MHz, CD2CI2) δ 7.68 (d, ,7=8,61 Hz, 1H), 7.47 (dd, J=2.15, 8.41 Hz, 1H), 7.16 (dd, J=2.45, 8.51 Hz, IH), 7.10 (d, J=2.35 Hz, 1H), 6.97 (m, IH), 6.67 id. J 2. 1 5 Hz, IH), 5.75 Ud. ./ 7.43. 14.48 Hz, I I I . 5.35 (m, i l l). 4.18-4.10 (m, 2H), 3.87-3.79 (m, ! H), 3.77-3,63 (m, 2H), 3.54 (ddd, J=4.01, 6.55, 15.65 Hz, IH), 3.36-3.22 (m, 3H), 3.10 (dd, .7=6.06, 18.98 Hz, IH), 2.98-

2.90 (m, IH), 2.80-2.75 (m, 2H), 2.73-2.66 (m, IH), 2.63-2.54 (m, 2H), 2.15-1.40 { in. 8H). m/z (ESI, +ve ion) 571.1 i M Π ) .

EXAMPLE 906. (1S,3'R, 6'R 7'R)-6-CHLORO-7'-(HYDROXYMETHYL)-3,4- DIHYDRO-2H, 15 'H-SPIRO[N APHTH ALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[I4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 3', 13 '-DIOXIDE OR (1S,3'R, 6 7 6-CHLORO-7'~ (ΗΥΟΚΟΧΥΜΕΤΉΥί)-3,4-ϋΙΗΥΟΚΟ-2Η,15Ή-8Ρ ΙΚΟ| ΑΡΗΤΗΑίΕ ^

1,22'-

|2ίί|0ΧΛ| 1ΉΤί!1Α| Μ4|ΠίΑ/.ΥΠ:ΤΗΑ(ΎΠ.ϋΙ i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE

A solution of (IS, 3 % 67?)-6-cMoro-7'-methylidene-3,4-dihydro-2H, 15Ή- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra<y^

15'-one 13',13'-dioxide (Example 904, ().018g, 0.031 mmol) in THF (1.5 mL) was cooled with ice hath.9-Borabicyclo[3.3.1]nonane (0.5 M solution in THF, 1.2 mL, 0.62 mmol) was added dropwise. After it was stirred at rt for 1 h, MeOH (10 mL) and trimethylamine N-oxide (0.208 g, 1.86 mmol) were added in one portion and the mixture was stirred at rt for 2 h. Then it was concentrated. The residue was stirred in MeOH (30 mL) at 68°C for 20 h. It was diluted with water and extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient eiution) to give the title compound (first eluting peak) as a white solid. ¾ NMR (400 MHz, CD2CI2) 67.58 (d, ./ 8.6! Hz, lH), 7.01 (dd, ./ 2.74.8.61 Hz, ill). 6.93 (d, ./ 2.35 Hz, 1H), 6.87 (dd, ./ 1.76.8.41 Hz, ill).6.76 (m, 2H), 3.91 (m, 2H), 3.73-3.66 (m, IH), 3.55-3.48 (m, 2H), 3.40 (dd, 3.8!.10.66 Hz, 1H), 3.25- 3.19 (m, IH), 3.05-2,95 (m, 2H), 2.87 (dd, .7=8.61, 15,65 Hz, IH), 2.65-2.56 (m, 2H), 2.30 (br. s., 2H), 1.93 (d, J=14.67 Hz, IH), 1.83-0.98 (m, 17H). m/z (ESI, +ve ion) 587.1 EXAMPLE 907. (1S,3'R,6'S, 7K)-6-CHLORO-7'-METHYL-3,4-DIHYDRO- 2H.15 'H-SPIRO[NAPHTHALENE- 1,22'-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [ 16,18,24] TRS EN] -15 '-ONE 13',13'-DIOXIDE OR (1S,3'R,6'S, 7¾ 6-CHLORO- 7"-METHYL-3 ₅ 4-DlHYDRO-2H,l 5'H-SPTRO[NAPHTHALENE-l ,22'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

A mixture of (i ₁ S ^, ,5'i?,6 ?)-6-chloro-7'-methylidene-3,4-dihydro-2H,15'H- spiro [naphthalene- 1 ,22'-

|2( ⁾ joxsij I3|t ia| U4|dia/aielracveioj 14.7.20 ^{; !} '.0 ^|1! ipemacosa| 16. i H.24|iricn|- 15'-one 13',13'-dioxide (Example 904, 0.016 g, 0.028 mmol) and platinum (IV) oxide (6 mg, 0.028 mmol) in EtOAc (14 mL) were stirred under H2 at rt for 20 min. The mixture was filtered through syringe filter to remove solid catalyst. The filtrate was concentrated and the residue was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/min CO2 on a Thar 80 SFC. Outlet pressure 100 bar; Temp.20 °C; Wavelength 220 nm) to give the title compound (2.7 mg, second eluting peak) as a white solid. ^] H NMR (400 MHz, CD2CI2) δ 7.72 (m, I Hi.7.34 (br. s„ ill).7,16 (d, J=5.48 Hz, 1H), 7.02-7.11 (m, 2H), 6.65 (br. s., 1H), 3.97 (br. s., 2H), 3.87-3.69 (m, 2H), 3.39 (br. s., 1H), 2.94 (br. s., 2H), 2.04 (br. s., 111).1.87 (br. s., 4H), 1.74-0.74 (m, 19H). fz (ESI, +ve i on) 571.1 (M+H) ⁺ .

EXAMPLE 908. (1S,3'R,6'R, 7 <il9¾;77¾ 6-CHLORO-10'-METHYL-3,4- DIHYDRO-2H, 17 Ή-SPIROj NAPHTHALENE- 1 ,24'- 1.12.221 ^' t ^' RIOXAj Ι5| ^' Π Ι!Λ| 1.IGjDlA/APH.Yl Αί ^' Υί 1.0| 16.72.Γ".0 ^! " 0 ^''! '| OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 'R, 6 R, 7'R, 1 O'RJI ¾>6-CHLQRO- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'- [δ,Ι^ΙΤΊυθΧΑΙΙΰΙΤΉΙΑίΙ,ΙόΙΟΤΑΖΑΡ Ε ΤΑΟΥΟίΟίΙό.Τ.ΖΙ ⁷ - ¹¹ ^ ³ · ⁶ .^ ¹ · ²⁶ ] QCTACQSA[18,20,26]TRIEN]-17'-QNE 15 ',15 '-DIOXIDE OR

(IS, 3 'R, 6'R, 7'S, 10 , 11 ¾)-6-CHLORO - 1 ()'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 ,24"-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[18,20,26]TOIEN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS 'R 6'R, 7'S 10'S 11 ¾)-6-CHLORO-l()'-METHYL-3,4-DIHYDRO-2H,l 7Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THL [1,16]DIA APENTACYCLO[16.7.2/1 ⁷ - ¹ ^0^^0 ²¹ - ²⁶ ] OCTACOSA[18,2Q,26jTRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7 'S 10 'S, 11 ',S')-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRO[NAPHTHALENE- 1.24-

1.12.221 ^' l ^' RIOXAj I | ^' S !SA| 1.1 jD! A/APS:Y1 Α(ΎΠ 0| 16.7.2.1 ^" ".0 ⁵ · ^, \ ⁽ > ^,| · ^, ' ^, | OCTACOSA[18,20,26]TOIEN]-17'-ONE 15',15'-DIOXIDE OR

(ISJ'R 6'R 7'S 10'R 11 'R)-6-CHLORO - 10'-METOYL~3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THIA[l,I6]DIAZAPENTACYCLO[16.7.2.i ⁷ - ¹ ^() ³ - ⁶ .0 ^2! - ²⁶ ][ 18,20,26]TRIEN] - 17-ONE 15', 1 S'-DIOXIDE OR (IS, 3 , 6'R 7'R 10 'S, 11 Y?)-6- CHLORO-10'-METHYL-3,4-DIHYDRO-2H,17'H-SPIRO [N APHTH ALENE - 1,24'- [8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(75;i7¾ ¾7¾70'S:7/y?)-6-CHLORO-10 ^, -METHYL-3,4-DIHYDRO-2H,17'H-

SP1RO [ APHTHALENE- 1 ,24'-

[8,12,22jTRIOXA[15jTHIA[l,16]DIAZAPENTACYCL()[16.7.2.1 ⁷ - ¹ ^0 ^3> ^0 ^2! - ²⁶ ] QCTACQSA[18,20,26]TRiEN]~17'~ONE 15',15'-DIOXIDE

Step 1: (5)-METHYL 6'-C1^0RO-5-(((lR,2R)-2^(2R,4S R) -HYOROXY-5- METHYL TETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)~ 3' ₅ 4 ₅ 4' _j 5-TETR _J < HYDRO-2H,2'H-SPlRO[BE ZO[B][l,4]OX/ZEPlNE-3,r" NAPHTHALENE] -7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((IR, 2R)-2-((2R, 4S, 5i?)-4-HYDROXY-5-METHYLTETRAHYDRO-2H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (<5)~METHYL e~CM ORO~5~(((lR/.2R)-2-((2S,4S,.5S}-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4\5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3, 1 '- APHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6'-C LORO-5-(((lR,2Ii)-2-((2R, 4R, 5S)-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL 6'-a-lLORO-5-(((lR.2RJ-2-((2S: 4R,5S)-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][ L4]OXAZEPINE-3J'-NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'~CHLORO-5~(((lR2R)-2-{(2R, 4R,5R)-4- HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [1 ,4]OXAZEPINE~3, 1 '-NAPHTH ALENE]-7-

C ARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-((( 1R.2R)-2-((2R, 4R, 5R)~4~ HYDROXY-5-METHYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

TFA (5.1 mL) was added slowly to a solution of (,S')-niethyl 6'-chloro-5- (((7/?,2/?)-2-formylcyxlobut )methyl)-3^4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox date (Intermediate AAl lA, Step 20A; 0.417g, 0.919 mmol) and 2-methyl-3-buten-l-ol (0.123 mL, 1.19 mmol) in DCM (10 mL) which was degassed with N ₂ It was stirred at rt for 22 min. The reaction mixture was added slowly to Na ₂ C0 ₃ (aq) solution (40 mL) and MeOH (20 mL). After it was stirred at rt for 15 min, the mixture was extracted with EtOAc (3x130 mL). The organic phase was dried over anhy drous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μτη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (51 mg, first eluting peak) as a white solid, m/z (ESI, +ve ion) 540.1 (M+H) ⁺ . Step 2 : S)-6'-CHLORO-5-(((H?, 2R)-2-((2R, 4S, JR)-5-METHYL-4-(2- S ULF AMO YLETHOXY)TETRAH YDRO-2H-P YRAN -2- YL)CYCLOBUTYL)METHYL)-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , ! '-NAPHTHALENE] -7-C ARBOXYLIC ACID

QR (5)-0 ^! -CHLQRQ-5-(((i/< 2/^^

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUlYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 1 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR (¾-6 ^f -CHLORO-5-(((i^ 2«j-2-^2X ^ ^)-5-METHY

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

OR (5 6'-CHLQRQ-5 2/^-2^

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SPi Oi Bi ^; N/C)l P | | i .4 K>X AZ! - Pi \ ! -3. 1 '-N M ! i 1 L\l J X i : i~?~C \RB()XY E

ACID

OR (S)-6'-CHLORO-5-(((/i?, 2i? 2-^

SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO[B] [ L4]()XAZEPINE-3,r-NAPHTHALENE]-7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((H?, 2R)-2-((2S, 4R,5S)-5-METl-lYL~4-(2~ SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (yS -6'-CHLORO-5 -((( 1R, 2R)-2-( ( 2R, 4R, 5R)-5 -METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5~TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLI C ACID OR (S)-6'-CHLORO-5-(((/R, 2R)-2-((2R, 4R, J/?)-5-METHYL-4-(2- SULFAMOYLETHOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

Sodium hydride (60% dispersion in mineral oil, 7.75 mg, 0.368 mmol) was added to a solution of (i ¾ methyl 6'-c loTO-5-(((lR R)-2-((2R, 4S)-4-hydroxy-5- methyltetrahydro-2H-pyran-2-yl) cyclobut}4)methyl)-3',4,4',5-tetrahydro-2I-L2'H- spiro[benzo[b] [l,4]oxazepme-3, ~naphthalene]-7-carboxylate (Example 908, Step 1, 0.051 g, 0.094 mmol) in THF (2.7 mL), which was cooled by ice bath. After it was stirred at rt for 18 min N,N-bis(4-methoxybenz l)ethenesulfonamide (Example 83.1 , Step 2, 0.056 g, 0.161 mmol) in THF (1 ml.) was added. It was stirred at rt for 2 h. Water (2 ml) and EtO Ac (120 mL) were added. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to pro vide the title compound (15 mg).

Hydrolysis I: The residue was dissolved in THF (3 mL), MeOH (6 mL) and 1 M

LiOH (6 mL) and the mixture was stirred at 50°C for 2 h. It was concentrated, acidified with IN HC1 to pH 2-4, extracted with EtO Ac 130 mL). The organic phase was washed with brine and dried over anh drous sodium sulfate and concentrated.

Hydrolysis II: The residue was dissolved in 1 :3 TFA/DCM (5 mL) and stirred at rt for 17 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5iim column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (l l mg) as a white solid. Step 3. (75; 3'R 6'R, 7'R, W'S.11 '5)-6-CHLORO-10'-METHYL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'-

[8, 12,22]TTUOXA[15]TmA[l ₅ 16]DTAZAPE TACYCLO[16.7.2. 1 ⁷ ' .0 ³ ' ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ', 15 '-DIOXIDE OR

(IS, 3 R, 6'R 7R, 10R 11 ¾')-6-CHLQRQ- 10'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1,24'-

[8, 12,22]TRIOXA[ I 5]TIflA[l,161D ZAPENTACYCLO[16 .2/i ⁷ - ¹ ^0 ³ - ⁶ .0 ²¹ - ² ^ OCTACOS A[ 18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR

(IS, 3 R, 6R, 7'S 10R, 11 ¾)-6-CHLORO- 10'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]THIA[1,16]DIAZAPENTACYCLO[16 .2. 1 ⁷ - ³ ^0 ³ '^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS, 3 , 6R, 7'S, 10 ' 11 ¾>6-CHLORO - 10'-METHYL-3 ,4-DIHYDRO-2H, 17 Ή- SPTRO[N APHTH ALENE-1 , 24'-

[8,12,22]TRIOXA[15]THIA[1,16]DIAZAPENTACYCLO[16.7.2.1 ⁷ - ¹¹ .0 ^J ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR

( IS, 3 R, 6 R, 7 ' 10 'S 11 '5)-6-CHLORO - 10'-METHYL-3,4-DIHYDRO-2H, 17 II- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THIA[ l,I6]DIAZAPENTACYCLO[16.7.2. i ⁷ - ¹¹ .0 ³ ^.0 ²¹ - ²⁶ ] OCTAC()SA[18,20,261TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3R, 6R, 7'S, lOR l ?)~6~CHLORO~ 10'-NlETHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO[N APHTHALENE- 1 ,24'-

[ 8, 12,22]TRIOXA[ 15]THIA[1 ,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^{5 1} .0 ³ · ⁶ .0 ²¹ · ²⁶ ] | 18,20,26]TRiEN]-17'-ONE 15',15'-DIOXTDE OR (1S,3'R 6'R 7R, 10'S, 7i «)-6- CHLORO-10'-METHYL-3,4-DIHYDRO-2H,17'H-SPIRO[NAPHTHALENE- 1,24'-

|;8,12,22jTRIOXA[15jTOIA[ l,16]DIAZAPENTACYCL()|;i6.7.2.1 ⁷ - ¹ ^() ³ > ^, 0 ^2! - ²⁶ ] OCTACOSAj l 8,20,26]TRIEN]-17'-ONE 15 ',13 '-DIOXIDE OR

(IS, 3 R, 6'R, 7'S.10% 11 'R)-6-CHLORO- 10'-ΜΕΤΉ YL~3,4-DIHYDRO-2H, 17Ή-

SPIRO [NAPHTHALENE- 1 ,24'-

[ 8,12,22]TRIOXA[ 15]TfflA[l,16]DIAZAPENTACYCLO[ 16.7.2. Γ· ^Η .0 ³ · ⁶ . ⁽⁾²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE

N,N-Dimethylpyridin-4-amine (DMAP) (0.032 g, 0.261 mmol) was added to a solution of (/ ¾ -6 ^* -chloro-5-(((7i¾ 2.^-2-^5; 4R)-5-methyl-4-(2- sulfamoylethoxy)tetrahydro-2H-pyran-2-yl) cyclobut ^methy^-S'^^'^-

acid (Example 908, Step 2, 0.011 g, 0.017 mmol) in DCM (50 mL) at 0°C . Then N 1 -((ethy limino)rnethylene)-N3 ,N3 -dimeih lpropane- 1 ,3 -di amine hydrochloride (EDC, 0.040 g, 0.208 mmol) was added slowly in portions and it was stirred at

0°C to rt for 22 h. It was concentrated and the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cm 5μηι column; Phenomenex,

Torrance, CA; MeCN in water with 0.1% TEA, gradient elution) to provide the title compound (7,5 mg) as a white solid. H NMR (400 MHz, CD2.CI2) δ 8.24 (br, s., 1H), 7.72 (d, J=8.61 Hz, I I I ). 7.16 (ddd, J=2.25, 8.36, 15.01 Hz, 21 1 ). 7.10 id. J-2.15 Hz, 11 1 ). 6,98 (d, ./ 8.02 Hz, i l l ). 6.74 (d, J=l .96 Hz, 11 1 ). 4.14-4.03 (ra, 2H), 3.91-3,70 (m, 5H), 3.46-3.35 (m, 2H), 3.29 (t, J=9,59 Hz, i l l ). 3.04-2,93 (m, 3H), 2.86-2,73 (m, 3H), 2.37-2.16 (m, 4H), 2.13-1.72 (m, 5H), 1.69-1.60 (m, 1H), 1.44 (t, ./ 12. 1 3 Hz, 1H), 1.14-1.29 (m, 2H), 0.89 (d, ./ 6,46 Hz, 3H). m /. (ESI, +ve ion) 615.0 (M-H-I) ¹ ,

EXAMPLE 910. (3R 6R 7R, llS,24S)-G-CHLORO-l l-HYDROXY-3',4'- DIHYDRO-2'H, 17H-SPIRO[8,22-DIOXA-15-THIA-l, 16-

D.1AZAPENTACYCLO[16.7,2.1 ⁷ - ¹¹ .0 ³ - ⁶ ,0 ^2L26 ] OCTACOSA-18,20,26-TRIENE- 24, r-NAPHTHALEN]-17-ONE 15, 15-DIOX1DE OR (3116R, 7S 1R,24S)~6'~ CHLORO- 11 -HYDROXY-3^4'-DIHYDRO-2'H, 17H-SPIRO[8,22-DIOXA- 15- THIA- 1 , 16-DIAZ APENT AC YCLO[ 16.7.2, ! ^" - ^l .0 ³ · ⁶ O ²³ · ²⁶ ] OCTACOS A- 18,20,26- TR1ENE-24 _S 1 ^, -NAPHTHALEN]-17-0NE 15,15-DlOXIDE OR

(3R, 6R, 7R, iii?, S 6'-CHLORO-l 1- HYDROXY-3',4'-DIHYDRO-2'H,17H- SPTRO[8,22-DIOXA- ! 5-THIA-l , 16-DIAZ APENT A

CYCLO[l 6.7.2, 1 ⁷ - ^{s l} .0 ³ · ⁶ 0 ²³ · ²⁶ ] OCT ACOS A- 18,20,26-TRIENE-24, 1 '- N ΑΡΗΊΉ ALEN] - 17 -O E 15,15-DIOXIDE OR (3R 6R, 7S 1S,24S)~&~

CHLORO- 11 -HYDROXY-3^4'-DIHYDRO-2'H, 17H-SPIRO[8,22-DIOXA- 15- ΤΙΠΑ- 1 , 16-DIAZ APENT AC YCLO [ 16.7.2, ! ^" - ^l .0 ³ · ⁶ O ²³ · ²⁶ ] OCTACOS A- 18,20,26-TRIENE-24, 1 '-NAPHTHALEN j - 17-ONE 15,15 -DIOXIDE

2,081

Step 1 : (S)-METHYL 6'-CHLORO-5-(((H2, 2R)-2-((2S, 4.S )~4~

HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- S'^^'^-TETRAHYDRO-ffl^'H-SPIROpENZOPl tl^lOXAZEPINE-a,! '- NAPHTHALENE]-7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((lR R)-2-((2S R 4 :lYO XYTETRAHYORO~2H~¥YRAN~2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 45)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- S'^^'^-TETRAHYDRO^H^'H-SPIROpENZOPl tl^lOXAZEPINE-a,! '- N APHTHALENE] -7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((i/?, 2/^-2-†2i?, 4i?)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H- SPI O [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

TFA (6 mL) was added slowly to a solution of (&)-methyl 6'-chloro-5- (((/i?,2i?)-2-formylc ]obutyl)me l)-3 4,4 5-tetTahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Intermediate

AA11A, Step 20A: 0.412 g, 0.908 mmol) and 3-buten-l-ol (0.10 mL, 1.18 mmoi) in DCM (12 mL) which was degassed with N2 It was stirred at rt for 35 mm. The reaction mixture was added slowly to Ν¾€θ3 (aq) solution (50mL) and MeOH

(15 mL). After the mixture was stirred at rt for 83 min, it was extracted with EtOAc (3x90 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/ram MeOH (0.2%DEA) + 60 g/min CO2 on a Thar 80 SFC. Outlet pressure 100 bar: Temp. 20 °C: Wavelength 220 nm). The title compound was obtained a single isomer (102 mg, second eluting peak) as a white solid, in / (ESI, +ve ion) 526, 1 (M+H) ⁺ Step 2: (S)-METHYL 6'-CHLORO-5-(((i ?,2 ? -2-ffS)-4-OXOTETRAHYDRO- 2H-PYRAN-2-YL)CYCLOBUT^L)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2 ^" H-SPIRO[BENZO[B][l,4]OXAZEPINE-3;r-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((iR,2R -2-^K)-4- OXOTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUWI METHYL)-3',4,4',5- TETRAHYDRO-2H,2 Ή-SPIRO [BENZO [B] [ 1 ,4]OXAZEPINE~3, 1 ^* - NAPHTHALENE! -7-CARBOXYLATE

A 50 ml, flask was charged with dimethyl sulfoxide (0.051 mL, 0.724 mmol) and DCM (3.5 mL) was cooled to -78°C. Oxalyl chloride (2.0 M solution in DCM, 0.18 ml, 0.36 mmol) was added dropwise slowly and the reaction stirred for 15 min. (5)~Methyl 6'-chloro-5-i((7i?,2i? -2-(^

pyran-2-yl)cyclohutyl)methyl)-:r,4,4V5 etrah) di -2H,2 ^' H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate (Example 910, Step 1, 0.127 g, 0.241 mmol) in DCM (3.5 mL) was added in one portion to above solution. It was stirred at -78°C for 20 min. Then triethylamine (0.17 mL, 1.2 mmol) was added and it was stirred at -78°C to rt for 2 h. It was quenehed with water (3mL) and extracted with EtOAc (130 mL). The organic phase was washed with 1 N HC1 solution (2 mL), brine and dried over anhydrous sodium sulfate. It was filtered through silica gel to provide the title compound (126 mg) as a white solid, m/z (EST, +ve ion) 524, 1 (M+H) ⁺ . Step 3 : (<S')-METHYL 6'-CHLORO-5-(((Hi 2R)-2-((2S, 4S)~4~HYDROXY-4- V NYLTETRAHYDRO-2H-PYR _j! 4N-2-YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((7i¾2i?^-2-(†25 i)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2H,2'I-i- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

C ARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((Hi 2R)-2-((2R, 4S)-4- HYDROXY -4- VINYLTETRAHYDRO -2H-P YRAN -2 - YL)CY ^T CLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((iR, 2R)-2-((2R, 4R)-4- HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MF -IYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARB OXYL ATE

Vinylmagnesium chloride (1.6 M solution in teirahvdrofuran, 0.50 mL, 0.79 mmol) was added dropwise to a solution of (5)-methyl 6'-chloro-5-(((/i?,2i?j- 2-((ft)-4-oxotetrahydro-2H-pyran-2^ 2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3,r-naphthalene]-7-caxbox late (Example 910, Step 2, 0, 126 g, 0.240 mmol) in THF (8 mL) at 0°C, It was stirred at 0°C for 20 min. It was quenched with NH4CI solution and extracted with EtOAc (180 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered through short plug of sihca gel and concentrated to give the title compound (133 mg) as an oil. m/z (ESI, +ve ion) 552. 1 (M+H) ⁺ .

Step 4; (5)-6'-CHLORO-5-(((7R, 2R)-2-((2S, 4',S')-4-HYDROXY-4- Y! NY ! . Π . I RA! JY ORO-21 i-PY R ΛΛ-2-ΥΙ . Y( .ΟΒί TY UYU J IYU~ 3',4,4',5-TETR _J ' HYDRO-2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,r"

NAPHTHALENE] -7-CARBOXYLIC ACID OR (5)-6'-CHLORO-5-((( 7i?,2i?j-2-

( .S 4i?)-4-I-rY ^T DROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2-

YL CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] 1 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID OR (S 6'-CHLORO-5-(((iA ⁵ , 2R)-2-((2R 4S 4-HYDROXY"-4-

VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3' ₅ 4 ₅ 4' _j 5-TETR _J < HYDRO-2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLIC ACID OR (S &-CHLORO -5 -(((IR Rj- 2- ( « _J ^«)-4-HYDROXY-4-\^rNYLTETPvAT-rYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] 1 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

Lithium hydroxide (1.0 M aqueous solution, 7.2 mL, 7.2 mmol) was added to a solution of (i ¾)-methyl 6'-cMoro-5-(((/^2R 2-†2i?)-4-hydroxy-4- vinyltetrahydro-2H-pyran-2-yl)cyclobutyi)methyl)-3',4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [ l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 910, Step 3 ; 0, 1 33 g, 0.241 mmol) in THF (16 mL) and MeOH (8 mL). it was stirred at 50°C for 3 h. The reaction mixture was concentrated, acidified with 1 N HC1 solution to pH 2-4, extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep C is 5}im column; Phenomenex, Torrance, CA; MeCN in water with 0. 1 % TFA, gradient elution) to provide the title compound (50 mg, second eluting peak) as a white solid, m / (ESI, +ve ion) 538.1 (M+H) .

Step 5 ; (S)-N ALLYLSULFONYL)-6'-CHL

HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO| BENZO[B;| |;i,4 |OXAZEPINE-3, l '-NAPHTHALENE]-7- CARBOXAMIDE OR (S -N-(ALLYLSULFONYL)-6'-CHLORO-5-(((H?, 2R 2- f 2^, ¥i?)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5"TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [ l,4]OXAZEPINE-3, l '-NAPHTHALENE] -7- CARBOXAMIDE OR (<S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((H?,2i¾)-2- ^25; 4tR)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '- APHTHALENE] -7- CARBOXAMIDE OR ( ₁ S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7i?, 2-¾ ⁾ -2- ^2R R)-4-HYDROXY-4-VI]SIYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, .4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] ~7~

CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (0.016 g, 0.13 mmol) was added to a solution of (S)-6'-chloro-5-(((/i?,2i? 2-(^^^^

2H~pyran-2-yl)cyclobu 4)m.ethyl)~3' l,4 ^! ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 910, Step 4; 0.023 g, 0.043 mmol) ) and prop-2-ene-l -sulfonamide (Example 900,

Step 5; 0,020g, 0, 167 mmol) in DCM (1.4 mL) at 0°C. Then Nl - ((ethylimino)methylene)-N3,N3-dimethyl propane-l ,3-diamine hydrochloride (EDC; 0.017 g, 0.090 mmol) was added in portions and it was stirred at 0°C to rt for 3 days. After it was concentrated the residue was pimfied by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenornenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (5.2 mg) as a white solid, m z (ESI, +ve ion) 641.1 (M+H) \

Step 6: (3R 6R, 7R, 1 IS, 12E, 2 S 6'-CHLORO-l 1 -HYDROXY-3',4'-DIHYDRO- 2Ή, 17H-SPIRO[8,22-DIOXA-l 5-THIA-l ,16-

DIAZAPENTACYCLOIie.T^. l'^^O'^.O^'^lOCTACOSA-lS^O^e-TRlENE- 24,r-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3R 6R 7S, 11R, Γ2Ε, 245)- 6 ^, -CHLORO-l l -HYDROXY-3^4'-DIHYDRO-2'H ₅ 17H-SPIRO[8 ₅ 22-DIOXA-15- THIA- 1 , 16-DI AZAPENTAC Y CLO [ 16.7.2.1 ⁷ - ^{"! 1} , 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- ΤΚΙΕΝΕ-24,Γ-ΝΑΡΗ1ΉΑΕΕ ]-17-ΟΝΕ 15, 15-DIOXIDE OR

(3R, 6R, 7R, 1 IR 12E, 24S)-6'-CHLORO- 11 -HYDROXY-3',4'-DIHYDRO- 2Ή, ! 7H-SPIRO[8,22-DIOXA-l 5-THIA-l ,16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ ' ⁿ .0 ³ ' ⁶ .0 ²ⁱ ' ²⁶ j OCTACOSA-18,20,26-TRIENE- 24, r-NAPHTHALEN] - 17-ONE 15, 15-DIOXIDE OR (3R 6R 7S, US, 12E, 24S)-G- CHLORO-11 -HYDROXY-3 ^, ,4 ^, -DIHYDRO-2'H,17H-SPIRO[8,22-DIOXA-15- ΊΉΙΑ- 1 , 16-DI AZAPENTAC YCLO[ 16.7.2.1 ⁷ - ^{"! 1} , 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- TRIENE-24, Γ-NAPHTHALEN] - 17-ONE 15,15-DIOXIDE

A 250 mL round bottom flask was charged with (S)-N-(allylsulfonyl)-6'- chioro-5-(((Hi 2R)~2~((2S, R)-4-hydroxy-4-vinyltetrahydro-2H-pyran-2- y cyclobut methy^-S'^^'.S-tetrahydro- H^'H-spirotbenzotbJ tl^Joxazepine-

3 ,1 '-naphthalene ]-7-carboxamide (Example 910, Step 5; 5.2 mg, 8.1 μηιοΐ) in toluene (17 mL). it was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (I mg, 1.6 μηιο]) in toluene (3 mL). The mixture was stirred at 106 °C under nitrogen for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex,

Torrance, CA; MeCN in water with 0. 1 % TFA, gradient elution) to provide the title compound (3 mg) as a white solid, m/z (ESI, +ve ion) 613.0 (M+H) \

Step 7 ; (3R, 6R, 7R, 1 IS, 24S -6 ^* -CHLORO- 1 1 -HYDROXY-3',4'~DIHYDRO~ 2 1 1.17H-SPIRO [8,22-DI OXA- 15-THIA- 1 , 16-

D1AZAPENTACYCLO[16.7.2.1 ^{7 1} .0 ³ - ⁶ .0 ²¹ - ²⁶ ] OCTACOSA-18,20,26-TRIENE- 24, l'-NAPHTHALEN]-l 7-ONE 15,15-DIOXIDE OR (3R 6R 7S, 11R, 24S)-6'- CHLORO-n -HYDROXY-3',4 ^, -DIHYDRO-2'H ₅ 17H-SPIRO[8 ₅ 22-DIOXA-15- THIA- 1 , 16-DI AZAPENTAC Y CLO [ 16.7.2.1 ^Ί · ^η .&· ⁶ .0 ²¹ · ²⁶ ] OCTACOS A- 18,20,26-TRIENE-24,l'-NAPHTHALEN]- 17-ONE 15, 15 -DIOXIDE OR (3R 6R. 7R, / /R,24S)-6'-CHLORO-l l- HYDROXY-3 ^f ,4'-DIHYDRO-2'H,17H- SPIRO [8,22-DIOXA- 15 -THIA-1 , 16-DI AZ APENTA

CYC I.OI 1 6.7.2. 1 ^" ^ U ' ".! ) ' ¹ OCTACOS A- 18,20,26-TR1E E-24,1'- N APHTHALEN ] - 17-ONE 15,15-DIOXIDE OR (3R 6R, ΖΧ ϋΔ^^-ό'- CHLORO-n -HYDROXY-3',4 ^, -DIHYDRO-2'H ₅ 17H-SPIRO[8 ₅ 22-DIOXA-15- ΊΉΙΑ- 1 , 16-DI AZAPENTAC YCLO[ 16.7.2.1 ^Ί · ^η .&· ⁶ .0 ²¹ · ²⁶ ] OCTACOS A- 18,20,26-TRIENE-24, 1 '-NAPHTHALEN] - 17-ONE 15,15 -DIOXIDE

Platinum (IV) oxide (1.1 mg, 4.9 μηιοΐ) was added to a solution of ( 6R 7R lS 2E,24S &-chloroA

dioxa-15-thia-l,16-diazapentacycIo [16.7.2, l - ⁿ .0 ³ ' ⁶ .0 ²ⁱ - ⁶ ]octacosa-l 8,20,26- triene-24,l'-naphthalen]-17-one 15,15-dioxide (Example 910, Step 6; 0,003 g, 5 μηιο]) in EtO Ac (5 mL). It was stirred under H ₂ for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient eluiion) to provide the title compound (1.2 mg) as a white solid. ¾ NMR (500 MHz, CD ₂ C] ₂ ) δ 8.06 (ra, IH), 7.71 (m, 1H), 7.18 (m, 1H), 7.09 (m, 1H), 6,93 id../ 0.7 Hz, 2H), 6.83 (m, 1H), 4.11 (m, 2H), 3.84-3,75 (m, 3H), 3.70-3.62 (m, 3H), 3.35 (m, 1H), 3.23 (m, III).2.82-2.73 (m, .21 i).2.33 (m, Ml).2.13 (s, 1H), 2.08 (d,J=3,18 Hz, 1H), 2.05 (m, 2H), 2,01-1.04 (m, 15H). m/z (ESI, +ve ion) 615.0 (M+H) ⁺ .

EXAMPLE 911. (lS,3'R,6'S,8'S,10'Z-6-CHLORO-S'- YOROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '60 ¹⁹ ^ ⁴ ]PENTACOSA [10,16,18,24]TETRAEN]-15'-ONE 13',13'-D10XIDE OR

CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-

1,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί 14 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ' ".i) ¹ '" ¹ |Ρ1·Ν i ^' ACOSA [ 10, 16, 18,24 jTETRAEN j- 15'-ONE 13', 13'-DIOXIDE

Step 1: (5 ^, )-6'-CHLORO-5-(((ii?,2 _; S)-2-(2-

OXOETHYL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETR _J ' HYDRO-2H,2'H-

SPIRO|BENZO[B;||;i,4|OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOX YLIC

ACID

A mixture of ©-methyl 6'-chloro-5-(((H?, 2 ?)-2-((E)-2- methoxyvinyi)cyclohulyl)me†hyi)-3',4,4V5 etrahydro-2i-I,2 i- spiro[benzo[b] [l,4]oxazepine-3, -naphtha]ene]-7-carboxylate (Example 865, Step 1 ; 0.057 g, 0.1 18 mmol) and lithium hydroxide (1.0 M aqueous solution, 0.95 ml, 0.95 mmol) in MeOH (0.5 mL) and TOP (0.8 mL) was stirred at 60 °C for 3 h. It was concentrated and was added 1 N HCl solution (2 mL) and acetone (6 mL) and stirred at rt for 18 h. It was concentrated and the residue was extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to provide the title compound (51 mg) as a white solid, m/z (ESI, +ve ion) 454, 1 ί VI H )

Step 2; i,S -6'-CIfl..ORO-5-((( /i?, 2i 2 lS)-2-HYDROXYPENT-4-EN-l- YL)CYCLOBUTYL) METHYX)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPlRO[BENZO[B] [l ,4]OXAZEPlNE-3,l ^, -NAPHTHALENE]-7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((/R, 2SJ-2 -^K)-2-HYDROXYPENT-4-EN-l - YL)CY ^T CLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

At 0°C, all lmagnesium bromide (1.0 M solution in diethyl ether, 0.67 mL, 0.67 mmol) was added dropwise to a solution of (S)-&-chloro-5-(((IR, 2S)-2- (2-oxoethyl) cyciobur}'i)methyl)~3',4,4',5-tetrahydro-2H,2'H~

spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 911, Step 1 ; 0.051 g, 0.112 mmol) in THF (1.9 mL). It was stirred at rt for 0.5 h. The reaction was quenched with NH ₄ C1 solution, acidified with 1 N HC1 solution to pH 2-3 and extracted with EtOAc (130 mL). The organic phase was washed with brine (1 mL), dried over anhydrous sodium sulfate, filtered through silica gel, and concentrated. The residue was purified by SFC (Method: 250 x 21.2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/rain CO2 on a Thar 80 SFC. Outlet pressure 100 bar; Temp. 20°C; Wavelength 220 nm) to provide the title compound (14.5 mg, second eluting peak) as a white solid, m/z (ESI, +ve ion) 496.3 ( +H) ⁺ .

Step 3 : (S)-N~(ALLYLSULFONYL)-6'-CHLORO-5-(((i.¾ 2S)-2-((S -2- HYDROXYPENT-4-EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [l ,4 jOXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXAMTDE OR (5)-N-(ALLYLSULFONYL)-6'- CHLORO-5-(((/R, ;¾)-2 ^' i?)-2-HYDROXYPENT-4-EN- 1 - YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO [BENZO [B] [ 1 ,4] OX AZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (9 mg, 0.07 mmol) was added to a solution of (5 -6 ^! -chloro-5-((( ¾25 -2- |«)-2½droxypent-4-en-l- l)c lobutyl)meth l)-3 4,4^5-tetrahydro-2H,2Ή-spiro[benzo[b] [l,4]oxazepine- 3, 1 -naphthalene] -7-carboxy He acid (Example 911, Step 2; 0.012 g, 0.024 mmol) and prop-2-ene-l -sulfonamide (Example 900, Step 5; 0.013 g, 0.109 mmol) in DCM (0.9 mL) at 0°C. Then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC, 9 mg, 0.047 mmol) was added portion by portion and it was stirred at rt for 16 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5um column; Phenomenex,

Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (5.7 mg) as a white solid, m/z (ESI, +ve ion) 599.3 N I ί ϊ > ^" .

Step 4: { iS. S'US/S ft'S. / ' )-6-C! U .ORO-X'-I iY OROXY- U-DH !Y DRO- 2H, 15 Ή-SPIRO [NAPHTHALEN E-1,22'-

^OJOXAtlSlTHIAt^MlDIAZATETRACYCLOI l^T^.O'^.O'^PE TACOSA

[ 10, 16, 18,24] TETR AEN] - 15'-ONE 1 3'. ! 3'-DIOXIDE OR ί /.V.3 % 6'S, 8 'S, 10'Z)-6- CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H,15'H~SPIRO[ Al ⁵ HTHALENE- 1,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[ 10, 16, 18,24] TETR AEN] - 15'-ONE 13', 13'~DIOXIDE

A 250 mL round bottom flask was charged with (j$ -N-(allylsulfonyl)-6'- chloro-5-((( 1R, 2S)-2-((S)-2-hydroxypent-4-en- 1 -yl)cyclobutyl)methyl)-3',4,4 ^, ₅ 5- tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r-naphthalene]-7- carboxamide (Example 911, Step 3: 5.7 mg, 9.5 μη οΐ) in toluene (43 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (1.2 mg, 1.9 μηιοΐ) in toluene (3 mL). The mixture was stirred at 106 °C under nitrogen for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC

(Gemini ^1M Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution). The title compound (1.1 mg, first eluting peak) was obtained as a white solid. Ή NMR (400 MHz, CD2CI2) δ 8.11 (m, III).7.68 (m, 1H), 7.19 (m, 1H), 7.15 (m, 1H), 7.08 (m, 1H), 6.89 (m, 1H), 5.94 (dd, ,/ 802.18,78 Hz, 1H), 5.58 (m. III).4,56 (br, s .1H), 4.11 (m, 2H), 3.61 (d, ./ 1 .09 Hz, 2H), 3.51 (br. s., 1H), 3.31 (d, ./ 14.87 Hz, ill).3.24 (br. s., 1H), 2,79-2.70 ins.2H), 2.27-2.15 (m, 3H), 2.09 (dd, ./ 7.04.13.69 Hz, ill .2.02-1.95 (m, 2H), 1,89-1.77 (m, 2H), 1.73-1.04 (m, 8H). m/z (ESI, +ve ion) 571.1 (Μ·Η)\

EXAMPLE 912. (IS, 3 R, 6 'S, 8 , 70'E)-6-CHLORO-8'-HYDROXY-3 ₅ 4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TTHIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [10,16, 18,24] TETRAEN] - 15 '-ONE 13', 13'-D10XIDE OR (IS, 3 R, 6'S, 8 'S, 10 'E)-6- CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'-

|20i() A| I 311 H1A| I J ! |OI.\/.\ Π·. ΓΗ. ΛίΎί ^' ί. Ol i -1.7.20· ".ί) ^{|:, !|} |Ρ1·Ν i ^' ACOSA [1(),16,18,24|TETRAEN1-15'-0NE 13',13'-DIOXIDE

The title compound (2.5 mg) was obtained as a single isomer (second eluting peak) from the reverse phase preparative HPLC in Example 911 as a white solid. Ή NMR (400 MHz, CD2CI2) δ 8.37 (br. s., ill).7.71 (m, III).7.18 (dd, ./ 2.35.8.41 Hz, Hi).7.06-7.13 (m, 21!}.6.95 id../ 8.22 II/. 111).6,89 (m, 111). 5.79-5.89 (m. 111).5,66 (ddd, ./ 6.06.8.80, 15.26 Hz, III).4.22 (dd, ,/ H I. 14.48 Hz, IH), 4.13-4.01 (m, 3H), 3.84 (d, .7=16,24 Hz, H), 3.73 (d, .7=13.89 Hz, 1H), 3.62-3.69 (m, IH), 3.26-3.15 (m, 2H), 2.81-2.71 (m, 2H), 2.30-2.18 (m, 3H), 2.15-1.18 {in.12H). m (ESI, +ve ion) 571.1 (VI H) .

EXAMPLE 913. (lS 'R,6'S,8'R,10'E)-6-C¥iLORO-V-HYDROXY-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[ 10, 16, 18,24] TETR AEN] - 15'-ONE 13', 13'-DIOXIDE OR (IS, 3 % 6 "S 8 ¾ 10 Έ)-6- CHLORO-8'-HYDROXY-3 ₅ 4-DIHYDRO-2H,15'HSPlRO [NAPHTHALENE- 122'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PENTACOSA

[10,16,18, 24]TETRAEN]-15'-ONE 13',13'-DI0X1DE

Step 1 : (,S 6'-CHLORO-5-(((iA ⁵ .2S)-2 -^S)-2-HYDROXYPENT-4-EN-l-

YL)CY ^T CLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID OR (,S 6'-CHLORO-5-(((iA ⁵ . ^-2-^K)-2-HYDROXYPENT-4-EN-l -

YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^, H-

SPIRO[BENZO [B] [ 1 ,4]OX ΑΖΕΡΓΝΕ-3, 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID

The title compound (11 mg) was obtained as a single isomer (first eluting peak) from the reverse phase preparative HPLC in Example 911, Step 2 as a white solid, m/z (ESI, +ve ion) 496.3 ( VI i ! ) .

Step 2: (5)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((iR,2^-2-^S)-2- HYDROXYPENT-4-EN-l-YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,l'- NAPHTHALENE] ~7-C ARBOX AMIDE OR (5)-N-(ALLYLSULFONYL)-6'- CHLORO-5-(((H¾ 2S) -2-^f?)-2-HYDROXYPENT-4-EN - 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (9 mg, 0.07 mmol) was added to solution of (5)-6'-οΜθΓθ-5-(((7Λ,2^-2- 5)-2½(1τοχνρβηί-4-βη-1- yl)cvxlobut5d)methyl)-3',4,4',5-tetrahydro-2H,2'H-spifo[benz o[b] l,4]oxazepine- 3, l '-naphthalene]-7-carbox lic acid (Example 913, Step I ; 0.012 g, 0.024 mmoi) and prop-2-ene-l -sulfonamide (Example 900, Step 5; 0.013 g, 0.109 mmol) in DCM (0.9 mL) at 0°C. Then N-(3-dimethy]aminopropy])-N'-ethylcarbodiimide hydrochloride (EDC, 9 mg, 0.047 mmol) was added portion by portion and it was stirred at rt for 16 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5 ₍ um column; Phenomenex, Torrance, CA; MeCN in water with 0, 1 % TFA, gradient elution) to provide the title compound (5.7 mg) as a white solid, m/z (ESI, +ve ion) 599.3 (M+H) ⁺ .

Step 3; (/X 3¾ 6 ^' ¾5' ?,irr )-6 ;HI O-8'-I-iYDROXY-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]TH1A[1,14]DL ZATEII ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [ 10,16,18,24] TETR AEN] - 15 '-ONE 13', 13'-DI OXIDE OR (IS, 3 'R, 6'S, 8 'S, 10Έ)-6- CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H,15'HSPIRO [NAPHTHALENE-

1,22'-

[20]OXA[13]TfflA[l,14]DIAZATETRACYCLO[14J.2.0 ^3>6 .0 ⁱ⁹ ^ ⁴ |PENTACOSA [ 10, 16,18, 24] TETRAEN] - 15 '-ONE 13', 13'~DIOXIDE

A 250 mL round bottom flask was charged with (5)-N-(allylsulfonyl)-6'- cWoro-5-(((ii¾ 2^-2-((^-2-hydroxypent-4-en-l-yl)cyclobu1yl)methyl)-3 ^, ,4,4',5- tetrahy dro-2H,2 'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naph thai ene] -7- carboxamide (Example 913, Step 2; 5.7 mg, 9.5 μηιοΐ) in toluene (43 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/¾ack-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (1.2 mg, 1.9 μτηοί) in toluene (3 mL). The mixture was stirred at 106°C under nitrogen for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC

(Gemini™ Prep Cie μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (1.1 mg, second eluting peak) as a white solid. ¾ NMR (400 MHz, CD2CI2) δ 8.46 (br, s., 1H), 7.69 (d, ./ 8.4! Hz, 1H), 7.16 (dd, J=2.45, 8.51 Hz, ill).7.13-7.06 (m, 2H), 6.98- 6.90 (m, 2H), 5.95 (td, ./ 7.3!.15.50 Hz, Hi).5.70-5.60 (m, ill .4.27 (dd, J=8.90, 14,77 Hz, IH), 4.15-4,04 (m, 3H), 3.78 (d, J=10.96 Hz, !ll).3.71-3.61 (m, 2H), 3.30-3.18 (m, 2H), 2,81-2.73 (m, 2H), 2.52-1,19 (m, 15H). m/z (ESI, +ve ion) 571.1 (M+H) ⁺ .

EXAMPLE 914. (1S,3'R,6'S,8'R, /0'2)-6-CHLORO-8'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRQj NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [10,16,18,24]TETRAEN]~15'~ONE 13 ^* ,13'-DIOXTDE OR (1S 6'S,8'S, I0'Z)-6- CHLORO-8'-HYDROXY-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE- 1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [ 10, 16, 18,24] TETR AEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound (1.8 mg) was obtained as a single isomer (first eluting peak) from the reverse phase preprartive HPLC in Example 913 as a white solid. ³ H NMR (400 MHz, CD2CI2) δ 8.24 (br. s, !H).7.71 (d, ,7=8,41 Hz, I Hi.7.17 (dd, J=2.45, 8.51 Hz, 1H), 7.09 (s, 2H), 6.95-7.01 (m, IH), 6.90 (m, 1H), 5.84 (m, 1H), 5.67-5.58 (in, IH), 4.87-4.77 (m, 1H), 4.14-4.06 (m, 2H), 3.87 (d,J=15.()6 Hz, 111).3.82-3.65 (ra, 311).3.21 (d, ./ 14.09 Hz, IH), 3,09-3.02 (m, IH), 2.82- 2.73 (m, 2H), 2.40-1.03 (m, 1 1! }. m /. (ESI, +ve ion) 571.1 (M+H) ^H" . EXAMPLE 915. {IS, 3 R, 6R, 8 Έ, 12 'R)-6-CHLORO- 12'-ETHYL-3,4-DIHYDRO- 2H,7¾15H-SPIRO[NAPHTHALENE-l,22'-

|2ujOXA| !3jTIUA| I 4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [8,16,18,24]TETRAENE]-7',15'-DIONE 13 ',13 '-DIOXIDE

To a solution of Example 422, S tep 1 (0.100 g, 0.167 mmol) in DCM (3.3 mL) was added slowly Dess-Martin periodmane (0.085 g, 0.200 mmol) in DCM (3.3 mL). It was stirred at rt for 10 min. The reaction was quenched with water (4 mL) and extracted with EtO Ac (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 12g ISCO Gold column and eluted with 0 % to 25 % EtO Ac

(containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (70 mg) as a white solid. Ή MR (500 MHz, CD2CI2) δ 8.14 Cor. s., Hi), 7.76 (m, ill).7.25 (d, ./ 1.71 Hz, III).7.20 (dd, ./ 2.32.8.44 Hz, III .7.10 (d, 220 Hz, 111).6.88-6.77 (ra, 2H), 6,63 (id. 7.82.15.65 Hz, ill).5,94 id. J=15.89 Hz, III).4.13-4.03 (m, 2H), 3,92-3.82 (m, 2H), 3.79-3,66 (m, 2H), 3.26 (d, ./ 1 .43 Hz, 1H), 3.03-2.95 (m, 2H), 2.82-2.69 (m, 2H), 2.41-2.32 (m, Ml). 2,21-2.06 (m, 3H), 2.04-1.96 (m, 3H), 1.94-1.68 (m, 6H), 1.44-1.35 (m, 1H), 1.23- 1.17 (m, 3H), m/z (ESI, +ve ion) 597, 1 (M+H) ⁺ .

EXAMPLE 917. (3R.6R. /¾ii.f;,22 _i S)-6'-CHLORO-7-HYDROXY-3',4'- DIHYDRO-2'H, 15H-SP1RO[9,20-DIOXA-13-TH1A-1 , 14-

DIAZATETRACYCLO[14.7.2.() ³ - ⁶ .() ⁱ⁹ - ²⁴ |PENTACOSA-l 1,16,18,24- TETRAENE-22, 1 '-N APHTH ALEN] - 15-ONE 13, 13-DIOXIDE OR

(3R, 6R, 7R, HE, 225 6 ^! ~CHLORO-7-HYDROXY-3' ₅ 4'-DIHYDRO-2 ^! H, 1 SPIRO [9,20-DIOXA- 13-THIA- 1,14-

DIAZATETRACYCLO| 14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTAC()SA-11, 16,18,24- TETRAENE-22, 1 '-NAPHTHALEN1 - 15-ONE 13, 3-DIOXIDE

Step 1 : (SJ-TERl -BUTYL 6'-CHLORO-5 -((( ¾ 2R)-2-((R)- 1 ,2- DIHYDROXYETHYL)CYCLO-BUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO- 2H,2'H-SPIRO[BENZO[B] [l ,4]OXAZEPI E-3,r-NAPTHALENE]-7-

CARBOXYLATE OR (Sj-TERT-BIJTYL 6'-CHLORO-5-(((/i?,2i?;-2-f S)-I,2- DIHYDR0XYETHYL)CYCL0BUTYL)ME;THYL)-3V4,4 5-TETRAHYDR0- 2H,2 ^" H-SPIRO[BENZO[B][l,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE

The title compound was obtained as the second eluting peak in Example 863, Step 2. Step 2: (S)-TERT-BUTYL 5 -((( //?, 2i? -2- fS)-2-(ALLYLOXY)-i- HYDROXYF;THYL CYCLOBUTYL)MF;mYL)-6'-CHLORO-3',4,4',5- TETRAH YDRO-2H,2'H-SPIRO [BENZO[B] [ 1 ,4] OXAZEPINE-3 ,Γ- NAPHTHALENEj -7-CARBOXYLATE OR (SJ-TERT-BUTYL 5-(((lS,2R)-2- ^.S}-2-( ,\l .i.Y! .i)XY }- 1 -HYDROXYETHYL)CYCLOBUTYL)METHYL)-6'- CHLORO-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE

Sodium hydride (60% dispersion in mineral oil, 8.77 μΐ, 0.417 mmol) was added to a solution of (S)-tert-butyl 6'-Ο1Ι1ΟΓΟ-5-(((7Λ,2Λ)-2-((8)-1,2- dihydroxj ⁷ e1hyl)cyclobutyl)me1hyl)-3',4,4',5-tetfahydro-2H,2'H- spiro|benzo|b] [l,4]oxazepine-3,r-naphthalene]-7-carboxylaie (Example 917, Step 1 ; 0.100 g, 0, 189 mmol) in DMF (6 mL). After it was stirred at 0 °C for 20 min, allyl iodide (0.024 mL, 0.265 mmol) in DMF (0.7 mL) was added dropwise and it was stirred at 0 °C to rt for 2 h. The reaction mixture was quenched with water (2 mL) and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 40g ISCO Gold column and eluted with 0 % to 30 % EtOAc

(containing 0.3 % AcOH)/hexane (containing 0.3 % AcOH) to provide the title compound (47.6 mg) as an oil; m/z (ESI, +ve ion) 568.3 (M+H) ⁺ . Step 3 : (5 -6'-CHLORO-5-(((7i?, 2R)-2-((S)~ 1 -HYDROXY-2-(((E)-3-

SULFAMOYLALLYL)OXY)ETHYL)CYCLOBUTYL)METHYL)-3 ^* ,4 ₅ 4',5- TETRAHYDRO-2H,2 Ή-SPIRO [BENZO [B] [ 1 ,4]OXAZEPINE-3, 1 ^* - NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((iR, 2R 2- ((! )- 1 -HYDROXY-2-(((E)-3-

SULFAMOYLALLYL)OXY)ETHYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO BENZO[B] [l ,4 T.OXAZEPINE-3, 1 '- NAPHTHALENE] -7-CARBOXYLIC ACID

A flask was charged with {S i n-huiyl 5-((( R,2Rj-2-^5)-2-(a]lyloxy)-l- hydroxye l)cyclobu1yl)methyl)-6 ^, -chloro-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 917, Step 2; 0,020 g, 0.035 mmol) and N,N-bis(4-rnethoxybenz>'l)eihenesiiifonarnide (Example 831 , Step 2; 0,073 g, 0.211 mmol) in 1 ,2-dichloroethane (1.8 mL). It was stirred at rt for 10 mrn to dissolve the solid starting material and then degassed with nitrogen. To the homogeneous solution was added a solution of

Hoveyda-Grubbs II (6 mg, 7 μπιοΐ) in DCM (1 mL) and it was stirred at 55 °C for 2 h. It was concentrated and the residue was dissolved in cold TFA and DCM

(TFA/DCM: 1 :3, 2 mL) and stirred at rt for 19 h. After concentration, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, C A; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (4.4 mg) as a film, m/z (EST, +ve ion) 591.1 (M+H) ⁺ .

Step 4: (3R 6R 7S, 77E,22S)-6 ^, -CHLORO-7-HYDROXY-3 ^, .4 ^, -DIHYDRO- 2Ή, 15H-SPIRO[9,20-DIOXA- 13-THIA-1 , 14-

DIAZATETRACYCLO[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA-11,16,18,24- TETRAENE-22, 1 '-NAPHTH ALEN] -15-ONE 13,13-DIOXIDE OR (3R, 6R, 7R, HE, 22,S -6'-CHLORO-7-HYDROXY-3',4'-DIHYD O-2 ^f H, 15H- SPIRO [9,20-DIOXA- 13-ΤΉΙΑ- 1 , 14-

DL ZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA~11,16,18,24- TETRAENE-22,l'-NAPHTHALEN]-15-ONE 13,13-DIOXIDE

4-Dimethylaminopyridine (DMAP) (9.1 mg, 0.074 mmol) was added to a solution of (S)-6'-chloro-5-(((7/t

sulfamoylallyl)oxy)e l)(^clobutyl)me l)-3^4,4 ^, ,5-tetrahydro-2H,2'H- spiroj benzoj bj[ l,4joxazepine-3, -naphthaIene]-7-carboxylic acid (Example 917, Step 3; 0.0044 g, 7,44.urnoi) in DCM (20 mL), which was cooled by ice bath. Then N-(3-dimethylaminopropyl)-N'-ethylcarbodiirnide hydrochloride (EDC, 10 mg, 0.052 mmol) was added and it was stirred at 0 °C to rt for 18 h. After concentration, the residue was purified by reverse phase preparative HPLC

(Gemini™ Prep Ci85μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (1.6 mg) as a film. ¾ NMR (500 MHz, CD2CI2) δ 8,26 (br. s . ill).7.70 (d, 83! Hz, 111).7.17 (dd, J=2.32, 8.44Hz, IH), 7.14-7.04 (m, 3H), 6.91 (m, IH), 6.85 (m, III).6.67 (d, J=15.41 Hz, 1H), 4.44 (ddd, J=1.71, 3.79, 15.28 Hz, IH), 4.09 (s, 2H), 3.93 (d, ./ 15.4! Hz, IH), 3.85-3.79 (m, IH), 3.70-3.62 (m, IH), 3.49 (dd../ !.47.9.05 Hz, IH), 3,42 is. IH), 3,36-3,28 (m, IH), 3.24-3.17 (ra, IH), 3,04 (dd, J=8.56, 15.41 Hz, IH), 2.79-2.71 (m, 2H), 2.42-2.28 (m, .21 i).2.07-1.43 (m, 9H). m/z (ESI, +ve ion) 573.0 < M 11 > . EXAMPLE 918. (3R, 6R, 7S, 1 IS, 12E, 2¥S)-6'-CHLORO-l l-HYDROXY-3',4'- DIHYDRO-2'H, 17H-SPIRO[8,22-DIOXA-15-THIA-l, 16- DIAZAPE TACYCLO[ 16.7.2.1 ^7,1 'Ο ³ · ⁶ .*) ^21,2<s ] OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-NAPHTH ALEN] - 17-ONE 15,15-DIOXIDE OR

{3R, 6R, 7R, 1 IS 2E.24S -6 ^* -CHLORO-l l-HYDROXY-3\4'~DffiYDRO~2 H, 17H- SPIRQ[8,22~DiOXA~ 1 5-THIA- 1 , 16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ . ⁿ 0 ³ - ⁶ .0 ^2!>26 ]OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-N APHTH ALEN] - 17-ONE 15, 15-DIOXIDE OR

(3R, 6R, 7R, I ill /.?/·. .?./.S>.:V-( H! .i)K()- ! l-HYDROXY-3',4'~DIHYDRO~ 2Ή, 17H-SPIRQ [8,22-DIQXA- 15-THIA- 1,16-

DIAZAPENTACYCLO|;i6.7.2.1 ⁷ ' ¹¹ 0 ³ ' ⁶ .0 ²¹ - ²⁶ ]OCTACOSA-12 ₅ 18,20,26- TETR AENE-24, 1 '-N APHTH ALEN] - 17-ONE 15,15-DIOXIDE OR

(5it 6it 7S ₎ 77i¾ 72E ₎ 2^5)-6 ^, -CHLORO-l l-HYDROXY-3 ^, ₅ 4 ^, -DIHYDRO-2'H,17H- SP1R0[8,22-DI0XA- 15-THIA- 1,16- DI A/APhYI Αί Ύί i .Oi 1 .7 2. i ¹ 'ϋ ^; ".0 ^' " jOC ACOSA- 12. 1 8.20.26- TETRAENE-24, 1 '-N APHTH ALEN] - 17-ONE 15, 15 -DIOXIDE

Step 1 : (S)-METHYL 6'-CHLORO-5-(((H?, 2R)~2~((2S, ^S)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (<S)-METHYL 6'-CHLORO-5- (((lli 2RJ -2-((2S, 4 .)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2H,2'I-i- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

C ARB OXYL ATE OR (S)-METHYL 6'-CHLORO-5-(((Hi 2R)-2-((2R, 45)-4~ HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 2Ti-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((III 2R)-2-((2R, i?)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE

TFA (6 mL) was added slowly to a soluiion of (5)-methyl 6'-chloro-5- (((i ?, 2 ?)-2-fbrmyl cyc]obuiy1)methyl)-3',4,4',5-tetra ydro-2I-I,2Ti- spiro[benzo[b] [l,4]oxazepme-3, ~naphthalene]-7-carboxylate (Intermediate AA11 A, Step 20A; 0.412 g, 0.908 mmol) and 3-buten-l-ol (0.10 mL, 1.18 mmol) in DCM (12 mL) which was degassed with T\ ^T 2 It was stirred at rt for 35 min. The reaction mixture was added slowly to Ν¾€(>3 (aq) solution (50 mL) and MeOH

(15 mL). After the mixture was stirred at rt for 83 min, it was extracted with EtOAc (3x90 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by SFC (Method: 250 x 21 ,2 mm IC-H column w/ 20 g/min MeOH (0.2%DEA) + 60 g/min CO2 on a Thar 80 SFC. Outlet pressure 100 bar: Temp. 20 °C: Wavelength 220 nm). The title compound ( 102 mg, second eluting peak) was obtained as a white solid, m/z (ESI, +ve ion) 526. 1 i .Yi H ) .

Step 2: (S)-METHYL 6'-CHLORO-5-(((H2, 2i?)-2-((S)-4-OXOTETRAHYDRO- 2H-PYRAN-2^L)CYCLOBUTYL)METI-IYL)-3',4,4',5-TETRAI-IYDRO- 2H,2'H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7- C ARB OXYL ATE OR (5)-METHYL 6'-CHLORO-5-(((H¾ 2/^2-ftK)-4- OXOTETRAHYDRO-2H-PYR _! 4N-2-YL)CYCL()BUTYL)METHYL)-3',4,4 ^, ,5- TETRAHYDRO-2H,2'H-SPIRO[BENZO| B] [l ,4]OXAZEPrNE-3,r- NAPHTHALENE] -7-CARBOXYLATE

A 50 mL flask was charged with dimethyl sulfoxide (0.051 mL, 0.724 mmol) and DCM (3.5 mL) was cooled to -78 °C. Oxalyl chlonde (2.0 M solution in DCM, 0.18 mL, 0.36 mmol) was added dropwise slowly and the reaction stirred for 15 min. (S)- Methyl 6'-cWoro-5-(((ii¾2i^-2-(72 i 5)-4-hydroxj'tetrahydro-2H- pyran-2-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ-naphthal ene] -7-carboxy late (Example 918, Step 1 ; 0.127 g, 0.241 mmol) in DCM (3.5 mL) was added in one portion to above solution. It was stirred at -78°C for 20 min. Then triethylamine (0.17 mL, 1.2 mmol) was added and it was stirred at -78°C to rt for 2 h. The mixture was quenched with water (3 mL) and extracted with EtOAc (130 mL). The organic phase was washed with IN HC1 solution (2 mL), brine and dried over anhydrous sodium sulfate. It was filtered through silica gel to provide the title compound (126 mg) as a white solid, m/z (ESI, +ve ion) 524.1 (M+H) ⁺ .

Step 3: (5 METHYL 6'-CHLORO-5-(((H2,2R)-2-((2S,4S)-4-HYDROXY-4- VEWLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)-

S'^^'^-TET AHYDRO-ffl^'H-SPIROpENZOPl tl^lOXAZEPINE-a,! '- NAPHTHALENE]-7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((//?, 2R)-2-((2S, 4«)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN -2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H ₅ 2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7-

CARBOXYLATE OR ©-METHYL 6 ^, -CHLORO-5-(((iR,2R -2-^2R ₎ 45)-4- HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] QXAZEP1NE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)- METHYL 6'-CHLORO-5-(((7R, 2R)-2-((2R, i?)-4- HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OX. ZEPI E-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE

Vinylmagnesium chloride (1.6 M solution in tetrahydrofuran, 0.50 mL, 0.79 mmol) was added dropwise to a solution of (-S)-methyl 6'-cMom-5-{{{lR,2R)- 2-( ft)-4-oxotetrahydro-2H-pyran-2-yl)cyd^

2H,2 ^, H-spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carb ox>'late (Example 918, Step 2; 0.126 g, 0.240 mmol) in THF (8 mL) at 0 °C. After it was stirred at 0°C for 20 min, it was quenched with NH4CI solution and extracted with EtOAc (180 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered through short plug of silica gel to provide the title compound (133 mg) as an oil. m/z (ESI, +ve ion) 552.1 (Μ+Ή) ^"1" .

Step : (S)~6'~CHLORO~5~(((Ji?, 2R)-2-((2S, /.S )-i-HY !)R()XY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)-

3 ⁱ ,4,4',5-TETRAHYDRO-2H,21i-SPIRO[BENZO[B] [I ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((/i?, i? -2- 5 4i?)-4-HYDROXY-4-VlNYLTETRAHYDRO-2H-PYRAlSI-2- YL)CYCLOBUTYL)METHYL)-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((7R, 2R)-2-((2R, 4S)-4-HYDROXY-4- VINYLTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [I ,4]OXAZEPINE-3,r- NAPHTHALENE]-7-C ARBOXYLIC ACID OR (Sy&-CULORO~5-(((IR, 2R)~2~ ((2/?,4rR)-4-HYDROXY-4-VI]SIYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, .4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [l,4] OXAZEPINE~3,r-NAPHTHALENE]-7-CARBOXYLIC ACID

Lithium hydroxide (1.0 M solution, 7.2 mL, 7.2 mmol) was added to a solution of ( I VS -methyl 6'-chl oro-5-((( 1R, 2R)-2-((2R)-4- ydroxy-4- vinyltetrahydro-2H-pyran-2-yl)cyclobut l)methyl)~3',4,4

spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylate (Example 918, Step 3; 0.133 g, 0.241 mmol) in THF (16 raL) and MeOH (8 mL). It was stirred at 50 °C for 3 h. The reaction mixture was concentrated, acidified with IN HCl solution to pH 2-4, extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (50 mg, second eluting peak) as a white solid, m / (ESI, +ve ion) 538, 1 ί VI H )

Step 5 : (S)-N-(ALLYLSULFONYL)-6 ^, -CHLORO-5-(((7R,2 y-2-CC2S', 4S)-4- HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO[B] [ 1 ,4] OXAZEP1NE-3, 1 '-NAPHTHALENE] -7- CARBOXAMIDE OR (5)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7R, 2R 2- f 2^, ¥i?)-4-HYDROXY-4-VrNYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUlTL)MEraYL)-3',4,4',5~TETRAHYDRO-2H,2'H- SPIRO[BE ZO[B][ l,4]OXAZEPINE-3,l'-NAPHTHALENE|-7- CARBOXAMIDE OR (S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((/R,2R -2- ( (2S, 4i?)-4-H YDROXY-4 - VIN Y LTETRAHY DRO-2H-P YRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4 ₅ 4 ^, ,5-TETRAHYDRO-2H ₅ 2'H- SPTRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENEJ-7-

CARBOXAMIDE OR ( ₁ S)-N-(ALLYLSULFONYL)-6'-CHLORO-5-(((7i?, 2-¾ ⁾ -2- ^2i¾ 4rR)-4-HYDROXY-4-VINYLTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ][1,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXAMIDE

N,N-Dimethylpyridin-4-amine (DMAP) (0.016 g, 0.13 rnmol) was added to a solution of (S &-chloro-5-(((lR, 2R)-2-((2R, 45 -4-hydroxy-4-vinyltetrahydro- 2H-pyran-2-yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H - spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 918, Step 4; 0.023 g, 0.043 rnmol) and prop-2-ene- 1 -sulfonamide (Example 900, Step

5; 0,020 g, 0.17 rnmol ) in DCM (1 .4 ml,) at 0°C. Then Nl- ((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (EDC) (0.017 g, 0.090 rnmol) was added in portions and it was stirred at 0 °C to rt for 3 days. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1 % TFA, gradient elution) to provide the title compound (5,2 nig) as a white solid, m/z (ESI, +ve ion) 641.1 (M+H) ⁺ .

Step 6: (3R 6R, 7S, US, 12E,24S)~6'~CHLORO-l l-HYDROXY-3',4'-DIHYDRO- 2'H, 17H-SPIRO[8,22-DIOXA-15-TfflA-l,16-

DIAZAPENTACYCLO[l 6.7.2. l ⁷ ' ⁿ 0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA- 12, 18,20,26- TETRAENE-24, 1 '-NAPHTH ALEN] - 17-ONE 15,15-DIOXIDE OR

(3R.6R, 7R, 1 IS 2E. ^S -6 ^* -CHLORO-l l-HYDROXY-3',4'-DIHYDRO-2'H, 17H- SPIRO[8,22-DiOXA- 1 5-THIA- 1 , 16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ ' ⁿ 0 ³ - ⁶ .0 ²¹ ' ²⁶ ]OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-NAPHTH ALEN] - 17-ONE 15, 15-DIOXIDE OR

(3R, 6R, 7R, HR, 12E, .?- >ίΥ-Π il .ORO- 1 1 -HYDROXY-3',4'-DIHYDRO- 2Ή, 17H-SPiRO[8,22-DIOXA-l 5-THIA- 1 , 16-

DIAZAPENTACYCLO[16.7.2.1 ⁷ ' ⁱⁱ 0 ³ ' ⁶ .0 ²ⁱ ' ²⁶ ]OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-N APHTH ALEN] - 17-ONE 15, I 5-DIOXIDE OR

{3/t R ^" S. I Hi. I ^? /· ^' .2 S)~ ⁽ -V\ \ i ORG- 1 I -! 1YDROXY-. . j'-ΟΠ lYDRO-2 ^' Π.17Π-

SPIRO[8,22-DIOXA- 15-THIA- 1,16-

DIAZAPENTACYCLO|16 .2 ⁷ - ^!! () ³ - ⁶ .0 ²ⁱ - ²⁶ ]OCTACOSA-12,18,20,26- TETRAENE-24, 1 '-NAPHTHALEN] - 17-ONE 15,15-DIOXIDE

A 250 mL round botiom flask was charged with (;S)-N-(al]ylsulfonyl)-6'- chloro-5-(((7i?,2i^-2-^ ^,4i?)-4-hydroxy-4-vinyltetrahydro-2H-pyran-2- yl)cyclobutyl)methyl)-3^4,4^5-tetrahydro-2H,2'H-spiro[benzo[ b][l,4]oxazepine- 3, -naphthalene]-7-carboxamide (Example 918, Step 5; 5,2 mg, 8.1 μιηοΐ) in toluene (17 mL). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation/back-filling with nitrogen. To the homogeneous solution was added a solution of Hove da-Grubbs II (1 mg, 1.6 μηιοΐ) in toluene (3 mL). The mixture was stirred at 106°C under nitrogen for 1 h. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex,

Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (3 mg) as a white solid. ^] H NMR (500 MHz, CD2CI2) δ 8.10 (s, ill).7.69 (d, ./ 8.56 Hz, 1H), 7.17 ins. IH), 7.08 (d, ,/ 2.20 Hz, 1H), 6.92 (m, 2H), 6.81 (s, 1H), 6.00-5.92 (m, IH), 5.83 (ddd, J=5.87, 8.93, 15.04 Hz, 1H), 4.30 (dd, J=8.68, 14.06 Hz, IH), 4.26-4.16 (m, IH), 4.12-4.05 (m, 2H), 3.97 (d,

J=12.23 Hz, IH), 3.86-3.70 (m, 4H), 3.62-3.54 (m, IH), 3.22-3.14 (m, 2H), 2.83- 2,71 (m, 2H), 2.24-1.55 (ra, 1 IH), 1,47-1,41 (m, IH), 1.41-1.33 (ra, 2H), m/z (ESI, +ve ion) 613,0 (M+H) ⁺ . EXAMPLE 919. {IS, 3 % 6'R, 7'S, 11 % 13 'i?)-6-CHLORO- 13'-METHYL-3,4- DIHYDRO-2H, 17 'H-SPIRO[N APHTH ALENE- 1.24'- |8.i2.22rS ^' R!()XAI i | ^' Π ΠΛ| L ! ; f >I Λ ΑΡΗΝΊ AC Y C! (>| 16.7,2. ! ^{" 1}

CTACOSAj l 8,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

(IS 'R, 6% 7'R, 11 ¾; 75'R)-6-CHLORO - 13'-METOYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24 ^! - [8/12,22]TRIOXA[I5]TIflA[l,161DIAZAPENTACYCLO[16.7.2. - ¹¹ 0 ³ - ⁶ .0 ^2l ' ²⁶ ]O CT ACQS A[l 8,20,26]TRIEN] - 17'-ONE 15', 15'-DIOXIDE

OR (1S,3'R, 6'R.7'R, 11 'R, 13 !R)-6-CHLORO-13'-]VlETHYL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'- [8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[167.2J ⁷ - ³ Hr'' ⁶ .0 ^2! - ²⁶ ]O CTACQSA[18,20,26]TR1EN]-17'-QNE 15 ',15 '-DIOXIDE

OR (1S3R, 6R, 7'S, 11 , 73K)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALENE-l,24'-

|H. i 222r R XAl Ι |ΤΠΙΛ| i .!6iDlA/APL\ Α( Π.ϋ| 16.72. f ^J ^Γ ^{21 ;} "|0 CT AC OS A[ 18,20,26 ] TRIEN] - 17-ONE 15 ', 15 '-DIOXIDE

OR (IS, 3 R, 6'R, 7'S 11 'S 13 ¾> 6-CHLORO- 13'-METHYL-3,4-DIHYDRO- 2H, ! 7 Ή-SPIRO [NAPHTHALENE- 1.24'-

[8,12,22]TRIOXA[15]TfflA[l,16]DIAZAPENTACYCLO[16,7.2.1 ⁷ - ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]O CTACOSA[18,20,26]TRIENj-17'-ONE 15',15 ^* -DIOXIDE

OR (1S,3'R,6'R.7'RJ1'S, /3',S -6-CHLORO-13'-METHYX-3,4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALENE- ! 2-1"-

18.1 .22 P ^' RIOXAi i ^ [Π Π A| 1. ! 6jD! A/APLYi ΑΓΥΠ 0| 16.7.2. ! ^{" 1 ι} !ί ^;, '.!ΐ '"|()

CTACOSAjl 8,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

OR (1S.3'R,6'R, 7'R, I I'R. /3^S -6-CHLORO-13'-METHYL-3,4-DiHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TMOXA[15]TmA[l,16]DIAZAPENTACYCLO[16.7.2.i ⁷ - ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]O

CT ACOS A[l 8,20,26]TRIEN]- 7'-ONE 15", 15-DIOXIDE

OR (1S,3'R, 6'R.7'R, 11 'S 7iS)-6-CHLORO-13'-METHYL ,4-DIHYDRO-

2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[ 15]THIA[1, 16] DIAZAPENTACYCLO

[16,7.2. l ⁷ ' 0 ³ -^0 ^2! - ²⁶ ]OCTACOSA[18,20,261TRIEN]-17'-ONE 15',I5'-DIOXIDE

OR ( /.V.3'R, 6'R, 7'S, 11 'S, 4¾)-6-CHLORO-14'-METHYL-3,4-DIHYDRO-

2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8, 12,22 jTRIOXA[ 15 ]THIA[ 1 , 16] DIAZAPENTACYCLO

[16.7.2. r- ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,26]TRiEN]-r7'-ONE 15 ', 5 '-DIOXIDE OR (IS 'R, 6% 7'S, 11 'S, i ?)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H. 17'H-SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRlOXA[15]THIA[l,16]DlAZAPENTACYCLO[16.7.2.1 ^7,11 ~0 ^3,6 .0 ^21,26 ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE

OR (1S,3%,6% 7% U 'R, /¥¾ -6-CHLORO-14'-METHYL-3,4-DiHYDRO- 2H, 17 Ή-SPIRO [NAPHTH ALENE- i .2-i'~

[8,12,22]TMOXA[15]TmA[l/i6]DIAZAPENTACYCLO[I67.2/l ⁷ - ¹¹ 0 ³ -^( ⁾²¹ - ²⁶ ]O

CT ACOS A[l 8,20,26]TRIEN]~17'-ONE 15", 15 -DIOXIDE

OR (1S, 3'R, 6'R. 7% 11 /·/ VV)-6-( ^' l Π .ΟΚΟ- ! I -\S! I ί ΙΥ Ι .-3.4-Ι ⁾ Π f Y DRO- 2H, 17 Ή-SPIRO [NAPHTHALEN L- I .24'·

[ 8 2,22]TRIOXA[ 15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^η ~0 ³ ' ⁶ .0 ²¹ · ²⁶ ]

OCTACOSA[l 8,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE

OR (IS, 3 6 % 7% 11 ¾ 14 ¾)-6-CHLORO - 14'-METHYL-3 ,4-DIHYDRO-

2H,17'H-SP1R0 [NAPHTHALE E- 1,24'- [8,12,22]TRIOXA[15]THIA[l, 161DIAZAPENTACY ^' CLO

[16.7.2. r- ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,26]TRIEN]-r7'-ONE 15 ',15 '-DIOXIDE

OR (1S, 3% 6'R. 7% 11 'S, i4'i?)-6-CHLQRQ-14'-METHYL-3,4-DIHYDRQ-

2H, 17 Ή - S P I RO [NAPHTH ALEN E- 1 ,24'-

[8,12,22]TOOXA[15]THIA[1 ,16]DTAZAPENTACYCLO[16.7.2.1 ⁷ " ⁿ 0 ³ ' ⁶ .0 ²¹ ' ²⁶ ]O CTACOSA[18,20,26]TR1EN]-17'-ONE 15', 15 '-DIOXIDE

OR (IS 'R, 6% 7'S, 11 % 74'S)-6-CHLORO-14'-METHYL-3,4-DIHYDRO-

2H, 17'H-SPIRO[NAPHTHALENE-l,24'-

[8, 12,22]TRIOXA[ 15]THIA[ 1 , 16] DIAZAPENTACYCLO

[16.7.2.1 ⁷ - ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,26]TRIEN]-r7'-ONE 15 ',15 '-DIOXIDE OR (IS, 3% 6% 7'S 11 % i^R)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16,7.2. 1 ⁷ - ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]O CTACOSA[ 18,20,26]TRIENj-17'-ONE 15',15'-DIOXIDE

2116

Step 1 : (S)-METHYL 6'-CHLORO-5-(((H?, 2i? 2-( 2¾^)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METJHYL)- S'^^'^-TETRAHYDRO- H^'H-SPIROtBENZOIBK l^lOXAZEPINE-S,! '- NAPHTHALENE] -7-CARBOXYL ATE OR (S)-METHYL 6'-CHLORO-5- (((/i?,2i? 2 S _; 4/?)-4-HYDROXYTETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l '-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/R, 2R)-2-((2R, 4S)-4- HYDROXYTETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METJHYL)- S'^^'^-TETRAHYDRO- H^'H-SPIROtBENZOIBK l^lOXAZEPINE-S,! '- NAPHTHALENE] -7-CARBOXYL ATE OR (5)-METHYL 6'-CHLORO-5- ((( IR 2R) -2-((2S, 4S)-4-HYDROXY TETRAH YDRO-2H-P YR AN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPTRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTH ALENEJ-7- CARBOXYLATE

To a solution of (S)-methyl 6'-chloro-5-(((/i?,2i? ⁾ -2-(Y5 -4-oxotetrahydro- 2H-pyran-2-yl) cyclobut>'l)me l)-3 ^f ,4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l.'-naphthalene]-7-carbox 'late (Example 900, Step 2; 0.353 g, 0.674 mmol) in THF (10 inf . ). cooled to -78 °C, was added dropwise lithium tri-s'ec-butyl(hydrido)borate (L-selectride ^® , 1.0 M solution in

tetrahydrofuran, 1.0 mL, 1.0 mmol). After it was stirred at -78 °C for 24 min, it was quenched with potassium sodium tartrate (aq) (5 mL), diluted with Ei/jO (10 mL) and stirred at rt for 1 h. The reaction mixture was extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded to a 24g SCO Gold column and eluted with 0 % to 30 % EtOAc/hexane to provide the title compound (308 mg) as a white solid, m/z (ESI, +ve ion) 526.1 ( M R )

Step 2: (S)-METHYL 6'-CHLORO-5-(((7R, 2-? 2-^2«, ^R)-4-((R)-2- HYDROXYPROPOXY) TETRAHYDRO-2H-PYRAN-2- YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR0[BENZ0|;B][ 1,4]0XAZEPINE-3,1'-NAPHTHALENE]-7-

CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((IR,2R)-2-((2S,4R}-4-((R)- 2-HYDROXYPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-((( 1R.2R)-2-((2R, 4Rj-4-((S)- 2-HYDROXYPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUT L)METHYL)-3 ^, .4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX ΑΖΕΡΓΝΕ-3 , 1 '-NAPHTHALENE] -7- C ARBOXYLATE OR (<S)-METHYL 6'-CHLORO-5-(((Hi2Rj-2-^2S; 4R)-4-((S)- 2-HYDROXYPROPOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3, l'-NAPH ^' raALENE]-7- CARBOXYLATE OR (S)-METHYL 6'~CULORO~5~(i(lR,2Il -2^Ii 4S)~4~((R)-- 2-HYDROXYPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6' m^RO--5-(((lR2RJ-2-((2S: 4SJ-4-((Rj- 2-HYDROXYPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO Bj[ L4]()XAZEPINE-3,r-NAPHTHALENEl-7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((//¾ 2R)-2-((2R 4S)-4-((S)- 2-HYDROXYPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO[BENZO[B][l ,4]OXAZEPINE-3, l '-NAPHTHALENEl-7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-((( 1R.2R)-2-((2S, 4S)-4-((S)- 2-HYDROXYPROPOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METHYL)-3 ^, .4,4 ^, ,5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

C ARB OXYL ATE OR (<S)-METHYL 6'~CHLQRQ~5~(((ii¾ 2R)-2-((2R, -ij<j-4-

^fS>l-HYDROXYPROPAN-2-YL)OXY)TETRAHYDRO-2H~PYR _J ' N"2" YL)CYCLOBUTTL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H ₅ 2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'-CnLORO-5-((( R2R)~2~((2S, 4Rj-4-- { { (S)- 1 -HYDROXYPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3^4,4' ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

CARBOXYLATE OR (5)-METHYL &~CRLORO~5~(((lR2R)--2-{(2R 4R 4- (((/?)-l-HYDROXYPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUlTL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((iR,2R)-2-((2S,4R)-4- (((R)-l-HYDROXYPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [1,4] OXAZEPINE-3, 1 '- APHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL G-C iLORO-5-{{{lR,2R)-2-((2R, 4S)-4- (((S)- 1 -HYDROXYPROP AN-2-YL)OXY)TETR A-HYDRO-2H-PYRAN-2- YL)CYCLOBUTYL) METHYL)-3',4,4',5-TETl AHYDRO-2H,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (5)-METHYL &-CHLORO-5-((( lR,2R)-2-((2S, 4S)-4-(((S)- l-HYDROXYPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

C ARBOXYL ATE OR (<S)-METHYL 6'~CHLQRQ~5~(((ii¾ 2R)-2-((2R, 4SJ-4- (({R)~ 1 -HYDROXYPROPAN-2- YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL CYCLOBUTYL) METHYL)-3 ^, ,4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((iR, 2R)-2-((2S, 4S)-4- { { (R)- 1 -HYDROXYPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBIJTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO[BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- ARBOXYLATE

2122

Boron trifluoride diethyl etherate (0.035 mL, 0.287 mmol) was added to a solution of (,S methyl 6'-chloro-5-(((H2, 2R)-2-((2S, ^^-hydrox tetrahydro^H- p}n"an-2-yl)cyclobutyl)methyl)-3V4,4V5 etrahydro-2H,2'H~

spiro[benzo[b] [l,4]oxazepine-3, -naphthalene]-7-carboxylate (Example 919, Step 1 ; 0.302 g, 0.574 mmol) and (±)-propylene oxide (0.056 mL, 0.804 mmol) in DCM (5.7 mL). It was stirred at it for 4 h. After concentration, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μιη column; Phenomenex, Torrance, CA; MeCN in water with 0. 1% TFA, gradient elution) to give the title compound (32 nig) as a white solid, m/z (ESI, +ve ion) 584.2 ⁽ M R )

Step 3: (S)-METHYL 6'-CHLGM} 5-(((lR R)-2-((2R4R)-4-((K)-2- (PYRIMIDIN-2-YLTHIO)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((H¾, 2R)-2-((2S, 4Rj-4-((R)- 2-(PYRIMIDIN-2-YLTHIO)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO| BENZO[B;||;i,4|OXAZEPINE-3, l'-NAPHTHALENE]-7- C ARBOXYLATE OR (S)-METHYL 6"-CHLORO-5-(((/R, 2R)-2-((2R, 4R)-4-((S}- 2-(PYRIMTDIN-2-YLTHIO)PROPOXY)TETRAHYDRO-2H-PYRAN-2-YL) CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL ^' [ I L( )R( )-5-( ! ! IR.2Rj -2-((2S.4R}~4~((S)- 2-(PYRIMIDIN-2-YLTHIO)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 'H- SP1RO [BENZO [B] [ 1 ,4] ΟΧΑΖΕΡΓΝΕ-3, 1 '-NAPHTHALENE] -7- C ARBOXYLATE OR (S)-METHYL 6"-CHLORO-5-(((/R, 2R)-2-((2R,

2-(PYRJMIDIN-2-YLTHIO)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO[B] [ l,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'-Π ! LORO- ! i i R)-2- ⁽ (2S. JS)- -i-i/Rj- 2-(PYRrMlDrN-2-Yi;TH10)PROPOXY)TE,TRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4', 5-TETRAHYDRO-2H,2 'H~

SPIRO [BENZO [B] [l ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-

C ARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/R, 2R)-2-((2R,

2-(PYmMDIN-2-YLTmO)PROPOXY)TET¾AHYDRO-2H-PYRAN-2- YL)CYCL )BUTYL) METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARBOXYLATE OR (<S)-METHYL 6'~CHLQRQ~5~(((ii¾ 2R)-2-((2S, 45 ^-^ 2-(PYmMDIN-2-YLTH10)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [1 ,4]OXAZEPINE-3, 1 '-NAPHTHALENE]-7- C ARBOXYLATE OR 5)-METHYL 6' -CRLORQ-5-((( R 2R)-2- (2R, 4R)-4- (((S)- 1 -(PYRIMIDIN-2-YL™I0)PR()PAN-2-YL)0XY)TETRAHYDR()-2H- PYRAN-2-YL)CYCLOBUTYL)METHYL)-3 ^F ,4,4',5-TETRAI-IYDRO-2H,2T-i- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (5)-METHYL e'-CHLORO-S-CCl /i ^ ^Y s ^.;-^- ( |¾ l -(PYRIMIDIN-2-YLTHIO)PROPAN-2-YL)OXY)TETRAHYDRO-2H- PYRAN-2-YL)CYCLOBUTYL)ME™YL)-;r ₅ 4 4',5-TETRAHYDRO-2H,2'H- SP! ROi BLX/O! H 1 . IOXA/LI N L- 3. Γ- ΝΑΡΙ Π I AI .LM ^: | -7- CARBOXYLATE OR (S)-METHYL 6"-CHLORO-5-(((/R, 2R -2-^2R, 4R ^- ^)-l-(PYRIMlDrN-2-YLTHIO)PROPAN-2-YL)OXY)TETRAHY^^ PYR N"2"YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR0[BENZ0|;B] [ 1 ,4]0XAZEPINE-3,1 '-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/i?, 2i? 2-ff25; 4 ? -4- ^iK)-] -(PYRLMIDIN-2^i raiO)PROPAN-2-YL)OXY)TETRAHYDRO-2H~ PYl AN-2 X)CYCLOBUTYL)METHYL)~3\4,4',5-TETRAHYDRO-2H,2 ^" H" SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- C ARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/R, 2R)-2-((2R, 4S)-4- (((S 1 -(PYRlMIDIN-2-YLTHIO)PROPAN-2-YL)OXY)TETRAHYDRO-2H- PYRAN-2-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/R, 2R)-2-((2S, 4S)~1- (((S)-l -(P YRJMIDlN-2- YLTHIO)PROP AN-2-YL)OXY)TETRAHYDRO-2H- PYRAN-2-YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO [B] [ 1 ,4] OXAZEPINE-3, Γ -NAPHTHALENE] -7- C ARBOXYLATE OR (5)-METHYL e-CULO .O-5 (( R2R)~2~((2R 4S)-4^ ^ί¾)- (PYRlM:IDIN-2-YLTHIO)PROPAN-2-YL)OX ίOTETRAHYDRO-2H- PYRAN-2-YL)CYCLOBUTYL)METHYL)-3 ^f ,4,4',5-TETRAI-IYDRO-2H,2T-i- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

C ARBOXYLATE OR (5)-METHYL <V-0 U .ORO- U !R 2R> - 2- i(2S. -iS> · 4 ^■ ( ( fR)- 1 -(PYRIMIDIN-2- YLTHIO)PROP AN-2-YL)OXY)TETR AHYDRO-2H-

SPIRO [BENZO [B ] [ 1 ,4] QXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE

2128

Triphenylphosphine (127 mg, 0.55 mmol) was added to a solution of (1 ¾>methyl 6'-chloro-5-(((Hi 2/^-2 ( 5, 4S)-4-((l -hydroj.ypropan-2- yl)oxy)tetrahydro-2H-pyran-2-yl)cyclobutyl)methyl)-3 4,4^5-tetrahydro-2H,2'H- spiro [benzo [b] [ 1 ,4] oxazepme-3 , -naphthalene] -7-carbox late (Exampl e 919, Step 2; 0.032g, 0.055 mmol) and 2-mercapto-pyrimidine (0.061 g, 0.548 mmol) in THF (0.27 mL). It was degassed by argon and was added diethyl azodi-carboxylate (40 wt % solution in toluene, 0.25 mL, 0.55 mmol). It was stirred at 60°C for 1.6 h. After concentration, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5μπι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (20 mg) as a film, m/z (ESI, +ve ion) 678.3 { M · Π } .

Step 4: (S)-METHYL 6'-€ΗΕΟΚΟ-5-(((./^2^ 2-ί Λ^ - -^)-2~

(TPYRlMmiN-2-YLSULFONYL)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/R, 2R)-2-((2S, 4R)-4-((S)- 2-(PYmMIDIN-2-YLSULFONYL)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7- CARBOXYL ATE OR (S)-METHYL 0'-CHLQRQ~5-(((/i¾ 2R)-2-((2R, ^-/-f/S)- 2-(PYmMmiN-2-YLSULFONYL)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

CARBOXYLATE OR (<S)-METHYL 6'-CHLORO-5-(((Hi2Rj-2-^2S; 4 ij- -^S)- 2-(PYmMmiN-2-YLSULFONYL)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CY ^T CLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((iR, 2R)-2-((2R, 4Sj -^-^)- 2-(PYRIMIDIN-2-YLSULFONYL)PR()POXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ₅ 5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((i/i 2R)-2-((2S, 4S)-4-((R)- 2-(PYRIMTDIN-2-YLSULFONYL)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUlTL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] QXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL 4S}- 4- (iS) - 2-(PYRIMIDIN-2-YLSULFONYL)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- C ARBOXYLATE OR (S)-METHYL 6"-CHLORO-5-(((/R, 2R)-2-((2S, 4S --/-ftS)- 2-(PYRIMIDIN-2-YLSULFONYL)PROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO[B][ L4]OXAZEPINE-3,r-NAPHTHALENE]-7-

CARBOXYLATE OR (5)-METHYL G- m,O O-5-{{{lR,2R)-2-((2RAR)-4- ^iS)-l-(PYRIMIDIN-2-YLSULFONYL)PROPAN-2-YL)OXY)

2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)-3 ^, ,4 ₅ 4 ^, ,5-TETRAHYDRO- 2H.2'H-SPIRO[BENZO[B]|;i ,4]OXAZEPI E-3,r-NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-((( 1R.2R)~2-((2S, 4RJ-4-

^f¾)-l-(PYRlMIDIN-2-YLSLXFONYL)PROPAN-2-YL)OXY)TETRAHYDR O- 2H-PYRAN-2-YL) CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2H,2'H-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6 -CI I \ 0RO-5~U i Hi.2Rj■ 24(2/ ~lR)■ -/ · {{(R)- 1 -(PYRIMIDIN-2-YLSULFONYL)PROPAN-2- YL)OXY)TETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ^, ,4 ₅ ^, ,5-^ΈTRAHYDRO-2H,2Ή-SPIRO[BENZO[B] [l,4]OXAZEPI^lE-3,l ^, - NAPHTHALENE]-7-CARBOXYLATE OR (,S')~METHYL 6'-CHLORO-5- (((IR, 2R)-2-((2S, 4R)-4-(((R)~\ -(PYRTMIDIN-2-YLSULFONYL)PROPAN-2- YL)OXY)TETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3\4,4',5-TETRAHYDRO-2H,2 ^" H"SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3,l '- NAPHTHALENE] -7-CARBOXYLATE OR fS)-METHYL 6'-CHLORO-5- {{(lR,2R)-2-((2R, 4S)-4-(((S)~\ -(PYRJMIDIN-2-YLSULFONYL)PROPAN-2- YL)OXY)TETRAHYDRO-2H-PYRAN-2-YL)CY CLOBUTYL)METHYL)- 3\4,4'.5-TLTR Ai I Y DRO-21 L2 ^" H -SPI R | BHN/0| B l | 1 .4| XA/l : PIN i ^; -3. ! - NAPHTHALENE] -7-CARBOXYLATE OR (5)-METHYL 6"-CHLORO-5- W i/i 2R)-2-((2S.4S)-4-(((S)- 1 -(PYRIMIDIN-2-YLSULFONYL)PROP AN-2- YL)OXY)TETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 4 ₅ 4 5-^Έ^¾AHYDRO-2H,2Ή-SPIRO[BENZO[B;| [ 1.4]OXAZEPINE-3,l ^, - NAPHTHALENE] -7-CARBOXYLATE OR (5 METHYL 6'-CHLORO-5- (((l 2R)-2-((2R, ^-^-^K)-l-(PYRIMIDIN-2-YLSULFONYL)PROPAN-2- YL)OXY)TETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 21i-SPIRO[BENZO[B] [I ,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5- (((l 2I{) -2^S S)-4-(^

YL)OXY)TETRAHYDRO-2H-PYRAN-2-YL)CYCLOBUTYL)METHYL)- 3',4,4',5-TETRAHYDRO-2H,2T-I-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,l ^f - NAPHTHALENE] -7-CARBOXYLATE

zl z

2134

To a stirred solution of (1 ¾>methyl 6'-cUoTO-5-i((lR,2 )-2-((2S, 4S) - ((l -(pyrirnidin-2-ylthio)propan-2-yl)oxy)tetrahydro-2H-p} ⁷ ran-2- yl)c lobutyl)methyl)-3\4,4 5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine- 3, -naphthalene]-7-carboxylate (Example 919, Step 3; 0.026g, 0.038 mmol) in toluene (0.17 mL) and water (0.017 mL) was added sodium tungstate dihydrate (2.5 mg, 3.8 μι ^η οΐ), phenylphosphonic acid (0.4 mg, 4 μι ^η οΐ) and tetrabutyl- ammonium sulfate (50 wt. % solution in water, 2 μΐ, 4 μηιοΐ). After 2 min, hydrogen peroxide 30% in water (0.04 mL, 0.4 mmol) was added in one portion and it was stirred at 55°C for 80 min. After concentration, the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5μηΊ column;

Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give the title compound (14 mg) as a white solid, m/z. (ESI, +ve ion) 710.1 (M+H) ⁺ .

Step 5; (5)-METHYL 6'-CIfl..ORO-5-((( /¾2^-2-f 2i?,4i?)-4-(((5)-l- SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO I BENZO [B] [1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENEJ-7- CARBOXYLATE OR (S)-METHYL 6"-CHLORO-5-(((/R, /^- -^25; ^-4- 1 J>J ( ((S)- 1 -SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYR AN-2- YL CYCLOBUTTL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] 11 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (S)-METHYL 6' :ilLORO~5 ((ni2R)-2-((2R, 4R)-4- (((R)- 1 -SULFAMOYLPROP AN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL G Ml.O O-5-{{{lR,2R)-2-((2S, 4R)-4- (((R)-l -SULFAMOYLPROP AN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5"TETRAHYDRO-2H,2'H- SPIR()[BENZO I B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (5)-METHYL (-:~V\ \\ £) ~ ii i R 2Ri-2-((2R,4Si~-i- (((5)-l-SLT..FAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-P

YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H~

SPIRO [BENZO [B] [1 ,4]OXAZEPTNE-3, 1 '-NAPHTH ALENEj-7-

C ARBOXYL ATE OR (S)-METHYL 6'~CHLORO-5~((( ¾ 2R) - 2-((2S. ^V)-4- (((5)-l-SULFAMOYLPROPAN-2-YL)OXY)TCTRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3' ₅ 4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- C ARBOXYLATE OR (S)-METHYL 6'~CHLQRQ~5~(((ii¾ 2R)-2-((2R, 4SJ-4- ^R)-l-SULFA-MOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l ₅ 4]OXAZEPINE-3, l ^* -NAPHTHALENE]-7- CARBOXYLATE OR (5)-METHYL 6' -CRLORO-5-((( R R)~2~((2S, 4S)~4~ {{(R)- 1 - SULFAMOYLPROP AN-2-YL)OXY)TETRAHYDRO-2H-P YRAN-2- YL)CYCLOBUTYL) METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7- CARBOXYLATE OR (5)-METHYL &~CRLORO~5~(((lIi2R)--2^R, 4R)~4-{(R)~ 2-SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUlYL)METHYL 3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] QXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE OR (S)-METHYL 6"-CHLORO-5-(((/R, 2R)-2-((2S, 4R)-4-({Ry 2-SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCXOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO[B] [ l,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((//¾ 2R)-2-((2R, 4R)-4-((S)~ 2-SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3 ^, ,4,4',5-TETRAHYDRO-2H,2'H~

SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-N APHTH ALENE] - 7 - CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((/R, 2R)-2-((2S, 4R)-4-((S)~ 2-S ULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUT L)METHYL)-3'.4,4 ^, ,5-TETRAFIYDRO-2H,2'H-

SPIRO [BENZO [B j[l,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-

C ARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-((( lR2R)-2-((2R. 4S)-4-((R)-

2-SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYX)-3',4,4',5-TETRAHYDRO-2H,2T-i- SPIRO[BENZO[B] [l ₅ 4]OXAZEPINE-3, l *-NAPHTHALENE]-7- CARBOXYLATE OR (S)-METHYL 6'-CHLORO-5-(((H 2R)-2-((2S, 4Si - -((R). 2-SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2 ^, H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-N APHTHALENE] -7-

C ARB OXYL ATE OR (5)-METHYL &~CRLORO~5~(((lR 2R) --2^R S)--4~((S 2-SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUlTL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [1,4] OXAZEPINE-3 , 1 '- APHTHALENE] - 7- CARBOXYLATE OR (5)-METHYL 6'-CHLORO-5-(((H¾, 2R)-2-((2S, 4S)-4-((S)- 2-SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2 'H- SP1RO [BENZO [B] [1,4] OXAZEPINE-3, 1 '- APHTHALENE] - 7- CARBOXYLATE

To a stirred solution of (/ ¾ methyl tf-chloro -M ill 2R)-2- ⁽ (2S. -/Λ )-4~ ((l-(pyrimidin-2-ylsulfonyl)propan-2-yl)oxy)tetrahydro-2H-py ran^

yl)cyciobutyl)methyl)-3',4,4',54etr^

3, -naphthalene]-7-carboxylate (Example 919, Step 4; 0.014 g, 0.020 mmol) in MeOH (0.7 mL) was added cesium carbonate (8 mg, 0.1 mmol). It was stirred at rt for 2 h. To this reaction mixture was added hydroxylamine-o-sulfonic acid (0.013 g, 0.118 mmol) in water (0.5 mL) and it was stirred at 50°C for 30 min. After it was cooled to rt, EtOAc (70 mL) was added. The organic phase was washed with brine, dried over anhydrous sodium sulfate. The solution was filtered through a short plug of silica gel and concentrated to provide the title compound (9.5 mg) as a white solid, m/z (ESI, +ve ion) 647.3 { \ I · Π } .

Step 6: (S^6'-CHLORO-5-(((lIi2Ii)-2-((2Ji, 4Ii)-4-((R)-2- SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID OR (5)-6'-CHLORO-5-(((H¾ 2R) -2-((2S, i -4-f ^)-2- SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)METOYL)-3',4,4 ⁱ ,5-TETRAI-IYDRO-2I-I,2T-I-SPIRO [BENZO[B] [ l,4]OXAZEPINE-3,l '-NAPHTHALENE]-7-CARBOXYLIC ACID OR (5)-6'-CHLORO-5 -(({lR2R)-2-((2R, 4R)-4-((S)-2- SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUTYL)MEra:YL)-3',4,4',5-TETRAHYDRO-2I-L2'I-i- SPIRO [BENZO [B] [1 ,4] OX AZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR S)-6'-CHLORO-5-(((7R, 2R)-2-((2S, ^-4-^)-2- SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAHYDRO-2H,2T-I- SPIRO[BENZQ[B] [l,4] OXAZEPINE-3 ,1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (5)-6'-CHLORO-5-(((H¾ 2R) -2-((2R, 2·

SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4 ^, ,5-TETRAFlYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (5)-6'-CHLORO-5-(((H¾, 2R)-2-((2S, 4S)-4-((R)-2- SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2-

YL)CYCLOBUlTL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B] [1,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC

ACID OR (S)-6'-CHLORO-5-(((H 2Rj-2-((2R 4S)-4-((S)-2-

SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)C^XL BUTYL)METHYL)-3',4v4',5-TE;rRAHYDRO-2H,2'H-

SP1RO [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((/R, 2R)-2-((2S, 4S)-4-{{S)-2~

SULFAMOYLPROPOXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)MEraYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIR()[BENZO[B] [ 1,4] OXAZEPINE-3, l'-NAPHTIiALENE]-7-CARBOXYLIC ACID OR (S)-6'-CHLORO-5-(((/R, 2R)-2-((2R, 4R)-4-(((S)-\ - SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLI C ACID OR (S)-6'-CHLORO-5-((( /¾2/y-2-^ 5; ^-4-^-l -

SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBU L)METHYL)-3',4,4\5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B][l,4]OXAZEPINE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID OR (5)-6'-CHLORO-5-(((H¾,2R;-2-^2R, 4R)~4~(((R)~l~

SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METOYL)-3',4,4',5-TETRAI-IYDRO-2I-I,2 ^, H-

SPIRQ [BENZO [B] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID O (5)-6'-CHLORO-5-(((7 i -2 5;

SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUlYL)METHYL)-3',4,4 ^, ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '- APHTHALENE] -7-C ARBOXYLIC ACID OK (S &-Cl^OKO-5-(((lR ]^-2-((2R 4S)-4-(((S)-l- SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPlRO[BENZO[B][l,4]OXAZEPlNE-3,l'-NAPHTHALENE]-7-CARBOXYLIC ACID OR (5)-6'-CHLORO-5-((( IR 2R)-2-((2S, 4S)-4-(((S)~\ -

SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2-YL) CYCLOBUTYL)ME ^r rHYL)-3 ^! ,4,4',5-TEm' HYDRO-2H,2 ^, H- SPIR()[BENZO I B j [ 1 ,4]OXAZEPHME-3, 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID OR (S)-6'-CilLORO-5-(((i¾ 2^- ^i?, ^ -4 ^ ?)- l- SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [1,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID OR (S)~6'~Cm,ORO'5^ 2R)-2'({2S S)-4'{{(R)-1 - SULFAMOYLPROPAN-2-YL)OXY)TETRAHYDRO-2H-PYRAN-2- YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H-

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-CARBOXYLIC ACID

2144

2145

Lithium hydroxide (ΓΜ aqueous solution, 0.44 ml,, 0.44 mmol) was added to a solution of (1 ¾>methyi ' -ch!oro -5-iU Hi R) - 2-((2S.4S)- -H ) - sulfamoylpropan-2-yl)oxy)tetrahydro^

tetrahy άΓθ-2Η,2'Η-8ρΐΓθ[Ϊ6ηζο[ΐ] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (Example 919, Step 5; 0.0095 g, 0.015 mmol) in THF (0.5 ml,) and MeOH (1 mL). It was stirred at 55°C for 2 h. It was concentrated, acidified with 1 N HCl solution to pH 2-3 and extracted with EtOAc (60 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate. The filtrate was filtered through a short plug of silica gel and concentrated to get the title compound (8 mg) as a white solid, m/z (ESI, +ve ion) 633.0 (M+H) ⁺ . Step 7; (1S, 3'R, 6'R, 7'S i 'S, /37?)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1.24'-

| 8. ! 2.22 |TR !()XAj Ι 5 | Π ΠΑ| U 6i D! Α/ΑΡΗΝΤΛίΎΠ .ΟΙ 16.7.2. 1 ¹ ϋ ^{' 1} " jO

CTACOSA[18,20,26]TR1EN]-17'-ONE 15", 15 -DIOXIDE OR

(IS, 3'R, 6'R, 7R, 11 'S, i.?K)-6-CHLORO-13'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[ 8,12,22]TRIOXA[ 15]TfflA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η 0 ³ · ⁶ .0 ^2! · ²⁶ ]Ο CTACOSA[1 8,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE

OR (1S.3R, 6R, 7'i?J77iJ3'i?)-6-CHLORO-13'-METHYL-3,4-DJHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'- [8,I2,22]TRIOXA[15]TIflA[l,161DIAZAPENTACYCLO[16.7.2. - ¹¹ 0 ³ - ⁶ .0 ^2l ' ²⁶ ]O CTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE

OR (IS, 3 R, 6R. 7'S 1VR, 13 'R)-6-CHLORO - 13'-METHYL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'-

[8, 12,22]TRIOXA[15]THIA[l ,I6]DIAZAPENTACYCLO[16,7.2. 1 ⁷ - ³ Hr'' ⁶ .0 ^2! - ²⁶ ]O CTACOSA[18,20,26]TR1EN]-17'-ONE 15', 15 '-DIOXIDE

OR (IS, 3 , 6R, 7'S, 11 ' 13 ¾ 6-CHLORO- 13'-METHYL-3,4-DIHYDRO- 2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO

[16.7.2.1 ⁷ - ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ',15 '-DIOXIDE OR (IS, 3'R, 6'R, 7R, 11 ¾ 7 JS)-6-CHLORO-l 3'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'- [8, 12,22]TRIOXA[l 5JTHI A[l, 16JDIAZAPENTACY CLO

[16.7.2. i ⁷ - ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,261TRIEN]-17'-ONE 15',15'-DIOXIDE OR ( !S 3'R.6'R, 7'R l 'R, 73'S)-6-CHLORO-l 3'-METHYL-3,4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHAJ,ENE-l,24'- [8/12,22]TRIOXA[15]TIflA[l,161DIAZAPENTACYCLO[16.7.2.! ⁷ - ¹¹ 0 ³ - ⁶ .0 ^2l ' ²⁶ ]O CTACQSA[18,20,26]TRIEN]~17'~QNE 15', 15 -DIOXIDE

OR (IS, 3'R 6'R.7R, 11 'S, i5¾)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'- [SJ^lTWOXAllSlTraAfi eiDTAZAPENTACYCLOtiej.l^^^^eO^^lO CTACOSA[18,20,26]TRIEN]-17'-ONE 15', 1 '-DIOXIDE

OR (IS, 3 , 6R, 7'S, 11 'S, i¥'S)-6-CHLORO- 14'-METHYL-3,4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALE E-l,24'-

|H. i 222r R XAl I5|TI ΗΛ| I . >!ί ⁾ !Λ/ΛΡ! 1 Λ(Ύ(Ί.Ο| 16.72. f ^J ^Γ ϋ ^{21 ;} "|0 CT AC OS A[ 18,20,26 ] TRIEN] - 17'-ONE 15 ', 15 '-DIOXIDE

OR (IS, 3'R 6'R, 7'S 11 'S 7 ^' ?)-6-CHLORO-14'-METHYL-3,4-DIHYDRO-

2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'-

[8, 12,22]TRIOXA[l 5]THIA[1, 16]DI AZAPENTACYCLO

[167.2. i^^-O^^C^^^lOCTACOSAIlS^O^eiTRIENj-n'-ONE 15 ^* ,15'- DIOXIDE

OR (IS, 3'R 6R.7R, 11 % i ¾)-6-CHLORO-14 ^f -METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALEN E- ί .24'·

[8,12,22]TRi:OXA[15]THIA[l,161DIAZAPENTACYCLO[ 16.7.2. I ⁷ -' Η) ³ · ⁶ .0 ^2! · ²⁶ ]Ο CTACOS A[l 8,20, 26] TRIEN] -17"-ONE 15', 15'-DIOXIDE

OR (1S3R,6R, 7¾ii'ii.i4'i?)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

|8.i2.22|TRIOXAj Ι5| ^' Π I!A| 1. i 6iD! A/APLYl Λ(ΎΠ.Ο| 16.72.1 ^' ϋ ^; ".0 ^' "I QCTACQSA[18,20,26]TRiEN]~17'~ONE 15',15'-DIOXIDE

OR (IS, 3'R 6'R.7'R, 11 'S i4¾>6-CHLQRQ-14'-METHYL-3,4-DIHYDRQ- 2H,17'H-SPIRO [NAPHTHALENE- 1,24'-

[8,12,22]TRIOXA [ 15] THI A [ 1 , 16] DT AZAPENTACYCLO

[16.7.2.1 ⁷ - ¹¹ 0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ',15 '-DIOXIDE OR (IS, 3'R 6'R, 7'R 11 ¾ 74K)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, 17'H-SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2.r- ¹ k ⁾³ -^0 ²¹ - ²⁶ ]O CT AC OS A[ 18,20,26 ] TRIEN] - 17-ONE 15 ', 15 '-DIOXIDE OR (IS,.3'R, 6'R, TS l 'R, 7^¾)-6-CHLOR0 4'-METHYL-3,4-DIHYDRO-

2H. 17'H-SPIRO [NAPHTHALENE- 1 ,24'-

[8, 12,22]TR10XA[ 15] THIA[ 1 , 16] DIAZ APENT AC YCLO

[ 16:7.2^ ⁷ · ^Η () ³ · ⁶ .0 ^2! · ²⁶ ]Ο(:ΤΑ(:θ8Α[18,2(),26]ΤΕΙΕΝ;μΐ 7'-()ΝΕ 15', 15'-DIOXIDE OR {IS, 3'R, 6% 7% 11 i4" ?)-6-CHLORO-14'-METOYL-3,4-DIHYDRO- 2H, 17 'H-SP1RO [NAPHTHALE E- 1,24'-

[8,12,22]TMOXA[15]TmA[ l,16]DIAZAPENTACYCLO[16 .2 ⁷ - ¹¹ 0 ³ -^( ⁾²¹ - ²⁶ ]O CT ACOS A[ 18,20,26]TRIEN]~17'-ONE 15", 15 -DIOXIDE N,N-Dimethylpyridin-4-amine (DMAP) (0.049 g, 0.40 mmol) was added to a solution of (/ ¾)-6'-chlQro-5-(((/i?, 2 ?)-2 ^

yl)oxy)tetrahydro-2H-pyran-2-yl)cyclobutyl)me1hyl)-3',4,4 ',5-tetTahydro-2H,2 spiro[benzo[b] [l,4]oxazepine-3, l'-naphthalene]-7-carboxylic acid (Example 919, Step 6; 0.009 g, 0.014 mmol) in DCM (20 mL) at 0°C. Then Nl- ((ethylimino)methylene)-N3,N3-dimethylpropane-l ,3-diamine hydrochloride (EDC, 0.035 g, 0.185 mmol) was added slowly in portions and it was stirred at

0°C to rt for 3 days. After it was concentrated the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis μιη column: Phenomenex, Torrance, CA; MeCN in water with 0.1 % TFA, gradient elution). The title compound (1.5 nig) was obtained as a single isomer (fourth eiuting peak). 'H NMR (400 MHz, CD2CI2) δ 8.28 (m, 1H), 7.72 (m, IH), 7.40 (m, 1 H), 7.18 (m, IH), 7,09 (m, IH), 6.99 (d, ,/ 8 22 Hz, I H i. 6.54 (d, .7=1 ,96 Hz, H), 4.37-4,29 (m, IH), 4.16-4.08 (m, 4H), 3.91-3.84 (m, IH), 3.81-3.72 (m, 2H), 3.34 (br. s., IH), 3.19 (m, IH), 2.73-2.80 (m, 2H), 2.43 (d, ./ 6.46 Hz, IH), 2.17-1.14 (m, 19H). irv'z (ESI, +ve ion) 615.0 ( W M Y .

EXAMPLE 920. (IS, 3 'R, 6 'R, 7'S 11 13 'R)-6-CHLORO - 13 '-METHYL-3 ,4- DIHYDRO-2H, 17 'H-SPIRO[NAPHTHALENE- 1 ,24'- [8,12,22]TMOXA[15]THIA[ l,I6]DIAZAPENTACYCLO[16.7.2. i ⁷ - ¹¹ .0^ ⁶ .0 ²¹ - ²⁶ ] OCTAC()SA[18,20,261TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR (IS, 3R, 6'R, 7R, 11 ¾ 7iW)-6-CHLORO-13'-NlETHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE- 1 ,24 ^! ~

[8/12,22]Tl lOXA[15]THIA[L16]DlAZAl ⁵ ENTACYCLO[ 16 .2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

OR (1S,3R,6R, 7R, I1 R, /3!R)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- i .24'-

[8,12,22]TMOXA[15]TmA[ i;i6]DIAZAPENTACYCLO[16 .2. i ⁷ - ¹ ^() ³ - ^{6 2!} - ²⁶ ]

OCTACOSA[l 8,20,26]TRIE ]-17'-ONE 15',15'-DIOXIDE

OR (1S,3R,6R, 7¾77 ?, 75 ?)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALEN E- ί .24'·

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[l 8,20,26]TRIEN]-17'-ONE 15', I 5'-DIOXIDE

OR (75; 3 R, 6R, 7% 11 'S, 13 '5 6-CHLORO- 13'-METHYL-3,4-DIHYDRO- 2H, 17 'H-SP1RO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]TIflA[l,161DIAZAPENTACYCLO[16.7.2. - ¹ ^0 ³ >^0 ^2! - ²⁶ ] QCTACQSA[18,20,26]TRIEN]~17'~ONE 15',15'~DiOXiDE

OR (IS, 3R, 6R.7R, 11 'S 5¾)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'-

[8J 2,22]TRIOXA[15]THIA[1 ,16]DIAZAPENTACYCLO[167.2.1 ⁷ - ³ ^0 ³ ' ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TR1EN]-17'-ONE 15',15'-D10XIDE

OR (1S3R, 6R, 7R, 11 , i3'5)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17Ή-SPIRO[NAPHTHALENE-l,24 ^, -

[8 ₅ 12,22]TRIOXA[15]THTA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DI0X1DE

OR (75 3R, 6R, 7R, 11 'S 7i'5)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]TH1A[1,16]DIAZAPENTACYCLO[16,7.2.1 ⁷ - ¹ ^0 ³ ^.0 ²¹ - ²⁶ ] OCTAC()SA[18,2Q,26jTRIEN]-17'-ONE 15',15'-DIOXIDE

OR (IS, 3 , 6R.7'S 11 'S i¥S)-6-CHLORO- 14'-METHYL-3,4-DTHYDRO- 2H, 17'H-SPIRO[NAPHTHAJ,ENE-l,24'- [8,12,22]TRIOXA[15]THIA[ lJ 61DIAZAPENTACYCLO

[16 .2J. ⁷ - ¹ V0 ³ -^0 ^2! - ²⁶ ]OCTACOSA[18,20 ₅ 26]TR1EN]-17'-ONE 15',15'-DiQXIDE OR (1S, 3'R, 6'R. 7'S S, i4'R)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'- [8, 12,22]TRIOXA [ 15] ΤΤΠ A [ 1 , 16] DTAZ APE T AC YCLO

[16.7.2. 1 ⁷ - ¹¹ .0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,26]TRIEN]-17'-O E 15',15'-DIQX1DE OR (IS 'R, 6'R, 7'R, 11 'R, 74¾>6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALE E-l,24'-

[8,12,22]TMOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DI0X1DE

OR (IS, 3R, 6'R, 7'R, 11 , /4'R)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, ! 7 Ή-SPIRO [NAPHTHALENE- 1.24'-

[8,12,22]TRIOXA[15]TOL [1,16]DIAZAPENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ ^^0 ²¹ - ²⁶ ] OCTACOSA[18,2Q,26jTRIEN]-17'-ONE 15',15'-DIOXIDE

OR (1S, 3'R, 6'R. 7'R l 'S, /^¾)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, i 7'H-SPIRO[NAPHTHALENE- 1,24'-

[8,12,22]II lOXA[15]IHIA[l,16]DlAZAl ⁵ ENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIE ]-17'-ONE 15', 15'-DIOXIDE

OR (1S.3'R, 6'R, 7'R, 7 / ¾ i4'' ?)-6-CHLORO-14'-METOYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8, 12,22]TRIOXA[l 5]TH1A[1, 16JDIAZAPENTACYCLO

[16.7.2. - ¹ 0 ³ -^0 ^2! - ²⁶ ]OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR (1S, 3'R, 6'R, 7'5 ^, , ii 'i?, 7¥'5)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALEN E- 1,24'- [ 8,12,22]TRIOXA[ 15]TfflA[l,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^Η .0 ³ · ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[l 8,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE

OR ( /.V.3'R, 6'R, 7'S, 11 'R, i^K)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, 17 'H-SP1RO [NAPHTHALENE- 1 ,24'-

|;8,12,22jTRIOXA[15jTHIA[ l,16]DIAZAPENTACYX:L()|;i6.7.2.1 ⁷ - ¹ ^0 ^3> ^0 ^2! - ²⁶ ] QCTACQSA[i 8,20,26]TRIEN]~17'~ONE 15',15'-DI0X1DE

The title compound (1.4 mg) was obtained as a single isomer (third eluting peak) from the reverse phase preparative HPLC in Example 919. ^! H NMR (400 MHz. CD2CI2) δ 8.15 (s.1H), 7.73 (d, J=8.61 Hz.1H).7.34 (dd,J=2.05, 8.31 Hz. 1H), 7.17 idd../ 2.35.8.41 Hz, 1H), 7.09 (ά. J 2.15 Hz.1H), 6.98 !d../ 8.4! Hz, IH), 6.49 (d.,7 2.1 Hz, 1H), 4.17-4,09 (m, 2H), 3.92-3.85 (m, 2H), 3,84-3.68 (m, 4H), 3.49-3.42 (m, IH), 3.24-3.09 (m, 2H), 2.81-2,74 (ra 2H), 2.70 (s, 1H), 2.49- 1.57 (m, 1 ! is.1.42 (d, .7=7.04 Hz, 3H). m/z (ESI, +ve ion) 615.1 (M+H). EXAMPLE 921. (IS, 3 R.6 R, 7'S.11 ¾ 13 'R)-6-CHLORO - 13 '-ΜΕΤΉ YL-3 , - DIHYDRO-2H, 17 Ή-SPIROj NAPHTHALENE- 1 ,24'- [ 8, 12,22]TRIOXA[ 15]THIA[1, 16] DIAZAPENTACYCLO

[ 16,7.2.1 ⁷ - ³³ ,0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR (IS, 3'R,6'R, 7'R, 11 ¾ 73K)-6-CHLORO-13'-MEraYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[I5]TIflA[l,161DIAZAPENTACYCLO[16.7.2. - ¹ ^0 ^3> ^0 ^2! - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15 ', 5 '-DIOXIDE

OR (1S,3'R,6'R.7R,irR13'Ry6-CRLORQA3'-METHYL-3A-OmYDRO- 2H, 17 Ή - S P I RO j N APHTH ALEN E- 1 ,24'-

[δ,Ι^ΙΤΊυθΧΑΙΙΰΙΤΉΙΑίΙ,ΙόΙΟΤΑΖ� �ΡΕΝΤΑΟΥΟΕΟίΙό.Τ.ΖΙ ⁷ - ¹¹ ^ ³ · ⁶ .^ ¹ · ²⁶ ]

OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIQXIDE

OR (1S3R, 6R, 7'S, 11 R, 73'R)-6-CHLORO-13'-METHYL-3.4-DIHYDRO- 2H, 17 'H-SPIRO[N APHTHALENE- 1 ,24'-

[8 ₅ 12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DI0X1DE

OR (IS, 3 R, 6R, 7'S 11 ' 13 ¾> 6-CHLORO- 13'-METHYL-3,4-DIHYDRO- 2H, ! 7 Ή-SPIRO [NAPHTHALENE- 1 ,24'- [8,12,22]TRIOXA[15]THL [1,16]DIAZAPENTACYCLO[16,7.2.1 ⁷ - ¹¹ .0 ³ ^.0 ²¹ - ²⁶ ] OCTACOSA[18,2Q,26jTRIEN]-17'-ONE 15',15'-DIOXIDE

OR (1S3'R,6'R.7R,11'S /3¾)-6-CHLORO-13'-METHYL-3,4-DIHYDRO- 2H, 17 'H-SPIRO[N APHTHALENE- 1,24'-

[8,12,22]Tl lOXA[15]THIA[l,16]DlAZAl ⁵ ENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ^e OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

OR (1S,3'R,6'R, 7'R, Il'R, /3¾ -6-CHLORO-13'-METHYL-3,4-DiHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1.24'-

|8.!2.22|TR!OXAj Ι5|ΠΠΑ| ! J 6iD! Α/ΑΡΗΝΤΛίΎΠ.ΟΙ 16.7.2. Γ ¹ '.Ο-'.ϋ ²¹ 18,20,26]TRIEN]-17-ONE 15',15'-DIOXIDE

OR (1S,3'R, 6'R.7'R, 11 'S /3S)-6-CHLORO-i:r-METHYL-3,4-DiHYDRO- 2H, 17 Ή-SPIRO [N APHTHALEN E- 1,24'- 18.12.221 ^' t ^' RIOXAj 1 | ^' Π Ι!Λ| 1.!6ίί)!Α/.ΛΡ!:\Ί Λί ^' Υί 1.0| 16.72.Γ".0 ^! " 0 ^''!' | 18,20,26]TRIEN]-17*-ΟΝΕ 15', 15'-DiQX!DE

OR (IS, 3 Ίί, 6'R.7'S, 11 'S 14 ¾)-6-CHLORO- 14'-METH YL-3,4-DIHYDRO- 2H, 17 Ή - S P I RO [N APHTH ALEN E- 1 ,24'- [δ,Ι^ΙΤΊυθΧΑΙΙΰΙΤΉΙΑίΙ,ΙόΙΟΤΑΖΑΡ Ε ΤΑΟΥΟίΟίΙό.Τ.ΖΙ ⁷ - ¹¹ ^ ³ · ⁶ .^ ¹ · ²⁶ ] QCTACQSA[18,20,26]TRIEN]-17'-QNE 15',15'-DIQXIDE

OR (IS 'R, 6'R, 7'S, 11 'S, i K)-6-CHLORO-14*-METHYL-3,4-DIHYDRO- 2H, 17'H-SPIRO[NAPHTHALE E-l,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16 .2J.~7,ii~l 6 ~.0-21 ,26~] OCTACOS A[ 18,20,26] TR1EN] -17'-QNE 15', 1 S'-DIOXIDE

OR (IS, 3'R, 6'R, 7'R, 11 'R, /4¾)-6-CHLORO-14'-METHYL-3,4-DIHYDRO- 2H, ! 7 Ή-SPIRO [NAPHTHALENE- 1.24'-

[8,12,22]TRIOXA[15]TfflA[l,16]DLAZAPENTACYCLO[16,7.2.i ⁷ - ¹¹ .0^ ⁶ .0 ²¹ - ²⁶ ] OCTAC()SA[18,2Q,26jTRIEN]-17'-ONE 15',15'-DIOXIDE

OR (1S,3'R,6'R.7%ii'^i^¾)-6-CHLORO-14'-METHYL-3,4-DTHYDRO- 2H, 17'H-SPIRO[NAPHTHALENE- 1,24*-

18.1 .22 P ^' RIOXAi i j! !l Λ[ 5. ! 6if L\ZAPHM At VCt (>| 16.7.2.1 ^" ".0 ⁵ · ^, \ ⁽ > ^,| · ^, ' ^, |

OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

OR (IS, 3'R, 6'R, 7'R, 11 'S, 4'¾>6-CHLORO-l 4'-METHYL-3,4-DIHYDRO- 2H, 17 Ή-SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TMOXA[15]TmA[l,16]DIAZAPENTACYCLO[16.7.2.i ⁷ - ¹ ^() ³ - ⁶ .0 ^2! - ²⁶ ] OCTACOSA[l 8,20 ₅ 26]TRIE ]-17'-ONE 15',15'-DIOXIDE

OR (IS, 3'R, 6'R.7'R, 11 'S 74'i?)-6-CHLORO-14'-METHYL-3,4-DmYDRO- 2H, 17 Ή-SPIRO [NAPHTHALEN E- 1,24'- [8,12,22]TRIOXA[ 15]THIA[1 ,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ¹¹ .0 ³ · ⁶ .0 ²¹ - ²⁶ ] | 18,20,26]TRIEN]-17'-ONE !5',15'-DIOXIDE

OR ( /.V.3'R, 6'R, 7'S, 11 % 14 ¾)-6-CHLORO- 14'-METHYL-3 ,4-DIHYDRO- 2H, 17 'H-SP1RO [NAPHTHALENE- 1 ,24'-

[8,12,22jTRIOXA[15jTHIA[l,16]DIAZAPENTACYCLO[16.7.2.1 ⁷ - ¹ ^0 ^3> ^0 ^2! - ²⁶ ] OCTACOSA[i8,20,26]TRIEN]-r7'-ONE 15',15'-DI0X1DE OR (1S,.3'R,6'R.7'S,U% /4'i?)-6-CHLORO-14'-METOYL-3,4-DIHYDRO- 2H.17'H-SPIRO[NAPHTHALENE- 1,24'-

[8,12,22]TllOXA[15]THIA[l,16]DlAZAl ⁵ ENTACYCLO[16 .2 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE

2157

The title compound (2.1 mg) was obtained as a single isomer (first eiuting peak) from the reverse phase preparative HPLC in Example 919. ¾ NMR (400 MHz, CD2CI2) δ 8.10 (br. s. , IH), 7.72 id . ./ 8.61 Hz, IH), 7.17 (dd, .7=2.25, 8,51 Hz, IH), 7.07 (m, 2H), 6.94 (d, J=8.02 Hz, IH), 6.64 (s, IH), 4.09 (d, ./ 7.04 Hz, 4H), 3.84 (d, ,/ 6.46 Hz, 2H), 3.77 (d,■/ 2.54 Hz, 2H), 3.74-3.69 (m, 3H), 3.65- 3,61 (m, 2H), 3.18-3.04 (rn, 2! I ). 2.81 -2,72 (m, 41 1 ). 2.48-2,38 (m, IH), 2, 1 8-1.23 (m, 12H). rrv'z (ESI, +ve ion) 615.1 (Μ+Η).·

EXAMPLE 922. (IS, 3 'R, 6'R, 7'S, 11 'S, 137?)-6-CHLORO- 13'-METHYL-3,4- DIHYDRO-2H, 17'H-SPIRO[NAPHTHALENE-l,24'- [ 8, 12,22]TRIOXA[ 15]THIA[1 ,16]DIAZAPENTACYCLO[ 16.7.2.1 ⁷ · ^{1 1} .0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15'-DIOXIDE OR

(IS, 3 % 6'R, 7R, 11 'S, 13 'i?)-6-CHLORO- 13'-METHYL-3,4-DIHYDRO-2H, 17Ή- SP1RO [NAPHTHALENE- 1.24'-

|;8,12,22jTRIOXA[15]TH:iA[ l,16]DIAZAPENTACYCLO|;i 6.7.2.1 ⁷ - ¹ ^() ³ > ^, 0 ^2! - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 % 6 7R, 11 R, 13 'R)-6-CHLORO-l 3'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'- 18.12.221 ^' t ^' RIOXAj Ι5| ^' Π Ι!Λ| 1.KsiD!A/APLYl Λί ^' Υί 1.0| 16.72.Γ".0 ^! " 0 ^''! '| QCTACQSA[I8,20,26]TRiEN]~17'~ONE 15', 15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7'S.ll R 13 !R)-6-CHLORO- 13 '-METHYL-3,4-DIHYDRQ-2H, 17Ή- SPIRO [NAPHTHALENE- 1 ,24'- [δ,Ι^ΙΤΊυθΧΑΙΙΰΙΤΉΙΑίΙ,ΙόΙΟΤΑΖΑΡ Ε ΤΑΟΥΟίΟίΙό.Τ.ΖΙ ⁷ - ¹¹ ^ ³ · ⁶ .^ ¹ · ²⁶ ] QCTACQSA[18,20,26]TRIEN]-17'-QNE 15 ',15 '-DIOXIDE OR

(IS, 3 ΊΙ 6'R, 7'S 11 ^! S 13 ¾>6-CHLORO- 13'-METHYL-3,4-DIHYDRO-2H, 17 I I- SPIRO [NAPHTHALENE- 1 ,24"-

[8 ₅ 12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ] OCTACQSA[18,20,26]TRIEN]-I7'-QNE 15 ',15 '-DIOXIDE OR

(IS, 3 R, 6'R, 7R, 11 ¾ 13 ¾> 6-CHLORO- 13'-METHYL-3,4-DIH YDRO-2H, 17 Ή- SPIRO [NAPHTHALENE- 1 ,24'-

[8,12,22]TRIOXA[15]TfflA[l,16]DIAZAPENTACYCLO[16 .2.I ⁷ - ¹ ^0^ ⁶ .0 ²¹ - ²⁶ ] OCTACOSA[18,2Q,26jTRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(lS,3R,6R R,llR,13'S)~6~ Ml.QRO ~MY -lY -i

SPIRO[N APHTHALENE- 1 ,24'-

[8,I2,22]TllOXA[15]THIA[l,16]DlAZAl ⁵ ENTACYCLO[16 .2.1 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ]

OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

(IS, 3 , 6R, 7R, I 1 ¾ / 3 ¾> 6-CHLORO- 13'-METHYL-3,4-DIHYDRO-2H ₅ 17 Ή- SPIRO[N APHTHALENE- 1 ,24'-

[8,12,22]TMOXA[15]TmA[l,I6]DIAZAPENTACYCLO[16 .2.i ⁷ - ¹¹ .() ³ - ⁶ .0 ^! - ²⁶ ] OCTACOSA [18,20,261TRIEN]-17'-ONE I5', I5'-DIOXIDE OR

(IS, 3 R, 6'R 7'S.11 % 14 ¾)-6-CHLORO- 14-METHYL-3 ,4-DIHYDRO-2H, 17 Ή- SPIRO [ APHTHALENE- 1 ,24'- [8,12,22]TRi:OXA[15]THIA|;i,161DIA APENTACYCLO[16:7.2T ⁷ ' ⁱ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE I5',I5'-DIOXIDE OR

(IS, 3 , 6'R, 7'S 11 'S.14 'R)-6-CHLORO- 14'-METHYL-3,4-DIHYDRO-2H, 17Ή- SP1RO [NAPHTHALENE- 1 ,24'-

|;8,12,22jTRIOXA[15jTHIA[l,16]DIAZAPEN ACYCL()|;i6 .2.1 ⁷ - ¹ ^0 ^3> ^0 ^2! - ²⁶ ] OCTACOSA[I8,20,26]TRiEN]-17'-ONE 15 ',15 '-DIOXIDE OR

(IS, 3 R, 6 R, 7'R, 11 14 ¾>6-CHLQRO- 14'-METHYL-3,4-DIHYDRO-2H, 17Ή- SPTRO[NAPHTH ALENE- 1 ,24'-

[8 ₅ 12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[16.7.2. ' ¹¹ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ]

OCTACOSA [18,20,26]TRiEN]-17'-QNE I5',15'-DIQXIDE OR

(i^ ^^Z'RJiTti^^-e-CHLORO-M'-METIiYL-S^-DIHYDRO-ffl T'H- SPIRO [NAPHTHALENE- 1 ,24'-

[8 ₅ ]2,22]TRIOXA[15]TfflA[i i6]DLAZAPENTACYCLO[16,7.2.1 ⁷ - ¹¹ .0^ ⁶ .0 ²¹ - ²⁶ ] OCTAC()SA[18,2Q,26jTRIEN]-17'-ONE 15', 15 '-DIOXIDE OR

(IS, 3 'R, 6'R, 7'R, 11 ¾ 14 ¾)-6-CHLORO- 14'-METOYL-3,4-DIHYDRO-2H, 17Ή- SPIRO[N APHTHALENE- 1 ,24'- [8,I2,22]Tl lOXA[15]THIA[l,16]DlAZAl ⁵ ENTACYCLO[16 .2 ⁷ - ¹ ^0 ³ -^0 ²¹ - ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE 15',15'-DIOXIDE OR

(IS 'R, 6'R, 7'R, 11 'S 74'R)-6-CHLORO- 14'-METHYL-3,4-DiHYDRO-2H, 17Ή- SPIRO[NAPHTHALENE-l,24'-

[8,12,22]TMOXA[15]THL [1,I6]DIAZAPENTACYCLO[16 .2 ⁷ - ¹ ^() ³ - ⁶ .0 ^! - ²⁶ ] OCTACOSAjl 8,2Q,26]TRiEN]-17'~ONE 15',15'-DIOXIDE OR

(IS, 3 'R.6'R, 7'S.11 'R, 14 ¾)-6-CHLORO- 14'-METHYL-3,4-DIHYDRO-2H, 17 Ή- SPIRQ[N APHTHALENE-1 ,24'-

[8,12,22]TRIOXA[15]THIA[l,16]DIAZAPENTACYCLO[ 16.7.2. ^-".Ο^.Ο ²¹ · ²⁶ ] OCTACOSA[18,20,26]TRIEN]-17'-ONE I5',I5'-DIOXIDE OR

SPIRO INAPHTHALENE- 1.24'-

1.12.221 ^' t ^' RIOXAj Ι5| ^' Π Ι!Λ| 1.IGjDlA/APKYl Λ(Ύ( ^' 1.0| 16.72.Γ".0 ^! " 0 ^''!' | QCTACQSA[18,20,26]TRIEN]~17'~ONE 15',15'-DIOXIDE

2161

The title compound (3,5 mg) was obtained as a single isomer (second eluting peak) from the reverse phase preparative HPLC in Example 919, 'H NMR (400 MHz, CD2CI2) 6 8.20 (111, 1H), 7,71 (m, lH), 7.09 (s, 3H), 6.96 (m, 1H), 6.56 i ns. 1H), 4.09 (d. ./ 7.24 Hz, 4H), 3.95-3.82 (m, 2H), 3.81-3.63 (m, 5H), 3.28 (br. s . 2H), 3.16 (d, 6 46 Hz, 11 1 ). 2.84-2.72 (m, 2H), 2,48-2.28 (m, 2H), 2.16-2,04 (111, 2H), 1 ,98-1.89 (m, I H i. 1.87-1,62 (m, 7H), 1.44 (t, J=12.23 Hz, i l l ). 1,32 (d, J=6.06 Hz, 3H). m/z (ESI, +ve ion) 615.1 (M+H).- EXAMPLE 923. {311 11 7S ^, ,225)-6 ^, -CHLORO-7-HYDROXY-3 ^, ,4 ^, -DIHYDRO- 2Ή, 15H-SPIRO [9,20-DIOXA- 13-THI A-l , 14-

DIAZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA-16 8,24-TRlE E-22,r- N APHTHALEN] -15 -ONE 13,13-DIOXIDE OR (3R, 6R, 7R,22S)-6-CHLORO-7- HYDROXY-3',4'~DIHYDRO-2'H, 15H-SPIRO[9,20-DIOXA- 13-THI A- 1 , 14-

DIAZATETRACYCLO[14.7.2.0 ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA-16, 18,24-TRIENE-22, 1 '- N APHTHALEN ] - 15 -ONE 13,13-DIOXIDE

Platinum (IV) oxide (0.22 mg, 0.97 μιηοΐ) was added to a solution of Example 917 (0.003 g, 4.9 μηΊθΙ) in EtOAc (1.6 mL). It was stirred under H ₂ atmosphere for 36 min. It was concentrated and the residue was purified by- reverse phase preparative HPLC (Gemini™ Prep Cis 5μηι column; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to provide the title compound (1.3 mg) as a film. ¾ NMR (400 MHz, CD2CI2) δ 7.74 (m, 1H), 7,44 (m, U i ). 7.28 (m, i l l ). 7.18 (m, IH), 7, 10 (m, U i ). 6.97 (m, I I I ). 4.13 (d, ./ -I I I Hz, 2H), 4.02 (m, IH), 3.98-3.89 (m, 2H), 3.79 (dd, ./ 6,26. 9.00 Hz, IH), 3.70-3.63 i ns. 2H), 3.58-3.53 (m, IH), 3.46 id. ./ 6.65 Hz, 2H), 3.22-3.1 7 (m, I H), 3.09-3.03 (m, IH), 2.83-2.76 (m, 2H), 2.51 (d, 7.43 Hz, 2H), 2.37-2,27 (m, 2H), 2.15-1. 18 (m, 9H). m/z (ESI, +ve ion) 575.1 (M+H) ⁺ .

EXAMPLE 924. (3R, 6R, 7R, 1 IS, 24S)-6'-CHLORO-l l-HYDROXY-3',4'- DIHYDRO-2'H, 17H-SPIRO[8,22-DIOXA-l 5-THIA- 1 , 16- ϋΙΑΖΑΡΕΝΤΑ€Υ€ΕΟ[16.7.2.1 ⁷ · ^π .0 ³ · ⁶ .0 ²¹ · ²⁶ ]Ο€ΤΑεθ8Α-18,20,26-ΤΜΕΝΕ- 24,l'-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3R 6R 7S, 1 lR,24S)-&- CHLORO-n -HYDROXY-3 ^, ,4 ^, -DIHYDRO-2'H ₅ 17H-SPIRO[8 ₅ 22-DIOXA-15- THIA- 1 , 16-DI AZAPENTAC YCLO [ 16.7.2.1 ⁷ - ^{"! 1} , 0 ³ · ⁶ .0 ²¹ · ²⁶ ] OCT ACOS A- 18,20,26- TRIENE-24, 1 ' -N APHTHALEN ] - 17-ONE 15,15-DIOX1DE OR

(3R, 6R, 7R, 1 IR 24S)-6'-CHLORO - 11 -H YDROXY-3 ',4'-DIH YDRO-2'H, 17H- SPIRO[8,22-DIOXA - 15-THIA- 1 , 16-

DL ZAPENTACYCLO[16,7.2.1 ⁷ ^0 ³ - ⁶ .0 ²¹ - ²⁶ ]OCTACOSA-18,20,26-Ti lENE- 24,r-NAPHTHALEN]-17-ONE 15,15-DIOXIDE OR (3R 6R 7S, 11S,24S)-G- CHLORO-l l -HYDROXY-3 ^, ,4 ^, -DIHYDRO-2'H ₅ 17H-SPIRO[8 ₅ 22-DIOXA-15- THIA- 1 , 16-DI AZAPENTAC YCLO [ 16.7.2.1 ⁷ - ^{"! 1} , 0 ³ ' ⁶ .0 ²¹ · ²⁶ ] OCTACOS A- 18,20,26-TRlENE-24, 1 '-N APHTHALEN] - 17-ONE 15,15 -DIOXIDE

Platinum (IV) oxide (1.1 mg, 5 μηιοΐ) was added to a solution dioxa~15 .hia-lJ6-diaza.pentacydoj^

tetraene-24,r-naphthalen]-17-one 15,15-dioxide (Example 851; 0.003 g, 5 μηιοΐ) in EtOAc (5 mL). It was stirred under ¾ for 1 h. After concentration the residue was purified by reverse phase preparative HPLC (Gemini™ Prep Cis μιη column; Phenonienex, Torrance, CA; MeCN in water with 0.1% TFA, gradient eiution) to provide the title compound (0.9 nig) as a white solid. Ή NMR (500 MHz, C ^' D'C b) δ 8.00 (m, 1H), 7.70 (m, lH), 7.17 (rn, 1H), 7.10 (m, 1H), 6,96 (s, 2 Hi.6.79 (m, li!).4.16-4.04 (m, 211).3.91-3.80 (m, 21!}.3,78-3.62 (m, 2H), 3.48- 3.31 (m, 3H), 3,28-3.15 (m, 2H), 2.83-2.71 (m, 2H), 2.56-2.47 (m, 1H), 2.38-2.29 (m, 1H), 2.14-2.06 (m, 1H), 2.03-1.35 (m, 16H). m/z (ESI, +ve ion) 615.0 {M il}

EXAMPLE 927. (1 S,3 ^, R,6'R,7 ^, S)-6-CHLORO-7 ^, -( ffiraYLAMINO)-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'- |2 ⁽ >X A| L? I U ΠΛ| ί 1 J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA

[16,I8,24]TRIEN]-15'-QNE 13',13'-DIOXIDE OR (lS,3'R,6'R,7 ^, R)-6-CHLORO- 7 ^, -(ME^ΉYLAMINO)-3,4-DIHYDRO-2H 5Ή-SPIRO[NAPHTHALENE-l,22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA 16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

(lS,3'R,6*R)-6-Chloro-3,4-dihydi -2H,7'H,15'H-spiro[naphthaleiie-l,22'- i;20]oxa[13]thia|;i,14]diazatetracyclo|14.7.2.0 ³ -^0 ^l9 - ²⁴ pentacosa[16,18

7',15'-dione 13',13'-dioxide (Example 832; 12 mg, 0,021 mmol) was dissolved in 0.53 mL of THF and 0.53 mL of DCE. To this mixture was added methvlamiiie

2,165 (2,0 M solution in tetrahydrofuran, 42.0 μΐ, 0.084 rnmol), acetic acid (4.81 μΐ, 0.084 mmol) and sodium triacetoxyborohydride (11. 13 mg, 0.053 mmol). The reaction was stirred at rt for overnight. 3mL of aq. NaaCCb solution and 10 mL of EtOAc were added. The organic layer was concentrated and purified by reversed phase preparative HPLC (Gemini™ Prep Cie 5 μίη column; Phenomenex, Torrance, CA; gradient elution of 30% to 95% MeCN in water, where both solvents contain 0.1 % TFA, 30 mm method) to give (l S,3'R,6'R,7'S)-6-chloro-7'- (methylaraino)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l ,14]diazatetra<yc^

15'-one 13',13'-dioxide or (l S,3 ^, R,6'R,7 ^, R)-6-chloro-7 ^, -(methylaniino)-3,4- dihydro-2H,15 ^, H-spiro[naphthalene-l,22'- [20]oxa[I 3]thia[ l, I 4]diazatetTacyclo^^

15'-one I3',13'-dioxide (4.2 mg, 7.16 μηιοΐ, second eluting major peak) from the reverse phase preparative HPLC. ' ! ! NMR (400MHz, D\1SO-d..) δ 8.39 (br. s., i l l ). 8.23 (br. s., i l l ). 7,67 id. ./ 8.4 Hz, IH), 7.29 (dd, ,/ 2.5. 8.8 Hz, I I I ). 7.21 (d, J=2.0 Hz, IH), 7.06 (d, J=8.6 Hz, IH), 6.96 (d, «7=8.2 Hz, 1H), 6.86 (s, IH), 4.07 (dd, J=12.3, 37.8 Hz, 2H), 3.93 (d, J=15.5 Hz, IH), 3.70 (d, J=15.1 Hz, IH), 3.64 (d, ./ 14. ! Hz, IH), 3.53 (br. s., I H), 3.03 (dd, J=10.6, 14.3 Hz, IH), 2.85 - 2,67 (m, 2H), 2.59 -2,50 (m , 2FI overlap with solvent) 2.34 (br. s. , 2H), 1 ,99 (d, J=10.4 Hz, IH), 1.95 - 1. 18 (m, Γ7Η), m/z (ESI, +ve ion) 586.2 { V! H i :

EXAMPLE 928. (l S,3'R,6'R,7'R)-6-CHLORO-7'-((2- HYDROXYETHYL)AM] O)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI MJ^.O'^.O^^lPENTACOSA [16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (l S,3'R,6'R,7'S)-6-CFILORO- 7'-((2-HYDROXYETHYL)AMINO)-3,4-DIHYDRO-2H, 15Ή- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 1 8,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 927, using (1 S,3'R,6 ^f R)-6-Chloro-3,4-dihydro-2H,7'H,l 5Ή- spiro [naphthalene- 1 ,22'- H.24|triene|·· 7 ^' .1 '-diune 13',13'-dioxide (Example 832) and ethanolamine (Aldnch), and the desired product, (1 S, 3'R,6'R,7'R)~6-chloro~7'-((2 -hydroxy ethy l)amino)-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- |20k)x i I3|ihia| 1 J4|di /.aletracyc!oj 14.7.2.0^0 ^! " ⁿ ipen[aeosa| 16. i 8.24|inenj- 15'-one 13',13'-dioxide or ( IS, 3'R,6'R,7'S)-6-chloro-7'-((2 -hydrox ethyl)amino)~ 3,4-dihydro-2H,15H-spiro[naphthalene-l,22'- 8.24|irieni- 15'-one 13',13'-dioxide was isolated as a single isomer (first eluting major peak) from the reverse phase preparative HPLC. Ή NMR (400MHz, ( P OD) δ 7.76 (d, ./ 84 Hz, 1H), 7.21 (dd, J=2.2, 8.5 Hz, ill).7.14 (d, ./ .2.2 Hz, 1H), 7.07 (dd, ./ 2.0.8.2 Hz, 111).7.01 (d, ./ 2.0 Hz, 1H), 6.99 (d, ./ 8.0 Hz, ill .4.20 - 4.14 (m, ill).4.04 (d../ 12 ! Hz, III).3.93 (dd,J=3.5, 15.1 Hz, 1H), 3.86 M.J 14.3 Hz, 1H), 3.81 - 3.73 (m, 2H), 3,69 (dd, J=8.2, 15.1 Hz, ill).3.53 (!../ 7.2 H/..1H), 3.25 - 3.18 (m, 2H), 3.14 - 3.04 (m, 1H), 2.88 - 2.77 (m, 2H), 2.77 - 2.65 (m, 1H), 2.57 - 2.36 (m, III).2,10 (d, ,/ 9.4 Hz, 31!}.2.01 - 1.77 (m, 6H), 1.75 - 1.61 (m, 4H), 1.61 - 1.45 (m, 3H). nv ^' z (ESI, +ve ion) 616.1

EXAMPLE 929. (lS,3'R,6'R,7 ^, S)-6-CHLORO-7 ^, -((2- HYDROXYETHYL)AMINO)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ(·ν ^' Χ)Ι 117.20 ^;ί '.ϋ |ΡΗ\ i ACOSA

[16,18,24]TRIEN]-15'-ONE 13',13'-D10XIDE OR (lS,3'R,6'R,7'R)-6-CHLORQ- 7'-((2-HYDROXYETHYL)AMINO)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was obtained as a single isomer (second eluting peak) from the reverse preparative phase HPLC in Example 928. ^! H NMR (500MHz, CD3OD) δ 7.76 (d, .7=8.6 Hz, ΓΗ), 7.20 (dd, J=2,3, 8.4 Hz, IH), 7.14 (d, J=2.2 Hz, IH), 7.10 (dd, ./ 2.0.8.1 Hz, IH), 6.99 (d, J=8.1 Hz, IH), 6.87 (d, ./ i.7 Hz, IH), 6.88 -6.86 (m, IH), 4.12 (dd, J=\ 1.5, 28.6 Hz, 211).4.01 (dd,J=7.1, 13.9 Hz, IH), 3.93 (d, ,/ 15.2 Hz, ! H), 3.87 - 3 , 81 (m, 2H), 3.75 (d, 13.7 Hz, 1 !!}.3.49- 3.40 (m, 2H), 3.22 - 3,03 (m, 3H), 2.87 - 2.74 (m, 2H), 2.63 - 2,50 (m, 2H), 2.14 - 2.02 Cm.2H), 2.00 - 1.67 (m, 8H), 1.67 - 1.54 (m, 3H), 1.54 - 1.44 (m, 2H). m/z (ESI, +ve ion) 616.1 EXAMPLE 930. (lS,3'R,6'R,7'R)-6-CHLORO-7'-((2,2,2- TRIFLUOROETHYL)AMINO)-3,4-DIHYDRO-2H,15H- SPTRO[NAPHTHALENE-l,22'-

|20i()XA| Γ, ΐΗΙΛΐ Ι..! |ί)!Λ/Λ ! :ΓΗ.Λ(·ν ^' .()Ι IL7.20 ' ".ί) ^{|:, ! 1} |Ρ1·Ν i ^' ACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7'S)-6-CHLORO- 7'-((2,2,2-TRIFLUOROETHYL)AMINO)-3,4-DIHYDRO-2H,15'H-

2,168 SPTRO[NAPHTH ALENE- 1 ,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[16,18, -15'-0NE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 927, using (lS,3 ^, R,6 ^, R)-6-Chloro-3 ₅ 4-dihydro-2H,7H,15 ^, H- spiro [naph thalene- 1 ,22'-

7',15'-dione 13',13'-dioxide (Example 832, 12 mg) and 2,2,2-trifluoroethylamine (Sigma), and the desired product, (lS ^e^T^-e-chloro-? ¹ -^^^- trifluoroethyl)amino)-3,4-dihydro~2H,15'H-spiro[naphthalene- l,^

[20]oxa[13]thia[l,14]diazatetracy^^

15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S)-6-chloro-7'-((2,2,2- triiluoroeihyl)amino

[20] oxa[ 13] thia[ 1 , 14] diazatetracy cl o [ 14 ,7.2 ,0 ³ · ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide was isolated as a single isomer (first eiuting major peak) from the reverse phase preparative HPLC. ^f H NMR (500MHz, CD3OD) δ 7,76 (d, J=8,6 Hz, I Hi..7.20 (dd, ,7=2,2, 8.3 Hz, IH), 7.13 (d, J=2:2 Hz, IH), 7.08 (dd, J=2.0, 8.3 Hz, IH), 6.98 (d, J=8.1 Hz, IH), 6.90 (d, J=2.0 Hz, IH), 4.11 (dd, ./ 1 .7.24.7 Hz, 2H), 4.02 - 3.94 (m, IH), 3.90 id../ 15.4 Hz, IH), 3.81 - 3.54 (m, 3H), 3,41 - 3.32 (m, 2H), 3.13 (dd, ,/ S.3.15.4 Hz, IH), 2,87 - 2.75 (m, 2H), 2.57 - 2.46 (m, 2H), 2,12 (d, ./ 1 .7 Hz, IH), 2.07 - 1.67 (m, 10H), 1.65 - 1.43 (m, 6H). m/z (ESI, +ve ion) 654.2 (M+H) ⁺ . EXAMPLE 931. (I S,3'R,6'R,7 ^f S)~6~CHLORO~7'~((2,2,2- TRIFLUOROETHYL)AMINO)-3 ,4 -DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI M.T^.O'^.O^^lPE TACOSA [16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (l S,3'R,6'R,7'R)-6-CHLORO- 7'-((2,2,2-TRlFLUOROETHYL)AMlNO)-3,4-DlHYDRO-2H,15'H- SP1RO [NAPHTHALENE- ! .22'·

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 1 8,24] TRIEN] - 15 '-ONE 3', 13 '-DIOXIDE

The title compound was obtained a as a single isomer (second eluting peak) from the reverse phase preparative HPLC in in Example 930. ¾ NMR (500MHz, CD3OD) δ 7.72 (d, J=8.5 Hz, IH), 7.23 (s, IH), 7. 18 (dd, ./ 2.2. 8.6 Hz, IH), 7.11 (d, J-2.2 Hz, IH), 7.04 (dd, =2.0, 8.1 Hz, IH), 6.94 (d, J=8. I Hz, IH), 4.08 (dd, ./ 1 2.2. 27.4 Hz, 2H), 3.99 (d, J=15.2 Hz, I H), 3.85 - 3.78 (m, IH),

3.72 (d, ./ ! 4.2 Hz, IH), 3.63 - 3.48 (m, 2H), 3.1 1 (dd, J=8.7, 15.3 Hz, IH), 2,84 -

2.73 (m, 3H), 2.61 - 2.54 (m, IH), 2.46 - 2,40 (m, IH), 2.08 (d, J=13.9 Hz, IH), 2.02 - 1.84 (m, 5H), 1.75 - 1.64 (m, 4H), 1.61 (br. s., 2H), 1.57 (br. s., IH), 1.54 -

1.39 (m, 5H). m/z (ESI, +ve ion) 654.2 ( M i l ) ^' .

EXAMPLE 932. (IS,3'R,6'R,7'Z>6-CHLORQ-3,4-DIHYDRQ-2H,7'H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[l ,14]DIAZATEmACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA [16,18,24]TRIENE]-7',15'-DIONE 7*-OXIME 13',13*-DIOXIDE AND

(lS,3 ^, R,6 ^! R,7'E)-6-CHLORO-3,4-DIHYDRO-2H ₅ 7'H,15'H- SPIRO[N APHTHALENE-1 ,22'-

[2()iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA

[16,1 ',15'~DIONE 7-OXIME 13",13'-DIOXIDE

To a 25-mL round-bottomed flask was added (1 S,3'R,6'R)-6-chloro-3,4- dihydro-2H,7'H,15'H-spiro[naphthalene- ^' l,22'- [20]oxa[13]tMa[l,14]cUazatetrac lo[14;7.2 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]triene]- 7',15'-dione 13',13'-dioxide (Example 832; 205 mg, 0.36 mrnol) and

hydroxyammonium chloride (24.9 mg, 0.359 mmol, Alfa Aesar), ammonium acetate (25.8 μΐ, 0.36 mmol, Sigma), 0.3 mL of pyridine and 7.2 mL of EtOH. The reaction mixture was heated to reflux for 2 h. The reactiom was concentrated and purified through a 4 g ISCO Gold column, eluting with 0-45% EtOAc( with 0.3% HOAc) in hexane to give (lS,3'R,6'R,7'Z)-6~chloro-3,4-dihydro-2H,7 ^! HJ5'H~ spiro [naphthalene- 1 ,22'-

|2 ⁽⁾ joxsij I3|t ia| U4|dia/aielracveioj 14,7.20 ^{; !} '.0 ^|1! ipemacosa| 16. i 8.24|inenei- 7 ^! ,15'-dione T-oxime 13V13'-dioxide and (lS,3 ^! R,6'R,7'Z)-6-chloro-3,4-dihydro- 2Η,7Ή, 15'H-spiro[naphthalene-l ,22'-

[20ioxa[13jthia[l,14jdiazatetracyclo[14.7.2.0 ^3>6 .0 ^!9 ' ²⁴ |pentacosa[ 16,18,24]trienej- 7',15'-dione 7'-oxime 13',13'-dioxide (0.195 g, 0.33 mrnol) as a mixture of Irans and cis isomers. ¾ NMR (400MHz, CD3OD) δ 7.75 (ΐ, J=8.0 Hz, ills.7.17 (dd, ./ 2.2.8.6 Hz, ill).7.10 (s, Hi).7.07 (d, ./ 2.0 Hz, 0.5! i).7.03 - 6.99 (m, III). 6.94 - 6.86 (ra, ill).6,85 (d, ./ ! .8 Hz, 0.5H), 4.10 - 3.96 (m, Ml).3.87 - 3.69 (m, 3H), 3.43 - 3.34 (m, 2H), 3,43 - 3.34 (m, 2H), 3.43 - 3.34 (m, 2H), 3,17 - 3.07 (m, 1H), 3.05 - 2.94 (m, 1H), 2.90 - 2.63 (m, 3H), 2.36 - 2.27 (m, 1H), 2,20 - 1.66 (m, 7H).1.58 (d, .7=12,3 Hz, 1H), 1.54 - 1,37 (m, 2H). m/z (ESI, +ve ion) 586.2 (M+H) ⁺ . EXAMPLE 933, (1S,3'R,6'R, 7'R)-6-CHLORO-7'-(HYDROXYAMINO)-3,4~ DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DL ZATEIIACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [16,I8,24]TRIEN]-I5'-ONE 13',13'-DIOXIDE OR (1S,3'R,6'R, 7'S)-6-CHLORO- 7 ^! -(HYDROXYAMINO)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

[20iOXA[13]THIA[l,14]DIAZATETRACYCLO[14.7.2.() ³ - ⁶ ,0 ^!9 - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE

A mixture of (lS,3 ^! R,6 ^* R,7'Z 6-chloro-3,4-dmydro-2IL7¾15TL spiro [naphthalene- 1 ,22'-

|2u|o\a| I 3|thia| !.l4|dia/atetrac>cio! M^^.u"'.! ⁾¹¹ ' ^!| |pentacosa| 16. i 8.24|tnene 7',15'-dione 7'-oxime 13',13'-dioxide and (lS,3'R,6'R,7'E 6-chloro-3,4-dihydro- 2Η,7Ή, 15'H-spiro[naphthalene-l ,22'-

7',15'-dione 7'-oxime 13',13'-dioxide (Example 932; 32 mg, 0.054 mmol) was disolved in 2 ml. of MeOH, and then sodium c anoborohydride (10.2 mg, 0.16 mmol, Aldrich), titanium chloride (63.4 μΐ, 0.11 mmol. Fisher Scientific) were added. The reaction mixture was stirred at rt overnight, and then cone, diluted with 30 mL of DCM and IN aq. NaOH soluiion was added to adject pH to 10. The organic layer was concentrated and purified by reversed phase preparative HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 30% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give (1S,3'R,6'R, 7'R)-6-chloro-7'-(hydroxyamino)-3,4- dihydro-2H,15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[i,14]diazaieti^^

15'-one 13',13'-dioxide or (1S,3'R,6'R, 7 ^! S)-6-ch3oro-7'-(hydroxyamino)-3,4- dihydro-2H,15H-spiro[naphthale^^

15'-one 13',13'-dioxide (19 mg, 0.032 mmol; major isomer). ¾ NMR (400MHz, CD3OD) 7.76 (d, J=8.6 Hz, III).7.25 - 7.19 (m, 2H), 7.14 (d, ./ 2.3 Hz, 1H), 7,04 (dd, ./ 2.2.8.2 Hz, 111).6.97 id. ,/ HO Hz, lH), 4.16 - 4.03 (m, l).3.94 - 3.83 (m, 1H), 3.77 (d, J=13.7 Hz, 1H), 3.30 - 3.20 (m.211).3.11 (dd,J=9.9, 15.0 Hz, 1H), 2.89 - 2.69 (m, 3H), 2.49 (d, J=12.7 Hz, 1H), 2.17 - 1.39 (m, 17!!). m/z (ESI, +ve ion) 588.2 (M+H) ⁺ .

EXAMPLE 934. N- iS^'R^'R^'SVe-CHLORO- 'JS'-DIOXIDO-lS'-OXO- 3,4-DIHYDRO-2H-SPIRO|NAPHTHALENE-l,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[16,18,24]TMEN]-7'^X)ACETAMlDEORN~((lS,3'R,6'R,7 ^, R)-6~CHLORO-

13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE- l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[ 16, 18,24] TRIEN] -7*-YL) ACETAMIDE

STEP 1 : (l S,3'R,6'R,7'S)-6-CHLORO-7'-((4-METHOXYBENZYL)AMINO)-

3 ,4-DIHYDRQ-2H, 15'H-SPIRQ [NAPHTHALENE- 1 , 22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA

[16, 18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE OR (l S,3'R,6'R,7'R)-6-CHLORO- 7'-((4-METHOXYBENZYL)AMINO)-3,4~DIHYDRO-2H,15'H"

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 1 8,24] TRIEN] - 15 '-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 927, using (l S,3'R,6'R)-6-Chloro-3,4-dihydiO-2H,7TL15'H- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia|;i,14]diazatetracycio[14;7.2 ³ - ⁶ .0 ¹⁹ - ²⁴ pentacosa[16,18,24]

7',15'-dione 13',13'-dioxide (Example 832, 12 mg) and 4-methoxybenzyiamine (Alfa Aesar), and the desired product, (l S,3'R,6'R,7'S)-6-chloro-7'-((4- methoxybenzyl)amino)-3,4-dihydro-2H,15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[ l,14]diazatetracycio[14.7.^ _^

15'-one 13', 13'-dioxide or (lS,3'R,6'R,7'R)-6-chloro-7'-((4- methoxybenz d)amino)-3,4-dihydro-2H,15'H-spiro[naphthalene-l ,22'~

[20]oxa[13]tMa[l,14]diazatetra^

15'-one 13',13'-dioxide ( 15.7 mg, 0.023 mmol) was isolated as a single isomer (first eluting major peak) from the reverse phase preparative HPLC. STEP 2: N-((l S,3¾,6'R,7'S)-6~CHLORO-13',l 3'-DIOXIDO-15 ^! -OXO-3,4- DIHYDRO-2H-SPIRO [NAPHTHALENE- 1 , 22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [16,18,24]TRlEN]-7'-YL)-N-(4-METHOXYBENZYL)ACET AMIDE OR N- ((IS^'R^'RJ'Ri-e-CHLORO- ^ '-DIOXIDO-lS'-OXO-S^-DIHYDRO^H- SP1RO [NAPHTHALENE- 1.22'·

[20]OXA[ 13]THIA[ 1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [ 16, 1 8,24]TRIEN] -7 ^* -YL)-N-(4-METHOXYBENZ YL)ACET AMIDE

To a 25-mL round-bottomed flask was added (l S,3'R,6'R,7'S)-6-chloro-7'-

((4-methoxybenzyl)amino)-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l ,14]diazatetra<y^^

15'-one 13', '-dioxide or (lS,3'R,6'R,7 ^« R)-6-chloro-7'-((4- methoxybenzyl)amino)-3,4-dihydro-2H,15'H-spiro[naphthalene-l ,22'- [20]oxa[I 3]thia[ l, I 4]diazatetTacyclo^^

15'-one I3',13'-dioxide (first eluting major peak out of preparative reverse phase HPLC (from Step 1, 11.0 mg, 0.016 mmoi), DMAP (1.94 mg, 0.016 mmoi, Aldrich), DIEA (5.5μί, 0.032 mmoi, Aldrich) and 1.5 mL of DCM, and then acetyl chloride (1.5 mg, 0.019 mrnol, Aldrich) was added. After 30 min, the reaction mixture was concentrated and purified by reversed phase preparative HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 60% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give the title product (1 1.6 mg, 0.016 mrnol).

STEP 3: N-((lS,3 ^, R,6 ^, R,7 ^, S)-6-CHLORO-13 ^, ,13 ^, -DIOXlDO-15 ^, -OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'-

| 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 1 | ί^!ΛΖΛ ί : ί AC YCT (>! i -1 7.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [ 16,18,24]TRlEN]-7'-YL)ACET AMIDE OR N-((lS,3'R,6'R,7'R)-6-CHLORO- lS^l S'-DIOXIDO-l S'-OXO-S^-DIHYDRO^H-SPIROI APHTHALENE-l^^- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA [16,18,24] TRIEN] - 7' - YL) ACET AMIDE The mixture of N-((lS,3'R,6'R,7'S)-6-chloro-l 3 ^f ,I3'-dioxido-15'-oxo-3,4- dihydro~2H~spiro[naphthalene-l,22'-

7'-yl)-N-(4-methoxybenzyl)acetamide or N-((lS,3'R,6'R,7'R)-6-chloro-13', 13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l ,22'- [20]oxa[l 3]thia[l, 14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,l 8,24]trien]- 7'-yl)-N-(4-methoxybenz l)acetamide (from Step 2; 1 1.6 mg, 0.016 mrnol) in 4 mL of 100% TFA was heated to 80 °C for 24 h. The mixture was concentrated and purified by reversed phase preparative HPLC (Gemini™ Prep Cig 5 urn column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give N- ((l S,3'R ₅ 6 ^, R,7 ^, S)-6-chloro-13 ^, ₅ 13 ^, -dioxido-15 ^, -oxo-3,4-dihydro-2H- spiro[naphthalene-l,22'-

[20]oxa[13]tMa[l,14]cUazate1rac lo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]trien|- 7'-y])acetamide or N-((lS,3'R ₅ 6 ^* R,7 ^, R)-6-chloro-13 ^, , 13 ^, -dioxido-15 ^, -oxo-3,4- dihy dro-2H-spiro [naphthal ene- 1,22'- 7'-yl)acetamide (5.2 mg, 0.009 mmol). 'HNMR (400MHz, CD3OD) δ 7.73 (d, J=8.4 Hz, IH), 7.17 (dd, J=2.3, 8.2 Hz, IH), 7.10 (dd, ,7=2,1, 4.6 Hz, 2H), 7.07 (dd, ./ 2.0.8.2 Hz, 1H), 6.95 (d, ./ 8.2 Hz, IH), 4.09 (dd, ./ ί 1.9.20.1 Hz, 2H), 3.80 - 3.65 Or, 4H), 3.38 (dd, ./ 7.6.15.5 Hz, IH), 3.19 (dd, ./ 7.9.15.4 Hz, IH), 2,84 - 2.70 (m, 2H), 2.50 - 2.39 (m, IH), 2,39 - 2.27 (m, IH), 2,05 (d, ./ ! 37 Hz, IH), 1.97 (s, 3H), 1,95 - 1.32 (m, 14H). m/z (ESI, +ve ion) 614.2 (M+H) ⁺ .

EXAMPLE 935. N-((lS,3'R,6'R,7'R)-6-CHLORO-l 3',I3'~DIOXIDO-I5'~OXO- 3 ,4 -DIHYDRO-2H-SPIRO [NAPHTHALENE- 1 ,22'- |2ujOXA| O Π ί Ι1Λ| I . I 4|f l A/A TL i ^' RACYCf.OI i 4.7.2.0 · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [16,18,24]TRIEN;|-7 ^, -YL)ACETAMIDE0RN-((1S,3 ^, R,6 ^, R,7'S)-6-CHL0R0-

13'J3'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

- 7'- YL) ACETAMIDE

STEP 1 : (1 S,3'R,6 ^, R,7'R)-6-CHLORO-7 ^, -((4-MEraOXYBENZYL)AMINO)- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DL4ZATETRACYCLO[14,7.2,0 ³ '^0 ¹⁹ - ²⁴ ]PEN^^

[16,18,24]TR1EN]-15'-0NE 13',13'-DIOXIDE AND (lS,3'R,6'R,7'S)-6- CHLORO-7'-((4-METHOXYBENZYL)AMINO)-3,4-DIHYDRO-2H,15H- SPIRO [NAPHTHALENE- 1,22"- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA [ 16, 18,24 ] TRIEN] -lS'-ONE 13 ',13 '-DIOXIDE

The title compound was obtamed as a single isomer (second eluting major peak) from the reverse phase preparative phase HPLC in Example 934, Step 1.

STEP 2: N-((lS,3'R,6 ^, R,7 ^, R)-6-CHLORO-13',13 ^, -DIOXIDO-15 ^, -OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [16,18,24] TRIEN] -7'-YL)-N-(4-METHOXYBENZYL)ACET AMIDE OR N- ((1 S,3'R,6'R,7'S)-6-CHLORO-13'J 3 -DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]ra ^j :A[l _s 14]DIAZAraTRACYCLO[14J.2 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [ 16,18,24]TRIEN]-7 ^, -YL)-N-(4-METHOXYBENZYL)ACETAMIDE

To a 25-mL round-bottomed flask was added (l S,3'R,6'R,7'R)-6~chloro-7'~ ((4-methoxybenzyl)amino)-3,4-dihydro-2I-L15'H-spiro|naphthai ene-l,22'- | 20 jox«ij I 3 |t ia| U |dia/aielracveioj 14.7.2 0 ^{; !} '.0 ^{| 1!} ipemacosa| 16. i H.24|incn |- 15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S)-6-chloro-7'-((4-methoxybenz 'l)amino)- 3,4-dihydro-2H,15'H-spiro[naphthalene-L22'-

15'-one 13', 13'-dioxide (first eluting major isomer out of preparative reverse phase HPLC from Step 1, 17.2 mg, 0.025 mmol), DMAP (3.04 mg, 0.025 mmol, Aldrieh), DIEA (8.68 μΐ, 0.05 mmol, Aldnch) and 2 mL of DCM, and then acetyl chloride (2.340 mg, 0.030 mmol, Aldrieh) was added. After 30 min, the reaction mixture was concentrated and purified by reversed phase preparative HPLC (Gemini™ Prep CJ S 5 μηι column; Phenomenex, Torrance, CA: gradient elution of 60% to 95%) MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give the title product (18.2 mg, 0.025 mmol).

STEP 3: N-((l S,3'R,6'R,7'R)-6-CHLOR()-13',13'-DIOXIDO-15'-OXO-3,4- DIHYDRO-2H-SPIRO[NAPHTHALENE-l ,22'~

| 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA

[16,18,24]TRlEN]-7'-YL)ACETA IDE OR N-((lS,3 ^, R,6 ^, R,7 ^, S)-6-CHLORO- 13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO|NAPH ^r rHALENE-l,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[16,18,24]TRIEN]-7'-YL)ACETAMlDE

The mixture of N-((lS,3'R,6'R,7'R)-6-chloro-13',13'-dioxido-15'-oxo-3,4- dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l , 14]diazatetracyclo[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ² '¾

7'-yl)-N-(4-memoxybenzyl)acetamide or -((lS,3'R,6'R,7'S)-6~chloro-13 ^, ,l 3'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l ,22'-

[20]oxa[ 13]thia[ 1, I 4]diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ^{! 9} ' ²⁴ ]pentacosa[16,18,24]trien]- 7'-yl)~N~(4~methoxybenzyl)acetamide (from Step 2; 18 mg, 0.025 mmol) in 4 mL of 100%) TFA was heated to 80 °C for 24 h. The mixture was concentrated and purified by reversed phase preparative HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, C A; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give N- ((lS,3'R R,7¾.)-6-chloro-13^i;rHlK)xido-15'^xo-3,4Hlihydro-2H- spiro [naphthalene- 1 ,22'-

7 ^! -yl)acetamideorN (lS,3 ^! R,6'R,7^)-6-chloro-13^13'-dioxido-15 ^! -oxo-3,4- dihy dro-2H-spiro [naphtha! en e- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra^

7'-yl)acetamide (8.2 mg, 0.013 mmol). ^! H NMR (400MHz, CD3OD) δ 7.76 (d, ./ 8.4 Hz, ill).7.20 (dd, ./ 2.2.8.5 Hz, ill).7.13 (d, 2.2 Hz, IH), 7.09 (dd, J=2.0, 8.0 Hz, IH), 7.01 (d, ,/ 20 Hz, I Hi..6.98 (d, .7=8.2 Hz, IH), 4,11 (dd, J=12.1, 14.5 Hz, 2H), 3.99 (d, J=15.1 Hz, 2H), 3.83 - 3.75 (m, IH), 3.72 (d,

.7=14.9 Hz, IH), 3.46 (dd, ,7=8.0, 15.5 Hz, IH), 3.10 (dd../ 9.4.15.3 Hz, IH), 2.87 - 2.73 (m, 2H), 2.44 - 2,30 (m, 2H), 2.14 (d, ./ 13.7 Hz, IH), 2.00 (br, 8., H), 1.97 (s, 3H), 1,94 - 1.63 (m, 7H), 1.60 - 1.36 (m, 6H). m/z (ESI, +ve ion) 614.2 (M+H) ⁺ .

EXAMPLE 936. \-{{ ! S..T R. ^' R..7' )-6-( ^' 5 H . OR (.)- 1 '. I T-DiOXHK)- 1 '-()XO- 3,4-DIHYDRO-2H-SPlRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[[14.7.2.0 ³ ' ⁶ .0 ^]9 ' ²⁴ ]PE TACOS A[!6,l 8,24]TRIEN]-7'-YL)-2-METHYLPROP AN AMIDE ORN- ((IS,3 ^, R,6'R,7'S)-6~CHLORO-13',13'-DIOXIDO-15'-OXO-3,4-DIHYDR O-2H- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 18 -7'-YL)-2-METHYLPROP AN AMIDE

STEP 1 : (1 S,3'R,6'R,7'R)~7'-AMrNO-6-CHLORO-3,4 )iHYDRO~2H, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i.()l i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[16,18,24]TRIE ]-15'-ONE 13',13'-DIOXIDE OR (lS,3'R,6'R,7 ^* S)-7'-AMIN()-6- C^^LORO-3,4-DIHYDRO-2H 5Ή-SPIRO[NAPH^ΉALENE-l,22 ^, - pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[16,18,24]TRIEN]-15'-ONE 13 ',13 '-DIOXIDE

To a 25-mL round-bottomed flask was added (1S,3'R,6'R, 7'R)-6-chloro- 7'-(hydroxyaniino)-3,4-dihydro-2H,15'H^

[20joxa 13]thia[l,14]diazatetracy ^

15'-one 13',I3'-dioxide or (1S,3'R,6'R, 7'S)-6-chloro-7'-(hydroxyamino)-3,4- dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]†iua[l,14]diazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide (Example 933; 35 mg, 0.06 mmol), ammonium acetate (45.9 mg, 0.60 mmol) and zinc (38.9 mg, 0,60 mmol) in 4 ml, of EtOH. The reaction mixture was heated to 90 °C for 30 min. The reaction mixture filtered and concentrated to give the crude desire product and directly go to next step.

STEP 2: N (IS,3 ^! R,6'R,7'R)-6 HLORO-i3',13 ^! -DIOXIDO-15 ^! ~OXO-3,4~ DIHYDRO-2H-SPIRO[NAPHTHALENE-L22'-

|;20]OXA[13|TfflA[l,14jDIAZATETRACYCLO|]14.7.2.0 ³ -^0 ^l9 - ²⁴ ]PENTACOS A! 16.18,24]TRIEN]-7'-YL)-2-METHYLPROPANAMIDE OR N- ((lS,3'R,6'R,7'S)-6-CHLORO-13',13'"DIOXIDO-15'~OXO-3,4~DIHYD RO-2H- SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [16, 18,24] TRIEN] -7'-YL)-2-METHYLPROP AN AMIDE

The title compound was prepared in an analogous manner to that described in Example 935, Sep.2, using (1 S,3'R,6'R,7'R)-7'-amino-6-chloro-3,4-dih dro- 2h, 15'h-spiro[naphthalene-l ,22'~

[20]oxa[13]tMa[l,14]cUazate1rac lo[14;7.2 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide or (lS,3¾,6'R,7'S)-7'-araino-6-chloro-3,4-dihydro-2h,15'h- spiro [naphthalene- 1 ,22'- X.24|lrienj- 15'-one 13',13'-dioxide (from Step 1), isobutyryl chloride (Fluka), and the desired product N-((lS,3¾,6'R,7 ^, R)-6-chloro-13\13 ^, -dioxido-15 ^, -oxo-3,4-dihydro-2H- spiro [naphthalene- 1 ,22'-

|20jox.ij I3|thia| I J4|dia/.aletracye!oj U . ^ ¹ " ⁿ ipen[aeosa| 16. i 8.24|inenj- 7'~y])cyclopropanecarhoxamide or N-((lS,3'R,6'R,7'S)-6-chloro-l 3',13'-dioxido-

15'-oxo-3,4~dihydro~2H~spiro[naphthalene-l,22'-

was isolated as a white solid. ^! H NMR (4()()MHz, CD3OD) δ 7.76 (d, 84 Hz, III).7.36 id. ,/ 7.5 Hz, !!!}.7.19 (dd, 2.4.8.5 Hz, 111).7.14 (d, J=2.0 Hz, 1H), 7.11 (dd, J=1.2, 7.8 Hz, 2H), 6.98 (d, J=8.0 Hz, Ml). 4.12 (dd,J=11.9, 17.4 Hz, 2H), 3.83 - 3.69 (m, 4H), 3.21 (dd,J=8.0, 15.3 Hz, 1H), 2.86 - 2.73 (m, 2H), 2,58 - 2.44 (m, 2H), 2.40 - 2.32 (m, 1H), 2.10 - 1.83 (m, 7H), 1.75 - 1.50 (m, 7H), 1,48 - 1.31 (m, 4H), 1.15 (d, .7=6,8 Hz, 3H), i ll (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 642.2 (M+H) ⁺ .

EXAMPLE 937, \-« ! S.3 ^' R.6'R.7 ^' R )-6-Ci U.ORO-i 3'. I 3'-DIOXIDO-l 5'-OXO- 3,4-DIHYDRO-2H~SPIRO[NAPHTHALENE-I,22 ^! ~

[20]OXA[13]THIA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[16,18,24]TRIENl-7'-YL)CYCLOPROPANECARBOXAMIDE OR N- U ! S.3 ^' R.6'R.7'S)-6-i ^' l H.ORO- ! .V.1 '-!)]()XHX ⁾ -l 5'-( ⁾ XO-3.4-DU !YDR()~2! !- SPIRO [NAPHTHALENE- 1 ,22'-

2,182, [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [ 16, 18,24]TRIEN] -7 ^* -YL)C YCLOPROP ANEC ARBOXAMIDE

The title compound was prepared in an analogous manner to that described in Example 935, Step 2, using (lS,3'R,6'R,7'R)-7'-animo-6-chloro-3,4-dihydro- 2h, 15'h-spiroj ^" naphthalene- 1 ,22'-

|2( ⁾ joxsij I3|t ia| U4|dia/aielracveioj 14.7.20 ^; ".0 ^1;i ipemacosa| 16. i 8.24|irienj~ 15'-one 13',13'-dioxide or (iS,:rR,6'R,7^)-7'-ammo-6-chloro-3,4-dihydro-2h,i5 ^, h- spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7.2.0 ³ · ⁶ .0 ^{!9 <24} ]pentacosa[16,I8,24]trien]- 15'-one 13',!3'-dioxide ( from Example 936, Step 1) and cyclopropane carbonyi chloride (Sigma), and the desired product, N (lS,3'R,6'R,7'R)-6-chloro-13',13'- dioxido- 15'-oxo-3,4-dihy dro-2H-spiro| naphthalene- 1 ,22'-

|20|ox;i| I3|ihia| I. i4|di;i/aielracvcio] 14.7.2 ίί ^{; !} '.0 ^ρ: |pcniacosa| 16. i H.24|iricn|- 7 ^! -yl)cyclopropanecarboxamide or N-((lS,3'R,6'R,7'S)-6-chloro-13',13'-dioxido- 15'-oxo-3,4-dihy dro-2H-spiro| naphthalene- 1 ,22'-

[20]oxa[13]thia[i,!4]diazatetracyclo[i4.7,2,0 ³ ' ⁶ 0 ^]9 ' ²⁴ ]pentacosa[16,.18,24]trien]- 7'-yl)cyclopropanecarboxamide was isolated as a white solid. ¾ NMR (400MHz, CD ₃ OD) 67.76 (d, J=8.6 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.14 - 7.09 (m, 2H), 6.97 (d, ./ 8.0 Hz, III .4.12 (dd, ./ I 1.9.18.0 Hz, 2H), 3.85 - 3.73 (m, 3H), 3.71 (d, ./ 1 .3 Hz, 111).3,20 (dd, ./ 7.6.14.1 Hz, III).2,87 - 2.73 (ra, 211).2,53 - 2.36 (m, 2H), 2,13 - 1.19 (m, 19H), 0.94 - 0.55 (m, 4H). m/z (ESI, +ve ion) 640.3 (M+H) ⁺ . EXAMPLE 938. N-((lS,3'R,6'R,7 ^! R)-6-CHLORO-13',13'-DIOXlDO-15'-OXO- 3,4-DIHYDRO-2H-SPlRO[NAPHTHALENE-l,22'-

[2()iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [ 16J 8,24]TRIEN]-7'-YL)METHANESULFONAMIDE OR N-((l S,3'RX.¾

6-CHLORO- 13', 13'-D10XIDO- 15'-OXO-3,4-DIHYDRO-2H-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[ 16, 18,24]TRIEN] -7'-YL)METHANESULFONAMIDE

The title compound was prepared in an analogous manner to that described in Example 935, Step 2, using (l S,3'R,6 ^, R,7'R)-7'-amino-6-chloro-3,4-dihydro- 2h, 15'h-spiro[naphthalene-.l ,22'-

[20]oxa[13]thia[l, 14]diazatetra<y^

15'-one 13',13'-dioxide or (l S,3 ^, R,6 ^, R,7'S)-7 ^, -amino-6-chloro-3,4-dihydro-2h,15'h- spiro [naph thalene- 1 ,22'-

15'-one 13',13'-dioxide ( from Example 936, Step 1) and methanesulfonyl chloride (Sigma), and the desired product, N-((lS,3'R,6'R,7'R)-6-chloro-13',13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[l, 14]diazatetracyclo[14;7,2.0 - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[16

7'-yl)methanesulfonamide or N-((lS,3'R,6'R,7'S)-6-chloro-13',13'-dioxido-15'- oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- 7'-yl)methanesulfonamide was isolated as a white solid. ^! H NMR (500MHz, CDJOD) δ 7.75 (d, J=9.0 Hz, IH), 7.21 (d, J=2.0 Hz, IH), 7.19 (dd, «/=2.2, 8,6 Hz, 1H), 7.12 (d, J=2.0 Hz, IH), 7.09 (dd, J=2.0, 8.1 Hz, IH), 6.95 id../ 8.1 Hz, IH), 3.89 (d, ./ 13.4 Hz, IH), 3.79 (d, ./ 14.2 Hz, 2H), 3.50 - 3.41 (m, 2H), 3.19 (dd, ,/ i 5.3.2 Hz, 2H), 2.93 is.3H), 2,86 - 2,74 (m, 2H), 2.67 - 2.57 (ra, IH), 2,49 (br, s., ill).2.12 - 2.01 (m, IH), 2,00 - 1.89 (m, 31!).1.89 - 1.78 (m, 2H), 1,77 - 1.56 (m, 5H), 1.56 - 1.45 (m, 5H), 1.39 - 1.33 (m, 2H). z (ESI, +ve ion) 650.2 (WW) . EXAMPLE 939. N-((lS,3 ^, R,6'R,7 ^, R)-6-CHLORO-13 ^, ,13 ^, -DIOXlDO-15 ^, -OXO- 3,4-DIHYDRO-2H-SPIRO|NAPHTHALENE-l,22'-

[20]OXA[13]THiA[l,14]DIAZATETRACYCLO[14.7,2.0 ³ - ⁶ ,0 ¹⁹ ^

[16,18,24]TRIEN]-7 ^, -YL)~2"HYDROXYACETAMlDE 0R -((1S,3'R,6 ^, R,7'S)- 6-CHLORO- 13', 13'-Dl OXIDO- 15'-OX()-3,4-DIHYDRO-2H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2θ!() Λ| I 311 HI Λ| I„ ! -I |ί)Ι.\/.νΠ: I RAC V( ^' i, 01 i -1,7.20 ^{:' i'} .0 ^li ' |Pi-:N i ACOSA [16,18,24]TR1E ] -7'-YL)-2 -HYDROXY ACET AMIDE

To a 25-rnL round-bottomed flask was added (lS,3'R,6'R,7'R)-7'-amino-6- chloro-3,4-dihydro-2H,15'H-spiro[naphthalene-L22'-

[20ioxa|13jthia[l,14jdiazatetrac clo[14.7.2.0 ³ ^0 ^!9 ' ²⁴ |pentacosa[ 16,18,24]trien]- 15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S)-7'-amino-6-ch]oro-3,4-dihydro-

2H, 15 ^! H-spiro[naph.thalene- 1,22'-

[20]oxa[13]thia|;i,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ¾pentacosa[16,l^ 15'-one 13',13'-dioxide (Trom Example 936, Siep I ; 5.9 mg, 10,3 μτηοί), DIEA (3.60 μί, 0.02 mmol, Aldrich), HATU (3.92 mg, 10.3 μηιοΐ), gly colic acid (0.78 mg, 10,3 μιηοΐ) and 1 mL of DMF, After 1 h, the reaction mixture was filtered and purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5 μm column; Phenomenex, Torrance, CA; gradient elution of 30% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give N- ((I S^'R^'R 'i^-e-chioro- ^ '-dioxido-lS'-oxo-S^-dihydro^H- spiro [naph thalene- 1 ,22'-

7'-yl)-2-hydroxyacetamide or N- iSJ'RX'R^'S -chloro-B'JS'-dioxido-l 5'- oxo-3 ,4-dihydro-2H-spiro | naphthalene- 1 , 22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7, 2.0 ³ - ⁶ .0 ^{! 9} - ²⁴ ]pentacosa[ 16,18,24]trien]- 7'-yl)-2-hydroxyacetamide (4.2 mg , 6.66 μι ^η οΐ). ¾ NMR (4GGMHz, CDCb) δ 7.73 (d, ,/ H.4 Hz, 1H), 7.17 i dd. ./ 2.3. 8.4 Hz, 1H), 7.10 (d, ,/ 4.3 Hz, 2H), 7.06 (dd, 1.4. 7.6 Hz, 1H), 6.94 (d, ,/ 8.2 Hz, 11 1 ). 4.08 (dd, J=\ 1 ,9, 25,6 Hz, 2H), 3.98 (dd, J=15,8, 19.4 Hz, 2H), 3,87 - 3,74 (m, 3H), 3.71 (d, J=14, 1 Hz, IH), 3.17 (dd, ./ 8.3. 15.4 Hz, IH), 2.84 - 2.70 (m, 2H), 2.49 (d, J=9S) Hz, 1H), 2,38 - 2.27 (m, IH), 2.09 - 1.82 (m, 6H), 1.78 - 1.59 (m, 5H), 1.59 - 1.29 (m, 7H). m!z (ESI, +ve ion) 630.2 (M+H) ⁺ .

EXAMPLE 940. N-((l S,3'R,6'R,7'S)-6-CHL()RO- 13', 13'-DIOXIDO- 15'-OXO- 3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'-

| 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖ.\ ί : ί AC YC i (>! i 4 7.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA [ 16, 18,24]TR1EN] -7'-YL)-N-METHYLACET AMIDE OR N-((lS,3'R,6 ^, R,7'R)-6- CHLORO - 13', 13'-DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H-

SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '6 0 ¹⁹ ^ ⁴ ]PENTACOSA [ 16, 18,24 jTRIEN] -7'-YL)-N-METHYL ACET AMIDE

The title compound was prepared in an analogous manner to that described in Example 934, Step 2 using (lS,3 ^! R,6'R,7^)-6-chloro-7'-(methylamino)-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

12ί>! χίΐ! i jihial U4|di.i/.alLracye!oj U .U^O ¹ " ⁿ ipen[aeosa| 16. i 8.24|inenj- 15'-one 13',13'-dioxide or (lS,3'R,6'R,7'R)-6-chloro-7'-(methylammo)-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

15'-one 13',13'-dioxide (Example 927, first eluting major peak out of preparative reverse phase HPLC) and acetyl chloride, and the corresponding desired product, N (lS,3 ^, R,6 ^, R,7 ^, S)-6-cMoro-13^13 ^, -dioxido-15 ^, -oxo-3,4-dihydro-2H- spiro [naphthalene- 1 ,22'-

|2( ⁾ joxsij I3|t ia| U4|dia/aielracveioj 14.7.20 ^{; !} '.0 ^|1! ipemacosa| 16. i 8.24|irienj~ 7'-yl)cyclopropanecarboxamide or N-((lS,3'R,6'R,R-6-chloiO-13',13'-dioxido-15'- oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[2 ⁽⁾ |oxa[13jthia[l,14jdiazatetracyclo[14.7.2.0 ^3>6 0 ^!9 ' ²⁴ ]pentaco

7'-y!)cyc!opropanecarboxamide was isolated, ^" Ή NMR (400MHz, CDsOD) δ 7.75 (d, J=8.4 Hz, 1H), 7.19 (d, ./ 8.H Hz, 1H), 7.12 (br. s., ill).6.97 (br. s., 3H), 4.13 (d, ./ 2448.3 Hz, 1H), 4.03 (t, ./ !! .(. Hz, 1H), 3.92 - 3.83 ins.1H), 3.79 (d, ./ 1 .5 Hz, 1H), 3,67 - 3.53 (m, 2H), 3.52 - 3.36 (m, 2! I ).3,27 - 3.15 (m, III). 2.83 (br. s., 3H), 2,56 (br. s., IH), 2.22 - 2.14 (m, 2H), 2.11 (s, 3H), 2.07 - 1,09 (m, 17!!). i ' / (ESI, +ve ion) 628.2 {M ID . EXAMPLE 941. N-((lS,3'R,6'R,7'R)-6-CI-ILORO-13V13'-DIOXIDO-15'-OXO- 3 ,4 -DIHYDRO-2H-SPIRO [NAPHTHALENE- 1.22'-

|2ujOXA| O Π ί Ι1Λ| I„ I 4|Di Α/.ΥΠΊ ^' ΗΛ(ΎΟ.ϋΙ i 4.7.2.0 ^• ^0 ^{|:, ! 1} |PHNT.\i SA [ 16, 18,24 jTRIEN ] -7'-YL)-N -METHYL ACET AMIDE OR N-((lS,3'R,0 ^! R,7 ^* S)-6- CHLORO - 13", 13-DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]TfflA[l,14]DIAZATETlACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [16,18,2 -7 '- YL )-N-METHYL ACET AMIDE

The title compound was prepared in an analogous manner to that describ in 934, Step 2 using (lS,3 ^, R,61l,7'R)-6~chloro-7'~(methylaiTiino)-3,4-diliydro- 2H, 15'H-spiro[naphthalene-l ,22'-

|2( ⁾ jox.ij I3|t ia| I. i4|dia/aielracvcio| 14.7.20 ^{; !} '.0 ^|1! ipemacosa| i(..IX.24|lrienj 15'-one 13', 13'-dioxide or (1 S,3 ^, R,6 ^* R,7 ^, S)-6-chloro-7 ^, -(methylamino)-3 ₅ 4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracy ^

15'-one 13',13'-dioxide (Example 927, second eluting major isomer out of preparative reverse phase HPLC) and acetyl chloride, and the corresponding desired product, N-((lS,3'R,6 ^! R,7'R)-6-chioro-13',13'-dioxido-15'-oxo-3,4- di hy dro-2H-spi ro [naphth al ene- 1 , 22'-

[20] oxa[ 13] thia[ 1 , 14] diazatetracy clo [ 14, 7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ ] pentacosa[16,18,24]trien] 7'-yl)cyclopropanecarboxamide or N-((lS,3'R,6'R,7'S)-6-chloro-13',13'-dioxido- 15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[16,18,24]trien] 7'-yl)cyclopropanecarboxarnide was isolated. Ή NMR (400MHz, CD3OD) δ 7,76 (d, J=8.6 Hz, IH), 7, 19 (dd, J=2.2, 8.4 Hz, 1H), 7.14 - 7.10 (m, IH), 7,07 (dd, J=1.9, 17.7 Hz, IH), 7.00 - 6.93 (m, 2H), 4, 13 - 3.93 (m, 3H), 3.89 (d, J=15.3 Hz, IH), 3.78 - 3.69 (m, 2H), 3.53 - 3.45 (m, IH), 3.17 - 3.01 (m, I H), 2.86 - 2.70 (m, 4H), 2,69 (s, IH), 2,36 (d, ,/ 8.4 Hz, IH), 2.30 - 2, 16 (rn, 2H), 2, 13 i s. 3H), 2,01 (dd, «7=6.8, 13, 1 Hz, 2H), 1.97 - 1,82 (m, 5H), 1.80 - 1.73 (rn, 3H), 1.71 - 1 ,62 (m, IH), 1.53 - 1.43 (m, 2H), 1.38 - 1.23 (m, 3H). m/z (ESI, +ve ion) 628.2 (M+H) ⁺ .

EXAMPLE 942. N-((l S,3'R,6'R,7'S)~6~CHLQRQ~ 13', 13'-DIOXIDO- 15'-OXO- 3,4-DmYDRO-2H-SPlRO[NAPHTHALENE-l ,22'-

[20iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[16, 18,24]TRlEN]-7'-YL)-N-METHYLCYCLOPROPANECARBOXAMIDE OR N-((lS,3 ^, R,6 ^, R,7 ^, R)-6-CHLORO-13 ^, ,13 ^, -DIOXIDO-15 ^, -OXO-3,4-DIHYDRO- 2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[ 16, 18,2 -7'-YL)-N-METHYLC YCLOPROP ANEC ARBOXAMIDE

The title compound was prepared in an analogous manner to that described in 934, Step 2 using (lS,3'R,6'R,7'S)-6-chloro-7 ^, -(methylamino)-3,4-dihydro- 2H, 15'H-spirofnaphthalene- 1 ,22'-

[20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 1 -1 , 7.2 0 "'.0 ¹⁹ - ²⁴ ]pentacosa[ 16, 18,24]trien] - 15'-one 13',13'-dioxide or (l S,3 ^, R,6'R,7 ^, R)-6-chloro-7 ^, -(methylamino)-3,4- dihy dro-2H, 15 Ή-spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ^{! 9} ^]pen^ 15'-one 13',13'-dioxide (Example 927, first eluting major peak out of reverse phase preparative HPLC) and cyclopropane carbonvl chloride (Sigma) , and the corresponding desired product, N-((lS,3 ^, R,6'R,7'S)-6-chloro-13',13'-dioxido-15'~ oxo-3 ,4-dihydro-2H-spiro | naphthalene- 1 ,22'- [20]oxa[.13]thia[l,.14]diazatetTacyclo^^

7'-yl)~N-methylcyclopropanecarboxamide or N-((lS,3'R,6'R,7'R)-6-chioro-13',13'" dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- |2( ⁾ joxsij I3|t ia| U4|dia/aielracveioj 14,7.20 ^{; !} '.0 ^|1! ipemacosa| i(..IX.24|lrienj- 7 ^! ~yl)-N-m.ethylcyclopropanecarboxamide was isolated, 'H NMR (400MHz, CD :.( ⁾ !)) δ 7.76 (d, J=8.6 Hz, ill).7.20 (d, ./ 8.7 Hz, I!!}.7.13 (t, J=2.3 Hz, ill). 7.01 - 6.94 (m, 3H), 4.16 - 4.00 ins.2H), 3.89 (d, ./ Hz, !!!).3.80 (d, ,/ 14.3 Hz, ill).3,65 - 3,42 (m, 3H), 3.30 - 3.19 (ra, ill).2,99 is, 2H), 2,87 - 2,74 (m, 2H), 2.73 (s, 1H), 2.59 - 2.49 (m, 1H), 2.33 - 2.21 (ni, IH), 2.20 - 2.00 (m, 3H), 2.00 - 1.15 (m, 15H), 0.96 - 0.81 (m, 4H). m (ESI, +ve ion) 654.2 iM H) .

EXAMPLE 943. N (lS,3'R,6 ^, R,7 ^! R)-6-CHLORO-13',13'-DIOXrDO-15'-O.XO- 3,4-DIHYDRO-2H-SPlRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL)[14.7.2.0 ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [16,18,24]TRTEN]-7'-YL)-N-METHYLCYCLOPROPANECARBOXAMIDE OR -((lS,3'R,6'R,7 ^, S)-6-CHLORO-13 ^, ,13'-D10XIDO-15'-OXO-3,4-DlHYDRO-2H- SPIRO INAPHTHALENE- 1.22'·

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [ 16, 18,24]TRIEN] -7'-YL)-N-METHYLC YCLOPROP ANEC ARBOXAMIDE

2,190 The title compound was prepared in an analogous manner to that described in 934, Step 2 using (lS,3 ^! R,6¾,7'R)-6-chloro-7'-(methylaniino)-3,4-dihydro- 2H,15'H-spiro[naphthalene-l,22'- [20joxa[l3]thia[l,l4]diazatetracycfo[14.7.2.0^

15*-one I3',13'-dioxide or ( iS,3'R,6'R,7'S)-6-chloro-7'-(methylarr!ino)-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22 ^, - [20]oxa[13]tMa[l,14]cUazate1τac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ · ²⁴ ]pentacosa[16,18,24]trien|- 15 ^, -one 13',13'-dioxide (Example 927, second eluting major peak out of reverse phase preparative HPLC) and cyclopropane carbonvl chloride (Sigma) , and the corresponding desired product, N-((lS,3'R,6'R,7'R)-6-chloro-13',13'-dioxido-15'- oxo-3 ,4-dihydro-2H-spiro | naphthalene- 1 , 22'- [20]oxa[.13]thia[l,.14]diazatetTacyclo^

7'-yl)-N-methylcydopropaneearboxamide or N-((lS,3'R,6'R,7'S)-6~chloro-13',13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- |2()joxsij I3|t ia| iJ4|dia/aielracveioj 14,7.20 ^{; !} '.0 ^|1! ipemacosa| i ⁽ ..IX.24|lrienj-

7 ^! ~yl)-N-m.ethylcyclopropanecarboxamide was isolated, 'H NMR (400MHz, CD3OD) δ 7.77 (d, J=8.0 Hz, IH), 7.20 (dd, J=0A, 8.8 Hz, 1H), 7.13 (br. s., 1H), 7.10 (id, ./ 2.3.8.2 Hz, III).7.05 - 6.94 (m, 2H), 4.16 - 3.88 (m, 4H), 3.80 - 3.70 (m, 2H), 3.37 (s, 3H), 3.22 - 3.11 (m, IH), 3,07 - 2.96 (m, 2H), 2.85 - 2,68 (m, 3H), 2,38 (br, s,, IH), 2.23 - 1.14 (m, 20H), 1,01 - 0,83 (m, 4H). m /, (ESI, +ve ion) 654.2 (M+H) ⁺ .

EXAMPLE 945. (lS,3 ^! R,6'S)-6-CHLORO-3,4~DIHYDRO-2H,9'H,15'H- SPIRO [NAPHTHALENE- 1 ,22'- |2Oi0XA| !3ΓΠΠ,\| I. i (!. !4|TRL\XATHTRA( ^' Yi ^' L()| I4.7.2.0 ^; ".0 ^! " ^I! !N ! AC OS A [ 16, 18,24] TRIENEJ-9' , 15 '-DIONE 13', 13 '-DIOXIDE

STEP 1 : (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2S)-2-((E)-3-ETHOXY-3- OXOPROP - 1 -EN - 1 - YL)C YCLOB UTYL)METHYL)-3' ,4,4', 5 -TETRAHYDRO- 2H.2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7-

CARBOXYLATE

To a 100-mL round-bottomed flask was added sodium hydride (60% dispersion in mineral oil: 21.3 mg, 0.53 mmol, Aldrich) and 10 ml, of THF. The reaction mixture was cooled to 0 °C, and triethyl phosphonoacetate (81 μΙ, 0.363 mmol, Aldrich) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, (S)-tert-butyl 6'-chloro-5-(((lR,2R)-2-formylcyclobut^1)methyl)-:r,4,4 ^! ,5- tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylate (Intermediate AA11A, Step 20 A; 120 mg, 0.242 mmol) was added in one portion. The reaction mixture was heated to 40 °C for 1 h. The reaction mixture was quenched with water. 40 mLof EtOAc and 20 niL of brine were added. The organic layer was concentrated, and go to next step directly.

STEP 2: (S)-TERT-BUTYL 6'-CHLORO-5-(((lR,2S)-2-(3-ETHOXY-3-

OXOPROPYL)CYCLOBUTYL)METHYL)-3',4,4 ^! ,5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B] [ 1 ,4] OX AZEPTNE-3 , 1 '-NAPHTHALENE] -7-

CARBOXYLATE

The crude product of (S)-tert-butyl 6'-chloro-5-(((lR,2S)-2-((E)-3-ethoxy

3-oxoprop-l-en-l -yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro[benzo[b] [l,4]oxazepine-3,l'-naphthalene]-7-carboxylate from Step 1 above was dissolved with 20 mL of EtOAc, and then platinum(IV) oxide (54.9 mg, 0.24 mmol) was added. The reaction mixture was stirred under Hi ballon at rt overnight, and then filtered through celite to remove solid catalyst. The filtrate was concentrated to give the crude desire product, and go to next step directly.

STEP 3: 3-((l S,2R)~2"(((S)-7"(TERT-BUTOXYCARBONYL)-6 ^, -CHLORO-

N APHTHALEN] -5 (4H)-YL)METHYL)CYCLOBUTYL)PROP ANOIC ACID

To a mixture of (S)-tert-butyl 6'-chloro-5-(((lR,2S)-2-(3-ethoxy-3- oxopi pyl)cyclobutyl)methyi)-3',4,4;5 etrahydiO-2H,2'H- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxylate from Step 2 abov in 3 mL of THF, 3 mL of MeOH and 1 mL of water, lithium hydroxide (102 mg 2,42 mmol, JT-Baker) was added. The reaction mixture was stirred at 50 °C overnight. The reaction mixture was acidified with 1 N aq, HCl solution, and then 50 mL of EtOAc was added. The organic layer was concentrated and purified through a 40 g ISCO Gold column, eluting with 0-35% EtOAc( with 0.3% HOAc) in hexane to give 3-((l S,2R)-2-(((S)-7-(tert-butoxycarbonyl)-6'-chloro- 3 ',4'-dihy dro-2H,2'H-spiro [benzo [b] [ 1 ,4] oxazepine-3 , 1 '-naphthalen] -5 (4H)~ yl)methyl)cyclobutyl)propanoic acid (1 15 mg, 0.21 mmol).

STEP 4: (S)-TERT-BUTYL 6*-CHLORO-5-(((lR,2S)-2-(3-OXO-3-((2- SULFAMOYLETHYL)AMINO)PROPYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDR0-2H,2'H-SPIR0|;BENZ0[B] [ 1 ,4]OXAZEPINE-3, 1

NAPHTHALENE] -7-CARBOXYL ATE

To a 100-mL round-bottomed flask was added 3-((l S,2R)-2-(((S)-7-(tert- butoxycarbonyl)-6'-chloro-3 ^, ,4 ^, -dihydro-2H,2'H-spiro[benzo[b][L4]oxazepine- 3, -naphthalen]-5(4H)-yl)methyl)cyclobutyl)propanoic acid (from Step 3; 10 mg, 0.019 mmol), DIEA (9.70 μΐ, 0.056 mmol, Aldrich), 2-aminoethanesulfonamide (2.76 mg, 0.022 mmol , Biodfin) and 2 mL of DMF. The reaction stirred at rt overnight. The reaction mixture was diluted with 30 mL of EtOAc and 10 mL of water. The organic layer was concentrated and purified through a 12 g ISCO Gold column, eluting with 0-40% EtOAc( with 0.3% HOAc) in hexane to give the title compound.

STEP 5: (S)-6'-CHLORO-5-(((lR,2S)-2-(3-OXO-3-((2-

SULFAMOYLETHYL)AMINO)PROPYL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '-

NAPHTHALENE] -7 -C ARB OXYLIC ACID

5 mL of 50% TFA in DCM was added to (S)-tert-butyl 6'-chloro-5-

(((l R,2S)-2-(3-oxo-3-((2-sulfanioyle1hyl)amino)propyl)cv lobutyl)methyl)- 3',4,4 ^, ,5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7- carboxylatefrom Step 4 above. After 3 h, the deprotection was completed. The reaction mixture was concentrated and dried under Hi-Vac overnight to give the crude title compound (9.2 mg. 0.013 mmol).

STEP 6: (1 S,3¾,6'S)-6-CHIX)RO~3,4~DIHYDRO-2H,9TI, 15Ή- SPIRO[NAPHTHALENE- 1.22 ^' -

[20]OXA[13]THIA[1,10,14]TRJAZATETRACYCLO[14.7.2.0 - ⁶ .0 ¹⁹ ' ²⁴ ]PENTAC OS A [ 16, 18,24] TRIENEJ-9' , 15 '-DIONE 13', 13 '-DIOXIDE

N,N-Dimethylpyridin-4-amine (DMAP) (7.0 mg, 0.058 mmol) was added to a solution of (S)-6'-chloro-5-(((l R,2S)-2-(3-oxo-3-((2- sdfamoylethyl)arruno)propyl)cyclobutyl)methyl)-3',4,4',5-tet rahydro-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, -naphthalene]-7-carboxylic acid (from Step 5; 10 mg, 0.017 mmol) in DCM (1 mL) at 0 °C, and then N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (13.0 mg, 0.068 mmol) was added slowly and it was stirred at rt overnight. The reaction mixture was diluted with Teac (30ml), washed with 1 N HC1 aq. solution (3 ml), brine (5 ml), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1 % TFA, 30 rnin method) to give (1 S,3'R,6'S)~6~chloro~3,4- dihvdro-2ii. 'H. !^i-spi! |nap !halene-i.22'~

e]-9',15'-dione 13',13'-dioxide (5.9 mg, 10.31 μτηοΐ). ¾ NMR (400MHz, CDsOD) δ 7.73 (d, 86 Hz, 111).7.17 (dd, ,/ i 8.8.2 Hz, 2H), 7.09 (dd, J=2.0, 14.1 Hz, 2H), 6.96 (d, ./ 8.2 Hz, 1H), 4.03 (dd, ./ 7.6.15.7 Hz, 1H), 3.85 (dd, J=7.0, 15.1 Hz, 1H), 3.69 (dd,■/ 14.7.34.2 Hz, 2H), 3.61 (s, 1H), 3.57 (dd, J=1.0, 8.0 Hz, ill).3.14 (dd, ,/ 6.7.15.6 Hz, ill).2,84 - 2.71 (m, 2H), 2,31 id. ,/ HO Hz, 1H), 2.24 - 1.54 (m, 13H), 1.54 - 1.46 (m, lH). rrv'z (ESI, +ve ion) 572.0 .

EXAMPLE 946. (18,3 ^! ,6Έ,13'8)-6-(:ΗίΟ Ο-3,4-ΟΙΗΥΒΚΟ-2Η,9·Η,16Ή-

SPIRO [NAPHTHALENE- 1,23'-

[21]OXA[14]miA[l,U),15]TRL^

TACOSAI 17,19,25]TRI:ENE]-9',16'-DI0NE 14*,14'-DK)XIDE OR

(lS,3'R,6^,13'R)-6-CHLi3RO-3,4-r)IHYDRO-2H,9'H,16TI- SPIRO[N APHTHALENE- 1.2.T-

[21]OXA[14]miA[l,10,15]imZAPENTACYCLO[15.7.2.1 ⁱ⁰ - ⁱ l0 -^0 ²⁰ - ²⁵ ]HEP TACOSA|;r7,19,25jTRIENE]-9',16'-DIONE 14',14'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 945, Steps 1-6, but replacing 2-aminoethanesulfonamide with pyrrolidine-3-sulfonamide in Step 4, and the desired product, (lS,3'R,6'S,13'S)-6- chloro-3,4-dihydro-2H,9'H,16'H-spiro[naphtha]ene-l,23 ^f -

|2i loxal I |ihia| 1.10.i |ma/apeniacvcio| l^ 7.2 ! ^{l!! i;} 0 ^;!' .(i ^{;n !<} |hepiacosai 17.1 .2 5]triene]~9',16'-dione 14',14'-dioxide or (lS,3'R,6'S,13'R)-6-ch]oro-3,4-dihydro- 2H,9'H, 16'H-spiro[naphthalene-l ,23 ^! -

|2! joxaj I |thia| i.io.i-Hna.'apentacyclol 15.7.2. ! ^{H) 1 :} .i! ^i! 'J ^)%: ' "|heptacosai 17.19.2 5]iriene]-9',16'-dione 14 ^! ,14'-dioxide was isolated (first eluting major peak) out of reverse phase preparative HPLC. ^! H NMR (40QMHz, CD3OD) δ 7.76 (d, ./ 8.6 Hz, 1H), 7.21 (dd, J=2.2, 8.3 Hz, 1H), 7.14 (dd, J=2.3, 8.6 Hz, 2H), 7.07 (d, J=IA Hz, 1H), 6.99 (d, ./ K.2 Hz, 1H), 4.21 - 3.97 (m, 5H), 3.85 - 3.74 (m, 2H), 3.58 - 3.47 (m, 2H), 2.89 - 2,72 (m, 3H), 2.69 - 2,40 (m, 5H), 2.30 (br. s., 1H), 2.14 (d, J=\3A Hz, ill).2,08 - 2.03 (m, I Hi.2.02 - 1.74 (m, 8H), 1,53 - 1.43 (m, 1H). m/z (ESI, +ve ion) 598.2 (M il) .

EXAMPLE 947, (lS,3'R,6 ^f S,13'R)-6-CHLORO-3,4-DIHYDRO-2H,9'H,16TI- SP1RO [NAPHTHALENE- i . -

|2i j()XA| !4!ΊΊ!!Λ| I. i 0.1 1 ΚΙΛ/ΛΡΙίΝ ^' ΓΛ(Ύ( .<)| i 5.7.2.1 ^{;li ;} .0 ^{; :} '.0 ^>i: 'ΊΙ I LP TACOSA[17,19,25]TRIENE]-9',16'-DIONE 14 ^f ,14'-DIOXIDE OR

(1 S,3'R,6 ^! S, 13'S)-6-CHLORO-3,4-DIHYDRO-2H,9 ^! H, 16Ή- SPIRGpM APHTHALENE- 1 ,23'~

[21 ]OXA| 14]THIA| 1 ,10, 15 jTRIAZAPENTACYCLOj 15.7.2.1 ¹⁰ . ¹³ .0 ³ · ⁶ .0 ²⁰ · ²⁵ ]ΗΕΡ

-9',16'-DIONE 14*, 14'-DIOXIDE

The title compound was obtain as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 946. ¾ NMR (400MHz, CDCb) δ 7.76 (d, ,/ 8. Hz, ill).7.21 (dd, ./ 2.2.8.3 Hz, ill .7.14 (dd, ,/ 2.3.8,6 Hz, 21 \) 7.07 (d, ./ 1.4 Hz, ill).6,99 id../ 8.2 Hz, 1H), 4.96 - 4,82 (m, 1H), 3.99 - 3.85 (m, 3H), 3.78 (d, J=9.6 Hz, 2H), 3,73 - 3.49 (m, 4H), 3.42 - 3.34 (ra, ill).3,21 (d../ 14.3 Hz, IH), 2.95 - 2.86 (m, !H), 2.68 (br. s„ IH).2.61 (br. s., ill).2,58 - 2,43 (m, ill).2.29 (br, s., Mi).2.04 (br. s„ ill).2,00 - 1.88 (m, 2H), 1.82 (br. s., 3H), 1.72 (br. s., 3H), 1.69 - 1.45 (m, 2H). m/z (ESI, +ve ion) 598.2 {W W) .

EXAMPLE 948. (lS,3'R,6 ^! S,14'S,15'R)-6~CHLORO-3,4-DlHYDRO- 2H,9'H, 17'H-SPIRO[NAPHTHALENE-l,24'-

[22]OXA[15]THIA[1,10,16]TOAZAPENTACYCLO[16.7.2.1 ^!0 ' ^!4 .0 ³ ' ⁶ .0 ²¹ - ²⁶ ]OCT ACOSA[l 8,20,26]TRIENE]-9',17'-DlONE IS'-OXIDE OR

(lS,3'R,6 ^! S,14'S,15'S)-6-CHLORO-3,4"DlHYDRO-2H,9'H,17 ^, H- SPIRO [NAPHTHALENE- 1 ,24'-

[22]OXA[l 5]THIA[1 , 10,16]TRIAZAPENTACYCLO[16.7.2, 1 ^10J4 .0 ³ - ⁶ .0 ²³ ' ²⁶ ]OCT AC -9',17'-DIONE 15'-OXIDE

The title compound was prepared in an analogous manner to that described in Example 945, Steps 1-6, but replacing 2-aminoethanesulfonamide with piperidine-3-sulfonamide in Step 4, and the desired product,

(lS,3'R,6'S,14'S,15 ^! R)-6-chloro-3,4-dihydro

122 ioxai i 5|ihia| i . !O. l |ina/.apenlacyclo| 16,7.2.1 >"·» (r'-.o-' ^{1 :} "|octaco a! ! 8.20.26 ]triene]-9', I7'-dione 15*-oxide or (lS,3'R,6'S,!4'S,15'S)-6-chloro-3,4-dihydro- 2H,9'H, 17'H-spiro[naphthalene-l .2-i ^' -

]triene]-9',17'-dione 15'-oxide was isolated (first eluting major peak) out of preparative reverse phase HPLC. ^f H NMR (400MHz, CDsOD) 67.78 id../ 8.4 Hz, 111).7,45 (br. s., IH), 7.18 (dd, ./ 2.2.8,4 Hz, IH), 7.12 (t, ,/ 69 Hz, I Hi. 7.02 (del.,/ 24.8.3 Hz, ill).6,87 (br. s . !!!).5.03 - 4.90 (m, !!!}.4.33 - 4,15 (m, IH).4.06 (dd, ,7=12,7, 21.3 Hz, 2H), 3,88 (d, J=14.9 Hz, ill).3,81 - 3.65 (m, 3H), 3.59 - 3.46 (m, IH), 3.27 - 3.09 (m, 2H), 2.93 (d, J=4.9 Hz, 1H), 2.90 - 2.72 (m, 2H), 2.66 - 2.42 {in. IH), 2.26 (d, ./ 5.7 Hz, IH), 2.17 - 1.92 (m, 6H), 1.85 - 1.58 (m, 8H). in /. (ESI, +ve ion) 612.2 i \\ U) .

EXAMPLE 949. (lS,3¾,6'S,14'S,15'S)-6-CHLOR()-3,4-DIHYDRO- 2H,9'H, 17'H-SPIRO [NAPHTHALENE- 1 ,24"-

[22]OXA[15]THIA[1,10,16]TRIAZAPENTACYCLO[16.7.2.1 ¹⁰ " ¹⁴ .0 ³ ' ⁶ .0 ²¹ ' ²⁶ ]OCT ACOSA[18,20,26]TRlENE]-9',17'-DlONE 15'-OXIDE OR

(lS,3'R,6'S,14'S,15'R)-6-CHLORO-3,4-DIHYDR()-2H,9'H,17'H- SPIRO [NAPHTHALENE- 1 ,24'-

[22] OXA[ 15]THIA[ 1 , 10, 16] TRIAZ APENT AC YCLO [ 16.7.2 , 1 ^1G - ¹⁴ .0 ³ · ⁶ . G ^{2 !} · ²⁶ ] OCT ACOS -9',17'-DIONE 15'-OXIDE

The title compound was obtain as a single isomer (second e!uting major peak) from the reverse phase preparative HPLC in Example 948. ¾ NMR (400MHz, CD3OD) δ 7.79 (d, ./ 8.6 Hz, IH), 7.42 (br. s., IH), 7.33 - 7.22 (m, IH), 7.18 (dd, ,/ 24.8.1 Hz, IH), 7,12 id,./ I.X Hz, IH), 6.86 (br, s., IH), 5.04 - 4.91 (m, IH), 4.54 (br. s., IH), 4.33 (d, ./ I ! .2 Hz, IH), 3.88 (d, J=13.3 Hz, IH), 3.78 - 3.70 (m, 2H), 3.56 (d, J=10.8 Hz, IH), 3.20 - 3.15 (m, IH), 3.15 - 3.03 (m, IH), 3,00 - 2.73 (m, 5H), 2.66 (d, J=8.4 Hz, H), 2,33 id../ 6.8 Hz, 111).2,15 - 2,03 (m, 3H), 1.99 - 1.88 (m, 5H), 1,85 - 1,66 (m, 6H), 1.63 - 1.56 (m, IH), m/z (ESI, +ve ion) 612.2 (M+H) ⁺ . EXAMPLE 950. (1 S,3'R,6'R,7'S,8'RJ 0'R)-6-CHLORO-7'-HYDROXY-3 ₅ 4- DIHYDRO-2H, 16'H-SPIRO[N APHTH ALENE-1 ,23 ^! -

[21]OXA[14]THIA[l _s 15]DIAZAPENTACYCLO[ 15.7.2.0 ³ \0 ⁸ - ¹⁰ .G ²⁰ - ²⁵ ]HEXACO SAj ;i7, 19,25 ]TRIEN]- 16'-ONE 14'.14'-DIOXIDE OR (l S,3'R,0'R,7 ^! S,8'S,l Q'S)-6- CHLORO-7"-HYDROXY-3 ₅ 4-DlHYDRO-2H, 1 6'H-SPIRO[NAPHTHALENE-

L23'-

[21]OXA[ 14]THlA[ l , 15]DIAZAPENTACYCLO[15.7.2.0 ³ -^0 ⁸ - ¹⁰ .() ²⁰ - ²⁵ lIiEXACO SA[ 17, 19,25]TRIEN]-16'- ONE 14', 14"-DIOXIDE

STEP 1 : (S)-TERT-BUTYL 5-(((lR,2R)-2-((S,E)-6-(N,N-BIS(4- METHOXYBENZYL)SULFAMOYL)- 1 -HYDROXYHEX-2-EN- 1 - YL)CYCLOBUTYL)METHYL)-6 ^, -CHLORO-3 ^, ,4,4 ^, ,5-TETRAHYDRO-2H,2 ^, H

SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3, 1 '-NAPHTHALENE] - 7- CARBOXYLATE

A flask was charged with (S)-tert-butyl 6'-chloro-5-((( lR,2R)-2-

spiro [benzo [b] [ 1 ,4] oxazepine-3 , Γ -naphthalene] -7-carboxy late (Intermediate AA13A, Step IB; 0.065 g, 0.124 mmol) and N,N-bis(4-methoxybenzyl)pent-4- ene- 1 -sulfonamide (Intermediate EE19; 0.100 g, 0,25 mmol,) in DCM (4.96 ml). It was stirred at rt for 10 min to dissolve the solid starting material and then subjected to three cycles of evacuation-'baek-filling with nitrogen. To the homogeneous solution was added a solution of Hoveyda-Grubbs II (7.77 mg, 0.012 mmol) and it was stirred at 30 °C overnight. The reaction mixture was concentrated and purified through a 40 g ISCO Gold column, eluting with 0-30 % EtOAc in hexane to give (S)-tert-butyl 5-(((l R,2R)-2-((l S,6S,E)-6-(N,N-bis(4- methoxybenzyl)sulfamoyl)- 1 -hy droxyhept-2-en- 1 -yl)cy clobut ^methy -e'- cMoro-S'^^S-tetrahydro^H^H-spirotb^

naphthalene]-7-carboxylate (55.8 mg, 0.062 mmol).

STEP 2: (S)-5-(((lR,2R)-2-((S)-((l S,2S)-2-(3-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)PROPYL)CYCLOPROPYL)(HYDROXY) METHYL)CYCLOBUTTL)METHYL)-6'-CHLORO-3',4,4',5-TETRAHYDRO- 2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3 ₅ l ^* -NAPHTHALENE]-7-

CARBOXYLIC ACID

AND (S)-5-(((l R,2R)-2-((S)-((l R,2R)-2-(3-(N,N-BIS(4-

METHOXYBENZYL)SULFAMOYL)PROPYL)CYCLOPROPYL)(HYDROXY) METHYL)CYCLOBUTYL)METHYL)-6'-CHLORO-3',4,4',5-TETRAHYDRO- 2H,2H-SPlRO[BENZO[B] [l,4]OXAZEPlNE-3,r-NAPHTHALENE]-7- CARBOXYLIC ACID

Diethylzinc (1.0 M solution in hexane, 171 μΐ, 0.17 mmol) was added to a stirred solution of (S)-tert-butyl 5-(((lR,2R)-2-((S,E)-6-( ,N-bis(4- memoxybenz>d)sulfamoyl)-l-hydroxyhex-2-en-l-yl)cyclobur&g t;d)methyl)-6'-chloro- 3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][l,4]oxazepine-3,r -naphthalene]-7- carboxylate (Step 1 ; 30.3 mg, 0.034 mmol) in 1 mL of DCM at -10 °C, following by addition of diidomethane (13.76 μ\, 0.171 mmol) under N ₂ in absence of light.

The reaction was warmed to rt and stirred overnight. Sat aq. NH4C1 solution was added to the reaction mixture, and more DCM was added. The organic layer was concentrated and purified through a 40 g ISCO Gold column, during with 0-30 % EtOAc in hexane to give (S)-5-(((lR,2R)-2-((S)-((lS,2S)-2-(3-(N,N-bis(4- methoxybenzy^sulfamoylipropy cydopropy ihydroxyimelhylicydobuty^methy l)-6'-chloro-3 ^, ,4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [l,4]oxazepine-3,r- naphthalene]-7-carboxylic acid or (S)-5-(((lR,2R)-2-((S)-((lR,2R)-2-(3-(N ₅ N- bis(4- memoxybenz\d)sulfamoyl)propyl)c>xlopropyl)(¾ydroxy)methy l)cydobutyl)methy l)~6'~chloro-3',4,4',5~tetrahydro-2H,2'H-spiro[benzo[bl [l,4]oxazepme-3, ~ naphthalene|-7-carboxylic acid (2.5 mg, 2,96 μιηοΐ, first eluting peak), and S)-5- (((1 R,2R)~2-((S)~((1 S,2S)-2-(3-(N,N-bis(4- methoxybenzyl)sulfamoyl)propyl)cydopropyl)(hydroxy)^^

l)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] l,4]oxazepine-3, - naphthalene] -7-carboxylic acid or (S)-5-((( 1 R,2R)-2-((S)-(( 1 R,2R)-2-(3-(N,N- bis(4- memoxybenzyl)sulfamoyl)propyl)cyclopropyl)(¾ydroxy)methyl)c 'dobutyl)methy l)-6'-chloro-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3,r- naphthalene]-7-carboxyiic acid (10.6 mg, 0.013 mmol, second eluting peak).

STEP 3: (S)-6'-CHLORO-5-(((lR,2R)-2-((S)-HYDROXY((l R,2R)-2-(3-

SULFAMOYLPROPYL)CYCLOPROPYL)METHYL)CYCLOBUTYL)METOY L)~3V4,4^5-TETRAHYDRO-2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r- APHTHALENE j-7-CARBOXYLlC ACID OR (S)-6'-CHLORO-5-(((lR,2R)-2- ((S)-HYDROXY((l S,2S)-2-(3-

SULFAMOYLPROPYL)CYCLOPROPYL)METHYL)CYCLOBUTYL)METOY L)-3^4,4^5-TETR _J ' HYDRO-2H,2 ^, H-SPIRO[BE ZO[B] [i,4]OXAZEPINE-3,r~ NAPHTHALENE] -7-CARBOXYLIC ACID

3 mL of 20% TFA/DCM was added to a mixture of (S)-5-(((lR,2R)-2- ((S)-((l S,2S)-2-(3-(N,N-bis(4- methoxybenzyl)sidfamoyl)propyl)cydopropyl)^

l)-6'-chloro-3',4,4',5-tetrahydfo-2H,2'H-spiro[benzo[b] [ l,4]oxazepine-3,r- naphthalene]-7-carboxylic acid or (S)-5-(((lR,2R)-2-((S)-((lR,2R)-2-(3-(N,N- bis(4- methoxybenzyl)sulfamoyl)propyl)cyclopropyl)(¾ydroxy)methyl) cyclobut\'l)methy l)-6'-chloro-3',4,4',5-tetrahydro-2H,2 ^, H-spiro[benzo[b] [l ,4]oxazepine-3, - naphthalene]-7-carboxylic acid (Step 2, second eluting peak; 10.2 nig, 0.012 mmol) and thioanisole (14.20 μΐ, 0.121 mmol) at 0 °C. After stirring for overnight, the reaction mixture was concentrated and purified reverse phase preparative HPLC (Gemini™ Prep Cis 5 μτη column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give (S)-6'-chloro-5-(((lR ₅ 2R)-2-((S)-hydroxy((l R,2R)-2-(3- sulfamoylpropyl)c clopropy])me1hyl)c\ ]obuty])me1hyl)-3',4,4 ^, ,5-tetrabydro- 2H,2H-spiro[benzo[b][l,4]oxazepine-3, -naphtiiaiene]-7-carboxylic acid or (S)- 6'-chloro-5-(((l R,2R)-2-((S)-hydroxy((lS,2S)-2-(3- sdfamoylpropyl)cyclopropyl)methyl)cyclobutyl)methyl)-3',4,4' ,5-tetrahydro- 2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (1.7 nig, 2.82 μιηοΐ).

STEP 4: (1 S,3 ^! R,6'R,7'S,8'R, 10'R)-6-CHLORO-7 ^, -HYDROXY-3,4-DIHYDRO- 2H, 16'H"SPIRO| NAPHTHALENE- 1 ,23'-

[21]OXA[14]TO A[1 ,15]DIAZAPE TACYCLO[15.7.2.0 ³ " ⁶ .0 ⁸ - ^]0 .0 ²⁰ ' ²⁵ ]HEXACO SA[17,19,25]TRIEN]-16'-ONE 14', 14'-DIOXIDE OR (lS,3'R,6'R,7'S,8'S,10 ^! S)-6~ €ΗΙ-,ΟΚΟ-7'-ΗΥΟ ΟΧΥ-3,4-Γ)ΙΪΙΥΟ Ο-2Η,16'Η-8ΡΙΚΟ[ΝΑΡΗΉ-ίΑίΕΝΕ- 1,23'-

[21]OXA[14]THIA[l _s 15]DIAZAPENTACYCLO[15.7.2.0 ³ \0 ⁸ - ¹⁰ .G ²⁰ - ²⁵ ]HEXACQ SA[17,19,25]TRIEN]-16'- ONE 14',14'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 323, Step 7, and the desired product, (IS,3'R,6'R,7'S,8'R,10'R)-6- chloro-7'-hy droxy-3,4-dihydro-2H, 16'H-spiro [naphthalene- 1 ,23'- [21]oxa[14]thia[l,15]diazapentac clo[15J.2.0 ³ '^0 ⁸ " ¹⁰ .0 ²⁰ ' ²⁵ ]hexacosa[17,19,25] en]-16'-one 14 ^* ,14'-dioxide or (lS,3'R,6 ^* R,7'S,8'S,10 ^! S)-6-chioro-7'~hydiOxy-3,4" dihydro-2H,16'H-spiro[naphthalene-l,23'-

en] -16'- one I4',14'-dioxide was isolated as a white solid. ¾ MR (500MHz, CDsOD) 57.77 (d, ./ 8.6 Hz, 1H), 7.20 (dd, ./ 2.O.8.3 Hz, III).7.13 (d, ./ 2.2 Hz, ill).7.10-7.03 (m, 2H), 6.96 (d, ,/ 5.6 Hz, 111).4.15 - 4.00 (m, 3H), 3.88 id.

J=16.1 Hz, IH), 3,71 id.../ 13.9 Hz, IH), 3.61 (dd, «7=3.7, 5.1 Hz, IH), 3.47 (td, J=1.7, 3.2 Hz, IH), 3.25 -3.13 (m, 3H), 2.85 - 2.75 (m, 2H), 2.46 - 2.40 (m, IH), 2.11 (d, ./ 13.9 Hz, IH), 2.05 - 1.75 (m, 7H), 0.99 - 0.52 (m, 8H). m/z (ESI, +ve ion) 585.2 (M+H) ⁺ .

EXAMPLE 951. (lS,3'R,6'R,7'S,8 ^! R,10 ^, R,13'R)-6-CHLOR()-7'-HYDROXY-13'- ΜΕΤΉ Ε-3,4-ΟΙΗΥϋΚΟ-2Η ₅ 16Ή-8Ρ¾0[ΝΑΡΗΊΉΑΕΕΝΕ-1,23"- |2! !ΟΧΛ| Ι ·ΙΙ Η1Λ| Ι ..Ι |ί)!,\/.\ΡΗΝ ΓΛίΎΠ.ΟΙ 15.7.20 ^{; !} '.O ^s ' ^» Η:ΧΛ( 0 SA[ 17,19,25] TRIEN]- 16'- ONE 14',14'-DIOXIDE OR

(lS,3'R,6 ^! R,7 ^, S,8'S,l()'S,13'R)-6-CHLOR()-7 ^, -HYDROXY-13'-METHYL-3,4- DIHYDRO-2H, 16'H-SPIRO [NAPHTHALENE- 1 ,23 ^* - pilOXAtMlTHIAt^lSlDIAZAPE TACYCLOIlS.T^.O^^O^^.^^lHEXACO S A[ 17, 19,25] TRIEN] - 16'-ONE 14', 14'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 950, Steps 1 to 4, but replacing N,N-bis(4-methoxybenzyl)pent-4-ene- 1 -sulfonamide (Intermediate EE! 9) with (R)-N,N-bis(4-methoxybenzyl)hex-5- ene-2-sulfonamide (Intermediate EE20) in Step 1, and the desired product,

(lS,3 ^, R,6 ^, R,7 ^, S,8 ^, R,10 ^, R,13 ^, R)-6-cWoro-7 ^, ½droxy-13 ^, -me l-3,4-d dro- 2H, 16'H-spiro| naphthalene- 1,23'- [21]oxa[14]thia[l,15]diazapentacy^

en]-16'- one 14',14'-dioxide or (lS,3 ^! R,6'R,7'S,8 ^, S,10'S,13 ^! R)-6-chioro-7'- hydroxy-13'-methyi-3,4-dihydro-2H,16 ^, H-spiro|naphthalene-l,23 ^! - [21 ]oxa[ 14]thia[l , 15]diazapentacyclo[l 5.7.2.0 ³ - ⁶ .0 ⁸ ' ¹⁰ .0 ²⁰ - ²⁵ ]hexacosa[l 7, 19,25]tn en]-16'-one 14',14'-dioxide was isolated as a white solid. Ή NMR (4003MHz, CD3OD) δ 7.77 (d, J=8.6 Hz, IH), 7.21 (dd, J=2.2, 8.4 Hz, 1H), 7.13 (d, J=2.2 Hz, HI).6.96 (d, ./ I.i ⁾ Hz, 2H), 6.89 (s, ill).4.15 - 4.01 (m, 2H), 3.88 id../ 14.7 Hz, ill).3,79 (ά . I 14.5 Hz, ill).3.53 - 3.45 (m, !!!}.3.31 - 3,22 (m, 2H), 2.93 - 2.77 (m, 3H), 2.74 (dd, ,7=2,1, 9.7 Hz, ill).2.37 (dd, ./ 7.2..16.0 Hz, IH), 2.25 - 1.92 (m, 7H), 1.90 - 1.75 (ni, 3H), 1.54 (d, J=7.0 Hz, 3H), 0.85 - 0.74 (m, 2H), 0.73 - 0.70 (m, IH), 0.65 (br. s., IH), 0.51 (t, ./ <>.3 Hz, 2H). m/z (ESI, +ve ion) 599.2 \\\-U) .

EXAMPLE 952. (1 S,3 ^! R,6 ^, R,7'R,8'E)-6-CHL()RO-7'-HYDR()XY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TOIA[1,14]DL ZATEI1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

2,205

The title compound was prepared in an analogous manner to that described in Example 719, Steps 1 and 2, using Intermediate AAllB and pent-4- ene- i -sulfonamide (Intermediate EE 19, Step 2), and the desired product,

(lS,3 ^, R,6'R,7 ^, R,8¾)-6-cMoro-7 ^, -hydroxy-3,4-dihydro-2H,15H-spiro[naphthden^

1 ">"> ^< -

[20joxa 13]thia[l,14]diazatetracycfo[M _^

n]-15'-one 13',13'-dioxide was isolated as a white solid, ^" Ή NMR (400MHz, CD3OD) δ 7.76 (d, J=8.6 Hz, IH), 7.28 (d, ,7=2,0 Hz, IH), 7.19 (dd, .7=2.3, 8.4 Hz, IH), 7.12 (d, ,7=2.2 Hz, IH), 7.03 (dd, ./ 2.0.8.2 Hz, IH), 6.94 (d, =8.0 Hz, IH), 5.76(td,J=5.8, 15.4 Hz, IH), 5.58 (dd, ,7=7,1, 15.6Hz, IH), 4, 10 (s, 2H), 4,01 - 3.88 (m, 3H), 3.69 (d, J=14.1 Hz, IH), 3,08 (dd, J=8.8, 15.3 Hz, IH), 2.88 - 2.71 (m, 2H), 2.62 - 2.51 (m, IH), 2.44 - 2.31 (m, 2H), 2.19 - 1.57 (m, 12H), 1.54 - 1.39 (m, IH). m/z (ESI, +ve son) 571.2 (M ·!!:· .

EXAMPLE 953. (lS,3'R,6 ^! R,7'R,8'E,12'R)-6-CHLORO-7'-HYDROXY-12'- ME ^r rHYL~3,4~DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE"l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE ',Β'-ΟΙΟΧΙΟΕ AND EXAMPLE 954.

(18,3¾,6 ^! 1,7¾,8Έ,12'8)-6"ΗΕ010-7'-ΗΥΒίΙΟΧΥ-Ι2'-Μ� �ΊΉΥΕ-3,4- DIHYDRO-2H, 15'H-SPIR0[NAPHTHALENE-1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compounds were prepared in an analogous manner to that described in Example 719, Steps 1 and 2, using Intermediate AAl lB and a racemic mixture of (R)-hex-5-ene-sulfonamide (Intermediate EE20) and (S)-hex- 5-ene-sulfonamide (Intermediate EE202), and the desired products,

(lS,3'R,6'R,7'R,8'E,12'R)-6-chloro-7'-hydro^^^

spiro [naphthalene- 1 ,22'- [2C)joxaj 13]thia[l,14]diazateto^

n]-15'-one 13',13'-dioxide (second eluting peak out of reverse phase preparative HPLC) and(iS ^! R,6'R,7'R,8'E,12'S)-6-chloro-7'-hydrox}-12'-m.ethyl~3, 4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]cUazatetracyclo^^

n]-15'-one 13',13'-dioxide (first eluting peak out of reverse phase preparative HPLC) were isolated. (lS,3*R,6'R,7'R,8'E,12'R)-6-chioro-7'-hydi xy-12'-methyl- 3,4-dihydro-2H,15'H-spiro|naphthalene-l,22'-

[20] oxa[ 13 ] thi a[ 1 , 14] di azatetracy cl o [ 14.7 , 2.0 ³ · ⁶ 0 ^!9 · ²⁴ ] pentacosa[8, 16,18,24] tetrae n]-i.5'-one 13',13'-dioxide (Example 953). ¾ NMR (500MHz, MeOH) δ 7.76 (d, ./ 8.6 Hz, IH), 7.42 (d, ,/ 1.5 Hz, IH), 7.19 (dd,■/ 2.2.8.6 Hz, IH), 7.12 id. J=2.0 Hz, IH), 7.09 (dd, ./ !.:\ 8.1 Hz, IH), 6.94 (d, 8.0 Hz, IH), 5.55 (d,

J=3.4 Hz, 2H), 4.10 (s, 2H), 4.00 - 3.90 (m, 2H), 3.79 (d, .7=2.4 Hz, IH), 3,70 (d, ./ 14.2 Hz, IH), 3.05 (dd, ./ 7.0.15.3 Hz, IH), 2.86 - 2.74 (m, 2H), 2.61 - 2.46 (m, 2H), 2.39 - 2.30 (m, IH), 2.16 - 2.02 (m, 3H), 1.98 - 1.82 (m, 4H), 1.81 - 1.62 (m, 4H), 1.47 id../ 7 ! Hz, 3H), 1.46 -1.41 (rn, IH), m/z (ESI, +ve ion) 585,2 (M+H) ⁺ ; (lS,3 ^, R,6 ^, R,7'R ₅ 8¾12 ^, S)-6-chloro-7 ^, -hydrox>'-12 ^f -methyl-3,4-dihydro- 2H, 15'H-spirofnaphthalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetrac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'-dioxide (Example 954). ¾ NMR (400MHz, CD3OD) δ 7.74 (d, ./ K.6 Hz, 1H), 7.19 idd. ,/ 2.2. 8.5 Hz, IH), 7.13 (d, ,/ 2.2 Hz, H i ). 6.99 - 6.87 (m, 3H), 5.90 - 5.81 (m, 1H), 5,54 (dd, ./ 7.9. 15.2 Hz, 1 H), 4.15 - 3.96 (ra, 4H), 3,69 (d, ./ 14.3 Hz, IH), 3.59 id,. «7=13.5 Hz, 1H), 3.49 id. .7=13.1 Hz, I I I ). 3.27 (dd, ./ 9.4. 15.3 Hz, IH), 2.88 - 2.73 (m, 2H), 2.56 - 2.37 (m, 2H), 2.24 - 2.15 (m, I H), 2.13 - 1.89 (m, 7H), 1 ,88 - 1.69 (m, 3H), 1.58 - 1.50 (m, IH), 1.51 (d, ,/ 6.X Hz, 3H). m . (ESI, +ve ion) 585.2 (M+H) ⁺ .

EXAMPLE 955. (1 S,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-7 ^* -(((2RH-METHOXY- 2-PROPANYL)OXY)-l 2'-METHYL-3,4-DIHYDRO-2H ₅ 15Ή-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THL [1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 13", 13 -DIOXIDE AND

(lS,3 ^, R,6'R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-7'-(((2S)-l-METHOXY-2- PROP AN YL)OXY)- 12'-METHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ -* 0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16, -15'- ONE 13 ',13 '-DIOXIDE

Sodium hydride (60% dispersion in mineral oil, 3.2 mg, 0.08 mmol) was added to a solution of (l S,3'R,6'R,7'S,8'E^.2'R)-6-chloro-7'-hydroxy-12'-meihyl- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'-

[20]oxa[13]thia[l ,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'-dioxide (Example 404, Step 1 ; 9.4 mg, 0.016 mmol) in THF (535 μΐ) at 0 °C. After 30 mm, 2-bromo-l-methoxy ropane (2.46 mg, 0.016 mmol, Bellen) was added. The reaction mixture was heated to 60 °C and stirred at for 48 h. The reaction mixture was quenched with water and 1 N HCl soluiton, 25 mL of EtOAc was added. The organic layer was concentrated and purified through a 4 g TSCO Gold column, eluting with 0-30% EtOAc( with 0.3% HO Ac) in hexane to give a mixture of (lS,3'R,6'R,7 ^! S,8'E,12'R)-6-chloro-7'-(((2R)-l- memoxy-2-propanyl)oxy)-12'-methyl-3,4-dihydro-2H,15'H-spiro[ naphthalene- 1 22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ^{! 9} - ²⁴ ]pentacosa[8, 16, 18,24]tetrae n]-15'-onel3 ^, ,13 ^, -dioxide aiid (lS,3'R,6 ^* R,7'S,8'E,12'R 6-chioro-7 ^, -(((2S)-l- methoxy-2-propanyl)oxy)-12'-methyl-3,4-dihydro-2H,15H-spiro[ naphthalene- 1 ,22'-

[20]oxa[13]thia[l ,14]diazatetracyclo[14.7^

n]-15'- onel3',13'-dioxide (1.7 mg, 2.59 μιηοΐ). ¾ NMR (5GGMHz, CD3OD) δ 7.75 (d, ./ 10.3 Hz, I I I ). 7.19 (dd, ,/ 1.7. 8.3 Hz, 1H), 7.13 (d, ./ 1.7 Hz, 1H), 7,02 - 6.98 (m, I I I ). 6.95 (dd, ,/ ! 0. 8.3 Hz, i l l ). 6,88 (dd, ./ 1 .7, 3.9 Hz, 11 1 ). 5,86 - 5.79 (m, I I I ). 5.64 - 5.57 (m, i l l ). 4,21 - 4.14 (m, 1H), 4.09 (dd, ,7=12,0, 14.9 Hz, 2H), 4.01 (ddd, ./ 3.7. 8.6, 23.7 Hz, 1H), 3.85 (dd, ./ 4.4. 14.9 Hz, 1H), 3.74 - 3.65 (ra, 2H), 3,33 - 3.29 (m, 3H overlap with solvent), 3,28 - 3.24 (m, 1 H), 3.08 (dd, J=9,7, 14.8 Hz, IH), 2,87 - 2,68 (m, 2H), 2.54 - 2.27 (m, 5H), 2, 12 (d, J=13.7 Hz, IH), 2.00 - 1.70 (m, 6H), 1.60 (dd, J=7.1, 11.2 Hz, IH), 1.52 (d, J=6.8 Hz, 3H), 1.49 - 1.42 (m, I H), 1.49 - 1.42 (m, IH), 1.10 (dd, ./ 6. 1 . 35.0 Hz, M l ). 0,93 (t, ./ 7. 1 Hz, IH), m/z (EST, +ve ion) 657,2 ! V! I ! )

EXAMPLE 956. (l S,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-CHLORO-12'-METHYL-7'-(2- P YTUMIDINYLMETHOXY)-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 1 ,T. 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (l S,3 ^, R,6'R,7 ^, S,8'E,12'R)-6-chloro-7'-hydroxy-12 ^, -met y1- 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20] oxa[ 13 ] thia[ 1 , 14] diazatetracy clo [ 14.7.2.0 ³ · ⁶ .0 ^!9 · ²⁴ ] pentacosa[ 8,16,18,24] tetrae n]-15'-one 13', 13'-dioxide (Example 404, Step 1 ) and 2-(chloromethyl)pyrimidine (TCI), and the desired product, i i

(2-pyriirudinylnietlioxy)-3,4-dihydro-2HJ

[20]oxa[ 13]thia[l ,14]diazatetracyclo[14.7.2,0 ³ - ^f \0 ¹⁹ - ²⁴ ]peniacosa[8,16, 18,24^ n]-15'-one I 3',13'-dioxide was isolated as a white solid. Ή NMR (400MHz, CDsOD) δ 8.82 (d, J=4.9 Hz, 2H), 7.75 (d, J=8.6 Hz, IH), 7.43 (t, ./ 5. 1 Hz, i l l ).

7.19 (t, J=6.0 Hz, IH), 7.13 is. -/ 5. 1 Hz, I H), 7.04 (d, J=6.5 Hz, IH), 6.93 - 6.85 (m, 2H), 5.97 - 5.82 (m, IH), 5,65 (dd, ./ 8.7. 15.2 Hz, I H), 4.65 (dd, ,/ i 1.3, 24,6 Hz, 2H), 4.15 - 4,00 (m, 4H), 3.83 (d, ,/ 1 -I 7 Hz, I H i. 3.67 (d, .7=14,5 Hz, H),

3.20 - 2.87 (m, 2H), 2.88 - 2.72 (ni, 2H), 2.63 (d, J=5.1 Hz, IH), 2.41 (br. s., 2H), 2,27 (br. s., IH), 2.1 1 id. ./ 14.3 Hz, IH), 2.03 - 1.84 (m, 6H), 1.80 - 1.66 i ns.

2H), 1.51 (d, ./ 6.5 Hz, 3H), 1.47 - 1 ,39 (m, IH) m/z (ESI, +ve ion) 677,4 (M+H) ⁺ .

EXAMPLE 957. (l S,3¾,6¾,7 ^! S,8 ^, E, 12 ^, R)-6-CHLORO-12'-METHYL-7'-((2- METHYL-2H-TETR/ ZOL~5"YL)METHOXY)-3,4-DIHYDRO-2H,15 ^! H- SPTRO[NAPHTHALENE-l,22'-

|20!ΟΧΛ| ΐ: ΐ!!1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.20 ^: ' ⁱ '.0 ^li ' |Pi-:N i ACOSA [8, 16, 18,24]TETRAEN]- '-ONE 13 I 3'-DIOXIDE

STEP 1 : 5 -(CHLOROMETHYL)-2-M L-2H-TETRAZOLE

To 5-(chIoromethyl)-2H-tetrazole (516 nig, 4.4 mmoi) in diethyl ether (8.7 mL), was slowly added trimethylsilydiazomethane (2.6 raL, .5.2 ramol, Aldrich) at 0 °C (this should be done slowly due to gas evolution). The yellow reaction was allowed to stir overnight at rt before being concentrated purified by

chromatography using ISCX) 40 G gold silica column, eluting with 5-50% EtOAc in hexanes. The product was collected and concentrated to afford the desired product as a colorless oil

STEP 2: (1 S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-l 2'-METHYL-7'-((2-METHYL-

2H-l\ETRAZOL~5-YL METHOXY)-3,4-DIHYDRO-2H,15 ^! H-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]()XA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2,0 ³ -V0 ^l9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1.T.13'-DIOXIDE The title compound was prepared in an analogous manner to that described in Example 720 using

3,4-dihydro-2H,15H-spiro[naphthalene-L22^

[20joxa 13]thia[l,14]diazatetracycfo[14.7 _^ ^

n]-15'-one 13',13'-dioxide (Example 404, Step 1) and 5-(chloromethyl)-2-methyl-

2H-tetrazoie from Step 1, and the desired product (lS,3'R,6'R,7'S,8'E,12'R)-6- cMoro-12'-methyl-7 ^, -((2-me l-2H-tetrazol-5-yl)methoxy)-3,4-dihydro-2H,15'H- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetra<yclo[K

n]-15'-one 13',13'-dioxide was isolated as a white solid. ¾ NMR (400MHz,

CD3OD) 7.76 (d,■/ 8.6 Hz, III).7.19 (d, ,/ H.7 Hz, 1H), 7.12 (d, ./ 2.2 Hz, III .

7,02 (d, ./ 7.2 Hz, ill).6.92 - 6.86 (m, 2H), 6.02 - 5,86 (m, !!!).5.62 (dd, ,/ 8.7.

15.2 Hz, 1H), 4.69 {dd../ 11.3.28.2 Hz, 2H), 4.41 (s, 3H), 4.21 -4.11 (m, 1H),

4.07 (dd, J=11.5, 15.3 Hz, 2H), 3.97 (dd, J=3.8, 8.7 Hz, 1H), 3.82 (d, J=14.7 Hz, ill).3.68 (d, J------14A Hz, !!!}.3.07 (dd, 10.!.15.0 Hz, 1H), 2.87 - 2.73 (m, 2H),

2.55 - 2.26 (m, 4H), 2.11 (d, ./ 13.3 Hz, 1H), 2.01 (s, 1H), 1.94 (br. s., 3H), 1.90 -

1.65 (m, 5H), 1.53 (d, ./ 6.8 Hz, 3H), 1.49 - 1.39 (m, 1H). m/z (ESI, +ve ion)

681.2 (M+H) ⁺ . EXAMPLE 958. (lS,3'R,6 ^! R,7'S,8 ^, E,12 ^, R)-6-CHLORO-12 ^! -METHYL-7'-(4H- 1 ,2,4-TRI AZOL-3 -YLMETHOXY)-3 ,4-DIHYDRO-2H, 15 Ή- SPTRO[NAPHTH ALENE- ! ,22'-

|2( >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.2 ^; ".O ¹ " ^M |PH\ i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-D10XlDE

IZ

STEP 1 : 3 - (CHLOROMETHYL) - 1 -((2-

(TRJMETHYLSILYL)ETH0XY)METHYL)-1H- 1 ,2,4-TRIAZOLE AND 3- (CHLOROMETHYL)-4-((2-(TRIMETHYLSILYL)ETH()XY)METHYL)-4H- 1,2,4-TRIAZOLE

Sodium hydride ( 60% dispersion in mineral oil, 292 mg, 7.31 mmol,

Aldrich) was adde, 3-(chloromethyl)-lH-l,2,4-triazole (573 mg, 4.88 mmol, Anichem ) in 20 mL. of THF at 0 °C. After 30 min, (2-

(chloromethoxy)ethyl)trimethylsilane (975 mg, 5.85 mmol, Aldrich) was added slowly. The ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was adjusted pH to 7 with 1 N aq. HCI solution, and then 15 mL of water and 30 mL of EtOAc was added. The organic layer was concentrated and purified by chromatography using iSCQ 40 G gold silica column, e!uting with 0-40% EtOAc hexanes. The product was collected and concentrated to afford the desired product. STEP 2: (l 1 2'R) 3-CHLORO- 12'-METI-IYL-7'-(4H-!,2,4-

TRIAZOL-3-YLMETHOXY)-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1 ,22'-

[20;|OXA[13]THIA[1 ,14]DIAZATCT ACYCLO[ 14 .2.0~3,6~ ~19,24~]PENT ACOSA[8,l 6,18,24]TETRAEN]-15'-ONE 13 ^* , 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (18,3 ^! ί ,6¾,7'8,8Έ;ΐ2¾)-6-ΰ1ι1θΓθ-7'½άΓθχν-12'-ίΉ6� �ν1" 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'- [20]oxa[13]thia[l,14]diazatetracyc ^

n]-15'-one 13',13'-dioxide(Example 404, Step 1) and 3-(chloromethyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazole with 3-(chloromethyl)-4-((2- (trimethylsilyl)ethoxy)methyl)-4H- 1 ,2,4-triazole ( 1 : 1 ). Tetrabutyiammonium fluoride (0,5 M solution in THF ) was added to deprotect SEM goup to give the desired final product (l S,3 ^* R,6'R,7'S,8'E,12'R)-6-chloro-12 ^, -methyi-7'-(4H-l,2,4- triazol-3-y]rnethoxy)-3,4-dihydro-2H,15'H-spiro[naphthalene- l,22'-

[20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14, 7.2.0 ³ · ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'-dioxide as a light-yellow solid, ¾ NMR (500MHz, CDsOD) δ 8.59 - 7.82 (m, I I I ). 7.71 (d, ,/ H. Hz, 1H), 7.14 (d, ./ 8.3 Hz, i l l ). 7.08 (s, i l l ). 7,01 (br. s . H i ). 6.85 (t, J 7.6 Hz, 2H), 5.94 (br, s., i l l ). 5,59 (dd, ,/ 8,8. 14.4 Hz, IH), 4,57 (br, s,, 2H), 4.13 - 3.96 (m, 3H), 3,94 (br. s,, 1H), 3.80 (d, .7=14.9 Hz, 1 1 1). 3.62 (d, J=15.4 Hz, IH), 3.67 - 3.60 (m, 1H), 3,33 (s, 2H), 3,06 ·· 2,98 (m, I H), 2.85 - 2,70 (m, 2H), 2,50 (br, s,, IH), 2.39 (br, s., 2H), 2,25 (br. s, , IH), 2,07 (d, .7=14.2 Hz, IH), 1 ,93 - 1 ,86 (m, 3H), 1.86 - 1.77 (m, 2H), 1,76 - 1 ,65 (m, 2H), 1.47 (d, J=6.4 Hz, 3H), 1.44 - 1.36 (m, IH). m/z (ESI, +ve ion) 666.2 (M+H) ⁺ .

EXAMPLE 964. 2-(((l S,3'R,6'R,7'S,8 ^, Z,12 ^, R)-6-CHLORO-12'-ETHYL-13',13'- DIOXIDO-lS'-OXO-S^-DIHYDRO^-SPIROINAPHTHALENE-l^^- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA

[8 ₅ 16 8,24]TETRAEN]-7 ^, -YL)OXY)-N-METHYLACETAMlDE

STEP 1 : (18,3¾,6'Κ,7 ^! 8,8'Ζ,12'Κ)-6-{:ΗΕ()Κ0-12'-ΕΤΗΥΕ-7'-ΗΥ0Κ0 ΧΥ-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[K

[ 8,16,18,24]TETRAENj-15'-C)NE 13',13'- DIOXIDE

The title compound was prepared in an analogous manner to that described m Example 719, Steps 1 and 2, using (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydroxyallyl)cyciobtm _' l)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiroj benzoj b][ 1,4 |oxazepine-3, -naphthalene]-7-carboxyiic acid (Intermediate AAI IA) and a raceraic mixture of (R)-hept-6-ene-3 -sulfonamide (Intermediate EE21) and (S)-hept-6-ene-3-sulfonarnide (Intermediate EE212), and the desired product, (lS,3'R,61l,7^,8 ^, Z,121 )-6-chloro-12'-e l-7'-hydroxy-3,4-dihydro- 2H, 15'H-spiroj naphthalene- 1,22'-

n]-15'-one 13',13'-dioxide was obtained as a single isomer (second eluting peak) from the reverse phase preparative HPLC. T-I NMR (500MHz, CD3OD) δ 7.75 (d, ./ 8.6 Hz, i l l ). 7.19 (dd, ./ 2.3. 8.4 Hz, 1 H), 7.12 (d, 2.2 Hz, 1H), 7.03 (dd, =2.0, 8.1 Hz, IH), 6.97 - 6.92 (ra, 211).5,62 - 5,55 (m, 2H), 4.49 (dd, ,/ 35.7.9 Hz, IH), 4.09 (dd, .7=12.5, 21.8 Hz, 2H), 3.88 (d, .7=15.7 Hz, IH), 3,71 (d, 7=14.4 Hz, IH), 3.62 (br. s., IH), 2.87 ·· 2.74 (m, 2H), 2.49 - 2.38 (m, 3H), 2.26 ·· 2.10 (m, 3H), 2.06 - 1.89 (m, 8H), 1.84 - 1.73 (m, 3H), 1.55 - 1.40 (m, IH), 1.16 (t,■/ 7.5 Hz, 3H). m/z (EST, +ve ion) 599,2 !YM!)

STEP 2: 2 ((lS,3'R,6'R,7 ^! S,8'Z,12'R)-6-CHL()RO-12'-ETHYL-13',13 ^! - DTOXIDO~15'~OXO-3,4-DIHYDRO~2H-SPTROj^

|2( >X A| i 1 ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.20 ^;ί' .ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN] -7'-YL)OXY)-N-METHYLACET AMIDE

The title compound was prepared in an analogous manner to that described m Example 720 using (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, Z,12 ^, R)-6-ch]oro-12 ^, -ethyl-7 ^, -hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

[20]oxa[13]thia[l,14]diazatefr^

n]-15'-one 13',13'-dioxide (Example 964, Step 1) and 2-chloro-N-methylacetamide (Aldnch), and the desired product, 2-(((lS,3'R,6 ^, R,7 ^, S,8'Z,12'R)-6-chloro-12 ^, - ethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthale ne-l,22'- |20jo\aj I |ihi«i| i. I4|dia/aicuac> ciol Ι4.7.2.ί! ^;ί '. ^{()1'ί n} |pen!acosa| H.I .18.24 licirae n]-7'-yl)oxy)-N-methylacetamide was isolated as a white solid. ^[ H MMR

(400MHz, CD3OD) δ 7.74 (d, ./ 8.4 Hz, IH), 7.19 (dd, ./ 2.2.8.6 Hz, !!!).7.12 (d, ./ 2.3 Hz, ill).7,00 (dd, ./ 2.0.8.4 Hz, IH), 6.95 (d, ,/ 80 Hz, IH), 6.90 (d, 7=1.6 Hz, IH), 5.77 (id, 7=6.9, 11.1 Hz, IH), 5.49 (t, J=\ 0.6 Hz, IH), 4,28 (dd, 7=2.9, 9.4 Hz, IH), 4.09 (ddd,J=12.1, 13.5, 25.8 Hz, 2H), 3.95-3.81 (m, 3H), 3.71 (d, ./ 14. ! Hz, IH), 3.68 - 3.59 (m, IH), 2.80 (s, 5H), 2.68 - 2.60 (m, IH),

2,45 - 2.28 (m, 2H), 2.27 - 2.10 (m, 3H), 2,05 - 1.89 (m, 7H), 1.88 - 1.75 (ra, 3H), 1.49 (t, .7=10.9 Hz, IH), 1.31 (s, IH), 1.17 (t, .7=7,5 Hz, 3H), m/z (ESI, +ve ion) 670.2 (M+H) ⁺ . EXAMPLE 965. (lS,3'R,6 ^! R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^! -ETHYL-7 ^, -((l- METHYL-lH-IMIDAZOL-2-YL)METHOXY)-3,4-DIHYDRO-2H ₅ 15H- SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.20 ^; ".ϋ |ΡΗ\ i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13 VI 3'-DIOXIDE

The title compound was prepared in an analogous manner to that described m Example 720 using (lS ^! R )¾,7^,8T i2¾.)-6-chloro-12'Hithyl~7 ^! 4iydroxy- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazatefra^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-(chloromethyl)-l-methyl- lH-imidazole (Matrix Scientific), and the desired product,

(lS,3¾,6 ^, R,7'S,8¾,12'R)-6-cWoro-12 ^, -e i-7 ^, -methoxy-3,4-dihydro-2H,15 ^, H- spiro[naphtha]ene-l,22'-

n]-15'-one was isolated as a white solid. Ή NMR ! 400 Mil/. CDJOD) δ 7.64 (d, ./ 8.6 Hz, IH), 7,45 (dd, J=2.0, 18.4 Hz, 211).7.09 (dd, 22. 8.5 Hz, IH), 7.02 (d, «7=2.2 Hz, IH), 6.90 (dd, ,/ 20.8.4 Hz, IH), 6,84 (d, ./ 8.0 Hz, IH), 6.74 (d, ./ 1.8 Hz, IH), 5.92 - 5.84 (m, IH), 5.59 (dd, ./ 9.2.15.3 Hz, IH), 4.64 (dd, ./ 14.5.28.6 Hz, 2H), 4.03 - 3.91 (m, 411 ).3.79 (s, 311:·.3.74 id. ,/ 160 Hz, IH), 3.57 (d, J=14.9 Hz, IH), 3.00 (dd, 10.2.15.3 Hz, IH), 2,76 - 2.62 (m, 2H), 2.53 - 2.44 (m, IH), 2.39 - 2.17 (m, 3H), 2.06 - 1.64 (m, 12H), 1.36 (t, ./ ! 1.5 Hz, IH), 1.13 (t,■/ 7.4 Hz, 3H). m /. (ESI, +ve ion) 693.2 (M+H .

z21 / EXAMPLE 966. (1 S^'i^e'R 'S^'E.l^-e-CHLORO-n'-ETHYL-?'-^- YU . H !Yi -i 3. i-OX.\!)l Λ :0!.-2-Υί }\Si: 1 ! K)XY>3. i~DU IYDRO-211.1 'i 1- SPIRO[N APHTHALENE-1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA [8,16,18,24]TETRAEN]~ '~0NE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (IS 'R >'R 'S,8'E 2'R)-6-chloro-12'-ethyl-7'-hydroxy- 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

n|-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-(chloromethyl)-5-methyl- 1,3,4-oxadiazole (Frontier Scientific Services), and the desired product,

(lS,3'R,6 ^, R,7'S,8 ^, E,12 ^, R)-6~chloro-12'-ethyl-7'-((5-methyl-L3,4-oxadiazol-2~ y l)methoxy )-3 ,4-dihy dro-2H, 15 'H-spiro [naphthalene- 1,22'-

[20]oxa[I3]thia[l,I4]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ^]9<24 ]pentacosa[8,16,18,24]tetrae nj~15'~one 13',13'-dioxide was isolated as a white solid, ^" Ή NMR {400. VII!/.

CD3OD) δ 7.64 (d, J=8.6 Hz, 1H), 7.08 (dd, J=2.2, 8.5 Hz, IH), 7.01 (d, J=2.2 Hz, ill).6.89 (dd, ,/ 2.0.8.2 Hz, IH), 6.81 (d, ./ 7.H Hz, IH), 6.75 (d,■/ 2.2 Hz, III). 5.86 - 5.77 (ra, IH), 5.51 (dd, ./ 8.H. 15.3 Hz, IH), 4.51 (dd, ,/ 135.18,8 Hz, 2H), 4.02 - 3.9.1 (111, 3H), 3,88 (dd, J=3.5, 8.6 Hz, IH), 3.74 (d, ,7=14,9 Hz, IH), 3.57 (d, J=14.1 Hz, IH), 3.17 (d, J=14.5 Hz, IH), 2.98 (dd, J=9.9, 15.4 Hz, IH), 2,76 - 2.61 (m, 2H), 2.47 (s, 3H), 2,37 - 2.15 (m, 3H), 2,07 - 1.95 (m, 2H), 1.91 - 1.64 (m.9H), 1.39 - 1,27 (m, !!!).1.26 - 1.18 (m, IH), 1.12 7.5 Hz, Ml) m/z (ESI, +ve ion) 695.3 (M+H) ⁺ .

EXAMPLE 967. (I S,3'R,6'R,7'S,8'E, 12"R)-6-CHLORO-7*-(( 1 ,3 -DIMETHYL - lH ^> YRAZOL-5-YL)METHOXY)-12'-ETHYL-; 4-DrHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O'^lPE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13 ^! -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-chloro-12'-ethyl-7 ^, -hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra<^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 5-(chloromethyl)-l,3- dimethyl-lH-pyrazole (Frontier Scientific Services), and the desired product, (ΙΒ,Β'Κ,ό ,Τ^,δΈ, ^-ό-οωοΓθ-Τ'^Ι^-ά^β^Ι-ΙΗ^ΓβζοΙ-β^ ηΐΘΑο )- 12 ^, -ethyl-3,4-dihydro-2H,15 ^, H-spiro[naphthalene-l,22'-

[20ioxa[13jthia[l,14jdiazatetracyclo[14.7.2.0 ³ ^0 ^!9 ' ²⁴ ipentacosa[ 8,16,18,24jtetrae n]-15'-one 13',13'-dioxide was isolated as a white solid, ^" Ή NMR (400MHz,

CD3OD) δ 8.07 - 8.01 (m, IH), 7.71 (d,J=8.6Hz, ill).7,21 (dd,J=2.2, 8.5 Hz, IH).7.11 (d, ./ .2.2 Hz, IH), 6.96 - 6.89 (m, 2H), 6.81 (d, J=1.6 Hz, IH), 5.98 (s, 1 IT), 5.92 - 5.84 (m, IH), 5,61 (dd, J=8.8, 15.3 Hz, IH), 4.44 id.,/ 12 I Hz, IH), 4.30 (d, ,7=12,3 Hz, IH), 4.22 - 4.15 (m, IH), 4.09 (dd, ,/ 11.7.21.1 Hz, 2H), 3.87 (dd, ./ 2.9.8.6 Hz, IH), 3.81 (d, ./ 14.9 Hz, 4H), 3.73 (d, J=I3.9 Hz, IH), 3.23 (d,

2,219 ./ 1 .3 Hz, 111).2,95 (d, ./ 29.! Hz, 2H), 2.85 - 2,72 (rn, 2H), 2.48-1,90 (m, I !!!). 1.89 - 1.75 (m, 5H), 1,72 - 1.52 (m, I I I).1.46 - 1.36 (m, IH), 1,27 (d, ./ 7.4 Hz, 3H). m/z (ESI, +ve ion) 707.4 (M+H) ⁺ . EXAMPLE 968, (lS,3 ^, R,6 ^, R ₅ 7*S,8 ^, E,12 ^, R)-6-CHLORO-7 ^, -(2-(l,3-DIOXOLAN- 2-YL)ETHOXY)-12'-ETHYL-3,4-DIHYDRO-2H,15'H-

SP1RO [NAPHTHALENE- I.2.T-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1.T.13*~DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3¾,6 ^! R,7^,8T^.2 ^! R)-6-chlori 12'-e l-7'-hydroxy- 3,4-dihydro-2H,15H-spiro[naphthalene-L22'- [20ioxa|13jthia[l,14jdiazatetracyclo[14.7.2.0 ³ ^0 ^!9 ' ²⁴ ipentacosa[ 8,16,18,24jtetrae n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-(2-bromoethyl)-l,3- dioxolane (Aldrich), and the desired product, (lS,3'R,6 ^! R,7'S,8'E, J 2'R)~6-chloro- 7 ^, -(2-(l,3-dioxolan-2~yl)ethoxy)-12 ^, -ethyl-3,4-dihydiO-2H,15 ^, H- spiro I naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14,7.2,0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pe

n]"15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (400MHz,

CD3OD) 7.76 (d,■/ HA Hz, III).7.19 (dd, J=0.6, 8.2 Hz, ill).7.13 (d, ./ I.K Hz, i l l).7,01 (dd, ./ ! .0, 8.0 Hz, III).6.93 id. ,/ 8.2 Hz, IH), 6.90 - 6,86 (m, IH), 5,87 (ddd, J=6.3, 13.9, 21.3 Hz, ill).5.58 (dd, ,7=8,6, 15.3 Hz, IH), 4,09 (d, ./ 2.7 Hz, 2H), 3.99 - 3.80 (m, 9H), 3,72 - 3,55 (m, 4H), 3.49 - 3.42 (m, 1H), 3.07 (dd, J=10.2, 16.6 Hz, 1H), 2.85 - 2.72 (m, 2H), 2.52 - 2,28 (m, 4H), 2.28 - 2.06 (m, 3H), 1.98 - 1.70 (ni, 8H), 1.51 - 1.40 (m, 1H), 1.20 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 699.2 {\i · Π) .

EXAMPLE 969. (lS,3 ^, R,6 ^, R,7 ^! S,8'E,12'R)-6-CHLORO-12'-ETHYL-7'-(2-((2S)- TETRAHYDRO-2H-PYRAN-2-YLOXY)ETHOXY)-3,4-DIHYDRO-2H,15'H-

SPIRO[NAPHTHAI.ENE~l,22'-

|20jOXA| !3ΓΠ!!.\| i.!4|D!AZAT! ^;' S ^' RA( ^' YCi.()i 14.7.2.0 3. .0 9.2 |F!-N f ACOSA[8,16,18,24]TETRAEN]-15'-ONE 13 ^* ,13'-DIOXIDE AND

(lS,3'R,6¾,7'S,8¾12¾)-6 HLORO-12 ^f -F^m _J -7' 2-((2R)-TETRAHYDRO-

2H-PYRAN-2~YLOXY)ETHOXY)-3,4-DIHYDRO-2H,15'H-

SPIRO [NAPHTHALENE- 1 ,22'-

[20;|OXA[13]THIA[1,14]DIAZATCTRACYCLO[14 .2.0~3,6~ ~19,24~]PENT ACOSA[8J6,18,24]TETRAEN]~15 ^! ~ ONE 13 ',13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720, using (lS,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-chloro-12 ^, -e1hyl-7 ^, -hydroxy- 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- iH.24|tetrae n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-(2- bromoethoxy)tetrahydro-2H-pyran (Aldrich), and the desired products, a mixture of (iS,:m,6'R,7'S,8'E,i2'R)~6~chloro~12'H«

yloxy)ethoxy)-3,4-dihydi -2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa|;i3]thia[U4]diazatetra^

n]-15'- one 13', 13-dioxide and (1 S,3'R,6'R,7'S,8'E,I2'R)~6~chloro~l 2'-ethyl-7'-(2- ((2R) etrahydro-2H-pyrai-2-yioxy)ethoxy)-3,4-dihydiO-2H,15'H- spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatefra<yc^

4]tetraen]-15'- one 13',13'-dioxide was isolated as a white solid, 'HNMR

(400MHz, ( f) :()!)) 67.75 (d, ./ 8.4 Hz, 1H), 7.19 (dd,■/ 2.3.8.4 Hz, lH), 7.13 (d,■/ 2.2 Hz, Hi).7.00 (dd, ./ l.<>.8.0 Hz, III .6.94 id../ 8. ⁽ Ϊ Hz, III).6.88 (d, ,/ i 8 Hz, 1H), 5.92 - 5.84 (m, ill).5,60 (dd, ./ 8.7.15.2 Hz, III).4.66 (ddd, ,/ 23.4.5, 6.8 Hz, IH), 4.13 - 4.01 (m, 3H), 3.96 - 3,81 (m, 5H), 3.69 (d, .7=15.8 Hz, 2H), 3.61 (d, J=9.6 Hz, IH), 3.09 (dd, J=10. i, 15.4 Hz, IH), 2.88 - 2.73 (m, 2H), 2.57 - 2.28 (m, 4H), 2.18 - 2.07 (m, 2H), 2.00 - 1.71 (m, 10H), 1.66 - 1.53 (m, 7H), 1,52 - 1.41 (m, ΓΗ), 1.21 (t, .7=7.5 Hz, 3H). m/'z (ESI, +ve ion) 727.2 (M+H) ⁺ .

EXAMPLE 970, (1 S,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-l 2'-ETHYL-7'-(2- HYDROXYETHOXY)-3,4-DIHYDRO-2H,15'H-SPiRO[NAPHTHALENE-l,22'- [20]OXA[13]THLA[1,14]DL ZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, ! 8,24]TETRAEN] - 15"-ONE 3', 13 ^* -DIOXIDE

2,222, (lS,3 ^, R,6'R ^, S,8¾12¾)-6-chloro-12 ^, -eth l-7 ^, -(2-((2S)-tetrahydro-2H- pyran-2-yloxy)ethoxy)-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- iH.24!tetrae n]-15'-one 13',13'-dioxide (from Example 969; 4.1 mg, 5.6 μηιοΐ) was stirred at 55 °C in 2 N hydrochloric acid (2 mL, 4 mraol) / THF (2 mL) for 30 mm, and then the reaction mixture was concentrated and purified by reverse phase preparative HPLC (Gernini ^TM Prep Ci85 μτη column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to give (lS,:rR,6'R,7'S,8T;i2'R)-6-chloro-12'-ethyl-7'-(2~ hydiOxyethoxy)-3,4"dihydro-2H,15'H"Spiro[naphthalene-l,22'~

[20joxa 13]thia[l,14]diazatetracyclo[14J _^

n]-15'-one 13',13'-dioxide (2.1 mg, 3,3 μτηοΓ). ¾ NMR (400MHz, CD3OD) δ 7.74 id../ 8.6!!/. lH), 7.19 (dil.I .2.3.8.6 Hz, ill).7.13 (d, =2.2Hz, 1H), 6.99 (dd, ./ 2.0.6.3 Hz, 1H), 6.95 (d, ,/ 8.2 Hz, 111).6.87 (d, ./ i.8 Hz, 1H), 5.91 - 5.82 (m, IH), 5.65 (dd, ./ 8.6.15.8 Hz, 1H), 4.15 - 4.01 (m, 3H), 3.91 - 3,82 (m, 2H), 3.72 - 3.62 (m, 3H), 3,58 - 3.49 (m, 111).3.45 - 3.38 (m, 3,08 (dd, J=10.6, 15.5 Hz, IH), 2.84 - 2.73 (m, 2H), 2.61 - 2.48 (m, lH), 2.46 - 2.27 (m, 3H), 2.18 - 2.05 (m, 2H), 2.00 - 1.80 (m, 8H), 1.54 - 1.37 (m, IH), 1.32 (s, 2H), 1.21 (t, 7.5 Hz, 3H). m/z (EST, + ve ion) 643,2 !V! I!)

EXAMPLE 971. TERT-BUTYL (((l S,3'R,6'R,7'S,8'E,12'R)-6-CHLOR()-12'- ETHYL- 13', 13"-DIOXroO-l 5"-OXO-3, 4-DIHYDRO-2H- SPIRO[NAPHTHALENE- 1.22 ^' -

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί <Λ( ^' Υ(·ί..ΟΙ i 4.7.2. · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24 jTETRAEN] -7'-YL)OXY) ACETATE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6 ^, R,7'S,8'E,12'R)-6-chloro-12 ^, -ethyl~7 ^! iydroxy- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazate1r^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and bromoacetic acid tot-butyl ester (Alfa Aesar), and the desired product, tot-butyl (((1S,3'R,6'R,7'S,8'E,12'R)- 6-ch]oro-12'-ethyl-13 13'-dioxido-i5'-oxo-3,4-dihydro-2H-spiro[naphtha]ene- 1,22'-

[20]oxa[13]thia[l,14]diazatetra^

n]-7'-yl)oxy)acetate was isolated as a white solid. ^! H NMR (400MHz, CDCh) δ 8.08 (br. s., IH), 7.72 id../ 8.6 Hz, ill).7,20 (dd, ./ 2.3.8.4 Hz, III).7.11 id. J=2.3 Hz, IH), 6.93 (d, J=8.0 Hz, 1H), 6.90 (dd, J=1.6, 8.2 Hz, 1H), 6.83 (d, J=l.6 Hz, IH), 5.89 - 5.82 (m, IH), 5.60 (dd, J=9.0, 15.3 Hz, IH), 4.20 - 4.12 (m, ill).4,09 (dd, ./ !2.i.19.8 Hz, 2H), 3.92 - 3.81 (ra, 4H), 3,74 id../ 14.3 Hz, IH), 3,25 (d, ./ 14.1 Hz, IH), 3.03 (dd, ./ 10.2.15.3 Hz, IH), 2.85 - 2.73 (m, 2H), 2,66 - 2.57 (m, IH), 2.42 - 2.23 (m, 3H), 2.21 - 2.13 (m, IH), 2.10 - 1.81 (m, 10H), 1.53 (s, 9H), 1.26 (m, 4H). m/z (ESI, +ve ion) 713.2 (M+H)+

EXAMPLE 972. (lS,3 ^, R,6 ^, R,7 ^! S,8'E,12'R)-6-CHLORO-12'-ETHYL-7'-(2- HYDROXY-2-METHYLPROP()XY)-3,4-DIHYDR()-2H,15 ^! H- SPIRO [NAPHTHALENE- 1,22'-

2,224 [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

To a 25 -mL round-bottomed flask was added tert-butyl

(((lS.3'R,6 ^, R,7 ^, S,8¾12 ^, R)-6-(Woro-12 ^, -e l-13^13 ^, -dioxido-15 ^, -oxo-3.4- dihydro-2H-spiro[naphthalene-l,22'-

12 ⁽ j aj i |thia| I J4|dia/.alclraeycioj N.7.2 ⁽ r'-.o ¹¹ ' 'Hpemncosa|8.l ,,i8.2 j!ein!0 n]-7'-yl)oxy)acetate (from Example 971; 15.4 mg, 0.022 mmol) in 1 mL of THF at 0 °C, methyl magnesium bromide (3.0 M solution in diethyl ether,! 2.87 μί, 0.11 mmol, Aldrich) was added. After 3 h, the reaction was quenched with aq NH ₄ C1, and then 40 mL. of EtOAc was added. The organic layer was concentrated and purified through a 24 g TSCO Gold column, eluting with 0-35% EtOAc( with 0.3% HOAc) in hexane to give (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-chloro-12 ^, -et-iyl-7 ^, -(2- hydroxy-2-methylpropoxy)-3,4-dihydro-2H,15'H-spifo[naphthale ne-l,22'- [20]oxa[13]mia[l,14]diazatetTacyclo[147.2.0 ³ ^0 ^]9 ' ²⁴ ]pentacosa[8,16,18,24]tetrae nj~15'~one 13',13'-dioxide (9.5 mg, 0.014 mmol) as a white solid. ^! H NMR

(500MHz, CD3OD) δ 7.75 (d, J=8.6 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.13 (s, 1H), 7.00 (d, ./ 7.8 Hz, 1H), 6.93 (d, ./ 8.1 Hz, III .6.86 is. III .5.85 (ddd, ./ 6.6. 14.7, 21.3 Hz, 111).5.61 (dd, H 6.14,9 Hz, 1H), 4.13 - 4,00 (m, Ml).3.86 (dd, J=4A, 7.6 Hz, 1H), 3.83 (br, s., 1H), 3.68 (d, .7=13.9 Hz, 111).3,28 (dd, J=5.4, 9.0 Hz, 2H), 3.14 (d, J=9.5 Hz, 1H), 3.08 (dd, J=10.0, 15.4 Hz, IH), 2.88 - 2.73 (m, 2H), 2,59 - 2.48 (m, !!!}.2.42 (br. s„ 111).2,40 - 2,26 (m, 211).2.18 - 2.06 (ra. 2H), 2.01 - 1.79 (m, HI I ).1,74 (dd, J=9.5, 18.8 Hz, IH), 1.49 - 1.42 (m, IH), 1,25 - 1.12 (m, 9H). m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 973. 2-(((l S,3'R,6'R,7'S,8'E, 12'R)-6-CHLORO-12'-ETIWL-I3', 13'- D10XIDO-l ^' -OXO-. -DH IYDRO-2I 1-SI R0|.V\1 ^, I IT! i.\i.h\h-l.22'~

|2ujOXA| Oil ί Ι1Λ| I . I 4|ΠίΛ/Λ T! RAC YO C)! I 14.7.20 ^,' ) ^{|U !,} |PHNT.U ^' OS A[8, 16,18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLACET AMIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^! R,6 ^, R,7'S,8'E,12'R)-6-ch3oro-12'-ethyl-7'-hydiOxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'-

[20]oxa[13]thia[l,14]diazatetrac'clo[14.7.2.0 ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n|-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-chloro-N, N- dimethylacetamide (Aldrich), and the desired product, 2- (((lS,3 ^! R,6'R,7'S,8'E,12'R)-6-chloro-12'-ethyl-13V13'-dioxido- 15 ^! -oxo-3,4- dihy dro-2H-spiro [naphthalene- 1 ,22'- i;20]oxa[13]thia|;i,14]diazatetracycio|14.7.2.0 ³ - ^f \0 ^l9 - ²⁴ ]peniacosa|;8,16,18,2 n]-7'-yl)oxy)-N,N-dimethylacetamide was isolated as a white solid. ^*! H NMR

(400MHz, ( f) :()!)) 67.75 (d, ./ 8.4 Hz, IH), 7.19 (dd, ./ 2.2.8.5 Hz, IH), 7.12 (d,■/ 2.2 Hz, IH), 6.99 (dd, ./ 2.2.8.2 Hz, IH), 6.93 id../ 8.2 Hz, IH), 6.84 (d, ,/ i 8 Hz, IH), 5.94 - 5.86 (m, IH), 5,62 (dd, J=9.0, 15.3 Hz, IH), 4.13 id.,/ 5.1 Hz, 2H), 4,09 (d, J=3.1 Hz, 2H), 4,07 - 4.02 (m, IH), 3.92 (dd, ,7=3,5, 9.0 Hz, IH), 3.84 (d, J=14.I Hz, IH), 3.68 (d, J=14.3 Hz, IH), 3.29 (d.J 1 ! Hz, IH), 3.10 i dd. ./ 10.6. 15.7 Hz, IH), 3,04 (s, M l ). 2.97 (s, M l ). 2.84 - 2.72 (m, 2H), 2.60 (dq, .7=3.4, 9.1 Hz, IH), 2.48 - 2.28 (m, 3H), 2. 19 - 2,08 (m, 2H), 2.04 - 1.83 (m, 8H), 1.76 (dd, =8.8, 18.0 Hz, IH), 1.51 - 1.41 (m, IH), 1.22 (d, ./ 7.4 Hz, 3H). m/z (ESI, +ve ion) 684.4 { \ I · Π ) .

EXAMPLE 974. 2-(((l S,3'R,6 ^, R,7'S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -ETHYL-13',13'- DIOXIDO-lS'-OXO-S^-DIHYDRO- H-SPIROINAPHTHALENE-l^^- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)-N-METHYLACETAMlDE

The title compound was prepared in an analogous manner to that described in Example 720 using (l S,3¾,6 ^! R,7^,8T^.2 ^! R)-6-chk)ro-12'-etlwl-7'-hydroxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- L22'-

[20]oxa[13]thia[ l, 14]diazatetTacyclo[147.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13', 13'-dioxide (Example 422, Step 1) and 2-ehloro-N~methylacetami.de (Aldrich), and the desired product, 2-(((l S,3¾,6 ^* R,7'S,8'E,12'R)-6-chloro-12 ^! - ethyl- 13', 13'-dioxido- 15'-oxo-3,4-dihy dro-2H-spiro| naphthalene- 1 ,22'- [20]oxa[13]thia[l ,14]diazate1r^

n]-7'-yl)oxy)-N-methylacetamide was isolated as a white solid. ¾ NMR

(400MHz, CD3OD) δ 7.75 (d, ,/ 8.4 Hz, IH), 7.19 (dd, J=2.9, 8.4 Hz, IH), 7.13 (d, ,/ 2.0 Hz, IH), 6.99 (dd, ,/ i 8. 8.6 Hz, IH), 6,95 i d. ./ 8.2 Hz, IH), 6.85 (d, ,/ 1 6 Hz, IH), 5.95 - 5,86 (m, IH), 5,64 idd,. ./ 9.2. 15,3 Hz, i l l ). 4.09 (d, .7=3.5 Hz, 2H), 4.07 - 4.02 (m, IH), 3.94 - 3.89 (m, 2H), 3.88 (d, ./ 4.7 Hz, 2H), 3.69 (d,

LLL I ./ 1 .3 Hz, 111).3,10 (dd, ./ 10.0.15.5 Hz, 111).2.81 - 2.80 (ra, 311).2,67 - 2,56 (m, III).2,48 - 2.27 (m, 41! ).2.12 (dd, ,7=7,2, 14.9 Hz, 2H), 2,04 - 1.83 (m, 10H), 1.80 - 1.73 (m, IH), 1.51 - 1.37 (m, 1H), 1.22 (t, J=7.4 Hz, 3H). m/z (ESI, +ve ion) 670.2 (M+H) ⁺ .

EXAMPLE 975. (lS^'^e'R.T'S^'E T^-e-CHLORO-T'-ETHOXY- '- E^ΉYL-3,4-DIHYDRO-2H 5Ή-SPIRO| APHTHALENE-l,22 ^, -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6 ^f R,7 ^, S,8'E,12'R)-6-chloro-12 ^, -ethyl-7 ^, -hydroxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

[20ioxa|13jthia[l,14jdiazatetrac clo[14.7.2.0 ^3>6 0 ^!9 ' ²⁴ ]pentacosa[8,16

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and ethyl iodide (Fluka), and the desired product, (lS,3 ^, R,6'R,7 ^, S,8'E,12 ^, R)"6-chloi -7'-ethoxy-12'-etliyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazate1r^

n]-15'-one 13',13'-dioxide was isolated as a white solid. \H NMR (500MHz, CD3OD) 07.75 (d,■/ 8,6 Hz, III).7.19 (dd, ./ 2.0.8.3 Hz, ill).7.12 (dd, ./ 2.4. 6,8 Hz, IH), 7.00 (dd, J=2.0, 6.4 Hz, ill).6.94 (dd, J=3.9, 8,3 Hz, ill).6.87 (d, ,/ 1 Hz, IH), 5.89 - 5.82 (m, IH), 5,59 (dd, J=8.8, 15.4 Hz, ill).4.09 (dd, ./ 12.2.16.6 Hz, 2H), 4.05 ·· 3.99 (m, IH), 3.90 - 3.82 (m, 2H), 3.68 (d, J=14.2 Hz, IH), 3.54 (dd,J=6.8, 9.8 Hz, IH), 3.44 - 3.38 (m, IH), 3.08 (dd,J=l().l, 15.3

2,228 Hz, 1 1 1 ). 2.86 - 2,74 (rn, 21 1 ). 2,51 - 2,40 (m, 2H), 2.40 - 2,27 (rn, 2H), 2.17 - 2,06 (m, 2H), 2,04 - 1.66 (m, I OH ). 1.45 (t, «7=12.0 Hz, 1H), 1.18 ί id. ./ 7.3. 17. 1 Hz, 6H). m/z (ESI, +ve ion) 627.2 (M+H) ⁺ . EXAMPLE 976. (lS,3'R,6'R,7 ^f S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -ETHYL-7 ^, -(2-

PYRIDlNYLMETHOXY)-3,4-DlHYDRO-2H,15'H~SPlRO[NAPHTHALENE"

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described m Example 720 using (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E, 12 ^, R)-6-ch]oro-12 ^, -ethyl-7 ^, -hydroxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

[20]oxa[ 13]thia[l ,14]cUazatetracyc^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-(bromomethyl)pyridine, hydrobromide (Aldrich), and the desired product, (lS,3'R,6'R,7'S,8'E,12'R)-6- chloro- 12'-ethy l-7'-(2- py ri diny Imethoxy )-3 ,4-dihy dro-2H, 15 Ή-spiro [naphtha! ene- 1,22 ^« -

[20]oxa[13]thia[l, 14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentaco

n]-15'-one 13',13'-dioxide was isolated as a white solid. 'H NMR (400MHz, CDJOD) δ 8.48 (d, ./ 4.5 Hz, i l l ). 7,86 (dt, 1 .6. 7.7 Hz, 1H), 7.74 (d, ./ 8.4 Hz, I H), 7.49 (d, ,7=7,8 Hz, IH), 7.34 (dd, .7=5.1, 7.0 Hz, 1H), 7.18 (dd, .7=2.2, 8,4 Hz, IH), 7.11 (d, ./ 2.2 Hz, IH), 7.07 (d, ./ 8.4 Hz, IH), 6.95 (s, IH), 6.84 (d, J=8.0 Hz, 111).6.09 - 6.00 (m, ill).5,63 idd../ 8.8.15.1 Hz, Hi).4.62 (d =13.5 Hz, 1H), 4.51 (d, .7=13,5 Hz, H), 4,04 (d, ./ 4.! Hz, 2H), 4,02 - 3.99 (m, 3.85 (d, ./ 14.3 Hz, 111).3.64 (d, J=14.3 Hz, IH), 3.07 (dd, J=10.0, 15.1 Hz, IH), 2.84 - 2.75 (m, 2H), 2.72 (s, 2H), 2.65 - 2.40 (m, 3H), 2.29 - 2.07 (m, 3H), 2.01 - 1.72 (m, 9H), 1.49 - 1.38 (m, IH), 1 , 19 (t, ./ 7.3 Hz, 3H), m/z (EST, +ve ion) 690,2

(M+uy.

EXAMPLE 977, (1 S,3 ^, R,6 ^! R,7'S,8'E,12'R)-6-CHLORO-12 ^! -ETHYL-7 ^! ~(2- PYR1M1DIN YLMETHOXY)-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO INAPHTHALENE- i.22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3¾,6 ^! R,7^,8T^.2 ^! R)-6-chlori 12'-e l-7'-hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene-! ,22'-

[20ioxa|13jthia[l,14jdiazatetrac clo[14.7.2.0 ³ ^0 ^!9 ' ²⁴ ipentacosa[ 8,16,18,24|tetrae n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-(chloromethyl)pyrimidine (TCI), and the desired product, (lS,3 ^, R,6'R,7'S,8 ^! E,12 ^! R)-6-chloro-12'-ethyl-7'-(2- pyrimidinylmethoxy)-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- i;20]oxa[13]thia|;i,14]diazatetracyclo|14.7.2.0 ³ -^0 ^l9 - ²⁴ ]pentacosa[8,l^

nl-15'-one 13',13 ^! -dioxide was isolated as a white solid. Ή NMR (500MHz, CD :.()!)) δ 8.84 (br. s., 2H), 7.74 (d, ./ 8.6 Hz, IH), 7.46 (t, J=4.9 Hz, IH), 7.19 idd../ 2.2.8.6 Hz, IH), 7.12 Ul.,/ 2.0 H . 111).6.98 (dd,J=2.0, 8.1 Hz, ill).6,92 (d, .7=8.1 Hz, IH), 6,82 (d, 7=1.7 Hz, IH), 5.90 - 5.84 (m, 1H), 5.65 (dd, .7=8.8, 15.2 Hz, IH), 4.64 (dd, J=14.2, 27.6 Hz, 2H), 4.08 (dd, J=12.5, 17.4 Hz, 2H), 4.04

- 3.98 (m, 2H), 3.82 (d, ./ 15.4 Hz, IH), 3.67 (d, ./ 14.2 Hz, IH), 3.09 (dd, ,/ 100.15,4 Hz, H), 2,86 - 2,74 (m, 2H), 2.68 - 2.61 (m, H), 2,45 - 2,26 (m,

3H), 2,15 - 2.07 (m, 2H), 2.00 - 1,84 (m, 9H), 1,76 (dd, 7=10.5, 19.8 Hz, IH), 1.48

- 1.41 (m, IH), 1.22 (ΐ, ./ 7.5 Hz, 3H), m/z (ESI, +ve ion) 691,2 (M+H) ⁺ .

EXAMPLE 978. (IS^'R^'R 'S^U^'Ri-e-CHLORO-^'-ETHYL^'-^R)- TETRAHYDRO-2-FURANYLMETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2θ!() Λ| I 311 HI Λ| I , N |PIA/.\ Π·. f ^' RACYCf ,Oj N.7.20 ' AO ^1* " ¹ |PH\ i ACOS A [8,Ι6,18,24]ΤΕΤΡνΑΕΝ]-15'- ONE 13 ',13 '-DIOXIDE AND

(lS,3¾,6'R,7^,8 i,I2'R)-6-CHIi3RO-12'-ETHYL-7'-((2S)-TETRAHYDRO-2- R RAWiAlh Π i \Y)-3.4-DiRYPRO~2i 1. i Ί i-SPIR j \ API Π H Ai J ^' Ni - l^'- pOJOXAI jTHIA^MjDLAZATETRAi^

-15'- ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E ₅ 12 ^, R)-6-chloro-12 ^, -ethyl-7 ^, -hydroxy- 3,4-dihydro-2H,15'H-spiro|naphthalene-l,22'-

[20]oxa[.13]thia[l,.14]diazatetTacyclo[1.4.7.2.0~3,6~.0~1 9,24~]pentacosa[8,16,18,2 4]tetraen]-.15'-one 13',13'-dioxide (Example 422, Step 1) and 3- (bromomethyl)tetrahydrofuran (ChemBridge), and the desired product, a mixture of(lS,3! ,6 ^, R,7'S,8'E,12'R)-6-chloro-12 ^, -ethyl"7'"((2R) etrahydiO-2- fiu"anylmethoxy)-3,4-dihydro-2H,15'H-spiiO[naphthaIene-l,22' -

n]-15'- one 13',13'-dioxide and (lS 6Ί\ 'SβΈ^2'R 6 hlQΐQ 2 ^ί -et γ ^^ ((2S)-tetrahydro-2-furanylmethox\ -3,4-dihydro-2H,15Ή-spiro|naphthalene- 1,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'- one 13',13'-dioxide was isolated as a white solid. *H NMR (500MHz,

CD3OD) 7.75 (d,■/ 8.6 Hz, III).7.18 (dd, ./ 2.2.8.8 Hz, ill).7.12 (d, ./ 2.2 Hz, ill).7,03 (ά. I 7.3 Hz, Hi).6.91 id.,/ 76!!/.2H), 5.89 (br. s., ill).5,63 - 5,51 (m, 1H), 4.09 (dd, ./ 12.5.17.9 Hz, 211).3.88 - 3.70 (m, 6H), 3.67 (d, J=13.9 Hz, III).3.62 - 3.49 (m, 2! I ).3.49 - 3.42 (m, 2H), 3.06 (dd, J=9.G, 15.4 Hz, 1H), 2.87 - 2,73 (m, 2H), 2.56 - 2.41 (m, Mil 2.18 - 1,96 (m, 4H), 1.93 (d, 8 I Hz, 4H), 1.89 - 1.69 (m, 5H), 1,67 - 1.58 (m, 2H), 1.50 - 1.41 (m, 1H), 1,19 (t, .7=7.5 Hz, 3H). m/z (ESI, +ve ion) 683.2 (M+H) ⁺ .

EXAMPLE 979. (1S,3¾,6¾,7¾,8T;12'R)-6-CHL0R0-12'-F;THYL-7 ^, -(2-(4- MORPHOLI YL)-2-OXOETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3'R,6 ^, R,7'S,8'E,12'R)-6-chloro-12 ^, -ethyl~7 ^! "hydroxy- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazate1r^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 4-(bromoacetyi)morpholme (Aldrich), and the desired product, (lS^'J^e'R.T'S^'E.n'RVe-chloro-l^-ethyl-T- (2-(4-mo holinyl)-2-o oetho y)-3,4-dihydro-2H,15Ή-spirofnaphthalene-l,22'- [20]oxa[13]thia[U4]diazatetra^

n]-15'-one 13', '-dioxide was isolated as a white solid. ^l R NMR (400MHz, CDsOD) 57.74 (d, ./ 8.8 Hz, 1H), 7.19 (dd, ./ 2.3.8.4 Hz, III).7.13 (d, ./ 2.0 Hz, ill).7.01 (dd, ,/ 1.8.8.2 Hz, 111).6,92 (d, J=8.0 Hz, Hi).6.85 (d, i 8 Hz, III). 6.01 - 5.88 (m, IH), 5.62 (dd, J=10.6, 15.7 Hz, IH), 4.14 (d, J=2.5 Hz, 2H), 4.09 (d, ,1=3.3 Hz, 2H), 4.07 - 4.03 (m, IH), 3.93 (dd, J=3.7, 9.0 Hz, IH), 3.85 (d, ------M .9 Hz, IH), 3.74 - 3.63 (m, 6H), 3,58 (dd, ./ 4.8.12.4 Hz, 5H), 3.20 - 3.04

(m, ill).2.84 - 2.73 (m, 211).2,65 - 2.47 (m, ill).2.49 - 2.41 (m, ill).2,41 - 2.28 (m, 2H), 2.22 - 2.07 (ni, 2H), 2.04 - 1.73 (m, 8H), 1.52 - 1.40 (ni, ill).1.22 (t, ./ 7.5 Hz, Ml), m/z (ESI, +ve ion) 726.2 (M+H) ⁺ .

EXAMPLE 980. (lS,3'R,6 ^! R,7'S,8 ^, E,12 ^, R 6"CHLORO-12 ^! ~ETHYL-7 ^, -(2~

ME^ΉOXYETHOXY)-3 ₅ 4-DIHYDRO-2H,15Ή-SPIRO|NAPHTHALENE-l,22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8, 16, J 8,24]TETRAEN] -15'-ONE 13', 13 ^! -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-chloro-12 ^, -ethyl-7 ^, -hydroxy- 3,4-dihydro-2H, 15'H-spiro|naphthalene-l ,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 147,2.0 ³ - ⁶ .0 ^{! 9} - ²⁴ ]pentacosa[8 ₅ ] 6,18,24]tetrae n]-15'-one 13',13'-dioxide (Example 422, Step 1) and! -bromo-2-methoxy ethane (Aldrich), and the desired product, (18,3'Κ,6'Κ,7'8,8Έ,12'Κ)-6-ΰ1ι3θΓθ-12 ^! -6ΑνΙ-7'- (2-methoxyethoxy)-3,4-dihydro-2H, 15'H-spirornaphthalene-.l ,22'- [20]oxa[13]thia[l,14]diazatetrac c^^^

n]-15'-one 13',13'-dioxide was isolated as a white solid. ^! H MR (400MHz, CD3OD) 7.75 (d, J=8.6 Hz, I I I ). 7.19 (dd, ./ 2.2. 8.8 Hz, i l l ). 7.12 (d, ./ 2.2 Hz, IH), 7,01 (dd, ./ 1 .6. 8.2 Hz, IH), 6.94 (d, ,7=8,2 Hz, IH), 6.88 (d, J=1.6 Hz, i l l ). 5.89 (ddd, J=6.1, 13.1, 21.5 Hz, IH), 5.60 (dd, J=9.0, 15.1 Hz, IH), 4.09 (dd, ./ 1 .7. 15.3 Hz, 2H), 4.05 - 3.99 (m, IH), 3.91 - 3.82 (m, 2H), 3.69 (d, ./ 14.5 Hz, IH), 3.62 - 3.57 (m, IH), 3,53 (dd, ./ 4. 1. 8.0 Hz, 2H), 3.50 - 3.45 (m, IH), 3.38 (s, 3H), 3.08 (dd, J=10,3, 15.2 Hz, IH), 2,87 - 2,73 (m, 2H), 2.55 - 2.40 (m, 2H), 2.40 ·· 2.26 (m, 2H), 2.11 (dd, J=7.4, 15.1 Hz, 2H), 1.98 - 1.65 (m, 1 0! I ). 1.46 (t, ./ 10.9 Hz, IH), 1.20 (t, ./ 7.4 Hz, 3H). m/z (ESI, +ve ion) 657.2 { \ I · Π } ,

EXAMPLE 981. (l S,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -ETHYL-7 ^, -(2- (METHYLSULFONYL)ETHOXY)-3,4-DIHYDRO-2H, .15'H-

SPIRO[NAPHTHALENE-l,22'- 2J>4 [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using ί I S.3'R.6'R.7'S.8 ^' h. 1 2'R )-6-ch!oro- 12'-eihyi-7'-in droxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

[20]oxa[ 13]thia[l ,14]cUazatetracyclo[^^^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-

(bromoethyl)methylsulfone (Accela ChemBio), and the desired product,

(lS,3 ^, R,61 ,7 ^, S,8T,12 ^, R)-6~cWoro-12'-ethyl-7 ^, 2-(methylsulfonyl)ethoxy)-3,4 dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ^{! 9} ' ²⁴ ]pentacosa[8,] 6, 18,24]ietrae n]-15'-one 13', '-dioxide was isolated as a white solid. ¾ NMR (500MHz,

CDsOD) 5 7.75 (d, ./ 8.6 Hz, IH), 7.19 (dd, ./ 1.7. 8.1 Hz, I H), 7.12 (d, ./ 1 .5 Hz, 1 IT), 7.00 (dd, J------1.7, 8.3 Hz, IH), 6,93 (d, J=7.9 Hz, IH), 6.86 (s, IH), 5.98 - 5.90

(m, IH), 5,63 (dd, J=9.0, 15.2 Hz, IH), 4.09 (dd, ,/ 1 2 7. 17,4 Hz, 2H), 4.06 - 4.02 C m. IH), 3.93 (dd, ./ 3.4. 8.8 Hz, IH), 3.90 - 3.80 (m, 2H), 3.76 - 3.70 (m, IH), 3.68 (d, ./ 14.2 Hz, IH), 3.29 (d,■/ 14.4 Hz, 2H), 3.09 (dd, .7=10.0, 15.4 Hz, IH), 3,01 (s, 3H), 2,87 - 2.74 (m, 2H), 2.56 - 2.41 (m, 2H), 2.41 - 2.28 (m, 2H), 2.19 - 2.07 (m, 2H), 2.01 - 1.92 (m, 4H), 1.92 - 1.71 (m, 6H), 1.46 (t, ./ 1 2.0 Hz, IH), 1.21 (t,■/ 7.5 Hz, 3H). m (ESI, +ve ion) 705.2 (M+H) ⁺ . EXAMPLE 982. (((lS ¾ >¾,7'S,8'E,12'R)-6-CHLORO-12'-ETHYL-13',l 3'- DIOXIDO-15'-OXO ,4-DIHYDRO-2H-SPIRO[ ^

|2ujOXA| 1 ΙΊ !!1Λ| l.l4|! !A/Ar!-;i ^' RA( ^' Y(-l.()l i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [8,16,18,24 jTETRAEN] -7'-YL)OXY)ACETONITRILE

The title compound was prepared in an analogous manner to that described in Example 720 using

3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

i;20]oxa[13]thia|;i,14]diazatetracyclo|14 .2 ³ - ^f \0 ¹⁹ - ²⁴ ]peniacosa|;8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (Example 422, Step 1) and chloroacetonitrile (Aldrich), and the desired product, (((lS,3¾,6 ^! R,7^,8T,,12 ^! R)-6-chloro-i2'-ethyl-13',13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-L22'- [20ioxa|13jthia[l,14jdiazatetracycIo[14J.2X) ^3>6 .0 ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-7'-yl)oxy)acetonitrile was isolated as a white solid, 'Ή NMR (500MHz,

CD3OD) δ 7.74 (d, J=8.6 Hz, 1H), 7.19 (dd, J=2.0, 8.1 Hz, IH), 7.12 (d, J=2.2 Hz, ill).7.00 (dd, ,/ 2.0.8.3 Hz, IH), 6.94 (d, ./ 8.3 Hz, IH), 6.85 (d,■/ i.7 Hz, III). 6.06 - 5.98 (ns. IH), 5,64 (dd, ./ 8.H, 15.9 Hz, 111).4.27 (s, 2H), 4.08 (dd, ,/ i 1,7, 17.6 Hz, 3H), 4.02 (dd, ./ 3.2.10.3 Hz, IH), 3.87 (d, ,7=14,9 Hz, IH), 3.69 (d, ./ 14.4 Hz, IH), 3.10 (dd, J=10.5, 15.7 Hz, IH), 2.87 - 2.74 (m, 2H), 2.60 - 2.41 (m, 2H), 2.40 - 2.30 (m, 2H), 2.18 - 2.08 (m, 2H), 2.02 - 1.80 (m, 9H), 1.77 (dd, J=7,8, 16,4 Hz, H), 1,48 (d, J=43.7 Hz, IH), 1.22 it, J=7.6 Hz, 3H), m/z (EST, +ve ion) 638.2 (M R) EXAMPLE 983. (18,3'Κ,6' ,7'8,8Έ,12¾)-6-α-ίΕΟ Ο-12'-ΕΤΗΥΕ-7'- (TETRAHYDRO-2H-PYRAN-4-YLMETHOXY)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCL )[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-!5'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3'R,6'R,7'S,8'E,12'R)-6-chioro-12'-ethyl-7'-hydroxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'-

nj-15'-one 13',13'-dioxide (Example 422, Step 1) and 4- (bromomethyl)tetrahydropyran (Combi-Bl ocks), and the desired product,

(lS,3 ^, R,6 ^, R,7 ^f S,8 ^, E,12 ^, R)-6-chloro-12 ^, -ethyi-7'-(tetrahydro-2H-pyran-4- ylmethoxy)-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa{13]thia[l,14]diazatefra<yd^^

n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (500MHz, CD3OD) δ 7.75 (d, J=8.6 Hz, IH), 7.19 (dd, J=2.2, 8.6 Hz, 1H), 7.12 (d, J=2.2 Hz, HI).7.00 (dd, ./ 1.7.6.4 Hz, III).6.94 (d, ,/ 8.3 Hz, IH), 6.89 (d, ./ 1.7 Hz, ill). 5,84 - 5.78 (m, IH), 5.58 (dd, ,/ 86.15.2 Hz, IH), 4,09 (dd, ./ 12.2, 15.9 Hz, 2H), 4,04 - 3.98 (m, I Hi.3.97 - 3,91 (m, 2H), 3,85 (d, «7=14.9 Hz, IH), 3.79 (dd, J=3.9, 8.6 Hz, IH), 3.69 (d, J=14.2 Hz, IH), 3.46 - 3.39 (m, 2H), 3.31 (dd, ./ 6.6. 9.0 Hz, 4H), 3.19 (dd, ,/ 6.2.9.4 Hz, IH), 3.09 (dd, J=9.9, 15.3 Hz, IH), 2.86 - 2,74 ( m. 2H), 2.50 (dq, ./ 3.:\ 9.2 Hz, IH), 2.45 - 2,26 (m, 3H), 2. 1 1 (dd, ./ 6.6. 14.7 Hz, 2H), 1.99 - 1.84 (m, 6H), 1.84 - 1.78 (m, 3H), 1.74 (dd, ./ 9.0. 16.1 Hz, IH), 1.62 (t, J=7.8 Hz, 2H), 1.46 (t, J=12.1 Hz, IH), 1.20 (t, J=7.6 Hz, 3H). m/z (ESI, +ve ion) 697.2 ( VI I D ^' .

EXAMPLE 984. (lS,3 ^, R,6'R,7 ^! S,8 ^, E,12 ^, R)-6-CHLORO-12'-ETHYL-7 ^, -(2-(4- MORPHOLI YL)ETHOXY)-3 ₅ 4-DIHYDRO-2H, 15Ή-

8ΡΚΟ[ΝΑΡΗΊΉΑ1,ΕΝΕ-1,22'-

[20]OXA[ 13]TfflA[l,14]DIAZATETl ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |;8,16, 18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (l S,3'R,6'R,7'S,8'E,12'R)-6-chloro-12 ^! -ethyl-7'-hydroxy- 3,4-dihydro-2H,15H-spiro[naphthalene-l,22'- i H.2 ] ictrao nj-15'-one 13', 13'-dioxide (Example 422, Step 1 ) and 4-(2-bromoethyl)morpholine (Aldnch), and the desired product, ( S,3 ^f R,6'R,7'S,8'E, 12'R)-6-chloro-12'-ethyl-7'- (2-( -mo holinyl)ethoxy)-3,4-dihydro-2H,1 Ή-spiΓo[na hthalene-l ,22'-

[20]oxa[13]thiaj l,14]diazatetracydo^

n]-15'-one ! 3',13'-dioxide was isolated as a white solid. 'H NMR (500MHz,

CD3OD) δ 7.75 (d, J=9.8 Hz, IH), 7.20 (dd, J=2.4, 6.6 Hz, IH), 7.12 (d, J=2,4 Hz, IH), 7.01 (dd, ./ 1 .7. 7.8 Hz, IH), 6.95 (d, ./ 8. 1 Hz, IH), 6.84 (d, ./ 1 .7 Hz, IH), 5.98 - 5.91 ins. ill).5,66 (dd../ 8.H. 15.9 Hz, 111).4.15 - 4.00 (ra, 5H), 3,94 (dd, 3.7..9.5 Hz, 1H), 3.86 (d, ,/ 139 Hz, ill).3.83 - 3.77 (m, 2H), 3,72 - 3.64 (m, 2H), 3.47 (td, ./ 1.7.3.2 Hz, 1H), 3.41 ·· 3.36 (m, 5H), 3.29 - 3.27 (m, 1H), 3.19 (td, ./ 1.6.3.4 Hz, ill).3.09 (dd, ./ 9.8.15.2 Hz, 1H), 2.87 - 2.74 (m, 2H), 2.59 - 2,49 (m, IH), 2.49 - 2.29 (m, 3H), 2.16 - 2,06 (m, 2H), 2.02 - 1.73 (m, 9H), 1.47 (t, J=\ 1.6 Hz, IH), 1.21 (i, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 712.1 {M l!)

EXAMPLE 985, (2R)-2-(((lS,3¾,6'R,7^,8T,12'R)-6-CHLORO-12 ^, -ETHYL- 13 ^, ,13 ^, -D10XIDO-15 ^, -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ₅ 22'- pOlOXAIlSlTHIAIl.MlDIAZATETRACYCLOiM.T^.O'^.O^^lPENTACOSA

[8,16,I8,24]TETR.AEN]-7'-YL)OXY)-N,N-DIMEmYLPROPANAMIDE AND (2S)-2-(((lS,3 ^, R,6 ^, R ₅ 7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -ETHYL-13 ^, ,13 ^, -DIOXIDO- 15 ^, -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[ APHTHALENE-l,22 ^, - ^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOIMJ^.O'^.O'^lPE TACOSA

[8,16,18,24]TETRAEN]-7 ^! -YL)OXY)-N,N 3iMETHYLPROPANAMrDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-chloro-12 ^, -ethyl-7 ^, -hydro3-'- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'-

|2ίί|οχ;ιΙ I3|ihia| I. i4|di;i/aielracvci<¾| 14.7.20 ^;i '.o ^pi ipeniacosa|8.i6..i8.24i!cirac n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-bromo-N, ^* - dimethylpropanamide (ChemBridge), and the desired product, a rruxtoe of (2R)- 2-((( 1 S,3'R,6'R,7'S,8'E, 12"R)-6-chloro- 12'-ethvl- 13 ',13'-dioxido- 15'-oxo-3,4- dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazate1racyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]"7'"yl)oxy)-N,N~dimethylpiOpanamide and (2S)-2~(((1S,3'R,6 ^! R,7'S,8 ^, E,12 ^, R)~6" chloro-12'-ethyl-13' 3'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22 ^L |20jo\aj I |ihi«i| i I4|dia/aicuac> ciol 14.72. ⁽ ! ^; " O ^1' ' ⁿ jpen!acosa|K.i6J8.24jieirae n]-7'-yl)oxy)-N,N-dimethylpropanamide was isolated. ¾ NMR (400MHz, CDsOD) 57.74 (d, ./ 8.6 !!/. ill).7.21 - 7.16 Or, III).7.13 (dd../ 2.2.5.1 Hz, ill).7.06 (dd, J------1.9, 8.1 Hz, 0.6H), 7.01 - 6.92 (ra, 2H), 6,82 (dd, J=2.3, 6.5 Hz,

1H), 5.93 - 5.85 (m, ill).5,62 (dd, ./ 9.3.15.2 Hz, 0.4H), 4,32 (q, ./ 6.7 Hz, IH), 4.16 (s, IH), 4.14 - 3.93 (m, 3H), 3.90 - 3.81 (m, IH), 3.78 - 3.64 (m, Ml).3.42 (d, ./ 5.7 Hz, IH), 3.13 (s, 3H), 3.11 - 3.04 (m, IH), 2.93 (s, 3H), 2.84 - 2.74 (m, 2H), 2,56 - 2.27 (m, 3H), 2.25 - 2.06 (m, 2H), 2,04 - 1.82 (m, 6H), 1.80 - 1.66 (m, 2H), 1,50 - 1.38 (m, IH), 1.37 - 1.26 (m, 5H), 1,26 - 1.20 (m, 3H). m/z (ESI, +ve ion) 698.2 (Vl-il) .

EXAMPLE 986. (lS,3'R,6 ^! R,7'S,8 ^, E,12 ^, R)~6"CHLORO-12'"ETHYL~7 ^, ~(l,3- OXAZOL-2-YLMETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DL ZATETRACYCLO[14,7.2,0^ ⁶ .0 ¹⁹ - ²⁴ ]I ^{^} ^^ ^{^}

[ 8,16,18 ₅ 24]TETRAEN]-15'-ONE 13 ^! ,13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^! R,6'R,7'S,8'E,12'R)-6-chloro-12'-ethyl"7' iydroxy- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-(chloromethyl)oxazole (Frontier Scientific Services), and the desired product, (1S,3'R,6'R,7'S,8'E,12'R)- 6-ch]oro-12'-ethyl-7 ^f l,3<)xazoi-2-ylmethox} -3,4-dihydro-2H,15 ^f H- spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetnK^

n]-15'-one 13',13'~dioxide was isolated as a white solid. Ή NMR (500MHz, CDCb) δ 7,95 (s, IH), 7,62 (d, ./ 8.8 Hz, IH), 7,60 (s, IH), 7.11 (dd, ./ 2.2.8.3 Hz, IH), 7.06 - 7.04 (m, IH), 7.01 (d, ./ 2.2 Hz, IH), 6.83 (d, ./ 8.1 Hz, IH), 6.80 {dd.,/ i.7.8,3 Hz, IH), 6.72 id../ 1.5 Hz, IH), 5.84 - 5.74 (m, IH), 5.51 (dd, ,/ 90.15,4 Hz, IH), 4.49 id../ 13.2 Hz, IH), 4,38 (d../ 13.4 Hz, IH), 4.10 - 4.04 (m, IH), 3.98 (dd, ,7=12,2, 24.9 Hz, 2H), 3,83 (dd, J=3.7, 9.0 Hz, IH), 3.73 (d, J=15.4 Hz, IH), 3.64 (d, ./ 1-1.2 Hz, IH), 3.13 (d, ./ 14.2 Hz, ill).2.99 - 2.94 (m, 1 IT), 2.91 (dd, ,/ !O I.15.3 Hz, ill).2,75 - 2,63 (m, 211).2.49 - 2.38 (ra, ill).2,32 -2,12 (m, 3H), 2.11 -2.03 (m, IH), 2.02- 1,78 (m, 5H), 1.74 (dd, «/=1.0, 10,0 Hz, 2H), 1.57 (dd, J=9.8, 19.3 Hz, 2H), 1.34 - 1.27 (m, IH), 1.16 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 680.2 { \ I · Π } , EXAMPLE 987. (lS,3'R,6 ^! R,7 ^, S,8'E,12'R)-6-CHLORO-12 ^! -ETHYL-7'-((2- METHYL-2H-TETPvAZOL-5-YL)METHOXY)-3,4-DIHYDRO-2H,15'H- SPTRO[NAPHTH ALENE- ! ,22'-

|20i() A| 1311 HI Λ| I„ ! -I |ί)Ι.\/.νΠ: I RAC V( ^' i, 01 i -1,7.20 ^{:' i'} .0 ^li ' |Pl-:N i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE i.T.l 3'-D10XlDE

2,241

The title compound was prepared in an analogous manner to that described in Example 720 using (ISJ'R^'RJ'S^'E ^'Ri^-chloro-n'-ethyl^'-iiydroxy- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l ,14]diazate1r^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 5-(chloromethyl)-2-methyl- 2H-tetrazole (Example 957, Step 1) and the desired product,

y l)methoxy )-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetn^

n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (5( ⁾ ( ⁾ MHz, CDJOD) δ 7.75 (d, ./ 8.6 Hz, 11 1 ). 7, 19 (dd, J=2.4, 8.6 Hz, 11 1 ). 7.12 (d, ,/ 2 2 Hz, 1H), 6.98 (dd, J=2.0, 8.1 Hz, IH), 6.90 (d, J=8.3 Hz, IH), 6.83 (d, J=2.0 Hz, 1H), 5.92 - 5.86 (m, I H), 5.62 (dd, ./ H.7. 15.3 Hz, IH), 4.67 (dd, ./ 9.8. 13.7 Hz, 2H), 4,42 (s, 3H), 4, 10 - 4.02 (m, 3H), 3.93 (dd, ,/ 4 0. 8.7 Hz, IH), 3,79 (d, ./ ! 5.2 Hz, IH), 3,68 (d, J=13.9 Hz, IH), 3.26 (d, .7=14.2 Hz, IH), 3.07 (dd, J=9,8, 15.4 Hz, IH), 2.86 - 2.73 (m, 2H), 2.55 - 2.41 (m, 2H), 2.32 (dd, J=8.8, 16.4 Hz, 2H), 2.19 - 2.07 (m, 2H), 2.01 - 1.80 (m, 8H), 1.74 (dd, J= 10.8, 18.8 Hz, IH), 1.45 (d, ./ 1 1.7 Hz, IH), 1 ,23 (t, ./ 7.6 Hz, 3H), m/z (EST, +ve ion) 695.2 { V! H }

EXAMPLE 988. (l S.S'R.ffl^T'S^'^^'R^e-CHLORO-l^-ETHYL-T-iil - METHYL- 1 H-TETR AZOL-5 - YL)METHOXY)-3 ,4-DIHYDRO-2H, 15 Ή-

SPIRO[NAPHTHALENE-l,22'-

Δ2ΛΔ [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETRAC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (l S,3¾,6'R,7'S,8 ⁱ E,12 ^f R)-6-chloro-12'-ethyl-7'-hydrox} _' - 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20joxa 13]thia[ l, 14]diazatetracyc

n]-15'-one 13', 13'-dioxide (Example 422, Step 1 ) and 5-(chloromethyl)-l-methyl- lH-tetrazole (Pnnceston Bio), and the desired product, (18,3¾,6Έ,7'8,8Έ, 12¾.)- 6-cWoro-12'-ethyl-7 ^, -((l-me l-lH-tetrazol-5-yl)methoxy)-3,4-dihydro-2H,15 ^, H- spiro I naphthalene- 1 ,22'- [20]oxa[13]thia[U4]diazate1r^

n]-15'-one 13',13'-dioxide was isolated as a white solid. ¾ NMR (500MHz,

CD3OD) 7.74 (d,■/ 8,6 Hz, IH), 7.19 (dd, ./ 2.2. 8.3 Hz, IH), 7.12 (d, J=2.0 Hz, IH), 7,00 (dd, ./ 1 .7. 8. 1 Hz, IH), 6.92 id. ,/ 8.3 Hz, H), 6.84 (d, ./ 1 .2 Hz, IH), 5,98 - 5.91 (m, IH), 5.62 (dd, ,/ 9 2. 15.3 Hz, IH), 4,81 (dd, J=13.2, 28.6 Hz, 2H), 4.11 (s, 3H), 4.07 (d, J=7.1 Hz, 2H), 4.06 - 4.03 (m, IH), 4.01 (dd, J=3.9, 8.8 Hz, 1 I I ). 3.85 (d, ./ 14.9 Hz, IH), 3.67 (d, ,/ 14.2 Hz, IH), 3.28 (d, ./ 14.2 Hz,

1 IT), 3.08 (dd, ,/ i n i . 15.3 Hz, IH), 2,86 - 2,73 (m, 2H), 2.60 - 2.53 (ra, IH), 2,45 - 2,25 (m, 3H), 2.19 - 2.06 (m, 2H), 2.03 - 1 ,93 (m, 3H), 1.91 - 1.71 (m, 6H), 1.50 ·· 1.41 (m, IH), 1.24 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 695.2 (M+H) ⁺ . EXAMPLE 989. 2-(((i S,3'R,6'R,7'S,8'E, 12 ^* R)-6-CHLORO- 12'~ETHYL-I3', 13'- DIOXIDO-15 ^! ~OXO-3,4 ^IHYDRO-2H-SPIRO[NAPH ^' mALENE-],22'- |2ujOXA| 1ΉΤί!1Α| Μ4|ΠίΑ/Α Π:ΤΗΑ(Ύα.ί)Ι i 4.7.2.U ' ".i ⁾¹ '" ¹ |Ρ1·Ν I ^' ACOSA [8,16,18,24 jTETRAEN] -7'-YL)OXY)-N,N- DIMETHYLETHANESULFON AMIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^! R,6'R,7^,8T i2¾)-6-chloro-12 ^! Hithyl-7'-hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

[20]oxa[13]thia[l,14]cUazatetracyclo[^^^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and 2-chloro-N,N- dimethylethenesulfonamide (Chembridge), and the desired product, 2- (((lS,3'R,6 ^! R,7^,8¾12 ^, R)-6-cmoro-12 ^, -e 1 3 3 ^, -^oxido-15 ^, -oxo-3,4- dihy dro-2H-spiro [naphthalan e- 1 ,22'-

n]-7'-yl)oxy)-N,N-dimethylethanesulfonamide was isolated as a white solid. ¾ NMR (500MHz, CD3OD) δ 7.76 (d, ./ H.3 Hz, 1H), 7.18 (dd, ./ 2.0.8.6 Hz, 1H), 7.12 (d, ,/ 2.2 Hz, !H), 7.07 (br. s„ 111).6,93 (br. s .111).6.88 (d, ,/ HO Hz, ill). 5.99 (br. s., 1H), 5.60 (dd, J=8.4, 15.0 Hz, lH), 4.06 (dd, J=13.0, 20.1 Hz, 2H), 3.99 - 3.77 (m, 4H), 3.71 - 3.64 (m, 2H), 3.27 (t, ./ 5.9 Hz, 2H), 3.07 (dd, ./ 10.0. 15.2 Hz, 1H), 2.87 (s, 6H), 2.84 - 2,72 (m, 2H), 2.59 - 2.24 (m, 4H), 2.18 - 2,08 (m, 2H), 1 ,99 - 1.68 (m, 10H), 1 .45 (t, J=U .6 Hz, 1 1 1 ). 1 .18 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 734.2 (M+H) ⁺ .

EXAMPLE 990. (IS,3¾,6'R,7 ^f S,8'E, I 2'R)-6-CHLORO-12'-EmYL-7'-(l,3- THIAZOL-2-YLMETHOXY)-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOI M.T^.O'^.O'^lPE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (l S,3'R,6 ^f R,7'S,8 ⁱ E,12 ⁱ R)-6-chloro-12'-etlty]-7'-hydroxy- 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[ l,14]diazatetracycio[14 7 _^

n]-15'-one 13', 13'-dioxide (Example 422, Step 1 ) and 2-(chloromethyl)thiaz.ole (Chembridge), and the desired product ί I S.3'R.6'R,, 7'S.8 ^' L. ! 2 ^' R )-6-chloro- 1 2'~ ethyl-7'-(l,3-thiazol-2-ylmethoxy)-3,4-dihydro-2H,15'H-spiro [naphthalene-l,22'- i;20]oxa[ 13]thia|;i ,14]diazatetracyclo| 14.7.2.0 ³ - ^f \0 ^l9 - ²⁴ ]peniacosa|;8,16, 18,^ n]-15'-one 13',13'-dioxide was isolated as a white solid. ^*! H NMR (500MHz,

CDCh) δ 7.73 (d, J=3.1 Hz, IH), 7.54 (d, J=2.7 Hz, IH), 7.16 (dd, J=2.7, 7.0 Hz, l U l 7.10 (d, ,/ 2.0 Hz, IH), 6.97 (d, J=11.7 Hz, I H), 6.88 - 6.74 i ns. IH), 6.20 - 6,03 (m, IH), 5.6 ! (dd, ,/ 9 0. 15,4 Hz, H), 4.49 (d, ./ 13.2 Hz, IH), 4,38 i d. ,/ 1 4 Hz, I H i. 4.10 - 4.04 (m, IH), 3,98 (dd, ./ 12.2. 24.9 Hz, 2H), 3.83 (dd, J=3.7, 9.0 Hz, IH), 3.73 (d, ./ 15.4 Hz, IH), 3.64 (d, J=14.2 Hz, IH), 3.13 (d, ./ 1 .2 Hz, ! 11 ).2,99 - 2.94 (m, III).2.91 (dd, J=10.1, 15.3 Hz, ill).2,75 - 2.63 (m, 2H), 2,49 - 2.38 (m, ill).2.32 - 2.12 (m, 3H), 2,11 - 2.03 (m, ill).2.02 - 1.78 (ni, 5H), 1.74 (dd, ./ 1.0.10.0 Hz, 2H), 1.57 (dd, ./ 98.19.3 Hz, 2H), 1.34 - 1.27 {in. III).1.16 (t,■/ 7.5 Hz, 3H). m (ESI, \e ion) 696.2 (M+H) ⁺ .

EXAMPLE 991. METHYL (((ΙΒ^'Κ,ό'ί ^ ,δΈ,η'Ι^-ό-εΗίΟίΙΟ-^'-ΕΤΗΥί- 13 ^, ,13 ^, -D10XIDO-15 ^, -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l ₅ 22'-

[20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-7'-YL)OXY)ACETATE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-chloro-12'-ethyl-7 ^, -hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and methyl bromoacetate (Alfa Aesar), and the desired product, methyl (((lS,3 ^f R,6'R,7'S,8'E,12'R)-6-chloro-12'- ethyl-13',13 ^! ~dioxido~15 ^! -oxo-3,4~dihydro~2H-spiro[naphthalene-l,22'-

n|-7'-yl)oxy)acetate was isolated as a white solid. ^! H NMR (400MHz, CDCb) δ 8,01 (s, IH), 7,62 (d, J=8.6 Hz, 1H), 7.10 (dd, «7=2.2, 8,4 Hz, 1H), 7.01 (d, .7=2.2 Hz, IH), 6.87 - 6.78 (m, 2H), 6.72 (s, IH), 5.81 - 5.72 (m, IH), 5.49 (dd, J=9.0, 15.3 Hz, IH), 4.10 - 3.74 (m, 7H), 3.70 (d, ./ 2.0 Hz, 3H), 3.64 id../ 13.7 Hz, 1 IT), 3.15 (d,J=14,3 Hz, IH), 2.93 idd../ 10.3.15.4 Hz, IH), 2.77 - 2.62 (m, 2H), 2,57 - 2.38 (ra, ill).2,32 - 2.13 (m, 3H), 2,06 (dd, ,/ 75.14.8 Hz, ill).1,99 - 1.70 is 9H), 1.58 (quin, J=9.6 Hz, ill).1.31 (t, .7=12.5 Hz, 1H), 1.24 - 1.07 (m, 3H). m/z (ESI, +ve ion) 671.2 (M M) . EXAMPLE 992. (((1 S,3' ,6 ^f R,7'S,8'E,l 2'R)-6-CHLO O-l 2-ETHYL-l 3',13'- DIOXIDO-15'-OXO-3,4 3IHYDRO-2H-SPiRO[NAPHTHALENE-l,22'- [20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I8,24]TETRAEN]-7'-YL)OXY)ACETIC ACID

Lithium hydroxide monohydrate (14.0 mg, 0.334 mmol, JT-Baker) was added in a solution of methyl (((18,3'ίΙ,6¾,7'8,8Έ,12¾)-6-€ΜθΓθ-12 ^! ~6 1- 13',13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- |20jo\aj I |ihi«i| i. I4|dia/aicua > ciol Ι4.7.2.ί! ^;ί ',(! ^{1'ί n} jpen!aco a|K.i6J8.2.jjietrae n]-7'-yl)oxy)acetate (from Example 991; 5.9 mg, 0.008 mmol) in 1 mL THF and 1 mL of MeOH. The rection mixture was heated to 50 °C for 1 h, LC-MS showed the reaction went completely.1 N HC1 soluiton was added until the pH of the reaction mixture was about 1-2.20 mL of EtOAc as added. The organic layer was concentrated and purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5 μηι column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give (2R)-2 ((lS,3 ^, R,61,7 ^, S,8T,121)~6~cWoro-12'-ethyl-13 3'"dioxido-15'-oxo-3,4- dihy dro-2H -spiro [naphthal ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatefra^ 24/ n]-7'-yl)oxy)propanoic acid (9.5 mg, 0,014 mraol). ¾N R (400MHz, CD3OD) δ 7.76 (d, ,7=8,4 Hz, IH), 7.19 (dd, .7=2.3, 8.4 Hz, IH), 7.12 (d, «7=2.2 Hz, 1H), 7.02 (dd, ./ 2.0.8.0 Hz, 1H), 6.93 - 6.87 (m, 2H), 6.00 ·· 5.90 (m, IH), 5.57 (dd, J=8.9, 15.2 Hz, IH), 4.07 (d, ./ 2.0 Hz, 2H), 4.05 - 3.99 (m, IH), 3.91 - 3.80 (m, 2H), 3,76 - 3.71 (m, IH), 3.76 - 3.71 (m, IH), 3,67 (d, ./ ! 3.9 Hz, ill).3.64 - 3.55 (m, IH), 3,06 (dd, ./ 10.1.15.0 Hz, IH), 2.83 - 2.73 (m, 2H), 2,51 (t, .7=6.5 Hz, 2H), 2.48 - 2.24 (m, 4H), 2.22 - 2.06 (m, 2H), 1.97 - 1.69 (m, 9H), 1.45 (t, ./ I 1.9 Hz, IH), 1.26 - 1.12 (m, Ml ⁾ , m/z (ESI, +ve ion) 657.2 ( +H) ⁺ . EXAMPLE 993. METHYL (((lS,3'R,6 ^, R,7 ^, S,12 ^, R)-6-CHLORO-12 ^, -ETHYL-

13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO|NAPHTHALENE- l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[16,18,24] TRIEN] -7'- YL)OXY) ACETATE

The title compound was prepared in an analogous manner to that described in Example 925, Step 1, using methyl Hi ! S.3 ^' R.6'R.7'S.8T. j 2 ^" R)-6-chloro- 12'~ ethy i- 13 ', 13 '-dioxido- 15 '-oxo-3,4-dihydro-2H-spiro [naphthalene- 1,22'- [20ioxa[13jthia[l,14jdiazatetracyclo[14.7.2.0 ^3>6 .0 ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae nj~7'~yl)oxy)acetate (Example 991), and the desired products, methyl

(((ISJl ^'RJ'S/ 'RVe-chloro-n'-ethyl-lS' S'-dioxido-lS'-oxo-S^-dihydro- 2H-spir o| naphthalene- 1 ,22'-

|2 ⁽⁾ joxsij I3|t ia| U |dia/aielracveioj 14.7.20 ^{; !} '.0 ^|1! ipcniacosa| 16. i 8.24|iricn|- 7'~y])oxy)acetate was isolated. Ή NMR (400MHz, CD3OD) δ 7,64 (d, J=8.4 Hz, IH), 7.08 (dd, ,7=2,2, 8.5 Hz, IH), 7.02 (d, J=2.2 Hz, 1H), 6.98 - 6.93 (m, 2H), 6.83 (d, ./ 8.2 Hz, 1H), 4.03 ·· 3.91 (m, 4H), 3.76 - 3.67 (m, 2H), 3.60 (s, 3H), 3.57 (d,■/ 14.! Hz, ill).3.43 - 3.37 (m, III .3.05 (dd, ./ 7.3.15.6 Hz, ill).2.76 - 2,62 (m, 2H), 2,58 - 2.49 (m, IH), 2,32 (br. s,, IH), 2.06 - 1.94 (m, 2H), 1.89 - 1,74 (m, 6H), 1.71 - 1.55 (m, 4H), 1.49 - 1.23 (m, 7H), 1.08 (t, J=7.4 Hz, 3H). m/z (ESI, +ve ion) 673.2 (M R) .

EXAMPLE 994. (((lS,3 ^! R,6'R,7'S,12¾)-6-CHLORO-12'-E HYL-13',13'- DIOXIDO- 15'-QXO-3,4-DIHYDRQ-2H-SPiRQ[NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIMJ^.O'^.O^^lPE TACOSA

[16,18,24]TRIEN]-7'-YL)OXY)ACETIC ACID

The title compound was prepared in an analogous manner to that described in Example 925, Step 1 using (((lS,3 ^, R,6'R,7 ^, S _s 8 ^, E _s 12 ^, R)-6-chloro-12 ^, -ethyl- 13', 13'-dioxido-.l 5'-oxo-3,4-dihy dro-2H-spiro| naphthalene- 1, 22'- [20]oxa[13]1hia[l,14]diazatetra<yclo[14.7.2.0 ³ ^0 ¹⁹ - ²⁴ ]pentacosa[8,16,18 n]-7'-yl)oxy)acetic acid (Example 992), and the desired product,

(((lS,3 ^! R,6 ^, R,7'S,12 ^, R)-6-ch3oro-12 ^! -ethyl 3^13 ^, -dioxido-15'-oxo-3,4-dihydro- 2H-spiro| naphthalene- 1 ,22'- 8.24|trieni- 7'-yl)oxy)acetic acid was isolated. Hi NM (4()()MHz, CD3OD) 07.75 (d, ./ 8. Hz, IH), 7.19 (dd, ./ 2.2.8.6 Hz, IH), 7.12 (d, ,/ 22 Hz, IH), 7.08 - 7.04 (m, 2H), 6.94 id. ,/ 7.4 Hz, IH), 4.11 (s, 2H), 4.06 (d, ./ 6.1 Hz, 2H), 4,08 - 4,03 (m, 2H), 3.89 - 3.78 (m, 2H), 3,70 (d, J=13.9 Hz, IH), 3.53 (br. s,, IH), 3.17 (dd, J=8,0, 15.1 Hz, IH), 2.86 - 2.73 (m, 2H), 2.63 (d, J=5.3 Hz, IH), 2.41 (br. s., IH), 2.10 (dd, ,/ 6.2.14.0 Hz, 2H), 2.00 - 1.85 (m, 5H), 1.84 - 1.68 (m, 4H), 1.64 - 1.54 (m, 2H), 1,50 id./ 8.6!!/.411).1.44 - 1.31 (m, IH), 1.18 (t, J=7.4 Hz, 3H), m/z (ESI, +ve ion) 659.2 {V! Hi

EXAMPLE 995. 2-(((l S,3'R,6'R,7'S,8'E, 12*R)-6-CHLORO- 12'~ETHYL-13', 13'- DiOXIDO-15 ^! ~OXO-3,4 ^IHYDRO-2H-SPIRO[NAPH HALENE-l,22'- |2ujOXA| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2,0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24 jTETRAEN] -7'-YL)OXY)-N-(2- (DIMETHYLAMINO)ETHYL)ACET AMIDE

To a 25 -mL round-bottomed flask was added (2R)-2- ίίί 1 S.:V .6'K.7'S.8 ^' :. ! 2 ^' K }-6-chloro- 12'-e!hyl- 1 '.1 T-diovdo- ! ^' -oxo-3.4- dihy dro-2H-spiro [naphthalene- 1 ,22'~

i;20]oxa[13]thia|;i,14]diazatetracyclo|14.7.2,0 ³ - ^f \0 ^l9 - ²⁴ ]peniacosa|;8,16,l^ n]-7'-yl)oxy)propanoic acid (from Example 992, 5,0 mg, 7.6 μηιοΐ) and HATU (7.0 mg, 18.2 μηιοΐ) in 1 mL of DMF, Nl,Nl ^» dimethylethane-l,2-diamiiie (2.0 mg, 22.8 μιηοΐ) was added. The reaction mixture was stirred at rt for 2 h, and then purified by reverse phase preparative HPLC (Gemini™ Prep Cie 5 μίη column; Phenornenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give 2- (((lS,3'R,6 ^! R,7^,8¾12 ^, R)-6-cmoro-12 ^, -e l-13 3 ^, -^oxido-15 ^, -oxo-3,4- dihy dro-2H-spiro [naphthalene- 1 ,22'- |20jo\aj I |ihia| i . I4|dia/aieinse} cioi 1 ,7,2.0 ^; "O ^1' ' ⁿ jpen!acosa|K.16.1 .24 jieirae n]-7'-yl)oxy)-N-(2-(diniethylaniino)ethyl)acetamide (4.1 nig, 5.6 μιηοΐ) as a white solid. Ή NMR (400MHz, CD ₃ ()D) δ 7.75 (d, ,/ H.6 Hz, 1H), 7.20 (dd, ./ 2.2.8.5 Hz, IH), 7.13 (d, ,/ 22 Hz, 1H), 7.01 (dd, ./ 2.0.8.2 Hz, 1H), 6,95 (d, ./ 8.2 Hz, 1H), 6.84 (d, .7=1,6 Hz, H), 5,93 (id.,/ 7 !.13.6 Hz, IH), 5.65 (dd,J=9.0, 15.1 Hz, IH), 4.10 (dd, J=12,l, 17.8 Hz, 2H), 4.06 - 4.01 (m, IH), 3.95 (dddd, J=13.1, 15.3, 19.2, 24.8 Hz, 3H), 3.85 (d, ./ 14.9 Hz, !!!).3.71 (d,■/ 12.5 Hz, IH), 3.65 (d, J=0.8 Hz, 2H), 3.3 (m, 2 H overlap with solvent), 3.10 (dd, J= 10.5, 15.4 Hz, IH), 2,98 (s, 6H), 2,85 - 2.76 (m, 2H), 2.66 - 2,58 (111, IH), 2,50 - 2.40 (m, I Hi. 2.36 (dd, ./ 8.6.16.0 Hz, 2H), 2.17 - 2.07 (m, 2H), 2.02 - 1.84 (m, 9H), 1.78 (dd, ./ 9.8.17.6 Hz, IH), 1.51 - 1.43 (m, IH), 1.22 (l, ./ 7.4 Hz, 3H), m/z (ESI, +ve ion) 727.2 (M+H) ⁺ .

EXAMPLE 996. 2-(((lS ₅ 3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -ETHYL-13 ^, ,13'- DIOXIDO- 15 ^* -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[N APHTHALENE- 1 ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM ^.O^^O^^lPENTACOSA

|;8,16,18,24]TETRAENj-7'-YL)OXY)-N-(2-HYDROXYETOYL)ACETAM IDE

The title compound was prepared in an analogous manner to that described in Example 995 using (2R)-2-(((lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-chloro-12 ^, -ethyl- 13',13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- 5 |20jo\aj I |ihi«i| i . I4|dia/aieuae> ck>j U. Z^.O^' O ^1' ' ⁿ jpen!acosa|H.i .i .24jieirae n]-7'-yl)oxy)propanoic acid (from Example 992) and 2-aminoethanol (Aldrich), and the desired product, 2-(((18,3¾,6¾,7'8,8Έ,12·Κ)-6-ΰωοΓθ-12 ^! -6ΛνΙ-13',13 ^! - dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae0 n]-7 ^, -yl)oxy)-N-(2-hydroxyethyl)acetamide was isolated as a white solid. ¾ MR (400MHz, CD3OD) δ 7.75 (d, ,/ 8.4 Hz, IH), 7.19 (dd,■/ 2.2.8.5 Hz, IH), 7.13 (d, 2.2 Hz, IH), 7.00 (dd, ,/ i 8.8.0 Hz, IH), 6,94 id../ 8.4 Hz, IH), 6.85 (d, ./ 1.8 Hz, IH), 5.96 - 5.88 (m, IH), 5.66 (dd, ./ 9.2.15.5 Hz, IH), 4.14 - 4.02 (m, 3H), 3.97 - 3.92 (m, IH), 3.90 (d, ./ 3.5 Hz, 2H), 3.88 - 3.83 (m, IH), 3.72 - 3.625 (m. Mi).3,41 - 3.37 (m, 2H), 3.10 (dd, J=10.0, 15.3 Hz, IH), 2,87 - 2,73 (m, 2H), 2.62 (dd, J=4,3, 10.0 Hz, IH), 2,47 - 2,28 (m, 3H), 2.17 - 2.07 (m, 2H), 2,04 - 1.84 (m, 9H), 1.78 (dd,J=9.0, 18.0 Hz, IH), 1.51 - 1.42 (m, IH), 1.22 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 700.2 (M+H)+. 0 EXAMPLE 997. (lS,3'R,6 ^, R,7'S,8 ^, E,12 ^, R)-7 ^! -(2-(l-AZETIDINYL)-2- OXOETHOXYi-e-CHLORO-n'-ETHYL^^-DIHYDRO^HJS'H- SPTRO[NAPHTH ALENE- 1 ,22'-

|2θ!() Λ| I 311 HI Λ| I ,, ! -I |ί)Ι.\/.νΠ: i R Λί ^' ΥΓί, Ol i -1,7.20 ^: ' ⁱ '.0 ^li ' |Pi-:N i ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

S

2,252,

The title compound was prepared in an analogous manner to that described m Example 995 using (2R)-2H((lS,3¾ VR7^,8 ^! E,12 ^! R)~6-chloro-12'-e l- 13',13 ^, -dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22 '- [20]oxa[13]thia[l,14]cUazatefracy^

n]-7'-yl)oxy)propanoic acid (from Example 992) and azetidine (Fluka), and the desired product (1 S,3¾,6'R,7'S,8*E, 12¾ -7 ^, -(2-(l~azetidmyl)-2-oxoethox} -6- chloro-12'"ethyl-3,4"dihydro-2H,15'H"SpiiO[naphthalene-l,22' - [20]oxa[13]thia[l,14]diazate1ra^

nj~15'~one i V. ! .V-dioxidc was isolated as a white solid, ^" Ή NMR {400. VII!/.

CD3OD) δ 7.75 (d, J=8.4 Hz, IH), 7.19 (dd, J=2.2, 8.6 Hz, IH), 7.13 (d, 7=2.2 Hz, IH), 7.00 (dd, ,/ I.' ⁾ .8.1 Hz, IH), 6.94 (d, J=8.0 Hz, IH), 6.84 (d,■/ 1.8 Hz, IH), 5.94 - 5.87 (ra, IH), 5,62 (dd, ./ 8.9, 15.0 Hz, IH), 4.32 (t, ./ 7.8 Hz, 2H), 4.11 - 4.02 (m, 5H), 3.95 (d, .7=6.5 Hz, 2H), 3.91 - 3.82 (m, 2H), 3.69 (d, ,7=14,3 Hz,

IH), 3.10 (dd, ./ 104.15.3 Hz, ill).2.85 - 2.77 (m, 2H), 2.61 - 2.53 (m, ill).2.47 -2.29 (m, SH), 2.17 - 2,08 (m, 2H), 2.04- 1.82 (m, 9H), 1.77 (dd, .7=9.3, 17.9Hz, IH), 1.46 (t, .7=14.0 Hz, IH), 1,22 (t, .7=7,5 Hz, 3H). m/z (ESI, +ve ion) 696,2 ( M I i )

EXAMPLE 998. (1 S,3'R,6'R,7'S,8'E, 12'Κ)-6-€ΗίΟΚΟ-7"-(2-(4,4-ΟΙΡίυθΚΟ- I -P 1 P ! . H ) 1 \ ^ ^' I . }-2-( ) X ( ) I Ί I K)XY)-i 2'-i: 11 !Yi. -3.4-1)11 ΙΥ!)Κ()-2Π. !5'| 1- SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETRAC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 995 using (2R)-2-(((lS ⁱ R,6'R,7'S,8'E,12'R)-6-ch]oro-12'-ethyl- 13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,2 2'- [20]oxa[13]tMa[l,14]cUazate1rac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)propanoic acid (from Example 992) and 4,4-difluoropiperidine hydrochloride (Oakwood), and the desired product, (1S,3'R,6'R,7'S,8'E,12'R)~6~ cMoro-7'-(2-(4,4-difluoro-l-piperidinyl)-2-oxoethoxy)-12'-et hyl-3,4-dihydro- 2H, 15'H-spiroj naphthalene- 1 ,22 ^, - [20]oxa[13]thia[l,14]dia atetτacyclo[147.2 ³ · ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae nj-15'~one 13', 13'-dioxide was isolated as a white solid, Ή NMR (400MHz,

CDsOD) 57,75 (d, ./ 8.4 Hz, 1H), 7.19 (dd, ./ 2.2.8.6 Hz, III).7.13 (d, ./ 2.0 Hz, ill).7.00 (dd, ,/ 2.·;··.8.4 Hz, 111).6,94 (d, ./ 7.8 Hz, Hi).6.84 (d, i 6 Hz, III). 5.96 - 5.88 (m, ill).5,63 (dd, J=9A, 15.4 Hz, 1H), 4.16 (dd, J=13.5, 17,8 Hz, 2H), 4.09 (d, =3.1 Hz, 2H), 4.07 - 4.02 (m, ill).3.93 (dd, J=3.4, 9.1 Hz, 1H), 3.85 (d, ./ Hz, IH), 3.74 - 3.69 (m, 2H), 3.68 - 3.61 (m, 3H), 3.37 (s, 4H), 3.10 (dd, ./ ! 0.5, 15.4 Hz, IH), 2.88 - 2.73 (ra, 211).2.62 - 2,54 (m, IH), 2.47 - 2,28 (m, 3H), 2.17 - 1.83 (m, 11H), 1.77 (dd, .7=5.9, 14.9 j]/. IH), 1.46 (t, .7=11.6 Hz, IH), 1.22 it../ 7.4 Hz, 3H). m/z (ESI, +ve ion) 760.2 (M+H) ⁺ . EXAMPLE 999. (1 S,3'R,6'R,7 ^! S,8'E, 12'R)-6-CHLORO-7'-(2-(l , 1 -DIOXIDO-4- TmOMORPHOLINYL)-2-OXOETHOXY)-12'-ETHYL-3,4-DIHYDRO- 2H, 15'H-SPIR0|;NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 995 using (2R)-2-(((l S,3 ^, R,6'R,7*S,8 ^, E,12 ^, R)-6-chioro-12 ^, -ethyl- 13', 13'-dioxido-.l 5'-oxo-3,4-dihydro-2H-spiro| naphthalene- 1, 22'- [20]oxa[13]thia[l, 14]diazatetra<y^

nj-7'-yl)oxy)propanoic acid (from Example 992) and thiomorpholine 1,1-dioxide (from TCI), and the desired product, ( i S,3'R,6'R,7'S,8'E,12'R)-6-chloro-7 ⁱ -(2-(l , l- dioxido-4 .hiomorpholinyl)-2-oxoethoxy)-12'-ethyl-3,4-dihydro-2H,15'H- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetracycfo[14.7 _^

n]-15'-one 13', 13'-dioxide was isolated as a white solid, ^" Ή NMR (400MHz, CD3OD) δ 7.75 (d, .7=8.4 Hz, 1H), 7.19 (dd, J=2,2, 8.5 Hz, 1H), 7.13 (d, J=2.2 Hz, IH), 7.00 (dd, ./ 1 .8. 7.2 Hz, 1H), 6.94 (d, ./ 8.2 Hz, 1H), 6.84 (d, ./ i .8 Hz, M l ). 5.98 - 5.90 ( ns. i l l ). 5,64 (dd, ./ 9.2. 15.3 Hz, 1 1 1 ). 4.20 (dd, .7=13.9, 20,9 Hz, 2H), 4.13 - 3.98 (111, 7H), 3,95 (dd, J=3.6, 9.1 Hz, IH), 3.85 (d, ,7=15, 1 Hz, IH), 3.69 id. J------14, 1 Hz, 1H), 3.21 (br. s„ 2H), 3.18 - 3.07 (m, 3H), 2,87 - 2.73 (ra,

21 \ ).2.63 - 2.52 (m, ill).2,48 - 2.28 (m, 31!).2.18 - 2.07 (m, 2H), 2,03 - 1.75 (m, 10H), 1.50 - 1.42 (m, Ml).1.23 (t, ./ 7.5 Hz, 3H). m/z (ESI, +ve ion) 774.2 { \ I · Π } .

EXAMPLE 1000. 2-(((lS,3'R,6'R,7 ^, S,8'E,12'R)-6-CHLORO-12'-ETHYL"13',13'- DIOXlDO-15'-OXO-3,4-DlHYDRO-2H-SPIRO[NAPHTHALE E-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-7'-YL)OXY)-N-4-PYRIDINYLACETAMIDE

The title compound was prepared in an analogous manner to that described in Exampie 995 using i2R)-2-(((lS,3'R,6 ^f R,7'S,8Ti, i2'R)-6-chloro-12'-e ]- 13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,2 2'-

[20]oxa[13]tMa[l,14]cUazate1rac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)propanoic acid (from Example 992) and 4-aminopyridine (Acros), and the desired product, 2-(((lS,:rR,6'R,7'S,8T;,12 ^! R)-6-chioro-i2 ^, -ethyl-13',i3'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-L22'- [20joxa 13]thia[l,14]diazatetracycfo[½

n]-7'-yl)oxy)-N-4-pyridinylacetamide was isolated as a white solid. ¾ NMR

(500MHz, CD3OD) δ 8.65 (br. s., 2H), 8.22 (br. s., 2H), 7.75 (d, J=8.6 Hz, ill). 7.18 (dd, ./ 2.3.8.4 Hz, ill).7.13 (d, ./ 2.0 Hz, 1H), 7.00 (dd, ,/ 2.i ⁾ .7.8 Hz, 1H), 6.94 id. ,/ 7.8 Hz, !!!}.6.84 (d, I.? Hz, ill).5,97 - 5,89 (m, 111).5.69 (dd, J=9.3, 15.2 Hz, 1H), 4.17 (s, 2H), 4.09 (dd, .7=12.0, 18,3 Hz, 2H), 4.03 (dd, .7=3.3, 8.9 Hz, lH), 4.00 (dd, ./ 6.8.13.0 Hz, 1H), 3.86 (d, ./ 15.4 Hz, 1H), 3.69 (d, ./ 14.4 Hz, III).3.25 - 3.18 ins.1H), 3.12 (dd, ./ 1(U.15.3 Hz, 1H), 2,87 - 2.74 (m, 2H), 2.72 - 2.63 (m, 1H), 2,47 - 2.26 (m, 3H), 2.10 (td, ./ 7.2.14,5 Hz, 2H), 2.02 - 1.89 (m, 6H), 1.85 (dd, J=6,l, 12.2 Hz, 2H), 1,79 (dd.7 0.5,, 18.1 Hz, 1H), 1.51 - 1.43 (m, 1H), 1.20 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 733.2 {M ID

EXAMPLE 1001. 2-(((lS,3'R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^, -ETHYL-13 ^, ,13'- DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALE E- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL)[14.7.2.() ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)-N-(2-METHOXYETHYL)ACETAMIDE

The title compound was prepared in an analogous manner to that described in Example 995 using (2R)-2-(((lS,3 ^! R,6¾,7'S,8T;,i2¾.)-6-chloro-12'Hithyl- 13',13 ^, -dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22 '- [20]oxa[13]thia[l,14]cUazatefracy^

n]-7'-yl)oxy)propanoic acid (from Example 992) and 2-m.ethoxyethanamine (Aldnch), and the desired product, 2- lS,3' ,6 ^, R,7 ^, S,8Έ,12'R)-6-chloro-12 ^, - ethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthale ne-l,22'- [20]oxa[.13]thia[l,.14]diazatetTacyd n]-7'-yl)oxy)-N-(2-methoxyethy])acetarnide was isolated as a white solid, ^] H NMR (400MHz, CD3OD) δ 7.64 (d, J=8,4 Hz, IH), 7.08 (dd, .7=2.2, 8.5 Hz, 1H), 7.02 (d, J=2.Q Hz, 1H), 6.88 (dd, =2.0, 8.4 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.73 (d,■/ i.8 Hz, Hi).5.85 - 5.76 (m, ill).5.54 (dd, J=8.9, 15.0 Hz, ill).4.03 - 3.92 (m, 3H), 3.82 (dd, ,/ 3.8.9.1 Hz, ill).3,78 (d, ./ 2.3 Hz, 2H), 3.76 - 3.73 (m, IH), 3,58 (d, ./ 13.9 Hz, IH), 3.42 - 3.31 (m, 4H), 3.28 (s, 3H), 2.99 (dd, .7=10,2, 15.3 Hz, IH), 2.73 - 2.63 (m, 2H), 2.55 - 2.45 (m, IH), 2.37 - 2.17 (m, 3H), 2.07 - 1.95 (m, 2H), 1,92 - 1.73 (m, 9H), 1.67 (dd, .7=8,4, 16.8 Hz, IH), 1,40 - 1.31 (m, IH), 1.11 (t, «7=7.5 Hz, 3H). m/z (ESI, +ve ion) 714.4 {.V! !O .

EXAMPLE 1002. 2-(((lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-12'-ETHYL-13',13'- DIOXIDO-15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TfflA[l,14]DiAZATETRACYCLO[14.7,2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA

[8 ₅ 16,18,24]TETRAEN]-7 ^, -YL)OXY)-N-(2-(4- MORPHOLINYL)ETHYL)ACETAMIDE

The title compound was prepared in an analogous manner to that described in Example 995 using (2R)-2-(((lS,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-chloro-12'-ethyl- 13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naph1h

|20i<^ai l3|ihKi| U-i|dia/:Ueiracyeio| N.7.2 O'^.o ¹ " ' ^l !pen[acosa|8.!6..i8.24i!cirac n]-7'-yl)oxy)propanoic acid (from Example 992) and 4-(2-aminoethyl)morpholine

(Avocado Research), and the desired product, 2~(((1S,3'R,6 ^! R,7'S,8 ^! E,12 ^! R)~6- chloro-12'"ethyl-13',13'"dioxido-15'-oxo-3,4"dihydro-2H~spir o[naphthaleiie-l,22'- [20joxa[13]thia[l,14]diazatetracy o[14.7.2 _^

n]-7'-yl)oxy)-N-(2-(4-morpholmyl)ethyl)acetamide was isolated as a white solid, ¾ NMR (400MHz, CDsOD) δ 7.75 (d, =8.6 Hz, 1H), 7.20 (dd, J=2.3, 8.4 Hz, ill).7.13 (d, ./ 2.2 Hz, 1H), 7.02 (dd, ./ 1.9.8.1 Hz, Hi).6.95 (d, J=8.0 Hz, III). 6.84 (d, J=l,8Hz, 1H), 5.96 -5,89 (m, 1H), 5.65 (dd,J=9.1, 15,2 Hz, ill).4.10 (dd, .7=12.1, 18.6 Hz, 3H), 4,05 - 3.99 (m, 2H), 3.99 - 3.89 (m, ill).3,85 (d, J=15.5 Hz, 2H), 3.73 - 3.64 (m, 4H), 3.38 - 3.32 (m, 4H overlap with solvent), 3.10 (dd, ./ 10.6.15.5 Hz, 2H), 2.87 - 2.74 (m, 2H), 2.62 id. J=9.0 Hz, 1H), 2.43 (br, s., III).2.40 - 2.29 (m, 2H), 2.12 (dd, J=8.0, 15.3 Hz, 2H), 2.04 - 1.83 (ra, 9H), 1,79 (dd, J=8.6, 17.4 Hz, 1H), 1.52 - 1.43 (m, ill).1.22 (t, .7=7.5 Hz, 3H), m/z (ESI, +ve ion) 769.4 (M+H) ⁺ .

EXAMPLE 1003. ETHYL (((lS,3'R,6'R,7'S,8'E,12'R)-6-CHLORO-12'-ETHYL- 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- [20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8,16, 18,24] TETRAEN]-7'-YL)OXY) ACETATE

To a 25-mL round-bottomed flask was added (1 S,3'R,6'R,7'S,8'E,12'R)-6- chloro-l2'-e1hyl-7'-hydroxy-3,4-dihydro-2H,l5 ^, H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l ,14]diazaie^

n]-15'-one 13',13'-dioxide (Example 422, Step 1 ; 14 mg, 0.023 mmol) and ethyl diazoacetate (4.84 μΐ, 0.047 mmol, Aldrich) in DCM (779 μΐ) and then rhodium (II) acetate dimer (1.0 mg, 2.3 μηιοΐ, Aldrich) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and purified by reverse phase preparative HPLC (Gemini™ Prep Cis 5 μιη column; Phenomenex, Torrance, CA; gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1 % TFA, 30 min method) to give ethyl

(((l S,3¾.,6 ^! R,7'S,8¾12 ^! R)-6-emoro^

dihydro-2H-spiro[naphthalene-l,22'-

[20joxa[13]thia[ l, 14]diazatetracycfo[14 _^

n]-7'-yl)oxy)acetate as a white solid (10.8 mg, 0,016 mmol). ¾ NMR (400MHz, CD3OD) δ 7.75 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.2, 8.4 Hz, IH), 7.13 (d, J=2.2 Hz, 1H), 7.00 (dd, ,/ 2.2. 8.2 Hz, IH), 6.94 (d, J=8.0 Hz, H i ). 6.84 (d,■/ 1 .8 Hz, I I I ). 5.92 - 5.84 (ra, IH), 5,61 (dd, J=9.0, 15,3 Hz, IH), 4.23 (q, ,/ 7 2 Hz, 2H), 4.09 (dd, .7=12.3, 14.9 Hz, 2H), 4,03 (s, 3H), 3.95 (dd, ./ 3.6. 8,9 Hz, IH), 3.84 (d, ./ 14.7 Hz, IH), 3.68 (d, J=13.9 Hz, IH), 3.10 (dd, J=10.2, 15.3 Hz, IH), 2.84 - 2.73 (m, 2H), 2.64 - 2,55 (m, IH), 2.47 - 2.26 (m, 31 1 ). 2.19 - 2,06 (m, 2H), 2.00 - 1 ,73 (m, I OH), 1.46 (t, J=l 1 .4 Hz, IH), 1.31 i l 7. 1 Hz, 3H), 1.22 it, J=7.4 Hz, 3H). m/z (ESI, +ve ion) 685.2 (M+H) ⁺ .

EXAMPLE 1004. METHYL (2R)-2-(((l S ₅ 3 ^, R,6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12'- ETHYL- 13 ', 13 '-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAt^MlDIAZATETRACYCLOI MJ^.O'^.O^^lPE TACOSA

[8, 16,18,24]TETRAEN]-7'-YL)OXY)PROPANOATE AND METHYL (2S)-2- (((lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E, 12 ^, R)-6-CHLORO-12 ^, -ETHYL-13 ^, ,13'-DIOXIDO-15 ^, -OXO- 3,4-DIHYDRO-2H-SPIR()[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[8,16, 18,24]TETRAEN]-7'-YL)OXY)PROPANOATE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3'R ₅ 6 ^, R,7 ^, S,8 ^, E, 12 ^, R)-6-chloro-12 ^, -e1hyl-7 ^, -hydroxy- 3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[U4]diazatetracy^^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and methyl 2-bromopropionate (Sigma), and the desired product, a mixture of methyl (2R)-2- (((l S,3¾,6 ^! R,7^,8¾12¾)-6-ehk^^

dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]mia[ l, 14]diazatetTacyclo[1 7.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-7'-yl)oxy)propanoate and methyl (2S)-2-(((l S,3'R,6'R,7'S,8'E,12'R)-6-chloro- 12'-ethyl-13 ^, ,13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[l ,14]cUazatetracyclo^

n]-7'-yl)oxy)propanoate was isolated as a white solid, ^*! H NMR (400MHz,

CDsOD) δ 7.75 (d, .7=8.6 Hz, IH), 7.19 (dd, J=2.2, 8.5 Hz, 1H), 7.13 (d, J=2.2 Hz, H I ). 6.99 (dd, ./ 2.3. 8.0 Hz, I I I ). 6.95 - 6.93 (m, IH), 6.96 - 6.91 (m, I I I ). 6.82 (d, i X Hz, IH), 5.91 - 5.84 (ra, IH), 5,61 (dd, J=9.3, 15.4 Hz, IH), 4.10 (dd, ,/ 1 2 3. 15,5 Hz, 2H), 4.03 (dd, .7=4.9, 11.9 Hz, 2H), 3.97 (dd, «7=3.5, 9,2 Hz, IH), 3.84 (d, J=14.9 Hz, IH), 3.71 (s, 3H), 3.68 (d, J=14.7 Hz, IH), 3.09 (dd, J=10.3, 15.4 Hz, IH), 2.87 - 2.73 (m, 2H), 2.56 - 2.48 (m , IH), 2.44 - 2.35 (m, IH), 2.33 - 2.08 (m, 4H), 1.99 - 1 ,82 (m, 8H), 1.76 (dd, .7=9.4, 18.2 Hz, ! H), 1.50 - 1.41 (m, IH), 1.35 (d, ,7=6,7 Hz, 3H), 1.22 (t, .7=7,5 Hz, 3H). m/z (ESI, +ve ion) 685,2 (M+H) ⁺ . EXAMPLE 1005. (2R)-2-(((lS,3'R,6'R,7'S,8 12 ^, R)-6-CHLORO-12 ^, -ETHYL- 13 ^, ₅ 13 ^, -DIOXIDO-15 ^, -OXO-3 ₅ -DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22 ^, - |2ujOXA| !3jTIUA| U4|niA/A I:TRA( ^' YCl.Oj i 4.7.2.0 " ) ¹ *" ¹ |PLNTACOSA [8,16,18,24]TETRAEN]-7 ^, -YL)OXY)PROPANOIC ACID AND (2R)-2- (((lS,3 ^, R ₅ 6 ^, R,7 ^, S,8Έ 2 ^, R)-6-CHLORO-12 ^, -E^ΉYL-13 ^3 ^, -DIOXTDO-^5 ^, -OXO- 3,4-DIHYDRO-2H~SPIRO[NAPHTHALENE-l,22 ^! ~

[20]OXA[13]TH1A[1 4]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16,I -7'-YL)OXY)PROPANOIC ACID

The title compound was prepared in an analogous manner to that described in Example 992 from a mixture of methyl (2R)-2-(((lS ₅ 3'R,6'R,7 ^, S,8'E,12'R)-6~ chloro-I2'-ethyl-13V13'-dioxido-15'~oxo-3,4-dihydro-2H-spiro |naphthalene-l,22'- [20]oxa[13]thia[l,14]cUazatetracyclo^

n]-7'-yl)oxy)propanoate and methyl (2S)-2-(((lS,3'R,6'R,7'S,8'E,12'R)-6-chloro- 12'-ethyl- 13', 13'-dioxido- 15'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)propanoate (Example 1004), and the desired product, a mixture of (2R)-2-(((lS,3 ^, R,6'R,7 ^, S,8 ^, E,12 ^, R)-6-chloro-12 ^, -ethyl-13 ^, ,13 ^, -dioxido-15 ^, -oxo-3,4- dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]cUazatetracyclo^

n]-7'-yl)oxy)propanoic acid and (2R.)-2-(((l S,3'R,6 ⁱ R,7'S,8'E,12'R)-6-chloro-l 2'- ethyl-13 ^, ,13 ^, -dioxido-15 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-L22'-

[20ioxa|13jthia[l,14jdiazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-7'-yl)oxy)propanoic acid was isolated as a white solid. ^] H NMR (400MHz, CDJOD) δ 7.76 (d, ./ 8.7 Hz, 111).7,19 (dd../ 2.3.8.4 Hz, 111).7.13 (d, ,/ 22 Hz, 1H), 6.99 (dd, ,7=1.8, 8.2 Hz, IH), 6,94 (d, J=8.2 Hz, 1H), 6.82 (d, .7=1.8 Hz, IH), 5.95 - 5.79 (m, IH), 5.64 (dd, J=9.3, 15.2 Hz, IH), 4.24 (q, J=6.6 Hz, IH), 4.08 (d, =2.9 Hz, 211).4.05 (t, ,/ 6.3 Hz, IH), 3.98 (ddd,■/ 3.3.7.2, 13.9 Hz, 2H), 3,85 (d, ./ 1 .3 Hz, IH), 3.68 (d, ,/ 14.1 Hz, IH), 3.10 (dd, 10.2.15,3 Hz, IH), 2,88 - 2.67 (m, 2H), 2.64 - 2.47 (m, IH), 2,42 - 2.34 (m, IH), 2.33 - 2.21 (m, 2H), 2.19 - 2.06 (m, 2H), 2.01 - 1.80 (m, 8H), 1.76 (dd, J=9.2, 18.4 Hz, IH), 1.50 - 1.42 (m, IH), 1.37 id. J=6.8 Hz, 3H), 1,21 (t, ./ 7.5 Hz, 3H). m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 1006. (2R)-2-(((lS,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-CHLORO-12'-ETHYL- 13 13 ^, -DIOXroO-15 ^, -OXO-3,4-DIHYDRO-2H-SPTRO| AP^m^ALE3SlE-l,22 ^, -

[20]ΟΧΑ[13]ΊΉΙΑ[!,14]ΟΙΑΖΑΤΈΤ^^

[8, 16, 18,24]TETRAEN]-7'-YL)OXY)PROPANAMIDE AND (2S)-2- (((1 S,3'R,6 ^f R,7'S,8 i,12'R)-6-CHLORO-l 2-ETHYL-l 3 ^f ,13'-DTOXIDO-15'-OXO- 3 ,4 -DIHYDRO-2H-SPIRO [NAPHTHALENE- 1.22'-

|2ίί!<)ΧΛ| 1 ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i..()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24 jTETRAEN] -7'-YL)OXY)PROP AN AMIDE

The title compound was prepared in an analogous manner to that described in Example 995 using a mixture of (2R)-2-(((lS,3'R,6'R,7'S,8'EJ2'R)-6-chioro- 12'-ethyl- 13', 13 ^! -di oxido- 15'-oxo-3,4-dihy dro~2H-spiro[naphthalene- 1,22'- [2Q]oxa[13]thia[l,14]diazaie^

n]-7'-yl)oxy)propanoic acid and (2R)-2-(((lS,3'R,6 ^! R,7'S,8'E,12 ^! R)~6-chloro-12'- ethyl-13' 3'-dioxido-15'"Oxo-3,4~dihydro-2H~spiro[naphthalene-L22'- [20joxa[13[thia[l,14[diazatetracycfo[l^ _^

n]-7'-yl)oxyjpropanoic acid (Example 1005) and ammonia (7 N solution in methanol, Aldrich), and the desired product, a mixture (2R)-2- (((IS^l ^'R 'S^'EJ^Ri-e-chloro-n'-et yl- lS'-dioxido-lS'-oxo-S^- dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)propanamide and (28)-2-(((18,3'ί ,6¾,7'8,8Έ,12¾)-6-ΰΜθΓθ-12 ^! ~ ethyl-13',13'-dioxido-15'-oxo-3,4-cUhydro-2H-spiro[nap

n]-7'-yl)oxy)propanamide was isolated as a white solid. ¾ NMR (400MHz, CDsOD) 57.65 (d, ./ 8.4 Hz, 1H), 7.10 (dd, ./ 2.2.8.5 Hz, III).7.03 (d, ./ 2.2 Hz, ill).6.90 (dd, J------1.9, 8.1 Hz, 111).6,84 (d, J=8.0 Hz, Hi).6.78 (d, i 8 !!/. III).

5.82 - 5.74 (m, ill).5,57 (dd, J=9.1, 15.2 Hz, 1H), 4.00 (d, J=23 Hz, 2H), 3.97 - 3.87 Cm.2H), 3.77 (dd, .7=5.9, 13.3 Hz, 2H), 3.60 (d, ./ 14.1 Hz, 1H), 3.00 (dd, ,7=10.2, 15.3 Hz, 1H), 2.79 - 2.64 (m, 2H), 2.49 - 2,41 (m, 1H), 2.34 - 2.13 (m, Ml).2,07 - 1.98 (m, 2H), 1.92 - 1.73 (m, 9H), 1,68 (dd, J=10.6, 18.4 Hz, 111).1.41 - 1.30 (m, 1H), 1.25 (d, .7=6.7 Hz, 3H), 1.11 (t, .7=7.5 Hz, 3H). m/z (ESI, +ve ion) 670.2 (M+H) ⁺ .

EXAMPLE 1007. METHYL 3-((( 1 S ,3 'R,6'R, T S, 8Έ, 12'R)-6-CHLORO - 12'- ETHYL-13',13'-DIOXIDO-15'-OXO-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[l,14]DIAZATEmACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)PROPANOATE

2,264

The title compound was prepared in an analogous manner to that described in Example 720 using (lS^'R^'R-T'S^'EJl'^-e-chloro-^'-elhyl-T'-hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra<yd^^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and methyl 3-bromopropanoate (Aldrich), and the desired product, methyl 3-(((lS,3'R,6'R,7'S,8 ^! E,12 ^! R)-6-chloro- 12'-ethyl- 13', 13'-dioxido- 15'-oxo-3,4-dihy dro-2H-spiro[naphthalene- 1,22'- ISJJjtctrao n]-7'-yl)oxy)propanoate was isolated as a white solid. Ή NMR (400MHz,

CD3OD) δ 7.75 (dd, ,/ 8,2 Hz, !!!}.7.23 - 7,16 (m, !!!).7.15 - 7.08 (m, 1H), 7,00 (d, ./ 7.8 Hz, Ui).6.94 (dd, ./ 2.2.8,0 Hz, 1H), 6.87 (s, 1H), 5.91 - 5,80 (m, III).5.60 (dd, J=7.0, 16.8 Hz, 1H), 4.19 - 3.98 (m, 3H), 3.87 (d, J=13.3 Hz, 2H), 3.74 - 3.68 (m, 4H), 3.11 (dd, ./ 9.4.15.7 Hz, ill).2.82 (br. s., 2H), 2.55 (t, ./ 5.3 Hz, 211).2.46 (br, s., 21 \) 2.38 - 2.27 (m, 2H), 2.12 (d, ./ 8.8 Hz, 2H), 2.08 - 2.03 (m, 6H), 1,96 (br. s .3H), 1.84 - 1.66 (m, 3H), 1,50 - 1,42 (m, 1H), 1.21 is.../ 6.7 Hz, 311:·. m/z (ESI, +ve ion) 685.2 !Vl I!) . EXAMPLE 1008, 3-(((lS,:rR,6'R,7'S,8'E,12'R)-6-CHLORO-12'-ETHYL-13',13 ^! - DIOXIDO-15 ^, -OXO-3 _s 4-DmYDRO-2H-SPIRO| APHm LENE-l _: ,22 ^, - [20]OXA[13]THIA[l 4]DIAZATCTRACYCLO|;i4.7.2.0 ³ ' ⁶ .0 ^l9 - ²⁴ ]PENTACOSA

[8,16,18,24]TF;TRAEN]-7'-YL)0XY)PR0PAN0IC ACID

The title compound was prepared in an analogous manner to that described in Example 992 using methyl 3-(((lS,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-chloro-12 ^, -ethyl- 13V13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22 '-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)propanoate (Example 1007), and the desired product, 3- (((18,3Έ.,6¾,7 ,8Έ,12¾)-6~^

dihy dro-2H-spiro [naphthalene- 1 ,22'- [2Q]oxa[13]thia[l,14]diazatetra^^

n]-7'-yl)oxy)propanoic acid was isolated as a white solid. ^l H NMR (400MHz, CD3OD) δ 7.76 (d, J=8.4 Hz, IH), 7.19 (dd, J=2.3, 8.4 Hz, 1H), 7.12 (d, J=2,2 Hz, 1H), 7.02 (dd, J=2.0, 8.0 Hz, ill).6.91 - 6.88 (m, 2H), 5.99 - 5.90 (ni, ill).5.57 (dd, M 15.2 Hz, IH), 4.11 - 4.00 (m, Ml).3.91 - 3.80 (m, 2H), 3.76 - 3.70 (m, IH), 3,67 (d, ./ 1 .9 Hz, !!!).3.62 - 3.55 (m, IH), 3.06 (dd, ./ 10.1 , 15.0 Hz, IH), 2,83 - 2.73 (m, 2H), 2.54 - 2.42 (m. Hi).2,40 - 2.27 (m, 2H), 2.18 - 2.08 (m, 2H), 1.97 - 1.69 (m, 9H), 1.45 (t, J=l 1.9 Hz, 2H), 1.19 (t, ./ 7.5 Hz, 3H). m/z (ESI, +ve ion) 671.2 (M+H) ⁺ . EXAMPLE 1009. ETHYL 3~(((18,3¾,6 ^! ί ,7'8,8Έ,12Ί )"6"€ΉίΟΙ Ο-12 ^! " ETHYL-B' S'-DIOXIDO-lS'-OXO-S^-DIHYDRO-ffl-

SPIRO [NAPHTHALENE- ,22'-

[20]OXA[13]THL [1,14]DIAZATEII ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18,24] TETRAEN j -7 '- YL)OXY)PROP AN O ATE

The title compound was prepared in an analogous manner to that described m Example 720 using (lS ^! R )¾,7^,8T i2¾ -6-chloro-12'Hithyl~7 ^! -hydroxy- 3,4-dihydro-2H, 15 Ή-spiro [naphthalene- 1 ,22'~

[20]oxa[13]thia[l,14]cUazatetracyclo^^^

n]-15'-one 13',13'-dioxide (Example 422, Step 1) and ethyl acrylate (Aldrich), and the desired product, ethyl S-^lSJ'R^l^T'S^'E _/ n^-e-chloro-n'-ethyl- ^ '- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracyclo[i47,2.0 ³ ' ⁶ 0 ^!9 ^

n]-7'-yl)oxy)propanoate was isolated as a white solid. ¾ NMR (400MHz,

CD3OD) δ 7.63 (d, J=7.7 Hz, IH), 7.08 (dd, J=2.2, 8.4 Hz, IH), 7.01 (d, J=2.0 Hz, IH), 6.89 (dd, ,/ 2.0.8.2 Hz, IH), 6.83 (d, ./ 7.6 Hz, IH), 6.85 - 6.80 (m, IH), 6.76 (d, ,7=1.8 Hz, IH), 5.79 - 5,71 (m, IH), 5.47 (dd, «/=8.6, 15,3 Hz, IH), 4.05 (q, J=7.0 Hz, 2H), 3.99 (d, J=3.1 Hz, 2H), 3.96 - 3.90 (m, IH), 3.76 (d, J=2.9 Hz, IH), 3.77 - 3.75 (m, IH), 3.75 - 3.70 (m, IH), 3.64 - 3.60 (m, IH), 3.57 (d, ./ 12.7 Hz, IH), 3,48 (id, J------6.2, 9.7 Hz, IH), 2,97 (dd, J=10.0, 15.3 Hz, IH), 2.77 - 2.61

(m, 2H), 2.43 (t, ./ 6,3 Hz, 2H), 2.40 - 2.17 (m, 4H), 2,01 (qd, ./ 7.!,, 14.3 Hz, 2H), 1.90 - 1.75 (m, 6H), 1.75 - 1.56 (m, 3H), 1.35 (t, ./ i i.9 Hz, IH), 1.17 (t, ./ 7.0 Hz, Ml).1.10 (t, ./ 7.5 Hz, 3H). m/z (ESI, +ve ion) 699.2 { M · Π ) .

EXAMPLE 1010. 3-(((lS,3'R,6 ^, R,7'S,8'E,12'R)-6-CHLORO-12 ^, -ETHYL-13 ^, ,13'- DI()XIDO-15'-OX()-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLPROPANAMIDE

The title compound was prepared in an analogous manner to that described in Example 995 using 3-(((lS,:rR,6'R 'S ₅ 8T;i2 ^! R)-6-chloro-12'-ethyl-13V13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-L22'-

[20]oxa[I3]thia[l,I4]diazatetTacyclo[1 7.2.0 ³ ^0 ^]9 ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)oxy)propanoic acid (Example 1008) and dimethylamine (40 wt % solution in water, Acros), and the desired product, 3-(((lS,3'R,6'R,7'S,8'E,12'R)~6-chloro- 12'-ethy 1- 13', 13'-dioxido- 15'-oxo-3,4-dihy dro-2H-spiro| naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazate1r^

n]"7'"yl)oxy)-N,N-dimethylpi panaiTiide was isolated as a white solid. ¾ NMR (400MHz, CD3OD) δ 7.64 (d, ,/ 8.6 Hz, IH), 7.08 (dd,■/ 2.3.8.4 Hz, 1H), 7.02 (d, ,/ 23 Hz, 111).6.89 (dd, ,/ 20.8.2 Hz, ill).6,83 id../ 8.2 Hz, ill).6.77 (d, J=l,8 Hz, 1H), 5.79 - 5.71 (m, IH), 5,47 (dd, J=8.6, 15,3 Hz, IH), 3.98 (d, ,7=2,9 Hz, 2H), 3.96 - 3.88 (m, IH), 3.78 - 3.71 (m, 2H), 3.66 - 3.60 (m, IH), 3.57 (d, ./ 14.3 Hz, IH), 3.48 (td,J=6.5, 9.4 Hz, !!!).2.99 (s, 3H), 2.96 {dd.,/ 9. .15,7 Hz, IH), 2.85 (s, 3H), 2.73 - 2.60 (ra, 211).2.50 (dt, ,/ 2.2.6.5 Hz, 2H), 2.41 -

2.17 (m, 4H), 2,05 - 1,95 (m, 2H), 1.90 - 1.62 (m, OH), 1.35 (t, ,/ i 14 Hz, IH), 1.10 (t, J=7.5 Hz, 3H). m/z (ESI, +ve ion) 698.2 {M ID

2,268 EXAMPLE 1011 . (lS,3 ^, R ₅ 6 ^, R,7 ^, S,8 ^, E,12 ^, R)-6-CHLORO-12 ^* -ETHYL-7 ^, -(3-(4- MORPHOLINYL)-3-OXOPROPOXY)-3.4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI M.T^.O'^.O^^lPE TACOSA

[8J 6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 995 using 3-(((l S,3'R,6'R,7'S,8'E,12'R)-6-chloro-12'-ethyI-13', 13'- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- I SJJj tctrao n|-7'-yl)oxy)propanoic acid (Example 1008) and morpholme, and the desired product, (lS,3 ^, R ₅ 6 ^, R,7 ^, S,8Έ, 12 ^, R)-6-ch]oro-12 ^, -e1hyl-7 ^, -(3-(4-moφho]in l)-3- oxopropoxy)-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]tMa[l,14]cUa-?atetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one 13',13'~dioxide was isolated as a white solid. ^" TI NMR (400MHz,

CD3OD) δ 7.75 (d, J=8.4 Hz, IH), 7.19 (dd, J=2.2, 8.4 Hz, IH), 7.13 (d, J=2,2 Hz, IH), 7.00 (dd, =l ,9, 8.1 Hz, IH), 6.94 (d, J=8.0 Hz, IH), 6.87 (d, J=1.6 Hz, IH), 5.90 - 5.83 (m, I H), 5.59 (dd, ./ H.6. 15.1 Hz, IH), 4.09 id. ./ 2.7 Hz, 2H), 4.07 - 4,01 (m, IH), 3.85 (dd, J=3.9, 8,6 Hz, 2H), 3.77 - 3.72 (m, IH), 3.72 - 3.64 (rn, 6H), 3,64 - 3.58 (m, 5H), 3.08 (dd, .7=10,3, 15.4 Hz, IH), 2,87 - 2,73 (m, 2H), 2.63 (t, ./ 6 3 Hz, 2Π ). 2.53 - 2.28 (m, 4H), 2. 8 - 2.07 (m, 2H), 2.01 - 1.73 (m, 9H), 1.46 (t J=12.2 Hz, 1H), 1.21 (t, J=7.4 Hz, 3H). m/z (ESI, +ve ion) 740.2 (M+H) ⁺ .

EXAMPLE 1012. (1 S,3 ^! R,6 ^, R,7'S,8'E,12'S)-6-CHL()RO-7'-HYDR()XY-12 ^! -(2- (TRIFLUOROMETHOXY)ETHYL)-3 ,4-DIHYTJRO-2H, 15 Ή- SPIROpSfAPHTHALENE-l^^-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, I 8,24]TETRAENl-15'-ONE 13', 13'-D )XIDE OR

(lS,3'R,6 ^! R,7'S,8'E,12'R)~6-CHLORO-7 ^! ~HYDROXY-12'-(2~

(TRIFLUOROMETHOXY)ETHYL)-3 ,4-DIH YDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ '« 0 ¹⁹ ^ ⁴ ]PE TACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13', '-DIOXIDE

STEP 1 : (3S)-l-(TRIFLUOROMETHOXY)-6-HEPTENE-3-SULFONAMIDE AND (3 R)- 1 -(TRIFLUOROMETHOXY)-6-HEPTENE-3-SULFONAMIDE

The title compound was prepared in an analogous manner to that described in Intermediates EE20 and EE202 using N,N-bis(4- methoxybenzyl)pent-4-ene-l -sulfonamide (Intermediate EE 19) and l-bromo-2- trifluoromethoxy -ethane (Oakwood), and the desired products (3S)-1- (rrifluoromethoxy)-6-heptene-3-sulfonarnide and (3R)-1 -(trif]uoromethoxy)-6- heptene-3-sulfonamide were isolated as a racemic mixture.

STEP 2. (1 S,3'R,6'R,7 ^, S,8 ^, E,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-12 ^, -(2- (TRJFLUOROMETHOXY)ETHYL)-3,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE-l,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~1S'~0NE 13", 13 -DIOXIDE or ( 1S,3'R,6'R,7'S,8'E,I2'R.)- 6-CHLORO-7 ^, -HYDROXY-12 ^, -(2-(TRlFLUORO ETHOXY)ETHYL)-3 _s 4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - i 5'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 719, Steps 1 and 2, using (S)-6'-chloro-5-(((lR,2R)-2-((S)-l- hydrox\'allyl)c 'clobutyl)methyl)-3 ^, ,4,4 ^, ,5-tetrahydro-2H,2 ^, H- spiroj benzoj bj [ 1,4 |oxazepine-3, -naphthaIene]-7-carboxyiic acid (Intermediate AA1 IA ) and a mixture of (3S)-.l -(tri ^" fluoromethoxy)-6-heptene-3-sulfonamide and (3R)-l-(trifluoromethoxy)-6-heptene-3-sulfonamide from Step 1 , and the desired products, (l S,3 ^, R,6 ^, R,7 ^, S,8'E,12'S)-6-chloro-7'-liydroxy-I2'-(2- (trifluoromethox\')ethyl)-3,4-dihydro-2H,15'H-spiro[naphthal ene-l,22'-

[20]oxa[I 3]thia[ l, I 4]diazatetTacyclo[1 7.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13', 13 '-dioxide or (lS,3'R,6'R,7'S,8'E,12'R)-6-chloro-7'-lwdroxy-12'-(2- (trifluoromethoxy)etliyl)-3,4-dihydro-2H,15'H-spiro[naplitha lene-l,22'- i;20]oxa[ 13]thia[l ,14]diazatetracyclo| 14.7.2.0 ³ -^0 ^l9 - ²⁴ ]pentacosa[8,16, l ^ n]-15'-one 13',13'~dioxide (first eluting major peak out of preparative reverse phase HPLC) was isolated. ^l H NMR (400MHz, CDsOD) δ 7.75 (d, J=8.4 Hz, 1H), 7.19 ίόά.,Ι 22.8.5 Hz, IH), 7,12 id../ 2.3 Hz, IH), 7.01 (dd,J=2.0, 8,2 Hz, IH), 6.94 (d, ,7=8,6 Hz, H), 6.89 (d, .7=1.8 Hz, IH), 5,91 - 5,82 (m, IH), 5.78 - 5.71 (m, IH), 4.43 - 4.30 (m, 2H), 4.30 - 4.23 (m, IH), 4.21 (dd, J=3.6, 8.1 Hz, IH), 4.09 (dd,J=l 1.9, 14.7 Hz, 2H), 3.86 (d, ,7=14.9 Hz, IH), 3.68 (d, ,7=14.1 Hz, IH), 3,08 (dd, ./ ! 0.0, 15.3 Hz, IH), 2.84 - 2.73 (ra, 2H), 2,54 -2,17 (m, 6H), 2. 3 (d, ,/ 1 -I 3 Hz, I Hi.1.99 - 1,79 (m, 7H), 1,74 (dd, 7=9.0, 18,2 Hz, IH), 1.50 - 1.41 (m, IH), 1.37 - 1.29 (m, IH). m/z (ESI, +ve ion) 683.2 (M R) .

EXAMPLE 1013. (lS,3 ^, R,6 ^! R,7'S,8 ^! E,12 ^! R)~6-CHLORO-7 ^! ~HYDROXY-12'-(2~ (TRIFLUOROMETHOXY)ETHYL)-3 ,4-DIH YDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PEOTACOSA

[8,16,18,24]IETRAEN]-15'-QNE 13',13 ^! -D10X1DE or (18,3 ^! ί ,6¾,7'8,8Έ,12'8)- 6-CHLOR()-7'-HYDROXY-12'-(2-(TRi:FLUOR()METI- )XY)ETmX)-3,4- DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'- [20]QXA[13]miA[l,14]DL^

[8, 16, 18,24]TETRAEN]-15'-ONE i.T.i 3'-DIOXIDE

The title compound was obtained as a single isomer (second eluting peak) from the reverse phase preparative HPLC in Example 1012, ^! H NMR (500MHz, CDsOD) δ 7,74 (d, .7=8.6 Hz, IH), 7,19 (dd, J=2.3, 8.4 Hz, IH), 7.15 (br. s., IH), 7.13 (d, J=2.2Hz, IH), 7.10 (dd, =1.7, 7.8 Hz, IH), 6.94 id../ 8.1 Hz, IH), 5.92 - 5.83 (m, 111}.5.67 (dd,J=6.2, 15.3 Hz, IH), 4.92 (s, IH), 4.84 (s, IH), 4.39 - 4,27 (m, 2H), 4.17 - 4.02 (m, 3H), 3,96 - 3,82 (m, IH), 3.64 (d, .7=13,9 Hz, IH), 3.52 - 3.46 (ra, 1H), 2,87 - 2.74 (m, 2H), 2.62 - 2.29 (m, 4H), 2.21 - 1.99 (m, 4H), 1.96 - 1.75 (m, 7H), 1.56 (i, .7=9.0 Hz, 1H). m/z (ESI, +ve ion) 683,2 iV! H)

EXAMPLE 1014. (1 S,3'R,6'R,7'S,8 ^! E, 1 O'R, 12'R)-6-CHLORO-7'-HYDROXY- 10^12'-DIMETHYL-3,4-DIHYD O-2H,15H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE AND EXAMPLE 1015. (1 S,3'R,6'R,7'S,8'E, 10'S, 12'R)-6-CHLORO-7'-HYDROXY- 10', 12'-DTMETHYL- 3,4 >IHYDRO-2H,15 ^! H-SPIRO[NAPH ^' mALENE-l,22'- |2ujOXA| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί <Λ( ^' Υ(·ί..ΟΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

Example 1014 Example 1015 STEP 1: (2S,4R)-4-METHYLHEX-5-EN-2-OL AND (2S,4S)-4-METHYLHEX- 5-EN-2-OL

To l-methyl-2-propenylmagnesium chloride (0.5 M soiution in THF, 87 ml, 43.4 mmol) was added slowly to the solution of (S)-2-methyloxirane (1.2 g,

20.66 mmol) in Et ₃ 0 (21 ml) at -10 to - 18 °C in a 500 niL single-necked round- bottomed flask at over . The resulting mixture was allowed to slowly warm up to it and stirred at rt overnight. The reaction mixture was thoroughly cooled in an ice hath before slowly quenched with ice cold saturated ammonium chloride. This mixture was further diluted with more ether and ice cold water. The organic layer was concentrated and purified through a 120 g ISCO Gold column, eluting with 0- 35% EtOAc in hexane to give a mixture of (2S,4R)-4-methylhex-5-en-2-ol and (2S,4S)-4-methylhex-5-en-2-oi (1.83 g, 16.03 mmol).

STEP 2: (2R,4R)-4-METHYLHEX-5-ENE-2-SULFON AMIDE AND (2R,4S)~4~ METHYLHEX-5-ENE- -SULFON AMIDE

The title compound was prepared according to the general procedure described in Intermediate EE22, Steps 3-6 using a mixture of (2S,4R)-4- methylhex-5-en-2-ol and (2S,4S)-4-methylhex-5-en-2-ol in Step 3.

STEP 3 : (S)-6'-CHLORO-5-((( 1 R,2R)-2-(( 1 S,4R,6R,E)- 1 -HYDROXY-(4R)- METHYL-6-S ULFAMOYLHEPT-2-EN- 1 -YL)CYCLOBUTYL)METHYL)- 3 ^f ,4,4',5-TETRAHYDRO-2H 2'H-SPIRO[BENZO[B] [ 1 ,4] OXAZEPINE-3, 1 "- NAPHTHALENE] -7-C ARBOXYLIC ACID AND (S)-6'-CHLORO-5-((( 1 R,2R)- 2-((l S,4R,6R,E)- 1 -HYDROXY-(4S)-METHYL-6-SULFAMOYLHEPT-2-EN - 1 - YL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO-2H,2'H- SPIRO [BENZO [B ] [ 1 ,4] OXAZEPINE-3 , 1 '-NAPHTHALENE] -7-C ARBOXYLIC ACID

To a 50 mL single-necked round-bottomed flask were added (S)-6'-chloro- 5-(((lR,2R 2~((S,E)-l~hydroxyh^

tetrahy dro-2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (Intermediate AA12A; 92 mg, 0.18 mmol), a mixture of (2S,4R)-4- methylhex-5-en-2-ol and (2S,4S)-4-methylhex-5-en-2-ol (160 mg, 0.90 mmol) from Step 2 above, and AcOH (3.607 ml,). The flask was stirred under nitrogen for 10 min before Hoveyda-Grabbs catalyst II (39,6 mg, 0.063 mmol) was added, The resulting mixture was stirred under Argon at it for a period of 5 h. The mixture was concentrated and the crude mixture was loaded onto a 40 g ISCO Gold column and subjected to combi-flash column chromatography, eluting with 0-70 % EtOAc EtOAc( with 0.3% HO Ac) in hexane to give a mixture of the desired products, and then futher purified by reverse phase preparative HPLC (Gemini™ Prep Cjg 5 μηι column; Phenomenex, Torrance, CA: gradient elution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give (S)-6'-chloro-5-(((l R,2R.)-2-((l S,4S,6R,E)-l-h droxy-(4R)- methyl-6-sulfamoylhept-2-e^

2H,2'H-spiro[benzo[b] [ 1 ,4] oxazepine-3, 1 '-naphthalene] -7-carboxylic acid (32.2 mg, 0.052 mmol, second eluting major peak and (S)-6'-chloro-5-(((lR,2R)-2- ((1 S,4S,6R,E)-l-hydroxy-(4S)-methyl-6-sulfamoylhept-2-en-l - yl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benz o[b][l,4]oxazepine-

3,1 '-naphthalene] -7-carboxylic acid (15.7 mg, 0.025 mmol, first eluting major peak).

STEP 4 : (l S,3'R,6 ^, R,7'S,8'E,10'R,12'R)-6-CHLORO-7'-HYDROXY-10',12'- DIMETHYL-3,4-DIHYDR()-2H, 15 ^! H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16, 18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE (Example 1014)

N,N-Dimethylpyridin-4-amine (DMAP) (31.4 mg, 0.26 mmol, Aldrich) was added to a solution of (S)-6'-chloro-5-(((lR,2R)-2-((l S,4R ₅ 6R,E)-l-h droxy- (4R)-methyl-6-sulfamoylhept-2-en-l-yl)cyclobuty^^

2H,2'H-spiro [benzo [b] [1,4] oxazepine-3 , 1 '-naphthalene] -7-carboxy lie acid (second eluting peak in Step 3; 31.7 mg, 0.05 ! mmol) in DCM (17.4 ml) at 0 °C, and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (49.2 mg, 0.26 mmol, Aldrich) was added portion by portion slowly. The resulting solution was stirred at rt for 20 h. The mixture was washed with IN HC1, the aqueous layer was extracted with EtOAc and the combined organic phase was dried over MgS04 filtered andconcentrated. The crade material was purified by chromatography through a 12 g ISCO gold column, eluting with 0-40 % EtOAc (containing 0.3% AcOH) in hexanes to give (1 S,3'R,6'R,7'S,8'E,10'R,12'R)-6- cMoro-7'-hydroxy-10',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[ naphthalene-l,22'- [20ioxa| 13]thia[ l, 14]diazatetracyclo[14.7.2.0 ³ ^0 ^!9 ' ²⁴ |pentacosa[ 8,16,18,24jtetrae n]-15'-one 13', 13'-dioxide (22,5 mg, 0.038 mmol) as a white solid. ^l H NMR (500MHz, CD3OD) δ 7.75 (d, «7=8.6 Hz, IH), 7.19 (dd, .7=2,3, 8,4 Hz, IH), 7.12 (d, J=2.2 Hz, IH), 7.00 (dd, ./ 2.2. 8.6 Hz, i l l ). 6.94 (d, ./ 8.8 Hz, IH), 6.83 (d, ./ 1 .2 Hz, IH), 6.00 - 5.92 (m, IH), 5.63 (dd. ./ 7.5. 14.5 Hz, IH), 4.29 - 4.21 (m, 2H), 4.09 (dd, ,/ 1 2 5. 19.6 Hz, 21 1 ). 3,85 id. ./ 15.2 Hz, IH), 3,66 (d, ./ 1 .9 Hz, IH), 3.22 (d, ,7=14,2 Hz, IH), 3,06 (dd, .7=9.5, 15.2 Hz, IH), 2.86 - 2.73 (m, 2H), 2.58 (br. s., IH), 2.49 - 2,39 (m, IH), 2.24 - 2.15 (m, 2H), 2.11 (d, .7=13.9 Hz, IH), 1 ,98 - 1.66 (m, (··! ! ). 1.48 (d, .7=7.1 Hz, 31 1). i 44 (dd. ./ 1 .( 9.3 Hz, 2H), 1.08 (d, J=6.6 Hz, 3H). m/z (ESI, +ve ion) 599.2 (M+H) ⁺ .

STEP 5: (lS,3 ^, R,6'R,7'S,8'E,10'S,12'R 6-CHLORO-7 ^, -HYDROXY-10', 12 ^! - DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- | 2 ⁽ !ί>Χ Λ| i 3 ! ! Π! Λ| ί 1 4 | ί^!ΛΖΛ ί : ί AC YC i (>! i 4 7.2 0 ' ".i ^{) 1} '" ¹ |Ρ1·Ν i ^' ACOSA [ 8,16,18,24]TETRAEN]-15'-ONE 13',13 ^* -DIOXIDE (Example 15) The title compound was prepared in an analogous manner to that described in Example 1014, Step 4, using (S)-6'-cMoro-5-(((lR,2R)-2-((lS,4S _s 6R,E)-l- hydrox -(4S)-methyl-6-sulfamoylhept-2-en-l-yl)cyclobutyl)methyl)-3' ,4,4',5- tetrahydro-2H,2H-spiro[benzo[b][l,4]oxazepine-3,l'-naphthale ne]-7-carboxylic acid (first eluting peak in Step 3), and the desired products,

(lS,31,6 ^, R,7^,8U10 ^, S,12'R)-6-cliioro-7 ^, ½droxy-10^12 ^! ~dimethyl"3,4-dihyd 2H, 15'H-spiro[naphthalene- 1 ,22'-

n]-15'-one 13',13'-dioxide was isolated as a white solid. ¾ N.V1R (500MHz,

CD3OD) = 7.63 (d, ./ 8.6 Hz, !!!).7.06 (dd,■/ 2.2.8.3 Hz, 1H), 7.00 (d, ./ 2.2 Hz, ill).6,93 (dd../ 2.( 8.1 Hz, Hi).6.82 id.,/ H I Hz, III).6.81 id.,/ i.7 Hz, IH), 5.80 (dd, ./ 4.2.15.7 Hz, 1H), 5.53 (ddd, J=l.6, 7.0, 15.8 Hz, IH), 4.16 (dd, J=3A, 6.8 Hz, IH), 4.02 - 3.94 (m, 3H), 3.73 (d, J=15.2 Hz, IH), 3.55 (d, ./ 14.2 Hz, IH), 3.17 (d, ./ 142 Hz, IH), 2,98 (dd, ,/ 98.15.4 Hz, IH), 2,74 - 2,61 (m, 2H), 2.33 - 2.14 (m, 3H), 1,98 (d, «7=13.4 Hz, IH), 1.87 - 1.7.5 (m, 3H), 1.72 - 1,56 (m, 4H), 1.54 - 1.43 (m, IH), 1.38 id../ 6.8 Hz, 3H), 1.36 - 1.32 (m, IH), 1.01 (d, ./ 6,8 Hz, 3H)m/z (ESI, +ve ion) 599.2 (M+H) ⁺ . EXAMPLE 1016. (18,3¾,6 ^! 1,7'8,8Έ,10Ί,12¾)-6-€ΗΕΟ1 Ο-7'-ΜΕΊΉΟΧΥ- 10^12'-DIMETHYL-3,4-DIHYDRO-2H,151I-SPIRONAPHTI-LALENE-l,22' - [20]OXA[13]THIA[1,14]DIAZATETRACY ^T CLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 1 ,T.13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (]S,3¾_/VR 'S,8T^.0 ^! R i2'R)-6HMoro-7 ^! ~hydroxy-10',12 ^! ~ dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa|;i3]thia[U4]diazatetra^

n]-15'-one 13',13'-dioxide (Example 1014) and methyl iodide, and the desired product (1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-cMoro-7'-methoxy-l 0', 12'-dime1hyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazate1ra<yd^^

n]-15'-one 13',13'-dioxide was isolated as a white solid. ^" Ή NMR (500MHz, CD3OD) δ 7.63 (d, J=8.6 Hz, IH), 7.07 (dd, J=2.3, 8.4 Hz, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.87 !dd../ 2.2.8.1 Hz, IH), 6.82 id. J 8.! Hz, IH), 6.70 id. 2.0!!/.1H), 5,96 (dd,J=4.5, 15.5 Hz, 111).5.38 (ddd, .7=1.7, 8,8, 15.7 Hz, IH), 4,19 (dqd, IH), 4,03 - 3.93 (m, 2H), 3.73 (d, ,7=15,2 Hz, IH), 3.67 (dd, .7=3.9, 8.8 Hz, IH), 3,55 id../ 14.2 R/. IH), 3.15 (s, 3H), 3.11 (d, J=13.9Hz, IH), 2.95 {dd../ 9.8.15.4 Hz, IH), 2.74 - 2,61 (n, 2H), 2,52 - 2,38 (m, 2H), 2. 5 - 2.04 (n, 2! I).2.01 id. ./ 14.2 Hz, IH), 1,86 - 1.72 (m, 3H), 1.70 - 1.58 (m, 3H), 1,39 (d, J=6.8 Hz, 3H), 1.38 - 1.31 (m, 2H), 0.99 (d, J=6.8 Hz, Ml), z (ESI, +ve ion) 613.2 (M+H) ¹ .

EXAMPLE 1017. (lS,3 ^! R,6'R,7'S,8'E,10 ^, R,12 ^! R)-6-CHLORO-7'-(2- METHOXYETHOXY)- 10', 12'-DIMETHYL-3 ₅ 4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3¾_/VR 'S,8T^.0 ^! Ri2'R)-6HMoro-7 ^! ~hydroxy-10',12 ^! ~ dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20joxa 13]thia[l,14]diazatetracycfo[14.7 _^

n]-15'-one 13',13'-dioxide (Example 1014) andl -bromo-2-methoxy ethane, and the desired product, (lS,3'R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,12'R)-6-chloro-7 ^, -(2-methox ^' ethox ^' )- 10', 12'-dimethyi-3,4-dihy dro-2H, 15'H-spiro[naphlhalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatefra<yd^^

n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (400MHz, CD3OD) δ 7.75 (d, J=8.6 Hz, IH), 7.19 (dd, J=2.2, 8.5 Hz, 1H), 7.12 (d, J=2.2 Hz, HI).6.99 (dd, ./ 2.3.8.0 Hz, III).6.94 (d, ,/ 8.0 Hz, IH), 6.83 (d, ./ 1.8 Hz, ill). 6,06 (dd, ./ 4.;\ 15.7 Hz, 111).5.52 (ddd, i 7.8,6, 15.6 Hz, IH), 4,29 (ddd, ,/ 29.7.0, 10.0 Hz, IH), 4,09 (dd, ./ 12.1.17.8 Hz, 2H), 3.92 (dd, ,/ 38.8.5 Hz, IH), 3.85 (d, ./ !5.1 Hz, IH), 3.67 (d, ./ 13.9 Hz, ill}.3.64 - 3.46 (m, 4H), 3.38 (s, 31!}.3.27 - 3,20 (m, 111).3.07 (dd, ,/ 9,7.15,4 Hz, H), 2.86 - 2.72 (m, 2H), 2.64 - 2.51 (m, 2H), 2,26 - 2.16 (m, 2H), 2.11 (d, ,7=14,1 Hz, H), 1.98 - 1,71 (m, 6H), 1.51 (d, J=7.0 Hz, 3H), 1.49 - 1.42 (m, 2H), 1.10 id../ 6.7 Hz, 3H). m/z (ESI, +ve ion) 657.2 (VI ID ^' . EXAMPLE 1018. (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E,10 ^, R,12 ^, R)-6-CHLORO-10 ^, ,12'-

DIMETHYL-7'-(2-(4-MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H,15H- SPTRO[NAPHTH ALENE- ! ,22'-

|20i()XA| Γ. ΐΗ1Λ| Ι..1 |ί)!Λ/.\! :ΓΗ.Λ( ^' .01117.20 ^: ' ⁱ '.0 ^li ' |Pl-:N i ACOSA 1.16, 18,24]TETRAEN]-15'-ONE I.T.I 3'-D10XlDE

2,279

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3¾,6'RJ'S,8¾;i0 ^, R,12¾)-6-chioro-7'-hydroxy-10Vi2'- dimethy3-3,4-dihydro-2H,15'i-I-spiro|naphthalene-l,22 ^! - [20]oxa[13]thia[l,14]diazate1r^

n]-15'-one 13',13'-dioxide (Example 1014) and 4-(2-bromoethyl)morpholine, and the desired product (IS^'R^'RJ'S^'E O'^^'Ri-e-chloro-lO^ '-dimethyl^'- (2-(4-mo holinyl)ethoxy)-3,4-dihydro-2H,15Ή-spiΓo[naphtha]ene-l,22 ^, - [20]oxa[13]thia[l,14]diazatetra<yclo^^

n]-15'-one 13',13'-dioxide was isolated as a white solid. ^l R NMR (500MHz, CDsOD) 57.62 (d, ./ 8.3 Hz, 1H), 7.07 (dd, ./ 2.2.8.6 Hz, III).7.00 (d, ./ 2.2 Hz, ill).6.88 (dd, ,/ 2.2.8.1 Hz, 111).6,83 (d, ./ 8.6 Hz, Hi).6.68 (d, i 5 Hz, III). 6.02 (dd, J=4.5, 15.5 Hz, 1H), 5.44 (ddd, .7=1.5, 8.9, 15.5 Hz, 1H), 4.17 (ddd, J=3.3, 7.0, 10.0 Hz, 1H), 3.97 (q, ,7=12.2 Hz, 4H), 3.86 (dd, .7=3.8, 8.9 Hz, 1H), 3,74 (d, ./ 14.9 Hz, ill).3.71 - 3.63 (m, 3H), 3.63 - 3.53 (m, 2H), 3.40 (hr. s,, 2H), 3,30 - 3.25 (m, 2H), 3.24-3.19 (m, 2H overlap with solvent), 3.11 (d, .7=14,2 Hz, 2H), 2.96 (dd, .7=9.9, 15.3 Hz, 1H), 2.76 - 2.61 (m, 2H), 2.53 - 2.43 (m, 2H), 2,15 - 2.05 (m, 2H), 1.98 (d, ./ 13.7 Hz, 1H), 1.87 - 1.81 (m, 3H), 1.81 - 1.68 (m, 3H), 1.63 (dd, .7=8,1, 17.4 Hz, ill).1,39 (d../ 7.1 Hz, 3H), 1.38 - 1.31 (m, 2H), 1.00 (d, .7=6,6 Hz, 3H). m/z (ESI, +ve ion) 712.1 (VI 11) .

EXAMPLE 1019. (Ιβ^Τ ,ό'Κ,Τ ,δΈ,ΙΟ'Β, 'Κ^β-ΟΗίΟΚΟ-Τ'-ΜΕΊΉΟΧΥ- 10',12'-DIMETHYL-3,4-DIHYDRO-2H,15H-SPIROpSiAPHTHALENE-l,22' -

2,280 [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETRAC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 1 ,T.13*~DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6 ^, R,7'S,8'E,10'S,12'R)-6~chloro-7 ^, ~hydiOxy-10',12'- dimethy3-3,4-dihydro-2H,15'i-I-spiro|naphthalene-l,22 ^! -

|20|ox;i| I3|ihia| i. i4|dia/aielracveioj 14,7.20 ^;i' .o ^pi ipeniacosa|8.!6,,i8.24i!cirac n]-15'-one 13',13'-dioxide (Example 1015) and iodomethane, and the desired product (lS,3'R,6'R,7 ^, S,8¾10^,12 ^, R)-6-cMoro-7'-methox>' 0 ^, ,12 ^, -dimethyl-3,4- dihy dro-2H, 15 Ή-spiro [naphtha] ene- 1 , 22'- [20]oxa[13]thia[l,14]diazatetra^

n]-15'-one 13',13'-dioxide was isolated as a white solid. ^! H N.V1R (500MHz, CDsOD) 57.75 id. 8.3 !!/. IH), 7.18 (dd,J=2.0, 6.8 Hz, IH), 7.13 (d,J=2.0Hz, IH), 7.03 (dd, ,7=1,7, 8.1 Hz, IH), 6,95 (d, J=8.1 Hz, IH), 6.91 (d, .7=1.5 Hz, IH), 5.93 idd../ 3.4.15.7 Hz, IH), 5.51 (ddd,J=1.2, 8.6, 13.4 Hz, IH), 4.16-4.11 (ni, IH), 4.10 (s, 2! I ).3.85 (d, ./ 15.2 Hz, !!!).3.76 (dd, ./ 3.2.8.1 Hz, IH), 3.68 (d, ,7=14.2 Hz, IH), 3.26 (s, 3H), 3.11 (dd, ,7=10,0, 15.2 Hz, IH), 2,88 - 2.74 (m, 2H), 2,53 - 2.44 (m, IH), 2.42 (br. s., IH), 2.32 (quin, .7=9,0 Hz, IH), 2.11 (d, ,7=14,4 Hz, IH), 2,00 - 1.87 (m, 4H), 1.86 - 1.58 (m, 5H), 1.54 (d, J=6.8 Hz, 3H), 1.46 (t, ./ 12.0 Hz, IH), 1.15 (d, ./ 6.H Hz, Ml) m/z (ESI, +ve ion) 613,2 (M il) ^'

EXAMPLE 1020. (lS,3'R,6'R,7'S,8 ^! E,l() ^! S,12'R)-6-CHL()R()-7'-(2- METHOXYETHOXY)- 10*, 12'-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6'R,7'S,8'E,l()'S,12'R)-6-chloro-7'-hydroxy-10'J2'- dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[ 13]thia[ U 4] diazateti^

n]-15'-one 13',13'-dioxide (Example 1015) and 1 -bromo-2-methoxy ethane, and the desired product, (lS,3¾,6'R,7'S,8'E,10'S,12'R)-6-chloro-7'-(2-methoxyethoxy) - 10', 12'-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22 ^! ~

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n|-15'-one 13',13'-dioxide was isolated as a white solid. ^" Ή NMR (500MHz, (. }}.()}>) δ 7.75 (d, .7=8.6 Hz, ill).7.19 (dd, J=2.2, 8.6 Hz, IH), 7,12 (d, J=2.0 Hz, IH), 7.04 (dd, ./ 1.7.8.1 Hz, IH), 6.95 (d, J=8.1 Hz, IH), 6.93 (d, ./ i.7 Hz, Ml). 5.91 (dd../ 3.8.15.8 Hz, IH), 5.53 (ddd,J=1.5, 8.1, 15.7 Hz, IH), 4.17 - 4.04 (m, 3H), 3.90 (dd, ,/ 3,2.7.8 Hz, IH), 3,86 (d, ./ 1 .2 Hz, IH), 3.68 (d, 14.2 Hz, IH), 3.61 - 3.44 (m. Hi).3,38 (s, 3H), 3.11 (dd, J=9.9, 15.3 Hz, ill).2.87 - 2.74 (m, 2H), 2.52 (dd, J=9.3, 18.6 Hz, IH), 2.43 - 2.35 (m, ill).2.34 - 2.29 (m, IH), 2.11 (d, ./ 13.2 Hz, IH), 2.01 - 1.87 (m, 4H), 1.83 (dd, J=9.5, 17.6 Hz, 211).1.78 - 1.71 (m, IH), 1.71 - 1.64 (m, IH), 1.63 - 1.56 (m, IH), 1.53 (d,J=6.8 Hz, 311). 1.50 - 1.43 (m, IH), 1.14 (d, J=6.6 Hz, 3H). m/z (ESI, +ve ion) 657.2 (M+H) ⁺ . EXAMPLE 1021. (18,3'Κ,6' ,7'8,8Έ,10' ,12'8)-6-€ΗΕΟΚΟ-7'-ΗΥΟ ΟΧΥ- 10', 12'-DIMETHYL-3,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- i.22'~ |2ujOXA| 1ΉΤί!1Λ| l.l4|DiA/AiTTRAC ^' Ya.i)i i 4.7.2, · ^, '.ί ^)|: " ¹ |P1-M ^' AC<)SA [8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE OR

(lS,3¾,6'RJ^,8^I0'8/12'S)-6 ;HLORO-7' iYDROXY-10V12'-DIMF™YL- 3.4-DiRYORO-2i 1. i Ί i-SPIR()|\ API Π H \i ANL- i 22'-

[20]OXA[13]TH1A[1,14]DL ZATEIIACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-0NE 3', 13 ^* -DI0XIDE

The title compounds were prepared in an analogous manner to that described in Example 1014, Steps 1 through 4, hut replacing (S)-2-methyloxirane with (R)-2-methyloxirane in Step 1. The desired product,

(lS,3'R,6'R,7'S,8'E,10'R,12 ^, S)-6-chloro-7 ^, -hydroxy-10',12'-dime

2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetTacyclo[147.2 ³ '^0 ^]9 ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,10'S,12'S)-6-chloro-7'-lwdroxy- 10', 12'-dimethyi-3,4-dihy dro-2H, 15'H-spiro[naphlhalene- 1 ,22'- |;20]oxa[13]thia[l,14]diazatetracycio|14.7.2.0 ³ - ^f \0 ^l9 - ²⁴ ]peniacosa|;8,16

n]-15'-one !3',13'-dioxide was isolated (first eluting major peak out of reverse phase preparative HPLC). ¾ NMR (400MHz, CDsOD) δ 7.76 (d, J=9.0 Hz, IH), 7.20 (dd../ 2.3.8.6 Hz, IH), 7.13 (d../ 2.3 Hz, IH), 7.01 (s, IH), 6.97 idd../ 1.8. 8,2 Hz, IH), 6.93 id../ 8.0 H/. IH), 6, 17 (dd, J=3.2, 15.6 Hz, IH), 5.61 (ddd, ,/ 1 7.5.1, 15.7 Hz, IH), 4,15 - 4.03 (m, 4H), 3.69 - 3,57 (m, 2H), 3.24 (dd, «/=9.9, 15.0 Hz, ill).2.87 - 2.74 (m, 2H), 2.66 (d, ./ 8.2 Hz, 2H), 2.36 - 2.29 (m, IH), 2,11 - 1.86 (ra, 7H), 1,85 - 1.65 (m, 3H), 1.60 - 1.43 (ra, 4H), 1,10 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 599.2 ( +H) ⁺ .

EXAMPLE 1022. (lS^'R-ffl^TS^'E O'S ^S^e-CHLORO-T-HYDROXY- 10U2'-DIMETHYL-3,4-DIHYDRO-2H,15H-SP

pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8 ₅ 16 ₅ 18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3 ^, R,6'R,7 ^, S,8 ^, E,10 ^, R,12 ^, S)-6-CHLORO-7 ^, -HYDROXY-10',12'-DTMETHYL- 3. l-!)!HVOR()-2i !.Ι 'ί i~Si ^! IR ⁽ )| \ΛΡ! ί Γ! l.\i.h\K-!.22'~

|2ίί|0ΧΛ| 1ΉΤΙΙ1Λ| l.l4|DIA/AITTRAC ^' Ya.i)i i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

The title was obtained as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 1021. ¾ NMR (500MHz, CD3OD) δ 7.59 (d, 86 Hz, III).7.30 (br. s., ill).7.05 id../ 8.3 Hz, 111).7,02 - 6,97 (m, 2H), 6.82 (d, ./ 83 Hz, ill).5.51 (dd, ,7=5,4, 16.6 Hz, Ml).5,40 (br. :s . IH), 4.10 (t, J=12.7 Hz, 2H), 3.85 (br. s., IH), 3.76 - 3.60 (m, 2H), 3.51 (d, J=14.2 Hz, IH), 3.38 (d, =16.9 Hz, IH), 2.73 - 2.62 ins.211).2.41 (br. s., 2H), 2.16 - 2,04 (m, IH), 1.92 - 1,68 (m, 6H), 1.66 - 1.53 (m, 2H), 1.51 - 1,41 (m, 2H), 1.40 (d, .7=7.1 Hz, 3H), 1,22 - 1.15 (m, IH), 0.95 (d, ,7=6,6 Hz, 3H). m/z (ESI, +ve ion) 599,2 (M+H) ⁺ . EXAMPLE 1023, (1 S,3 ^, R,6 ^! R,7'S,8 ^! E,10 ^! R,12'R)-6-CHl,ORO-12'-E ^' raYL-7'- HYDROXY - 10'-METHYL-3,4-DlHYDRO-2H, 15 Ή-SPIRO [N APHTHALENE-

1,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,6 7 ^, S,8T 0 ^, S,12'R)-6-CHLORO-12'-ETHYL"7'"HYDROXY-10'~ METHYL-3,4-DIHYDRO-2H,15'H-SPIRO|NAPHTHALENE-l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8, 16, 18,24]TETRAEN]-15'-ONE 13', 13'-DIOXIDE

The title compounds were prepared in an analogous manner to that described in Example 1014, Steps 1 to 4, but replacing (S)-methyl oxirane with (S)-2-ethyloxirane, and the desired product, (lS,3 ^, R,6'R,7 ^, S,8 ^! E,10'R,12'R)-6~ cMoro-12'-ethyl-7'-hydroxy-10'-methyl-3,4-dihydro-2H,15H-spi ro[naphthalene- 1,22'-

n|-15'-one 13'.13'-dioxide or (IS^'Re'R 'S^'E O'SJ^^-e-chio o-n'-ethyl-?'- hydroxy-10'-methyl-3,4-dihydro-2H,15H-s^

[20]oxa{13]thia[l,14]diazatetra<yclo^

n]-15'-one 13',13'-dioxide was isolated (first elutmg major peak out of reverse phase preparative HPLC). ^! H NMR (500MHz, CDsOD) δ 7.75 (d, ./ 8.4 Hz, ill). 7.19 (dd, ,/ 20.8.6 Hz, ill).7, 12 (d, ./ 2.0 Hz, 1H), 6.99 (dd, ,/ 1.7.8,3 Hz, H), 6.95 (dd, ./ 1.2.8.3 Hz, ill).6.81 (d, ./ 1.7 Hz, 1H), 5.89 (dd, ./ 5.-1.15.4 Hz, 1H), 5.64 (dd, ./ 7.1.15.4 Hz, III).4.28 (dd, ./ 4.4.6.8 Hz, ill).4.10 (dd, ./ ! 2.2. 22,7 Hz, 3H), 3.85 (d, !.\2 Hz, 1H), 3.66 (d, ./ 13.9 Hz, IH), 3.22 (d, ./ 1 .9 Hz, 111).3,06 (dd, J=9.7, 15.3 Hz, IH), 2.86 - 2.73 (m, 2H), 2.56 (br. s„ IH), 2.46 (br. s., IH), 2.25 - 2.08 (m, 4H), 1.95 - 1.65 (m, 7H), 1.60 - 1.43 (m, 2H), 1.12 (t, ./ 7.5 Hz, Ml).1.10 (d, ./ 6. Hz, 3H). m (ESI, +ve ion) 613.2 (M il) . EXAMPLE 1024. (lS,3 ^! R,6'R,7'S,8T i0'S,12'R)~6-CHLORO-12 ^! ~ETHYL-7 ^! - HYDROXY- 10'-METHYL-3,4-DIHYDRQ-2H, 15 Ή-SPIRO [N APHTHALENE-

122'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS^'R-e^T'S^'E O'^^'R^e-CHLORO-l^-ETHYL-T-HYDROXY-lO'- METHYL-3,4-DlHYDRO-2H,15^SPIRO| APHTHALENE-l,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.2 ϋ ^; ".ϋ |ΡΗ\ i ACOSA

[8,I6,18,24]TETiLAEN]-15'-QNE 13 VI 3 '-DIOXIDE

The title compounds was obtained as a simgle isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 1023. ¾ MMR (500MHz, METHANOL-c ) δ 7.76 (d../ K.6 Hz, III).7.19 (dd, ,/ 2.1.8.4 Hz, 1H), 7,12 (d, ,/ 2.n Hz, Hi).7.06 (d, ,/ 7 Hz, III).6.95 (br. s., ill).6,93 id. ,/ 8 i Hz, I Hi..5.92 (dd, ,7=4,2, 15.9 Hz, ill).5,66 (dd, ./ 6.0.16.5 Hz, 1H), 4.28 (dd, J=3.2, 6.8 Hz, 1H), 4.10 (s, 2H), 3.96 (br. s., Ml).3.85 (d, J=14.9 Hz, lH), 3.67 (d, J=13.9 Hz, 1H), 3.11 (dd, J=9.5, 15.2 Hz, 1H), 2.87 - 2.74 (m, 2H), 2,45 - 2,28 (m, 3H), 2.13 - 1,93 (m, 6H), 1.93 - 1.63 (m, 7H), 1.47 (t,J=11.2Hz, 1H), 1.21 (t, «/=7.6 Hz, 3H), 1.12 (d, J=6,8 Hz, 3H). m/z (ESI, +ve ion) 613.2 ( +H) ⁺ .

EXAMPLE 1025 , ( 1 S,3'R,6'R,7'S ,8'E, 10'R, 12'R)-6-CHLORO- 12'-ETHYL-7'-(2- METHOXYETHOXY)- 10'-METHYL-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

|;20]OXA[13iTHIA[l,14jDIAZATETRACYCLO|14.7.2.0 ³ -V0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAEN]-15'-ONE !3', 13'-D )XIDE or

(18,3 ^, Κ,6 ^ί Κ 7 ,8Έ/10'8.12'Κ)-6-εΗΙ.ΟΚΟ-12 ^, -ΕΊΉΥ1,-7'-(2- METHOXYETHOXY)- 10'-METHYL-3,4-DIHYDRO-2H.15Ή- SPIRO[NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[ 1 , 141 Dl AZ ATETRAC YCLO [ 14.7.2.0 ³ · ⁶ .0 ¹⁹ · ²⁴ jPENTACOS A

[8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (l S,3'R.6'R.7'S,8'E,10'R,12'R)-6-chioiO- 12'-etliyl-7'- hydroxy-10'-met yl-3,4-dihydro-2H, ] 5'H-spiroi naphthalene- 1 ,22'- [20]oxa[13]thia[ 1 , 14]diazatetracycio[14,7.2,0 ³ ' ⁶ .0 ^l9 - ² ]pentacosa[8, 16, 18,24]tetrae n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6'R,7 ^! S,8'E,10'S, 12'R)-6-chloro-12'-ethyi-7'- hydroxy-10'-methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,2 2'- ⁿ |peniacosa| H. I 6. i 8.24 |ieirae n]-15'-one 13', 13'-dioxide (from Example 1023) andl-bromo-2-methoxy ethane (Aldrich), and the desired product, (l S,3'R,6'R,7'S,8 ^, E.10 ^, R. i2 ^* R)-6-chIoiO-12'- ethyl-7'-(2-methoxyethoxy)-] 0'-meihyl-3,4-dihydro-2H,i 5'H-spiro[naphtha]ene- 1 ,22'-

[ 20]oxa[ 13 ]thia[ 1 , 14] diazatetracyclo[ 14.7.2. ⁽ > ··".0 ¹⁹ · ² ] pentacosa[ 8, 16,18,24]tetrae n|-15'-one 13', 13'-dioxide or (lS,3'R,6'R,7'S,8'E,10'S, 12'R)-6-chioro-12'-ethyI-7'- (2-methoxy ethoxy )- 10'-methy 1-3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra^ n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (500MHz, CDJOD) δ 7.75 (d, J=8.3 Hz, IH), 7.19 (dd, 7=2.3, 8.4 Hz, IH), 7.12 (d, J=2,0 Hz, IH), 6.99 (dd, =1.7, 8.1 Hz, IH), 6.93 (d, J=8.1 Hz, IH), 6.82 (d, J=1.5 Hz, IH), 6.04 (dd, ./ 3.7. 15.2 Hz, I H), 5.54 - 5.47 (m, IH), 4.14 - 4.03 (m, 3H), 3.95 (dd, ,/ 8. 8.4 Hz, IH), 3,85 (d, ./ 15.4 Hz, IH), 3,67 (d, ,/ 14.2 Hz, IH), 3.62 - 3.46 (m, 4H), 3.38 (s, 3H), 3.22 (d, .7=14,2 Hz, IH), 3.06 (dd, .7=9.7, 15.3 Hz, IH), 2,85

- 2.73 (m, 2H), 2.62 - 2.52 (m, 2H), 2.24 - 2.09 (m, 4H), 1.98 - 1.85 (m, 3H), 1.84

- 1 ,68 (m, 4H), 1.55 (t, J=\ 3.0 Hz, IH), 1 ,45 (t, ./ I 1 .7 Hz, IH), 1 , 14 - 1.08 (m, 6H). m/z (ESI, +ve ion) 671.2 ( +H) ⁺ .

EXAMPLE 1026. (1 S,3'R,6'R,7'S,8'E, 10'R, 12'R)-6-CHLORO- 12'-ETHYL- 10'- YU . H !Y i -7'-ί 2-ί 4-ΜΟΚ ΪΊ lO! JN Y ! .)! ! ί iOXV )-3. !-!)!! !Y !)R()-2i !. 1 5'! !- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOI MJ^.O'^.O'^lPE TACOSA

[8,16, 18 , 24] TETRAEN] - 15 ^! -ONE 13', 13 ^! -DIO.XIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (18,3¾,6¾,7'8,8Έ,10¾,12¾)-6-ΰΜθΓθ-12'-6 1-7'- hydroxy-10'-methyl-3,4-dihydro-2H, 15H-sp

[20]oxa[ 13]thia[ 1,14] diazateti^

n]-15'-one 13',13'-dioxide or

hydroxy-10'-methyl-3,4-dihydro-2H,15 ^, H-spiro[naphlhalene-l.,22'- [2Q]oxa[13]ihia[l,14]diaza ^^

n]-15'-one 13',13'-dioxide (from Example 1023) and 4-(2-bromoethyl)morpholine (Aldnch), and the desired product, (IS^TRXR^'S^'E O'R/n' Ve-chloro-n'- ethyl-10 ^, -methyl-7'-(2-(4-mo holinyl)ethoxy)-3,4-dihydro-2H,15Ή- spiro [naphtha] ene- 1 ,22'-

[20]oxa[13]thia[U4]diazatetra^

n]-15'-one 13',13'-dioxide OΓ(lS,3 ^, R.6 ^, R,7 ^, S.8 ^, E.10 ^, S,12 ^, R)-6-chloΓO-12 ^, -eth l-10 ^, - methyl-7'-(2-(4-mo holinyl)ethox )-3,4-dihydro-2H,15Ή-spiro[naphthalene-

1,22'-

n|-15'-one 13',13'-dioxide was isolated as a white solid. ^! H NMR (500MHz, CD3OD) δ 7.75 (d, 86 Hz, 1H), 7.19 (dd, ./ 27.8.1 Hz, 1H), 7, 13 (d, ./ 2.2 Hz, 111).6.99 (dd, J=1.5, 7.8 Hz, 1H), 6.79 id../ 1.7 !!/.1H), 6.11 (dd,J=4.4, 15.7 Hz, ill).5.57 (ddd, .1 2.0.9.0, 14.2 Hz, ill).5.61 - 5.52 (m, III).4.11 (dd, ./ 11.7, 27.1 Hz, 4H), 4.00 (dd, 39.8,8 Hz, 1H), 3.99 - 3,98 (m, 1H), 3.87 (d, ./ 15.7 Hz, ill).3,82 - 3.75 (m, 2H), 3.73 - 3.65 (m, 2H), 3,43 - 3.38 (m, 2H), 3.37 (s, 2H), 3.30 - 3.27 (m, 2H), 3.23 (d, ./ 14.2 Hz, 2H), 3.08 (dd, ./ 9.7.15.5 Hz, 1H), 2.87 - 2.73 (m, 2H), 2.65 - 2,54 (m, 2H), 2.27 - 2.03 (m, 6H), 1.99 - 1.89 (m, 2H), 1.89 - 1.69 (m, 5H), 1.61 - 1.39 (m, 2H), 1.16 - 1.09 (m, 6H). m/z (EST, +ve ion) 726.4 {V! Hi

EXAMPLE 1027. (lS,3 ^! R,6 ^, R,7'S,8'E,10'S,12'R)-6-CHLORO-12 ^! -ETHYL-10 ^! -

METHYL-7'-(2-(4-MORPHOLINYL)ETHOXY)-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1S,3'R,6¾,7'S,8¾10¾,12'R)-6~CHLORO

MORPHOLINYL)ETHOXY)-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^]9 ^ ⁴ ]PE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15 ^! -ONE 13', 13 ^! -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^! R,6'R,7'S,8'E,10'S, 12'R)~6-chloro-] 2'-e l-7'- hydroxy-10'-methyl-3,4-dihydro-2

[20]oxa[ 13]thia[l ,14]cUazatefracy^

n]-15'-one 2 ^' -erhvj-7'~ hydroxy- 10'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20joxa 13]thia[ l, 14]diazatetracycfo[14.7.2 _^

n]-15'-one 13 ', 13 '-dioxide (from Example 1024) and 4-(2-bromoethyl)morpholine

(Aldrieh), and the desired product, (lS,3 ^! R,6'R,7'S,8'E,10'R,12'R)-6-chloro-12'- 6 1-10'~ηΐ6 1-7'-(2-(4~ηιοφ^1^1)6Λοχν)-3,4-ά¾ ^ΐΌ-2Η,15Ή- spiro I naphthalene- 1 ,22'-

n]-15'-one 13',13'-dioxide or (lS,3 ^* R,6'R,7'S,8'E,10'S,12'R)-6-chloro-12'~ethyi-10'- methy3-7'-(2-(4-morphoIinyl)ethoxy)-3,4-dihydro-2H, 15'H-spiro[naphthaiene-

[20]oxa[13]thia[U4]diazatetra<ycto^

n]-15'-one 13',13'-dioxide was isolated as a white solid. ^! H N.V1R (500MHz,

CDsOD) 5 7.75 (d, ./ 7.8 Hz, 1H), 7.19 (dd, ./ 2.7. 8.6 Hz, I I I ). 7.14 (d, ./ 2.2 Hz, 1H), 7.05 (dd, ,7=2,7, 6.6 Hz, IH), 6,96 (d, J=8.1 Hz, 1H), 6.91 (d, .7=1.7 Hz, IH), 5.99 (dd, J=3.2, 16.1 Hz, IH), 5.59 (dd, J=8.7, 15.8 Hz, IH), 5.63 - 5.54 (m, IH), 4.15 - 4.03 (m, 3H), 3.99 (d, ,7=4.9 Hz, 2H), 3.91 - 3.77 (m, 4H), 3.68 (d,■/ i 3.4 Hz, 111).3.52 (dd, 66.13,9 Hz, 2H), 3.41 (br. s., 2H), 3.28 (br. s .2H), 3.22 - 3.03 (m, 3H), 2.86 - 2,74 (m, 3H), 2.60 - 2.51 (m, IH), 2.43 (br. s., IH), 2,37 - 2.29 Cm. IH), 2.15 - 1.71 (m, lOH), 1.61 (t, J=12.6 Hz, IH), 1.49 it../ 12.3 Hz, IH), 1.23 (i, ./ 7.0 Hz, 3H), 1.16 (d, ./ 6.4 Hz, 311). m/z (ESI, +ve ion) 726.4 {\i · H)

EXAMPLE 1028. (3R,6R,7S,8E,llS,15S,25S 6'-CHLOR()-7-HYDROXY-3',4'- DIHYDRO-2'H, 18H-SPIR0[ 13,23-DIOXA- 16-THIA-l , 17- DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ³³ ' ³⁵ .0 ²² ' ²⁷ ]OCTACOSA-8,19,21,27- TETRAENE-25,r-NAPHTHALEN]-18-ONE 16, 16-D10XIDE OR

(3R,6R,7S,8E,llR,15R,25S)-6'-CHLORO-7-HYDROXY-3',4'-DIHYDRO- 2*H,18H-SPIRO[l 3,23-DIOXA-l 6-THIA-l ,17-

DL ZAPENTACYCLO[17,7.2,0^^0 ¹¹ - ¹ l0 ²² - ²⁷ ]OCTACOSA-8,19,21,27- T -25 , 1 '-NAPHTH ALEN] - 18-ONE 16, 16-DIOXIDE

The title compounds were prepared in an analogous manner to that described in Examples 323 and 324, Steps 1 to 7, but replacing 1,2- epoxycyclopentane with 3,4-epoxytetrahydrofuran (TCI America) in Step 1, and the desired product, (3R,6R,7S,8E,llS,15S,25S)-6 ^! -chIoro-7-hydroxy-3',4'- dihydro-2'H,l 8H-spiro| 13,23-dioxa-l 6-thia-l,l 7- diazapentacyclo[17.7.2,0 ³ -^0 ¹¹ ' ¹ l0 ²² - ²⁷ ]octacosa-8,19,21,27 etraene-25,r- naphthalenj-18-one 16,16-dioxide or (3R,6R,7S,8E,llR,15R,25S)-6'-chIoro-7- hydrox'-3',4'-dihydro-2'H,18H-spiro[13,23-dioxa-16-thia-l,17 - diazapentacyc!o[i7.7.2.0 ³ ' 0 ^iU ^

naphthaien]~18-one 16,16-dioxide was isolated (first eiuting major peak out of reverse phase preparative HPLC). '!! NMR (4()()MHz, CD ₃ OD) 07.66 (d,■/ H.6 Hz, 1 1 1 ). 7.09 (d, ,/ H O Hz, i l l ). 7.03 (d, 2.5 Hz, IH), 6.92 - 6,83 (m, 2H), 6.73 - 6,68 (m, IH), 6.01 - 5.84 (m, 1H), 5.56 (dd, .7=8.3, 14.2 Hz, IH), 4.72 (br, s., 2H), 4.53 (d, ./ 9.8 Hz, 2H), 4.19 (dd, .7=6.7, 8.2 Hz, IH), 4.08 - 3.94 (m, 3H), 3.88 (d, ./ 7.6 Hz, ! ! ! ). 3.80 (d, ./ 10.4 Hz, I H), 3.72 (d, ,7=15.3 Hz, IH), 3.59 (d, ,/ i 7 Hz, IH), 3.02 (dd, J=8,8, 14.9 Hz, IH), 2,75 - 2.51 (m, 4H), 2,37 - 2. 19 (m, 2H), 2.03 (d, .7=14,9 Hz, IH), 1.93-1,57 (m, 6H). 1.42 - 1.32 (m, IH), m/z (ESI, +ve ion) 613.2 (M+H) ⁺ .

EXAMPLE 1029. (3R,6R,7S,8E,1 1R,15R,25S)-6'-CHLORO-7-HYDROXY- 3',4'-DlHYDRO-2'H, 18H-SP1R0[ 13,23-DIOXA- 16-THIA- 1,17-

DIAZAPENTACYCLO|;i7.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² - ²⁷ ]OCTACOSA-8,19,21,27- TETR AENE-25 , 1 '-NAPHTH ALEN] - 18-ONE 16,16-DIOXIDE OR

(3^6¾78,8Ε,118,158,258)-6'-€ΗΕ01 0-7^^10ΧΥ-3',4 ^! -ϋ1ΗΥΟί Ο- 2Ή, 18H-SP1RO [ 13,23 -DIOXA- 16-THIA- 1,17- DIAZAPENTACYCLO[ 17.7, 2.0 ³ · ⁶ .0 ^{1 ] J 5} , 0 ²² · ²⁷ ] OCTACOS A-8, 19,21 ,27- TETRAENE-25 , 1 '-ΝΑΡΗΊΉ ALEN] - 18-ONE 16, 16-DIOXIDE

The title compound was obtained as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 1028. Ή NMR (500MHz, CD3OD) δ 7.76 (d, J=8,6 Hz, IH), 7.20 (d, ./ 6. 1 Hz, IH), 7.12 (d, J=2.2 Hz, 2H), 7.03 - 6.93 (m, 2H), 6.17 (br. s., IH), 5.74 (dd, J=3A, 16.4 Hz, IH), 4.61 - 4.40 (m, IH), 4.27 - 4.14 i ns. IH), 4.12 (d, =11.0 Hz, 2H), 4.06 - 3.92 (m, 2H), 3.92 - 3.79 (m, 2H), 3,76 (d, ./ 1 .9 Hz, ! ! ! ). 3.24 - 3.04 (m, IH), 2.90 - 2,74 (m, 4H), 2.70 - 2.51 (m, 2H), 2,51 - 2,22 (m, 2H), 2.11 (d, J=13,2 Hz, 2H), 2.01-1.72 (m, 6H). 1.47 (t, J=9.8 Hz, IH). m/z (ESI, +ve ion) 613.2 (M+H) ⁺ . EXAMPLE 1030. (3R,6R,7S,8E,1 lR,15S,25S)-6'-CHLORO-7-HYDROXY~3',4'- DIHYDRO-2'H, 18H-SPIRO [ 13 ,23 -DIOXA- 16-THIA- 1,17- DIAZAPE TACYCLO[17.7.2.0 ³ ' ⁶ .0 ⁿ - ¹⁵ .0 ²² ' ²⁷ ]OCTACOSA-8,19,21,27- TETRAENE-25 , 1 '-NAPHTH ALEN] - 18-ONE 16,16-DIOXIDE OR

(3R,6R,7S,8E,1 1 S,15R,25S)-6'-CHLORO-7-HYDROXY-3',4'-DIHYDRO- 2'H, 8H-SPrRO[l 3,23 -DIOXA- 16-THIA- 1 ,17-

DIAZAPENTACYCLO[17.7.2.0 ³ . ⁶ .0 ⁿ ' ¹⁵ .0 ²² ' ²⁷ jOCTACOSA-8,19,21,27- TETR -25 , 1 '-NAPHTH ALEN] - 18-ONE 16, 16-DIOXIDE

The title compounds were prepared in an analogous manner to that described in Examples 325 and 326, Steps 1 to 8, but replacing the mixture of (lR,2S)-2-allyicyclopentanoi and (lS,2R)-2-aIlylcyclopentanol with a mixture of (3S,4S)-4-allyUetrahydrofuran-3-ol and (3R,4R)-4-allyltetrahydrofuran-3-ol (prepared from 3,4-epoxytetrahydrofuran (TCI America) using a similar procedure described in Example 323 in Step 1) in Step 1, and the desired product,

(3R,6R,7S,8E,l l R,15S,25S)-6'-chloro-7-hydroxy-3 ^, ,4 ^, -dihydro-2 ^, H,18H- spiro[13,2; dioxa-16~thia~l,r7~diaz

8,19,21 ,27-tetraene-25, 1 '-naphthalen] -18-one 16,16-di oxide or

(3R,6R,7S,8E,l l S,15R,25S)-6'-chloro-7-hydrox^

spiro[13,23-dioxa~16-thia-l,17-diaz^^

8,19,21,27-tetraene-25,r-naphthalen]-18-one 16,16-dioxide was isolated (first eiutmg major peak out of reverse phase preparative HPLC). ^] H NMR (400MHz, CD3OD) δ 7.75 (d, 8 6 Hz, IH), 7.19 (dd, ./ 2 2. 8.5 Hz, 1H), 7, 13 (d, ./ 2.2 Hz, IH), 7,07 (dd, J=2.0, 8.2 Hz, i l l ). 6.99 - 6.94 (m, 2H), 5,85 - 5.71 (m, 2H), 4.64 (td, ./ 5. 1 . 8.1 Hz, IH), 4.37 - 4.27 (m, 2H), 4.18 (dd, ./ 4.2. 7.5 Hz, IH), 4.14 - 4.07 (m, 3H), 3.83 id. ./ 15. i Hz, IH), 3.69 (d, ./ 14.7 Hz, IH), 3.62 (dd, ,/ 5.6. 8.3 Hz, 1H), 3.13 (dd, ,/ 9,2.15.3 Hz, III).2,87 - 2.66 (m. Mi).2,49 - 2.26 (m, 4H), 2.12 (d, .7=13,5 Hz, H), 2.00 - 1,77 (m, 6H), 1.74 (dd, .7=9.6, 19,2 Hz, H), 1.48 (t, J=11.6 Hz, IH). m/z (ESI, +ve ion) 613.2 {M l!) . EXAMPLE 1031 , (3R,6R,7S,8E, 11 S, 15R,25S)-6 ^, -CHLORO-7-HYDROXY-3 ^, ,4'- DIHYDRO-2'H, 18H-SP1RO [ 13 ,23 -DIOXA- 16-THI A- 1,17- DIAZAPENTACYCLO[17.7.2.0 ³ - ⁶ .0 ⁿ ' ¹⁵ .0 ²² - ²⁷ ]OCTACOSA-8 ₅ 19,21 ₅ 27- TETRAENE-25 , 1 '-N APHTH ALEN] - 18-ONE 16,16-DIOXTDE OR

(3R,6R,7S,8E,llR,15S,25S)-6'-CHLORO-7-HYDROXY-3 4 ^! ~D.lHYDRO- 2Ή, 18H-SPIRO [ 13,23 -DIOXA- 16-THIA- 1,17-

DIAZAPENTACYCLO|;i7.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² - ²⁷ ]OCTACOSA-8,19,21,27- TETRAENE-25 , 1 *-N APHTH ALEN] - 18-ONE 16, 16-DIOXIDE

The title compound was obtained as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 1030, ^" Ή NMR (400MHz, MeOH) δ 7,74 (d, J=8.6 Hz, IH), 7.19 (d, J=6.5 Hz, 2H), 7.13 (d, ./ 2.2 Hz, IH), 7.08 (dd, ./ 2.O.8.2 Hz, IH), 6.95 (d, ./ 8.2 Hz, IH), 5.83 - 5.74 (m, IH), 5,70 (dd, J=6.1, 15.5 Hz, IH), 4.33 - 4.18 (ra, 3H), 4,18-4,12 (m, 3H), 4.03 (t, «/=5.0 Hz, IH), 3.66 - 3.45 (m, 5H), 2,93 - 2,74 (m, 3H), 2.55 - 2.43 (m,

2H), 2.42 - 2.24 (ni, 2H), 2.05 (d, J=11.2 Hz, IH), 1.96 - 1.87 (m, 3H), 1.86 - 1.69 {in.3H), 1.64 - 1.54 (m, IH). m/z (ESI, +ve ion) 613.2 { \ I · Π } ,

EXAMPLE 1032. (3R,6R,7S,8E,1 lR,15S,25S)-6'-CHLORO-7-METHOXY-3 ^, ,4 ^! - DIHYDRO-2'H,18I-LSPIRO[13,23-DIOXA-16-THIA-l,17-

DI AZAPENTACYCLO [17.7.2, 0 ³ · ⁶ .0 ^{1 ] ] s} .0 ²² · ²⁷ ] OCTACOS A-8, 19,21 ,27- TETRAENE-25 , 1 '-N APHTH ALEN] - 18-ONE 16, 16-DlQXIDE OR (3R ₅ 6R S ₅ 8E ₅ l l S,15R,25S)-6'-CHLORO-7-METHOXY-3 ^, ,4 ^, -DIHYDRO- 2Ή, 18H-SPIRO[l 3,23-DIOXA-l 6-TH! A- 1 , 17-

DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² ' ²⁷ ]OCTACOSA-8,19,21,27- TETRAENE-25 , 1 '-NAPHTH ALEN] - 18-GNE 16,16-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (3R,6R,7S,8E, 1 lR,15S,25S)-6'-chloro-7-hydroxy-3',4'- dihy dro-2'H, 18H-spiro[ 13,23-dioxa- 16-thia- 1. i 7- diazapentacyclo[177.2.0 ³ -^0 ¹¹ ' ¹ -\0 ²² ' ²⁷ ]octacosa-8,19,21,27-tetraene-25,r- naphthalen] - 18-one 16, 16-di oxide or (3R,6R,7S,8E, I IS, 15R,25 S)-6'-chl oro-7- hy droxy-3 ',4 ^! -dihy dro-2'H, 18H-spiro[ 13 ,23 -dioxa- 16-thia- 1,17- diazapentacyclo[ 177.2.0 ' ^{6 11} ' ¹ ^0 ' ⁷ ]octacosa-8,19,21,27-tetraene-25,r~ naphtha! enj-18-one 16,16-dioxide (Example 1030) and methyl iodide, and the desired product, (3R,6R,7S,8E, ! ! R,I5S,25S)-6'-chloro-7-methoxy-3',4 ^f -dihydro- 2Ή, 18H-spiro [ 13,23-dioxa- 16-thia- 1 , 17- diazapentacycloj l 7.7.2.Q ^½ Ο ^{11 1} ·^

naphthalen] - 18-one 16, 16-di oxide or (3R,6R,7S,8E, I IS, 15R,25 S)-6'-chl oro-7- methoxy-3 ',4'-dihy dro-2'H, 18H-spiro[ 13 ,23 -dioxa- 16-thia- 1,17- diazapentacyclo[ 177.2.0 ' ^{6 11} ' ^l5 .0 ' ⁷ ]octacosa-8,19,21,27-tetraene-25,r- naphthaienj-l 8-one 16,16-dioxide was isolated as a white solid. 'H NMR

(400MHz, CD3OD) δ 7.74 (d, ,/ 7.7 Hz, H i ). 7.18 (dd, ,/ 2 3. 8,6 Hz, ! ! ! }. 7.12 (d, J=2.2 Hz, IH), 7.06 (dd, ./ i .K. 8.2 Hz, i l l ). 6.97 - 6.91 (m, 21 1 }. 5.93 - 5.83 (m, IH), 5.59 (dd, J=8.8, 15.3 Hz, IH), 4.67 (dd, J=0.6, 7.8 Hz, IH), 4.36 - 4.28 (m, 2H), 4, 16 - 4.10 (m, IH), 4.09 (s, 2H), 3.81 (d,J=15, l Hz, IH), 3.72 - 3,69 (m. 11 1 ). 3,66 id ./ 1 5. i Hz, ! ! ! ). 3.62 - 3.54 (m, I I I ). 3.22 (s, M i l 3. 13 (dd, i O.ii. 14.5 Hz, 1H), 2.86 - 2.62 (m, 3H), 2.55 - 2,29 (m, 4H), 2. (d, J=13.7 Hz, 1H), 1.99 - 1.67 (m, 7H), 1.52 - 1.41 (m, 1H). m/z (ESI, +ve ion) 627.2 { \ I · Π } .

EXAMPLE 1033. (3R,6R,7S,8E,1 lR,15S,25S)-6'-CHLQRO-7-(2- METHOXYETHOXY)-3 ^! ,4'-DlHYDRO-2'H,18H-SPlRO[13,23-DIOXA~16" THIA-l ,17-DIAZAPENTACYCLO[ 177.2.0 ³ ' ⁶ ,0 ^{ii J 5} .0 ²² - ²⁷ ]OCTACOSA- 8,19,21 ,27-TETRAENE~25, 1 ^* -N APHTH ALEN] - 18-ONE 16, 16-DlQX!DE OR (3R,6R,7S,8E,11 S, 15R,25S)-6 ^, -CHLORO-7-(2-METHOXYETHOXY)-3 ^, ,4'- DIHYDRO-2'H, 18H-S PIRO [ 13 ,23 -DIOXA - 16-THI A- 1 ,17- DIAZAPENTACYCLO[17.7.2.0 ³ - ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]OCTACOSA-8,19,21,27- TETRAENE-25 , 1 '-ΝΑΡΗΊΉ ALEN] -18-ONE 16,16-DIQX!DE

The title compound was prepared in an analogous manner to that described in Example 720 using (3R,6R,7S,8E,1 lR, I 5S,25S)-6'-chloro-7-hydroxy-3',4'- dihy dro-2'H, 18H-spiro[ 13,23-dioxa- 16-thia-l ,17- diazapentacyclo[17.7.2.0 ' ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]octacosa-8,19,21,27-tetraene-25,r- naphthalen]-18-one 16,16-dioxide or (3R,6R,7S,8E,l lS,15R,25S)-6'-chloro-7- hy droxy-3 ^, ,4'-dihy dro-2'H, 18H-spiro[ ! 3 ,23-di oxa- 16-thia- 1,17- diazapentacyclo[ 17.7.2.0 ' ⁶ .0 ¹¹ ' ¹ ^0 ²² ' ⁷ ]octacosa-8,19,21,27-tetraene-25, - naphthalen|-18-one 16,16-dioxide (Example 1030) andl-bromo-2-methoxyethane (Aldnch), and the desired product, (3R,6R,7S,8E,1 lR,15S,25S)-6'-chioro-7-(2- methoxyethoxy)-3',4'-dihydro-2'H, l 8H-spiro| 13,23-dioxa-l 6-thia-l,17- diazapentacy clo[ 17.7.2, 0 ³ · ⁶ .0 ^{1 5} .0" ²⁷ ]octacosa-8, 19,21 ,27-tetraene-25, 1 '- naphthalan] -18-one 16,16-dioxide or (3R,6R,7S,8E,1 lS,15R,25S)-6'-chloro-7-(2- methoxyethoxy)-3',4'-dihydro-2 ^, H,18H-spiro[ 13,23-dioxa-l 6-thia-l, 17- diazapentacyclo[ 17.7.2.0 ³ ^ Q ^{i U} ^0^

naphthalan] ~18-one 16,16-dioxide was isolated as a white solid. ¾ NMR

(500MHz, CD3OD) δ 7.75 (d, ./ 8.6 Hz, 1H), 7.19 (dd, ./ 2.2. 8.6 Hz, 1H), 7.13 (d, ./ 2.0 Hz, i l l ). 7,05 (dd, ./ 2.0. 8. 1 Hz, 11 1 ). 6.97 (d, ,/ ! 7 Hz, 1 H), 6.95 (d, J=8.1 Hz, IH), 5.87 - 5.79 (m, 1H), 5.63 (dd, ,7=8,4, 15.3 Hz, IH), 4,68 - 4.63 (m, IH), 4.36 - 4.29 (m, 2H), 4.11 (t, J=8.6 Hz, 3H), 3.87 - 3.80 (m, 2H), 3.68 (d, ./ 14.2 Hz, IH), 3.61 - 3.40 i ns. 6H), 3.38 - 3.36 { in. 3H), 3.12 (dd, ,/ 9.4. 15.0 Hz, H), 2,87 - 2,66 (m, 31 1 ). 2.59 - 2.50 (rn, H), 2.46 - 2,30 (m, 3H), 2.12 (d, J=14.2 Hz, IH), 2.02 - 1.66 (m, 6H), 1.47 (t, J=l 1.9 Hz, IH), m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 1034. (3R,6R,7S,8E,1 lS,15R,25S)-6'-CHLORO-7-(2- METHOX YETHOXY)- 3',4 ^! -DlHYDRO-2'H, 18H-SPIRO [ 13 ,23 -DIOXA- 16- THIA-l,1 7-DIAZAPENTACYCLO|;i 7.7.2.0 ³ -^() ^{i l} > ¹ () ²² ^OCTACOSA- 8, 19,21,27-TETRAENE-25,1 '-N APHTH ALEN] - 18-ONE 16, 16-DIOXIDE OR (3R,6R,7S,8E,l lR,15S,25S)-6'-CHLORO-7-(2-METHOXYETHOXY)-3 ^, ,4'- DIHYDR()-2'H, 18H-SPIRO[ 13,23-DI()XA-16-THIA-l,17- DI AZAPENTACYCLO [17.7.2.0 ^; ".0 ^{1 ] ] s} .0 ²² · ²⁷ ] OCTACOS A-8, 19,21 ,27- TETR -25 , 1 '-ΝΑΡΗΊΉ ALEN] - 18-ONE 16, 16-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 1 using

dihy dro-2'H, 18H-spiro[ 13,23-dioxa- 16-thia- 1,17- diazapeniacyclo[ 17:7.2A) ³ ' ^{6 l l} - ^! l0 ²² - ²⁷ ]octacosa-8 9,2L27 etraene-25 ^ naphthalen]-18-one 16,16-dioxide or (3R,6R,7S,8E,1 1 R,15S,25S)-6'-chloro-7- hydroxy-3',4'-dmydro-2'H, 18H-spiro[13,23-dioxa-l 6-thia-l ,17- diazapentacyclo[17.7.2.0 ³ - ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]octacosa-8,19,21,27-tetraene-25,r- naphthalenj-18-one 16, 16-dioxide (Example 1031 ) and! -bromo-2-methoxy ethane (Aldrich), and the desired product, (3R,6R,7S,8E,l l S, 15R,25S)-6'-chloro-7-(2- metlioxyethoxy)-3',4'-dihydro-2'H, 18H-spiro[ 13,23-dioxa-l 6-thia-l ,17- diazapen1acyclo[ 17.7.2.0 ³ ' ⁶ .0 ^l ^^^

naphthalen]-18-one 16,16-dioxide or (3R,6R,7S,8E,1 l R,15S,25S)-6'-chloro-7-(2- methoxyethoxj -S'^'-dihydro^'HJ SH-s irot ^S-dioxa-ie-thia-l,!?- diazapentacyclo[17.7.2.0 ³ - ⁶ .0 ¹¹ ' ¹⁵ .0 ²² ' ²⁷ ]octacosa-8,19,21,27-tetraene-25,r- naphthalen]-.] 8-one 16, 16-di oxide was isolated as a white solid. ^] H NMR

(500MHz, ( f ⁾ :( ⁾ ! ⁾ } δ 7.74 (d, .7=8,6 Hz, IH), 7.23 - 7.18 (m, 1H), 7.19 (dd, .7=2.2, 8.6 Hz, IH), 7.13 (d, J=2.2 Hz, IH), 7.07 (dd, ./ 2.0. 8.1 Hz, IH), 6.94 (d, J=8.0 Hz, IH), 5.86 - 5.80 (m, I H), 5.58 (dd, ,7=6.4, 15.7 Hz, IH), 4.31 (dd, ./ 5. 1. 9.3 Hz, IH), 4,25 - 4, 14 (m, 3H), 4.13 (s, 2H), 3.69 (t, ,/ 5.7 Hz, IH), 3.65 - 3.55 (m, 3H), 3,54 - 3.49 (m, 3H), 3.49 - 3.40 (m, 3H), 3,38 (s, 3H), 2,92 - 2.74 (m, 3H), 2.54 - 2.43 (m, 2H), 2.40 - 2.28 (m, 2H), 2.08 - 2.02 (m, IH), 1.97 - 1.88 (m, 3H), 1 .83 - 1.70 ( ns. 3H), 1 ,60 - 1.54 (m, I H). m/z (ESI, +ve ion) 671.2 (M+H) ⁺ .

EXAMPLE 1035. (3R,6R,7R,8E,1 lR,15S,25S)-6'-CHLORO-7-HYDROXY- S'^'-DIHYDRO^'H, 18H-SPIRO[ 13,23 -DIOXA-16-THIA- 1 , 17-

DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² " ²⁷ ]OCTACOSA-8,19,21,27-

TETRAENE-25 , 1 '-NAPHTHALEN] - 18-ONE 16, 16-DIOXIDE OR

(3R,6R,7R,8E,l l S, 15R,25S)-6'-CHLORO-7-HYDROXY-3',4'-DIHYDRO- 2Ή, 18H-SPIRO[l 3, 23 -DIOXA-16-THIA- 1 , 17- DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ³³ ' ³⁵ .0 ²² ' ²⁷ ]OCTACOSA-8,19,21 ,27- TETRAEN E-25 , 1 '- APHTHALEN]-! 8-ONE 16, 16-DIOXIDE

The title compounds were prepared in an analogous manner to that described in Examples 325 and 326, Step 1 to 8, but replacing Intermediate

AA11 A with Intermediate AA1 IB in Step 7, and the desired products,

(3R,6R,7R,8E,l l R,15S,25S)-6'-chloro-7-hydroxy-3 ^, .4 ^, -dihydro-2H.18H- spiro[ 13,23-dioxa~16-thia-lJ 7-diazapert^

8,19,21 ,27-tetraene-25, 1 '-naphtha! en j -18-one 16, 16-di oxide or

(3R,6R,7R,8E,l l S,15R,25S)-6'-chloro-7 iydiOxy-3',4'-dihydro-2'H,18H- spiro[13,23-dioxa-16 hia-l ,17-diazape^

8,19,21,27-tetraene-25,l'-naphthalen]-18-one 16,16-dioxide was isolated (first eiuting major peak out of reverse phase preparative HPLC). ¾ NMR (400MHz, CDsOD) δ 7.71 (d, ./ 8.61 Hz, 1 H) 7.09 - 7.24 (m, 4 H) 6.94 - 7.01 (m, 1 H) 5.47 - 5,68 (m, 2 H) 4.10 - 4.36 (rn, 6 H) 3.91 - 4,04 (m, 2 H) 3.69 (d, i 3 69 Hz, I H) 3.46 - 3.62 (m, 2 H) 2.81 (d, J=4.89 Hz, 3 H) 1.66 - 2.53 (m, 13 H). m/z (ESI, +ve ion) 613.2 (M+H) ⁺ .

EXAMPLE 1036, (3R,6R,7R,8E,1 l S,i5R,25S)-6'-CHLORQ-7-HYDROXY~ 3',4'"D1HYDR0-2'H, 18H-SPIRO[l 3,23-DIOXA-l 6-THIA-l ,17- DIA APENTACYCLOtnj^.O^^O^^ O^-^ jOCTACOSA-S, ^^.! ^?- TETRAENE-25 , 1 '-N APHTH ALEN | - 1 8-ONE 16, 16-DIOXIDE OR

(3R,6R,7R, 8E, 11 , 15 S,25 S)-6'-CHLORO-7-HYDROXY-3 ',4'-DlHYDRQ- 2H,18H-SPIRO[l 3,23-DIOXA-16-THIA-l ,17-

DIAZAPENTACYCLO[17.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² " ²⁷ ]OCTACOSA-8,19 ₅ 21,27- TETRAENE-25 , 1 '-NAPHTH ALEN] - 1 8-ONE 16, 16-DIOXIDE

The title compound was obtained as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 1035, ^! H NMR (400MHz, MeOH) δ 7.77 (d, J=8.6 Hz, IH), 7.55 (d, ,7=2,0 Hz, IH), 7.23 - 7.18 (m, 2H), 7.13 (d, ,/ 2.3 Hz, 1H), 6.95 (d, ./ 8.2 Hz, i l l ). 5.47 (dd, J=8.0, 15.3 Hz, IH), 5.31 - 5.22 (m, I I I ). 4.29 - 4.04 i ns. 6H), 3.90 (dd, ./ 8.5. 15.6 Hz, I I I ). 3.76 (d, .7=14.3 Hz, IH), 3.58 (dd, J=3,4, 8.7 Hz, IH), 3.43 (d, ./ 8.2 Hz, IH), 3,07 - 3.01 (m, IH), 2.87 - 2.73 (m, 3H), 2.67 - 2.54 (m, 2H), 2.31 (d, J=14.9 Hz, IH), 2, 14 - 2.04 (m, 2H), 1.99 - 1.57 (m, 7H), 1.51 - 1.40 (m, IH). m/z (ESI, +ve ion) 613.2 (M+H) ⁺ .

EXAMPLE 1037. (l S,3 ^! R,6 ^, R,7'S,10 ^, S, 12'S)-6-CHLORO-7' iYDROXY-12'- (METHOXYMETHYL)- 10'-METHYL-3 ,4-DIHYDRO~2H, 15 Ή- SPIROpSfAPHTHALENE-l^^-

[20]OXA[ 13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13', 13'-DIOXIDE OR (l S,3'R,6'R,7'S,10'R,12 ^! S)-6- CHLORO-7'-IlYDROXY-12'-iMETHOXYMETOYL)-10'-METHYL-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22 ^! -

[20]OXA[13]ra ^j :A[l _s 14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ⁱ⁴ ]PE TACOSA [16,18,24]TRIEN]-15'-ONE 13',13'-DIOXIDE

2,300

The title compound was prepared in an analogous manner to that described in Example 925, Step 1, using ( iS,3'R R,7'S,8¾10'R, 12'S)-6-chloro-7'-hydroxy- 12 ^! -(methoxymethyl)- 10'-methyl-3,4-dihydro-2H, 15 ^! H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ^!9 ' ²⁴ ipentacosa[ 8,16,18,24|ietrae n]-15'-one 13^ 13'-dioxide or (l S,3'R,6¾,7'S,8 , 10'SJ 2^)-6-chloro-7'-hydroxy- 12'-(methoxymethyl)- 10'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'~ [20]oxa[13]thia[l,14]diazatetracy^^

n]-15'-one 13',13'-dioxide (Example 471), and the desired product,

(1 S,3'R,6'R,7'S, 10'S, 12 ^, S)-6-chloro-7 ^, -hydroxy-12 ^* -(methoxy methyl)- 10'-methyl- 3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[ 16,18,24]trien]-

15'-one 13', 13'-dioxide or ( ! S,3'R,6 ^, R,7'S,10'R,12'S)-6-chloro-7'-hydroxy- ! 2 ⁱ - (methoxymethyl)-10'-methyl-3,4-dihydro-2H _^

[20]oxa[13]thia[l,14]diazatetracy^^

15'-one 13',13'-dioxide was isolated. ¾ NMR (500MHz, CD3OD) 0 7.75 (d,■/ 8.4 Hz, IH), 7.19 (dd, J=2.2, 8.6 Hz, 1H), 7.13 (d, ./ 2.2 Hz, 1H), 7,07 (dd, ./ 2.0. 8.1 Hz, IH), 6.96 (d, J=8,3 Hz, IH), 6.88 (d, .7=1.7 Hz, H), 4.41 - 4.36 (m, IH), 4.12 (dd, J=11.7, 20.3 Hz, 2H), 3.89 (dd, ./ 4.2. 9.8 Hz, IH), 3.84 - 3.77 (m, 3H), 3.69 (d, ,/ 1 3.9 Hz, IH), 3.40 (s, 3H), 3.20 (d, ./ 14 2 Hz, I H), 3.09 (dd, ./ 8.4. 15.5 Hz, IH), 2,86 - 2,73 (m, 2H), 2.45 - 2.36 (m, H), 2.19 - 2.06 (m, 3H), 2.03 - 1.97 (m, IH), 1.97 - 1.90 (m, 2H), 1.80 - 1.58 (m, 7H), 1.48 (t, ./ I 1 .7 Hz, IH), 1.26 - 1.15 (m, 2H), 0.93 (d, ./ 5.6 Hz, 3H). m/z (ESI, +ve ion) 631.2 { \ I · Π } . EXAMPLE 1038. (18 'Κ,6' ,7'8,10' ,12'8)-6-0-ίΕΟΚΟ-7'-ΗΥΟ ΟΧΎ-12'- (METHOXYMETHYL)- 10'-ΜΕΤΉ YL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL)[14J.2X) ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[16,18,24]TRI E ]-15'-ONE 13', 1 IT-DIOXIDE OR (18,3¾,όΤ,7'8,10'8,12'S)-6- CHLORO-7'-HYDROXY- 12'-(METHOXYMETHYL) - 10'-METHYL-3 ,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

[ 16, 18,24]TRI EN] - 15'-ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 925, Step 1, using (lS,3'R,0 ^* R,7'S,8'E,I0'S,12'S)-0-ehloro-7'- hy droxy-12'-(methoxy methyl)-! 0'-methyl-3,4-dihydro-2H, 15Ή- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6'R,7 ^! S,8'E,10 ^, R,12 ^! S)-6-chloro-7 ^, -hydiOxy- 12'-(methoxymethyl)-10'-methy -3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- 3|lhisi| !.14|dia/-aieUi:c> c!ol 1 .7.2.0 ^{; n} ]pen!acoKa|H.I6.i8.2-i]icirae n]-15'-one 13',13'-dioxide ( Example 472), and the desired product,

(1 S,3 ^! R,6'R,7'S,10Έ, 12'8)-6-ΰΜθΓθ-7'¾'άίΌχν-12·-(ιη6Λοχνηΐ6 1)- 1 O'-methyl- 3 ,4-dihy dro-2H, 15 Ή-spiro [naphthal ene- 1,22'- [20]oxa[13]thia[l,14]diazatetra<ycto^^

15'-one 13',13 ^* -dioxide or (lS^'R^'R^'SJO'S/^'S^b-chloro-T'-hydroxy-n'- (methoxy methyl)-! O'-methy 1-3 ,4-dihy dro-2H,15'H-spiro|naphthalene-l, 22'- |20jo\aj I3|ihi«i| i. I4|dia/aieuae> doi U/Z^.O^'.O ^1' ' ⁿ jpen!aco a| I6.i8.24|ineni- 15 ^f -one 13',13'~dioxide was isolated. ^l H NMR (500MHz, CD3OD) δ 7.77 (d, 8,6 Hz, IH), 7.21 - 7.17 (m, 2H), 7, 13 (d, J=2.2 Hz, IH), 7.05 (dd, ./ 2.0. 8, 1 Hz, IH), 6.92 (d, ./ 8. 1 Hz, IH), 4.11 (d, ./ 3.4 Hz, 2H), 4.09 - 4.05 (m, IH), 3.96 - 3.85 { in. 3H), 3.74 (d, ,/ 14.2 Hz, IH), 3.53 - 3.43 (m, 2H), 3.42 (s, 2H), 3.41 - 3.39 (m, IH), 3.38 - 3.35 (m, 2H), 3,31 (s, 3H), 3, 1 1 (dd, ./ 7.2, 15,5 Hz, I H), 2.86 - 2,74 (m, 2H), 2.70 - 2.63 (m, H), 2,50 - 2,43 (m, IH), 2.09 (d, .7=13.7 Hz, IH), 1.99 - 1.85 (m, 5H), 1.80 - 1.63 (ni, 5H), 1.72 - 1.62 (m, 3H), 1.59 - 1.50 (m, 2H), 1 .50 - 1.42 ( ns. IH), 0,94 (d, J=6.6 Hz, 3H). ni , (ESI, +ve ion) 631 .2 (M+H) ⁺ . EXAMPLE 1039. (IS^'R^'RJ'S^'EJO'S/n'Si-e-CHLORO-?'^-

METHOXYE ^r rHOXY)-12'-(METHOXYMETHYL)-10'-METHYL-3,4- DIHYDRO-2H, 15 'H-SPIRO [NAPHTHALENE- 1 ,22 ^* - pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16, 18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE OR

(l S,3'R,6¾,7'S,8 ,10¾, 12'S)-6-CHLORO-7'-(2-METHOXYETI-IOXY)-12 ^f - (METHOXYMETHYL)- 10'-METH YL-3 , -DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATET ACYCLOIl^T^.O'^.O'^lPENTACOSA

~l S'-ONE 13", 13 -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (l S,3'R,6'R,7'S,8 ^, E,10 ^, S, 12'S 6-chloro-7'-hydroxy-12'- (methoxy methyl)- 10'-methy 1-3 ,4-dihy dro-2H, 15 'H-spiro [naphthal ene- 1,22'- [20]oxa[13]thia[l ,14]diazatefra^

n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6 ^, R,7 ^, S,8 ^, E, 10 ^, R,12 ^, S)-6-chloro-7 ^, -hydro5-y- 12'-(methoxymethyl)- 10'-methyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene-l ,22'- [20joxa[13]thia[ l, 14]diazatetracycfo[14.7

n]-15'-one 13', 13'-dioxide (Example 472) and l-bromo-2-methoxy ethane

(Aldrich), and the desired product, (l S,3'R,6'R,7'S,8'E,lG'S,12 ^* S)-6-chloro-7 ^* -(2- methoxvethoxv)- 12' -(methoxy methyl)- 10'-methy 1-3 ,4-dihy dro-2H, 15 Ή- spiro [naph thalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracycto^^

n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6 ^, R,7'S _s 8 ^, E _s 10 ^, R,12 ^, S)-6-chloro-7 ^, -(2- methoxy ethoxy)- 12'-(methoxymethyl)- 10'-methyl-3,4-dihy dro-2H, 15Ή- spiro [naphtha] ene- 1 ,22'-

n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (4C ⁾ C ⁾ MHz, CDJOD) δ 7.76 (d, ./ 8.6 Hz, 11 1 ). 7, 19 (dd, ./ 2.1 8.6 Hz, 11 1 ). 7.13 (d, ,/ 2 2 Hz, 1H), 7.05 (dd, ,7=2,2, 8.2 Hz, IH), 6,98 (d, J=2.0 Hz, 1H), 6.94 (d, .7=8.2 Hz, IH), 5.88 (dd, ,7=4.1, 15.8 Hz, IH), 5.53 (ddd, J=1.8, 7.5, 15.8 Hz, IH), 4.22 (dd, ./ 4.4. 10.1 Hz, IH), 4.1 1 is. 21 1 ). 4.01 (dd. ./ 4.7. 11.2 Hz, ! ! ! ). 3.95 {dd. ,/ 4. ! . 1 1.3 Hz, I H), 3.89 (dd, ,7=3,9, 8.4 Hz, 2! I ). 3,84 (s, IH), 3.69 (d, .7=14.5 Hz, IH), 3.61 - 3.55 (m, IH), 3.53 - 3.44 (m, 3H), 3,43 (s, 3H), 3,39 - 3.38 (m, i l l ). 3.37 (s, 2H), 3.11 (dd, J=9.4, 15.5 Hz, IH), 2.89 - 2.73 (m, 2H), 2.57 - 2.45 (m, 2H), 2.40 - 2,29 (m, I I I ). 2. 1 I (d, J=13.9 Hz, IH), 2.01 - 1.66 (ra, 71 1 ). 1,61 (t, .7=12,9 Hz, IH), 1.48 (t, .7=12.7 Hz, IH), 1.12 (d, ,7=6,7 Hz, 3H). m/z (ESI, +ve ion) 687.2 (M+H) ⁺ .

EXAMPLE 1040, (1 S,3'R,6'R,7'S,10'R, 12'S)-6-CHLORO-7'-(2- METHOXYETHOXY)~12'-(METHOXYMETHYL)-10'-METHYL-3,4- D1HYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

|;20]()XA[ 13 |THIA[ l,14jDlAZATETRACYCLO| 14.7.2.0 ³ -^0 ^l9 ' ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13 ', 13 '-DIOXIDE OR (l S,3'R,6'R,7'S,10'S,12'S)-6- CHLORO-7'-(2-METHOXYETHOXY)- 12'-(METHOXYMETHYL)~ 10'- MEra^L-3,4-DIHYDRO-2H ₅ 15^SPmO[NAPHTHALENE-l,22"-

|20!ΟΧΛ| ΐ: ΐ!!1Λ| Κ,! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 (Γ ".Ο ¹ " ^Μ |ΡΗ\ i ACOSA [16,18,24]TR1EN]-15'-0NE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described m Example 925, Step 1, using (18 ₅ 3'Κ,6'Κ7'8,8Έ,10'8,12 ^! 8)-6-οωοΓθ-7 ^! ~(2- methoxyethox\ -12'-(methoxymethyl)-10'-methyl-3,4-dihydro-2H,15'H- spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracy^

n]-15'-one 13',13'-dioxide or (lS,3 ^, R,6 ^, R,7'S _s 8 ^, E _s 10 ^, R,12 ^, S)-6-chloro-7 ^, -(2- methoxyethoxy)-12'-(methoxymethyl)-10'-me1hyl-3,4-dihydro-2H ,15'H- spiro [naphtha] ene- 1 ,22'- [20]oxa[13]thia[U4]diazatetra^

n]-15'-one 13',13'-dioxide (Example 1039), and the desired products,

(lS,3'R,6'R,7'S,10'R,12'S)-6-dilorc 7'-(2-meihoxyethoxy)-12'-(raethoxymethyi)-

10'-methyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[13]tMa[l,14]diazatetracyclo[[14.7.2.0 ³ - ⁶ .0 ^]9 ' ²⁴ ]pentacosa[16,18,24]trien]- 15'-one 13',13'-dioxide or (lS,3'R,6'R,7 ^! S,l( ⁾ 'S,12'S)-6-chIoiO-7'-(2- methoxy ethoxy)- 12'-(methoxymethyl)- 10'-methyl-3,4-dihy dro-2H, 15Ή- spiro [naphthalene- 1 ,22'-

12ί>! χίΐ! i jihial U4|dia/.aletracye!ojj !4.7.2.0 ^i: '.O ⁱ " ⁿ |peniacosa| 16. i 8.24|inersj- 15'-one 13',13'-dioxide was isolated. ^l H NMR (500MHz, CD3OD) δ 7.77 (d, ,/ 8.6 Hz, 111).7.21 -7.17(m, 2H), 7,13 (d, J=2.2 Hz, IH), 7.05 (dd, J=2.0, 8, 1 Hz, ill). 6.92 (d, ,7=8,1 Hz, IH), 4.11 (d, .7=3.4 Hz, 2H), 4,09 - 4,05 (m, 1H), 3.96 - 3.85 (m, 3H), 3.74 (d, ./ 14.2 Hz, 1H), 3.52 - 3.44 (m, 2H), 3.42 (s, 2H), 3.31 (s, 3H), 3.11 (dd, ./ 7.2.15.5 Hz, ill).2.86 - 2.74 (m, 2H), 2.70 - 2.63 (m, ill).2.50 - 2,43 (m, IH), 2.09 (d, 137 Hz, ill).1.99 - 1.85 (ra, 5H), 1,80 - 1.63 (m, 5H), 1,58 - 1.52 (m, 2H), 1.51 - 1.28 (m, 5H), 0,94 (d, J=6.6 Hz, 3H). m/z (ESI, +ve ion) 689.2 (M+H) ⁺ .

EXAMPLE 1041. ί 1 S.3 ^' R.6'R,7'S.8 ^' h. IU ^' S.1 I ' S .12' R )-(>-(. ^' I if . O R O- 7'- HYDROXY- 10', 11 ', 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή-

SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE AND EXAMPLE 1042. (lS,3'R,6'R,7'S,8'E,10'R,irS,12'R)-6-CHLOR()-7'-HYDROXY-l()' ,ll',12'- TRIMETHYL-3, 4-DIHYDRO-2HJ 5'H-SPTRO[NAPHTHALENE-1 ,22'-

|20i )X A| 1 11111, \| I ,, ! -I |DI.\/.Vn-. i RACVCiO i -1.7.20 ^;ί '.0 ^1: ' |Ρ! ^; .Ν i ACOSAi 8,I6,18,24]TETRAE ]-15'- ONE 13 ',13 '-DIOXIDE

Example 1041 Example 1042

STEP 1 : (2S,3S,4S)-3,4-DLMETHYLHEX-5-EN-2-OL, (2S,3S,4R)-3,4- DIMETHYLHEX-5-EN-2-OL, (2R,3R,4S)-3,4-DIMETHYLHEX-5-EN

AND (2R,3R,4R)-3,4-DIMETHYLHEX-5-EN-2-()L

The title compounds were prepared in an analogous manner to that described in Example 1014, Step 1, but replacing (S)-2-methyioxirane with (2S, 3S)-2,3-dimethyl oxirane, and the desired products, a mixture of (2S,3S,4S)-3,4- dimethylhex-5-en-2-ol, (2S,3S,4R)-3,4-dimethylhex~5~en-2-ol, (2R,3R,4S)-3,4- dimethylhex-5-en-2-ol and (2R,3R,4R)-3,4-dimethylhex-5-en-2-ol were isolated and then submitted for DAS chiral speration to give a mixture of (2R,3R,4R)-3,4- dimethylhex-5-en-2-ol and (2R,3R,4S)-3,4-dimethy1hex-5-en-2-ol as the first eluting major peak out of chiral chromagraphy, and another mixture of

(2R,3S,4R)-3,4-dimethylhex-5-en-2-ol, (2R,3S,4S)-3,4-dimethylhex-5-en-2-ol as the second eluting major peak out of chiral chromagraphy.

STEP 2: (1S,3'R,6'R,7'S,8'E,10'S,1 rS,12'R)-6-CHLORO-7'-HYDROXY- 10', 11', 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTH ALENE-

1 ,22'-

| 2u jOXA| 1 Ι Ι 1 . 1 4 |ΠΙΛ/ΛΤΓ Η Λ Ι 14.7.2.0 '^O ¹ ' ¹ --' ¹ | l -NTA( SAj 8,16,18,24]TETRAENj-15'-ONE 13',13'-DIOXIDE AND

(1 S,3'R,6'R,7'S,8'E, 10'R,1 1 "S, 12'R)-6-CHLORO-7"-HYDROXY- 10', 11 ', 12'- TRIMETHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHAL-ENE-l,22'-

[20]OXA[ 13]TH1A[ 1 , 14]DIAZ ATETRAC YCLO 14.7.2.0 ³ · ⁶ .0 ¹⁹ - ²⁴ ]PENTACOS A[ 8,16, 18,24]TETRAEN1-15'- ONE 13', 13 '-DIOXIDE

The title compounds were prepared in an analogous manner to that described in Example 1014, Steps 2-4, using a mixture of (2R,3S,4R)-3,4- dimethy hex-5-en~2~ol, (2R,3S,4S)-3,4-dimethylhex-5-en-2-ol (Step I, second eluting major peak) and the desired products, (1 S,3'R,6'R,7'S,8'E,10'S,H'S,12'R)- 6-chloro-7'-hydroxy-10',ir,12' rimethyl-^

1,22'- [20]oxa[13]thia[l,14]diazatefra^^

n]-15'-one 13',13'-dioxide (first eluting major peak out of reverse phase preparative HPLC) and (lS,3 ^! l ,6'RJ'S,8' 10 ^, R,irS,12 ^, R)-6-chloro-7 ^, -hydroxy- 10', 11 ', 12'-trimethyl-3,4-dmydro-2H, 15'H-spiro|naphthalene-l ,22'- 6. i 8.24 |leiraen ]-15'- one 13',13'-dioxide (second eluting major peak out of reverse phase preparative HPLC) were isolated. (lS,3'R,6'R,7'S,8'E,10'S,ll'S,12 ^* R)-6-chloro-7'- hy droxy-10', 11 ', 12'-trimethyl-3,4-dihydro-2H, 15'H-spiro| naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazateto

n]-15'-one 13',13'-dioxide (Example 1041). ¾ NMR (500MHz, CD3OD) δ 7.75 (d,■/ 8.6 Hz, Hi).7.18 (dd, ./ 2.0.8.6 Hz, III .7.12 id. J=2.0 Hz, III).7.07 (d, ,/ H I Hz, IH), 6.94 (s, IH), 6.92 (d, 8.3 Hz, 1H), 5,95 (dd, ./ 6.5.15.0 Hz, IH), 5,64 (dd, ./ 8.3.15,2 Hz, IH), 4.20 (dd, ,/ 33.8.4 Hz, IH), 4.11 (d, ./ 1 .2 Hz, 3H), 3,83 (d, ./ 15.2 Hz, IH), 3.64 (d, J=14.2 Hz, IH), 3.10 (dd, ./ 9.8.15,4 Hz, IH), 2.87 - 2.71 (m, 211).2.55 (br. s„ IH), 2.47 - 2.34 (m, IH), 2.33 -2,17 (m, 2H), 2.11 (d, .7=13,2 Hz, IH), 2,00 - 1,77 (m, 6H), 1.72 (dd, .7=10.0, 19,1 Hz, IH), 1.51 id../ 6.8 Hz, 3H), 1.49 - 1,43 (m, IH), 1.09 id../ 7.1 Hz, 3H), 1.07 id../ 7 ! Hz, 3H). m/z (ESI, +ve ion) 613.2 (M+H); (1S,3'R,6'R,7'S,8'E,1()'R,1 l'S,12'R)-6- chloro-7'-h ydroxy - 10', 11 ', 12'-trimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthal ene- 1,22'-

[20]oxa[13]thia[l,14]diazatetracyelol4.7.^ _^

]-15'- one 13',13'-dioxide (Example 1042). 'HNMR (500MHz, CD3OD) δ 7.76 (d, ./ 8.6 Hz, IH), 7.19 (dd, J=2.2, 8,3 Hz, IH), 7.15 - 7,10 (m, 2H), 7,05 (d, «/=l,2 Hz, IH), 6.96 (d, J=8.1 Hz, IH), 5.77 (dd, J=5.5, 15.8 Hz, IH), 5.64 (dd, J=7.8, 15.7 Hz, IH), 4.35 (dd, ./ 2.2.6.6 Hz, IH), 4.21 - 4.09 (m, 3H), 3.82 (d, ./ 15.4 Hz, IH), 3,65 id../ 13.9 Hz, IH), 3,17 (dd, J=9.3, 16.1 Hz, IH), 2.86 - 2.74 ins. 2H), 2,39 (dd, ./ 7.6.17,6 Hz, IH), 2.32 - 2.22 (m, IH), 2,13 - 2.03 (m, 2H), 2.03 - 1.93 (m, 3H), 1.93 - 1,67 (m, 5H), 1.53 - 1.45 (m, IH), 1.39 (d, J=7.1 Hz, 3H), 1.10 (d, ,7=6.8 Hz, 3H), 1.07 id../ 6.8 Hz, 3H). m/z (ESI, + ve ion) 613.2 (M+H). EXAMPLE 1043. (1 S,3'R,6'R,7'S,8'E, 10'S,11'R, 12'S)-6-CHL0R0-7'- HYDROXY- 10', 1 Γ , 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ "* 0 ^{] 9} ^ ⁴ ]PE TACOS

A[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR EXAMPLE 1044. (lS,3'R,6'R,7'S,8'E,10'R,irR,12'S)-6-CHLORO-7'-HYDROXY-10',l l',12'- TRiMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14,7.2,0 ³ ^ 0 ¹⁹ - ²⁴ ]PENTACQS A[8, 16, 18,24]TETRAEN ] - 15 '-ONE 13 ', 13 '-DIOXIDE

Example 1043 Example 1044

The title compounds were prepared in an analogous manner to that described in Example 1041 Step 2 using a mixture of (2R,3R,4R)-3,4- dimethylhex-5-en-2-ol and (2R,3R,4S)-3,4-dimethylhex-5-en-2-ol (Example 1041, Step 1, the first eluting major peak out of chiral chroraagraphv), and the desired product, (1 S,3'R,6'R,7'S,8'E,10'S,1 l'R,12'S)~6~chloro~7'~hydroxy- 10', 11 ', 12'-trimethy 1-3, 4-dihydro-2H, 15 'H-spiro [naphthalene- 1, 22'- [20]oxa[ 13]thia[l ,14]cUazatetracyclo^

n]-15'-one 13',13'~dioxide (Example 1043, first eluting major isomer out of reverse phase preparative HPLC) was isolated. ¾ NMR (500MHz, CDsOD) δ 7.73 (d, ./ 8.3 Hz, ! ! ! ). 7.42 (br. s., I I I ). 7.19 (dd, ,/ 2.2. 8.6 Hz, 1H), 7.13 (d, ,/ 2 2 Hz, 1 H), 7.07 (d, J=7.6 Hz, i l l ). 6,93 i d. ./ 7.6 Hz, i l l ). 5.92 (dd, ./ 6.1, 15,9 Hz, I H i.. 5.65 - 5,59 (m, IH), 4.17 (dd, «7=12.2, 15,2 Hz, 2H), 4.01 - 3.89 (m, 2H), 3.80 - 3.66 (m, IH), 3.51 (dd, ./ 1 -1.2. 26.2 Hz, 2H), 2.84 - 2.74 (m, 2H), 2.55 (br. s., 2H), 2.50 - 2,37 (m, 1H), 2.23 (dd, .7=3.3, 7,0 Hz, IH), 2.01 - 1,59 (m, 9H), 1.50 (d, J=7.3 Hz, 3H), 1.09 (d, J=7.1 Hz, 3H), 1.06 (d, J=l .1 Hz, 3H). m/z (ESI, +ve ion) 613.2 (M+H). (1S,3'R,6'R,7'S,8'E,10'R, 1 l ^! R,12 ^* S)-6-chloro-7 ^* - hydroxy-10 ^f , 1 , 12'-trimethyl~3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[l,14]diazatetra^

n]-15'-one 13',13'-dioxide (Example 1044, second eiuting peak out of reverse phase preparative HPLC) was isolated. ^] H NMR (500MHz, CDsOD) δ 7.72 (d, J=8.3 Hz, IH), 7.48 (br. s,, IH), 7.19 (dd, J=2, l , 8.4 Hz, IH), 7.15 - 7, 11 (m, 2H), 6.94 (d, J=8.0 Hz, IH), 5.69 (dd, J=6.0, 15.8 Hz, IH), 5.53 - 5.33 (m, IH), 4.22 (dd, ./ 0.5. 10.8 Hz, 2H), 4.00 - 3.88 (m, 2H), 3.85 - 3.73 (m, I H), 3.64 - 3,57 (m, IH), 3.57 - 3.46 (m, IH), 2.84 - 2,74 (m, 2H), 2.63 - 2.52 (m, IH), 2.52 - 2,39 (m, IH), 2.10 - 2.01 (m, 2H), 2,01 - 1,92 (m, 2H), 1.92 - 1.80 (m, 4H), 1 ,76 - 1.62 (m, 2H), 1.55 (d, J=10.0 Hz, IH), 1.39 (d, J=7.3 Hz, 3H), 1.07 (d, J=6.6 Hz, 3H), 0.99 (d, ./ 5.9 Hz, 3H). m/z (ESI, +ve ion) 613.2 (M+H).

EXAMPLE 1045. (lS,3 ^, R,6 ^, R,7'S,10'S,l l ^, S,12'R)-6-CHLORO-7'-HYDROXY- 10', 1 1 ',12'~TRIMETHYL~3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE- l. -

[20]OXA[ 13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [16,18,24]TRIEN]-15'-ONE 13 ', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 925, Step 1, using (lS,3'R,6'R,7'S,8'E,I0'S,irS, ! 2'R)-6-chloro-7'- hydroxy-10', 11 ', 12'-trimethy -3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [2Q]oxa[13]thia[l,14]diazaie^

n]-15'-one 13',13'-dioxide (Example 1041), and the desired products,

(lS,3'R,6 ,7'S,10^,irS,12'R)-6-chloro-7 ^, ½droxy-10^11 2' nmethyl~3,4- dihydro-2H,15'H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]dia^

15'-one 13',13'-dioxide was isolated. ¾ NMR (500MHz, CDsOD) δ 7.76 (d, J=8.6 Hz, III).7.19 (dl.■/ 2.4.7.1 Hz, 2H), 7.12 id../ 2.0 Hz, 1H), 7.06 (dd, ./ 2.0.8.1 Hz, 111).6.93 id.,/ H I Hz, ill).4.11 {όό.,Ι 122.18.1 Hz, 2H), 4,01 (dq,J=2.7, 7.2 Hz, 1H), 3.86 (dd, «/=5.1, 15.4 Hz, 1H), 3.73 (d, .7=14,2 Hz, 1H), 3.62 - 3,58 (m, 111).3.16 (dd, J=6.8, 15.7 Hz, 1H), 2.86 - 2.74 (m, 2H), 2.55 - 2.49 (m, 1H), 2.43 - 2.38 (m, III).2,23 - 2.18 ins. ill).2.10 (d, ./ 13.7 Hz, !!!).2.05 - 1.99 (m, 1H), 1,95 - 1.86 (m, 3H), 1.71 - 1.63 (m, 2H), 1,54 (dd, J=3.8, 72!!/. III).1.49 (br, s., I Hi.1.46 (d, .7=7,1 Hz, 3H), 1.45 - 1,23 (m, 4H), 1.09 (d, .7=7.1 Hz, 3H), 0.91 (d, J=6.8 Hz, Ml), m/z (ESI, +ve ion) 615.2 ( III.

EXAMPLE 1046. (1S,3 ^! R,6'R,7'S,10'R,1 l'S,12'R)-6-CHLORO-7'-HYDROXY- 10V11^12'-TRIMETHYL-3,4~D1HYDRO-2H,15'H"SPIRO[NAPHTHALENE-

122'- pOlOXAtlSlTHIAt^MlDIAZATETRACYCLOtMJ^.O'^.O^^lPE TACOSA

[16,18,24] TRIEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 925, Step 1, using (lS,3'R,6'R,7'S,8'E,10'R,irS,12'R)-6-chloro-7 ^! - hydroxy-10 ll\12'-trimethyl-3,4-dihydro

[20]oxa[ ! 3]thia[ 1, ! 4]diazatetracyc n]-15'-one 13',13'-dioxide ( Example 1042), and the desired products,

(1 S,3'R,0 ^! R,7'S, Jim, i rS, 12^

dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracycfo[½

15*-one 13',13'-dioxide was isolated. ¾ NMR (400MHz, CD3OD) δ 7.64 (d, 86 Hz, IH), 7.07 (dd, ./ 2.2.8.4 Hz, IH), 7.00 (dt, ./ 2.1.4.1 Hz, 2H), 6.89 (d, =l,8 Hz, IH), 6.84 (d, ./ N.O Hz, IH), 4.04 - 3.97 (m. Ml).3.71 (d, ,/ 15.! Hz, IH), 3.64 (d, ,/ 8.2 Hz, IH), 3.54 (d, 1 .7 Hz, ill).3.08 - 2,92 (m, IH), 2.74 - 2,61 (m, 2H), 2,27 (d, ./ 7.2 Hz, 2H), 2.00 - 1.87 (m, 2H), 1,83 - 1,76 (m, 2H), 1.76 - 1.48 (m, 6H), 1.42 - 1.33 (m, 2H), 1.31 (d, J=7.2 Hz, 3H), 1.29 - 1.23 (m, 3H),

0.92 (d, ./ 6.K Hz, 3H), 0.82 (d, ,/ 6.8 Hz, 3H). m (ESI, +ve ion) 615.2 (M il) .

EXAMPLE 1047. (1S,3'R,6 ^! R,7'S,8'E,10'S,1 l'S,12'R)-6-CHLQRQ-7'- VHTHOXY -10',ΙΓ,12'-TRlMETHYL - 3,4-DlH YDRO-2H, 15 Ή- SPTRO[NAPHTH ALENE- 1 ,22'-

|2 ⁽ >X A| i ? I U ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA

[8, 16, 18,24]TETRAE j-15'-QNE i.T.i 3'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (1S,3 ^! R,6'R,7'S,8'E,10'S,1 l'S,12'R)-6-chloi -7'-hydroxy- 10',ΙΓ, 12'-trimethyl-3,4-dihydro-2H, 15'H-spiro[naphtha]ene-l ,22'- |2i!|o\a| I |thia| 1.1 |diaxateSrac> c!o! i Ι·1.7.2.0· ^: '.ί ^)|; ' ' ^, |peniacosa|8.i .l8.24|tetra en]-15'-one 13',13'-dioxide (Example 1041) and iodomethane, and the desired product, (lS,3 ^f R,6'R,7'S,8'E,10'S,irS,12 ^f R)-6-chioro-7'-methoxy-10 ⁱ ,ir,12'- trimethy 1-3 ,4 -dihy dro-2H, 15 Ή-spiro [naphtha! ene- 1,22'-

/. I [20]oxa[13]thia[l,14]diazate1ra^

n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (400MHz,

CD3OD) δ 7.75 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.2, 8.5 Hz, 1H), 7.13 (d, J=2.3 Hz, HI).7.05 (dd, ./ 2.0.8.0 Hz, III).6.94 (d, ,/ 8.2 Hz, 1H), 6.90 (d, ./ 2.0 Hz, ill). 6,01 (dd, ./ 6.K. 15.5 Hz, 111).5.50 (dd, 90.15,5 Hz, !!!}.4.35 - 4, 11 (m, 2H), 4.10 (s, 2H), 3,83 (d, J=15.5 Hz, IH), 3.73 (dd, «/=3.3, 9.0 Hz, 1H), 3.65 (d, J=14.1 Hz, IH), 3.24 (s, 3H), 3.10 (dd, J=10.0, 15.3 Hz, IH), 2.87 - 2.73 (m, 2H), 2,62 (br. s., IH), 2.53 - 2,44 (m, !!!).2.37 - 2,28 (m, IH), 2.25 (dt, ,/ 36.6.9 Hz, IH), 2.11 (d, .7=13,7 Hz, H), 2.00 - 1,65 (m, 6H), 1.54 (d, ./ 70 Hz, 3H), 1.47 (t, J=12.5 Hz, IH), 1.12 (d, J=2.0 Hz, 3H), 1.10 (d, J=1.8 Hz, 3H). m/z (ESI, +ve ion) 627.2 (M+H) ⁺ .

EXAMPLE 1048. (lS,3 ^, R,6 ^, R,7 ^, S _s 8 ^, E,10 ^, S,H ^, S,12 ^, R)-6-CHLORO-7 ^, -(2- METHOXYETHOXY)- 10', 1 Γ, 12'-TRIMETHYL-3 ,4-DII-FtDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (18,3¾,6ΊΙ,7 ,8Έ,10 ^! 8,1Γ8,12¾)-6-ΰ1ι1θΓθ-7'~1ινάΐΌχν- 10 12'4riniethyl-3,4-dihydro-2H

[20]oxa[I3]thia[l,I4]diazatetTacyd

n]-15'-one 13',13'-dioxide (Example 1041) and l-bromo-2-methoxy ethane (Aldrich), and the desired product, (1 S,3'R,6'R,7'S,8'E,1 Q'S,1 I'S,12'R.)-6-chloro- 7'-(2-methoxy ethoxy)- 10', 11 ', 12 ^! ~tnmethyS -3,4-dihy dro-2H, 15Ή- spiro [naphthalene- 1 ,22'- [20joxa[13]thia[l,14]diazatetracycfo[½

n]-15'-one 13',13'-dioxide was isolated as a white solid, ^" Ή NMR (500MHz,

CD3OD) δ 7.63 (d, J=8,6 Hz, 1H), 7.06 (dd, J=2.2, 8.6 Hz, IH), 7.00 (d, J=2.2 Hz, ill).6.93 (dd, ,/ 1.6.8.2 Hz, IH), 6.80 (dd, ./ 4.6.4463.4 Hz, 2H), 5.87 (dd, J=9.0, 15.4 Hz, IH), 5.39 (dd, 90.15,6 Hz, IH), 4,00 (dd, 3.4.7.1 Hz, ill). 3.97 (s, 2H), 3.74 (dd, ,7=3,5, 9.2 Hz, IH), 3,69 (d, ./ 14.7 Hz, IH), 3.53 (d, ./ 14.4 Hz, IH), 3.49 - 3.29 (m, 5H), 3.25 (s, 3H), 2.97 (dd, ./ 9.7.15.3 Hz, IH), 2.74 - 2.60 (m, 2H), 2,57 - 2.46 (m, IH), 2.42 - 2.35 (m, IH), 2,27 - 2.09 (m, 2H), 1,99 (d../ 1 .411/. IH), 1.87 - 1.68 (m, 5H), 1,60 (dd,J=9,8, 19.1 Hz, IH), 1,40 (d, .7=7,1 Hz, 3H), 1.37 - 1.30 (m, IH), 0,97 (d, J=7.1 Hz, 6H). m/z (ESI, +ve ion) 671,4 (M+H) ⁺ .

EXAMPLE 1049. (ΙΒ^^,όΊ ^ ,δΈ,ΙΟ'β,ΙΙ^, 'Κνό-ΟΗΕΟΚΟ-ΙΟ',Ι ,Π'-

TMMETHYL-7'-(2-(4-MORPHOLI YL)ETHOXY)-3,4-DIHYDRO-2H,15H-

SPTRO[NAPHTHALENE-l,22'-

|2θ!() Λ| I 311 HI Λ| I„ ! -I |ί)Ι.\/.νΠ: E R. AC VC ^' E C)i 147.20 ' ".O ¹ '" ¹ |Pi-:N i ACOS A [8,16,18,24]ΤΕΤΡ^4ΕΝ]-15'-ΟΝΕ 13',13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (1S,3 ^! R,6'R,7'S,8'E,10'S,1 l'S,12'R)-6-chioro-7'-hydroxy- 10^11\12 ^, -^β 1-3,4-ά άτο-2Η ₅ 15Ή-8ρΪΓθ[ ^η αρΗΛ3]βηβ-1,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide (Example 1041) and 4-(2-bromoethyl)morpholine

(Aldrich), and the desired product, (18,3¾,6¾,7'8,8Έ,10 ^! 8,11 ,12¾)-6-οωοΓθ- 10*, 11 ', 12' rimethyl-7'-(2-(4-morpholm}'])ethoxy)-3,4-dihydro-2H, 15Ή- spiro[naphthalene-l,22'-

[20]oxa[13]thia[l,14]diazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή NMR (400MHz,

CD3OD) 57.77 (d, J=8.4 Hz, IH), 7.19 (dd, J=2.2, 8.3 Hz, IH), 7.15-7.11 (m, IH), 7.09 (dd, =1.8, 8.4 Hz, IH), 6.94 (d, J=1.8 Hz, IH), 6.88 (d, J=7.8 Hz, IH), 6.14 (dd, ./ 6.5.15.8 Hz, IH), 5.50 (dd, ,7=9.2, 15.7 Hz, IH), 4.16 - 4.09 (m, IH), 4,07 (s, 2H), 3,89 (dd, =3.0, 8.9 Hz, IH), 3.84 id../ 145 Hz, IH), 3.79 (t, 47 Hz, 4H), 3,69 (dd, .7=5.1, 11.2 Hz, IH), 3.64 (d, .7=13.7 Hz, IH), 3.55 - 3.48 (m, lH),3.40-3.33 (m, 2 H overlap with solvent), 3.09 (dd, J=9.8, 15.7 Hz, IH), 2.86 - 2,72 (rn, Hi!}.2.58 - 2,19 (m, 3H), 2.12 hi.,/ 127 Hz, IH), 1.99 - 1.91 (ra, 2H), 1.91 - 1.64 (m, Hi).1,50 (d, ./ 7.0 Hz, 3H), 1.48 - 1.41 (m, H), 1.09 (d, ./ 7.2 Hz, 3H), 1.06 (d, ./ 7.0 Hz, 3H). m/z (ESI, +ve ion) 726.3 {W W) .

EXAMPLE 1050. ETHYL (((1S,3'R,6 ^! R,7'S,8'E,10'S,1 l'S,12 ^, R)-6-CHLORO- 10 1^12'-TRIMETHYL-13',13 ^! -DIOXIDO-15 ^! -OX()-3,4-DIHYDRO-2H- SPIRO [NAPHTHALENE- 1,22"-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] -7'-YL)OXY) ACETATE

The title compound was prepared in an analogous manner to that described in Example 720 using (1S,3¾.,6 ^! R,7'S,8 ^! E,10 ^! S,1 l'S,12'R)-6-chloro-7'-hydroxy- 10 ^, ,i ,12 ^, -trimethyl-3,4-dihydro-2H,15'H-spirofnaphthalene-l,22' -

n]-15'-one 13',13'-dioxide (Example 1041) and ethyl aciyiate, and the desired product ethyl (((1 S,3*R,6'R,7'S,8'E, 1 O'S, 11 'S, 12'R)-6-chloro-10' ₅ 11 M 2'-trirneih> 1 -

13',13'"dioxido-15'-oxo-3,4-dihydro-2H-spiro[napMialene-l ,22'-

[20]oxa[13]thia[l,14]diazate1ra<y^

n]-7'-yl)oxy)acetate was isolated as a white solid. ¾ NMR (400MHz, CD3OD) δ 7.75 (d, =8.4 Hz, IH), 7.19 (dd, =2.2, 8.5 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.04 (dd, ,/ 2.O.8.2 Hz, 1H), 6.94 (d, ./ 8.0 Hz, III .6.89 id. J=2.0 Hz, IH), 5.97 (dd, ,/ 68.15,5 Hz, ill).5.54 (dd, ./ 8.1.15.4 Hz, !!!).4.26 - 4.18 (m, 21 \) 4.13 (dd, J=3,l, 7.2 Hz, IH), 4,11 (s, 2H), 4,02 (d, ./ 2.2 Hz, 2H), 3.95 (dd, «/=3.5, 9,0 Hz, IH), 3.82 (d, J=15.3 Hz, 1H), 3.65 id../ 13.9 R/. IH), 3.12 (dd, J=9.6, 15.3 Hz, 1 IT), 2.87 - 2.73 (m, 2H), 2,63 - 2.55 (m, 2H), 2.32 (t, ,/ 92 Hz, IH), 2.27 - 2.20 (111, IH), 2,11 id,../ 13.3 Hz, IH), 2.01 - 1.83 (m, 5H), 1.76 (dd, .7=9.4, 18.4 Hz, IH), 1.54 (d, J=7.0Hz, 3H), 1.52 - 1.44 (m, IH), 1.31 (t, J=7.1 Hz, 4H), 1.10 (t, ,7=6.6 Hz, 6H). m/z (ESI, +ve ion) 699.2 (M+H) ⁺ . EXAMPLE 1051. (((Ιβ^'ΙΙ,ό'Κ,Τβ,δΈ,ΙΟ'β.ΙΙ'β,Ι^-ό-ΟΗ^Κ Ο-ΙΟ'.ΙΓ,ΙΪ- TRIMETHYL- 13 ', 13'-DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H-

SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAENj-7 ^! -YL)OXY)ACETIC ACID

2,316 The title compound was prepared in an analogous manner to that described in Example 992 using ethyl ( ({ I J'! VR.7'S.8'! ^; .. I U'S. I I ^" S. ! 2 ^' R)-6-ch!oro- 10', 1 j2'4rimethyl~13 ^, J3'-dioxido-15'-oxo-3,4-dihydi -2H"SpiiO[naphthalene- 122'-

n]-7'-yl)oxy)acetate (Example 1050), and the desired product,

(((lS,3 ^! R,6'R,7'S,8 10'S,ll'S,12'R)-6-chIoro-10',ir,12'-tnmethyl 3',13'- dioxido-15'-oxo-3,4~dihydro~2H-spiro[na

[20]oxa[13]thia[l,14]diazatetracyc ^

n]-7'-yl)oxy)acetic acid was isolated as a white solid. ¾ NMR (500MHz, CD3OD) 07.74 (d,■/ 8.6 Hz, III).7.19 (dd, ./ 2.3.8.4 Hz, ill .7.12 id../ 2.2 Hz, III). 7,03 (dd../ 2.0.8.1 Hz, 111).6.93 id.,/ !-! I Hz, !H), 6.88 id../ I.? Hz, ill).5,99 (dd, ./ 6,8.15,4 Hz, I Hi,.5.55 (dd, ,7=9,3, 15.4 Hz, ill).4,16 - 4.11 (m, III).4.10 (s, 2H), 3.99 (d, J=4.2 Hz, 2H), 3.97 - 3.94 (m, IH), 3.83 (d, J=15.2 Hz, 1H), 3.65 (d, ./ 14.2 Hz, ill).3,1 I (dd, ./ 9.7.15.3 Hz, 111).2.86 - 2.73 (rn, 2H), 2.63 - 2,56 (111, 2H), 2.31 (t, .7=9.2 Hz, 1H), 2.26 - 2.20 (m, IH), 2.11 (d, ,7=13,4 Hz, IH), 2.00 ·· 1.80 (m, 6H), 1.78 - 1.70 (m, IH), 1.54 (d, .7=7.1 Hz, 3H), 1.51 - 1.40 (m, IH), 1.10 (d, ./ 7.! Hz, 6H). fz (ESI, +ve ion) 671.2 {\MI} . EXAMPLE 1052. 2-(((lS,3'R,6'R,7'S,8'E,10'S,irS,12'R)-6-CHLORO-

10', 11 ',12'~TRIMETHYL~13', 13'-DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H- SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-7'-YL)OXY)-N,N-DIMETHYLACETAMIDE

z 31 / The title compound was prepared in an analogous manner to that described in Example 995 using (((ΙΒ^'Κ,όΊ ^ ,δΈ,ΙΟ'βαΐ^/Ι^^-ό-οΙιΙθΓθ-Ιθ ΐ Γ,^'- trimethyl-13', 13'-dioxido-l 5'-oxo-3,4-dihydro-2H-spiro[naphthalene- 1 ,22'- |20jo\aj I3|ihi;i| i I4|dia/aicuac> ciol 14.72. ⁽ ! ^; " O ^1' ' ⁿ jpen!acosa|H.i .i .24jieirae n]-7'-yl)oxy)acetic acid (Example 1051) and dimethylamine (40 wt % solution in water, Acros), and the desired product, 2-(((lS,3'R,6'R,7'S,8'E,10'S,ll ^! S,12'R)-6- chloro-10', 1 Γ, 12'-tnmethyl~ 13', 13"-dioxido-l 5*-oxo-3,4-dihydro-2H- spiro [naphthalene- 1 ,22'-

n|-7'-yl)oxy)-N,N-dimethylacetamide was isolated as a white solid. Ή NMR (400MHz, CD3OD) δ 7.75 (d, ,/ 8.4 Hz, Hi).7.19 (dd, 22.8,5 Hz, !!!}.7.13 (d, ./ 2.2 Hz, 1H), 7.04 (dd, J=2.0, 8.2 Hz, ill).6.94 (d, ./ 8.0 Hz, IH), 6.89 (d, ./ 1.8 Hz, III).6.01 !dd../ 6.7.15.4 Hz, III).5.56 (dd../ H.7.15.9 Hz, III .4.22 - 4,03 (m, 6H), 3.92 (dd, ,/ 3.3.9,2 Hz, III).3.84 (d, 15.5 Hz, ill).3,65 id. J=13.9 Hz, 111).3,18 - 3.08 (m, ill).3.04 (s, 311).2.97 (s, 3H), 2.88 - 2.71 (111, 3H), 2.64 - 2.56 (m, 2H), 2.36 - 2.20 (m, 2H), 2.11 (d, ./ 13.1 Hz, 1H), 2.01 - 1.88 {in.4H), 1.75 (dd, ,/ v.2.17.8 Hz, ill).1.54 (d, ./ 7. ϊ Hz, Ml).1.47 (t, ./ 1 .9 Hz, IH), 1.11 (d, ./ 1.6 Hz, 3H), 1.10 (d, 16 Hz, 3H). m/z (EST, +ve ion) 698.3 (M+H) ^" * ^' .

EXAMPLE 1053, (1 S,3'R,6 ^! R,7'S,8'E,10'R,1 rS,12'R)-6-CHLORO-7 ^! - ΜΙΊΙΙΟΧΥ - 10', 1 Γ , 12'-TRlMETHYL - 3,4-DlH YDRO-2H, 15 Ή- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE

2,318

The title compound was prepared in an analogous manner to that described in Example 720 using (1S,3'R,6'R,7'S,8 ^! E,1() ^! RJ rS,12'R)-6-chloro-7'-hydroxy- 10', 1 l ^f ,12'-trimethyl-3,4-dihydro-2HJ5 ^f H-spiro|naphthalene-l,22'- [20]oxa[13]thia[U4]diazatetra^

n]-15'-one 13',13'-dioxide (Example 1042) and methyl iodide, and the desired product, (Ιβ^'Κ,ό'Κ,Τ'β,δΈ,ΙΟ'Κ,ΙΙ'β,Π'Κ^ό-οωοΓ θ-Τ'^βώο^-ΙΟ'.ΙΙ',Ι^- trimethy]-3,4-dihydro-2H,.15'H-spiro[naphthalene-l,22'-

n|-15'-one 13',13'-dioxide was isolated as a white solid. ^! H NMR (500MHz, CD3OD) δ 7.76 (d, 86 Hz, III).7.19 (dd, ,/ 22.8.3 Hz, ill).7, 15 - 7.10 (m, 2H), 7,05 (d,«/=1.2Hz, 1H), 6.96 (d, .7=8.1 Hz, IH), 6.10 (dd, ,7=4,1, 15.8 Hz, 111).5.46 (dd, J=9.G, 16.4 Hz, IH), 4.35 (dd, ./ 2.2.6.6 Hz, ill).4.21 - 4.09 (m, 3H), 3.82 (d, ./ 15.4 Hz, 1 H), 3.65 (d, ./ 13.9 Hz, 1 H), 3.24 is.3H), 3.17 ( dd, ./ 9.3.16.1 Hz, 111).2.86 - 2,74 (ra, 211).2,39 (dd, ./ 7.6.17.6 Hz, IH), 2.32 - 2.22 (m, IH), 2.13 - 2.03 (m, 2H), 2.03 - 1.93 (m, 3H), 1.93 - 1.67 (m, 5H), 1.53 - 1.45 (m, IH), 1.39 (d, ,7=7.1 Hz, 3H), 1.10 (d, J=6.8Hz, 3H), 1.07 id../ 6.8!!/. Ml), m/z (ESI, +ve ion) 627.2 ( +H) ⁺ .

EXAMPLE 1054. (1S,3'R,6'R,7'S,8'E,10'S,1 l'S,12'R)-6-CHL()RO-12'-ETHYL- 7"-HYDROXY-l 0', 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή-

SP1RO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l 4]DIAZATETRACYCLO|;i4.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,I8,24]TETRAENl-15'-ONE 13',13'-DTOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,ll'S,12'R)~6-CHLORO-12'-ETHYL-7'-HY DROXY- 10', 1 r-DI ETHYL-3 ,4-DIHYDRO-2H, 15 'H-SP1RO [NAPHTHALENE - 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(1 S,3'R,6'R, 7'S,8'E, 1 O'S, 1 I'R, 12'S)-6-CHLORO- 12'-ETHYL-7'-HYDROXY- 10', 11 '-DIMETHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,irR,12'S)-6-CHLOR()-12'-ETHYL-7' -HYDROXY- 1 Q',1 -DIMETHYL-3 ,4~DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TOIA[1,14]DLAZATETRACYCLO[147.2X) ³ '^0 ¹⁹ - ²⁴ ]P

[8,16,18,24]TETiL4EN]-15'- ONE 13 ',13 '-DIOXIDE

The title compounds were prepared in an analogous manner to that described in Example 1041, Steps 1 to 3, but replacing the mixture of (1S,2S)~1,2~ dimethyloxirane and (lR,2R)-l,2-dimethyioxiraiie with a mixture of (2S,3S)-2- ethyl-3-methyloxirane and (lR,2R)-l-ethyi-2-methylcyciopropane (pewpared according to the procedure by Hobson, Lindsay A.et al.; Organic and

Biomolecular Chemistry, 2012 , vol.10, # 37 p.7510 - 7526) in Step 1, and the desired product, (1S,3'R,6'R,7'S,8'E,10'S,1 rS,12'R)-6-chioro-12'-ethyl-7*- hydroxy-10 ^f ,ir-dimethyl-3,4-dihydiO-2H,15'H-spiro[naphtha]ene-l,2 2 ⁱ - [20]oxa[13]thia[l,14]<fcazatetracyc ^

n]-15'-one 13',13'-dioxide or (Ιβ^'Κ,ό'Κ^'β,ΒΈ,ΙΟΊΙ,Ι Γβ,^'ί^-ό-οΜθΓθ-η'- ethy l-7'-hydr oxy- 1 ⁽⁾ ', 1 -dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]1hia[ l, 14]diazatetTacyclo[147.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae n]-15'-one 13', 13'-dioxide or (1S,3'R,6'R,7'S,8'E,10'S,1 l 'R,12'S)~6~chloro~12'~ ethyl-7'-hy droxy- 10', 1 l'-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[ 13]thia[l ,14]cUazatetracyclo^

n]-15'-one 13',13'~dioxide or (lS,3'R,6'R,7 ^! S,8'E, 10'R,irR,12'S)-6-chloro-12'- ethyl-7'-hy droxy- 10', 1 r-dimethyl-3,4-dihy dro-2H, 15 Ή-spiro [naphtha! ene- 1 ,22'- [20joxa[13]thia[ l, 14]diazatetracycfo[14.7^

n]-15'- one 3',13'~dioxide was isolated (first eluting major isomer out of preparative reverse phase HPLC). ¾ NMR (400MHz, CD3OD) δ 7.75 (d, J=8.6 Hz, IH), 7.19 (dd, J=2.2, 8.6 Hz, IH), 7.12 (d, J=2.2 Hz, IH), 7.04 (dd, =1.7, 8.1 Hz, I H), 6.92 (d, ./ K.O Hz, 2H), 5.95 (dd, ,/ 6.5. 15.7 Hz, IH), 5.63 (dd, ./ 8. ! . 14.6 Hz, IH), 4.21 (dd, ,/ 3.5. 8,6 Hz, I H), 4.09 (s, 2H), 3.96 (dd, J=4,9, 9.6 Hz, IH), 3.83 (d, .7=14,3 Hz, H), 3,65 (d, .7=14.3 Hz, IH), 3.10 (dd, J=9.8, 15.1 Hz, IH), 2.89 - 2.69 (m, 2H), 2.63 (br. s., IH), 2.46 - 2.36 (m, I H), 2.35 - 2.23 (m, 2H), 2, 17 - 2.04 (m, 3H), 1.99 - 1.65 (m, 7H), 1 ,51 - 1.42 (m, I H), 1.26 - 1.21 (m, 3H), 1 ,09 (d, «/=7.2 Hz, 3H), 1.06 (d, .7=7,0 Hz, 3H). ni/z (ESI, +ve ion) 627.2

( M I i )

EXAMPLE 1055 , (1 S,3'R,6 ^! R,7'S,8 ^! E, 10'R, 11 'S, 12'R)-6-CHLORO-l 2'-ETHYL- 7'-HYDROXY - 10', 11 '-DIMETHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO INAPHTHALENE- 1.22'-

[20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA

[8,16,18,24]TETiL E ]-15'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R, 7'8,8'E, 10'S, 1 Γ8, 12'R)-6-CHLORO- 12'-ETHYL-7'-HYDROXY-

10'J l '-DIMETHYL-3,4-DIHYDRO-2H, 15'H-SPIRO[NAPHTHALENE-l,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'S,l l 'R,12'S)-6-CHLORO-12'-ETHYL-7'-HYDROXY- 1 Q',1 -DTMETHYL-3 ,4-DTHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'~ |2 ⁽ >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC VCE C)l i J 7.2 (Γ ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24]TETiL4EN]-15'-ONE BVD'-DIQXIDE OR

(1S,3¾,6 ^! R;7^,8T,1()'RJ1 ^, R 2'S)-6 HL0R0-12'-E HYL-7 ^! -HYDR0XY- 10^11'-DIMETHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-1,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16.18,24]TETRAEN]-15'- ONE 13',13'-DIOXIDE

The title compound was obtained as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 1054. Ή NMR (400MHz, CD3OD) δ 7.76 (d, J=8.4 Hz, Hi).7.19 (dd, 22.8,5 Hz, !!!}.7.11 (dd, «7=2.0, 8,0 Hz, 2H), 7.05 (d, .7=2.0 Hz, IH), 6,96 (d, J=8.0 Hz, IH), 5,77 (dd, J=6.1, 15.7 Hz, IH), 5.61 (ddd, .7=1.6, 6.7, 16.0 Hz, IH), 4.35 (dd, J=2.9, 7.4 Hz, IH), 4.14 (dd, ,7=12.3, 18.4 Hz, 2H), 3.99 (dd, ./ 4.8.7.7 Hz, IH), 3.84 (d, ,7=15.3 Hz, 111).3.66 (d, ,7=14.1 Hz, IH), 3.20 - 3.10 (m, IH), 2,88 - 2.73 (m, 2H), 2,47 - 2.33 (m, IH), 2.33 - 2.19 (m, IH), 2.19 - 1.92 (m, 6H), 1.92 - 1.69 (m, 6H), 1.53 - 1.44(m, IH), 1.25 {I. J 7.4 I ! . l).1.11 (d,J=6.8Hz, 3H), 1.06 (d,, =6.8Hz, 3H). m/z (ESI, +ve ion) 627.2 (M-i-H) ⁺ ,

2,322, EXAMPLE 1056. (1 S,3'R,6'R,7'S,8'E, lO'S, 11 ^* R, 12"S)-6-CHLORO-l 2'-ETHYL- 7'-HYDROXY- 10', 11 '-DIMETHYL-3 ,4-DIHYDRO-2H, 15 Ή- SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA

[8,16,18,24]TETRAEN] S'~ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,10'R,irS,12'R)-6-CHLORO-12'-ETHYL-7'-HYDROXY- 10',ll'-DlMETHYL-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22' - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(lS,3'R,6 ^, R,7'S,8'E,10'R,ll'R,12'S)-6~CHLORO-12 ^! ~ETHYL-7 ^, -HYDROXY- 10^11 ^, -DIMETHYL-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPHTHALENE-1.22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'S,ll'S,12'R)-6-CI-ILORO-12'-ETHYL- 7'-HYDROXY- 10',I l'-DTMETHYL-3 ,4-DTHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- |20i()XA| ΐ: ΐΗ1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA [8, 16 -15'-ONE i.T.i 3'-DK)XIDE

The title compound was obtained as a single isomer (third eluting peak) from the reverse phase preparative HPLC in Example 1054. Ή NMR (400MHz, CD3OD) δ 7.74 (d, .7=3893.7 Hz, IH), 7.19 (dd, .7=2.2, 8.5 Hz, 2H), 7.13 (d, .7=2.3 Hz, 111).7.10 (d, 7 X2 Hz, ill).6.94 (d, J=8.4 Hz, IH), 6.01 (dd, 5.2.15,2 Hz, 1H), 5.63 - 5.58 (m, ill).4.19 - 4. (m, ill).4.07 - 4.01 (m, IH), 3,80 (q, «7=4.8 Hz, IH), 3.64 - 3.43 (m, 4H), 2.86 - 2.73 (m, 2H), 2.69 (br. s., IH), 2.60 (br. s., IH), 2.50 - 2.34 (m, IH), 2.30 - 2.17 (m, IH), 2.13 - 1.94 (m, 3H), 1.94 - 1.86 (m, l).1.86- 1.55 (m,5H), 1.21 (t, J=7.3 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 1.06 (d, J=0,8 Hz, 3H). m/z (ESI, +ve ion) 627.2 ( +H) ⁺ .

EXAMPLE 1057. (lS,3¾,6¾,7'S,8'E,10'S,irS,12 ^f R)-6-CHLORO-12'-ETHYL- Τ-ΜΕΤΉΟΧΥ-Ι 0', 11 '-DlMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE-l,22'-

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^! S,8'E,10'R,irS,12'R)-6-CHLORO-12'-ETHYL-7'-METHOXY- 10',ll'-DlMETHYL-3,4-DlHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22' - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE OR

(lS,3'R,6 ^! R,7'S,8'E,10'S,ll'R,12'S)-6-CHLORO-12'-ETHYL-7'-ME ^' raOXY- 10^11 ^, -DIME^ΉYL-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPH^ΉALE E-1.22 ^, - [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -*0 ¹⁹ ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,irR,12'S)-6-CHLOR()-12'-ETHYL-7'-ME THOXY- 10',I l'-DIMETHYL-3 ,4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'~ |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC i (>! i 47.20 ^; ".O ¹ " ^M |PH\ i ACOSA

[8,16,18,24]TETRAEN]-15'- ONE 13 ',13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (IS^'R^'R^yS^'E O'S l'S _^ ^'^-e-chio o-n'-ethyl-?'- hydroxy- 10', 11 '-dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'-

n]-15'-one 13',13'-dioxide or (lS^'R^'R.T'S.S'E.lO'I^ll'S RJ-e-chloro-l - e1hyl-7'-hydrox>'-10',l -dimethy]-3,4-dihydro-2H,15Ή-s iroΓna hthalene-l,22'- [20]oxa[13]thia[l,14]diazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ · ²⁴ ]pentacosa[8,Ί6,18,24]tetrae n]-15'-one 13',13'-dioxide or

ethy l-7'-hydroxy- 1 ()', 1 -dimethyl-3,4-dihydro-2H,l 5'H-spiro| naphthalene- 1 ,22'-

n]-15'-one 13*, '-dioxide or (18,3¾,6Ί 7'8,8Έ,10¾,11¾,12 ^! 8)-6~ΰΜθΓθ-12 ^! " ethyl-7'-hydroxy-10', 1 l'-dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[U4]diazate1r^

n]-15'- one 13',13'-dioxide (Example 1056), and the desired product,

(IS^'R^'l^y'S^'E O'SJl'S 'Ri-e-chloro-n'-e^l^'-methoxy-lO'Jl'- dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1, 14]diazatetracy clo[ 14.7.2.0 ^3>6 .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13*,13'-dioxide or (18,3¾,6Ί ,7'8,8Έ,10*¾1Γ8,12¾)-6~ΰΜθΓθ-12'" ethyl-7'- methoxy- 1 ()', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiroj naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatefra^^

n]-15'-one 13',13'~dioxMe or (1S,3'R,6'R,7'S,8'E,10'S,1 l'R,12'S)-6-chloro-12'- ethyl-7'- methoxy- 10', 1 l'-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20joxa 13]thia[l,14]diazatetracycfo[14.7.^ _^

n]-15'-one 13',13" -dioxide or (1S,3'R,6'R,7'S,8'E,10'R,1 l'RJ2 ^f S)-6-chloro-12 ^f - ethyl-7'- methoxy- 10', 11 '-dimethyl-3,4-dihy dro-2H, 15 Ή-spiroj naphthalene- 1 ,22'- [20]oxa[13]tMa[l,14]cUazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'- one 13',13'-dioxide was isolated as a white solid, ^" Ή NMR (400MHz, CDCh) δ 7.54 (d, J=8.6 Hz, IH), 7.02 (dd, ./ 2.3.8.6 Hz, IH), 6.93 (d, .7=2,2 Hz, IH), 6.76 (s, 2H), 6.67 (s, IH), 5.81 (dd, ./ 6.4.15.6 Hz, Ml).5.29 (dd, J=8.5, 15.9 Hz, IH), 3.97 (q, ./ 7.0 Hz, IH), 3.92 (s, 2H), 3.89 (br. s., IH), 3.64 (d, ,/ 155 Hz, IH), 3.56 - 3.48 (m, 2H), 3,07 (s, 3H), 2,81 (dd, ./ 5.1.15.3 Hz, IH), 2,65 - 2.54 (m, 2H), 2.39 (br. s., IH), 2.33 - 2,24 (m, IH), 2.20 - 2.02 (m, 2H), 1.95 - 1.77 (m, 3H), 1.72 - 1.55 (m, 5H), 1.44 (dd, J=9.4, 18.6 Hz, IH), 1.28 - 1.19 (m, 2H), 1 1! 7.1 Hz, Mil 0.93 id../ 7.2 H/.3H), 0,87 (d,J=7.0Hz, 3H). m/z (ESI, +ve ion) 641.2 ( +H) ⁺ .

EXAMPLE 1058. (3R,6R,7S,8E,10S,1 lR,15S,25S)-6'-CHLORO-7-HYDROXY- 10-METHYL~3',4'-DIHYDRO-2'H, 18H-SPIRO[ 13,23-DIOXA- 16-ΊΉΙΑ- 1 , 17- DIAZAPENTACYCLO|;i7.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² - ²⁷ ]OCTACOSA-8,19,21,27- TETR AENE-25 , 1 '-NAPHTH ALEN] - 18-ONE 16,16-DIOXTDE OR

(3R,6R,7S,8EJ0R,llR,15S,25S)-6'-CHLORO-7-HYDROXY-10-METHY L-3',4'- DIHYDRO-2'H, 18H-SP1RO [ 13,23 -DIOXA- 16-THIA- 1,17- DIAZAPENTACYCL()[17.7.2.() ³ - ^f () ⁱⁱⁱⁱ⁵ .0 ²² ' ²⁷ jOCTACOSA-8,19,21,27- TETRAENE-25 , 1 '-NAPHTH ALEN] - 18-ONE 16, ! 6-DIOXIDE OR

{3R.6R.7S.8I·. I OS. I I . ! ^R.25S)-6'-Cl U ,()R )-7-l Γν DROXY - 1 -\Π ^; . Ι I Y I -3'.-!'- DIHYDRO-2'H, 18H-SPIRO [ 13,23 -DIOXA- 16-THIA- 1,17- DIAZAPENTACYCLO|;i7.7.2.0 ³ ' ⁶ .0 ¹¹ - ¹⁵ .0 ²² ' ²⁷ ]OCTACOSA-8,19,21,27- TETRAENE-25 , 1 '-NAPHTH ALEN] - 18-ONE 16, 16-DIOXIDE OR

(3R,6R,7S,8E, 1 OR, 11 S, 15R,25 S)-6'-CHLORO-7-HYDROXY- 10-METHYL-3',4'- DIHYDR()-2'H,18H-SPIRO[13,23-DIOXA-16-THIA-l,17- DTAZAPENTACYCLOP 7.7 2.0 ^; ".0 ^{1 ] J 5} .0 ²² · ²⁷ ] OCTACOS A-8, 19,21 ,27- TETRAENE-25 , 1 '-NAPH ^' ffl ALEN] - 18-ONE 16, 16-DlGXIDE

The title compounds were prepared in an analogous manner to that described in Example 1041 using 3,4-epoxytetrahydrofuran (TCI America) and 1- methyl-2-propenylmagnesium chloride in Step 1 , and the desired product, (S^eR S^EJOS/riRJSS^SSi-e'-chloro-T-hydroxy-lO-methyl-S^'-dihydro- 2Ή, 18H-spiro| 3,23-dioxa- 16-thia- 1, 17- dia.zapentacydo[17.7.2,Q ³ ^ Ο ¹¹ ·^ _^

naphthalen]-18-one 16,16-dioxide or (3R,6R,7S,8E, lGR,l lR,15S,25S)-6'-chloro- 7-hy droxy -10-methyl-3',4'-dihy dro-2'H, 18H-spiro[ 13,23-dioxa- 16-thia- 1,17- diazapentacydo[17 .2.0 ³ W

naphthalen]~ 8~one 16,16-dioxide or (3R,6R,7S,8E,10S, 1 lS,15R,25S)-6'-chloro- 7-hydroxy-10-methyl-3\4'-dihydi -2 ^, H,18H-spiro[13,23-dioxa-16 hia-l,r7- <iiazapentacydo[17 .2.0 ³ ' .0 ⁿ " ^l ^0 ²² ' ²⁷ ]octacosa-8,19,21,27-1^a∞

naphthalen]-18-one 16,16-dioxide or (3R,6R,7S,8E,10R, 1 l S,15R,25S)-6'-chloro- 7-hydroxy-10-methyl-3^4'-dihydro-2¾18H-spiro[13,23-dioxa-16 -thia-l,17- diazapentac} lo( 17 .2.0 ³ ' ⁶ .0 ⁱⁱ ' ⁱ ^0 ²² - ²⁷ ]octacosa-8,19,21,27 etraene-25,l^ naphthalen]-18-one 16,16-dioxide was isolated (fourth eluting major peakr out of preparative reverse phase HPLC). ¾ NMR (500MHz, ( ! ⁾ < ⁽ )!)) δ 7.75 id. .7=8.6 Hz, IH), 7.19 (dd, 23.8.4 Hz, 1H), 7.13 (d, .7=2.0 Hz, 1H), 7,05 (dd, J=2.0, 8.1 Hz, IH), 6.96 (d, J=8J Hz, IH), 6.91 (d, .7=1.7 Hz, H), 5.86 (dd, .7=6.0, 15.5 Hz, IH), 5.70 (dd, J=6.1, 16.1 Hz, IH), 4.29 (dd, J=4.6, 10.5 Hz, IH), 4.26 - 4.20 (m, 2H), 4.15 - 4.13 {in. IH), 4.11 (d, ./ 3.9 Hz, 2H), 3.84 id../ 14.9 Hz, IH), 3.73 - 3,58 (m, 3H), 3. 0 (dd, .7=9.5, 15,7 Hz, H), 2.92 - 2,73 (m, 3H), 2.64 (d, 6 Hz, H), 2,56 - 2,39 (m, IH), 2.28 - 2.15 (m, H), 2.13 (d, ./ 13.2 Hz, IH), 2,02 - 1.61 (m, 7H), 1.57 - 1.43 (m, IH), 1.10 {±./ 7.1 Hz, 3H). ni/z (ESI, +ve ion) 627.2 ί\!·1Ι) . EXAMPLE 1059. (1 S,3'R,6'R,8'E, 10'S, 1 l'S)-6-CHLORO- 1 ()', 1 l'-DIMETHYL- 3,4-DIHYDRO-2H,7 ⁱ H,I5'H-SPIRO[ APHTOALENE-l,22 ^f - |2 ⁽ >X A| i ? I ! f ΠΛ| ί i J li^f AZ.Vf l: E RAC YCE C)l i J 7.20 ' ".U ^1* " ¹ |PH\ i ACOSA

[8, 16, 18,24] TETRAE E] -7', 15'-DIONE 13', 13'-D10XIDE OR

(lS,3¾,6'R,8 10¾, ¾)-6-CHLORO-10 ⁱ ,ir-DTMETOYL-3,4-DiHY ^' DRO- 2H,7'H,15'H~SPIRO[NAPHTHALENE-i,22 ^! ~

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [8, 16, 18 ,24] TETRAENE] -7', 1 S'-DIONE 13', 13'-DI()XIDE

STEP 1: (2R,3S)-2,3-DIMETHYLBUTANE-l,4-DIOL Meso-2,3-dimethylsuccinic acid (4.1 g, 28.1 mmol, Aldrich) in THF (28 ml) was transferred into a 3 neck round bottom flask fitted with an addition funnel, nitrogen inlet and thermometer and the flask was cooled to 0 °C. Lithium aluminum hydride (2.0 M solution in tetrahydrafuran, 72.9 ml, 72.9 mmol, Aldrich) was then cannulated into the addition funnel, and then added into the stirred cooled mixture dropwise over 15 min. After the addition was completed the reaction was allowed to warm to rt overnight under a nitrogen atmosphere. The next day the reaction was quenched with MeOH dropwise at 0 °C and then 20 % OH aq solution was added slowly. The reaction mixture was stirred at 0 °C for 20 min, 50 mL of EtOAc was added and the organic phase was dried over MgS04 filtered and concentrated. The crude material was purified by

chromatography through a 120 g ISCO gold column, eluting with 50-100 % EtOAc in hexanes to give (2R,3S)-2,3-dimethylbutane- 1 ,4-dioI (2.7 g, 22.9 mmol).

STEP 2: (2 ,3S)-4-((TERT-BUTYLDIMETOYLSILYL)OXY)-2,3- DIMETHYLBUTAN-1 -OL AND (2S,3R)-4-((TERT-

BUTYLDIMETHYLSILYL)OXY)-2,3-DlMETHYLBUTAN-l-OL

To a suspension of sodium hydride (60% dispersion in mineral oil, 1.35 g, 33.6 mmol, Aldrich) in THF (90 ml) at 0 °C under a N2 atmosphere was added a solution of (2R,3S)-2,3-dimethylbutane-l ,4-diol (2.65 g, 22.4 mmol) from Step I above in THF (15mL) dropwise over 20 min. After addition the reaction was heated at 55°C for 45 min and then it was cooled down to 0°C and treated with a solution of tert-butyldimethylsilyl chloride (3.38 g, 22.4 mmol) in THF (15 mL). The reaction was stirred at rt overnight. The next day the reaction was quenched with saturated NH4C1 and diluted with EtOAc. The separated aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated in vacuo. The crude material was purified by chromatography through a 120 g ISCO gold column, eluting with 0-20 % EtOAc in hexanes to give a mixture of (2R,3S)-4-((tert- butyklimethylsilyl)oxy)-2,3-dim.ethylbiitan~l -ol and (2S,3R)-4-((tert- butyldimemylsilyl)oxy)-2,3-dimethylbutan-l-ol (3.7 g, 15.9 mmol). STEP 3 : (2R,3 S)-4-((TERT-BUTYLDIMETHYLSILYL)OXY)-2,3- DIMETHYLBUTANAL AND (2S,3R)-4-((TERT- ΒυΤΥΊ.ΟΙΜΕΤΗΥΙ.8ΐΕΥΕ)ΟΧΥ)-2,3-ΒΙΜΕΤ ΗΥΊ.ΒυΤΑΝΑΙ-,

To a white slurry solution of(diacetoxyiodo)benzene (5.34 g, 16.6 mmol, Aldrich) and a mixture of (2R,3S)-4-((tert-butyldimethylsilyl)oxy)-2,3- dimethylbutan- ^' l-ol and (2S,3R)-4-((teit-butyldimethylsilyl)oxy)-2,3- dimethylbutan-l-ol from Step 2 above in DCM (50 ml) was added 2,2,6,6- tetramethylpiperidinooxy (0.118 g, 0.75 mmol, Acros) in one portion at it, and then the stirred for overnight. The reaction mixture was poured into 100 ml of DCM and washed with 30 mL of sodium bicarbonate saturated, aq solution and 30 mL of brine, dried o v er MgSCk The sol v ent was removed. The crude material was purified by chromatography through a 120 g ISCO gold column, eluting with 0-10 % EtOAc in hexanes to give a mixture of (2R,3S)-4-((tert- butyldimethylsilyl)oxy)-2,3-dimethylbutanal and (2S,3R)-4-((tert- but dimethylsilyl)oxy)-2,3-dimethylbutanal (1.8 g, 7.8 mmol, 51.9 %).

STEP 4: (2S,3S)-2 _s 3-DlMETHYLPENT-4-EN-l-OL AND (2R,3R)-2,3- DIMETHYLPENT-4-EN- 1 - OL A solution of methyl phenylphosphonium bromide (8,06 g, 22.58 rnmol, Aldnch) in T ^' HF (75 ml) was treated with butyllithium (2.5M solution in hexane, 7.53 ml, 18.8 mmol, Aldrich) at 0 °C. After 10 min, the resulting yellow mixture was allowed to stir at rt for 20 min. After this time, a mixture of (2R,3S)-4-((tert- butyldimethylsilyl)oxy)-2,3-dimethylbutanal and (2S,3R)-4-((tert- butyldimethylsilyl)oxy)-2,3-dimethylbutanal (1.73 g, 7.5 mmol) from step 3 in THF (5 ml) was added to the reaction at -78 °C. After 10 min, the reaction mixture was stirred at 0 °C for 2 h and then quenched with saturated aq. NH ₄ C1 solution and water (20 ml). The mixture was poured into a separator}' funnel containing ether (50 ml). After separating the layers, the aqueous layer was extracted with ether (3 x 50 ml). The organic layers were combined, dried with MgS0 ₄ , and evaporated in vacuo to give the crude desired product.15 mL of 1 N HCl/ether (Aldrich) was added this crude product in 10 mL of DCM, the reaction mixture was stirred at rt for 30 min, TLC showed the deprotection was completely. The reaction mixture was concentrated and purified by chromatography through a 40 g 1SCO gold column, eluting with 0-30 % EtOAc in hexanes to give a mixture of (2S,3S)-2,3-dimethylpent-4-en-l-ol and (2R,3R)-2,3-dimethylpent-4-en-l-ol.

STEP 5: (2S,3S)-2,3-DIMETHYLPENT-4-ENE-l-SULFONAMIDE AND (2R,3R)-2,3-DIMETHYLPENT-4-ENE-l-SULFONAMlDE

The title compound was prepared according to the general procedure described in intermediate EE22, Steps 3-6 using a mixture of (2S,3S)-2,3- dimethylpent-4-en-l -ol and (2R,3R)-2,3-dimethylpent-4-en-l-ol in Step 4.

STEP 6: (S)-6'-CHLORO-N-(((2S,3S)-2,3-DIMETHYLPENT-4-EN-l- YL)SULFONYL)-5-(((lR,2R)-2-((S)-l- HYDROXY ALLYL)CYCLOBU L)ME HYL)-3 4,4',5-TETRAfrYDRO- 2H,2H-SPIRO[BENZO[B] [l ,4]OXAZEPINE-3,r-NAPHTHALENE]-7- CARBOXAM1DE AND (3S)-6'-CHLORO-N-(((2R,3R)-2^-DIMETHYL-4- PENTEN- 1 - YL)SULFONYL)-5-((( 1 R,2R)-2-(( 1 S)- 1 -HYDROXY-2-PROPEN- 1 - YL)CYCLOBUTYL)METOYL)-3',44',5-TETRAI-IYDRO-2TI-SPIRO[l ,5- -3 , 1 '-NAPHTHALENE] -7-CARBOXAMIDE

The title compound was prepared in an analogous manner to that described in Example 719, Step 1, using (S)-6'-chloro-5-(((lR ₅ 2R)-2-((S)-l- hydroxyall l)c clobutyl)methyl)-3',4,4',5-tetrahydfo-2H,2'H- spiro[benzo[b][l,4]oxazepine-3, l '-naphthalene]-7-carboxylic acid (Intermediate AAl lA) and (2S,3S)-2,3-dimethylpent-4-ene-l-sulfonamide and (2R,3R)-2,3- dimethylpent-4-ene-l -sulfonamide from Step 5 above, and the desired product, a mixture of (S)-6'-chloro-N-(((2S,3S)-2,3-dimethy lpent-4-en- 1 -y sulfonyfJ-S-

spiro[benzo[b] [ 1 ,4]oxazepine-3, 1 '-naphthalene] -7-carboxamide and (3 S)-6'~ chloro-N-(((2R,3R)-2,3-dimethy3-4-penten-l-yl)sulfonyl)-5-(( (l R,2R)-2-((l S)-l - hydrox>'-2-propen-l-yl)cA ]obuty])methyl)-3^4,4 5-tetrahydro-2'H-spiro[l ,5- benzoxazepine-3, 1 '-naphthalene] -7-carboxamide was isolated.

STEP 7: (S)-5-(((lR,2R)-2-ACRYLOYLCYCLOBUTYL)METHYL)-6'-

CHL0R0-N-(((2S ₅ 3S)-2,; DIMETHYLPF;NT-4-EN-1-YL)SLT..F0NYL)- 3' _; 4' ₅ 5.TETRAHYDRO-2H,2'H-SPIRO[BENZO[B][ l,4]OXAZEPINE-3,r- NAPHTHALENE] -7-CARBOXAMIDE AND (3S)-5-(((l R,2R)-2-

ACRYL0YLCYCL0BUTYL)METHYL)-6*-CHL0R0-N-(((2R,3R)-2,3- DIMETHYL-4-PENTEN-l-YL)SULFONYL)-3 4,4',5-TETRAHYDRO-2'H-

SPIRO[l,5-BENZOXAZEPINE-3,r-NAPHTHALENE]-7-CARBOXAMIDE

To a 250-niL round-bottomed flask, Dess-Martin periodinane (556 mg, 1.31 mmol, Aldrich) was added a mixture of (S)-6'-chloro-N-(((2S,3S)-2,3- dimethy lpent-4-en- 1 -y 3)suIfony l)-5 -((( 1 R,2R)-2-((S)- 1 - hydroxyallyl)c lobu d)methyl)-3',4,4',5-tetrahydro-2H,2'H- spiro [benzo[b] [ 1 ,4] oxazepine-3 , 1 '- aphtha! ene] -7-carboxamide and (3 S)~6'~ cWoro-N-(((2R,3R)-2,3-<Ume l-4^enten-l-yl)sulfonyl)-5-(((l R,2R)-2-((l S)-l - hydrox '-2-propen-l-yl)cA ]obuty])me1hyl)-3^4,4 5-tetrahydro-2'H-spiro[l ,5- benzoxazepine-3,r-naphthalene]-7-carboxamide (685 mg, 1.092 mmol) from Step 6 above in DCM (22 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was was concentrated and purified by chromatography through a 80 g ISCO gold column, eluting with 0-20 % EtOAc(contammg 0.3% HO Ac) in hexane to give (S)-5-(((lR,2R)-2-acryloylcyclobut\'l)methyl)-6'-chloro-N- (((2S,3S)-2,3-dimethylpent-4-en-l -yl)si^^

spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxami de and (S)-5- (((lR,2R)-2-acr oylc\ lobutyl)me l)-6'-chloro-N-(((2R,3R)-2,3-dimethylpent- 4-en-l-yl)sulfonyl)-3',4,4',5-tetrahydro-2H,2H-spiro[benzo[b ] [l,4]oxazepine-3,r- naphthalene] -7-carboxamide (520 mg, 0.83 mmol).

STEP 8: (lS,3'R,6'R,8'E,10'S,i i ' S)-6-CHLORO- 10', 1 l'-DIMETHYL-3,4- DIHYDRO-2H,7'H, i 5' I i-SPlROj X APi I T! ΙΛΙ .ί ^' Μ: · I ..?.?'·

[20]ΟΧΑ[13]ΤΗΐΑ[1 ,14]ΟΙΑΖ^^

[8, 16, 1 8 , 24] TETRAENE] -7', 15'-DIONE 13', 13'-DIOXIDE A 500 mL of round bottom fl ask was charged with a mixture of (S)-5- (((lR,2R)-2-acr oylc clobutyl)methyl)-6 ^, -chloro-N-(((2S,3S)-2,3-dimethylpent- 4-en-l -yl)sulfonyl)-3^4,4',5-tetrahyclro-2H,2H-spiro[benzo[b] [ l,4]oxazepine-3, - naphthalene] -7-carboxamide (from Step 6) and (S)-5-(((lR,2R)-2- acryloylc lobutyl)me1hyl)-6'-chloro-N-(((2R,3R)-2,3-dirnethylpent-4-en -l- yl)sulfollyl)-3 ^, ,4,4',5 etrallydro-2H,2Ή-s iro[benzo[b] [ l,4]oxaze ine-3 Γ- naphthalene]-7-carboxamide (400 mg, 0.64 mmol) from Step 7 above in DCE (220 mL), It was stirred at rt under N ₂ bubbling through the reaction mixture for 10 min. To the homogeneous solution was added Hoveyda-Grubbs 11 (120 mg, 0.19 mmol, Aldrich) at rt, and then the mixture was heated to at 80 °C for 5 h under a N ₂ atmosphere. The reaction mixture was concentrated and purified by chromatography through a 220 g 1SCO gold column, eluting with 0-40% EtOAc (containing 0.3% AcOH) in hexane to give (1 S,3'R,6 ^! R,8'E,10'S, 1 l'S)-6-chloro- l O^ir-dime^l-S^-dih dro^H UlSH-spirotnaphthalene-l^T- [20]oxa[13]thia[l ,14]diazate1racyclo[14.7.2.0 ³ ^^ _^

ne]-7',15'-dione 13 ',13 '-dioxide or (l S,3'R,6'R,8'E,10'R,l l'R)-6-Chloro-10',H'- dimethyl-3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]thia[ l, 14]diazatetTacyclo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8, 16,18,24]tetrae ne]-7',15'-dione 13',13'-dioxide (143 mg, 0.24 mmol, first eluting major peak) and (lS,3'R,6'R,8'E,10'R,l l 'R)-6-Chloro-10',ir-dimethyl-3,4-dihydro-2H,7'HJ spiro [naph thalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetra^^

ne]-7',15'-dione 13 ',13 '-dioxide or (l S,3'R,6 ^* R,8'E,10'S,irS)-6-chloro-10 ^* ,l l'- dimethyl-3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l ,22'-

[20]oxa[13]thia[ l, 14]diazatetTacyclo[147.2.0 ³ ^0 ^{] 9} ' ²⁴ ]pentacosa[8, 16,18,24]tetrae ne]-7',l S'-dione 13', 13'-dioxide (1 S,3'R,6'R,8'E, 10'S, 1 l ^* S)-6-chloro-l 0', 1 1 '- dimethyl-3,4-dihydro-2H,7'H,15 ^, H-spiro[naphthalene-l,22'-

[2Q]oxa[ 13]thia 1 , 14] diazatetra^

ne]-7',15'-dione 13', 13'-dioxide (145 mg, 0.024 mmol, second eluting major isomer). ¾ NMR (400MHz, CDCb) δ 8.18 (br. s., i l l ). 7.66 (d, ./ 8. Hz, I I I ). 7.19 ίόά.,Ι 22.8.5 Hz, ill).7,11 id../ 3651.5 Hz, ill).7,04 (s, ill).6,94 - 6.88 (m, 2H), 6,84 (dd, J 6.8.16.2 Hz, 1H), 5.98 (d, J=14,9 Hz, I Hi.4.09 (s, 2H), 3.80 (d, J=15.3 Hz, 1H), 3.71 - 3.61 (m, 2H), 3.56 - 3.46 (m, 2H), 3.35 (d, ./ !H.4 Hz, IH), 3.09 - 2.98 (m, 2H), 2.82 - 2.76 (m, 2H), 2.51 (br. s., 1H), 2,40 (br. s., 1H), 2.06- 2.00 (m, III).1.95 - 1.66(m,6H), 1,31 (d, J=6.7 Hz, 3H), 1.14 (d, J=T4.5 Hz, IH), 1.03 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 597.2 ί\ί H) .

EXAMPLE 1060. (IS,3'R,6'R,7'S,8'E,10'S,1 l ^, S)-6-CHLORO-7'-HYDROXY- 10', 1 l'-DIMETHYL-3,4-DIHYDRO-2H, 15 ^! H-SPIRO [NAPHTHALENE- 1 ,22'- |2ί!!0ΧΛ| Π ΙΊ I Ι1Λ| 1.14|! IA/.\ TL i ^' RACYCf.OI i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETR _j! 4ENl-15'-ONE 13 ^! ,13'-DIOXIDE OR

(1S,3'R,6'R,7'R,8'E,10'S,11 ^, S)-6-CHLORO-7'-HYDROXY-10 ^* ,l 1 '-DIMETHYL- 3 ,4-DlH YDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

POIOXAIISITHIAII.MIDIAZATETRACYCLOIT^T^.O'^.O^^IPENTACOSA

[8,16,I8,24]TETRAENl-15'-ONE 13',13'-DIOXIDE OR

(lS,3 ^, R,6 ^! R,7'S,8'E,10'R,ll'R)-6-CHLORO-7'-HYDROXY-10 ir-DLMETHYL- 3 ,4-DIHYDRO-2H, 15 ^! H-SPlRO [NAPHTHALENE- 1 ,22'-

[20iOXA[13]THIA[l,14]DIAZATETRACYCLO[14.7.2.0 ³ > ^, 0 ^!9 - ²⁴ ]PENTACOSA [8J6,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR AMG3101256.

(1 S,3'R,6'R,7'R,8'E, 10'R, 11 'R)-6-CHLORO-7'-HYDROXY-10',l 1 '-DIMETHYL- 3,4-DIHYDRO-2H,l 5TI-SPIRO[N APHTH ALENE-1, 22'-

[20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETR AC YCLO [ 14.7.2.0~3,6~.0~19,24~]PENT ACOS A[8, 16, 18,24] TETRAEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

An 25 mL of round bottom flask was charged with

(1 S,3'R,6'R,8 ^! E, lO'S, i l'S)-6-chloro- 10', 1 l ^! -dimethyl-3,4~dihydro-2H,7 ^! H, 15Ή- spiro [naphthalene- 1,22'-

ne]-7 ^* , l 5 -dione 13', 13'-dioxide or (1 S,3'R,6'R,8'E,1 Q'R,i i'R)~6~Chloro-iO', l ! '- dimethyl-3,4-dihydro-2H,7'H, 15'H-spiro[naphthalene-l ,22'- [2C)joxa[13]thia[ l, 14]diazatetracycfo[½

ne]-7',15'-dione 13',13'-dioxide (Example 1059; 140 mg, 0.234 mmol, first eluting major isomer) and 3 mL of THF, and then borane tetrahydrofuran complex (1.0 M soution in tetrahydrofuran, 350 μΐ, 0.35 mmol, Aldrich) was added at 0 °C. ^r riie reaction mixture was stirred at 0 °Cfor 1 h,. The reaction mixture was quenched with MeOH and added saturated aq. NH4C1 solution, and then 30 mL of EtOAc. The organic layer was concentrated and purified by chromatography through a 40 g ISCO gold column, eluting with 0-40% EtOAc (containing 0.3% AcOH) in hexane to give (l S,3'R,6'R,7'S,8 10 ^f S, l l'S)-6-chloro-7'-hydroxy- ! Ο', 1 1'- dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene-l ,22'- [20]oxa[13]tMa[l,14]diazatetracy^

nj-15'-one 13 ',13 '-dioxide or (1S,3'R,6'R,7'R,8'E,10'S,1 l'S)-6-chIoro-7'-hydroxy- 10', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthal ene- 1 ,22 ^s - [20]oxa[13]thia[l,14]diazatefra^

]~15'-one 13', 13'-dioxide or (1 S,3'R,6'R,7'S,8'E, 10'R, 11 ^! R)-6-chk>ro-7'-hydroxy~ 10', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20joxa 13]thia[l,14]diazatetracy ^

n]-15'-one 13',13"-dioxide or

10', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphlhalene- 1 ,22'- [20]oxa[13]tMa[l,14]diazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ pentacosa[8,16,18,24]tetraen ]-15'--one 13',13'-dioxide (25.1 mg, 0.042 mmol, second eluting major peak). ^] H NMR (500MHz, CDsOD) δ 7.75 (d, J=8,6 Hz, IH), 7.19 (dd, .7=2.2, 8.6 Hz, 1H), 7.12 (d, ./ 2.2 Hz, 1H), 7.02 (dd, J=2.0, 8.1 Hz, 1H), 6.94 id../ 8.1 Hz, 1H), 6.89 (d,■/ i.7 Hz, Hi).5.89 (dd, ./ 7.6.15.2 Hz, ill .5.69 (dd, ./ 8.6.15.2 Hz, !!!). 4.20 (dd, ./ 3.5.8.7 Hz, 111).4.13 (dd, ,/ 45.15,0 Hz, ill.4,09 is.2H), 3,85 id. J=15.2 Hz, ill).3.67 (d, .7=14,2 Hz, H), 3.12 - 3,02 (m, 2H), 2.86 - 2.74 (m, 2H), 2.49 - 2.39 (m, 2H), 2.27 (quin, J=9.2 Hz, IH), 2.11 (d, J=13.7 Hz, IH), 2.05 - 1.80 (m, 7H), 1.74 (dd,J=9.5, 19.1 Hz, !!!).1.50 - 1.42 (m, IH), 1.16 id. 7.1 Hz, 3H), 1.02 (d, J=7,l Hz, 3H). m/z (ESI, +ve ion) 599.2 (M+H) ⁺ .

EXAMPLE 1061. (lS,3 ^! R,6 ^, R,7'R,8'E,10'S,ll'S)-6-CHLORO-7 ^! -HYDROXY- 10'Jl'-DIMETHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0~3,6~.0~19,24~] PENT ACOS A[8, 16, 18,24]TETRAEN] - 15'-QNE 13', 13'-D10XIDE OR

(lS,3'R,6 ⁱ R,7'S,8¾10'S,ll'S)-6-CHLORO-7 ⁱ -HYDROXY-I0',Il'-DIMETHYL- 3.4-DIHYDRO-2J !.Ι 'ί i~Si ^! IRO| \ΛΡ! ΠΊ !.\ί Ι·.\! ^; -Ι.22'-

[20]OXA[13]THIA[l,14]DIAZATETRACYCLO[14.7.2.0^^0 ¹⁹ - ²⁴ ]i TACOSA [8,16,18,24]TETRAENj-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7 ^f S,8'E,I0'R,irR)-6-CHLORO-7'-T-iYDROXY-10',ll'-DIMETI-I YL- 3,4-DMYDRO-2H, 15'H-SPIRO[N APHTHALENE- 1 ,22'-

[20]OXA[13]THIA[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,I8,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR AMG3101256.

(1S,3'R,6'R,7'R,8'E,10'R,1 rR)-6-CHLQRQ-7'-HYDRQXY~10',l 1 '-DIMETHYL- 3 ,4-DIHYDRQ-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[ 1 , 14 ] DI AZ ATETRAC YCLO [ 14.7.2.0-3,6-0-19,24-]PENT ACQS A[8, 16, 18,24] TETRAEN] - 15 '-ONE 13 ', 13 '-DIOXIDE

The title compound was obtained as a single isomer (first eluting major peak) from the reverse phase preparative HPLC in Example 1060. Ή NMR (400MHz, ( f) :()!)) 67.77 (d, ./ 8.4 Hz, 1H), 7.50 (d, J=1.8 Hz, ill).7.20 (dd, ./ 2.2.8.5 Hz, ill .7.16 - 7.11 (m, 2H), 6.94 (d,J=8.2Hz, 1H), 5.53 - 5.44 (m, 2H), 4,11 (s, 2H), 3.98 - 3.86 (m, 2H), 3.73 (d, J=13.9 Hz, !!!}.3.64 (br. s., 1H), 3,04 (dd, J=4.4, 15.4 Hz, 1H), 2.89 - 2.73 (m, Ml).2,59 (d, J=6.1 Hz, 2H), 2.36 - 2.29 (m, ill).2.20 - 2.03 (m, 2H), 1.97 - 1.81 (m, 5H), 1.77 - 1.63 (m, 2H), 1.50 - 1.41 (m, 1H), 1.23 id../ 6.8 Hz, 3H), 0.94 (d, J==7.() Hz, Ml), m/z (ESI, +ve son) 599.2 (M+H) ⁺ .

EXAMPLE 1062. (1 S,3 ^! R,6'R,7'R,8'E, 10'R, 11 'R)-6-CHLORO-7 ^, -HYDROXY- 10'Jl'-DIMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ '^0 ¹⁹ ' ²⁴ ]PENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'S,8'E,10'R,irR)-6-CIlLORO-7'-HYDROXY-10',ll '-DIM:ETHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO[[ 14,7.2.0 ³ · ⁶ .0 ^Ι9 · ²⁴ ]ΡΕΝΤ ACOS A[8,16,18,24]TETRAEN]-15'-QNE 13 ', 13 '-DIOXIDE OR

(lS,3'R61 7 ^, S,8T 0^,irS)-6 mORO-7 ^, ~HYDROXY-10',ir-DlMETHYL- 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ '«0 ¹⁹ ^ ⁴ ]PE TACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(18 ₅ 3'11,6 ^, Κ,7 ^, Κ,8Έ^Ο ^, 8^Γ8)-6-ΟΗίΟ^-7 ^, -ΙΐΥΟΚΟΧΥ-10 1Γ-ΟΙΜΕΤΗΥί- 3,4-DTHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

|2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί ACYC i (>! i 4.7.20-3.6 -.0· 19.2-1 · |Ι ^' \Ύ ACOS Α[ 8, 16, 18,24] TETRAEN] -15'— ONE 13', 13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 1060 using (1 S,3'R,6'R,8'E, 10'R, 11 'R)-6-chloro- 10', 11 '-dimethyl-S^- dihydro-2H,7'H,15'H-spiro[naphthalene-l,22'-

[20]oxa[ 13]thia[ 1 , 14] diazatetra^

e]-7',15 ^* -dione 13',13'-dioxide or (lS,3'R,6'R,8'E,10'S,ll'S)-6-chloro-10',l 1'- dimethyl-3,4-dihydro-2H,7'H, I 5'H-spiro[naphthalene-l ,22'- [20]oxa[ 13 ]thia[ 1,14] diazatetracy clo[ 14.7.2. u"'.0 ¹⁹ - ²⁴ pentacosa[8, 16, 18,24]tetraen ej-7',15'-dione 13',13'-dioxide (Example 1059, second eluting major peak), and the desired product, (lS,3'R,6¾,7'R,8T 10'R,ri¾)-6-chloro-7'-hydroxy-10',l Γ- dimethyl-3,4-dihy dro-2H, 15'H-spiro[naph†Jialene- 1 ,22'- .iH.24|teiraen ]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,l( ⁾ 'R,irR)-6-chloro-7'4iydroxy- 10', 1 r-dimethyl-3,4-dihydro-2H,15'H-spirofnaphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetra^

]-15'-one 13',13'-dioxide or (18,3Έ,6¾,7¾,8Έ,1()'8,1Γ8)-6-Λ1οίΌ-7'4ι>^Γθχ ν-

10', 1 r-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthal ene- 1 ,22' ~

[20]oxa[ 13]thia[ 1 , 14] diazatetracy clo[ 14.7.2, 0 ³ ' ⁶ .0 ¹⁹ - ²⁴ pentacosa[8, 16, 18,24]tetraen ]-15'-one 13',13'-dioxide or (lS,3 ^* R,6'R,7 ^! S,8'E,10'S,l l'S)-6-chloro-7'-hydroxy- 1 ()', 11 '-dimethyl-3,4-dihydro-2H, 15'H-spiro| naphthalene- 1 ,22'- [20]oxa[ 13]thia[ 1, 14] diazatetracy clo[ 14.7,2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide was isolated (first elutmg major peak out of reverse phase preparative HPLC). ¾ NMR (500MHz, (O DD) δ 7.73 (d, ./ K.3 Hz, III). 7.19 (dd, ,/ 23.8.4 Hz, ill).7, 12 (d, ./ 2.2 Hz, IH), 6.99 - 6.87 (m, 3H), 5.87

(dd, .7=6.8, 13.4 Hz, IH), 5.46 (dd, J=8.6, 15.2 Hz, III).4.11 (br. s., 2H), 4.04 (dd, J=4.9, 15.2 Hz, IH), 3.98 (br. s., 1H), 3.64 (d,J=13.0 Hz, IH), 3.52 - 3.37 (m, 4H), 3.07 (dd, ./ 7.6.15.2 Hz, IH), 2,86 - 2.74 (m, 2H), 2.59 (br. s., IH), 2.44 (br. s., IH), 2.21 - 1.73 (m, 10H), 1.61 - 1.46 (m, IH), 1.13 (d, ./ 6.8 Hz, 3H), 1.01 (d, J=6,8 Hz, 3H). m/z (ESI, +ve ion) 599.2 ( +H) ⁺ .

EXAMPLE 1063. (1S,3'R,6'R,7'S,8'E,10'R,11 'R)-6-CHLORO-7*-HYDROXY- 10Vi -DIMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- |2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-l.()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETR _J! 4EN1-15'-0NE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 10'R, 11 'R)-6-CHLORO-7'-HYDROXY- 10',11 '-DIMETHYL- 3,4-DIHYDRO-2H,15'H-SPiRO[NAPHTHALENE-l,22'-

[20]OXA[13]TfflA[l,14]DIAZATETlACYCLO[[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)S A[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR OR

(lS,3'R,6'R,7'S,8'E,10'S,ll'S)-6-Cffl-mO-7'-HYDROXY-10',l l'-DrMETHYL- 3 ,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DIOXIDE OR

(lS,3'R,61 7 ^, R,8¾10'S;irS)-6-CHLORO-7'-HYDROXY-10 ^! ;il'-DIME ^r rHYL~ 3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147.2.0~3,6~ ~19,2 ~]PEOT ACOS A[8, 16, 18,24]TETRAEN]-15'--ONE 13', 13'-DIOXJDE

The title compound was obtained as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 062. ^" Ή NMR (400MHz, ( f) :()!)) 67.73 (d, ./ 8.4 Hz, IH), 7.19 (dd,■/ 2.5.8.4 Hz, 2H), 7.13 (d,■/ 2.3 Hz, IH), 7.00 (dd, ./ 2.2.9.4 Hz, IH), 6.93 id../ 8. ⁽ Ϊ Hz, IH), 6.05 - 5,93 (m, IH), 5.62 (ddd,J=1.6, 4,3, 15.8 Hz, IH), 4,14 (s, 2H), 4,06 - 4.02 (m, IH), 4,00 (dd, ./ 5.3.15,3 Hz, IH), 3.68 - 3.47 (m, 3H), 3,22 - 3.09 (m, IH), 2.86 - 2.73 (m, 2H), 2.67 (d, J=10.2 Hz, IH), 2.45 (br. s., IH), 2.39 (br. s., IH), 2.15 - 1.94 (rn, 4H), 1.91 (br. s., 2H), 1.79 (br. s,, 3H), 1.71 - 1.50 (ra, IH), 1.13 id, J=7.0 Hz, 3H), 1.01 (d, «/=6.8 Hz, 3H). m/z (ESI, +ve ion) 599.2 (M+H) ⁺ .

EXAMPLE 1064. (1S,3'R,6 ^* R,7'S,8'E,1Q'S,11'Si-e-CHLORO-y-METOOXY- 10^11'-DIMETHYL-3,4-DIHYDRO-2H,15H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 10'S, 11 'S)-6-CHLORO-7 ^* -METHOXY-l 0 ^f , 11 '-DIMETHYL- 3. l-! ⁾ !HVOR()-2i !.Ι 'ί i-Si ^! IR()| ΝΛΗ! i l l J-.\! .-!.22'-

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i,.()l i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETR _J! 4EN1-15'-0NE 13 ^! ,13'-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 11 'R)-6-CHLORO-7'-METHOXY-l 0', 11 '-DIMETHYL - 3.4-f)iHYi)RO-2l 1. i i-SPIR()|\ API Π ΗΛΙ.ΓΝΙ - 1 ,22'-

[20]OXA[13]TOL [1,14]DL ZATEIIACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,I6,I8,24]TETRAEN1-15'-0NE 13',13'-DIOXIDE OR

(1 S,3'R,6 ^! R,7'R,8'E, 10'R, 11 'R)~6-CHLORO-7'~METHOXY-10', 11 '-DIMETHYL- 3 ,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL)[14.7.2.0 ³ - ⁶ .0 ^!9 - ²⁴ ]PENTACOSA

[8, 16, 18,24]TETRAEN]-15'-ONE 13", 13-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (1S,3'R,6 ^! R,7'S,8 ^! E,10 ^! SJ l'S)-6-chloro-7'-hydroxy-10',l Γ- dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-l,22'- [20joxa[13]thia[l,14]diazatetracyc

n]-15'-one 13',13'-dioxide or (1 S,3'R,0'R,7'R,8'E,10'S,1 l'S)-6-chioro-7'-hydroxy- 10', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]cUazatetracyc^

]-15'-one !3', i3'-dioxide or (lS,3'R,6'R,7 ^f S,8'E,10'R, il'R)-6-chloro-7'-hydroxy- 10', 1 T-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene-l ,22 ^s - IKJ4jtctrao n|-15'-one 13'.13'-dioxide or (18,3¾,6¾,7'¾8Έ,10¾,11¾)-6-ΰ1ι1ο™-7'-1ι^Γθχν - 10', 1 r-dimethyl-3,4-dihydro-2H,15'H-spirofnaphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetr^

]-15'-one 13',13'-dioxide (Example 1060) and methyl iodide, and the desired product, (lS,:rR,6 ^f R,7'S,8 i,i0 ⁱ S,l !'S)-6-chloro-7'Hnethoxy-10',ll'-dimethyl-3,4- dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'- IKJ4jtctrao nj-15'-one 13'.13'-dioxide or (lS,3 ^! R,6'R,7'R,8'E,10'S,irS)-6-chioro-7'-methoxy- 10', 11 '-dimethyl-3,4-dihydro-2H, 15'H-spirofnaphthalene-l ,22'-

2,343 [20]oxa[13]thia[l ,14]diazatefra^

n]-15'-one 13',13 ^! ~dioxMe or (lS 3¾ >¾ ^,8'E, 10'RJ. rR)-6-chloro-7'-m.ethoxy- 10', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20joxa| 13]thia[ l, 14]diazatetracycfo[½

n]-15'-one 13', 13"-dioxide or (l S^'R _^ e'R 'R.S'E O'I^l l'R^e-chloro-T-metho y- 10', 1 l'-dimethyI-3,4-dihy dro-2H, 15'H-spiro[naphlhalene-l ,22'- [20]oxa[13]tMa[l,14]cUazatetrac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-15'-one I 3',13'-dioxide was isolated as a white solid. Ή NMR (500MHz,

CD3OD) δ 7.75 (d, J=8.3 Hz, IH), 7.18 (dd, J=2.2, 8.6 Hz, 1H), 7.12 (d, J=2,0 Hz, IH), 7.02 (dd, =l ,7, 8.1 Hz, IH), 6.93 (d, J=8.1 Hz, IH), 6.87 (d, J=1.5 Hz, IH), 5.99 (dd, ./ 7.3. 15.2 Hz, I H), 5.52 (dd, J=9.3, 15.4 Hz, IH), 4.18 (dd, ./ 4.9. 14.9 Hz, IH), 4,08 is. 2H), 3,85 i d. ./ 15.2 Hz, IH), 3,73 (dd, ./ 3.4. 9.3 Hz, I H), 3.67 (d, .7=14.2 Hz, IH), 3.24 (s, 3H), 3.12 - 3.04 (m, 2H), 2,86 - 2,73 (m, 2H), 2.58 - 2.46 (m, 2H), 2.39 - 2.27 (m, IH), 2.11 (d, ./ 13.4 Hz, i l l ). 2.08 - 1.99 (m, 2H), 1 .98 - 1.79 (ra, 5H), 1 ,75 (dd, J=10.5, 19.6 Hz, IH), 1.49 - 1 .39 (m, IH), 1 , 15 (d, J=6.8 Hz, 3H), 1.05 (d, «7=6.8 Hz, 3H). m/z (ESI, +ve ion) 613.2 (M+H) ⁺ .

EXAMPLE 1065.

METHOXYETHOXY)-10',1 r-DIME ^'" fflYL-3,4-DIHYDRO-2H,15'H- SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[14.7.2.0 ³ "^0 ^{] 9} ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 -DIOXIDE OR

(1 S,3'R,6'R,7 ^! R,8'E, lO'S, 11 ^, S)-6-CHLORO-7'-(2-METHOXYETHOXY)-10 ^, ₅ 11 '-

DIMETHYL-3,4-DIHYDRO-2H, 15TI-SPIRO[NAPHTHALENE-l,22'- [20]OXA[ 13]THI A[ 1 , 14]DI AZ ATETRAC YCLO

[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA[8, 16,18,24]TETRAEN]-15'--ONE 13',13'~

DIOXIDE OR (lS,3'R,6'R,7 ^! S,8'E,10'R,l l ^! R)-6-CHLORO-7 ^! -(2- METHOXYETHOXY)- 10', 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1 ,22 ^* -[20] OXA[ 13]THI A[ 1 , 14]

DIAZATETRACYCLO[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ² ]PENTACOSA[8,16,18,24]TETRAENj- 15'--ONE 13', 13'-DIOXIDE OR (1S,3TL6'R,7'R,8'E,1Q'R,1 l'R)-6-CHLORO-7'- (2-METHOXYETHOXY)- 10', 11 '-DIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO[NAPHTHALENE- 1.22-

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/.ΥίΤΤΗΛ(ΎΠ.ϋΙ i 4.7.2 U · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [ 8, 16, 18,24]TETRAEN]-15'— ONE 13', 13'-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^, R,6'R,7'S,8'E,l()'S,irS)-6-chloro-7'-hydroxy-l()',ir- dimethyl-3,4-dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]thia[U4]diazatetra<yc^^^

n]-15'-one 13', 13 '-dioxide or (1S,3'R,6'R;7'R,8'E,10'S,1 l'S)-6-chioro-7'-hydroxy- 10', 11 '-dimethy 1-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- |20ίοχ;ιί I3|lhia| U |dia/aielracveioj 14.7.2 ίί ^{; !} '.o ^1;i peniacosaiS. i 6J 8.24|iein¾cn ]-15'~one 13',13'-dioxide or (18,3Ί ,6¾,7 ^! 8,8Έ,10ΊΙ,1Γ1)-6-ΰωοΐΌ-7'-1ΐ}^Γθχν- 1 ()', 11 '-dimethy 1-3,4-dihy dro-2H, 15'H-spiro| naphthalene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetTacy lo[147.2.0 ³ '^0 ^]9 ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'~dioxide or (1S,3'R,6'R,7'R,8'E,10'R,1 l ^* R)-6-chloro-7'-hydroxy- 10', 1 T-dimethyl-3,4-dihy dro-2H, 15'H-spirojnaphthal ene- 1 ,22'- iH.24|teiraen ]-15'— one 13',13'-dioxide (Example 1060) andl-bromo-2-methoxyethane

(Aldnch), and the desired product, ( 1S,3'R,6'R,7'S,8'E,10'S,1 l'S)-6~chloro~7'~(2~ methoxy ethoxy)- 10', 1 Γ-cUmethy l-3,4-dihydro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa[13]tMa[l,14]diazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',!3'~dioxide or (1S,3'R,6'R,7'R,8'E,10'S,1 l'S)-6-chloro-7'-(2- methoxy ethoxy)- 10', 11 '-dimethyl-3 ,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- i 4.7.2.< ⁾ ' ".n ^| ' ^l jpenia€osa|8.i J .24jteirae n|-15'-one 13',13'-dioxide or (Ιβ^'ΙΙ,ό'Κ,Τβ,δΈ,ΙΟ'Κ,ΙΙ'^-ό-οΗΙθΓθ-� �^- methoxy ethoxy )-10',i -dimethyl-3,4-dihydro-2H,15'H-spiro[naphtha]ene- 1,22'- [20]oxa[13]tMa[l,14]diazatetracyc^

n]-15'-one 13',13'-dioxide or (1S,3'R,6 ^! R,7 ^* R,8'E,1C)'R,1 l'R)-6-chloro-7'-(2- methoxy ethoxy)- 10', 1 l'-dimethyl-3 ,4-dihy dro-2H,l 5'H-spirofnaphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracycio[14.7.2,0 ³ ' ⁶ .0 ¹⁹ ' ² '¾

n]-15'-one 13',13'-dioxide was isolated as a white solid. Ή MR (400MHz, CD3OD) 7.64 (d,■/ 8 Hz, III).7.06 (dd, ./ 1.8.8.8 Hz, ill).6.99 (d, ./ 2.2 Hz, ill).6,94 (d, ./ 8.0 Hz, Hi).6.79 (s, Hi).6.75 (d, ,/ 82 Hz, ill).5.95 (dd, ./ H!.8.16.8 Hz, 1H), 5.38 (dd, ,1=9.1, 15.4 Hz, 1H), 4.04 (dd, ./ 5.7.15.3 Hz, 1H), 3.94 (s, 2H), 3.82 - 3.70 (m, 2H), 3.54 (d, ,/ 14.3 Hz, 1H), 3.51 - 3.29 (m, 5H), 3.25 (s, 2H), 2.93 (dd, J=10.4, 15.3 Hz, IH), 2,78 - 2.60 (m, 2H), 2.51 (br, s., 1H), 2.43 - 2.31 (m, ill).2,22 (dd, ./ 7.9.16.5 Hz, III).1.99 (d, ,7=9,2 Hz, 2H), 1.95 - 1.44 (m, 8H), 1.36 - 1.27 (m, IH), 0.97 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 657.2 !Y! Π) .

EXAMPLE 1066. (18,3Ί ,6¾,7'ίΙ,8Έ,10¾,1 l'R)-6-CHLORO-7'-METHOXY- 10^11 ^, -DIME^ΉYL-3,4-DIHYDRO-2H,15Ή-SPIRO[NAPH^ΉALENE-1.22 ^, - [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14.7.2.0 ³ -^0 ¹⁹ ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1 S,3'R,6'R,7'S,8'E, 10'R, 11 'R)-6-CHLORO-7'-METHOXY-l ()', 11 '-DIMETHYL- 3,4-DTHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'-

[8,16,18,24]TETiL4E ]-15'-ONE 13 13'-D10X1DE OR

(Ιβ^ ,ό'Κ,Τ'Κ,δΈ,ΙΟ'β,ΙΙ'β^ό-ΟΗ^ΚΟ-Τ-ΜΕΤΉΟ ΧΥ-ΙΟ^ΙΙ'-ΟΙΜΕΤΗΥΧ- 3,4-ΟΙΗΥΌΚΟ-2Η,15Ή-8ΡΙΚΟ[ΝΑΡΗΤΗΑϋΕΝΕ -1,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8 ₅ 16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R R 7'S,8E;iO'SJl'S)-6-CHLORO-7'-METHOXY-10Vn'-DIMETHYL- 3. l-!)!HVORO-2i !.Ι 'ί t-SPIRO|.V\PI i l l f Λ! I :N ! · - ! .2 ~

|2ujOXA| 1ΉΤί!1Λ| Μ4|ΠίΛ/.Υί Π<Λ(ΎΠ.ϋΙ i 4.7.2 U · ^, '.ί ^)|: " ¹ |Pl-N i ^' AC<)SA [8,16 -15 ^, -ONE 13 ^! J3 ^* -DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 720 using (lS,3 ^! R,6'R ₅ 7'R,8'E,10'R,i rR)-6-Chloro-7'-hydroxy- 10', 1 Γ "dimethyl-3,4~dihy dro-2H, 15'H-spiro[naphlhalene-l ,22'- [20]oxa[13]thia[l,14]cUazatetracyclo^

n]-l 5'-one 13 ^* , 13'-dioxide or (1 S,3'R,6'R,7 ^! S,8'E, 10'R, 11 ^! R)~6-Chloro-7 ^! ~hydroxy- 10', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa|;i3]ftia[U4]diazatetra^

en]-15'-one 13',13'-dioxide or (lS,3¾ ₅ 'RJ¾,8T^10'S,l i'S)-6-Chioro-7'-hydroxy- 10', 1 r-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthal ene- 1 ,22'- [20]oxa[13]thia[l,14]diazatetracyd^^

n]-15'-one 13',13'-dioxide or (IS^'R^'R^'S^'EJO'S/irS^b-Chloi ^'-hydroxy- 1 ()', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro| naphthalene- 1 ,22'- ⁿ jpenlacosa|K.i6J8.24jieira en]-15'-one 13 ',13 '-dioxide (Example 1062), and the desired product,

(lS,3'R,6'R,7'R,8'E,10'R,irR)-6-chloro-7 ^, -methoxy-10',ll'-dimethyl-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetrac>'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,10'R,irR)-6-chloi -7'-methoxy- 1 ()', 11 '-dimethyl-3,4-dihydro-2H, 15'H-spiro| naphthalene- 1 ,22'- |20jo\aj I |ihi«i| i . I4|dia/aieuae> ck>j U. Z^.O^.O ^1' ' ⁿ jpen!acosa|K.i6J .24jieirae n]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'R,8'E,10'S,irS)-6-chloro-7'-methoxy- 10', 11 '-dimethy 1-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [2Q]oxa i3]thia[l,14]dia.zaieto

n]-15'-one 13',13'-dioxide or (lS,3'R,6'R,7'S,8'E,10'S,l l'S)-6-chloro-7'-rnethoxy- 10', 11 '-dimethyl-3,4-dihy dro-2H, 15'H-spiro[naphthalene- 1 ,22'- [20]oxa|;i3]thia[l 4]diazatetracyclo[147.2.0 ³ ^0 ^]9 ' ²⁴ ]pentacosa[^

n]-15'-one 13',13'-dioxide was isolated as a white solid, Ή NMR (500MHz, CD3OD) δ 7.74 (d, J=8.6 Hz, 1H), 7.18 (dd, J=2.4, 8.6 Hz, IH), 7.12 (d, J=2.2 Hz, 1H), 7.01 - 6.83 (m, 3H), 6.07 (hr. s., IH), 5.27 (dd, J=9.4, 15.8 Hz, IH), 4.07 (t, ./ 11.0 Hz, 3H), 3,67 (d, ./ 1 .4 Hz, !!!).3.56 (t, ./ 8.3 Hz, 2H), 3.48 - 3.38 (m, 2H), 3.23 (s, Hi.2.86 - 2.71 (m, 2H), 2,68 - 2.56 (m, ill).2.27 - 1.59 (m, 7H), 1.56 - 1.33 (m, 2H), 1.33 - 1.18 (s, l).1.07 (d, J=6.6 Hz, 6H). m/z (ESI, +ve ion) 613.2 (M+H) ⁺ .

EXAMPLE 1067, (1 S,3'R,6'R,8'E, lO'S, 11'S, 12 ^* R)-6-CHLORO-l 0', 11 ', 12'- TRiMETHYL-3,4-DIHYDRO-2H,7'H,15'H-SPIRO[NAPHTOALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAENE]-7', 15'-DIONE 13', 13'-D10XJDE AND

(1 S,3'R,6'R,8'E, 10'R, 11 'S, 12'R)-6-CHLORO-l 0', 11 ', 12'-TRIME ^r rHYL-3,4- DTHYDRO~2H,7'H, 15'H-SPIRO[NAPHTHALENE-l ,22"-

|20i()XA| ΐ: ΐΗ1Λ| Κ4 |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 ϋ ^;ί '.ϋ |ΡΗ\ i ACOSA [8, 16, -7', 15'-DIONE 13', 13'-D10XIDE

The title compound was prepared in an analogous manner to that described in Example 1059, Steps 1 to 7, but replacing the mixture of ((2R,3R)-2,3- dimethylpent-4-en-l-ol and (2S,3S)-2,3-dimethylpent-4-en-l-ol with a mixture of (2R,3S,4R)~3,4-dime 1hex~5-en-2~oi, (2R,3S,4S)-3,4-dimethylhex-5-en-2-ol in Step 5, and the desired product, a mixture of (1S,3 ^! R,6'R,8 ^! E,10 ^! S,1 ! ^' S.12'R)~A~ chloro 0',ll',12'4nmethyi-3,4-dihydro^^^ _^

[20]oxa[13]thia[l,14]diazaietracycio[14,7.2,0-^0 ^l9 - ²⁴ ]pentacos

ne]-7',15'-dione 13',13'-dioxide and (lS,3'R,6'R,8'E,10'R,irS,12'R)-6~chloro- 10', 11 ', 12'-trimethyl-3,4-dihy dro-2H,7'H, 15'H-spiro[naphthalene- 1 ,22'- [20joxa 13]thia[l,14]diazatetracycfo[M _^

ne]-7\15 ^* -dione 13',13'-dioxide was isolated. ¾NMR (400MHz, CDCb) δ 8.48 - 8.37 (m, IH), 7.79 (d, J=8.4 Hz, IH), 7.40 (s, 0.67H), 7.26 (d, J=1.6 Hz, 0.33H), 7.22 (dd, ./ 2.2.8.6 Hz, IH), 7.12 - 7.09 (m, IH), 6.88 - 6.82 (m, 2H), 6.58 - 6.46 (m, IH), 6,00 (d, ./ 1 .8 Hz, 0.67H), 5.83 (dd, ,/ ί.Ο.15.8 Hz, 0.33H), 4.12 - 4.05 (m, 2H), 3,96 - 3.83 (m, 3H), 3.24 (d, ,7=14,5 Hz, IH), 3.10 - 2,91 (m, 2H), 2.85 - 2.72 Cm.2H), 2.42 - 2.16 (m, 2H), 2.05 - 1.60 (m, 8H), 1.56 (d, ./ 7.2 Hz, 2H), 1.50 (d, J=7.4Hz, !!!).1.47 - 1.38 (m, IH), 1.21 id../ 7.0!!/.211).1.12 (d, J=6.8 Hz, IH), 1,09 - 1,00 (m, 3H)irv'z. (ESI, +ve ion) 611.2 (M il) . EXAMPLE 1068. (1S,3'R,6'R,7'R,8'E,10'S,1 rS ₅ 12'R)-6-CHLORO-7'- HYDROXY- 10', II', 12'-TRlMETHYL-3,4-DlHYDRO-2H, 15Ή-

2,349 SPTRO[NAPHTH ALENE- 1 ,22'-

|20i()XA| ΐ: ΐΗ1Λ| Κ.! |ί)!Λ/Λ! :ΓΗ.Λ( ^' Χ)Ι 117.2 ϋ ^;ί' .ϋ |ΡΗ\ i ACOSA [8,16,18,24]TETRAE ]-15'--QNE 13' _S 13'-DI0X1DE OR

(1 S,3'R,6 ^! R ,7 ^* R,8'E, 10'R, 11 'S, 12'R)-6-CHLORO-7'-HYDROXY- 10', 11 ', 12'- TRIMETHYL-3.4-DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [8, 16, 18,24]TETRAEN] - 15'--ONE 13', 13'-DK)XIDE

An 50 mL of round bottom flask was charged with a mixture of

(1 S,3'R,6'R,8'E, 10'S, 11 *S, 12'R)-6-chloro- 10", 11 ', 12' rimethyi-3,4~dihydro- 21 i.7'i !. I 5'H-spiro[naphthalene-l ,22 ^! -

ne]-7' ₅ 15'-dione 13',13'-dioxide and (18,3¾,6¾,8Έ,1()¾,1Γ8,12¾)-6-ΰ1ι1θΓθ- 10^11V12' rinieihyi-3,4-dihydro-2Il,7Tl,15H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,^ ne]-7',15'-dione 13',13'-dioxide (Example 1067; 46 mg, 0.075 mmol) in 2 mL THF at -20 °C, and then (R)-(+)-2-methyl-CBS-oxazaborolidine (1.0 M solution in toluene, 90 μ\, 0.090 mmol) and borane tetrahvdrofuran complex (1.0 M in tetrahvdrofuran, 90 μΐ, 0.090 mmol) were added under N?.. The reaction mixture was stirred at -20 °C for 30 min, and LC-MS showed the reaction was completely. The reaction was quenched with MeOH, and concentrated and purified by- reversed phase preparative HPLC (Gemini™ Prep Cis 5 μηι column;

Phenomenex, Torrance, CA; gradient eiution of 30% to 95% MeC in water, where both solvents contain 0.1% TFA, 30 min method) to give (lS,3'R,6'R,7'R,8'E,10'S,irS,12'R)~6~chk^^^

dihy dro-2H, 15 Ή-spiro [naphthalene- 1 ,22'-

n]-15'-one 13'.13'-dioxide or (lS,3'R,6'R,7'R,8'E,10'R,irS,12'R)-6-chlorQ-7'- hydroxy-10 ^f ,ll'J2' .rnTiethyl-3,4-dihydro-2H,15H-spiro[naphtha]ene-l,22

[20]oxa[13]thia[l,14]diazateiracyclo[14;7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]p

n]-15'— one 13',13'-dioxide (32.5 mg, 0.053 mmol) (first eluting major peak out of preparative reverse phase HPLC). ^! H NMR (400MHz, CD3OD) δ 7.77 (d, ./ 8.6 Hz, 1H), 7.58 (d, ,/ 20 Hz, I Hi.7.23 - 7.17 (m, 2H), 7.13 (d, «/=2.2 Hz, 1H), 6.94 (d, J=8.2 Hz, IH), 5.40 - 5.31 (m, 2H), 4.12 (s, 2H), 3.90 (dd, J=8.9, 15.7 Hz, HI).3.76 (d, ./ 14.5 Hz, 1H), 3.70 (dd, ,/ 6.5.14.7 Hz, 1H), 3.39 (d, ./ 5.3 Hz, ill).3,04 (ά . I 1 .1 Hz, ill).2.87 - 2,73 (rn, 2H), 2.68 - 2,57 (m, 2H), 2.44 (d, J=7,2 Hz, IH), 2.27 (d, .7=6.8 Hz, H), 2.08 (d, J=12.9 Hz, IH), 1,98 - 1.82 (m, 5H), 1.74 - 1.59 (m, 2H), 1.49 (d, J=2.7 Hz, IH), 1.42 (d, J=7.2 Hz, 3H), 1.18 (d, ./ 7.2 Hz, l).0.97 (d, ,/ 6.X Hz, 3H). m/z (ESI, +ve ion) 613.2 ( M II) .

EXAMPLE 1069. (lS,3 ^! R,6'R,7'R,8'E,10'R,irS,12'R)~6"CHLORO-7 ^! ~

HYDROXY- 10', 1 Γ, 12'-TRIMETHYL-3,4-DIHYDRO-2H, 15Ή- SPIRO [NAPHTHALENE- 1,22'- [20]OXA[13]TH1A[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE OR

(lS,3'R,6 ⁱ R,7'R,8'EJ0'S,ll'S,12'R)-6-CHLORO-7 ⁱ -HYDROXY-I0',ll',i2 ⁱ - TRIMETHYL-3,4-DIHYDRO-2H,15'H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THL\[1,14]DIAZATETRACYCLO[14.7.2.0^^0 ¹⁹ - ²⁴ ]1 TACOSA [8,16,18,24]TETRAENj-15'--ONE 13',13'-DIOXIDE

The title compound was obtained as a single isomer (second eluting major peak) from the reverse phase preparative HPLC in Example 1068. Ή NMR (400MHz, CD3OD) δ 7.77 (d, ,/ 8.4 Hz, IH), 7.65 (d, J=2.2 Hz, IH), 7.21 (dd, ,/ 20.7.7 Hz, 2H), 7, 13 (d, ./ 2.3 Hz, IH), 6.95 (d, ,/ 8.2 Hz, IH), 5.41 (dd, J=9.0, 15.3 Hz, IH), 5.15 (dd,J=8.3, 15.9 Hz, IH), 4.13 (s, 2H), 3.96 - 3.81 (m, 2H), 3.73 (d, ./ 14.9 Hz, IH), 3.42 (d, ./ 8.8 Hz, IH), 3.06 (d, ./ 1.17 Hz, IH), 2,87 - 2.73 ins.2H), 2,61 (br. s .2H), 2.11 - 1.84 (rn, 8H), 1.76 - 1,61 (m, 2H), 1.52 - 1.40 (m, IH), 1,36 (d, J=7.4 Hz, l).1.08 id..7=6.7 Hz, 3H), 0.98 (d, ,/ 67 Hz, 3H). m/z (ESI, +ve ion) 613.2 {M l!) .

EXAMPLE 1070, (1S,3'R,6'R,7'R,8'E,1 l'S,12'R.)-6-CHLORO- ! Γ,12'- DlMETHYL-13',13'-D10XlDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-7'-YL AC

To a mixture of (1S,3'R,6'R,7'R,8'E,1 l ^, S,12 ^, R)-6-chloro-7 ^, -hydroxy- 1 Γ.12'-dimethyl-3,4-dihydro-2H,l 5'H-spiro| naphthalene- 1, 22'- [20]oxa[13]thia[l,14]diazatetra<y^

n]-15'-one 13',13'-dioxide (Example 208;252 mg, 0.421 mmol), 4- dimethylaminopyridine (5.14 mg, 0.042 mmol, Aldrich) and triethylamine (21 μΐ, 1.47 mmol, Aldrich) in DCM (2.1 mL) at rt was added neat acetic anhydride (119 μΐ, 1.26 mmol) all at once. The reaction was stirred at rt for 2 h then partitioned between 20 ml of DCM and 20 mL of water. The aqueous separation was exiracied again with 20 ml DCM. The cornbined organic exiracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated and purified by chromatography on 80 g RediSep Rf Gold column eiuting with 20% EtOAc in hexane to give (18,3'Κ,6'Κ,7'^8Έ,1Γ8,12¾)-6-ο1ι1θΓθ-11',12'-ώη� �6 1-13',13·- dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'-

[20]oxa[13]thia[i,14]diazatetracyclo[14.7,2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa

acetate (228 mg, 0.356 mmoi). ^! H NMR (400MHz, CDCh) δ 8.06 (s, 1H), 7.74 (d, ,/ X.4 Hz, IH), 7.22 (dd, 2.3.8.4 Hz, 1H), 7.12 (d, ./ 2.3 Hz, IH), 6.98 - 6,93 (m, 2H), 5.77 - 5.66 (m, IH), 5.65 - 5,55 (m, IH), 5.30 (br, s., ill).4.24 (q, J=7.2 Hz, IH), 3.91 (d, J=14.1 Hz, IH), 3.74 (d, J=13.5 Hz, IH), 3.22 (d, J=14.3 Hz, IH), 3.01 (dd../ 8.7.15.2 Hz, !!!).2.81 (d,J==4.3 Hz, 2H), 2,60 - 2.45 (m, 2H), 2,34 (s, l).2.10 - 1.68 (m, 13H), 1.48 id../ 7.2 Hz, 3H), 1.46 - 1.36 (m, IH), 1,08 (d, J=5.9 Hz, 3H). m/z (ESI, +ve ion) 641.2 (M+H) . EXAMPLE 1071. ((lS,3 ^f R,6'S,7'E,9'S,l l'S,12'R)-6-CHLORO-i i',12'- DIMETHYL- 13' , 13 '~D.1O.XID0- 15 ^! ~OXO-3 ,4~DIHYDRO-2H- SPIRO [NAPHTHALENE- 1 ,22'~

[20iOXA|;i3]THIA|;i,14]DIAZATETRACYCL )[14.7.2.0 ^3>, 0 ^!9 - ²⁴ ]PENTACOSA [7J6,18,24]TETRAEN]-9'-YL)ACETIC ACID

To a solution of (1S,3'R,6 ^f R,7'R,8'E,l l'S,12'R)-6-ch]oro-ir,12'-dimetlty]- 13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l,2 2'- [20]oxa[ 13]thia[ 1 , 14] diazatetracycio[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n|-7'-yl acetate (Example 1070; 20 mg, 0.033 mmol) and chlorotrimethylsilane (18.13 mg, 0.17 mmol) dissolved in THF (1 raL) cooled by an acetone-dry ice bath was added lithium diisopropylamidesolution (2.0 M in

THF/heptane/ethyl benzene, 0,05 mL, 0.10 mmol, Aldrich) all at once. The reaction was left stirring at -78 °C for 3 h then the cold bath was removed and the reaction equilibrated to rt over 30 min. The reaction was stirred at rt for 2 h then partitioned between 20 ml each saturated aqueous ammonium chloride and ethyl acetate. The aqueous separation was extracted again with 20 ml ethyl acetate. LC-MS showed the mixtue of the desired product and TMS ester were formed. The combined organic extracts were cone amd purified by reverse phase preparative HPLC (Gemini™ Prep Cm 5 μιη column; Phenomenex, Torrance, CA: gradient elution of 40% to 95% MeC in water, where both solvents contain 0.1% TFA, 30 min method) to give ((18,3¾,6 ,7Έ,9'8,1 l'S,12¾)-6-chloro- 1 l 12'-dimemyl-13^13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naph thalene-l,22'- [20]oxa[13]thia[l,14]diazatetra^

n]-9'-yl)acetic acid (5.3 mg, 8.27 μηιοΐ). ¾ NMR (500MHz, CDCh) δ 7.88 (br. s., ill).7.61 (d, .7=8,6 Hz, ill).7.1 I (dd, ./ 1.8, 8.4 Hz, Hi).7.02 (s, Hi).6.93 - 6.83 (m, 2H), 6,75 (br. s .1H), 5.55 (dd, ,/ 72.15,3 Hz, H), .5.07 (dd, .7=8.8, 15.4 Hz, 1H), 4.04 (s, 2H), 3.80 (d, ./ 7.3 Hz, IH), 3.71 - 3.56 (m, 2H), 3.26 - 3.14 (m, 2H), 2.72-1.91 (m, ! !!!}.1.84 (dd../ 3.9.9.0Hz, IH), 1.74 (d, J=4.6 Hz, IH), 1,67 - 1.48 {Ml.2H), 1.44 - 1.39 (m, IH), 1,37 (d../ 7.3 Hz, 3H), 1.32 - 1.13 (rn, 3H), 0,94 (d, «7=6.8 Hz, 3H). m/z (ESI, +ve ion) 641.2 (M+H) .

EXAMPLE 1072, 2-(( lS,3 ^f R,6'S,7Ti,9'R,l l*S,12¾)-6-CHLORO-l Γ,12'- DIMETHYL- 13' , 13 '-DIOXIDO - 15 '-QXO-3 ,4-DIHYDRQ-2H~

SPIRO [NAPHTHALENE- 1 ,22'- ^OlOXAtlSlTHIAt^MlDIAZATET ACYCLOIM.T^.O'^.O^^lPE TACOSA [ 7, 16, 18,24]TETRAEN] -9'-YL)-N,N-DIMETHYLACETAMIDE

The title compound was prepared in an analogous manner to that described in Example 995 using ((lS,3¾ VSJ¾9'RJ.l^J2'R)-6-chloro-ir ₅ l2'-diniethyl- 13',l3'-dioxido-l5 ^, -oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'- [20]oxa[13]thia[l,14]diazate1r^

n]-9'-yl)acetic acid (Example 206) and dimethylamine (40 wt % solution in water, Acros), and the desired product, 2-((lS,3'R,6'S,7 ^, E,9 ^, R,irS,12 ^, R)-6-chloro- llA12'-dimethyl-13',13 ^! -dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthaiene-l,22 '^ |2ίί|οχ;ιΙ I3|ihia| i. i |di;i/aieiracvdoj 14.7.20 ^;i' .o ^pi ipeniacosa|7.i6J8.24i!cirac n]-9'-yl)-N,N-dimethylacetamide was isolated as a white solid. ¾ NMR

(500MHz, CDCb) δ 7.92 (s, 1H), 7.73 (d, ,/ 8. Hz, ill).7.20 (dd, ./ 2.2.9.0 Hz, ill).7,11 (d, ,/ 2.2 Hz, Hi).7.04 (s, 111).7.00 - 6.93 (rn, 2! I).5,89 (dd, ./ 4.8. 15.5 Hz, 1H), 5.32 (dd, .7=7,8, 15.9 Hz, ill).4,29 - 4.23 (m, IH), 4.17 (s, H), 4.15 (s, 2H), 3.85 (d, J=15.7Hz, IH), 3.66 (d, J=14.2 Hz, IH), 3.20 (d, J=14.2 Hz, IH), 3.08 (dd,■/ 8.3.15.2 Hz, IH), 3.04 (s, 3H), 2.96 (s, 3H), 2.82 - 2.74 (m, 2H), 2.64 (br. s., IH), 2,56 (br. s . !!!).2.36 (dd, 4.0, 15,0 Hz, IH), 2.30 - 2.18 (m, 2H), 2.03 (t, .7=8.4 Hz, 3H), 1.98 - 1.89 (m, 2H), 1.87 - 1.71 (m, 4H), 1.50 (d, ./ 7.1 Hz, 5H), 1.01 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 668.2 ! VI · II) ^' .

EXAMPLE 1073, 2-((lS,3'R,6'S,7'E,9'R,l l'S,12 ^, R)-6-CHLORO-l Γ,12'- DlMETHYL-13',13'-DIOXIDO-l 5'-OXO-3,4-DIHYDRO-2H- SPIRO INAPHTHALENE- 1.22 ^J -

|2θ!() Λ| I 311 HI Λ| I„ ! -I |ί)Ι.\/.νΠ: I RAC V( ^' i, 01 i -1,7.20 ^{:' i'} .0 ^li ' |Pi-:N i ACOSA

[7,16,18 ,24] TETR AEN] -9'-YL)-N-METHYLACETAMIDE

The title compound was prepared in an analogous manner to that described in Example 995 using ((l S,3'R,6'S,7'E,9'R,irS,12'R)-6-chloiO-l l ',12'-dimethyl- 13', 13'-dioxido- 15'-oxo-3,4-dihydro-2H-spiro j naphthalene- 1,22'- [20]oxa[13]thia[l, 14]diazatetra<yd^^

n]-9'-yl)acetic acid (Example 206) and methanamine (30 wt % solution in water, Aldrich), and the desired product, 2-((lS,3'R,6'S,7'E,9'R,l l 'S,12'R)-6-chloro- l lV12'-dimethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-l ,22'- Hjaj teirae n|-9'-yl)-N-methylacetamide was isolated as a white solid. ^! H NMR (400MHz, CD3OD) δ 7.65 (d, 8 6 Hz, 1H), 7.08 (dd, ./ 2 3. 8.4 Hz, 1H), 7,02 (d, ./ 2.3 Hz, IH), 6,99 (t, .7=3645,7 Hz, IH), 6,95 (d, J=1.8 Hz, IH), 6,85 (d, J=8.0 Hz, IH), 5.76 (dd, J=5.1, 15.5 Hz, IH), 5.21 (dd, J=6.7, 15.0 Hz, IH), 4.07 - 4.00 (m, 3H), 3.71 (d, ,7=15.7 Hz, IH), 3.52 (d, ./ 14.5 Hz, IH), 3.15 (d, ./ 14. 1 Hz, IH), 3.05 (dd, .7=8.6, 15.7 Hz, IH), 2.72 - 2.65 (m, 2H), 2,62 (s, 3H), 2,54 - 2,43 (m, 2H), 2.16 - 2.06 (m, 2H), 2,00 - 1.77 (m, 8H), 1.76 - 1.57 (m, 2H), 1 ,46 - 1.32 (m, 2H), 1.27 (d, ./ 7.2 Hz, 3H), 0.92 (d, ./ 6.8 Hz, 3H). m (ESI, \ e ion) 654.2 ( M i l ) .

EXAMPLE 1074. (1 S,3 ^! R,6'S,7'E,9'R,1 rS,12'R)-6-CHLORO-9'-(2-(3- HYDROXY-l -AZETIDINYL)-2-()XOETHYL)-i r,12'-DIMETHYL-3,4- DIHYDRO-2H, 5 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[ 13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA [7,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE

The title compound was prepared in an analogous manner to that described in Example 995 using ((lS,3'R,6'S,7Ti,9'R,l l'S,12'R)-6-chloro-l 1 ^f ,12'-diraethyl- 13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[napM

[20]oxa[13]thia[l,14]cUazatetracyc^

n]-9'-yl)acetic acid (Example 206) and 3-(hydroxy)azetidine hydrochloride (Oakwood), and the desired product, (IS,3'R,6'S,7*E,9*R,1 l'S,I2¾.)~6~chloro~9'~ (2-(3-hydroxy - 1 -azetidinyl)-2-oxoethyl)- 1 Γ, 12'-dimethyl-3,4-dihy dro-2H, 15Ή- spiro[naphthalene-l,22'-

|20jo\aj I3|ihi«i| i I4|dia/aicuac> ciol 14.72. ⁽ ! ^; " (s ^1' ' ⁿ jpenlacosa|7.!6JS.2-ljlcirae n]-15'-one 13',13'-dioxide was isolated as a white solid. ^l R NMR (400MHz,

CDsOD) 57.76 (d, ./ 8.4 Hz, 1H), 7.19 (dd, ./ 2.3.8.4 Hz, III).7.13 (d, ./ 2.2 Hz, 1H), 7.10 (dd,J=l,9, 8.1 Hz, 1H), 7,05 (d, J=1.8 Hz, IH), 6.96 (d, J=8.0 Hz, III). 5.90 (dd, J=5,l, 15.7 Hz, IH), 5,39 - 5,32 (m, IH), 4.61 - 4.55 (m, IH), 4,40 (t, J=9.5 Hz, IH), 4.22 - 4.11 (m, 4H), 3.97 (dt ./ 4.1.9.5 Hz, IH), 3.82 (d, J=15.3 Hz, IH), 3.76 (id../ 5.3.10.5 Hz, IH), 3.63 (d. J 13.9 Hz, IH), 3.17 !dd../ 8.7. 15,0 Hz, IH), 2.85 - 2.73 (m, 2H), 2,61 (dd, ./ 7.2.16.4 Hz, 2H), 2.23 (†, ,/ 8.7 Hz, IH), 2,19 - 2.12 (m, IH), 2.11 - 1.78 (m, 9H), 1.73 (dd, J=10.0, 19.2 Hz, IH), 1.57 - 1.44 (m, 2H), 1.41 (d../ 7. ⁽ ϊ Hz, l).1.37 - 1.29 (m, IH), 1.03 idd../ 1.3. 6.9 Hz, Ml), ni (ESI, +ve ion) 696.2 (M+H) ⁺ .

2,357 EXAMPLE 1075. ((lS,3 ^f R,6'SJ i,9'R,irS,12'R)-6-CHLORO-l 1',12'- DIMETHYL- 13' , 13 '-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRQ-2H~

SPIRO [NAPHTHALENE- 1 ,22'-

^OlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O'^.O^^lPE TACOSA [7,16,18,24]TETRAEN]-9'-YL)ACETONITRILE

STEP 1: 2-((lS,3¾,6'S ₅ 7¾9 ^, R,ll ^, S ₅ 12 ^, R)-6-CHLORO-11^12 ^, -DIMETHYL- i;r ₅ 13' IOXIDO-15'-OXO-:i4-DrHYDRO-2H~SPIRO[NAPHTHALENE-l,22 ^! ~ [20]OXA[13]TH1A[1 4]DLZATET1ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [7,16,18 ,24] TETRAEN] -9'-YL) ACET AMIDE

The title compound was prepared in an analogous manner to that described in Example 995 using ((18,3¾,6Έ,7Έ,9¾,1Γ8,12¾)-6-ΰΜοη 1Γ,12'-ώηΐ6 1- 13 ^, ,13'-dio ido-15'-oxo-3,4-dihydro-2H-spiro[naphtha]ene-l,22 ^, - [20]oxa[13]thia[l,14]diazatetracyc^^^

n]-9'-yl)acetic acid (Example 206) and 28% ammonium hydroxide. STEP 2: . ((1S,3'R,6'S,7'E,9'R,1 l'S,12'R)-6-CHLORO-i r,12'-DlME ^' raYL- 13 13'-DIOXIDO - 15 '-OXO-3 ,4-DIHYDRO-2H-SPlRO [NAPHTHALENE- 1 ,22'- [2()iOXA|;i3]THIA|;i,14]DIAZATETRACYCLO[14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [7,16,18,24]TETRAEN]-9'-YL)ACETONiTRILE

A solution of 2-((lS,3*R,6'S,7'E,9'R,l l'S,12'R)-6-ehioro-l l ^! ;i2'-dimethyl- 13 13'-dio ido-15'-oxo-3,4-dihydro-2H-spiro[naphtha]ene-l,22 ^, - [20]oxa[13]thia[l,14]diazatetracyc ^

n]-9'-yl)acetamide (Step 1:5.8 nig, 9.06 μηιοΐ) in phosphoras oxychloride (41.5 μΐ, 0.45 mmol) was heated at 60 °C from 2 h. The reaction was concentrated and purified by reverse phase preparative HPLC (Gemini™ Prep Ci85 μίη column; P enomenex, Torrance, CA: gradient eiution of 40% to 95% MeCN in water, where both solvents contain 0.1% TFA, 30 min method) to give

((lS,:rR,6 ^f S,7T9'R,irSJ2'R)-6-chiorc ll',12 ^f -dimeihyi-13',i3 ⁱ -dioxido-15'-oxo- 3,4-dihydro-2H-spiro[naphthalene- 1 ,22 ^! ~

n]-9'-yl)acetonitnle (4.5 mg, 7.23 μιηοΐ) as a white solid. ^l H NMR (500MHz, CD3OD) δ 7.76 (d, 86 Hz, 1H), 7.19 (dd, ./ 22.8.6 Hz, 1H), 7, 13 (d, ./ 2.0 Hz, IH), 7.11 (dd, J=2.0, 8.1 Hz, 1H), 7.04 (d, =1.7 Hz, IH), 6.96 (d, .7=8.1 Hz, IH), 6.01 (dd../ 5.1.15.7 Hz, IH), 5.35 (dd../ 5.7.15.5 Hz, !!!).4.15 (s, 2H), 4.05 (dd, 2.2.7.8 Hz, IH), 3.82 (d, ,/ 15.2 Hz, IH), 3.62 (d, J=13.9 Hz, IH), 3.18 (dd, .7=9.3, 15.9 Hz, IH), 2.85 - 2.74 (m, 2H), 2.68 - 2.60 (m, IH), 2.52 - 2.45 (m, 3H), 2.25 (qum, J=8.9 Hz, IH), 2.11 - 1.99 (m, 4H), 1.95 - 1.70 (m, 5H), 1.65 - 1.47 (m, 3H), 1.46 (d,J=7.1 Hz, 3H), 1.07 id. J 6.8 Hz, 3H). nv ^' z (ESI, +ve ion) 622,2 (M+H) ⁺ .

EXAMPLE 1076. N-((lS,3'R,6 ^! R,7'R,8'E,12'R)-6-CHL()RO-12'-ETHYL-13',13 ^! - DIOXTDO-15'-OXO-3,4-DII-IYDRO-2H-SPIRO|SiAPHTHALENE-l,22'- |2 ⁽ !ί>ΧΛ| i ? ! ! Π!Λ| ί ! 4 |ί^!ΛΖΛ ί : ί AC YC ί (>! i 47.2 ϋ ^; ".O ¹ " ^M |PH\ i ACOSA

[8, 16, 18,24]TETRAEN] -7'-YL)ACET AMIDE

STEP 1 : (3S)-5-(((lR,2R)-2-((l S)-l-AMINO-2-PROPEN-l - YL)CYCLOBUTTL)METTT^)-6'-CHLORO-N-((3R)-6-HEPTEN-3-

YLSULFON^-S'^^'^-TETRAHYDRO^'H-SPIROtl^-BENZOXAZEPINE- 3, 1 '-NAPHTHALENE]-7-CARBOXA IDE

The title compound was prepared in an analogous manner to that described in Example 599, Steps 1 to 5, but replacing Intermediate EE20 with Intermediate EE21 in Step 4, and the desired product, (3S)-5-(((lR,2R)-2-((l S)-l -amino-2- propen-l-yl)cyclobutyl)methyl)-6'-chloro-N-((3R)-6-hepten-3- ylsulfonyl)- 3',4,4',5-tetrahydro-2'H-spiro[ 1 ,5-benzoxazepine-3, 1 '-naphthalene] -7-carboxamide was isolated as a white solid.

STEP 2: N-((l S,3'R,0'R,7'R,8'E, 12'R)-6-CHLORO- 12'-ETHYL- 13', 13'- DIOXIDO- 15 ^* -OXO-3 ₅ 4-DIHYDRO-2H-SPIRO[N APHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ '^0 ¹⁹ ^ ⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN]-7'-YL)ACET AMIDE The title compound was prepared in an analogous manner to that described in in Example 599, Steps 6 to 9 from (3S)-5-(((lR,2R)-2-((lS)-l-amino-2-propen- l-yl)c lobut5d)methyl)-6'-chloro-N-((3R)-6-hepten-3-ylsulfonyl)-3', 4,4',5- tetrahydro-2'H-spiro[l,5-benzoxazepine-3,l.'-naphthalene]-7- carboxamide

(Example 1076, Step 1), but replacing methyl bromoacetate with acetyl chloride (Aldrich) in Example 599, Step 9, and the desired product, N- ((lS,:m,6¾,7'R,8¾12'R)-6-diioro-12'^

2H-spiro[naphthalene- 1 ,22'- iH.24!tetrae n|-7'-yl)acetamide was isolated as a white solid. ^! H NMR (400MHz, CD3OD) δ 7,77 (d, J=8.4 Hz, !!!).7.19 (dd, ,/ 2.5.8,6 Hz, !H), 7.12 (d, 2.3 Hz, ill).7, 10 - 7.02 (m, 2H), 6.87 (d, ./ 8.0 Hz, Ml).6.03 (dd, J=6.7, 14.7 Hz, 1H), 5.55 (dd, ./ 7.5.15.2 Hz, 1H), 4.62 - 4.46 (m, 1H), 4.16 - 4.00 (m, 2H), 3.92 - 3.81 (m, 2H), 3.74 - 3.60 (ra, ill).3,05 (dd, ./ 9.K. [5.1 Hz, 111).2.86 - 2.74 (ra, 2H), 2,63 -

2.30 (m, 3H), 2.22 - 2.02 (m, 4H), 1.95 (s, 3H), 1.95 - 1.61 (m, 9H), 1.43 (d,J=8.6 Hz, 1H), 1.15 (t, ./ 7.5 Hz, 311). m/z (ESI, +ve ion) 640.2 (M+H) ^H \

EXAMPLE 1077, N-((lS,3'R,6 ⁱ R,7'S,8 ⁱ E,12'R)-6-CHLORO-12'-ETHYL-13 ⁱ ,13'- DIOXIDO-15'-OXO-3,4 3IHYDRO-2H-SPiRO[NAPHTHALE E-l,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA

[8,16,18,24]TETRAEN]-7 ^, -YL)-2-METHYLPROPANAMIDE

2,361 The title compound was prepared in an analogous manner to that described in Example 1076, but replacing acetyl chloride with 2-methylpropanoyl chloride (Aldrich) m Step 9, and the desired product Vii I S.3 ^' R >'R.7'S.8'!-;.i 2'Ri-6- chloro-12'-ethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spir o[naphthalene-l,22'- |20jo\aj I |ihi«i| ! . ! 4|diaya!cua > c!o! 14.7.2. ⁽ ϊ ^; -'.O ^1' ' ⁿ jpen!acosa|H.I J8.24jieirae n]-7'-yl)-2-me lpropanamide was isolated. ¾ NMR (400MHz, CDsOD) δ 7.75 (d, ./ 8.6 Hz, III .7.19 (dd, ./ 2.3.8.8 Hz, 1H), 7.13 (d, ./ 2.0 Hz, 1H), 7.02 (dd, J=2.0, 8.0 Hz, 111).6.97 (d, ,/ ! 6 Hz, 1H), 6.95 (d, J=8.0 Hz, ill).5,88 - 5,73 (m, 1H), 5.66 (dd, ,7=0,6, 15.8 Hz, ill).4,48 (d, J=8.4 Hz, 1H), 4.15 - 4.04 (m, 2H), 4.01 (d, ./ 6.1 Hz, 1H), 3.93 (d, J=15.3 Hz, 1H), 3.69 (d, J=14.5 Hz, ill).3.07

(dd, ,/ 9.2.15.3 Hz, 1H), 2.87 - 2.73 (m, 2H), 2.46 - 2.33 (m, 4H), 2.15 - 2.03 (m, l).2,00 - 1.84 (m, ?!!}.1.84 - 1.66 (m, 3H), 1,46 (t, ./ I I.! Hz, ill).1.19 (l, J=7,5 Hz, 3H), 1.10 (dd, ,7=5,0, 6.7 Hz, 6H). m/z (ESI, +ve ion) 668.2 i\S-R}\ EXAMPLE 1078. Ν-((18,3Έ,6' ,7¾,8Έ,12'Κ)-6-€ΗΙ,ΟΚΟ-12'-ΕΤΗΥΙ.-13',13'- DIOXIDO-15 ^! ~OXO-3,4 ^IHYDRO-2H-SPIRO[NAPH HALENE-l,22'- |2ίί!<)ΧΛ| 13ΙΊ !!1Λ| Ι.Ι4|! !Λ/.νΓ!·Ί <Λ( ^' Υ(·ί..ΟΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8, 16,18,24 ]TETRAEN]-7'-YL)ACET AMIDE AND EXAMPLE 1079. N- ((1 S,3 ⁱ R,6'R,7'R,8'Z,12'R)-6-CHLORO-12'-ETHYL-l 3', 13"-DIOXIDO-l 5"-OXO- 3,4-DIHYDRO-2H~SPIRO[NAPHTHALENE-l,22 ^! ~

[20]OXA[13]THLA[1,14]DL ZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8,16, 18,24]TETRAEN]-7"-YL)ACET AMIDE

Example 1078 Example 1079

2,362, STEP 1 : (3 S)-5 - ((( 1 R,2R)-2-(( 1R)-1 - AMINO-2-PROPEN- 1 - YL)CYCLOBUTYL)METHYL)-6'-CHLORO-N~((3R)-6-HEPTEN-3~

YLSULFONYL)-3',4,4',5-TETRAHYDRO-2'H-SPIRO[l ,5-BENZOXAZEP NE- 3, 1 '-ΝΑΡΗΤΗ ALENEJ-7-C ARBOXAMIDE

The title compound was prepared in an analogous manner to that described in Example 599, Steps 1 to 5, but replacing (R)-(+)-2-methyl-2- propanesulfinamide with (S)-(-)-2-methyl-2-propane-sulfinamide in Step I, and the desired product, (3S)-5-(((l R,2R)-2-((.l R)-l-amino-2-propen-l- yl)cyclobutyl)niethyl)-6 ^, -chloro-N-((3R)-6-hepten~3-} lsul^

tetTahydro-2'H-spiro[l,5-benzoxazepine-3,r-naphthalene]-7 -carboxarnide was isolated.

STEP 2. N-^lS _^ I' / R ' ^ ^'Ri-e-CHLO O-n'-ETHYL-LI'JS'- DIOXID()-15 ^, -()XO-3,4-DIHYDR()-2H-SPIRO[NAPHTHALENE-l ,22'- [20]OXA[ 13]THIA[ 1,14]DIAZATETRACYCLO[[14,7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]PENTACOS A[8, 16,18,24]TETRAEN]-7 ^! -YL)ACETAMIDE AND N-

((l S,3'R,6'R,7'R,8'Z,12'R)-6-CHL()R()-12'-ETHYL-13',13 ^! -DI()XIDO-15 ^! -OXO- 3,4-DIHYDRO-2H-SPTRO| AP^^THALENE-l ,22 ^, -

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[14 .0 ³ ' ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] -7'-YL)ACET AMIDE

The title compound was prepared in an analogous manner to that described in Example 599, Steps 6 to 9, using (3S)-5-(((lR,2R)-2-((lR)-l-amino-2-propen- l-y])cyclobutyl)methyl)-6'-chloro-N-((3R)-6-hepten-3-ylsulfo nyl)-3',4,4',5- teirahydro~2H-spiro[l,5-benzoxazepine-3,r-naphthalene]~7-car boxarni

(Example 1078, Step 1), but replacing methyl bromoacetate with acetyl chloride (Aldnch) in Example 599, Step 9 and the desired products, N- ((1 S,3'R,6'R,7'R,8'E, 12'R)-6-chloro-l 2'-ethy 1- 13", 13'-dioxido- 15'-oxo-3,4-dihydro- 2H-spiro[naphthalene- 1 ,22 ^! ~

[20]oxa[13]tMa[l,14]diazatetrac'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)acetamide (second eluting peak) and

cMoro-12'-ethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-sp iro[naphthalene-l,22'--

n]-7'-yl)acetamide (first eluting peak) were isolated as a white solid. N- ((1 S,3'R,6'R,7'R,8'E, 12'R)-6-chloro-l 2'-ethy 1- 13", 13'-dioxido- 15'-oxo-3,4-dihydro- 2H-spiroj naphthalene- 1 ,22'- i;20]oxa[13]thia|;i,14]diazatetracyclo|14.7.2.0 ³ - ^f \0 ¹⁹ - ²⁴ peniacosa[8,16,18,24] ]-7'-y])acetamide (Example 1078). ^! H NMR (500MHz, CDsOD) 67.80 id../ 8.6 Hz, ill).7.41 (d, ,/ 1 7 Hz, I Hi.7.18 (ddd, ,7=2,1, 8.4, 14.2 Hz, 2H), 7.11 (d, J=2.2 Hz, IH), 6.93 (d, J=8.1 Hz, IH), 5.49 - 5.37 (m, 2H), 4.15 - 4.05 (m, 3H), 3.87 - 3.77 (m, 2H), 3.73 - 3.63 (m, ill).3.21 (d, ./ 14.7 Hz, !!!).3.06 (dd, ./ 5.!. 15,4 Hz, IH), 2.85 - 2,73 (m, 2H), 2.69 - 2.62 (m, IH), 2.46 - 2,27 (m, 2H), 2.10 - 1,98 (m, 4H), 1.98 - 1.93 (m, H), 1,93 (s, 3H), 1,92 - 1,78 (m, 5H), 1.77 - 1.62 (m, 2H), 1.50 - 1.42 (m, IH), 1.18 (t, ./ 7.5 Hz, 3H). m/z (ESI, +ve ion) 640.2 iVi H) ; and N-((lS,3¾,6'R,7¾,8'Z,12'R)-6-chloro-i2 ⁱ -ethyi-13',i3 ⁱ -dioxido-15 ^f - oxo-3,4-dihydro-2H-spiro[naphthalene-l,22'~

[20]oxa[13]thia[l,14]diazatetracyclo[14.7.2.0 ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n]-7'-yl)acetamide Example 1079], ¾ NMR (4()()MHz, CD3OD) δ 7.76 (d,■/ HA Hz, ill).7,20 (dd, ./ 2.3.8.6 Hz, IH), 7.13 (d, ,/ 22 Hz, IH), 7.09 (s, IH), 7.04 (dd, ./ 2.0.8,0 Hz, H), 6.94 (d, .7=8.0 Hz, IH), 5,53 - 5,37 (m, IH), 5.29 (t, ./ 10. i Hz, IH), 4.62 (t, J=8.5 Hz, IH), 4.09 (dd, ./ 12.1.22.3 Hz, 2H), 3.78 - 3.66 (m, 3H), 3.19 - 3.10 (m, IH), 2.87 - 2.73 (m, 2H), 2.59 (br. s., IH), 2.48 - 2.30 (m, 2H), 2.26 - 2,00 (m, 4H), 1.99 - 1.90 (m, 3H), 1.88 (s, 3H), 1,87 - 1,70 (m, 6H), 1 ,53 - 1.45 (m, IH), 1.17 (t, 74 Hz, 3H). m/z (EST, +ve ion) 640,2 (M+H) ⁺ .

EXAMPLE 1080, N-((lS,3'R,6'R,7'R,12'R)-6-CHLORO-12 ^! -ETHYL-13',13'- DIOXIDO-15'-OXO-3,4-DiHYDRO-2H-SPIRO[NAPHTHALENE-l,22'- pOlOXAtlSlTHIAtl ^DIAZATETRACYCLOIM.T^.O^^O^^lPENTACOSA [ 16, 18,24 ] TRIEN] - 7- YL) ACETAMIDE

The title compound was prepared in an analogous manner to that described in Example 925, Step 1, using Ν-ίίΙβ^Ί ,ό^^ΊΙ,ΒΈ,ηΐ^-ό-ΰΜθΓθ-^'-βΑνΙ- 13',13'-dioxido-15 ^, -oxo-3,4-dihydro-2H-spifo[naphthalene-l,22'- [20]oxa[.13]thia[l,.14]diazatetTacyclo[14.7.2.0~3,6~.0~19,24 ~]pentacosa[8,16,.18,2 4]tetraen]-7'-yl)acetamide (Example 1078), and the desired products, N- ((IS,31 ,6¾,7¾,m)-6-enloro-12'-e%

spiro [naph thalene- 1 ,22'-

[20]oxa[13]thia[l,14]diazatetracyclo[14,7.2,0 ³ ' ⁶ .0 ¹⁹ - ² '¾

yl)acetamide was isolated. ¾ NMR (400MHz, CDsOD) δ 7.76 (d, J=8.4 Hz, IH), 7.22 (d, ./ 2.2 Hz, !!!).7.19 (dd, ,/ 2.3.8.6 Hz, IH), 7.12 (d, ./ 2.2 Hz, IH), 7.10 (dd, ,/ 2.0.7,4 Hz, !H), 6,96 (d, 8.0 Hz, IH), 4, 1 I (dd, ./ I 1.9, 22,9 Hz, 2H), 3,83 - 3.71 (m, 3H), 3.66 (br. s., IH), 3,16 (dd, ./ 7.0.14.9 Hz, IH), 2.86 - 2.73 (m, 2H), 2.54 - 2.39 (m, 2H), 2.14 - 2.03 (m, 2H), 2.02 - 1.62 (m, 10! I).1.97 (s, 3H), 1.61 - 1.35 (m, 5H), ! ,!? U../ 7.5 !!/.3H). m/z (EST, +ve ion) 642.2 \\\-U)

2,365 EXAMPLE 1081. Ν-((18 3Έ >¾^¾,8Έ;ΐ2'Κ)-6-€Η1,ΟΚΟ-12 ^! -ΕΊΉΥΙ.-13',13'- DIOXIDO- 15'-OXO-3,4-DIHYDRO-2H-SPIRO[NAPHTHALE E- 1 ,22'- [20]OXA[13]THIA[l,14]DIAZAraTRACYCLO[147.2 ³ ' ^{6 19} ^ ⁴ PENTACOSA[ 8,16,18,24]TETRAEN]-7'-YL)-2-METHYLPROPANAMIDE AND EXAMPLE 1082. Ν^Ιβ^Ί ,ό^^'ίΙ,δ'Ζ,ηΐ^-ό^ΉΕΟΙ Ο-η'-ΕΤΗΥί- Β'-ΟΙΟΧΙΒΟ- 15'-OXO-3,4-DlHYDRO-2H-SPlRO[NAPHraALE E-l,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACY ^T CLO[14,7.2,0 - ⁶ .0 ^I9 ' ²⁴ PENTACOSA[ 8 i6,18,24]TETRAEN]-7'-YL)-2-METHYLPROPANAMIDE

Example 1081 Example 1082

The title compounds were prepared in an analogous manner to that described in Examples 1078 and 1079, but replacing acetyl chloride with 2- methylpropanoyl chlonde (Aldrich) in Step 9, and the desired products, N- ((1 S,3¾,6'R,7'R,8¾ 12¾)~6~chloro~^

2H-spiro[naphthalene- 1 ,22 ^! ~

[20]oxa[13]tMa[l,14]diazatetrac 'clo[14.7.2.0 ³ ' ⁶ .0 ¹⁹ - ²⁴ ]pentacosa[8,16, 18,24]tetrae n]-7'-yl)-2-methy]propanamide and N-((l S,3'R,6'R,7'R,8'Z, 12'R)-6-ch]oro-12'~ ethyl-13',13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthale ne-l,22'- I SJJj tctrao n]-7 ^, -yl)-2-methylpropanamide were isolated. Ν-((18,3'Κ,6'Κ,7'Κ,8Έ,12'Κ)-6- chloro-12'-ethyl-13', 13'-dioxido-15'-oxo-3,4-dihydro-2H-spiro[naphthalene-.l ,22'- [20]oxa{13]thia[l, 14]diazatetra<yclo[^ n]-7'-y])-2-me lpropanarmde (Example 1081). ^] H NMR (400MHz, CD3OD) δ

7.80 (d, ,7=8,6 Hz, 1H), 7.41 (d, .7=2.0 Hz, IH), 7.21 - 7,12 (m, 2H), 7.11 (d, J=2,0 Hz, IH), 6.95 (d, J=8.2 Hz, IH), 5.43 (d, =5.3 Hz, 2H), 4.13 - 4.06 (m, 3H), 3.95

- 3.76 (m, 3H), 3.69 (d, ./ 5.7 Hz, 2H), 3.19 - 3.01 (m, IH), 2.84 - 2.74 (m, 2H), 2,67 (d, ./ ! 2,3 Hz, IH), 2.53 - 2.26 (m, 3H), 2.11 - 1.88 (m, 7H), 1.88 - 1.79 (m,

2H), 1,76 - 1.59 (m, 2H), 1.54 - 1.42 (m, IH), 1,18 (t, .7=7.4 Hz, 3H), 1,06 id. ./ 6.8 Hz, 3H), 1.00 (d, ./ 6.8 Hz, 3H). m/z (ESI, +ve ion) 668.2 (M+H) ⁺ ; N- ((lS,:m,6¾,7¾,8'Z,12'R)-6-chloro-12'-e ^^

2H-spiro[naphthalene- 1 ,22'- IKJ4jtctrao n]-7'-yl)-2-methylpropanamide (Example 1082). ¾ NMR (5()()MHz, CD3OD) δ 7,75 (d, ./ 8.6 Hz, !!!).7. 8 (dd, ,/ 2.3.8,4 Hz, H), 7.12 (d, 2.2 Hz, H), 7, 10 (br. s., IH), 7.04 (d, ./ 8.! Hz, IH), 6.94 (d, ./ 8.1 Hz, IH), 5.49 (td, ./ 6.7.10.8 Hz, IH), 5.30 (t, J=10.0 Hz, IH), 4.62 (q, ./ 8.6 Hz, ill).4.08 (t, ./ 30 1.3 Hz, 2H), 3.75 (d, J=14,7 Hz, H), 3.69 (br. s., 2H), 3,13 (dd, ./ 7.0.15.3 Hz, IH), 2,86

- 2,74 (m, 2H), 2.62 - 2.51 (m, H), 2.46 - 2,23 (m, 4H), 2.18 - 2.01 (m, 4H), 1.98

- 1.78 (m, 6H), 1.75 - 1.66 (m, 2H), 1.49 (L ./ 11.4 Hz, IH), 1.16 (i.J 7.5 Hz, 3H), 1.04 (i, ./ 6.7 Hz, 6H). m/z (ESI, +ve ion) 668.2 {\Mi}\ EXAMPLE 1083. N-((lS,3'R,6 ^, R,7 ^, R,12'R)-6-CHLORO-12'-EraYL-13',13'- DIOXID()-15 ^, -()XO-3,4-DIHYDR()-2H-SPIRO[NAPHTHALENE-l,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ PENTACOSA[ 16, 18,24]TRIEN]-7'-YL)-2-METHYLPROPANAMIDE

The title compound was prepared in an analogous manner to that described in Example 925, Step 1 , using N-^l S^'R.e'R.TR.S'E TR^e-chloro-l^-ethyl-

13',13'-dioxido- 15 ^, -oxo-3,4-dihydro-2H-spifo[naphthalene-l,22'-

n]-7'-yl)-2-methylpropanamide (Example 1081), and the desired product, N-

((l S,3¾,6 ^* R,7'R, 12 ^! R)-6-dilori 12'-ethyM

spiro [naph thalene- 1 ,22'-

7'-yl)-2-methylpropanamide was isolated. ¾ NMR (500MHz, CD ₃ OD) δ 7.77 (d,

J=8.2 Hz, 1H), 7.42 (d, J=5.9 Hz, 1H), 7.22 i d. ./ 1 .5 Hz, I I I ). 7.19 (dd, ./ 2. ! .

8,4 Hz, IH), 7. 15 - 7,09 (m, 2H), 6.96 (dd, ,/ 1 .2. 8,0 Hz, IH), 4. 1 1 (dd, ,/ 1 2.0.

18, 8 Hz, 2H), 3.82 - 3,76 (m, 2H), 3.74 (d, «7=14.7 Hz, 1H), 3.64 (ddd, «7=4.6, 8, 8,

13.2 Hz, 1H), 3.15 (dd, J=7.2, 15.3 Hz, IH), 2.85 - 2.73 (m, 2H), 2.56 - 2.41 (m, 3H), 2. 1 1 - 2.02 (m, 2! I ). 1 ,99 (d, .7=6.8 Hz, I H), 1 .96 - 1 .82 (m, 5H), 1.79 - 1 ,62

(m, 3H), 1 ,62 - 1.45 (m, 4H), 1.43 - 1.33 (m, 2H), 1 ,33 - 1.24 (m, 2H), 1. 17 (t,

J=7.5 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.6 Hz, 3H). m/z (ESI, +ve ion)

670.3 ( \! I I ) . EXAMPLE 1084. (IS, 3 % 6'ii)-6-CHLORO-3,4~DIHYDRO-2H, 15 Ή- SPIRO I NAPHTHALENE- 1 ,22'-[20] OXA[ 13] THI A[ 1 , 14 j

DIAZ A TETR A C YCLO [14.7.2.0 ³ · ⁶ .0 ¹⁹ ' ²⁴ ]PENTACOS A[ 16, 18,24]TRIENJ- 15'-

A mixture of Example 858 (0.004g, 7 μηιοΐ) and platinum (IV) oxide (1,6 mg, 7 μηιοΐ) in EtOAc (1.2 mL) was stirred under H ₂ at rt for 40 min. The reaction mixture was filtered through syringe filter to remove solid catalyst. The filtrate was concentrated to provide the title compound (3.4 mg) as a white solid. ¾ NMR (400 MHz, CD2CI2) 58.11 (m, !il}.7.72 (m, ill).7.17 (m, Ml).7.09 (in, 1H), 6.99 (m, 1H), 6.93 (s, 2H), 4.11 (m, 211), 3.90 iddd../ 4.70.10.27, 14.97 Hz, 111).3.77-3.64 (ra, 211).3,323.22 (m, 2H), 3,06 (dd, ./ 7.92.15.36 Hz, ill). 2.84-2.72 (111, 2H), 2,33-2.26 (m, I Hi,.2.20 (d, .7=4.70 Hz, IH), 2.14-1,00 (m, 18H). m/z (ESI, +ve ion) 557.2 (Μ+Η).·

EXAMPLE 1085, (Ι8 'Κ,6Έ,7'8,8Έ,11'8)-6-α-ΪΙ.Ο Ο-7'-ΗΥΒ ΟΧΥ-11'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,I5'H-SPlRO [NAPHTHALENE- 1,22'-

[20]OXA[13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

STEP 1: 2-ALLYLPROPANE- 1 , 3-DIOL

To a 2 litter three-neck Morton flask, equipped with an overhead stirrer, addition funnel and gas inlet was added lithium aluminum hydride (1.0 M solution in THF, 250 mL, 250 mrnol). A solution of diethyl allylmalonate (29.7 mL, 150 mmol) in 100 mL of THF was then added using an addition funnel slowly enough allowing the reaction temperature was below 45 °C (the addition time is aroimd 2.5 h). After addition of the starting material the reaction was heated to reflux using heating mantle for around 1 h. The reaction flask was submerged in a water- ice bath to cool to 5 °C and then quenched very slowly with 9.5 mL of water followed by 19 mL of 10% aqueous NaOH and 28 mL of water. The reaction mixture was stirred at rt for around 50 min and the resulting slurry was diluted with around 100 mL of ether and filtered with a Buchner funnel. The filtrate was dried with anhydrous Na ₂ S04, filtered and concentrated to yield the title compound (16.2 g, 140 mmol, crude yield 93.0%) as clear colorless oil.

STEP 2: (R)-2-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4- EN-l-OL AND (S)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN-l-OL

To a 2 litter three-neck Morion flask, equipped with a stir bar, N ₂ inlet, thermocouple and addition funnel was added sodium hydride (60% dispersion in mineral oil, 3.73 g, 93.0 mmol) and 300 mL of THF and the flask was then submerged in an ice-bath. Once the temperature reached about 5 °C, a solution of 2-allylpropane- 1 , 3-diol (10.8 g, 93.0 mmol) in 70 mL of THF was added dropwise by addition funnel in about 30 min. During the process of addition obvious gas evolution and slight temperature change were observed. A neat tert- butylchlorodiphenylsilane (24.2 mL, 93.0 mmol) was added and the reaction temperature rose from 6 °C to 10 °C during addition with an observation of gas evolution. The reaction was warmed to rt and sit in hood for overnight. The reaction was quenched with water and extracted with EtOAc. The EtOAc extract was washed with saturated NaCl and dried with anhydrous Na ₂ S0 ₄ , filtered, and concentrated to give a residue. The residue was loaded onto a 330 g silica gel column and eluted with a gradient of 0-40% EtOAc in Hexane to give the title compound (28.3 g, 80.0 mmol, 86 % yield) as clear colorless oil.

STEP 3: (S)-2-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4- 5 EN- 1 -YL ΜΕΤΉ ANESULFON ATE AND (R)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN-l-YL

METHANESLILFONATE

0

To a solution of (R)-2-(((tert-butyldiphenylsily l)oxy)methyl)pent-4-en-l -ol and (S)-2-(((tert-butyldiphenylsily])ox ')methy])pent-4-en-l -ol (Step 2; 5.00 g, 14.1 mmol) in 47 mL of DCM was added triethylamine (2.16 ml,, 15.5 mmol) and DMAP (0.0520 g, 0.423 mmol) followed by an addition of methanesulfonyl5 chloride (1.09 mL, 14.1 mmol) via syringe in around 1 nun and the resulting

reaction was stirred at rt for 3.5 h. The reaction mixture was partitioned with saturated aq. NH Cl and DCM. The organic phase was dried with anhydrous Na?.SC)4, filtered and concentrated to yield the title compound (6.90 g, 15.9 mmol, crude yield 1 13 %) as a clear oil with a tint of redness.

0

STEP 4: (S)-2-((2-(((TERT-BUTYLDIPHENYLSILYL)OXY)METHYL)PENT- 4-EN - 1 -YL)THIO)PYRIMIDINE AND (R)-2-((2-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN- 1 - YL TH10 PYR1M1D1NE

D

To a solution of (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en-l-yl methanesulfonate and (R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en-l -yl methanesulfonate (Step 3; 6.90 g, 14.0 mmol,) in 70 mL of DMF was added 2- mercaptopyrimidine (1.89 g, 16.8 mmol) and followed by an addition of K2CO3 (2.33 g, 16.8 mmol) in one portion. The resulting bright yellow slurry was stirred at rt for overnight and then more 2-mercaptopyrimidine (0.5 g, 4.44 mmol) and K2CO3 (1.0 g, 7.21 mmol) were added. The reaction was stirred at rt for 3 h and 45 min. The reaction was quenched with saturated aqueous NH4CI and extracted with ether. The organic extract was dried with anhydrous Na?.SQ4, filtered and concentrated to give a residue. This residue was dissolved in DCM and loaded onto a 120 g gold-capped ISCO Redisep silica gel column eluting with a gradient of 0-95% of EtOAc in hexane to afford 6.3 g of oil, NMR suggested that it is a mixture of desired product with around 50% of starting material. The isolated mixture was then re-dissolved 20 mL of EtOH and treated with a solution of 2- mercaptopyrimidine (0.9 g, 8.00 mmol) and NaOEt (21 w/vv solution in ethanol, 3.14 ml, 8.42 mmol) in 15 mL of EtOH at rt for overnight and at at 65 °C for 7 h. The reaction was quenched with saturated aqueous NH4CI and extracted with ether. The organic extracts were combined, dried with anhydrous Na_S04, filtered and concentrated to give a residue, which was purified by chromatograph on a 120 g gold-capped ISCO Redisep silica gel column eluting with a gradient of 0-50% of EtOAc in hexane to provide the title compound (4.76, 10.6 mmol, 76%) as a colorless oil.

STEP 5 : (S)-2-((2-(((TERT-BUTYLDIPHETSIYLSILYL)OXY)METHYL)PENT- 4-EN- 1 -YL)SULFONYL)PYRTMIDINE AND (R)-2-((2-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN-l-

YL)SULFONYL)PYRlMIDiNE

To a solution of (S)-2-((2-(((tert-butyldiphen lsilyl)oxy )methyl)pent-4-en- l-yl)thio)pyrimidine and (R)-2-((2-(((tert-bu1yldiphenylsilyl)oxy)methyl)pent-4- en-l-yl)thio)pyrimidine (Step 4: 4.76 g, 10.6 mmol) in 53 mL of DCM was added 3-chloroperoxybenzoic acid (77%, 5.23 g, 23.3 mmol) at ice-bath and the resulting reaction was then stirred at rt for 1 hour and 45 min, and LCMS indicated the formation of the desired product. Purification by column chromatography afforded the title compound (3.60 g, 7.49 mmol, 70.6%).

STEP 6: (S)-2-(((TERT-BUTTLDIPHENYLSILYL)OXY)METHYL)PENT-4- ENE-1 -SULFONAMIDE AND (R)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-ENE-l -SULFONAMIDE

A solution of (S)-2-((2-(((tert-butyldiphenylsilyl)oxy)methyl)pent-4-en-l- yl)sulfonyl)pyrimidine and (R)-2-((2-(((tert-butyldiphenylsilyl)oxy)methyl)pent- 4-en-l-yl)sulfonyl)pyrimidine (Step 5; 3.60 g, 7.49 mmol) in 74.9 mL of MeOH was treated with sodium methoxide (25 wt % solution in MeOH, 1 .67 mL, 7.49 mmol) at rt for 1 h and the reaction was then concentrated to give a crude oil. To this oil was added 74.9 mL of water, sodium acetate (0.402 mL, 7.49 mmol), around 25 mL of MeOH and hydroxylamine-0-sulfomc acid (1.03 g, 8.24 rnmol) in one portion and the resulting reaction was stirred at .50 °C for 1.5 h and then at 60 °C for overnight. The reaction was partitioned with water and ether. The ether extracts were combined, dried with anhydrous Na_S04, filtered and concentrated to give crude, which was dissolved in DCM and loaded onto an 80 g ISCO

Redisep silica gel column eiuting with a gradient of 0-100% EtOAc in hexane to afford the title compound (1.65 g, 3.95 rnmol, 52.8%).

STEP 7: (S)-N-(((S)-2-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN- 1 -YL)S ULFON YL)-

6 ^! -CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAI-IYDRO- 2H,2H-SPIRO[BENZO[B] [l,4]OXAZEPINE-3,l'-NAPHTHALE E]-7- CARBOXAMIDE AND (S)-N-(((R)-2-(((TERT- BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN- ! -YL)SULFONYL)- 6'-CHLORO-5-(((lR,2R)-2-((S)-l-

HYDROXYALLYL)CYCLOBOTYL)METHYL)-3',4,4',5-TETRAHYDRO-

2Η,2Ή-8ΡΚ()|;ΒΕΝΖΟ[Β| [ 1,4]ΟΧΑΖΕΡΙΝΕ-3,1·-ΝΑΡΗΤΗΑΕΕΝΕ]-7- CARBOXAMTDE

To a solution of Intermediate AA1 1 A and (S)-2-(((tert- butyldiphenylsilyl)oxy)methyl)pent-4-ene-l-sulfonamide and (R)-2-(((tert- but diphenylsiiyl)oxy)niethyl)pent-4-ene-l-sulfonainide (Step 6, 241 nig, 0.577 rnmol) in DCM (7.1 mL.) was added DMAP (44.4 mg, 0.363 rnmol) and triethylamine (89 μΐ, 0.641 rnmol). The reaction mixture was cooled to 0 °C and EDC (82 mg, 0.427 mmol) was added in one portion. The reaction mixture was stirred for 25 h and 50 min and more EDC (60 mg, 0.313 mmol) was added. The reaction mixture was stirred for a further 2 h and 10 min and was then partitioned between DCM and an aqueous ammonium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was dissolved in a minimal amount of DCM and hexane, loaded onto a 24 g ISCO Gold column and eluted with a gradient of 0-30% EtOAc (containing 0.3% AcOH) in hexane. The title compound (158 mg, 0.182 mmol) was isolated in 85% yield.

STEP 8: (1S,3 ^! R,6'R,7'S,8'E,1 l'S)-l l'-(((TERT~BUTYL

(DIPHE TYL)SILYL)OXY)METHYL)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[14.7.2.0 -^0 ^!9 - ²⁴ 1PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'- DIOXIDE

To a solution of the title compound (from Step 7; 158 mg, 0.182 mmol) in 1, 2-dichloroethane (130 mL) was bubbled with argon for 10 min and followed by an addition of (1, 3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro (o- isopropoxyphenylmethyiene)ruthenium (22.8 mg, 0.036 mmol) and the resulting reaction mixture was stirred at 40°C for 8 h and 15 min. Air was then blown through the mixture for 1 hour and the reaction mixture was concentrated under reduced pressure. The dark residue was taken-up in 3 mL of DCM, loaded onto a 4 g ISCO Gold column, and then eluted with a gradient of 0-70% EtOAc

(containing 0.3% AcOH) in hexane to afford the title compound (45 mg, 0.054 mmol, 29.4%).

STEP 9: (1S,3'R,6'R,7'S,8'E,1 l'S)-6-CHLORO-7'-HYDROXY-l Γ- (HYDR0XYME™YL)-3,4-DIHYDR0-2H,15'H-SPIR() [NAPHTHALENE- l. -

[20]OXA[13]TO1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16,18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

The title compound (from Step 8; 45 mg, 0.054 mmol) was treated with tetrabutyl ammonium fluoride (1.0 M solution in tetrahydrofuran, 536 jiL, 0.536 mmol) at rt for 22 h and 45 min. The reaction was diluted with acetonitrile and purified by preparative HPLC (system: Agilent 1100: column: Phenomenex Gemini C181.10 A, CI 8, 10 microns X 30 mm T.D. X 250 mm; mobile phase: \:H O w/0.1% TFA, B:ACN w/0.1%TFA; method: 0:00-1:0050% B, 50-95%B 1 : 00-20.99 min, 100% B 21.00-25.00 min, 50 ml/min) to give 6 mg of impurity contaimng sample. This sample was further purified by preparative TLC on a stock Anal tech plate using 10% MeOH in DCM as a co-solvent to afford the title compound (3 mg, 9 %) as a white solid. ¾ NMR (400 MHz, CD3OD) δ 7.72 (d, J ------ 8.4 Hz, 1 H), 7.17 (dd, J ------ 2.3, 8.4 Hz, 1 H), 7.10 id../ 2.2 Hz, 1 H), 7.07 - 6,99 (m, 2 H), 6.90 id../ 8.0 Hz, 1 H), 6.06 - 5.89 (ra, 1 H), 5.66 (dd, ,/ 7.0, 15,3 Hz, 1 H), 4.13 - 4.00 (m, 3 H), 3.77 - 3.50 (m, 6 H), 3,38 (d, ./ 14.1 Hz, 1 H), 3.26 - 3.10 (m, 1 H), 2.88 - 2.69 (m, 2 H), 2.52 - 2.27 (m, 3 H), 2.23 - 2.10 (m, 2 H), 2.09 - 2.01 {in.1 H), 1.98 - 1.83 (m, 3 H), 1.81 - 1.66 (m, 3 H), 1.56 - 1.41 (m, 1 !!}. m/z (ESI, +ve ion) 601.2 i M il ) .

EXAMPLE 1086. (lS,3'R,6'R,7'S,8 ^! E,irR)-6-CHLORO-7'-HYDROXY-l Γ- (HYDR0XYMETOYL)-3,4-DIHYDR0-2H,I5'H-SPIR0 [NAPHTHALENE- l. -

[20]OXA[13]THLA[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTACOSA |8,16,18,24]TETRAEN]-15 ^! -ONE 13',13'-DIOXIDE

STEP 1: (ISJ'R^'RJ'S^'E/ll'^-ll'-C TERT-BUTYL

(DIPHE TYL)SILYL)OXY)METHYL)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[14.7.2.0- ⁶ .0 ^!9 - ²⁴ 1PENTACOSA[8,16,18,24]TETRAEN]-15'-ONE 13',13'-

The title compound was the other isomer isolated from the reaction described in Example 1085, Step 8 (43 mg, 0.051 mmol, 28.1%).

STEP 2: (lS,3'R,6'R,7'S,8'E,i R)-6-CHLORO-7'-HYDROXY-i - (HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO !NAPI IT! ϊΛΙ.ΗΝΙί-· 1,22'-

|2ίί|0ΧΛ| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥΠ:ΤΗΑ(ΎΠ.ϋΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA [8,16,18,24]TETRAENj-15'-C)NE 13 ^! J3 ^* -DIOXIDE The title compound was prepared from (1S,3'R,6'R,7'S,8'Z,11 'R)-l Γ- (((tert-butyl (diphenyl)silyl)oxy)methyl)-6-chloro-7'-hydrox\'-3,4-dihydro - 2h, 15 'h-spiro[naphthalene- 1 ,22'- [20] oxa[ 13]thia[ 1 , 14] diazatetracy clo

[ 14.7.2.0 ³ ' ⁶ .0 ⁱ⁹ - ²⁴ ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (Example 1086, Step 1) by a procedure similar to the one described in Example 1085, Step 9 as a TFA salt. ¾ NMR (400MHz, CD2CI2) δ 7.90 - 7.66 (m, 1 H), 7.16 (dd, J = 2,2, 8.5 Hz, 1 H), 7.09 (d, ./ 2.2 Hz, 1 !!}.6.98 - 6.86 (m, 3 !!}.5.89 - 5.79 (m, 1 H), 5.79 - 5.68 (m, 1 H), 4.20 (dd, ,/ 4,1, 7.6 Hz, 1 H), 4.17 - 4.02 (m, 3 H), 3.87 - 3,77 (m, 1 H), 3,76 - 3,64 (m, 3 H), 3.45 - 3,33 (m, 1 H), 3.30 - 3,20 (m, 1 H), 3.04 (dd, J = 9.2, 15.3 Hz, 1 H), 2.86 - 2.67 (m, 2 H), 2.47 - 2.24 (m, 3 H), 2.10 - 1.88 (m, 6 H), 1.88 - 1.73 (m, 3 H), 1.73 - 1.60 (m, 1 H), 1.47 - 1.33 (m, 1 H). m/z (ESI, +ve ion) 601,2 (VI 11) .

EXAMPLE 1087. (1 S,3'R,6'R,7'S,8'E,1 l'R)-6-CHLORO-7'-HYDROXY-l Γ- (METHOXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

|2ujOXA| 1ΉΤί!1Λ| Ι.Ι4|ΠίΑ/.ΥΠ:ΤΗΛ(ΎΠ.ϋΙ i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-ONE 13',13'-DIOXIDE

To a solution of (18,3¾,6Ί,7'8,8Έ,11Ί)-6-€ωοΓθ-7 ^! ΐ}^Γθχγ-1 Γ- (hy droxyme1hyl)-3,4-dihydro-2h, 15'h-spiro | naphthalene- 1 ,22'- [20]oxa[13]1hia[l,14]diazatetra<yclo[14.7.2.0 ³ ^0 ¹⁹ ' ²⁴ ]pentacosa

[8,16,18,24]tetraen]-15'-one 13',13'-dioxide ^" TFA salt (Example 1086; 6.0 mg, 0.053 mmol) in THF (526 μΙ_) at 0 °C was slowly added sodium hydride (60% dispersion in mineral oil, 10.5 mg, 0.263 mmol). The reaction mixture was stirred at 0 °C for 10 min and then at rt for 5 rain. The mixtiire was cooled to 0 °C and 50 μΐ, of a solution of iodomethane in THF (prepared by adding 3 mg of iodomethane in 100 μΐ, of THF) was added. The reaction mixture was stirred at 0 °C for 40 min and the ice-bath was then removed. Another 50 μΙ_. of the previously prepared iodomethane solution in THF was added and the mixture was stirred at rt for 16 h. The reaction mixture was then diluted with THF (100 μί) and quenched by adding a drop of acetic acid. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative TLC plate: the residue was dissolved in a minimal amount of DCM and loaded onto Analtech plate (L!niplate, 10x20x250 microns, silica gel HLF w binder and uv254). The plate was eluded first with 50% EtOAc (containing 0.3% AcOH) in hexane. The plate was dried and 20 mL of EtOAc (containing 0.3% AcOH) was added to the previous eluent. This corresponded to

approximately 60% EtOAc (containing 0.3% AcOH) in hexane. The plate was eluded and then dried again. The eluent was replaced with 80%) EtOAc

(containing 0.3% AcOH) in hexane and the plate was eluted one last time. Four bands were cut and collected, numbered from top to bottom, and extracted with 100% EtOAc (containing 0.3% AcOH). Each fraction was then concentrated and fraction 3 provided the title compound (1.25 mg, 2.03 μιτιοΐ,, 3.86 % yield). ¾ N.V1R (400 MHz, CD2Q2) δ 7.76 - 7.65 (m, 1 H), 7.17 (dd, J = 2.2, 8.5 Hz, 1 H), 7.09 (d, ,/ 2.3 Hz, 1 H), 6.94 - 6.87 (m, 3 H), 5.87 - 5.77 (m, 1 H), 5.76 - 5.66 (m, 1 H), 4.22 - 4. 16 (m, 1 H), 4.11 - 4.07 (m, 3 H), 3.81 (d, ,/ 15.3 Hz, 1 H), 3.77 - 3.65 (m, i H), 3.44 - 3.34 (m, 3 H), 3.32 (s, 3 H), 3,28 - 3.21 (m, 1 H), 3,05 (dd, ./ 9.3, 15.4 Hz, 1 H), 2.80 - 2.73 (m, 2 H), 2.48 - 2.28 (m, 3 H), 2.17 - 2.11 (m, 1 H), 2.06 - 2.01 (m, 2 H), 1.98 - 1.89 (m, 2 H), 1.87 - 1.75 (m, 3 H), 1.74 - 1 ,62 (m, 2 H), m/z (ESI, +ve ion) 615,2 (M+H) ⁺ .

EXAMPLE 1088. (1 S,3 ^! R,6 ^* R,7'R,8'E, 1 1'8 6-(:ΗΕΟΜ)-7 ^* 1ΥϋΜ)ΧΥ-11'- (METHYL)-3,4-DIHYDRO-2H,15'H-SPIRO [NAPHTHALENE- 1 ,22'- | 2( !ί>Χ Λ| i ? ! ! Π! Λ| ί ! 4 | ί^!ΛΖΛ ί : ί AC YCT (>! i 4 7.2 ϋ ^; ".O ¹ " ^M |PH\ l ACOSA [8, 16, 18,24]TETRAEN]-15'-ONE i .T. i 3'-DIOXIDE

To a solution of (S)-(+)-3-bromo-2-methyl-l -propanol (4.56 mL, 44.1 mmol) in THF (110 mL) in a 250 mL round-bottomed flask equipped with an N ₂ inlet and stir bar was added copper (I) iodide (0.420 g, 2.20 mmol) and followed by an addition of vinylmagnesium bromide (1.0 M solution in tetrahydrofuran, 44.1 mL, 44.1 mmol) via a syringe over about 20 min. The resulting dark black reaction mixture was stirred at rt for overnight. The reaction was submerged in an ice-bath and another 1.0 equivalent of vinyl magnesium bromide was added over 15 min. The reaction was stirred at rt for 8 h and 40 min and followed by an addition of another 4 mL of Grignard and the reaction was stirred at rt for overnight. The reaction was quenched with saturated aqueous NH4CI and extracted with DCM. The organic layer (it is a mixture of THF and DCM and is the top layer in the separation funnel) was collected, washed with saturated NaCl, dried with anhydrous sodium sulfate, filtered and concentrated to a afford the title compound as a light amber crude oil (5.1 g, crude yield 1 15%).

STEP 2: (R)-2-METHYLPENT-4-EN-l-YL 4-

METHYLBENZENESULFONATE

To a solution of (R)-2-methylpent-4-en-l-ol (4.42 g, 44.1 mmol) in DCM (110 mL) was added pyridine (17.8 mL, 221 mmol) and followed by an addition of J-toluenesulfonyl chloride (8.83 g, 46.3 mmol) at ice-bath. The reaction was then stirred at rt over the weekend. The reaction was quenched with aqueous 1.2 M HC1 and extracted with DCM. The organic layer was washed with aqueous 1.2 M HC1 and brine, dried with sodium sulfate, filtered and concentrated. The residue was loaded onto a 330 g gold-capped IS CO Redisep silica gel column running with a gradient of 0-50% DCM in hexane to elute first peak and then eluting with a gradient of 50 - 100% of EtOAc to collect multiple fractions. These fractions were combined and concentrated to give an oil, which was loaded onto another 330 g gold capped silica gel column (ISCO Redisep) eluting with a gradient of 0-20% EtOAc in hexane to afford the title compound (total 3.67 g with about 30% impurity).

STEP 3: (R)-2-((2-METHYLPENT-4-EN-l-YL) TRIG) PYRJMIDINE

To a solution of 2-rnercaptopyrimidine (1.73 g, 15.4 mmol) in 20 mL of EtOH was added sodium ethoxide (2.1 w/w solution in EtOH, 5.76 mL, 15.4 mmol) followed by an additon of a solution of (R)-2-methylpent-4-en- l -yl 4- methylbenzenesulfonate (Step 2, 3.57 g, 14.0 mmol) in EtOH. The reaction was stirred at rt for 24 h and then at 65 °C for overnight. The reaction was quenched with saturated NEUC! and extracted with DCM. The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated and purified by a 120 g gold- capped Redisep silica gel column eluting with a gradient of 0-100 % of EtOAc in hexane to afford the title compound (total 2.3 g with impurity) as an oil. STEP 4: (R)-2-((2-METHYLPENT-4-EN- 1 - YL) SULFONYL) PYRIMIDINE

To a solution of (R)-2-((2-methylpent-4-en-l-yl) thio) pyrimidine (Step 3, 2.3 g, 1 1.8 mmol) in DCM (39.5 mL) was added 3 -chloroperoxy benzoic acid (77%, 4.38 g, 19.5 mmol) at ice-bath and the resulting reaction mixture was stirred at rt for overnight. The reaction was concentrated and hexane was added and the mixture was then filtered to remove solid. The filtrate was concentrated and purified by a 80 g gold-capped Redsep column eluting with a gradient of 0- 100% of EtOAc in hexane to afford the title compound (1.16 g, 5.13 mmol, 43,3%).

STEP 5 : (R)~2~METHYLPENT~4~ENE- 1 - SULFONAMIDE

= 0' O

To a solution of (R)-2-((2-methylpent-4-en-l-yl)sulfonyl)pyrimidine (Step 4; 1.16 g, 5.13 mmol) in MeOH (51.3 mL) was added sodium methylate (1.17 mL, 5.13 mmol) and the reaction was stirred at rt for 4 h. To this reaction was added sodium acetate (0.421 g, 5.13 mmol) and sulfonic acid (0.709 g, 5.64 mmol) and the resulting reaction was stirred at 50 °C for 15 min followed by an addition of 35 mL of water. The reaction was stirred at 50 °C for overnight and the partitioned with ether and aqueous NH4CI. The organic extracts were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by a 40 g gold-capped Redsep column eluting with a gradient of 0- 100% of EtOAc in hexane to afford the title compound (total 0.76 g with about 50% of one impurity).

STEP 6: (S)-6 ^! "CHL0R0-5"(((1R,2R)"2-((R)-1-

HYDROXY ALLYL)CYCLOBU L)METHYL)-N-(((R)-2-METHYLPENT-4-

EN-l -YL)SULFONYL)-3^4,4 ^! ,5-TETRAHYDRO-2H,2'H- SPIRO[BENZO[B] [l,4]OXAZEPINE-3, 1 '-NAPHTHALENE j-7- CARBOXAMIDE

The title compound was prepared from Intermediate AAl IB and (R)-2- methylpent-4-ene-l -sulfonamide (Step 5) by a procedure similar to the one described in Example 1085, Step 7. This compound was isolated by preparative HPLC (system: Agilent 1 100; column: Phenoraenex Gemini CI 8 110 A, CI 8, 10 microns X 30 mm I.D. X 250 mm; mobile phase: A:H ₂ Q w/0.1 % TFA, B:ACN w/0.1%TFA; method: 0:00-1 :00 10% B, 50-100%B 1 :00-18.00 mm, 100% B 21.00-25.00 mm, 50 ml/min) as a TFA salt.

STEP 7: (1S,3 ^! R,6'R,7'R,8'E,1 rS)-6-CHLORO-7'-HYDROXY-l Γ-(ΜΕΊΉΥΕ)- 3,4-DIHYDRO-2H,15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[13]TO A[1 ,14]DIAZATETRACYCLO[147 ³ "* 0 ^{] 9} ^ ⁴ ]PE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13 ^! -DIOXIDE The title compound (42.2 mg, 0,072 mmol, 92%) was prepared from (S)- 0 ^! -ch!oro-5 -((( ! R,2R)-2-((^

methylpent-4-en-l-yl)sulfonyl)-3',4,4',5-tetrahydro-2h,2 ^, h- spiro[benzo[b][l,4]oxazepine-3,r-naphthalene]-7-carboxamide (Step 6) by a procedure similar to the one described in Example 1085, Step 8. Ή NMR

(400MHz, CD2C12) δ 7.72 (d, J= 8.4 Hz, 1 H), 7.29 (dd, J= 2.0, 8.2 Hz, 1 H), 7.17 (dd, ./ 2.2, 8.5 Hz, 1 H), 7.09 (dd,■/ 2.2, 4.9 Hz, 2 H), 6.95 (d,■/ 8.2 Hz, 1 H), 5,99 - 5.89 (m, 1 H), 5,78 (dd, ./ 8.2, 15.3 Hz, I H), 4,26 (dd, J = 5.5, 8.2 Hz, 1 H), 4.11 (s, 2 H), 3.89 (dd,./= 8.7, 15,7 Hz, 1 H), 3.80 - 3.71 (m, 1 H), 3.64 (d,J= 14.3 Hz, 1 H), 3.35 (dd, J =3.9, 15.8 Hz, 1 H), 3.31 - 3.24 (m, 1 H), 3.11 (dd, ,/ 8.9, 15.4 Hz, 1 H), 2.84 - 2.69 (m, 2 H), 2.62 (qum, ,/ 9.0 Hz, 1 H), 2.42 - 2.25 (m, 3 H), 2.05 - 2.01 (m, 1 H), 2.00 - 1.76 (m, 5 H), 1.74 - 1.62 (m, 1 H), 1.60 - 1.51 (m, 1 H), 1.51 - 1.39 (m, 1 H), 1.12 (d,J= 6.8 Hz, 3 H). m/z (ESI, +ve ion) 585.2 (M+H) ⁺ .

EXAMPLE 1089. (1S,3'R,6 ^! R,7'R,8'E,1 l¾)-6-CHLORO-7'-HYDROXY-l 1'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15H-SPIRO [NAPHTHALENE-

122'- pOlOXAtlSJTO At^MlDIAZATEmACYCLOtl^y^.O'^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(lS,3'R,6'R,7'R,8'E,ll'S)-6-CHLOR()-7'-HYDROXY-ll'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'-

|2ί!!0ΧΛ| Π ΙΊ I Ι1Λ| 1.14|! IA/.\ TL i ^' RACYCf.OI i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETR _! 4ENl-15'-ONE 13',13'-DIOXIDE

STEP 1: (S)-N-(((S)-2-(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN- 1 -YL)S ULFON YL)- 6 ^! -CHLORQ-5-(((lR,2R)-2-((R)-l- HYDROXY ALLYL)CYCLOBUTYL)METI-IYL)-3 ^f ,4,4',5-TETRAFIYDRO- 2H,2H-SPIRO[BENZO[B][l,4]OXAZEPINE ,l'-NAPHTHALE E]-7- CARBOXAMIDE AND (S)-N-(((R)~2"(((TERT-

BUTYLDIPHENYLSILYL)OXY)METHYL)PENT-4-EN-l-YL)SULFONYL)- 6'-CHLORO-5-(((l R,2R)-2-((R)- 1 - HYDROXY ALLYL)CYCLOBUTYL)METHYL)-3',4,4',5-TETRAHYDRO- 2i!.2 ^, !!"SFIR()|Bi;NZ()|Bi| i.4iOXA/LPINl 3. Γ-ΝΛΡΙ ΓΠ L\LLN!:j-7- CARBOXAMTDE

The title compound was prepared from Intermediate AA1 IB and (S)-2- (((tert-butyldiphenylsilyl)oxy )methyl)pent-4-ene- 1 -sulfonamide and (R)-2-(((tert- but'lcliphenylsilyl)ox\')niethyl)pent-4-ene-l -sulfonamide (Example 1085, Step 6) by a procedure similar to the one described in Example 1085, Step 7.

STEP 2: (1S,3 ^! R,6'R,7'R,8 ^! E,1 l'R)-l l'-(((TERT-BUTYL

(DIPHE TYL)SILYL)OXY)METHYL)-6-CHLORO-7 ^, -HYDROXY-3,4- DIHYDRO-2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1 , 14]DI AZATETRACYCLO

[14 .2.0- ^f 0 ^!9 - ²⁴ ]PENTACOSA[8,16,18,24]TETlAEN]-15'-ONE 13',13'- DIOXIDE AND (1S,3'R,6'R,7'R,8'EJ l'S)-U'-(((TERT-BUTYL (DIPHENYL)SiLYL)OXY)METHYL)-6-CHLORO-7'-HYDROXY-3,4- DIHYDRO-2H, 15 Ή- SPIRO [N APHTH ALENE- 1 ,22'- [20] OXA[ 13]THI A[ 1,14] Dl AZATETRAC Y CLO

[14.7.2.0 ³ - ⁶ .0 ⁱ⁹ - ²⁴ ]PENTACOSA[8,16J8,241TETRAEN]-15'-ONE 13',13'- DIOXIDE

The title compound was prepared using the intermediate isolated from

Example 1089, Step 1 by a procedure similar to the one described in Example 1085, Step 8.

STEP 3: (1S,3'R,6'R,7'R,8'E,1 l'R)-6-CHLORQ-7'-HYDROXY~l Γ- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15H-SPIRO [NAPHTHALENE- 122'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ "*0 ^]9 ^ ⁴ ]PE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13', 13 '-DIOXIDE OR

(1 S,3'R,6'R,7'R,8'E, 11 'S)-6-CHLORO-7'-HYDROXY - 11 '- (HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO !NAPI ΓΠ !ALHNIi- 1,22'-

|2ίί!<)ΧΛ| 13ΙΊ !!1Λ| l.l4|! !A/.Vr!-;i ^' RA( ^' Y(-i.()l i 4.7.2 O · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-ONE 13',13'-DIOXIDE The title compound (20 nig, 0.033 mmol, 31.7%) was prepared from the intermediate in Example 1089, Step 2 by a procedure similar to the one described m Example 1085, Step 9. Ή X.YiR (400 Iz, CD2CI2) δ 7,70 (d, ./ 8.4 Hz, 1 H), 7.39 (d, J= 1,8 Hz, ! H), 7.16 (dd, J= 2.2, 8.5 Hz, 1 H), 7,08 (d, J = 2.2 Hz, 1 H), 7.04 (dd, J = 1.9, 8.1 Hz, I H), 6.91 (d, ./ = 8.0 Hz, 1 H), 5,78 - 5.62 (m, 2 H), 4.11 - 4.05 (m, 2 H), 4.05 - 3.99 (m, 1 H), 3.93 (dd, J = 4.2, 15.4 Hz, 2 H), 3.74 - 3.61 (m, 3 H), 3.35 (dd../ 7.4.15.5 Hz, 1 H), 3.20 (d, ./ 14.3 Hz, 1 H), 2.97 (dd, ,/ 7.0, 15.3 Hz, 1 H), 2,84 - 2.66 (m, 2 H), 2,49 (br. s,, 2 H), 2.37 (dd, J --- 4,4, 13.4 Hz, 1 H), 2.14 - 2.07 (rn, 1 H), 2.04 - 1.84 (m, 5 H), 1.83 - 1.73 (m, 2 H), 1.69 - 1.51 (m, 2 H), 1.35 (t, ./ 12.1 Hz, 1 H). m/z (ESI, +ve ion) 601.2 (M+H) ⁺ .

EXAMPLE 1090. (1S,3'R,6 ^! R,7'R,8'E,1 rS)-6-CHLORO-7 ^! -HYDROXY-H'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H,15H-SPIRO [NAPHTHALENE- 122'- pOlOXAtlSJTO At^MlDIAZATETRACYCLOtl^y^.O'^.O^^lPE TACOSA

[8,16,18,24]TETRAEN]-15'-ONE 13 ',13 '-DIOXIDE OR

(1S,3'R,6'R,7'R,8'E,1 l'R)-6-CHLORO-7'-HYDROXY-l .1'- (HYDROXYMETHYL)-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1,22'~

|2ujOXA| !3jTIUA| Μ4|ηΐΛ/Λ Ι·: ^' ΠίΛ(ΎΠ.Ο! i 4.7.2.0 · ^, '.ί ^)|: " ¹ |P1-M ^' .\C<)SA

[8,16,18,24]TETRAENj-15'-ONE 13',13 ^* -DIOXIDE

The title compound was isolated as the other isomer from the reaction of Example 1089, step 3. ¹⁹ FNMR suggested that it is a TFA salt. ¾ N.V1R

(400MHz, CD2CI2) δ 7.71 (d, ./ 8.6 Hz, 1 H), 7.26 id. 8.0 Hz, 1 H), 7.16 (dd, ,/ 2.1, 8,5 Hz, 1 H), 7.11 - 7.03 (rn, 2 H), 7.01 - 6.86 (rn, 1 H), 5.98 - 5.87 (rn, 1 H), 5.85 - 5.76 (rn, 1 H), 4.31 - 4.21 (m, 1 H), 4.14 - 4.04 (rn, 2 H), 3,90 - 3.60 (m, 5 H), 3.59 - 3.49 (m, 1 H), 3.34 - 3.21 (m, 1 H), 3.10 (dd, J = 9.0, 14.9 Hz, 1 H), 2,83 - 2.68 (ra, 2 H), 2,65 - 2.53 (m, 1 H), 2,43 - 2.24 (ra, 3 H), 2, 10 - 1.75 (ra, 7 H ';.. 1.68 (quin, ./ 9.4 Hz, 1 H), 1.60 - 1,49 (m, 1 H), 1.49 - 1,37 (m, 1 H), m/z (ESI, +ve ion) 601.2 ( M i l ) . EXAMPLE 1091. (18,3'Κ,6Έ,7'Κ,8Έ)-6-α-ΪΕΟ Ο-7'-ΜΕπ-ΙΟΧΥ-3,4- DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'-

[20]OXA[13]TH1A[1,14]DIAZATET1 ACYCLO[14.7.2.0 ³ - ⁶ .0 ¹⁹ - ²⁴ ]PENTA(X)SA [8, 16, 18,24]TETRAEN] - 15"-ONE 3', 13 ^* -DIOXIDE "

To a solution of (lS,3'R,6'R,7'R,8'E)-6-chloro-7'-hydroxy-3,4-dihydro- 2H, 15'H-spiro[naphthalene- 1 ,22'-

[20]oxa[13]thia[ l,14]diazatetracyclo[14.7.2.0 ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa[8,16,18,24]tetrae n|-15'-one 13', 13'-dioxide (Example 952; 10 mg, 0.018 mmol) in THF (175 ,uL) in a vial with a septum cap was added sodium hydride (60% dispersion in mineral oil, 3.50 mg, 0.088 mmol) at ice-bath and the reaction was then stirred at rt for 20 min and followed by an addition of a solution of methyl iodide (1.64 iL, 0.026 mmol) in THF (100 μΐ,). The resulting reaction was stirred at rt for about 2 h and quenched with saturated Ni hil and extracted with EtOAc three times. The combined extracts were dried with anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in DCM and purified by a 4 g gold- capped Redsep column eluting with a gradient of 0-100% EtOAc in hexane to afford the title compound (5.6 mg, 9.57 μηιοΐ, 54.7%) as a colorless resin. ¾

N.V1R (400MHz, CD2CI2) δ 8.27 (br. s., 1 H), 7.72 (d,■/ 8.6 Hz, 1 H), 7.25 (d, J ------ 1 .6 ! ! . 1 H), 7.17 (dd. ,/ 2 2. 8.5 Hz, 1 H), 7.09 id. ,/ 2 2 ! !/. 1 H), 6,99 -

6.88 (m, 2 H), 5.71 (td, ./ 5.2, 15.8 Hz, 1 H), 5.38 (dd, ./ 8.3, 15.9 Hz, 1 H), 4.04 - 3.89 (ra, 2 H), 3.70 - 3.63 (m, 1 H), 3.51 (dd, ./ 4.1 , 8.2 Hz, 1 H), 3.33 (s, 3 H), 3.26 - 3.16 (m, 2 H), 2,97 (dd, ./ 9.3, 15.2 Hz, 1 H), 2,83 - 2,68 (m, 2 H), 2.57 - 2.29 (m, 3 H), 2.20 - 2.02 (m, 3 H), 1.97 - 1.76 (m, 4 H), 1.75 - 1.67 (m, 1 H), 1.65 - 1.35 (m, 5 H). m!z (ESI, +ve ion) 585.2 (M+H) ⁺ .

EXAMPLE 1092. (lS,3 ^, R,6 ^, R,7'R,8 ^, Z,12 ^, R)~6"CHLORO-7'~HYDROXY-12'- ETHYL-3,4-DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1 ,22'- [20]OXA[ 13]THIA[1,14]DIAZATETRACYCLO[!4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA

- 15'-ONE 13', 13'-DIOXIDE

STEP 1 : (S)-6 ^, -CHLORO-N-((R)-HEPT-6-EN-3-YLSULFONYL)-5-(((l R,2R)-2- ((R,E)-l -HYDROXYHEX-2-EN-l -YL)CYCLOBUTYL)METHYL)-3',4,4',5- TETRAHYDRO-2H,2'H-SPIRO[BENZO[B] [ 1 ,4]OXAZEPINE-3, 1 '- NAPHTHALENE] -7 -C ARB OXAMIDE

The title compound was prepared from intermediate AA12B and

Intermediate EE21 by a procedure similar to the one described in Example 1085, Step 7 (12! mg, 0.181 mmol, 99%). STEP 2: (lSJ ^! R )'RJ'R,8 ^! ZJ.2 ^! R)~6-CHLORO-7 ^! -HYDROXY-12 ^! -E ^' fflYL-3,4- DIHYDRO-2H, 15'H-SPIRO [ APHTHALENE- 1,22'-

[2()iOXA|;i3]THIA|;i 4]DIAZATETRACYCLO[ 14J.2X) ³ - ⁶ :) ^!9 - ²⁴ ]PENTACOSA [8, 16,18,24]TETRAEN]~1S'~0NE 13', 13 '-DIOXIDE

The title compound (5.0 mg, 8.34 μηιοΐ, 8.59%) was prepared from (S)-6'- chloro-N-((R)-hept-6-en-3-ylsulfonyl)-5-(((l R,2R)-2-((R,E)- 1 -hydroxyhex-2-en- l-} l)cyclobutyl)meihyl)-3',4 4' ₅ 5-tetrahydro-2H,2'H- spii [benzo[bl[l,4]oxazepine-3, -naphthalene]-7-carboxamide (Step 1) by a procedure similar to the one described in Example 1085, Step 8. Ή NMR

(400MHz, CD2CI2) δ 8.29 (br. s,, 1 H), 7,72 i d. J = 8.4 Hz, 1 ! ! }. 7.18 (dd, ,/ 2,3, 8.4 Hz, 1 H), 7.09 id. ./ 2.3 Hz, 1 H), 6.99 - 6.90 (m, 3 H), 5.53 - 5.44 (m, 1 H), 5.44 - 5.37 (m, 1 I I ). 4.18 (L ,/ 7.2 Hz, 1 H), 4.14 - 4.08 (m, 1 H), 4.08 - 4.01 (m, 1 H), 3,81 - 3.68 (m, 3 H), 3,29 (d, ./ 14.5 Hz, 1 H), 2.80 - 2,69 (m, 2 H), 2.56 - 2.43 (m, I H), 2.40 - 2.10 (m, 4 H), 2.07 - 1.88 (m, 5 H), 1.88 - 1.74 (m, 4 H), 1.73 - 1.61 (m, I H), 1.48 - 1.34 (m, 2 H), 1.14 i t. ./ 7.4 Hz, 3 H). m/z (ESI, +ve ion) 599.2 (M+H) ⁺ . EXAMPLE 1093. (IS,3 ^, R,6'R,7'R,8'E,12'R)-6-CHLORO-7 ^, -METHOXY-I2'- EraYL-3,4-DIHYDRO-2H,15'H-SPIR() [NAPHTHALENE- 1 ,22'- [20]OXA[13]THIA[1,14]DIAZATETRACYCLO[ !4,7.2,0 - ⁶ .0 ^I9 ' ²⁴ ]PENTACOSA [8, 16, 18,24]TETRAEN] - 15'-ONE 13', 13'-DiOXIDE

STEP 1 : ( 1 S,3'R,6'R,7'R,8Ti, 12'R)-6-CHLORO-7 ^f -HYDROXY-12'-ETHYL-3,4- DIHYDRO-2H, 15'H-SPIRO [NAPHTHALENE- 1.22'-

|2( ⁾ jOXA| 1ΉΤί!1Λ| Μ4|ΠίΑ/.ΥΠ:ΤΗΛ(ΎΠ.ϋΙ i 4.7.2 U · ^, '.ί) ^|: " ¹ |P1-M ^' .\C<)SA

-15'-C)NE 13 ^! ,13 ^* -DIOXIDE

The title compound(15 mg, 0.025 mmol, 25.8%) was the other isomer isolated from the reaction described in Example 1092, Step 2.

STEP 2: (lS,3 ^! R,6'R,7'R,8 ^! E,12 ^! R)-6-CHLORO-7 ^! -METHOXY-12 ^, -ETHYL-3,4- DIHYDRO-2H, 15H-SPIRO [NAPHTH ALENE-1 ,22'-

[20]OXA[13]TO A[1,14]DIAZATETRACYCLO[147 ³ "*0 ^]9 ^ ⁴ ]PE TACOSA

[8, 16, 18 , 24] TETRAEN] - 15'-ONE 13', 13 ^! -DIOXIDE

To a solution of (lS,3'R,6 ^! R,7 ^, R,8'E,12'R)-6-chIoiO-7'-hydroxy-12'-ethyI- 3,4-dihydro-2h, 15'h-spiro [naphthalene-! ,22'- [20]oxa|13]thia[l,14]diazatetracycio[14.7.2.0 ^;i ' ⁶ .0 ¹⁹ ' ²⁴ ]pentacosa

[8,16,18,24]tetraen|-15'-one 13',13'-dioxide (Step 1; 9 mg, 0.015 mmol) in THF (150 μΕ) in a glass vial with a septum cap was added sodium hydride (60% dispersion in mineral oil, 1.80 mg, 0.075 mmol) at ice-bath and the reaction was stirred at this temperature for 10 min and at rt for another 10 mm. The reaction was returned to the ice-bath, and to this reaction was added a solution of methyl iodide (4.26 mg, 0.030 mmol) in THF (400 μΐ,). The reaction was stirred at rt for about 4 h and then quenched with saturated NH ₄ C1 and extracted with EtOAc. The organic extract was concentrated and purified by prearative TLC on a Analtech Uniplate Silica gel HLF (w/binder and 254) 10X20 cmX250 micron plate eiuting with 30% EtOAc in hexane to afford the title compound (1.61 mg, 2.63 μη οΐ, 17.5%) as a white solid. ³ H NMR (400MHz, CD2CI2) δ 8.08 (br. s„ 1 H), 7.72 (d, ./ 8.4 Hz, 1 H), 7.31 (s, 1 H), 7.17 (dd, ./ 2.3, 8.4 Hz, 1 H), 7.09 (d, ./ 2.3 Hz, 1 H), 6.95 - 6.86 (m, 2 H), 5.55 - 5.45 (m, 1 H), 5.35 (s, 1 H), 4.09 (s, 2 H), 3.99 - 3 ,80 (m, 2 H), 3.66 i d. ./ 14.3 Hz, 1 H), 3.3 1 ( dil . J 3 I . 8,0 Hz, 1 H), 3.23 (s, 3 H), 3.20 (d, «/ = 14.1 Hz, 1 H), 2.96 (dd, ./ 7.6, 15.3 Hz, 1 H), 2.81 - 2.70 (111, 2 H), 2.55 - 2.42 (m, 2 H), 2.42 - 2.28 (m, 1 H), 2.21 - 2.01 (m, 3 H), 1.99 - 1.76 (m, 5 H), 1.71 (d, J = 7.4 Hz, 1 I I I 1.65 - 1 ,53 (m, 2 H), 1.45 - 1.31 (m, 1 ! ! }. 1. 13 (t, J = 7.5 Hz, 3 H). m/z (ESI, +ve ion) 613.3 (M+H) ⁺ . EXAMPLE 1094. (1 S,3 ^, R,6 ^! R,7'R)-6-CHLORO-7'-ME ^" fflOXY-3,4-DIHYDRO- 2H, 15 Ή-SPIRO [NAPHTHALENE- 1 ,22'-

[20 iOXA|;i3]THIA|;i ,14]DIAZATETRACYCLO[ 14.7.2.() ^3>, 0 ^{! 9} - ²⁴ ]PENTACOSA [ 16, 18,24]TRIEN] - 15'-ONE 13', 13'-DIOXIDE

To a solution of Example 1 091 (3. 1 mg, 5.30 μηιοΐ) in EtOAc (883 μΕ) in a glass vial was added platinum (iv) oxide (0.241 mg, 1.06 μπιοΐ). The vial was capped with a septum and evacuated and back-filled with hydrogen, and the reaction was stirred at rt for 26 h. The reaction mixture was concentrated on Genevac, resuspended in DCM and eluted through a Pasteur Pipette silica gel column (1 cm height) with 50% EtOAc in hexane. The eluent was collected and concentrated on Genevac to afford the title compound (2.6 mg, 4.43 μτηοΐ, 84%). ^l H NMR (400MHz, CD2CI2) δ 8.79 (br. s,, 1 H), 7,73 id. ./ 8.6 Hz, 1 IT), 7.24 - 7.14 (m, 3 H), 7.09 (d, ./ = 2.3 Hz, 1 H), 6,94 (d, ./ 8.0 Hz, 1 H), 4.10 - 4.08 (m, 2 H), 3.81 (d, J = 15.3 Hz, 1 H), 3.70 (d, J = 14.1 Hz, 1 H), 3.63 - 3.48 (m, 2 H), 3.45 (s, 3 ! ! }. 3.21 (d, ./ 14.3 Hz, 1 H), 3.12 - 3.03 (m, 2 H), 2.83 - 2.70 (m, 2 H), 2,68 - 2.57 (ra, 1 H), 2,48 - 2.37 (m, 1 H), 2,08 - 2.01 (ra, 2 H), 1.96 - 1.89 (ra, 1 H), 1.89 - 1.77 (m, 4 H), 1.74 - 1.58 (m, 4 H), 1.51 - 1.36 (m, 5 H). m/z (ESI, +ve ion) 587.2 (M+H) ⁺ .

EXAMPLE 1095. (lS,3 ^, R,6'R,7 ^, R,8 ^, E)-6-CHLORO-7 ^, -(2- (METHYLSULFONYL)ETHOXY)-3,4-DIHYDRO-2H, 15'H-SPIRG

[NAPHTHALENE- 1 ,22'-

[20]OXA[13]THIA[l ,14]DiAZATETRACYCLO[14.7,2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTACOSA [8,16.18,24]TETRAEN]-15'-ONE 13',13'-DIOXIDE

To a solution of Example 991 (10 mg, 0,018 mrnol) in THF (175 μ,Τ) in a vial with a septum cap was added sodium hydride (60% dispersion in mineral oil, 3.50 mg, 0.088 mrnol) at ice-bath. The reaction was then stirred at rt for 20 min and followed by an addition of a solution of 2-(bromoethyl)methylsulfone (4.91 mg, 0.026 mmol) in THF (100 μΐ,). The reaction was stirred at rt for about 2 h and at 50 °C to 60 °C for around 3 h. The reaction was quenched with saturated NH4CI and extracted with DCM. The DCM extracts were combined, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in DCM and loaded onto an Analtech preparative TLC plate (Uniplate silic gel HLF, n binder, w/254; 10X20cm X 250 microns) and eluted with 3% MeOH in DCM to afford the title compound (7.6 mg, 0.011 mmol, 64.1%) as a white solid. ¾ NMR (400MHz, CD2CI2) δ 7.72 (d, J = 8,6 Hz, 1 H), 7.24 (s, 1 H), 7.17 (dd, J = 2.3, 8.6 Hz, 1 H), 7.09 (d, ./ 2.3 Hz, 1 H), 6.98 - 6.89 (m, 2 H), 5.81 - 5.71 (m, 1 H), 5.37 (dd, ./ 8.6, 16.0 Hz, 1 H), 4.16 - 3.98 (m, 4 H), 3.93 (d, J ------ 15.3 Hz, 1

H), 3.77 - 3.63 (m, 3 H), 3,61 - 3.50 (m, 1 H), 3,39 - 3.30 (m, 1 H), 3.21 - 3.07 (m, 2 H), 3,04 (s, 3 H), 3.00 - 2.90 (m, 1 H), 2,83 - 2.67 (m, 2 H), 2.58 - 2.47 (ra, 1 H), 2.47 - 2.35 (m, 2 H ). 2.18 - 2.00 (m, 3 H ). 1.99 - 1.86 (m, 3 I I ). 1.85 - 1.77 ( m. 1 H), 1.76 ·· 1.67 (m, 1 H), 1.66 - 1.51 (ni, 2 H), 1.48 - 1.34 (ni, 2 H). m/z (ESI, +ve ion) 677.2 (M+H) ⁺ . EXAMPLE 1096. (lS,3'R,6'R,7'R)-6-CHLQRO-7'-(2-

(METHYLSULFONYL)ETHOXY)-3,4-DIHYDRO-2H, .15'H-SPIRO

[NAPHTHALENE- 1 ,22'-

|;20]OXA[ 13 iTHIA[ l,14jDIAZATETRACYCLO| 14.7.2.0 ³ -^0 ¹⁹ - ²⁴ ]PENTA(X)SA [16,18,24]TRIEN] - 15'-ONE 13', 13 ^* -DIOXIDE

The title compound was prepared from Example 1095 by a procedure similar to the one described in Example 1094. ¾ NMR (4()()MHz, CD2CI2) δ 9.26 (br. s., 1 H), 7.74 (d, J = 8.6 Hz, 1 H), 7.17 (dd, ./ 2.2, 8.5 Hz, 1 H), 7.12 - 7.04 (m, 3 ! ! }. 6.93 (d, ,/ 8.0 Hz, 1 H), 4.34 ! dl. ./ 2.2, 10.0 Hz, 1 H), 4.14 - 4.10 (m, 1 H), 4,06 - 4.02 (m, 1 H), 3,83 - 3.71 (m, 1 H), 3,70 - 3.46 (m, 4 H), 3,28 - 3.15 (ni, 3 H), 3.07 - 2.92 (m, 4 H), 2.84 - 2.70 (m, 2 H), 2.67 - 2.44 (m, 2 H), 2.09 (d, J= 12.3 Hz, 1 H), 2.02 (br. s., 1 H), 2.00 - 1.87 (m, 4 H), 1.87 - 1.72 (m, 4 H), 1.71 - 1.53 (m, 6 H), 1,44 - 1.33 (m, 1 H). m/z (ESI, +ve ion) 679.2 ( +H) ⁺ . BIOLOGICAL ASSAYS

Cell free Mcl-1 :Bim affinity assay (Mcl-1 HTRF)

The inhibition of the Mcl-l/Bim interaction was measured using a time- resolved fluorescence resonance energy transfer (TR-FRET) assay. The recombinant human Mcl-l (C-terminally 6xHis tagged Mci-1 containing residues 171 -327) was generated at Amgen Inc (Thousand Oaks, CA). A biotinylated peptide derived from human Bim (residues 51-76) was purchased from CPC Scientific (San Jose, CA). The TR-FRET assay was conducted in a 384- well white OptiPlate™ (PerkinElmer, Waltham, MA) in a total volume of 40 μΕ. The reaction mixture contained 0.1 nM Mcl-l (171-327), 0.05 nM biotin-Bim(51-76), 0,05 nM LANCE ^® Eu-W1024 Anti-6xHis (PerkinElmer), 0.072 nM Streptavidin- XLent (Cisbio, Bedford, MA), and serially diluted test compounds in the binding buffer of 20 mM Hepes, pH 7.5, 150 mM aCl, 0.016 mM Brij ^® 35, and 1 mM dithiothreitoi. Test compounds were pre-incubated with Mcl-l(171-327) and biotin-Bim (51-76) for 60 min before addition of the detection mixture (LANCE ^® Eu-W1024 Anti-6xHis and Streptavidin-XLent). The reaction plates were further incubated overnight and then were read on an Envision ^® muitimode reader (PerkinElmer). Fluorescence signals were measured at 620 nm (40-nm bandwidth) and 665 nm (7.5-nm bandwidth) with a 60 ₍ us delay after excitation at 320 nm (75-nm bandwidth). The signal ratio at 665/620 nm corresponded to the Mcl-l /Bim interaction and was used in all data analyses. The ICso values of test compounds were determined from duplicate data by analyzing competition curves using a four-parameter sigmoidal model in GraphPad Prism (GraphPad Software, San Diego, CA) or in Genedata Screener ^® (Genedata, Basel, Switzerland).

Cell viability- assay (OPM-2 10 FBS)

The human multiple myeloma cell line, OPM-2, was cultured in complete growth medium containing RPMI 1640 and 10% fetal bovine serum (FBS). Cells were seeded into 384- well plates at 3000 cells/well density in complete growth medium containing 10% FBS, and incubated for 16 h with serially diluted test compounds in a 37°C incubator with 5% CO2. Cell viability was tested using CellTiter-Glo ^® assay (Promega, Madison, WI) according to the manufacturer recommendations. Luminescence was determined using an EnVision ^® Multiiabel plate reader 25 min after the addition of detection reagent. ICso values were then calculated with Xlfit using a logistical 4-parameter fit model in GraphPad Prism (GraphPad Sofiware. San Diego, CA) or in Genedata Screener® (Genedata Basel, Switzerland).

Results for compounds tested in these biological assays are set forth below.

Ci-1 OP -2 10S Men OP 10 ^' -,RR fuMj rBS (uM) # HTRF ίμ : ΓΒ3 :μ ) .00034 .2544 54 .000781 .7745

.00685 NA 55 .006245 2.38005 85 .4605 56 .00304 1.79010855 .2985 57 ,0004905 .555005395 0.329 58 .0009935 1.18005635 1.455 59 .00427 7.45

.00063 .15529 60 .004075 2.69

.00297 .6295 61 .000241 ,2775005225 3.65 62 .000266 .3618

,00337 .404 63 .000728 .80967006855 .3115 64 .0006785 .39933003925 1.1 65 .00238 1.1677003925 .8695 66 .002315 .492

.00221 3.58 67 .00151 .45

.00395 7.92 68 .000359 .2475

.02015 15.2 69 .0005295 .276004945 1.2203 70 .0011595 .044167

,00085 .8175 71 .00262 3.16000806 1.0755 72 .00032425 .44475003705 .276 73 .000728 1.66003 35 3.21 74 .00113 .381000465 .683 75 .001655 .875002465 .1665 76 .000405 .145670020531 .3118 77 .0005925 .442000422 .97 78 .00145 .587

.0008 1.7 79 .00418 3.62

.00066 1.2767 80 .008985 6.53001925 NT 81 .03855 6.44000492 .621 82 .0078 2.92006225 .546 83 .000419 .487000168 8.16 84 .01315 5.9006205 3.6 85 .00188 1.91

.00155 1.285 86 .00404 NT005355 2.59 87 .003315 3.54006135 2.57 88 .00171 1.040054925 .78 89 .000666 .7980065025 .87267 90 .00044025 .3225004615 .971 91 .00306 NT002005 .0541 92 .000781 NT0057033 .842 93 .00049375 .402000995 .53646 94 .0004665 ,4315001149 NA 95 .0004595 .572

.0023 NT 96 .03165 NT003675 NT 97 .0126 NT006285 1.28 98 .015485 NT005625 .5245 99 .02075 NT000321 .4445 100 .002445 NA

.00362 2.21 101 .002585 13

.00559 1.83 102 .002725 18.6

.00393 1.81 103 .00143 N/A007905 .4865 104 .04 13 Ci-1 OP -2 10S Men OP 10 ^' -,

# HTRR fuM j r BS (uM ⁾ # HTRF ίμ : ί ^: Β3 : μΜ ⁾

105 .000589 .33 156 .000831 .266

106 .0169 N/A 57 .000558 .48033

107 .000597 17.3 58 .007595 9.36

108 .001127 2.25 159 .00266 3.305

109 .00134 12.2 160 .000397 5.295

110 .00134 5.58 161 .001315 .086

11 1 .03075 7.8 162 .0009785 8.4

112 ,00063 .1724 163 .005075 18.9

1 13 .000998 1 .15 164 .00144 21 .9

114 .003595 3.4 65 .0038 25

115 .002705 N/A 66 .000418 2.07

116 .0008565 NT 167 .00025143 .12162

117 .002155 NT 168 .000255 .10724

118 .0349 NT 169 .0006105 .405

119 .02445 NT 170 .002005 .7035

120 .000927 NT 176 .000566 .709

121 .0122 NT 186 .00791 4.66 22 .007175 NT 87 .000248 .426

123 .004305 NT 88 .01 135 3.9

124 .0287 NT 89 .003485 1.21 1

125 .00864 NT 195 .005725 NT

126 .0004475 .496 196 .02225 NT

127 .000341 1 .85 197 .001 125 2.6

128 .0006035 2.52 198 .00324 N/A

129 ,00579 N/A 199 .006045 10.2

130 .000386 .2285 200 .003575 3.87

131 .00183 1 .82 201 .00269 N/A

132 .00707 5.73 202 .0002175 .5655

133 .0020025 2.75 203 ,0003665 2.79

134 .0004945 1 .041 204 .000732 .6865

135 .000771 1 .52 205 .003165 3.29

136 .00025897 .12978 206 .0000514 3.34

137 ,00041625 .419 207 .0001033 2.285

138 .000223 .372 209 .005255 5.37 39 .0001825 .284 210 .00159 1.53

140 .00024933 .0962 21 1 .001 1 1 2.37

141 .03665 N/A 212 .00296 18.2

142 .0004225 NT 213 .0010835 .835

143 .002 NT 214 .0123 2.28

144 .00147 3.43 215 .00132 8.74

145 .000286 17 216 .00977 26.2

146 .000276 .556 217 .003815 2.66

147 .00059 .994 218 .000216 3.67

148 .00028467 .4585 219 .0024 1.83

149 .00077 1 .3275 220 .001995 2.66

150 .005375 N/A 221 .01085 NT

151 .003565 9.17 222 .009085 30.8

152 .0196 29.2 225 .02305 N/A

153 .001225 N/A 226 .02565 N/A

154 .0002585 7.58 227 .03285 21 .4

155 .0008455 1 1.6 228 .0131 23.1 Ci-1 OP -2 10S Men OP 10 ^' -,

# HTRR fuM j r BS (uM ⁾ # HTRF ίμ : ί ^: Β3 : μΜ ⁾

229 .001625 1 .715 305 .000177 .9975

230 .0323 N/A 306 .0012 1.135

231 .0452 23.1 307 .000127 .3015

232 .00164 3.47 308 ,0003825 .2135

233 .00466 4.7 309 .0000805 .4135

234 .00167 1 .925 310 .000109 .7925

235 .00086975 .4375 31 .000138 1 .4

236 .006425 13.7 312 .000153 1.002

237 .00232 2.26 313 .00018535 .21975

238 .00157 17.6 314 .00013585 2.125

239 .00143 3.82 315 .000774 .421

240 .00254 3.73 316 ,0000986 .162

241 .004855 7.39 317 .000223 .1965

242 .00305 .46733 318 .0002725 .42967

243 .01092 12.1 320 .0003285 .342

244 ,00213 .4095 321 .002285 2,18

245 .01197 6.1 322 .0004005 .1228

246 .0358 N/A 323 .002025 2.98

247 .0129 31.2 324 .00168 1.94

248 .000701 2.165 325 .000297 .2075

249 .0284 N/A 326 .005505 20

256 .005585 27.8 328 .0004405 .428

257 .00456 7.8 329 .002585 3.48

259 .04435 23 330 .000794 2.105

260 .001435 3.34 331 .0002485 ,2835

261 .0339 N/A 332 .00389 5.58

262 .01715 13.9 333 .00096033 3.45

263 .00842 N/A 334 .00692 2.66

264 .00537 31 .1 335 .000263 2.125

265 .0002855 .0815 336 .001505 N/A

266 .000728 1 .0715 337 .000705 .38333

267 .004035 1 .525 338 .000241 5.62

268 .0046 3.62 339 .002705 N/A

269 .0257 5.56 340 .0001895 .941

270 .00103 .1 158 341 .007075 N/A

271 .00489 20.9 342 .005 N/A

272 .000396 1 .1915 343 .007275 6.49

276 .01315 6.41 344 .0021 1 .91 15

288 .0002235 .2795 345 .000877 .488

292 .000092875 1 .109 346 .001895 2.27

293 ,00036 27.6 347 .00722 5,55

294 .0002555 .41 348 .00686 3.56

295 .00018975 .15125 349 .0038267 1.0492

296 .0004965 .5245 350 .003735 N/A

297 .000654 .4775 353 .009095 N/A

298 .000425 ,86 361 .000519 .509

299 .0002755 .2795 362 .000639 .476

300 .0002405 .817 363 .000793 .483

301 .000245 .8445 364 .00312 30.9

303 .0002 .567 365 .0007515 2,96

304 .0001513 2.28 367 .0421 N/A Ci- 1 OP -2 10S Men OP 10 ^' -,

# H RR f uM j F 3S (uM) # HTRF ίμ : ί ^: Β3 ^: μΜ ⁾

368 .00374 NT 429 .00415 1 .315

369 .0039833 NT 430 .0007425 .21633

370 .0045 NT 431 .000512 .14033

371 .02075 NT 432 ,0009965 NT

372 .009485 14.6 433 .0032267 NT

373 .000731 .404 434 .000273 NT

374 .00286 2.94 435 .002565 NT

375 .007735 5.7 436 .0002425 NT

376 .000403 .2225 437 .003765 NT

377 .000303 .1805 438 .000731 NT

378 .0002405 .14 439 .00032125 NT

379 .0002 15 .1278 440 .00244 NT

385 .001055 .4845 441 .0006315 NT

386 .00062983 .27267 442 .0002924 NT

387 .001645 1 .252 443 .001505 NT

393 .00021325 .13677 444 .0007845 NT

394 .0012635 1 .25 445 .0004605 NT

395 .000403 .75 5 446 .0004935 .419

396 .0003841 .18637 447 .000378 NT

397 .000228 .1431 448 .000951 NT

398 .000233 .0883 449 .000716 .773

399 .000239 .165 450 .00676 NT

400 .0000856 .0996 451 .01 1485 NT

401 .000531 .4525 452 .000277 .775

402 ,01865 13.6 453 .006735 21

403 .000495 .10665 454 .00021987 .33765

404 .0004415 NT 455 .00016602 .071575

405 .000543 NT 456 .0005405 .701

406 .0006015 NT 457 .00026333 .2965

407 .00012697 14.4 458 .0002012 .12187

408 .00031 15 .09885 459 .00337 3.3

409 .00127 .751 460 .0003336 .13154

410 .000144 .208 461 .001795 .775

41 1 .00129 2.41 462 .0005225 .264

412 .0002665 .325 463 .0004165 .122

413 .0003575 .3745 464 .001485 .65

414 .000188 .1605 465 .00047 .0564

415 .000276 2.64 466 .0003315 .1275

416 .000377 1 .059 467 .00145 1 .51

4 7 .0002145 .8335 468 .0002985 .2615

418 .0002745 .1 108 469 .0009735 .334

419 .0003335 .3105 470 .000726 .355

420 .000349 NT 471 .000188 .141

421 .000686 .674 472 .0002695 .2065

422 .0008655 NT 473 .00036883 .15983

423 .00024875 .19832 474 ,0001945 .426

424 .0005015 .2475 475 .0007185 1 .535

425 .0004 .3045 476 .006695 8.35

426 .002105 .941 477 .00031 15 .2865

427 .0004145 .204 478 .0001965 ,4685

428 .0003335 .1765 479 .00537 8.12 Ci-1 OP -2 10S Men OP 10 ^' -,

# HTRR fuM j r BS (uM ⁾ # HTRF ίμ : ί ^: Β3 ^: μΜ ⁾

480 .0003935 1 .075 531 .0011535 .81 1

481 .000541 1 .87 532 .0004275 .1555

482 .00752 7.64 533 .000583 14.2

483 .02015 12 534 .00078825 .0993

484 .0003305 .4115 535 .0003885 .1625

485 .000471 .5575 536 .00 99 21.3

488 .01 1715 5.3 539 .00278 N/A

487 .001046 5.8 540 .0002355 .094133

488 .00521 12.9 543 .0005355 .699

489 .0008665 1 .225 544 .000193 1.52

490 .00209 7.98 546 .00028 .854

491 .000774 3.48 547 ,0002395 2.22

492 .000755 3.82 548 .0002745 .4775

493 .000983 .66 549 .0005545 .285

494 .00881 3.68 550 .0005815 7.29

495 .002485 NT 551 .00343 N/A

498 .00633 NT 552 .0004815 2.51

497 .004 NT 553 .004 NT

498 .00903 NT 554 .001835 NT

499 .024 NT 555 .00477 2.81

500 .00708 NT 556 .00165 .78133

501 .0014935 NT 557 .0010755 1.0363

502 .002305 NT 558 .000284 .891

503 .003985 NT 559 .0005985 4.4233

504 ,00255 NT 560 .00483 12.2

505 .010445 NT 561 .003575 8.47

508 .01555 NT 562 .00 1 15 .9855

507 .0183 NT 583 .00269 4.5

508 .008015 2.47 584 .000308 3.04

509 .0001875 .235 585 .0006095 12.6

510 .0012535 .587 586 .0003835 .282

5 1 .00 5 .311 587 .00369 4.51

512 .000998 .362 568 .001 1 1 ,31

513 .000395 .18375 569 .0010195 .759

514 .0003905 .165 570 .00844 3.02

515 .00487 2.52 571 .0347 20.3

516 .00027 .0725 572 .0454 13.9

517 .001865 .467 573 .0313 23.1

5 8 .00049 .257 574 .000393 .188

5 9 .001435 .33887 575 .00321 2.07

520 .000279 .1425 576 .0003815 ,2205

521 .000291 .168 581 .00943 N/A

522 .000284 .15225 597 .00146 NT

523 .00182 .232 598 .00149 NT

524 .0003645 .1 255 599 .00151 .8515

525 .0004155 .186 600 ,0006485 .104

526 .0010575 .862 601 .001335 N/A

527 .0002175 .0647 602 .00174 .727

528 .0002525 .0896 603 .000867 .4385

529 ,00097 .7535 604 .0095775 NT

530 .0007635 .134 605 .00094333 NT Ci-1 OP -2 10S Men OP 10 ^' -,

# H RR fuM j r BS (uM ⁾ # HTRF ίμ : ί ^: Β3 ^: μΜ ⁾

608 .01354 NT 659 .00337 10.9

609 .00384 N/A 660 .0003755 .4165

610 .000923 1 .14 661 .00251 2.76

61 .0002755 8.49 662 .001 1 15 1 .3867

612 .000362 15.2 683 .00031 167 3.1085

6 3 .000329 1 .5425 685 .00289 1 .315

614 .001 13 8.07 666 .00206 2.44

615 .000696 .643 667 .0002445 .378

618 .0001785 .48218 668 .017 1 1 .6

617 .0002205 1 1 .5 669 .00137 .272

618 .0001725 .607 670 .0024833 1 .0003

619 .000187 .40067 671 .0198 5.65

620 .00071 4.08 672 .000193 .2855

621 .000225 3.67 673 .000 835 .445

622 .0002235 .257 674 .0082 1 .09

623 .0006415 .483 675 .000437 .48

624 .000338 .455 676 .002035 3.91

625 .0383 N/A 677 .009575 3.55

626 .000305 2.2 678 .008025 7.29

627 .01007 N/A 679 .0004295 .205

628 .0039 N/A 680 .0268 NT

629 .0023 N/A 681 .029 NT

630 .001615 N/A 682 .00178 NT

631 .0002985 2.53 683 .002315 2.09

632 .000187 .8775 684 .0 1 N/A

633 .0231 17.8 685 .00266 7.18

634 .01 15 2.14 686 .000597 .993

635 .0009845 .0985 687 .0002065 .1485

636 .0291 4.74 688 .01415 13.6

637 .00017073 .10744 689 .0025325 .8358

638 .000243 .13086 690 .01955 19

639 .0008095 .3485 691 .00181 2.33

640 ,02085 5.4 692 .0006 1 ,52

641 .00053725 .28225 693 .0002345 .742

642 .00053875 .35075 694 .0007635 .9685

643 .0003365 .151 695 .00204 NT

644 .01 135 4.26 696 .000305 NT

645 .0005885 .125 697 .0007465 NT

646 .0453 23.7 698 .00067875 NT

647 .00018785 .13146 699 .00064886 NT

648 .001445 .154 700 .02765 NT

649 .01385 6.63 701 .00144 2.025

650 .003715 2.25 702 .007665 13.4

651 .000316 .229 703 .00509 2.06

652 .002395 4.46 704 .0405 N/A

653 .00072233 .37067 705 .02805 22.8

654 .0076033 3.51 706 .00451 NT

655 .0008845 .947 707 .00225 NT

656 .00137 .237 708 .00 12 NT

657 ,01 125 24.7 709 .010495 NT

658 .000285 .259 710 .0256 NT Ci-1 OP -2 10S Men OP 10 ^' -,

# HTRR fuMj r BS (uM ⁾ # HTRF ίμ : ί ^: Β3 ^: μΜ ⁾

71 1 .008215 NT 763 .002925 NT

712 .00099525 NT 764 .000 1335 11 .2

713 .0017067 NT 765 .00389 NT

714 .001815 1 ,365 766 .006495 NT

715 .00726 13.7 767 .00655 NT

716 .0173 23.5 768 .00224 NT

7 7 .0286 N/A 769 .00097133 NT

718 .0014575 1 .82 770 .001335 NT

719 .00036609 .1 1667 771 .00409 NT

720 .000327 .0542 772 .005195 NT

721 .000539 .073525 773 .002355 NT

722 .01194 .473 774 .00172 NT

723 .0004855 .1375 775 .00294 NT

724 .000485 .4205 776 .00271 NT

726 .0122 2.145 777 .0138 .912

727 .0003645 .147 778 .00689 NT

728 .000437 .2685 779 .005546 NT

729 .00031 .1 185 780 .0048433 NT

730 .0003075 .157 781 .01 545 N/A

731 .0003015 .1 17 783 .001041 NT

732 .000244 .1695 784 .00269 14.2

733 .0002835 .069667 785 .003025 16

734 .001 1 5 .134 786 .001035 1.48

735 .0006815 .20233 787 .02145 N/A

736 .0008905 .19233 791 .00621 23.3

737 .01515 3.39 793 .00044 .5365

738 .003215 1 .76 794 .00151 1.895

739 .00014137 24.2 795 .00038 .392

740 .000543 .1702 796 .00045 .195

741 .0135 3.11 798 .00242 9.26

742 .002 NT 801 .00193 20.7

743 .0124 NT 802 .00451 3.31

744 .019345 NT 803 .00106 .804

745 .003345 NT 804 .000658 .377

746 .003265 NT 805 .001063 .7185

747 .0147 NT 807 .0423 NT

748 .00501 NT 808 ,0015359 NT

749 .002495 NT 815 .0012636 NT

750 .00541 NT 816 .00472 NT

751 .007725 NT 817 .02935 NT

752 .004395 NT 818 .013567 NT

754 .00893 NT 823 .0482 NT

755 .000632 NT 824 .0201 NT

755 .00349 NT 825 .026433 NT

756 .001 2 NT 826 .01048 NT

757 .004105 NT 827 .00354 NT

758 .0004604 1 .18 829 .0098667 NT

759 .00398 NT 830 .021 133 NT

760 .0158 NT 831 .00135 4.46

761 .0017833 NT 832 .0082575 NT

762 .00057583 NT 833 .005125 NT ci-1 OP -2 10S Men OP 10 ^' -,

# HTRR fuM j r BS (uM ⁾ # HTRF ίμ : ί ^: Β3 : μΜ ⁾

834 .0041 NT 915 .016238 NT

835 .00344 NT 917 .004105 NT

836 .0006275 .7055 918 .00275 15.1

837 .001195 4.08 919 .002315 6.1 1

838 .00139 1 .22 920 .001855 4.35

840 .00438 NT 921 .00209 9.16

841 .001052 1 .59 922 .0009745 2.4

843 .0068 NT 923 .01775 NT

844 .01105 NT 924 .00507 N/A

845 .0043233 NT 927 .04625 NT

846 .0021779 2.7626 928 NT NT

850 .001995 N/A 929 .04 NT

851 .001001 19.7 930 .0196 NT

853 .01173 NT 931 NT NT

857 .00846 NT 932 .003685 NT

858 .0278 NT 933 .015 NT

859 .0158 1 1 .5 934 .0020675 NT

861 .0015903 NT 935 .00207 NT

862 .00275 NT 936 .00474 NT

863 .005375 NT 937 .004745 NT

866 .00953 NT 938 .00594 NT

867 .006815 NT 939 .006665 NT

870 .008255 NT 940 .01855 NT

872 .006355 NT 941 .008325 NT

876 .0183 N/A 942 .03635 NT

877 .02625 NT 943 .0162 NT

878 .009455 7 945 .01205 NT

881 .02225 NT 946 .00415 NT

882 .001 14 NT 947 .0137 NT

883 .0485 NT 948 .01029 NT

884 .0012855 NT 949 .008425 NT

885 .018332 .616 950 .00149 NT

886 ,00252 12.3 951 .013095 NT

891 .001335 NT 952 .0012825 6.38

892 .00817 NT 953 .0008 2.5

893 .002515 NT 954 .00354 21.5

894 .00534 NT 955 ,0012333 .567

895 .0405 25.8 956 .0002755 .21 1

898 .00403 NT 957 .0004415 .3085

900 .00433 N/A 958 .000253 3.89

901 .000568 5.5 964 .001006 NT

904 .0162 NT 965 .000403 .6932

905 .0141 NT 966 .0003485 .754

906 .00903 NT 967 .001065 .461

907 .0189 NT 968 .001895 NT

908 .002475 5.83 969 .002905 NT

910 .0058 N/A 970 .000859 NT

9 1 .00808 NT 971 .00844 NT

912 .00778 NT 972 .001595 NT

913 .0061 NT 973 .000378 NT

914 .00187 NT 974 .000716 NT Ci-1 OP -2 10S Men OP 10 ^' -,

# HTRR fuM j r BS (uM ⁾ # HTRF ίμ : ί ^: Β3 ^: μΜ ⁾

975 .002155 NT 1025 .00041 1 .141 15

976 .01044 NT 1026 .00 125 .2885

977 .0003285 .2655 1027 .000945 .218

978 .00171 NT 1028 .003485 N/A

979 .000305 NT 1029 .004425 N/A

979 .0425 16.9 1030 .000195 .27067

980 .0007555 NT 1031 .006575 N/A

981 .0009425 NT 1032 .000422 .575

982 .00314 NT 1033 .0003665 .20513

983 .00123 NT 1034 .00404 8.05

984 .00109 NT 1035 .01405 24.5

985 .0014633 NT 1036 .00136 1 1 .3

986 .0004755 .2705 1037 .0008305 .7435

987 .000616 .3925 1038 .00 18 2.2

988 .0005365 1 .0015 1039 .0003885 .198

989 .000851 .3305 1040 .0010425 2,19

990 .003085 2.23 1041 .00018325 .0772

991 .000644 NT 1042 .00078 .39333

992 .00010255 2.34 1043 .00609 6.74

993 .00201 .373 1044 .03585 N/A

994 .0002205 N/A 1045 .000294 1.137

995 .000872 1 .682 1046 .000785 2.52

996 .0004875 8.19 1047 .00042387 .29963

997 .000336 .96167 1048 .00029925 .090833

998 .002135 NT 1049 .0002635 , 265

999 .000373 NT 1050 .000589 .288

1000 .00314 NT 1051 .00001965 1 .895

1001 .000573 .861 1052 .0001099 .09565

1002 .000448 1 ,225 1053 ,001 1945 1.48

1003 .000844 .273 1054 .00021 15 .10105 004 .0006355 .023628 1055 .00039367 .257 005 .0001565 4.11 1056 .004535 5.25

1006 ,00081 1 1 .6 1057 .000601 ,6275

1007 .0012 .074 1058 .0002495 .4555

1008 .0002315 5.59 1059 .009695 4.91

1009 .00123 .70233 1060 .0001785 .1 583

1010 .000377 .298 1061 ,0007105 1.107

101 1 .0003475 .5235 1062 .007875 12.6

1012 .0006975 NT 1063 .011277 18.35

1013 .01815 NT 1064 .0003635 .15683

1014 .000267 .329 1065 .000402 .09485

1015 .0002755 .2348 1066 .01785 15.2

1016 .0004835 .291 1067 .00555 5.71

1017 .000339 .31 1068 .000442 1.955

1018 .000356 .285 1069 .001675 1.505

1019 .0004975 .475 1070 .001066 1.2285

1020 .001055 .759 1071 NT NT

1021 .00909 27 1072 .001356 1.5067 022 .0235 22.7 1073 .0006175 1 .1 15

1023 .0003075 .501 1074 .0009875 3,85

1024 .0002965 .414 1075 .00615 2.15

The foregoing description is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, compositions and methods. Variations and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, as defined in the appended claims. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. All patents and other publications recited herein are hereby incorporated by reference in their entireties.