NOVEL PSYMBERlN DERIVATIVES, COMPOSITIONS, AND THEIR USE AS

ANTINEOPLASTIC AGENTS Cross Reference to Related Applications This application claims priority to provisional application U.S. Serial No.

61/076, 375, filed June 27, 2008, incorporated by reference.

FIELD OF THE INVENTION

This invention provides certain novel psymberin, irciniastatin, and pederin derivatives and compositions comprising these compounds. The compounds and compositions of the invention have been found to exhibit good potency against a variety of cancer cell lines and as such may be useful in the treatment or prevention of a wide range of cancers.

BACKGROUND

Natural products that elicit a specific and unique biological response in mammalian cells represent valuable starting points for the development of new pharmaceuticals for the treatment of various diseases. For example, two species of marine sponges, lrcinia ramose and Psammocinia sp, have been shown to contain cytotoxic ingredients which are thought to have potential use as anticancer agents. By 2004, two research groups led independently by Pettit and Crews disclosed the isolation of irciniastatin and psymberin on the basis of their potent inhibitory activity in human tumor cell assays. Irciniastatin has been isolated from the Indo-Pacific marine sponge lrcinia ramose (Pettit, G. R., et al., J. Med. Chem., 2004, 47, 1149-1152). For the structures of Irciniastatin A and

Irciniastatin B, see, e.g., PCT Publication WO2005/054809. Psymberin has been isolated from a marine sponge, Psammocinia sp, which has been collected from the waters of Papua New Guinea. Psymberin has the following chemical structure:

Psymberin

Psymberin and irciniastatin A are stereoisomers of one another (constitutionally identical compounds), each having several stereocenters. By 2005, de Brabander et al. identified each compound's stereochemistry and published a stereo-specific synthetic route. Jiang, X.; Garcia-Fortanet, J.; de Brabander, J. K. J. Am. Chem. Soc. 2005, 127, 11254, and references cited therein. For a formal total synthesis, see: Ning, S.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 8, 1093. See also US2005/054809; US2006/079120; and US2007/0015821. These compounds exhibit inhibitory activity toward several different cancer cell lines. Their use in treating cancer has also been suggested. See, e.g., Robert H. Cichewicz, et a!., Org. Lett., 2004, Vol. 6, No. 12, 1951- 1954.

The pederin compounds are also regarded as potentially useful in the treatment of cancer on the basis of their ability to inhibit protein synthesis.

For a review, see: Narquizian, R.; Kocienski, P. J.; The Pederin Family of Antitumor Agents: Structures, Synthesis and Biological Activity. In The Role of Natural products in Drug Discovery, Mulzer, J., Bohlmann, R., Eds.; Ernst Schering Research Foundation Workshop 32; Springer: New York, 2000; pp 25- 56.

However, there remains a need in the art for novel compounds which exhibit good potency against mammalian (including human) cancer cell lines. The present invention addresses this need.

SUMMARY OF THE INVENTION

The present invention provides certain psymberin derivatives (collectively referred to herein as "compounds of the invention"), as described herein.

In one embodiment, the compounds of the invention have the general structure shown in Formula (I):

(I) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , and R ⁸ are each selected independently of each other and wherein:

n is an integer from 0 to 7;

q is an integer from 0 to 2;

ring A is selected from the group consisting of: a phenyl ring, a cyclohexyl ring, a 6-membered cycloalkenyl ring, a 6-membered heterocycloalkyl ring containing from 1 to 3 ring hetero atoms each independently selected from N, S, and O, a 6-membered heterocycloalkenyl ring containing from 1 to 3 ring hetero atoms each independently selected from N, S, and O, or a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms;

R ¹ is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkenyl, alkenylalkyl-, alkynylalkyl-, arylalkyl-, benzofusedcycloalkyl, benzofusedheterocycloalkyl, heteroarylfusedcycloalkyl, heteroarylfusedheterocycloalkyl, heteroarylalkyl-, and heterocycloalkenyl,

wherein each of said alkenyl, alkynyl, aryl, heteroaryl, cycloalkenyl, alkenylalkyl-, alkynylalkyl-, arylalkyl-, benzofusedcycloalkyl, benzofusedheterocycloalkyl, heteroarylfusedcycloalkyl, heteroarylfusedheterocycloalkyl, heteroarylalkyl-, and heterocycloalkenyl of R ¹ is optionally independently unsubstituted or substituted with from 1-5 independently selected R ⁹ groups;

R ² is selected from the group consisting of: H, -OH, alkoxy, -O-haloalkyl, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹ V -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said alkoxy, -O-haloalkyl, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ² is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3 to 8 membered ring cycloalkyl ring, a 3-8 membered heterocycloalkyl ring, a 3-8 membered heterocycloalkenyl ring or a 3-8 membered cycloalkenyl ring,

wherein each said ring is optionally unsubstituted or substituted with from

1 to 6 independently selected R ⁹ groups;

R ³ is selected from the group consisting of: H, -OH, alkoxy, -O-(haloalkyl) -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -CN, -C(O)R ¹⁰ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said alkoxy, -O-haloalkyl, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ⁴ is selected from the group consisting of: H, -OH, halo, alkoxy, -O-(haloalkyl), -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ),

-S(O)NHR ¹⁰ , -S(O)N(R ¹ V -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said alkoxy, -O-haloalkoxy, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ⁵ is selected from the group consisting of: H, aryl, heteroaryl, alkyl, heteroarylalkyl-, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, heteroarylalkyl-, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl of R ⁵ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ⁶ selected from the group consisting of H and R ⁷ ,

or, alternatively, R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a six membered heterocyclic ring containing (including the oxygen atom shown attached to R ⁵ ) from 1 to 3 ring hetero atoms selected from N, O, and S, which ring is optionally further substituted with from 1

QR to 3 independently selected R groups;

each R ⁷ (when present) is independently selected from the group consisting of: -OH, halo, alkoxy, -O-(haloalkyl), SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ ) _2, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl,

wherein each of said alkoxy, -O-haloalkyl, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, any two R ⁷ groups attached to the same ring carbon are taken together to form a cycloalkyl ring or a heterocycloalkyl ring,

or, alternatively, any two R ⁷ groups attached to the same ring carbon are taken together to form a group selected from =O, =NOR ¹⁰ , and =NOH;

each R ^7A (when present) is independently selected from the group consisting of: -OH, halo, alkoxy, -O-haloalkyl, -SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ )2, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said alkoxy, -O-haloalkyl, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively when q is 2, two groups R ^7A are taken together with the carbon atom to which they are attached to form a group selected from =0, =NOR ¹⁰ , and =NOH;

R ⁸ is a moiety selected from the group consisting of:

(C ₁ -C ₁₂ alkenylene)

each R (when present) is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR ¹⁵ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -C(O)N(R ¹⁵ )(R ¹⁶ ), -SR ¹⁵ , -

S(O)N(R » 1' 5°\ )( / rR~j 1' 6 ^D _\ ), -S(O) ₂ N(R 1'5°w)(iR-»1 ¹ 6 ^D _λ ) -C(=NOR ,1'5° _M )R-,16 -N(R ,1 ^I 5 ³ x)C(O)R ,1 ¹ 6 ⁰ , -CH ₂ - N(R ¹⁵ )C(O)R ¹⁶ , -CH ₂ -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -CH ₂ -R ¹⁵ ; -CH ₂ N(R ¹⁵ )(R ¹⁶ ), - N(R ¹⁵ )S(O)R ¹⁶ , -N(R ¹⁵ )S(O) ₂ R ¹⁶ , -CH ₂ -N(R ¹⁵ )S(O) ₂ R ¹⁶ , -N(R ¹⁵ )S(O) ₂ N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )S(O)N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -CH ₂ -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )C(O)OR ¹⁶ , -CH ₂ -N(R ¹⁵ )C(O)OR ¹⁶ , -S(O)R ¹⁵ , -N ₃ , -NO ₂ , -S(O) ₂ R ¹⁵ , and -O-N=(heterocycloalkyl),

or, alternatively, when two or more R ⁹ groups are present and 2 R ⁹ groups are attached to the same atom, said two R ⁹ groups which are attached to the

same atom can be taken together to form a group selected from =NOR ¹⁵ , =O, =CH ₂₎ =CHalkyl, =C(alkyl) ₂ , and =NR ¹⁴ ;

each R ^9A (when present) is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR ¹⁵ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -C(O)N(R ¹⁵ )(R ¹⁶ ), -SR ¹⁵ , - S(O)N(R ¹⁵ XR ¹⁶ ), -CH(R ¹⁵ XR ¹⁶ ), -S(O) ₂ N(R ¹⁵ )(R ¹⁶ ),-C(=NOR ¹⁵ )R ¹⁶ , - P(O)(OR ¹⁵ XOR ¹⁶ ), -N(R ¹⁵ XR ¹⁶ ), -alkyl-N(R ¹⁵ )(R ¹⁶ ), -N(R ¹⁵ )C(O)R ¹⁶ , -CH ₂ - N(R ¹⁵ )C(O)R ¹⁶ , -CH ₂ -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -CH ₂ -R ¹⁵ ; -CH ₂ N(R ¹⁵ )(R ¹⁶ ), - N(R ¹⁵ )S(O)R ¹⁶ , -N(R ¹⁵ )S(O) ₂ R ¹⁶ , -CH ₂ -N(R ¹⁵ )S(O) ₂ R ¹⁶ , -N(R ¹⁵ )S(O) ₂ N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )S(O)N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -CH ₂ -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )C(O)OR ¹⁶ , -CH ₂ -N(R ¹⁵ )C(O)OR ¹⁶ , -S(O)R ¹⁵ , -N ₃ , -NO ₂ , -S(O) ₂ R ¹⁵ , and -O-N=(heterocycloalkyl),

or, alternatively, when two or more R ^9A groups are present and 2 R ^9A groups are attached to the same ring atom, said two R ^9A groups which are attached to the same atom can be taken together to form a group selected from =0, =CH ₂ , , =CHalkyl, =C(alkyl) ₂ , =NR ¹⁴ , =NOR ¹⁵ ;

each R ^9B (when present) is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR ¹⁵ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -C(O)N(R ¹⁵ )(R ¹⁶ ), -SR ¹⁵ , - S(O)N(R ¹⁵ XR ¹⁶ ), -CH(R ¹⁵ XR ¹⁶ ), -S(O) ₂ N(R ¹⁵ )(R ¹⁶ ),-C(=NOR ¹⁵ )R ¹⁶ , - P(O)(OR ¹⁵ XOR ¹⁶ ), -N(R ¹⁵ XR ¹⁶ ), -alkyl-N(R ¹⁵ )(R ¹⁶ ), -N(R ¹⁵ )C(O)R ¹⁶ , -CH ₂ - N(R ¹⁵ )C(O)R ¹⁶ , -CH ₂ -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -CH ₂ -R ¹⁵ ; -CH ₂ N(R ¹⁵ )(R ¹⁶ ), - N(R ¹⁵ )S(O)R ¹⁶ , -N(R ¹⁵ )S(O) ₂ R ¹⁶ , -CH ₂ -N(R ¹⁵ )S(O) ₂ R ¹⁶ , -N(R ¹⁵ )S(O) ₂ N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )S(O)N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -CH ₂ -N(R ¹⁵ )C(O)N(R ¹⁶ )(R ¹⁷ ), -N(R ¹⁵ )C(O)OR ¹⁶ , -CH ₂ -N(R ¹⁵ )C(O)OR ¹⁶ , -S(O)R ¹⁵ , -N ₃ , -NO ₂ , -S(O) ₂ R ¹⁵ , and -O-N=(heterocycloalkyl),

or, alternatively, when two or more R ^9B groups are present and 2 R ^9B groups are attached to the same ring atom, said two R ^9B groups which are attached to the same atom can be taken together to form a group selected from =0, =CH ₂ , , =CHalkyl, =C(alkyl) ₂ , =NR ¹⁴ , =NOR ¹⁵ ;

each R ¹⁰ is independently selected from the group consisting of: aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ¹⁰ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

each R ¹¹ is independently selected from the group consisting of: H, -OH, -O-alkyl, -O-(haloalkyl), -NH(R ¹⁰ ), -N(R ¹⁰ ) ₂ , -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O)NH ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -S(O) ₂ NH ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)NH ₂ , -C(O)R ¹⁰ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ¹¹ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

G (when present) is selected from the group consisting of -O- and -NR ¹¹ -;

R ¹² is selected from the group consisting of: H, -OH, halo, alkoxy, -O-(haloalkyl), -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ¹² is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ¹³ is selected from the group consisting of: H, -OH, halo, alkoxy, -O-(haloalkyl), -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ¹³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ¹⁴ is selected from the group consisting of: H, -OH, -O-alkyl, alkoxy,

-O-(haloalkyl), -NH(R ¹⁰ ), -N(R ¹⁰ ) ₂ , -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O)NH ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -S(O) ₂ NH ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)NH ₂ , -C(O)R ¹⁰ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ¹⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heterocyclyl, heterocyclylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, arylcycloalkyl-, and arylheterocyclyl,

wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-, heterocyclyl, heterocyclylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, arylcycloalkyl-, and arylheterocyclyl of R ¹⁵ , R ¹⁶ , and R ¹⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ¹⁸ groups,

or, alternatively, R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently selected from the group consisting of:

each R ¹⁸ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, -NO ₂ , halo, heteroaryl, HO- alkyoxyalkyl, -CF ₃ , -CN, alkyl-CN, -C(O)R ¹⁹ , -C(O)OH, -C(O)OR ¹⁹ , -C(O)NHR ²⁰ , - C(O)NH ₂ , -C(O)NH ₂ -C(O)N(alkyl) ₂ , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR ¹⁹ , -S(O) ₂ R ²⁰ , -S(O)NH ₂ , -S(O)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), - S(O) ₂ NH ₂ , -S(O) ₂ NHR ¹⁹ , -S(O) ₂ NH(heterocyclyl), -S(O) ₂ N(alkyl) ₂ , - S(O) ₂ N(alkyl)(aryl), -OCF ₃ , -OH, -OR ²⁰ , -O-heterocyclyl, -O-cycloalkylalkyl, -O- heterocyclylalkyl, -NH ₂ , -NHR ²⁰ , -N(alkyl) ₂ , -N(arylalkyl) ₂ , -N(arylalkyl)- (heteroarylalkyl), -NHC(O)R ²⁰ , -NHC(O)NH ₂ , -NHC(O)NH(alkyl), - NHC(O)N(alkyl)(alkyl), -N(alkyl)C(O)NH(alkyl), -N(alkyl)C(O)N(alkyl)(alkyl), - NHS(O) ₂ R ²⁰ , -NHS(O) ₂ NH(alkyl), -NHS(O) ₂ N(alkyl)(alkyl), -N(alkyl)S(O) ₂ NH(alkyl) and -N(alkyl)S(O) ₂ N(alkyl)(alkyl),

or, alternatively, two R ¹⁸ moieties on adjacent carbons are linked together to form a moiety selected from:

R ¹⁹ is selected from the group consisting of: alkyl, cycloalkyl, aryl, arylalkyl-, and heteroarylalkyl-;

R ²⁰ is selected from the group consisting of: alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl-, heteroaryl, and heteroarylalkyl-;

each R ²¹ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl-, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl-, aryl, arylalkyl-, heteroaryl, heteroarylalkyl-, halo, -CN, -OH, -Oalkyl, -C(O)H, -C(O)alkyl, -C(O)OH, -C(O)Oalkyl, -C(O)NH ₂ , -C(O)NHalkyl, -C(O)N(alkyl) ₂ , -SH, -Salkyl, -S(O)alkyl, -S(O)NH ₂ , -S(O)NHalkyl, -S(O)N(alkyl) ₂ , -S(O) ₂ NH ₂ , -S(O) ₂ NHalkyl, and -S(O) ₂ N(alkyl) ₂ ;

each R ²² is independently selected from the group consisting of -OH, -O-alkyl, -C(O) ₂ H, -C(O) ₂ alkyl, -C(O)NH ₂ , -C(O)NHalkyl, -C(O)N(alkyl) ₂ ;

each R ²³ is independently selected from the group consisting of -OH and -Oalkyl;

p is an integer from O to 6;

r is an integer from O to 3; and

s is an integer from 1 to 2;

with the following two (2) provisos:

Proviso (i): The compound(s) of Formula (I) do not have a structure:

OH O ; and

Proviso (ii): When: (a) R ¹ form a moiety selected

(b) l R ⁴ is -OH, and (c) R ⁸ is selected from the group consisting of

-OH,

(Ci-C ₁₂ alkylene) R ²³

alkenyleneK \ ^y

then either q is 0 or q is 1 or 2 and R ^7A is not -OH, =O, or

OCH ₃ .

In other embodiments, the invention provides compositions, including pharmaceutical compositions, comprising one or more compounds of the invention (e.g., one compound of the invention), or a tautomer, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent.

In other embodiments, the invention provides a method for inhibiting aberrant cell proliferation in a cell, cell culture, tissue, or patient in need thereof, comprising exposing a cell, cell culture, tissue, or patient in need thereof an effective amount of a compound or composition of the invention. The methods may be performed in vivo, ex vivo, and/or in vitro, for research and/or therapeutic purposes.

In other embodiments, the invention provides a method for inducing apoptosis in a cell, cell culture, tissue, or cells of a patient in need thereof, comprising exposing a cell, cell culture, tissue, or patient in need thereof an effective amount of a compound or composition of the invention. The methods may be performed in vivo, ex vivo, and/or in vitro, for research and/or therapeutic purposes.

In other embodiments, the invention provides various methods of treating or preventing certain cancers, as described herein. In view of the nanomolar and sub-nanomolar potency of psymberin in every human tumor cell line tested, and in view of the data described below, the compounds of the invention are

expected to exhibit broad activity against a broad range of cancer cell types. Non-limiting examples of cancers treatable or preventable according to methods of the present invention include: breast, skin (e.g., melanoma), lung (e.g., non- small cell lung cancer and small cell lung cancer), colon (colorectal), stomach (gastric), prostate, kidney (renal), liver, head and neck, esophageal, ovarian, pancreatic, brain cancers, bone sarcomas, soft tissue sarcomas, multiple myeloma, leukemias, and lymphomas (e.g., AML, CML, Hodgkins Disease, and Non-Hodgkin's lymphoma). These methods generally comprise administering a composition comprising an effective amount of one or more compounds of the invention to a patient in need thereof. Such methods optionally additionally comprise administering an effective amount of one or more additional therapeutic agents suitable for treating the patient being treated.

These and other embodiments of the invention, which are described in detail below or will become readily apparent to those of ordinary skill in the art, are included within the scope of the invention.

DETAILED DESCRIPTION:

In one embodiment, the compounds of the invention have the structural Formula (I) as described above and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof.

In one embodiment, in Formula (I), ring A, together with R ⁶ , R ⁷ , R ^7A , and R ⁸ , form a moiety selected from the group consisting of:

wherein the wavy line represents the point of attachment to the rest of Formula (I).

In one embodiment, in Formula (I), R ¹ is selected from the group consisting of: alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl-,

wherein each of said alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1 -5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ¹ is selected from the group consisting of: alkyl, arylalkyl-, and heteroarylalkyl-,

wherein each of said alkyl, arylalkyl-, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1-5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ² is selected from the group consisting of: H, -O-alkyl, -O-haloalkyl, alkyl, and arylalkyl-,

wherein each of said -O-alkyl, -O-haloalkyl, alkyl, and arylalkyl- of R ² is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ² is selected from the group consisting of: H, -O-alkyl, -O-fluoroalkyl, and alkyl,

wherein each of said -O-alkyl, -O-fluoroalkyl, and alkyl of R ² is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3 to 8 membered cycloalkyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Such cycloalkyl rings may be monocyclic or (ring number permitting) multicyclic. Non-limiting examples of such monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which may be optionally substituted with one or more independently (e.g., from 1 to 3) selected R ⁹ groups. Non-limiting examples of such multicyclic cycloalkyl rings include 1-decalinyl, norbomyl, and adamantyl, each of which may be optionally substituted with one or more independently selected R ⁹ groups. Further non-limiting examples of cycloalkyl

rings include the following (each of which may be unsubstituted or optionally ssuubbssttiittuuttted with one or more (e.g., from 1 to 6) independently selected R ⁹ groups):

In one embodiment, in Formula (I), R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a cyclopropyl ring, which ring is unsubstituted.

In one embodiment, in Formula (I), R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a cyclopropyl ring, which ring is substituted with from 1 to 3 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered cycloalkenyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Such cycloalkenyl rings may be monocyclic or (ring number permitting) multicyclic. Non-limiting examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cyclohepta-1 ,3-dienyl, each of which may be optionally substituted with one or more (e.g., from 1to 3) independently selected R ⁹ groups. Non-limiting examples of multicyclic cycloalkenyl include norbornylenyl, which may be optionally substituted with one or more independently selected R ⁹ groups. Additional non- limiting examples of 3-8 membered cycloalkenyl rings include unsaturated versions of the cycloalkyl rings noted above, each of which may be optionally substituted with one or more (e.g., from 1 to 6) independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered heterocycloalkyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Such 3-8 membered heterocycloalkyl rings may be monocyclic or (ring number permitting) multicyclic. Non-limiting examples of such monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, and lactone, each of which may be optionally substituted with one or more (e.g., from 1 to 3) independently selected R ⁹ groups. In another embodiment, in Formula (I), such heterocyclic rings contain one or more oxo groups.

In one embodiment, in Formula (I), R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered heterocycloalkenyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Non-limiting examples of heterocycloalkenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2- dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-

dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyi, dihydrothiophenyl, and dihydrothiopyranyl, each of which may be optionally substituted with one or more (e.g., from 1 to 6) independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ³ is selected from the group consisting of: H, -OH ₁ -O-(haloalkyl) -S(R ¹⁰ ), and alkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

In one embodiment, in Formula (I), R ³ is selected from the group consisting of: H, -OH, alkoxy, -O-haloalkyl, and alkyl,

wherein each of said alkoxy, -O-haloalkyl, and alkyl, of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ¹ is selected from the group consisting of: alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl-,

wherein each of said alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1-5 independently selected R ⁹ groups;

R ² is H; and

R ³ is selected from the group consisting of alkoxy and - O-haloalkyl.

In one embodiment, in Formula (I), R ⁴ is selected from the group consisting of: -OH, halo, alkoxy, -O-(haloalkyl), -S(R ¹⁰ ), -S(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , and heteroaryl,

wherein each of said alkoxy, -O-(haloalkyl), and heteroaryl of R -.4 i ■s optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ⁴ is selected from the group consisting of: -OH, fluoro, alkoxy, -O-(fluoroalkyl), and -S(R ¹⁰ ),

wherein each of said alkoxy, and -O-(fluoroalkyl) of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ⁵ is selected from the group consisting of: H, alkyl, cycloalkyl, and heterocycloalkyl,

wherein each of said alkyl, cycloalkyl, and heterocycloalkyl of R ⁵ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ⁵ is selected from the group consisting of: H and alkyl,

wherein said alkyl of R ⁵ is optionally unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), R ⁶ is H.

In one embodiment, in Formula (I), R ⁶ is R ⁷ , wherein R ⁷ is - O-alkyl.

In one embodiment, in Formula (I), is a compound of the Formula (I):

(0-

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

ring A, together with R ⁵ , R ⁶ , R ⁷ , R ^7A , R ⁸ , and the atoms to which they are shown attached, form a moiety selected from the group consisting of:

wherein the wavy line represents the point of attachment to the rest of Formula (I);

R i4 i :s selected from the group consisting of H and OH;

R ⁵ (when present) is methyl;

R (when present) is H;

q is 0, 1 , or 2, and each R ,7A (when present) is independently selected from the group consisting of OH and F;

n is 0, 1 , or 2 and each R ⁷ (when present) is -CH ₃ ,

or, alternatively, n is 2 and two R ⁷ groups are taken together with the ring carbon atom to which they are attached to form a cyclopropyl ring; and

R ¹ ' R ² , R ³ , R ⁸ , and R ^9B are each independently as defined in Formula (I) above, or in any of the embodiments set forth below.

In one such embodiment, R ¹ is selected from the group consisting of: alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl-, wherein each of said alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1 -5 independently selected R ⁹ groups.

In another such embodiment, R ¹ is selected from the group consisting of: alkyl, arylalkyl-, and heteroarylalkyl-,

wherein each of said alkyl, arylalkyl-, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1 -5 independently selected R ⁹ groups.

In another such embodiment, R ² is selected from the group consisting of: H, -O- alkyl, -O-haloalkyl, alkyl, and arylalkyl-, wherein each of said -O-alkyl, -O-haloalkyl, alkyl, and arylalkyl- of R ² is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another such embodiment, R ² is selected from the group consisting of: H, -O- alkyl, -O-fluoroalkyl, and alkyl,

wherein each of said -O-alkyl, -O-fluoroalkyl, and alkyl of R ² is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another such embodiment, R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3 to 8 membered monocyclic or multicyclic cycloalkyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups.

In another such embodiment, R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a cyclopropyl ring, which ring is unsubstituted.

In another such embodiment, R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a cyclopropyl ring, which ring is substituted with from 1 to 3 independently selected R ⁹ groups.

In another such embodiment, R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered monocyclic or multicyclic cycloalkenyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups.

In another such embodiment, R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered monocyclic or multicyclic heterocycloalkyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups.

In another such embodiment, R ³ is selected from the group consisting of: H, -OH, -O-(haloalkyl) -S(R ¹⁰ ), and alkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another such embodiment, R ³ is selected from the group consisting of: H, -OH, alkoxy, -O-haloalkyl, and alkyl,

wherein each of said alkoxy, -O-haloalkyl, and alkyl, of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a 1 ,3-dioxane which is optionally substituted

QR with from 0 to 2 independently selected R groups and the compounds of the invention have the general structure shown in Formula (1.1):

(1.1 ) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ¹ , R ² , R ³ , R ⁴ , each R ⁷ , each R ^7A , R ⁸ , and each R ^9B are each selected independently of each other and as defined in Formula (I).

In one embodiment, R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a substituted heterocycloalkyl and the compounds of the invention have the general structure shown in Formula (I.2):

(I.2) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ¹ , R ² , R ³ , R ⁴ , each R ⁷ , each R ^7A , R ⁸ , and R ¹¹ are each selected independently of each other and as defined in Formula (I).

In one embodiment, R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a substituted heterocycloalkyl and the compounds of the invention have the general structure shown in Formula (1.3):

(I.3) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ¹ , R ² , R ³ , R ⁴ , each R ⁷ , each R ^7A , R ⁸ , and R ¹¹ are each selected independently of each other and as defined in Formula (I).

In one embodiment, R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a substituted heterocycloalkyl and the compounds of the invention have the general structure shown in Formula (1.4):

(I.4) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ¹ , R ² , R ³ , R ⁴ , each R ⁷ , each R ^7A , R ⁸ , and R ¹¹ are each selected independently of each other and as defined in Formula (I).

In one embodiment, R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a substituted heterocycloalkyl and the compounds of the invention have the general structure shown in Formula (1.5):

(1.5) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ¹ , R ² , R ³ , R ⁴ , each R ⁷ , each R ^7A , R ⁸ , each R ^9B , and R ¹¹ are each selected independently of each other and as defined in Formula (I).

In one embodiment, in Formula (I), n is 0.

In one embodiment, in Formula (I), n is greater than 0 and each R ⁷ is independently selected from the group consisting of: -OH, halo, alkoxy, -O-haloalkyl, -S(R ¹⁰ ), alkyl, cycloalkyl, and heterocycloalkyl,

wherein each of said alkoxy, -O-haloalkyl, alkyl, cycloalkyl, and heterocycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), n is greater than 0 and each R ⁷ is independently selected from the group consisting of: fluoro, alkyl, and cycloalkyl,

wherein each of said alkyl and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), n is 2 or more and two R ⁷ groups attached to the same ring carbon are taken together to form a cycloalkyl ring or a heterocycloalkyl ring. In one such embodiment, n is an integer from 2 to 7 and

each R ⁷ not taken together with another R ⁷ to form said cycloalkyl ring or said heterocycloalkyl ring is independently selected. In another such embodiment, n is 2.

In one embodiment, in Formula (I), n is 2 or more and two R ⁷ groups attached to the same ring carbon are taken together to form a cyclopropyl ring. In one such embodiment, n is an integer from 2 to 7 and each R ⁷ not taken together to form a cyclopropyl ring is independently selected. In another such embodiment, n is 2.

In one embodiment, in Formula (I), n is 2 or more and two R ⁷ groups attached to the same ring carbon are taken together to form a group selected from =0, =NOR ¹⁰ , and =NOH. In one such embodiment, n is an integer from 2 to 7. In another such embodiment, n is 2.

In one embodiment, in Formula (I), q is 0.

In one embodiment, in Formula (I), q is 1.

In one embodiment, in Formula (I), q is 2.

In one embodiment, in Formula (I), q is 1 or 2 and each R ^7A is independently selected from the group consisting of: -OH, halo, alkoxy, -O-haloalkyl, -S(R ¹⁰ ), -S(O) ₂ R ¹⁰ , and -C(O)NHR ¹⁰ ,

wherein each of said alkoxy and -O-haloalkyl of R ^7A is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), q is 1 or 2 and each R ^7A is independently selected from the group consisting of: -OH, halo, alkoxy, and -O-fluoroalkyl,

wherein each of said alkoxy and -O-fluoroalkyl of R ^7A is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In one embodiment, in Formula (I), q is 2 and two groups R 7A are taken together with the carbon atom to which they are attached to form a groups selected from =0, =NOR ¹⁰ , and =NOH.

In one embodiment, in Formula (I), R ⁸ is -OH,

In one embodiment, in Formula (I), R ⁸ is

In one embodiment, in Formula (I), R ⁸ is

In one embodiment, in Formula (I), R is

In one embodiment, in Formula (I), R is

In one embodiment, in Formula (1), R ⁸ is a moiety selected from the group consisting of:

_R22 /(C ₁ -C ₁₂ alkylene). - J S _ζ - _R22 /(C ₁ -C ₁₂ alkylene). ^* yJ S _ζ

O . R ²³ alkenylene)

,and

In one embodiment, in Formula (I), R is a moiety selected from the group consisting of:

/ OH

It shall be understood that, in embodiments wherein R ¹⁵ , R ¹⁶ and/or R ¹⁷ are present and independently selected from the group consisting of:

any unfulfilled valences in the rings shown shall be satisfied by either hydrogen or R 21

In one embodiment, the compounds of the invention have the general structure shown in Formula (II):

(II) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (11.1):

(11.1 ) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (11.1 -A):

(IU-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (II.2):

(II.2) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (II.2-A):

(II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ is selected from the group consisting of: alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl-,

wherein each of said alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1 -5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ is selected from the group consisting of: alkyl, arylalkyl-, and heteroarylalkyl-,

wherein each of said alkyl, arylalkyl-, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1-5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (H.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ² is selected from the group consisting of: H, -O-alkyl, -O-haloalkyl, alkyl, and arylalkyl-,

wherein each of said -O-alkyl, -O-haloalkyl, alky!, and arylalkyl- of R ² is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ² is selected from the group consisting of: H, -O-alkyl, -O-fluoroalkyl, and alkyl,

wherein each of said -O-alkyl, -O-fluoroalkyl, and alkyl of R 2 is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3 to 8 membered cycloalkyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Such cycloalkyl rings may be monocyclic or (ring number permitting) multicyclic. Non-limiting examples of such monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which may be optionally substituted with one or more independently (e.g., from 1 to 3) selected R ⁹ groups. Non-limiting examples of such multicyclic cycloalkyl rings include 1-decalinyl, norbomyl, and adamantyl, each of which may be optionally substituted with one or more independently selected R ⁹ groups. Further non- limiting examples of cycloalkyl rings include the following (each of which may be unsubstituted or optionally substituted with one or more (e.g., from 1 to 6) independently selected R ⁹ groups):

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (II.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein;

R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a cyclopropyl ring, which ring is unsubstituted.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or

Formula (!1.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a cyclopropyl ring, which ring is substituted with from 1 to 3 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered cycloalkenyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Such cycloalkenyl rings may be monocyclic or (ring number permitting) multicyclic. Non-limiting examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cyclohepta-1 ,3-dienyl. each of which may be optionally substituted with one or more (e.g., from 1to 3) independently selected R ⁹ groups. Non-limiting examples of multicyclic cycloalkenyl include norbornylenyl, which may be optionally substituted with one or more independently selected R ⁹ groups. Additional non-limiting examples of 3-8 membered cycloalkenyl rings include unsaturated versions of the cycloalkyl rings noted above, each of which may be optionally substituted with one or more (e.g., from 1 to 6) independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (II.1-A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered heterocycloalkyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Such 3-8 membered heterocycloalkyl rings may be monocyclic or (ring number permitting) multicyclic. Non-limiting examples of such monocyclic

heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, and lactone, each of which may be optionally substituted with one or more (e.g., from 1 to 3) independently selected R ⁹ groups. In another embodiment, in Formula (I), such heterocyclic rings contain one or more oxo groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ and R ² are taken together with the carbon atom to which they are shown attached to form a 3-8 membered heterocycloalkenyl ring, wherein said ring is optionally unsubstituted or substituted with from 1 to 6 independently selected R ⁹ groups. Non-limiting examples of heterocycloalkenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyI, 2- imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, and dihydrothiopyranyl, each of which may be optionally substituted with one or more (e.g., from 1 to 6) independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of: H, -OH, -O-(haloalkyl) -S(R ¹⁰ ), and alkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of: H, -OH, alkoxy, -O-haloalkyl, and alkyl,

wherein each of said alkoxy, -O-haloalkyl, and alkyl, of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹ is selected from the group consisting of: alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl-,

wherein each of said alkyl, arylalkyl-, benzofusedcycloalkyl, heteroarylfusedcycloalkyl, and heteroarylalkyl- of R ¹ is optionally independently unsubstituted or substituted with from 1-5 independently selected R ⁹ groups;

R ² is H; and

R ³ is selected from the group consisting of alkoxy and -

O-haloalkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of: -OH, halo, alkoxy, -O- (haloalkyl), -S(R ¹⁰ ), -S(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , and heteroaryl,

wherein each of said alkoxy, -O-(haloalkyl), and heteroaryl of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (M.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of: -OH, fluoro, alkoxy, -O-

(fluoroalkyl), and -S(R ¹⁰ ),

wherein each of said alkoxy, and -O-(fluoroalkyl) of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (II.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ is selected from the group consisting of: H, alkyl, cycloalkyl, and heterocycloalkyl,

wherein each of said alkyl, cycloalkyl, and heterocycloalkyl of R ⁵ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ is selected from the group consisting of: H and alkyl,

wherein said alkyl of R ⁵ is optionally unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁶ is H.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁶ is R ⁷ and wherein R ⁷ is -O-alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a 1 ,3-dioxane, which 1 ,3-dioxane.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ and R ⁶ are taken together with the atoms to which they are shown attached to form a 1 ,3-dioxane, which 1 ,3-dioxane is substituted with from 1 to 3

QR independently selected R groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is 0.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is greater than 0 and each R ⁷ is independently selected from the group consisting of: -OH, halo, alkoxy, -O-haloalkyl, -S(R ¹⁰ ), alkyl, cycloalkyl, and heterocycloalkyl,

wherein each of said alkoxy, -O-haloalkyl, alkyl, cycloalkyl, and heterocycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is greater than 0 and each R ⁷ is independently selected from the group consisting of: fluoro, alkyl, and cycloalkyl,

wherein each of said alkyl and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (II.1-A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is 2 or more and two R ⁷ groups attached to the same ring carbon are taken together to form a cycloalkyl ring or a heterocycloalkyl ring. In one such embodiment, n is an integer from 2 to 7 and each R ⁷ not taken together with another R ⁷ to form said cycloalkyl ring or said heterocycloalkyl ring is independently selected. In another such embodiment, n is 2.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A.), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is 2 or more and two R ⁷ groups attached to the same ring carbon are taken together to form a cyclopropyl ring. In one such embodiment, n is an integer from 2 to 7 and each R ⁷ not taken together to form a cyclopropyl ring is independently selected. In another such embodiment, n is 2.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is 2 or more and two R ⁷ groups attached to the same ring carbon are taken together to form a group selected from =O, =NOR ¹⁰ , and =NOH. In one such embodiment, n is an integer from 2 to 7. In another such embodiment, n is 2.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 0.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 1.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or

Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 2.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 1 or 2 and each R ^7A is independently selected from the group consisting of: -OH, halo, alkoxy, -O-haloalkyl, -S(R ¹⁰ ), -S(O) ₂ R ¹⁰ , and -C(O)NHR ¹⁰ ,

wherein each of said alkoxy and -O-haloalkyl of R ^7A is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1 ), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 1 or 2 and each R ^7A is independently selected from the group consisting of: -OH, halo, alkoxy, and -O-fluoroalkyl,

wherein each of said alkoxy and -O-fluoroalkyl of R ^7A is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 2 and two groups R ^7A are taken together with the carbon atom to which they are attached to form a groups selected from =0, =NOR ¹⁰ , and =NOH.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (II.1-A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

G is O, R ¹² is -OH, R ¹³ is alkyl, and each R ^9A is independently selected from -OH and -alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (II), Formula (11.1), Formula (11.1 -A), Formula (II.2), or Formula (II.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

G is NH, R ¹² is -OH, R ¹³ is alkyl, and each R ^9A is independently selected from -OH and -alkyl.

In one embodiment, the compounds of the invention have the general structure shown in Formula (III):

and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , R ⁸ , each R ^9A , and R ^9A' are selected independently of each other and wherein:

each R ^7A (when present) is selected from the group consisting of: halo, -O-(haloalkyl), SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹ V -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ ) ₂ , ary!, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, when q is 2 or more and two groups R ^7A are attached to the same ring carbon, two groups R ⁷ can be taken together with the ring carbon atom to which they are attached to form a group selected from =NOR ¹⁰ and =NOH;

R ⁸ is a moiety selected from the group consisting of:

alkylene)

=R ^9A is selected from the group consisting of =0, =CH ₂ , =CHalkyl, =C(alkyl) ₂ , =NOR ¹⁰ , and =N0H;

and ring A, n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ^9A R ²² , and R ²³ are each as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (111.1):

(111.1 ) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , R ⁸ , and each R ^9A are selected independently of each other and wherein:

each R ^7A (when present) is selected from the group consisting of: halo, -O-(haloalkyl), SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ),

-S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ ) ₂ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, when q is 2 or more and two groups R ^7A are attached to the same ring carbon, two groups R ⁷ can be taken together with the ring carbon atom to which they are attached to form a group selected from =NOR ¹⁰ and =NOH;

R ⁸ is a moiety selected from the group consisting of:

✓ (C ₁ -C ₁₂ alkylene) S _R 23

(C ₁ -C ₁₂ alkenylene)

and n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ^9A R ²² , and R ²³ are each as defined in

Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (111.1 -A):

(III.1 -A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , R ⁸ , and each R ^9A are selected independently of each other and wherein:

each R ^7A (when present) is selected from the group consisting of: halo, -O-(haloalkyl), SH, -S(R ,1 ^ι 0 ^υ ), -S(O)R 1 ⁱ 0 ^υ , -S(O)(OR »1 ⁱ 0 ^υ \), -S(O) ₂ R ,10, -S(O) ₂ (OR ,1 ^I O ^U _x ),

-S(O)NHR ,1 ^I 0 ^U , -S(O)N(R ¹ V -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ ) ₂ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, when q is 2 or more and two groups R ^7A are attached to the same ring carbon, two groups R ⁷ can be taken together with the ring carbon atom to which they are attached to form a group selected from =NOR ¹⁰ and =NOH;

R ⁸ is a moiety selected from the group consisting of:

(C ₁ -C ₁₂ R ²³

-(C ₁ -C ₁₂ alkenylene)

and n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^9A , R ²² , and R ²³ are each as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (III.2):

(III.2) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , R ⁸ , and each R ^9A are each selected independently of each other and wherein:

R ⁵ is selected from the group consisting of: H, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁵ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ⁶ selected from the group consisting of H and R ⁷ ;

each R ^7A (when present) is selected from the group consisting of: halo, -O-(haloalkyl), SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ ) ₂ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, when q is 2 or more and two groups R ^7A are attached to the same ring carbon, two groups R ⁷ can be taken together with the ring carbon atom to which they are attached to form a group selected from =NOR ¹⁰ and =NOH;

R ⁸ is a moiety selected from the group consisting of:

/(C ₁ -C ₁₂ alkylene)

and n, q, R ³ , R ⁴ , R ⁷ , and R ^9A R ²² , and R ²³ are each as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (III.2-A):

I.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^7A , R ⁸ , are selected independently of each other and wherein:

R ⁵ is selected from the group consisting of: H, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R is optionally

independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ⁶ selected from the group consisting of H and R ⁷ ;

each R ^7A (when present) is selected from the group consisting of: halo, -O-(haloalkyl), SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂₎ -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) _2> -CN, -C(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) _2> -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹ °) _2> aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, when q is 2 or more and two groups R ^7A are attached to the same ring carbon, two groups R ⁷ can be taken together with the ring carbon atom to which they are attached to form a group selected from =NOR ¹⁰ and =NOH;

R ⁸ is a moiety selected from the group consisting of:

and n, q, R ³ , R ⁴ , R ⁷ , and R ^9A R ²² , and R ²³ are each as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (III.3):

(111.3) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ^7A , R ⁸ , are selected independently of each other and wherein;

each R ^7A (when present) is selected from the group consisting of: halo, -O-(haloalkyl), SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ¹⁰ , -S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ NHR ¹⁰ , -S(O) ₂ N(R ¹⁰ ) ₂ , -CN, -C(O) ₂ R ¹⁰ ,

-C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ ) ₂ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, when q is 2 or more and two groups R ^7A are attached to the same ring carbon, two groups R ⁷ can be taken together with the ring carbon atom to which they are attached to form a group selected from =NOR ¹⁰ and =NOH;

R ⁸ is a moiety selected from the group consisting of:

alkylene)

(Ci-C ₁₂ alkenylene)

and n, q, R ³ , R ⁴ , R ⁷ , and R ^9A R ²² , and R ²³ are each as defined in Formula (I),

In another embodiment, the compounds of the invention have the general structure shown in Formula (III.3-A):

(III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ^7A , R ⁸ , are selected independently of each other and wherein:

each R i7A (when present) is selected from the group consisting of: halo, -O-(haloalkyl), SH, -S(R ¹⁰ ), -S(O)R ¹⁰ , -S(O)(OR ¹⁰ ), -S(O) ₂ R ¹⁰ , -S(O) ₂ (OR ¹⁰ ), -S(O)NHR ,10 , -S(O)N(R i1 ^I 0 ^U ) ₂ , -S(O) ₂ NHR 10 , -S(O) ₂ N(R »1 ^ι 0 ^υ \) ₂ , -CN, -C(O) ₂ R ,10 ,

-C(O)NHR ¹⁰ , -C(O)N(R ¹⁰ ) ₂ , -C(O)R ¹⁰ , -N ₃ , -NO ₂ , -O-=C(R ¹⁰ ) ₂ , aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁷ is optionally

independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups,

or, alternatively, when q is 2 or more and two groups R -.7A are attached to the same ring carbon, two groups R ⁷ can be taken together with the ring carbon atom to which they are attached to form a group selected from =NOR 10 ^υ and =NOH;

R is a moiety selected from the group consisting of:

alkylene) / '(C3-C12

322 0

, and

and n, q, R ³ , R ⁴ , R ⁷ , and R ^9A R ²² , and R ²³ are each as defined in Formula (I).

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of: H, -OH, -O-(haloalkyl) -S(R ¹⁰ ), and alkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of: H, -OH, alkoxy, -O-haloalkyl, and alkyl,

wherein each of said alkoxy, -O-haloalkyl, and alkyl, of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of H, -OH, halo, and -O-alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1 ), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of: -OH, halo, alkoxy, -O- (haloalkyl), -S(R ¹⁰ ), -S(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , and heteroaryl,

wherein each of said alkoxy, -O-(haloalkyl), and heteroaryl of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1 ), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of: -OH, fluoro, alkoxy, -O- (fluoroalkyl), and -S(R ¹⁰ ),

wherein each of said alkoxy, and -O-(fluoroalkyl) of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of H, -OH, halo, and -O-alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1 ), Formula (III.1-A), Formula (III.2),

or Formula (III.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ is selected from the group consisting of: H, alkyl, cycloalkyl, and heterocycloalkyl,

wherein each of said alkyl, cycloalkyl, and heterocycloalkyl of

R ⁵ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1 ), Formula (III.1-A), Formula (III.2), or Formula (III.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ is selected from the group consisting of: H and alkyl,

wherein said alkyl of R ⁵ is optionally unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1 ), Formula (III.1-A), Formula (III.2), or Formula (III.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁶ is H.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), or Formula (III.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁶ is R ⁷ , wherein R ⁷ is -O-alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include

pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 0.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1 -A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 1 and R ^7A is independently selected from halo and haloalkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is an integer from 0 to 2.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1 ), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is 2 and each R ⁷ is independently selected from alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (III), Formula (111.1), Formula (III.1-A), Formula (III.2), Formula (III.2-A), Formula (III.3), or Formula (III.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 0;

n is an integer from 0 to 2;

R is selected from the group consisting of H, -OH, halo, and -O-alkyl; R ⁴ is selected from the group consisting of H, -OH, halo, and -O-alkyl; each R ⁷ (when present) is independently selected from alkyl;

R ⁸ is a moiety selected from the group consisting of:

and each R ,9A is independently selected from alkyl.

In one embodiment, the compounds of the invention have the general structure shown in Formula (IV):

(IV) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

ring A, n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ^9A' ,

R ¹² , R ¹³ , and G are selected independently of each other and wherein:

=R ^9A is selected from the group consisting of =0, =CH ₂₎ =CHalkyl, =C(alkyl) ₂ , =NOR ¹⁰ , and =NOH;

and wherein ring A, n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (IV.1):

(IV.1 ) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (IV.1 -A):

(IV.1 -A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (IV, 2):

(IV.2) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and wherein:

R ⁵ is selected from the group consisting of: H, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁵ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ⁶ selected from the group consisting of H and R ⁷ ; and

n, q, R ³ , R ⁴ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (IV.2-A):

(IV.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , R ⁵ , R ⁶ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and wherein:

R ⁵ is selected from the group consisting of: H, aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ⁵ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups;

R ⁶ selected from the group consisting of H and R ⁷ ; and

n, q, R ³ , R ⁴ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (IV.3):

(IV.3) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , each R ⁷ , each R ^7A , each R ⁹ , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In one embodiment, the compounds of the invention have the general structure shown in Formula (IV.3-A):

(IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n, q, R ³ , R ⁴ , each R ⁷ , each R ^7A , each R ^9A , R ¹² , R ¹³ , and G are selected independently of each other and as defined in Formula (I).

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of: H, -OH, -O-(haloalkyl) -S(R ¹⁰ ), and alkyl,

wherein each of said aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl, and cycloalkyl of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of: H, -OH, alkoxy, -O-haloalkyl, and alkyl,

wherein each of said alkoxy, -O-haloalkyl, and alkyl, of R ³ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ³ is selected from the group consisting of H, -OH, halo, and -O-alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1 -A), Formula

(IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of: -OH, halo, alkoxy, -O- (haloalkyl), -S(R ¹⁰ ), -S(O) ₂ R ¹⁰ , -C(O)NHR ¹⁰ , and heteroaryl,

wherein each of said alkoxy, -O-(haloalkyl), and heteroaryl of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of: -OH, fluoro, alkoxy, -O- (fluoroalkyl), and -S(R ¹⁰ ),

wherein each of said alkoxy, and -O-(fluoroalkyl) of R ⁴ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁴ is selected from the group consisting of H, -OH, halo, and -O-alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), and Formula (IV.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ is selected from the group consisting of: H, aikyl, cycloalkyl, and heterocycloaikyi,

wherein each of said aikyl, cycloalkyl, and heterocycloaikyi of

R i5 ^■ is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), and Formula (IV.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁵ is selected from the group consisting of: H and aikyl,

wherein said aikyl of R ⁵ is optionally unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), and Formula (IV.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁶ is H.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1 -A), Formula (IV.2), and Formula (IV.2-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ⁶ is R ⁷ , wherein R ⁷ is -O-alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 0.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1-A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 1.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 2.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1-A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 1 or 2 and each R ^7A is independently selected from the group consisting of: -OH, halo, alkoxy, -O-haloalkyl, -S(R ¹⁰ ), -S(O) ₂ R ¹⁰ , and -C(O)NHR ¹⁰ ,

wherein each of said alkoxy and -O-haloalkyl of R ^7A is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein;

q is 1 or 2 and each R ^7A is independently selected from the group consisting of: -OH, halo, alkoxy, and -O-fluoroalkyl,

wherein each of said alkoxy and -O-fluoroalkyl of R ^7A is optionally independently unsubstituted or substituted with from 1 to 5 independently selected R ⁹ groups.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 2 and two groups R ^7A are taken together with the carbon atom to which they are attached to form a groups selected from =O, =NOR ¹⁰ , and =NOH.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

q is 1 and R ^7A is independently selected from halo and haloalkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1-A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is an integer from 0 to 2.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

n is 2 and each R ⁷ is independently selected from alkyl.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1 ), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

G is O.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1-A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

G is selected -NH- and -N(alkyl)-.

In another embodiment, the compounds of the invention have the general structure shown in Formula (IV), Formula (IV.1), Formula (IV.1 -A), Formula (IV.2), Formula (IV.2-A), Formula (IV.3), or Formula (IV.3-A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof, wherein:

R ¹² is -OH, R ¹³ is alkyl, and each R ^9A is independently selected from -OH and alkyl.

In one embodiment, each variable shown in the various formulas is selected independently of the other.

In another embodiment, 1 to 3 carbon atoms of the compounds of the invention may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.

In another embodiment, the compounds of the invention have a structure shown in the Table 1 below and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers thereof. IC ₅₀ values for the compounds according to the invention that were measured were obtained according to the procedures described below. For example, compound 1 in Table 1 exhibited an IC ₅₀ value of 260 nM. The IC ₅₀ values indicated in Table 1 correspond to the following ranges:

A: about 0.055 nM to about 1.0 nM;

B: about 1.0 nM to about 50 nM;

C: about 50 nM to about 300 nM;

D: about 300 nM to about 600 nM;

E: about 600 nM to about 10 μM;

F: >10 μM. Table 1 :

In another embodiment, the invention provides a composition comprising at least one compound of the invention, or a tautomer or isomer thereof, or salt or solvate of said compound or said tautomer, and a suitable carrier or diluent. In another embodiment, the invention provides a pharmaceutical composition comprising at least one compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a pharmaceutical composition comprising at least one solvate of a compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent,

In another embodiment, the invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable salt of a compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a pharmaceutical composition comprising at least one tautomer of a compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a pharmaceutical composition comprising at least one compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or diluent.

Non-limiting examples of additional therapeutic agents for use in combination with the compounds of the invention include drugs selected from the group consisting of: 5-fluorouracil/ leucovorin, irinotecan, oxaliplatin, bevacizumab, and/or cetuximab (for the treatment of, e.g., colorectal cancer); doxorubicin, paclitaxel, docetaxel, capecitabine, gemcitabine, trastuzumab, anastrozole, and/or tamoxifen (for the treatment of, e.g., breast cancer); paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, etoposide, vinblastine, bevacizumab, and/or erlotinib (for the treatment of, e.g., lung cancers); carboplatin, cisplatin, docetaxel, and/or etoposide (for the treatment of, e.g., prostate cancer); temozolomide (for the treatment of, e.g., GBM (glioblastomas); doxorubicin, docetaxel, paclitaxel, gemcitabine, carboplatin, cisplatin, camptothecin, and/or cyclophosphamide (for the treatment of, e.g., ovarian cancer); smooth muscle cell proliferation inhibitors, angiogenesis inhibitors, and mTOR inhibitors such as deforolimus (ARIAD Pharmaceuticals Inc.) (for the treatment of, e.g., non-small-cell lung cancer, endometroid carcinoma, sarcoma, prostate tumor, and/or breast tumor), and gemcitabine (for the treatment of, e.g., pancreatic cancer). In some embodiments, the treatment is performed in further combination with a Chk1 inhibitor. Examples of suitable Chk1 inhibitors are known to those of ordinary skill in the art. In another embodiment, the compounds of the invention may be combined with one or more antibodies designed to deliver a compound of the invention to target cells or tissues.

In another embodiment, the invention provides a compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, in pure form.

In another embodiment, the invention provides a compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, in isolated form.

In another embodiment, the invention provides a compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, in pure and isolated form.

Esters and prodrugs of the compounds of the invention, or tautomers or isomers thereof, or pharmaceutically acceptable salts or solvates of said compounds or said tautomers, are also contemplated as being included within the scope of the invention, and are described more fully below.

In another embodiment, the invention provides a method of preparing a pharmaceutical composition comprising the step of admixing at least one compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a method of inhibiting aberrant cell proliferation comprising exposing a population of aberrantly proliferating cells to an amount (e.g., an effective amount) of at least one compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer.

In another embodiment, the invention provides a method of inducing apoptosis comprising exposing a population of cells to an amount (e.g., an effective amount) of at least one compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer.

In another embodiment, the invention provides a method of treating or preventing cancer in a patient in need thereof comprising administering to said patient an amount (e.g., an effective amount) of at least one compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer. Non-limiting examples of cancers include: breast cancer, skin cancer (e.g., melanoma), lung cancer (e.g., non- small cell lung cancer and small cell lung cancer), colon cancer (colorectal cancer), stomach cancer (gastric cancer), prostate cancer, kidney (renal) cancer, liver (hepatic) cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, brain cancers, bone sarcomas, soft tissue sarcomas, multiple myeloma, leukemias, and lymphomas (e.g., AML (acute myelogenous

(myeloid) leukemia), CML (chronic myelogenous (myeloid), Hodgkins Disease, and Non-Hodgkin's lymphoma).

In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is skin cancer. In one embodiment, the skin cancer is melanoma. In one embodiment, the cancer is lung cancer. In one embodiment, the lung cancer is non-small cell lung cancer. In one embodiment, the lung cancer is small cell lung cancer. In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is stomach cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is head and neck cancer. In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is brain cancer. In one embodiment, the cancer is a bone sarcoma. In one embodiment, the cancer is a soft tissue sarcoma. In one embodiment, the cancer is multiple myeloma. In one embodiment, the cancer is a leukemia. In one embodiment, the cancer is a lymphoma. In one embodiment, the cancer is AML (acute myelogenous (myeloid) leukemia). In one embodiment, the cancer is CML (chronic myelogenous (myeloid) leukemia). In one embodiment, the cancer is Hodgkins Disease. In one embodiment, the cancer is Non-Hodgkin's lymphoma.

In one embodiment, the various cancers described herein are treated by administration of at least one compound of the invention in combination with at least one additional active ingredient. Agents suitable for use in combination with at least one compound of the invention are known to those of ordinary skill in the art. Selection of such agents will depend on the indication being treated and determined by the attending physician, clinician, researcher, or other practitioner. Non-limiting examples of such additional active agents are provided for explanatory purposes only and include: 5-fluorouracil/ leucovorin, irinotecan, oxaliplatin, bevacizumab, and/or cetuximab (for the treatment of, e.g., colorectal cancer); doxorubicin, paclitaxel, docetaxel, capecitabine, gemcitabine, trastuzumab, anastrozole, and/or tamoxifen (for the treatment of, e.g., breast cancer); paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, etoposide, vinblastine, bevacizumab, and/or erlotinib (for the treatment of, e.g., lung

cancers); carboplatin, cisplatin, docetaxel, and etoposide (for the treatment of, e.g., prostate cancer); temozolomide (for the treatment of, e.g., GBM (glioblastomas); doxorubicin, docetaxel, paclitaxel, gemcitabine, carboplatin, cisplatin, camptothecin, and/or cyclophosphamide (for the treatment of, e.g., ovarian cancer); and gemcitabine (for the treatment of, e.g., pancreatic cancer). In some embodiments, the treatment is performed in further combination with a Chk1 inhibitor. Examples of suitable Chk1 inhibitors are known to those of ordinary skill in the art.

In one embodiment, the invention provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of the invention in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient, the combined quantities of the compound of formula I and the other pharmaceutically active ingredient being effective for the intended use(s), such as those described herein.

In various embodiments, the invention provides any one of the methods disclosed above and below wherein the compound is selected from the group consisting of the exemplary compounds of the invention described herein, such as in Table 1.

In various embodiments, the invention provides any one of the pharmaceutical compositions disclosed above and below wherein the compound is selected from the group consisting of the exemplary compounds of the invention described below. Other embodiments of this invention are directed to any one of the embodiments above or below that are directed to compounds of Formula I, or the use of compounds of Formula I (e.g. the embodiments directed to methods of treatment, pharmaceutical compositions and kits).

In another embodiment, the invention provides for the use of a compound of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, in the manufacture of a medicament for use in the treatment or prevention of one or more cancers, as described herein.

In another embodiment, the invention provides a kit comprising: (a) one or more compounds of the invention, or a tautomer or isomer thereof, or pharmaceutically acceptable salt or solvate of said compound or said tautomer, preferably provided as a pharmaceutical composition and in a suitable container or containers and/or with suitable packaging; (b) optionally one or more additional active agents, which if present are preferably provided as a pharmaceutical composition and in a suitable container or containers and/or with suitable packaging; and (c) instructions for use, for example written instructions on how to administer the compound or compositions. DEFINITIONS

The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe that same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl", "haloalkyl", arylalkyl-, alkylaryl-, "alkoxy" etc. "At least one" means one or more than one, for example, 1 , 2, or 3, or in another example, 1 or 2, or in another example 1.

"One or more" means one or more than one, for example, 1 , 2, or 3, or in another example, 1 or 2, or in another example 1.

"Patient" includes both human and non-human animals. Non-human animals include those research animals and companion animals such as mice, primates, monkeys, great apes, canine (e.g., dogs), and feline (e.g., house cats).

"Pharmaceutical composition" (or "pharmaceutically acceptable composition") means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the invention or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, or they may contain one or more pharmaceutically acceptable carriers or diluents. The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the

present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.

"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being as described herein or independently selected from the group consisting of halo, alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) ₂ , -O-C(O)-alkyl, -O-C(O)-aryl, -O- C(O)-cycloalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

"Haloalkyl" means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.

"Heteroalkyl" means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl radical. Suitable such heteroatoms include O, S, S(O), S(O) ₂ , and -NH-, -N(alkyl)-. Non-limiting examples include ethers, thioethers, amines,

hydroxymethyl, 3-hydroxypropyl, 1 ,2-dihydroxyethyl, 2-methoxyethyl, 2- aminoethyl, 2-dimethyiaminoethyi, and the like.

"Alkenyi" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyi groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyi chain. "Lower alkenyi" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyi" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyi groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. More generally, the suffix "ene" on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety, e.g., -CH ₂ CH ₂ - is

ethylene, and ^ ^~ \J ^~ \ is para-phenylene.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

o

"Alkenylene" means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include -CH=CH-, -C(CH ₃ )=CH-, and -CH=CHCH ₂ -.

"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non- limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.

Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. Further non-limiting examples of cycloalkyl include the following:

"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may

be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. "Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term "oxide," when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S- oxide, or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such =0 groups may be referred to herein as "oxo." An example of such a moiety is pyrrolidinone (or pyrrolidone):

"Heterocycloalkenyl" (or "heterocyclenyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms,

preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon- carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Example of such moiety is pyrrolidenone (or pyrrolone):

It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

there is no -OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms of the compounds of the invention are also contemplated as being within the scope of the invention. Thus, for example, the formulas:

and are considered equivalent in the various compounds of the invention.

"Arylcycloalkyl" (or "arylfused cycloalkyl") means a group derived from a fused aryl and cycloalkyl as defined herein. Preferred arylcycloalkyls are those wherein aryl is phenyl (which may be referred to as "benzofused") and cycloalkyl consists of about 5 to about 6 ring atoms. The arylcycloalkyl can be optionally substituted as described herein. Non-limiting examples of suitable arylcycloalkyls include indanyl (a benzofused cycloalkyl) and 1 ,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moiety is through a non-aromatic carbon atom.

"Arylheterocycloalkyl" (or "arylfused heterocycloalkyl") means a group derived from a fused aryl and heterocycloalkyl as defined herein. Preferred arylheterocycloalkyls are those wherein aryl is phenyl (which may be referred to as "benzofused") and heterocycloalkyl consists of about 5 to about 6 ring atoms. The arylheterocycloalkyl can be optionally substituted, and/or contain the oxide or oxo, as described herein. Non-limiting examples of suitable arylfused heterocycloalkyls include:

The bond to the parent moiety is through a non-aromatic carbon atom.

It is also understood that the terms "arylfused aryl", "arylfused cycloalkyl", "arylfused cycloalkenyl", "arylfused heterocycloalkyl", arylfused heterocycloalkenyl", "arylfused heteroaryl", "cycloalkylfused aryl", "cycloalkylfused cycloalkyl", "cycloalkylfused cycloalkenyl", "cycloalkylfused heterocycloalkyl", "cycloalkylfused heterocycloalkenyl", "cycloalkylfused heteroaryl, "cycloalkenylfused aryl", "cycloalkenylfused cycloalkyl", "cycloalkenylfused

cycloalkenyl", "cycloalkenylfused heterocycloalkyl", "cycloalkenylfused heterocycloalkenyl", "cycloalkenylfused heteroaryl", "heterocycloalkylfused aryl", "heterocycloalkylfused cycloalkyl", "heterocycloalkylfused cycloalkenyl", "heterocycloalkylfused heterocycloalkyl", "heterocycloalkylfused heterocycloalkenyl", "heterocycloalkylfused heteroaryl", "heterocycloalkenylfused aryl", "heterocycloalkenylfused cycloalkyl", "heterocycloalkenylfused cycloalkenyl", "heterocycloalkenylfused heterocycloalkyl", "heterocycloalkenylfused heterocycloalkenyl", "heterocycloalkenylfused heteroaryl", "heteroarylfused aryl", "heteroarylfused cycloalkyl", "heteroarylfused cycloalkenyl", "heteroarylfused heterocycloalkyl", "heteroarylfused heterocycloalkenyl", and "heteroarylfused heteroaryl" are similarly represented by the combination of the groups aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl, as previously described. Any such groups may be unsubstituted or substituted with one or more ring system substituents at any available position as described herein.

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. The term (and similar terms) may be written as "arylalkyl-" to indicate the point of attachment to the parent moiety.

Similarly, "heteroarylalkyl", "cycloalkylalkyl", "cycloalkenylalkyl", "heterocycloalkylalkyl", "heterocycloalkenylalkyl", etc., mean a heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, etc. as described herein bound to a parent moiety through an alkyl group. Preferred groups contain a lower alkyl group. Such alkyl groups may be straight or branched, unsubstituted and/or substituted as described herein.

Similarly, "arylfused arylalkyl-", arylfused cycloalkylalkyl-, etc., means an arylfused aryl group, arylfused cycloalkyl group, etc. linked to a parent moiety through an alkyl group. Preferred groups contain a lower alkyl group. Such alkyl groups may be straight or branched, unsubstituted and/or substituted as described herein.

"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-

limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

"Cycloalkylether" means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom. "Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl, adamantylpropyl, and the like.

"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like. ηeteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.

"Heterocyclylalkyl" (or "heterocycloalkylalkyl") means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.

"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.

"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridy I methyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Cyanoalkyl" means a NC-alkyl- group in which alkyl is as previously defined. Preferred cyanoalkyls contain lower alkyl. Non-limiting examples of suitable cyanoalkyl groups include cyanomethyl and 2-cyanoethyl.

"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1 - naphthoyl.

"Heteroaroyl" means an heteroaryl-C(O)- group in which the heteroaryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include pyridoyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, π-propoxy, isopropoxy and π-butoxy. The bond to the parent moiety is through the ether oxygen.

"Alkyoxyalkyl" means a group derived from an alkoxy and alkyl as defined herein. The bond to the parent moiety is through the alkyl.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

"Aralkyloxy" (or "arylalkyloxy") means an aralkyl-O- group (an arylaklyl-O- group) in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2- naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen. "Arylalkenyl" means a group derived from an aryl and alkenyl as defined herein. Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms. The arylalkenyl can be optionally substituted by one or more substituents. The bond to the parent moiety is through a non-aromatic carbon atom.

"Arylalkynyl" means a group derived from a aryl and alkenyl as defined herein. Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more substituents. The bond to the parent moiety is through a non-aromatic carbon atom.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Alkylsulfonyl" means an alkyl-S(O ₂ )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

"Arylsulfonyl" means an aryl-S(O ₂ )- group. The bond to the parent moiety is through the sulfonyl.

"Spriocycloalkyl" means a cycloalkyl group attached to a parent moiety at a single carbon atom. Non-limiting examples of spirocycloalkyl wherein the parent moiety is a cycloalkyl include spiro [2.5] octane, spiro [2.4] heptane, etc. The alkyl moiety linking fused ring systems (such as the alkyl moiety in heteroarylfused heteroarylalkyl-) may optionally be substituted with spirocycloalkyl or other groups as described herein. Non-limiting spirocycloalkyl

groups include spirocyclopropyl, spriorcyclobutyl, spirocycloheptyl, and spirocyclohexyl.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylfused cycloalkylalkyl- moiety or the like includes substitution on any ring portion and/or on the alkyl portion of the group.

When a variable appears more than once in a group, e.g., R ⁸ in -N(R ⁸ ) ₂ , or a variable appears more than once in a structure presented herein such as Formula (I), the variables can be the same or different. With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art. With respect to the compositions and methods comprising the use of "at least one compound of the invention, e.g., of Formula (I)," one to three compounds of the invention, e.g., of Formula (I) can be administered at the same time, preferably one.

Compounds of the invention may contain one or more rings having one or more ring system substituents. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being as described herein or independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,

heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -0-C(O)- alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(=N-CN)-NH ₂ , -C(=NH)-NH ₂ , -C(=NH)- NH(alkyl), YiY ₂ N-, YiY ₂ N-alkyl-, Y ₁ Y ₂ NC(O)-, Y ₁ Y ₂ NSO ₂ - and -SO ₂ NY ₁ Y ₂ , wherein Y ₁ and Y ₂ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moieties are rings such as heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl rings. Additional non-limiting examples include methylene dioxy, ethylenedioxy, - C(CH ₃ ) ₂ - and the like which form moieties such as, for example:

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The line — ,as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example:

means containing both and

The wavy line '^-^^ , as used herein, indicates a point of attachment to the rest of the compound. For example, each wavy line in the following structure:

indicates a point of attachment to the core structure, as described herein.

Lines drawn into the ring systems, such as, for example: indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.

"Oxo" is defined as a oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system.

It is noted that the carbon atoms for compounds of the invention may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

represents

The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the

like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene θt al, Protective Groups in organic Synthesis (1991), Wiley, New York.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery 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.

For example, if a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound 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, for example, (Ci-

C ₈ )alkyl, (C ₂ -Ci ₂ )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl 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)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC ₂ )alkylamino(C ₂ -C ₃ )alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C ₂ )alkyl, N,N-di (Cr C ₂ )alkylcarbamoyl-(C1 -C2)alkyl and piperidino-, pyrrolidino- or morpholino(C ₂ - C ₃ )alkyl, and the like.

Similarly, if a compound of the invention contains 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, for example, (C-ι-C ₆ )alkanoyloxymethyl, 1 - ((C _r C ₆ )alkanoyloxy)ethyl, 1-methyl-1-((Ci-C ₆ )alkanoyloxy)ethyl, (Cr

C ₆ )alkoxycarbonyloxymethyl, N-(Ci-C ₆ )alkoxycarbonylaminomethyl, succinoyl, (Ci-C ₆ )a!kanoyl, α-amino(CrC ₄ )aikanyl, arylacyl and α-aminoacyl, or α- aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) ₂ , -P(O)(O(Ci -C ₆ )alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of the invention incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-Ci _O )alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, — C(OH)C(O)OY ¹ wherein Y ¹ is H, (d-C ₆ )alkyl or benzyl, -C(O Y ² ) Y ³ wherein Y ² is (CrC ₄ ) alkyl and Y ³ is (C _r C ₆ )alkyl, carboxy (CrC ₆ )alkyl, amino(Ci-C ₄ )alkyl or mono-N— or di-N,N-(CrC ₆ )alkylaminoalkyl, -C(Y ⁴ ) Y ⁵ wherein Y ⁴ is H or methyl and Y ⁵ is mono-N — or di-N,N-(Ci-C ₆ )alkylamino morpholino, piperidin-1 -yl or pyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated

and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H ₂ O. One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5£1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001 ). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of the invention can form salts which are also within the scope of this invention. Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be

formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1 -19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are

considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci- ₄ alkyl, or Ci- ₄ alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L- isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (Cβ- ₂₄ )acyl glycerol. Compounds of the invention, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure

enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.). Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and

chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ CI, respectively.

Certain isotopically-labelled compounds of the invention (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labelled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

Polymorphic forms of the compounds of the invention, and of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention.

Suitable doses for administering compounds of the invention to patients may readily be determined by those skilled in the art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency of administration, use with other active ingredients, and/or indication for which the compounds are administered. Doses may range from about 0.001 to 500 mg/kg of body weight/day of the compound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of a compound of the invention, or a pharmaceutically acceptable salt or solvate of said compound. In another embodiment, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. In another embodiment, a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses. As discussed above, the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering

such factors as age, condition and size of the patient as well as severity of the symptoms being treated.

When used in combination with one or more additional therapeutic agents, the compounds of this invention may be administered together or sequentially. When administered sequentially, compounds of the invention may be administered before or after the one or more additional therapeutic agents, as determined by those skilled in the art or patient preference.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.

Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described above. The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. Certain assays are exemplified elsewhere in this document.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.

Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's

Pharmaceutical Sciences, 18 ^th Edition, (1990), Mack Publishing Co., Easton,

Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions.

As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

The compounds of this invention may also be delivered subcutaneously.

In one embodiment, the compound is administered orally.

In some embodiments, it may be advantageous for the pharmaceutical preparation compring one or more compounds of the invention be prepared in a unit dosage form. In such forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

PREPARATIVE EXAMPLES

Compounds of the invention can be made using procedures known in the art. The following reaction schemes show typical procedures, but those skilled in the art will recognize that other procedures can also be suitable.

Experimental Procedures

To a solution of compound 6 (22g, 91.4 mmol) in DCM (200 ml) was added pyridine (22 ml) and the resulted solution was cooled to 0 ⁰ C. Tf ₂ O (23 ml, 137 mmol) was added dropwise and the reaction was allowed to stir at 0 ⁰ C overnight. The reaction mixture was diluted with DCM (200 ml) and washed with aq. NH ₄ CI (200 ml), NaHCOs and brine sequentially. After being dried over NaSO ₄ and concentration, the residue was purified by FC (silica gel,

EtOAc/Hexane, 1/10) to give phenol triflate 6a (34 g, 91.3 mmol, 99%). ¹ HNMR (CDCI ₃ ) δ 6.45 (S ₁ 1 H), 4.34 (q, J = 7.0 Hz, 2H) ₁ 3.89 (s, 3H) ₁ 3.87 (s, 3H), 2.15 (s, 3H) ₁ 1.36 (t, J = 7.0 Hz, 2H); MS (ES) calculated for Ci ₂ H ₁₂ F ₃ O ₆ S [M + H] ⁺ 341.03, found 341.03.

6a 6b

To a solution of compound 6a (34 g, 91.3 mmol) in degassed anhydrous THF (500 ml) were added Pd(PPh ₃ ) ₄ (4 g, 3.5 mmol), LiCI (12 g, 274 mmol) , and then allyltributyltin (43 ml, 137 mmol). The reaction was heated to reflux under N ₂ and allowed to stir at reflux condition overnight. After the reaction was cooled to room temperature, it was diluted with EtOAc (300 ml). The reaction mixture was filtered off a celite pad, washed with EtOAc and the organic solution combined. After washing with 10% aq. NH ₄ OH (200 ml), brine (200 ml), and dried over MgSO ₄ , it was concentrated and purified by FC (silica gel, EtOAc/Hexane 1/20 to 1/10) to afford compound 6b (22.8 g, 95%). ¹ HNMR (CDCI ₃ ) δ 6.37 (s, 1 H) ₁ 5.89-5.82 (m, 1 H), 5.02-4.93 (m, 2H), 4.35 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.35 (dd, J = 1.5, 1.5 Hz, 1 H), 3.34 (dd, J = 1.5, 1.5 Hz, 1 H), 2.08 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H); ¹³ C NMR (CDCI ₃ ) δ 159.4, 155.7, 137.0, 135.7, 118.0, 117.4, 115.9, 93.9, 61.2, 56.3, 55.9, 35.2, 14.5, 11.0; MS (ES) calculated for Ci ₅ H ₂ iO ₄ [M + H] ⁺ 265.14, found 265.32.

To a solution of compound 6b (12.26 g, 46 mmol) in anhydrous

DCM (150 ml) was added BBr ₃ (200 ml, 1.0 M in DCM, 200 mmol) at -78 ⁰ C. The reaction mixture was allowed to stir at -78 ⁰ C for 30 minutes and the acetone ice bath was changed to ice bath. The reaction was further stirred at 0 ⁰ C for 3-4 h, and additional 45 minutes at rt. The reaction was cooled to 0 ⁰ C before water (100 ml) was added. It was extracted with EtOAc (300 ml) and washed with water. Organic layer was dried and concentrated, the residue was purified by FC (acetone/Hexane 1/10) to give the phenol 6c ( 9.2 g, 39 mmol, 85 %) as a brown solid. ¹ HNMR (CDCI ₃ ) δ 11.5 (s, 1 H), 6.34 (s, 1 H), 5.97-5.89 (m, 1 H), 5.84 (s, 1 H), 5.03-4.99 (m, 1 H), 4.90-4.86 (m, 1 H), 4.38 (q, J = 7.5 Hz, 2H), 3.72 (dd, J =

1.5, 1.5 Hz, 1 H), 3.71 (dd, J = 1.5, 1.5 Hz, 1 H), 2.11 (s, 3H), 1.38 (t, J = 7.5 Hz, 3H); ¹³ C NMR (CDCi ₃ ) δ 171.7, 162.1 , 159.2, 142.3, 136.6, 1 15.1 , 101.8, 61.7, 35.8, 14.3, 11.1.

6C 7

To a solution of compound 6c (7 g, 29.6 mmol) in DCM (150 ml) was added 2, 6-lutidine (14 ml, 120 mmol)) at 0 ⁰ C. After stirring for 5 minutes at 0 ⁰ C, TIPSOTf (24 ml, 90 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 2h. After the reaction is complete judged by TLC, it was diluted with EtOAc (300 ml). The organic layer was washed with NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The residue was purified by FC (EtOAc/Hexane 1/10) to give product 7 ( 15.4 g, 95%) as a oil: ¹ HNMR (CDCI ₃ ) δ 6.25 (s, 1 H), 5.90-5.82 (m, 1 H), 5.01 -4.91 (m, 2H), 4.28 (q, J = 7.5 Hz, 2H), 3.31 (dd, J = 1.5, 1.5 Hz, 1 H), 3.30 (dd, J = 1.5, 1.5 Hz, 1 H), 2.09 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H), 1.30-1.21 (m, 6H), 1.11-1.05 (m, 36 H); ¹³ C NMR (CDCI ₃ ) δ 169.3, 155.4, 151.1 , 136.8, 135.9, 120.7, 120.4, 115.6, 107.3, 61.0, 35.5, 18.2, 18.1 , 14.4, 13.4, 13.2, 11.9; MS (ES) calculated for C ₃₁ H ₅₇ O ₄ Si ₂ [M + H] ⁺ 549.38, found 549.36.

To a solution of 7 (15.4 g, 28.4 mmol) in THF/H ₂ O (100/20 ml) were added NMO (7 g, 60 mmol) and OsO4 (18 ml, 2.5% wt in f-BuOH, 1.5 mmol) at 0 ⁰ C. After stirring at ambient temperature for 12 h, 10% Na ₂ S ₂ O ₃ solution (50 ml) was added and mixture was further stirred for 5 h. It was then extracted with EtOAc (250 ml) and the combined organic extracts were washed with water and dried over MgSO ₄ . After concentration, the residue obtained was filtered through a short silica gel column and washed with EtOAc. Removal of the solvent gave the crude diol. NaIO ₄ (19.2 g, 90 mmol) was added to a solution of crude diol in 90% MeOH/H ₂ O (120 ml). After stirring at room temperature for 1 h, EtOAc (300 ml) was added and the reaction mixture was washed with water and dried over

MgSO ₄ . After concentration the residue was purified by FC (silica gel) to give the aldehyde 7a (13.7 g, 88%) as a syrup: ¹ HNMR (CDCI ₃ ) δ 9.60 (t, J = 2.5 Hz, 1 H), 6.33 (s, 1 H), 4.29 (q, J = 7.5 Hz, 2H), 3.59 (d, J = 2.0 Hz, 2H), 2.07 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H), 1.29-1.22 (m, 6H), 1.11-1.05 (m, 36 H); ¹³ C NMR (CDCI ₃ ) δ 199.4, 168.8, 156.0, 151.9, 130.3, 121.3, 120.9, 108.6, 61.4, 46.3, 18.2, 18.1 , 17.9, 14.4, 13.4, 13.2, 12.5.

To a suspension of predried KO ¹ Bu (6.5 g, 58 mmol) in THF (100 ml) at -78 ⁰ C was added cis-2-butene (15 ml). At -78 ⁰ C n-Butyl lithium (36 ml, 1.6 M in Hexane, 58 mmol) was added slowly over a period of 10 minutes. The resulting yellow reaction mixture was warmed to -46 ⁰ C for 30 minutes and then cooled to -78 ⁰ C and (-)-methoxydiisopinocamphenyl borane (18.3 g, 58 mmol) in THF (30 ml) was added drop wise. The reaction mixture was stirred for 30 minutes at -78 ⁰ C. Freshly distilled BF ₃ OEt (7.4 ml, 58 mmol) was added to the reaction mixture at -78 ⁰ C followed by addition of aldehyde 7a (8 g, 14.8 mmol). The reaction was stirred at -78 ⁰ C for 6 h. The reaction misture was poured into pH 7 buffer (100 ml) at -78 ⁰ C and then 30 % H ₂ O ₂ (20 ml) was added. The reaction mixture was put in an ice bath and it was further stirred from 0 ⁰ C to room temperature overnight. The reaction mixture was extracted with EtOAc. The organic layers combined, washed with saturated Na ₂ SO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting crude oil was purified by FC (silica gel; hexane to 2% EtOAc/hexane) to afford 8 (8 g, 89%) as a single diastereomer by NMR. Enantioselectivity was determined by HPLC using a Chiralcel OD-H column with 1% isopropanol in hexane and a flow rate of 1 ml/min. [α] ²⁰ _D + 36.5 (c = 0.1 , DCM)- ¹ HNMR (CDCI ₃ ) δ 6.25 (s, 1 H), 5.92-5.85 (m, 1 H), 5.12-5.05 (m, 2H), 4.43-4.36 (m, 1 H), 4.26-4.20 (m, 1 H), 3.63 (br, 1 H), 3.17 (d, J = 6.0 Hz, 1 H), 2.93 (dd, J = 2.5, 14.0 Hz, 1 H), 2.41 (dd, J = 11.0, 14.5 Hz, 1 H), 2.34-2.31 (m, 1 H), 2.12 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.31- 1.18 (m, 6H), 1.13-1.06 (m, 36 H); ¹³ C NMR (CDCI ₃ ) δ 170.9, 156.0, 151.4, 141.2, 137.1 , 120.6, 120.4, 115.0, 107.4, 74.3, 61.8, 45.3, 36.1 , 18.2, 18.1 , 15.6,

14.4, 13.4, 13.3, 12.5; MS (ES) calculated for C ₃₄ H ₆₃ O ₅ Si ₂ [M + H] ⁺ : 607.42, found 607.38; C ₃₄ H ₆₂ NaO ₅ Si ₂ [M + Na] ⁺ : 629.40, found 629.34.

8 8a To a solution of compound 8 (6 g, 9.88 mmol) in DCM was added amberlyst resin (1 g). The reaction mixture was allowed to stir at room temperature for 2 h. The resin was filtered off and the filtrate concentrated. The residue was purified by FC to give a the desired product 8a (5.54 g, 99%) as oil. [α] ²⁰ D + 35.65 (c = 1.0, DCM). ¹ HNMR (CDCI ₃ ) δ 6.30 (s, 1 H), 5.85-5.78 (m, 1 H), 5.14-5.10 (m, 2H), 4.11 -4.07 (m, 1 H), 2.85 (dd, J = 2.5, 16.5 Hz, 1 H), 2.62 (dd, J = 11.0, 16.0 Hz, 1 H), 2.55 (q, J = 6.5 Hz, 1 H), 2.06 (s, 3H), 1.35-1.26 (m, 6H), 1.19 (d, J = 6.5 Hz, 3H), 1.12-1.09 (m, 36H); ¹³ C NMR (CDCI ₃ ) δ 163.1 , 159.0, 157.7, 141.0, 139.5, 118.3, 116.2, 110.1 , 109.8, 79.7, 42.3, 29.6, 18.2, 16.0, 13.5, 13.3, 11.9; MS (ES) calculated for C ₃₂ H ₅₇ O ₄ Si ₂ [M + H] ⁺ : 561.38, found 561.30.

To a solution of 8a (969 mg, 1.73 mmol) in THRH ₂ O (10/1 ml) were added NMO (405 mg, 3.46 mmol) and OsO ₄ (2 ml, 2.5 % wt in ¹ BuOH, 0.173 mmol) at 0 ⁰ C. After stirring at ambient temperature for 12 h, 10% Na ₂ S ₂ O ₃ (25 ml) solution was added. After 5 h, the crude was extracted with EtOAc and the combined organic extracts were washed with water and dried over MgSO ₄ . After concentration, the residue obtained was filtered through a short silica gel column and washed with EtOAc. Removal of the solvent gave the crude diol. NaIO ₄ (1.11 g, 5.19 mmol), was added to a solution of crude diol in 90% MeOH/H ₂ O (16 ml). After stirring at room temperature for 1 h, EtOAc was added and the reaction mixture was washed with water and dried over MgSO ₄ . after concentration, the residue was purified by FC (silica gel) to give the aldehyde 5 (876.6 mg, 90%) as a syrup. [α] ²⁰ _D + 58.40 (c = 1.0, DCM). ¹ HNMR (CDCI ₃ ) δ 9.83 (s, 1 H), 6.31 (s, 1 H), 4.66-4.61 (m, 1 H), 4.12-4.08 (m, 1 H), 2.91 (dd, J = 3.0, 16.0 Hz, 1 H), 2.79- 2.69 (m, 2H), 2.07 (s, 3H), 1.33-1.27 (m, 9H), 1.13-1.10 (m, 36 H); ¹³ C NMR

(CDCI ₃ ) δ 202.7, 162.4, 159.3, 158.1 , 140.3, 1 18.3, 109.9, 109.5, 75.7, 60.6, 50.0, 29.8, 21.2, 18.2, 18.1 , 14.4, 13.5, 13.4, 12.0, 9.4; MS (ES) calculated for C ₃ IH ₅₅ O ₅ Si ₂ [M + H] ⁺ : 563.36, found 563.44.

To a solution of ligand 13 (2.12 g, 5.4 mmol) in propylnitrile (40 ml) was added BH ₃ THF complex (5.4 ml, 5.4 mmol) at rt and the mixture was stirred at 45 ⁰ C for 1 h before cooled to -78 ⁰ C. Ketene acetal 10 (7.71 g, 41 mmol) was then added at -78 ⁰ C, followed by the addition of aldehyde 9 (4.43 g, 27 mmol) as a solution in propylnitrile (10 ml) over 4 h via syringe pump. The reaction was stirred for another 2 h before quenched with pH 7 buffer (50 ml). The reaction mixture was warmed to room temperature and diluted with EtOAc, the organic solution was washed with NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The residue was purified by FC to give a mixture of TMS protected hydroxyl ester and free hydroxyl ester. The TMS protected product was treated with 2.0 M HCI/Et ₂ O (2.0 eq.) at 0 ⁰ C for 1 h at room temperature. The reaction was directly concentrated and purified by FC to give 10a (combined 7.16 g, 95%): [α] ²⁰ _D + 15.95 (c = 0.5, DCM). ¹ HNMR (CDCI ₃ ) δ 7.34-7.26 (m, 5H), 4.53 (d, J = 12.0 Hz, 1 H), 4.14 (q, J = 7.0 Hz, 2H), 3.91 -3.89 (m, 1 H), 3.75-3.65 (m, 2H), 3.16 (br, 1 H), 1.75-1.65 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 1.19 (s, 3H), 1.17 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 177.5, 138.2, 128.6, 128.4, 128.0, 127.8, 77.7, 75.5, 73.5, 69.4, 60.7, 47.0, 31.7, 21.8, 20.6, 18.1 , 14.3.

To a solution of methyl isobutyrate 23 (5g, 49 mmol) in THF was added slowly a solution of LDA (52 mmol, generated from n-BuLi and diisopropyl amine) in THF at -78 ⁰ C, the reaction was stirred for 20 minutes. The resulting solution was treated with a solution of Benzyl 3-bromopropyl ether 22 in HMPA and stirred at -78 ⁰ C for 12 h, aq. HCI (1 N) was added and the resulting mixture extracted with ether, Organic layer washed with water, saturated NaHCO ₃ , dried and concentrated, it was purified by to give the desired ester 24 (11.6 g, 80%). ¹ HNMR (CDCI ₃ ) δ 7.36-7.26 (m, 5H), 4.49 (s, 2H), 3.65 (s, 3H), 3.45 (t, J = 6.5

Hz, 2H), 1.62-1.52 (m, 4H), 1.18 (s, 6H); ¹³ C NMR (CDCI ₃ ) δ 178.3, 138.5, 128.3, 127.6, 127.5, 72.8, 70.5, 51.7, 42.0, 37.1 , 25.3, 25.1.

10a 11 To a solution of compound 10a (5.45 g, 19.4 mmol) in DCM (30 ml) was added 2, 6-lutidine 4.66 ml, 40 mmol) at 0 ⁰ C. After stirring for 5 minutes at 0 ⁰ C, TBSOTf (9.18 ml, 40 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 2h. After the reaction is complete judged by TLC, it was diluted with EtOAc. The organic layer was washed with NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The residue was purified by FC (EtOAc/hexane 1/10) to give the TBS protected product 11 (7.56 g, 99%) as a oil. [α] ²⁰ D + 41.85 (c = 1.0, DCM). ¹ HNMR (CDCI ₃ ) δ 7.36-7.26 (m, 5H), 4.48 (dd, J = 12.0, 15.5 Hz, 2H), 4.14-4.03 (m, 3H), 3.55-3.46 (m, 2H), 1.80 (ddt, J = 3.0, 7.5, 14.5 Hz), 1.66 (ddt, J = 5.0, 15.0, 15.5 Hz, 1 H), 1.22 (t, J = 7.5 Hz, 3H), 1.15 (s, 3H), 1.09 (s, 3H), 0,86 (s, 3H) _S 0,03 (s, 3H), 0.01 (s, 3H),; ¹³ C NMR (CDCI ₃ ) δ 177.2, 138.7, 128.5, 127.8, 127.7, 74.0, 73.0, 67.9, 60.6, 48.4, 34.2, 26.2, 22.1 , 20.4, 18.5, 14.3, -3.8, -4.0; MS (ES) calculated for C ₂₂ H ₃₉ O ₄ Si [M + H] ⁺ : 395.26, found 395.24; C ₂₂ H ₃₈ NaO ₄ Si [M + Na] ⁺ : 417.24, found 417.34.

To a solution of compound 11 (7.56 g, 19.2 mmol) in anhydrous pentane (50 ml) was added Trimethylsilyl methyl lithium (58 ml, 58.2 mmol) dropwise at 0 ⁰ C. The mixture was stirred at 0 ⁰ C for 4 h with TLC monitoring (Et ₂ O/Hexane 1/10). After the reaction is complete judged by TLC, to this suspension was added dry methanol (10 ml) and the resulting emulsion was stirred for another 1 h at room temperature. The mixture was diluted with Et ₂ O/water. Aqueous layer was extracted with Et ₂ O, dried over Na ₂ SO ₄ and concentrated. The residue was purified by FC (EtOAc/Hexane 1/10) to give the methyl ketone 4 (5.81 g, 82%) as a oil. [α] ²⁰ _D + 7.45 (c = 1.0, DCM) ¹ HNMR (CDCI ₃ ) δ 7.35-7.27 (m, 5H), 4.49 (d, J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 4.04 (dd, J = 2.5, 7.5 Hz, 1 H), 3.50-3.48 (m, 2H), 2.13 (s, 3H), 1.78-1.72 (m, 1 H), 1.62-1.55 (m, 1 H), 1.10 (s, 3H), 1.06 (s, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.03 (s,

3H); ¹³ C NMR (CDCI ₃ ) δ 213.7, 138.7, 128.6, 127.7, 74.1 , 73.1 , 67.7, 53.5, 34.5, 27.1 , 26.2, 22.1 , 20.3, 18.5, -3.8; MS (ES) calculated for C ₂ IH ₃₇ O ₃ Si [M + H] ⁺ : 365.25, found 365.36; C ₂ i H ₃₆ NaO ₃ Si [M + Na] ⁺ : 387.23, found 387.09.

To a solution of compound 24 (5 g, 18.9 mmol) in anhydrous pentane (50 ml) was added Trimethylsilyl methyl lithium (58 ml, 58.2 mmol) dropwise at O ⁰ C. The mixture was stirred at O ⁰ C for 4 h with TLC monitoring (Et ₂ O/Hexane 1/10). After the reaction is complete judged by TLC, to this suspension was added dry methanol (10 ml) and the resulting emulsion was stirred for another 1 h at room temperature. The mixture was diluted with Et ₂ O/water. Aqueous layer was extracted with Et ₂ O, dried over Na ₂ SO ₄ and concentrated. The residue was purified by FC (EtOAc/Hexane 1/10) to give the methyl ketone 25 (5.81 g, 82%). ¹ HNMR (CDCI ₃ ) δ 7.36-7.26 (m, 5H), 4.49 (s, 2H), 3.44 (t, J = 6.5 Hz, 2H), 2.12 (s, 3H), 1.62-1.58 (m, 2H), 1.52-1.46 (m, 2H), 1.12 (s, 6H); ¹³ C NMR (CDCI ₃ ) δ 219.0, 138.9, 128.8, 128.0, 73.3, 71.0, 48.0, 36.8, 25.6, 25.5, 24.7. MS (ES) calculated for Ci ₅ H ₂₃ O ₂ [M + H] ⁺ : 235.17, found 235.34; C ₁₅ H ₂₂ NaO ₂ [M + Na] ⁺ : 257.15, found 257.32.

To a solution of compound 4 (1.34 g, 3.6 mmol) in DCM (15 ml) at 0 ⁰ C was added Et ₃ N (2 ml, 14.4 mmol) and then TMSOTf (1.3 ml, 7.2 mmol). The reaction was allowed to stir at room temaparature for 1 h. The reaction was diluted with hexane, washed with aq. NaHCO ₃ and dried over Na ₂ SO ₄ . The solution was directly passed through a short pad of silica gel plug with EtOAc/Hexane (1/20) washing. The combined organic solution was concentrated to give compound 12 (1.58 g, 100%) as a light yellow oil. The crude 28 was used for the next step without any further purification. ¹ HNMR (CDCI ₃ ) δ 7.33-7.25 (m, 5H), 4.48 (s, 2H), 4.11 (s, 1 H), 3.95 (s, 1 H), 3.87 (dd, J = 3.0, 8.0 Hz, 1 H), 3.55- 3.45 (m, 2H), 1.93-1.86 (m, 1 H), 1.61-1.54 (m, 1 H), 1.02 (s, 3H), 0.94 (s, 3H) ₁ 0.87 (s, 9H), 0.18 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 165.0,

139.0, 128.5, 127.8, 127.6, 88.2, 73.2, 72.9, 68.6, 45.4, 33.8, 26.4, 24.7, 19.8, 18.6, 0.28, -3.8.

To a solution of compound 25 (1.64 g, 7 mmol) in DCM (20 ml) at 0 ⁰ C was added Et ₃ N (3.9 ml, 28 mmol) and then TMSOTf (2.52 ml, 14 mmol). The reaction was allowed to stir at room temaparature for 1 h. The reaction was diluted with hexane, washed with aq. NaHCO ₃ and dried over Na ₂ SO ₄ . The solution was directly passed through a short pad of silica gel plug with

EtOAc/Hexane (1/20) washing. The combined organic solution was concentrated to give compound 26 (2.32 g, 100%) as a light yellow oil. The crude 12 was used for the next step without any further purification.

14 14a

To a solution of compound 14 (8.87 g, 47.2 mmol) in anhydrous THF (150 ml) was added CuI (2.3 g, 11.8 mmol) and the resulting suspension was cooled to - 15 ⁰ C. Vinyl magnesium bromide (180 ml, 0.5 M in THF, 94.4 mmol) was added dropwise through an additional funnel under N ₂ . The reaction was allowed to stir at - 15 ⁰ C for 3 h with TLC monitoring. The reaction was quenched by aq. NH ₄ CI (100 ml) and then diluted with Et ₂ O (200 ml). The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FC (Hexane to EtOAc/Hexane 1/30). to give the alcohol 14a (8.9 g, 82 %) as a oil. ¹ HNMR (CDCI ₃ ) δ 4.83(s, 1 H), 4.78(s, 1 H), 3.83-3.78 (m, 1 H), 3.61 (dd, J = 3.5, 10.0 Hz, 1 H), 3.46 (dd, J = 7.0, 10.0 Hz, 1 H), 2.37 (d, J = 3.5 Hz, 1 H), 2.17 (d, J = 6.5 Hz, 2H), 1.77 (s, 3H), 0.90 (s, 3H), 0.07 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 142.6, 113.1 , 69.8, 67.0, 41.8, 26.1 , 22.8, 18.5, -5.2.

O f*~\ ^OH

14

27

To a solution of compound 14 (5 g, 26.5 mmol) in anhydrous THF (100 ml) was added CuI (1.3 g, 0.25 equiv.) and the resulting suspension was cooled to -15 ⁰ C. Phenyl magnesium Chloride (30 ml, 1.9 M in THF, 53 mmol) was added drop wise under N ₂ . The reaction was allowed to stir at -15 ⁰ C for 3 h with TLC monitoring. The reaction was quenched by aq. NH ₄ CI (100 ml) and then

diluted with Et ₂ O (200 ml). The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FC (Hexane to EtOAc/Hexane 1/30) to give the alcohol 27 (5.8 g, 82 %) as an oil. ¹ HNMR (CDCI ₃ ) δ 7.32-7.21 (m, 5H), 3.89 (m, 1 H), 3.62(dd, J = 4.0, 9.5 Hz, 1 H), 3.49 (dd, J = 6.5, 10.0 Hz, 1 H), 3.82-2.75 (m, 2H), 2.42 (d, J = 4.5 Hz, 1 H), 0.92 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 138.7, 130.1 , 129.9, 129.7, 129.0, 128.9, 126.8, 73.2, 66.7, 40.0, 26.3, 18.7, -4.9.

OH I QMe

,OTBS ^\^^OTBS

14a 15

To a solution of compound 14a (30 g, 130 mmol) in anhydrous DCM (300 ml) was added freshly dried MS 4A (5 g, powder), proton sponge (50 g, 234 mmol) and then Me ₃ OBF ₄ (23g, 156 mmol). The suspension was allowed to stir at room temperature overnight. The reaction mixture diluted with DCM, filtered and the filtrate was washed with water, aq. HCI, NaHCO ₃ , brine. The organic layer was concentrated and the residue was purified by FC (Hexane to Et ₂ O/Hexane 1/20) to give 15 (3Og, 95%) as a volatile oil: ¹ HNMR (CDCI ₃ ) δ 4.80

(s, 1 H), 4.75 (s, 1 H), 3.62 (dd, J = 6.0, 10.5 Hz, 1 H), 3.58 (dd, J = 4.5, 10.5 Hz,

1 H), 3.42 (s, 3H), 3.41 -3.36 (m, 1 H), 2.23 (dd, J = 5.5, 14.5 Hz, 1 H), 2.16 (dd, J =

7.5, 14.5 Hz, 1 H), 1.77 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³ C NMR (CDCI ₃ ) δ

143.0, 1 12.6, 80.6, 65.1 , 58.1 , 40.0, 26.1 , 23.1 , 18.5, -5.1 , -5.2. MS (ES) calculated for C ₁₃ H ₂₉ O ₂ Si [M + H] ⁺ : 245.19, found 245.18.

27 ²⁸

To a solution of compound 27 (5 g, 18.7 mmol) in anhydrous DCM (100 ml) was added freshly dried MS 4A (3 g, powder), proton sponge (8 g, 37.6 mmol) and then Me ₃ OBF ₄ (4.2 g, 28 mmol). The suspension was allowed to stir at room temperature overnight. The reaction mixture diluted with DCM, filtered and the filtrate was washed with water, aq. HCI, NaHCO ₃ , brine. The organic layer was concentrated and the residue was purified by FC (Hexane to Et ₂ O/Hexane 1/20) to give 28 (5 g, 95%) as an oil. ¹ HNMR (CDCI ₃ ) δ 7.30-7.19 (m, 5H), 3.61 (dd, J = 5.5, 10.5 Hz, 1 H), 3.58 (dd, J = 5.0, 10.5 Hz, 1 H), 3.43 (m, 1 H), 3.36 (s, 3H), 2.87 (dd, J = 5.5, 14.0 Hz, 1 H), 2.75 (dd, J = 7.0, 14.0 Hz, 1 H),

0.92 (s, 9H) ₁ 0.06 (s, 6H); ¹³ C NMR (CDCI ₃ ) δ 139.4, 129.9, 128.6, 126.6, 83.6, 64.5, 58.4, 38.2, 26.4, 18.7, -4.9.

I OMe ^HC \ OMe

15 15a

A solution of compound 15 (5 g, 20.4 mmol) in THF (50 ml) was treated with BH ₃ THF (22.5 ml, 1.0 M in THF, 22.5 mmol) solution at 0 ⁰ C for 1 h. To this solution was added aq. NaOH (1 N, 100 ml) solution followed immediately by aq. 30 % H ₂ O ₂ (11 ml) . The ice bath was then removed and the mixture was allowed to stir at room temperature for another hour before diluted with EtOAc. The solution was washed with water and brine, dried (MgSO ₄ ) and concentrated. FC (EtOAc/Hexane 1/4) of the residue give compound 15a (4.7 g, 88%) as a pair of diastereomers. ¹ HNMR (CDCI ₃ ) δ 3.68-3.26 (m, 5H, both isomers), 3.43 (s, 3H, isomer I), 3.42 (s, 3H, isomer II), 2.83 (br, 1 H, isomer II), 2.66 (br, 1 H, isomer I), 1.89-1.76 (m, 1 H, both isomers), 1.56-1.36 (m, 2H, both isomers), 0.93 (d, J = 7.0 Hz, 3H, isomer I), 0.90 (d, J = 7.0 Hz, 3H, isomer II), 0.89 (s, 9H, isomer I), 0.88 (s, 9H, isomer II), 0.05 (s, 6H); ¹³ C NMR (CDCI ₃ ) δ 81.1 , 80.0, 68.6, 68.1 , 65.5, 65.0, 58.1 , 57.8, 36.6, 35.7, 33.7, 32.5, 26.0, 18.4, 18.0, 17.7, -5.2, -5.3.

15a 15b

To a solution of compound 15a (1.9 g, 5.2 mmol) in anhydrous DMF (15 ml) was added NaH (380mg, 10 mmol) at 0 ⁰ C, after stirring for 15 minutes, BnBr (1.18 ml, 10 mmol) was added .The reaction was allowed to stir at rt for 2 h. The reaction mixture was quenched by aq NH ₄ CI, extradited with

EtOAc, washed with aq NaHCO ₃ and brine. The organic layer was died (Na ₂ SO ₄ ) and concentrated. The residue was purified by FC (Hexane to Et ₂ O/Hexane 1/20) to give compound 15b (1.68 g, 92%) as a oil. ¹ HNMR (CDCI ₃ ) δ 7.40-7.38 (m,

5H), 4.57 (s, 2H), 3.72-3.30 (m, 5H), 3.48(s, 3H, isomer I), 3.46 (s, 3H, isomer II),

2.10-1.99 (m, 1 H), 1.65-1.56 (m, 1 H), 1.39-1.30 (m, 1 H), 1.06 (d, J = 7.0, 3H, isomer I), 1.04 (d, J = 7.0 Hz, 3H, isomer II), 0.96 (s, 9H), 0.12 (s, 6H); ¹³ C NMR

(CDCI ₃ ) δ 139.0, 128.6, 127.8, 127.7, 127.6, 80.6, 80.0, 76.5, 75.9, 73.2, 73.1 , 66.0, 65.8, 58.4, 58.1 , 36.2, 36.1 , 30.7, 30.3, 26.2, 18.6, 18.5, 17.4, -5.1.

BnO.

15b ^15c

To a solution of compound 15b (1.68 g, 4.77 mmol) in THF (10 ml) was added TBAF (10 ml, 1.0 M in THF) at room temperature. The reaction was allowed to stir at rt overnight before diluted with EtOAc. The mixture was washed with water and brine. The organic layer was died (Na ₂ SO ₄ ) and concentrated.

The residue was purified by FC (Hexane to EtOAc/Hexane 1/5) to give compound 15c ( 1.14 g, 99%) as a oil. ¹ HNMR (CDCI ₃ ) δ 7.36-7.26 (m, 5H), 4.50

(s, 2H), 3.71-3.27 (m, 8H), 2.13-1.19 (m, 3H), 0.98 (d, J = 7.0 Hz, 3H); ¹³ C NMR

(CDCI ₃ ) δ 138.9, 138.8, 128.6, 127.8, 80.2, 79.7, 76.2, 76.0, 73.3, 64.3, 64.1 , 57.4, 57.1 , 35.3, 34.8, 30.6, 30.4, 18.0, 17.9. f^ OMe (^l O ^M e

28 29

To a solution of compound 28 (4.2 g, 15 mmol) in THF (80 ml) was added TBAF (30 ml, 1.0 M in THF) at room temperature. The reaction was allowed to stir at rt overnight before diluted with EtOAc. The mixture was washed with water and brine. The organic layer was died (Na ₂ SO ₄ ) and concentrated. The residue was purified by FC (Hexane to EtOAc/Hexane 1/5) to give compound 29 (2.63 g, 99%) as a oil. ¹ HNMR (CDCI ₃ ) δ 7.31-7.21 (m, 5H), 3.65 (m, 1 H), 3.51-3.44 (m, 2H), 3.40 (s, 3H), 2.91 (dd, J = 5.5, 13.5 Hz, 1 H), 2.74 (dd, J = 7.0, 13.5 Hz, 1 H), 2.17 (br, 1 H); ¹³ C NMR (CDCI ₃ ) δ 138.0, 129.3, 128.4, 126.3, 82.8, 63.2, 57.4, 36.8.

^Bn °- OMe ^BπC \ OMe

15c 16

A solution of oxylyl chloride (3 ml, 35 mmol) in DCM (50 ml) at -78 ⁰ C was added DMSO (4.97 ml, 70 mmol) slowly. 5 minutes later, alcohol 15c (4.25 g, 17.8 mmol) in DCM (30 ml) was added followed by DCM washing (10 ml). Et ₃ N (9.7 ml, 70 mmol) was then added at -78 ⁰ C. The reaction mixture was allowed to stir at -78 ⁰ C for 15 minutes before the cold bath removed. The reaction was keep stirring from -78 ⁰ C to rt , then at rt for 0.5 h. The reaction was diluted with EtOAc, washed with NaHCO3, brine, dried and concentrated. The residue was purified by FC (EtOAc/Hexane 1/9) to give aldehyde 16 (3.95 g, 94%) as a yellow oil. . ¹ HNMR (CDCI ₃ ) δ 9.64 (d, J = 2.0 Hz, isomer I), 9.61 (d, J

= 2.0 Hz, 1 H, isomer II), 7.36-7.26 (m, 5H), 4.52-4.47 (m, 2H), 3.68-3.64 (m, 1 H), 3.43 (s, 3H, isomer I), 3.39 (s, 3H, isomer II), 3.34-3.31 (m, 2H), 2.07-1.98 (m, 1 H), 1.83-1.75 (m, 1 H), 1.51 -1.41 (m, 1 H), 0.98 (d, J = 7.5 Hz, 3H); ¹³ C NMR (CDCI ₃ ) δ 204.0, 203.8, 138.7, 138.6, 128.5, 127.7, 127.6, 84.6, 84.1 , 75.6, 75.2, 73.2, 73.0, 58.5, 58.3, 34.0, 33.7, 30.0, 29.8, 18.1 , 16.9; MS (ES) calculated for CuH ₂ iO ₃ [M + H] ⁺ : 237.15, found 237.12.

29 30

A solution of oxylyl chloride (2.76 ml, 31.6 mmol) in DCM (20 ml) at -78 ⁰ C was added DMSO (4.5 ml, 63.3 mmol) slowly. 5 minutes later, alcohol 29

(2.63 g, 15.8 mmol) in DCM (30 ml) was added followed by DCM washing (10 ml). Et ₃ N (8.8 ml, 63.3 mmol) was then added at -78 ⁰ C. The reaction mixture was allowed to stir at -78 ⁰ C for 15 minutes before the cold bath removed. The reaction was keep stirring from -78 ⁰ C to rt , then at rt for 0.5 h. The reaction was diluted with EtOAc, washed with NaHCO3, brine, dried and concentrated. The residue was purified by FC (EtOAc/Hexane 1/9) to give aldehyde 30 (2.47 g,

94%) as a yellow oil. . ¹ HNMR (CDCI ₃ ) δ 9.69 (d, J = 2.0 Hz, 1 H), 7.32-7.22 (m,

5H), 3.80 (m, 1 H), 3.41 (s, 3H), 3.01 (dd, J = 5.0, 9.0 Hz, 1 H), 2.92 (dd, J = 8.5,

14.5 Hz, 1 H); ¹³ C NMR (CDCI ₃ ) δ 203.2, 136.4, 129.4, 128.5, 126.8, 86.4, 58.6, 36.4.

To a solution of aldehyde 16 (4g, 17 mmol) in DCM (100 ml) was added TMSCN (5.6 ml, 42.5 mmol) at 0 ⁰ C, AICI ₃ was added 5 minutes later. The reaction mixture was stirred from 0 ⁰ C to room temperature overnight. The reaction was quenched by aq NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified by FC (silica gel, Acetone/Hexane 1/4) to give 16a and 16b (3.88 g, 87%) as an inseparable mixture (16a/16b, 2/1 ). ¹ HNMR (CDCI ₃ ) δ 7.38-7.28 (m, 5H), 4.55-4.34 (m, 3H), 3.65-3.53 (m, 1 H), 3.39-3.26 (m, 2H), 3.53, 3.51 (s, 3H, 16b), 3.46-3.45 (s, 3H, 16a) 2.01 -1.43 (m, 3H), 1.00-0.97 (m, 3H); MS (ES) calculated for Ci ₅ H ₂₂ NO ₃ [M + H] ⁺ : 264.16, found 264.10.

To a solution of aldehyde 30 (2.46 g, 15 mmol) in DCM (100 ml) was added TMSCN (5.6 ml, 42.5 mmol) at 0 ⁰ C, AICI ₃ (2 g, 15 mmol) was added 5 minutes later. The reaction mixture was stirred from 0 ⁰ C to room temperature overnight. The reaction was quenched by aq NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified by FC (silica gel, Acetone/Hexane 1/4) to give 31a and 31 b (2.9 g, 99%) as an inseparable mixture (2/1 ). ¹ HNMR (CDCI ₃ ) δ 7.35-7.22 (m, 5H, isomer I and II), 4.28 (dd, J = 3.0, 6.0 Hz, 1 H, isomer I), 4.26 (dd, J = 4.5, 8.0 Hz, 1 H, isomer II), 3.64 (m, 1 H, isomer I and II), 3.51 (s, 3H, isomer I), 3.48 (s, 3H, isomer II), 3.28 (d, J = 9.5 HZ, 1 H, OH, isomer II), 3.16 (dd, J = 5.5, 14.5 Hz, 1 H, isomer II), 3.16 (d, J = 9.0 Hz, 1 H, OH, isomer I), 2.99 (dd, J = 7.0, 14.0 Hz, 1 H, isomer I), 2.90 (dd, J = 7.5, 14.0 Hz, 1 H, isomer I), 2.83 (dd, J = 8.0, 14.0 Hz, 1 H, isomer II).

To a solution of compound 16a/16b (1.23g, 4.68 mmol) in DCM (15 ml) was added NEt ₃ (1.15 ml, 8.24 mmol), DMAP (61 mg, 0.5 mmol) and the mixture was cooled to 0 ⁰ C. To the solution was added TBDPSCI (1.82 ml, 7 mmol). The reaction was stirred at rt overnight before being diluted with EtOAc and washed with aq NH ₄ CI, NaHCO ₃ and brine sequentially. After dried over Na ₂ SO ₄ , it was concentrated and purified by FC (Et ₂ O/Hexane 1/10) to give the protected cyanohydrin. Toa a solution of this cyanohydrin in H ₂ OATHF (16 ml, 1/3) was added PdCI ₂ (177 mg) followed by acetamide (1.18 g, 20 mmol). The reaction mixture was stirred vigorously at rt for 10 h. The reaction was diluted with EtOAC and washed with NaHCO ₃ and brine. After dried over Na ₂ SO ₄ , it was concentrated and purified by FC (EtOAc/Hexane 1/4) to give compound 17 (1.3 g, 53% over two steps) as the major product. ¹ HNMR (CDCI ₃ ) δ 7.71-7.31 (m,

15H), 6.58 (br, 1 H), 5.35 (br, 1 H), 4.47 (s, 1 H), 4.44 (d, J = 2,5 Hz, 1 H), 4.38, 4.34 (d, J = 2.0 Hz, 1 H), 3.38 (m, 1 H), 3.29, 3.26 (dd, J = 5.5, 9.0 Hz, 1 H), 3.19, 3.13 (dd, J = 6.5, 9.0 Hz, 1 H), 3.11 (s, 3H), 1.90, 1.83 (m, 1 H), 1.59, 1.45 (m, 1 H), 1.10, 1.04 (m, 1 H), 1.13 (s, 9H), 0.88, 0.82 (d, J = 6.5 Hz, 3H); MS (ES) calculated for C

₃₁ H ₄₂ NO ₄ Si [M + H] ⁺ : 520.29, found 520.35.

To a solution of compound 31 a/31 b (1.0 g, 5.2 mmol) in DCM (15 ml) was added NEt ₃ (1.15 ml, 8.24 mmol), DMAP (61 mg, 0.5 mmol) and the mixture was cooled to 0 ⁰ C. To the solution was added TBDPSCI (1.82 ml, 7 mmol). The reaction was stirred at rt overnight before being diluted with EtOAc and washed with aq NH ₄ CI, NaHCO ₃ and brine sequentially. After dried over Na ₂ SO ₄ , it was concentrated and purified by FC (Et ₂ O/Hexane 1/10) to give the protected cyanohydrin. Toa a solution of this cyanohydrin in H ₂ OZTHF (16 ml, 1/3) was added PdCI ₂ (177 mg) followed by acetamide (1.18 g, 20 mmol). The reaction mixture was stirred vigorously at rt for 10 h. The reaction was diluted with EtOAC and washed with NaHCO ₃ and brine. After dried over Na ₂ SO ₄ , it was concentrated and purified by FC (EtOAc/Hexane 1/4) to give compound 32a (1.22 g, 60% over two steps) as the major product. ¹ HNMR (CDCI ₃ ) δ 7.72-7.11 (m, 15H), 6.66 (br, 1 H), 6.07 (br, 1 H), 4.41 (d, J = 2.0 Hz, 1 H), 3.53 (ddd, J = 2.0, 4.5, 9.0 Hz, 1 H), 3.10 (s, 3H), 2.96 (dd, J = 9.0, 14.0 Hz, 1 H), 2.77 (dd, J = 4.5, 14.0 Hz, 1 H), 2.38 (s, 3H), 1.17 (s, 9H), 1.13 (s, 9H) ); ¹³ C NMR (CDCI ₃ ) δ 174.5, 139.2, 136.5, 136.1 , 133.2, 132.9, 130.6, 130.6, 129.9, 129.5, 128.7, 128.6, 128.4, 128.3, 126.5, 85.7, 76.0, 59.0, 37.0, 27.5, 19.9.

A solution of aldehyde 5 (910mg, 1.7 mmol) and silylenolether 12

(1.58g, 3.6 mmol) was codistilled with toluene several times before dissolved in anhydrous DCM (25 ml). The solution was cooled to -78 ⁰ C and freshly distilled BF ₃ OEt ₂ (2.2 ml, 18 mmol) was added dropwise. The reaction was allowed to stir

at -78 ⁰ C overnight. The reaction was quenched by adding saturated NaHCθ ₃ (30 ml) before warmed up to room temperature. It was extracted with EtOAc. Combined oraganic layer was washed with brine and dried over Na ₂ SO ₄ . After concentration the residue was purified by FC (EtOAc/Hexane 1/9) to give product (1.15 g, 91 %) as colorless oil. The excess enolether was recovered as the hydroxyketone 4. [α] ²⁰ _D + 28.59 (c = 0.1 , DCM); ¹ HNMR (CDCI ₃ ) δ 7.34-7.26 (m, 5H), 6.30 (s, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.36 (ddd, J = 2.5, 5.0, 12.5 Hz, 1 H), 4.31-4.27 (m, 1 H), 4.05 (dd, J = 2.5, 7.5 Hz, 1 H), 3.49 (dd, J = 5.5, 8.0 Hz, 2H), 3.24 (d, J = 2.0 Hz, 1 H), 2.89 (dd, J = 2.5, 16.0 Hz, 1 H), 2.78-2.71 (m, 2H), 2.08 (s, 3H), 1.83-1.69 (m, 2H), 1.62-1.54 (m, 5H), 1.35- 1.25 (m, 8H), 1.18-1.05 (m, 42 H), 0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 217.4, 163.1 , 159.0, 157.7, 141.4, 138.5, 128.6, 127.9, 118.3, 109.7, 78.3, 74.0, 73.2, 67.9, 67.5, 53.8, 42.9, 41.7, 34.7, 29.9, 26.2, 22.3, 20.2, 18.5, 18.3, 18.2, 17.9, 13.5, 13.4, 12.0, 9.6, -3.7, -3.8; MS (ES) calculated for C ₅₂ H _9I O ₈ Si ₃ [M + H] ⁺ : 927.60, found 927.73; C ₅₂ H ₉₀ NaO ₈ Si ₃ [M + Na] ⁺ : 949.58, found 949.68;

1

A solution of aldehyde 5 (1.59 g, 3 mmol) and silylenolether 26 (2.32 g, 7 mmol) in anhydrous DCM (60 ml) was cooled to -78 ⁰ C and freshly distilled BF ₃ OEt ₂ (3.8 ml, 30 mmol) was added dropwise. The reaction was allowed to stir at -78 ⁰ C overnight. The reaction was quenched by adding saturated NaHCO ₃ (30 ml) before warmed up to room temperature. It was extracted with EtOAc. Combined oraganic layer was washed with brine and dried over Na ₂ SO ₄ . After concentration the residue was purified by FC (EtOAc/Hexane 1/9) to give product (1.83 g, 75%, one diastereomer) as colorless oil. The excess enolether was recovered as the hydroxyketone 33. [αf° _D + 27.37 (c = 0.1 , DCM); ¹ HNMR (CDCI ₃ ) δ 7.35-7.27 (m, 5H), 6.30 (s, 1 H), 4.48 (s, 2H), 4.39 (ddd, J = 3.0, 4.5, 12.0 Hz, 1 H), 4.29 (m, 1 H), 3.44 (t, J = 7.5 Hz, 2H), 3.32 (d, J = 2.5 Hz, 1 H), 2.88 (dd, J = 3.0, 16.5 Hz, 1 H), 2.79 (dd, J = 12.0, 16.0 Hz, 1 H), 2.74 (dd, J = 3.0, 18.0 Hz, 1 H), 2.66 (dd, J = 9.0, 18.0 Hz, 1 H), 2.09 (s, 3H), 1.86 (m, 1 H), 1.63-1.60 (m, 2H), 1.52-1.47 (m, 2H), 1.35-1.24 (m, 8H), 1.18-1.06 (m, 48 H); ¹³ C

NMR (CDCI ₃ ) δ 218.1 , 163.3, 159.3, 158.0, 141.7, 138.9, 128.8, 128.1 , 128.0, 118.6, 110.1 , 110.0, 78.5, 73.4, 70.8, 68.6, 53.9, 48.2, 41.9, 41.3, 36.6, 30.1 , 30.1 , 25.6, 24.7, 24.6, 18.7, 18.4, 18.4, 13.9, 13.8, 13.7, 13.6, 13.5, 13.3, 12.2, 9.8, 1.5. MS (ES) calculated for C ₄₆ H ₇₇ O ₇ Si ₂ [M + H] ⁺ : 797.52, found 797.53.

18 18a

To a solution of compound 18 (1.15 g, 1.54 mmol) in anhydrous THF (30 ml) was added catecholborane (20 ml, 1.0 M in THF, 20 mmol) at -78 ⁰ C. After stirring at 0 ⁰ C for 15 h, the reaction was quenched by 10 ml anhydrous MeOH and aq. solution of Sodium potassium tartrate (50 ml). The mixture was further stirred at rt for 1 h before a normal workup process with EtOAc. The residue was purified by FC (EtOAc/Hexane 1/8) to give the desired product 18a (1.05 g, 92%) (de, 15/1). [α] ²⁰ _D + 44.37 (c = 0.1 , DCM); ¹ HNMR (CDCI ₃ ) δ 7.37- 7.28 (m, 5H), 6.30 (s, 1 H), 4.87 (br, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 4.35 (ddd, J = 2.5, 5.5, 12.5 Hz, 1 H), 4.25 (br, 1 H), 4.14 (d, J = 10.0 Hz, 1 H), 4.06 (d, J = 9.5 Hz, 1 H), 3.66 (dd, J = 2.5, 7.5 Hz, 1 H), 3.60-3.52 (m, 2H), 2.98 (dd, J = 3.0, 16.5 Hz, 1 H), 2.80 (dd, J = 12.0, 16.0 Hz, 1 H), 2.10 (s, 3H), 2.11-2.09 (m, 1 H), 1.87-1.78 (m, 2H), 1.66-1.59 (m, 1 H), 1.35-1.25 (m, 6H), 1.17-1.11 (m, 39 H), 1.02 (s, 3H), 0.87 (s, 9H), 0.75 (s, 3H), 0.10 (s, 3H), 0.07 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 163.5, 158.9, 157.6, 141.8, 138.6, 128.6, 127.9, 118.4, 109.7, 81.3, 78.7, 77.9, 73.1 , 72.7, 67.6, 43.1 , 40.8, 35.0, 33.3, 29.9, 26.2, 23.5, 21.0, 18.4, 18.3, 18.2, 13.5, 13.4, 12.1 , 9.9, -3.8, -4.1 ; MS (ES) calculated for C ₅₂ H ₉₃ O ₈ Si ₃ [M + H] ⁺ : 929.62, found 929.68; C ₅₂ H ₉₂ NaO ₈ Si ₃ [M + Na] ⁺ : 951.60, found 951.66.

34

To a solution of compound 33 (190 mg, 0.238 mmol) in anhydrous THF (10 ml) was added catecholborane (4.76 ml, 1.0 M in THF, 4.76 mmol) at - 78 ⁰ C. After stirring at 0 ⁰ C for 15 h, the reaction was quenched by 10 ml anhydrous MeOH and aq. solution of Sodium potassium tartrate (50 ml). The mixture was further stirred at rt for 1 h before a normal workup process with EtOAc. The residue was purified by FC (EtOAc/Hexane 1/8) to give the desired product 34 (174 mg, 92%) (de, 15/1). ¹ HNIvIR (CDCI ₃ ) δ 7.35-7.27 (m, 5H), 6.30 (s, 1 H), 4.50 (s, 2H), 4.39 (ddd, J = 4.0, 4.0, 1 1.0 Hz, 1 H), 4.12 (m, 1 H), 3.74 (br, 1 H), 3.62 (d, J = 10.0 Hz, 1 H), 3.50-3.41 (m, 2H), 3.21 (br, 1 H), 2.89-2.79 (m, 2H), 2.09 (s, 3H), 1.82 (m, 1 H), 1.69-1.54 (m, 4H), 1.44 (m, 1 H), 1.35-1.22 (m, 7H), 1.13-1.10 (m, 38H), 0.87 (s, 3H), 0.85 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 162.8, 158.8, 157.5, 141.3, 138.3, 128.4, 127.7, 127.6, 118.0, 109.6, 109.5, 79.3, 79.2, 74.1 , 73.0, 71.1 , 42.5, 34.8, 34.5, 29.7, 23.8, 22.9, 22.7, 18.0, 13.2, 13.1 , 11.8, 8.7.

18a TBb

To a solution of compound 18a (2.14g, 2.3 mmol) in pyridine (4 ml) was added Ac ₂ O (2 ml) and DMAP (35 mg, 0.287 mmol) at 0 ⁰ C. The reaction was allowed to stir at rt for 8 h before diluted with EtOAc. The mixture was washed with aq. HCI, NaHCO ₃ , brine sequentially. After dried over Na ₂ SO ₄ , it was concentrated and purified by FC (EtOAc/Hexane 1/10 to 1/4) to give 18b (1.82 g, 78 %) as a oil. ¹ HNMR (CDCI ₃ ) δ 7.33-7.25 (m, 5H), 6.28 (s, 1 H), 5.09 (m, 1 H), 4.98-4.95 (m, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.02 (ddd, J = 2.5, 7.0, 12.0 Hz, 1 H), 3.64 (dd, J = 2.0, 8.0 Hz, 1 H), 3.53-3.50 (m, 2H), 2.92 (dd, J = 2.5, 16.0 Hz, 1 H), 2.58 (dd, J = 12.0, 16.0 Hz, 1 H), 2.09 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 2.04-2.00 (m, 1 H), 1.95-1.87 (m, 1 H), 1.73-1.58 (m, 2H), 1.35-1.25 (m, 6H), 1.16-1.10 (m, 39 H), 0.89 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 171.1 , 170.7, 162.9, 158.9, 157.6, 141.2, 138.6, 128.5, 128.0, 127.8, 118.3, 109.9, 109.7, 78.2, 74.7, 74.0, 73.2, 71.7, 67.5, 42.9, 39.6, 33.7, 32.4, 30.5, 26.4, 21.4, 21.3, 20.7, 19.6, 18.7,

18.2, 13.5, 13.3, 11.8, 8.9, -3.7; MS (ES) calculated for C ₅₆ H ₉₇ O ₁₀ Si ₃ [M + H] ⁺ : 1013.64, found 1013.70; C ₅₆ H ₉₆ NaOi ₀ Si ₃ [M + Na] ⁺ : 1035.62, found 1035.72.

34 To a solution of compound 34(1.35 g, 1.7 mmol) in pyridine (4 ml) was added Ac ₂ O (2 ml) and DMAP (35 mg, 0.287 mmol) at 0 ⁰ C. The reaction was allowed to stir at rt for 8 h before diluted with EtOAc. The mixture was washed with aq. HCI, NaHCO ₃ , brine sequentially. After dried over Na ₂ SO ₄ , it was concentrated and purified by FC (EtOAc/Hexane 1/10 to 1/4) to give 35 (1.5 g, 98 %) as a oil. [α] ²⁰ _D + 41.19 (c = 0.1 , DCM); ¹ HNMR (CDCI ₃ ) δ 7.36-7.26 (m, 5H), 6.29 (s, 1 H), 5.10 (m, 1 H), 4.77 (d, J = 10.0 Hz, 1 H), 4.49 (s, 2H), 4.08 (ddd, J = 2.5, 6.5, 12.0 Hz, 1 H), 3.44-3.42 (m, 2H), 2.92 (dd, J = 2.5, 16.0 Hz, 1 H), 2.65 (dd, J = 12.0, 16.0 Hz, 1 H), 2.14 (m, 1 H), 2.08 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.70 (m, 1 H), 1.64-1.50 (m, 2H), 1.35-1.25 (m, 9H), 1.15 (d, J = 7.0 Hz, 3H), 1.12-1.09 (m, 36H), 0.88 (br, 6H); ¹³ C NMR (CDCI ₃ ) δ 171.2, 170.9, 162.9, 159.0, 157.7, 141.1 , 138.8, 128.6, 127.9, 127.8, 118.4, 110.0, 109.8, 78.0, 77.0, 76.7,

73.2, 72.0, 71.2, 39.7, 37.3, 35.0, 32.4, 31.9, 30.5, 24.4, 23.4, 23.1 , 22.9, 21.4,

21.3, 18.3, 18.2, 14.4, 13.5, 13.4, 13.3, 11.9, 9.2.

1 ^8b 18c

To a solution of compound 18b (1.82 g, 1.79 mmol) in EtOH (15ml) was charged Pd/C (180 mg) and the flask was sealed with rubber stopper. The inner atmosphere was exchanged three times with H ₂ before it was allowed to stir under H ₂ (double layer balloon) overnight. The reaction was filtered off a celite pad followed by washing with EtOH twice. The combined organic solution was concentrated and purified by FC (E/H 1/4 )to give the alcohol 18c (1.65 g, 99%) as oil: ¹ HNMR (CDCI ₃ ) δ 6.29 (s, 1 H), 5.10-5.07 (m, 1 H), 4.98 (dd, J = 2.0, 10.0 Hz, 1 H), 4.13 (ddd, J = 2.0, 6.0, 12.0, Hz), 3.8-3.75 (m, 1 H), 3.71-3.66 (m, 1 H),

3.66 (dd, J = 2.5, 8.5, Hz), 2.89 (dd, J = 2.5, 16.0 Hz, 1 H), 2.67 (dd, J = 12.0, 16.5 Hz, 1 H), 2.13-2.06 (m, 2H), 2.09 (s, 6 H), 2.03 (s, 3H), 1.87-1.71 (m, 3H), 1.65-1.58 (m, 2H), 1.56 (s, 3H), 1.35-1.25 (m, 6H), 1.15 (d, J = 7.0 Hz, 3H), 1.12- 1.09 (m, 36 H), 0.91 (s, 3 H), 0.90 (s, 9H), 0.84 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H); ¹³ C NMR (CDCi ₃ ) δ 171.0, 163.0,159.1 , 157.7, 141.1 , 118.4, 109.7, 77.9, 74.8, 73.8, 72.0, 60.0, 43.1 , 40.0, 36.3, 32.7, 30.2, 26.4, 21.4, 21.3, 20.8, 19.6, 18.7, 18.2, 13.5, 13.3, 11.9, 9.6, -3.6; MS (ES) calculated for C ₄₉ H ₉₁ Oi ₀ Si ₃ [M + H] ⁺ : 923.59, found 923.65; C ₄₉ H ₉₀ NaO ₁₀ Si ₃ [M + Na] ⁺ : 945.57, found 945.62.

To a solution of compound 35(2.59 g, 2.9 nnmol) in EtOH (40 ml) was charged Pd/C (180 mg) and the flask was sealed with rubber stopper. The inner atmosphere was exchanged three times with H ₂ before it was allowed to stir under H ₂ (double layer balloon) overnight. The reaction was filtered off a celite pad followed by washing with EtOH twice. The combined organic solution was concentrated and purified by FC (E/H 1/4 ) to give the alcohol 36 (1.96 g, 85%) as oil: [α] ²⁰ _D + 36.26 (c = 0.1 , DCM); ¹ HNMR (CDCI ₃ ) δ 6.30 (s, 1 H), 5.09 (m, 1 H), 4.79 (dd, J = 2.0, 9.5 Hz, 1 H), 4.12 (ddd, J = 2.5, 6.0, 12.0 Hz, 1 H), 3.60 (t, J = 6.0 Hz, 2H), 2.89 (dd, J = 2.5, 16.5 Hz, 1 H), 2.66 (dd, J = 12.5, 16.0 Hz, 1 H), 2.13-2.05 (m, 2H), 2.08 (br, 6H), 2.02 (s, 3H), 1.72 (ddd, J = 5.0, 10.0, 15.0 Hz, 1 H), 1.59-1.47 (m, 2H), 1.38-1.22 (m, 8H), 1.15 (d, J = 7.0 Hz, 3H), 1.12-1.09 (m, 38H), 0.88 (br, 6H); ¹³ C NMR (CDCI ₃ ) δ 170.9, 170.5, 162.7, 158.8, 157.5, 140.8, 118.1 , 108.6, 109.5, 77.5, 76.4, 71.9, 63.3, 39.6, 37.0, 34.4, 32.2, 30.1 , 27.1 , 23.3, 22.8, 21.1 , 21.0, 18.0, 17.9, 13.2, 13.1 , 11.6, 9.1.

18c 18d

To a solution of compound 18c (1.15 g, 1.24 mmol) in DCM (20 ml) was added DMP (790 mg, 1.86 mmol) at 0 ⁰ C. The reaction was allowed to stir at rt for 2 h. After the reaction is complete, it was cooled to 0 ⁰ C and aq Na ₂ S ₂ O ₃ (10 ml) was added. The mixture was stirred at rt for 15 minutes before diluted

with EtOAc, washed with aq NaHCO ₃ , brine, and dried over Na ₂ SO ₄ . The residue was purified by FC (E/H 1/10) to give the aldehyde 18d (1.08 g, 95%) as a colorless oil. ¹ HNMR (CDCI ₃ ) δ 9.86(s, 1 H), 6.29 (s, 1 H), 5.09-5.06 (m, 1 H), 4.89 (dd, J = 2.0, 10.0 Hz, 1 H), 4.15 (dd, J = 4.0, 5.5 Hz), 4.07 (ddd, J = 2.5, 7.0, 12.5 Hz, 1 H), 2.93 (dd, J = 2.5, 16.0 Hz, 1 H), 2.77 (ddd, J = 1.0, 4.0, 18.0 Hz, 1 H), 2.68-2.61 (m, 2H), 2.10 (s, 3 H), 2.08 (s, 3H), 2.02 (s, 3H), 2.08-2.06 (m, 1 H), 1.81 -1.75 (m, 1 H), 1.35-1.25 (m, 6H), 1.15 (d, J = 7.0 Hz, 3H), 1.13-1.10 (m, 36 H), 0.88 (s, 3 H), 0.88 (s, 3H), 0.87 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 201.3, 170.9, 162.9, 159.0, 157.7, 141.1 , 118.3, 109.7, 78.0, 74.4, 71.7, 71.3, 48.7, 42.8, 39.8, 33.3, 30.4, 26.2, 21.4, 21.3, 20.6, 20.2, 18.4, 18.2, 13.5, 13.3, 1 1.9, 9.1 , -3.8, -4.6.

To a solution of compound 36 (1.53 g, 1.93 mmol) in DCM (20 ml) was added DMP (1.23 g, 2.89 mmol) at 0 ⁰ C. The reaction was allowed to stir at rt for 2 h. After the reaction is complete, it was cooled to 0 ⁰ C and aq Na ₂ S ₂ O ₃ (10 ml) was added. The mixture was stirred at rt for 15 minutes before diluted with EtOAc, washed with aq NaHCO ₃ , brine, and dried over Na ₂ SO ₄ . The residue was purified by FC (E/H 1/10) to give the aldehyde 37 (1.83 g, 95%) as a colorless oil): ¹ HNMR (CDCI ₃ ) δ 9.78 (s, 1 H), 6.29 (s, 1 H), 5.10 (m, 1 H), 4.77 (dd, J = 2.0, 10.0 Hz, 1 H), 4.10 (m, 1 H), 2.90 (dd, J = 2.5, 16.0 Hz, 1 H), 2.65 (dd, J = 12.5, 16.5 Hz, 1 H), 2.53-2.38 (m, 2H), 2.09 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H), 1.74 (ddd, J = 5.5, 10.0, 15.0 Hz, 1 H), 1.66 (m, 1 H), 1.52 (m, 1 H), 1.35-1.24 (m, 6H), 1.16 (d, J = 7.0 Hz, 3H), 1.13-1.10 (m, 36H), 0.91 (s, 3H), 0.89 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 202.4, 171.6, 171.2, 171.0, 163.0, 159.3, 157.9, 141.2, 118.6, 110.1 , 110.0, 78.0, 76.4, 72.1 , 60.8, 40.1 , 39.3, 37.2, 32.8, 30.6, 30.1 , 23.6, 23.4, 21.6, 21.5, 21.4, 18.4, 18.4, 14.6, 13.7, 13.6, 13.4, 12.1 , 9.5.

18d 19, BZ = 5/1

An alumna foil wrapped round bottom flask containing CrCI ₂ (2.28 g, 18.6 mmol) was flamed dried under high vacuum and then cooled to room temperature. The adapter was quickly replaced by a rubber stopper and an Ar balloon was place on the top. Aldehyde 18d (1.14 g, 1.24 mmol) was codistilled with toluene three times before put under high vacuum. To a suspension of CrCI2 (2.28 g, 18.6 mmol) in anhydrous THF (20 ml) was added a solution of aldehyde (1.14g, 1.24 mmol) and CHI ₃ (2.44g, 6.2 mmol) in THF (20ml plus 10 ml washing) at O ⁰ C. Color should turn to reddish brown after 10 to 15 minutes. The reaction was allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc and water was added. The mixture was extracted with EtOAc, washed wirth brine and dried over Na ₂ SO ₄ . After concentration the residue was purified by FC (E/H 1/20 to 1/10) to give the vinyl iodide 19 ( 1.17 g, 90 %) as a light yellow oil as a mixture as trans/cis isomer (5/1). ¹ HNMR (CDCI ₃ ) δ 6.52-3.46 (m, 1 H), 6.28 (s, 1 H), 6.06 (d, J = 14.5 Hz, 1 H), 5.09-5.05 (m, 1 H), 4.91 (dd, J = 1.5, 10.5 Hz, 1 H), 4.07 (ddd, J = 2.5, 6.5, 12.0 Hz, 1 H), 3.50 (dd, J = 4.0, 7.0 hz, 1 H), 2.90 (dd, J = 2.0, 16.0 Hz, 1 H), 2.63 (dd, J = 12.0, 16.0 Hz, 1 H), 2.38-2.32 (m, 1 H), 2.25-2.19 (m, 1 H), 2.12-2.10 (m, 1 H), 2.08 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.99-1.96 (m, 1 H), 1.78-1.72 (m, 1 H), 1.34-1.24 (m, 6H), 1.15 (d, J = 7.0 hz, 3H), 1.12-1.09 (m, 36 H), 0.89 (s, 9H), 0.88 (s, 3H), 0.85 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 171.0, 170.7, 162.8, 159.0, 157.7, 144.4, 141.0, 139.1 , 118.3, 109.8, 109.7, 83.7, 78.1 , 77.9, 77.1 , 76.3, 74.4, 71.6, 43.4, 43.2,

40.2, 39.5, 32.7, 30.4, 26.3, 21.4, 21.3, 21.1 , 20.9, 20.1 , 18.5, 18.2, 18.1 , 13.5,

13.3, 11.9, 9.2, -3.1 , -3.9; MS (ES) calculated for C ₅₀ H ₉₀ IO ₉ Si ₃ [M + H] ⁺ : 1045.50, found 1045.72.

37 38

An alumna foil wrapped round bottom flask containing CrCI ₂ (2.28 g, 18.6 mmol) was flamed dried under high vacuum and then cooled to room temperature. The adapter was quickly replaced by a rubber stopper and an argon balloon was place on the top. Aldehyde 37 (1.0 g, 1.26 mmol) was codistilled with toluene three times before put under high vacuum. To a suspension of CrCI ₂ (2.28 g, 18.6 mmol) in anhydrous THF (20 ml) was added a solution of aldehyde (1.14g, 1.24 mmol) and CHI ₃ (2.44g, 6.2 mmol) in THF (20ml plus 10 ml washing) at 0 ⁰ C. Color should turn to reddish brown after 10 to 15 minutes. The reaction was allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc and water was added. The mixture was extracted with EtOAc, washed wirth brine and dried over Na ₂ SO ₄ . After concentration the residue was purified by FC (E/H 1/20 to 1/10) to give the vinyl iodide 38 (0.935 g, 80 %) as a light yellow oil as a mixture as trans/cis isomer (5/1). MS (ES) calculated for C ₄₄ H ₇ BlOsSi ₂ [M + H] ⁺ : 915.41 , found 915.50.

To an oven dried seal tube was charged amide 17 (500 mg, 0.99 mmol), CuI (31 mg, 0.16 mmol), and Cs ₂ CO ₃ (326 mg, 1 mmol) sequentially. Under argon, Dimethylethylenediamine (0.035 ml, 0.32 mmol) was then added followed by a solution of vinyl iodide 19 (346 mg, 0.33 mmol) in toluene. The tube was filled with argon and quickly capped and sealed. The reaction was stirred vigorously at 70 ⁰ C for 20 h. After the reaction was cooled to rt, it was diluted with EtOAc and filtered off a short pad of silica gel and washed with EtOAc. The combined organic solution was concentrated and purified by FC (A/H 1/20 to 1/10) to give the enamide 19a (450 mg, 95%) as oil. The excess amide was recovered. For characterization purpose, a small amount of E/Z mixture was separated. E isomer; ¹ HNMR (CDCI ₃ ) δ 8.18 (d, J = 11.0 Hz, 1 H), 7.69-7.30 (m, 15H), 6.62 (dd, J = 12.0, 13.5 Hz, 1 H), 6.29 (s, 1 H), 5.10 (br, 1 H), 5.03 (m, 1 H), 4.92 (d, J = 9.0 Hz, 1 H), 4.47 (s, 1 H), 4.45 (dd, J = 5.0, 10.0 Hz, 1 H), 4.37 (dd, J = 1.5, 19.5 Hz, 1 H), 4.07 (ddd, J = 2.5, 6.5, 12.5 Hz, 1 H), 3.42 (m, 2H), 3.27 (m, 1 H), 3.19-3.08 (m, 4H), 2.92 (dd, J = 2.5, 16.5 hz, 1 H), 2.63 (dd, J = 12.5, 16.5

Hz, 1 H), 2.30 (m, 1 H), 2.15 (m, 2H), 2.12-1.72 (m, 13 H), 1.60 (m, 1 H), 1.35-1.25 (m, 8H), 1.18-1.10 (m, 49 H), 0.90-0.80 (m, 18 H), 0.02 (s, 3H), -0.04 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 171.1 , 170.8, 168.4, 163.0, 159.0, 157.7, 141.2, 136.3, 135.9, 130.5, 128.5, 128.3, 128.1 , 127.8, 127.7, 127.6, 123.1 , 118.4, 110.0, 109.7, 82.1 , 78.2, 76.4, 75.6, 74.7, 73.1 , 73.0, 71.8, 43.3, 39.4, 33.9, 30.5, 27.3, 26.4, 21.5, 21.4, 21.1 , 20.4, 18.6, 18.3, 18.2, 16.9, 13.5, 13.4, 11.9, 9.1 , -2.8, -3.9; MS (FAB) calculated for C ₈ IH ₁₂₉ NNaO ₁₃ Si ₄ [M + Na] ⁺ : 1458.8439, found 1458.8439.

To an oven dried seal tube was charged amide 17 (410 mg, 0.81 mmol), CuI (26 mg, 0.135 mmol), and Cs ₂ CO ₃ (264 mg, 0.81 mmol) sequentially. Under Argon, Dimethylethylenediamine (0.029 ml, 0.27 mmol) was then added followed by a solution of vinyl iodide 38 (260 mg, 0.27 mmol) in toluene. The tube was filled with argon and quickly capped and sealed. The reaction was stirred vigorously at 70 ⁰ C for 20 h. After the reaction was cooled to rt, it was diluted with EtOAc and filtered off a short pad of silica gel and washed with EtOAc. The combined organic solution was concentrated and purified by FC (A/H 1/20 to 1/10) to give the enamide 39 (334 mg, 95%) as oil. The excess amide was recovered. The mixture was carried through the next step without separation of the isomers. MS (ES) calculated for C ₇₅ H ₁₁₅ NNaO ₁₂ Si ₃ [M + Na] ⁺ : 1328.76, found 1328.77.

The compound 19a (450 mg, 0.31 mmol) was treated with a NaOMe solution in MeOH at rt for 5h before quenched by water. The mixture was then extracted with EtOAc thoroughly. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude was dissolved in DCM. At 0 ⁰ C, pyridine, DMAP and then Ac ₂ O was added sequentially. The reaction was allowed to stir at 0 ⁰ C for 1 h before quenched with aq NH ₄ CI. the aq layer was

extracted with EtOAc. Combine organic layer was washed with NH ₄ CI and brine. After dried and concentrated, the residue was purified by FC (A/H 1/20 to 1/6) to give 20 as a mixture (368 mg, 95%) of four isomers (E/Z was separable on PTLC hence a small part was separated for characterization purpose). The mixture was carried on to the next reaction directly. NMR data of the major E isomer (NMR spectrum of the Z isomer is attached): ¹ HNMR (CDCI ₃ ) δ 8.19 (d, J = 10.5 Hz, 1 H), 7.69-7.26 (m, 15H), 6.65 (dd, J = 11.5, 13.5 Hz, 1 H), 6.53 (s, 1 H), 5.00 (m, 1 H), 4.86 (s, 1 H), 4.47 (s, 1 H), 4.43-4.36 (m, 2H), 4.26 (s, 1 H), 4.15 (d, J = 9.0 Hz, 1 H), 4.06 (d, J = 10.5 Hz, 1 H), 3.43 (m, 2H), 3.26 (m, 1 H), 3.18 (m, 1 H), 3.14-3.08 (m, 4H), 3.03 (d, J = 16.5 Hz, 1 H), 2.86 (dd, J = 12.5, 16.0 Hz, 1 H), 2.42 (m, 1 H), 2.33 (s, 3H), 2.26 (m, 1 H), 2.05-1.99 (m, 4H), 1.88 (m, 2H), 1.62 (m, 1 H), 1.40-1.30 (m, 4H), 1.15-1.10 (m, 29 H), 1.01 (s, 3H), 0.89 (s, 9H), 0.92 (d, J = 7.0 Hz, 3 H, isomer I), 0.86 (d, J = 7.0 Hz, 3H, isomer II), 0.82 (s, 3H), 0.14 (s, 3H), 0.05 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 168.6, 168.4, 168.3, 162.7, 157.0, 153.0, 142.2, 136.2, 135.8, 130.5, 130.4, 128.4, 128.2, 128.0, 127.6, 127.5, 115.0, 113.5, 84.9, 81.6, 78.8, 77.8, 76.2, 75.5, 73.0, 72.9, 72.4, 43.0, 34.9, 33.1 , 30.3, 30.0, 29.7, 27.2, 26.2, 23.7, 21.1 , 19.7, 18.4, 18.3, 18.2, 16.8, 13.3, 12.0, 9.99, -3.3, -3.9; MS (FAB) calculated for C ₇₀ Hi ₀₇ NNaOi ₂ Si ₃ [M + Na] ⁺ 1260.6999, found 1260.7005.

The compound 39(265 mg, 0.20 mmol) was treated with a NaOMe solution in MeOH at rt for 5h before quenched by water. The mixture was then extracted with EtOAc thoroughly. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude was dissolved in DCM. At 0 ⁰ C, pyridine, DMAP and then Ac ₂ O was added sequentially. The reaction was allowed to stir at 0 ⁰ C for 1 h before quenched with aq NH ₄ CI. the aq layer was extracted with EtOAc. Combine organic layer was washed with NH ₄ CI and brine. After dried and concentrated, the residue was purified by FC (A/H 1/20 to 1/6) to give 40 as a mixture (210 mg, 95%) of four isomers. The mixture was carried on to the next reaction directly. MS (ES) calculated for C ₆₄ H ₉₄ NOnSi ₂ [M + H] ⁺

1108.64, found 1108.63, calculated for C ₆₄ H ₉₃ NNaOnSi ₂ [M + Na] ⁺ 1130.62, found 1130.68.

Under an atmosphere of Argon, a solution of compound 20 (300 mg, 0.24 mmol) in HFI (4 ml) at 0 ⁰ C was added MeOH (0.2 ml) and then a solution o DIB (320 mg, 0.96 mmol) dropwise as a solution in HFI (2ml). The reaction stirred at rt for 70 h. The reaction mixture was diluted with EtOAc and filted througha short pad of silica gel. The filtrated was concentrated and then purified by FC (acetone/hexane 1/10 to 1/2 to give two crude fraction which was repurified with EtOAc/toluene 1/10 to 1/2) to give 20a and epi-20a. (90 mg each, 60% combined). Another -15% side product was obtained as a mixture, which is not fully characterized. 20a: ¹ HNMR (CDCI ₃ ) δ 7.69-7.24 (m, 15H), 6.52, 6.51 (s, 1 H), 5.19 (m, 1 H), 4.43-4.38 (m, 3H), 4.26 (br, 1 H), 4.08 (br, 1 H), 3.97 (br, 1 H), 3.72, 3.70 (s, 1 H), 3.52-3.48 (m, 2H), 3.34 (s, 3H), 3.33 (s, 3H), 3.29 (m, 1 H), 3.22-3.00 (m, 6h), 2.92-2.85 (m, 1 H), 2.31 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 1.84-1.44 (m, 3H), 1.37-1.31 (m, 3H), 1.13-1.10 (m, 30 H), 0.90 (s, 9H), 0.80 (s, 3H), 0.77 (s, 3H), 0.74, 0.71 (d, J = 6.5 Hz, 3H), 0.04 (s, 6H); ¹³ C NMR (CDCI ₃ ) δ 172.4, 172.2, 168.5, 162.7, 157.0, 152.9, 142.3, 136.3, 135.9, 132.8, 130.3, 130.1 , 128.4, 128.0, 127.9, 127.6, 127.5, 113.3, 82.3, 79.1 , 76.2, 75.5, 72.9,

72.2, 56.2, 43.3, 34.5, 30.4, 30.0, 29.6, 27.3, 25.9, 21.0, 19.6, 18.1 , 16.8, 14.3,

13.3, 12.0, 9.8, -4.4, -4.9. MS (FAB) calculated for C _7I H ₁₀₉ NO ₁₃ NaSi ₃ [M + Na] ⁺ 1290.7104, found 1290.7100; NMR spectrum of epi-20a is attached.

S = R R

To a solution of compound 20a (48 mg, 0.038 mmol) in DCM (1 ml) was added pyridine (0.30ml) , Ac ₂ O (0.15 ml) and DMAP (2.5 mg, 0.02 mmol) sequentially. The reaction mixture was stirred at rt overnight before quenched with aq NH ₄ CI, the aq layer was extracted with EtOAc thoroughly. The combine organic layer was washed with brine, dried over NaSO ₄ and concentrated. The residue was roughly purified by FC then directly put to the next step. To a solution of Acetate compound (20 mg, 0.015 mmol) in MeOH (2 ml) was charged Pd/C (5 mg) and the flask was sealed with rubber stopper. The inner atmosphere was exchanged three times with Hydrogen. Before it was allowed to stir under H ₂ (double layer H ₂ balloon) overnight. The reaction was filtered off a celite pad followed by washing with MeOH twice. The combined organic solution was concentrated and purified by FC to give the alcohol 21 (17.3 mg, 95%). epi-21 was obtained in the same sequence, epi-21 could be isolated by PTLC, so for characterization purpose they are separated and NMR of each pure diastereomer was recorded (epi-21 -I, epi-21 -II). 21 : ¹ HNMR (CDCI ₃ ) δ 7.68-7.33 (m, 10 H), 6.52 (s, 1 H), 5.39 (m, 1 H), 5.07 (dm, J = 10.0 Hz, 1 H), 4.49 (dd, J = 2.0, 10.0 Hz, 1 H), 4.19 (br, 1 H), 4.11 (m, 1 H), 3.55 (br, 1 H), 3.39, 3.38 (s, 3H), 3.34 (dm, J = 12.5 Hz, 1 H), 3.23 (m, 2H), 3.13 (dm, J = 16.5 Hz, 1 H), 2.99, 2.98 (s, 3H), 2.68-2.61 (m, 2H), 2.32 (s, 3H), 2.14 (m, 1 H), 2.09 (m, 1 H), 2.02 (s, 3H), 1.98, 1.97 (s, 3H), 1.77-1.39 (m, 6H), 1.37-1.30 (m, 3H), 1.18 (d, J = 7.0 Hz, 3H), 1.13-1.11 (m, 29 H), 0.88 (s, 9H), 0.82 (s, 3H), 0.77, 0.76 (s, 3H), 0.66, 0.61 (d, J = 7.0 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 172.3, 172.1 , 170.5, 168.7, 162.3, 157.0, 153.0, 141.8, 136.3, 135.7, 132.9, 132.8, 130.4, 130.3, 130.1 , 128.0, 127.9, 119.6, 119.5, 114.6, 113.4, 83.0, 82.5, 81.7, 79.2, 71.4, 68.1 , 67.3, 57.6, 56.5, 33.5, 32.4, 30.0, 27.3, 25.9, 21.3, 21.1 , 19.6, 18.1 , 18.0, 17.5, 17.2, 13.3, 11.9, 11.8, -4.4, -5.0; MS (FAB) calculated for C ₆₆ Hi ₀₅ NOi ₄ Na Si ₃ [M + Na] ⁺ 1242.6741 , found 1242.6745. For ep/-21-l: ¹ HNMR (CDCI ₃ ) δ 7.86 (d, J = 10.0 Hz, 1 H), 7.73-7.34 (m, 10H), 6.52 (s, 1 H), 5.34 (m, 1 H), 4.90 (d, J = 10.0 Hz, 1 H), 4.47, (d, J = 1.5 Hz, 1 H), 4.08 (m, 1 H), 3.65 (dm, J = 10.5 Hz, 1 H), 3.42 (dd, J = 5.0, 11.0 Hz, 1 H), 4.47 (d, J = 1.5 Hz, 1 H), 4.08 (m, 1 H), 3.65 (dm, J = 10.5 Hz, 1 H), 3.42 (dd, J = 5.0, 11.0 Hz, 1 H), 3.23 (s, 3H), 3.27-3.10 (m, 4H), 3.00-2.95 (m, 1 H), 2.97 (s, 3H), 2.66 (dd, J = 12.0, 16.0 Hz, 1 H), 2.34 (s, 3H), 2.30 (m, 1 H), 2.01 (s, 3H), 1.97 (s, 3H), 2.03-1.94 (m, 2H), 1.78-1.42 (m, 8H), 1.36-1.28 (m, 3H), 1.16-1.10 (m, 36 H), 0.92 (s, 3H), 0.87 (s, 9H), 0.64 (d, J = 6.5

Hz, 3H), 0.05 (s, 3H), 0.01 (s, 3H).. MS (FAB) calculated for C ₆₆ Hi ₀₅ NO ₁₄ NaSi ₃ [M + Na] ⁺ 1242.6741 , found 1242.6745.

21 Psymberin 1 Substrate 21 was codistilled with toluene three times before use. To a solution of compound (25 mg, 0.02 mmol) in anhydrous THF (1 ml) was charged with phenyl selenocynate (18 mg, 0.08 mmol) followed by Bu ₃ P( 0.025 ml, 0.1 mmol). The reaction should turn to dark red immediately. The reaction was allowed to stir at rt for 2 h. The reaction was quenched by adding MeOH (0.5 ml) and the mixture was stirred for additional 15 minutes before it was concentrated. The residue was purified by FC to give a mixture of selenated product (The mixture was resulted from the liability of phenol acetate and TIPS group. Part of them is taken off under reaction conditions. However, this has no sequence since the phenol is not affected. Furthermore, a blank reaction with H ₂ O ₂ with compound 6c also proved that the subsequent oxidative elimination will not affect the phenol). The mixture was carried to the next step directly. To a solution of substrate at 0 ⁰ C was added THF (2 ml) and then 30 % aq H ₂ O ₂ (0.2 ml). The mixture was stirred at rt for 45 minutes and then at 50 ⁰ C for 1 to 2 h. The reaction mixture was dilute with EtOAc and then washed with Na ₂ SO ₃ thoroughly. After dried and concentrated, the residue was then dissolved in THF (1 ml), to this solution was added TBAF (0.1 M, 0.3 ml). The reaction mixture was stirred at 50 ⁰ C for 20 h and TLC shows only one compound has bright UV. The reaction was added water (1 ml) and diluted with EtOAc (20 ml), the aq layer was separated and pH was adjusted to 6 with aq NaHSO4 solution. The aq layer was then extracted with EtOAc thoroughly. Combined organic layer was washed with brine, dried and concentrated. PTLC of the residue gave psymberin 1 (8.1 mg, 67% over three steps) as a light yellow glass.[α] ²³ _D = + 19.5 (MeOH, c = 0.2 ¹ HNMR (CDCI ₃ ) δ 11.13 (s, 1 H), 7.22 (br, 1 H), 7.12 (d, J = 10.0 Hz, 1 H), 6.31 (s, 1 H), 5.44 (dd, J = 9.0, 10.0 Hz, 1 H), 4.81 (s, 1 H), 4.80 (s, 1 H), 4.54 (ddd, J = 4.0, 4.0, 12.5 Hz, 1 H), 4.43 (dd, J = 2.5, 3.0 Hz, 1 H), 4.40 (s, 1 H), 4.17 (br, 1 H), 3.94

(dm, J = 8.5 Hz, 1 H) ₁ 3.89 (m, 1 H), 3.75 (m, 1 H), 3.66 (dd, J = 4.0, 10.5 Hz, 1 H), 3.53 ( d, J = 11.0 Hz, 1 H), 3.38 (s, 3H), 3.37 (s, 3H), 2.87 (dd, J = 3.0, 16.0 Hz, 1 H), 2.80 (dd, J = 12.5, 16.5 Hz, 1 H), 2.38 (dd, J = 9.0, 14.5 Hz, 1 H), 2.18 (dd, J = 4.5, 14.5 Hz, 1 H), 2.06 (m, 1 H), 2.01 (s, 3H), 1.88 (m, 1 H), 1.80 (m, 1 H), 1.75 (s, 3H), 1.62 (m, 1 H), 1.09 (d, J = 7.5 Hz, 3H), 0.96 (s, 3H), 0.91 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 173.8, 170.7, 162.5, 161.4, 142.2, 139.9, 113.6, 113.3, 101.7, 101.5, 82.2, 80.7, 79.6, 78.6, 74.0, 73.3, 71.6, 58.2, 56.5, 42.8, 39.0, 37.8, 32.3, 29.9, 28.6, 23.3, 22.9, 14.0, 10.7, 9.7; MS (ES) calculated for C ₃ iH ₄₇ O ₁₁ Na [M + Na] ⁺ 632.30, found 632.23.

The same procedure for the synthesis of psymberin 1 was performed for compound ep/-21. The only difference is that treatment with TBAF can not remove the acetate on the secondary alcohol in this case. After removal of silyl group by TBAF, the residue was finally dissolved in MeOH (1 ml) and aq LiOH (1 N, 0.2 ml) was added. The reaction mixture was stirred at rt overnight. To this reaction was added water and EtOAc, the aq layer was separated and pH was adjusted to 6 with aq. NaHSO ₄ solution. The aq. layer was then extracted with EtOAc thoroughly. Combined organic layer was washed with brine, dried and concentrated. PTLC of the residue gave ep/-psymberin as a light yellow glass. ¹ HNMR (CDCI ₃ ) δ 11.24 (s, 1 H), 7.37 (d, J = 9.5 Hz, 1 H), 6.28 (s, 1 H), 5.04 (dd, J = 2.5, 10.0 Hz, 1 H), 4.83 (s, 1 H), 4.80 (s, 1 H), 4.56 (ddd, J = 3.5, 9.0, 13.0 Hz, 1 H), 4.36 (d, J = 4.0 Hz, 1 H), 4.12 (m, 1 H), 3.80 (dm, J = 11.5 Hz, 1 H), 3.73 (m, 1 H), 3.49 (dd, J = 5.0, 11.0 Hz, 1 H), 3.43 (s, 3H), 3.35 (s, 3H), 3.31 (d, J = 10.5 Hz, 1 H), 2.95 (dd, J = 4.0, 16.5 Hz, 1 H), 2.90 (dd, J = 12.0, 16.5 Hz, 1 H), 2.33 (dd, J = 9.0, 14.5 Hz, 1 H), 2.20 (m, 1 H), 2.04 (s, 3H), 1.95 (m, 1 H), 1.77 (s, 3H), 1.73 (m, 1 H), 1.65 (m, 1 H), 1.44 (m, 1 H), 1.13 (d, J = 7.5 Hz, 3H), 0.96 (s, 3H), 0.88 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 172.8, 170.8, 162.5, 160.9, 142.1 , 140.3, 113.5, 101.5, 86.5, 81.3, 80.8, 80.0, 74.8, 73.0, 71.3, 57.9, 56.5, 42.8, 39.4, 37.5, 32.3, 32.2, 28.4, 23.0, 22.4, 12.7, 10.8, 9.9; MS (ES) calculated for C ₃₁ H ₄₇ O ₁₁ Na

[M + Na] ⁺ found 632.23.

Under an atmosphere of Argon, a solution of compound 40 (420 mg, 0.38 mmol) in HFI (4 ml) at O ⁰ C was added MeOH (0.46 ml) and then a solution o DIB (498 mg, 1.5 mmol) dropwise as a solution in HFI (2 ml). The reaction stirred at rt for 40 h. The reaction mixture was diluted with EtOAc and filtered through a short pad of silica gel. The filtrated was concentrated and then purified by FC (acetone/hexane 1/10 to 1/2 to give two crude fraction A (220 mg), B (183 mg). This mixrure was carried on in the same way, which was described above to synthesize natural psymberin, to give the following four products. All the stereochemistry was assigned according to the NMR of natural psymberin and epi-psymberin.

¹ HNMR (CDCI ₃ ) δ 11.24 (br, 1 H), 7.43 (d, J = 10.0 Hz, 1 H), 6.27 (s, 1 H), 5.02 (dd, J = 2.5, 10.0 Hz, 1 H), 4.83 (s, 1 H), 4.81 (s, 1 H), 4.55 (m, 1 H), 4.37 (d, J = 4.5 Hz, 1 H), 4.18 (m, 1 H), 3.79 (m, 2H), 3.49 (s, 3H), 3.46 (m, 1 H), 3.40 (s, 3H), 3.00 (dd, J = 4.0, 17.0 Hz, 1 H), 2.94 (dd, J = 12.0, 16.5 Hz, 1 H), 2.40 (dd, J = 9.0, 15.0 Hz, 1 H), 2.25 (dd, J = 3.5, 15.0 Hz, 1 H), 2.07 (s, 3H), 1.83 (s, 3H), 2.00 (m, 1 H), 1.18 (d, J = 7.0 Hz, 3H), 0.99 (s, 3H), 0.92 (s, 3H); ¹³ C NMR

(CDCI ₃ ) δ 173.0, 162.6, 142.5, 140.4, 113.6, 101.6, 88.2, 81.7, 81.0, 80.2, 79.1, 73.4, 71.5, 58.1, 56.6, 43.0, 38.4, 37.7, 33.1, 32.9, 28.7, 27.5, 23.8, 23.2, 19.3, 10.9, 10.0; LCMS calculated for C ₃₁ H ₄₇ NaNO ₁ , [M + Na] ⁺ 616.3, found 616.3.

¹ HNMR (CDCI ₃ ) δ 11.17 (br, 1H), 7.10 (d, J= 10.0 Hz, 1H), 6.31 (s, 1 H), 5.09 (dd, J = 6.0, 10.0 Hz, 1 H), 4.81 (s, 1 H), 4.77 (s, 3H), 4.55 (m, 1 H), 4.42 (d, J = 3.5 Hz, 1H), 4.14 (m, 1H), 3.76 (ddd, J = 3.5, 4.0, 9.5 Hz, 1H), 3.46 (m, 1H), 3.40 (s, 3H), 3.35 (s, 3H), 2.93 (dd, J= 3.5, 17.0 Hz, 1H), 2.86 (dd, J= 7.5, 16.0 Hz, 1H), 2.32 (dd, J = 9.5, 14.5 Hz, 1H), 2.13 (dd, J = 3.5, 14.5 Hz, 1H), 1.96 (s, 3H), 1.74 (s, 3H), 1.12 (d, J= 7.0 Hz, 3H), 0.95 (s, 3H), 0.85 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 172.4, 171.2, 162.6, 161.7, 142.3, 140.3, 113.9, 113.5, 101.9, 101.6, 88.1, 82.8, 80.7, 80.5, 79.6, 72.9, 71.7, 57.9, 57.0, 42.9, 38.8, 37.3, 33.4, 33.1, 28.6, 27.5, 23.4, 23.1, 19.5, 10.8, 9.8; LCMS calculated for C ₃₁ H ₄₈ NO ₁₁ [M + H] ⁺ 594.3, found 594.3.

¹ HNMR (CDCI ₃ ) δ 11.17 (br, 1H), 7.11 (d, J= 10.0 Hz, 1H), 6.32 (s, 1H), 5.34 (dd, J= 8.0, 9.5 Hz, 1H), 4.83 (s, 1H), 4.78 (s, 1H), 4.59 (m, 1H), 4.44 (d, J = 4.0 Hz, 1H), 4.31 (br, 1H), 4.10 (d, J = 9.5 Hz, 1H), 3.77-3.72 (m, 2H), 3.63 (d, J= 10.0 Hz, 1H), 3.42 (s, 3H), 3.41 (s, 3H), 3.38-3.35 (m, 1H), 2.97 (dd, J =3.0, 16.5Hz, 1H), 2.85 (dd, J= 12.5, 17.0Hz, 1H), 2.28 (dd, J =9.5, 14.5 Hz, 1H), 2.06 (d, J= 14.5 Hz, 1H), 2.00 (s, 3H), 1.75 (s, 3H), 1.15 (d, J =7.0 Hz, 3H), 0.99 (s, 3H), 0.91 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 172.6, 171.0, 162.6, 161.6, 142.3, 140.2, 113.7, 113.6, 102.0, 101.7, 82.9, 81.0, 80.8, 80.7, 73.6, 72.7, 71.5, 57.9,

56.7, 43.0, 37.4, 33.5, 32.8, 31.8, 30.1 , 28.7, 27.5, 23.2, 23.1 , 22.3, 10.8, 9.8; LCMS calculated for C _3i H ₄₈ NOn [M + H] ⁺ 594.3, found 594.3.

¹ HNMR (CDCI ₃ ) δ 11.11 (br, 1 H), 6.32 (s, 1 H), 5.44 (dd, J = 7.5, 10.0 Hz, 1 H), 4.80 (br, 2H), 4.50 (dt, J = 4.0, 12.0 Hz, 1 H), 4.45 (d, J = 3.0 Hz, 1 H), 3.99 (d, J = 9.5 Hz, 1 H), 3.78 (m, 2H), 3.59 (d, J = 10.5 Hz, 1 H), 3.39 (s, 3H), 3.36 (s, 3H), 2.84 (dd, J = 3.5, 16.5 Hz, 1 H), 2.78 (dd, J = 12.0, 16.5 Hz, 1 H), 2.39 (dd, J = 9.0, 14.5 Hz, 1 H), 2.18 (dd, J = 3.5, 14.5 Hz, 1 H), 1.98 (s, 3H), 1.75 (s, 3H), 1.85 (m, 2H), 1.72 (m, 2H), 1.57-1.41 (m, 3H), 1.09 (d, J = 7.0 Hz, 3H), 0.93 (s, 6H); ¹³ C NMR (CDCI ₃ ) δ 174.1 , 171.0, 162.7, 162.0, 142.5, 140.0, 113.9, 113.4, 101.7, 101.6, 83.1 , 81.1 , 80.3, 78.8, 74.4, 73.4, 73.2, 60.9, 58.2, 56.7, 43.1 , 37.9, 33.5, 32.8, 32.5, 28.8, 27.7, 23.1 , 22.0, 21.6, 14.6, 10.9, 9.6; LCMS calculated for C _3I H ₄₈ NO ₁₁ [M + H] ⁺ 594.3, found 594.3.

To an oven dried seal tube was charged amide 43(28 mg, 0.172 mmol), CuI (5 mg, 0.028 mmol), and Cs ₂ CO ₃ (60 mg, 0.18 mmol) sequentially. Under argon dimethylethylenediamine (0.007 ml, 0.057 mmol) was then added followed by a solution of vinyl iodide 19 (60 mg, 0.057 mmol) in toluene (1.5 ml). The tube was filled with argon and quickly capped and sealed. The reaction was stirred vigorously at 70 ⁰ C overnight. After the reaction was cooled to rt, it was diluted with EtOAc and filtered off a short pad of silica gel and washed with EtOAc. The combined organic solution was concentrated and purified by PTLC to give the enamide 44 (55 mg, 90%) as oil. The excess amide was recovered. The mixture was carried through the next step without separation of the two

isomers. NMR of the major trans isomer: ¹ HNMR (CDCI ₃ ) δ 7.33 (d, J = 10.5 Hz, 1 H), 7.28-7.15 (m, 5H), 6.76 (dd, J = 10.5, 14.0 Hz, 1 H), 6.29 (s, 1 H), 5.17 (m, 1 H), 5.08 (m, 1 H), 4.97 (m, 1 H), 4.11 (dd, J = 2.5, 6.0, 12.5 Hz, 1 H), 3.44 (m, 1 H), 2.87 (dd, J = 2.0, 16.0 Hz, 1 H), 2.66-2.63 (m, 3H), 2.24-2.20 (m, 2H), 2.08 (br, 6H), 2.00 (s, 3H), 1.99-1.96 (m, 2H), 1.35-1.26 (m, 6H), 1.14-1.10 (m, 36H), 0.89-0.85 (m, 15H), 0.03 (br, 6H); MS (ES) calculated for C ₆ OHiO ₂ NOi ₀ Si ₃ [M + H] ⁺ 1080.68, found 1081.17.

was treated with a NaOMe solution in MeOH (0.08 M, 1 ml) at rt for 5h before quenched by water. The mixture was then extracted with EtOAc thoroughly. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude was dissolved in DCM. At 0 ⁰ C, pyridine, DMAP and then Ac ₂ O was added sequentially. The reaction was allowed to stir at 0 ⁰ C for 1 h before quenched with aq NH ₄ CI. the aq layer was extracted with EtOAc. Combine organic layer was washed with NH ₄ CI and brine. After dried and concentrated, the residue was purified by PTLC to give 45 as a mixture (40 mg) of two isomers (E/Z). The mixture was carried on to the next reaction directly. MS (ES) calculated for C ₄₉ H ₈ INO ₉ Si ₂ [M + H] ⁺ 882.54, found 882.63.

Under an atmosphere of Argon, a solution of compound 45 (40 mg, 0.0476 mmol) in HFI (0.5 ml) at 0 ⁰ C was added MeOH (0.04 ml) and then a solution o DIB (32 mg, 0.096 mmol) dropwise as a solution in HFI (0.5ml). The reaction stirred at rt for 20 h. The reaction mixture was diluted with EtOAc and filted througha short pad of silica gel. The filtrated was concentrated and then purified by FC (acetone/hexane 1/10 to 1/2) to give a crude, which was treated with TBAF (0.1 M, 4 ml) at 50 ⁰ C overnight. The residue was carefully purified to

yield the desired compound 46a (12 mg, 50%) and the epi-isomer 46b (4 mg, 20%).

The following compounds are synthesized in a similar way as described above.

MS (ES) calculated for C ₅₂ H ₉₄ NOi ₀ Si ₃ [M + H] ⁺ 976.62, found 976.79. calculated for C ₅₂ H ₉₃ NNaO ₁₀ Si ₃ [M + Na] ⁺ 998.60, found 998.60.

1HNMR (CDCI ₃ ) δ 11.25 (br, 1H), 6.30 (s, 1H), 5.82 (d, J= 10.0 Hz,

1H), 5.38 (dd, J = 7.0, 10.0 Hz, 1H), 4.53 (m, 1H), 3.94 (d, J= 10.0 Hz, 1H), 3.91 (m, 1H), 3.84 (br, 1H), 3.65 (dd, J = 4.5, 9.5 Hz, 1H), 3.59 (d, J= 9.5 Hz, 1H), 3.38 (s, 3H), 3.06 (dd, J = 3.0, 16.5 Hz, 1H), 2.83 (dd, J = 12.5, 17.0 Hz, 1H), 2.10 (s, 3H), 2.09 (s, 3H), 2.07-1.71 (m, 5H), 1.13 (d, J = 7.0 Hz, 3H), 1.00 (s, 3H), 0.93 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 172.8,.9; LCMS calculated for C ₂₅ H ₃₈ NO ₉ [M + H] ⁺ 496.3, found 496.3.

1HNMR (CDCI ₃ ) δ 11.21 (s, 1H), 6.32 (s, 1H), 6.05 (d, J= 10.0 Hz,

1H), 5.08 (dd, J = 2.5, 10.0 Hz, 1H), 4.58 (dt, J = 4.5, 11.0Hz, 1H), 4.14 (br, 1H), 4.09 (m, 1H), 3.74 (d, J= 12.5 Hz, 1H), 3.50 (dd, J = 4.5, 11.5 Hz, 1H), 3.32 (s, 3H), 3.29 (d, J= 10.0 Hz, 1H), 2.96-2.87 (m, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.98- 1.26 (m, 5H), 1.13 (d, J = 7.5 Hz, 3H), 0.96 (s, 3H), 0.88 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 171.5, 171.1, 162.7, 161.6, 140.3, 113.7, 101.7, 86.8, 81.6, 79.9, 75.0,

73.3, 56.5, 52.8, 43.0, 39.6, 32.5, 32.3, 30.1, 28.7, 23.8, 22.6, 20.8, 14.2, 13.1, 11.0, 10.1 ; LCMS calculated for C ₂₅ H ₃₈ NO ₉ [M + H] ⁺ 496.3, found 496.3.

This compound is synthesized in a similar way as descirbed above. ¹ HNMR (CDCI ₃ ) δ 11.24 (s, 1H), 7.30-7.12 (m, 5H), 6.29 (s, 1H), 6.07 (br, 1H), 5.85 (d, J = 11.0 Hz, 1 H), 5.35 (dd, J = 6.0, 9.5 Hz, 1 H), 4.52 (m, 1 H), 3.97 (m, 1H), 3.91 (d, J = 10.0 Hz, 1H), 3.85 (s, 1H), 3.64 (dd, J = 3.5, 8.0 Hz, 1H), 3.59 (d, J = 11.0 Hz, 1 H), 3.35 (s, 3H), 2.98 (dd, J = 3.0, 11.5 Hz, 1 H), 2.83 (dd, J = 12.5, 16.5 Hz ₁ 1H), 2.62 (t, J = 7.0 Hz, 1H), 2.38-2.22 (m, 3H), 2.04 (s, 3H), 2.01- 1.55 (m, 7H), 1.11 (d, J = 7.0 Hz, 1H), 0.99 (s, 3H), 0.83 (s, 3H); ¹³ C NMR (CDCi ₃ ) δ 174.5, 170.9, 162.7, 161.1, 141.6, 140.3, 128.9, 128.8, 126.5, 113.5, 102.4, 101.7, 82.9, 80.3, 79.9, 73.3, 72.2, 60.9, 56.6, 43.3, 38.6, 36.5, 32.8, 30.4, 28.8, 27.4, 14.6, 10.9, 10.1; LCMS calculated for C ₃₃ H ₄₇ NO ₉ [M + H] ⁺ 600.3, found 600.3.

¹ HNMR (CDCI ₃ ) δ 11.21 (s, 1H), 7.30-7.15 (m, 5H), 6.31 (s, 1H), 6.01 (d, J= 10.0Hz, 1H), 5.35 (br, 1H), 5.11 (d, J = 2.5, 10.0 Hz, 1H), 4.57 (dt, J = 4.5, 11.5Hz, 1H), 4.20 (m, 1H), 4.09 (d, J= 10.5 Hz, 1H), 3.76 (d, J= 12.0 Hz, 1H), 3.49 (dd, J = 5.0, 11.5 Hz, 1H), 3.31 (s, 3H), 2.94-2.85 (m, 2H), 2.65 (t, J = 8.0 Hz, 1H), 2.28 (t, J = 8.0 Hz, 1H), 2.02 (s, 3H), 2.00-1.94 (m, 2H), 1.78-1.59 (m, 5H), 1.13 (d, J = 7.0 Hz, 1H), 0.96 (s, 3H), 0.86 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 174.2, 171.0, 162.6, 161.4, 141.7, 140.4, 128.9, 126.5, 113.7, 102.1, 101.7, 86.8, 81.4, 79.9, 75.0, 734., 56.5, 43.0, 39.6, 36.3, 35.6, 32.5, 32.3, 30.1, 28.7, 27.4,

22.6, 13.1, 11.0, 10.1; LCMS calculated for C ₃₃ H ₄₇ NO ₉ [M + H] ⁺ 600.3, found 600.3.

¹ HNMR (CDCI ₃ ) δ 11.13 (s, 1H), 7.10 (d, J = 10.0 Hz, 1H), 6.30 (s, 1 H), 5.48 (dd, J = 8.5, 10.0 Hz, 1 H), 4.52 (ddd, J = 4.0, 4.5, 12.0 Hz, 1 H), 4.39 (br, 1H), 4.37 (s, 1H), 4.34 (d, J = 2.5 Hz, 1H), 3.93 (m, 1H), 3.89 (m, 1H), 3.76 (m, 1H), 3.68 (m, 1H), 3.55 (d, J= 10.0 Hz, 1H), 3.39 (s, 3H), 3.26 (s, 3H), 2.91 (dd, J = 8.0, 14.0 Hz, 1H), 2.86-2.78 (m, 3H), 2.08 (m, 2H), 2.01 (s, 3H), 1.86- 1.75 (m, 3H), 1.09 (d, J = 7.0 Hz, 3H), 0.99 (s, 3H), 0.92 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 174.1, 170.9, 162.8, 161.3, 140.1, 138.7, 129.9, 128.7, 126.7, 113.6, 102.1, 101.8, 83.8, 82.3, 79.9, 78.7, 74.4, 73.6, 73.4, 71.8, 60.8, 58.7, 56.7, 43.1, 39.2, 36.3, 32.6, 30.2, 28.9, 23.5, 21.5, 14.6, 14.0, 10.9, 9.7; LCMS calculated for C ₃₄ H ₄₈ NOn [M + H] ⁺ 646.3, found 646.4.

¹ HNMR (CDCI ₃ ) δ 11.28 (br, 1H), 7.42 (d, J = 10.0 Hz, 1H), 6.34 (s, 1H), 5.11 (dd, J= 3.0, 10.0Hz, 1H), 4.59 (m, 1H), 4.27 (d, J = 5.5 Hz, 1H), 4.18- 4.13 (m, 2H), 3.84 (m, 1H), 3.77 (m, 1H), 3.52 (m, 1H), 3.42 (s, 3H), 3.34 (s, 3H), 2.98-2.89 (m, 4H), 2.09 (s, 3H), 1.99-1.46 (m, 5H), 1.17 (d, J= 7.0 Hz, 3H), 1.00 (s, 3H), 0.92 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 173.4, 162.7, 138.3, 130.1, 128.7, 126.8, 101.7, 86.6, 83.7, 81.7, 80.2, 77.2, 75.0, 73.1, 71.5, 58.4, 56.7, 43.0, 39.6, 35.9, 32.5, 28.6, 22.6, 12.9, 10.9, 10.0, 9.9; MS (ES) calculated for C ₃₄ H ₄₇ NNaO ₁₁ [M + Na] ⁺ 668.30, found 668.33.

¹ HNMR (CDCI ₃ ) δ 11.13 (br, 1 H), 6.31 (s, 1 H), 5.48 (dd, J = 7.5, 10.0 Hz, 1 H), 4.50 (dt, J = 4.0, 11.5 Hz, 1 H), 4.38 (d, J = 3.0 Hz, 1 H), 3.79 (m, 2H), 3.59 (d, J = 10.0 Hz, 1 H), 3.38 (s, 3H), 3.27 (s, 3H), 2.91 (dd, J = 8.5, 14.0 Hz, 1 H), 2.88-2.75 (m, 3H), 1.97 (s, 3H), 1.87-1.80 (m, 2H), 1.75-1.68 (m, 2H), 1.58-1.43 (m, 3H), 1.09 (d, J = 7.5 Hz, 3H), 0.94 (s, 3H), 0.93 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 174.0, 171.0, 162.7, 161.8, 140.0, 138.9, 138.8, 130.0, 129.9, 129.8, 128.7, 128.6, 126.7, 113.8, 101.7, 83.8, 83.1 , 80.1 , 78.8, 74.2, 73.4, 73.3, 58.7, 58.2, 56.7, 43.1 , 36.2, 33.5, 32.8, 32.3, 28.8, 27.7, 22.0, 21.7, 10.9, 9.7; LCMS calculated for C ₃₄ H ₄₈ NOi ₀ [M + H] ⁺ 630.3, found 630.3.

1HNMR (CDCI ₃ ) δ 11.25 (br, 1 H), 7.44 (d, J = 10.0 Hz, 1 H), 6.28 (s,

1 H), 5.05 (dd, J = 2.5, 10.0 Hz, 1 H), 4.53 (ddd, J = 3.5, 5.0, 12.5 Hz, 1 H), 4.26 (d, J = 5.0 Hz, 1 H), 4.13 (m, 1 H), 3.73 (m, 2H), 3.40 (d, J = 10.5, Hz, 1 H), 3.35 (s, 3H), 3.28 (s, 3H), 2.93-2.81 (m, 4H), 1.98 (s, 3H), 1.94 (m, 1 H), 1.69-1.43 (m, 6H), 1.11 (d, J = 7.5 Hz, 3H), 0.92 (s, 3H), 0.85 (s, 3H); ¹³ C NMR (CDCI ₃ ) δ 173.4, 171.1 , 162.5, 161.5, 140.3, 138.5, 130.1 , 128.7, 126.8, 113.8, 102.0, 101.6, 88.3, 83.7, 81.8, 80.0, 79.1 , 73.6, 71.5, 58.5, 56.6, 43.0, 38.3, 35.9, 33.1 , 32.8, 28.7, 27.5, 23.8, 19.4, 10.9, 10.0; LCMS calculated for C ₃₄ H ₄₇ NNaO ₁₀ [M + Na] ⁺ 652.3, found 652.4.

Assessment of Biological Propertities

The protocol that was used to determine the observed biological activity is described as follows.

Cell proliferation assay

Ten human tumor cell lines were selected for the study: ACHN (kidney),

DU145 and PC3 (prostate), H226 and Hop-62 (lung), HCT116 and SW620 (colon), MB231 (breast), MB435 (melanoma) cell lines were obtained from ATCC (Manassas VA); MKN45 (gastric) cells were obtained from Riken BioResource Center, Japan. In addition, normal human dermal fibroblasts were assayed as a normal cell control . Cells are trypsinized to remove from flask and plated @ 2,000 cells /well in a Costar white, clear bottom 96 well assay plate and allowed to attach overnight. Five-fold serial dilutions were prepared, ranging from 1OuM to 25 pM (9 point dose-response). Compound dilutions were added to the plates, and the cells incubated at 37 degrees C for 4 days without media or compound replenishment. Final DMSO concentration in all wells was 0.1%. The number of viable cells at the end of the 4 day incubation was measured using the CellTiter- GIo Luminescent Cell Viability Assay (Promega, Technical bulletin 288). This assay determines the number of viable cells in culture based on the quantitation of ATP which is present, which signals the presence of metabolically active cells. The amount of ATP is directly proportional to the number of cells present in culture. Luminescence is read on a Victor Il plate analyzer. Total number of luminescent counts was plotted for each data point, and an IC ₅₀ determined A control plate was assayed to confirm that all cell lines were actively growing during the course of the assay.

All cell lines tested, including the normal human dermal fibroblasts, were sensitive to synthetic psymberin with IC ₅₀ values ranging from 0.2-0.8 nM (Table 2). The psymberin C8-9 epimer demonstrated -10,000 fold reduced toxicity in all cell lines. Table 2

To determine potency of compounds of the invention, effects on cell proliferation were measured in the human non-small cell lung carcinoma (NSCLC) cell line Hop62 using the protocol described above. In these assays, IC ₅₀ values ranged from 0.055 nM for the most active molecule to >10 uM (highest concentration tested) (Table 3). IC ₅₀ values in Table 3 correspond to the following ranges:

A: about 0.55 nM to about 1.0 nM;

B: about 1.0 nM to about 50 nM;

C: about 50 nM to about 300 nM;

D: about 300 nM to about 600 nM;

E: about 600 nM to about 10 μM;

F: >10 μM.

Table 3

Anti-cancer activity of C11-deoxypsymberin and its C8-9 epimers (structures shown below) against a wide range of cancer cell lines was as shown in Table 4.

beπn

Table 4. Anti-cancer Activity of Cl 1-Deoxypsymbeπn and Its Epimers.

Induction of apoptosis in human tumor cell lines

FACS analysis:

To determine the mechanism for cell death, Hop62 NSCLC cells were treated with 80 nM psymberin for 24, 30, 48 and 54 hours. Cells were harvested with trypsin and 1.0 x10 ⁶ cells were fixed in 70% MeOH or EtOH for 30 minutes, washed in PBS and resuspended in DNA stain solution (PBS containing 0.1% Triton X-100, 0.1 mM EDTA, 0.05 mg/ml RNase and 50ug/ml propidium iodide). Stained cells were analyzed on a FACS Caliber, and data analyzed to determine percentage of cells in sub-G1 as a measure of apoptotic cells.

Within 24 hours of addition of 8OnM psymberin, there was a 2.8 fold increase in the number of cells in sub-G1 (1.79% increased to 6.78%), indicative of a loss of DNA due to apoptotic cell death (Table 5). At tested time points, there was no cell cycle arrest observed.

Table 5

Caspase 3/7 induction

To confirm that psymberin induced cell death through activation of apoptosis, activation of Caspase 3/7 was assayed using the Caspase-Glo 3/7 Assay from Promega Corp.

Hop62 cells were plated as described for the proliferation assays. Serial dilutions of psymberin were added to the cells 24 hours after plating, and caspase 3/7 activation assayed at 1 , 8, 24 and 30 hours post compound addition. At each respective timepoint, Caspase-Glo 3/7 reagent is added and measured for luminescence (Wallac 1420 VICTOR 2, Perkin Elmer, Waltham,

Massachusetts). Caspase3/7 activation was observed by 8 hours post compound addition, and reached maximal levels by 24 hours (Table 6). The EC ₅₀ at 24 hours was 3.3 nM.

Table 6 Caspase Activity (Caspase GIo 3/7) in HOP62 Cells

Psymberin Dose Response (Fold Increase over Control)

The ability of selected compounds of the invention to induce apoptosis in a panel of human tumor cell lines is reported in Table 7. Compound numbers correspond to the numbering scheme in Table 1. A greater than 2-fold induction of caspase activation is considered an induction of the apoptotic cell death pathway.

Table 7

While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.