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Title:
PIPERIDINE AND MORPHOLINE RENIN INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2007/117560
Kind Code:
A2
Abstract:
Described are compounds which are orally active and bind to renin to inhibit its activity. They are useful in the treatment or amelioration of diseases associated with renin activity. Also described are methods of use of these compounds for treating or ameliorating a renin mediated disorder in a subject.

Inventors:
BALDWIN JOHN J (US)
CLAREMON DAVID A (US)
TICE COLIN M (US)
CACATIAN SALVACION (US)
DILLARD LAWRENCE W (US)
ISHCHENKO ALEXEY V (US)
YUAN JING (US)
XU ZHENRONG (US)
MCGEEHAN GERARD (US)
ZHAO WEI (US)
SIMPSON ROBERT D (US)
SINGH SURESH B (US)
Application Number:
PCT/US2007/008521
Publication Date:
October 18, 2007
Filing Date:
April 05, 2007
Export Citation:
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Assignee:
VITAE PHARMACEUTICALS INC (US)
BALDWIN JOHN J (US)
CLAREMON DAVID A (US)
TICE COLIN M (US)
CACATIAN SALVACION (US)
DILLARD LAWRENCE W (US)
ISHCHENKO ALEXEY V (US)
YUAN JING (US)
XU ZHENRONG (US)
MCGEEHAN GERARD (US)
ZHAO WEI (US)
SIMPSON ROBERT D (US)
SINGH SURESH B (US)
International Classes:
C07D211/22; A61K31/445; A61P9/12; C07D265/30
Domestic Patent References:
WO2001014328A22001-03-01
WO2006042150A12006-04-20
WO2007070201A12007-06-21
Foreign References:
US5244910A1993-09-14
US5442044A1995-08-15
EP0385593A11990-09-05
EP0483403A11992-05-06
Attorney, Agent or Firm:
DAVIS, Steven G. et al. (Brook Smith & Reynolds, P.C.,530 Virginia Road, P.O. Box 913, Concord MA, US)
Download PDF:
Claims:

CLAIMS

What is claimed is: A compound represented by the following structural formula:

wherein:

G a is a) (Ci-C 9 )alkyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 9 )cycloalkylalkyl, halo(Cι- C 9 )alky], halo(C 3 -C 7 )cycloalkyl, halo(C 4 -C 9 )cycloaIkylalkyl, saturated heterocyclyl optionally substituted with 1 to 3 groups independently selected from fluorine, (Ci-C 3 )alkyl, halo(Ci-C 3 )aIkyI, and oxo; or b) phenyl, napthyl, hctcroaryl, or bicyclic heteroaryl each optionally substituted with 1 to 3 groups independently selected from the groups consisting of:

1) fluorine, chlorine, bromine, cyano, nitro, (Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, (C 5 - C6)cycloalkenyl, (C 5 -C8)cycloalkylalkenyl, (C2-C6)alkynyl, (C 3 -C 6 )cycloalkylethynyl, haIo(C|-C 6 )alkyl, halo(C 3 - C 6 )cycloalkyl, halo(C 4 -C 7 )-cycloalkylalkyl, halo(C 2 - C 6 )alkenyl, halo(C 3 -C 6 )alkynyl, halo(C 3 - C6)cycloalkylethynyl, (Ci-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C|-C 6 )alkoxy, halo(C 3 - C 6 )cycloalkoxy, halo(C 4 -C 7 )cycloalky]alkoxy, (C 3 - C6)alkenyloxy and (C|-C 6 )alkanesulfonyl; or

2) phenyl, heteroaryl, phcnoxy, hctcroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroaryloxy, each optionally substituted with 1 to 3 groups

independently selected from the group consisting of fluorine, chlorine, cyano, (C|-C 3 )alkyl, halo(C|-C 3 )alkyl, (C 1 -C 3 )- alkoxy, halo(Ci-C 3 )alkoxy, and aminocarbonyl; G b is hydrogen, (C|-C 8 )alkyl, (C 4 -C 8 )cycloalkylalkyl, fluoro(C|- C 8 )alkyl, fluoro(C 4 -C 8 )cycloalkylalkyl, (C r C 8 )alkoxy, (C 4 -

Cg)cycloalkylalkoxy, fluoro(C|-C8)alkoxy, hydroxy(C|-C8)alkyl, (Ci- C 5 )alkoxy(Ci-C 5 )alkyl, halo(Ci-C 5 )alkylamino(C r C 5 )alkyl, (C r C 5 )alkoxy(Ci-C 5 )hydroxyalkyl, (C 3 -C 4 )cycloalkoxy(Ci-C 5 )alkyl, fluoro(Ci- C 5 )alkoxy(C i -C 5 )alkyl , fluoro(C 3 -C 4 )cycloalkoxy(C , -C 5 )alkyl, (C i - C 8 )alkylthio(Ci-C 5 )aIkyl, (C r C 5 )alkoxy(C|-C 5 )alkoxy, hydroxy(Q-

C8)alkoxy, (C 3 -C 4 )cycloalkoxy(C|-C 5 )alkoxy, fluoro(C|-C 5 )alkoxy(C|- Cs)alkoxy, fluoro(C 3 -C 4 )cycloalkoxy(C|-C 5 )aIkoxy : , (C|-C 3 )alkoxy(C|- C 3 )alkoxy(Ci-C 3 )alkyl, fluoro(C1-C 3 )alkoxy(Ci-C 3 )alkoxy(C|-C 3 )alkyl, aminocarbonylamino(Ci-Cg)alkyl, aminocarbonylamino(Ci-C 8 )alkoxy., (Ci- C 5 )alkanoylamino(Ci-C 5 )alkyl, (Ci-C 5 )alkanoylamino(C]-C 5 )alkoxy, fluoro(C i -C 5 )alkanoylam ino(C i -Cs)alkyl, fluoro(C i -C5)alkanoyl amino(C i - C 5 )alkoxy, (Cι-C 3 )alkoxy(Ci-C 5 )alkanoylamino(CrC 5 )alkyl, (C r C 3 )alkoxy(C i -C 5 )alkanoylamino(C i -C 5 )alkoxy, (C 3 - C4)cycloalkanecarbonyllamino(Ci-C 5 )alkyl, (C 3 - Q)cycl oalkanecarbonyl lamino(C j -C5)alkoxy, am inosυl fonylamino(C i -

C8)alkyl, aminosulfonylamino(Ci-C8)alkoxy, (Ci-C5)alkanesulfonyl- am ino(C i -C5)alkyl, (C i -C5)alkanesulfonylamino(C i -C5)al koxy, formylamino(C|-C 5 )alkyl, formylamino(Ci-C 5 )alkoxy, (Ci- C 5 )alkoxycarbonylamino(C i -C5)alkyl, (C i -C 5 )alkoxycarbonyl-am ino(C i - C5)alkoxy, (Ci-C 5 )alkylaminocarbonylamino(Ci-C 5 )alkyl, (Ci-

C 5 )alkylaminocarbonyl-amino(Ci-C 5 )alkyl, di(C|-

C5)alkylaminocarbonylamino(C|-C 5 )alkoxy, aminocarbonyl(Ci-C 5 )alkyl, am inocarbony 1(C i -Cs)alkoxy, (C i -C 5 )alkylaminocarbonyl (C i -C 5 )alkyl, (C i - C5)alkylaminocarbonyl-(Ci-C 5 )alkoxy, aminocarboxy(Ci-C5)alkyI, aminocarboxy(Ci-C 5 )alkoxy, (Ci-C 5 )alkylamino-carboxy(Ci-C 5 )alkyl, (Ci-

C 5 )alkylaminocarboxy(C i -C5)alkoxy, (C i -C 8 )alkoxycarbonylamino, (C i - C8)alkylaminocarbonylamino, (Ci-C 8 )alkanoylamino, fluoro(Ci-

Cs)alkoxycarbonylaminb, fluoro(Ci-C8)alkylaminocarbonylamino, or fluoro(Ci-Cg)alkanoylamino;

G c is -H, halogen, OH, (Ci-C4)alkanoylamino, or (Ci-C 3 )alkoxy; provided that i) G b and G c are not both hydrogen and ii) when G c is OH or halogen, G b is not (Ci-Cs)alkoxy ! , (C4- fluoro(Ci-C8)alkoxy, (Ci-C 5 )alkoxy(Ci- C 5 )alkoxy, hydroxy(Ci-Cg)alkoxy, (C 3 -C 4 )cycloalkoxy(Ci- C5)alkoxy, fluoro(Ci-C 5 )alkoxy(Ci-Cs)alkoxy, flυoro(C 3 - C4)cycloalkoxy(C]-C5)alkoxy, aminocarbonylamino(Ci-

Cs)alkoxy, (Cι-C5)alkanoyl-amino(Cι-C 5 )aIkoxy, fluoro(C|- C 5 )alkanoylamino(C] -C 5 )alkoxy, (C 1 -C 3 )aIkoxy(C 1 - C5)alkanoyl-amino(C 1 -Cs)alkoxy, (C 3 - C4)cycloalkanecarbonyllamino(Ci-C 5 )alkoxy, aminosulfonylamino(Ci-Cs)alkoxy, (Ci-

C5)alkanesulfonylamino(C|-C 5 )alkoxy 5 formylamino(C|- C5)alkoxy, (C 1 -C5)alkoxy-carbonylamino(C 1 -Cs)alkoxy, di(C 1 -C 5 )alkylaminocarbony lam ino(C j -C 5 )alkoxy, aminocarbonyl(Ci-C5)alkoxy, (Ci-Cs)alkylaminocarbonyl(Ci- C 5 )alkoxy, aminocarboxy(C|-Cs)alkoxy, (Ci-

C 5 )alkylaminocarboxy(Ci-C 5 )alkoxy, (Ci- Cij)alkoxycarbonylamino, (Ci-C 8 )alkylaminocarbonylamino, (C|-C 8 )alkanoylainino, fluoro(C]-C 8 )alkoxycarbonylamino, fluoro(Ci-C 8 )alkylaminocarbonylamino, or fluoro(Ci- Cg)alkanoylamino;

A 4 is CH 2 or O; Q is a divalent radical selected from:

Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8

N M N /; X N M M n oorrr T N Il » I N I w arhee arettianc Nhe adn tdo T the O* *O o* O truncated bonds

Q9 Q10 Q11 Q12 Q13 and

T is a mimic of the Leu-Val cleavage site of angiotensinogen or an enantiomer, diastereomer or salt thereof.

2. The compound of Claim 1, wherein: G a is: a) (C 3 -C 7 )cycloalkyl; or b) phenyl, heteroaryl, or bicyclic heteroaryl optionally substituted with 1 to 3 groups independently selected from the groups consisting of:

1) fluorine, chlorine, bromine, cyano, nitro, (Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, (C 5 - C 6 )cycloalkenyl, (C 5 -Cg)cycloalkylalkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkylethynyl, halo(C|-C 6 )alkyl, halo(C 3 - C 6 )cycloalkyl, halo(C 4 -C 7 )-cycloalkylalkyl, halo(C 2 -

Cc)alkenyl, halo(C 3 -C 6 )alkynyl, halo(C 3 -C 6 )cycloalkylethynyl, (Ci-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C4-C 7 )cycloalkylalkoxy, halo(Ci-C 6 )alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C4- C 7 )cycloalkylalkoxy, (C 3 -C ό )alkenyloxy and (C |- C6)alkanesulfonyl; or

2) phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroaryloxy, each optionally substituted with 1 to 3 groups independently selected from the group consisting of fluorine,

chlorine, cyano, (Ci-C 3 )alkyl, halo(Ci-C3)alkyl, (C i -C 3 )- alkoxy, halo(Ci-C 3 )alkoxy, and aminocarbonyl; G b is (Ci-C 8 )alkyl, (C 4 -C 8 )cycloalkylalkyl, fluoro(C,-C 8 )alkyl, fluoro(C4-Cg)cycloalkylalkyl, (Ci-C 8 )alkoxy, (C 4 -C 8 )cycloalkylalkoxy, fluoro(d-C 8 )alkoxy, hydroxy(Ci-Cg)alkyl, (Ci-C 5 )alkoxy(C r C s )alkyl, haIo(C,-C 5 )alkylamino(Ci-C 5 )alkyl, (C|-C 5 )alkoxy(Ci-C 5 )hydroxyalky], (C 3 - C4)cycloalkoxy(C|-C 5 )alkyl 3 fluoro(C 1 -C 5 )alkoxy(Ci-C 5 )alkyl, fluoro(C 3 - C4)cycloalkoxy(C|-C 5 )alkyl ; (Ci-C 5 )alkylthio(C|-C 5 )alkyl, (C,- C 5 )alkoxy(C|-C 5 )alkoxy, hydroxy(Ci-C 8 )alkoxy, (C 3 -C 4 )cycloalkoxy(Ci- C 5 )alkoxy, fluoro(CrC 5 )alkoxy(Ci-C 5 )alkoxy, fluoro(C 3 -C 4 )cycloalkoxy(C t -

C 5 )alkoxy, (C|-C 3 )alkoxy(Ci-C 3 )alkoxy(Ci-C 3 )alkyI, fluoro(C r C 3 )alkoxy(C|-C 3 )alkoxy(C|-C 3 )alkyl, aminocarbonylamino(C|-Cs)alkyl, aminocarbonyIamino(C i -C 8 )alkoxy, (C i -C 5 )alkanoylamino(C i -Cs)alkyl, (C i - C 5 )alkanoylamino(Ci-C 5 )alkoxy, fluoro(Ci-C 5 )alkanoylamino(Cι-C5)alkyl, fluoro(Ci-Cs)alkanoylamino(Ci-C5)alkoxy, (C|-C 3 )alkoxy(Ci-

Cs)alkanoylamino(C i -Cs)alky], (C ] -C 3 )alkoxy(C j -C 5 )alkanoylamino(C i - C5)alkoxy, (C3-C4)cycloalkanecarbonyllamino(Ci-C 5 )alkyl, (C 3 - C 4 )cycloalkanecarbonylIamino(Ci-C 5 )alkoxy, aminosulfonylamino(Ci- C 8 )alkyl, arninosulfonylamino(Ci-C 8 )alkoxy, (Ci-C 5 )alkanesulfonyl- amino(Ci-C5)alkyl, (Ci-C 5 )alkanesulfonylamino(C)-C 5 )alkoxy, formylamino(C|-C 5 )alkyl, formylamino(Ci-Cs)alkoxy, (Ci- C 5 )alkoxycarbonylamino(C|-C 5 )alkyI, (Ci-Cs)alkoxycarbonyι-arnino(Cι- C5)alkoxy, (Cι-C5)alkylaminocarbonylamino(Ci-C 5 )alkyl, (Ci- C5)alkylaminocarbonyl-amino(Ci-C5)alkyl, di(Ci- C5)alkylaminocarbonylamino(Ci-C 5 )alkoxy, aminocarbonyl(Ci-C5)alkyI, aminocarbonyl(C i -Cs)alkoxy 5 (C i -C 5 )alkylaminocarbonyl(C i-C5)alkyl, (C i - Cs)alkylaminocarbonyl-(C i -C 5 )alkoxy, aminocarboxy(C i -Cs)alkyl, am inocarboxy(C i -C 5 )alkoxy, (C i -C 5 )alkylam ino-carboxy (C i -C 5 )alkyl , (Ci- C5)alkylaminocarboxy(C|-C 5 )alkoxy, (Cι-C 8 )alkoxycarbonylamlno, (Cr CsJalkylaminocarbonylamino, (C|-C 8 )alkanoylamino, fluoro(Ci-

C8)alkoxycarbonylamino, fluoro(Ci-C 8 )alkylaminocarbpnylamino, or fluoro(Ci-C 8 )alkanoylamino;

G c is -H 5 halogen, OH, (C r C 4 )alkanoylamino, or (C|-C 3 )alkoxy; provided that when G c is OH or halogen, then G b is not (Ci-Cg)alkoxy, (C4- C8)cycloalkylalkoxy, fluoro(C 1 -Cg)alkoxy, (C 1 -C 5 )aIkoxy(C 1 -C 5 )alkoxy, hydroxy(C 1 -C 8 )alkoxy 5 (C 3 -C 4 )cycloalkoxy(C 1 -C 5 )alkoxy, flυoro(C 1 - C 5 )alkoxy(Ci-Cs)alkoxy, fluoro(C 3 -C 4 )cycloalkoxy(Ci-C 5 )alkoxy, aminocarbonylamino(C 1 -Cβ)alkoxy, (C 1 -C 5 )alkanoylamino(C 1 -Cs)alkoxy, fluoro(C 1 -Cs)alkanoy lamino(C 1 -Cs)alkoxy, (C 1 -C 3 )aIkoxy(C 1 - C 5 )alkanoylamino(Ci-C 5 )alkoxy, (C 3 -C 4 )cycloalkanecarbonyllamino(Ci- C 5 )alkoxy, aminosulfonylamino(Ci-C 8 )alkoxy, (Cj- C 5 )alkanesulfonylamino(C r C 5 )alkoxy ! formylamino(Ci-Cs)alkoxy, (Ci-

C 5 )alkoxycarbonyl-am ino(C 1 -Cs)alkoxy, (C 1 - C5)alkyIaminocarbonylamino(C]-C 5 )alkyl, (Ci-

C 5 )alkylam inocarbonylamino(C 1 -C 5 )alkyl, arninocarbonyl(C 1 -Cs)alkyl, (C 1 - C 5 )alkylaminocarbonyl(Ci-Cs)alkyl, aminocarboxy(C|-C 5 )alkyl or (Ci- Cs)alkylamino-carboxy(Ci-C5)alkyl,

A 4 is CH 2 or O; and

Q is a divalent radical selected from:Ql, Q2, Q4, Q5, Q9, or Ql O

V ft wherein N and T N N af e attached to the s truncated bonds

Q1 Q2 Q4 Q5 Q9 O.λQ

or an enantiomer, diastereomer or salt thereof.

3. The compound of Claim 2, wherein:

G a is: a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-ρyridyl, 2-imidazolyl, 2-thiazolyl, 2- benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3- dihydro-7-benzofuryl, 7-benzothienyl, l 3 3-benzodioxol-4-yl, 7- indazolyl, or 8-quinolinyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of

fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, t-butyl, isobutyl, trifluoromethyl, allyl, cyclohexyl, cyclohexen-1 -yl, cyclopropylethynyl, methoxy, trifluoromethoxy, neopentyloxy, methylthio, allyloxy, cyclopropylmcthoxy, 2-(cyclopropyl)ethoxy, cyclopentyloxy, cyclopentylmethoxy, benzyloxy, hydroxyl, aminocarbonyl, methoxycarbonyl, phenyl, phenoxy, benzyloxy, and heteroaryloxy, wherein the phenyl phenoxy, benzyloxy and hctcroaryloxy groups are optionally substituted with 1 to 3 substituents independently selected from fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, and aminocarbonyl;

G b is methyl, ethyl, propyl, butyl, hexyl, 5-pentenyl, 3,3,3- trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4- (cyclopropyl)butyl 5 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4- hydroxyhexyl, 3-ethoxypropyl, 4-methoxy butyl, 4-ethoxybutyl, 2- (ethoxy)ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, 2- cyclopropylethoxy, 3-(2,2,2-triflluoroethylamino)propyl, 3- (formylamino)propyl, 3-(acetylamino)propyl 5 3-(propionylamino)propyl, 3- (butanoylamino)propyl, 3-((2-methoxypropionyl)amino)propyl, 3- (cyclopropanecarbonylamino)propyl, 3-(trifluoroacetylamino)propyl, 3- (methoxycarbonylamino)propyl, 3-(ethoxycarbonylamino)propyl, 2-

(methoxycarbonylamino)ethoxy, 2-(ethoxycarbonylamino)ethoxy, 3- (methylaminocarbonylamino)propyl, 3-

(dimethylaminocarbonylamino)propyl, 2-(acetylamino)elhoxy, aminocarbonylmethoxy, (methylamino)carbonylmethoxy or 3- (aminosulfonylamino)propyl;

G c is H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino, provided that when G c is F or OH, G b is not 2-(ethoxy)ethoxy, 3-methoxypropoxy, 3- cthoxypropoxy, 3-propoxypropoxy, 2-cyclopropylethoxy, 2- (methoxycarbonylamino)ethoxy, 2-(ethoxycarbonylamino)ethoxy, 2-

(acetylamino)ethoxy, aminocarbonylmethoxy, (methylamino)carbonylmethoxy or 3-(aminosulfonylamino)propyl;

A 4 is CH 2 or O; Q is Ql

wherein N and T are attached to the truncated bonds

Q1 ; and

T is selected from the groups consisting of:

1) Tl - T9 wherein G d is (C 1 -C 8 )BIlCyI, (C 3 -C 7 )cycolaklyl or (C 3 - C 7 )cycloalky 1(C i -C 2 )alky 1 ;

T7 T8 T 9

I O 2) Tl O wherein G d and G e are independently selected from (Ci-C 8 )alkyl, (C 3 -C 7 )cycolaklyl or (C 3 -C 7 )cycloalkyl(C r C 2 )alkyl;

W

-213 -

3) Tl I — Tl 4 wherein G* is a heteroaryl or heterocyclyl group, preferably G r is 2-pyridyl, l-piperidinyl or 4-morpholinyl; and

T11 T12 T13

4) Tl 5 wherein G ε is a heteroaryl group

or an enantiomer, diaslereomer or salt thereof.

The compound of Claim 3, wherein the compound is represented by the following structural formula:

or an enantiomer, diastereomer or salt thereof.

5. The compound of Claim 4, wherein:

T is selected from the group consisting of Tl - Tl 4:

H

or an enantiomcr, diastereomer or salt thereof.

6. The compound of Claim I, wherein the compound is selected from the group consisting of:

or an enanti

7. The compound of Claim I 5 wherein the compound is selected from the group consisting of:

or an enantiomer, diastereomer or salt thereof.

8. A pharmaceutical composition comprising a compound of Claim 1 , or enantiomer, diastereomer, or salt thereof and a pharmaceutically acceptable carrier or excipient.

9. A method of ameliorating or treating renin related disorders in a subject in need thereof comprising administering to said subject an effective amount of a compound of Claim 1 or an enantiomer, diastereomer, or salt thereof.

10. The method of Claim 9, wherein said disorder is hypertension, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, post-surgical hypertension, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety states, or cognitive disorders.

1 1. A method for treating or ameliorating an aspartic protease mediated disorder in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Claim 1, or an enantiomer, diastereomer, or salt thereof.

12. A method of ameliorating or treating renin related disorders in a subject in need thereof comprising administering to the subject a compound of Claim 1 in combination therapy with one or more additional agents said additional agent selected from the group consisting of ct-blockers, β-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosterone synthase inhibitors, aldosterone-receptor antagonists, and endothelin receptor antagonists.

13. The method of Claim 12, wherein: the α-blockers are selected from the group consisting of doxazosin, prazosin, tamsulosin, and terazosin; the β-blockers are selected from the group consisting of atenolol, bisoprol, metoprolol, acetutolol, esmolol, celiprolol, taliprolol, acebutolol, oxprenolol, pindolol, propanolo!, bupranolol, penbutolol, mepindolol, carteolol, nadolol, and carvedilol, or pharmaceutically acceptable salts thereof; the calcium channel blockers are selected from the group consisting of dihydropyridines (DHPs) and non-DHPs, wherein the DHPs are selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, modiphine, nisoldipine, nitrendipine, and nivaldipine and their pharmaceutically acceptable salts and the non-DHPs are selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verampimil, or pharmaceutically acceptable salts thereof; the diuretics is a thiazide derivative selected from the group consisting of an amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon; the ACE inhibitors are selected from the group consisting of alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril; dual ACE/NEP are selected from the group consisting of include omapatrilat, fasidotril, and fasidotrilat; the ARBs are selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan; the aldosterone synthase inhibitors are selected from the group consisting of anastrozole, fadrozole, and exemestane;

the aldosterone-rcccptor antagonists are selected from the group consisting of spironolactone and eplerenone; and the endothelin antagonists are selected from the group consisting of bosentan, enrasentan, atrasentan, darusentan, sitaxentan, and tezosentan, or pharmaceutically acceptable salts thereof.

14. The method of Claim 13, wherein the compound and the additional agents arc administered by sequential administration or simultaneous administration.

Description:

PIPERIDINE AND MORPHOLINE RENIN INHIBITORS

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 60/789,723, filed April 5, 2006, the entire teachings of which are incorporated herein by reference.

BACKGROLTND OF THE INVENTION

In the renin-angiotensin-aldosterone system (RAAS) the biologically active peptide angiotensin II (Ang II) is generated by a two-step mechanism. The highly specific asparlic protease renin cleaves angiptensinogen to angiotensin I (Ang 1), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is known to work on at least two receptor subtypes called AT] and AT 2 . Whereas ATi seems to transmit most of the known functions of Ang FI 5 the role of AT 2 is still unknown. jModulation of the RAAS represents a major advance in the treatment of cardiovascular diseases (Zaman. M. A. et al Nature Reviews Drug Discovery 2002. /. 621-636). ACE inhibitors and AT] blockers have been accepted as treatments of hypertension (Waeber B. et al, "The renin-angiotensin system: role in experimental and human hypertension", in Berkenhager W. H., Reid J. L. (eds): Hypertension. Amsterdam, Elsevier Science Publishing Co, 1996, 489-519; Weber M. A. 5 Am. J. Hypertens., 1992, 5, 247S). In addition, ACE inhibitors are used for renal protection (Rosenberg M. E. el al, Kidney International, 1994, 45, 403; Breyer J. A. et al.,

Kidney International, 1994, 45, S 156), in the prevention of congestive heart failure (Vaughan D. E. et ah, Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al, Am. J. Med. . . 1988, 84 (SuppL 3A), 83) and myocardial infarction (Pfeffer M. A: et al, N Engl J: Med, 1992, 527, 669). Interest in the development of renin inhibitors stems from, the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9. 645). The only substrate known for renin is angioiensinogen, which can only be processed (under physiological . ' ■ conditions) by renin. In contrast. ACE can also cleave bradykinin besides Ang I and can be bypassed by chymase. a serine protease (Husain A., J. Hypertens., 1993, 11.

1 155). In patients, inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Israili Z. H. et al, Annals of Internal Medicine, 1992, 117, 234). Chymase is not inhibited by ACE inhibitors. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors. Blockade of the ATI receptor (e.g., by losartan) on the other hand overexposes other AT-receptor subtypes to Ang II, whose concentration is dramatically increased by the blockade of ATI receptors. In summary, renin inhibitors are not only expected to be superior to ACE inhibitors and ATi blockers with regard to safety, but more importantly also with regard to their efficacy in blocking the RAAS.

Only limited clinical experience (Azizi M. el al., J. Hypertem., 1994, 12, 419; Neutel J. M. et al, Am. Heart, 1991, 122, 1094) has been generated with renin inhibitors because their peptidomimetic character imparts insufficient oral activity (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. It appears that only one compound has entered clinical trials (Rahuel J. et al, Chem. Biol, 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1 139). Thus, metabolically stable, orally bioavailable and sufficiently soluble renin inhibitors that can be prepared on a large scale are not available. Recently, the first non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et al, Chem. Biol, 1999, 6, 127; Patent Application WO 97/0931 1 ; Maerki H. P. et al, Il Farmaco, 2001,5(5,21). The present invention relates to the unexpected identification of renin inhibitors of a non-peptidic nature and of low molecular weight. Orally active renin inhibitors of long duration of action which are active in indications beyond blood pressure regulation where the tissular renin- chymase system may be activated leading to pathophysiological^ altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis, are described.

SUMMARY OF THE INVENTION

Compounds of Formula I have now been found which are orally active and bind to renin to inhibit its activity. They are useful in the treatment or amelioration of diseases associated with renin activity.

In one embodiment the present invention is directed to a compound represented by Formula I

or an enantiomer, diastcrcomcr or salt thereof.

G a is a) (C|-C 9 )alkyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 9 )cycloalkylalkyl, halo(C r

Cc))alkyl, halo(C 3 -C 7 )cycloalkyl, halo(C 4 -C 9 )cycloalkylalkyl, saturated heterocyclyl optionally substituted with 1 to 3 groups independently selected from fluorine, (Ci- C 3 )alkyl, halo(Ci-C3)alkyl, and oxo; or b) phenyl, napthyl, heteroaryl, or bicyclic heteroaryl each optionally substituted with 1 to 3 groups independently selected from the groups consisting of:

1) fluorine, chlorine, bromine, cyano, nitro, (Ci-C 6 )alkyl, (C 3 - C 6 )cycloalkyl, (C 4 -C 7 )cycloalkylalkyl, (C 2 -C 6 )alkenyl, (C 5 -C 6 )cycloalkenyl, (C 5 - C 8 )cycloalkylalkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkylethynyl, halo(C)-C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )-cycloalkylalkyl, halo(C 2 -C 6 )alkenyl, halo(C 3 - C 6 )alkynyl, halo(C 3 -C 6 )cycloalkylethynyl, (Ci-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 - C 7 )cycloalkylalkoxy, halo(C|-Cg)aIkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C 4 - C 7 )cycloalkylalkoxy, (C 3 -C 6 )alkenyloxy and (Ci-C 6 )alkanesulfonyl; or

2) phenyl, heteroaryl, phenoxy, heteroaryl oxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroaryloxy, each optionally substituted with 1 to 3 groups independently selected from the group consisting of fluorine, chlorine, cyano, (Ci-C 3 )alkyl, halo(Ci-C 3 )alkyl, (C 1 -C 3 )- alkoxy, halo(Ci-C 3 )alkoxy, and aminocarbonyl.

-A -

G b is hydrogen, (C,-C 8 )alkyl, (C 4 -C 8 )cycloalkylalkyl, fluoro(Ci-C 8 )alkyl, fluoro(C4-C8)cycloalkylalkyl, (Ci-C 8 )alkoxy, (C 4 -Cg)cycloalkylalkoxy, fluoro(Ci- C 8 )alkoxy, hydroxy(Ci-C 8 )alkyl, (C 1 -C 5 )alkoxy(Ci-C 5 )alkyl, halo(C r C 5 )alkylam ino(C i -C 5 )alkyl, (C i -C 5 )alkoxy(C i -C 5 )hydroxyalky I , (C 3 - C 4 )cycloalkoxy(C|-C 5 )alkyl, fluoro(Ci-C 5 )alkoxy(Ci-C 5 )alkyl, fluoro(C 3 -

C 4 )cycloalkoxy(C i -C 5 )alkyl, (C , -C 5 )alkylthio(C i -C 5 )alkyl, (C i -C 5 )alkoxy(C i - C 5 )alkoxy, hydroxy(C|-C 8 )alkoxy, (C 3 -C 4 )cycloalkoxy(Ci-C 5 )alkoxy, fluoro(Ci- Cs)alkoxy(C i -C 5 )alkoxy, fluoro(C 3 -C 4 )cycloalkoxy(C i -C 5 )alkoxy, (C i - C 3 )alkoxy(C i -C 3 )alkoxy(C , -C 3 )alkyl, fluoro(C i -C 3 )alkoxy(C i -C 3 )alkoxy(C i - C 3 )alkyl 5 aminocarbonylamino(Ci-C 8 )alkyl, aminocarbonylamino(Ci-C 8 )alkoxy,

(Ci-C5)alkanoylamiήo(Ci-C 5 )alkyl, (Cι-C 5 )alkanoylamino(Ci-C 5 )alkoxy, fluoro(Ci- C5)alkanoylamino(C i -Cs)alkyl, fluoro(C i -C 5 )alkanoylamino(C i -C5)alkoxy, (C i - C 3 )alkoxy(C , -C 5 )alkanoylaraino(C ,-C 5 )alkyl, (C , -C 3 )alkoxy(Ci - C 5 )alkanoylamino(C|-C 5 )alkoxy, (C 3 -C 4 )cycloalkanecarbonyllamino(Ci-C 5 )alkyl, (C3-C 4 )cycloalkanecarbonyllamino(Ci-C 5 )alkoxy 5 aminosulfonylamino(Ci-C 8 )alkyl :> aminosulfonylamino(Ci-Cg)alkoxy, (Ci-C 5 )alkanesulfonyl-amino(Ci-C5)alkyl, (Cr C 5 )alkanesulfonylamino(C]-C 5 )alkoxy, formylamino(Ci-C 5 )alkyl, formylamino(C|- C 5 )alkoxy, (Ci-C 5 )alkoxycarbonylamino(C]-C 5 )alkyl, (C|-C 5 )alkoxycarbonyl- amino(C|-Cs)alkoxy, (C|-C 5 )alkylaminocarbonylamino(Ci-C 5 )aIkyl, (C]- C 5 )alkylaminocarbonyl-amino(C|-C 5 )alkyl, di(C|-C 5 )alkylaminocarbonylamino(C|- C 5 )alkoxy, aminocarbonyl(Ci-Cs)alkyl, aminocarbonyl(Ci-C 5 )alkoxy, (Ci- C 5 )alkylaminocarbonyl(C|-Cs)alkyl, (Cι-C 5 )alkylaminocarbonyl-(Ci-C 5 )alkoxy, aminocarboxy(Ci-C 5 )alkyl, aminocarboxy(Ci-C 5 )alkoxy, (Ci-Cs)alkylamino- carboxy(C i -Cs)alkyl, (C i -C5)alkylaminocarboxy(C i -Cs)alkoxy, (C i - C 8 )alkoxycarbonylamino, (Ci-Cs^lkylaminocarbonylamino, (C|-C 8 )alkanoylamino, fluoro(C)-C 8 )alkoxycarbonylamino, fluoro(C|-C 8 )alkylaminocarbonylamino, or fluoro(Ci-Cg)alkanoylamino.

G c is -H, halogen, OH, (C|-C 4 )alkanoylamino, or (Ci-C 3 )alkoxy; provided that i) G b and G c are not both hydrogen and ii) when G c is OH or halogen, G b is not (C,-C 8 )alkoxy, (C 4 - C 8 )cycloalkylalkoxy, fluoro(C i -C 8 )alkoxy, (C i -C 5 )alkoxy(C i -C 5 )alkoxy,

hydroxy(C i -C 8 )alkoxy, (C 3 -C 4 )CyClOaIkOXy(C i -Cs)alkoxy, fluoro(C i -Cs)alkoxy(C i- Cs)alkoxy, fluoro(C 3 -C 4 )cycloalkoxy(Ci-Cs)alkoxy, aminocarbonylamino(Ci- Cg)alkoxy, (C|-C 5 )alkanoyl-amino(Ci-C 5 )alkoxy, fluoro(C|-C 5 )alkanoylamino(Ci- C 5 )alkoxy, (Ci-C 3 )alkoxy(C|-C 5 )alkanoyl-amino(C|-C 5 )alkoxy, (C 3 - C 4 )cycloalkanecarbonyllamino(C|-C 5 )alkoxy, aminosulfonylamino(Cι-C 8 )alkoxy, (C i -Cs)alkanesulfonylamino(C i -Cs)alkoxy, formylam ino(C i -C 5 )alkoxy, (C i - C5)alkoxy-carbonylamino(Cι-Cs)alkoxy, di(C|-C5)alkylaminocarbonylamino(Cr Cs)alkoxy, aminocarbonyl(Ci-Cs)alkoxy, (Ci-C5)alkylaminocarbonyl(Ci-Cs)alkoxy, aminocarboxy(Cι-C5)alkoxy, (Ct-C5)alkylaminocarboxy(Ci-C 5 )alkoxy, (Ci- C 8 )alkoxycarbonylamino, (Ci-C^alkylaminocarbonylamino, (Cι-Cg)alkanoylamino, fluoro(Ci-Cs)alkoxycarbonylamino, fluoro(C|-C 8 )alkylaminocarbonylamino, or fluoro(Ci-C 8 )alkanoylamino.

A 4 is CH 2 or O.

Q is a divalent radical selected from:

Q1 Q2 Q3 Q4 QQ55 QQ66 Q Q77 Q8

0 V Q/ 0 w arhee arettianc Nhe adn tdo T the

. / Vr truncated bonds Q9 Q10 Q11 Q12 Q13

T is a mimic of the Leu- VaI cleavage site of angiotensinogen.

In another embodiment the present invention is directed to pharmaceutical compositions comprising a compound described herein or an enantiomer, diastereomer, or salt thereof and a pharmaceutically acceptable carrier or excipient.

In another embodiment the present invention is directed to method for treating or ameliorating an aspartic protease mediated disorder in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof.

In another embodiment the present invention is directed to a method for treating or ameliorating a renin mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound described herein or an enantiomer, diastereomer, or salt thereof.

In another embodiment the present invention is directed to a method for treating or ameliorating a renin mediated disorder in a subject in need thereof comprising administering to the subject a compound described herein in combination therapy with one or more additional agents said additional agent selected from the group consisting of α-blockers, β-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosterone synthase inhibitors, aldosterone-receptor antagonists, and endothelin receptor antagonists.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

In a first embodiment, the invention provides compounds of Formula I

G a is a) (Ci-CcOalkyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 9 )cycloalkylalkyl, halo(C r C 9 )alkyl, halo(C 3 -C 7 )cycloalkyl, halo(C 4 -C 9 )cycloalkylalkyl, saturated heterocyclyl optionally substituted with 1 to 3 groups independently selected from fluorine, (Ci-C 3 )alkyl, halo(C|-C 3 )alkyl, and oxo; or b) phenyl, napthyl, heteroaryl, or bicyclic heteroaryl each optionally substituted with 1 to 3 groups independently selected from:

1) fluorine, chlorine, bromine, cyano, nitro, (Ci-C6)alkyl, (C 3 -C 6 )cycloalkyl, (C 4 - C 7 )cycloalkylalkyl/(C 2 -C6)alkenyl, (C 5 -C 6 )cycloalkenyl, (Cs-C 8 )cycloalkylalkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkylethynyl, halo(Ci-C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(CrC 7 )-cycloalkylalkyl, halo(C 2 -C 6 )alkenyl, halo(C 3 -C 6 )alkynyl, halo(C 3 - 5 C 6 )cycloalkylethynyl, (Ci-C 6 )alkoxy 5 (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C 3 -C6)cycloalkoxy, halo(C 4 -C 7 )cycloalkylalkoxy, (C 3 - C6)alkenyloxy and (Ci-C6)alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroaryloxy, each optionally substituted with 1 to 3 groups independently selected 10 from: fluorine, chlorine, cyano, (Ci-C 3 )alkyl, halo(Ci-C 3 )alkyl, (C|-C 3 )-alkoxy, halo(Ci- C 3 )alkoxy, and aminocarbonyl;

G b is hydrogen, (C,-C 3 )alkyl, (C 4 -C 8 )cycloalkylalkyl, fluoro(C,-C 8 )alkyl, fluorosi s Cg)cycloalkylalkyl, (Ci-C 8 )alkoxy, (C 4 -C 8 )cycloalkylalkoxy, fluoro(Ci-C 8 )alkoxy, hydroxy(Ci-C 8 )alkyl, (C 1 -C 5 )alkoxy(Ci-C5)alkyl ! halo(Ci-C 5 )alkylamino(C,- C 5 )alkyl, (Ci-C 5 )alkoxy(C|-C 3 )hydroxyalkyl 5 (C 3 -C 4 )cycloalkoxy(C|-C 5 )alkyl, fluoro(C i -C 3 )alkoxy(C , -C 5 )alkyl 5 fluoro(C 3 -C 4 )cycloalkoxy(C , -C 5 )alkyl, (C , - C 5 )alkylthio(CrC 5 )alkyl, (Ci-C 5 )alkoxy(Cι-C 5 )alkoxy, hydroxy(C r C 8 )alkoxy, (C 3 - 0 C 4 )cycloalkoxy(C i -C 5 )alkoxy, fluoro(C i -C 5 )alkoxy(C i -C 5 )alkoxy, fluoro(C 3 -

C 4 )cycloalkoxy(C i -C 3 )alkoxy, (C i -C 3 )alkoxy(C i -C 3 )alkoxy(C ( -C 3 )alkyl 5 fl uoro(C , - C 3 )alkoxy(C i -C 3 )alkoxy(C i -C 3 )alkyl, aminocarbonylamino(C i-C 8 )alkyl, aminocarbonylamino(Ci-C8)alkoxy, (Ci-C5)alkanoylamino(Ci-Cs)alkyl, (Ci- Cs)alkanoylam ino(C i -Cs)alkoxy, fluoro(C i -Cs)alkanoylam ino(C i -C 5 )alkyl, 5 fluoro(C i -C 5 )alkanoylam ino(C i -C 5 )alkoxy, (C i -C3)alkoxy(C i -C 5 )alkanoylam ino(C i - C 5 )alkyl, (C|-C3)alkoxy(CrC5)alkanoylamino(C]-C5)alkoxy, (C 3 - C4)cycloalkanecarbonyllamino(Cι-C 5 )alkyl, (C 3 -C4)cycloalkanecarbonyllamino(Ci- C5)alkoxy, aminosuJfonylamino^i-C^alkyl, aminosulfonylamino(C|-Cg)alkoxy, (C i-Cs)alkanesulfonyl-amino(C i -Cs)alky\ > (C i -C 5 )alkanesulfonylamino(C i - 0 C 5 )alkoxy, formylamino(Ci-C 5 )alkyl, formylamino(Ci-C 5 )alkoxy > (Ci-

C 5 )alkoxycarbonylamino(C i-Cs)alkyl, (C i -C 5 )alkoxycarbonyl-amino(C i -C 3 )alkoxy, (C i -C 5 )alkylaminocarbonylamino(C i -C 5 )alkyl, (C i -C 5 )alky laminocarbonyl-

amino(Ci-C5)alkyl, di(Ci-C5)alkylaminocarbonylamino(Ci-C 5 )alkoxy, aminocarbonyl(Ci-C5)alkyl, aminocarbonyl(Cι-C 5 )alkoxy, (C|- C 5 )alkylaminocarbonyl(Ci-C 5 )alkyl, (Ci-C 5 )alkylaminocarbonyl-(Ci-C 5 )alkoxy, aminocarboxy(Cι-C5)alkyl, aminocarboxy(Ci-C 5 )alkoxy, (Ci-C 5 )alkylamino- carboxy(Ci-C5)aIkyl, (Ci-C 5 )alkylaminocarboxy(C|-C5)alkoxy, (Ci-

C 8 )alkoxycarbonylamino , (Ci-C^alkylaminocarbonylamino, (C|-C 8 )alkanoylamino, fluoro(C1-C 8 )alkoxycarbonylamino, fluoro(Ci-C 8 )alkylaminocarbonylamino, or flυoro(C i -C s)alkanoylam i no;

G c is H , halogen, OH , (C|-C 4 )alkanoylamino, or (C|-C 3 )alkoxy;

provided that (i) G b and G c are not both hydrogen and (ii) when G c is OH or halogen, G b is not (Ci-C8)alkoxy, (C 4 -C 8 )cycloalkylalkoxy, fluoro(C|-C8)alkoxy, (Ci-C 5 )alkoxy(Ci-C5)alkoxy , hydroxy(Ci-C 8 )alkoxy, (C 3 -C 4 )cycloalkoxy(Ci- C 5 )alkoxy, fluoro(Ci-C 5 )alkoxy(C|-C5)alkoxy, fluoro(C 3 -C 4 )cycloalkoxy(Cj- C 5 )alkoxy, aminocarbonylamino(C|-C8)aIkoxy, (Ci-Cs)alkanoyl-amino(Cι- C 5 )alkoxy, fluoro(C i -C5)alkanoylamino(C i -C 5 )alkoxy, (C i -C 3 )alkoxy(C i - C 5 )alkanoyI-amino(Ci-C5)alkoxy, (C3-C4)cycloaIkanecarbonyllamino(Ci-C 5 )alkoxy 5 aminosulfonylamino(Ci-C8)alkoxy 5 (Ci-Cs)alkanesulfonylamino(Ci-C5)alkoxy, formylamino(Ci-C5)alkoxy, (C|-C 5 )alkoxy-carbonylamino(C|-C 5 )alkoxy, di(Cι- C 5 )alkylam inocarbonylam ino(C i -C 5 )alkoxy, aminocarbonyl(C i -C5)alkoxy, (C i - C 5 )alkylaminocarbonyl(C i -C5)alkoxy, aminocarboxy(C i -C5)alkoxy, (Cr C 5 )alkylaminocarboxy(Ci-C5)alkoxy, (Ci-C8)alkoxycarbonylamino, (Ci- C 8 )alkylaminocarbonylamino, (C|-C8)alkanoylamino 5 fluoro(Ci- C 8 )alkoxycarbonylamino, fluoro(Ci-C 8 )alkylaminocarbonylamino, or fluoro(Ci- C8)alkanoylamino;

A 4 is CH 2 or O;

Q is a divalent radical selected from:

Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8

w arhee arettianc Nhe adn tdo T the truncated bonds

Q9 Q10 Q11 Q12 Q13

T is a mimic of the Leu- VaI cleavage site of angiotensinogen.

The term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein includes the substituents (T) disclosed in the following references:

LuIy, ct al.. U.S. Pat. No. 4,645,759, issued Feb. 24, 1987, which is hereby incorporated by reference, discloses mimics of the Lcu-Val cleavage site of angiotensinogen having the formula

wherein R 4 , Rs, R 6 , R 7 , R 8 , R9 and X are as defined therein;

LuIy, et al., U.S. Pat. No. 4,652,551, issued Mar. 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein wherein R 4 , Rs-, RO, R7, Rs 5 R9 and X are as defined therein;

LuIy, et al., U.S. Pat. No. 4,680,284, issued JuI. 14, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 is as defined therein;

LuIy, et al., U.S. Pat. No. 4,725,584, issued Feb. 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 and R 4 are as defined therein;

LuIy, et al., U.S. Pat. No. 4,725,583, issued Feb. 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 and R 5 are as defined therein;

Rosenberg, et al., U.S. Pat. No. 4,837,204, issued Jun. 6, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 , R 5 , R 6 , R 7 and X are as defined therein;

LuIy, et al., U.S. Pat. No. 4,845,079, issued JuI. 4, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 , R 5 , R 6 , R 7 , Rs and R 9 are as defined therein;

Sham, U.S. Pat. No. 4,826,958, issued May 2, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 , R5, R 6 , R 7 , R 9 and X are as defined therein;

Rosenberg et al., U.S. Pat. No. 4,857,507, issued Aug. 15, 1989, which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

!'

R;. wherein R 4 , Rs, R 6 , R 7 , Rg 3 R 9 and E are as defined therein;

LuIy 5 et al., U.S. Pat. No. 4,826,815, issued May 2, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 , Rs, R 6 , R 7 , R 8 , R 9 and X are as defined therein;

Bender, et al., U.S. Pat. No. 4,818,748, issued Apr. 4, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 1 , J 5 L, M and Q are as defined therein;

Fuhrer, et al., U.S. Pat. No. 4,613,676, issued Sep. 23, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 , R 4 , R 5 and R 6 are as defined therein;

Riniker, et al., U.S. Pat. No. 4,595,677, issued Jun. 17, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 and R 4 are as defined therein;

Buhlmayer, et al., U.S. Pat. No. 4,727,060, issued Feb. 23, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 , R 4 , R 5 and R 6 are as defined therein;

Buhlmayer, et al., U.S. Pat. No. 4,758,584, issued JuI. 19, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 , R 4 , Rs and R 6 are as defined therein;

Szelke, et al., U.S. Pat. No. 4,609,643, issued Sep. 2, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— A— B— Z— W

wherein A, B, Z and W are as defined therein;

Szelke, et al., U.S. Pat. No. 4,650,661 , issued Mar. 17, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— A-B — Z-W

wherein A, B, Z and W arc as defined therein;

Szelke, et al., U.S. Pat. No. 4,713,445, issued Dec. 15, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

—A— B — Z-W

wherein A, B, Z and W are as defined therein;

lizuka, ct al., U.S. Pat. No. 4,656,269, issued Apr. 7, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, X and R 2 are as defined therein;

Iizuka, et al. , U.S. Pat. No. 4,711,958, issued Dec. 8, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X is as defined therein;

Klcinman, et al., U.S. Pat. No. 4,729,985, issued Mar. 8, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R], R 2 , m, W , R 3 and R 4 are as defined therein;

Hoover, U.S. Pat. No. 4,668,769, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X and R 2 are as defined therein;

Hoover, et al., U.S. Pat. No. 4,814,342, issued Mar. 21 , 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X, W and Z 1 are as defined therein;

Bindra, et al., U.S. Pat. No. 4,749,687, issued Jun. 7, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiolensinogen having the formula

wherein Ri, R 2 and R3 are as defined therein;

Hoover, et al., U.S. Pat. No. 4,814,342, issued Mar. 1 , 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X, W and Z 1 are as defined therein;

Matsueda, et al., U.S. Pat. No. 4,698,329, issued Oct. 6, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

^NH X

R. A wherein R 3 and X are as defined therein;

Matsueda, et al., U.S. Pat. No. 4,548,926, issued Oct. 22, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

^NH x Bui wherein But and X are as defined therein;

Wagnon, el al., U.S. Pat. No. 4,725,580, issued Feb. 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Zj, X, Y and R 4 are as defined therein;

Wagnon, et al., U.S. Pat. No. 4,746,648, issued May 24, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Zi, X, Y and R 4 are as defined therein;

Cazaubon, et al., U.S. Pat. No. 4,481,192, issued Nov. 6, 1984, which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

— Statyl i — Ala — Statyb — R'

wherein Statyl ι, Ala, Statyl 2 and R' are as defined therein;

Hansen, et al., U.S. Pat. No. 4,722,922, issued Feb. 2, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , R5, n and Re are as defined therein;

Hansen, et al., U.S. Pat. No. 4,510,085, issued Apr. 9, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 is as defined therein;

Baran, et al., U.S. Pat. No. 4,657,931 , issued Apr. 14, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

H OH OH

R ] O wherein Ri, n and R 5 are as defined therein;

Hansen, et al., U.S. Pat. No. 4,514,332 issued Apr. 30, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri, n and R 5 are as defined therein;

Natarajan, et al., U.S. Pat. No. 4,757,050, issued JuI. 12, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri, R 2 , R 3 , q, R9 and Rio are as defined therein;

Gordon, U.S. Pat. No. 4,749,781, issued Jun. 7, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri, R 2 , R 3 and R9 are as defined therein;

Ryono, et al., U.S. Pat. No. 4,665,193, issued May 12, 1987, which is hereby. incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

R-i O

R- R? wherein Ri, R 2 , R 3 , R 4 and A are as defined therein;

Ryono, et al., U.S. Pat. No. 4,616,088, issued Oct. 1, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val. cleavage site of angiotensinogen having the formula

wherein Ri, R 2 , R3, R 4 and A are as defined therein;

Ryono, et al., U.S. Pat. No. 4,629,724, issued Dec. 16, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri, R 2 , R 3 , R 4 , R, R 12 and A are as defined therein;

Patel, U.S. Pat. No. 4,820,691, issued Apr. 11, 1989, which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein R] and R 3 are as defined therein;

Thaisrivongs, U.S. Pat. No. 4,705,846, issued Nov. 10, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiolensinogen having the formula

— Eio — Fi I — Gi 2 — H 13 — 1 14 — Z

wherein Ej 0 , Fn, G] 2 , Hi 3 , I 14 and Z are as defined therein;

Hudspeth, et al., U.S. Pat. No. 4,743,585, issued May 10, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— T— (C) n — W— (D) n —V— (E) n — U

wherein T, C, W, D 3 V, E 3 U and n are as defined therein;

Hudspeth, el al. 5 U.S. Pat. No. 4,735,933, issued Apr. 5, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

v w/ I T

wherein Y, W and U are as defined therein;

Kaltenbronn, et al., U.S. Pat. No. 4,804,743, issued Feb. 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— T-U — V — W

wherein T, U, V and W are as defined therein;

Pinori, et al., U.S. Pat. No. 4,560,505, issued Dec. 24, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Tyr and Lys are as defined therein;

Yamato, et al., U.S. Pat. No. 4,683,220, issued July 28, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

Boger, et al., U.S. Pat. No. 4,668,770, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

E

wherein R 3 , R 4 , q, B, D and E are as defined therein;

Boger, U.S. Pat. No. 4,668,663, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , m , E 5 B and F are as defined therein;

Bock, et al., U.S. Pat. No. 4,636,491, issued Jan. 3, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , m' and E are as defined therein;

Bock, et al., U.S. Pat. No. 4,663,310, issued May 5, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein G, R 4 , J, B and L are as defined therein;

Boger, et al., U.S. Pat. No. 4,661,473, issued Apr. 28, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having lhe formula

wherein G, R 4 , J, B and L are as defined therein;

Vcber, et al., U.S. Pat. No. 4,479,941, issued Oct. 30, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 and E are as defined therein;

Boger, el al., U.S. Pat. No. 4,470,971, issued Sep. 1 1 5 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , R 5 , B and E are as defined therein;

Veber, et al., U.S. Pat. No. 4,384,994, issued May 24, 1983, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri, R 2 , R 3 , R 4 and B are as defined therein;

Boger, et al., U.S. Pat. No. 4,812,442, issued Mar. 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— G— J

wherein G and J are as defined therein;

Evans, U.S. Pal. No. 4,665,055, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 , R 5 , B and C are as defined therein;

Evans, et al., U.S. Pat. No. 4,609,641, issued Sep. 2, 1986, which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein Ri, R2, X, Y, B and C are as defined therein;

Palchett, et al., U.S. Pat. No. 4,839,357, issued Jun. 13, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein G and J are as defined therein;

Boger, et al., U.S. Pat. No. 4,812,442, issued Mar. 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— G — J

wherein G and J are as defined therein;

Boger, U.S. Pat. No. 4,665,052, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , R 5 , m and F are as defined therein;

Veber, et al., U.S. Pat. No. 4,478,826, issued Oct. 23, 1984, which is hereby incorporated by reference, discloses mimics of the Lcu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , R 4n , B and E are as defined therein;

Boger, et al., U.S. Pat. No. 4,485,099, issued Nov. 27, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , R 5 , m and F are as defined therein;

Boger, et al., U.S. Pat. No. 4,477,440 issued Oct. 16, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , m", E, F and G are as defined therein;

Raddatz, et al., U.S. Pat. No. 4,721,776, issued Jan. 26, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 , R 4 , R 5 , n, B and D are as defined therein;

Holzemann, et al., U.S. Pat. No. 4,709,010, issued Nov. 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R, Ri, R 2 , n and Y are as defined therein;

Raddatz, et al., U.S. Pat. No. 4,812,555, issued Mar. 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R3, R 4 , n and E are as defined therein;

Raddatz, et al., U.S. Pat. No. 4,755,592, issued JuI. 5, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— W— E— W— Y

wherein W, E, W and Y are as defined therein;

Raddatz, et al., U.S. Pat. No. 4,666,888, issued May 19, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ru E, G and Y are as defined therein;

Wagnon, et al., U.S. Pat. No. 4,840,935, issued Jun. 20, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 , R5, Q and X are as defined therein;

lizuka, et al., U.S. Pat. No. 4,841 ,067, issued Jun. 20, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n and X are as defined therein;

Raddatz, et al., U.S. Pat. No. 4,829,053, issued May 9, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— N(R 2 )- CH(R 3 )- CR 4 - (CHRs) n - C(O)- E— N(R 6 )- {CH(R 7 )) S — D

wherein n, s, R 2 , R3, R 4 , R5, R 6 , R7, E and D are as defined therein;

Biswanath et al., U. S. Pat. No. 5,164,388, issued Nov 17, 1992, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 4 and R5 are as defined therein;

European Patent Application No. EP0264106, published Apr. 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R^, R 5 , R 6 and R 7 are as defined therein including R 4 is hydrogen or loweralkyl; R 5 is hydrogen, loweralkyl or an amino acid residue; R 6 is loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl and R 7 is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or an N-heterocycle;

European Patent Application No. EP0272583, published Jun. 29, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 5 , R 6 , R 7 and R 8 are as defined therein including R 5 is hydrogen or loweralkyl; R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an amino acid residue; and R 7 and Rs are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl;

European Patent Application No. EP0309766, published Apr. 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Rs 3 R 6 and A are as defined therein including R 5 is hydrogen or loweralkyl; R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl or heterocyclic; and A is — CH(OH) — (CH) q — R 7 wherein q is 0-5 and R 7 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, substituted thioalkyl,

subslϊtuted sulfone, substituted sulfoxide, substituted amine, quaternized amine, heterocyclic, carboxyalkyl, alkoxycarbonylalkyl or amidoalkyl;

European Patent Application No. EP0300189, published Jan. 25, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 is as defined therein including R 4 is loweralkyl;

European Patent Application No. EP0283970, published Sep. 28, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 is as defined therein including R 4 is loweralkyl;

European Patent Application No. EP0255082, published Feb. 3, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 and R 4 are as defined therein including R 2 is hydrogen, alkyl, cyclcoalkyl, cycloalkylalkyl, aryl or arylalkyl; R 3 is hydrogen, alkyl or arylalkyl; and R4 is — X — (CH 2 ) n R 7 wherein X is absent, O or S, n' is 0-4 and R 7 is hydrogen,

hydroxy, amino, heteroaryl or — CH(Rg) — (CH 2 ) P — Y — (CH 2 ) q — Rio wherein p, q, Y and Rio are as defined therein*

European Patent Application No. EP0230242, published JuI. 29, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 and R 4 are as defined therein including R 2 is hydrogen, alkyl, , cycloalkylalkyl, aryl or arylalkyl; R 3 is hydrogen, alkyl or alkenyl; and R 4 is — N(R 5 )- CH(R 6 )- (CH 2 )H- Ar or — N(R 5 )- CH(R 6 )- CH=CH- (CH 2 ) m — Ar wherein n is 0-6, m is 0-4, R 5 is hydrogen or alkyl and R 6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, thioalkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl or arylalkoxycarbonylaminoalkyl;

European Patent Application No. EP0310015, published Apr. 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 , R4 and R 9 are as defined therein including R 2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylaikyl; R 3 is hydrogen, alkyl, aryl or arylalkyl; R9 is hydroxy or fluoro; and R 4 is — (CH 2 ) P — X — (CH 2 ) q — R 7 wherein p is 0-4, q is 0-4, X is — CF 2 — , — C(O) — or — CH(R 8 ) — wherein R 8 is alkyl, alkoxy, thioalkoxy, alkylamino, hydroxy, azido or halo and R 7 is hydrogen, hydroxy, amino, aryl or heteroaryl;

European Patent Application No. EP0315574, published May 10, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

fB a a boron alum) wherein R 2 , X 3 Y, R 3 and R 4 are as defined therein including R 2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl or heterocyclic; X and Y are independently selected from O or -N(Ri 3 )- wherein Ri 3 is hydrogen, alkyl or substituted alkyl; and R 3 and R 4 are independently selected from hydrogen, alkyl or aryl; or the boron containing substituent is a boron containing cyclic group;

Japanese Patent Application No. J63275552, published Nov. 14, 1988 discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

European Patent Application No. EP0252727, published Jan. 13, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Y and R are as defined therein including Y is O or NH and R is alkyl, cycloalkyl or halogenated alkyl;

European Patent Application No. EP0244083, published Nov. 4, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X is as defined therein including X is alkoxy, alkyalamino, cycloalkyloxy, morpholino and haloalkoxy.

European Patent Application No. EP0216539, published Apr. 1 , 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, Y and R 2 are as defined therein including n is 0-1, Y is O or NH and R 2 is alkyl;

European Patent Application No. EP0206807, published Dec. 30, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, Z and R are as defined therein including n is 0-1, Z is O or NH and R is alkyl;

European Patent Application No. EPO 190891, published Aug. 13, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n and X 1 are as defined therein including n is 0-1 and X 1 is alkoxycarbonyl, aralkoxycarbonyl, or -C(O)NRi R 2 wherein Ri is hydrogen, alkyl or aralkyl and R 2 is alkyl or — CH 2 — Y — R wherein Y is O or NH and R is alkyl or aralkyl;

European Patent Application No. EP0181 1 10, published May 14, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R3 and R 4 are as defined therein including R3 is -CHO or -CH 2 OH and R 4 is isobutyl or benzyl;

European Patent Application No. EP0297816, published Jan. 4, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, Ri and R 2 are as defined therein including n is 0-1, Ri is -NH 2 , alkylamino, alkoxy, or 2-alkoxycarbonylpyrrolidin-l-yl and R 2 is alkyl, alkenyl, haloalkenyl or azide substituted alkenyl;

European Patent Application No. EP0297815, published Jan. 4, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Y and R 2 are as defined therein including Y is --CH(OH)- or -C(O)-- and R 2 is— CF 2 C(O)NHCH 3 ,- CF 3 or— CF 2 CH(CH 2 CH(CH 3 ) 2 )CO 2 C 2 H 5 ;

European Patent Application No. EP0212903, published Mar. 4, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein m, Ri, R 2 , R 3 , R 4 and W 2 are as defined therein including m is 0-1, Ri and R 2 are independently selected from hydrogen, alkyl, alkenyl, phenyl, naphthyl, cycloalkyl, cycloalkenyl, phcnylalkyl, naphthylalkyl, cycloalkylalkyl and cycloalkenylalkyl, R 3 and R 4 are independently selected from alkyl, phenyl, naphthyl, cycloalkyl, adamantyl, phenylalkyl, naphthylalkyl, cycloalkylalkyl and adamantylalkyl; or R 3 is hydrogen and R 4 is — CH(R 7 )(CH 2 ) p (Q) r CH(R 8 )(CH 2 ) q — Y wherein p and q are independently selected from 0,1,2,3,4,5 and 6, r is 0-1, Q is — CH 2 -, — CH=CH-, — O— , -NH-, — CH(OH) — or — C(O) — , Y is methyl, phenyl, — C(O)OR 9 , C(O)NR 9 Ri 0 , — C(O)NHC(O)OCH 2 C 6 H 55 -NH 2 , -NHC(O)CH 2 C 6 H 5 , -NHCH(CH 2 C 6 H 5 )C(O)OR 9 or

— NHCH(CH 2 C O H 5 )C(O)NR 9 R 10 wherein R 9 and R t0 are independently selected from hydrogen, alkyl, phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl or adamantyl, and R 7 and R 8 are independently selected from hydrogen, alkyl, phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl or adamantyl; or R 3 and R 4 taken together with the nitrogen to which they are attached form a pyrrole, indoline, isoindoline, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, perhydroazepine or morpholine ring; and W 2 is — NHCH((CH 2 ) 3 R 6 ) — C(O) — wherein R6 is — NH 2 , — NHC(=NH)NH 2 or -CH 2 NH 2 ;

PCT Patent Application No. WO 88/03022, published May 5,- 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, Y and D are as defined therein including n is 0-1 , Y is isobutyl, allyl or benzyl and D is 2-carboxypyrrolidin-l-yI or --ZR wherein Z is O or NH and R is alkyl, phenyl or substituted alkyl or substituted phenyl;

German Patent Application No. DE3725137, published Aug. 6, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R, Ri, R 2 , R 3 , R 4 , R 5 , R 6 , B and Y are as defined therein including R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Ri is hydroxy, alkoxy or aryloxy, R 2 is hydrogen or Ri and R 2 taken together is oxo (=0), R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, fluoro, chloro, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, B is a peptide chain containing from 1 to 10 amino acid residues and Y is hydroxy or a protecting group for the peptide carboxy group;

British Patent Application No. GB2203740, published Oct. 26, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri, R 2 , R 3 , R 4 and B are as defined therein including Ri is a hydrophobic or hydrophilic side chain, R 2 is hydroxy or amino, R 3 is hydrogen or R 2 and R 3 taken together is oxo (=0), R 4 is a hydrophobic or hydrophilic side chain and B is -NHCH(R 6 )C(R 7 )(R 8 )C(R 9 )(RI O )CH 2 C(O)NR 1 1 R 12 wherein R 6 is R 1 , R 7 and R 8 are the same as R 2 and R 3 , R 9 and Rio are independently selected from hydrogen and fluoro and Ri 1 and R] 2 are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and — CH(Ri 3 )C(O)R) 4 wherein R 13 is alkyl or hydroxyalkyl and R H is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl;

British Patent Application No. GB2200115, published JuI. 27, 1988. discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

R 1 , R 2 , R 3 , R 4 , R 5 , D and Y are as defined therein including Ri is hydrogen or alkyl, R 2 is an amino acid side chain, R 3 is hydrogen, hydroxy, aryloxy or amino, R 4 and R 5 are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and — CH(R) 2 )C(O)Ri 3 wherein R| 2 is alkyl or hydroxyalkyl and Ri 3 is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl; or — NR 4 Rs represents pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or substituted piperazinyl; D is a bond, O, -N(R 1 ) — or — CH(Ri) — and Y is — C(O) — , — S(O) 2 — or — P(O) — ;

German Patent Application No. DE3830825, published Mar. 23, 1989, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Rj 0 and X are as defined therein including R 4 is a hydrophilic or hydrophobic amino acid side chain, R 5 is hydroxy or amino, R is hydrogen or R 5 and R 6 taken together are oxo (=0), R 7 and R 8 are independently

selected from hydrogen and fluoro, R 9 and Rio are independently selected from hydrogen, alkyl and — CH(Rn)C(O)Ri 2 wherein Rn is alkyl or hydroxyalkyl and Ri 2 is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl, benzyl or — NH — (CH 2 CH 2 ), ! , — Rl wherein m is 1-20 and R| is as defined therein; and X is a bond or O, NH or — C(Ri 3 )(Ri 4 ) — wherein Ri 3 and Ri 4 are independently selected from hydrogen, fluoro or R 4 ;

Japanese Patent Application No. J62246546, published Oct. 27, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein m, R 4 and R 5 are as defined therein including m is 0-1 , R 4 is alkyl, cycloalkyl or phenyl and R 5 is alkyl or substituted alkyl as defined therein;

European Patent Application No. EP0274259, published JuI. 13, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 4 and R 5 are as defined therein including R 4 is alkyl, hydroxyalkyl, (heterocyclic)alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl and R5 is hydrogen or alkyl;

European Patent Application No. EP0228192, published JuI. 8, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein m, n, Rs, R 6 and R 7 are as defined therein including m and n are independently selected from 0 and 1, R 5 is alkyl, cycloalkyl or phenyl, R 6 is alkyl and R 7 is alkyl or substituted alkyl as defined therein;

European Patent Application No. EP0273893, published JuI. 6, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 5 , R 6 and Y are as defined therein including R 5 is alkyl or cycloalkyl, R 6 is hydrogen or alkyl and Y is -SCH(CH 3 ) 2 or --S(O) 2 CH(CH 3 ) 2 ;

European Patent Application No. EP0310070, published Apr. 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri, R 5 and R 7 are as defined therein including R| is hydrogen, alkyl, haloalkyl, alkylcycloalkyl, alkylcycloalkenyl or alkoxycarbonyl, R 5 is hydrogen or alkyl and R 7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;

European Patent Application No. EP0310071, published Apr. 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 1 , R 5 and R 7 are as defined therein including R| is hydrogen, alkyl, haloalkyl, alkylcycloalkyl, alkylcycloalkenyl or alkoxycarbonyl, R 5 is hydrogen or alkyl and R 7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;

European Patent Application No. EP0310072, published Apr. 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R|, R 5 and R 7 are as defined therein including Rj is hydrogen, alky], haloalkyl, alkylcycloalkyl, alkylcycloalkenyl or alkoxycarbonyl, K $ is hydrogen or alkyl and R 7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;

European Patent Application No. EP0310073, published Apr. 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formulae

<yy

wherein R], R 5 and R 7 are as defined therein including Ri is hydrogen, alkyl, haloalkyl, alkylcycloalkyl, alkylcycloalkenyl or alkoxycarbonyl, R 5 is hydrogen or alkyl and R 7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;

European Patent Application No. EP0313847, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R|, R 5 and R 6 are as defined therein including Ri is hydrogen, alkyl, haloalkyl, alkylcycloalkyl, alkylcycloalkenyl or alkoxycarbonyl, Rs is hydrogen or alkyl and R 6 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;

European Patent Application No. EP0296581, published Dec. 28, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri and R 3 are as defined therein including R] is hydrogen, arylalkyl, aryl, (heterocyclic)alkyl or heterocyclic and R 3 is hydrogen, alkyl, haloalkyl, arylalkyl, (heterocyclic)alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, thioalkoxyalkyl, hydorxyalkoxyalkyl, aminoalkoxyalkyl, hydroxythioalkoxyalkyl, carboxyalkyl, aminothioalkoxyalkyl, guanidinoalkyl, aminocarbonylalkyl or imidazolylalkyl;

European Patent Application No. EP0231919, published Aug. 12, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Ri and R 3 are as defined therein including Rj is an N-heterocyclic ring and R 3 is hydrogen, alkyl, cycloalkylalkyl, haloalkyl, arylalkyl, (heterocyclic)alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, tioalkoxyalkyl, hydroxyalkoxyalkyl, aminoalkoxyalkyl, hydroxythioalkoxyalkyl, carboxyalkyl, aminothioalkoxyalkyl, guanidinoalkyl, aminocarbonylalkyl or imidazolylalkyl;

PCT Patent Application No. WO 87/05302, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

-E 10 -F 1 1 -G 12 -H 13 -I 14"

wherein Eio, Fn, Gi 2 , Hi 3 , 114 and Z are as defined therein, including — Eio — Fn — is

tfr

wherein Ri is hydrogen, alkyl, aryl, cycloalkyl, heterocyclic, alkoxy or thioalkoxy, Rn is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic)alkyl, alkoxyalkyl or thioalkoxyalkyl, R 22 is hydrogen or alkyl and R 23 is hydroxyalkyl, aminoalkyl, aryl or alkyl, Gi 2 is absent or an amino acid residue, H] 3 is absent or an amino acid residue, Ij 4 is absent or an amino acid residue and Z is hydroxy, substituted alkoxy, substituted amino or cyclic amino;

PCT Patent Application No. WO 87/02986, published May 21, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— E i o — F 1 1 — G 12 — H J 3 — 1 14 — Z

wherein Eio, Fn, Gi 2 , Hi 3 , Iu and Z are as defined therein including — Ei 0 — Fn — is

wherein Ri is hydrogen, alkyl, aryl, cycloalkyl, heterocyclic, alkoxy or thioalkoxy, Rn is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic)alkyl, alkoxyalkyl or thioalkoxyalkyl, R 21 is hydroxy or amino, R 22 is hydrogen or alky] and R 23 is hydroxy, amino, hydroxyalkyl, aminoalkyl, aryl or alkyl, G 12 is absent or an amino acid residue, H] 3 is absent or an amino acid residue, 114 is absent or an amino acid residue and Z is hydroxy, substituted alkoxy, substituted amino or cyclic amino;

PCT Patent Application No. WO 89/00161 , published Jan. 12, 1989, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein R 2 , R 4 , R 5 , X, Y and Z are as defined therein including R 2 is hydrogen or alkyl, R^ is hydrogen, alkyl, cycloalkyl, aryl, heterocyclic, hydroxyalkyl or

arninoalkyl, R 5 is hydrogen, alkyl, arylalkyl, (heterocyclic)alkyl or cycloalkyl, X is ' -CH(OH)-, -CH(NH 2 )-, — C(O)- , -CH(OH)CH(OH)-, -CH(OH)CH 2 -, -CH(NH 2 )CH 2 -, — C(O)-CH 2 -, — CH 2 -NH-, -CH 2 — O — or — P(O)(A)B — wherein A is hydroxy or amino and B is absent, O, NH or CH 2 , Y is absent or — NI-ICH(Rs)C(O) — and Z is hydroxy, substituted alkoxy, substituted amino or N-heterocyclic;

PCT Patent Application No. WO 88/07053, published Sep.' 22, 1988, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein r, t, RQO > RIOO, RI IO, Rm, Gj 2 , Hu, I M and Z are as defined therein including r is 0-3, t is 0-3, R90 is hydrogen or alkyl, Rioo is hydrogen, alkyl, ary], cycloalkyl, heterocyclic, alkoxy or thioalkoxy, Rno and Rm are independently selected from hydrogen, alkyl, aryl, arylalkyl and halo, G| 2 is absent, an amino acid residue or

wherein R 50 is hydrogen, alkyl, arylalkyl., (heterocyclic)alkyl, cycloalkylalkyl or adamantyl, and R 60 and Rβi are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or Rβo and Rei taken together form a carbocyclic or heterocyclic spirocycle, Hn is absent an amino acid residue or

wherein R 5 o is hydrogen, alkyl, arylalkyl, (heterocyclic)alkyl, cycloalkylalkyl or adamantyl, and R 60 and R 6 ] are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R 6 o and R^ 1 taken together form a carbocyclic or heterocyclic spirocycle, I 14 is absent an amino acid residue or

wherein R50 is hydrogen, alkyl, arylalkyl, (heterocyclic)alkyl., cycloalkylalkyl or adamantyl, and R 60 and Rei are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R 60 and taken together form a carbocyclic or heterocyclic spirocycle and Z is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or cyclic amino;

PCT Patent Application No. WO 88/02374, published Apr. 1, 1988, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formulae

a) —E,o—Fπ—C(.dbd.Y)— G 12 -Hi 3 -Z

b) -E 10 -F n -W

c) -E 10 -F 1 1 -Gi 2 -Hi 3 -W

d) wherein Eio, Fn , Gi 2 , Hi 3 , G 121 , H] 3 ), I] 4 , W, Y and Z are as defined therein including — Eio — F] 1 — is

wherein R and Ri are independently selected from alkyl, cycloalkyl, aryl, substituted alkyl as defined therein, alkoxy or thioalkoxy, Rn is alkyl, cycloalkyl, aryl,

substituted alkyl as defined therein, alkoxy, thioalkoxy, hydrogen, hydroxyalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic)alkyl, alkoxyalkyl and thioalkoxyalkyl, R 22 is hydrogen or alkyl, R2 3 is hydroxy, hydroxyalkyl, amino, aminoalkyl, aryl or alkyl, R 24 is aryl, amino, alkylamino, dialkylamino, trialkylamino, heterocyclic, hydroxy, alkoxy, alkanoyloxy, mercapto, carboxy, alkoxycarbonyl, dialkylaminoalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyclicamino, cycloalkylamino, guanidinyl, cyano, N- cyanoguanidinyl, cyanoamino, hydroxyalkylamino, di(hydroxyalkyl)amino, arylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, heterocyclicalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, mercaptoalkyl, carboxyalkyl, alkoxycarbonylalkyl, dialkylaminoalkoxycarbonylalkyl, aminocarbonyl alkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, cyclicaminoalkyl, cycloalkylaminoalkyl, guanidinylalkyl, cyanoalkyl, N- cyanoguanidinylalkyl, cyanoaminoalkyl, hydroxyalkylaminoalkyl or di(hydroxyalkyl)aminoalkyl, Wi and W 2 are independently selected from hydroxy and amino, W 3 and W 4 arc independently selected from hydrogen and fluoro, W is as defined therein, Y is O, S 5 NH or — N(alkyl) — , Z is as defined therein, Gn is absent or an amino acid residue, Hn is absent or an amino acid residue, G] 2I is absent or an amino acid residue, H 131 is absent or an amino acid residue and I 14 is absent or an amino acid residue;

PCT Patent Application No. WO 86/06379, published Apr. 5, 1989, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

— E— F — G — H-Z

wherein E, F, G, H and Z are as defined therein including — E — F — is

Rift

wherein Rio a is hydrogen or alkyl, Rio b is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic)alkyl, cycloalkenyl or cycloalkenylalkyl, RlOc is hydrogen or alky], U is — C(O) — , — CH(OH) — or — CH(NH 2 ) — and Wi and W 2 are independently selected from hydrogen, fluoro, chloro and bromo, G is absent or an amino acid residue, H is absent or an amino acid residue and Z is hydroxy, thiol, amino, substituted alkoxy, substituted thioalkoxy, substituted alkylamino, Lys-OH, LyS-NH 2 , Ser-OH or Ser-NH 2 ;

European Patent Application No. EP0271862, published Jun. 22, 1988, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

— Y — W-U

wherein Y, W and U are as defined therein including Y is Sta, Cysta or PhSta, W is Leu, He, N-MeLeu, VaI or absent and U is -NHCH 2 CH(CH 3 )CH 2 CH 35 -NHCH 2 Ph, -NHCH(CH 2 OH)CH(CH 3 )CH 2 CH 33 — NHCH 2 CH(OH)CH 2 SCH(CH 3 ); ! , -NHCH 2 CH(OH)CH 2 S(O)CH(CH 3 ) 2 , — NHCH 2 CH(OH)CH 2 S(O) 2 CH(CH 3 ) 2 ,

-NHCH 2 CH 2 Ph, -NHCH 2 (pyrid-2-yl), -NH 2 , -NHCH 2 CH=CH 2 , -OEt,

— OMe, — NH(piperidin-4-yl), -NHCH :

European Patent Application No. EP0275480, published JuI. 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— W-U — V

wherein W, U and V are as defined therein including W is Sta, PhSta or Cysta, U is absent, Leu, He, VaI, N-MeLeu or N-MeIIe and V is -NHCH 2 Ph, — NHCH 2 cyclohexyI, — NH(piperidin-4-yl), — NHCH 2 (pyrid-2-yl), -NHCH 2 CH(CH 3 )CH 2 CH 3 , -OMe, -OEt, -NHCH(CH 2 OH)CH(CH 3 )CH 2 CH 3 , — NHCH 2 CH 2 (morpho]in-l-yl),

PCT Patent Application No. WO 88/03927, published Jun. 2, 1988, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

-T-(C) n — W— (D) n —V— (E) n — U

wherein T, C, W, D, V, E, U and n are as defined therein including n is 0-1 , T is Sta, PhSta, Cysta, Leu, CyclohexylAla or Phe, W is absent, Leu, GIy or He, V is absent, Leu or He, C is —CH 2 NH—, -CH(OH)CH 2 - or -CH(OH)-CH=CH-C(O)-, D is — CH 2 NH-, E is — CH 2 NH- or — CH 2 N(Cbz) — and U is -NHCH 2 Ph, — NHCH 2 cyclohexyl, -NH 2 , — NH(piperidin-4-yl), -NHCH 2 (pyrid-2-yl), -NHCH 2 CH(CH 3 )CH 2 CH 3 , -OMe, — OEt,

European Patent Application No. EP0314060, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— W-U

wherein W and U are as defined therein including W is Sta, Cysta, PhSta, ChSta, DFKSta, DFKCys, DFKChs, ASta or ACys and U is — NHCH 2 CH 2 (morpholin-l- yl), -NHCH 2 CH(CH 3 )CH 2 CH 3 , -NHCH(CH 2 OH)CH(CH 3 )CH 2 CH 3 , — LeuNHCH 2 Ph, — LeuNHCH 2 cyclohexyl, — LeuNH(piperidin-4-yl), — LeuNHCH 2 (pyrid-2-yl) or

European Patent Application No. EP0310918, published Apr. 12, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 and R 4 are as defined therein including R 3 is isobutyl, cyclohexylm ethyl or benzyl and R4 is phenyl, furyl, vinyl, ethyl or 1 ,2-dihydroxyethyl;

French Patent Application No. FR8700560, published JuI. 2, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R, U and B are as defined therein including R is hydrogen or hydroxyalkyl, U is Leu, AIa, VaI or He and B is pyridyl;

European Patent Application No. EP0236948, published Sep. 16, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein X is as defined therein including X is isobutyl or benzyl;

European Patent Application No. EP0281316, published Sep. 7, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 and R 5 are as defined therein including R 3 is allyl, cyclohexyl or phenyl, R 4 is nitromethyl, alkoxycarbonyl or — CH 2 S(O) n — R d wherein n is 0-2 and R d is heterocyclic and R 5 is hydrogen or alkyl;

German Patent Application No. DE3825242, published Feb. 9, 1989, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein R 3 and Z are as defined therein including R 3 is hydroxy or amino and Z is substituted carbonyl, substituted thiocarbonyl, substituted iminocarbonyl or unsubstituted or substituted phosphono, aminomethyl, thiomethyl, sulfinylmethyl, sulfonylmethyl or phosphonomethyl;

European Patent Application No. EP0275101, published JuI. 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 2 , R 3 , R a , Rb, n, X and Q are as defined therein including R2 is an amino acid side chain, R3 is hydrogen, alkyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 2-pyridylmethyl or an amino acid side chain, R.sub.a is an amino acid side chain, R.sub.b is hydrogen or alkyl or R.sub.a and R.sub.b taken together are — CH 2

— CH 2 — , n is 1 -10, X is hydrogen, CH 2 , alkoxy, substituted alkoxy, alkyl, phenyl, benzyl, cyclohexyl, cyclohexylmethyl or 2-pyridylmethyl and Q is hydrogen, alkyl, arylakyl, alkoxycarbonyl or an amino acid residue;

PCT Patent Application No. WO 89/01488, published Feb. 23, 1989, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

-E 10 -Fu-G 12 -H 13 -Ii 4 -Z

wherein E 1 O , Fn, G| 2 , H 13 , 1 1 4 and Z are as defined therein including —E| 0 --Fn -- is

wherein Ri is hydrogen, alkyl, aryl, cycloalkyl., heterocyclic, alkoxy or thioalkoxy, Rn is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic)alkyl, alkoxyalkyl or thioalkoxyalkyl, R 2 i is hydroxy or amino, R 22 is hydrogen or alkyl and R 23 is hydroxy, amino, hydroxyalkyl, aminoalkyl, aryl or alkyl, R 24 is R| hydroxy, amino, hydroxyalkyl or aminoalkyl, Gi 2 is absent or an amino acid residue, Hi 3 is absent or an amino acid residue, T] 4 is absent or an amino acid residue and Z is hydroxy, substituted alkoxy, substituted amino or cyclic amino;,

European Patent Application No. EP0275101 , published JuI. 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formulae

wherein Rl, G12, H13 and X are as defined therein including Ri is hydrogen, alkyl, aryl, cycloalkyl, heterocyclic, alkoxy or thioalkoxy, Gi 2 is absent, an amino acid residue or an amino acid residue wherein the alpha-amino group has been replaced by O, H|3 is absent, an amino acid residue or an amino acid residue wherein the

alpha-amino group has been replaced by 0 and X is hydrogen, alkyl or substituted alkyl as defined therein;

European Patent Application No. EP0312291, published Apr. 19, 1989, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein R], Y, X and E are as defined therein including Ri is hydrogen, alky], aryl, cycloalkyl, l,3-dithiolan-2-yl or l ,3-dithian-2-yl, X is — CH 2 — C(Ri 3 )(Ri 4 ) wherein Rn and R 14 are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl, substituted alkyl, alkanoyloxy, substituted aminocarbonyloxy, substituted carbonylamino, substituted aminocarbonylamino, substituted sulfinyl, substituted sulfonyl, substituted sulfide, amino, alkylamino, dialkylamino or heterocyclic, Y is CH 2 , O, S, SO or SO 2 or X and Y taken together is — (CH 2 ) 4 — and E is hydrogen, aryl, heterocyclic, alkyl, cycloalkyl or substituted alkyl;

European Patent Application No. EP0312283, published Apr. 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein Rj, X and E are as defined therein including Rj is hydrogen, alkyl, aryl, cycloalkyl, l,3-dithiolan-2-yl or l,3-dithian-2-yl, X is — CH 2 — C(Ri 3 )(R] 4 ) — wherein Ri 3 and Ri 4 are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl, substituted alkyl, alkanoyloxy, substituted aminocarbonyloxy, substituted carbonylamino, substituted

aminocarbonylamino, substituted sulfinyl, substituted sulfonyl, substituted sulfide, amino, alkylamino, dialkylamino or heterocyclic and E is hydrogen, aryl, heterocyclic, alkyl, cycloalkyl or substituted alkyl;

European Patent Application No. EP0312158, published Apr. 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein r, R 7 , R 4 , Ri 0 , R 9 , Rio a , Q and J arc as defined therein including r is 1-4, R 7 is alkyl, aryl or cycloalkyl, R 4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or , substituted alkyl, Ri 0 and Rιo a are independently selected from hydrogen and alkyl, R9 is — (CH 2 ) S — NRn R 12 wherein s is 1-2 and Rn and Ri 2 are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic)alkyl, aminoalkyl, hydroxyalkyl, alkylarninoalkyl, dialkylaminoalkyl, carboxy, alkyl substituted by — SO 3 H, aminocarbonylalkyl, alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, Q is — CH(OH) — ,

— CH(N(R 8 )) — , — CH(OH)CH 2 - Or — CH(N(Rg))CH 2 — wherein R 8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino or substituted alkoxy;

European Patent Application No. EP0312157, published Apr. 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein r, R 7 , R 4 , Ri 0 , R 9 , Ri Oa5 Q and J are as defined therein including r is 1-4, R 7 is alkyl, aryl or cycloalkyl, R 4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, Ri 0 and Rio a are independently selected from hydrogen and alkyl,

R 9 is — (CH 2 ) S — NR11R12 wherein s is 1 -2 and Rn and R) 2 are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic)alkyl, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyl substituted by — SO 3 H, aminocarbonylalkyl, alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, Q is — CH(OH) — ,

— CH(N(R 8 )) — , — CH(OH)CH 2 — or — CH(N(RS))CH 2 — wherein R 8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino, substituted alkoxy, heterocyclic, heterocyclicamino or substitute guanidino;

European Patent Application No. EP0314239, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein r, R 7 , R 4 , Q and J are as defined therein including r is 1-4, R 7 is alkyl, aryl or cycloalkyl, R4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, Q is -CH(OH) — , -CH(N(R 8 )) — , -CH(OH)CH 2 — or — CH(N(R 8 ))CH 2 — wherein R 8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is amino, hydroxy, substituted alkylamino or substituted alkoxy;

South African Patent Application No. 866642, published Feb. 24, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

alkylamide)

whcrcin R' and R" are as defined therein including R' is fluoro and R" is hydrogen or fluoro;

European Patent Application No. EP0273696, published JuI. 6, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R 2 , Rio and E are as defined therein including n is 0-5, R 2 is hydrogen or alkyl, Rio is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic)alkyl, alkoxyalkyl, thioalkoxyalkyl, hydroxyalkyl or aminoalkyl and E is — CH(W) — G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is — Q — C(O) — T-U — V wherein Q is a bond or — CH(R 13 ) — wherein R )3 is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T and U are independently absent or selected from an amino acid residue and V is hydroxy, substituted alkoxy, amino or substituted amino;

European Patent Application No. EP0278158, published Aug. 17, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R 7 , Rio and E are as defined therein including n is 0-3, R 7 is alkyl or substituted alkyl, R] 0 is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl,

(heterocyclic)alkyl, alkoxyalkyl, thioalkoxyalkyl, hydroxyalkyl or aminoalkyl and E is — CH(W) — G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is — Q — C(O) — T — U — V wherein Q is a bond or — CH(R] 3 ) — wherein R13 is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T

and U are independently absent or selected from an amino acid residue and V is hydroxy, substituted alkoxy, amino or substituted amino;

German Patent Application No. DE3721855, published Sep. 22, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R 2 , R 3 , R 4 , R 5 , R 6 , E and D are as defined therein including n is 1 -2, R 2 is hydrogen or alkyl, R 3 is hydrogen, alkyl, aryl, arylalkyl, (heterocyclic)alkyl, cycloalkyl, alkoxy or cycloalkylalkyl, R 4 is (H, OH), (H 3 NH 2 ) or 0, R 5 is hydrogen or alkyl, R 6 is hydrogen or alkyl, E is 0-2 amino acid residues and D is

— CH 2 CHOHCH 2 OH 5 substituted sulfonyl, substituted sulfonylalkyl, substituted carbonyl, substituted phosphonyl, phenyl, phenylalkyl, furyl, furylalkyl, thienyl, thienylalkyl, pyridyl, pyridylalkyl or other (heterocyclic)alkyl;

European Patent Application No. EP0309841, published Apr. 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R 3 , R 4 , R5, Re and E arc as defined therein including n is 1-2, R 3 is hydrogen or alkyl, R 4 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, alkoxy or cycloalkylalkyl, R 5 is (H 5 OH), (H 7 NH 2 ) or O, R 6 is hydrogen, alkyl or alkenyl and E is — SR 7 , — SOR 7 , — SO 2 R 7 , — SO 2 OR 7 or — SO 2 NR 7 Re wherein R 7 and R 8 are independently selected from R 4 ;

European Patent Application No. EP0292800, published Nov. 30, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R 3 , R 4 , Rs, Re, E, Q and Y are as defined therein including n is 1-2, R 3 is hydrogen or alkyl, R 4 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R 5 is (H,OH), (H 5 NH 2 ), or O 3 R 6 is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl;

European Patent Application No. EP0249096, published Dec. 16, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R 3 , R 4 , R 5 , R 6 , E, Q and Y are as defined therein including n is 1 -2, R 3 is hydrogen or alkyl, R 4 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R 5 is (H,OR )2 ), (H 3 NRi 2 Ri 3 ), or O wherein Rj 2 and R1 3 are independently selected from hydrogen and alkyl, R 6 is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl; and

European Patent Application No. EP0264795, published Apr. 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein n, R 2 , R 3 , R 4 , E and Y are as defined therein including n is 1-2, R 2 is hydrogen or alkyl, R 3 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R 4 is hydrogen or alkyl, E

is — C(O)NH-, — C(S)NH-, — C(O)O — , — SO 2 — , — SO 2 NH-, or — PO(OA)O — wherein A is hydrogen or alkyl and Y is carboxy, carboxyalkyl, substituted carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, substituted alkoxycarbonylalkyl, aminocarbonyl, substituted aminocarbonyl, aminocarbonylalkyl, substituted aminocarbonylalkyl, hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl; or E-Y is pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, pyrrolidinosulfonyl, piperidinosulfonyl or morpholinosulfonyl.

Ocain and Delninger, U.S. Pat. No. 5,023,338, issued June 1 1 3 1999, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 1 is as defined therein.

Albright et. al., U.S. Pat. No. 5,104,869, issued Apr. 14, 1992, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 5 , R 6 and A are as defined therein

Albright et. al., U.S. Pat. No. 5,106,835, issued Apr. 21 , 1992, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 5 , R 6 and A are as defined therein

Ashton et. al., U.S. Pat. No. 5,1 14,925, issued May 19, 1992, which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula:

wherein R 2 , Y and n are as defined therein.

Ruger et. al., U.S. Pat. No. 5,185,324, issued Feb 9, 1993, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 2 and R 4 are as defined therein.

Doherty and Sircar, U.S. Pat. No. 5,071 ,837, issued Dec. 10, 1991 , which is hereby incorporated by reference, discloses mimics of the Lcu-Val cleavage site of angiotensinogen having the formulae: — DFKCYS — AEM

— DFCYS— AEM

wherein DFKCYS, DFCYS and AEM are as defined therein

Raddatz et. al., U.S. Pat. No. 5,147,857, issued Sep. 15, 1992, which is hereby incorporated by reference, discloses mimics of the Lcu-Val cleavage site of angiotensinogen having the formula:

wherein R 3 , R 4 , R 5 , R 6 , R 7 and Z are as defined therein;

Almquist et. al., U.S. Pat. No. 5,268,361 , issued Dec. 7, 1993, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 5 , R 6 and R 7 are as defined therein;

Toyoda et. al., U.S. Pat. No. 5,272,268, issued Dec 21 , 1993, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein Y and R 1 are as defined therein;

Hanson et. al., U.S. Pat. No. 5,330,996, issued July 19, 1994, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 6 , R 7 and R 8 are as defined therein;

Henrung et. al., U.S. Pat. No. 5,360,791, issued Nov. 1 , 1994, which is hereby incorporated by reference, discloses mimics of the Lcu-Val cleavage site of angiotensinogen having the formula:

wherein R 1 , R 2 , R 3 , R 4 , m, n and D are as defined therein;

Morisawa et. al., U.S. Pat. No. 5,378,689, issued Jan. 3, 1995, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 4 , R 5 and R 6 are as defined therein;

Morishima et. al., U.S. Pat. No. 5,424,309, issued Jun. 13, 1995, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

R*

-N— CH- CH- A R 5 OH wherein R 5 , R 6 and A are as defined therein;

Albright et al., U.S. Pat. No. 5,459,131, issued Oct. 17, 1995, which is hereby incorporated by reference, discloses mimics of the Lcu-Val cleavage site of angiotensinogen having the formula:

R 0 OH I I

- N — CH — CH — λ

I * Rs wherein R 5 , R 6 and A are as defined therein;

Branca et al., U.S. Pat. No. 5,688,946, issued Nov 18, 1997, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined therein

Shibat et. al., U.S. Pat. No. 5,750,696, issued May 12, 1998, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R , R and E are as defined therein;

Hamby et. al., U.S. Pat. No. 5,198,426, issued Mar. 30, 1993, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 4 , R 5 , R 6 and R 7 are as defined therein;

Rosenberg., U.S. Pat. No. 5,258,368, issued Nov. 2, 1993, which is hereby incorporated by reference, discloses mimics of the Leυ-Val cleavage site of angiotensinogen having the formula:

wherein R 4 , R 5 , R 6 and D are as defined therein;

European Patent Application No. EP035321 1, published Jan. 31 , 1990, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein R 3 , R 4 , R 5 and q are as defined therein;

European Patent Application No. EP0362002, published Apr. 4, 1990, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

— NHCHR 2 C(=O)CF 2 CHR 3 NHC(=O)X'

wherein R 2 , R 3 and X' are as defined therein;

European Patent Application No. EP0369065, published Nov. 7, 1990, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein A, B and R are as defined therein;

European Patent Application No. EP0416393, published Mar. 13, 1991 , which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula

wherein R 4 , R 5 , R 6 and Z are as defined therein;

European Patent Application No. EP0438233, published July 24, 1991 , which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

H H I R 5

wherein R 5 and R 6 are as defined therein;

European Patent Application No. EP043831 1 3 published July 24, 1991, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula

wherein and X are as defined therein;

European Patent Application No. EP0483271, published May 6, 1992, which is hereby incorporated by reference, discloses mimics of the Leu- VaI cleavage site of angiotensinogen having the formula:

wherein are as defined therein;

European Patent Application No. EP0501280, published Sep. 2, 1992, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula:

wherein R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined therein;

The teachings of all documents cited above are incorporated by herein by reference in their entirety. All documents cited herein arc incorporated by reference.

A second embodiment of the invention is a compound of Formula I wherein:

G a is a) (C3-C 7 )cycloalkyl; or b) phenyl, heteroaryl, or bicyclic heteroaryl optionally substituted with 1 to 3 groups independently selected from:

1) fluorine, chlorine, bromine, cyano, nitro, (C]-C 6 )alkyl, (C 3 -C 6 )CyClOaIlCyI,, (C 4 - C 7 )cycloalkylalkyl, (C 2 -C δ )alkenyl, (C 5 -C 6 )cycloalkenyl, (Cs-C 8 )cycloalkylalkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 5 )cycloalkylethynyl, halo(C,-C6)alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 4 -C 7 )-cycloalkylalkyl, ha]o(C 2 -C 6 )alkenyl, halo(C 3 -C 6 )alkynyl, haIo(C 3 - 5 C 6 )cycloalkylethynyl, (C)-C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 4 -C 7 )cycloalkylalkoxy, halo(C|-C6)alkoxy, halo(C 3 -C 6 )cycloalkoxy, halo(C4-C 7 )cycloalky!alkoxy, (C 3 - C ό )alkenyloxy and (C|-C 6 )alkanesulfonyl; or 2) phenyl, heteroaryl, phenoxy, heteroaryloxy, phenylthio, heteroarylthio, benzyl, heteroarylmethyl, benzyloxy and heteroaryloxy, each optionally substituted with 1 to 3 groups independently selected 10 from: fluorine, chlorine, cyano, (Ci-C 3 )alkyl, halo(Ci-C3)alkyl, (Ci-C 3 >alkόxy 5 halo(Ct- C 3 )alkoxy, and aminocarbonyl;

G b is (C|-C 8 )alkyl, (C 4 -C 8 )cycloalkylalkyl, fluoro(Ci-C 8 )alky], fluorosi s C 8 )cycloalkylalkyl, (Ci-C 8 )alkoxy, (C4-C 8 )cycloalkylalkoxy, fluoro(Ci-C 8 )alkoxy, hydroxy(Ci-Cg)aIkyl, (Ci-C 5 )alkoxy(C|-C 5 )alkyl, halo(C r C 5 )a!kylamino(C,- C 5 )alkyl, (C|-C 5 )alkoxy(Ci-C 5 )hydroxyalkyl 5 (C 3 -C 4 )cycloalkoxy(Ci-C 3 )a]kyl, fluoro(Ci-C 5 )alkoxy(Ci-C 5 )alky], f]uoro(C 3 -C 4 )cycloalkoxy(C|-C 5 )alkyl, (C r C 5 )alkylthio(C|-C 5 )alkyl, (Ci-C 5 )alkoxy(C|-C 5 )alkoxy. hydroxy(C r C 8 )alkoxy, (C 3 - 0 C|)cycloalkoxy(C|-C 5 )alkoxy, fluoro(Ci-C 5 )alkoxy(C|-Cs)alkoxy, fluoro(C 3 -

C 4 )cycloalkoxy(C|-C 3 )alkoxy, (Ci-C 3 )alkoxy(Ci-C 3 )alkoxy(C]-C 3 )alkyl 3 fluoro(C|- C 3 )alkoxy(Ci-C 3 )alkoxy(Ci-C 3 )alkyl, aminocarbonylamino(C|-Ca)alkyl, aminocarbonylamino(Ci-C 8 )alkoxy 3 (Ci-Cs)alkanoylamino(Ci-C 5 )alkyl, (Ci- C 5 )alkanoylamino(Ci-Cs)aIkoxy, fluoro(Ci-C 5 )alkanoylamino(Cι-C 5 )alkyl, 5 fluoro(C i -Cs)alkanoylamino(C i -C 5 )alkoxy, (C \ -C 3 )alkoxy(C i -C 5 )alkanoy lamino(C i - C 5 )alkyl, (C|-C 3 )alkoxy(Ci-C 5 )alkanoylamino(Ci-C 5 )alkoxy, (C 3 - C 4 )cycloalkanecarbonyllamino(Ci-C 5 )alkyl, (C 3 -C4)cycloalkanecarbonyllamino(Cι- Cs)alkoxy, aminosulfonylamino(C|-C 8 )alkyl, aminosulfonylamino(Ci-C 8 )alkoxy, (Ci-C 5 )alkanesulfonyl-amino(Ci-C 5 )alkyl, (C|-C5)alkanesulfonylamino(Ci- 0 C5)alkoxy, formylamino(C]-C 5 )alkyl, formylamino(Ci-C5)alkoxy, (Ci-

C5)alkoxycarbonyIamino(Ci-C 5 )alkyl, (Ci-Cs)alkoxycarbonyl-amino(Cι-C 5 )alkoxy, (Ci-C 5 )alkylaminocarbonylamino(Ci-C 5 )alkyl, (Ci-Cs)alkylaminocarbonyl-

amino(Ci-Cs)alkyl, di(C|-C 5 )alkylaminocarbonylamino(Ci-C 5 )alkoxy, aminocarbonyl(Ci-C 5 )alkyl, aminocarbonyl(Ci-C 5 )alkoxy, (C|- C 5 )alkylaminocarbonyl(C|-C 5 )aIkyl, (Ci-C 5 )alkylaminocarbonyl-(C|-C 5 )alkoxy, aminocarboxy(C i -C 5 )alkyl , am inocarboxy(C i -C 5 )alkoxy, (C i -C 5 )alkylam ino- carboxy(C|-C 5 )alkyl, (Ci-C 5 )alkylaminocarboxy(Ci-C 5 )alkoxy, (C|-

C 8 )alkoxycarbonylamino, (C|-C 8 )alkylaminocarbonylamino, (Ci-C«)alkanoylamino 5 fluoro(Ci-C8)alkoxycarbonylamino, fluoro(Ci-C8)alkylaminocarbonylamino, or fluoro(Ci-C 8 )alkanoylamino;

G c is H, halogen, OH, (C|-C4)alkanoylamino, or (C|-C 3 )alkoxy;

provided that when G c is OH or halogen, then G b is not (Ci-C 8 )alkoxy, (C 4 - C8)cycloalkylalkoxy, fluoro(C 1 -Cs)alkoxy, (Ci -C 5 )alkoxy(C 1 -C 5 )alkoxy, hydroxy(C]-C8)alkoxy, (C 3 -C 4 )cycloalkoxy(Cj-C 5 )alkoxy, fluoro(C|-C 5 )alkoxy(Ci- C5)alkoxy, fluoro(C 3 -C 4 )cycloalkoxy(Ci-C 5 )alkoxy, aminocarbonylamino(Cι-

Cg)alkoxy, (C 1 -Cs)alkanoylamino(C 1 -Cs)alkoxy, fluoro(C i-C 5 )alkanoylamino(C 1 - C 5 )alkoxy, (C|-C 3 )alkoxy(Ci.-C 5 )alkanoylamino(C|-C 5 )alkoxy > (C 3 - C 4 )cycloalkanecarbonyllarnino(C 1 -C 5 )alkoxy, aminosulfonyIamino(Ci-C 8 )alkoxy, (C|-C5)alkanesulfonylamino(Ci-C 5 )alkoxy, formylamino(C|-C 5 )alkoxy, (C]- C5)alkoxycarbonyl-amino(Ci-Cs)alkoxy, (Ci-Cs)alkylaminocarbonylamino(Ci-

Cs)alkyl, (Ci-C 5 )alkylaminocarbonylamino(Ci-C 5 )alkyl, aminocarbonyl(C|-Cs)alkyl, (Ci-C 5 )aIkylaminocarbonyI(Ci-C 5 )alkyl, aminocarboxy(Cι-C 5 )alkyl, (Cj- C 5 )alkylamino-carboxy(Ci-C 5 )alkyl,

A" is CH 2 or O;

Q is a divalent radical selected from:Ql , Q2, Q4, Q5, Q9, or QlO

the

Q1 Q2 Q4 Q5 Q9 Q10

T is as described above.

A third embodiment of the invention is a compound of Formula I, wherein G a is a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7- benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, l > 3-benzodioxol-4-yl, 7- indazolyl, or 8-quinolinyl optionally substituted with 1 to 3 substituents independently selected from: fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, t-butyl, isobutyl, trifluoromethyl, allyl, cyclohexyl, cyclohexen-1-yl, cyclopropylethynyl, methoxy, trifluoromethoxy, neopentyloxy, methylthio, allyloxy, cyclopropylmethoxy, 2- (cyclopropyl)ethoxy, cyclopentyloxy, cyclopentylmethoxy, benzyloxy, hydroxy!, aminocarbonyl, methoxycarbonyl, phenyl, phenoxy, benzyloxy, and heteroaryloxy, wherein the phenyl phenoxy, benzyloxy and heteroaryloxy groups are optionally substituted with 1 to 3 substituenls independently selected from fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, and aminocarbonyl;

G b is methyl, ethyl, propyl, butyl, hexyl, 5-pentenyl, 3,3,3-trifluoropropyl, 4,4- difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3 -hydroxy propyl, 4- hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 3-ethoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 2-(ethoxy)ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 3- propoxypropoxy, 2-cyclopropylethoxy, 3-(2,2,2-triflluoroethylamino)propyl, 3- (formylamino)propyl, 3-(acetylamino)propyl, 3-(propionylamino)propyl, 3- (butanoylamino)propyl, 3-((2-methoxypropionyl)amino)propyl, 3-

(cyclopropanecarbonylamino)propyl, 3-(trifluoroacetylamino)propyl, 3- (methoxycarbonylamino)propyl, 3-(ethoxycarbonylamino)ρropyl, 2- (methoxycarbonylamino)ethoxy, 2-(ethoxycarbonylamino)ethoxy, 3- (methylaminocarbonylamino)propyl, 3-(dimethylaminocarbonylamino)propyl, 2- (acetylamino)elhoxy, aminocarbonylmethoxy, (methylamino)carbonylmethoxy or 3- (aminosulfonylamino)propyl;;

G c is H 5 F 3 OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino, provided that when G c is F or OH, G b is not 2-(ethoxy)ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, 2-cycIopropylethoxy, 2-(methoxycarbonylamino)ethoxy, 2- (ethoxycarbonylarnino)ethoxy, 2-(acetylamino)ethoxy, aminocarbonylmethoxy, (methylamino)carbonylmethoxy or 3-(aminosulfonylamino)propyl;

A 4 is CH 2 or O;

Q is Ql

wherein N and T are attached to the truncated bonds

Q1

T is selected from 1) Tl - T9 wherein G d is (C|-C 8 )alkyl, (C 3 -C 7 )cycolaklyl or (C 3 - C 7 )cycloalkyl(C , -C 2 )alkyl;

or 2) TlO wherein G d and G e are independently selected from (Ci-Cs)alkyl 3 (C . C 7 )cycolaklyl or (C 3 -C 7 )cycloalkyl(Ci-C 2 )alkyl;

or 3) Tl 1 - Tl 4 wherein G f is a heteroaryl or heterocyclyl group, preferably G r is 2- pyridyl, 1-piperidinyl or 4-morpholinyl;

T11 T12 T13

or 4) Tl 5 wherein G δ is a heteroaryl group

A fourth embodiment of the invention is a compound of Formula I defined by Formula Ia:

wherein G a , G b , G c , A 4 and T are as defined above for compounds of Formula I. Preferably the groups Tl — Tl 4 have the stereochemistry shown below and G d , G e , G 1 and G ε are as defined above for Formula I:

Another embodiment of the invention is each of the following compounds and their enantiomers, diastereomers, and salts:

methyl 2-((3- chlorophenyl)(l-(l- cyclohexyl-3,5-dihydroxy-

6-methylheptan-2- ylcarbamoyl)piperidin-3- yl)methoxy)ethylcarbamate methyl 2-((3- chlorophenyl)( 1 -( 1 - cycIohexyl-3-hydroxy-5-

(2-morpholinoethylamino)- 5-oxopentan-2- ylcarbamoyl)piperidin-3- yl)methoxy)ethylcarbamate methyl 2-((3- chlorophenyl)( 1 -( 1 - cyclohexyl-3,4-dihydroxy- 6-(pyridin-2-yl)hexan-2- ylcarbamoyl)piperidin-3- yl)methoxy)ethyl carbamate methyl 2-((3- chlorophenyl)( 1 -( 1 - cyclohexyl-3-hydroxy-4-

(4-methyl-4H-l ,2,4-triazoI-

3-ylthio)butan-2- ylcarbamoyl)piperidin-3- yl)methoxy)ethylcarbamate methyl 2-((3- chlorophenyl)( 1 -(I - cyclohexyl-4,4-difluoro-5- (2-morpholinoethylamino)- 3,5-dioxopentan-2-

ylcarbamoyl)piperidin-3- yl)methoxy)ethylcarbamate ethyl 3-(3-((3- chlorophenyl)(2-

(methoxycarbonylamino)et hoxy)methyl)piperidine- 1 - carboxamido)-4- cyclohexyl-2-oxobutanoate

Another embodiment of the invention is each of the compounds listed below and their salts, especially their pharmaceutically acceptable salts:

methyl 2-((R)-((R)-l -((2S,3S)-5-

(butylamino)- 1 -cyclohexyl-3- hydroxy-5-oxopentan-2- ylcarbamoyl)piperidin-3-yl)(3- chlorophenyl)methoxy)ethylcarba mate

(2R,3S)-isopropyl 3-((R)-3-((R)-(3- chlorophenyl)(2-

(mcthoxycarbonyl am i no)ethoxy)met hyl)piperidine- 1 -carboxamido)-4- cyclohexyI-2-hydroxybutanoate methyl 2-((R)-(3-chIoropheny 1)((R)- l -((lS,2S)-3-cycIohexyl-l - (diethoxyphosphoryl)- 1 - hydroxypropan-2- ylcarbamoyl)piperidin-3- yl)methoxy)ethylcarbam ate

When any variable (e.g., aryl, heterocyclyl, Ri, R 2 , etc.) occurs more than once in a compound, its definition on each occurrence is independent of any other occurrence. "Alkyl" means a saturated aliphatic branched or straight-chain mono- or divalent hydrocarbon radical having the specified number of carbon atoms. Thus, "(Ci-C 8 )alkyl" means a radical having from 1-8 carbon atoms in a linear or branched arrangement. "(Ci-C 6 )alkyl" includes methyl, ethyl, propyl, butyl, pentyl, and hexyl. "Cycloalkyl" means a saturated aliphatic cyclic hydrocarbon radical having the specified number of carbon atoms. Thus, (C 3 -C 7 )cycloalkyl means a radical having from 3-8 carbon atoms arranged in a ring. (C 3 -C 7 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl gππips where the halogens are independently selected from fluorine, chlorine, and bromine Saturated heterocyclic rings are A-, 5-, 6-, and 7-mcmbered heterocyclic rings containing 1 to 4 heteroatoms independently selected from N, O 3 and S, and include pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophenc, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1 ,3-dioxane, 1 ,4- dioxane, 1 ,3-dithiane, 1,4-dithiane, morpholine, thiomorpholine, thiomorpholine 1 ,1- dioxide, letrahydro-2H-l ,2-thiazine 1,1-dioxide, and isothiazolidine 1 ,1-dioxide. Oxo substituted saturated heterocyclic rings include tetrahydrothiophene 1 -oxide, tetrahydrothiophene 1 ,1 -dioxide, thiomorpholine 1 -oxide, thiomorpholine 1 ,1 - dioxide, tetrahydro-2H-l ,2-thiazine 1 ,1-dioxide, and isothiazolidine 1 ,1-dioxide, pyrrolidin-2-one, piperidin-2-one, piperazin-2-one, and morpholiπ-2-one. "Hctcroaryl" means a monovalent hetero aromatic monocyclic and polycylic ring radical containing 1 to 4 heteroatoms independently selected from N, O, and S. Hctcroaryl rings include furyl, thienyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridinyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl,

benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, 1.2,3-triazolyl, 1 ,2,4- triazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,5-thiadiazolyl-l -oxide, 1,2,5- thiadiazolyl- 1,1 -dioxide, 1,3,4-thiadiazolyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl, and pteridinyl.

Bicyclic heteroaryl rings are bicyclo[4.4.0] and bicyclo[4,3.0] fused ring systems of which at least one ring is aromatic containing 1 to 4 heteroatoms independently selected from N, O, and S, and include indole, quinoline, isoquinoline, quinazolinc, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, benzodioxole, bcnzimidazolc, indazole, benzisoxazole, bcnzoxazole, and benzothiazole.

Bicycloalkyl rings are fused, bridged and spiro ring systems and include bicyclo[1.1.0]butanc, bicyclo[1.2.0]pcntane, bicyclo[2.2.0]hexanc, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.2.0] octane, bicyclo[2.2.1]hcptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[3.3.2]decane and bicyclo[3.3.3]undecane, spiro[2.2]pentane, spiro[2.3]hexane, spiro[3.3]heptane, spiro[2.4]heptane, spiro[3.4]octane and spiro[2.5]octane.

Tricycloalkyl rings are fused, bridged and spiro ring systems and include tricyclo[3.3.1.0 3 ' 7 ]nonane (noradamantane) and tricyclo[3.3'.l .l 3 ' 7 ]decane (adamantane).

"Alkoxy" means an alkyl radical attached through an oxygen linking atom. "(Ci-Ci)-alkoxy" includes the methoxy, ethoxy, propoxy, and butoxy.

"Aromatic" means an unsaturated cycloalkyl ring system.

"Aryl" means an aromatic monocyclic or polycyclic ring system. Aryl systems include phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl.

"Hetero" refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O. A hetero ring may have 1 , 2, 3, or 4 carbon atom members replaced by a heteroatom.

"Oxo" refers to =0. When an oxo group is a substituent on a carbon atom, they form a carbonyl group (-C(O)-). When one oxo group is a substituent on a

sulfur atom, they form a sulfinyl (sulfoxide -S(O)-) group. When two oxo groups are a substituent on a sulfur atom, they form a sulfonyl (sulfone -S(O) 2 -) group.

In certain instances herein when describing functional groups, "alkane", '"cycloalkane" and the like are used interchangeably with "alkyl" and "cycloalkyl", respectively. Thus, by way of example, "alkanesulfonyl" means an alkyl group attached to a sulfonyl moiety, and "cycloalkanesulfonyl" refers to a cycloalkyl group attached to a sulfonyl moiety.

Enantiomers, Diastereomers, and Salts Certain compounds of Formula I may exist in various stereoisomeric or tautomeric forms. The invention encompasses all such forms, including active compounds in the form of essentially pure enantiomers, racemic mixtures, and tautomers, and including forms not depicted structurally..

The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/calionic salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionale, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

The compounds of the invention include pharmaceutically acceptable anionic salt forms, wherein the anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride,

citrate, dihydrochloride, edetate, edisylate, eslolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

The anionic salt form of a compound of the invention includes the acetate, bromide, camsylate, chloride, edisylate, fumarate, hydrobromide, hydrochloride, iodide, isethionate, lactate, mesylate, maleate, napsylate, salicylate, sulfate, and tosylate salts.

When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included. "Solvates" refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or its pharmaceutically acceptable salts or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound and its pharmaceutically acceptable salts, solvates or hydrates also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline

solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deform ability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidifying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. It may be necessary and/or desirable during synthesis to protect sensitive or reactive groups on any of the molecules concerned. Representative conventional protecting groups are described in T. W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999. Protecting groups may be added and removed using methods well known in the art. The invention also includes various isomers and mixtures thereof. "Isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). Certain of the disclosed aspartic protease inhibitors may exist in various stereoisomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastercomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol "*" in a structural formula represents the presence of a chiral carbon center. "R" and "S" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "R*" and "S*" denote the relative configurations of

substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, a mixture of both configurations is present.

"Racemate" or "racemic mixture" means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.

"Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bondj to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.

Atoms (other than H) attached to a carbocyclic ring may be in a cis or trans configuration. In the "cis" configuration, the substituents are on the same side in relationship to the plane of the ring; in the "trans" configuration, the substituents are on opposite sides in relationship to the plane of the ring. A mixture of "cis" and "trans" species is designated "cis/trans".

"R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule.

The point at which a group or moiety is attached to the remainder of the compound or another group or moiety can be indicated by " ^ru^ " which represents " " ", " — -"" " or . "

The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enatiomer over the weight of the enantiomer plus the weight of its optical isomer.

When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the inhibitor has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of inhibitor free from the corresponding optical isomer, a racemic mixture of the inhibitor and mixtures enriched in one enantiomer relative to its corresponding optical isomer.

When a disclosed aspartic protease inhibitor is named or depicted by structure without indicating the stereochemistry and has at least two chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).

The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the levels of aspartic protease products is effective in treating the disease state or in treating infections in which the infectious agent depends upon the activity of an aspartic protease. In hypertension elevated levels of angiotensin I, the product of renin catalyzed cleavage of angiotensinogen are present. Thus, the compounds of the invention can be used in the treatment of hypertension, heart failure such as (acute and chronic) congestive heart failure; left ventricular dysfunction; cardiac hypertrophy; cardiac fibrosis; cardiomyopathy (e.g., diabetic cardiac myopathy and post-infarction cardiac myopathy); supraventricular and ventricular arrhythmias; arial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae;

atherosclerosis; angina (whether unstable or stable); renal failure conditions, such as diabetic nephropathy; glomerulonephritis; renal fibrosis; scleroderma; glomerular sclerosis; microvascular complications, for example, diabetic retinopathy; renal vascular hypertension; vasculopathy; neuropathy; complications resulting from diabetes, including nephropathy, vasculopathy, retinopathy and neuropathy, diseases of the coronary vessels, proteinuria, albumenuria, post-surgical hypertension, metabolic syndrome, obesity, restenosis following angioplasty, eye diseases and associated abnormalities including raised intra-ocular pressure, glaucoma, retinopathy, abnormal vascular growth and remodelling, angiogenesis- related disorders, such as neovascular age related macular degeneration; hyperaldosteronism, anxiety states, and cognitive disorders (Fisher N.D.; Hollenberg N. K. Expert Opin. Invesiig. Drugs. 2001, 10, 417-26).

A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I, comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor. The compositions of the invention are renin inhibitors. Said compositions contain compounds having a mean inhibition constant (IC 50 ) against aspartic proteases of between about 5,000 nM to about 0.001 nM; preferably between about 50 nM to about 0.001 nM; and more preferably between about 5 nM to about 0.01 nM. The compositions of the invention reduce blood pressure.

The invention includes a therapeutic method for treating or ameliorating an aspartic protease mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or the enantiomers, diastereomers, or salts thereof or composition thereof.

Administration methods include administering an effective amount (i.e., a therapeutically effective amount) of a compound or composition of the invention at different times during the course of therapy or concurrently in a combination form. The methods of the invention include all known therapeutic treatment regimens. "Prodrug" means a pharmaceutically acceptable form of an effective derivative of a compound (or a salt thereof) of the invention, wherein the prodrug

may be: 1) a relatively active precursor which converts in vivo to a compound of the invention; 2) a relatively inactive precursor which converts in vivo to a compound of the invention; or 3) a relatively less active component of the compound that contributes to therapeutic activity after becoming available in vivo (i.e., as a metabolite). See "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

"Metabolite" means a pharmaceutically acceptable form of a metabolic derivative of a compound (or a salt thereof) of the invention, wherein the derivative is an active compound that contributes to therapeutic activity after becoming available in vivo. "Effective amount" means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated. The effective amount of a compound of the invention in such a therapeutic method is from about 10 mg/kg/day to about 0.01 mg/kg/day, preferably from about 0.5 mg/kg/day to 5 mg/kg/day. The invention includes the use of a compound of the invention for the preparation of a composition for treating or ameliorating an aspartic protease mediated chronic disorder or disease or infection in a subject in need thereof, wherein the composition comprises a mixture one or more compounds of the invention and an optional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction.

"Renin protease mediated disorder or disease" includes disorders or diseases associated with the elevated expression or overexpression of renin and conditions that accompany such diseases.

An embodiment of the invention includes administering a renin inhibiting compound of Formula I or composition thereof in a combination therapy (see USP 5821232, USP 6716875, USP 5663188, or Fossa, A. A.; DePasquale, M. J.; Ringer, L. J.; Winslow, R. L. "Synergistic effect on reduction in blood pressure with

coadministration of a renin inhibitor or an angiotensin-converting enzyme inhibitor with an angiotensin II receptor antagonist" Drug Development Research 1994, 33(4), 422-8) with one or more additional agents for the treatment of hypertension including α-blockers, β-blockers, calcium channel blockers, diuretics, natriuretics, saluretics, centrally acting antiphypertensives, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiolensin- receptor blockers (AR-Bs), aldosterone synthase inhibitors, aldosterone-receptor antagonists, or endothelin receptor antagonists. oc-Blockers include doxazosin, prazosin, tamsulosin, and terazosin. β-Blockers for combination therapy are selected from atenolol, bisoprol, mctoprolol, acctutolol, csmolol, ccliprolol, taliprolol, acebutolol, oxprenolol, pindolol, propanolol, bupranolol, pcnbutolol, mcpindolol, carteolol, nadolol, carvedilol, and their pharmaceutically acceptable salts.

Calcium channel blockers include dihydropyridines (DHPs) and non-DHPs. The preferred DHPs are amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine, nimodiphine, nisoldipine, nitrendipine, and nivaldipine, and their pharmaceutically acceptable salts. Non- DHPs are flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verampimil, and their pharmaceutically acceptable salts. A diuretic is, for example, a thiazide derivative selected from amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon.

Centrally acting antiphypertensives include clonidine, guanabenz, guanfacine and methyldopa.

ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, movellopril, perindopril, quinapril, quinaprilal, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril. Preferred ACE inhibitors are benazepril, enalpril, lisinopril, and ramipril.

Dual ACE/NEP inhibitors are, for example, omapatrilat, fasidotril, and fasidotrilat.

Preferred ARBs include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan.

Preferred aldosterone synthase inhibitors are anastrozole, fadrozole, and exemestane. Preferred aldosterone-receptor antagonists are spironolactone and eplerenone.

A preferred endothelin antagonist is, for example, bosentan, enrasentan, atrasentan, darusentan, sitaxsentan, and tezosentan, and their pharmaceutically acceptable salts.

An embodiment of the invention includes administering an HIV protease inhibiting compound of Formula I or composition thereof in a combination therapy with one or more additional agents for the treatment of AIDS including reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, other HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors (including attachment, co-receptor and fusion inhibitors), antisense drugs, and immune stimulators. Preferred reverse transcriptase inhibitors are zidovudine, didanosine, zalcilabine, stavudine, lamivudine, abacavir, tenofovir, and emtricitabine.

Preferred non-nucleoside reverse transcriptase inhibitors are nevirapine, delaviridine, and efavirenz.

Preferred HIV protease inhibitors are saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, and fosamprenavir.

Preferred HlV integrase inhibitors are L-870,810 and S- 1360.

Entry inhibitors include compounds that bind to the CD4 receptor, the CCR5 receptor or the CXCR4 receptor. Specific examples of entry inhibitors include enfuvirtide (a peptidomimetic of the HR2 domain in gp41 ) and sifurvitide. A preferred attachment and fusion inhibitor is enfuvirtide.

An embodiment of the invention includes administering β-secretase inhibiting compound of Formula I or composition thereof in a combination therapy with one or more additional agents for the treatment of Alzheimer's disease including tacrine, donepezil, rivastigmine, galantamine, and memantine.

Combination therapy includes co-administration of the compound of the invention and said other agent, sequential administration of the compound and the other agent, administration of a composition containing the compound and the other agent, or simultaneous administration of separate compositions containing the compound and the other agent.

The invention further includes the process for making the composition comprising mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques. The compositions of the invention include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), and injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenteral Iy). The composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation. Compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for ocular administration include sterile solutions or ocular delivery devices. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

The compositions of the invention may be administered in a form suitable for once-weekly or once-monthly administration. For example, an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a decanoate salt) or to provide a solution for ophthalmic administration.

The dosage form containing the composition of the invention contains a therapeutically effective amount of the active ingredient necessary to provide a therapeutic effect. The composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the invention or salt form thereof and may be constituted into any form suitable for the selected mode of administration. The composition may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed.

For oral administration, the composition is preferably in the form of a tablet or capsule containing, e.g., 500 to 0.5 milligrams of the active compound. Dosages will vary depending on factors associated with the particular patient being treated (e.g., age, weight, diet, and time of administration), the severity of the condition being treated, the compound being employed, the mode of administration, and the strength of the preparation. The oral composition is preferably formulated as a homogeneous composition, wherein the active ingredient is dispersed evenly throughout the mixture, which may be readily subdivided into dosage units containing equal amounts of a compound of the invention. Preferably, the compositions are prepared by mixing a compound of the invention (or pharmaceutically acceptable salt thereof) with one or more optionally present pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water).

Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta- lactose), corn sweeteners and natural and synthetic gums (e.g., acacia and tragacanth). Disintegrating agents include starch, methyl cellulose, agar, and bentonite.

Tablets and capsules represent an advantageous oral dosage unit form. Tablets may be sugarcoated or filmcoated using standard techniques. Tablets may also be coated or otherwise compounded to provide a prolonged, control-release therapeutic effect. The dosage form may comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component. The two components may further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release. A variety of enteric and non-enteric layer or coating materials (such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof) may be used.

Compounds of the invention may also be administered via a slow release composition; wherein the composition includes a compound of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).

Biodegradable and non-biodegradable slow release carriers are well known in the art. Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent. Such particles degrade/dissolve in body fluids to release the active compound(s) therein. The particles are preferably nanoparticles (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter). In a process for preparing a slow release composition, a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent. The resulting mixture is added into an aqueous solution containing an optional surface-active agcnt(s) to produce an emulsion. The organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.

The compound of Formula I may be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed

oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles. Suitable ' dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired.

The compounds may be administered parenterally via injection. A parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier. Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation. Such aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl). A sterile, non-volatile oil may be employed as a solvent or suspending agent. The parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient. Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

Compounds of the invention may be administered intranasally using a suitable intranasal vehicle. Compounds of the invention may also be administered topically using a suitable topical transdermal vehicle or a transdermal patch.

For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette. Preferably, the compositions are sterile and aqueous based, using purified water. In addition to the

compound of the invention, an ophthalmic composition may contain one or more of: a) a surfactant such as a polyoxyethylene fatty acid ester; b) a thickening agents such as cellulose, cellulose derivatives, carboxyvinyl polymers, polyvinyl polymers, and polyvinylpyrrolidones, typically at a concentration n the range of about 0.05 to about 5.0% (wt/vol); c) (as an alternative to or in addition to storing the composition in a container containing nitrogen and optionally including a free oxygen absorber such as Fc), an anti-oxidant such as butylated hydroxyanisol, ascorbic acid, sodium thiosulfatc, or butylated hydroxytoluene at a concentration of about 0.00005 to about 0.1 % (wt/vol); d) ethanol at a concentration of about 0.01 to 0.5% (wt/vol); and e) other excipients such as an isotonic agent, buffer, preservative, and/or pH-controlling agent. The pH of the ophthalmic composition is desirably within the range of 4 to 8.

METHODS OF PREPARATION

In the discussion below G a , G b , G c , A 4 , Q, T are defined as described above for compounds of Formulae I and Ia. In cases where the synthetic intermediates and final products of Formula I described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W.

Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999). Such protecting group manipulations are assumed in the discussion below and not described explicitly.

In the first process of the invention a compound of Formula I is prepared by reaction of an intermediate of formula II wherein Z 1 is a leaving group such as halide, 1-imidazolyl, aryloxide, or alkoxide with a group of formula III which contains one reactive primary or secondary amine:

Il III

Intermediates of formula II are prepared by reaction of piperidine and morpholine intermediates of formula IV by reaction with intermediates of formula V wherein Z 1 and Z 2 are independently selected from halide, 1 -imidazolyl, 3-methyl-l - imidazolium, alkylthio, arylthio, aryloxide and alkoxide:

IV V Il

For example, when Q is Ql (C=O) in II and V, Z 1 and Z 2 are both chloride or 1- imidazolyl. When Q is Q3 in II and V, Z is 1 -imidazolyl and Z is 3-methyl-l- imidazolium. When Q is Q4 or Q6 in II and V, Z 1 and Z 2 are both SMe. When Q is Q6 or Q8 in II and V, Z 1 and Z 2 are both chloride. When Q is Q9, Ql 1, Q12 or Ql 3 in II and V 5 Z 1 and Z 2 are both MeO.

Intermediates of formula IV are prepared from intermediates of Formula VI:

Vl IV wherein E is an amine protecting group, including carbamate, amide, and sulfonamide protecting groups known in the art (T.W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999).

Intermediates of Formula VI wherein G c = OH are prepared from ketone intermediates of formula VII by addition of an organometallic reagent of formula VIII, wherein M is, for example, Li, MgCl, MgBr, or MgI:

VII VIII Vl G ° = OH

Intermediates of Formula VI wherein G b is a group OG bb , attached through an ether linkage, are prepared by reaction of alcohol intermediates of formula IX

with alkylating agents of formula X wherein Z 3 is a leaving group such as halide, alkanesulfonate, haloalkanesulfonate or arylsulfonale under basic conditions:

ix x vi _ H

Alcohol Intermediates of formula IX are prepared by reduction of ketone intermediates of formula VII with, for example, a hydride reducing agent such NaBHU, LiAlH 4 , or diisobutylaluminum hydride:

VII IX or by addition of of an organometallic reagent of formula XI wherein M is, for example, Li, MgCl, MgBr 3 or MgI to an aldehyde of Formula XII:

Xl XH IX

Ketone intermediates of formula VII are prepared by the addition of an organometallic reagent of formula XI to a carboxylic acid derivative of formula XII wherein Z" 1 is an alkoxide, dialkylamino group, or an N-alkoxy-N-alkylamino group:

Xl XIII VII Organometallic reagents of formula XI are prepared by known processes including halogen-lithium exchange, ortho-lithiation, and treatment of halides G a - HaI with magnesium or lithium metal.

Aldehyde intermediates of formula XII are prepared by reduction of carboxylic acid derivatives of formula XIII wherein Z is an alkoxy or N-alkoxy-N- alkylamino group using, for example, a hydride reducing agent such as LiAlHj or diisobutylaluminum hydride:

XIIt XII

Ketone intermediates of formula VII are also prepared by oxidation of alcohol intermediates of formula IX:

IX VII

In the second process of the invention a compound of Formula I is prepared by reaction of a piperidine or morpholine intermediate of formula IV with an intermediate of Formula XIV wherein Z 1 is a leaving group such as halide, aryloxide, or alkoxide and Q is attached to a nitrogen atom that is part of T:

IV XIV I

Intermediates of Formula XIV are prepared by reaction of III by reaction with intermediates of formula V wherein Z 1 and Z 2 are independently selected from halide, l-imidazolyl, 3-methyl-l-imidazolium, alkylthio, arylthio, aryloxide and alkoxide:

T + ZV 0 ^ . zV Q (12)

III V XIV

For example, when Q is Ql (C=O) in V and XIV, Z 1 and Z 2 are both chloride or 1 - imidazolyl. When Q is Q3 in V and XIV, Z 1 is 1-imidazolyl and Z 2 is 3-methyl-l- imidazolium. When Q is Q4 or Q6 in V and XIV, Z 1 and Z 2 are both SMe. When Q is Q6 or Q8 in V and XIV, Z 1 and Z 2 are both chloride. When Q is Q9, Ql 1, Q 12 or Q 13 in V and XIV, Z ' and Z 2 are both MeO.

Preparation of intermediates of Formula III is described in the references cited above.

In the third process of the invention a compound of Formula I is prepared from another, optionally protected, compound of Formula I:

I I

For example, when G a is a bromophenyl, iodophenyl or trifluoromethanesulfonyloxyphenyl group in a compound of Formula I, it may be transformed into compounds of formula I wherein G a is (i) a biphenyl group using a Suzuki coupling, (ii) an alkynylbenzene using a Sonogashira coupling, (iii) an allylbenzene using a Stille coupling, (iv) a cyanobenzene using CuCN, or (v) a methoxycarbonylbenzene using a palladium catalyzed carbonylation in the presence of methanol. A second example is the transformation of a compound of Formula I wherein G c = OH to the analogous compound wherein G c = H by dehydration followed by hydrogenation or in a single step by deoxygenation using Raney nickel. A third example is the deoxygenation of a compound of Formula I wherein Q = QI l to a compound of Formula I where Q = QlO. A fourth example is the alkylkation of a compound of Formula I wherein G a is a hydroxyphenyl group to provide a compound of formula I wherein G a is an alkoxyphenyl, cycloalkoxyphenyl, cycloalkylalkoxyphenyl, or arylalkoxyphenyl group.

In a fourth process o ' f the invention optionally protected compounds of Formula I wherein G c = OH are prepared from optionally protected ketone compounds of formula XV by addition of an organometallic of formula VIII:

-307 -

XV VIII I

G C = OH

The following abbreviations have the indicated meanings:

Abbreviation Meaning

Aq aqueous

Boc fe/t-butoxy carbonyl or ?-butoxy carbonyl

(BoC) 2 O di-terf-butyl dicarbonate

Brine saturated aqueous NaCI

Cbz Benzyloxycarbonyl

CbzCI Benzyl chloroform ate

CDI carbonyl diimidazole

CH 2 CI 2 methylene chloride

CH 3 CN or MeCN acetonitrile

Cpd compound

D day

DAST diethylaminosulfur trifluoride

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene

DCC N.N'-dicyclohexylcarbodiimide

DCU N,N'-dicyclohexylurea

DIAD diisopropyl azodicarboxylate

DIEA N,N-diisopropylethylamine

DMAP 4-(dimethylamino)pyridine

DMF N,N-dimethylformamide

DMPU 1 ,3-dimethyl-3 ,4,5,6-tetrahydro-2(1 H)-pyrimidinone

2,4-DNP 2,4-dinitrophenylhydrazine

EDCHCI 1 -[3-{dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

Equiv equivalents

Et ethyl

Et 2 O ethyl ether

EtOAc EtOAc

Fm oc l-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-

Fmoc-OSu l-[r(9H-fluoren-9-ylmethoxy)carbonylloxy]-2,5-

pyrrolidinedione h, hr hour

HOBt 1 -hydroxybenzotriazole

HATU 2-(7-Aza-lH-benzotrlazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate

HBTlJ "' ■ 2-(1H-Benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate

KHMDS potassium hexamethyldisilazane

LAH or LiAlH 4 lithium aluminum hydride

LC-MS liquid chromatography-mass spectroscopy

LHMDS lithium hexamethyldisilazane

Me methyl

MeCN acetonitrile

MeOH methanol

MsCI methanesulfonyl chloride

Min minute

MS mass spectrum

NaH sodium hydride

NaHCO 3 sodium bicarbonate

NaN 3 sodium azide

NaOH sodium hydroxide

Na 2 SO 4 sodium sulfate

NMM N-methylmorpholine

NMP N-methylpyrrolidinone

Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(0)

PE petroleum ether

Ph phenyl

Qυant quantitative yield

Rt room temperature

Satd saturated

SOCI 2 thionyl chloride

SPE solid phase extraction

TBS t-butyldimethylsilyl

TBSCI t-butyldimethylsilyl chloride

TEA triethylamiπe or Et 3 N

TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical

Teoc 1-[2-(trimethylsilyl)ethoxycarbonyloxy]-

Teoc-OSu 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione

TFA trifluoroacetic acid

THF tetrahydrofuran

TIc thin layer chromatography

TMS trimethylsilyl TMSCI chlorotrimethylsilane or trimethylsilyl chloride retention time

TsOH p-toluenesulfonic acid

Purification Methods

Prep HPLC refers to preparative reverse phase HPLC on a C-18 column eluted with a water/acetonitrile gradient containing 0.01% TFA run on a Gilson 215 system.

Analytical Methods LC-MS (3 min)

Column: Chromolith SpeedRod, RP- 18e, 50 x 4.6 mm; Mobil phase: A: 0.01%TF A/water, B: 0.01%TFA/CH 3 CN; Flow rate: 1 mL/min; Gradient:

LC-MS (16 min) Column: Chromolith SpeedRod, RP-18e, 50 x 4.6 mm; Mobil phase: A: 0.01%TF A/water, B: 0.01%TFA/CH 3 CN; Flow rate: 1 mL/min; Gradient:

PREPARATIONS

Pipcridinc and morpholine compounds of formula IV wherein G a , G b , G c and A have the meanings described above for compounds of formulae I and Ia are useful for the preparation of compounds of formula I and Ia. The following procedures describe the preparation of intermediates of formula IV.

PREPARATION 1 (R)-tert-bu\yl S-fN-methoxy-Af-methylcarbarnovQpiDeridine-i -carboxylatc

(R)-I -(/erZ-butoxycarbonyOpiperidine-S-carboxylic acid (25 g, 0.1 1 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv), EDCHCl (26.3 g, 0.14 mol, 1.25 equiv) and DIEA (48 mL, 0.28 mol, 2.5 equiv) were dissolved in CH 2 Cl 2 (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2 x 15OmL), satd aq NaHCO 3 (15OmL), brine (100 mL), and dried over Na 2 SO 4 . Concentration afforded (R)-tert- butyl 3-(N-methoxy-iV-methylcarbamoyl)-piperidine-l-carboxylate (24.42g, 82%) as a clear oil.

PREPARATION 2 (S * )-l -(3-chlorophenyl * )-5-methoxy-l-(rRVpiperidin-3-vnpentan-l-ol

TFAZCH 2 CI 2

Step 1. (R)-/e/7-butyI 3-(mcthoxy(mcthyl)carbamoyl)pipcridine-l-carboxylate

To a stirred solution of λ-piperidine-1 , 3-dicarboxylic acid l-lert-buϊyl ester (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol). The mixture was stirred for 1 h in an ice-water bath. A suspension of triethylamine (207 in L, 1.41 mol) and N, O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. After TLC showed the reaction was complete, solvent was evaporated to give a residue, which was dissolved in CH 2 Cl 2 (1.2 L) and washed successively with 0.5 N aq HCl, sat'd aq Na 2 CO 3 and brine, dried over anhydrous sodium sulfate and evaporated to give the crude compound (R)-tert-huty\ 3- (methoxy(methyl)-carbamoyl)piperidine-l-carboxylate (250 g, 91%), which was used in the next step directly without purification. 1 H NMR (400 MHz 5 CDCl 3 ): 1.44 (s, 9H), 1 .60-1.78 (m, 2H), 1.90 (m, I H), 2.65 (m, IH), 2.75-2.85 (m, 2H), 3.16 (s, 3H), 3.71 (s, 3H) 5 4.05-4.19 (m, 2H). MS (E/Z): 273 (M+H + ).

Step 2. CR.)-tert-buty\ 3-(3-chlorobenzoyl)piperidine-l-carboxylate

To a solution of l-bromo-3-chlorobenzene (15 g, 78.3 mmol) in anhydrous THF (150 mL) cooled to -78°C was added dropwise a solution of 2.5 M n-BuLi in hexanc (31.3 mL, 78.34 mmol). The reaction mixture was stirred at -78°C for 1 h

and a solution of (R)-/ert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-l - carboxylate (17.8 g, 65.3 ramol) in anhydrous THF (50 mL) was added dropwise. After addition, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH 4 Cl (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography (PE/EtOAc 5:95) to give (K)-iert-buty\ 3-(3- chlorobenzoyl)piperidine-l-carboxylate (12.9 g, 51%). 1 H NMR (400 MHz, CDCl 3 ): 1 .45 (s, 9H), 1.54-1.73 (m, 2H), 1.75 (m, IH), 2.00 (m, IH), 2.71-2.78 (m, IH), 2.93 (m, 2H), 3.30-3.35 (m, IH), 4.22 (m, IH), 7.39-7.42 (t, IH), 7.52 (d, IH), 7.89 (d, IH), 7.90 (m, I H). MS (E/Z): 324 (M+H + ).

Step 3. (R)-/ert-butyl 3-((S)-l-(3-chlorophenyl)-l -hydroxy-5- methoxypenty Opiperidine- 1 -carboxylate A 250 mL three-necked flask was charged with magnesium turnings (2.88 g,

0.12 mol) and a small crystal of iodine in THF (20 mL). The flask was evacuated and refilled with N 2 . A solution of l-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (40 mL) was added dropwise to the above mixture. After heating under reflux for 1 h, most of magnesium was consumed, the reaction mixture cooled to rt. Another 250 mL three-necked flask was charged with fi?)-3-(3-chloro-benzoyl)- piperidine-1-carboxylic acid tert-bnly\ ester (3.24 g, 10 mmol) and THF (50 mL), which was evacuated and refilled with N 2 . The mixture was cooled with dry ice- acetone bath and the Grignard reagent derived from l-chloro-4-methoxybutane (20 mL) was added dropwise. After addition, the mixture was allowed to warm slowly to rt and stirred for 2 h. The mixture was quenched with sat'd aq NH 4 Cl (100 mL), extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography (EA / PE 10:90) to give (R)-tert-butyl 3-((S)-I -(3- chlorophenyl)-l-hydroxy-5-methoxypentyl)piperidine-l -carboxylate (3.0 g, 73%). 1 H NMR (400MHz, CDCl 3 ): 1.45 (s, 9H), 1.52-1.58 (m, 3H), 1.75 (m, IH), 1.92 (m 5 2H), 2.52 (m, 2H), 3.25 (s, 3H), 3.27 (m, 2H), 3.95 (m, IH), 4.35 (m, IH), 7.20-7.26 (m, 3H) 3 7.36 (m, IH). MS (E/Z): 412 (M+H + ).

Step 4. (S)-l-(3-chlorophenyl)-5-methoxy-l-((R)-piperidin-3-yl)penta n-l-ol

(R)-/βr/-butyl 3 -((S)-I -(3-chloropheny I)-I -hydroxy-5- methoxypentyl)piperidine-l-carboxylate (4.1 g, 0.01 mol) was dissolved in 20% TFA/CH 2 C1 2 (40 mL). The reaction mixture was stirred at rt for 2 h, tic showed the reaction was complete. A solution of sat'd aq Na 2 CO 3 was added dropwise to adjust the pH to 8~9 and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give crude (S)-l-(3-chlorophenyl)-5-methoxy-l-((R)- piperidin-3-yl)pentan-l-ol (3.0 g, 97%), which was used without purification.

The compounds listed below were prepared following procedures analogous to those described above:

(S)- 1 -(3-fluoro-4-methylphenyl)-5-methoxy- 1 -((R)-piperidin-3-yl)pentan- 1 -ol using

3-fluoro-4-methylbromobenzene in Step 2

(S)-5-i"nethoxy-l-((R)-pipcridin-3-yl)-l-(2,3,5-trifluoro phenyl)pcntan-l -ol using

2,3,5-trifluorobromobenzene in Step 2.

(S)-5-ethoxy- 1 -((R)-piperidin-3-yl)-l -(2,3,5-trifluorophenyl)pentan- 1 -ol using 2,3,5- trifiuorobromobenzene in Step 2 and 4-ethoxybutylmagnesium chloride in Step 3.

(S)-l-(3-fluoro-5-methylphenyl)-5-methoxy-l-((R)-piperidi n-3-yl)pentan-l-ol using

3-fluoro-5-methylbromobenzene in Step 2

(S)-l-(2-fluorophenyl)-5-methoxy-l-((R)-piperidin-3-yl)pe ntan-l-ol using 2- fluorobromobenzene in Step 2. (S)-l-(3,5-difluorophenyl)-5-methoxy-l-((R)-piperidin-3-yI)p entan-l-ol using 3,5- difluorobromobenzene in Step 2.

(S)-l -(2,3-difluorophenyl)-5-methoxy-l-((R)-piperidin-3-yl)pentan -l -ol using 2,3- difluorobromobenzene in Step 2.

(S)- 1 -(2-fIuoro-3-methylphenyl)-5-methoxy- 1 -((R)-piperidin-3-yl)pentan-l -ol using 2-fluoro-3-mcthyliododbcnzcne in Step 2.

(S)-I -(3-fluoro-2-methyIphenyl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l -ol using

2-mcthyl- # 3-fluorobromobenzene in Step 2.

(S)- 1 -(2-fluoro-5-methylphenyl)-5-methoxy- 1 -({R)-piperidin-3-yl)pentan- 1 -ol using

2-flυoro-5-methylbromobenzene and n-BuLi in Step 2.

(S)- 1 -(5-fluoro-2-methylphenyI)-5-methoxy- 1 -((R)-piperidin-3-yI)pentan- 1 -ol using

2-methyl-5-fluorobromobenzene in Step 2. (S)-l -(2-chlorophenyl)-5-methoxy-l-((R)-piperidin-3-yl)pentan-l-o l using 2- chlorobromobenzene in Step 2.

(S)-5-methoxy-l-((R)-piperidin-3-yl)-l-(2-(trifluorometho xy)phenyl)pentan-l -ol using 2-(trifluoromethoxy)bromobenzene and n-BuLi in Step 2.

(S)-l-(3,5-dimethylphcnyl)-5-mcthoxy-l-((R)-piperidin-3-y l)pentan-l -ol using 3,5- dimcthylbromobcnzcnc in Step 2.

(S)-5-methoxy-l -(3-(methylthio)phenyl)-l-((R)-piperidin-3-yl)pentan-l-ol using 3-

(methylthio)bromobenzene and n-BuLi in Step 2.

(S)- 1 -(2-fluoro-6-methoxyphenyl)-5-methoxy- 1 -((R)-piperidin-3-yl)pentan- 1 -ol using 2-fluoro-6-methoxybromobenzene and n-BuLi in Step 2. (S)-S-methoxy- 1 -((R)-piperidin-3-yl)- 1 -(2-(trifluoromethyl)phenyl)pentan- 1 -ol using

2-(trifluoromethyl)bromobenzene and n-BuLi in Step 2.

(S)-I -(5-fluoro-2-methoxyphenyl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l -oI using 2-methoxy-5-fluorobromobenzene and n-BuLi in Step 2.

(S)-5-methoxy-l -((R)-piperidin-3-yl)-l -(3-(trifluoromethoxy)phenyl)pentan-l-ol using 3-(trifluoromethoxy)bromobenzene and n-BuLi in Step 2.

(S)-I -(3-fluoro-5-methylphenyl)-5-methoxy-l-((R)-pϊperidin-3-yl) pentan-l-oI using

3-iluoro-5-methylbromobenzene and n-BuLi in Step 2.

(S)-I -(2,3-dimethy]phenyl)-5-methoxy-l-((R)-piperidin-3-yl)pentan -l-ol using 2,3- dimethylbromobenzene and n-BuLi in Step 2. (S)-I -(2,5-dimcthylphenyl)-5-mcthoxy-l-((R)-piperidin-3-yl)pentan -l-ol using 2,5- dimethylbromobenzene and n-BuLi in Step 2.

(S)-5-methoxy-l-(3-methoxyphenyl)-l-((R)-piperidin-3-yl)p entan-l-ol using 3- methoxybromobenzene and n-BuLi in Step 2.

(S)-I -(2,3 -difluorophenyl)-5-methoxy-l-((R)-piperidin-3-yl)pentan-l-ol using 2,3- difluorobromobenzene and n-BuLi in Step 2.

(S)-l-(3-chloro-2-methylphenyl)-5-methoxy-l -((R)-piperidin-3-yI)pentan-l -ol using

3-chIoro-2-methylbromobenzene and n-BuLi in Step 2.

(S)-l-(3-chloro-5-fluorophcnyl)-5-mcthoxy-l-((R)-piperidi n-3-yl)pentan-l-ol using 3-bromo-5-chloroiodobenzene and n-BuLi in Step 2.

(S)-l-(3-chloro-2,4-difluorophenyl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l-ol using 3-chloro-2,4-difluorobromobenzene in Step 2.

(S)-l-(2-(allyloxy)-3-bromophenyl)-5-methoxy-l-((R)-piper idin-3-yl)pentan-l-ol using 2-allyloxy-l,3-dibromobenzene and n-BuLi in Step 2. l-(2-(allyloxy)-5-fluorophenyl)-5-ethoxy-l-((R)-piperidin-3- yl)pentan-l-ol using 2- allyIoxy-5-fluorobromobenzene and n-BuLi in Step 2.

(S)-5-melhoxy-l -((R)-piperidin-3-yl)-l-(2,3,5-trifluorophenyl)pentan-l -ol using 2,3,5-trifluorobromobenzene and n-BuLi in Step 2.

PREPARATION 3

Step 1. (R)-λ?r/-butyl 3-(3-chloro-2-fluorobcnzoyl)piperidine-l-carboxylate

To a stirred solution of 1 -chloro-2-fluoro-benzene (13.0 g, 0.1 mol) in THF (250 ltiL) at -75°C was added dropwise 2.5 M BuLi in hexane (40 mL, 0.1 mol) during 45 min. After additional stirring for 30 min at -75°C, a solution of (R)-Ze/-/- butyl 3-(methoxy(methyl)~carbamoyl)piperidine-l-carboxylate (21.76 g, 0.08 mol) in THF (100 mL) was added dropwise over 30 min. The mixture was allowed to warm from -70 0 C to 0 0 C. The mixture was quenched with sat'd aq NH 4 Cl,

extracted with EtOAc (3 x) and the combined organic layers were dried over Na 2 SO 4 . Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-/er/-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-l - carboxylate (19.2 g, 70%). 1 H NMR (400MHz, CDCl 3 ): 1.45 (s, 9H), 1.63 (m, 2H), 1.76 (m, 1 H), 2.06 (m, IH) 5 2.87(m, IH), 3.15(m, IH), 3.25 (m, IH), 3.9 (m, IH), 4.2 (m, IH), 7.18 (m, IH), 7.60 (m, 2H). MS (E/Z): 342 (M+H + ).

Step 2. (R)-Zert-butyl 3-((S)-l-(3-chloro-2-fluorophenyl)-l -hydroxy-5- m ethoxypenty l)piperidine- 1 -carboxylate A flame dried 250 mL three-necked flask was charged with magnesium turnings (7.02 g, 0.293 mol), a small crystal of iodine and THF (30 mL). The flask was evacuated and refilled with N 2 . A solution of 1 -chloro-4-methoxybutane (28.69 g, 0.234 mol) in TI-IF (120 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent was used as follows To another 100 mL three-necked flask was added (R)-/er/-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine- 1 -carboxylate (10 g, 0.0293 mol) and THF (100 mL). The flask was evacuated and refilled with N 2 . The mixture was cooled with dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with satd aq NH 4 Cl (50 mL), extracted with EtOAc (3 x), and the combined organic layers were dried over Na 2 SO 4 . Evaporation of the solvent gave the crude product. The LC-MS analysis of the crude product indicated the presence of two isomers (95:5). Flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-/er/-butyl 3-((S)-I -(3- chloro-2-fluorophenyl)-l-hydroxy-5-methoxypentyl)piperidine- l -carboxylate (9.4 g, 75% yield). 1 H NMR (400MHz, DMSO): 0.68 (m, IH), 1.50-1.01 (m, 7 H), 1.37 (s, 9H), 1.75 (m, 2H), 2.01 (m, IH), 3.11 (s, 3H), 3.17(m, 2H), 3.85 (m, IH), 7.2 (t, IH), 7.45 (m, 2H). MS (E/Z): 430 (M+H + ).

Step 3. (S)-l -(3-chloro-2-fluorophenyl)-5-mcthoxy-l -((R)-piperidin-3-yl)pentan-l- ol

A solution of (R)-tert-butyl 3-((S)-l-(3-chloro-2-fluorophenyl)-l-hydroxy-5- methoxypentyl)piperidine-l-carboxylate (100 mg) in 20% TFA/CH 2 Cl 2 was stirred at 0 0 C for 30 min. The mixture was neutralized by addition of sat'd aq NaHCO 3 , extracted with CH 2 Cl 2 (3 x) and dried over Na 2 SO 4 . Evaporation of the solvent gave" (S)-I -(3-chloro-2-fluorophenyl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l -ol (70 mg, 91 %), which was used without further purification. 1 H NMR (400MHz, CDCl 3 ): 0.90(m, IH), 1.52-1.24 (m,6 H), 1.78 (m,lH ), 1.83 (m,lH), 1.93 (m, IH) 5 2.21 (m ,1 H), 2.40 (m, 1 H) 5 2.83 (m,lH), 3.00 (m, IH) 3 3.12 (s,3H), 3.3 l(m, 2 H), 3.63 (m, IH), 7.06 (m, IH), 7.30(m,l H), 7.55 (t, IH). MS (E/Z): 330 (IVH-H + ).

The compounds listed below were prepared following procedures analogous to those described above:

(S)-l-(2,3-dichlorophenyl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l -ol using 1 ,2- dichlorobenzene in Step 1.

(S)-5-methoxy-l -((R)-piperidin-3-yl)-l -(2,3,4-trifluorophenyl)pentan-l-ol using

1 ,2,3-trifluorobenzene in Step 1.

1 -(3-chloro-2-fluorophenyl)-5-ethoxy- 1 -((R)-piperidin-3-yl)pentan- 1 -ol using 4-

(ethoxy)butylmagnesium chloride in Step 2. (S)-l-(2,3-dichlorophenyl)-5-ethoxy-l-((R)-piperidin-3-yl)pe ntan-l -ol using 1,2- dichlorobenzene in Step 1 and 4-(ethoxy)butylmagnesium chloride in Step 2.

PREPARATION 4

Step I . te/7-Butyl 3-((R)-I -hydroxy- l -phenylhex-5-enyl)piperidine-l -carboxylate

A stirred solution of /er/-butyl 3-benzoylpiperidine-l-carboxylate (160 mg, 0.55 mmol) in dry THF (2 mL) was cooled to -70°C and 4-pentenylmagnesium bromide in THF (1.8 mL of —2.5 M, 2.8 mmol) was added dropwise. The mixture was stirred at -78°C and allowed to warm to rt overnight. The reaction was quenched with satd aq ammonium chloride. The aqueous layer was extracted with Et 2 O (3 x). The combined organic layers were washed with brine, dried over Na 2 SOi), filtered and evaporated to dryness. The crude material was purified by flash chromatography on a prepacked silica cartridge eluted with an EtOAc/hexanes gradient. terl-Butyl 3-((R)-I -hydroxy- l-phenylhex-5-enyl)piperidine-l -carboxylatc (174 mg, 88%) was isolated as an oil. MS ESI +ve m/z 382 (M+Na) + .

Step 2. 4-Cyclopropyl-l-phenyl-l -(piperidin-3-yl)butan-l-ol

To a 0 0 C solution of diethyl zinc (1.0 mL of IM in hcxanc, 1 mmol) in dry dichloroethane (2 mL), chloroiodomethane (0.14 ml, 2.0 mmol) was added dropwise over five minutes. The reaction was removed from the ice bath and allowed to stir at rt for 40 min A dichloroethane solution (1 mL) of tert-buty\ 3-((R)-I -hydroxy- 1- phenylhex-5-enyl)piperidine-l-carboxylate (174 mg, 0.480 mmol) was added dropwise. The reaction was allowed to stir overnight. The reaction was quenched with satd ammonium chloride. The aqueous layer was extracted 3x with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and evaporated to dryness. The crude material was purified via preparative HPLC (C-18 column, 10 to 90% CH 3 CN in H 2 O containing 0.01 % CF 3 CO 2 H over 10 min, 20 mL/min) to afford the trifluoroacetic acid salt of 4-cyclopropyl-l -phenyl- 1- (piperidin-3-yl)butan-l-ol (32 mg, 24%). MS ESI +ve m/z 274 (M+l).

PREPARATION 5 Methyl (S r )-4-(3-chlorophenyl)-4-hvdroxy-4-r(R)-piperidin-3-vπbutylca rbamate

Step 1. [3-(2,2,5,5-tetramethyl-l-aza-2,5-disilacycIopent-l-yl)propy l]magnesium bromide A 250 mL, round bottom flask was charged with magnesium turnings (0.528 g, 21.7 mmol, 1.16 equiv) and THF (10 mL). The flask was degassed and heated to 100°C. A small crystal of iodine was then added. A solution of l-(3-bromopropyl)- 2,2,5, 5-tetramethyl-l-aza-2,5-disilacyclopcntane (5.239 g, 1 8.7 mmol, 1.0 equiv) in THF (15 mL) was added dropwise to the boiling THF mixture over 10 min. The reaction mixture was stirred and heated under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent (A) was used in the next step.

Step 2. (R)-/er/-buty\ 3-((5)-4-amino-l-(3-chlorophenyl)-l-hydroxybutyl)piperidine- 1 -carboxylate

To a 250 mL, round bottom flask were added (3-chlorophenyl)((λ)-N-Boc- piperidin-3-yl)methanone (0.800 g, 2.47 mmol) and THF (10 mL). The flask was evacuated and refilled with N 2 . The mixture was cooled with a dry ice-acetone bath and the [3-(2,2,5,5-tetramethyl-l-aza-2,5-disilacyclopent-l-yl)propy I]rnagnesium bromide solution (A) 5 obtained in Step 1 , was added via a cannula. The reaction mixture was allowed to slowly warm to -8 0 C while stirring overnight. The mixture was quenched with 10% aq Na 2 COa (10 mL), stirred at rt for 3 h, extracted with CH 2 Cl 2 (3 x), and dried over Na 2 SO 4 . The crude product was purified by reversed- phase HPLC (Phenomenex® Luna 5μ C 18(2) 10OA, 250 x 21.20 mm, 5 micron, 10% →90% CH3CN/H 2 O, 0.1 % CF 3 COOH over 13 min and then 90%

CH 3 CN/H 2 O, 0.1% CF 3 COOH over 3.5 min, flow rate 25 mL/min) to give 0.883 g (72%) of TFA salt of (λ)-/er/-butyI 3-((5)-4-amino-l-(3-chlorophenyl)-l - hydroxybυtyl)piperidine-l -carboxylate. LC-MS (3 min) / R = 1.30 min, w/z 383, 385 (MH + X 327, 329; 1 H NMR (400 MHz, CD 3 OD) D 7.36 (m, I H), 7.27-7.13 (m, 3H), 4.26 (br S 5 I H), 3.89 (d, J= 12.9 Hz, I H), 2.82-2.68 (m, 2H), 2.44 (br s, I H) 5 2.36 (t, J= 12.2 Hz 5 IH), 1.97-1.79 (m, 2H), 1.64-1.08 (m, 16H), 1.34 (s); 13 C NMR (IOO MHz, CD 3 OD) D 156.69, 148.15, 135.39, 130.69, 127.74, 127.36, 125.41, 81.04, 78.10, 40.95, 28.69, 26.64, 26.51, 23.30.

Step 3. (λ)-/eλ7-butyl 3-((5)-4-(methoxycarbonylamino)-l -(3-chlorophenyl)-l- hydroxybutyl)-piperidine-l-carboxylate

To a 100 mL round bottom flask were added the TFA salt of (R)-lert-butyl 3- ((5)-4-amino-l -(3-chlorophenyl)-l-hydroxybutyl)piperidine-l-carboxylate (0.8164 g, 1.64 mmol, 1.0 equiv), DMAP (0.542 g), CH 2 Cl 2 (40 mL) and triethylamine (6 mL). The mixture was cooled in an ice bath and a solution of methyl chloroformate (0.550 g, 5.82 mmol, 3.5 equiv) in CH 2 Cl 2 (10 mL) was added. The reaction mixture was allowed to slowly warm to rt and stirred overnight. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ Cl 8(2) 10OA, 250 x 21.20 mm, 5 micron, 70% →90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CNTH 2 O, 0.1%

CF 3 COOH over 1.5 min, flow rate 25 mL/min) to give 0.5020 g (69%) of (R)-tert- butyl 3-((5)-4-(methoxycarbonyl-amino)-l-(3-chlorophenyl)-l - hydroxybutyl)piperidine-l-carboxylate. LC-MS (3 min) / R = 1.91 min, m/z 463 (MNa + ), 441 (MH + ), 343 341; 1 H NMR (400 MHz, CDCl 3 ) D 7.37-7.36 (m, IH), 7.28-7.17 (m, 3HX 4.90 (br s, 2H), 4.37 (d, J= 12.0 Hz 5 IH), 3.97 (d, J= 12.3 Hz 5 I H), 3.64 (s, 3H), 3.16-3.04 (m, 2H) 5 2.58-2.49 (m, 2H), 1.98-1.86 (m, 2H), 1.76- 1.70 (m, IH), 1.61 -1.56 (m, IH), 1.45 (s, 9H), 1.48-1.13 (m, 5H); 13 C NMR (IOO MHz 5 CDCl 3 ) D 157.60, 155.31, 146.51, 134.31 , 129.36, 126.72, 125.96, 123.76, 80.08, 77.65, 52.21, 46.45, 44.9I 5 44.56, 40.91, 35.97, 28.42, 25.33, 25.25, 24.34.

Step 4. Methyl (5)-4-(3-chloroρhenyl)-4-hydroxy-4-((7?)-piperidin-3- yl)butylcarbamate

A mixture of (R)-tert-buty\ 3-((ιS)-4-(methoxycarbonylamino)-l -(3- chlorophenyl)-l-hydroxybutyl)piperidine-l-carboxylate (0.0322 g, 0.073 mmol), obtained as described above, in CH 3 CN (30 mL) and 2 N aq HCl (25 mL) was vigorously stirred at rt for 24 h. The solvents were removed in vacuo to give the HCl salt of methyl (.S)-4-(3-chlorophenyl)-4-hydroxy-4-((i?)-piperidin-3- yl)butylcarbamate, which was used without further purification. LC-MS (3 min) / R = 0.98 min, m/z 343, 341 (M+H + ), 323.

PREPARATION 6 ^-((^^-π-chloroDhenvπ^-hvdroxy^-rr^-piperidin-S-vπbutvπa cetamide

Step 1. (R)-ter(-buty\ 3-((S)-4-acetamido-l~(3-chlorophenyl)-l-hydroxybutyl)- piperidine- 1 -carboxylate To a 100 mL, round bottom flask were added TFA salt of (λ)-/ør/-butyl 3-

((6}-4-amino-l-(3-ch]orophenyl)-l -hydroxybutyl)piperidine-l -carboxylate (0.374 g, 0.75 mmol, 1 .0 equiv), DMAP (0.1615 g), CH 2 Cl 2 (10 mL ), and triethylamine (3 mL). The mixture was cooled in an ice bath and a solution of acetic anhydride (0.280 g, 2.74 mmol, 3.6 equiv) in CH 2 Cl 2 (10 mL) was added. The reaction mixture was allowed to slowly warm to rt while stirring overnight (16 h). After the. solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C 18(2) 10OA, 250 x 21.20 mm, 5 micron, 70% →90% CH 3 CN/H2O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H2O, 0.1% CF 3 COOH over 1.5 min, flow rate 25 mL/min) to give 0.2589 g (81%) of (R)-tert- butyl 3-((ιS)-4-acetamido-l -(3-chlorophenyl)-l-hydroxybutyl)-piperidine-l - carboxylate. LC-MS (3 min) / R = 1.72 min, m/z AAl, 449 (MNa + ), 425 (MH + ), 325, 327; 1 H NMR (400 MHz, CDCl 3 ) D 7.38-7.37 (m, I H), 7.28-7.18 (m, 3H), 6.06 (br

s, IH), 4.36-4.34 (m, IH), 3.97-3.95 (m, IH), 3.35-3.26 (m, IH), 3.13-3.05 (m, IH), 2.99 (br s, 2H), 2.55-2.49 (m, 2H), 1.97 (s, 3H), 1.44 (s, 9H) 3 1.95-1.15 (m, 6H); 13 C NMR (100 MHz, CDCl 3 ) D 171.41; 155.17, 146.75, 134.24, 129.33, 126.63, 126.01 , 123.83, 79.68, 77.60, 46.34, 44.69, 39.71, 35.91, 28.43, 25.40, 25.23, 24.15, 22.99.

Step 2. N-(( 1 S)-4-(3-chlorophenyl)-4-hydroxy-4-((λ)-piperidin-3-yl)butyl )acetamide

A mixture of (R)-tert-buty\ 3-((5)-4-acetamido-l -(3-chlorophenyI)-l - hydroxybutyl)-piperidine-l-carboxylate (0.1773 g, 0.4172 mmol) in CH 3 CN (50 mL) and 2 N aq HCl (45 mL) was vigorously stirred at rt for 24 h. The solvents were removed in vacuo to give the HCl salt of λ r -(( 1 S}-4-(3-chlorophenyl)-4-hydroxy-4-

((/?)-piperidin-3-yl)butyl)acetamide, which was used in the next step without further purification. LC-MS (3 min) / R = 0.91 min, m/z 325, 327 (MH + ).

The following piperidines were prepared following procedures analogous to those described in Preparations 5 and 6:

N-((S)-4-(2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl )butyl)acetamide using

(2-fluorophenyl)((/?)-N-Boc-piperidin-3-yl)methanone in Step 2 of Preparation 5.

N-((S)-4-(2-fluoro-5-methylphenyl)-4-hydroxy-4-((R)-piper idin-3- yl)butyl)acetamide using (2-fluoro-5-methylphenyl)((/?)-./V-Boc-piperidin-3- yl)methanone in Step 2 of Preparation 5.

N-((S)-4-(3-fluoro-5-methylphenyl)-4-hydroxy-4-((R)-piper idin-3- yl)butyl)acetamide using (3-fluoro-5-methylphenyl)((/?)-N-Boc-piperidin-3- yl)methanone in Step 2 of Preparation 5.

N-((S)-4-(2,3-difluorophenyl)-4-hydroxy-4-((R)-piperidin- 3-yI)butyl)acetamide using (2,3-difluorophenyl)((λ)-N-Boc-piperidin-3-yl)methanone in Step 2 of

Preparation 5.

N-((S)-4-(3,5-difluorophenyl)-4-hydroxy-4-((R)-piperidin- 3-yl)butyl)acetamide using (3,5-difluorophenyl)((λ)-N-Boc-piperidin-3-yl)methanone in Step 2 of

Preparation 5. N-((S)-4-(2-chloro-3-fluorophenyl)-4-hydroxy-4-((R)-piperidi n-3-yl)butyl)acetamide using (2-chloro-3-fluorophenyl)((^)-N-Boc-piperidin-3-yl)methanone in Step 2 of

Preparation 5.

N-((S)-4-(3-chloro-2-fluorophenyl)-4-hydroxy-4-((R)-piper idin-3-yl)butyl)acetamide using (3-chloro-2-fluorophenyl)((7?)-N-Boc-piperidin-3-yl)rnethano ne in Step 2 of

Preparation 5.

N-((S)-4-(3-chloro-5-fluorophenyl)-4-hydroxy-4-((R)-piperidi n-3-yl)butyl)acetamide using (3-chIoro-5-fluorophenyl)((7?)-λ' ' -Boc-piperidin-3-yl)methanone in Step 2 of

Preparation 5.

N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl )butyl)-2,2,2- trifluoroacetamide using trifluoroacetic anhydride in Step 1 of Preparation 6.

N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl )butyl)butyramide using butyric anhydride in Step 3 of Preparation 6.

(R)-N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin- 3-yl)butyl)-2- methoxypropanamide using (R)-2-methoxypropanoic acid and EDC in place of acetic anhydride in Step 3 of Preparation 6.

(S)-N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin- 3-yl)butyl)-2- methoxypropanamide using (S)-2-methoxypropanoic acid and EDC in place of acetic anhydride in Step 3 of Preparation 6.

N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl )butyl)propionamide using propionic anhydride in Step 3 of Preparation 6.

N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3- yl)butyl)cyclopropanecarboxamide using cyclopropanecarboxylic acid and EDC in place of the anhydride in Step 3 of Preparation 6.

PREPARATION 7 l-(TS r )-4-f3-ChlorophenvD-4-hvdroxy-4-( ' r-/?Vpiperidin-3-vnbutvn-3-methylurea

Step 1. (R)-tert-buty\ 3-(GS>4-(methylaminocarbonylamino)-l-(3-chlorophenyl)-l- hydroxybutyl)-piperidine- 1 -carboxylate

To a stirred mixture of the TFA salt of (R)-tert-butyl 3-((S)-4-amino-l-(3- chlorophenyl)-l-hydroxybutyl)piperidine-l -carboxylate (0.0388 g, 0.078 mmol, 1.0 equiv) in THF (5 mL) and CH 2 Cl 2 (5 mL) at rt were added of DIEA (0.7 mL) and p- nitrophenyl chloroformate (0.0350 g, 0.17 mmol, 2.2 equiv). The mixture was stirred at rl for 3 h. One half of the resulting solution was withdrawn and 33 wt% MeNH 2 in EtOH (1.5 mL) was added. The resulting mixture was stirred at rt for 1 h. The solvents were removed in vacuo and the residue was purified by reversed-phase preparative HPLC (Phenomenex® Luna 5μ Cl 8(2) 10OA, 250 x 21.20 mm, 5 micron, 70% -→90% CH 3 CNZH 2 O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 7 min, flow rate 25 mL/min) to give (R)-lert- butyl 3-((->)-4-(methylamino-carbonylamino)-l-(3-chlorophenyl)- l- hydroxybutyl)piperidine-l -carboxylate (0.0043 g). LC-MS (3 min) / R = 1 .71 min, m/z 442, 440 (M+H + ), 340.

Step 2. 1 -((5 f )-4-(3-chlorophenyl)-4-hydroxy-4-((λ)-piperidin-3-yl)butyl) -3- methylurea

A mixture of (/?)-/er/-butyl 3-((iS)-4-(rnethylarninocarbonylarnino)-l-(3- chlorophenyl)-l -hydroxybutyl)piperidine-l -carboxylate, CH 3 CN (20 mL) and 2 N aq

HCl (15 mL) was vigorously stirred at rt for 2 d. The solvents were removed in vacuo to give the HCl salt of l-((iS)-4-(3-chlorophenyl)-4-hydroxy-4-((7?)-piperidin-

3-yl)butyl)-3-methylurea, which was used without further purification. LC-MS (3 min) t R = 0.93 min, m/z 342, 340 (M+H + ).

3-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl )butyl)- 1 ,1 - dimethylurea was prepared using procedures analogous to those above, using dimethylamine in Step 1.

PREPARATION 8

(S'M-fAminosulfonylarninoVl -O-chlorophenyl)- l-e(7?Vpiperidin-3-yl)butan-l -ol

ne rt

Step 1. (Iiytert-butyl 3-((5)-4-(aminosulfonylamino)-l-(3-chlorophenyl)-l- hydroxybutyl)-piperidine- 1 -carboxylate To a 50 mL round bottom flask were added the TFA salt of (R)-(ert-buty\ 3-

((5)-4-amino-l -(3-chlorophcnyl)-l-hydroxybutyl)piperidine-l -carboxylate (0.0803 g, 0.16 mmol, 1.0 equiv), sulfamide (0.2368 g, 2.46 mmol, 15 equiv), 1 ,4-dioxane (5 mL) and DIEA (1 mL). The resulting mixture was heated at 1 10 0 C for 2 h. After the solvents were removed in vacuo, the residue was purified by rcversed-phase HPLC (Phenomenex® Luna 5μ C 18(2) 10OA, 250 x 21.20 mm, 5 micron, 70% -→90% CH3CN/H2O, 0.1% CF 3 COOH over 8 min and then 90% CH 3 CN/H 2 O, 0.1% CF 3 COOH over 1.5 min, flow rate 25 mL/min) to give 0.0438 g (59%) of (R)-IeN- butyl 3-((5)-4-(aminosulfonylamino)-l-(3-chloropheny])-l-hydroxybu tyl)piperidine- 1 -carboxylate. LC-MS (3 min) / R = 1.74 min, m/z 486, 484 (MNa + ), 362.

Step 2. (S)-4-(aminosulfonylamino)-l -(3-chIorophenyl)-l -((7?)-piperidin-3-yl)butan- l -ol

A mixture of (R)-tert-buty\ 3-((5)-4-(aminosulfonylamino)-l-(3- chlorophenyl)-l -hydroxybutyl)piperidine-l -carboxylate (0.0438 g, 0.095 mmol), CH 3 CN (35 mL) and 2 N aq HCl (30 mL) was vigorously stirred at rt for 24 h. The solvents were removed in vacuo to give the HCl salt of (.S)-4-(aminosulfonylamino)- l-(3-chlorophenyl)-l-((λ)-piperidin-3-yl)butan-l-ol, which was used without further purification. LC-MS (3 min) / R = 0.93 min, m/z 364, 362 (MH + ), 285, 283.

PREPARATION 9 I J J -trifluoro-6-melhoxy-2-(piperidin-3-vDhexan-2-ol

Stepl . l -/er/-butyl 3-ethyl piperidine-l,3-dicarboxylate

Ethyl nipecotate (1.55 mL, 10 mmol), (Boc) 2 O (2.4 g, 1.1 equiv), triethylamine (2.8 mL, 2.1 equiv) and dichloromethane (70 mL) were mixed and stirred overnight at rt. The reaction mixture was diluted with EtOAc (200 mL), washed with 5% aq HCl (2 x 25 mL), sat'd aq NaHCO 3 (30 mL) and brine (20 mL), and dried over Na 2 SO 4 . After concentration, the crude product was purified by chromatography on a 40-g silica cartridge eluted with a 0-30% EtOAc in hexanes gradient to afford l-ter/-butyl 3-ethyl piperidine-l,3-dicarboxylate (2.6Ig 5 100%) as a clear oil.

Step 2. /e/7-butyl 3-(2,2,2-trifluoroacetyl)piperidine-l-carboxylate

\ -ten-butyl 3-ethyl piperidine-l,3-dicarboxylate (424 mg, 1.65 mmol) and CsF (ca 10 mg) were combined in a vial under N 2 . Dry THF (3 mL) was added, followed by Me 3 SiCF 3 (256 μL, 1.05 equiv). After stirring for 3 h, 4N aq HCl (4mL) was added to the vial and the mixture was stirred for 1 h. The mixture was extracted with diethyl ether (2 x 15 mL). The combined organic layers were washed with brine (8 mL), dried over Na 2 SO 4 , and concentrated to afford /e/V-butyl 3-(2,2,2- trifluoroacetyl)piperidinc-l-carboxylate (173mg. 37%)

Step 3. /er/-butyl 3-(l,l,l-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine- l- carboxylate

Under protection of N 2 gas, tert-butyl 3-(2,2,2-trifluoroacetyl)piperidine-l- carboxylate (102 mg, 0.363 mmol) was dissolved dry THF(8 mL) and cooled to -

78 0 C (dry ice/acetone bath). 1.22 M methoxybutylmagnesium chloride in THF (600μL, 2 eqυiv) solution was added slowly. After 10 min, the reaction was allowed to warm up to rt slowly. After 2 h, satd aq NH 4 Cl (15 mL) solution was added to the reaction mixture. The mixture was diluted with diethyl ether and the layers were separated. The aqueous layer was extracted with diethyl ether (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na 2 SO 4 . After concentration, the crude product was purified by prep HPLC to afford lert- butyl 3-(l , 1 , 1 -trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-l -carboxylate (20mg, 15%).

Step 4. lJ ,l-trifluoro-6-methoxy-2-(piperidin-3-yl)hexan-2-ol

7e/7-butyl 3-( 1 ,1,1 -trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-l - carboxylate (20mg) was dissolved in 1 :1 TFA/dichloromethane (4 mL). The mixture was stirred for 30 min. The mixture was concentrated to afford 1 ,1 ,1 -trifluoro-6- methoxy-2-(piperidin-3-yl)hexan-2-ol which was used without purification.

PREPARATION 10

(R)-3-((S)- 1 -(3-ChlorophenvP- 1 ,,5-dimethoxypentyDpiperidine

A rt

Step 1. (R)-terl-bυty\ 3-((6)-l-(3-chlorophenyl)-l,5-dimethoxypentyl)piperidine-l- carboxylate To a mixture of (R)-Ie rt-buty\ 3-((.S>l -(3-ch]orophenyl)-l-hydroxy-5- methoxypentyl)-piperidine-l -carboxylate (0.1874 g, 0,45 mmol, 1.0 equiv) and 60% NaH in oil (0.345 g, 8.6 mmol, 19 equiv) in THF (15 mL) was added iodomethane (1.195 g, 8.4 mmol, 18.5 equiv). The resulting mixture was heated at 7O 0 C for 16 h and then quenched with water, extracted with EtOAc and dried over Na 2 SO 4 . After

the solvent was removed, the crude (R)-terl-buty\ 3-((S)-l-(3-chlorophenyl)-l,5- dimethoxypentyl)piperidine-l-carboxylate (0.3175 g) was used in the next step without further purification. LC-MS (3 min) t R = 2.44 min m/z 450, 448 (M+Na + ), 426 (M+H + ), 340, 338, 294.

Step 2. (R)3--((S)1 -3--chlorophenyl-1,5-dimethoxypenty1)piperidine

A quarter of the (R)-tert-butγ\ 3-((S)-l-(3-chlorophenyl)-l ,5- dimethoxypentyl)piperidine-l-carboxylate obtained in Step 1 (ca. 75 mg, ca. 0.1 mmol) was dissolved in CH 3 CN (30 mL) and 2 N HCl (25 mL). The mixture was vigorously stirred at rt for 2 d. The solvents were removed in vacuo to give the HCl salt of (R )-3-((S ) )-l-(3-chlorophenyl)-l,5-dimethoxypentyl)-piperidine, which was used without further purification. LC-MS (3 min) t R = 1.22 min, m/z 328, 326 (M+H + ).

(R)-3-((S)-l-(3-chloro-2-fluorophenyl)-l,5-dimethoxypenty l)piperidine was prepared using procedures analogous to those described above, using (R)-tert-b\λty\ 3-((5)-l -(3-chloro-2-fluorophenyl)-l-hydroxy-5-methoxypentyl)piperid ine-l - carboxylate in Step 1.

PREPARATION 1 1 (1 S)-1(3-chlorophenyl1)-2-(2 -methoxyethoxy)- 1-(3)-piperidin-3-y1)ethanol

Step 1. (3R)-tert-buty\ 3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-l-carboxylate

A flame dried 250 mL round bottom flask was charged with sodium hydride (60% in oil, 1.45 g, 36.2 mmol) and trimethyloxosulfonium iodide (8.05 g, 36.5 mmol). The flask was evacuated and refilled with N 2 . Dry DMSO (50 mL) was added and the mixture was stirred at rt for 1 h. A portion of this solution (14.5 mL, 10.5 mmol, 1.5 equiv) was added by syringe to a 150 mL round bottom flask which had been charged with (R)-ter;-butyl 3-(3-chlorobcnzoyl)-piperidine-l-carboxylate (2.27 g, 7 mmol) and THF (30 mL) and placed under N 2 . The resulting mixture was stirred for 1 h at rt. The reaction mixture was quenched with brine and extracted with EtOAc (3 x). The combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to give (3R)-ter-/-butyl 3-(2-(3- chlorophenyl)oxiran-2-yl)piperidine-l-carboxylate as a mixture of two isomers (2,32 g, 6.9 mmol, 99% yield), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl 3 ): 1.40 (s, 9H), 1.55-1.72 (m, 3H), 1.85 (m, IH), 2.01 (m, IH), 2.35-2.60 (m, 2H), 2.65 (d, IH), 3.063 (d, IH), , 4.05 (m, I H) 3 4.15 (m, IH) 5 7.26 (m, 3H) 5 7.34 (s,lH); MS (E/Z): 338 (M+H + )

Step 2. (R)-I ert-buty\ 3-((S)-l-(3-chlorophenyl)-l-hydroxy-2-(2- methoxyethoxy)ethyl)piperidine- 1 -carboxylate A stirred solution of BF 3 -Et 2 O (12.9 mg, 0.0592 mmol) and NaH (22.6 mg,

0.296 mmol) in 2-melhoxyethanol (10 mL) was warmed to 55-600C and (3R)-tert- butyl 3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-l -carboxylate (100 mg, 0.296 mmol) was added dropwise. After addition, the reaction mixture was stirred at the same temperature overnight. The reaction mixture was concentrated and the residue was partitioned between H 2 O and EtOAc. The organic layer washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo, LC-MS analysis of the crude product indicated the presence of two isomers. The crude product was purified by preparative HPLC to give the major isomer (R)-tert-butyl 3-((S)-I -(3- chlorophenyl)-l-hydroxy-2-(2-methoxyethoxy)ethyl)piperidine- l -carboxylate ( 30 mg, 0.073 mmol); 1 H NMR (400MHz, CDCl 3 ): 1.33 (s, 9H), 1.65 (m, IH), 1.74 (m, IH), 1.96 (m, IH), 2.47 (m, 2H), 3.26 (m 5 2H), 3.33 (s, 3H), 3.46 (m 5 2H) 5 3.61 (m,

2H), 3.79 (m, IH), 3.84 (m, IH), 3.99. (m, I H), (m,lH), 7.22 (m, 3H) 5 7.42 (s, IH); MS (E/Z): 414 (M+H + )

The minor isomer (R)-*er/-butyl 3-((R)-l-(3-chlorophenyl)-l-hydroxy-2-(2- methoxyethoxy)ethyl)piperidine-l-carboxylate was also isolated (25 mg, 0.061 mmol). 1 H NMR (400MHz, CDCl 3 ): 1.26 (m, 2H), 1.45 (s, 9H), 1.57 (m, IH), 1.76 (m, IH), 2.51 (m, 2H), 3.27 (m, 2H), 3.33 (s, 3H), 3.47 (m, 2H), 3.62 (m, 2H), 3.80 (m, IH), 3.87 (m, IH), 4.01 (m, IH) 5 4.33 (m, IH), 7.24 (m, 3H) 5 7.40 (s, IH); MS (E/2): 414 (M+H + )

Step 3. (l S)-l-(3-chlorophenyl)-2-(2-methoxyethoxy)-l -((3R)-piperidin-3- yl)ethanol

A solution of (R)-/er/-butyl 3-((S)-l-(3-chlorophenyl)-l-hydroxy-2-(2- methoxyethoxy)-ethyl)piperidine-l-carboxylate (30 mg, 0.073 mmol) in 20 %

TFA/CH 2 C1 2 (5 mL) was stirred at O 0 C for 30 min. Evaporation of the solvent afforded (1 S)-l-(3-chlorophenyl)-2-(2-methoxy-ethoxy)-l-((3R)-piperidin -3- yl)ethanol (30 mg, 0.073 mmol 100%). MS (E/Z): 314 (M+H + ).

PREPARATION 12 (R)-ter(-Buty\ 3-((#)-f3-ethoxypropoxy)(phenyl)methvDpiperidine-l-carboxyla te

Stepl . (R)-tert-buty\ 3-(N-methoxy-7V-methylcarbamoyl)piperidine-l-carboxylate

(R)-I -(/erZ-butoxycarbonyOpiperidine-S-carboxylic acid (25 g, 0.11 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv)

and EDCHCl (26.3 g, 0.14 mol, 1.25 equiv) and diisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in 400ml (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2 X 15OmL), satd aq NaHCO 3 (15OmL), brine (100 mL), and dried over Na 2 SO 4 . Concentration afforded (R)-lert-buty\ 3-(N-methoxy-N-methylcarbamoyl)- piperidine-1 -carboxylate (24.42g, 82%) as a clear oil. LC-MS (3 min) I R — 1.41 min, m/z 295 (M+Na). 1 H NMR (CDCl 3 ) D 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H), 2.79 (m, 2H), 2.64 (m, IH), 1.89 (m, IH), 1.71-1.52 (m, 2H), 1.51 -1.33 (m, 1 OH). Chiral HPLC indicated 100% purity. The crude product was used for next step without further purification.

Step 2. (R)-tert-b\x\y\ 3-benzoylpiperidine-l-carboxylate

(R)-/ert-buty\ 3-(N-methoxy-λ/ ' -methylcarbamoyl)piperidine- 1 -carboxylate (13.6g, 50 mmol) was dissolved in anhydrous THF (200 mL) and cooled to -10 0 C (ice/MeOH bath). Phenylmagnesium bromide solution in THF (100 mL of 1.0 M, 100 mmol, 2 equiv) was added slowly. After 15 min, the reaction mixture was warmed up to rt slowly and stirred for 1 hour. LC-MS showed the reaction was complete. 5% Aq HCI (100 mL) was added slowly to quench the reaction and the mixture was stirred for 20 min. After separation, the aqueous layer was extracted with ether (2 X 200 mL). The combined organic layers were washed with satd aq

NaHCO 3 (150 mL), brine (100 mL), and dried over Na 2 Sθ4. Concentration afforded crude (R)-tert-butγ\ 3-benzoylpiperidine-l -carboxylate (16.45g, 110%) as a clear oil which was used for the next step without further purification. LC-MS (3 min) t R = 1.91 min, m/z 302 (M+Na). 1 M NMR (CDCl 3 ) D 7.94 (d, 2H), 7.54 (t, IH), 7.47 (t, 2H), 4.28 (br d, IH), 4.09 (d, IH), 3.38 (t, IH), 2.92 (br t, IH), 2.72 (t, IH), 2.01 (d, I H), 1.79-1.45 (m, 3H) 1.42 (s, 9H). Chiral HPLC indicated 100% purity.

Step 3. 3-((λ)-hydroxy(phenyl)methyl)piperidine-l -carboxylate

A solution of (R)-/er/-butyl 3-benzoylpiperidine-l -carboxylate (10.3 g, 35.64 mmol) anhydrous toluene (120 mL) was cooled to -78 0 C and (7?)-2-methyI~CBS- oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol, 0.5 equiv) was added slowly. After 5 min, catecholborane (1 1.4 mL, 107 mmol, 3 equiv) was added

slowly. The reaction mixture was then transferred into the freezer (~14.2°C) and left overnight. LC-MS (16 min) showed 9:1 ratio of the R to S isomer. The mixture was cooled to O 0 C and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aq NaOH (2 x 150 mL), water (150 mL), 5% aq HCl (100 mL), brine (100 mL), and dried over Na 2 SO 4 . After concentration, the crude product was purified by flash chromatography on a 120 g silica gel column eluted with a 4-35% EtOAc in hexanes gradient. The purified product was recrystalized from an ether hexanes mixture to afford (R)-lert-buty\ 3- (C/?)-hydroxy(phenyl)methyl)piperidine-l-carboxylate (4.45 g, 43%) as white solid with the ratio of R/S isomers 23.5: 1. LC-MS (3 min) t R = 1.70 min; LC-MS (3 min) t R = 10.62 min, m/z 314 (M+Na). 1 H NMR (CDCl 3 ) D 7.28 (m, 5H), 4.46 (d, IH), 3.87 (d, IH), 3.89-3.51 (br s, free exchange IH), 3.00 (m, 2H), 2.68 (t, IH), 2.52 (t, IH), 1.94 (m, IH), 1.76 (m, IH), 1.65 (m, IH), 1.42-1.20 (m, 10H).

Step 4. (R)-tert-Buiy\ 3-(C/?)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-l- carboxylate

An oven dried flask was charged with 3-((R)- hydroxy(phenyl)methyl)-piperidine-l-carboxylate (3.18 g, 10.9 mmol) and 60% NaH in mineral oil (2.19g, 54.8, 5 equiv). The flask was purged with N 2 gas, cooled to O 0 C and anhydrous THF (100 mL) was added slowly. The mixture was allowed to warm to rt slowly. A solution of 3-ethoxypropyl methanesulfonate (6.Og, 32.9 mmol, 3 equiv) in anhydrous THF (50 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction completed. The reaction mixture was cooled to O 0 C slowly and water was added dropwise to quench the reaction. After separation, the aqueous layer was extracted with ether three times. The combined organic layers were washed with 5% aq HCl, satd aq NaHCO 3 , brine, and dried over Na 2 SO 4 . After concentration, the crude product was purified by flash chromatography on a 120-g silica gel cartridge eluted with a 0-30% EtOAc in hexanes gradient) to afford (R)-fert-buty\ 3-((/?)-(3- cthoxypropoxy)(phenyl)methyl)pipcridine-l-carboxylate (3.7Og, 90%) as a clear oil. Chiral HPLC indicated 95.5% purity. LC-MS (3 min) t R = 2.38 min, m/z 400 (M+Na). 1 H NMR (CDCl 3 ) □ 7.26 (m, 5H), 4.39 (d, IH), 3.89 (t, 2H), 3.53-3.40 (m,

4H), 3.38-3.23 (m, 2H), 2.75-2.60 (m, 2H), 1.85-1.47 (m, 4H), 1.45 (s, 9H), 1.40- 1.22 (m, 2H), 1.15 (t, 3H), 1.10-0.96 (m, IH).

PREPARATION 13 Methyl 2-((RM3-chlorophenyO((RVpiperidin-3-yl)rnethoxy ' )ethylcarbarnate

Step 1 : (7?)-/e/7-Butyl 3-((#)-(3-chlorophenyl)(hydroxy)methyl)piperidine-l- carboxylate To a solution of (R)-tert-bυtyl 3-(3-chlorobenzoyl)piperidine-l-carboxylate

(5.60 g, 17.29 mmol) and (λ)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 9 mL, 9.00 mmol) cooled to -78°C was added catecholborane (5.6 mL, 54.0 mmol) dropwise. After 20 min, the reaction temperature was allowed to warm to -15°C and stirred overnight. The reaction was quenched at O 0 C by careful addition of water and diluted with ether. The resulting suspension was filtered through Celite and washed with ether. The filtrate was washed successively with 1 M aq NaOH (3 x 50 mL), 1 M aq HCl (3 x 50 mL), satd aq NaHCO 3 and brine, and dried over Na 2 SO 4 . The solution was filtered, the filtrate was evaporated under vacuum, and the residue was purified by preparative HPLC to afford (λ)-/ert-butyl 3-((/?)-(3- chlorophenyl)(hydroxy)methyl)piperidine-l-carboxylate (2.44 g) and (R)-I erl-butyl

3-((iS)-(3-chlorophenyl)(hydroxy)methyl)piperidine-l-carboxy late (1.21 g). MS: 348 (IVB-Na) + .

Step 2: (R)-ter tButyl 3-((R )-(3-chlorophenyl)(2-ethoxy-2- oxoethoxy)methyl)piperidine- 1 -carboxylate

To a suspension of 60% NaH in oil (960 mg, 24.0 mmol) in anhydrous THF at 0 0 C was added a solution of (R)-tert-buty\ 3-((R)-(3-chlorophenyl)(2-ethoxy-2- oxoelhoxy)methyl)-piperidine-l-carboxylate (1.429 g, 4.40 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at rt for 30 min and a solution of ethyl bromoacetate (2.204g, 13.2 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting suspension was heated at reflux for 3 h and cooled to 0 0 C again. The same amount of NaH as before was added and stirred for 30 min at rt, followed by addition the same amount of ethyl bromoacetate, and the mixture was heated at reflux overnight. The reaction mixture was cooled to 0 0 C and quenched by careful addition of aq NH 4 Cl. The mixture was extracted with EtOAc (3 x). The combined organic phases were washed with brine, dried OVeI- Na 2 SO 4 , and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-ethoxy-2- oxoethoxy)methyl)piperidine-l -carboxylate (1.62 g). MS: 412 (M-HH) + .

Step 3: (R)-tert-Butyl 3-(( R)-(2-amino-2-oxoethoxy)(3- chlorophenyl)methyl)piperidine-l -carboxylate

(R)-(ert-Buty\ 3-((R)-(3-chlorophenyl)(2-ethoxy-2- oxoethoxy)methyl)piperidine-l-carboxylate (1.50 g, 3.65 mmol) was dissolved in 7 M NH 3 in MeOH, and stirred at rt for 6 h. The mixture was evaporated under reduced pressure to afford the (R)-t ert-buty1 3-((R )-(2-amino-2-oxoethoxy)(3- chlorophenyl)methyl)piperidine-l -carboxylate in quantitative yield. MS: 383 (M+H) + .

Step 4: (R)-tert-Buty1 3-((R )-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-l- carboxylate

(λ)-/er/-Butyl 3-((λ)-(2-amino-2-oxoethoxy)(3- chlorophenyl)rnethyl)piperidine-l-carboxylate (1.10 g, 2.60 mmol) was dissolved in anhydrous toluene (30 mL) and cooled to 0 0 C. Red-Al (65% in toluene, 2.6 mL, 8.64 mmol) was added dropwise. After the addition, the reaction was stirred at rt for 12 h and quenched by adding water slowly. The resulting mixture was filtered through Celite, washing with THF. The filtrate was evaporated under reduced pressure to give crude (R)-terl-butyl 3-((λ)-(2-aminoethoxy)(3- chlorophenyl)methyl)piperidine-l-carboxylate (1.05 g), which was used for next step without further purification.

Step 5: (R)-Ie rl-Butyl 3-((λ)-(3-chlorophenyl)(2-

(methoxycarbonylamino)ethoxy)methyl) piperidine- 1 -carboxylate

To a solution of (R)-tert-b\ity\ 3-(C#)-(2-aminoethoxy)(3- chlorophenyl)methyl)piperidine-l -carboxylate (1.05 g, ca. 2.6 mmol), Et 3 N (3.96 mL, 2.85 mmol), and DMAP (174 mg, 1.43 mmol) in anhydrous CH 2 Cl 2 (20 mL) cooled to 0 0 C was added a solution of methyl chloroformate (1.35 g, 14.25 mmol) in dichloromcthane (20 mL) within 30 min. The reaction was stirred overnight, and evaporated under vacuum. The residue was purified by flash chromatography on silica gel to afford (R)-tert-bu\.y\ 3-((/?)-(3-chlorophenyl)(2-(methoxy- carbonylamino)cthoxy)mcthyl)piperidine-l -carboxylate (0.65 g). MS: 427 (M+H) + .

Step 6: Methyl 2-((λ)-(3-chlorophenyl)((R)-piperidin-3-yl)mcthoxy)ethylcar bamate

To a stirred solution 3-((i?)-(3-chlorophenyl)(2- (methoxycarbonylamino)-ethoxy)methyl)piperidine-l -carboxylate (91 mg, 0.21 mmol) in CH 2 Cl 2 (3 mL) at rt was added TFA (0.5 mL). The mixture was stirred until complete removal of the Boc group had occurred. The solvent was removed under vacuum to give methyl 2-((/?)-(3-chlorophenyl)((λ)-piperidin-3- yl)methoxy)ethylcarbamate as its TFA salt. MS: 327 (M+H) + .

The following compound was prepared using procedures analogous to those described above: methyl 2-((3-fluorophenyl)(piperidin-3-yl)methoxy)ethyIcarbamate using tert-butyl 3-(3-fluorobenzoyl)piperidine-l-carboxylate in Step 1.

PREPARATION 14 N-Q-CCRVO-chloro^-fluorophenvπrfRI-piperidin-S-vπmethoxy'i ethvπacetamide

TFAZCH 2 CI 2

Step 1. (R)-/er/-butyl 3-((3-chloro-2-fluorophenyl)(hydroxy)methyl)piperidine-l- carboxylate

To a solution of (R)-fer/-buty\ 3-(3-chloro-2-fluorobenzoyl)piperidine-l- carboxylate (7.75 g, 22.7 mmol) in MeOH (160 mL) was added NaBH 4 (6.9 g, 182 mmol) in portions such that the temperature remained below 40 0 C. After addition, the mixture was stirred at rt for 3 h. TLC showed the start material had disappeared. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 and evaporated to give (R)-/er/-butyl 3-((3-chloro-2- fluorophenyl)(hydroxy)methyl)piperidine-l -carboxylate (4.35 g, 56%) which was used in the next step without purification. MS (E/Z): 344 (M.+H + ).

Step 2. (R)-(ert-buty\ 3-((3-chIoro-2-fluorophenyl)(2-ethoxy-2- oxoethoxy)methyl)piperidine- 1 -carboxylate

To a stirred suspension of NaH (0.608 g, 15.2 mmol) in THF (100 mL) at 0- 5°C was added dropwise a solution of (R)-/e/V-butyl 3-((3-chloro-2- fluorophenyl)(hydroxy)methyl)-piperidine-l -carboxylate (4.35 g, 12.68 mmol) in THF (30 mL). The reaction mixture was stirred for an additional 1 h at rt. A solution of ethyl bromoacetate (2.52 g, 15.2 mmol) in THF (30 mL) was added dropwise and the mixture was refluxed for 5 h. TLC showed the starting material had disappeared. The reaction mixture was poured into sat'd aq NH 4 Cl, extracted with EtOAc (3 x 100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford (R)-terl- butyl 3- ((3-chloro-2-fluorophenyl)(2-cthoxy-2-oxoethoxy)methyl)piper idine-l -carboxylate (4.368 g, 80%). 1 H NMR (400MHz, CDCl 3 ): 0.861 (m, 2H), 1.25 (m, 6H), 1.38&1.43 (s, 9H), 1.59-2.10 (m, 3H), 2.75 (m, IH), 3.80 (s, IH) 5 3.96 (m, 2H), 4.18 (m, 2H), 4.62 (m, IH), 7.12 (m, IH), 7.33 (m, 2H); MS (E/Z): 430 (M+l)

Step 3. (R)-/e/-/-butyl 3-((3-chloro-2-fluorophenyl)(2- hydroxyethoxy)methyl)piperidine- 1 -carboxylate To a solution of (R)-/er/-butyl 3-((3-chloro-2-fluorophenyl)(2-ethoxy-2- oxoethoxy)-methyl)piperidine-l -carboxylate (4.368 g, 10.2 mmol) in MeOH (85 mL) was added NaBH 4 (3.18 g, 81.5 mmol) in portions such that the temperature remained below 40 0 C. After addition, the mixture was stirred at rt for 2~3 h. TLC showed the starting material had disappeared. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 and evaporated to give (R)-(ert-buty\ 3-((3-chloro-2-fluorophenyl)(2-hydroxyethoxy)methyl)piperidi ne-l -carboxylate (3.5 g, 89%). 1 H NMR (400MHz, CDCl 3 ): 1.18 (m, IH), 1.38-1.46 (s, 9H) 3 1.65 (m, IH), 1.85 (m, 2H) 3 2.66 (m, IH), 3.25 (m, IH) 3 3.38 (m, 2H), 3.69 (m, 3H), 3.93 (m, IH) 3 4.52 (m, 6H) 3 MS (E/Z): 388 (M+l)

Step 4. (R)-/er/-butyI 3-((3-chloro-2-fluorophenyl)(2- (methylsulfonyloxy)ethoxy)methyl)-piperidine-l -carboxylate

To a solution of (K)-leri- butyl 3-((3-chloro-2-fIuorophenyl)(2- hydroxyethoxy)methyl)-piperidine-l-carboxylate (3.5 g, 9 mmol) in dry CH 2 Cl 2 (50 mL) was added Et 3 N (3.2 g, 4.2 mL, 27 mmol, 4 eq) at 0 ~ -5°C. Then a solution of MsCl (1.23 g, 10.8 mmol, 1.2 eq) in dry CH 2 Cl 2 (2O mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. TLC showed the starting material had disappeared. Water (30 mL) was added and the mixture was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were washed with 10% aq citric acid, sat'd aq NaHCO 3 and brine, then dried over Na 2 SOn, filtered and concentrated to give 3/2-3- [(3-chloro-2-fluoro- phenyl)-(2- methanesulfόnyloxy-ethoxy)-methyl]-piperidine-l-carboxylic acid /e/7-butyl ester (4.13 g, 99%), which was used in the next step without purification. 1 H NMR (400MHz, CDCl 3 ): 1.35 (m, 4H), 1.46 (s, 9H), 1.62 (m, 3H), 1.83 (m, I H), 2.52-2.81 (m, 2H), 3.05 (m, 3H), 3.56 (m, 2H), 3.92 (m, I H), 4.30 (m, 2H), 4.48 (m, IH), 7.13(m, IH), 7.28 (m, IH), 7.35 (m, IH); MS (E/Z): 466 (M+)

Step 5. (R)-/er/-butyl 3-((2-azidoethoxy)(3-chloro-2- fluoroρhenyl)methyl)piperidine- 1 -carboxylate 3R-3 [(3-chloro-2-fluoro-phenyl)-(2-methanesulfonyIoxy-ethoxy)-me thyl]- piperidine-1 -carboxylic acid terl-buty\ ester (4 g, 8.6 mmol) was dissolved in anhydrous DMF (30 mL), solid NaN 3 (0.84 g, 12.9 mmol) was added and the reaction mixture was heated at 80 0 C overnight. The reaction mixture was cooled to rt and EtOAc (100 mL) was added. The mixture was washed with water (3 x 30 mL), dried over Na 2 SO 4 and evaporated. The residue was separated on a silica column to give (R)-/er/-butyl 3-((2-azidoethoxy)(3-chloro-2- fluoropheny])methyl)piperidine-l -carboxylate (2.6 g, 73%). 1 H NMR: (400MHz, CDCl 3 ): 1.24 (m, IH), 1.38&1.46 (s, 9H), 1.67 (m, 3H) 3 1.83 (m, IH), 2.58-2.81 (m, 2H) 1 3.32 (m, 2H), 3.45 (m, 2H), 3.92 (m, IH), 4.20 (m, IH), 4.50 (m, IH), 7.13(t, 1 H), 7.34 (m, 2H), 8.02 (s, 1 H);

Step 6. (R)-/er/-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2-

fluorophenyl)methyl)piperidine-l-carboxylate

To a solution of (R)-/er/-butyl 3-((2-azidoethoxy)(3-chloro-2- fluorophenyl)methyl)-piperidine-l-carboxylate (2.6 g, 6.31 mmol) in EtOAc (50 mL) was added wetted Pd/C (0.1 g) and the mixture was stirred overnight under a hydrogen atmosphere maintained by a balloon. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give (R)-/er/-butyl 3-((2- aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-l -carboxylate which was submitted to reverse phase the preparative HPLC to give (R)-/er/-butyl 3-((S)-(2- aminoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-l -carboxylate (990 mg, 81 %) and (R)-/er/-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2- fluorophenyl)methyl)piperidine-l -carboxylate (792 mg, 65%). MS (E/Z): 387 (M+H + ).

Step 7. (R)-terl-buiy\ 3-((R)-(2-acetamidoethoxy)(3-chloro-2- fluorophenyl)methyl)piperidine-l -carboxylate

To a solution of (R)-/er/-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2- fluorophenyl)rnethyl)-piperidine-l -carboxylate (160 mg, 0.41 mmol) and Et 3 N (1 mL) at 0 0 C was added acetyl chloride (32.3mg, 0.41 mmol). The mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give crude (R)-/e/7-butyl 3-((R)-(2-acetamidoethoxy)-(3-chloro-2- fiuorophenyl)methyl)piperidine-l -carboxylate (95 mg, 54%), which was used in the next step without further purification. 1 H NMR: (400MHz, CDCl 3 ): 1.20 (m, I H), 1.40 (s, 9H), 1.70 (m, 2H), 1.98 (s, 3H), 2.60 (m, 2H), 3.48 (m, 4H), 3.90 (m, IH), 4.42 (m, IH) 3 5.82 (ra, IH), 7.10(m, IH), 7.20 (m, IH), 7.34 (m, IH); MS (E/Z): 429 (M+l). MS (E/Z): 429 (M+)

Step 8. N-(2-((R)-(3-chloro-2-fluorophenyl)((R)-piperidin-3- yl)methoxy)ethyl)acetamide

(R)-/er/-butyl 3-((R)-(2-acetamidoethoxy)(3-chloro-2- fluorophenyl)methyl)pipcridine-l -carboxylate (95 mg, 1.88 mmol) was dissolved in 20% v/v TFA/CH 2 C1 2 (8 mL ) at 0 0 C, the mixture was allowed to warm to rt for 1 h and then concentrated in vacuo to give N-(2-((R)-(3-chloro-2-fluorophenyl)((R)-

piperidin-3-yl)methoxy)ethyl)acetamide (63 mg, 87%), which was used without further purification. MS (E/Z): 329 (M+)

PREPARATION 15 (Syi -Cbenzofuran-7-yiy5-methoxy-l -((R>piperidin-3-yl)pentan-1 -ol

3. MeO(CH 2 J 4 MgCI

Step 1. l -(2,2-diethoxyethoxy)-2-bromobenzene

A solution of KOH pellets (85%, 0.68 g, 10.3 mmol) in water (1.5 mL) was added to 2-bromophenol (1 mL, 8.6 mmol). The mixture was diluted with DMSO (20 mL) and bromoacetaldehyde diethyl acetal (1.43 mL, 9.5 mmol) was added. The mixture was heated at 100 °C for 6 h, cooled to rt, diluted with ether (175 mL), washed with water (3 x 40 mL) and 5% aq NaOH (40 mL), and dried over MgSO 4 . Removal of the solvent left l -(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, quant) as an oil.

Step 2. 7-bromobenzofuran A stirred mixture of polyphosphoric acid (~5 g) and chlorobenzene (8 mL) was heated at reflux and a solution of l-(2,2-diethoxyelhoxy)-2-bromobenzene (2.62 g, 9.0 mmol) in chlorobenzene (3 mL) was added dropwise over 10 min. The mixture was heated at reflux for 1.5 h. The mixture was allowed to cool to rt and IM aq NaOH (20 mL) was added, followed by ether (175 mL). The mixture was washed with water (2 x 20 mL) and brine (20 mL), and dried over MgSO 4 . Evaporation of the solvent left a residue which was purified by a chromatography on a 140-g silica

cartridge eluted with hexanes and a 0-10% EtOAc in hexanes gradient. Appropriate fractions were pooled and concentrated to afford 7-bromobenzofuran (0.65 g, 38% from 2-bromophenol) as a clear colorless oil.

Step 3. 7-Bromo-2-(trimethylsilyl)benzofuran

A stirred solution of diisopropylamine (0.65 mL, 4.7 mmol) in THF (15 L) was cooled to 5°C and n-BuLi (2.5 M in hexanes, 1.9 mL, 4.7 mmol) was added dropwise over 5 min. The mixture was stirred at 5°C for 15 min and cooled to - 70 0 C. Chlorotrimethylsilane (0.59 mL, 4.7 mmol) was added followed by a solution of 7-bromobenzofuran (0.46 g, 2.35 mmoi) in THF (5 mL). The mixture was stirred at -70 0 C for 1.5 h and poured into sat'd aq NH 4 Cl (80 mL). The mixture was diluted with 5% aq HCI (20 mL) and extracted with ether (2 x 80 mL). The combined ether extracts were washed with sat'd aq NaHCO 3 (50 mL), dried over MgSO 4 and concentrated to leave crude 7-bromo-2-(trimethylsilyl)benzofuran (0.62 g, 98%) as a yellow oil.

Step 4. (R)-terZ-butyl 3-((S)-l-(benzofuran-7-yl)-l-hydroxy-5- methoxypentyl)piperidinc-l-carboxylate

A stirred solution of 7-bromo-2-(trimethylsilyl)benzofuran (620 rag, 2.3 mmol) in THF (15 mL) was cooled to -70 0 C and n-BuLi (2.5 M in hexanes, 0.85 mL, 2.1 mmol) was added dropwise over 2 min. The mixture was stirred at -70 0 C for 15 min and a solution of (R)-/e/7-butyl 3-(N-methoxy-N- methylcarbamoyl)piperidine-l-carboxylate (341 mg, 1.30 mmol) in THF (5 mL) was added dropwise over 2 min. The mixture was stirred at -70 0 C for 1 h, poured into satd aq NaHCO 3 (100 mL) and extracted with ether (2 x 100 mL). The combined ether extracts were washed with brine (40 mL) and dried over MgSO 4 . Removal of the solvent afforded crude (R)-/er/-butyl 3-((benzofuran-7-yl)carbonyl)piperidine-l - carboxylate (727 mg) as an oil. This material was dissolved in THF (15 mL) and cooled to -70 0 C. 4-Methoxybutylmagnesium chloride (1.52 M in THF, 2.0 mL, 3.04 mmol) was added dropwise over 2 min. The mixture was stirred at -70 0 C for 2 h and poured into sat'd aq NaHCO 3 (100 mL). The mixture was extracted with ether (2 x

100 mL) and the combined ether extracts were washed with brine (35 mL) and dried over MgSO 4 . Removal of the solvent left an oil which was purified by chromatography on a 40-g silica cartridge eluted with a gradient from 0 tol 00% EtOAc in hexanes to afford (R)-/er/-butyl 3-((S)-I -(benzofuran-7-yl)-l -hydroxy-5- methoxypentyl)piperidine-l-carboxylate (240 mg, 44%) as an oil.

Step 4. (S)-l-(benzofuran-7-yl)-5-methoxy-l-((R)-piperidin-3-yl)pent an-l-ol

(R)-/er/-butyl 3-((S)- 1 -(benzofuran-7-yl)- 1 -hydroxy-5- methoxypentyl)piperidine-l-carboxylate (240 mg, 0.58 mmol) was dissolved in MeCN (20 mL) and 5% aq HCl (10 mL) was added. The mixture was stirred at rt for 1 d and solid K 2 CO 3 was added. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO 4 and concentrated to leave an oil (150 mg) which was purified by reverse phase preparative HPLC to afford (S)-I- (benzofuran-7-yl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l-ol (120 mg, 81%) as an oil.

The following piperidines were prepared following procedures analogous to those described above:

(S)-5-methoxy-l-(2-methylbenzofuran-7-yl)-l-((R)-piperidi n-3-yl)pentan-l-ol using

7-bromo-2-methylbenzofuran and n-BuLi in Step 4.

(S)-I -(2-isobutylbenzofuran-7-yl)-5-methoxy-l-((R)-piperidin-3-yl )pentan-l -ol using 7-bromo-2-isobutylbenzofuran and n-BuLi in Step 4.

(S)~5-methoxy-l-((R)-piperidin-3-yl)-l -(thiophen-3-yl)pentan-l-ol using 3- bromothiophene and n-BuLi in Step 4.

(S)-5-methoxy-l -((R)-piperidin-3-yl)-l-(pyridin-2-yl)pentan-l-ol from 2- bromopyridine and n-BuLi in Step 4.

(S)-5-methoxy-l -((R)-piperidin-3-yl)-l-(quinolin-8-yl)pentan-l-oI from 8- bromoquinoline and n-BuLi in Step 4. (S)- l-(lH-indazol-7-yl)-5-methoxy-l-((R)-piperidin-3-yl)pentan-l -ol from 7- bromoindazole and n-BuLi

(S)-5-methoxy-l-((R)-piperidin-3-yl)-l-(2-(trimethylsilyl )benzo[b]thiophen-7- yl)pentan-l-ol from 7-bromo-2-(trimethylsilyl)benzothiophene and n-BuLi in Step 4. (S)-5-methoxy-l-(2-methylbenzofuran-7-yl)-l-((R)-piperidin-3 -yl)pentan-l-ol from 7-bromo-2-methylbenzofuran and n-BuLi in Step 4.

(S)-l-(2-fluorobenzofuran-7-yl)-5-methoxy-l -((R)-ρiperidin-3-yl)pentan-l -ol from 7-bromo-2-fluorobenzofuran and n-BuLi in Step 4.

(S)-l-(5-fluorobenzofuran-7-yl)-5-methoxy-l-((R)-piperidi n-3-yl)pentan-l -ol from 7-bromo-5-fluoro-2-(trimethylsilyl)benzofuran and n-BuLi in Step 4. (S)-l-(2-/er/-butylbenzofuran-7-yl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l-ol from 7-bromo-2-(t-butyI)benzofuran and n-BuLi in Step 4. (S)-5-methoxy-l -((R)-piperidin-3-yl)-l-(2-(trimethylsilyl)benzo[b]thioρhen -4- yl)pentan-l-ol from 4-bromo-2-(trimethylsilyl)benzothiophene and n-BuLi in Step 4.

PREPARATION 16 fSVl -(benzorb1thiophen-2-yl)-5-methoxy-l-( ' fR)-piperidin-3-vπpentan-l-ol

Step 1. (R)-/e/-/-butyl 3-(benzo[b]thiophene-2-carbonyl)piperidine-l-carboxylate A solution of benzothiophene (117 μL, 1 mmol) in dry THF (4 mL) was cooled to -7O 0 C. A solution of 1.6M n-BuLi in hexanes (950 μL, 1.5 equiv) was added dropwise. After 10 min, a solution of Weinreb amide (282 mg, 1 equiv) in dry THF (2.5 mL) was added dropwise. The mixture was allowed to warm to rt and stirred overnight. Sat'd aq NH 4 Cl (30 mL) was added and the mixture was extracted with ether (2 x 50 mL). The combined ether layers were washed with brine (20 mL)

and dried over Na 2 SO 4 . After concentration, the crude product was purified by chromatography on a 12-g silica cartridge eluted with a gradient from 0 to 15% EtOAc in hexanes to afford (R)-ter/-butyl 3-(benzo[b]thiophene-2- carbonyl)piperidine-l-carboxylate (292 mg, 85%).

Step 2. (R)-fer/-butyl 3-((S)-l -(benzo[b]thiophen-2-yl)-l -hydroxy-5- methoxypenty l)piperidine- 1 -carboxylate

A solution of (R)-tert-buty\ 3-(benzo[b]thiophene-2-carbonyl)piperidine-l - carboxylate (146 mg, 0.423 mmol) in dry THF (5 mL) was cooled to -7O 0 C. A solution of 1.34 M 4-methoxybutylmagnesium chloride in THF (630 μL, 2 equiv) was added slowly. After 10 min, the reaction mixture was allowed to warm up to rt slowly and stirred for another 2 h. Sat'd aq NH 4 Cl (20 mL) was added and the mixture was extracted with ether (2 x 40 mL). The combined ether layers were washed with brine (20 mL) and dried over Na 2 SO 4 . After concentration, the crude product was purified by by chromatography on a 12-g silica cartridge eluted with a gradient from 0 Io 35% EtOAc in hexanes to afford (R)-/er/-butyl 3-((S)-I- (benzo[b]thiophen-2-yl)-l-hydroxy-5-methoxypentyl)piperidine -l -carboxylate (160.7 mg, 88%).

Step 3. (S)-I -(benzo[b]thiophen-2-yl)-5-methoxy-l-((R)-piperidin-3-yl)pen tan-l-ol hydrochloride

(R)-ferf-butyl 3-((S)-I -(benzo[b]thiophen-2-yl)- l-hydroxy-5- methoxypcnty])piperidinc-l -carboxylate (160 mg, 0.37 mmol) was dissolved in 1 : 1 2 N aq HCl solution/acetonitrilc (50 mL). The mixture was stirred overnight at rt and neutralized with 5% aq NaOH. The acetonitrile was removed by evaporation. The aqueous residue was extracted by CH 2 Cl 2 (2 x 40 mL). The combined organic layers were concentrated to afford (S)-l-(benzo[b]thiophen-2-yl)-5-methoxy-l -((R)- piperidin-3-yl)pentan-l-ol (102 mg, 83%) which was used without purification.

The following piperidines were prepared using procedures analogous to those described above using the heterocycle and base indicated below in Step 1.

(S)- 1 -(2,2-difluorobenzo[d] [ 1 ,3 Jdioxol-4-yI)-5-methoxy-l -((R)-piperidin-3- yl)pentan-l-ol using 2,2-difluorobenzo[d][l ,3]dioxoIe and s-BuLi in Step 1.

(S)-5-methoxy- 1 -(I -methyl- lH-imidazol-2-yl)-l -((R)-piperidin-3-yl)pentan- l-ol using 1 -methylimidazole and n-BuLi in Step 1. l-(5-chloro-l-methyl-lH-imidazol-2-yl)-5-methoxy-l-(piperidi n-3- yl)pentan-l-ol using 5-chloro-l -methyl- lH-imidazole and n-BuLi in Step 1.

(S)-5-methoxy-l-((R)-piperidin-3-yl)-l-(thiazol-2-yl)pent an-l-ol using thiazole and n-BuLi in Step 1.

(S)-5-mcthoxy-l-(5-methylthiazol-2-yl)-l-((R)-piperidin-3 -yl)pentan-l -ol using 5-mcthylthiazoIc and n-BuLi in Step 1.

4-chloro-2-((R)-(3-methoxypropoxy)((R)-piperidin-3-yl)methyl )pyridine using 4-chloropyridine and n-BuLi/Me 2 N(CH 2 ) 2 OLi in Step 1 .

PREPARATION 17 4-bromo-2-('trimethylsily0benzothiophene

Me 3 SiCI, LDA

Step 1. (3-bromophenyl)(2,2-diethoxyethyl)sulfane

To a stirred solution of 3-bromothiophenol (5,0 g, 26 mraol) in DMSO (40 mL) was added a solution of KOH pellets (85% by wt, 2.15 g, 32 mmol) in water (4 inL) followed by bromoacetaldehyde diethyl acetal (4.5 mL, 29 mmol). The mixture was stirred at rt for 5 d, diluted with ether (300 mL) and washed with water (3 x 100 mL). The combined water washes were extracted with ether (100 mL). The combined ether extracts were washed with brine (100 mL), dried over MgSO 4 and concentrated to afford (3-bromophenyl)(2,2-diethoxyethyl)sulfane (8.23 g, 100%) as a colorless oil.

Step 2. 4-bromobenzothiophene

A stirred mixture of (3-bromophenyl)(2,2-diethoxyethyl)sulfane (8.23 g, 26 mmol), polyphosphoric acid (20 mL) and chlorobenzene (30 mL) was heated at 130 0 C for 1 h. The mixture was allowed to cool to rt and 1 M aq NaOH (100 mL) was added. The mixture was extracted with ether (2 x 100 mL). The combined ether extracts were washed with water (25 m) and brine (25 mL) and dried over MgSO 4 . Removal of the solvent left an oil (29.55 g) which was chromatographed on a 120-g silica cartridge eluted with hexanes. Fractions containing the desired product were concentrated to afford an oil (3.33 g) which resubmitted to chromatography under the same conditions to afford ~80% pure 4-bromobenzothiophene (1.16 g, 20%).

Step 3. 4-bromo-2-(trimethylsilyl)benzothiophene

A stirred solution of ~80% pure 4-bromobenzothiophene (580 mg, 2.7 mmol) and chlorotrimethylsilane (0.70 mL, 5.4 mmol) in dry THF (10 mL) was cooled to - 70 0 C and 2 M LDA in 1 :1 THF/heptane (1.35 mL, 5.4 mmol) was added dropwise over 2 min. The mixture was stirred at -70 0 C for 1.5 h and diluted with ether (80 mL) and 5% aq HCl (20 mL). The organic layer was separated, washed with sal'd aq NaHCO 3 (20 mL) and dried over MgSO 4 . Removal of the solvent left 4-bromo-2- (trimethylsilyl)benzothiophene (740 mg, 95%) as an amber oil.

4~Bromo-2-(trim ' ethylsilyl)-benzofuran was made following procedures analogous to those described in Example 90, using 3-bromophenol in Step 1.

PREPARATION 18 7-bromo-2-methylbenzofuran

A stirred solution of 7-bromobenzofuran (493 mg, 2.5 mmol) in dry THF (5 mL) was cooled to -70 0 C and 2M LDA in 1 :1 THF/heptane (1.4 mL, 2.8 mmol) was added dropwise over 2min. The mixture was stirred at -70 0 C for 1 h and methyl

iodide (0.19 mL, 3.0 mmol) was added. The mixture was stirred at -7O 0 C for 3 h and at 0 0 C for 1 h. The mixture was poured into 5% aq HCl (60 mL) and extracted with ether (2 x 50 mL). The combined ether extracts were washed with sat'd aq NaHCO 3 (20 mL) and dried over MgSO 4 . Removal of the solvent left an oil (470 mg) which was purified by chromatography on a 40-g silica cartridge eluted with hexanes to afford 7-bromo-2-methylbenzofuran (277 mg, 52%, estimated purity -80%).

PREPARATION 19 (S)-l-(2-tert-butylbenzofuran-7-yl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l -ol

Step 1. 7-bromo-2-tert-bulylbenzofuran

3,3-Dimethylbut-l-yne (1.6 g, 20 mmol) was added to a solution of 2,6- dibromophenol (5.0 g, 20 mmol) and Cu 2 O (1.7 g, 12 mmol) in dry pyridine (50 mL) under N 2 , then the mixture was heated to about 55 0 C and stirred overnight. The mixture was filtered and the filtrate was concentrated to give a residue, which was dissolved in EtOAc. This solution was washed with brine and dried over Na 2 SO 4 . The solvent was removed and the residue was purified by column chromatography to afford 7-brorno-2-tert-butyl-benzofuran (1.3 g, 26%). 1 H NMR (CDCl 3 ): 1.40(S, 9H) 3 6.41(s, IH), 7.04(1, IH), 7.38(d, IH), 7.42(d, IH).

Step 2. (R)-tert-butyl 3-(2-tert-butylbenzofuran-7-carbonyl)piperidine-l -carboxylate

Under protection of N 2 , a solution of 7-bromo-2-tert-butyl-benzofuran (0.5g, 1.98 mmol) in anhydrous THF (5 mL) was cooled to -78 0 C and 2.5 M n-BuLi solution in hexanes (0.87 mL, 2.18mmol) was added dropwise slowly. The reaction mixture was stirred at -78 0 C for Ih and a solution of (R)-tert-butyl 3- (methoxy(methyl)carbamoyl)piperidine-l-carboxylate (0.65 g, 2.38 mmol) in anhydrous THF (5 mL) was added dropwise slowly. The reaction mixture was warmed to rt and stirred overnight. The mixture was quenched with satd aq NH 4 CI (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over Na 2 SO 4 . Solvent removal and flash column chromatography afforded (R)-tert-butyl 3-(2-tert-butyIbenzofuran-7-carbonyl)piperidine-l- carboxylate (0.41 g, 54%). 1 H NMR (CDCl 3 ): 7.83(d, IH), 7.19(d, IH), 7.26(t, I H), 6.440(s, I H), 4.1 (d, IH), 3.75(s, IH), 2.83(t, IH), 2.27(d, IH), 1.82(d, IH), 1.590(m, 4H), 1.426(s, 9H), 1.406(s, 9H)

Step 3. (R)-tert-butyl 3-((S)-l-(2-tert-butylbenzofuran-7-yl)-l-hydroxy-5- methoxypentyl)piperidine- 1 -carboxylate

A 50 mL three-necked flask was charged with (R)-tert-butyl 3-(2-tert- butylbenzofuran-7-carbonyl)piperidine-l -carboxylate (0.41g, 1.08mmol) and anhydrous THF (8 mL). The flask was evacuated and refilled with N 2 . The mixture was cooled with dry ice-acetone bath and the Grignard reagent derived from 1 - chloro-4-methoxy-butane (5.4 mL, 2M) was added. The reaction mixture was allowed to slowly warm to rt while stirring overnight. The mixture was quenched with said aq NH 4 Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried OVCrNa 2 SO 4 and concentrated in vacuo to afford (R)- tert-butyl 3-((S)-l-(2-tert-butylbenzofuran-7-yl)-l-hydroxy-5- methoxypentyOpiperidine- 1 -carboxylate (0.5 g, 100%). 1 H NMR:(CDC13): 1.34(s, 9H), 1.46(s, 9H), 1.51 (m, 9H), 2.02 (m, IH), 2.18(m, IH), 2.50(m, 2H), 2.67(t, IH) 5 3.23(m, 5H), 3.99(s, lH), 4.43(s, IH), 6.35(s, IH), 7.16(t, IH) 5 7.23(d, IH), 7.39(dd, IH),

Step 4. (S)-I -(2-tert-butylbenzofuran-7-yl)-5-methoxy-l-((R)-piperidin-3- yl)pentan-l-ol

(R)-tert-butyl 3-((S)- 1 -(2-tert-butylbenzofijran-7-y I)- 1 -hydroxy-5- methoxypentyl)piperidine-l-carboxylate (250 mg, 0.53 mmol) was dissolved in 20% TFAZCI-I 2 Cl 2 (4 mL). The reaction mixture was stirred at rt for 1 h. The mixture was quenched with satd aq NaHCO 3 (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over Na 2 SO 4 . The filtrate was evaporated to give a residue, which was purified by preparative HPLC to afford pure (S)-I -(2- tert-butylbenzofuran-7-yl)-5-methoxy-l-((R)-piperidin-3-yl)p entan-l-ol (185 mg, 94%). 1 H NMR(CDCl 3 ): 0.95(s, IH) 5 1.24(m, 2H), 1.36 (s, 9H), 1.49(m, 3H), 1.64(m, 2H), 2.02 (m, 2H), 2.55(m, 2H), 2.82(s, IH), 3.1(s, IH), 3.25(m, 5H) 3 3.66(m, IH), 6.35(s, IH), 7.18(t, IH), 7.28(d, IH) 3 7.42(d 3 IH) 3 8.96(s, IH), 9.33(s, IH)

The following compounds were prepared using procedures analogous to those described above:

(S)-I -(2-isobutylbenzofuran-7-yl)-5-methoxy-l-((R)-piperidin-3-yl )pentan- l-ol using 4-methylpentyne in place of 3,3-dimethylbut-l-yne in Step 1.

PREPARATION 20

(SV 1 -r2-(cvclopropy1methoxy)-3-fluorophenyl ' )-5-methoxy- 1 -((R)-piperidin-3- vPpentan-1-ol

TFA/CH 2 CI 2

Step 1. (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-l- carboxylate

A 50 mL three-necked flask was charged with magnesium turning (240 mg, 10 mraol) and a small crystal of iodine. The flash was evacuated and refilled with N 2 . A portion of a solution of l-bromo-2cyclopropylmethyl-S-fluoro-benzene (2.1 g, 8.57 mrnol) in dry THF (10 mL) was added dropwise to trigger the reaction. When the color of iodine had disappeared, the residual solution was added dropwise slowly. The mixture was stirred under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent was used for the next step. To another 100-mL three-necked flask was added (R)-tert-butyl 3-

(methoxy(methyl)-carbamoyl)piperidine-l-carboxylate (1.55 g, 5.7 mmol) and THF (15 mL). The flask was evacuated and refilled with N 2 . The mixture was cooled in a dry ice-acetone bath and the Grignard reagent prepared above (10 mL) was added slowly. The reaction mixture was stirred at — 20 to -10 0 C for 2.5 h. The mixture was quenched with sat'd aq NH 4 Cl (20 mL), extracted with EtOAc (3 x), and the combined organic layers were dried over Na 2 SO 4 . Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl 3-(2- (cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-l -carboxylate (1.5 g, 70%). 1 H NMR (400MHz, CDCl 3 ): 0.27 (m, 2H) , 0.57 (m, 2H) 1.20 (m, IH), 1.43 (s, 9H), 1.60-1.51 (m, 4H) 3 1.73 (m, IH ), 2.02 (m, IH), 2.79 (m, I H), 3.47 (m, IH), 3.98 (m, 3H) 5 4.20 (m,l H), 7.04 (m, IH), 7.20 (m, 2H). MS (E/Z): 378 (M+H + ).

Step 2. (R)-tert-butyl 3-((S)-l-(2-(cyclopropylmethoxy)-3-fluorophenyl)-l -hydroxy- 5-methoxypentyl)piperidine-l -carboxylate

A flame dried 50 mL three-necked flask was charged with magnesium turnings (380 mg, 15.8 mmol) and a small crystal of iodine in THF (5 mL). The flask was evacuated and refilled with N 2 . Then a solution of l -chloro-4- methoxybutane (1.6 g, 13.2 mmol) in THF (10 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of the magnesium was consumed. The resulting Grignard reagent was used as follows. To another 100 mL three-necked flask was added (R)-tert-buty\ 3-(2-

(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-l-carboxylat e (0.5 g, 1.32 mmol) and THF (10 mL). The flask was evacuated and refilled with N 2 . The mixture was cooled with a dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with sat'd aq NH 4 Cl (10 mL), extracted with EtOAc (3 x), and the combined organic layers were dried over Na 2 SO 4 . Evaporation of the solvent and purification by flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-ter(-buty\ 3-((S)-l-(2-(cyclopropylmethoxy)-3-fluorophenyl)-l - hydroxy-5-methoxypentyl)piperidine-l-carboxylate (560 mg, 91%). 1 H NMR (400MHz, CDCl 3 ): 0.35 (m, 2H), 0.63 (m, 2H) 5 1.05 (m, IH), 1.43 (s, 9H), 1.55-1.20 (m, 9H), 1 .85 (m, I H), 2.55 (m, I H) 3 2.67 (m, IH) 5 3.27 (s, 3H) 3 3.33 (m, 2H) 5 3.85 (m, I H) 3 4.05 (m, 2H), 4.25 (m.lH), 6.97 (m, 3H). MS (E/Z): 466 (M+H + ).

Step 3. (S)- 1 -(2-(cyclopropylrnethoxy)-3-fluorophenyl)-5-rnethoxy- 1 -((R)- piperidin-3-yl)pentan-l-ol-

A solution of (R)-/e/-/-butyl 3-((S)-I -(2-(cyclopropylmethoxy)-3- fluorophenyl)-l-hydroxy-5-methoxypentyl)piperidine-l-carboxy late (120 mg) in 20% TFA/CH2CI2 (20 mL) was stirred at 0 0 C for 5 min. The solvent was neutralized by addition of sat'd aq NaHCO 3 , and the mixture was extracted with CH 2 Cl 2 (3 x). The combined organic layers were dried over Na 2 SO 4 and evaporated to give the crude product. LC-MS analysis of the crude product indicated the presence of two isomers (10:1). The crude product was purified by reverse phase prep HPLC to afford the major isomer, (S)-l-(2-(cyclopropylmethoxy)-3-fJuorophenyI)-5-methoxy- l -((R)-piperidin-3-yl)pentan-l-ol (40 mg, 42%). 1 H NMR (400MHz 3 CD 4 O): 0.36 (m, 2H) 3 0.63 (m, 2H), 0.86 (m, IH) 3 1.55-1.1 1 (m, 1 IH), 1.82 (m, IH) 3 2.29 (m,

2H) 5 2.45 (m,lH), 2.66 (t, IH) 5 2.94 (d,lH), 3.24 (s, 3H), 3.31(m, 2H), 3.91 (m, 2H) 3 6.98 (m, 2H), 726 (m, IH). MS (E/Z): 366 (M+l). In addition, 2-fluoro-6-((S)-l- hydroxy-5-rnethoxy-l-((R)-piperidin-3-yl)pentyl)phenol was isolated as a byproduct.

PREPARATION 21 PIPERIDγNES FROM WEINREB AMIDES AND 2-BROMOPHENOLS

(S)-5-methoxy- 1 -(2-(2,2-(dimethyl)propoxy)phcnyl)- 1 -((R)-pipcridin-3-yl)pentan-l - oi hydrochloride

I) TBSCI,

Imidazole, CH 2 CI 2 2) tBuLi, THF

R=H, OTBS

r- R R== T I BS u R=H

Step 1 . Bromo-2-[(ϋer/-butyl)dimethylsiloxy]benzene

A solution of 2-bromophenol (5 mL, 47 mmol), imidazole (8 g, 1 18 mmol) and IeH- butyldimethylsilyl chloride (8.6 g, 57 mmol) in DMF (50 mL) was stirred at rt overnight. The reaction was treated with water (150 mL) and extracted with Et 2 O (4 x 25 mL). The organic phase was washed with 50% aq lithium chloride solution twice, dried over MgSO 4 and filtered. The solvent was evaporated and the crude product was purified by filtration through silica gel, washing with 1 : 1 EtOAc/hexanes to afford bromo-2-[(ter/-butyl)dimethylsiloxy]benzene (13.4 g, 99%).

Step 2. 2-((S)-l -hydroxy-5-methoxy-l-((R)-N-Boc-piperidin-3-yl)pentyl)[re/-/ - butyldimethylsiloxy]benzene

A solution of bromo-2-[(te/7-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et 2 O (35 mL) was cooled to -78 0 C and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-lert-huty\ 3-(N-methoxy-N-methylcarbamoyl)piperidine-l-carboxylate (1.0 g, 3.7 mmol) in Et 2 O was added slowly. The reaction was allowed to stir and warm to rt over a two-hour period. Saturated aq ammonium chloride was added to quench

the reaction. The aq phase was extracted with Et 2 O three times. The combined organic layers were washed with brine and dried over MgSO 4 . The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2- /e/"/-butyldimethylsiloxyphenyl)((R)-N-Boc-piperidin-3-yl)me thanone and (2- hydroxyphenyI)((R)-N-Boc-piperidin-3-yI)methanone. A -20°C solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagensium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et 2 O. The combined organic layers were dried over MgSO 4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-l-hydroxy-5-methoxy-l-((R)-N-Boc-piperidin-3-yl)penty l)[/er/- butyidimethylsiloxyjbenzene (874 mg, 47%) and 2-((S)-l-hydroxy-5-methoxy-l- ((R)-N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%).

To a solution of 2-((S)-I -hydroxy-5-methoxy-l -((R)-N-Boc-piperidin-3- yl)pentyl)[/er/-butyldimethylsiloxy]benzene (710 mg, 1.40 mmol) in tetrahydrofuran (7 mL) was added IM tetrabutylammonium fluoride in THF (2.1 mL, 2.1 mmol). The mixture was stirred at rt for one hour. The mixture was diluted with EtOAc (20 mL) and washed with brine twice. The organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to give a residue, which was purified by by flash chromatography on silica gel eluting with EtOAc/hexanes to give 2-((S)-I - hydroxy-5-methoxy-l-((R)-N-Boc-piperidin-3-yl)pentyl)[/er/- butyldimethylsiloxy]benzene (450 mg, 81%).

Step 3. ((S)-5-methoxy-l-(2-(2,2-(dimethyl)propoxy)phenyl)-l-((R)-pi peridin-3- yl)pentan-l-ol hydrochloride

A solution of 2-((S)-I -hydroxy-5-methoxy-l -((R)-N-Boc-piperidin-3- yl)penlyl)phenol (195 mg, 0.500 mmol), l-bromo-2,2-dimethylpropane (1.0 ml, 7.5 mmol), and cesium carbonate (230 mg, 0.71) in NMP (2 mL) was heated and stirred in a microwave reactor for 20 min at 13O 0 C. After removal of solvent, the mixture

was redissolved in methylene chloride and filtered. The filtrate was evaporated Io give a residue which was used without any further purification.

A solution of crude (R)-/er/-butyl-3-((S)-l-hydroxy-5-methoxy-l -(2-(2,2- (dimethyl)propoxy)phenyl)pentyl)piperidine-l-carboxylate in MeCN (50 mL) was treated with 2M aq hydrochloric acid (50 mL) and stirred at rt overnight. The solvent was evaporated to afford ((S)-5-methoxy-l-(2-(2,2-(dimethyl)propoxy) phenyl)- l -((R)-piperidin-3-yl)pentan-l-ol hydrochloride (122 mg, 67%) as an oil.

The following piperidines were prepared using procedures analogous to those described above, replacing l -bromo-2,2-dimethylpropane in Step 3 with the alkylating agent indicated and using DMF as solvent at rt in place of NMP at elevated temperature:

PREPARATION 22

GRVtert-butyl 3-ff S)-I -(2-f2-chlorophenyr)phenvn-l -hvdroxy-S- m ethox ypentvDpi peridine- 1 -carboxyl ate

s MgCI

Step I . (3R)-l-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl) piperidine

To a solution of 2 -bromo-2-chloro-biphenyl (5.34 g, 20 mmol) in anhydrous THF (50 mL) cooled to -78°C was added dropwise a solution of 1.6 M n-BuLi in hexane (12.5 mL, 20 mmol). The reaction mixture was stirred at -78°C for 1 h and a solution of (R)-tert-buty\ 3-(iV-methoxy-iV-methylcarbamoyl)-piperidine-l- carboxylate (5.44 g, 20 mmol) in anhydrous THF (50 mL) was added. The mixture was allowed to warm to it and stirred overnight. The mixture was quenched with satd aq NH 4 Cl (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated to give the crude product, which was purified by flash column chromatography to afford (3R)-l-(tert- butoxycarbonyl)-3-((2-(2-chlorophenyl))bcnzoyl)piperidine (4.43 g, 55%).

Step 2. (3R)-tert-butyl 3-((S)-I -(2-(2-ch!orophenyl)phenyl)~l-hydroxy-5- methoxypentyl)-piperidine-l -carboxylate A 250 mL three-necked flask was charged with magnesium turning (2.88 g,

0.12 mol) and a small crystal of iodine. The flask was evacauated and refilled with N 2 . A solution of 1 -chloro-4-methoxybutane (15 g, 0.12 mol) in THF (60 ml) was added dropwise to the above mixture. After heating under reflux for 2 h most of magnesium had been consumed and the Grignard solution was cooled to rt. A 250

mL three-necked flask was charged with (3R)-l -(tert-butoxycarbonyl)-3-((2-(2- chlorophenyl))benzoyl)piperidine (4.43 g, 1 1 mmol) and THF (50 mL), evcuated and refilled with N 2 . The mixture was cooled in a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. The mixture was quenched with satd aq NH 4 Cl (100 mL) and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated to give the crude product which was purified by flash column chromatography to afford pure (3R)-tert-butyl 3-((S)-l-(2-(2-chlorophenyl)phenyl)- l-hydroxy-5-mefhoxypentyl)piperidine-l -carboxylate (2.5 g, 47%).

The following piperidines were prepared using procedures analogous to those described above substituting the bromobiphenyls indicated in Step 1 followed by B oc removal under standard conditions:

PREPARATION 24

Methyl ('4SV4-( ' 6-chloro-3'-mcthylbiphcnyl-2-yl)-4-hydroxy-4-rpiperidin-3- yHbutvlcarbamate

Step 1. (R)-tert-butyl S-Cβ-chloro-S'-methylbiphenylcarbony^piperidine-l- carboxylate

To a solution of 6-bromo-2-fluoro-3'-methylbiphenyl (2 g, 7.14 mmol) in anhydrous THF (30 mL) cooled to -78 0 C was added dropwise a solution of 1.6 M of n-BuLi in hcxane (4.46 mL). The reaction mixture was stirred at -78 °C for Ih

and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-l- carboxylate (1.94 g, 7.14 ramol) in anhydrous THF (20 mL)was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with satd aq NH 4 Cl (40 mL) and extracted with EtOAc (40 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated to give crude product, which was purified by flash column chromatography to afford (R)-tert- butyl 3-(6-chloro-3'-methylbiphenylcarbonyl)piperidine-l-carboxyla te (1 g, 34%). 1 H NMR (400MHz, CD 3 OD): 0.80-1.20 (m, 8H), 1.30 (s, IH), 1.40 (s, IH), 1.40- 1.60 (m, 2H) 5 2.00-2.18 (s, IH), 2.30-2.40 (s, 3H) 5 2.60-2.80 (m, 2H), 3.50-3.80 (m, 2H), 7.00-7.15 (s, 2H), 7.20-7.30 (d, IH), 7.30-7.40 (t, 2H), 7.39-7.48 (t, IH), 7.60- 7.70 (d, IH); MS (E/Z): 414 (M+H + )

Step 2. (R)-tert-butyl 3-((S)-4-amino- 1 -(6-chloro-3'-methylbiphenyl-2-yl)- 1 - hydroxybutyl)piperidine- 1 -carboxylate To a solution of (R)-tert-butyl 3-(6-chIoro-3'- methylbiphenylcarbonyl)piperidine-l -carboxylate (800 mg, 1.94 mmol) in anhydrous THF (15 mL) cooled to -78 0 C was added dropwise a solution of 2 M (3- (2,2,5, 5-tetramethyl-l ,2,5-azadisilolidin-l-yl)propyl)magriesiurn chloride in THF (0.968 mL, 1.94 mmol). After addition, the reaction mixture was allowed to warm slowly to room temperature while stirring overnight. The mixture was quenched with satd aq NH 4 Cl (15 mL) and extracted with CH 2 Cl 2 (3 x). The combined organic layers were dried over Na 2 SO 4 and concentrated to give crude (R)-tert-butyl 3-((S)- 4-amino-l -(6-chloro-3'-methylbiphenyl-2-yl)-l-hydroxybutyl)piperidine -l- carboxylate (900 mg), which was used in the next step without further purification. "

Step 3. (R)-terl-butyl 3-((S)-l-(6-chloro-3'-methylbiphenyl-2-yl)-l-hydroxy-4- (rnethoxycarbonylamino)butyl)piperidine- 1 -carboxylate

To a solution of (R)-tert-butyl 3-((S)-4-amino-l -(6-chloro-3'- methylbiphenyl-2-yl)-l-hydroxybutyl)piperidine-l -carboxylate (800 mg, 1.69 mmol) in anhydrous CH 2 Cl 2 (15 mL) were added 4-dimethyaminopyridine (1.24 g, 10.17 mmol) and Et 3 N (2.35 mL, 16.95 mmol). The mixture was cooled with an ice bath and methyl chloroformate (0.65 mL, 8.47 mmol) in CH 2 Cl 2 (5 mL) was added.

The reaction mixture was allowed to warm slowly to rt while stirring overnight. The solvent was removed in vacuo and the residue was purified by column chromatography to afford (R)-tert-butyl 3-((S)-l-(6-chloro-3'-methylbiphenyl-2-yl)- l-hydroxy-4-(methoxycarbonylamino)butyl)piperidine-l-carboxy late (700 mg, 78%). 1 H NMR (400MHz 5 CD 3 OD): 1.00-1.70 (m, 17H) 5 2.30-2.50 (d, 3H) 5 2.50- 2.70 (s, IH), 2.90-2.31 (m, 2H), 3.50-3.52 (m, 3H), 3.80-4.20 (m, 2H) 5 6.0-7.15 (m, 3H), 7.15-7.40 (m, 3H), 7.50-7.70 (m, IH); MS (E/Z): 531 (M+H + )

Step 4. Methyl (4S)-4-(6-chloro-3'-methylbiphenyl-2-yl)-4-hydroxy-4-(piperi din-3- yl)butyl carbamate

To a solution of (R)-tert-butyl 3-((S)-l-(6-chloro-3'-methylbiphenyl-2-y])-l- hydroxy-4-(methoxycarbonylamino)butyl)piρeridinc-l-carboxyl atc (600 mg, 1.13 mg) in CH 3 CN (18 mL) was added 2N aq HCl (15 mL) and the reaction mixture was vigorously stirred overnight at rt. The solvents were removed in vacuo to give methyl (4S)-4-(6-chloro-3'-rnethylbiphenyl-2-yl)-4-hydroxy-4-(piper idin-3- yl)butylcarbamate as its hydrochloride salt (500 mg, 95.8%). 1 H NMR (400MHz, CD 3 OD): 1.00-1.20 (m, I H) 3 1.30-1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.40-2.50 (d, 3H), 2.75-2.90 (I, I H), 2.90-3.05 (m, 3H), 3.05-3.12 (t, IH), 3.20-3.30 (m, IH), 3.30-3.40 (m, I H), 3.60-3.70 (d, 4H) 5 6.90-6.98 (d, IH), 7.00-7.12 (m, IH) 5 7.25- 7.50 (m, 4H), 7.75-7.85 (d, IH); MS (E/Z): 431 (M+H + )

The following pipcridines were prepared using procedures analogous to those described above:

N-((S)-4-(6-fluoro-3'-mcthylbiphcnyl-2-yl)-4-hydroxy-4-(( R)-piperidin-3- yl)butyl)acetamide using acetyl chloride in place of methyl chloroformatc in Step 3.

N-((S)-4-(biphcnyl-2-yl)-4-hydroxy-4-((R)-piperidin-3-yl) butyl)acetamide using 2-bromobiphenyl in Step 1 and acetyl chloride in place of methyl chloro formate in Step 3.

N-((S)-4-(3'-chloro-6-methylbiphenyl-2-yl)-4-hydroxy-4-(( R)-piperidin-3- yl)butyl)acetamide using 6-bromo-2-chloro-3'-methylbiphenyl in Step 1 and acetyl chloride in place of methyl chloroformate in Step 3.

Methyl (S)-4-(6-chloro-3'-methylbiphenyl-2-yl)-4-hydroxy-4-((R)-pip eridin-

3-yl)butylcarbamate using 6-bromo-2-chloro-3'-methylbiphenyl in Step 1.

N-((4S)-4-(2',6-difluoro-5'-methylbiphenyl-2-yl)-4-hydrox y-4-((R)- piperidin-3-yl)butyI)acetamide using 2'-bromo-2,6'-difluoro-5-methylbiphenyl in Step 1 and acetyl chloride in place of methyl chloroformate in Step 3.

PREPARATION 25 N-f2-f(RVf6-fluoro-3'-methylbiphenyl-2-vnffRVpiperidin-3- yOmethoxylethyOacetamide

Step 1. (R)-tert-butyl 3-(6-fluoro-3'-methylbiphenylcarbonyl)piperidine-l- carboxylate

A stirred solution of 6-bromo-2-fluoro-3'-raethyl-biphenyl (7 g 5 26.4 mmol) in THF (70 mL) under N 2 was cooled to -78 0 C and 2.5 M n-BuLi in hexanes (10.56 mL, 26.4 mmol) was added dropwise slowly. The reaction mixture was stirred at - 78 °C for 1 h and a solution of the Weinreb amide (R)-tert-butyl 3- (methoxy(methyl)carbamoyl)piperidine-l -carboxylate (7.18 g, 26.4 mmol) in THF (70 mL) was added dropwise slowly. The reaction mixture warmed to rt and stirred overnight. The mixture was quenched with satd aq NH 4 Cl and extracted with EtOAc (3 x). The combined organic extracts were dried over Na 2 4 . Solvent removal and flash column chromatography gave (R)-tert-butyl 3-(6-fluoro-3'- methylbiphenylcarbonyl)piperidine-l -carboxylate (4 g, 40%). 1 H NMR (400MHz, CDCI 3 ): 0.89 (m, I H), 1.39 (s, 9H), 1.55 (m, I H), 1.73 (m, IH), 2.03 (m, I H), 2.40 (s, 3H), 2.81 (m, IH), 3.09 (m, IH), 3.25 (m, IH), 3.80 (m, 2H), 3.95 (m, 2H), 7.09- 7.41 (m, 7H).

Step 2. (3R)-tert-butyl 3-((6-fluoro-3'-methylbiphenyl-2- yl)(hydroxy)methyl)piperidine-l -carboxylate

To a solution of (R)-tert-butyl 3-(6-fluoro-3'- melhylbiphenylcarbonyl)piperidine-l -carboxylate (3.5 g, 6.29 mmol) in MeOH (50 mL) was added NaBH 4 (0.95 g, 25 mmol) in portions at rt. After addition, the mixture was stirred for 2 h. Tie showed the starting material had disappeared. The solvent was removed in vacuo to leave a residue which was partitioned between water and EtOAc. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 and evaporated to give (3R)-tert-butyl 3-((6-fluoro-3'-methylbiphenyl-2- yl)(hydroxy)methyl)piperidine-l -carboxylate (3.5 g, 100%), which was used in the next step without purification.

Step 3. (3R)-tert-butyl 3-((2-ethoxy-2-oxoethoxy)(6-fluoro-3'-methylbiphenyl-2- yl)methyl)piperidine- 1 -carboxylate

To a suspension of NaH (0.42 g, 17.6 mmol) in THF (50 mL) at 0-5 0 C was added dropwise a solution of (3R)-tert-butyl 3-((6-fluoro-3'-methylbiphenyl-2- yl)(hydroxy)methyl)piperidine-l -carboxylate (3.5 g , 8.8 mmol) in THF (30 mL) and

the reaction mixture was stirred for 1 h at it. A solution of ethyl bromoacetate (2.92 g, 17.6 mmol) in THF (30 mL) was added dropwise to the above mixture, and then refluxed for 12 h. Tie showed the starting material had disappeared. The reaction mixture was poured into satd aq NH 4 Cl and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford (3R)-tert-butyl 3-((2-ethoxy-2- oxoethoxy)(6-fluoro-3'-methylbiphenyl-2-yl)methyl)piperidine -l-carboxylate (1 .1 g, 38%). 1 H NMR (400MHz, CDCl 3 ): 1.26 (m, 3H), 1.40 (s, 9H), 2.10 (m, IH), 2.39 (s, 3H), 2.51 (m, IH), 3.51 (m, IH), 3.78 (m, IH), 3.96 (m, 2H) 5 4.16 (m, 3H), 4.23 (m, 2H), 4.69 (m, 2H), 6.97 (m, 2H), 7.06 (m, IH), 7.20 (m, IH), 7.29-7.41 (m, 3H).

Step 4. (3R)-tert-butyl 3-((6-fluoro-3'~methylbiphenyl-2-yl)(2- hydroxyethoxy)methyl)piperidine-l -carboxylate

To a solution of (3R)-tert-butyl 3-((2-ethoxy-2-oxoethoxy)(6-fluoro-3'- methyIbiphenyl-2-yl)methyl)piperidine-l -carboxylate (1.1 g, 2.3 mmol) in EtOH (20 mL) was added NaBH 4 (0.7 g, 18.1 mmol) in portions. After addition, the mixture was stirred at rt overnight. TIc showed the start material had disappeared. The solvent was removed in vacuo to leave a residue, which was partitioned between water and EtOAc. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and evaporated to give (3R)-tert-butyl 3-((6-fluoro-3'- methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl)piperidine-l-car boxylate (1 g, 99%) which was used in the next step without purification.

Step 5. (3R)-tert-butyI 3-((6-fluoro-3'-methylbiphenyl-2-yl)(2- (methanesulfonyloxy)ethoxy)methyl)piperidine-l -carboxylate

To a solution of (3R)-tert-butyl 3-((6-fluoro-3'-methylbiphenyl-2-yl)(2- hydroxyethoxy)methyl)piperidine-l -carboxylate (1 g, 2.3 mmol) in dry CH 2 CI 2 (15 mL) was added Et 3 N (0.9 g, 9.0 mmol) at ca 0 to -5 0 C. A solution of MsCl (0.5 g, 4.5 mmol) in anhydrous CH 2 Cl 2 (4 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. Tie showed the starting material had disappeared. Water was added and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic extracts were washed with

10% aq citric acid, satd aq NaHCO 3 and brine, dried over Na 2 SO 4 , filtered and concentrated to give (3R)-tert-butyl 3-((6-fluoro-3'-methylbiphenyl-2-yl)(2- (methanesulfonyloxy)ethoxy)methyl)piperidine-l-carboxylate (1.1 g, yield 94%), which was used in the next step without purification.

Step 6. (3R)-tert-butyl 3-((2-azidoethoxy)(6-fluoro-3'-methylbiphenyl-2- yl)methyl)piperidine-l-carboxylate

(3R)-tert-butyl 3-((6-fluoro-3'-methylbiphenyl-2-yl)(2- (methanesulfonyloxy)ethoxy)methyl)piperidine-l-carboxylate (1.1 g, 2 mmol) was dissolved in anhydrous DMF (15 mL), solid NaN 3 (280 mg, 4 mmol) was added and the reaction mixture was heated to 80 0 C for 5 h. The mixture was cooled to rt and diluted with EtOAc and water. The organic phase was separated, washed with water and dried over MgSO 4 . Removal of the solvent gave (3R)-tert-butyl 3-((2- azidoethoxy)(6-fluoro-3'-methylbiphenyl-2-yl)methyl)piperidi ne-l -carboxylate (0.89 g, yield 90%) which was used in the next step without purification.

Step 7. (3R)-tert-butyl 3-((2-aminoethoxy)(6-fluoro-3'-rnethylbiphenyl-2- yl)methyl)piperidine-l-carboxylate

A solution of (3R)-tert-butyl 3-((2-azidoethoxy)(6-fluoro-3'-methylbiphenyl- 2-yl)methyl)piperidine-l -carboxylate (0.89 g) in methanol (20 mL) was added to wetted Pd/C (200 mg). After 3 cycles of evacuation and refilling with H 2 , a balloon. ofH 2 was attached to the vessel and the mixture was stiired overnight. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give the crude amine. Purification by preparative HPLC gave (3R)-tert-butyl 3-((R)-(2- aminoethoxy)(6-fluoro-3'-methylbiphenyl-2-yl)methyl)piperidi ne-l -carboxylate

(220 mg, 26%). 1 H NMR (400MHz, CDCl 3 ): 1.10 (m, 2H), 1.43 (s, 9H), 1.49 ( m, ' 2H) 9 1.89 (m, IH), 2.10 (m, IH), 2.39 (s, 3H) 3 3.16 (m, 2H), 3.51 (m, 2H) 3 4.15 (m, IH), 6.97 (m, 3H), 7.10 (m, I H), 7.30-7.48 (m, 3H).

Step 8. (3R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(6-flυoro-3'-methylbiphenyl-2- yl)methyl)piperidine-l -carboxylate

To a solution of (3R)-tert-butyl 3-((R)-(2-aminoethoxy)(6-fluoro-3'- methylbiphenyl-2-yl)methyl)piperidine-l-carboxylate (86 mg, 0.2 mmol) in anhydrous CH 2 Cl 2 (8 mL) was added Et 3 N (0.5 ml, 20 mmol). The mixture was cooled with an ice bath and acetyl chloride (15 mg, 0.2 mmol) in CH 2 Cl 2 (4 mL) was added. The reaction mixture was stirred at rt for 0.5 h, then washed with water, dried over MgSO 4 , filtered and concentrated to give (3R)-tert-butyl 3-((R)-(2- acetamidoethoxy)(6-fluoro-3'-methylbiphenyl-2-yl)methyl)pipe ridine-l-carboxylate (80 mg, 85%), which was used in the next step without purification.

Step 9. N-(2-((R)-(6-fluoro-3 r -methylbiphenyl-2-yl)((R)-piperidin-3- yl)methoxy)ethyl)acetamide

A solution of (3R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(6-fluoro-3'- methylbiphenyl-2-yl)methyl)piperidine-l-carboxylate (80 mg) in 20% TFA/CH 2 C1 2 (5 mL) was stirred at 0 0 C for 30 min. The solvent was neutralized by adding satd aq NaHCO 3 and extracted with CH 2 Cl 2 (3 x). The combined organic extracts were dried over Na 2 SO 4 and evaporated to give N-(2-((R)-(6-fluoro-3'-methylbiphenyl-2- yl)((R)-piperidin-3-yl)methoxy)ethyl)acetamide (20 mg, 32%).

The following piperidines were prepared using procedures analogous to those described above:

methyl 2-((R)-(6-fluoro-3'-methylbiphenyl-2-yl)((R)-piperidin-3~ y])methoxy)ethylcarbamate using methyl chloroformate in place of acetyl chloride in Step 8.

3-((R)-(6-fluoro-3'-methylbiphenyl-2-yl)(3- methoxypropoxy)methyl)piperidine using 3-methoxypropyl methanesulfonate in Step 3 and eliminating Steps 4-8.

PREPARATION 26 N-((R)-4-(6-fluoro-3'-melhylbiphenyl-3-yl)-4-((S)-piperidin- 3-yl)butyl)acetamide

Burgess reagent H 2 , Pd(OH) 2

Preparative HPLC

Step 1. (S)-tert-butyl 3-(4-acetamido-l-(6-fluoro-3'-methylbiphenyl-3-yl)but-l - enyl)piperidine- 1 -carboxylate

To a solution of (R)-tert-butyl 3-((S)-4-acetamido-l -(6-fluoro-3'- methylbiphenyl-3-yl)-l-hydroxybutyl)piperidine-l-carboxylate (380 mg, 0.76 mmol) in anhydrous toluene (8 mL) was added Burgess reagent (352 mg, 1.47 rnmol). The reaction mixture was stirred under reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and H 2 O. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo and the residual oil was purified by preparative tic to afford (S)-tert-butyl 3- (4-acetamido- 1 -(δ-fluoro-S'-methylbiphenyl-S-yObut- 1 -enyl)piperidine- 1 - carboxylate (1 10 mg, 30% yield). 1 H NMR (400MHz, MeOH):7.33-7.39 (m, 2 H), 7.13-7.23 (m, 2 H), 6.95-7.03 (m, 3 H), 5.29-5.33 (m, 1 H), 3.93-4.15 (m, 1 H) 5 . 3.78-3.91 (m, 1 H), 3.00-3.04 (m, 2 H), 2.40-2.53 (m, 1 H), 2.37 (d, 3 H), 1 .89 (s, 3 H), 1.75 (m, 1 H), 1.44-1.62 (m, 4 H), 1.41 (s, 9 H), 1.16-1.32 (m, 3H), 1.01 (m, 1 H). MS (E/Z): 481 (M+H + )

Step 2. (S)-tert-butyl 3-((R)-4-acetamido-l-(6-fluoro-3'-methylbiphenyl-3- yl)butyl)piperidine-l -carboxylate

To a solution of (S)-tert- butyl 3-(4-acetamido-l-(6-fluoro-3'-methylbiphenyl- 3-yl)but-l -enyl)pipcridine-l -carboxylate (1 10 mg, 0.85 mmol) in anhydrous MeOH

(3 mL) was added anhydrous Pd(OH) 2 (20 mg). The reaction mixture was stirred overnight under a hydrogen atmosphere (monitored by LC-MS) and filtered through a plug of silica. The filtrate was concentrated in vacuo to afford a mixture with two isomers. Purification by preparative HPLC gave (S)-tert-butyl 3-((R)-4-acetamido- l-(6-fluoro-3'-methylbiphenyl-3-yl)butyl)piperidine-l-carbox ylate (40 mg, 36% yield). 1 H NMR (400MHz 5 MeOH):7.31-7.37 (m, 2 H), 7.20 (d, 2 H), 7.13 (d, 2 H), 6.97-7.01 (m, 3 H), 3.95-4.18 (m, 1 H) 3 3.80-3.92 (m, 1 H), 3.03 (m, 2 H), 2.61-2.72 (m, 1 H), 2.42-2.52 (m, 1 H), 2.38 (d, 3 H) 3 1.90 (s, 3 H), 1.78 (m, 1 H), 1.42-1.65 (m, 4 H), 1.43 (s, 9 H), 1.15-1.31 (m, 3H), 1.03 (m, 1 H). MS (E/Z): 483 (M+H + )

Step 3. N-((R)-4-(6-fluoro-3'-methylbiphenyI-3-yl)-4-((S)-piperidin- 3- y l)buty l)acetam ide

(S)-tert-butyl 3-((R)-4-acetamido-l-(6-fluoro-3'-methylbiρhenyl-3- yl)butyl)piperidine-l-carboxylate (40 mg, 0.083 mmol) was dissolved in a solution of 20% (V /V) TFA/CH 2 C1 2 (3 mL). The reaction mixture was stirred at rt for 1 h (monitored by HPLC ) and a solution of satd aq NaHCO 3 was added dropwise to adjust the pH to 7-8. The resulting mixture was extracted with CH 2 Cl 2 (3 x 5 mL) and the combined extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo to afford N-((R)-4-(6-fluoro-3'-methylbiphenyl-3-yl)-4-((S)- piperidin-3-yl)butyl)acetamide (30 mg, 94%). MS (E/Z): 383 (M+H + ).

The following compounds were prepared using procedures analogous to those described above:

methyl (R)-4-(6-fluoro-3'-methylbiphenyl-2-yl)-4-((S)-piperidin-3- yl)butylcarbamate starting with methyl (S)-4-(6-fluoiO-3'-methylbiphenyI-2-yl)-4- hydroxy-4-((R)-piperidin-3-yl)butylcarbamate.

PREPARATION 27 a) 6-Bromo-2-fluoro-3'-methvlbiphenvl

Step 1. l-Bromo-3-fluoro-2-iodobenzene

To a solution of diisopropylamine (76 mL, 0.4 mol) in dry THF (664 mL) and n-hcxane (220 mL) was added 2.5 M n-BuLi (160 mL. 0.4 mol) dropwise at — 78°C during a period of l*h. The mixture was stirred for 1 h at -78 0 C. Then a solution of 1 -bromo-3-fiuoro-benzene (69 g, 0.4 mol) in dry THF (300 mL) at — 78°C was added to the above mixture dropwise. After stirring for an additional 1 h at -78 0 C, the mixture was added a solution of iodine (101 g, 0.4 mol) in dry THF (400 mL) dropwise at — 78°C. The temperature was raised from — 78°C to rt during 2 h. After stirring for 18 h at rt, the mixture was concentrated in vacuo to give crude product (120 g) which was distilled under reduced pressure to afford l-bromo-3- fluoro-2-iodobenzene (1 10 g). 1 H NMR (400MHz, DMSO): 7.24-7.19 (t, IH), 7.38- 7.32 (m, IH), 7.55-7.53 (d, IH).

Step 2. 6-Brorno-2-fluoro-3'-methylbiphenyl

Pd(Ph 3 P) 4 in a 500-mL round-bottom flask under N 2 atmosphere was treated sequentially with a solution of l -bromo-3-fluoro-2-iodo-benzene (30 g, 0.1 mol) in toluene (250 mL), a solution of 2N aq Na 2 CO 3 (200 mL) and 3-methyl phcnylboronic acid in ethanol (62 mL). This mixture was heated at reflux under N 2 for 12 h, then cooled to rt. The mixture was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , evaporated and purified by column chromatography to give 6-bromo-2-fluoro-3'- methyl-biphenyl (12 g). 1 H NMR (400MHz, CD 3 OD): 7.03 (m, 2H), 7.48-7.04 (m, 4H), 7.50 (d, IH).

b) 6-Bromo-2-chloro-3 '-methyl-biphenyl

Step 1. l-bromo-3-chloro-2-iodobenzene

To a solution of diisopropylamine (76 mL, 0.4 mol) in anhydrous THF (664 niL) and n-hexane (220 mL) was added 2.5 M «-BuLi (160 mL, 0.4 mol) dropwise * at —78 0 C over 1 h. The mixture was stirred for 1 h at —78 0 C and a solution of 1 - bromo-3-chlorobenzene (76 g, 0.4 mol) in anhydrous THF (300 mL) was added dropwise at —78 0 C. After stirring for an additional 1 h at the same temperature, a solution of iodine (101 g, 0.4 mol) in anhydrous THF (400 mL) was added dropwise at —78 0 C. The temperature was raised from —78 0 C to room temperature during 2 h. After stirring for 18 h at rt, the mixture was concentrated in vacuo to give the crude product (120 g) which was distilled under reduced pressure to give l -bromo-3- fluoro-2-iodobenzene (1 15 g, 91%). 1 H NMR (400MHz, CDCl 3 ): 7.12-7.18 (t, IH), 7.35-7.41 (dd, IH), 7.49-7.54 (dd, IH); MS (E/Z): 317 (M+H + )

Step 2. 6-bromo-2-chloro-3'-methyI-biphenyl

A 500-mL round-bottom flask under N 2 atmosphere was charged sequentially with Pd(Ph 3 P) 4 , l-bromo-3-fluoro-2-iodobenzene (10 g, 0.032 mol) in toluene (80 mL), 2N aqueous sodium carbonate (55 mL) and 3-methylphenylboronic acid (5.16 g, 0.032mol) dissolved in ethanol (40 mL). This mixture was heated at reflux under N 2 for 12 h and cooled to rt. The mixture was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , and concentrated. The residue was purified by column chromatography to give 6-bromo-2-chloro-3'-methyl-biphenyl (6 g, 67%). 1 H NMR (400MHz, CD 3 OD): 6.90-7.00 (t, 2H), 7.14-7.24 (m, 2H), 7.26-7.33 (t, IH), 7.44-7.50 (d, IH), 7.58-7.62 (d, IH); MS (E/Z): 281 (M+H + )

The following biaryls were prepared from aryl halides and the boronic acids indicated using the procedures described in Preparations 27a Step 2 and 27b Step 2:

PREPARATION 28 (SV5-methoxy- 1 -(2-phenoxyphenvQ- 1 -((R)-piperidin-3-yQpentan- 1 -ol

Step 1. 2-(Phenoxy)phenyllithium

To a solution of diphenyl ether (8.60 g. 50.0 mmol) in Et 2 O (75 mL) was added n-BuLi (1.6 M in hexane, 32.8 mL, 52.5 mmol). The mixture was refluxed for 48 h, and the resulting solution of 2-(phenoxy)phenyllithium was used in the next step without any further analysis.

Step 2. (3R)-I -(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine To a solution of (R)-tert-butyl 3-(N-methoxy-N- methylcarbamoyl)piperidine-l-carboxylatc (4.40 g, 16.2 mmol) in anhydrous THF (18 mL) at -10 0 C 5 was added dropwise the solution of 2-phenoxyphenyllithium

prepared in Step 1 (80 mL, 32 mmol). The mixture was then warmed to rt, and stirred until no starting material remained (~ 30 min). The reaction was quenched with 1 N HCl (~ 30 mL) and extracted with Et 2 O (4 x 10 mL). The combined organic layers were washed with satd aq NaHCO 3 and brine, and dried over Na 2 SO 4 . The solvent was removed to give (3R)-l-(tert-butoxycarbonyl)-3-(2- phenoxybenzoyl)piperidine (7.44 g, quantitative).

Step 3. (R)-tert-Butyl 3-((S)-l-hydroxy-5-methoxy-l-(2-phenoxyphenyl)pentyl) piperidine-1-carboxylate To a solution of (3R)-I -(tert-butoxycarbonyl)-3-(2- phenoxybcnzoyl)piperidine (6.17 g, 16.2 mmol) in THF (30 mL) at -10 0 C was added dropwise 2.54 M 4-methoxybutylmagnesium chloride in THF (15 mL, 38 mmol). The resulting solution was warmed to rt slowly, and stirred over night. The reaction was quenched with satd NH 4 Cl (10 mL) and extracted with Et 2 O (4 x 10 mL). The combined organic layers were washed with water and brine. The solvent was removed and the residue was purified by flash chromatography to give (R)-lert-butyl 3-((S)-I -hydroxy-5-methoxy-l -(2-phenoxyphenyl)pentyl)piperidine-l-carboxylate (1.97 g, 26 % from (R)-tert-butyl 3-(N-methoxy-N-methylcarbarnoyl)piperidine-l- carboxylate).

Step 4. (S)-5-Methoxy-l -(2-phenoxyphenyl)-l -((R)-piperidin-3-yl)pentan-l -ol

To a solution of (R)-tert-butyl 3-((S)-l-hydroxy-5-methoxy-l-(2- phenoxyphenyl) pentyl)piperidine-l -carboxylate (1.97 g, 4.19 mmol) in MeCN (100 mL) was added 2 N aq HCl (100 mL) slowly at rt. The resulting solution was stirred at rt until no starting material remained (-16 h), basified to pH = 10 with 10 N aq NaOH, and evaporated under reduced pressure to remove MeCN. The aq layer was extracted with CH 2 Cl 2 (4 x 10 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed in vacuo to afford (S)-5- methoxy-l -(2-phenoxyphenyl)-l-((R)-piperidin-3-yl)pentan-l-ol (1.56 g, quantitative) as a free amine.

Thc following piperidines were prepared following procedures analogous to those described above:

(S)- 1 -(2-fluoro-5-(4-fluorophenoxy)phenyl)-5-methoxy-l -((R)-piperidin-3- yl)pentan-l-ol using 4,4'-difluorodiphenyl ether in Step 1.

PREPARATION 29 CS ' )-l-(2-C3-Fluorophenoxy ' )phenylV5-methoxy-l-( ' (R)-piperidin-3-yl')pentan-l-ol

Step 1. 2-(3-Fluorophenoxy)phenyllithium

To a stirred solution of l-(3-fluorophenoxy)-2-bromobenzene (1.27 g, 4.75 mmol) in THF (10 mL) at -70 0 C was added 1.7 M t-BuLi in pentane (5.6 mL, 9.50 mmol) dropwise to keep the temperature below -70 0 C. The resulting solution was stirred at -7O 0 C for 30 min, and used for the next step directly.

Step 2. (3R)- 1 -(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidin e

To a solution of (R)-tert-butyl 3-(N~methoxy-N- methylcarbamoyl)piperidine-l-carboxylate (0.65 g, 2.37 mmol) in THF (4 mL) at - 2O 0 C was added dropwise the solution of 2-(3-fluorophenoxy)phenyllithium prepared in Step 2 above. After the addition was complete, the resulting solution was allowed to warm to rt slowly, and left at rt for 1 h. The reaction was quenched with IN HCl (~6 mL), and extracted with Et 2 O (4 x 10 mL). The combined organic

layers were washed with satd aq NaHCO 3 and brine, and dried over Na 2 SO 4 . Removal of the solvent left the crude ketone (1.49 g, quantitative), which was used for next step without further purification.

Step 3. (R)-tert-Butyl 3-((S)-l-(2-(3-fluorophenoxy)phenyl)-l-hydroxy-5-methoxy pentyl)piperidine-l-carboxylate

To a solution of (3R)-l-(tert-butoxycarbonyl)-3-((3- fluorophenoxy)benzoyl)piperidine (0.95 g, 2.37 mmol) in THF (3 mL) at -20°C was added 1.45 M 4-methoxybutyl magnesium chloride in THF (3.3 mL, 4.76 mmol) dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (~20 min). The reaction was quenched with satd aq NH 4 Cl (4 mL) and extracted with Et 2 O (4 x 5 mL). The combined organic layers were washed with water and brine, and the solvent was removed in vacuo to give a crude product which was purified by flash column chromatography to afford (R)- /er/-butyl 3-((S)-I -(2-(3-fluorophenoxy)phenyl)-l -hydroxy-5- methoxypentyl)piperidine-l-carboxylate (0.50 g, 43%).

Step 4. (S)-l-(2-(3-Fluorophenoxy)phenyl)-5-methoxy-l-((R)-piperidin -3- yl)pentan-l-ol To a solution of (R)-tert-bulyl 3-((S)-l-(2-(3-fiuorophenoxy)phenyl)-l- hydroxy-5-methoxy pentyl)piperidine-l-carboxylate (0.50 g, 1.03 mmol) in MeCN (60 mL) was added 2 N aq HCl (60 mL) slowly at rt. The resulting solution was stirred at rt overnight, then basified to pH = 10 with 10 N aq NaOH. The mixture was evaporated under reduced pressure to remove MeCN. The aq layer was extracted with CH 2 Cl 2 (4 x 10 mL), and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The solvent was removed under vacuum to give (S)-l -(2-(3-fluorophenoxy)phenyl)-5-methoxy-l -((R)-piperidin-3-y])pentan-l -ol (0.40 g, quantitative) as a free amine.

The following piperidines prepared using the above procedures using the halodiphenyl ethers listed below in Step 1.

The following piperidines were prepared using the above procedures except that in Step 1 Grignard reagents were prepared from the halodiphenyl ethers listed below instead of organolithiums.

PREPARATION 30

(R)-tert-butyl 3-((S)-I -(2-(o-toIyloxy)phenyl)-l -hydroxy-5- methoxypentyl)piperidine- 1 -carboxylate

Step 1. (2-(O-tolyIoxy)phenyl)((R)- 1 -(tert-butoxycarbonyl)piperidin-3- yl)methanone

To a solution of l-(o-tolyloxy)-2-iodobenzene (40 g, 0.13 mol) in anhydrous THF (500 mL) cooled to -78°C was added dropwise 1.6 M n-BuLi in hexanes (52 mL, 0.13 mol). After stirring for 1 h at -78°C, a solution of (R)-lert-buty\ Z-(N- methoxy-N-rnethylcarbarnoyl)-piperidine-l -carboxylate (35 g, 0.13 mol) in anhydrous THF (500 mL) was added dropwise. The mixture was allowed to warm to rt and stirred overnight. Saturated aq NH 4 Cl (500 mL) was added and the mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na 2 SO 4 . Solvent removal and flash column chromatography afforded (2-(o- tolyloxy)phenyl)((R)-l-(tert-butoxycarbonyl)piperidin-3-yl)m ethanone (23 g, 45%).

Step 2. (R)-tert-butyl 3-((S)-l-(2-(o-tolyIoxy)phenyl)-l -hydroxy-5- methoxypentyl)piperidine-l -carboxylate

A 500-mL 5 three-necked flask was charged with magnesium turnings (12 g, 0.5 mol) and a small crystal of iodine. The flask was evacuated and refilled with N 2 . A solution of 1 -chloro-4-methoxybutane (50 g, 0.4 mol) in THF (200 mL) was added dropwise to the mixture. The reaction mixture was stirred at reflux for 2 h and most of magnesium was consumed. The solution of Grignard reagent was cooled to it.

A 1000 mL, three-necked flask was charged with the (2-(o- tolyloxy)phenyl)((R)-l-(tert-butoxycarbonyl)piperidin-3-yl)m cthanone (20 g, 0.05 mol) and THF (250 mL). The flask was evacuated and refilled with N 2 , the mixture was cooled with a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. After quenching with satd aq NH4CI (500 mL), the mixture was extracted with EtOAc (3 x 150 mL) and the combined organic layers were dried over Na 2 SO 4 . The solvent was removed and the crude product was purified by flash column chromatography to afford the (R)-tert-butyl 3-((S)-l -(2-(o-tolyloxy)phenyl)-l- hydroxy-5-methoxypentyl)piperidine-l-carboxylate (20 g, 83%).

Step 3. (S)-I -(2-(o-tolyloxy)phenyl)-5-methoxy-l -((R)-piperidin-3-yl)pentan-l-ol The Boc protecting group was removed using 1 : 1 5% aq HCl/MeCN ar rt.

The following piperidincs were prepared from the iododiphenyl ether indicated using procedures analogous to those described above.

PREPARATION 31 l-(3-Fluorophenoxy)2-bromobenzene -

B(OH) 2

To a stirred solution of 3-fluorophenylboronic acid (2.1O g, 15 mmol), 2- bromophenol (1.77 g, 10 mmol) and Cu(OAc) 2 (0.93 g, 5 mmol) in anhydrous CH 2 Cl 2 (25 mL) was added activated 4 A molecular sieves (~ 0.1 g), followed by anhydrous Et 3 N (3.5 mL, 25 mmol). The resulting dark green solution was stirred at rt for 48 h. The mixture was evaporated under reduced pressure and the residue was washed several times with Et 2 O (~ 150 mL). The Et 2 O solution was washed with satd aq NH 4 Cl, and 1 N aq HCl. The organic layer was evaporated and the crude product was purified by flash column chromatography to give l-(3-fluorophenoxy)- 2-bromobenzene (1.28 g 3 48 %) as clear oil.

The following halodiphenyl ethers were prepared following the procedure

PREPARATION 32

1 -CO-tolyIoxy>2-iodobenzene

To a solution of 2-(o-tolyloxy)aniline (40 g, 0.2 mol) in IN aq HCl (400 mL, 0.4 mol, 2 equiv) cooled to 0 0 C was added dropwise a solution OfNaNO 2 (18 g, 0.26 mol, 1.3 equiv) in water (520 ml). The mixture was stirred for 1 h at 0 0 C and a solution of KI (83 g, 0.5 mol, 2.5 equiv) in water (500 mL) was added dropwise with vigorous stirring. After 0.5 h the mixture was warmed to 90-100 0 C for 1 h 5 cooled to rt and washed with satd NaHSO 3 until the aqueous layer become clear. The mixture was extracted with EtOAc (3 x 200 mL) and the combined organic layers were washed with aq Na 2 S 2 O 4 and dried over Na 2 SO 4 . After evaporation of the solvent, the solution was passed through a short silica gel column to afford l-(o- tolyloxy)-2-iodobenzene (40.0 g, 65%).

PREPARATION 33

HALODIPHENYL ETHERS FROM PHENOLS AND

FLUORONITROBENZENES l-fσ-IodophenoxyV∑-chlorobenzene

Step 1. l -(2-Iodophenoxy)-2-nilrobenzene

To a solution of 2-iodophenol (1 1. 82 g, 52.7 mmol) and l-fluoro-2- nitrobenzene (5.0 g, 35.1 mmol) in DMSO (50 niL was added K 2 CO 3 (14.5 g, 105.3 mmol), followed by CsF (8.0 g, 52.7 mmol). The resulting suspension was stirred at 5O 0 C until no starting material remained (~5 h), cooled to rt and partitioned between water (50 mL) and CH 2 Cl 2 (50 mL). The water layer was separated and extracted with CH 2 Cl 2 (2 x 10 mL). The combined organic layers were washed with 1 aq N NaOH (10 mL) and brine, and dried over Na 2 SO 4 . Solvent was removed under vacuum to give l-(2-iodophenoxy)-2-nitrobenzene (1 1.2 g, 93%) as an oil, which was used for next step without purification.

Step 2. 2-(2-lodophenoxy)benzenamine

A solution of 1 -(2-iodophenoxy)-2-nitrobenzene (9.60 g, 28.1 mmol) and SnCl.2H 2 O (13.0 g, 56.0 mmol) in ethanol (25 mL) and water (5 mL) was rcfluxed until no starting material remained (~ 1 h). The ethanol was removed in vacuo and the aq layer was basified to pH>10 and extracted with CH 2 Cl 2 (4 x 10 mL). The combined organic layers were dried over Na 2 SO 4 , and the solvent was removed to give a crude 2-(2-Iodophenoxy)benzenamine (8.57 g, 98%), which was used for the next step without purification.

Step 3. l -(2-Iodophenoxy)-2-chlorobenzene

λ solution of crude 2-(2-iodophenoxy)benzenamine (8.57 g, 27.6 mmol) in MeCN (60 mL) was cooled to 0 0 C and treated with HBF 4 (54 wt% in Et 2 O, 4.93 mL, 35.9 mmol). The reaction mixture was stirred at O 0 C for 5 min and of t-BuONO (4.10 g, 35.9 mmol) was added dropwise. The resulting mixture was stirred at O 0 C for 10 min, cooled to -20 0 C, and added to a solution of CuCl (41 g, 414.1 mmol) and CuCl 2 (70 g, 414.1 mmol) in water (500 mL) at O 0 C. The mixture was stirred vigorously at 25 0 C for 2 h, and partitioned between EtOAc and water. The water layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under vacuum. Flash column chromatography gave l -(2-iodophenoxy)-2-chlorobenzene (5.35 g, 58 %).

The following halodiphenyl ethers were prepared following procedures analogous to those described above using the starting materials and reagents indicated:

PREPARATION 34

(R)-I -O-Chloro^-fluorophenvπ-S-methoxy-l-rrRVmorpholin^-vπpenta n-l-ol

Step 1. (R)-2-(Benzyloxymethyl)morphoIine

To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H 2 O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition, the reaction mixture was stirred at 40 0 C for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol) then toluene (70 mL) and stirred at 65 0 C overnight. The mixture was cooled, diluted with toluene (27 mL) and H 2 O (92

mL). The toluene layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethy])morpholine (-14 g), which was used without purification. MS m/z 208 (M+H + ).

Step 2. (R)-tert-ButyI 2-(benzyloxymethyl)morpholine-4-carboxylate

To a solution of crude (R)-2-(benzyloxymethyl)morpholine (~14 g) in acetone (100 mL) and H 2 O (30 mL) at O 0 C, was added K 2 CO 3 (25.2 g, 182.7 ramol), followed by (Boc) 2 O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (~30 min). Acetone was removed under vacuum and the aqueous solution was extracted with CH 2 Cl 2 (4 x 10 mL). The combined organic layers were washed with H 2 O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)- •tert-butyl 2-(benzyloxymelhyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1 H NMR (400MHz 3 CDCl 3 ): 7.34 (m, 5 H), 4.56 (s, 2 H), 3.88 (d, 2 H), 3.82 (br, 1 H) 5 3.40 (m, 1 H), 3.48 (m, 3 H) 5 2.94 (m, 1 H), 2.76 (m, 1 H), 1.44 (s, 9 H); MS m/z 330 (M+Na + ).

Step 3. (R)-tert- Butyl 2-(hydroxymethyl)morpholine-4-carboxylate To a solution of (K)-lert-buϊy\ 2-(benzyloxymethyl)morpholine-4- carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H 2 balloon overnight. After filtration, the solvent was removed under vacuum and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99 %) as a clear oil. 1 H NMR (400MHz, CDCl 3 ): 3.88 (d, 2 H) 5 3.82 (br, 1 H) 3 3.64 (d, 1 H) 3 3.56 (m 3 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.90 (br, 1 H), 1.44 (s 3 9 H); MS m/z 218 (M+H + ).

Step 4. (R)-4-(tert-ButoxycarbonyI)morpholine-2-carboxylic acid Satd aq NaHCO 3 ( 15 mL) was added to a solution of (R)-/er/-butyl 2-

(hydroxymethyl)-rnorphoIine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at O 0 C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g3 10.0 mmol) was then

added slowly within 20 min at O 0 C. After addition the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na 2 CO 3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5 x 10 mL). These EtOAc extracts were combined, dried over Na 2 SO 4 and concentrated to give (R)-4-(/e/7-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92 %) as a white solid. 1 H NMR (400MHz, CDCl 3 ): 4.20 (br, 1 H), 4.12 (d, 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H + ).

Step 5. (R)-ter(-Buty\ 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate

To a solution of (R)-4-(/er/-butoxycarbonyl)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at O 0 C were added N,O- dimethylhydroxylamine hydrochloride (1.36 g, 13.62 mmol), DIEA (3.9 mL, 22.7 mmol), HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). The resulting solution was warmed to rt and stirred until no starting material remained (~ 2 h). The mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layers weie washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3 x 10 mL), water (2 x 10 mL) and brine (10 mL), and dried over Na 2 SO 4 . The solvent was removed under vacuum to give (R)-/-butyl 2-

(methoxy(methyl)carbamoyl)morphoIine-4-carboxyIate (1.40 g, quant.), which was used for the next step without further purification; 1 H NMR (400MHz, CDCl 3 ) δ: 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na + ).

Step 6. (R)-terl-Buty\ 2-(5-methoxypentanoyl)morpholine-4-carboxylate

To a solution of(R.)-tert-bυty\ 2-(methoxy(rnethyl)carbamoyl)morpholine-4- carboxylate (1.37 g, 5.0 mmol) in THF (10 mL) at -20 u C, there was added (4- methoxybutyl)magnesium chloride in THF (1.47 M 5 10.2 mL, 15,0 mmol) dropwisc such that the temperature remained below -2O 0 C. After addition, the resulting solution was warmed to rt, and quenched with 1 N aq HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with ether (3 x 5 mL). The

combined organic layers were washed with satd aq NaHCO 3 (10 mL) and brine (5 mL), and dried over Na 2 SO 4 . The solvent was then removed in vacuo to give (R)- /er/-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.41 g, 93 %), which was used for the next step without purification; MS m/s 324 (M+Na + ).

Step 7. (R)-/er/-Butyl 2-((R)-l-(3-chloro-2-fluorophenyl)-l-hydroxy-5- methoxypentyl)-morpholine-4-carboxylate

To a solution of l-bromo-3-chloro-2-fluorobenzene (1.42 g, 6.77 mmol) in THF (8 mL) at -7O 0 C, was added /-BuLi in pentane (1.7 M, 7.96 mL, 13.5 mmol) dropwise such that the temperature remained below -7O 0 C. The resulting solution (A) was stirred at the same temperature for another 30 min, and used directly in the next step.

To a solution of (R)-/e/*/-butyi 2-(5-methoxypentanoyl)morphoIine-4- carboxylate (0.64 g, 2.12 mmol) in toluene (5 mL) at -2O 0 C, solution A prepared above was added dropwise. The resulting solution was allowed to warm to rt slowly, and kept at same temperature for 1 h. The reaction was quenched with satd aq NH 4 Cl (8 mL) and extracted with diethyl ether (4 x 10 mL). The combined organic layers were washed with water and brine, and solvent was removed in vacuo to give a crude product, which was purified by flash column chromatography to afford (R)-tert-butyl 2-((R)-l-(3-chloro-2-fluorophenyl)-l -hydroxy-5- methoxypentyl)morpholine-4-carboxylate (0.40 g, 43%). 1 H NMR (400MHz, CDCl 3 ) δ: 7.44 (dd, 1 H), 7.32 (dd, 1 H), 7.04 (dd, 1 H), 4.18 (br, 1 H) 3 3.80 (m, 3 H) 3 3.42 (dd, 1 H), 3.24 (st, 5 H), 3.04-2.80 (m, 3 H), 2.04 (rn, 1 H), 1.68 (m, 1 H), 1.44 (s, 9 H), 1.30 (m, 3 H) 5 0.86 (m, 1 H); MS m/z 454 (M+Na + ).

- Step 8. (R)- 1 -(3-Chloro-2-fluorophenyl)-5-methoxy-l -((R)-morpholin-2-yl)pentan- l-ol

To a solution of (R)-terf-butyl 2-((R)-l-(3-chloro-2-fluorophenyl)-l- hydroxy-5-methoxypentyl)morpholine-4-carboxylate (0.38 g, 0.88 mmol) in MeCN (50 mL), 2 N aq HCl (50 mL) was added slowly at rt. The resulting solution was stirred at rt overnight, basified to pH = 10 with 10 N aq NaOH, and evaporated under reduced pressure to remove MeCN. The aqueous layer was extracted with

CH 2 CIz (4 x 5 mL). The combined organic layers were washed with brine and dried OVCr Na 2 SO 4 . The solvent was removed in vacuo to give (R)-l-(3-chloro-2- fluorophenyl)-5-methoxy-l-((R)-morpholin-2-yl)pentan-l-ol (0.27 g, 93%) as a free amine. The crude product was used for next step without purification; MS m/z 332 (M+H + ).

PREPARATION 35 f±VfRSVl-π-chlorophenylVS-methoxy-l-frRSVmorpholin-σ-vπp entan-l -ol

Step 1. (±)-/er/-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxyIate

To a stirred solution of (±)-4-(/er/-butoxycarbonyl)morpholine-2-carboxylic acid (1.51 g, 6.53 mmol), N,O-dimethylhydroxylamine hydrochloride (0.83 g, 8.49 mmol) and J-Pr 2 NEt (3.1 mL, 17.6 mmol) in CH 2 Cl 2 (30 mL) was added solid HATU (3.01 g 5 7.85 mmol). The mixture was stirred at rt for 3 d, diluted with ether (175 mL), washed with 5% aq HCl (2 x 50 mL) and satd aq NaHCO3 (50 mL) and dried over MgSO 4 . Removal of the solvent left (±)-/<*r/-butyl 2- (methoxy(melhyl)carbamoyl)rnorpholine-4~carboxylate (1.73 g, 96%) as an oil.

Step 2. (±)-/e/7-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxyIate

A stirred solution of (±)-/er/-butyl 2-

(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.73 g, 6.4 mmol) in dry THF (40 mL) was cooled in an ice-salt bath and 1.34 M 4-methoxybutylmagnesium

chloride in THF (10 mL, 1.34 mmol) was added dropwise over 3 min. The cooling bath was allowed to expire and the mixture was stirred at rt for 6 h, poured into ice cold 3% aq HCl (100 mL) and extracted with ether (2 x 100 mL). The combined ether extracts were washed with satd aq NaHCCh (35 mL), dried over MgSO 4 and concentrated to afford (±)-ter(-buty\ 2-(5-methoxypentanoyi)morpholine-4- carboxylate (1.78 g, 93%) as an oil.

Step 3. (±)-(R)-/ert-butyl 2-((R)-l-(3-chlorophenyl)-l -hydroxy-5- methoxypentyl)morpholine-4-carboxylate A stirred solution of (±)-/er/~butyl 2-(5-methoxypentanoyl)morpholine-4- carboxylate (258 mg, 0.86 mmol) in CH 2 Cl 2 (5 mL) was cooled to -70 C and 0.5 M 3-chlorophenylmagnesium bromide in THF (4 mL, 2.0 mmol) was added dropwise over 5 min. The cooling bath was allowed to expire. After 1.5 h the mixture had reached rt and was poured into satd aq NaHCO 3 (50 mL). The mixture was extracted with ether (2 x 50 mL). The combined ether extracts were washed with brine (10 mL), dried over MgSO 4 and concentrated to afford an oil (398 mg). This material was chromatographed on a 12-g silica cartridge eluted with a gradient of 0-100% EtOAc in hexanes to afford (±)-(R)-/<?/7-butyl 2-((R)-I -(3-chlorophenyl)-l -hydroxy- 5-rnethoxypentyl)morpholine-4-carboxylate (274 mg, 76%).

Step 4. (±)-(R)-l-(3-chlorophenyl)-5-methoxy-l-((R)-morpholin-2-yl) pentan-l -ol

(±)-(R)-ter/-butyl 2-((R)-l-(3-chlorophenyl)-l-hydroxy-5- methoxypentyl)morpholine-4-carboxylate (274 mg, 0.66 mmol) was dissolved in MeCN (10 mL) and 5% aq HCl (5 mL) was added. The mixture was stirred at rt for 2 d. Solid K 2 CO 3 (~1 g) was added to the mixture, followed by water (25 mL). The mixture was extracted with ether (2 x 50 mL). The combined ether extracts were washed with brine (10 mL), dried over MgSO 4 and concentrated to afford a white solid (0.15 g). This material was purified by prep HPLC to afford the TFA salt of (±)-(R)- l -(3-chlorophenyl)-5-methoxy-l -((R)-morpholin-2-yl)pentan-l-ol (163 mg, 55%) as a syrup.

The following morpholines were prepared following procedures analogous to those described above:

(RS)-l-(3-chloro-2-fluorophenyl)-5-methoxy-l-((RS)-morpho lin-2-yl)pentan-l -ol - ol using 2-fluoro-3-chlorophenyllithium and THF as solvent in Step 3. (RS)-l-(benzo[b]thiophen-7-yl)-5-methoxy-l-((RS)-morpholin-2 -yl)pentan-l-ol using 7-Iithiobenzothiophene, generated from 7-bromobenzothiophene and n-BuLi, and ether as solvent in Step 3.

(R)-l-(3-chloro-2-fluorophenyl)-5-mcthoxy-l-((R)-morphoIi n-2-yl)pentan-l -oI using (R)-4-(^er/-butoxycarbonyl)morpholine-2-carboxylic acid in Step 1 and 2- fluoro-3-chlorophenyllithium and THF as solvent in Step 3.

PREPARATION 36 fRVl-( ' 6-Fluoro-3'-mcthylbiphenyl-2-yl)-S-methoxy-l-( ' ( ' R)-morpholin-2-yπpentan- l-ol

TEMPO NaBr ' NaHCO 3 + acetone

Step 1. (R)-2-(Benzy]oxymethyl)moφholine

To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H 2 O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition was complete, the reaction mixture was stirred at 40 0 C for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol), followed by toluene (70 mL), and stirred at 65°C overnight. The mixture was cooled, diluted with toluene (27 mL) and H 2 O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 50 mL). The combined organic layers

were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (~14 g), which was used without purification. MS m/z 208 (M+H + ).

Step 2. (R)-/<?/7-ButyI 2-(benzyloxymethyl)morpholine-4-carboxylate To a solution of crude (R)-2-(benzyloxymethyl)morpholine (~14 g) in acetone (100 mL) and H 2 O (30 mL) at 0 0 C, there was added K 2 CO 3 (25.2 g, 182.7 mmol), followed by (BoC) 2 O (14.6 g, 67.0 mmol). The resulting solution was warmed to rl, and stirred until no starting material remained (~30 min). Acetone was removed under vacuum, and the aqueous solution was extracted with CH 2 Cl 2 (4 x 10 mL). The combined organic layers were washed with H 2 O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)-/£τ7-butyI 2-(benzyloxymelhyl)rnorpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1 H NMR (400MHz 5 CDCl 3 ): 7.34 (m, 5 H) 3 4.56 (s, 2 H) 5 3.88 (d, 2 H), 3.82 (br, 1 H), 3.40 (m, 1 H) 5 3.48 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.44 (s, 9 H); MS m/z 330 (M+Na + ).

Step 3. (R)-/er/-Butyl 2-(hydroxymethyl)rnorpholine-4-carboxylate

To a solution of (R)-/er/-butyl 2-(benzyIoxymethyl)morpholine-4- carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g) 5 and the resulting mixture was stirred at rt under a H 2 balloon overnight. After filtration, the solvent was removed under vacuum, and the residue was purified by flash column chromatography to give (R)-ter (-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99 %) as a clear oil. 1 H NMR (400MHz, CDCl 3 ): 3.88 (d, 2 H), 3.82 (br, 1 H), 3.64 (d, 1 H), 3.56 (m, 3 H), 2.94 (m, 1 H) 5 2.76 (m, 1 H) 5 1.90 (br, 1 H) 5 1.44 (s, 9 H); MS m/z 218 (M+H + ).

Step 4. (R)-4-(/e/Y-Butoxycarbonyl)morpholine-2-carboxyiic acid

Satd aq NaHCO 3 (15 mL) was added to a solution of (R)-ter/-butyl 2- (hydroxymethyl)-morpholine~4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at 0 0 C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at 0 0 C. After addition, the mixture was warmed to rt

and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na 2 CO 3 (15 mL). The aqueous solution was washed with ElOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5 x 10 mL). The combined organic layers were dried over Na 2 SO -I and the solvent was removed to give (R)-4-(/er/-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92 %) as a white solid. 1 H NMR (400MHz, CDCl 3 ): 4.20 (br, 1 H), 4.12 (d, 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H) 5 3.62 (m, 1 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H + ).

Step 5. (R)-/er/-Butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate

To a solution of (R)-4-(/er/-butoxycarbonyI)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at 0°C C, was added DIEA (3.9 mL, 22.7 mmol), followed by HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). MeONMHMe. HCl (0.48 g, 4.92 mmol) was added and the resulting solution was warmed to rt and stirred until no starling material remained (~ 2 h). The mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3 x 10 mL), water (2 x 10 mL) and brine (10 mL), and dried over Na 2 SO 4 . The solvent was removed under vacuum to give (R)-/er/-butyl 2- (methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used without further purification. 1 H NMR (400MHz, CDCl 3 ): 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H) 3 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na + ).

Step 6. (R)-/ert-Butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate

To a stirred solution of (R)-/e/Y-butyl 2-

(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.37 g, 5.0 mmol) in THF (10 mL) at -20°C, there was added 1.47 M 4-methoxybutylmagnesium chloride in THF (10.2 mL, 15.0 mmol) dropwise to keep the temperature below -20 0 C. After addition, the resulting solution was warmed to rt and quenched with 1 N aq HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with ether (3 x 5 mL). Combined organic layers were washed with satd aq NaHCO 3 (10

mL) and brine (5 mL) and dried over Na 2 SO 4 . Removal of the solvent under vacuum gave (R)-/e/*/-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.41 g, 93 %), which was used without purification. MS m/s 324 (M-HNa + ).

Step 7. (R)-tert-Butyl 2-((R)-I -(6-fluoro-3'-methylbiphenyI-2-yl)-l -hydroxy-5- methoxypentyl)-morpholine-4-carboxylate

To a solution of 2-brorno-6-fluoro-3'-rnethylbiphenyl (1.90 g, 7.17 mmol) in ether (8 mL) at -78°C, there was added /-BuLi in pentane (1 .70 M, 8.43 mL, 14.33 mmol) dropwise to keep the temperature below -70°C. The resulting solution was stirred at -78°C.

To a solution of (R)-/er/-butyl 2-(5-methoxypentanoyl)morpholine-4- carboxylate (0.68 g, 2.26 mmol) in toluene (8 mL) at -20 0 C there was added the above lithium reagent dropwise to keep the solution temperature below -20 0 C. After addition, the resulting mixture was warmed to rt slowly, and quenched with saturated NH 4 Cl (8 mL). The organic layer was separated, and aqueous layer was extracted with ether (3 x 5 mL). Combined organic layers were washed with water (10 mL), concentrated, and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-((R)-l-(6-fluoro-3'-methylbiphenyl-2-yl)-l- hydroxy-5-methoxypentyl)-morpholine-4-carboxylate (0.48 g, 44 %) as a foam. 1 H NMR (400MHz, CDCl 3 ): 7.40 (m, 1 H), 7.32 (m, 2 H), 7.20 (d, 1 H), 7.04 (m, 3 H), 3.84 (m, 1 H), 3.78 (m, 2 H), 3.40-3.24 (ms, 7 H), 2.82 (s, 3 H), 1.70-1.20 (m, 5 H), 1.44 (s, 9 H), 0.94 (m, 1 H); MS m/z 510 (M+Na + ).

Step 8. (R)-I -(6-Fluoro-3'-methyIbiphenyl-2-yl)-5-methoxy-l-((R)-morpholi n-2- yl)-pentan-l -ol

To a solution of (R)-/er/-butyl 2-((R)-l -(6-fluoro-3'-methyIbiphenyl-2-yl)-l- hydroxy-5-methoxypentyl)morpholine-4-carboxylate (0.46 g, 0.96 mmol) in acetonitrile (50 mL) was added 2 N aq HCl (50 mL). The resulting solution was stirred at rt overnight and basified with 10 N aq NaOH to pH 10. Acetonitrile was removed under vacuum, and the aqueous residue was extracted with CH 2 Cb (4 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over

Na 2 SO 4 , and concentrated to give (R)-l-(6-fluoro-3'-methyIbiphenyI-2-yl)-5- methoxy-l-((R)-morpholin-2-yl)pentan-l-ol (0.38, quant.). MS m/z 388 (M+H + ).

The following morpholines were prepared using procedures analogous to those described above: (R)-I -(6-chloro-3'-methylbiphenyl-2-yl)-5-methoxy-l-((R)-morpholi n-2- yl)pentan-l-ol using 2-bromo-6-chloro-3'-methylbiphenyl in Step 7.

(R)-l-(6-fluoro-3'-(trifluoromethoxy)biphenyl-2-yl)-5-met hoxy-l-((R)- morpholin-2-yl)pentan- 1 -ol using 2-bromo-6-fluoro-3'-(trifluoromethoxy)biphenyl in Step 7. (R)-5-methoxy-l -(3-methoxy-3'-methylbiphenyl-2-yI)-l -((R)-morpholin-2- yl)pentan-l -ol using 2-bromo-3-methoxy-3'-methylbiphenyl in Step 7.

(R)-I -(3'-cthyl-6-fluorobiphenyl-2-yl)-5-mcthoxy-l -((R)-morpho]in-2- yl)pcntan-l -ol using 2-bromo-3'-ethyl-6-fluorobiphcnyl in Step 7.

(R)-l-(6-fluoro-3'-mcthoxybiphenyl-2-yl)-5-methoxy-l -((R)-morpholin-2- yl)pcntan-l-ol using 2-bromo-6-fluoro-3'-methoxybiphenyl in Step 7.

(R)-I -(3'-chloro-6-fluorobiphenyl-2-yl)-5-methoxy-l -((R)-morpholin-2- yl)pentan- 1 -ol using 2-bromo-3'-chloro-6-fluorobiphenyl in Step 7.

(R)-l-(3'-cyclopropyl-6-fluorobiphenyl-2-yl)-5-methoxy-l- ((R)-morpholin- 2-yl)pentan-l-ol using 2-bromo-3'-cyclopropyl-6-fluorobiphenyl in Step 7. (R)-I -(6-chloro-3'-ethylbiphenyl-2-yl)-5-methoxy-l-((R)-morpholin -2- yl)pentan-l-ol using 2-bromo-6-chloro-3'-ethylbiphenyl in Step 7.

(R)- 1 -(6-chloro-3',4'-dimethylbiphenyl-2-yl)-5-methoxy- 1 -((R)-morpholin-2- yl)pentan-l -ol using 2-bromo-6-chloro-3 l 3 4'-dimethylbiphenyI in Step 7.

(R)-I -(3'-ethoxy-6-fluorobiphenyl-2-yl)-5-methoxy-l-((R)-morpholi n-2- yl)pentan-l -ol using 2-bromo-3'-ethoxy-6-fluorobiphenyl in Step 7.

(R)-I -(6-fluoro-3-methoxy-3'-methylbiphenyI-2-yl)-5-methoxy-l -((R)- morpholin-2-yI)pentan-l -ol using 2-bromo-6-fluoro-3-methoxy-3'-methyIbiphenyI in Step 7.

(R)-l-(6-chloro-3'-methoxybiphenyl-2-yl)-5-methoxy-l -((R)-morpholin-2- yl)pentan-l-ol using 2-bromo-6-chloro-3'-methoxybiphenyI in Step 7.

(R)-l -(6-fluoro-3'-(mcthylthio)biphcnyl-2-yl)-5-methoxy-l-((R)-mo rpholin- 2-yl)pentan-l-ol using 2'-bromo-6'-fluoro-3-(methylthio)biphenyl in Step 7.

1 -(3',6-dichlorobiphenyl-2-yl)-5-methoxy-l -((R)-morpholin-2-yl)pentan-l -ol using 2-bromo-3',6-dichlorobiphenyl in Step 7.

(R)-l-(6-chloro-3'-isopropylbiphenyl-2-yl)-5-methoxy-l-(( R)-morpholin-2- yl)pentan-l-ol using 2-bromo-6-chloro-3'-isopropylbiphenyl in Step 7.

(R)-l -(6-chloro-3'-(methylthio)biphenyl-2-yl)-5-methoxy-l -((R)-morpholin- 2-yl)pentan-l-ol using (2'-bromo-6'-chlorobiphenyl-3-yl)(methyl)sulfane in Step 7.

(R)- 1 -(6-fluoro-3 '-(trifluoromethyl)bipheny l-2-yl)-5-methoxy- 1 -((R)- morpholin-2-yl)pentan-l-ol using 2-bromo-6-fluoro-3'-(trifluoromethyl)biphenyl in Step 7.

(R)-5-methoxy-l-((R)-morpholin-2-yl)-l-(2-(o-toIyloxy)phe nyl)pentan-l -ol using 1 -(o-tolyloxy)-2-iodobenzene in Step 7.

The following morpholines were prepared starting in Step 5 with racemic 4- (/er/-butoxycarbonyl)morpholine-2-carboxylic acid:

(RS)-5-methoxy-l -((RS)-morpholin-2-yl)-l-(2-(o-tolyloxy)phenyl)pentan-l- ol

(RS)- 1 -(6-chloro-3'-methylbiphenyl-2-yl)-5-methoxy- 1 -((RS)-morpholin-2- yl)pentan-l -ol.

PREPARATION 37 (2S)-2-π-( " 6-fluoro-3'-methylbiphenyl-2-vπ-5-methoxypentvnmorpholine

Step 1. (S)-tert-butyl 2-(l-(6-fluoro-3'-methylbiphenyl-2-yl)-5-methoxypent-l- enyl)moφholine-4-carboxyIate A mixture of (R)-tert-butyl 2-((R)-l-(6-fluoro-3'-methylbiphenyI-2-yI)-l- hydroxy-5-methoxypentyl)morpholine-4-carboxylate ( 188 mg, 0.39 mmol) and Burgess' reagent (186 mg, 0.78 mmol) in toluene (3 mL) was heated to reflux under a N 2 atmosphere for 2 h, then cooled to rt and diluted with EtOAc, washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and evaporated. The residue was purified by flash chromatography to give (S)-tert-butyl 2-(l-(6-fluoro-3'-methylbiphenyl-2-yl)- 5-methoxypent-l-enyl)morpholine-4-carboxylate (133 mg, 73%). MS m/z 470 (M+H) + .

Step 2. (2S)-tcrt-butyl 2-(l-(6-fluoro-3'-methylbiphenyl-2-yl)-5- methoxypentyl)morpholine-4-carboxylate

(S)-tert-butyl 2-(l-(6-fluoro-3'-methylbiphenyl-2-yl)-5-methoxypent-l- enyl)morpholine-4-carboxylate (133 mg, 0.28 mmol) was dissolved in methanol and hydrogenated under 50 psi of hydrogen in the presence of 10% Pd(OH) 2 /C as catalyst for 48 h. The reaction mixture was filtered and evaporated to give (2S)-tert- butyl 2-(l -(6-fiuoro-3'-methylbiphenyl-2-yl)-5-methoxypentyl)morpholin e-4- carboxylate in nearly quantitative yield. MS m/z 470 (M+H) + .

Step 3. (2S)-2-(l-(6-fluoro-3'-methylbiphenyl-2-yl)-5-methoxypentyl) morpholine (2S)-tert-butyl 2-(l -(6-fluoro-3'-methylbiphenyl-2-yl)-5- methoxypentyl)morpholine-4-carboxylate from Step 2 was dissolved in 1 M HCl in MeOH and stirred at 50°C for 10 min, the solvent was removed under reduced pressure to give (2S)-2-(l-(6-fluoro-3'-methylbiphenyl-2-yl)-5- methoxypentyl)morpholine as its HCl salt in quantitative yield. MS m/z 494 (M+Na) + .

PREPARATION 38

N-(2~((S)-(6-fluoro-3'-mcthylbiphenyl-2-yl)((R)-morpholin -2- yl)methoxy)ethyl)acetamide

Step 1. (R)-tert-butyl 2-((S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3'-methylbiphenyl-2- yl)methyl)morpholine-4-carboxylate

To a slurry of 60% NaH in oil (0.75 g, 18.7 mmol) in THF (30 mL) was added a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3'-methylbiphenyl-2- yl)(hydroxy)methyl)morpholine-4-carboxylatc (2.5 g, 6.23 mmol) in THF (20 mL) dropwisc at and then the reaction mixture was stirred for about Ih at it. A solution of ethyl 3-bromopropionate (1.55 g, 9.35 mmol) in THF (20 mL) was added dropwise while the temperature was maintained at -15 to -5 0 C. The mixture was allowed to warm slowly to rt and stirred for ~2 h until the reaction was complete by tic analysis. The reaction was cooled in an ice bath, quenched with satd aq NH 4 Cl (120 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over NaSO 4 , concentrated and purified by flash chromatography to afford (R)- tert-butyl 2-((S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3'-methylbiphenyl-2- yl)methyl)morpholine-4-carboxylate (570 mg, 19 %). MS (E/Z): 488 (M+H + )

Step 2. (R)-tert-butyl 2-((S)-(6-fluoro-3'-methylbiphenyl-2-yl)(2- hydroxyethoxy)methyl)morpholine-4-carboxylate

To a solution of (R)-tert-butyl 2-((S)-(2-ethoxy-2-oxoethoxy)(6-fiuoro-3'- methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (570 mg, 1.17 mmol) in CH 3 OH (20 mL) at rt, NaBH 4 (355 mg, 9.36 mmol) was added in portions. The mixture was stirred for~0.5 h at rt and then evaporated. The residue was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO 4 and evaporated to give semi-crude (R)-tert-butyl 2- ((S)-(6-fluoro-3'-methylbiphenyl-2-yl)(2-hydroxyethoxy)methy l)moφholine-4- carboxylate (498 mg, 96 %), which was used in the next step reaction without further purification. MS (E/Z): 446 (M+H + )

Step 3. (R)-tert-butyl 2-((S)-(6-fluoro-3'-methyIbipheny]-2-yl)(2- (methylsulfonyloxy)ethoxy)methyl)moφholine-4-carboxylate

To a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3'-methylbiphenyl-2-yl)(2- hydroxyethoxy)methyl)morpholine-4-carboxylate (498 mg, 1.12 mmol) in dry CH 2 Cl 2 (15 mL) was added Et 3 N (472 mg, 4.68 mmol) at ~0 to -5 0 C. A solution of MsCl (267 mg, 2.34 mmol) in dry CH 2 Cl 2 (10 mL) was added dropwise at the same temperature. The mixture was allowed to warm to rt gradually. Tie showed the stating material had disappeared. Water (10 mL) was added and the aqueous layer was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO 3 and brine, dried over Na 2 SO 4 , filtered and concentrated to afford crude (R)-tert-butyl 2-((S)-(6-fluoro-3'-methylbiphenyJ-2- yl)(2-(methylsulfonyloxy)ethoxy)methyl)moφholine-4-carboxy! ate (554 mg, 95 %). which was used in the next step without further purification. MS (E/Z): 524 (M+H + )

Step 4. (R)-tert-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3'-methylbiphcnyl-2- yl)methyl)morpholine-4-carboxylate

To a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3'-methylbiphenyl-2-yl)(2- (methylsulfonyloxy)ethoxy)methyl)morpholine-4-carboxylate (554 mg, 1.0 mmol) in anhydrous DMF (18 mL), solid NaN 3 (230 mg, 3.51 mmol) was added and the reaction mixture was heated to 70 0 C for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (1 10 mL), and water (30 ml). The organic phase was washed with water (3 x 30 mL), dried over Na 2 SO 4 and evaporated to

give (R)-tert-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3'-methylbiphenyl-2- yl)methyl)morpholine-4-carboxylate (423 mg, 90%). MS (EJZ): 471 (M+H + )

Step 5. (R)-tert-butyl 2-((S)-(2-aminoethoxy)(6-fluoro-3 l -methylbiphenyl-2- yI)methyl)morpholinc-4-carboxylate

To a solution of (R)-tert-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3'- methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (423 mg, 0.9 mmol) in EtOAc (20 mL) was added wetted Pd/C (42 mg) and the mixture was hydrogenated overnight using a balloon of hydrogen. The mixture was filtered through a pad of Celite and the solvent was removed to give (R)-tcrt-butyl 2-((S)-(2-aminoethoxy)(6- fluoro-3'-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylat e (430 mg, 100%). MS (E/Z): 445 (M+H + )

Step 6. (R)-tert-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3'-methylbiphenyl-2- yl)methyl)morpholine-4-carboxylate

To a round-bottom flask were added (R)-tert-butyl 2-((S)-(2- aminoethoxy)(6-fluoro-3'-methylbiphenyl-2-yl)mcthyl)morpholi ne-4-carboxylate (280 mg, 0.63 mmol), tricthylamine (0.19 mL, 1.89 mmol) and anhydrous CH 2 Cl 2 (15 mL). The mixture was cooled in an ice bath and a solution of acetyl chloride (49.2 mg, 0.045 mL, 0.63 mmol) was added. The reaction mixture was allowed to waπn slowly to rt and stirred until the reaction was complete (ca 1—2 h). The solvent was removed by evaporation, and the residue was purified by preparative tic to give (R)-tert-butyl 2-((S)-(2-acctamidoethoxy)(6-fluoro-3'-methylbiphenyl-2- yl)methyl)morpholinc-4-carboxylate (202 mg, 66%). 1 H NMR (300 MHz 3 CDCl 3 ): δ=l .45 (s, 9 H), 1.93 (s, 3 H) 5 2.38 (s, 3 H), 2.87-3.2 (m, 6 H), 3.32-3.92 (m, 5 H), 4.28 (d, 1 H), 7.01-7.25 (m, 3 H), 7.28-7.37 (m, 4 H) 3 9.41-9.54 (s, IH). MS (E/Z): 487 (M+H + )

Step 7. N-(2-((S)-(6-fluoro-3 I -methyIbiphenyl-2-yl)((R)-morpholin-2- yl)methoxy)ethyl)acetamide

(R)-lert-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3'-methylbiphenyl-2- y ] )mcthyl)morpholine-4-carboxylate (202 mg, 0.42 mmol) was dissolved in 20%

TFA in CH 2 CI 2 (8 mL) and stirred for about Ih at rt. The mixture was neutralized with satd aq NaHCU 3 and the product was extracted with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give N-(2-((S)-(6-fluoro-3'-methylbiphenyl-2-yl)((R)-mθφholin-2 - yl)melhoxy)ethyl)acetamide (130 mg, 82 %). 1 H NMR (300 MHz 5 CDCl 3 ): δ=l .98 (s, 3 H), 2.39 (s, 3 H), 2.90-3.3 (m, 6 H) 9 3.31-3.41 (m, 2 H), 3.6-4.0 (m, 3 H), 4.33 (d, 1 H), 6.56-6.57 (s, IH), 6.97-7.14 (m, 3 H), 7.27-7.40 (m, 4 H), 9.40-9.55 (s, IH). MS (E/Z): 387 (M+H + ).

The following compounds were prepared using procedures analogous to those described above:

methyl 2-((S)-(6-fluoro-3'-methylbiphenyl-2-yl)((R)-morpholin-2- yl)methoxy)ethylcarbamate using methyl chloroformate in place of acetyl chloride in Step 6.

EXAMPLE 1 methyl 2-((R)-((R)-1 -((2S,3S)-5-(butylamino)-l -cyclohexy!-3-hydroxy-5- oxopentan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)metho xy)ethylcarbamate

Step 1. tert-Butyl (2S,3S)-5-(butylamino)-l-cyclohexyl-3-hydroxy-5-oxopentan-2- yl carbamate

To a stirred solution of Boc-cyclohexylstatine (345 mg, 1.1 mmol), n- butylamine (0.22 mL, 2.2 mmol) and DIEA (0.39 mmol, 2.2 mmol) in CH 2 Cl 2 (10 mL) was added solid HATU (630 mg, 1.65 mmol). The mixture was stirred at rt for 18 h, diluted with ether (90 mL), washed with 5 aq HCl (20 mL), satd aq NaHCO 3

(20 mL) and brine (20 mL) and dried over MgSO 4 . Removal of the solvent left tert- butyl (2S,3S)-5-(butylamino)-l-cyclohexyl-3-hydroxy-5-oxopentan-2- ylcarbamate (394 mg, 97%) as a white solid which was used without purification.

Step 2. (3S,4S)-4-Amino-N-butyl-5-cyclohexyl-3-hydroxypentanamide tert-butyl (2S,3S)-5-(butylamino)-l-cyclohexyl-3-hydroxy-5-oxopentan-2- ylcarbamate (394 mg, 1.1 mmol) was dissolved in 4M HCl in dioxane (5 mL, 200 mmoland stirred at rt for 4 h. Removal of the solvent left a sticky solid (344 mg). This material was taken up in 10% aq K2CO3 (20 mL) and extracted with CH2C12 (4 x 30 mL). The combined CH2C12 exctracts were dried over MgSO4 and concentrated to afford (3S,4S)-4-Amino-N-butyl-5-cyclohexyl-3- hydroxypentanamide (279 mg, 97%).

Step 3. (3S,4S)-4-Amino-N-butyl-3-(tert-butyldimethylsilyloxy)-5- cyclohexylpentanamide

A solution of the HCl salt of (3S,4S)-4-amino-N-butyl-5-cyclohexyl-3- hydroxypentanamide (279 mg, 1.03 mmol), TBSCl (31 1 mg, 2.06 mmol) and imidazole (281 mg, 4.12 mmol) in dry DMF (2 mL) was stirred at rt for 2 d. The mixture was diluted with EtOAc ( 90 mL), washed with 1 : 1 water/brine (3 x 20 mL), dried over Na 2 SO 4 and concentrated to leave crude (3S,4S)-4-amino-N-butyl-3-(tert- butyldimethylsilyloxy)-5-cyclohexylpentanamide (31 1 mg, 78%) as a yellow syrup.

Step 4. 4-Nitrophenyl (2S,3S)-5-(butylamino)-3-(tert-butyldimethylsilyIoxy)-l- cyclohexyl-5-oxopentan-2-ylcarbamate To a stirred solution of crude (3S,4S)-4-amino-N-butyI-3~(tert- butyldirnethylsilyloxy)-5-cyclohexylpenranarnide (31 1 mg, 0.81 mmol) in MeCN were added powdered NaHCO3 (203 mg, 2.43 mmol) and p-nitropheny3 chloroformate (244 mg, 1.21 mmol) and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure. The residue was taken up in 1 :1 EtOAc/Et2O (90 mL), washed with water (20 mL) and brine (20 mL), dried over

MgSO 4 and concentrated to leave an orange oil. This material was chromatographed on a 40-g silica cartridge eluted with a 0 to 100% ethyl acetate in hexanes gradient

to afford 4-nitrophenyl (2S,3S)-5-(butylamino)-3-(tert-butyldirnethylsilyloxy)-l- cyclohexyl-5-oxopcntan-2-ylcarbamate (39 mg, 8%).

Step 5. Methyl 2-((R)-((R)-l -((2S,3S)-5-(butylamino)-l-cyclohexyl-3-hydroxy-5- oxopentan-2-ylcarbamoyl)pipcridin-3-yl)(3-chlorophcnyl)mctho xy)cthylcarbamate

A solution of methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3- yl)methoxy)elhylcarbamate (40 mg, 0.12 mmol) and DIEA (0.10 mL, 0.55 mmol) in CH2C12 (1 mL) was added to 4-nitrophenyl (2S,3S)-5-(butylamino)-3-(tert- butyldimethylsilyloxy)-l-cyclohexyl-5-oxopentan-2-ylcarbamat e (39 mg, 0.07 mmol). The mixture was stirred at it for 3 h, diluted with ether (100 mL), washed with 5% aq HCl (20 mL) and 1 M aq NaOH (20 mL) and dried over MgSO 4 . Removal of the solvent left an oil (43 mg) which was dissolved in MeCN (2 mL) and treated with Et 4 N + F " (25 mg, 0.18 mmol). The solution was stirred at rt for 3 h and submitted directly to preparative HPLC to afford Methyl 2-((R)-((R)-l-((2S,3S)- S-φutylamino^l-cyclohexyl-S-hydroxy-S-oxopentan^-ylcarbamoy Opiperidin-S- yl)(3-chlorophenyl)methoxy)ethylcarbamate (30 mg, 38%) as an oil. 1 H NMR (CD 3 OD) 0.92 (t, 3H), 1.0-1.9 (22H), 2.26 (m, IH), 2.35 (m, IH), 2.92 (m, 2H), 3.17 (m, 2H), 3.23 (m, 2H), 3.30 (2H), 3.61 (s, 3H) 5 3.80 (br d, IH), 3.88 (br d, IH), 3.94 (m, IH), 4.03 (d, IH), 4.15 (br d, IH), 7.21 (d, IH), 7.34 (3H); LC-MS (16 min) t R = 9.89 min, m/z = 623. It is noted that although the compound described in this example was the only compound prepared, the other compounds of the invention described herein could be prepared in accordance with the methods taught herein.

EXAMPLE 2 IN VITRO ACTIVITY STUDIES - IC 50 FOR RENIN The compounds of the invention are believed to have enzyme-inhibiting properties. In particular, they inhibit the action of the natural enzyme renin. The latter passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the blood, lungs, the kidneys and other organs by angiotensin converting enzyme to form the octapeptide angiotensin II. The octapeptide increases blood pressure both directly by binding to its receptor, causing arterial vasoconstriction, and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone

aldosterone, accompanied by an increase in extracellular fluid volume. That increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors.

The action of renin inhibitors in vitro is demonstrated experimentally by means of a test which measures the increase in fluorescence of an internally quenched peptide substrate. The sequence of this peptide corresponds to the sequence of human angiotensinogen. The following test protocol is used: All reactions are carried out in a flat bottom white opaque microtiter plate. A 4 μL aliquot of 400 μM renin substrate (DABCYL-γ-Abu-Ile-His-Pro-Phc-His-Leu-Val- Ile-His-Thr-EDANS) in 192 μL assay buffer (50 mM BES 5 150 mM NaCl, 0.25 mg/mL bovine serum albumin, pH7.0) is added to 4 μL of test compound in DMSO at various concentrations ranging from 10 μM to 1 nM final concentrations. Next, 100 μL of trypsin-activated recombinant human renin (final enzyme concentration of 0.2-2 nM) in assay buffer is added, and the solution is mixed by pipetting. The increase in fluorescence at 495 nm (excitation at 340 nm) is measured for 60-360 min at rt using a Perkin-Elmer Fusion microplate reader. The slope of a linear portion of the plot of fluorescence increase as a function of time is then determined, and the rate is used for calculating percent inhibition in relation to uninhibited control. The percent inhibition values are plotted as a function of inhibitor concentration, and the IC50 is determined from a fit of this data to a four parameter equation. The IC 50 is defined as the concentration of a particular inhibitor that reduces the formation of product by 50% relative to a control sample containing no inhibitor. (Wang G. T. et al. Anal. Biochem. 1993, 210, 351 ; Nakamura. N. ct al. J. Biochem. (Totyo) 1991, 109, 741 ; Murakami . . K. et al. Anal Biochem. 1981, 110, 232).

EXAMPLE 3

IN VITRO ACTIVITY STUDIES- IC 50 FOR RENIN

AIl reactions are carried out in a low volume, black, 384 well microtiter plate (greiner bio-one). Compounds are diluted in 100% DMSO, and a 10OnL aliquot of each compound concentration is stamped into the plate using a Hummingbird (Genomic Solutions). 5μL of 60OpM renin (trypsin-activated recombinant human renin) is then added to the plate, followed by 5μL of 2μM substrate (Arg-Glu-Lys(5-FAM)-Ue-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-L ys(5,6- TAMRA)- Arg-CONPb). Both renin and substrate are made up in buffer containing 5OmM HEPES, 125mM NaCl, 0.1% CHAPS, with the pH adjusted to 7.4. After 2 hours of reaction at room temperature, the plates are read on a Viewlux (PerkinElmer) with an excitation/emission of 485/530nm, and using a 505nm cutoff filter. The percent inhibition values are plotted as a function of inhibitor concentration, and the IC 50 is determined from a fit of this data to a four parameter equation. The IC50 is defined as the concentration of a particular inhibitor that reduces the formation of product by 50% relative to a control sample containing no inhibitor.

EXAMPLE 4 IC50 VALUES OF THE DISCLOSED COMPOUNDS

FOR RENIN

The IC50 value of the disclosed compound of Example 1 for renin was determined according to the protocol described in Example 2. The value obtained was 1 13 nM. Generally, in these in vitro systems of Examples 2 and 3, the compounds of the invention are believed to exhibit inhibition activity at minimum concentrations of from approximately 5 x 10 '5 M to approximately 10 '12 M. Preferred compounds of the invention would be expected to exhibit inhibition activity at minimum concentrations of from approximately 10 "8 M to approximately 10 " 12 M. (Wang G. T. et al. Anal. Biochem. 1993, 210, 351; Nakamura, N. et al. J. Biochem. (Tokyo) 1991, 109, 741 ; Murakami, K. et al. Anal Biochem. 1981, 110, 232).

EXAMPLE 5

IN VITRO ACTIVITY OF THE DISCLOSED COMPOUNDS IN HUMAN PLASMA

The action of renin inhibitors in vitro in human plasma is demonstrated experimentally by the decrease in plasma renin activity (PRA) levels observed in the presence of the compounds. Incubations mixtures contain in the final volume of 250 μL 95.5 mM N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, pH 7.0, 8 mM EDTA, 0.1 mM neomycin sulfate, 1 mg/ml sodium azide, 1 mM phenylmethanesulfonyl fluoride, 2% DMSO and 87.3% of pooled mixed-gender human plasma stabilized with EDTA. For plasma batches with low PRA (less than 1 ng/ml/hr) ~2 pM of recombinant human renin is added to achieve PRA of 3-4 ng/ml/hr. The cleavage of endogenous angiotensinogen in plasma is carried out at 37°C for 90 min and the product angiotensin I is measured by competitive radioimmunoassay using DiaSorin PRA kit. Uninhibited incubations containing 2% DMSO and fully inhibited controls with 2 μM of isovaleryl-Phe-Nle-Sta-Ala- Sta-OH are used for deriving percent of inhibition for each concentration of inhibitors and fitting dose-response data into a four parametric model from which IC50 values, defined as concentrations of inhibitors at which 50% inhibition occurs, is determined.

EXAMPLE 6

EFFICACY OF THE DISCLOSED INHIBITORS IN A TRANSGENIC RAT MODEL

The efficacy of the renin inhibitors is also evaluated in vivo in double transgenic rats engineered to express human renin and human angiotensinogen (Bohlender J, Fukamizu A, Lippoldt A, Nomura T, Dietz R, Menard J, Murakami K 3 Lulϊt FC 3 Ganten D. High human renin hypertension in transgenic rats. Hypertension 1997, 29, 428-434).

Experiments are conducted in 5-10 week-old double transgenic rats (dTGRs). The model has been described in detail earlier. Briefly, the human renin construct are used to generate transgenic animals (hRen) made up the entire genomic human renin gene (10 exons and 9 introns), with 3.0 kB of the 5'-promoter region and 1.2 kB of 3' additional sequences. The human angiotensinogen construct made up the entire human angiotensinogen gene (5 exons and 4 introns), with 1.3 kB of 5'-flanking and 2.4 kB of 3'-flanking sequences are used to generate rats

producing human angiotensinogen (hAogen). The hRen and hAogen rats are rederived using embryo transfer from breeding pairs obtained under license from Ascencion Gmbh (Germany). The hAogen and hRen are then crossed to produce the double transgenic dTGR) off-spring. The dTGr rats are maintained on irradiated rodent chow (5VO2, Purina Mills Inc) and normal water. Radio telemetry transmitters (TAl 1PAC40, Data Sciences International) are surgically implanted at 5-6 weeks of age. The telemetry system provides 24-h recordings of systolic, mean, diastolic arterial pressure (SAP, MAP, DAP, respectively) and heart rate (HR). Prior to dosing, baseline hemodynamic measures are obtained for 24 hours. Rats are then dosed orally with vehicle or drug and monitored up to 48 hours post-dose.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.