HK1083502B

HK1083502B - Phenyl substituted piperidine compounds for use as ppar activators

Info

Publication number: HK1083502B
Application number: HK06103485.0A
Authority: HK
Inventors: Scott William Bagley; Thomas Andrew Brandt; Robert Wayne Dugger; William Andrew Hada; Cheryl Myers Hayward; Zhengyu Liu
Original assignee: Pfizer Products Inc.
Priority date: 2002-11-26
Filing date: 2003-11-14
Publication date: 2009-08-28

Description

Phenyl substituted piperidine compounds as PPAR activators

Background

The present invention relates to Peroxisome Proliferator Activated Receptor (PPAR) agonists, in particular, to PPAR α agonists, to pharmaceutical compositions comprising such agonists and to the use of said agonists for the treatment of atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity, osteoporosis and syndrome X (also known as metabolic syndrome) in mammals, including humans.

Atherosclerosis is an arterial disease that is recognized as a leading cause of death in the united states and western europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stages in this sequence are the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of fatty deposits, which are mainly present in smooth muscle cells and macrophages in the intimal layers of arteries and aorta. Furthermore, it is speculated that most of the cholesterol found within fatty streaks will cause the formation of "fibrous plaques" consisting of accumulated intimal smooth muscle cells that are lipid-loaded and surrounded by extracellular lipids, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers cell debris and deeper deposits of more extracellular lipids. Lipids are mainly free and esterified cholesterol. Fibrous plaques are slow to form and may become calcified and necrotic in time, leading to the development of "collateral lesions" which are the cause of arterial occlusion and a tendency to form mural thrombosis and arterial muscle spasm, which are characteristic of advanced atherosclerosis.

Epidemiological studies have demonstrated that hyperlipidemia is a major risk factor in cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders in the pharmaceutical field have re-emphasized the reduction of plasma cholesterol levels, particularly low density lipoprotein cholesterol, as a fundamental step in the prevention of CVD. The upper limit of the "normal value" currently considered is far below the previously understood value. As a result, most people in western countries are now aware of high risk. Other independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension and males. Cardiovascular disease is very common in diabetic patients, at least in part due to the presence of multiple independent risk factors in this group of people. Thus, the successful treatment of hyperlipidemia in the general population, particularly in diabetic patients, is of exceptional medical importance.

Although insulin was discovered early and subsequently used extensively in the treatment of diabetes, the subsequently discovered sulfonylureas, biguanides and thiazolidinediones such as troglitazone, rosiglitazone or pioglitazone and their use as oral hypoglycemic agents have led to improved treatment of diabetes. The use of insulin typically requires multiple daily administrations. Determining an appropriate dosage regimen for insulin requires frequent assessment of urine glucose or blood glucose. Overdosing with insulin can cause hypoglycemia, ranging from mild blood sugar abnormalities to coma, and even death. Treatment of non-insulin dependent diabetes mellitus (type II diabetes, NIDDM) typically involves a combination of dietary management, exercise, oral hypoglycemic agents such as thiazolidinediones, and in more severe cases, insulin is administered. However, clinically available hypoglycemic agents have limited their use due to side effects. In the case of insulin-dependent diabetes mellitus (type I diabetes), insulin is often the primary treatment.

U.S. Pat. Nos. 5,658,944, WO92/10468, WO97/36579, WO98/05331 and WO00/23407 describe drugs for the treatment of atherosclerosis, obesity and diabetes.

T.Komoto et al, chem.pharm.Bull, 48(12)1978-1985(2000) and JP14173426A describe fibrates containing a piperidine moiety. International publication No. WO93/12086 describes aryl amide derivatives, which are useful in the treatment and prevention of various thrombosis, embolism, arteriosclerosis, hypertension, etc. International publication No. WO02/30896 describes 2, 2-diphenylbutanamide derivatives which are useful as peripherally acting analgesic and neuropathic pain control agents. Us patent 5,411,972 describes aryl amide derivatives for the treatment of hyperlipidemia. Us patent 6,362,203 describes 4-hydroxy-4-phenylpiperidine derivatives which have a peripheral analgesic effect. U.S. patent 5,994,356 describes carboxylic acid derivatives having aggregation-inhibiting activity.

International publication Nos. WO02/064549 and 02/064139 describe certain compounds that are PPAR α activators.

Us patent 3,801,581 describes certain α -phenyl-fatty acids and derivatives thereof substituted with azacycloalkyl residues, which are useful as anti-inflammatory and anti-inflammatory agents. International publication No. WO01/81310 describes certain 1-aroyl-piperidinyl benzamidines which inhibit factor Xa or tryptase.

International publication No. WO01/90101 describes arylmethylamine derivatives useful as tryptase inhibitors. International publication No. WO01/85716 describes nitro-substituted 2-piperidone compounds useful for the treatment of cancer. International publication No. WO00/14066 describes 4, 4-diarylpiperidine derivatives, which have opioid receptor activity. Us patent 6,153,755 describes a process for the preparation of piperidine compounds and intermediates thereof.

International publication No. WO96/02250A1 describes haloperidol analogs and uses thereof. International publication No. WO02/28834 describes the preparation of aryl-piperidinemethanols and intermediates thereof.

U.S. patent 6,376,494 describes cycloalkyl substituted aryl-piperazine, piperidine and tetrahydropyridine compounds as 5-hydroxytryptamine agents useful for the treatment of anxiety,Depression, cognitive deficits, and prostate cancer. Us patent 6,303,637 describes heterocyclic potassium channel inhibitors that are useful for the treatment of autoimmune diseases, cardiac arrhythmias, and the like. U.S. Pat. No. 6,323,229 describes N-acyl and N-aroyl aralkyl amide compounds useful for treating or preventing migraine, depression and 5-HT₁Other diseases for which agonists or antagonists are useful. U.S. Pat. No. 6,153,758 describes heteroaryl-aryl diphosphines for use as chiral catalysts in stereocontrolled reactions.

Published European patent application 0548798 describes various heterocyclic-containing antiviral agents.

International publication No. WO93/07141 describes heterocyclic 3-phenylpyrrolidin-2-one compounds useful for inhibiting the production of tumor necrosis factor. International publication No. WO92/19594 describes pyrrolidine dione derivatives, which inhibit phosphodiesterase IV and Tumor Necrosis Factor (TNF). U.S. patent 5,420,154 relates to 4- (substituted phenyl) -2-pyrrolidone derivatives which inhibit Tumor Necrosis Factor (TNF). U.S. patent 4,476,311 provides 4-carboxy-pyrrolidin-2-one compounds having analgesic and anti-inflammatory activity.

Thus, while various anti-atherosclerotic and anti-diabetic treatments exist, there remains a need in the art to develop alternative treatments.

Summary of The Invention

The present invention provides compounds of formula I

An isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;

wherein

m and n are independently of each other 1 or 2;

v and Y are each independently of the other a) methylene or b) carbonyl;

f and G independently of one another are a) hydrogen, b) halogen, C) optionally substituted by 1 to 9 fluorine (C)₁-C₄) Alkyl, d) (C)₃-C₆) Cycloalkyl, e) hydroxy, f) (C) ₁-C₄) Alkoxy or g) (C)₁-C₄) An alkylthio group;

x is a) -Z or B) -B-C (R)¹R²)-Z；

B is a) oxygen, B) sulfur, c) sulfinyl, d) sulfonyl, e) methylene or F) -N (H) -;

z is a) -C (O) OH, b) -C (O) O- (C)₁-C₄) Alkyl, C) -C (O) O- (C)₀-C₄) Alkyl-aryl, d) -C (O) -NH₂E) hydroxyaminocarbonyl, f) tetrazolyl, g) tetrazolylaminocarbonyl, h)4, 5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl, i) 3-oxoisoxazolidin-4-yl-aminocarbonyl, j) -C (O) N (H) SO₂R⁴Or k) -NHSO₂R⁴(ii) a Wherein R is⁴Is a) (C)₁-C₆) Alkyl, b) amino or C) mono-N-or di-N, N- (C)₁-C₆) Alkylamino, wherein R⁴In (C)₁-C₆) The alkyl substituents are optionally independently substituted with 1-9 fluoro;

R¹is a) H, b) (C₁-C₄) Alkyl or C) (C)₃-C₆) A cycloalkyl group;

R²is a) H, b) (C₃-C₆) Cycloalkyl or c) a 1-4 membered straight or branched carbon chain which is fully or partially saturated or fully unsaturated; wherein the carbons in the carbon chain may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen and sulfur; and wherein the sulfur may be optionally mono-or di-substituted with an oxo group;

wherein R is²The carbons in the middle carbon chain are optionally independently substituted as follows: a) the carbon being optionally independently halogenatedMono-, di-or tri-substituted, b) the carbon is optionally independently hydroxy or (C) ₁-C₄) Alkoxy monosubstituted and c) the carbon is optionally monosubstituted by oxo; and is

Wherein R is²Wherein the carbon in the carbon chain is optionally mono-substituted with Q;

wherein Q is a partially or fully saturated or fully unsaturated 3-to 8-membered ring, optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused, partially or fully saturated or fully unsaturated 3-to 6-membered rings independently of one another; wherein the bicyclic ring optionally has 1-4 heteroatoms independently selected from oxygen, sulfur, and nitrogen;

wherein ring Q is optionally mono-, di-, or tri-substituted independently with: a) halogen, b) (C)₂-C₆) Alkenyl, C) (C)₁-C₆) Alkyl, d) hydroxy, e) (C)₁-C₆) Alkoxy, f) (C)₁-C₄) Alkylthio, g) amino, h) nitro, i) cyano, j) oxo, k) carboxy, l) (C)₁-C₆) Alkoxycarbonyl or m) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group; wherein, on the Q ring (C)₁-C₆) Alkyl and (C)₁-C₆) The alkoxy substituents are optionally mono-, di-or tri-substituted independently with: a) halogen, b) hydroxy, C) (C)₁-C₆) Alkoxy, d) (C)₁-C₄) Alkylthio, e) amino, f) nitro, g) cyano, h) oxo, i) carboxy, j) (C)₁-C₆) Alkoxycarbonyl or k) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group; wherein, on the Q ring (C) ₁-C₆) The alkyl substituent is optionally substituted with 1-9 fluorines;

or wherein R is¹And R²Bonded together to form a 3-6 membered fully saturated carbocyclic ring, optionally having 1 heteroatom selected from oxygen, sulfur and nitrogen to form a heterocyclic ring;

e is a) carbonyl, b) sulfonyl or c) methylene;

w is a) a single bond, b) carbonyl, C) -N (H) -, d) -N ((C)₁-C₄) Alkyl) -, e) (C)₂-C₈) Alkenyl, f) oxygen, g) - (C₁-C₄) alkyl-O-, h) -NH- (C₁-C₄) Alkyl-or i) - (C₁-C₆) Alkyl-; wherein, in W, (C)₁-C₆) Alkyl and (C)₂-C₈) Alkenyl is optionally mono-or disubstituted independently with the following substituents: a) oxo, b) halogen, C) (C)₁-C₆) Alkoxycarbonyl, d) (C)₁-C₆) Alkyl, e) (C)₂-C₆) Alkenyl, f) (C)₃-C₇) Cycloalkyl, g) hydroxy, h) (C)₁-C₆) Alkoxy, i) (C)₁-C₄) Alkylthio, j) amino, k) cyano, l) nitro, m) mono-N-or di-N, N- (C)₁-C₆) Alkylamino or n) -NH- (C)₁-C) alkylamino;

or wherein W is CR⁷R⁸Wherein R is⁷And R⁸Bonded together to form a 3-6 membered fully saturated carbocyclic ring;

a is a) mono-N-or di-N, N- (C)₁-C₆) Alkylamino radical, b) (C)₂-C₆) Alkanoylamino, C) (C)₁-C₆) Alkoxy, d) a partially or fully saturated or fully unsaturated 3-to 8-membered ring, which optionally has 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or e) a bicyclic ring consisting of two fused, partially or fully saturated or fully unsaturated 3-to 6-membered rings independently of one another; wherein the bicyclic ring optionally has 1-4 heteroatoms independently selected from oxygen, sulfur, and nitrogen; and is

Wherein ring a is optionally mono-, di-or trisubstituted independently by: a) oxo, b) carboxy, C) halogen, d) (C)₁-C₆) Alkoxycarbonyl, e) (C)₁-C₆) Alkyl, f) (C)₂-C₆) Alkenyl, g) (C)₃-C₇) Cycloalkyl, h) (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, i) hydroxy, j) (C)₁-C₆) Alkoxy radical,k)(C₁-C₄) Alkylthio, l) (C)₁-C₄) Alkylsulfonyl, m) amino, N) cyano, o) nitro or p) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group; wherein, on ring A, (C)₁-C₆) Alkyl and (C)₁-C₆) The alkoxy substituents are optionally mono-, di-or tri-substituted independently with: a) halogen, b) hydroxy, C) optionally substituted by 1-9 fluorine₁-C₄) Alkyl, d) (C)₃-C₆) Cycloalkyl, e) (C)₁-C₆) Alkoxy, f) amino or g) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group;

or wherein the A ring is optionally mono-substituted with a partially or fully saturated or fully unsaturated 3-8 membered ring optionally having 1-4 heteroatoms independently selected from oxygen, sulfur and nitrogen; and wherein the 3-8 membered ring is optionally mono-, di-or tri-substituted independently with: a) halogen, b) hydroxy, C) optionally substituted by 1-9 fluorine₁-C₄) Alkyl, d) (C)₃-C₆) Cycloalkyl, e) (C)₁-C₆) Alkoxy, f) amino, g) mono-N-or di-N, N- (C)₁-C₆) Alkylamino or h) (C) ₁-C₄) An alkylthio group;

with the following conditions:

1) when V and Y are each methylene and m and n are each 1, thereby forming a six membered piperidinyl ring, then that ring is substituted at a position other than the 4-position with a phenyl ring (labeled J);

2) when E is a carbonyl group, W is a single bond and X is-B-C (R)¹R²) -Z, wherein R¹And R²Are each hydrogen, B is-O-or-N (H) -and Z is-C (O) OH or-C (O) O- (C)₁-C₄) Alkyl, then one of F or G must be a) - (C₁-C₄) Alkyl, b) (C)₃-C₆) Cycloalkyl, C) (C)₁-C₄) Alkoxy or d) (C)₁-C₄) An alkylthio group.

More particularly, the present invention provides the above compoundsWith the further proviso that: 3) when E is carbonyl, W is a single bond, X is-Z and Z is-C (O) OH, -C (O) O- (C)₁-C₄) Alkyl, -C (O) NH₂Then one of F or G must be a) - (C₁-C₄) Alkyl, b) (C)₃-C₆) Cycloalkyl, C) (C)₁-C₄) Alkoxy or d) (C)₁-C₄) An alkylthio group.

More specifically, the present invention provides the above compound wherein V and Y are each methylene or one of V and Y is carbonyl and the other is methylene.

More specifically, the present invention provides the above compounds, wherein

E is a carbonyl group;

w is a) a single bond, b) oxygen, C) -N (H) -, d) -N (H) - (C₁-C₄) Alkyl-, e) - (C₁-C₄) Alkyl-, f) - (C₁-C₄) alkyl-O-or g) -CR⁷R⁸Wherein R is⁷And R⁸Bonded together to form a three-membered fully saturated carbocyclic ring; and is

A is a partially or fully saturated or fully unsaturated 3-to 8-membered ring, optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur, and nitrogen;

wherein ring a is optionally mono-, di-or trisubstituted independently by: a) oxo, b) carboxy, C) halogen, d) (C)₁-C₆) Alkoxycarbonyl, e) (C)₁-C₆) Alkyl, f) (C)₂-C₆) Alkenyl, g) (C)₃-C₇) Cycloalkyl, h) (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, i) hydroxy, j) (C)₁-C₆) Alkoxy, k) (C₁-C₄) Alkylthio, l) (C)₁-C₄) Alkylsulfonyl, m) amino, N) cyano, o) nitro or p) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group; wherein, on ring A, (C)₁-C₆) Alkyl and (C)₁-C₆) Alkoxy substituents are optionally independently takenSubstituted mono-, di-or trisubstituted: a) halogen, b) hydroxy, C) optionally substituted by 1-9 fluorine₁-C₄) Alkyl, d) (C)₃-C₆) Cycloalkyl, e) (C)₁-C₆) Alkoxy, f) amino or g) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group;

or wherein the A ring is optionally mono-substituted with a partially or fully saturated or fully unsaturated 3-8 membered ring optionally having 1-4 heteroatoms independently selected from oxygen, sulfur and nitrogen; and wherein the 3-8 membered ring is optionally mono-, di-or tri-substituted independently with: a) halogen, b) hydroxy, C) optionally substituted by 1-9 fluorine ₁-C₆) Alkyl, d) (C)₃-C₇) Cycloalkyl, e) optionally substituted by 1-9 fluorines₁-C₆) Alkoxy, f) amino, g) mono-N-or di-N, N- (C)₁-C₆) Alkylamino or h) (C)₁-C₄) An alkylthio group.

More specifically, the present invention provides the above compounds, wherein

A is a) phenyl optionally substituted independently with 1 or 2 substituents selected from: 1) - (C)₁-C₆) Alkyl, 2) -CF₃、3)-OCF₃、4)-(C₁-C₆) Alkoxy, 5) (C₃-C₇) Cycloalkyl, 6) halogen or 7) hydroxy; or b) thiazolyl optionally independently substituted with: 1)1 or 2 methyl groups or 2) phenyl optionally independently substituted with 1 or 2 substituents selected from the group consisting of: a) - (C)₁-C₆) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₆) Alkoxy, e) (C)₃-C₇) Cycloalkyl, f) halogen, g) - (C₁-C₄) Alkylthio or h) hydroxy.

More specifically, the present invention provides the above compounds, wherein

F and G are each independently of the other a) hydrogen, b) halogen, C) (C)₁-C₄) Alkyl or d) (C)₁-C₄) An alkoxy group;

x is a) -Z or B) -B-C (R)¹R²)-Z；

B is a) oxygen, B) sulfur or c) -N (H) -;

z is a) -C (O) OH, b) -C (O) O- (C)₁-C₄) Alkyl, c) -C (O) NH₂Or d) tetrazolyl;

R¹is a) hydrogen or b) methyl; and is

R²Is a) hydrogen or b) a fully or partially saturated or fully unsaturated 1-to 4-membered straight or branched carbon chain; wherein the carbons in the carbon chain may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen and sulfur;

wherein Q is a partially or fully saturated or fully unsaturated 3-8 membered ring, optionally having 1-4 heteroatoms independently selected from oxygen, sulfur, and nitrogen.

More specifically, the present invention provides the following compounds, wherein

R¹Is a) hydrogen or b) methyl; and is

R²Is a) hydrogen, b) methyl or c) -O-CH₂-phenyl.

More specifically, the present invention provides compounds wherein m is 1, n is 1, V and Y are each methylene to form a piperidinyl ring;

x is-B-C (R)¹R²)-Z；

B is oxygen; and is

The phenyl ring (labeled J) is attached to the 3-position of the piperidinyl ring.

In particular, the present invention provides compounds of formula I-A

Wherein R is¹And R²Independently of one another, a) hydrogen or b) methyl;

f and G are independently of each other a) hydrogen or b) methyl; and is

Z is-C (O) OH.

In particular, the present invention provides compounds of formula I-A wherein

W is a) oxygen, b) -N (H) -, C) -N (H) - (C)₁-C₄) Alkyl-, d) - (C₁-C₄) Alkyl-or e) - (C₁-C₄) alkyl-O-; and is

A is phenyl optionally substituted with: a) - (C)₁-C₄) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₄) Alkoxy, e) cyclopropyl, f) halogen, g) - (C₁-C₄) Alkylthio or h) hydroxy.

In particular, the invention also provides compounds of formula I-A, wherein

W is a single bond; and is

A is thiazolyl optionally substituted with: a)1 or 2 methyl groups or b) phenyl optionally substituted with: 1) - (C)₁-C₄) Alkyl, 2) -CF₃、3)-OCF₃、4)-(C₁-C₄) Alkoxy, 5) cyclopropyl, 6) halogen or 7) - (C₁-C₄) An alkylthio group.

x is-Z; and is

In particular, the present invention provides compounds of formula I-B

Wherein F and G are each independently a) hydrogen, b) methyl, c) fluoro or d) methoxy; and is

Z is a) -C (O) OH, b) -C (O) O- (C)₁-C₄) Alkyl or c) -C (O) NH₂。

More specifically, the present invention provides compounds of formula I-B, wherein

W is a) - (C₁-C₄) Alkyl-or b) - (C₁-C₄) alkyl-O-; and is

A is phenyl optionally substituted with: a) - (C)₁-C₄) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₄) Alkoxy, e) cyclopropyl, f) halogen or g) hydroxy.

W is a single bond; and is

A is thiazolyl optionally substituted with: a)1 or 2 methyl groups or b) phenyl optionally substituted with: 1) - (C)₁-C₄) Alkyl, 2) -CF₃、3)-OCF₃、4)-(C₁-C₄) Alkoxy, 5) cyclopropyl or 6) halogen.

In particular, the invention provides compounds of formula I-C

Wherein R is¹And R²Independently of one another, a) hydrogen or b) methyl;

f and G are independently of each other a) hydrogen or b) methyl; and is

Z is-C (O) OH.

More particularly, the present invention provides compounds of formula I-C wherein W is a) oxygen, b) -N (H) -, C) -N (H) - (C)₁-C₄) Alkyl, d) - (C₁-C₄) Alkyl-or e) - (C₁-C₄) alkyl-O-; and is

More specifically, the present invention also provides compounds of formula I-C, wherein W is a single bond; and is

In particular, the invention provides compounds of formula I-D

Wherein F and G are independently of each other a) hydrogen, b) methyl, c) fluorine or d) methoxy; and is

Z is a) -C (O) OH, b) -C (O) O- (C)₁-C₄) Alkyl or c) -C (O) NH₂。

More specifically, the present invention provides compounds of formula I-D, wherein

W is a) - (C₁-C₄) Alkyl-or b) - (C₁-C₄) alkyl-O-; and is

A is phenyl optionally substituted with: a) - (C) ₁-C₄) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₄) Alkoxy, e) cyclopropyl, f) halogen, g) - (C₁-C₄) Alkylthio or h) hydroxy.

More specifically, the invention also provides compounds of formula I-D, wherein

W is a single bond; and is

A is a) thiazolyl optionally substituted with: 1)1 or 2 methyl groups or 2) phenyl optionally substituted with: i) - (C)₁-C₄) Alkyl, ii) -CF₃、iii)-OCF₃、iv)-(C₁-C₄) Alkoxy, v) cyclopropyl or vi) halogen; or b) phenyl optionally substituted with: 1) - (C)₁-C₄) Alkyl, 2) CF₃、3)-OCF₃、4)-(C₁-C₄) Alkoxy, 5) cyclopropyl, 6) halogen or 7) - (C₁-C₄) An alkylthio group.

More specifically, the present invention provides the following compounds:

2- {3- [1- (4-lsopropyl-phenylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid;

(S) -2- {3- [1- (4-isopropyl-phenylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid;

(R) -2- {3- [1- (4-isopropyl-phenylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid;

2-methyl-2- (3- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(S) -2-methyl-2- (3- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(R) -2-methyl-2- (3- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(S) -2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(R) -2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

2- (3- {1- [3- (4-lsopropyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(S) -2- (3- {1- [3- (4-isopropyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(R) -2- (3- {1- [3- (4-isopropyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(S) -2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(R) -2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

2- (3- {1- [2- (4-lsopropyl-phenoxy) -2-methyl-propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(S) -2- (3- {1- [2- (4-isopropyl-phenoxy) -2-methyl-propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(R) -2- (3- {1- [2- (4-isopropyl-phenoxy) -2-methyl-propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

2-methyl-2- (3- {1- [3- (4-trifluoromethyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(S) -2-methyl-2- (3- {1- [3- (4-trifluoromethyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(R) -2-methyl-2- (3- {1- [3- (4-trifluoromethyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(S) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(R) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -acetic acid;

(S) - (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -acetic acid;

(R) - (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -acetic acid;

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-phenyl ester;

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-phenyl ester;

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-phenyl ester;

(S) -2- (3- {1- [ (4-tert-butyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(R) -2- (3- {1- [ (4-tert-butyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

2- (3- {1- [ (4-tert-butyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid;

(S) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(R) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester;

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester;

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester;

2- {3- [1- (4-isopropyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid;

(S) -2- {3- [1- (4-isopropyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid;

(R) -2- {3- [1- (4-isopropyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid;

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(S) -2-methyl-2- {3- [1- (4-trifluoromethoxy-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid;

(R) -2-methyl-2- {3- [1- (4-trifluoromethoxy-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid;

2-methyl-2- {3- [1- (4-trifluoromethoxy-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid;

(S) -2-methyl-2- (3- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(R) -2-methyl-2- (3- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

2-methyl-2- (3- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester;

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester;

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester;

(S) - (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid;

(R) - (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid;

(2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid;

(S) -2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(R) -2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid;

(S) -3- (3-carboxymethoxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(R) -3- (3-carboxymethoxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

3- (3-carboxymethoxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

(S) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

(R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(S) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

(R) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

2-methoxy-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

(S) -2-methoxy-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

(R) -2-methoxy-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

2-fluoro-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

(S) -2-fluoro-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

(R) -2-fluoro-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid;

2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzamide;

(S) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzamide;

(R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzamide;

(R) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester;

(S) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester;

3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester.

The invention also provides compounds of formula III

Which is a racemate or an enantiomer thereof, or a pharmaceutically acceptable salt of said compound,

wherein, P²Is methyl, ethyl or benzyl;

f and G independently of one another are a) hydrogen, b) halogen, C) optionally substituted by 1 to 9 fluorine (C) ₁-C₄) Alkyl, d) (C)₃-C₆) Cycloalkyl, e) hydroxy, f) (C)₁-C₄) Alkoxy or g) (C)₁-C₄) An alkylthio group;

R¹is a) H, b) (C₁-C₄) Alkyl or C) (C)₃-C₆) A cycloalkyl group;

R²is a) H, b) (C₃-C₆) Cycloalkyl or c) a fully or partially saturated or fully unsaturated 1-to 4-membered straight or branched carbon chain; wherein the carbons in the carbon chain may optionally be replaced by 1 or 2 heteroatoms independently selected from oxygen and sulfur; and wherein the sulfur is optionally mono-or di-substituted with an oxo group;

wherein R is²The carbons of the medium carbon chain may optionally be substituted as follows: a) the carbon is optionally mono-, di-or tri-substituted independently by halogen, b) the carbon is optionally hydroxy or (C)₁-C₄) Alkoxy substituted and c) the carbon is optionally mono-substituted with an oxo group; and is

Wherein R is²Wherein the carbon in the carbon chain is optionally mono-substituted with Q; wherein Q is a partially or fully saturated or fully unsaturated 3-to 8-membered ring, optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused, partially or fully saturated or fully unsaturated 3-to 6-membered rings independently of one another; wherein the bicyclic ring optionally has 1-4 heteroatoms independently selected from oxygen, sulfur, and nitrogen;

wherein ring Q is optionally mono-, di-, or tri-substituted independently with: a) halogen, b) (C) ₂-C₆) Alkenyl, C) (C)₁-C₆) Alkyl, d) hydroxy, e) (C)₁-C₆) Alkoxy, f) (C)₁-C₄) Alkylthio, g) amino, h) nitro, i) cyano, j) oxo, k) carboxy, l) (C)₁-C₆) Alkoxycarbonyl or m) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group; wherein, on the Q ring (C)₁-C₆) Alkyl and (C)₁-C₆) The alkoxy substituents are optionally mono-, di-or tri-substituted independently with: a) halogen, b) hydroxy, C) (C)₁-C₆) Alkoxy, d) (C)₁-C₄) Alkylthio, e) amino, f) nitro, g) cyano, h) oxo, i) carboxyl, j)(C₁-C₆) Alkoxycarbonyl or k) mono-N-or di-N, N- (C)₁-C₆) An alkylamino group; wherein, on the Q ring (C)₁-C₆) The alkyl substituents are also optionally substituted with 1-9 fluoro;

or wherein R is¹And R²Bonded together to form a 3-6 membered fully saturated carbocyclic ring, optionally having 1 heteroatom selected from oxygen, sulfur and nitrogen to form a heterocyclic ring.

More specifically, the present invention provides compounds of the formula

Wherein R is¹And R²Are respectively a) hydrogen or b) methyl;

f and G are each independently a) hydrogen, b) methyl or c) halogen;

P²is methyl, ethyl or benzyl;

or a pharmaceutically acceptable salt thereof.

More specifically, the present invention provides compounds such as the following:

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester;

(3S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester;

(3R) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester;

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid ethyl ester;

(3S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid ethyl ester;

(3R) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid ethyl ester;

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester;

(3S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester;

(3R) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester; or a D-or L-tartrate salt thereof.

The invention also provides a process for obtaining a compound of formula III (S) or III (R)

Wherein R is¹And R²Are respectively a) hydrogen or b) methyl;

f and G are each independently a) hydrogen, b) methyl or c) halogen;

P²is methyl, ethyl or benzyl;

the method comprises the chiral chromatographic treatment of the compound of the formula III

To give compounds of the formulae III (S) and III (R).

Wherein R is¹And R²Are respectively a) hydrogen or b) methyl;

f and G are each independently a) hydrogen, b) methyl or c) halogen;

P²is methyl, ethyl or benzyl;

the method comprises the following steps:

(a) reacting the compound of formula III with L- (+) -tartaric acid or D- (-) -tartaric acid in the presence of a solvent;

(b) separating the formed compound by fractional crystallization; and

(c) Treating the isolated compound with a base to obtain compounds of formulae III (S) and III (R);

more specifically, the present invention provides the above process, wherein the solvent in step (a) is ethanol or tetrahydrofuran.

More specifically, the present invention provides the above process, wherein the base in step (c) is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

More specifically, the present invention provides the above method, further comprising:

(d) reacting an alcohol of formula A-W-OH

Wherein W is a) - (C₁-C₄) Alkyl-or b) - (C₁-C₄) alkyl-O-with the proviso that the first atom in W attached to the hydroxyl group is a carbon atom; a is phenyl optionally substituted with: a) - (C)₁-C₄) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₄) Alkoxy, e) cyclopropyl, f) halogen, g) - (C₁-C₄) Alkylthio or hydroxy; or

Wherein W is a single bond; a is thiazolyl optionally substituted with: a)1 or 2 methyl groups or b) phenyl optionally substituted with: 1) - (C)₁-C₄) Alkyl, 2) -CF₃、3)-OCF₃、4)-(C₁-C₄) Alkane (I) and its preparation methodOxy, 5) cyclopropyl, 6) halogen, 7) - (C₁-C₄) Alkylthio or 8) hydroxy;

with Carbonyldiimidazole (CDI) to give compounds of the formula

(e) Reacting the compound formed in step (d) with a compound of formula III (S) or formula III (R) from step (c) in the presence of a reaction inert solvent at a temperature of about room temperature to about 100 ℃ to provide a compound of the formula

Wherein R is¹And R²Are respectively a) hydrogen or b) methyl;

f and G are each independently a) hydrogen, b) methyl or c) halogen;

P²is methyl, ethyl or benzyl; and is

The other variables are as defined above.

More specifically, the present invention provides the above process, wherein the reaction inert solvent is tetrahydrofuran, ethyl acetate, toluene or dichloromethane.

(f) hydrolyzing the compound formed in step (e) with a base in the presence of an aqueous solvent to obtain a compound of the formula

Wherein the variables are as previously defined.

More specifically, the present invention provides the above process, wherein the base in step (f) is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; the solvent is methanol, ethanol or tetrahydrofuran.

Another aspect of the invention provides a method of treating a mammal (including a human) for: obesity, overweight, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetes (especially type II), hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complications, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, inflammation, osteoporosis, thrombosis, or congestive heart failure, which method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of obesity in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for inducing weight loss in a mammal (including a human being) comprising administering to the mammal a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of overweight in mammals, including humans, comprising administering to a mammal in need of such treatment an overweight-treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of hypertriglyceridemia in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the treatment of hypertriglyceridemia.

In another aspect, the present invention provides a method for the treatment of hyperlipidemia in a mammal (including a human being) comprising administering to a mammal in need of such treatment a hyperlipidemia treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of hypoalphalipoproteinemia in a mammal (including a human being) comprising administering to a mammal in need of such treatment a hypoalphalipoproteinemia treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of metabolic syndrome in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of diabetes (especially type II) in a mammal (including a human being) comprising administering to a mammal in need of such treatment a diabetes treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of hyperinsulinaemia in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the treatment of hyperinsulinaemia.

In another aspect, the present invention provides a method for the treatment of impaired glucose tolerance in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of insulin resistance in a mammal (including a human being) comprising administering to a mammal in need of such treatment an insulin resistance treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for treating diabetic complications (such as neuropathy, nephropathy, retinopathy or cataracts) in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for treating diabetic complications.

In another aspect, the present invention provides a method for the treatment of atherosclerosis in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of hypertension in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of coronary heart disease in a mammal (including a human being) comprising administering to a mammal in need of such treatment an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of hypercholesterolemia in a mammal (including a human being) comprising administering to a mammal in need of such treatment a hypercholesterolemia treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of inflammation in a mammal (including a human being) comprising administering to a mammal in need of such treatment an inflammation treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

In another aspect, the present invention provides a method for the treatment of osteoporosis in a mammal (including a human being) comprising administering to a mammal in need thereof an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the treatment of osteoporosis.

In another aspect, this invention provides a method for treating congestive heart failure in a mammal (including a human being) comprising administering to a mammal in need thereof an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, for the treatment of congestive heart failure.

The dosage of the compounds of the present invention ranges from about 0.001 to about 100 mg/kg/day of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. More specifically, the dosage of the compounds of the present invention ranges from about 0.005 to about 5 mg/kg/day of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

The present invention also provides pharmaceutical compositions comprising a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, further comprising a pharmaceutically acceptable excipient, carrier or diluent. Preferably, the composition comprises a therapeutically effective amount of a compound of formula I.

The invention also provides pharmaceutical compositions for treating the following diseases in mammals (including humans): obesity, overweight, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetes (especially type II), hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complications, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, inflammation, osteoporosis, or congestive heart failure comprising a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient, diluent, or carrier.

The present invention also provides a pharmaceutical composition for the treatment of obesity in a mammal (including a human being) which comprises an obesity treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for inducing weight loss in a mammal, including a human, comprising a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of overweight in a mammal (including a human being) comprising an overweight treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, in combination with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of hypertriglyceridemia in a mammal (including a human being) comprising an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the treatment of hypertriglyceridemia, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for treating hyperlipidemia in a mammal (including a human being) comprising an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for treating hyperlipidemia, in combination with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of hypoalphalipoproteinemia in a mammal, including a human, comprising a hypoalphalipoproteinemia treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of metabolic syndrome in a mammal (including a human being) comprising a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug in an amount effective to treat metabolic syndrome, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of diabetes, especially type II, in a mammal, including a human, comprising a diabetes treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of hyperinsulinaemia in a mammal (including a human being) comprising an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the treatment of hyperinsulinaemia, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of impaired glucose tolerance in a mammal, including a human, which comprises a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug in an amount effective to treat impaired glucose tolerance, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of insulin resistance in a mammal, including a human, comprising an insulin resistance treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for treating diabetic complications (such as neuropathy, nephropathy, retinopathy or cataracts) in mammals (including humans), which comprises a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, in an amount effective to treat the diabetic complications, together with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for treating atherosclerosis in a mammal (including a human being), comprising an atherosclerosis treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of hypertension in a mammal (including a human being) which comprises a hypertension treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of coronary heart disease in a mammal, including a human, comprising an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the treatment of coronary heart disease, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of hypercholesterolemia in a mammal (including a human being) comprising a hypercholesterolemia treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of inflammation in a mammal, including a human, comprising an inflammation treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical composition for the treatment of osteoporosis in a mammal (including a human being) which comprises an osteoporosis treating amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable excipient, diluent or carrier.

This invention also provides a pharmaceutical composition for the treatment of congestive heart failure in a mammal, including a human, which comprises an amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, in an amount effective to treat congestive heart failure, in association with a pharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising

A first compound which is a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug;

A second compound that is a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, a microsomal triglyceride transfer protein (MTP)/Apo B secretion inhibitor, a Cholesteryl Ester Transfer Protein (CETP) inhibitor, a bile acid absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a mixed squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an acyl coenzyme A: cholesterol Acyltransferase (ACAT) inhibitors or bile acid sequestrants; and/or optionally

A pharmaceutically acceptable excipient, diluent or carrier.

Specific embodiments of the second compound are HMG-CoA reductase inhibitors and CETP inhibitors.

Specific embodiments of HMG-CoA reductase inhibitors are lovastatin, rosuvastatin (rosuvastatin), pitavastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin or pharmaceutically acceptable salts thereof.

Specific embodiments of CETP inhibitors include, for example, [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.

In another aspect, the invention provides a method for treating atherosclerosis in a mammal, comprising administering to a mammal having atherosclerosis:

a second compound which is a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a mixed squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, wherein the first and second compounds are present in an amount to produce a therapeutic effect.

One embodiment of the above method is wherein the second compound is an HMG-CoA reductase inhibitor and a CETP inhibitor.

In another embodiment of the above method, wherein the HMG-CoA reductase inhibitor is lovastatin, rosuvastatin, pitavastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a kit comprising:

a. a first compound which is a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier, excipient, or diluent in a first unit dosage form;

b. a second compound which is a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a mixed squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant, in a second unit dosage form;

c. A device containing said first and second dosage forms, wherein the amounts of the first and second compounds are such as to produce a therapeutic effect.

Specific embodiments of HMG-CoA reductase inhibitors are lovastatin, rosuvastatin, pitavastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin or pharmaceutically acceptable salts thereof.

a second compound that is a diabetes therapeutic selected from the group consisting of: aldose reductase inhibitors, glucocorticoid receptor antagonists, glycogenolysis inhibitors, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors Formulations, insulin analogues, insulin pro-peptides (insulinotropes), sulfonylureas, sulfonylurea analogues, biguanides, imidazolines, insulin secretagogues, linagli, glitazones, non-glitazone PPAR γ agonists, PPAR β agonists, glycosidase inhibitors, acarbose, miglitol, emiglitate, voglibose, canaglibose, β -agonists, phosphodiesterase inhibitors, vanadates, vanadium complexes (e.g. insulin, insulin analogues, insulin secretagogues), PPAR β -agonists, glitazones, PPAR β -agonists, and vanadium complexes (e.g. insulin, insulin analogues, insulin secretagogues, insulin agonists, non-glitazones, PPAR β -agonists) Peroxyvanadium complexes, amylin antagonists, glucagon antagonists, gluconeogenesis inhibitors, somatostatin analogues, anti-lipolytic agents, nicotinic acid, acipimox, pramlintide (Symlin)^TM) And nateglinide; and/or optionally

A pharmaceutically acceptable excipient, diluent or carrier.

Specific embodiments in the second compound are: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide,Glimepiride, repaglinide, meglitinide, metformin, phenformin, buformin, miglitol, emiglidol, diditaloprid, idadrogen, efacridone, flulopendron, ciglitazone, pioglitazone, rosiglitazone, englitazone, darglitazone, lomaktosten, and lomaktosten.

More specific embodiments of the second compound are: glibenclamide,Glimepiride, repaglinide, metformin and pioglitazone.

In another aspect, the invention provides a method of treating diabetes in a mammal comprising administering to a mammal having diabetes:

a first compound which is a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and

a second compound that is a diabetes therapeutic selected from the group consisting of: aldose reductase inhibitors, glucocorticoid receptor antagonists, glycogenolysis inhibitors, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, insulin analogs, insulin pro-peptides, sulfonylureas, sulfonylurea analogs, biguanides, imidazolines, insulin secretagogues, linagli, glitazones, non-glitazone PPAR γ agonists, PPAR β agonists, glycosidase inhibitors, acarbose, miglitol, emiglitate, voglibose, canaglibose, β -agonists, phosphodiesterase inhibitors, vanadates, vanadium complexes (e.g., as in the case of the glucocorticoid receptor antagonists, glycogenolytic inhibitors, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, insulin secretagogues, insulin analogs, insulin secretagogues, glitazones, non-glitazone PPAR γ agonists, PPAR β agonists) Peroxyvanadium complexes, amylin antagonists, glucagon antagonists, gluconeogenesis inhibitors, somatostatin analogs, anti-lipolytic agents, nicotinic acid, acipimox, pramlintide (Symlin) ^TM) And nateglinide, wherein the first and second compounds are present in an amount effective to produce a therapeutic effect.

A specific embodiment of the above method is wherein the second compound is chlorpropamide, glyburide, tolbutamide, tolazamide, acetohexamide, thiohexamide, or mixtures thereof,Glimepiride, repaglinide, meglitinide, metformin, phenformin, buformin, miglitol, emiglidol, diditaloprid, idadrogen, efacridone, flulopendron, ciglitazone, pioglitazone, rosiglitazone, englitazone, darglitazone, lomaktosten, and lomaktosten.

A specific embodiment of the above method is wherein the second compound is GrignardThe urea,Glimepiride, repaglinide, metformin and pioglitazone.

In another aspect, the invention provides a kit comprising:

a. a first compound which is a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable excipient, diluent or carrier in a first unit dosage form;

b. a second compound in a second unit dosage form, said second compound being a diabetes therapeutic selected from the group consisting of: aldose reductase inhibitors, glucocorticoid receptor antagonists, glycogenolysis inhibitors, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, insulin analogs, insulin pro-peptides, sulfonylureas, sulfonylurea analogs, biguanides, imidazolines, insulin secretagogues, linagli, glitazones, non-glitazone PPAR γ agonists, PPAR β agonists, glycosidase inhibitors, acarbose, miglitol, emiglitate, voglibose, canaglibose, β -agonists, phosphodiesterase inhibitors, vanadates, vanadium complexes (e.g., as in the case of the glucocorticoid receptor antagonists, glycogenolytic inhibitors, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, insulin secretagogues, insulin analogs, insulin secretagogues, glitazones, non-glitazone PPAR γ agonists, PPAR β agonists ) Peroxyvanadium complexes, amylin antagonists, glucagon antagonists, gluconeogenesis inhibitors, somatostatin analogs, anti-lipolytic agents, nicotinic acid, acipimox, pramlintide (Symlin)^TM) And nateglinide; and

Embodiments of the second compound are chlorpropamide, glyburide, tolbutamide, tolazamide, acetohexamide, thiohexamide, thiohexa,Glimepiride, repaglinide, meglitinide, metformin, phenformin, buformin, miglitol, emiglidol, diditaloprid, idadrogen, efacridone, flulopendron, ciglitazone, pioglitazone, rosiglitazone, englitazone, darglitazone, lomaktosten, and lomaktosten.

Specific embodiments of the above method are wherein the second compound is glibenclamide,Glimepiride, repaglinide, metformin and pioglitazone.

A second compound selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, neuropeptide Y antagonist, beta₃-adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (APO-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A agonists, monoamine reuptake inhibitors, sympathomimetics, serotonergics, dopamine agonists, melanocyte-stimulating hormone receptor agonists or mimetics, 5HT2c agonists, melanocyte-stimulating hormone receptor analogs, cannabinoid receptor antagonists, melanin concentrating hormone antagonists, leptin, OB protein, leptin analogs, leptin receptor agonists, somatotropin neuropeptide antagonists, lipase inhibitors, anorectic agents, bombesin agonists, neuropeptide-Y antagonists, thyroxine, thyromimetics, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor modulators, Orexin receptor antagonists,A urothelin (urocortin) binding protein antagonist, a glucagon-like peptide-1 receptor agonist, ciliary neurotrophic factor, human guinea pig related protein (AGRP), ghrelin (ghrelin) receptor antagonist, histamine 3 receptor antagonist or inverse agonist or a neurointerleukin U receptor agonist; and/or optionally

A pharmaceutically acceptable excipient, diluent or carrier.

Specific embodiments of the second compound are orlistat, sibutramine and bromocriptine.

In another aspect, the present invention provides a method of treating obesity in a mammal comprising administering to a mammal suffering from obesity:

a second compound selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, neuropeptide Y antagonist, beta₃-adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (APO-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A agonists, monoamine reuptake inhibitors, sympathomimetics, serotonergics, dopamine agonists, melanocyte-stimulating hormone receptor agonists or mimetics, 5HT2c agonists, melanocyte-stimulating hormone receptor analogs, cannabinoid receptor antagonists, melanin concentrating hormone antagonists, leptin, OB protein, leptin analogs, leptin receptor agonists, somatotropin neuropeptide antagonists, lipase inhibitors, anorectic agents, bombesin agonists, neuropeptide-Y antagonists, thyroxine, thyromimetics, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor modulators, An orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human guinea pig-related protein (AGRP), a ghrelin receptor antagonist, a histamine 3 receptor antagonist or an inverse agonist or a neurointerleukin U receptor agonist; wherein The first and second compounds are used in amounts that produce a therapeutic effect.

In embodiments of the above method, the second compound is orlistat, sibutramine, and bromocriptine.

In another aspect, the invention provides a kit comprising:

b. a second compound which is phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, neuropeptide Y antagonist, beta in a second unit dosage form, and a pharmaceutically acceptable excipient, diluent or carrier₃-adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (APO-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A agonists, monoamine reuptake inhibitors, sympathomimetics, serotonergics, dopamine agonists, melanocyte-stimulating hormone receptor agonists or mimetics, 5HT2c agonists, melanocyte-stimulating hormone receptor analogs, cannabinoid receptor antagonists, melanin concentrating hormone antagonists, leptin, OB protein, leptin analogs, leptin receptor agonists, somatotropin neuropeptide antagonists, lipase inhibitors, anorectic agents, bombesin agonists, neuropeptide-Y antagonists, thyroxine, thyromimetics, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor modulators, An orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human guinea pig-related protein (AGRP), a ghrelin receptor antagonist, a histamine 3 receptor antagonist or an inverse agonist or a neurointerleukin U receptor agonist; and

Embodiments of the second compound are orlistat, sibutramine and bromocriptine.

a second compound which is an antihypertensive; and/or optionally

A pharmaceutically acceptable excipient, diluent or carrier.

Specific embodiments of antihypertensive agents are calcium channel blockers, Angiotensin Converting Enzyme (ACE) inhibitors and diuretics.

In another aspect, the invention provides a method of treating hypertension in a mammal comprising administering to a mammal having hypertension:

a second compound which is an antihypertensive; wherein the first and second compounds are present in amounts that produce a therapeutic effect.

In another aspect, the invention provides a kit comprising:

b. a second compound in a second unit dosage form, said second compound being an antihypertensive, and a pharmaceutically acceptable excipient, diluent or carrier; and

Embodiments of the anti-osteoporosis agent are selective estrogen agonists/antagonists such as lasofoxifene, raloxifene, TSE-424 and azinoxifene, and bisphosphonates such as alendronate and resiindronate.

The term "treatment" herein includes prophylactic and palliative treatment.

By "pharmaceutically acceptable" it is meant that the carrier, diluent, excipient, and/or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, a "therapeutically effective amount of a compound" means an amount that, when used in the manner of this invention, is effective to exhibit therapeutic or biological activity at the active site of a mammalian patient without adverse side effects (such as excessive toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio.

Unless otherwise indicated, the term "compound for use in the methods of the invention" and the like is to be understood as including all active forms of such compounds, including, for example, the free forms thereof, such as the free acid or base forms, as well as all prodrugs, polymorphs, hydrates, solvates, tautomers, stereoisomers (such as diastereomers and optical isomers, and the like), and pharmaceutically acceptable salts, as described above. It will be appreciated that any suitable active metabolite of the compound in any suitable form is included.

Metabolic syndrome, also known as syndrome X, refers to a common clinical condition defined as the presence of increased insulin concentrations associated with other diseases including viceral obesity, hyperlipidemia, dyslipidemia, hyperglycemia, hypertension and potentially hyperuricemia and renal dysfunction.

The term "prodrug" refers to those compounds that are prodrugs that, upon administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug is converted to the desired drug form by exposure to physiological pH or enzymatic action). Exemplary prodrugs of compounds of formula I that release the corresponding free acid upon cleavage and the hydrolyzable ester-forming residue include, but are not limited to, those compounds having a carboxyl group in which the free hydrogen is substituted with: (C)₁-C₄) Alkyl, (C)₂-C₇) Alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-benzofuranone, 4-crotonolactone, gamma-butyrolactone-4-yl, di-N, N- (C)₁-C₂) Alkylamino radical (C)₂-C₃) Alkyl (e.g.. beta. -dimethylaminoethyl), carbamoyl- (C) ₁-C₂) Alkyl, N-di (C)₁-C₂) Alkylcarbamoyl- (C)₁-C₂) Alkyl and piperidin-1-yl-, pyrrol-1-yl-or morpholin-4-yl (C)₂-C₃) An alkyl group.

The following paragraphs describe exemplary rings described with respect to the generic rings contained herein.

The term het refers to a substituted or unsubstituted 5-, 6-or 7-membered saturated, partially saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur; including any bicyclic ring wherein any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic ring; the nitrogen atoms can be in an oxidized state to give the form of N-oxide; substituted with 0-3 independent substituents.

Examples of 5-6 membered aromatic rings optionally having 1 or 2 heteroatoms independently from each other selected from oxygen, nitrogen and sulphur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

Examples of partially saturated, fully saturated or fully unsaturated 5-to 8-membered rings optionally having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other representative 5-membered rings include 2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1, 2-dithiocyclopentyl, 1, 3-dithiocyclopentyl, 3H-1, 2-oxathiolanyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3, 4-oxatriazolyl, 1, 2, 3, 5-oxatriazolyl, 3H-1, 2, 3-dioxazolyl, 1, 2, 4-dioxazolyl, 1, 3, 2-dioxazolyl, 1, 3, 4-dioxazolyl, 5H-1, 2, 5-oxathiazolyl and 1, 3-oxathiolanyl.

Other examples of the 6-membered ring include 2H-pyranyl, 4H-pyranyl, pyridyl, piperidyl, 1, 2-dioxin yl, 1, 3-dioxin yl, 1, 4-dioxane yl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3, 5-triazinyl, 1, 2, 4-triazinyl, 1, 2, 3-triazinyl, 1, 3, 5-thioalkyl, 4H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 6H-1, 2-oxazinyl, 1, 4-oxazinyl, 2H-1, 2-oxazinyl, 4H-1, 4-oxazinyl, 1, 2, 5-oxathiazinyl, 1, 4-oxazinyl, o-isooxazinyl, p-isooxazinyl, 1, 2, 5-oxathiazinyl, 1, 2, 6-oxathiazinyl, 1, 4, 2-oxadiazinyl, and 1, 3, 5, 2-oxadiazinyl.

Other examples of 7-membered rings include azaOxygen radical and oxygen radicalRadicals and sulfur heteroAnd (4) a base.

Other examples of 8-membered rings include cyclooctyl, cyclooctenyl, and cyclooctadienyl.

Examples of bicyclic rings consisting of two fused, independently of one another, partially saturated, fully saturated or fully unsaturated 5-or 6-membered rings, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen, include indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta (b) pyridyl, pyrano (3, 4-b) pyrrolyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, benzo (c) thienyl, 1H-indazolyl, indolizinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, 7-bicyclo [4.2.0] octan-1, 3, 5-trienyl, indenyl, isoindolyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, 2H-1-benzopyranyl, pyrido (3, 4-b) -pyridyl, pyrido (3, 2-b) -pyridyl, pyrido (4, 3-b) -pyridyl, 2H-1, 3-benzoxazinyl, 2H-1, 4-benzoxazinyl, 1H-2, 3-benzoxazinyl, 4H-3, 1-benzoxazinyl, 2H-1, 2-benzoxazinyl, and 4H-1, 4-benzoxazinyl.

Alkenyl means a straight chain unsaturated hydrocarbon or a branched chain unsaturated hydrocarbon group. Examples of such groups (assuming the indicated length includes specific examples) are ethenyl, propenyl, butenyl, pentenyl, hexenyl and heptenyl, and all isomeric forms and straight and branched chain forms thereof.

Halogen means fluorine, chlorine, bromine or iodine.

Alkyl refers to a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon group. Examples of such groups (assuming that the indicated length includes specific examples) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl. The term also includes saturated hydrocarbons (straight or branched chain) with one hydrogen atom removed from each of the two ends.

Alkoxy means a straight-chain saturated alkyl group or a branched-chain saturated alkyl group bonded through oxygen. Examples of such alkoxy groups (assuming that the indicated length includes specific examples) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, heptyloxy and octyloxy.

The number of carbon atoms of the various hydrocarbon-containing moieties is indicated by a pre-conjugate indicating the minimum and maximum number of carbon atoms in the moiety, i.e. a pre-conjugate C_i-C_jRefers to the moiety from the integer "i" to the integer "j" carbon atoms. Thus, for example, C₁-C₃Alkyl means alkyl of 1 to 3 carbon atoms or methyl, ethyl, propyl and isopropyl, and all isomeric forms and straight-chain or branched forms thereof.

Aryl refers to a substituted or unsubstituted 6 membered aromatic ring, including polyaromatic rings. Examples of aryl groups include phenyl, naphthyl, and biphenyl.

The term mono-N-or di-N, N- (C) for use in the present invention₁-C_x) Alkyl means when it is di-N, N- (C)₁-C_x) (C) independently selected when alkyl (x is an integer)₁-C_x) An alkyl moiety.

It will be understood that if a carbocyclic or heterocyclic moiety can be bonded or attached to the indicated substrate through different ring atoms, all possible points are possible when the particular position of attachment is not specified, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" refers to 2-, 3-, or 4-pyridyl, the term "thienyl" refers to 2-or 3-thienyl, and the like.

The "carbon" in the following term "the carbon is optionally independently mono-, di-or tri-substituted by halo, the carbon is optionally mono-substituted by hydroxy, the carbon is optionally mono-substituted by oxo" (as in claim 1) refers to each carbon in the carbon chain including the linking carbon.

Some of the variables in the formulae employed in the present invention may occur between other variables, linking one variable to another, e.g., variable "W" occurs in formula I between and links variables "E" and "A". Variables like "W" are defined by a moiety having a single bond at each end of the moiety. This means that the sections can be read from left to right or from right to left and inserted into the appropriate locations. Thus, both orientations of these portions are included within the scope of the present invention.

The term "pharmaceutically acceptable salt" refers to non-toxic anionic salts comprising anions such as, but not limited to, chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate, and 4-toluenesulfonyl. The term also relates to non-toxic cationic salts such as, but not limited to, sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N, N-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benzylamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol).

The terms "reaction inert solvent" and "inert solvent" as used herein refer to a solvent or mixture thereof that does not interact with starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.

The ordinarily skilled chemist will recognize that certain compounds of the present invention will contain one or more atoms, which may be of a particular stereochemical or geometric configuration, thereby giving rise to stereoisomers and configurational isomers. All isomers and mixtures thereof are included in the present invention. Hydrates and solvates of the compounds of the invention are also included in the invention.

The invention also includes isotopically-labeled compounds, which are identical in structure to the compounds of the invention, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³⁵S、¹⁸F and³⁶and (4) Cl. The scope of the present invention includes those compounds of the present invention, drugs thereof, and pharmaceutically acceptable salts of said compounds and said prodrugs which contain the aforementioned isotopes and/or isotopes of other atoms. Certain isotopically-labeled compounds of the present invention, e.g., those into which a radioactive isotope such as ³H and¹⁴the compounds of C are useful in drug and/or substrate tissue distribution assays. Containing tritium³H and carbon-14 i.e¹⁴The C isotope is particularly preferred because of its ease of preparation and detection. In addition, with heavier isotopes such as deuterium²H substitution may yield certain therapeutic advantages because it has greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared by well-known or cited procedures by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

All patents and patent applications mentioned herein are incorporated herein by reference.

DTT refers to dithiothreitol. DMSO refers to dimethylsulfoxide. EDTA refers to ethylene diamine tetraacetic acid.

Detailed Description

In general, the compounds of the invention can be prepared by methods analogous to those known in the chemical art, in particular according to the methods described in the description of the invention. As a further feature of the present invention, certain processes for producing the compounds of the present invention are provided, which are illustrated by the following reaction schemes. Other methods are described in the experimental section.

It should first be noted that in preparing the compounds of formula I, certain preparative methods for preparing the compounds described herein may require protection of distal functional groups (e.g., primary amine, secondary amine, carboxyl groups in the precursors of formula I). The need for such protection will depend on the nature of the distal functional group and the conditions of the preparation method, and can be readily determined by one skilled in the art.

The use of such protection/deprotection methods is well known to those skilled in the art. For a general description of protecting groups and their use, see t.w.g. ene,Protective Groups in Organic Synthesis，John Wiley & Sons，New York，1991。

for example, in the following reaction schemes, certain compounds of formula I contain primary amine or carboxylic acid functional groups that, if not protected, interfere with reactions at other molecular sites. Such functional groups may be protected by suitable protecting groups and may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those conventionally used in peptide synthesis (e.g., N-t-butyloxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amine protection, lower alkyl or benzyl esters for carboxylic acid protection), which are generally chemically inert under the reaction conditions described and can generally be removed without chemically altering the other functional groups in the compounds of formula I.

Reaction scheme I

The desired compounds of formula I, wherein X is-B-C (R), are prepared according to scheme I¹R²) -Z, m ═ n ═ 1, V is methylene, Y is methylene, F, G, R¹、R²A, W and E are as defined above, B is O, Z is carboxy and the piperidinyl ring is substituted at the 3-position with a phenyl ring (as in compounds of formula II): acylating the corresponding compound of formula III with an acid chloride, sulfonyl chloride, isocyanate or carboxylic acid; or treating the corresponding compound of formula III with an alcohol and carbonyldiimidazole; or alkylating the corresponding compound of formula III with an alkyl halide; re-hydrolysis to form a compound of formula II wherein Z is CO₂P²And P is²For the well-known carboxyl protecting group (see Greene, cited above), the corresponding carboxylic acid is prepared. Alternatively, when the ester is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted.

Typically, the desired compound of formula III is acylated with a suitable acid chloride or a suitable sulfonyl chloride, and the reaction is carried out in a reaction inert solvent such as dichloromethane in the presence of an amine base such as triethylamine at a temperature of from about 10 ℃ to about 50 ℃, typically at room temperature, for a period of from about 6 to about 18 hours; acylation with a suitable isocyanate, in a reaction-inert solvent such as toluene, in the presence of a tertiary amine base such as Hunig's base, at a temperature of from about 10 ℃ to about 150 ℃, typically room temperature, for about 6 to about 18 hours; or acylation with the appropriate carboxylic acid, in a reaction inert solvent such as methylene chloride in the presence of a carbodiimide (e.g., 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), at a temperature of from about 10 c to about 50 c, typically at room temperature, for from about 6 to about 24 hours. Alternatively, the acylation of the desired compound of formula III with an activated complex obtained by the reaction of the appropriate alcohol with carbonyldiimidazole in a reaction inert solvent such as toluene at a temperature of from about 10 ℃ to about 130 ℃, typically room temperature, for about 12 to about 24 hours in the presence of a catalyst such as 4-dimethylaminopyridine in a reaction inert solvent such as toluene at a temperature of from about 10 ℃ to about 130 ℃, typically room temperature, for about 12 to about 24 hours. The desired compound of formula III is alkylated with a suitable alkyl halide in a polar solvent such as dimethylformamide in the presence of a base such as lithium diisopropylamide at a temperature of about-80 ℃ to 50 ℃ for about 6 to about 18 hours. The ester moiety can then be hydrolyzed with a base such as potassium carbonate in the presence of an aqueous alcoholic solvent such as methanol/water at a reaction temperature of about 40 ℃ to about 80 ℃, preferably at reflux temperature, for about 2 hours to about 18 hours to provide the compound of formula II. Alternatively, in some cases, the protecting group P may be removed by hydrogenation (or transfer hydrogenation), preferably at atmospheric pressure over a catalyst such as 10% palladium on charcoal in a polar solvent such as methanol at room temperature for 1 to 24 hours.

The desired compound of formula III, wherein, F, G, R¹And R²As described above and P²For the known carboxyl-protecting groups, by alkylation of the corresponding compounds of the formula IV, followed, if necessary, by protection of the carboxyl group formed and subsequent removal of the amine-protecting group P¹. Typically, the compound of formula IV is mixed with a suitable alkyl haloalkyl carboxylate in the presence of a base such as cesium carbonate in a polar solvent such as dimethylformamide at a temperature of from about 10℃ to about 100℃, typically room temperature, for a period of from about 2 to about 18 hours. Alternatively, the compound of formula IV may be combined with a suitable trichloroalkylmethanol (e.g., chlorobutanol) in a corresponding ketone solvent (e.g., acetone) in the presence of a strong base such as sodium hydroxide at a temperature of from about-20 deg.C to about 60 deg.C, typically at room temperature, for a period of from about 6 to about 24 hours. Protecting the resulting compound having a carboxyl group (e.g. with P)²Protecting group), i.e., with a suitable alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of from about 15 deg.C to about 100 deg.C for a period of from about 1 hour to about 24 hours, or with a suitable alcohol as solvent in the presence of a catalytic amount of an acid such as concentrated sulfuric acid The reaction should be carried out at a temperature of about 20 ℃ to about 120 ℃, preferably at reflux temperature, for about 1 hour to about 24 hours. The amine protecting group (P) is then removed by treatment with an acid such as trifluoroacetic acid¹) The reaction is carried out in a reaction-inert solvent such as methylene chloride at a temperature of from about 0 ℃ to about 50 ℃, preferably room temperature, for less than 1 hour, for example when the protecting group P is present¹In the case of t-butyl carbonate, it is preferably carried out for 30 minutes.

The desired compound of formula IV wherein F and G are as described above and P¹For the well-known amine protecting groups, they are prepared by demethylation of the corresponding compounds of formula V, if necessary to protect the amine formed. Typically, the compound of formula V is combined with a strong protic acid, such as 48% hydrobromic acid, at a reaction temperature of from about 20 ℃ to about 150 ℃, preferably at reflux temperature, and the reaction is carried out for a period of from about 1 hour to about 6 hours, preferably 3 hours. The compound having an amine group formed is protected by mixing with di-tert-butyl carbonate and the reaction is carried out in the presence of a base such as sodium bicarbonate in a polar solvent such as tetrahydrofuran/water at a temperature of from about 15 c to about 100 c, preferably at reflux temperature, for a period of from about 30 minutes to about 6 hours.

The desired compounds of formula V, wherein F and G are as described above, are prepared by Suzuki coupling of the corresponding compounds of formula VI followed by reduction. Typically, the compound of formula VI is combined with a suitable diethylpyridylborane and the reaction is carried out in a reaction inert solvent such as toluene in the presence of a base such as aqueous sodium carbonate and a catalyst such as tetrakis (triphenylphosphine) palladium (0) in ethanol at a temperature of from about 10 ℃ to about 120 ℃, typically at reflux temperature, for a period of from about 3 to about 18 hours. The methoxy-substituted-3-phenyl-pyridine formed is then reduced by hydrogenation, preferably at 55psi pressure, using a catalyst such as platinum (IV) oxide, in a polar protic solvent such as acetic acid at room temperature for 1 hour to 18 hours, preferably 6 hours. The compounds of formula VI are commercially available and/or can be prepared by conventional methods, which are well known to those skilled in the art of organic synthesis.

Reaction scheme II

The desired compounds of formula I, wherein X is-B-C (R), are prepared according to scheme II¹R²) -Z, m ═ n ═ 1, one of V and Y is methylene and the other is carbonyl, F, G, R¹、R²A, W and E are as described above, B is O, Z is carboxy and the piperidinyl ring is substituted at the 3-position with a phenyl ring (as in compound of formula VII), the corresponding compound of formula VIII is acylated with an acid chloride, sulfonyl chloride or isocyanate; or treating the corresponding compound of formula VIII with an alcohol and carbonyldiimidazole; or alkylating the corresponding compound of formula VIII with an alkyl halide; optionally hydrolyzing the resulting compound to remove the carboxyl protecting group P²(see Greene, cited above) to produce the corresponding carboxylic acid. Alternatively, when the ester is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted. Generally, the reaction proceeds as described above for the preparation of compounds of formula II in scheme I, although stronger bases (e.g. lithium diisopropylamide) may be required at the time of the acylation reaction.

A compound of the formula VIII wherein, F, G, R¹And R²As described above and P²Known carboxyl protecting groups can be prepared by demethylation of the corresponding compounds of the formula IX and subsequent alkylation of the phenol formed, if desired with protection of the carboxyl group. Generally, the reaction proceeds as described above for the preparation of compounds of formula IV and III in scheme I, although protection of the amide functionality is not necessary.

The desired compounds of formula IX having a 5-phenyl-2-piperidone core, wherein F and G are as described above, can be prepared by reduction of the corresponding compounds of formula X with concomitant intramolecular cyclization of the aminocarboxylic acid moiety formed. Typically, the compound of formula X is combined with a reducing agent such as hydrogen and a catalyst such as Raney nickel, preferably at a pressure of 55psi in a polar solvent such as methanol/ammonia, at a temperature of from about 10 deg.C to about 150 deg.C, typically at room temperature, for a period of from about 6 hours to about 18 hours. Compounds similar to compound IX but having a 3-phenyl-2-piperidone core may be prepared as described above except that the nitrile and ester moieties in the compound of formula X may be exchanged by methods well known to those skilled in the art of organic synthesis.

The desired compound of formula X, wherein F and G are as described above, can be prepared by Michael reaction of the corresponding methoxybenzyl nitrile (as shown in compound XI, wherein F and G are as described above) with an acrylate derivative. Typically, the compound of formula XI is mixed with methyl acrylate and treated with a basic catalytic solution such as sodium methoxide at a reaction temperature of about-10 deg.C to about 50 deg.C, the reaction temperature being maintained by external cooling. The compounds of formula VI are commercially available and/or can be prepared by conventional methods, which are well known to those skilled in the art of organic synthesis.

Reaction scheme III

The desired compound of formula I wherein X is-B-C (R)¹R²) -Z, m ═ n ═ 1, V is methylene, Y is methylene, F, G, R¹、R²A, W and E are as described above, B is O, Z is carboxy and the piperidinyl ring is substituted at the 3-position with a phenyl ring (as shown in compounds of formula II in scheme I), and can be prepared in optically pure form by a shorter route than that described in scheme I, as shown in scheme III.

If desired, in scheme III, the compounds of the formula III, where F, G, R¹And R²As described above and P²Known carboxyl protecting groups can be prepared in optically pure form by crystallization from optically pure acids via salt formation.

In general, the compound of formula III is mixed with L-tartaric acid in the presence of a solvent such as ethanol or tetrahydrofuran/water, the diastereoisomers are separated by fractional crystallization, and the salts are subsequently neutralizedDecomposition to give one of the corresponding pure enantiomers of the compound of formula III in scheme III. Alternatively, the D-tartaric acid isomer can be used to obtain the other enantiomer of the compound of formula III in scheme III. Preferred P²The radical is methyl. Alternatively, the compounds of formula III(s) and III (r) may be prepared by separation of the compounds of formula III by chiral chromatography as is well known in the art. For example, the compounds of formulae III (S) and III (R) can be prepared by isolating the compound of formula III using simulated moving bed chromatography.

The desired compound of formula III, wherein, F, G, R¹And R²As described above and P²Known carboxyl protecting groups can be obtained by reduction of the corresponding compounds of formula XIX. Generally, the compound of formula XIX is reduced by hydrogenation, preferably over a catalyst such as platinum (IV) oxide or Pt/C at a pressure of 55psi in an acidic medium such as acetic acid or an alcoholic solution of an acid such as hydrochloric acid or sulfuric acid, at a temperature of from about 20 ℃ to about 60 ℃ for from about 1 hour to about 18 hours; preferably, the reduction is carried out with Pt/C in a solution of hydrogen chloride in methanol at 50 ℃ for 2 hours.

The desired compound of formula XIX, wherein, F, G, R¹And R²As described above and P²Known carboxyl protecting groups can be prepared by alkylating the corresponding compounds of the formula XX, if desired with protection of the carboxyl group formed. Typically, the compound of formula XX is reacted with a suitable alkyl haloalkyl carboxylate in the presence of a base such as potassium carbonate in a polar solvent such as dimethylformamide at a temperature of from about 10 ℃ to about 120 ℃, typically 95 ℃, for a period of from about 2 to about 18 hours. Preferred P²The protecting group is methyl. Alternatively, the compound of formula XX may be mixed with a suitable trichloroalkylmethanol (e.g., chlorobutanol) in a corresponding ketone solvent (e.g., acetone) in the presence of a strong base such as sodium hydroxide at a temperature of from about-20 ℃ to about 60 ℃, typically at room temperature, for a period of from about 6 to about 24 hours. The resulting compound having a carboxyl group is mixed with a suitable alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a reaction temperature of about 15 ℃ to about 100 ℃ for about 1 hour To about 24 hours or with a suitable alcohol as solvent in the presence of a catalytic amount of acid such as concentrated sulfuric acid at a reaction temperature of about 20 c to about 120 c, preferably under reflux for about 1 hour to about 24 hours.

The desired compounds of formula XX, wherein F and G are as described above, are prepared by subjecting the corresponding compounds of formula XXI and formula XXII, which are commercially available or can be prepared by methods described in the literature, to a Suzuki coupling reaction. Typically, a compound of formula XXI is combined with a suitable diethylpyridylborane, as shown in formula XXII, and the reaction is carried out in a reaction inert solvent such as toluene in the presence of a base such as aqueous sodium carbonate and a catalyst such as tetrakis (triphenylphosphine) palladium (0) in ethanol at a temperature of from about 10 ℃ to about 120 ℃, typically at reflux temperature, for a period of from about 3 to about 18 hours.

It will be appreciated that optically pure compounds of formula I may be prepared by other methods than those described above and are well known to those skilled in the art. During their synthesis, certain compounds of formula I or intermediates of the invention have asymmetric carbon atoms and are thus enantiomers or diastereomers. Depending on their physicochemical differences, the diastereomeric mixtures can be separated into the individual diastereomers by methods well known in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated, for example, by chiral HPLC methods, or by converting mixtures of enantiomers into mixtures of diastereomers by reaction with a suitable optically active compound, such as an alcohol, separating the diastereomers and converting (hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Likewise, enantiomeric mixtures of compounds of formula I containing an acid or base moiety or intermediates in their synthesis can be separated into the corresponding pure enantiomers by formation of diastereomeric salts with optically pure chiral bases or acids (e.g., 1-phenyl-ethylamine or tartaric acid), separation of the diastereomers by fractional crystallization, followed by neutralization and decomposition of the salts to give the corresponding pure enantiomers. All isomers including diastereomers, enantiomers, and mixtures thereof form part of the invention. In addition, certain compounds of the present invention are atropisomers (e.g., substituted biaryl compounds) which are also considered to be part of the present invention.

A compound of formula I wherein X is-B-C (R)¹R²)-Z，F、G、R¹、R²A, W and E are as described above, B is O and Z is carboxy, and m, n, V and Y are varied and can be prepared by methods analogous to the reaction schemes described above.

Reaction scheme IV

According to scheme IV, the desired compounds of formula I, wherein X is-B-C (R)¹R²)-Z，m、n、V、Y、F、G、R¹、R²A, W and E are as described above, B is S and Z is carboxy (as in the compound of formula XXIII): removal of the amine protecting group P from the corresponding compound of formula XXIV¹Then acidylating with acyl chloride, sulfonyl chloride or isocyanate; or treatment with an alcohol and carbonyldiimidazole; or alkylation with an alkyl halide; optionally hydrolyzing the resulting compound to remove the carboxyl protecting group P²(see Greene, cited above) to produce the corresponding carboxylic acid. Alternatively, when the ester is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted. Generally, the reaction is carried out as described above for the preparation of compounds of formula II in scheme I.

A compound of the formula XXIV, wherein m, n, Y, V, F, G, R¹And R²As described above and P¹And P²Known protecting groups can be obtained from the corresponding compounds of formula XXV by deprotection of thiophenol followed by alkylation. Typically, a compound of formula XXV is combined with a base such as sodium hydroxide in a polar protic solvent such as methanol at a temperature of from about 20 ℃ to about 150 ℃, preferably at reflux temperature, usually for about 12 hours From time to about 24 hours. The thiophenol formed is then alkylated as described for the preparation of the compound of formula III in scheme I.

A compound of the formula XXV, wherein m, n, Y, V, F and G are as described above, P¹Are well known amine protecting groups and Ac is acetyl, can be prepared from the corresponding compound of formula XXVI by phase transfer catalyzed aromatic nucleophilic substitution. Typically, a compound of formula XXVI is reacted with a phase transfer catalyst such as tris [2- (2-methoxyethoxy) ethyl]The amine (TDA-1) and the nucleophilic reagent, such as potassium thioacetate, are combined in a non-polar solvent, such as toluene, at a reaction temperature of about 20 deg.C to about 150 deg.C, preferably at reflux temperature, typically for about 12 hours to about 24 hours.

A compound of the formula XXVI wherein m, n, Y, V, F and G are as described above, P¹Are well known amine protecting groups and TfO is trifluoromethanesulfonic acid, and can be prepared from the corresponding compound of formula XXVII by trifluoromethanesulfonization. Typically, a compound of formula XXVII (which is prepared, for example, as described in scheme I for compounds of formula IV) is combined with triflic anhydride and a base such as pyridine in a non-polar solvent such as dichloromethane at a reaction temperature of from about-80 ℃ to about room temperature, preferably 0 ℃, typically for from about 1 hour to about 5 hours.

If desired, the phenylthio compound of formula XXIII may be oxidized to the corresponding phenylsulfinyl or phenylsulfonyl compound by treatment with an oxidizing agent such as m-chloroperoxybenzoic acid in a reaction-inert solvent such as methylene chloride at a temperature of about-78 deg.C for the preparation of the sulfoxides and about 0 deg.C and about 25 deg.C for the preparation of the sulfones for about 1 to about 6 hours.

Reaction scheme V

The desired compounds of formula I, wherein X is Z, m ═ n ═ 1, V is methylene, Y is methylene, F, G, A, W and E are as described above, Z is carboxy and the piperidinyl ring is substituted in the 3-position with a phenyl ring (as in compounds of formula XXVIII), can be prepared according to scheme V by acylating the corresponding compound of formula XXIX with an acid chloride, sulfonyl chloride, isocyanate or carboxylic acid; or treating the corresponding compound of formula XXIX with an alcohol and carbonyldiimidazole; or alkylating the corresponding compound of formula XXIX with an alkyl halide; the resulting compound of formula XXVIII is then hydrolyzed, wherein the carboxyl group is protected with a well-known carboxyl protecting group (see Greene, cited above), to produce the corresponding carboxylic acid. Alternatively, when the ester is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted. Generally, the reaction is carried out as described above for the preparation of compounds of formula II in scheme I.

A compound of the formula XXIX wherein F and G are as described above and P²The known carboxyl protecting groups can be prepared by reduction of the corresponding compound of formula XXX followed by resolution to give optically pure material. Generally, the reduction and resolution are carried out as described in scheme III for the preparation of compounds of formula III.

Desired compounds of formula XXX wherein F and G are as described above and P²For the well-known carboxyl protecting group, the corresponding compounds of formula XXXI (wherein F and G are as described above and P is)²Known carboxyl protecting groups) and compounds of formula XXXII, which are commercially available or prepared according to conventional methods. Typically, this reaction is prepared as described above in scheme III for the preparation of compounds of formula XX.

Reaction scheme VI

According to scheme VI, the desired compound of formula I, wherein X is-B-C (R)¹R²)-Z，m、n、V、Y、F、G、R¹、R²A, W and E are as described above, B is methylene and Z is carboxy (as in the compound of formula XXXIII)Shown) removal of the amine protecting group P from the corresponding compound of formula XXXIV¹Then acidylating with acyl chloride, sulfonyl chloride or isocyanate; or treatment with an alcohol and carbonyldiimidazole; or alkylated with an alkyl halide; optionally hydrolyzing the resulting compound to remove the carboxyl protecting group P ²(see Greene, cited above) to produce the corresponding carboxylic acid. Alternatively, when the ester is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted. Generally, the reaction is carried out as described above for the preparation of compounds of formula II in scheme I.

A compound of the formula XXXIV is provided, wherein m, n, Y, V, F, G and R²As mentioned above, R¹Is- (C)₁-C₄) Alkyl or (C)₃-C₆) Cycloalkyl radicals, P¹And P²Known protecting groups may be prepared by alkylation of the corresponding compound of formula XXXV. Typically, the compound of formula XXXV is treated with a strong base such as lithium hexamethyldisilazide in an inert solvent such as tetrahydrofuran, preferably at about-78 deg.C for about 30 minutes to about 3 hours. A suitable alkylating agent such as an alkyl or cycloalkyl bromide or iodide is then added and allowed to react for about 1 to 24 hours at a temperature of about-78 c to about 25 c.

Alternatively, a compound of the desired formula I, wherein X is-B-C (R)¹R²)Z、m、n、V、Y、F、G、R²A, W and E are as described above, R¹Is hydrogen, B is methylene and Z is carboxyl (as in the formula XXXIII), the amine protecting group P can be removed from the corresponding compound of formula XXXV¹Then acidylating with acyl chloride, sulfonyl chloride or isocyanate; or treatment with an alcohol and carbonyldiimidazole; or alkylated with an alkyl halide; optionally hydrolyzing the resulting compound to remove the carboxyl protecting group P ²(see Greene, cited above) to produce the corresponding carboxylic acid. Alternatively, when the ester is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted. Generally, the reaction is carried out as described above for the preparation of compounds of formula H in scheme I.

A compound of the formula XXXV is provided, wherein m, n, Y, V, F, G and R²As mentioned above, P¹Is a well-known amine protecting group and P²The known carboxyl protecting groups can be prepared by reduction of the corresponding compounds of formula XXXVI. Typically, the compound of formula XXXVI is hydrogenated over a suitable catalyst such as palladium on charcoal at 5-10% w/w under a hydrogen pressure of 15-55p.s.i., preferably 55, and the reaction is carried out for about 2 to about 24 hours. Alternatively, the reduction reaction may be carried out in a suitable alcoholic solvent, preferably methanol, in the presence of magnesium metal, which dissolves during the reaction. Under these conditions, the reduction reaction may be accompanied by a transesterification reaction with an alcoholic solvent. This change does not normally affect the outcome of the subsequent reaction.

A compound of the formula XXXVI wherein m, n, Y, V, F, G and R²As mentioned above, P¹Is a well-known amine protecting group and P²The known carboxyl protecting groups can be prepared from the corresponding compounds of formula XXXVII by the Wittig-Horner reaction. Typically, a compound of formula XXXVII is added to a Wittig-Horner reagent formed by heating 2-diphenylphosphinyl-2-alkoxyacetate and chlorodiphenylphosphine in a reaction-inert solvent such as tetrahydrofuran in the presence of a base such as sodium hydride, the reaction being carried out at about-78 ℃ to room temperature, and the resulting mixture is refluxed, if necessary, for about 10 to 60 minutes.

Desired compounds of formula XXXVII wherein m, n, Y, V, F and G are as previously described and P¹The amine protecting groups, which are well known, can be prepared by reduction of the corresponding compound of formula XXXVIII (which is prepared as described in the previous schemes, see, for example, scheme V, wherein a compound of formula XXIX is prepared, which can be protected by the methods described herein). Typically, a compound of formula XXXVIII is reacted with a reducing agent such as diisobutylaluminium hydride in an aprotic solvent such as toluene, the reaction being carried out at from-78 ℃ to room temperature, preferably-78 ℃. In some cases, compounds of formula XXXVIII, which may be over-reduced to the corresponding alcohol, can be oxidized to the corresponding compound of formula XXXVII by treatment with a suitable oxidizing agent such as manganese dioxide in a suitable inert solvent such as diethyl ether at room temperature for about 1 to about 12 hours or a combination of oxalyl chloride and dimethyl sulfoxide under typical Swern oxidation conditions.

Reaction scheme VII

Scheme VII provides an alternative method for preparing the desired compounds of formula I, wherein X is-B-C (R)¹R²) Z, m, n, V, Y, F, G, A, W and E are as defined above, R¹Is H, R²As previously described, wherein the first carbon atom of the chain is replaced by an oxygen atom, B is methylene and Z is carboxy (as in the compound of formula XXXIX), by hydrolysis of the amide to produce the corresponding carboxylic acid from the corresponding compound of formula XXXX. Optionally, when the amide is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted.

Desired compounds of formula XXXX, wherein m, n, V, Y, F, G, A, W and E are as described above, R¹Is H, R²As mentioned previously, in which the first carbon atom of the chain is replaced by an oxygen atom and Ph is phenyl, the amine-protecting group P can be removed from the corresponding compound of formula XXXXI¹Then acidylating with acyl chloride, sulfonyl chloride or isocyanate; or treatment with an alcohol and carbonyldiimidazole; or with an alkyl halide. Generally, the reaction is carried out as described above for the preparation of compounds of formula II in scheme I.

The desired compound of formula XXXXI, wherein m, n, V, Y, F and G are as described above, R¹Is H, R²As previously mentioned, in which the first carbon atom of the chain is replaced by an oxygen atom, P¹For the amine protecting group, Ph is phenyl, and can be prepared by reduction of the corresponding compound of formula XXXXII. Typically, a compound of formula XXXXII is acylated, for example with acetic anhydride, in the presence of a base such as pyridine, followed by hydrogenation with a catalyst such as palladium on charcoal in a reaction inert solvent, or by transfer hydrogenation with ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on charcoal in a reaction inert solvent such as methanol or ethanol at a temperature of from about 0 ℃ to about 80 ℃, typically from about 25 ℃ to about 50 ℃.

Alternatively, the corresponding thiocarbonate may be treated with an aryl chlorothioformate in the presence of a base such as pyridine followed by reduction with tri-n-butyltin hydride in a reaction inert solvent such as toluene in the presence of a free radical initiator such as azobisisobutyronitrile at elevated temperatures, typically from about 80 ℃ to about 110 ℃.

The desired compound of formula XXXXII, wherein m, n, V, Y, F and G are as described above, R¹Is H, R²As described above, in which the first carbon atom of the chain is replaced by an oxygen atom, P¹Are amine protecting groups and Ph is phenyl, can be prepared from the corresponding compound of formula XXXVII (prepared as described in scheme VI) by aldol condensation. Typically, a compound of formula XXXVII is treated with the desired 4-benzyl-3-alkoxyacetyl-oxazolidin-2-one in the presence of di-n-butylborotrifluoromethane sulfonate under conditions described in the following references: hulin et al (j.med.chem., 1996, 39, 3897). By appropriate selection of the enantiomerically pure chiral auxiliary, the absolute configuration of the two new chiral centers can be controlled.

According to another aspect of scheme VII, the desired compounds of formula I, wherein X is-B-C (R)¹R²) Z, m, n, V, Y, F, G, A, W and E are as defined above, R ¹Is H, R²As previously described, wherein the first carbon atom of the chain is replaced with a sulfur atom, B is methylene and Z is carboxyl (represented by a compound of formula XXXIX): by removal of the amine protecting group P¹Deprotecting a compound of formula xxxiii; then acidylating with acyl chloride, sulfonyl chloride or isocyanate; or treatment with an alcohol and carbonyldiimidazole; or alkylated with an alkyl halide; optionally hydrolyzing the resulting compound to remove the carboxyl protecting group P²(see Greene, cited above) to produce the corresponding carboxylic acid. Alternatively, when the amide is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted. Generally, the reaction is carried out as described above for the preparation of compounds of formula II in scheme I.

Desired compounds of formula XXXIII, wherein m, n, V, Y, F and G are as described above, R¹Is H, R²As previously mentioned, in which the first carbon atom of the chain is replaced by a sulfur atom, P¹Is a well-known amine protecting group and P²For the well-known carboxyl protecting group, S can be carried out from the corresponding compound of the formula XXXXIV by coupling the methanesulfonyloxy group with the thiolate anion_N2 substitution. Typically, a compound of formula XXXXIV is treated with an alkyl or aryl thiol in the presence of a suitable base such as potassium hydroxide or potassium tert-butoxide, in a reaction inert solvent such as tetrahydrofuran or dimethylformamide at a temperature of from about 0 ℃ to about 50 ℃, usually about 25 ℃.

Desired compounds of formula XXXXIV wherein m, n, V, Y, F and G are as described above, P¹Is a well-known amine protecting group and P²Known carboxyl protecting groups can be prepared from the corresponding compounds of formula XXXXV by mesylation. Typically, a compound of formula XXXXV is treated with a suitable mesylating agent such as methanesulfonic anhydride or methanesulfonyl chloride in the presence of a suitable base such as pyridine in a reaction inert solvent such as pyridine, tetrahydrofuran or dimethylformamide at a temperature of from about 0 ℃ to about 50 ℃, typically about 25 ℃.

Desired compounds of formula XXXXV, wherein m, n, V, Y, F and G are as described above, P¹Is a well-known amine protecting group and P²The known carboxyl protecting groups can be prepared by reduction of the corresponding compounds of formula XXXXVI. Typically, the compound of formula XXXXXVI is reduced in a reaction inert solvent with a catalyst such as palladium on carbon, or the transfer hydrogenation is carried out with ammonium formate in refluxing methanol in the presence of a catalyst such as palladium on carbon in a reaction inert solvent such as methanol or ethanol at a temperature of from about 0 ℃ to about 80 ℃, typically from about 25 ℃ to about 50 ℃.

Desired compounds of formula XXXXVI wherein m, n, V, Y, F and G are as described above, P¹Is a well-known amine protecting group and P²For the well-known carboxyl protecting groups, they can be prepared from the corresponding compounds of formula XXXVII (prepared as described in scheme VI) by Darzens condensation. In general, a compound of formula XXXVII is reacted with a suitable α -halo ester, such as ethyl 2-chloroacetate, in the presence of a suitable base, such as sodium hydride, in a reaction-inert solvent Such as tetrahydrofuran, at a temperature of from about 25 c to about 80 c, typically at reflux temperature.

According to another aspect of scheme VII, the desired compounds of formula I, wherein X is-B-C (R)¹R²) Z, m, n, V, Y, F, G, A, W and E are as defined above, R¹Is H, R²As previously described, wherein the first carbon atom of the chain is replaced by an oxygen atom, B is methylene and Z is carboxyl (as shown for the compound of formula XXXIX), can be prepared from the corresponding compound of formula XXXXXV by alkylation. Typically, compounds of formula XXXXV are treated with alkyl, cycloalkyl or benzyl bromide or iodide in the presence of cesium hydroxide or carbonate, tetrabutylammonium iodide and molecular sieves as described in the following references: dueno et al Tetrahedron Letters 1999, 40, 1843.

Reaction scheme VIII

According to scheme VIII, the desired compounds of formula I, wherein X is-B-C (R)¹R²) -Z, m ═ n ═ 1, V is methylene, Y is methylene, F, G, R¹、R²A, W and E As mentioned above, B is NH, Z is carboxy and the piperidinyl ring is substituted in the 3-position by a phenyl ring (as shown for the compound of formula XXXXVI), this being obtained from the corresponding compound of formula XXXXVIII by removal of the amine protecting group P ¹Preparing; then acidylating with acyl chloride, sulfonyl chloride or isocyanate; or treatment with an alcohol and carbonyldiimidazole; or alkylated with an alkyl halide; optionally hydrolyzing the resulting compound to remove the carboxyl protecting group P²(see Greene, cited above) to produce the corresponding carboxylic acid. Alternatively, when the ester is a suitable prodrug of a carboxylic acid, the hydrolysis step may be omitted. Generally, the reaction is carried out as described above for the preparation of compounds of formula II in scheme I.

The desired compound of formula XXXXVIII, wherein, F, G,R¹And R²As mentioned above, P¹Is an amine protecting group and P²The piperidine nitrogen (P) can be selectively protected from the corresponding compound of formula XXXXIX for well-known carboxyl protecting groups¹) Then alkylated and if desired protected by carboxyl groups formed (P)²). Typically, a compound of formula XXXXIX is combined with a suitable protecting anhydride in a biphasic mixture of an aqueous base such as aqueous sodium hydroxide and a polar solvent such as tetrahydrofuran at a temperature of from about 0 ℃ to about 50 ℃, preferably room temperature, for 1 to 6 hours, preferably 2 hours. The resulting aniline is then alkylated and optionally protected as described for the compound of formula III in scheme I.

The desired compounds of formula XXXXIX, wherein F and G are as described above, can be prepared from the corresponding compounds of formula L by simultaneous reduction of the nitro function and the pyridine ring. In general, this reduction can be carried out as described for the preparation of compounds of formula V in scheme I.

The desired compounds of formula L, wherein F and G are as described above, can be prepared from the corresponding compounds of formula LI via Suzuki coupling as described for the compounds of formula V in scheme I.

According to another aspect of scheme VIII, there are provided compounds of formula I wherein X ═ Z ═ NHSO₂R₄Where m ═ n ═ 1, V is methylene, Y is methylene, F, G, A, W and E are as described above, and the piperidinyl ring is substituted in the 3-position with a phenyl ring (as shown for the compound of formula LII) can be prepared from the corresponding compound of formula LIII by removal of the amine protecting group P¹Preparing; then acidylating with acyl chloride, sulfonyl chloride or isocyanate; or treatment with an alcohol and carbonyldiimidazole; or alkylated with an alkyl halide. In general, these reactions can be carried out as described for the preparation of compounds of formula xxxxxi.

The desired compound of formula LIII, wherein, P¹For amine protecting groups, F and G are as described above, the piperidine nitrogen (P) may be selectively protected from the corresponding compound of formula XXXXIX¹) And acylating the aniline group formed. Selective protection of Compounds of formula XXXXIX, e.g. for preparation of Compounds of formula XXXXVIIIThe method described in (1) is carried out. The aniline formed is then acylated with trifluoromethanesulfonic anhydride in a reaction-inert solvent such as dichloromethane in the presence of an amine base such as triethylamine at a temperature of from about-20 c to about 50 c, typically 0 c, for a period of from about 0.5 to about 2 hours.

A compound of formula I wherein X is-B-C (R)¹R²)-Z，F、G、R¹、R²A, W and E are as above, B is NH and Z is carboxy, and m, n, V and Y have other modifications and can be prepared by analogous methods to those described in the schemes above. A compound of formula I wherein X ═ Z ═ -NHSO₂R₄F, G, A, W and E As noted above, m, n, V and Y have other modifications and can be prepared by analogous methods to those described in the schemes above.

The starting materials and reagents used in the above reaction schemes (e.g., 3-bromoanisole, diethyl- (3-pyridyl) borane, 3-bromopyridine, 3-methoxyphenylboronic acid, 3-bromophenol, 5-chloro-2-methylbenzoic acid, 2-nitro-4-bromotoluene, prodrug residues, protected forms, and others) are readily available or can be readily synthesized by one skilled in the art using conventional methods of organic synthesis. Some of the preparation methods described in the present invention will require protection of the distal functional group (e.g., carboxyl). The need for such protecting groups depends on the nature of the distal functional group and the conditions of the preparation process, which can be readily determined by the skilled person. General description for protecting groups (e.g. halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxymethyl, arylmethyl and tri (C)₁-C₄) Alkylsilyl) and their use, see t.w. greene, protective groups in Organic Synthesis, John Wiley & Sons，New York，1991。

Other methods of preparation of the compounds of formula I are readily apparent to those skilled in the art of organic chemistry and are illustrated in the literature and in the preparations and examples below.

Compounds of formula I wherein Z is tetrazol-5-yl may be prepared from the corresponding compounds of formula I wherein Z is carboxy,wherein the carboxyl group is converted to a carboxamide group (Z ═ CONH)₂) The formamide is dehydrated to a nitrile (Z ═ CN) and the nitrile is reacted with a suitable azide to form a tetrazolyl group. Typically, the acid is converted to the acylimidazole by reaction with carbonyldiimidazole in an aprotic solvent such as methylene chloride at a temperature of about 15 ℃ to about 40 ℃ for about 30 minutes to about 4 hours, conveniently at room temperature for 1 hour. The acylimidazole formed is then converted to the corresponding amide by bubbling ammonia gas through the reaction mixture at a temperature of from about 10 ℃ to about 40 ℃ for from about 3 minutes to about 30 minutes, preferably at room temperature for about 5 minutes or until completion as determined by TLC analysis. The amide is then converted to the nitrile by treatment with trifluoroacetic anhydride and triethylamine in an inert solvent such as dichloromethane at about 0 deg.C for about 25 minutes to about 2 hours, preferably 30 minutes. The nitrile is treated with sodium azide and ammonium chloride in dimethylformamide at a temperature of about 90 c to about 130 c for about 7 hours to about 60 hours, preferably at 120 c for 24 hours, to obtain the desired tetrazolyl group.

The desired compounds of formula I wherein Z is 4, 5-dihydro-5-oxo-1, 2, 4-oxadiazol-3-yl can be prepared from the corresponding compounds of formula I wherein Z is CN by converting the nitrile to an amidoxime and reacting the amidoxime with a carbonylation reagent to form the corresponding 4, 5-dihydro-5-oxo-1, 2, 4-oxadiazole derivative. Typically, the reaction of converting the nitrile to the amide oxime employs hydroxylamine hydrochloride, the reaction being carried out in an alcohol solvent in the presence of a base such as potassium carbonate at a temperature of from about 60 ℃ to about 110 ℃, the reaction being carried out for a period of from about 5 hours to about 24 hours, preferably in refluxing ethanol for a period of about 18 hours. The reaction of amidoxime to the corresponding 4, 5-dihydro-5-oxo-1, 2, 4-oxadiazole derivative was carried out using carbonyldiimidazole and triethylamine in refluxing ethyl acetate for about 24 hours.

Prodrugs of compounds of formula I may be prepared according to analogous methods well known to those skilled in the art. Exemplary methods are described below.

Prodrugs of the invention in which the carboxylic acid of formula I has its carboxyl group replaced by an ester are prepared by combining the carboxylic acid with a suitable alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of from about 0 c to about 100 c for about 1 to about 24 hours. Alternatively, the acid is mixed with a suitable alcohol as solvent in a catalytic amount of acid, such as concentrated sulfuric acid, at a temperature of about 20 ℃ to about 100 ℃, preferably at reflux temperature, for a period of about 1 hour to about 24 hours. Another method is to react the acid with a stoichiometric amount of alcohol in the presence of a catalytic amount of acid in an inert solvent such as toluene or tetrahydrofuran, with the concomitant removal of water produced during the reaction, either by physical means (e.g., Dean-Stark trap) or chemical means (e.g., molecular sieves).

Prodrugs of the invention in which the alcohol functional group is derivatized to an ether may be prepared by reacting an alcohol with a suitable alkyl bromide or iodide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of from about 0 ℃ to about 100 ℃ for from about 1 to about 24 hours. Alkanoylaminomethyl ethers can be obtained by reacting an alcohol with bis- (alkanoylamino) methane in the presence of a catalytic amount of an acid in an inert solvent such as tetrahydrofuran, according to the method described in U.S. Pat. No. 4,997,984. Alternatively, these compounds can be prepared as described in the following references: hoffman et al, J.org.chem.1994, 59, 3530.

Glucosides are prepared by reacting an alcohol with a sugar in the presence of an acid in an inert solvent such as toluene. Typically, the water formed in the reaction is removed as it forms, as described above. Another method is to react the alcohol with a suitably protected glucosyl halide in the presence of a base, followed by deprotection.

N- (1-hydroxyalkyl) amides and N- (1-hydroxy-1- (alkoxycarbonyl) methyl) amides can be prepared by reacting the parent amide with the appropriate aldehyde under neutral or basic conditions (e.g., sodium ethoxide in ethanol) at 25 ℃ to 70 ℃. N-alkoxymethyl or N-1- (alkoxy) alkyl derivatives can be obtained by reacting an N-unsubstituted compound with the necessary alkyl halide in the presence of a base in an inert solvent.

The compounds of the present invention may also be used in combination with other agents useful in the treatment of the diseases/conditions described herein.

In combination therapy, the compounds of the present invention and other agents may be administered to a mammal (e.g., a human, male or female) by conventional methods. The compounds of the present invention may be administered in combination with natural compounds that act to lower plasma cholesterol levels. These natural compounds are commonly referred to as nutraceuticals and include, for example, garlic extract and niacin. Niacin is available in a sustained release form under the name Niaspan. Nicotinic acid may also be used in combination with other therapeutic agents such as lovastatin as an HMG-CoA reductase inhibitor as further described below. This combination therapy is known as ADVICOR^TM(KosPharmaceuticals Inc.)。

Any cholesterol absorption inhibitor may be used as the second compound in the combination therapeutic aspect of the present invention. The term cholesterol absorption inhibition refers to the ability of a compound to prevent cholesterol contained within the intestinal lumen from entering the intestinal cells and/or from within the intestinal cells into the blood stream. Such cholesterol absorption inhibitory activity is readily determined by one skilled in the art according to standard assays (e.g., J. lipid Res. (1993) 34: 377- > 395). Cholesterol absorption inhibitors are well known to those skilled in the art and are described, for example, in the following documents: PCT WO 94/00480. An example of a recently approved cholesterol absorption inhibitor is ZETIA ^TMEtimibe (Merck/Schering-Plough).

Any HMG-CoA reductase inhibitor may be used as the second compound in the combination therapeutic aspect of the invention. The term HMG-CoA reductase inhibitor refers to a compound that is capable of inhibiting the biotransformation of hydroxymethylglutaryl-coenzyme A to mevalonate catalyzed by HMG-CoA reductase. Such inhibition is readily determined by one skilled in the art using standard assays (e.g., meth. enzymol. 1981; 71: 455-) -509, the contents of which are incorporated herein by reference). Many such compounds are described and referred to hereinafter; however, other HMG-CoA reductase inhibitors are well known to those skilled in the art. U.S. Pat. No. 4,231,938 describes certain musical compositionsThe compound isolated after culturing the microorganism of the genus Mycoplasma, such as lovastatin. Furthermore, U.S. Pat. No. 4,444,784 describes synthetic derivatives of the above compounds, such as simvastatin. In addition, U.S. Pat. No. 4,739,073 describes certain substituted indoles, such as fluvastatin. In addition, U.S. Pat. No. 4,346,227 describes ML-236B derivatives, such as pravastatin. In addition, EP-491226A describes certain pyridyl dihydroxy heptenoic acid compounds, such as cerivastatin. Furthermore, U.S. Pat. No. 5,273,995 describes certain 6- [2- (substituted-pyrrol-1-yl) alkyl groups ]Pyran-2-ones, e.g. atorvastatin and hemicalcium salts thereofOther HMG-CoA reductase inhibitors include rosuvastatin and pitavastatin.

Any MTP/Apo B secretion (microsomal triglyceride transfer protein and/or apolipoprotein B secretion) inhibitor may be used as the second compound in the combination therapeutic aspect of the invention. The term MTP/ApoB secretion inhibitor refers to compounds that inhibit the secretion of triglycerides, cholesterol esters and phospholipids. Such inhibition can be readily determined by one skilled in the art using standard assays (e.g., Wetterau, J.R. 1992; Science 258: 999). Various such compounds are well known to those skilled in the art, including immunoputapride (bayer) and other compounds such as those disclosed in the following references: WO96/40640 and WO 98/23593.

Any HMG-CoA synthase inhibitor may be used as the second compound in the combination therapeutic aspect of the present invention. The term HMG-CoA synthase inhibitor refers to a compound capable of inhibiting the biosynthesis of hydroxymethylglutaryl-coenzyme a from acetyl-coenzyme a and acetoacetyl-coenzyme a catalyzed by the enzyme HMG-CoA synthase. Such inhibition can be readily determined by one skilled in the art using standard assays (e.g., Meth Enylmol. 1975; 35: 155-. Many such compounds are described and referred to below, but other HMG-CoA synthase inhibitors are well known to those skilled in the art. U.S. patent 5,120,729 describes certain β -lactam derivatives. U.S. Pat. No. 5,064,856 describes certain spiro-lactone derivatives produced by culturing the microorganism MF 5253. U.S. Pat. No. 4,847,271 describes certain oxetane compounds such as 11- (3-hydroxymethyl-4-oxo-2-oxetanyl) -3, 5, 7-trimethyl-2, 4-undec-dienoic acid derivatives.

Any compound capable of reducing the expression of the HMG-CoA reductase gene may be used as the second compound in the combination therapeutic aspect of the invention. These agents may be HMG-CoA reductase transcription inhibitors that prevent or reduce DNA transcription or translation inhibitors that prevent or reduce the transcription of mRNA encoding HMG-CoA reductase into proteins. Such compounds may either directly affect transcription or translation, or be bioconverted by one or more enzymes in the cholesterol biosynthesis cascade to compounds having the above-described functions, or may result in the aggregation of isoprene metabolites having the above-described activities. Such adjustments can be readily determined by one skilled in the art based on standard tests (e.g., meth. enzymol. 1985; 110: 9-19). HMG-CoA reductase gene expression inhibitors are well known to those skilled in the art, for example, U.S. Pat. No. 5,041,432 describes certain 15-substituted lanosterol derivatives. The following references discuss other oxysterols capable of inhibiting HMG-CoA reductase synthesis (prog. lip. Res.1993; 32: 357-416).

Any compound having CETP inhibitor activity may be used as the second compound in the combination therapeutic aspect of the invention. The term CETP inhibitor refers to compounds that inhibit Cholesteryl Ester Transfer Protein (CETP) -mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETP inhibitory activity is readily determined by one skilled in the art according to standard assays (e.g., U.S. patent 6,140,343). Various CETP inhibitors are known to those skilled in the art, and for example, these compounds are disclosed in commonly assigned U.S. Pat. No. 6,140,343 and commonly assigned U.S. Pat. No. 6,197,786. The CETP inhibitors disclosed in these patents include compounds such as [2R, 4S ]4- [ (3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino ] -2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, which is also known as torcetrapib. U.S. patent 5,512,548 describes certain polypeptide derivatives having CETP inhibitor activity, and certain CETP inhibiting rose-lactone derivatives and ester-containing cholesterol ester analogs are disclosed in the following documents, respectively: j.albiot, 49 (8): 815 +, 816(1996), and bioorg.med.chem.lett.; 6: 1951-1954(1996).

Any squalene synthetase inhibitor can be used as the second compound of the present invention. The term squalene synthetase inhibitor refers to a compound which inhibits the condensation of two molecules of farnesyl pyrophosphate with squalene, which reaction is catalyzed by squalene synthetase. Such inhibition is readily determined by one skilled in the art using standard assays (e.g., meth. enzymol. 1969; 15: 393. 1985; 110: 359. 373, the contents of which are incorporated herein by reference). Various such compounds are well known to those skilled in the art, for example, U.S. Pat. No. 5,026,554 describes the fermentation products of the microorganism MF5465(ATCC 74011), including zaragozic acid. Reviews of other squalene synthetase inhibitors have been published (see, e.g., curr. op. ther. patents (1993) 861-4).

Any squalene epoxidase inhibitor may be used as the second compound in the combination therapeutic aspects of the invention. The term squalene epoxidase inhibitor refers to a compound which is capable of inhibiting the biotransformation of squalene to squalene-2, 3-epoxide, catalyzed by squalene epoxidase, with molecular oxygen. Such inhibition can be readily determined by one skilled in the art using standard assays (e.g., Biochim. Biophys. acta 1984; 794: 466-. Various such compounds are well known to those skilled in the art, for example, U.S. Pat. Nos. 5,011,859 and 5,064,864 describe certain fluorinated analogs of squalene. EP 395,768A describes certain substituted allylamine derivatives. WO9312069A describes certain amino alcohol derivatives. U.S. patent 5,051,534 describes certain cyclopropoxy-squalene derivatives.

Any squalene cyclase inhibitor may be used as the second compound in the combination therapeutic aspects of the invention. The term squalene cyclase inhibitor refers to a compound which inhibits the biotransformation of squalene-2, 3-epoxide to lanosterol, the reaction being catalyzed by squalene cyclase. Such inhibition can be readily determined by one skilled in the art using standard assays (e.g., FEBS Lett. 1989; 244: 347-. Inhibitors of squalene cyclase are well known to those skilled in the art. For example, WO9410150 and french patent 2697250 describe squalene cyclase inhibitors.

Any combination of squalene epoxidase/squalene cyclase inhibitors may be used as the second compound in the combination therapeutic aspects of the invention. The term mixed squalene epoxidase/squalene cyclase inhibitor refers to compounds which are capable of inhibiting the biotransformation of squalene to lanosterol via a squalene-2, 3-epoxide intermediate. In certain experiments, it was not possible to distinguish between squalene epoxidase inhibitors and squalene cyclase inhibitors. However, these experiments are well known to those skilled in the art. Thus, the inhibition achieved by the mixed squalene epoxidase/squalene epoxidase inhibitors is readily determinable by the skilled person according to standard tests described above for squalene cyclase or squalene epoxidase inhibitors. Various squalene epoxidase/squalene cyclase inhibitors are well known to those skilled in the art. U.S. Pat. Nos. 5,084,461 and 5,278,171 describe certain azadecalin derivatives. EP468,434 describes certain piperidinyl ether and thioether derivatives such as 2- (1-piperidinyl) pentylisopentyl sulfoxide and 2- (1-piperidinyl) ethyl sulfide. WO9401404 describes certain acyl-piperidines such as 1- (1-oxopentyl-5-phenylthio) -4- (2-hydroxy-1-methyl) -ethyl) piperidine. U.S. patent 5,102,915 describes certain cyclopropoxysqualene derivatives.

Any ACAT inhibitor may be used as the second compound in the combination therapeutic aspect of the invention. The term ACAT inhibitor refers to a compound capable of inhibiting the binding of a protein by acyl CoA: intracellular esterification of dietary cholesterol by cholesterol acyltransferase. Such inhibition is readily determined by one skilled in the art based on standard assays, such as the method of Heider et al, Journal of lipid research, 24: 1127(1983). Various such compounds are well known to those skilled in the art, for example, U.S. Pat. No. 5,510,379 describes certain carboxy sulfonates, and WO96/26948 and WO96/10559 both describe urea derivatives having ACAT inhibitory activity. Examples of ACAT inhibitors include compounds such as the following: avasimibe (Pfizer), CS-505(Sankyo), and Edlucimibe (Eli Lilly and Pierre Fabre).

Lipase inhibitors may be used as the second compound in the combination therapeutic aspect of the invention. The term lipase inhibitor refers to compounds which are capable of inhibiting the metabolic cleavage of dietary triglycerides into free fatty acids and monoglycerides. Lipolysis is carried out in two steps under normal physiological conditions, involving acylation of the activated serine moiety of the lipase. This results in the production of a fatty acid-lipase hemiacetal intermediate. This intermediate is then cleaved to release the diglyceride. After further deacylation, the lipase-fatty acid intermediate is cleaved to form free lipase, monoglyceride and fatty acid. The free fatty acids and monoglycerides formed are incorporated into the bile acid-phospholipid micelles, which are then absorbed at the brush border of the small intestine. The micelles eventually enter the peripheral tissues as chylomicrons. Such lipase inhibitory activity can be readily determined by one skilled in the art using standard assays (e.g., Methods enzymol.286: 190-231).

Pancreatic lipase mediates the metabolic cleavage of fatty acids at the 1-and 3-carbon positions by triglycerides. The main metabolic site of the ingested fat is by pancreatic lipase in the duodenum and anterior segment of the jejunum, which is normally secreted in amounts far exceeding the amount required to break down fat in the upper small intestine. Since pancreatic lipase is the major enzyme required for absorption of dietary triglycerides, the formulation is useful for the treatment of obesity and other related diseases. This pancreatic lipase inhibitory activity can be readily determined by one skilled in the art using standard assays (e.g., Methods enzymol.286: 190-231).

Gastric lipase is an immunologically distinct lipase, responsible for approximately 10 to 40% of dietary fat digestion. Gastric lipase is secreted in response to mechanical stimulation, food intake, provision of a fat diet, or stimulation of sympathetic agents. Gastric lipolysis of ingested fat has the physiological importance of providing the required fatty acids in the intestine to elicit pancreatic lipase activity, and has the importance of being useful for fat absorption in various physiological and pathological conditions associated with pancreatic insufficiency. See, e.g., c.k.abrams et al, Gastroenterology, 92, 125 (1987). Such gastric lipase inhibitory activity can be readily determined by one skilled in the art using standard assays (e.g., Methods enzymol.286: 190-231).

Various inhibitors of gastric and/or pancreatic lipases are known to those skilled in the art. Preferred lipase inhibitors are inhibitors selected from the group consisting of: lipstatin, tetrahydrolipstatin, valilactone, lipstatin, ebelactone A and ebelactone B. The compound tetrahydrolipstatin is particularly preferred. Lipase inhibitors, N-3-trifluoromethylphenyl-N '-3-chloro-4' -trifluoromethylphenyl urea and various urea derivatives related thereto are disclosed in U.S. Pat. No. 4,405,644. Lipase inhibitors esterascin are disclosed in us patents 4,189,438 and 4,242,453. The lipase inhibitors cyclo-O, O' - [ (1, 6-hexanediyl) -di- (iminocarbonyl) ] dioxime and the various related bis (iminocarbonyl) dioximes can be prepared as described in: petersen et al, Liebig's Annalen, 562, 205-.

Various pancreatic lipase inhibitors are described below. The pancreatic lipase inhibitors tapestristatin, (2S, 3S, 5S, 7Z, 10Z) -5- [ (S) -2-carboxamido-4-methyl-valeryloxy ] -2-hexyl-3-hydroxy-7, 10-hexadecanolide and tetrahydrotapestristatin (orlistat), (2S, 3S, 5S) -5- [ (S) -2-carboxamido-4-methyl-valeryloxy ] -2-hexyl-3-hydroxy-hexadecane 1, 3 acid lactone and various substituted N-formylleucine derivatives and stereoisomers thereof are disclosed in U.S. patent 4,598,089. For example, tetrahydropatatin is prepared as described in: us patent 5,274,143; 5,420,305, respectively; 5,540,917, respectively; and 5,643,874. The pancreatic lipase inhibitor, FL-386, 1- [4- (2-methylpropyl) cyclohexyl ] -2- [ (phenylsulfonyl) oxy ] -ethanone, and various related substituted sulfonate derivatives thereof are disclosed in U.S. patent 4,452,813. Pancreatic lipase inhibitors, WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-formate, and various carbamates and pharmaceutically acceptable salts related thereto are disclosed in U.S. Pat. No. 5,512,565; 5,391,571, and 5,602,151. Preparation of pancreatic lipase inhibitors, valilactone, and microbial cultures by the actinomycete strain MG147-CF2 are disclosed in Kitahara et al, J.antibiotics, 40(11), 1647-1650 (1987). Preparation of pancreatic lipase inhibitors, ebelelectone A and ebelelectone B, and microbial cultures by the actinomycete strain MG7-G1 are disclosed in Umezawa et al, J.antibiotics, 33, 1594-. The use of ebeleptone A and B for inhibiting monoglyceride formation is disclosed in Japanese Kokai 08-143457, published 6/4/1996.

Other commercially available compounds useful for hyperlipidemia, including hypercholesterolemia, and aiding in the prevention or treatment of atherosclerosis include bile acid sequestrants, e.g.Andand fibric acid derivatives, e.g.And

diabetes can be treated by administering to a patient suffering from diabetes (particularly type II), insulin resistance, impaired glucose tolerance, etc., or any diabetic complication such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of formula I in combination with other agents useful in the treatment of diabetes (e.g., insulin). This includes antidiabetic drugs (and specific drugs) as described below.

Any glycogen phosphorylase inhibitor may be used as the second agent in combination therapy with the compounds of formula I. The term glycogen phosphorylase inhibitor refers to a compound that inhibits the biotransformation of glycogen to glucose-1-phosphate, which reaction is catalyzed by glycogen phosphorylase. Such glycogen phosphorylase inhibitory activity can be readily determined by one skilled in the art using standard assays (e.g., J.Med.chem.41(1998) 2934-. Various glycogen phosphorylase inhibitors are well known to those skilled in the art, including those described in WO96/39384 and WO 96/39385.

Any aldose reductase inhibitor may be used as the second agent in combination therapy with the compounds of formula I of the present invention. The term aldose reductase inhibitor refers to a compound that inhibits the biotransformation of glucose to sorbitol, a reaction catalyzed by aldose reductase. Aldose reductase inhibition is readily determined by one skilled in the art based on standard assays (e.g., J.Malone, Diabetes, 29: 861-864 (1980). "Red Cell sorbent, an Indicator of metabolic Control"). Various aldose reductase inhibitors are well known to those skilled in the art.

Any sorbitol dehydrogenase inhibitor may be used in combination with the compounds of formula I of the present invention. The term sorbitol dehydrogenase inhibitor refers to a compound that inhibits the bioconversion of sorbitol to fructose, a reaction catalyzed by sorbitol dehydrogenase. Such sorbitol dehydrogenase inhibitory activity can be readily determined by one skilled in the art using standard assays (e.g., Analyt. biochem (2000) 280: 329-331). Various sorbitol dehydrogenase inhibitors are known, for example, U.S. Pat. Nos. 5,728,704 and 5,866,578 describe compounds and methods for treating or preventing diabetic complications by inhibiting sorbitol dehydrogenase.

Any glucosidase inhibitor may be used in combination with the compounds of formula I of the present invention. Glucosidase inhibitors are capable of inhibiting the enzymatic hydrolysis of complex sugars by glycoside hydrolases such as amylase or maltase to form bioavailable monosaccharides such as glucose. The rapid metabolic action of glucosidase, especially after ingestion of large amounts of sugar, results in a hyperglycemic state in the diet, which in obesity or diabetes patients results in increased insulin secretion, increased fat synthesis and reduced fat degradation. As this hyperglycemia occurs, hypoglycemia often occurs due to the need to increase insulin levels. Furthermore, chyme remaining in the stomach is known to promote gastric juice production, which in turn stimulates or promotes the development of ulcerative gastritis or duodenal ulcer. Thus, glucosidase inhibitors are known to be useful in accelerating the passage of sugars through the stomach and inhibiting the absorption of glucose by the intestine. In addition, the conversion of sugar to adipose tissue lipids and subsequent dietary fat entry into the adipose tissue deposit may also be reduced or delayed, thereby simultaneously contributing to the reduction or prevention of deleterious abnormal effects caused thereby. Such glucosidase inhibitory activity is readily determined by one skilled in the art based on standard assays (e.g., Biochemistry (1969) 8: 4214).

Preferred glucosidase inhibitors generally include amylase inhibitors. Amylase inhibitors are glucosidase inhibitors, which inhibit the degradation of starch or glycogen to maltose by enzymatic processes. Such amylase inhibitory activity can be readily determined by one skilled in the art using standard assays (e.g., Methods Enzymol (1955) 1: 149). This inhibition of enzymatic degradation is beneficial for reducing the amount of bioavailable sugars, including glucose and maltose, and at the same time reducing the adverse conditions caused thereby.

Various glucosidase inhibitors are known to those skilled in the art, examples of which are as follows. Preferably, the glucosidase inhibitor is an inhibitor selected from the group consisting of: acarbose, lipolytics, voglibose, miglitol, emiglitate, canaglibose, amylstatin, trestatin, pranamicin-Q, and saticostatin. Glucosidase inhibitors, acarbose and various related aminosugar derivatives thereof are disclosed in U.S. Pat. Nos. 4,062,950 and 4,174,439, respectively. A glucosidase inhibitor, a lipolytic enzyme, is disclosed in us patent 4,254,256. Glucosidase inhibitors, voglibose, 3, 4-dideoxy-4- [ [ 2-hydroxy-1- (hydroxymethyl) ethyl ] amino ] -2-C- (hydroxymethyl) -D-epi-cyclohexanehexol, various N-substituted pseudo-aminosugars related thereto are disclosed in U.S. patent 4,701,559. Glucosidase inhibitors, miglitol, (2R, 3R, 4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3, 4, 5-piperidinetriol, and various related 3, 4, 5-trihydroxypiperidines are disclosed in U.S. patent No. 4,639,436. Glucosidase inhibitors, emiglitate, ethyl p- [2- [ (2R, 3R, 4R, 5S) -3, 4, 5-trihydroxy-2- (hydroxymethyl) piperidin-1-yl ] ethoxy ] -benzoate, various derivatives related thereto and pharmaceutically acceptable acid addition salts thereof are disclosed in U.S. patent 5,192,772. A glucosidase inhibitor, MDL-25637, 2, 6-dideoxy-7-O-beta-D-glucopyranosyl-2, 6-imino-D-glycerol-L-glucose-heptac sugar alcohol, various co-related homodisaccharides and pharmaceutically acceptable acid addition salts thereof are disclosed in U.S. Pat. No. 4,634,765. Glucosidase inhibitors, canaglibose, 6-deoxy-6- [ (2R, 3R, 4R, 5S) -3, 4, 5-trihydroxy-2- (hydroxymethyl) piperidin-1-yl ] - α -D-glucopyranoside sesquihydrate, deoxynojirimycin derivatives related thereto, various pharmaceutically acceptable salts thereof and methods of synthesizing the same are disclosed in U.S. patents 5,157,116 and 5,504,078. Inhibitors of oligosaccharidases, salbostatin and various pseudosugars related thereto are disclosed in U.S. patent 5,091,524.

Various amylase inhibitors are well known to those skilled in the art. Amylase inhibitors, amylase aprotinin and various related cyclic peptides are disclosed in U.S. patent 4,451,455. The amylase inhibitor AI-3688 and various loop polypeptides related thereto are disclosed in U.S. Pat. No. 4,623,714. Amylase inhibitors, trestatins, consisting of a mixture of trestatin a, trestatin B and trestatin C, and various corelated amino sugars containing trehelose are disclosed in us patent 4,273,765.

Other antidiabetic compounds which may be used as a second agent in combination therapy with the compounds of formula I of the present invention include, for example, the following: biguanides (e.g., metformin), insulin secretagogues (e.g., sulfonylureas and meglitinides), glitazones, non-glitazone PPAR γ agonists, PPAR β agonists, DPP-IV inhibitors, PDE5 inhibitors, GSK-3 inhibitors, glucagon antagonists, f-1, 6-BPase inhibitors (Metabasis/Sankyo), GLP-1/analogs (AC2993, also known as exendin-4), insulin and insulin mimetics (Merck natural products). Other examples include PKC-beta inhibitors and AGE blockers.

The compounds of formula I of the present invention may be used in combination with other anti-obesity agents. Any of the anti-obesity agents can be used as the second agent for such combined use, and examples thereof are as follows. The slimming activity is readily determined by the person skilled in the art according to standard tests well known in the art.

Suitable weight reducing agents include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, beta₃Adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (e.g., sibutramine), sympathomimetics, 5-hydroxytryptamine drugs, cannabinoid receptor antagonists (e.g., rimonabant (SR-141, 716A)), dopamine agonists (e.g., bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin receptor agonists, somatotropin neuropeptide antagonists, lipase inhibitors (e.g., tetrahydropatatin, i.e., orlistat), bombesin agonists, anorectic agents (e.g., bombesin agonists), neuropeptide-Y antagonists, thyroxine, thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., Axokine)^TM) Human guinea pig related protein (AGRP), ghrelin receptor antagonists, Histamine 3 receptor antagonists or inverse agonists, neurointerleukin U receptor agonists, and the like.

Any thyromimetic agent may be used as a second agent in combination therapy with a compound of formula I of the present invention. Such thyromimetic activity is readily determined by one skilled in the art according to standard assays (e.g., Atherosclerosis (1996) 126: 53-63). Various thyromimetic agents are well known to those skilled in the art, such as those disclosed in the following references: us patent 4,766,121; 4,826,876, respectively; 4,910,305, respectively; 5,061,798, respectively; 5,284,971, respectively; 5,401,772, respectively; 5,654,468, respectively; and 5,569,674.

Other anti-obesity agents include sibutramine, which is prepared as described in U.S. Pat. No. 4,929,629, and bromocriptine, which is prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888.

The compounds of formula I of the present invention may also be used in combination with other antihypertensive agents. Any of the antihypertensive agents can be used in such combination therapy as a second agent, examples of which are provided below. Such antihypertensive activity is readily determined by one skilled in the art based on standard tests (e.g., measuring blood pressure).

Examples of currently marketed products containing antihypertensive agents include calcium channel blockers, e.g. ProcardiaAndangiotensin Converting Enzyme (ACE) inhibitors, e.g.And

osteoporosis is a systemic skeletal disease characterized by low bone mass and degeneration of bone tissue, with the result that bone fragility increases and fractures easily. In the united states, the disease affects over 2500 million people and causes over 130 million fractures per year, including 500,000 spine, 250,000 hip, and 240,000 carpal fractures per year. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying from the disease each year and over 50% of survivors being disabled.

Elderly people are at the highest risk for osteoporosis and, as the population ages, the problem is expected to increase significantly. Worldwide incidence of fractures has increased 3-fold over the next 60 years, and one study estimates that by 2050, hip fractures will reach 450 million worldwide.

Women are at greater risk of osteoporosis than men. Bone loss is markedly accelerated in women within 5 years after menopause. Other factors that increase this risk include smoking, alcohol abuse, sedentary and low calcium intake.

As is well known to those skilled in the art, anti-resorptive drugs (e.g., progestogens, polypeptides)Phosphonates, bisphosphonates, estrogen agonists/antagonists, estrogens, estrogen/progestin combination therapy, Estrone, estriol, or 17 α -or 17 β -ethinyl estradiol) may be used in combination with a compound of formula I of the present invention.

Exemplary progestogens may be from commercial sources and include: megestrol, allylpregnen, amadenone acetate, anagestone acetate, chlormadinone acetate, engestrol, chlorgestrel acetate, chlormeprogesterone acetate, demegestone acetate, desogestrel, dixonogen, dydrogesterone, dehydrogesterone, dehydrogestrel, norethindrone acetate, etonogel acetate, etonogestrel, flurogest acetate, gestodene caproate, gestrinone, halogen progesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, medrenone acetate, medrenol acetate, medynodiol diacetate, norethindrone acetate, norethindrone, norgestrel, oxoropioprogesterone, progesterone, quinigestrel acetate, quinigestrel, and tetrol.

Preferred progestogens are medroxyprogesterone, norethindrone and norethindrone.

Exemplary bone resorption inhibiting polyphosphoric acid compounds include various types of polyphosphonic acid compounds disclosed in U.S. patent 3,683,080, which is incorporated herein by reference. Preferably, the polyphosphonic acid compound is a geminal diphosphonic acid compound (also known as a bisphosphonate). Disodium tiludronate is a particularly preferred polyphosphonate. Ibandronic acid is a particularly preferred polyphosphonic acid. Alendronate and resindronate are particularly preferred polyphosphonic acids. Zoledronic acid is a particularly preferred polyphosphonic acid.

Other preferred polyphosphonic acids are 6-amino-1-hydroxy-hexylidene diphosphonic acid and 1-hydroxy-3- (methylpentylamino) -propylidene-diphosphonic acid. The polyphosphonates may be administered in the acid form, soluble alkali metal salts or alkaline earth metal salts. Hydrolyzable esters of polyphosphonic acids are also included. Specific examples include ethane-1-hydroxy-1, 1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1, 1-diphosphonic acid, methane dichlorodiphosphonic acid, methane hydroxydiphosphonic acid, ethane-1-amino-1, 1-diphosphonic acid, ethane-2-amino-1, 1-diphosphonic acid, propane-3-amino-1-hydroxy-1, 1-diphosphonic acid, propane-N, N-dimethyl-3-amino-1-hydroxy-1, 1-diphosphonic acid, propane-3, 3-dimethyl-3-amino-1-hydroxy-1, 1-diphosphonic acid, phenylamino methane diphosphonic acid, N-dimethylamino methane diphosphonic acid, N-1, 1-diphosphonic acid, N-dimethyl-1, 1-diphosphonic acid, N-amino methane diphosphonic acid, n (2-hydroxyethyl) aminomethane diphosphonic acid, butane-4-amino-1-hydroxy-1, 1-diphosphonic acid, pentane-5-amino-1-hydroxy-1, 1-diphosphonic acid, hexane-6-amino-1-hydroxy-1, 1-diphosphonic acid, and pharmaceutically acceptable esters and salts thereof.

In particular, the compounds of the present invention may be used in combination with mammalian estrogen agonists/antagonists. Any estrogen agonist/antagonist may be used as the second compound of the invention. The term estrogen agonist/antagonist refers to a compound that is capable of binding to the estrogen receptor, inhibiting bone turnover and/or preventing bone loss. In particular, an estrogen agonist is defined herein as a compound that is capable of binding to the estrogen receptor site of mammalian tissue and mimicking the effect of estrogen in one or more tissues. An estrogen antagonist is defined herein as a compound that is capable of binding to the estrogen receptor site of mammalian tissue and preventing the action of estrogen in one or more tissues. Such activity is readily determined by one skilled in the art by standard assays, including estrogen receptor binding assays, standard bone histomorphometry and bone density methods, as well as Eriksen E.F. et al, BoneHistomorphometry, Raven Press, New York, 1994, pages 1-74; grier s.j. et al, application of dual energy X-ray absorptiometry in animals, inv.radio., 1996, 31 (1): 50-62; wahner h.w. and Fogelman i., assessment of osteoporosis: use of dual-energy X-ray absorptiometry in clinical practice, Martin Dunitiz, London 1994, pages 1-296). Many such compounds are described and referred to hereinafter.

Other preferred estrogen agonists/antagonists are 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acrylic acid, which is disclosed in Willson et al, Endocrinology, 1997, 138, 3901-.

Other preferred estrogen agonists/antagonists are tamoxifen: (ethylamine, 2- (-4- (1, 2-diphenyl-1-butenyl) phenoxy) -N, N-dimethyl, (Z) - -, 2-hydroxy-1, 2, 3-propane tricarboxylate (1: 1)) and related compounds, which are disclosed in U.S. patent 4,536,516, the contents of which are incorporated herein by reference.

Other related compounds are 4-hydroxyttamoxifen, which is disclosed in U.S. patent 4,623,660, the contents of which are incorporated herein by reference.

Preferred estrogen agonists/antagonists are raloxifene: (methanone, (6-hydroxy-2- (4-hydroxyphenyl) benzo [ b ] thiophen-3-yl) (4- (2- (1-piperidinyl) ethoxy) phenyl) -hydrochloride) which is disclosed in U.S. Pat. No. 4,418,068, the contents of which are incorporated herein by reference.

Other preferred estrogen agonists/antagonists are toremifene: (ethylamine, 2- (4- (4-chloro-1, 2-diphenyl-1-butenyl) phenoxy) -N, N-dimethyl-, (Z) -, 2-hydroxy-1, 2, 3-propane tricarboxylate (1: 1), which is disclosed in U.S. Pat. No. 4,996,225, the contents of which are incorporated herein by reference.

Other preferred estrogen agonists/antagonists are starcromann: 1- (2- ((4- (-methoxy-2, 2, dimethyl-3-phenyl-chroman-4-yl) -phenoxy) -ethyl) -pyrrolidine, which is disclosed in U.S. patent 3,822,287, the contents of which are incorporated herein by reference.

Other preferred estrogen agonists/antagonists are idoxifene: (E) -1- (2- (4- (1- (4-iodo-phenyl) -2-phenyl-but-1-enyl) -phenoxy) -ethyl) -pyrrolidone, which is disclosed in U.S. patent 4,839,155, the contents of which are incorporated herein by reference.

Other preferred estrogen agonists/antagonists are 2- (4-methoxy-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy ] -benzo [ b ] thiophen-6-ol, which is disclosed in U.S. patent 5,488,058, the contents of which are incorporated herein by reference.

Other preferred estrogen agonists/antagonists are 6- (4-hydroxy-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -benzyl) -naphthalen-2-ol, which is disclosed in U.S. patent 5,484,795, the contents of which are incorporated herein by reference.

Other preferred estrogen agonists/antagonists are (4- (2- (2-aza-bicyclo [2.2.1] hept-2-yl) -ethoxy) -phenyl) - (6-hydroxy-2- (4-hydroxy-phenyl) -benzo [ b ] thiophen-3-yl) -methanone, which compound, together with methods for its preparation, is disclosed in WO95/10513, assigned to Pfizer inc.

Other preferred estrogen agonists/antagonists include the compounds TSE-424(Wyeth-Ayerstlaboratories) and azaxifen.

Other preferred estrogen agonists/antagonists include compounds as indicated in U.S. patent 5,552,412, the contents of which are incorporated herein by reference. Particularly preferred compounds of the invention are:

cis-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-ol;

(-) -cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-ol (also known as lasofoxifene);

cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-ol;

cis-1- (6 '-pyrrolidin-1-yl-ethoxy-3' -pyridyl) -2-phenyl-6-hydroxy-1, 2, 3, 4-tetrahydronaphthalene;

1- (4' -pyrrolidin-1-yl-ethoxyphenyl) -2- (4 "-fluorophenyl) -6-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline;

cis-6- (4-hydroxyphenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-ol; and

1- (4' -pyrrolidin-1-yl-ethoxyphenyl) -2-phenyl-6-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline.

Other estrogen agonists/antagonists are described in U.S. Pat. No. 4,133,814 (the contents of which are incorporated herein by reference). U.S. Pat. No. 4,133,814 describes derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3-aroyl benzothiophene-1-oxide.

Other anti-osteoporosis agents which may be used in combination with the compounds of formula I of the present invention include, for example, the following: parathyroid hormone (PTH), a bone anabolic agent; parathyroid hormone (PTH) secretagogues (see, e.g., U.S. patent 6,132,774), particularly calcium receptor antagonists; a calcitonin; and vitamin D analogs.

The starting materials and reagents for the compounds of formula I and combination reagents described above for use in the present invention are readily available or can be readily synthesized by one skilled in the art using conventional methods of organic synthesis. For example, many of the compounds employed in the present invention are related to or derived from those compounds having great scientific value and commercial need, and many such compounds are commercially available or reported in the literature or are readily prepared by methods generally described in the literature from other conventionally available materials.

Certain compounds of formula I of the present invention or intermediates in their synthesis have asymmetric carbon atoms and thus are enantiomers or diastereomers. Mixtures of diastereomers may be separated into individual diastereomers by well-known methods, such as chromatography and/or fractional crystallization, depending on differences in their physicochemical properties. Enantiomers may be separated by chiral HPLC or by converting a mixture of enantiomers to a mixture of diastereomers by reaction with a suitable optically active compound, such as an alcohol, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, enantiomeric mixtures of compounds of formula I containing an acid or base moiety or intermediates in their synthesis can be separated into their pure enantiomers of the compounds by the following description: i.e. diastereoisomers with optically pure chiral bases or acids, such as 1-phenyl-ethylamine or tartaric acid, the diastereoisomers being separated by fractional crystallization and the salts being then decomposed by neutralization to give the corresponding enantiomers. All such isomers, including diastereomers, enantiomers, and mixtures thereof, are considered to be part of the present invention. In addition, certain compounds of the present invention which are atropisomers (e.g., substituted biaryl compounds) are also considered to be part of the present invention.

More specifically, the compounds of formula I of the present invention can be obtained by fractional crystallization of diastereomeric salts formed between a basic intermediate and an optically pure chiral acid. The salts are removed by neutralization techniques and the enantiomerically pure compounds are provided. Alternatively, the compounds of formula I according to the invention can be obtained in enantiomerically enriched form by chromatography (preferably high pressure liquid chromatography [ HPLC ]]) Resolution of the racemate of the final compound or of an intermediate in its synthesis, preferably the final compound, by chromatography on an asymmetric resin, preferably Chiralcel^TMAD or OD (from Chiral Technologies, Exton, Pennsylvania)) using a mobile phase composition of hydrocarbons (preferably heptane or hexane) containing 0-50% isopropanol (preferably 2-20%) and 0-5% alkylamine (preferably 0.1% diethylamine). The product containing fractions were concentrated to give the desired material.

Certain compounds of formula I of the present invention are acidic and form pharmaceutically acceptable salts with pharmaceutically acceptable cations. Certain compounds of formula I of the present invention are basic and form pharmaceutically acceptable salts with pharmaceutically acceptable anions. All of these salts are within the scope of the present invention and can be prepared by conventional methods, for example by mixing the acid and the base, usually in stoichiometric proportions, and if desired, reacting in an aqueous, nonaqueous or partially aqueous medium. If necessary, the salt is recovered by: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or in the case of an aqueous solution, freeze-drying. The compound may be obtained in crystalline form by dissolving the compound in a suitable solvent such as ethanol, hexane or a water/ethanol mixture.

One skilled in the art will recognize that certain compounds of the present invention exist in several tautomeric forms. All such tautomeric forms are considered to be part of the present invention. For example, the present invention includes all enol-ketone forms of the compounds of formula I of the present invention.

Furthermore, compounds of formula I of the present invention are also within the scope of the present invention when they form hydrates or solvates.

The compounds of formula I, prodrugs thereof, and salts of the compounds and prodrugs of the present invention are suitable for therapeutic use as agents that activate peroxisome proliferator-activated receptors (PPAR) activity in mammals, particularly humans. Thus, it is believed that the compounds of the present invention decrease total body fat and increase HDL cholesterol by activating PPAR receptors, stimulating the transcription of key genes involved in fatty acid oxidation and High Density Lipoprotein (HDL) assembly (e.g., apolipoprotein Al gene transcription). In view of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and related components thereof in mammals, particularly humans, and increase HDL cholesterol and apolipoprotein Al. These compounds are therefore useful in the treatment and correction of various dyslipidemias which have been observed to be associated with the development and incidence of atherosclerosis and cardiovascular diseases including hypoalphalipoproteinemia and hypertriglyceridemia.

In view of the positive correlation between triglycerides, LDL cholesterol and their related apolipoproteins in the blood and cardiovascular, cerebrovascular and peripheral vascular diseases, the compounds of formula I of the present invention, their prodrugs and the salts of the compounds and prodrugs are useful for the prevention, prevention and/or regression of atherosclerosis and its related diseases by virtue of their pharmacological actions. These diseases include cardiovascular diseases (e.g., angina pectoris, cardiac ischemia and myocardial infarction) and complications due to cardiovascular diseases.

Thus, whereas the compounds of formula I, prodrugs thereof, and salts of the compounds and prodrugs of the present invention have the ability to reduce plasma triglycerides and total plasma cholesterol and increase plasma HDL cholesterol, they are useful in the treatment of diabetes, including impaired glucose tolerance, diabetic complications, insulin resistance, and metabolic syndrome, as described previously. In addition, the compounds of formula I are useful in the treatment of polycystic ovary syndrome. In addition, given that the compounds of formula I, prodrugs thereof, and salts of the compounds and prodrugs of the present invention are capable of increasing hepatic fatty acid oxidation, the compounds of formula I may also be useful in the treatment of obesity.

The use of the compounds of formula I, prodrugs thereof, and salts of the compounds and prodrugs of the present invention as pharmaceuticals in the treatment of the above-mentioned diseases in mammals, such as humans, males, or females, is illustrated by one or more of the following general and in vivo experiments. In vivo assays (with appropriate modifications known to those skilled in the art) can be used to determine the activity of other lipid or triglyceride controlling agents as well as the compounds of the invention. Thus, the protocols described below can also be used to illustrate the use of combinations of agents described herein (i.e., compounds of the invention). In addition, this assay provides a means by which the activities of the compounds of formula I, prodrugs thereof, and salts of the compounds and prodrugs (or other agents described herein) of the present invention can be compared to one another and to the activities of other known compounds. These comparisons are used to determine dosage levels in the treatment of such diseases in mammals, including humans. Of course, the following protocols may be varied by those skilled in the art.

PPAR FRET assay

Measuring coactivator recruitment by nuclear receptors following receptor ligand association is a method of evaluating the ability of ligands to produce a functional response through nuclear receptors. The PPAR FRET (fluorescence resonance energy transfer) assay measures ligand-dependent interactions between nuclear receptors and coactivators. The GST/PPAR (α, β, and γ) Ligand Binding Domains (LBD) were labeled with europium-labeled anti-GST antibodies, and the SRC-1 (sterol receptor coactivator-1) synthetic peptide containing amino-terminal long-chain biotin molecules was labeled with streptavidin-linked Allophycocyanin (APC). Binding of the ligand to PPAR LBD causes a conformational change, allowing SRC-1 binding. Upon SRC-1 binding, the donor FRET molecule (europium) is in close proximity to the acceptor molecule (APC), resulting in a fluorescence energy transfer between the donor (337nm excitation and 620nm emission) and the acceptor (620nm excitation and 665nm emission). The increase in the ratio of 665nm emission to 620nm emission is a measure of the ability of the ligand-PPAR LBD to recruit SRC-1 to synthesize the peptide and thus of the ability of the ligand to produce a functional response through the PPAR receptor.

[1] GST/PPAR LBD expression

Human PPAR α LBD (amino acids 235-507) was fused to the carboxy terminus of glutathione S-transferase (GST) in pGEX-6P-1(Pharmacia, Piscataway, N.J.). GST/PPAR alpha LBD fusion protein is used as BL21[ DE3 ] ]pLysS cell expression, induced with 50. mu.M IPTG, at room temperature for 16 hours (A at about 0.6)₆₀₀Lower induction cells). The fusion protein was purified on glutathione Sepharose 4B beads, eluted with 10mM reduced glutathione and dialyzed against 1 XPBS at 4 ℃. The fusion proteins were quantified by the Bradford assay (M.M.Bradford, Analst.biochem.72: 248-254; 1976) and stored in 1 XPBS containing 40% glycerol and 5mM DTT at-20 ℃.

[2] FRET assay

The composition of the FRET assay reaction mixture is: 1 XPTRT buffer (50mM Tris-Cl pH8.0, 50mM KCl, 0.1mg/ml BSA, 1mM EDTA and 2mM DTT) containing 20 nGST/PPAR α LBD, 40nM SRC-1 peptide (amino acid 676-₂Purchased from American Peptide co., Sunnyvale, CA), 2nM europium-bound anti-GST antibody (Wallac, Gaithersburg, MD), 40nM streptavidin-bound apc (Wallac), and control and test compounds. The final volume was 100. mu.l with water and transferred to a black 96-well plate (Microfuor B, Dynex (Chantilly, Va)). The reaction mixture was incubated at 4 ℃ for 1 hour and fluorescence was read on a Victor 2 plate reader (Wallac). Data are provided as the ratio of emission at 665nm to emission at 615 nm.

Lipid modulating Activity in mice

[1] Triglyceride reduction

The hypolipidemic therapeutic activity of the compounds of the present invention was demonstrated by methods based on standard procedures. For example, the in vivo activity of the compounds of the invention to reduce plasma triglyceride levels can be determined using hybrid B6CBAF1/J mice.

Male B6CVAF1/J mice (8-11 weeks old) were obtained from the Jackson Laboratory and were housed 4-5 mice each and maintained under 12 hours light/12 hours dark conditions. Mice were fed Purina rodent chow and water ad libitum. Mice were provided daily (9AM) by gavage with vehicle (water or 0.5% methylcellulose 0.05% Tween 80) or vehicle containing the desired concentration of test compound. 24 hours after the last dose (day 3), retro-orbital blood was collected in heparinized hematocrit tubes. Triglyceride measurements were performed using a commercially available trigyceride E kit from Wako (Osaka, Japan).

[2] HDL cholesterol is elevated.

The activity of the compounds of the invention in increasing plasma levels of High Density Lipoprotein (HDL) in mammals can be demonstrated using transgenic mice expressing the human apoAl and CETP transgene (HuAlCETPTg). Transgenic mice used in this study were previously described in the following references: walsh et al, j.lipid res.1993, 34: 617-623, Agellon et al, J.biol.chem.1991, 266: 10796-10801. Mice expressing the human apoAl and CETP transgenes were obtained by mating transgenic mice expressing the human apoAl transgene (HuAlTg) with CETP mice (hucettg).

Male HuAlCETPTg mice (8-11 weeks old) were grouped according to their human apo Al levels and were allowed free access to Purina rodent chow and water. Mice were provided with vehicle (water or 0.5% methylcellulose 0.05% Tween 80) or vehicle containing the desired concentration of test compound daily by gavage for 5 days. HDL-cholesterol and human apoAl were measured at the beginning (day 0) and 90 minutes after dosing (day 5) using a standard procedure-based method. Mouse HDL was isolated from apoB-containing lipoproteins by dextran sulfate precipitation as described in the following references: francone et al, j.lipid.res.1996, 37: 1268-1277). Cholesterol was measured enzymatically using a commercially available cholesterol/HP kit (Boehringer MannHeim, Indianapolis, IND) and spectrophotometrically on a microplate reader. Human apoAl was measured using a sandwich enzyme-linked immunosorbent assay as described in the following documents: francone et al, j.lipid.res.1996, 37: 1268-1277).

Measurement of glucose reduction in ob/ob mice

The hypoglycemic activity of the compounds of the invention is determined by determining the amount of test compound that lowers the glucose level in male ob/ob mice relative to the vehicle without the test compound. The assay also determines the approximate Minimum Effective Dose (MED) value of the test compound to reduce plasma glucose concentration in mice.

Male C57BL/6J-ob/ob mice (from Jackson Laboratory, Bar Harbor, ME) 5-8 weeks old were housed in cages, 5 per cage, according to standard animal breeding protocols. After a one-week acclimation period, mice were weighed and 25 μ L of blood was taken from the retro-orbital sinus prior to receiving any treatment. Blood samples were immediately diluted (1: 5) with saline containing 0.025% sodium heparin and placed on ice for metabolite analysis. Mice were assigned to several treatment groups so that each group had similar mean plasma glucose concentrations. After grouping, mice were orally administered the following vehicle for 4 days each day, the composition of the vehicle being: (1) 0.25% w/v methylcellulose in water without adjusting the pH; or (2) 0.1%P105 Block copolymer surfactant (BASF Corporation, Parsippany, NJ) 0.1% saline solution without pH adjustment. On day 5, the mice were weighed again and then tested compounds or vehicle alone were taken orally. All compounds were administered in a vehicle consisting of: (1) 0.25% w/v aqueous solution of methylcellulose; (2)10％DMSO/0.1％Solutions in 0.1% saline without pH adjustment; or 3) pure PEG 400 without pH adjustment. Mice were bled 3 hours later from the retro-orbital sinus and blood metabolite levels were measured. Freshly collected samples were centrifuged at 10,000Xg for 2 minutes at room temperature. Taking the supernatant for analysis of glucose, e.g., using Abbott VP ^TM(Abbott Laboratories, Diagnostics Division, Irving, TX) and VP SuperAutomatic analyzers (Abbott Laboratories, Irving, TX), or by Abbott Spectrum CCX^TM(Abbott Laboratories, Irving, TX) using A-Gent^TMGlucose-UV test reagent system (Abbott Laboratories, Irving, TX) (improvement of the methods described in Richterich and Dauwalder, Schweizerschiceditinische Wochschrift, 101: 860(1971)) (hexokinase method), using the 100mg/dl standard. Plasma glucose was then calculated by the following equation: plasma glucose (mg/dl) ═ sample value x8.14, where 8.14 is the dilution factor, plasma hematocrit was adjusted (assuming hematocrit of 44%).

Animals administered the vehicle maintain a substantially constant high blood glucose level (e.g., greater than or equal to 250mg/dl), while mice treated with an appropriate dose of the compound having hypoglycemic activity significantly inhibit glucose levels. The hypoglycemic activity of the test compounds was determined by statistical analysis of the mean plasma glucose concentrations between the test compound group and the vehicle-treated group at day 5 (unpaired t-test). The above-described test with a series of test compound doses allows the determination of an approximate Minimum Effective Dose (MED) value for reducing plasma glucose concentrations in vivo.

Measurement of insulin, triglyceride and cholesterol levels in ob/ob mice

The compound can be clinically used as a hyperinsulinemia reversal drug, a triglyceride reducing drug and a cholesterol reducing drug. These activities can be determined by testing the amount of compound that reduces the level of insulin, triglycerides or cholesterol in male ob/ob mice relative to a control vehicle without the test compound.

Since the cholesterol level in the blood is closely related to the development of cardiovascular, cerebrovascular or peripheral vascular disease, the compounds of the invention prevent, arrest and/or regress atherosclerosis by their cholesterol-lowering effect.

Since insulin concentrations in the blood are associated with a promoting effect on vascular cell growth and increased renal sodium retention (among other effects, such as promoting glucose utilization), and these functions are known to cause hypertension, the compounds of the present invention can prevent, arrest and/or resolve hypertension by their insulin-lowering effect.

Since the concentration of triglycerides in the blood affects the total blood lipid level, the compounds of the present invention can prevent, prevent and/or resolve hyperlipidemia by their activity of lowering triglycerides and/or free fatty acids.

Free fatty acids affect overall blood lipid levels and are independently negatively associated with insulin sensitivity in various physiological and pathological states.

Male C57BL/6J-ob/ob mice (from Jackson Laboratory, Bar Harbor, ME) 5-8 weeks old were housed in cages of 5 mice per cage and allowed free access to standard rodent chow according to standard animal feeding procedures. After a one-week acclimation period, mice were weighed and 25 μ L of blood was taken from the retro-orbital sinus prior to receiving any treatment. Blood samples were immediately diluted (1: 5) with saline containing 0.025% sodium heparin and placed on ice for plasma glucose analysis. The test compounds were administered orally by gavage in the form of about 0.02% -2.0% (weight/volume (w/v)) solutions in: (1) 10% DMSO/0.1%A 0.1% aqueous salt solution of a P105 block copolymer surfactant (basf corporation, Parsippany, NJ) without pH adjustment, or (2) a 0.25% w/v aqueous solution of methylcellulose without pH adjustment. Alternatively, the test compound is dissolved or suspended in pure PEG 400 and administered orally by gavage. Once daily (s.i.d.) or twice daily (b.i.d.) for 1 to, e.g., 15 days. Control mice received 10% DMSO/0.1% P105 in 0.1% saline without pH adjustment, or in 0.25% w/v methylcellulose in water without pH adjustment, or pure PEG 400 without pH adjustment.

After 3 hours from the last administration, the mice were sacrificed and blood was collected in 0.5mL serum separation tubes containing 3.6mg of a 1: 1 w/w mixture of sodium chloride and potassium oxalate. Freshly collected samples were centrifuged at 10,000Xg for 2 minutes at room temperature, and the serum supernatant was transferred and diluted with 1TIU/ml aprotinin in 0.1% saline (1: 1 v/v) without pH adjustment.

The diluted serum samples were then stored at-80 ℃ for analysis. Thawed diluted serum samples were analyzed for insulin, triglycerides, free fatty acids, and cholesterol levels. Serum insulin concentration was takenRIA insulin kit (diabody method; as specified by the manufacturer) was purchased from Binax, South Portland, ME. The coefficient of variation is less than or equal to 10%. Measurement of serum Triglycerides Using Abbott VP^TMAnd VP SuperAutomatic analyzers (Abbott Laboratories, Irving, TX), or by Abbott Spectrum CCX^TM(Abbott Laboratories, Irving, TX) using A-Gent ^TMTriglyceride test reagent system (A)bbott Laboratories, Diagnostics Division, Irving, TX) (lipase-coupled enzymatic method; a modification of the following, Sampson et al, Clinical Chemistry 21: 1983(1975)). Serum Total Cholesterol levels Using Abbott VP^TMAnd VP SuperAutomatic analyzers (Abbott Laboratories, Irving, TX) and A-Gent^TMCholesterol test reagent systems (cholesterol esterase-coupled enzyme; modification of the method described below, Allain et al, Clinical Chemistry 20: 470(1974)) used at 100 and 300mg/dl standards. Serum free fatty acid concentrations were determined using a kit from WAKO (Osaka, Japan), and also suitably using Abbott VP^TMAnd VPSuperAutomatic analyzers (Abbott Laboratories, Irving, TX) or with Abbott Spectrum CCX^TM(Abbott laboratories, Irving, TX). Serum insulin, triglyceride, free fatty acid and total cholesterol levels are then calculated by the following equations: serum insulin (μ U/ml) ═ sample value x 2; serum triglyceride (mg/dl) ═ sample value x 2; serum total cholesterol (mg/dl) sample value x 2; serum free fatty acid (μ Eq/l) ═ sample value x 2; where 2 is the dilution factor.

Mice administered with vehicle maintained substantially constant elevated serum insulin (e.g., 275 μ U/ml), serum triglycerides (e.g., 235mg/dl), serum free fatty acids (1500mEq/ml), and serum total cholesterol (e.g., 190 mg/dl). The reducing activity of test compounds on serum insulin, triglycerides, free fatty acids and total cholesterol was determined using a statistical analysis (unpaired t-test) of the mean serum insulin, triglyceride or total cholesterol concentrations between the test compound groups and the vehicle-treated control groups.

Measurement of energy expenditure in rats

As is well known to those skilled in the art, animals typically consume more oxygen in the process of increasing energy consumption. In addition, metabolic fuels such as glucose and fatty acids are oxidized to carbon dioxide and water, and simultaneously produce heat, collectively referred to in the art as heat production. Thus, thermogenesis can be measured indirectly by measuring oxygen consumption in animals, including humans. Indirect calorimetry is routinely employed by those skilled in the art to measure energy expenditure in animals, such as humans.

It will be appreciated by those skilled in the art that increased energy expenditure and the concomitant burning of metabolic fuels results in thermogenesis, which is effective in the treatment of, for example, obesity.

The ability of the compounds of formula I of the present invention to form a thermogenic response can be demonstrated according to the following scheme: this in vivo screen was designed to evaluate the efficacy of compounds as PPAR agonists, using overall oxygen consumption as an effective endpoint measure. The process comprises the following steps: (a) obese Zucker rats were administered for about 6 days, and (b) oxygen consumption was measured. Male obese Zucker rats weigh about 400g to about 500g and are housed in individual cages under standard laboratory conditions for about 3 to about 7 days before the study is initiated. The compounds of the invention and the vehicle are administered orally by gavage at a single daily dose of about 3p.m. to about 6p.m. for about 6 days. The compounds of the invention were dissolved in a carrier comprising about 0.25% methylcellulose. The volume administered was about 1 mL.

Approximately 1 day after the last administration of the compound of the invention, oxygen consumption was measured using an open loop indirect calorimeter (Oxymax, Columbus Instruments, Columbus, OH 43204). The Oxymax gas sensor was calibrated with a mixture of nitrogen and gas (about 0.5% carbon dioxide, about 20.5% oxygen, about 79% nitrogen) prior to each experiment. The rats were removed from the cages and their body weights were recorded. Rats were placed in a sealed chamber (43 x 10cm) of Oxymax, the chamber was placed on an activity monitor, and then the flow rate of air through the chamber was set at about 1.6L/min to about 1.7L/min. The oxygen consumption (mL/kg/h) of the rats was then calculated using the Oxymax software based on the air flow rate through the chamber and the difference in oxygen content at the inlet and outlet. The activity monitor had 15 infrared beams spaced about 1 inch apart on each axis, and when two consecutive beams were interrupted, the motion activity was recorded and the results were recorded as counts.

Oxygen consumption and locomotor activity were measured approximately every 10 minutes for about 5 hours to about 6.5 hours. The resting oxygen consumption for each rat was calculated by removing the first 5 values and the values obtained during exercise activity over about 100 counts and then averaging the values.

In vivo atherosclerosis assay

The anti-atherosclerotic effect of the compounds of the invention can be determined by the amount of the compound required to reduce aortic lipid deposition in rabbits. Male new zealand white rabbits were fed with a feed comprising 0.2% cholesterol and 10% peanut oil for 4 days (once daily). Blood was taken from the edge of the rabbit ear vein and total plasma cholesterol values were determined from these samples. The rabbits were then divided into treatment groups, such that each group had similar mean ± SD values for total plasma cholesterol concentration, HDL cholesterol concentration, and triglyceride concentration. After grouping the rabbits, the compounds were administered daily to the rabbits in the form of a feed mix or in small pieces of gelatin-based confectionery. Control rabbits received only the vehicle for administration, either as feed or gelatin dessert. The cholesterol/peanut oil diet was fed with the compound throughout the study. Blood can be obtained from the marginal ear vein at any time during the study to determine plasma cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride values. After 3-5 months, the rabbits were sacrificed and the aorta was removed from the thoracic arch to the iliac branch. Adventitia is removed from the aorta, cut longitudinally, and then stained with Sudan IV, Holman et al Lab.invest.1958, 7, 42-47 as described in the following references. The percentage of stained surface area was measured by densitometry using an optical Image analysis System (Image Processing Solutions; North Reading MA). A reduction in the percentage of stained surface area in the compound-receiving group compared to the control group of rabbits was used to indicate a reduction in lipid deposition.

The compounds of the present invention may be administered by any method that provides for systemic and/or topical delivery of the compounds of the present invention. These methods include oral, parenteral, intraduodenal, and the like. Typically, the compounds of the invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous, or intramedullary) may also be employed. For example, parenteral administration may be used when oral administration is not appropriate, or when the patient is unable to ingest the drug.

Generally, the compounds of the present invention will be employed in amounts sufficient to achieve the desired therapeutic effect (e.g., lowering blood lipid).

Generally, an effective dose of a compound of formula I of the present invention, prodrugs thereof, and salts of the compound and prodrugs thereof is from about 0.001 to about 100 mg/kg/day, preferably from about 0.005 to about 5 mg/kg/day.

The dosage of the combination for use in combination with a PPAR agonist should be effective for the condition being treated. The dosage can be determined by standard assays, such as those mentioned above and provided herein. The combination agents may be administered simultaneously or sequentially in any order.

For example, an effective dose of an HMG-CoA reductase inhibitor will generally be from about 0.01 to about 100 mg/kg/day.

The compounds of the present invention are typically administered in the form of a pharmaceutical composition comprising at least one compound of the present invention, together with a pharmaceutically acceptable excipient, diluent or carrier.

Thus, the compounds of the present invention may be administered alone or together in any of the conventional oral, parenteral, rectal or transdermal dosage forms.

For oral administration, the pharmaceutical composition may be in the form of a solution, suspension, tablet, pill, capsule, powder, or the like. Tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate, may be formulated with various disintegrants such as starch, preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are also often used for tableting purposes. LikeSolid compositions of the type may be employed as fillers in soft and hard-filled gelatin capsules; preferred materials herein also include lactose (lactose) or lactose (milk sugar) and high molecular weight polyethylene glycols. In soft gelatin capsules, the preferred dosage form is in an oil such as olive oil, Miglyol^TMOr Capmul^TMA solution or suspension of (a). Antioxidants may be added if necessary to prevent long-term degradation. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of the invention may be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as with diluents such as water, ethanol, propylene glycol, glycerin and the like.

For parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts, may be employed. The aqueous solution may be suitably buffered if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are particularly suitable for administration by intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this case, the sterile aqueous medium employed is readily available to those skilled in the art by standard techniques.

For transdermal (e.g., topical) administration, a sterile aqueous or partially aqueous solution similar to but thinner than the parenteral solutions described above is prepared (typically at a concentration of about 0.1% to 5%).

Methods for preparing various pharmaceutical compositions using certain amounts of active ingredients are well known or will be apparent to those skilled in the art in light of the present disclosure. For example, methods for preparing pharmaceutical compositions are described inRemington’s Pharmaceutical SciencesMack publishing company, Easter, Pa., 19 th edition (1995).

The pharmaceutical compositions of the invention may contain from 0.1% to 95% of a compound of the invention, preferably from 1% to 70%. In either case, the composition or formulation administered may contain an amount of a compound of the invention effective to treat a disease in a subject, such as atherosclerosis.

Since one aspect of the invention relates to the treatment of the diseases described herein with a combination of active ingredients, which can be administered separately, the invention also relates to the combination of the separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions, a compound of formula I of the present invention, a prodrug thereof, or a salt of the compound or prodrug, and a second compound as described above. The kit comprises means for containing the separated compositions, such as a container, a divided bottle or a divided foil package. Typically, the kit contains instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the dosages of the individual components combined is required by the prescribing physician.

An example of a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs are generally composed of a sheet of relatively rigid material and a foil, preferably of transparent plastics material, overlying it. During packaging, the recess is formed by the plastic foil. The recess has the size and shape of the tablet or capsule being packaged. Next, the tablet or capsule is placed in the recess and the plastic foil is sealed with a relatively hard material sheet on the side opposite the formed recess. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the tablet. Preferably, the strength of the sheet material is such that the tablet or capsule can be removed from the blister pack by pressing the recess by hand, thereby forming an opening in the sheet material at the location of the recess. The tablet or capsule is then removed through the opening.

Preferably, a memory aid is provided on the cartridge, such as a number near the tablet or capsule, such that the number corresponds to the date on which the indicated tablet or capsule should be taken. Other examples of memory aids are calendars printed on the card, such as the following "first week, monday, tuesday,. et al. Other variations of the memory aid will be apparent. The "daily dose" may be a single tablet or capsule, or several pills or capsules taken within a day.

Alternatively, the daily dose of a compound of the invention may be one tablet or one capsule while the daily dose of the second compound may be several tablets or several capsules, or vice versa. The memory aid should reflect this.

In other embodiments of the invention, dispensers are provided which can dispense one daily dose at a time in the order in which they are required for use. Preferably, the dispenser is provided with a memory aid to further assist in compliance with the administration protocol. An example of a memory aid is a mechanical counter, which indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery powered microchip memory connected to a liquid crystal reader, or an audible reminder signal, which may for example read the date the last daily dose was taken and/or remind the time at which the next medication should be taken.

The compounds of the invention are administered in conventional formulations, either alone or in combination with other compounds of the invention or with additional compounds. The following formulation examples are illustrative only and are not meant to limit the scope of the present invention.

In the following formulations, "active ingredient" refers to the compounds of the present invention.

Preparation 1: gelatin capsule

Hard gelatin capsules were prepared using the following ingredients:

tablets were prepared using the following ingredients:

preparation 2: tablet formulation

Mixing the above materials, and tabletting.

Alternatively, tablets containing 0.25-100mg of active ingredient are prepared according to the following formulation:

preparation 3: tablet formulation

The active ingredient, starch and cellulose were passed through a 45 mesh U.S. sieve and mixed thoroughly. The resulting powder was mixed with a solution of polyvinylpyrrolidone and then passed through a 14 mesh U.S. sieve. The resulting granules were dried at 50-60 ℃ and passed through an 18 mesh U.S. sieve. Then, sodium carboxymethyl starch, magnesium stearate and talc, which had previously passed through a 60-mesh U.S. sieve, were added to the granules, mixed and then compressed on a tablet machine to obtain tablets.

Suspensions containing 0.25-100mg of active ingredient per 5mL dose were prepared according to the following formulation:

preparation 4: suspension

The active ingredient is passed through a 45 mesh U.S. sieve and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Diluting benzoic acid solution, correctant and pigment with part of water, adding, and stirring. Sufficient water is then added to produce the desired volume.

Preparing an aerosol solution comprising:

preparation 5: aerosol and method of making

The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ℃ and then transferred to a filling device. The required amount is then added to the stainless steel container and diluted with the remaining propellant. The container is then valved.

The suppository is prepared according to the following formula:

preparation 6: suppository

The active ingredient is passed through a 60 mesh U.S. sieve and suspended in saturated fatty acid glycerides that have been melted in advance with the minimum amount of heating necessary. The mixture was then poured into suppository molds of nominally 2g capacity and allowed to cool.

An intravenous formulation was prepared according to the following formulation:

preparation 7: intravenous solution

Solutions of the above ingredients were administered intravenously to the patient at a rate of about 1 mL/min.

Soft gelatin capsules were prepared according to the following formulation:

preparation 8: soft gelatin capsule

The active ingredients may also be a combination of therapeutic agents.

General Experimental methods

NMR spectra were recorded at room temperature using a Varian XL-300(Varian Co., Palo Alto, California), Bruker AM-300 spectrometer (Bruker Co., Billerica, Massachusetts) or Varian Unity 400. Chemical shifts are expressed in ppm (δ) relative to a residual solvent internal reference. The peak shape is expressed as: s, singlet; d, double peak; dd, doublet, t, triplet, q, quartet; m, multiplet; brs ═ broad singlet; 2s, two single peaks. Atmospheric Pressure Chemical Ionization (APCI) mass spectra in alternating cation and anion mode were obtained on a Fisons Platform II spectrometer, Fisons Instruments Manchester u.k. Chemical ionization mass spectra were obtained on a Hewlett-Packard 5989 instrument (Hewlett-Packard Co., Palo Alto, California) (ammonia ionization, PBMS). When describing the chloride or bromide ion containing strength, the expected strength ratio (about 3: 1,³⁵Cl/³⁷cl-ions and the mixture of the Cl-ions and the solution in a ratio of 1: 1,⁷⁹Br/⁸¹br-ions) and gives low mass ionic strength. Optical rotations were measured at indicated temperatures using a sodium D line (K589 nm) by a Perkin-Elmer 241 polarimeter (Perkin-Elmer Instruments, Norwalk, CT) and measured as [ α [, ]]_D ^{Temperature of}Concentration (c ═ g/100mL) and solvent.

Column chromatography was performed on glass columns or Flash 40(Biotage, Dyar corp. chrlottesville, VA) columns under low nitrogen pressure on Baker Silica Gel (40 μ M) (j.t. Baker, phillips burg, n.j.) or Silica Gel 50(FM Sciences, Gibbstown, n.j.). Radial chromatography was performed using a color-mode tube (chromaton) (model 7924T, Harrison Research, Palo Alto, CA). Unless otherwise indicated, commercially available reagents were used. Dimethylformamide, 2-propanol, tetrahydrofuran, toluene and dichloromethane used as reaction solvents were all anhydrous grades and were supplied by Aldrich chemical company (Milwaukee, Wis.). Micro-analysis adopts SchwarzkopfMicroanalytical Laboratory, Woodside, NY. The terms "concentration" and "evaporation" mean the removal of the solvent on a rotary evaporator at a mercury pressure of 5-200mm, the bath temperature being below 45 ℃. The reaction is carried out at "0-20 ℃ or" 0-25 ℃ C "meaning that the vessel is initially cooled in an insulated ice bath and then warmed to room temperature. The abbreviations "min" and "h" denote minutes and hours, respectively. The abbreviation "rt" means "room temperature". Other abbreviations are readily understood by those skilled in the art, such as "N₂"represents nitrogen and" CH₂Cl₂"for dichloromethane," THF "for tetrahydrofuran," NaHCO ₃"denotes sodium bicarbonate.

Preparation example 1

3- (3-methoxyphenyl) -1H-piperidine

The method A comprises the following steps: 3- (3-methoxyphenyl) pyridine

3-Bromoanisole (17.4g, 93.03mmol) was dissolved in 650mL of tetrahydrofuran and 210mL of water in a 2L round-bottomed flask equipped with a magnetic stirrer. Diethyl- (3-pyridyl) borane (15.73g, 106.99mmol), sodium carbonate (44.4g, 418.64mmol) and dichlorobis (triphenylphosphine) palladium (II) (9.8g, 13.95mmol) were added and the mixture was heated under reflux for 4 h and then cooled to room temperature. The mixture was diluted with 300mL of water and extracted with ether (2X 300 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (1: 1 ethyl acetate/hexane). The product fractions were concentrated under reduced pressure to yield 17.75g (99%) of the title compound as a pale yellow oil.

MS(APCI)186.1(M+H)⁺。

¹H NMR(400MHz，CDCl₃) δ 8.85(d, 1H), 8.60(d, 1H), 7.92(dd, 1H), 7.39(m, 2H), 7.13(dd, 1H), 7.08(t, 1H), 6.94(dd, 1H), 3.85(s, 3H). 3- (3-methoxyphenyl) -1H-piperidine

3- (3-methoxyphenyl) pyridine (17.75g, 95.4mmol) was dissolved in 200mL of methanol. 30mL of 12N hydrochloric acid and 1.8g of platinum (II) oxide were added and the suspension was hydrogenated at 55psi for 6 hours. The reaction mixture was filtered through celite and the filter plug was washed with 200mL of methanol. The filtrate was concentrated under reduced pressure. The resulting slurry was taken up in 200mL of water, basified with 5N aqueous sodium hydroxide solution and extracted with ethyl acetate (3X 300 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid formed is taken up in 200mL of diethyl ether. Anhydrous hydrogen chloride gas was bubbled through the ether solution and the white precipitate formed was collected by filtration. The white solid was recrystallized from hot ethanol/diethyl ether to obtain 10.22g (47%) of the title compound as a white solid.

LC-MS 192.4(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ9.86(br s，1H)，9.61(br s，1H)，7.21(m，1H)，6.79(t，2H)，6.73(s，1H)，3.79(s，3H)，3.55(d，3H)，3.21(t，1H)，2.88(m，2H)，2.08(m，3H)，1.63(m，1H)。

The method B comprises the following steps:

3- (3-methoxyphenyl) pyridine

3-bromopyridine (37.49g, 237.2mmol) and 3-methoxyphenylboronic acid (36.06g, 237.3mmol) were dissolved in 300mL dimethoxyethane in a 1L round-bottomed flask equipped with a magnetic stirrer. Sodium carbonate (50.3g, 474.6mmol) in 200mL water was added.

Tetrakis (triphenylphosphine) palladium (0) (6.85g, 5.93mmol) was added and the mixture heated to reflux for 4 h, then cooled to room temperature and diluted with 400mL water. The mixture was extracted with diethyl ether (2X 300 mL).

The organic phases were combined and extracted with 1N hydrochloric acid (2X 300 mL). The acidic extracts were combined and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with diethyl ether (2 × 500mL) and the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 43.89g (99%) of the title compound as a pale yellow oil.

MS(APCI)186.1(M+H)⁺。

A2L hydrogenation vessel was charged with 4.4g of platinum (II) oxide and purged with nitrogen. A solution of 3- (3-methoxyphenyl) pyridine (43.89g, 235.47mmol) in 500mL of acetic acid was added. The suspension was hydrogenated at 45psi for 6 hours. The catalyst was filtered through celite and the filter plug was washed with 200mL of acetic acid. The filtrate was concentrated under reduced pressure. The resulting oil was taken up in 500mL of water and basified with 5N aqueous sodium hydroxide solution. The basic layer was extracted with ether (2 × 500mL) and the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid formed is taken up in 200mL of diethyl ether. Anhydrous hydrogen chloride gas was bubbled through the ether solution to form a white precipitate, which was collected by filtration. The white solid was recrystallized from hot ethanol/diethyl ether to obtain 22.50g (58%) of the title compound as a white solid.

LC-MS 192.4(M+H)⁺。

Preparation example 2

Preparation of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid alkyl ester

The method C comprises the following steps: preparation of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate

3-hydroxyphenyl-1H-piperidines

3-methoxyphenyl-1H-piperidine (methods A and B: 22.50g, 98.8mmol) was slowly dissolved in hydrobromic acid (100mL) and the resulting mixture was heated at 140 ℃ for 4 hours. After cooling to room temperature, hydrobromic acid and water were distilled off and the brown oil formed was azeotropically distilled with toluene (3X 100mL) and dried under high vacuum for 18 h. The tan solid formed was used without purification in the next step.

MS(APCI)178.1(M+H)⁺。

¹H NMR(400MHz，DMSO_d6)δ8.80(br s，1H)，8.51(br s，1H)，7.10(t，1H)，6.65(t，2H)，6.63(s，1H)，3.26(d，2H)，3.00-2.80(m，3H)，2.48(br s，2H)，1.77-1.59(m，2H)。

3- (3-hydroxy-phenyl) -piperidine-1-carboxylic acid tert-butyl ester

3-hydroxyphenyl-1H-piperidine (15.85g, 61.39mmol) was dissolved in 140mL of 2: 1 tetrahydrofuran/water. Sodium bicarbonate (5.16g, 61.39mmol) and di-tert-butyl dicarbonate (13.40g, 61.39mmol) were added and the reaction was heated to reflux for 4 hours and then cooled to room temperature. The mixture was diluted with 300mL of water and extracted with ethyl acetate (3X 250 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The yellow oil formed was used in the next step without purification.

LC-MS 276.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.16(t，1H)，6.77(d，1H)，6.71(d，1H)，6.69(dd，1H)，4.15(t，2H)，2.72(t，2H)，2.62(t，1H)，1.98(m，1H)，1.76(m，1H)，1.58(m，1H)，1.47(s，9H)。

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid tert-butyl ester

3- (3-hydroxy-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (17.03g, 61.39mmol) was dissolved in 420mL of acetone in a 3-neck 1L round bottom flask equipped with a mechanical stirrer. 1, 1, 1-trichloro-2-methyl-2-propanol hydrate (21.80g, 122.78mmol) was added and the solution was cooled to 0 ℃. Sodium hydroxide particles (19.65g, 491.12mmol) were added to the solution in 4 portions over 4 hours at 0 ℃. The reaction mixture was warmed to room temperature between additions and then cooled again. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours and then concentrated under reduced pressure. The resulting residue was taken up in water (500mL), acidified with 6N hydrochloric acid, stirred for 10 min and then extracted with ethyl acetate (3X 300 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid tert-butyl ester as a brown oil which was used in the next step without purification.

LC-MS 362.4(M+H)⁺。

3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid tert-butyl ester

Cesium carbonate (24.00g, 73.67mmol) and benzyl bromide (8.03mL, 67.53mmol) were added sequentially to a solution of 3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid tert-butyl ester (22.31g, 61.39mmol) and dimethylformamide (100mL) at room temperature. The resulting mixture was heated to 60 ℃, stirred for 1.5 hours, cooled to room temperature and diluted with water (600 mL). The aqueous solution was extracted with diethyl ether (2X 300 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (7: 1 hexane/ethyl acetate) to give 3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil.

¹H NMR(400MHz，CDCl₃)δ7.30(m，3H)，7.23(m，2H)，7.09(t，1H)，6.83(d，1H)，6.70(d，1H)，6.59(dd，1H)，5.19(s，2H)，4.14(d，2H)，2.65(m，2H)，2.54(m，1H)，1.93(m，1H)，1.71(m，1H)，1.60(s，6H)，1.46(s，9H)。

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester

3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid tert-butyl ester was dissolved in 125mL of 20% trifluoroacetic acid in dichloromethane and stirred for 20 min. The reaction mixture was evaporated under reduced pressure. The resulting oil was taken up in 400mL of water, basified with 5N aqueous sodium hydroxide solution and extracted with ethyl acetate (3X 300 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 11.72g (54%, 3 steps) of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate as a pale yellow oil.

LC-MS 354.4(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.29(m，3H)，7.23(m，2H)，7.08(t，1H)，6.81(d，1H)，6.69(d，1H)，6.58(dd，1H)，5.19(s，2H)，3.11(m，2H)，2.61(m，3H)，1.93(m，1H)，1.75(m，1H)，1.61(s，6H)，1.57(m，1H)。

The method D comprises the following steps: preparation of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid ethyl ester L-tartrate

3- (3-hydroxyphenyl) pyridines

3-bromophenol (49.42g, 285.66mmol) and diethyl- (3-pyridyl) borane (40.00g, 272.05mmol) were dissolved in 945mL of a 4: 2: 1 THF/water/ethanol mixture in a 2L round bottom flask equipped with a magnetic stirrer. Sodium carbonate (57.7g, 544.11mmol) and tetrakis (triphenylphosphine) palladium (0) (3.14g, 2.72mmol) were added and the mixture was heated to reflux for 2 h, then cooled to room temperature and stirred for 18 h. The mixture was diluted with 400mL of water and extracted with ethyl acetate (3X 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 1L. The organic solution was diluted with 500mL of water and acidified with 12N hydrochloric acid. The layers were separated and the organic phase was extracted with water (2X 300 mL). The acidic extracts were combined and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ether (3 × 500mL) and the extracts were combined, washed with 500mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 40.91g (88%) of 3- (3-hydroxyphenyl) pyridine as a pale yellow oil which crystallized on standing.

LC-MS 172.1(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.74(d，1H)，8.49(dd，1H)，8.04(dd，1H)，7.49(dt，1H)，7.30(t，1H)，7.09(dd，1H)，7.04(t, 1H), 6.84(dd, 1H). 2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid ethyl ester

To a solution of 3- (3-hydroxyphenyl) pyridine (40.91g, 0.239mol) in 500mL dimethylformamide was added potassium carbonate (148.62g, 1.075mol) and ethyl 2-bromoisobutyrate (157.8mL, 1.075 mol). The mixture was heated to reflux under nitrogen for 18 hours and then cooled to room temperature. The resulting brown suspension was diluted with 1L of water and extracted with ether (3X 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 1L. The organic solution was diluted with 1L of water and acidified with 6N hydrochloric acid. The layers were separated and the organic phase was extracted with 500mL of water. The acidic extracts were combined and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ether (4 × 500mL) and the extracts were combined, washed with 500mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid ethyl ester as a pale yellow oil which was used in the next step without purification.

LC-MS 286.4(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ8.82(brs，1H)，8.59(d，1H)，7.89(d，1H)，7.40(m，1H)，7.35(t，1H)，7.21(d，1H)，7.10(t，1H)，6.86(dd，1H)，4.24(q，2H)，1.64(s，6H)，1.25(t，3H)。

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid ethyl ester L-tartrate salt

To a 2L hydrogenation vessel, 5.0g of platinum (II) oxide was added and nitrogen was purged. A solution of the crude product, ethyl 2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionate (ca. 68.20g, 238.96mmol) in 800mL of acetic acid was added. The suspension was hydrogenated at 45psi for 18 hours. The catalyst was filtered through celite and the filter plug was washed with 200mL of acetic acid. The filtrate was concentrated under reduced pressure. The resulting oil was taken up in 500mL of water and basified with 5N aqueous sodium hydroxide solution. The basic layer was extracted with ether (3 × 500mL) and the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid formed is taken up in 500mL of diethyl ether. L- (+) -tartaric acid was added to the ether solution and stirred at room temperature for 48 hours, a white precipitate formed, which was collected by filtration. The white solid was recrystallized from hot ethanol (1.5L) to yield 78.0g (74%, 2 steps) of the title compound as a white solid.

LC-MS 292.4(M+H)⁺。

¹H NMR(400MHz，DMSO_d6)δ7.21(t，1H)，6.89(d，1H)，6.71(s，1H)，6.63(dd，1H)，4.15(q，2H)，3.90(s，2H)，3.25(d，2H)，2.90(m，3H)，1.84(d，2H)，1.73(d，1H)，1.64(t，1H)，1.51(s，6H)，1.15(t，3H)。

The method E comprises the following steps: preparation of (3S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester

3-pyridin-3-yl-phenols

Diethyl (3-pyridyl) borane (11.80g, 80.0mmol), 3-bromophenol (16.60g, 96.0mmol), Pd (PPH)₃)₄A mixture of (0.92g, 0.80mmol) and sodium carbonate (17.0g, 160.0mmol) in toluene/water/ethanol (160/80/40mL) was purged with nitrogen for 5 minutes and then heated to reflux under nitrogen for 2 hours. After removal of the solvent, the aqueous residue was partitioned between ethyl acetate/brine (400/250 mL). The separated organic layer was washed with brine, filtered and concentrated. The solid residue was taken up in 130mL of 3M hydrochloric acid, stirred for 15 min, diluted with brine (150mL) and extracted with ethyl acetate (2X 250 mL). The separated aqueous layer was cooled in an ice/water bath, adjusted to pH 10 with solid sodium hydroxide and sodium carbonate, and extracted with ethyl acetate (2 × 300 mL). The organic extracts were dried over sodium sulfate and concentrated to give 12.60g (92%) of 3-pyridin-3-yl-phenol as a light yellow solid:¹H NMR(CDCl₃) δ 6.99(m, 1H), 7.08(m, 1H), 7.22(m, 1H), 7.36(m, 1H), 7.43(m, 1H), 8.00(dd, 1H), 8.60(d, 1H), 9.00(s, 1H), MS m/z (relative intensity) 171(m, 1H)⁺，100)，142(17)，115(21)。

2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid ethyl ester

3-pyridin-3-ylA mixture of phenol (5.14g, 30.0mmol), ethyl 2-bromoisobutyrate (26.3g, 135.0mmol) and potassium carbonate (18.7g, 135.0mmol) in anhydrous DMF (60mL) was heated at 95 ℃ for 5 hours under a nitrogen atmosphere. After cooling, brine (200mL) was added and the mixture was extracted with ethyl acetate (250 mL). The separated organic layer was washed with brine, filtered and concentrated. The oil residue was taken up in 80mL of 3M hydrochloric acid, stirred for 15 minutes, diluted with brine (100mL) and extracted with ethyl acetate (2X 150 mL). The separated aqueous layer was cooled in an ice/water bath, adjusted to pH 10 with solid sodium carbonate and extracted with ethyl acetate (2 × 200 mL). The organic extracts were dried over sodium sulfate and concentrated to yield 6.70g (78%) of ethyl 2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionate as a light brown oil:¹H NMR(CDCl₃) δ 1.22(t, 3H), 1.61(s, 6H), 4.22(q, 2H), 6.82(dd, 1H), 7.08(s, 1H), 7.20(dd, 1H), 7.38(m, 2H), 7.81(dd, 1H), 8.59(br s, 1H), 8.80(br s, 1H), MS m/z (relative intensity) 285(m, m)⁺，11)，212(22)，171(100)。

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester

2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid ethyl ester (6.0g, 21.03mmol) was dissolved in methanol (70mL), followed by addition of 37% hydrochloric acid (5.3mL) and 10% Pt/C (0.60 g). The mixture was shaken in a Parr flask at 50psi hydrogen pressure and 50 ℃ for 5 hours, filtered through a pad of celite, rinsing with methanol. GC/MS indicated complete hydrogenation and only 50% conversion of the methyl ester. Concentrated sulfuric acid (2.0mL) was added to the filtrate and the resulting solution was refluxed overnight under nitrogen atmosphere. After removal of excess methanol, the residue was treated with saturated sodium carbonate (150mL) and extracted with ethyl acetate (2X 200 mL). The organic extracts were washed with water, dried over sodium sulfate and concentrated to give 4.80g (82%) of methyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate as a yellow oil: ¹H NMR(CDCl₃) δ 1.59(s, 6H), 1.78(br, 1H), 1.97(brd, 1H), 2.02(br, 2H), 2.61(m, 3H), 3.06-3.13(m, 2H), 3.76(s, 3H), 6.61(dd, 1H), 6.70(s, 1H), 6.83(d, 1H), 7.14(t, 1H), MS m/z (relative intensity) 277(m, 1H)⁺，2)，218(6)，176(100)。

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester tartrate

Methyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (4.80g, 17.31mmol) was dissolved in THF (80mL) and then L- (+) -tartaric acid (2.86g, 19.04mmol) was added. The resulting mixture was refluxed for 3 hours under nitrogen atmosphere. The mixture was collected as a hot solid by vacuum filtration, washed with THF, and further dried to yield 7.13g (96%) of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester tartrate as a white solid:¹H NMR(DMSO-d₆) δ 1.50(s, 6H), 1.60-1.73(m, 2H), 1.83(d, 2H), 2.80-2.94(m, 3H), 3.24(d, 2H), 3.67(s, 3H), 3.87(s, 2H), 6.60(d, 1H), 6.69(s, 1H), 6.89(d, 1H), 7.21(t, 1H), MS m/z (relative intensity) 277(m, 1H)⁺，2)，218(6)，176(100)。

(3S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester tartrate (19.00g) was dissolved in anhydrous THF/water at reflux (475/22.3 mL). The solution was slowly cooled and left at room temperature for 3 days. The solid was collected by vacuum filtration and further dried to yield 8.91g (47%) of a white solid.

8.84g of the above solid was dissolved in anhydrous THF/water (221/13.3mL) under reflux. The solution was slowly cooled and left at room temperature for 3 days. The solid was collected by vacuum filtration and further dried to yield 5.50g (62%) of a white crystalline solid in 93.1% ee with an overall yield of 29%.

The re-dissolved tartrate salt (5.50g) was partitioned between saturated aqueous sodium carbonate (60mL) and ethyl acetate (80 mL). The separated aqueous layer was extracted with ethyl acetate (50mL) and the combined organic extracts were dried over sodium sulfate. Removal of the solvent gave 3.54g (99%) of (3S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester as colorless oil:¹H NMR(CDCl₃)δ1.54(m，1H)，1.58(s，6H)，1.70(br，1H)，1.75(br，1H)，1.95(br d，1H)，2.59(m，3H)，3.05-3.12(m, 2H), 3.76(s, 3H), 6.60(dd, 1H), 6.70(s, 1H), 6.83(d, 1H), 7.14(t, 1H), MS m/z (relative intensity) 277(m, m 1H)⁺，2)，218(6)，176(100)。

Conditions for HPLC analysis: daicel Chiralpak AD, 4.6X 250 mm; hexane/2-propanol/diethylamine (95/5/0.2); 1.5 mL/min; 270 nm.

Method F: preparation of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester

2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid methyl ester

A mixture of 3-pyridin-3-yl-phenol (0.86g, 5.0mmol), methyl 2-bromoisobutyrate (3.60g, 20.0mmol) and potassium carbonate (2.76g, 20.0mmol) in anhydrous DMF (10mL) was heated at 93 ℃ under a nitrogen atmosphere for 3 hours. After cooling, brine (40mL) was added and the mixture was extracted with ethyl acetate (50 mL). The separated organic layer was washed with brine, filtered and concentrated. The oil residue was taken up in 10mL of 3M hydrochloric acid, stirred for 10 min, diluted with brine (10mL) and extracted with ethyl acetate (2X 30 mL). The separated aqueous layer was cooled in an ice/water bath, adjusted to pH 10 with solid sodium carbonate and extracted with ethyl acetate (2X 40 mL). The organic extracts were dried over sodium sulfate and concentrated to give 1.09g (80%) of methyl 2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionate as a yellow oil: ¹HNMR(CDCl₃) δ 1.62(s, 6H), 3.79(s, 3H), 6.82(dd, 1H), 7.08(s, 1H), 7.20(d, 1H), 7.38(m, 2H), 7.81(d, 1H), 8.59(d, 1H), 8.80(s, 1H), MS m/z (relative intensity) 271 (m)⁺，20)，212(30)，171(100)。

2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester

Methyl 2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionate (4.07g, 15.0mmol) was dissolved in methanol (40mL) and then 37% hydrochloric acid (3.8mL) and 10% Pt/C (0.41g) were added. The mixture was shaken in a Parr flask at 50psi hydrogen pressure and 50 ℃ for 2 hours, filtered through a pad of celite, rinsing with methanol. After removal of the solvent, the residue was treated with saturated aqueous sodium carbonate (100mL) and washed withExtraction with ethyl acetate (2X 100 mL). The organic extracts were washed with water, dried over sodium sulfate and concentrated to give 3.70g (89%) of methyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate as a yellow oil:¹HNMR(CDCl₃) δ 1.57(br m, 1H), 1.60(s, 6H), 1.78(br, 1H), 1.86(br, 1H), 1.97(br d, 1H), 2.61(m, 3H), 3.06-3.13(m, 2H), 3.76(s, 3H), 6.61(dd, 1H), 6.70(s, 1H), 6.83(d, 1H), 7.14(t, 1H), MS m/z (relative intensity) 277(m, m 1H)⁺，2)，218(6)，176(100)。

Preparation example 3

Resolution of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid alkyl esters

The method E comprises the following steps: resolution of 2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid methyl ester

Concentrated sulfuric acid (25mL) was added to a solution of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid ethyl ester L-tartrate (preparation 2, method D; 110.0g, 249.17mmol) in 500mL of methanol. The solution was heated to reflux for 18 hours and then cooled to room temperature. Methanol was removed under reduced pressure and the resulting oil was taken up in 1L of water, basified with 5N sodium hydroxide and extracted with ethyl acetate (2X 500 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The oil formed was taken up in 500mL of ethanol and L- (+) -tartaric acid (37.4g, 249.17mmol) was added and the suspension was heated until all solids were dissolved. The hot solution was cooled to room temperature and stirred for 18 hours. The white precipitate (2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid methyl ester- (L) -tartrate) was collected by filtration.

The white solid was recrystallized from hot THF to give 56.23g of the partially resolved product (1: 3R/S), which was subjected to a second recrystallization in 5.8% water/THF (1.52L) to give 27.95g of (S) -2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid methyl ester- (L) -tartrate salt (26.2%, 92.2% ee; [ alpha. -F.;)]_D ²⁵＝12.3°(c 0.61，CH₃OH); HPLC analysis: chiralpak AD 1.5mL/min, 5% isopropanol/hexane w/0.5% diethylamine, retention time 6.15 min (R) and 7.46 min (S)), as a white solid. By using D-tartaric acid was subjected to a similar crystallization procedure to obtain (R) -2-methyl-2- (3-pyridin-3-yl-phenoxy) -propionic acid methyl ester- (D) -tartrate.

LC-MS 278.4(M+H)⁺。

¹H NMR(400MHz，DMSO_d6)δ7.22(t，1H)，6.89(d，1H)，6.70(s，1H)，6.61(dd，1H)，3.84(s，2H)，3.68(s，3H)，3.25(d，2H)，2.83(m，2H)，1.84(d，2H)，1.69(m，2H)，1.51(s，6H)。

Method F: resolution of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester

To a solution of L- (+) -tartaric acid in 2.5% water/2-butanone (105mL) at reflux was added a solution of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (preparation 2, method C; 9.11g, 25.8mmol) in 2.5% water/2-butanone (20 mL). The resulting solution was cooled to room temperature with stirring. As the mixture cooled, a white solid precipitated out. The suspension was stirred at room temperature for 64 hours. The precipitate was collected by buchner funnel and washed with 2-butanone and dried in vacuo to yield 5.66g (44%) of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate-L- (+) -tartrate (87.5% ee). The white solid was slurried in 2.5% water/2-butanone (59.5mL) and heated to reflux. Water was added slowly until the milky suspension became clear. The resulting solution was cooled to room temperature with stirring. As the mixture cooled, a white solid precipitated out. The suspension was stirred at room temperature for 64 hours. The precipitate was collected by a buchner funnel and washed with 2-butanone and dried in vacuo to yield 4.86g (37% overall yield) of (S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester-L- (+) -tartrate (98% ee; [ alpha ];, [ alpha ]; (r) ]_D ²⁵＝11.2°(c 0.86，CH₃OH); HPLC analysis: chiralpak AD 1.5mL/min, 5% isopropanol/hexane w/0.5% diethylamine, retention time 6.65 min (R) and 8.08 min (S)).

A similar crystallization procedure was performed with D-tartaric acid to obtain (R) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester- (D) -tartrate: (R) -enriched benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate was recovered from the L- (+) -tartaric acid resolution mother liquor and the resolved (S) enantiomer was obtained by partitioning between 0.5M aqueous sodium hydroxide and diethyl ether.

The ether phase was concentrated to give an orange oil and chiral HPLC confirmed the enantiomeric ratio of 83: 17, R: S.

D- (-) -tartaric acid (3.80g, 25.3mmol) was suspended in 105mL 2-butanone containing 2.5% water, and the suspension was then heated to reflux, resulting in a clear solution. (R) -enriched benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (9.10g, 25.7mmol) was dissolved in 15mL 2-butanone containing 2.5% water and then added to a solution of D- (-) -tartaric acid at reflux. The reaction solution was stirred at reflux for 15 minutes, then slowly cooled to room temperature and stirred for 16 hours. The white precipitate formed was collected by filtration and washed with 2-butanone and then dried in vacuo to give (R) -benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate- (D) -tartrate (9.64g, 89%, 93% e.e.) as a white solid.

LC-MS，354.4(M+H)⁺。

¹H NMR(400MHz，DMSO_d6)δ7.31(m，3H)，7.15(m，2H)，6.88(d，1H)，6.69(s，1H)，6.57(dd，1H)，5.16(s，1H)，3.85(s，1H)，3.22(d，1H)，2.87(q，1H)，2.81(m，2H)，1.80(t，2H)，1.71(m，1H)，1.58(m，1H)，1.52(s，6H)。

Example 1

2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid benzyl ester

To a solution of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (preparation 2, method C; 0.54g, 1.52mmol) in 5mL of dichloromethane were added 4-isopropylphenylacetic acid (0.33g, 1.83mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.58g, 3.04mmol) and stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure and the resulting oil was flash chromatographed, eluting with 30% ethyl acetate/hexanes to give 0.696g (89%) of benzyl 2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionate as a clear oil.

LC-MS 514.6(M+H)⁺。

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.25(d, 6H), 1.52(m, 2H), 1.59(s, 6H), 1.75(m, 1H), 1.86(m, 1H), 2.13(m, 1H), 2.47(m, 1H), 2.82(t, 1H), 2.91(m, 1H), 3.71(m, 3H), 4.72(d, 1H), 5.18(s, 2H), 6.42(d, 0.5H), 6.51(s, 0.5H), 6.58(t, 1H), 6.71(s, 0.5H), 6.83(m, 0.5H), 7.06(m, 1H), 7.18(m, 3H), 7.21(m, 2H), 7.29(m, 3H).

2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

10% Palladium on charcoal (50mg, 10 wt%) was added to a solution of benzyl 2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionate (494mg, 0.96mmol) in methanol (15mL), and the resulting mixture was hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through a plug of celite and the plug of celite was washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to give 319mg (78%) of 2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid as a clear oil.

LC-MS 424.5(M+H)⁺。

¹H NMR(400MHz，DMSO_d6)δ1.18(m，6H)，1.33(s，6H)，1.70(m，3H)，2.08(t，1H)，2.37(t，1H)，2.55(m，1H)，2.84(m，1H)，2.90(q，1H)，3.65(m，2H)，3.78(d，1H)，3.95(d，1H)，4.42(dd，1H)，6.32(d，1H)，6.49(s，1H)，6.63(m，2H)，6.98(dt，1H)，7.14(m，3H)。

Examples 1-1 to 1-64 were prepared from similar starting materials using a similar procedure as described in example 1.

Examples 1 to 1

2- (3- {1- [ (3-methoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.31(m, 0.5H), 1.42(m, 0.5H), 1.55(s, 6H), 1.62(m, 0.5H), 1.76(d, 0.5H), 1.92(dd, 0.5H), 2.18(t, 0.5H), 2.51(t, 0.5H), 2.60(d, 0.5H), 2.89(t, 0.5H), 2.95(t, 0.5H), 3.76(m, 5H), 4.62(m, 1H), 6.52(s, 0.5H), 6.62(d, 0.5H), 6.78(m, 4H), 7.21(t, 1H), 7.19(m, 1H).

APCI-MS(m+1＝412.3)。

Examples 1 to 2

2- (3- {1- [ (4-methoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.24(m, 1H), 1.45(m, 1H), 1.55(s, 6H), 1.63(m, 0.5H), 1.71(m, 0.5H), 1.83(d, 0.5H), 1.95(d, 0.5H), 2.04(t, 0.5H), 2.56(m, 1H), 2.89(m, 1H), 3.63(m, 2H), 3.68(s, 1H), 3.76(s, 2H), 4.61(dd, 1H), 6.45(s, 0.5H), 6.63(d, 0.5H), 6.75(t, 1H), 6.86(m, 3H), 7.13(m, 3H).

APCI-MS(m+1＝412.3)。

Examples 1 to 3

2- (3- {1- [ (4-fluoro-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.21(m, 1H), 1.47(m, 1H), 1.55(s, 6H), 1.72(m, 1H), 1.93(t, 1H), 2.12(t, 0.5H), 1.52(t, 0.5H), 1.59(m, 1H), 2.96(m, 1H), 3.65(d, 1H), 3.71(s, 1H), 3.82(d, 1H), 4.61(m, 1H), 6.60(s, 0.5H), 6.63(d, 0.5H), 6.74(t, 1H), 6.77(s, 0.5H), 6.85(d, 0.5H), 6.98(m, 2H), 7.18(m, 3H).

APCI-MS(m+1＝400.2)。

Examples 1 to 4

2- (3- {1- [ (4-hydroxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.56(s，6H)，1.69(t，1H)，1.90(m，1H)，2.51(t，1H)，2.61(m，1H)，2.93(m，1H)，3.62(q，1H)，3.67(s，1H)，3.81(dd，1H)，4.62(dd，1H)，6.32(s，1H)，6.76(m，4H)，7.02(m，2H)，7.13(m，1H)。

APCI-MS(m+1＝398.2)。

Examples 1 to 5

2- {3- [1- (4-isopropyl-benzoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.23(d，6H，5.4Hz)，1.57(s，6H)，1.70(d，2H)，2.06(d，2H)，2.89(brm，4H)，3.51(brm，3H)，3.85(brs，1H)，4.74(brs，1H)，6.83(brm，4H)，7.25(brm，2H)，7.32(brm，2H)。

APCI-MS(m+1＝410.3)。

Examples 1 to 6

2- (3- {1- [ (2, 4-dimethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.55(t，6H)，1.70(m，1H)，1.86(m，1H)，2.61(m，2H)，2.92(m，2H)，3.43(d，1H)，3.64(dd，1H)，3.79(s，3H)，3.83(s，3H)，4.66(m，2H)，6.46(d，1H)，6.49(dd，1H)，6.68(m，1H)，6.78(d，1H)，6.91(d，1H)，7.17(m，3H)。

APCI-MS(m+1＝442.3)。

Examples 1 to 7

2-methyl-2- (3- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.55(s，6H)，1.72(m，1H)，1.94(t，1H)，2.25(t，1H)，2.61(m，2H)，2.98(m，2H)，3.78(m，4H)，4.64(m，2H)，6.61(m，1H)，6.76(d，1H)，6.87(d，1H)，7.15(q，1H)，7.36(d，2H)，7.57(d，2H)。

APCI-MS(m+1＝450.2)。

Examples 1 to 8

2- (3- {1- [3- (3-methoxy-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.47(m，1H)，1.59(m，6H)，1.79(m，1H)，2.00(t，1H)，2.40(t，1H)，2.60(m，2H)，2.95(m，2H)，3.77(d，3H，9.1HZ)，4.64(d，2H)，6.78(m，4H)，6.90(d，1H)，7.19(m，3H)。

APCI-MS(m+1＝426.3)。

Examples 1 to 9

2-methyl-2- {3- [1- (pyridin-2-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.67(dd，6H)，1.78(m，2H)，2.09(d，1H)，2.80(m，1H)，2.87(t，1H)，3.79(t，1H)，2.91(d，1H)，4.16(d，1H)，4.22(d，1H)，6.77(dd，2H)，6.96(s，1H)，7.18(m，1H)，7.26(m，1H)，7.49(d，1H)，7.72(dd，1H)，8.54(d，1H)。

APCI-MS(m+1＝383.2)。

Examples 1 to 10

2-methyl-2- {3- [1- (pyridin-3-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.57(d，6H)，1.69(m，2H)，1.84(d，2H)，2.50(dt，1H)，3.00(t，1H)，3.56(d，1H)，3.80(d，1H)，3.93(d，1H)，4.63(d，1H)，6.49(s，1H)，6.82(m，2H)，7.21(m，1H)，7.43(dd，1H)，8.04(d，1H)，8.51(d，1H)，8.57(d，1H)。

APCI-MS(m+1＝383.2)。

Examples 1 to 11

2-methyl-2- {3- [1- (pyridin-4-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CD₃OD)δ1.55(d，6H)，1.80(m，2H)，2.03(d，1H)，2.66(t，1H)，2.78(t，1H)，3.24(t，1H)，4.03(t，1H)，4.19(q，1H)，4.52(t，1H)，6.76(m，1H)，6.83(d，1H)，6.93(dd，1H)，7.20(q，1H)，7.99(dd，2H)，8.79(d，2H)。

LC-MS(m+1＝383.5)。

Examples 1 to 12

2- [3- (1-Cyclohexylacetyl-piperidin-3-yl) -phenoxy ] -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.00(m，3H)，1.26(m，4H)，1.54(s，6H)，1.77(m，7H)，1.99(d，1H)，2.28(m，2H)，2.61(m，2H)，3.14(q，1H)，3.96(dd，1H)，4.58(m，1H)，6.78(d，2H)，6.82(s，1H)，7.12(q，1H)。

LC-MS(m+1＝388.5)。

Examples 1 to 13

(S) -2- (3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

LC-MS(m+1＝424.4)。

[α]_D ²⁵＝-79.6°(c 2.03，CH₃OH)。

Examples 1 to 14

(R) -2- (3- {1- [ (4-isopropyl-phenyl) acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

LC-MS(m+1＝424.4)。

[α]_D ²⁵＝82.2°(c 2.17，CH₃OH)。

Examples 1 to 15

2- [3- (1-isobutyryl-piperidin-3-yl) -phenoxy ] -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.10(m，6H)，1.24(s，1H)，1.60(m，6H)，1.81(m，1H)，2.02(m，1H)，2.58(m，2H)，2.81(m，1H)，3.02(m，1H)，3.95(m，1H)，4.68(m，1H)，6.79(d，1H)，6.81(s，1H)，6.90(d，1H)，7.19(m，1H)。

APCI-MS(m+1＝334.2)。

Examples 1 to 16

2-methyl-2- [3- (1-phenylacetyl-piperidin-3-yl) -phenoxy ] -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.56(m，6H)，1.84(m，1H)，1.91(m，1H)，2.16(t，1H)，2.56(m，2H)，2.91(m，2H)，3.77(m，4H)，4.68(m，2H)，6.57(s，1H)，6.77(m，2H)，6.87(d，1H)，7.13(m，1H)，7.24(m，3H)，7.31(m，2H)。

APCI-MS(m+1＝382.2)。

Examples 1 to 17

2-methyl-2- {3- [1- (3-phenyl-propionyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.41(m，1H)，1.61(s，6H)，1.75(m，1H)，1.97(m，1H)，2.38(m，1H)，2.61(m，4H)，2.93(m，3H)，3.78(d，2H，13.7Hz)，4.67(m，2H)，6.78(m，3H)，6.89(d，1H)，7.22(m，6H)。

APCI-MS(m+1＝396.3)。

Examples 1 to 18

2-methyl-2- [3- (1-m-tolylacetyl-piperidin-3-yl) -phenoxy ] -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.47(m，1H)，1.59(s，6H)，1.63(m，1H)，1.78(m，1H)，1.93(dd，1H)，2.12(t，1H)，2.33(s，3H)，2.56(t，1H)，2.61(d，1H)，2.91(t，1H)，2.96(t，1H)，3.67(q，1H)，3.71(d，1H)，3.83(d，1H)，4.64(m，1H)，6.57(s，1H)，6.71(t，1H)，6.81(m，1H)，6.89(m，1H)，7.02-7.21(m，4H)。

APCI-MS(m+1＝396.3)。

Examples 1 to 19

2-methyl-2- {3- [1- (pyridine-2-carbonyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.54(m，6H)，1.73(m，1H)，1.97(m，1H)，2.85(m，2H)，3.12(t，1H)，3.19(t，1H)，3.67(d，1H)，3.78(d，1H)，4.46(d，1H)，4.73(d，1H)，6.74(d，1H)，6.80(d，1H)，6.95(s，1H)，7.14(t，1H)，7.21(t，1H)，7.42(brm，1H)，7.62(brm，1H)，7.86(m，1H)，8.66(brs，1H)。

APCI-MS(m+1＝369.2)。

Examples 1 to 20

2-methyl-2- {3- [1- (pyridine-3-carbonyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CD₃OD)δ1.53(s，6H)，1.78(m，2H)，2.04(m，1H)，2.78(m，1H)，2.90(m，1H)，3.20(q，1H)，3.62(m，2H)，4.66(d，1H)，6.69(s，1H)，6.78(m，1H)，6.87(s，1H)，6.97(m，1H)，7.12(m，1H)，7.22(m，1H)，7.55(brs，1H)，7.74(d，1H)，7.93(brs，1H)。

APCI-MS(m+1＝369.2)。

Examples 1 to 21

2- [3- (1-benzoyl-piperidin-3-yl) -phenoxy ] -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.29(m，1H)，1.47(s，3H)，1.53(s，3H)，1.76(m，2H)，1.92(m，1H)，2.02(d，1H)，2.70(m，1H)，2.87(q，1H)，3.11(q，1H)，3.69(m，1H)，4.67(m，1H)，6.60(d，1H)，6.68(m，1H)，6.80(dd，1H)，7.01(dt，1H，7.1Hz)，7.42(m，5H)。

APCI-MS(m+1＝368.5)。

Examples 1 to 22

2- (3- {1- [ (3-fluoro-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.35(m，1H)，1.59(s，6h)，1.70(t，1H)，1.93(t，1H)，2.24(t，1H)，2.58(m，2H)，2.97(m，1H)，3.73(m，3H)，4.65(m，1H)，6.63(m，1H)，6.78(m，1H)，6.89(m，4H)，7.16(brs，1H)，7.28(m，2H)。

APCI-MS(m+1＝400.2)。

Examples 1 to 23

2- (3- {1- [ (3-chloro-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.58(s，6H)，1.65(m，1H)，1.76(m，1H)，2.00(m，1H)，2.24(m，1H)，2.61(m，2H)，2.99(m，1H)，3.72(m，2H)，3.83(m，1H)，4.65(m，1H)，6.64(m，1H)，6.78(m，2H)，6.91(d，1H)，7.16(m，5H)。

APCI-MS(m+1＝416.2)。

Examples 1 to 24

2- (3- {1- [ (4-chloro-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.37(m，1H)，1.58(s，6H)，1.70(m，1H)，1.99(m，1H)，2.25(m，1H)，2.61(m，2H)，2.97(m，1H)，3.70(m，2H)，3.82(d，1H)，4.64(m，1H)，6.60(brs，1H)，6.67(d，1H)，6.77(m，1H)，6.89(d，1H)，7.17(m，2H)，7.27(m，1H)。

APCI-MS(m+1＝416.2)。

Examples 1 to 25

2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.42(m，1H)，1.58(s，6H)，1.74(dt，1H)，1.95(t，1H)，2.25(t，1H)，2.57(m，2H)，2.98(t，1H)，3.01(t，1H)，3.69(d，1H)，3.76(s，1H)，3.82(m，1H)，4.66(m，1H)，6.61(m，1H)，6.76(m，2H)，6.86(d，1H)，7.14(m，2H)，7.26(m，1H)。

Examples 1 to 26

2-methyl-2- {3- [1- (3-piperidin-1-yl-propionyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.42(m，1H)，1.55(s，3H)，1.62(s，3H)，1.86(m，4H)，2.17(d，1H)，2.21(m，2H)，2.68(m，4H)，2.88(t，1H)，3.08(m，1H)，3.25(brs，2H)，3.42(m，1H)，3.59(m，1H)，3.79(m，2H)，4.42(d，1H)，6.82(m，3H)，7.21(t，1H)。

APCI-MS(m+1＝403.3)。

Examples 1 to 27

2-methyl-2- {3- [1- (3-methyl-butyryl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CDCl₃)δ0.96(d，6H)，1.58(s，6H)，1.69(m，1H)，1.82(m，1H)，2.08(m，2H)，2.24(m，2H)，2.54(m，4H)，3.03(m，1H)，3.90(d，1H)，4.65(d，1H)，6.80(m，2H)，6.93(d，1H)，7.20(m，1H)。

APCI-MS(m+1＝348.2)。

Examples 1 to 28

2- (3- {1- [ (4-ethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.42(dt, 3H), 1.58(d, 6H), 1.70(m, 1H), 1.92(dd, 1H), 1.97(m, 1H), 2.55(t, 1H), 2.63(m, 1H), 2.95(q, 1H), 3.65(q, 1H), 3.69(s, 1H), 3.84(t, 1H), 4.04(q, 2H), 4.11(m, 1H), 4.66(dd, 1H), 6.42(s, 1H), 6.67(d, 1H), 6.83(m, 3H), 7.16(m, 3H)

APCI-MS(m+1＝426.3)。

Examples 1 to 29

2- (3- {1- [ (2-methoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.55(s, 6H), 1.71(m, 1H), 1.91(dd, 1H), 2.14(t, 0.5H), 2.51(t, 0.5H), 2.59(d, 1H), 2.84(t, 0.5H), 2.95(t, 0.5H), 3.55-3.85(m, 8)H)，4.63(m，1H)，6.57(m，1H)，6.73(t，1H)，6.85(m，3H)，7.19(m，3H)。

APCI-MS(m+1＝412.3)。

Examples 1 to 30

2-methyl-2- [3- (1-o-tolylacetyl-piperidin-3-yl) -phenoxy ] -propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.54(d, 6H), 1.68(m, 1H), 1.96(m, 1H), 2.23(d, 3H), 2.62(m, 1H), 2.91(dt, 1H), 3.69(m, 3H), 4.66(m, 2H), 6.54(s, 0.5H), 6.59(d, 0.5H), 6.74(dd, 1H), 6.81(s, 0.5H), 6.89(d, 0.5H), 7.14(m, 5H).

APCI-MS(m+1＝396.3)。

Examples 1 to 31

2-methyl-2- [3- (1-p-tolylacetyl-piperidin-3-yl) -phenoxy ] -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.57(s，6H)，1.93(m，1H)，2.19(m，1H)，2.33(s，3H)，2.60(brm，2H)，3.72(m，4H)，3.86(brm，1H)，4.66(brm，1H)，6.56(m，1H)，6.64(m，1H)，6.78(m，3H)，6.95(m，1H)，7.16(m，3H)。

APCI-MS(m+1＝396.3)。

Examples 1 to 32

2- (3- {1- [ (3, 5-dimethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.51(s, 6H), 1.71(m, 1H), 1.89(m, 1H), 2.13(t, 1H), 2.50(m, 1H), 2.89(m, 2H), 3.23(m, 3H), 3.61(m, 2H), 3.71(d, 6H), 3.82(d, 1H), 4.59(d, 1H), 6.31(m, 2H), 6.52(m, 1H), 6.68(m, 2H), 6.79(d, 1H), 6.98(d, 0.5H), 7.08(dt, 2H).

APCI-MS(m+1＝442.3)。

Examples 1 to 33

2-methyl-2- (3- {1- [ (3-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.55(s，6H)，1.65(d，1H)，1.79(m，1H)，1.97(m，1H)，2.27(brm，1H)，2.62(brs，2H)，3.02(brm，1H)，3.81(brm，4H)，4.65(brs，2H)，6.63(s，1H)，6.77(m，2H)，6.91(brs，1H)，7.17(m，2H)，7.48(m，4H)。

APCI-MS(m+1＝450.3)。

Examples 1 to 34

2- (3- {1- [ (3, 5-bis-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.58(s，6H)，1.69(q，1H)，1.85(d，1H)，2.03(m，1H)，2.42(m，1H)，2.67(m，1H)，3.11(m，1H)，3.83(m，4H)，4.64(m，2H)，6.76(m，3H)，6.93(brm，1H)，7.20(q，1H)，7.71(s，2H)，7.79(s，1H)。

APCI-MS(m+1＝518.3)。

Examples 1 to 35

2-methyl-2- (3- {1- [ (3-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.33(m，1H)，1.51(m，1H)，1.61(s，6H)，1.75(m，1H)，1.96(t，1H)，2.26(t，1H)，2.57(m，1H)，2.97(dt，1H)，3.73(m，4H)，4.68(m，1H)，6.61(m，1H)，6.77(m，1H)，6.87(m，1H)，6.97(d，0.5H)，7.16(m，4H)，7.37(m，1H)。

LC-MS(m+1＝466.4)。

Examples 1 to 36

2-methyl-2- (3- {1- [3- (3-trifluoromethoxy-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.62(s，6H)，1.78(d，1H)，2.01(d，1H)，2.62(m，4H)，2.97(m，3H)，3.79(d，1H)，4.65(m，1H)，6.79(m，2H)，6.89(d，1H)，7.06(m，2H)，7.16(m，2H)，7.29(m，2H)。

LC-MS(m+1＝480.4)。

Examples 1 to 37

2-methyl-2- {3- [1- (piperidin-1-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，DMSO_d6) δ racemic mixture: 1.25(m, 1H), 1.42(m, 1H), 1.50(s, 6H), 1.72(m, 3H), 1.90(d, 1H), 2.63(m, 1H), 2.71(m, 1H), 2.93(brs, 1H), 3.09(m, 1H), 3.40(m, 1H), 3.63(t, 1H), 4.34(m, 3H), 6.63(m, 1H), 6.73(s, 0.5H), 6.81(s, 0.5H), 6.89(dd, 1H, 7.9Hz), 7.21(m, 1H), 9.37(brs, 1H), 13.02(brs, 1H).

LC-MS(m+1＝389.5)。

Examples 1 to 38

2-methyl-2- {3- [1- (morpholin-4-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，DMSO_d6) δ racemic mixture: 1.50(s, 6H), 1.68(m, 1H), 1.77(m, 1H), 1.90(m, 1H), 2.71(dt, 1H), 3.11(m, 3H), 3.42(m, 1H), 3.62(t, 1H), 3.78(m, 1H), 3.92(m, 1H), 4.39(dd, OH), 6.64(m, 1H), 6.73(s, 0.5H), 6.82(s, 0.5H), 6.86(dd, 1H), 7.21(m, 1H), 10.20(s, 1H).

LC-MS(m+1＝391.5)。

Examples 1 to 39

2-methyl-2- {3- [1- (piperazin-1-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，DMSO_d6) δ racemic mixture: 1.50(s, 6H), 1.71(m, 2H), 1.89(m, 1H), 2.69(m, 2H), 3.10(t, 1H), 4.68(m, 2H), 6.64(s, 1H), 6.72(s, 0.5H), 6.81(s, 0.5H), 6.89(dd, 1H), 7.20(m, 1H), 9.97(brs, 1H).

LC-MS(m+1＝390.0)。

Examples 1 to 40

2- (3- {1- [ (1H-benzoimidazol-2-yl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，DMSO_d6) δ racemic mixture: 1.50(d, 6H), 1.74(m, 2H), 1.91(m, 1H), 2.71(m, 1H), 3.21(m, 2H), 3.97(dd, 1H), 4.45(m, 3H), 6.65(d, 1H), 6.72(s, 0.5H), 6.84(s, 0.5H), 6.89(dd, 1H), 7.21(q, 1H), 7.50(m, 2H), 7.78(m, 2H).

LC-MS(m+1＝422.5)。

Examples 1 to 41

2- {3- [1- (benzo [1, 3] dioxol-5-yl-acetyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.59(s，6H)，1.75(m，1H)，1.94(m，1H)，2.27(m，1H)，2.58(m，2H)，2.98(m，2H)，3.63(d，1H)，3.68(s，1H)，3.87(d，1H)，4.66(t，1H)，5.96(d，2H)，6.60(s，1H)，6.69(m，3H)，6.77(m，1H)，6.92(d，1H)，7.19(t，1H)。

LC-MS(m+1＝426.4)。

Examples 1 to 42

2- (3- {1- [ (2-hydroxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.55(m，1H)，1.59(s，3H)，1.64(s，3H)，1.69(m，1H)，1.80(dd，1H)，2.00(t，1H)，2.57(t，1H)，2.61(m，1H)，3.15(q，1H)，3.76(d，2H)，4.18(m，1H)，4.65(m，1H)，6.90(m，5H)，6.98(m，2H)，7.04(d，1H)，7.19(t，1H)。

LC-MS(m+1＝398.4)。

Examples 1 to 43

2- (3- {1- [ (4-tert-butyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.32(d, 9H), 1.54(d, 6H), 1.69(t, 1H), 1.81(t, 1H), 1.92(d, 0.5H), 2.06(t, 0.5H), 2.61(m, 1H), 2.97(t, 0.5H), 3.07(t, 0.5H), 3.71(abq, 1H), 3.79(s, 1H), 3.89(d, 0.5H), 4.02(d, 0.5H), 4.60(dd, 1H), 6.48(d, 0.5H), 6.52(s, 0.5H), 6.69(dd, 0.5H), 6.75(dd, 0.5H), 6.71(s, 0.5H), 7.12(t, 0.5H), 7.19(m, 2H), 7.38(m, 1H).

LC-MS(m+1＝438.5)。

Examples 1 to 44

2- (3- {1- [ (4-ethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.23(t，3H)，1.62(s，6H)，1.74(m，1H)，1.92(m，1H)，2.63(q，2H)，3.87(m，2H)，6.59(brm，1H)，6.77(d，1H)，7.15(s，4H)。

LC-MS(m+1＝410.5)。

Examples 1 to 45

2- {3- [1- (4-isobutyl-benzoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ0.89(d，6H)，1.57(s，6H)，1.71(m，1H)，1.85(m，2H)，2.07(m，1H)，2.48(d，2H)，2.78(brm，1H)，2.89(brm，2H)，6.77(m，2H)，6.88(m，1H)，7.17(m，3H)，7.32(d，2H)。

LC-MS(m+1＝424.4)。

Examples 1 to 46

2- (3- {1- [ (4-isobutyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ0.89(d，6H)，1.58(s，6H)，1.85(m，1H)，1.91(m，1H)，2.45(d，2H)，2.61(m，1H)，3.75(m，2H)，3.88(m，1H)，4.66(m，2H)，6.60(m，1H)，6.76(d，1H)，7.14(m，6H)。

LC-MS(m+1＝438.4)。

Examples 1 to 47

2-methyl-2- (3- {1- [4- (2, 2, 2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl) -benzoyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.48(brs，1H)，1.57(m，6H)，1.75(m，2H)，2.09(m，1H)，2.80(m，1H)，3.72(m，1H)，4.75(brs，1H)，6.61(m，1H)，6.84(m，3H)，7.39(m，2H)，7.73(m，2H)。

LC-MS(m+1＝534.4)。

Examples 1 to 48

(S) -2- (3- {1- [ (4-tert-butyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

LC-MS(m+1＝438.5)。

[α]_D ²⁵＝-66.9°(c 1.12，CH₃OH)。

Examples 1 to 49

(S) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

APCI-MS(m+1＝466.2)。

[α]_D ²⁵＝-65.7°(c 0.60，CH₃OH)。

Examples 1 to 50

(R) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

APCI-MS(m+1＝466.2)。

[α]_D ²⁵＝64.2°(c 1.16，CH₃OH)。

Examples 1 to 51

(R) -2- (3- {1- [ (4-tert-butyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 1.32(d, 9H), 1.54(d, 6H.), 1.69(t, 1H), 1.81(t, 1H), 1.92(d, 0.5H), 2.06(t, 0.5H), 2.61(m, 1H), 2.97(t, 0.5H), 3.07(t, 0.5H), 3.71(abq, 1H), 3.79(s, 1H), 3.89(d, 0.5H), 4.02(d, 0.5H), 4.60(dd, 1H), 6.48(d, 0.5H), 6.52(s, 0.5H), 6.69(dd, 0.5H), 6.75(dd, 0.5H), 6.71(s, 0.5H), 7.12(t, 0.5H), 7.19(m, 2H), 7.38(m, 1H).

LC-MS(m+1＝438.5)。

[α]_D ²⁵＝72.6°(c 1.31，CH₃OH)。

Examples 1 to 52

(S) -2- (3- {1- [ (4-cyclohexyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.44(m，4H)，1.53(s，6H)，1.67(m，1H)，1.75(m，1H)，1.89(m，6H)，2.04(t，1H)，2.55(brm，2H)，2.61(q，1H)，3.00(m，1H)，3.76(abq，1H)，3.95(dd，1H)，4.59(dd，1H)，6.49(d，0.5H)，6.51(d，0.5H)，6.69(dd，0.5H)，6.74(dd，0.5H)，6.80(s，0.5H)，6.89(d，0.5H)，7.09(t，0.5H)，7.16(m，3H)，7.21(m，1H)。

LC-MS(m+1＝464.5)。

Examples 1 to 53

(S) -2- (3- {1- [ (4-methanesulfonyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.28(m，1H)，1.49(m，1H)，1.54(d，6H)，1.79(m，2H)，1.98(t，1H)，2.36(t，0.5H)，2.51(t，0.5H)，2.71(q，1H)，3.12(d，3H)，3.95(m，3H)，4.59(dd，1H)，6.61(s，0.5H)，6.72(m，1.5H)，6.81(s，0.5H)，6.90(d，0.5H)，7.16(m，1H)，7.53(t，2H)，7.93(t，2H)。

LC-MS(m+1＝460.5)。

Examples 1 to 54

(S) -2- {3- [1- (biphenyl-4-yl-acetyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.49(s，3H)，1.55(s，3H)，1.65-1.98(m，3H)，2.14(t，1H)，2.65(m，1H)，3.06(m，1H)，3.86(abq，2H)，3.97(d，1H)，4.08(d，1H)，4.61(dd，1H)，6.52(s，0.5H)，6.61(d，0.5H)，6.69(dd，0.5H)，6.74(dd，0.5H)，6.81(s，0.5H)，6.91(d，0.5H)，7.10(t，0.5H)，7.18(t，0.5H)，7.34(m，3H)，7.43(m，2H)，7.62(m，4H)。

LC-MS(m+1＝458.5)。

Examples 1 to 55

(S) -2-methyl-2- {3- [1- (naphthalen-2-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 1.54(m, 6H), 1.68(m, 1H), 1.80(m, 1H), 1.91(m, 1H), 2.02(m, 1H), 2.58(t, 1H), 2.66(m, 1H), 3.07(m, 1H), 3.99(m, 3H), 4.62(dd, 1H), 6.33(d, 0.5H), 6.44(s, 0.5H), 6.66(d, 0.5H), 6.74(d, 0.5H), 6.80(s, 0.5H), 6.90(d, 0.5H), 6.99(t, 0.5H), 7.18(t, 0.5H, 7.9Hz), 7.46(m, 3H), 7.73(d, 1H), 7.84(m, 3H).

LC-MS(m+1＝432.4)。

Examples 1 to 56

(S) -2-methyl-2- (3- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CD₃OD)δ1.53(s，6H)，1.68(m，1H)，1.83(m，2H)，2.04(m，1H)，2.48(s，1H)，2.76(t，1H)，6.73(m，1H)，6.80(brm，1H)，6.91(brm，1H)，7.19(t，1H)，7.78(d，2H)，7.90(s，1H)，8.13(d，2H)。

LC-MS(m+1＝533.1)。

Examples 1 to 57

(S) -2-methyl-2- {3- [1- (naphthalen-1-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 1.47(s, 3H), 1.53(s, 3H), 1.84(m, 2H), 1.98(d, 1H), 2.23(t, 1H), 2.70(m, 2H), 3.04(t, 1H), 3.14(t, 1H), 3.90(d, 1H), 4.04(d, 1H), 4.23(abq, 1H), 4.33(d, 1H), 4.63(t, 1H), 6.44(d, 0.5H), 6.49(s, 0.5H), 6.65(dd, 0.5H), 6.75(d, 0.5H), 6.82(s, 0.5H), 6.91(d, 0.5H), 7.02(t, 0.5H), 7.18(t, 0.5H), 7.37(t, 1H), 7.49(m, 3H), 8.49 (d, 1H), 8.5H).

LC-MS(m+1＝432.2)。

Examples 1 to 58

(S) -2-methyl-2- (3- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CD₃OD)δ1.53(s，6H)，1.76(m，2H)，1.93(t，1H)，2.27(t，0.5H)，2.59(t，0.5H)，2.66(q，1H)，3.10(q，1H)，3.87(abq，1H)，3.94(s，1H)，4.01(dd，1H)，4.58(dd，1H)，6.64(m，1H)，6.73(dt，1H)，6.80(d，0.5H)，6.90(d，0.5H，7.9Hz)，7.16(dt，1H)，7.46(t，2H)，7.64(t，2H)。

LC-MS(m+1＝450.2)。

Examples 1 to 59

2- (4- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

MS(APCI)424.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃) Delta racemic mixture：7.18(m，4H)，7.11(d，1H)，6.87(d，1H)，6.79(dd，2H)，4.73(t，1H)，3.91(d，0.5H)，2.82(d，0.5H)，3.75(d，0.5H)，3.73(s，1H)，3.66(d，0.5H)，2.89(m，2H)，2.62(t，0.5H)，2.52(t，1H)，2.13(t，0.5H)，1.93(dd，1H)，1.73(dd，1H)，1.56(d，6H)，1.24(m，6H)。

Examples 1 to 60

2-methyl-2- (4- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

MS(APCI)450.2(M+H)⁺。

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 7.59(d, 2H), 7.38(t, 2H), 7.12(d, 1H), 6.86(m, 3H), 4.71(d, 1H), 3.82(m, 3H), 3.02(t, 0.5H), 2.97(t, 0.5H), 2.59(m, 1.5H), 2.24(t, 0.5H), 1.97(dd, 1H), 1.78(dd, 1H), 1.64(m, 1H), 1.57(d, 6H), 1.18(m, 1H).

Examples 1 to 61

2- {4- [1- (4-isopropyl-benzoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

MS(APCI)410.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃) δ racemic mixture: 7.34(m, 4H), 7.19(d, 1H), 7.03(d, 1H), 6.87(m, 1H), 6.76(d, 1H), 4.63(t, 1H), 3.78(dd, 1H), 3.22(q, 1H), 2.92(m, 1H), 2.84(t, 1H), 2.74(m, 1H), 2.03(d, 1H), 1.91(m, 0.5H), 1.78(m, 1.5H), 1.53(d, 6H), 1.27(d, 6H).

Examples 1 to 62

2-methyl-2- {4- [1- (pyridin-2-yl-acetyl) -piperidin-3-yl ] -phenoxy } -propionic acid

MS(APCI)383.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃) Racemic mixture of deltaAn object: 8.48(d, 1H), 7.80(t, 1H), 7.38(d, 1H), 7.32(q, 1H), 7.14(d, 1H), 7.01(d, 1H), 6.83(dd, 1H), 4.58(dd, 1H), 4.03(dd, 1H), 3.98(m, 1H), 3.12(t, 0.5H), 3.09(t, 0.5H), 2.67(q, 1H), 2.59(t, 0.5H), 2.41(t, 0.5H), 1.96(t, 1H), 1.78(m, 3H), 1.52(d, 6H).

Examples 1 to 63

2- (4- {1- [3- (4-isopropyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

MS(LC-MS)438.5(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.15(m，5H)，7.06(d，1H)，6.89(d，1H)，4.73(d，1H)，3.82(t，1H)，2.93(m，4H)，2.62(m，2H)，2.51(q，1H)，2.43(t，1H)，1.98(t，1H)，1.77(t，1H)，1.63(t，1H)，1.58(s，6H)，1.40(m，1H)，1.22(t，6H)。

Examples 1-64 were prepared in a similar manner to example 1 using the appropriate alkyl haloalkyl carboxylate of preparation 2, method D.

Examples 1 to 64

(3- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -phenoxy) -acetic acid

¹H NMR(400MHz，CDCl₃)δ7.75(brm，1H)，7.16(m，4H)，6.74(m，2H)，6.51(d，1H)，4.72(brm，1H)，4.63(s，2H)，3.86(m，1H)，3.80(s，1H)，3.73(m，1H)，3.00(m，1H)，2.90(brm，1H)，2.64(m，2H)，2.17(brm，1H)，1.94(m，1H)，1.82(d，1H)，1.65(q，1H)，1.24(d，6H)。

LC-MS(m+1＝396.4)。

Example 2

2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

To a solution of 4-isopropylphenol (1.007g, 7.39mmol) in 15mL dimethylformamide was added potassium carbonate (2.04g, 14.79mmol) and ethyl bromoacetate (1.23mL, 11.09 mmol). The reaction was stirred at room temperature for 48 hours. The mixture was diluted with 500mL of water and extracted with ether (2X 200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 10% ethyl acetate/hexane, to give 1.61g (98%) of ethyl- (4-isopropylphenoxy) acetate as a clear oil.

MS(APCI)223.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.14(d，2H)，6.84(d，2H)，4.59(s，2H)，4.27(q，2H)，2.86(m，1H)，1.30(t，3H)，1.21(d，6H)。

A mixture of ethyl- (4-isopropylphenoxy) acetate (1.61g, 7.24mmol) and 2N sodium hydroxide (aq) (10.9mL) in 20mL of methanol was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The resulting residue was taken up in water (100mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 100 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.32g (94%) of 4-isopropylphenoxyacetic acid as a white solid.

MS(APCI)195.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.17(d，2H)，6.86(d，2H)，4.66(s，2H)，2.87(m)，1H)，1.22(d，6H)。

To a solution of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (preparation 2, method C; 30mg, 0.085mmol) in 1mL of dichloromethane were added 4-isopropylphenoxyacetic acid (33mg, 0.17mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (33mg, 0.17mmol) and stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure and the resulting oil was flash chromatographed, eluting with 30% ethyl acetate/hexanes to give 35mg (78%) of benzyl 2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionate as a clear oil.

LC-MS 530.6(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.24(m，5H)，7.14(m，3H)，6.89(m，2H)，6.83(m，1H)，6.71(s，1H)，6.61(d，1H)，5.19(s，2H)，4.64(m，3H)，4.07(d，1H)，3.04(t，1H)，2.97(m，1H)，2.89(m，1H)，2.47(m，2H)，1.95(m，1H)，1.82(m，1H)，1.61，(s，6H)，1.21(d，6H)。

10% Palladium on charcoal (4mg, 10 wt%) was added to a solution of benzyl 2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl-phenoxy } -2-methyl-propionate (35mg, 0.066mmol) in methanol (2mL), the resulting mixture was hydrogenated at atmospheric pressure for 3 hours the reaction mixture was filtered through a plug of celite and the plug of celite was washed thoroughly with ethyl acetate the combined filtrates were concentrated under reduced pressure to give 29mg (99%) of 2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl ] -phenoxy) -2-methyl-propionic acid as a clear oil.

LC-MS 440.5(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.19(t，1H)，7.14(t，2H)，6.87(m，3H)，6.81(m，2H)，4.66(m，3H)，4.04(dd，1H)，3.05(m，1H)，2.85(m，1H)，2.65(m，2H)，2.02(t，1H)，1.82(t，1H)，1.65(m，1H)，1.59，(s，6H)，1.21(d，6H)。

Examples 2-1 to 2-11 were prepared from similar starting materials using a similar procedure as described in example 2.

Example 2-1

2- (3- {1- [2- (4-isopropyl-phenoxy) -2-methyl-propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.22(m，6H)，1.58(m，6H)，1.65(m，6H)，1.85(m，2H)，2.12(t，1H)，2.53(m，2H)，2.87(m，2H)，2.93(t，1H)，4.79(m，3H)，6.60(s，1H)，6.76(m，4H)，6.92(d，1H)，7.08(t，2H)，7.18(m，1H)。

LC-MS(m+1＝468.5)。

Examples 2 to 2

2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.55(m，1H)，1.59(d，6H)，1.67(m，1H)，1.83(t，1H，13.3Hz)，2.03(t，1H)，2.67(m，2H)，3.05(m，1H)，3.96(dd，1H)，4.59(d，1H)，4.61(t，1H)，4.70(s，1H)，6.81(m，2H)，6.92(m，3H)，7.14(m，2H)，7.20(m，1H)。

LC-MS(m+1＝482.4)。

Examples 2 to 3

(S) -2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ1.22(m，6H)，1.59(s，6H)，1.67(m，1H)，1.80(t，1H)，2.02(t，1H)，2.65(m，2H)，2.85(6，1H)，3.03(dt，1H)，4.04(dd，1H)，4.64(m，4H)，6.79(m，1H)，6.89(m，3H)，7.17(m，3H)。

LC-MS(m+1＝440.5)。

[α]_D ²⁵＝-73.8°(c 1.97，CH₃OH)

Examples 2 to 4

(R) -2- (3- {1- [ (4-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

LC-MS(m+1＝440.5)。

[α]_D ²⁵＝74.1°(c 1.95，CH₃OH)。

Examples 2 to 5

(S) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.55(m，1H)，1.59(d，6H)，1.67(m，1H)，1.83(t，1H)，2.03(t，1H)，2.67(m，2H)，3.05(m，1H)，3.96(dd，1H)，4.59(d，1H)，4.61(t，1H)，4.70(s，1H)，6.81(m，2H)，6.92(m，3H)，7.14(m，2H)，7.20(m，1H)。

LC-MS(m+1＝482.4)。

[α]_D ²⁵＝-55.0°(c 1.14，CH₃OH)。

Examples 2 to 6

(R) -2-methyl-2- (3- {1- [ (4-trifluoromethoxy-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

LC-MS(m+1＝482.4)。

[α]_D ²⁵＝63.9°(c 1.13，CH₃OH)。

Examples 2 to 7

2- (3- {1- [ (3-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.23(dd，6H)，1.53(s，6H)，1.78(m，1H)，1.86(t，1H)，2.00(m，1H)，2.59(m，1H)，2.71(m，2H)，2.87(m，1H)，3.12(q，1H)，4.06(m，1H)，4.54(t，1H)，4.74(m，2H)，6.75(t，2H)，6.81(d，1H)，6.86(s，2H)，6.90(d，1H)，7.19(t，2H)。

LC-MS(m+1＝440.5)。

Examples 2 to 8

2- (3- {1- [ (4-tert-butyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.28(s，9H)，1.54(s，6H)，1.79(m，1H)，1.84(t，1H)，1.99(m，1H)，2.61(t，1H)，2.72(m，1H)，3.13(q，1H)，4.02(d，1H)，4.53(t，1H)，4.74(m，2H)，6.75(d，1H)，6.82(d，1H)，6.89(m，3H)，7.19(t，1H)，7.32(dd，2H)。

LC-MS(m+1＝454.5)。

Examples 2 to 9

2-methyl-2- [3- (1-m-tolyloxyacetyl-piperidin-3-yl) -phenoxy ] -propionic acid

¹H NMR(400MHz，CD₃OD)δ1.52(s，6H)，1.74(m，1H)，1.86(t，1H)，2.00(brm，1H)，2.31(d，3H)，2.61(t，1H)，2.71(m，1H)，3.13(q，1H)，4.02(d，1H)，4.53(t，1H)，4.75(m，2H)，6.78(m，4H)，6.91(d，1H)，7.17(m，2H)。

LC-MS(m+1＝412.5)。

Examples 2 to 10

2-methyl-2- (3- {1- [ (3-trifluoromethyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CD₃OD)δ1.54(s，6H)，1.74(m，1H)，1.87(t，1H)，2.02(m，1H)，2.62(t，1H)，2.74(m，1H)，3.17(t，1H)，3.97(d，1H)，4.53(t，1H)，4.82(m，2H)，6.75(d，1H)，6.83(d，1H)，6.92(t，1H)，7.22(m，4H)，7.48(t，1H)。

LC-MS(m+1＝466.5)。

Examples 2 to 11

(S) -2- (3- {1- [ (3-isopropyl-phenoxy) -acetyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.23(dd，6H)，1.53(t，6H)，1.78(m，1H)，1.89(t，1H)，1.99(m，1H)，2.59(t，1H)，2.67(m，1H)，2.87(m，1H)，3.13(q，1H)，4.05(m，1H)，4.54(t，1H)，4.76(abq，1H)，4.85(m，1H)，6.75(t，2H)，6.82(d，1H)，6.85(t，2H)，6.90(d，1H)，7.19(dt，2H)。

LC-MS(m+1＝440.5)。

Example 3

2- (3- {1- [3- (4-isopropyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid

To a solution of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (preparation 2, method C; 99mg, 0.28mmol) in 2mL dichloromethane were added 4-isopropyl-trans-cinnamic acid (59mg, 0.31mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (81mg, 0.42mmol) and stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure and the resulting oil was flash chromatographed, eluting with 30% ethyl acetate/hexanes to give 89mg (60%) of benzyl 2- (3- {1- [3- (4-isopropyl-phenyl) -acryloyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionate as a clear oil.

LC-MS 530.6(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.67(d，2H)，7.45(d，2H)，7.31(m，3H)，7.19(m，4H)，7.11(t，1H)，6.84(m，2H)，6.71(s，1H)，6.61(dd，1H)，5.18(s，2H)，2.90(m，1H)，2.60(m，1H)，1.98(m，1H)，1.83(m，1H)，1.61，(s，6H)，1.24(d，6H)。

10% Palladium on charcoal (10mg, 10% by weight) was added to a solution of benzyl 2- (3- {1- [3- (4-isopropyl-phenyl) -acryloyl ] -piperidin-3-yl-phenoxy } -2-methyl-propionate (89mg, 0.17mmol) in methanol (2mL) and the resulting mixture was hydrogenated at atmospheric pressure for 3 hours the reaction mixture was filtered through a plug of celite and the plug of celite was washed thoroughly with ethyl acetate the combined filtrates were concentrated under reduced pressure to give 73mg (99%) of 2- (3- {1- [3- (4-isopropyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -2-methyl-propionic acid, the oil was clarified.

MS(APCI)438.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.13(m，5H)，6.90(d，1H)，6.79(m，2H)，4.66(m，1H)，3.78(m，1H)，3.05(m，1H)，2.91(m，3H)，2.62(m，3H)，2.37(m，1H)，1.96(t，1H)，1.75(m，1H)，1.59，(s，6H)，1.21(d，6H)。

Examples 3-1 and 3-2 were prepared from similar starting materials using a similar procedure as described in example 3.

Example 3-1

2-methyl-2- (3- {1- [3- (4-trifluoromethyl-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.47(m，1H)，1.58(s，6H)，1.79(d，1H)，2.00(brs，1H)，2.47(m，1H)，2.64(m，3H)，3.02(brs，3H)，3.79(d，1H)，4.64(brs，1H)，6.79(m，2H)，6.89(m，1H)，7.19(t，1H)，7.32(brs，2H)，7.53(brs，2H)。

LC-MS(m+1＝464.5)。

Examples 3 to 2

2-methyl-2- (3- {1- [3- (4-trifluoromethoxy-phenyl) -propionyl ] -piperidin-3-yl } -phenoxy) -propionic acid

¹H NMR(400MHz，CDCl₃)δ1.53(m，1H)，1.60(m，6H)，1.64(m，1H)，1.77(m，1H)，2.00(m，1H)，2.45(t，1H)，2.61(m，4H)，2.97(m，4H)，3.79(d，1H)，4.64(m，1H)，6.81(m，3H)，6.93(dd，1H)，7.13(t，2H)，7.21(m，2H)。

LC-MS(m+1＝480.4)。

Example 4

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-phenyl ester

To a solution of 4-isopropylphenol (1.54g, 11.32mmol) in 10mL of toluene was added 1, 1-carbonyldiimidazole (1.84g, 11.32 mmol). The solution was stirred at room temperature for 18 hours. Benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (preparation 2, method C; 2.0g, 5.66mmol) was added to 5mL of toluene and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with water (200mL), acidified with 1N hydrochloric acid and extracted with ether (2X 150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 10% ethyl acetate/hexane, to give 1.76g (60%) of the desired product 4-isopropyl-phenyl 3- [3- (L-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate as a clear oil.

LC-MS 516.5(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.29(m，3H)，7.21(m，4H)，7.11(t，1H)，7.03(d，2H)，6.86(d，2H)，6.74(s，1H)，6.62(dd，1H)，5.19(s，2H)，4.32(br d，2H)，2.90(m，1H)，2.68(m，1H)，2.01(m，1H)，1.81(m，1H)，1.62，(s，6H)，1.23(d，6H)。

10% Palladium on charcoal (180mg, 10 wt%) was added to a solution of 3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-phenyl ester (1.76g, 3.41mmol) in methanol (15mL) and the resulting mixture was hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through a plug of celite and the plug of celite was washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to give 1.26g (87%) of 4-isopropyl-phenyl 3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate as a clear oil.

¹H NMR(400MHz，DMSO_d6)δ1.17(d，6H)，1.33(s，6H)，1.59(brm，1H)，1.63(t，1H)，1.74(d，1H)，1.89(m，1H)，2.64(m，1H)，2.87(m，2H)，3.01(m，1H)，4.02(m，1H)，4.11(dd，1H)，6.68(m，3H)，7.02(m，3H)，7.21(d，2H)。

LC-MS(m+1＝426.5)。

Examples 4-1 to 4-4 were prepared using similar starting materials using similar procedures as described in example 4.

Example 4-1

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 3-isopropyl-phenyl ester

¹H NMR(400MHz，CDCl₃)δ1.24(d，6H)，1.52(s，6H)，1.73(m，2H)，1.84(d，1H)，2.03(d，1H)，2.73(brm，2H)，2.91(m，2H)，3.09(q，1H)，4.18(d，1H)，4.31(t，1H)，6.77(dd，1H)，6.85(brs，2H)，6.90(d，1H)，6.96(s，1H)，7.09(d，1H)，7.14(t，1H)，7.27(t，1H)。

LC-MS(m+1＝426.2)。

Example 4 to 2

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-tert-butyl-phenyl ester

¹H NMR(400MHz，CDCl₃)δ1.34(s，9H)，1.59(s，6H)，1.67(m，2H)，1.84(m，1H)，2.06(m，1H)，2.78(m，1H)，2.91(brm，1H)，2.98(br m，1H)，4.32(brm，1H)，6.81(dd，1H)，6.86(s，1H)，7.01(m，3H)，7.23(m，1H)，7.36(d，1H)。

LC-MS(m+1＝440.5)。

Examples 4 to 3

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-phenyl ester

LC-MS(m+1＝426.5)。

[α]_D ²⁵＝68.1°(c 0.83，CH₃OH)。

Examples 4 to 4

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-phenyl ester

LC-MS(m+1＝426.5)。

[α]_D ²⁵＝-77.4°(c 0.92，CH₃OH)。

Example 5

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester

To a solution of 4-isopropylbenzyl alcohol (0.86g, 5.75mmol) in 10mL of toluene was added 1, 1' -carbonyldiimidazole (0.87g, 5.40 mmol). The solution was stirred at room temperature for 18 hours. Benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (preparation 2, method C; 1.27g, 3.59mmol) was added to 5mL of toluene and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with water (200mL), acidified with 1N hydrochloric acid and extracted with ether (2X 150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 10% ethyl acetate/hexane, to give 1.07g (56%) of the desired product, 4-isopropyl-benzyl 3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate, as a clear oil.

LC-MS 547.4(m+H₂O)⁺。

¹H NMR(400MHz，CDCl₃)δ7.32-7.20(m，9H)，7.09(t，1H)，6.82(d，2H)，6.69(s，1H)，6.60(dd，1H)，5.18(s，2H)，5.11(abq，2H)，4.22(br s，2H)，2.90(m，1H)，2.74(m，2H)，2.57(m，1H)，1.94(m，1H)，1.75(m，1H)，1.61，(s，6H)，1.53(m，1H)，1.24(d，6H)。

A mixture of 4-isopropyl-benzyl 3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate (1.07g, 2.02mmol), potassium carbonate (0.56g, 4.04mmol), methanol (15mL) and water (3mL) was heated under reflux for 3 hours, cooled to room temperature and then concentrated under reduced pressure. The resulting residue was taken up in water (150mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was filtered through a 20g plug of silica, eluting with 300mL of dichloromethane, then 300mL of ethyl acetate. The product containing fractions were combined and then concentrated under reduced pressure to yield 835mg (94%) of 4-isopropyl-benzyl 3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate as a clear glassy solid.

¹H NMR(400MHz，DMSO_d6)δ1.16(d，6H)，1.46(s，6H)，1.58(q，1H)，1.68(d，1H)，1.84(d，1H)，2.55(t，1H)，2.84(brm，3H)，4.00(m，2H)，5.01(s，2H)，6.62(d，1H)，6.70(s，1H)，6.84(m，1H)，7.20(m，5H)。

LC-MS(m+1＝440.5)。

Examples 5-1 to 5-12 were prepared from similar starting materials using a similar procedure as described in example 5.

Example 5-1

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

¹H NMR(400MHz，DMSO_d6)δ1.48(s，6H)，1.61(q，1H)，1.71(d，1H)，1.86(d，1H)，2.58(brm，1H)，2.82(brm，1H)，2.91(brm，1H)，3.99(m，2H)，5.17(s，2H)，6.63(d，1H)，6.71(s，1H)，6.25(d，1H)，7.18(t，1H)，7.56(brm，1H)，7.72(d，1H，7.5Hz)。

LC-MS(m+1＝466.5)。

Examples 5 and 2

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester

LC-MS(m+1＝440.5)。

[α]_D ²⁵＝-57.3°(c 0.65，CH₃OH)。

Examples 5 to 3

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester

LC-MS(m+1＝440.5)。

[α]_D ²⁵＝-63.8°(c 0.81，CH₃OH)。

Examples 5 to 4

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-cyclohexyl-benzyl ester

¹H NMR(400MHz，CD₃OD)δ1.43(t，3H)，1.54(s，6H)，1.76(m，2H)，1.84(d，3H)，1.98(d，1H)，2.51(m，1H)，2.62(m，1H)，2.86(brm，2H)，4.11(m，3H)，5.08(s，2H)，5.49(s，2H)，6.74(dd，1H)，6.79(s，1H)，6.87(brs，1H)，7.18(m，3H)，7.26(m，2H)。

LC-MS(m+1＝480.5)。

Examples 5 to 5

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-ethyl-benzyl ester

¹H NMR(400MHz，CDCl₃)δ1.23(t，3H)，1.60(s，6H)，1.76(d，1H)，1.99(m，3H)，2.64(q，2H)，2.80(m，2H)，4.20(m，2H)，5.10(s，2H)，6.80(m，2H)，6.94(d，1H)，7.20(t，2H)，7.26(m，3H)。

LC-MS(m+1＝426.3)。

Examples 5 to 6

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 3-trifluoromethyl-benzyl ester

¹H NMR(400MHz，CDCl₃)δ1.60(s，6H)，1.64(m，1H)，1.78(d，1H)，2.02(d，1H)，2.66(brm，1H)，2.82(brm，2H)，4.21(brm，2H)，6.79(m，2H)，6.92(d，1H)，7.21(t，1H)，7.54(m，3H)。

LC-MS(m+1＝466.2)。

Examples 5 to 7

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethoxy-benzyl ester

¹H NMR(400MHz，CDCl₃)δ1.59(s，6H)，1.62(m，1H)，1.77(d，1H)，2.01(d，1H)，2.66(brm，1H)，2.80(brm，2H)，4.20(brm，2H)，5.14(s，2H)，6.79(m，2H)，6.92(d，1H)，7.20(m，3H)，7.38(d，2H)。

LC-MS(m+1＝482.2)。

Examples 5 to 8

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid benzyl ester

¹H NMR(400MHz，CD₃OD)δ1.55(s，6H)，1.68(q，1H)，1.77(d，1H)，1.96(d，1H)，2.60(t，1H)，2.88(brm，2H)，4.15(d，2H)，5.12(s，2H)，6.74(d，1H)，6.79(brs，1H)，6.88(brs，1H)，7.17(t，1H)，7.33(m，5H)。

LC-MS(m+1＝420.2)。

Examples 5 to 9

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-fluoro-benzyl ester

¹H NMR(400MHz，CD₃OD)δ1.54(s，6H)，1.66(q，1H)，1.79(d，1H)，1.96(d，1H)，2.60(t，1H)，2.87(brm，1H)，4.14(d，2H)，5.10(s，2H)，6.74(d，1H)，6.78(brs，1H)，6.88(brs，1H)，7.08(t，2H)，7.17(t，1H)，7.39(t，2H)。

LC-MS(m+1＝438.1)。

Examples 5 to 10

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-fluoro-3-trifluoromethyl-benzyl ester

¹H NMR(400MHz，CD₃OD)δ1.56(d，6H)，1.67(q，1H)，1.78(d，1H)，1.97(d，1H)，2.62(t，1H)，2.87(brm，2H)，4.14(d，2H)，5.16(s，1H)，6.74(dd，1H)，6.79(brs，1H)，6.88(brs，1H)，7.17(t，1H)，7.33(t，1H)，7.71(m，2H)。

LC-MS(m+1＝484.1)。

Examples 5 to 11

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 3-fluoro-4-trifluoromethyl-benzyl ester

¹H NMR(400MHz，CD₃OD)δ1.54(s，6H)，1.69(q，1H)，1.81(d，1H)，1.99(d，1H)，2.66(t，1H)，2.90(m，2H)，4.16(brm，2H)，5.20(s，1H)，6.74(dd，1H)，6.80(s，1H)，6.89(d，1H)，7.18(t，1H)，7.33(brs，2H)，7.68(t，1H)，7.6Hz)。

LC-MS(m+1＝484.1)。

Examples 5 to 12

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 3-trifluoromethoxy-benzyl ester

¹H NMR(400MHz，CD₃OD)δ1.54(s，1H)，1.68(q，1H)，1.79(d，1H)，1.97(d，1H)，2.62(t，1H)，2.87(brm，1H)，4.15(d，2H)，5.17(s，2H)，6.74(dd，1H)，6.79(s，1H)，6.88(brs，1H)，7.15(t，1H)，7.22(d，1H)，7.28(s，1H)，7.36(m，1H)，7.46(t，1H)。

LC-MS(m+1＝482.1)。

Example 6

To a solution of 4-isopropylbenzyl alcohol (4.51g, 30.02mmol) in 50mL of toluene was added 1, 1' -carbonyldiimidazole (4.87g, 30.02 mmol). The solution was stirred at room temperature for 18 hours. The white precipitate was filtered off and the filtrate was concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 15% ethyl acetate/hexane, to give 6.41g (87%) of imidazole-1-carboxylic acid- (4-isopropyl) benzyl ester as a clear oil.

¹H NMR(400MHz，CDCl₃)δ8.16(s，1H)，7.43(t，1H)，7.37(d，2H)，7.27(d，2H)，7.05(d，1H)，5.39(s，2H)，2.93(m，1H)，1.25(d，6H)。

To a solution of 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid ethyl ester (preparation 2; method D; 7.60g, 17.21mmol) in 20mL toluene was added imidazole-1-carboxylic acid- (4-isopropyl) benzyl ester (4.20g, 17.21mmol) and stirred at room temperature for 18 h. The reaction was diluted with water (300mL), acidified with 1N hydrochloric acid and extracted with ether (2X 200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 10% ethyl acetate/hexane, to give 6.23g (77%) of 4-isopropyl-benzyl 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate as a clear oil.

LC-MS 468.5(m+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.30-7.20(m，4H)，7.15(t，1H)，6.84(d，2H)，6.73(s，1H)，6.66(dd，1H)，5.10(abq，2H)，4.22(q，4H)，2.90(m，1H)，2.76(brm，2H)，2.61(m，1H)，1.98(m，1H)，1.75(m，1H)，1.67(s，1H)，1.59，(s，6H)，1.25(d，6H)。

A mixture of 4-isopropyl-benzyl 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate (6.23g, 13.32mmol), potassium carbonate (3.68g, 26.64mmol), methanol (100mL) and water (20mL) was heated under reflux for 3 hours, cooled to room temperature and then concentrated under reduced pressure. The resulting residue was taken up in water (250mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5.86g (99%) of 4-isopropyl-benzyl 3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylate as a clear glassy solid.

LC-MS 440.5(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.33-7.150(m，5H)，6.87(brs，1H)，6.79(s，1H)，6.74(dd，1H)，5.09(s，2H)，4.15(br d，2H)，2.89(m，3H)，2.61(m，1H)，1.96(m，1H)，1.89(m，1H)，1.64(q，1H)，1.54(s，6H)，1.23(d，6H)。

Examples 6-1 and 6-2 were prepared from similar starting materials using a similar procedure as described in example 6.

Example 6-1

(3S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

4- (trifluoromethyl) benzyl alcohol (0.88g, 5.0mmol) was dissolved in toluene (5mL) and 1, 1' -carbonyldiimidazole (0.89g, 5.5mmol) was added. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. Then a solution of (3S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid methyl ester (preparation 2; method E) (1.39g, 5.0mmol) in toluene (8mL) was added and the reaction mixture was heated at 60 ℃ for 2 hours. After cooling, the reaction solution was diluted with ethyl acetate (30mL) and washed with 1M hydrochloric acid (30mL) and brine (30 mL). The separated organic layer was dried over sodium sulfate and concentrated to give 2.43g (100%) of (3S) -3- [3- (1-methoxycarbonyl-1-methyl-ethoxy) -phenyl ]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as light yellow oil:¹H NMR(CDCl₃) δ 1.58(s, 8H), 1.77(brm, 1H), 2.00(br m, 1H), 2.61(br, 1H), 2.80(br, 2H), 3.74(s, 3H), 4.21(br s, 2H), 5.19(s, 2H), 6.63(dd, 1H), 6.72(s, 1H), 6.83(brd, 1H), 7.16(t, 1H), 7.46(br s, 2H), 7.60(d, 2H); MS m/z (relative intensity) 479 (m)⁺，25)，420(20)，395(20)，276(20)，220(60)，202(42)，176(45)，159(100)。

Reacting (3S) -3- [3- (1-methoxycarbonyl-1-methyl-ethoxy) -phenyl]4-trifluoromethyl-benzyl-piperidine-1-carboxylate (2.43g, 5.0mmol) and potassium carbonate (1.38g, 10.0mmol)The MeOH/water (10/3mL) mixture was refluxed under nitrogen for 1.5 hours. After removal of the solvent, the residue was taken up in water (40mL) and the pH was carefully adjusted to 2 with 3M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2X 40 mL). The organic extracts were washed with brine (50mL), dried over sodium sulfate, and concentrated to give 2.40g of a viscous pale yellow oil. Hexane (24mL) was added to the oil residue and the mixture was heated to reflux with stirring. A white solid formed and ethanol (1.6mL) was added dropwise to the mixture in reflux to redissolve the solid. The resulting solution was cooled to room temperature under vigorous stirring to prevent the product from precipitating as an oil. White solid gradually formed and stirring was continued overnight. The first portion of product gave 1.78g of solid, 99.5% ee; the second portion of product gave 0.15g, 96.3% ee. A total of 1.93g (83%) of (3S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl are obtained ]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white crystalline solid:¹H NMR(CDCl₃)δ1.58(s，8H)，1.77(br m，1H)，2.00(brm，1H)，2.61(br，1H)，2.80(br m，2H)，4.19(br s，2H)，5.18(s，2H)，6.76(d，1H)，6.80(s，1H)，6.89(br，d，1H)，7.18(t，1H)，7.45(br s，2H)，7.59(d，2H)；MS m/z 466(MH⁺)。

conditions for HPLC analysis: daicel Chiralpak OJ, 4.6X 250 mm; hexane/2-propanol/TFA (90/10/0.1); 1.5 mL/min; 210 nm.

Example 6 to 2

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester

¹H NMR(400MHz，CD₃OD)δ7.24-7.15(m，3H)，7.06(d，2H)，6.78-6.73(m，3H)，5.07(s，2H)，4.14(d，2H)，2.95-2.50(m，3H)，1.90-1.45(m，5H)，1.54(s，6H)，0.95(m，2H)，0.66(m，2H)。

MS(LC-MS)436.1(M-H)^-。

Example 7

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid methyl ester

(S) -2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionic acid benzyl ester-L- (+) -tartrate (preparation 3, method F; 119mg, 0.24mmol) was dissolved in 2mL of dichloromethane and 1mL of water. Sodium bicarbonate (79mg, 0.95mmol) and methyl chloroformate (37mL, 0.47mmol) were added and the biphasic mixture and the resulting mixture were stirred at room temperature for 2 hours. The mixture was diluted with water (50mL), acidified with 1N hydrochloric acid and extracted with ether (2X 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 90mg (93%) of (S) -3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid methyl ester as a clear oil.

LC-MS 412.3(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.30(m，2H)，7.25(m，3H)，7.09(t，1H)，6.83(d，1H)，6.70(s，1H)，6.60(dd，1H)，5.19(s，2H)，4.18(brd，2H)，3.70(s，3H)，2.68(m，2H)，2.56(m，1H)，1.95(m，1H)，1.73(m，1H)，1.61，(s，6H)，1.53(m，1H)。

10% Palladium on charcoal (18mg, 10 wt%) was added to a solution of (S) -3- [3- (1-benzyloxycarbonyl-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid methyl ester (90mg, 0.22mmol) in methanol (3mL), and the resulting mixture was hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through a plug of celite and the plug of celite was washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to give 65mg (92%) of (S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid methyl ester as a clear oil.

LC-MS 322.3(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.18(t，1H)，6.89(d，2H)，6.79(s，1H)，6.74(dd，1H)，4.11(brd，2H)，3.69(s，3H)，2.82(br，2H)，2.61(m，1H)，1.95(m，1H)，1.78(m，1H)，1.65(m，1H)1.55，(s，6H)。

Examples 7-1 to 7-5 were prepared from similar starting materials using a similar procedure as described in example 7.

Example 7-1

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 2-methoxy-ethyl ester

¹H NMR(400MHz，CD₃OD)δ1.55(s，6H)，1.68(m，1H)，1.79(d，1H)，1.97(d，1H)，2.61(t，1H)，2.84(brm，2H)，3.37(s，3H)，3.60(t，2H)，4.14(d，2H)，4.21(brs，2H)，6.74(dd，1H)，6.80(s，1H)，6.89(d，1H)，7.17(t，1H)。

LC-MS(m+1＝366.4)。

Example 7-2

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid isopropyl ester

¹H NMR(400MHz，CD₃OD)δ1.25(s，6H)，1.57(s，6H)，1.67(q，1H)，1.77(d，1H)，1.97(d，1H)，2.59(t，1H)，2.83(brs，2H)，4.12(d，2H)，4.82(m，1H)，6.74(dd，1H)，6.79(s，1H)，6.89(d，1H)，7.18(t，1H，7.9Hz)。

LC-MS(m+1＝350.4)。

Examples 7 to 3

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid ethyl ester

¹H NMR(400MHz，CD₃OD)δ1.25(t，3H)，1.57(s，6H)，1.67(q，1H)，1.77(d，1H)，1.97(d，1H)，2.60(t，1H)，2.83(brs，2H)，4.12(m，4H)，6.74(dd，1H)，6.80(s，1H)，6.89(d，1H)，7.19(t，1H)。

LC-MS(m+1＝336.3)。

Examples 7 to 4

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid isobutyl ester

¹H NMR(400MHz，CD₃OD)δ0.95(d，6H)，1.56(s，6H)，1.67(q，1H)，1.79(dd，1H)，1.95(m，2H)，2.61(t，1H)，2.86(brm，2H)，3.86(d，2H)，4.13(d，2H)，6.75(dd，1H)，6.80(s，1H)，6.89(d，1H)，7.19(t，1H，7.9Hz)。

LC-MS(m+1＝364.3)。

Examples 7 to 5

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid cyclohexylmethyl ester

¹H NMR(400MHz，CD₃OD)δ1.02(q，2H)，1.26(m，3H)，1.56(s，6H)，1.72(m，7H)，1.99(d，1H)，2.60(t，1H)，2.88(brm，2H)，3.89(d，2H)，4.13(d，2H)，6.75(dd，1H)，6.80(s，1H)，6.89(d，1H)，7.19(t，1H)。

LC-MS(m+1＝404.2)。

Example 8

2-methyl-2- {3- [1- (4-trifluoromethyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid

To a solution of 4-trifluoromethylbenzylamine (170mL, 1.19mmol) in 5mL of toluene was added 1, 1' -carbonyldiimidazole (193mg, 1.19 mmol). The solution was stirred at room temperature for 18 hours. A solution of benzyl 2-methyl-2- (3-piperidin-3-yl-phenoxy) -propionate (preparation 2, method C; 421mg, 1.19mmol) in 5mL of toluene was added and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with water (100mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 35% ethyl acetate/hexanes, to give 473mg (72%) of the desired product, 2-methyl-2- {3- [1- (4-trifluoromethyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid benzyl ester as a clear oil.

LC-MS 599.4(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.58(d，2H)，7.43(d，2H)，7.26(m，6H)，7.10(t，1H)，6.83(d，1H)，6.70(s，1H)，6.60(dd，1H)，5.19(s，2H)，4.80(m，1H)，4.49(d，2H)，4.07(d，1H)，3.91(d，1H)，2.76(m，2H)，2.59(m，1H)，1.97(m，1H)，1.78(m，1H)，1.60，(s，6H)。

10% Palladium on charcoal (53mg, 50 wt%) was added to a solution of 2-methyl-2- {3- [1- (4-trifluoromethyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid benzyl ester (111mg, 0.226mmol) in methanol (5mL) and the resulting mixture was hydrogenated at 50psi for 4 hours. The reaction mixture was filtered through a plug of celite and the plug of celite was washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The resulting oil was flash chromatographed, eluting with 2% methanol/chloroform, to give 46.6mg (51%) of 2-methyl-2- {3- [1- (4-trifluoromethyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid as a clear oil.

LC-MS 465.5(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.60(d，2H)，7.46(d，2H)，7.18(t，1H)，6.91(d，1H)，6.83(s，1H)，6.74(dd，1H)，4.42(s，2H)，4.09(t，1H)，2.85(m，2H)，2.64(m，1H)，1.99(m，1H)，1.81(m，1H)，1.70(m，2H)，1.54(s，6H)。

Examples 8-1 to 8-6 were prepared from similar starting materials using a similar procedure as described in example 8.

Example 8-1

2- {3- [1- (4-isopropyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.22(m，6H)，1.55(s，6H)，1.64(m，1H)，1.78(d，1H，12.9Hz)，1.97(d，1H)，2.62(t，1H)，2.83(m，2H)，4.08(m，2H)，4.31(s，2H)，6.73(dd，1H)，6.82(t，1H)，6.91(d，1H)，7.18(m，5H)。

LC-MS(m+1＝439.5)。

Example 8 to 2

2-methyl-2- {3- [1- (4-trifluoromethoxy-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.54(s，6H)，1.59(m，1H)，1.68(m，1H)，1.79(d，1H)，1.99(d，1H)，2.64(t，1H)，2.84(q，2H)，4.08(t，2H)，4.36(s，1H)，6.74(dd，1H)，6.82(t，1H)，6.92(d，1H)，7.18(m，3H)，7.37(d，1H)。

LC-MS(m+1＝481.3)。

Examples 8 to 3

(S) -2-methyl-2- {3- [1- (4-trifluoromethoxy-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -propionic acid

LC-MS(m+1＝481.5)。

Examples 8 to 4

(S) -2- {3- [1- (4-isopropyl-benzylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ1.22(m，6H)，1.55(s，6H)，1.64(m，1H)，1.78(d，1H)，1.97(d，1H)，2.62(t，1H)，2.83(m，2H)，4.08(m，2H)，4.31(s，2H)，6.73(dd，1H)，6.82(t，1H)，6.91(d，1H)，7.18(m，5H)。

LC-MS(m+1＝439.5)。

Examples 8 to 5

(S) -2- {3- [1- (cyclohexylmethyl-carbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CD₃OD)δ0.91(q，2H)，1.23(m，3H)，1.56(s，6H)，1.70(m，6H)，1.98(d，1H)，2.61(t，1H)，2.80(q，2H)，2.98(d，2H)，4.04(t，2H)，6.74(dd，1H)，6.81(s，1H)，6.91(d，1H)，7.18(t，1H)。

LC-MS(m+1＝403.3)。

Examples 8 to 6

2- {3- [1- (4-isopropyl-phenylcarbamoyl) -piperidin-3-yl ] -phenoxy } -2-methyl-propionic acid

¹H NMR(400MHz，CDCl₃)δ7.25-7.19(m，3H)，7.13(d，2H)，6.93(d，1H)，6.84(s，1H)，6.81(d，1H)，6.38(s，1H)，4.06-3.98(m，2H)，2.91-2.73(m，4H)，2.02(m，1H)，1.82(m，1H)，1.70-1.50(m，2H)，1.21(d，6H)。

LC-MS(m+1＝425.3)

Example 9

(R) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

5-chloro-2-methylbenzoic acid (5.04g, 29.5mmol) was dissolved in 100mL of ethanol in a 250mL round bottom flask equipped with a water condenser. 0.5mL of concentrated sulfuric acid was added and the solution was heated to reflux. The solution was heated for 48 hours and then cooled to room temperature. The ethanol was removed under reduced pressure. The resulting oil was taken up in 300mL of diethyl ether and washed with saturated aqueous sodium bicarbonate (2X 300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5.12g (87%) of ethyl 5-chloro-2-methylbenzoate as a clear oil.

¹H NMR(400MHz，CDCl₃)δ7.88(d，1H)，7.35(dd，1H)，7.18(d，1H)，4.36(q，2H)，2.56(s，3H)，1.40(t，3H)。

Ethyl 5-chloro-2-methylbenzoate (16.60g, 83.56mmol) and diethyl- (3-pyridyl) borane (13.52g, 91.92mmol) were dissolved in 100mL tetrahydrofuran in a 500mL round bottom flask equipped with a magnetic stirrer. Sodium carbonate (26.57g, 250.69mmol) and 50mL of water were added followed by palladium acetate (0.38g, 1.67mmol) and (2' -dicyclohexylphosphono) -biphenyl-2-yl) -dimethyl-amine (AmPhos, 0.92g, 2.51mmol) and 25mL of ethanol. The mixture was heated to reflux for 6 hours and then cooled to room temperature. The mixture was diluted with 600mL of water and extracted with ether (2X 300 mL). The organic phases were combined and extracted with 1N hydrochloric acid (3X 200 mL). The acidic extracts were combined and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ether (3 × 500mL), the extracts combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 19.57g (97%) of ethyl 5- (3-pyridyl) -2-methylbenzoate as a brown oil.

MS(LC-MS)242.2(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ8.87(d，1H)，8.61(dd，1H)，8.13(d，1H)，7.95(dd，1H)，7.62(dd，1H)，7.44(dd，1H)，7.37(d，1H)，4.40(t，2H)，2.65(s，3H)，1.42(q，3H)。

A500 mL hydrogenation vessel was charged with 2.0g of platinum (II) oxide and purged with nitrogen. A solution of ethyl 5- (3-pyridyl) -2-methylbenzoate (19.57g, 81.10mmol) in 200mL of acetic acid was added. The suspension was hydrogenated at 45psi for 18 hours. The catalyst was filtered through celite and the filter plug was washed with 200mL of acetic acid. The filtrate was concentrated under reduced pressure. The resulting oil was taken up in 500mL of water and basified with 5N aqueous sodium hydroxide solution. The basic layer was extracted with ethyl acetate (2 × 500mL), and the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was placed in 200mL of hot ethanol. To ethanol was added L- (+) -tartaric acid (12.17g, 81.1mmol) and stirred at room temperature for 48 hours, a white precipitate formed, which was collected by filtration. The white solid was recrystallized from hot 5% water/ethanol (300mL) and then 350mL hot 20% water/ethanol to give 11.25g (35%, 95.8% ee) of ethyl (S) -5- (3-piperidinyl) -2-methylbenzoate-L-tartrate as a white solid. The mother liquors were combined and then concentrated under reduced pressure. The resulting oil was taken up in 300mL of water and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ethyl acetate (2 × 300mL), and the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was placed in 200mL of hot ethanol. To the ethanol solution was added D- (-) -tartaric acid (6.82g, 45.4mmol) and stirred at room temperature for 48 hours, a white precipitate formed, which was collected by filtration. The white solid was recrystallized from hot 5% water/ethanol (300mL) followed by 350mL hot 20% water/ethanol to give 13.51g (42%, 100% ee) of ethyl (R) -5- (3-piperidinyl) -2-methylbenzoate-D-tartrate as a white solid.

MS(LC-MS)248.2(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.73(d，1H)，7.24(dd，1H)，7.18(d，1H)，4.35(q，2H)，3.18(t，2H)，2.78(t，1H)，2.68(m，2H)，2.54(s，3H)，2.38(br，1H)，2.01(d，1H)，1.82(m，1H)，1.64(6，2H)，1.40(t，3H)。

HPLC analysis: chiralcel AD, 1mL/min, 10% ethanol/heptane 0.025% diethylamine, rt 8.36 min, 9.00 min.

(R) -5- (3-piperidinyl) -2-methylbenzoic acid ethyl ester-D-tartaric acid (2.02g, 5.08mmol) was dissolved in 100mL of ethyl acetate and washed with 100mL of saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The resulting oil was taken up in 10mL of toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (1.37g, 5.08mmol) was added. The reaction was stirred at room temperature under nitrogen for 72 hours. The reaction was diluted with water (200mL), acidified with 1N hydrochloric acid and extracted with ether (2X 150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 10% ethyl acetate/hexane, to give 2.12g (93%) of the desired product (R) -4-trifluoromethyl-benzyl 3- (3-ethoxycarbonyl-4-methyl-phenyl) -piperidine-1-carboxylate as a clear oil.

MS(LC-MS)450.1(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.75(brs，1H)，7.60(brs，2H)，7.46(brs，2H)，7.23(s，1H)，7.18(d，1H)，5.20(s，2H)，4.36(q，2H)，4.23(brm，2H)，2.92(br，2H)，2.77(m，1H)，2.55(s，3H)，2.02(d，1H)，1.82(d，1H)，1.61(m，4H)，1.39(t，3H)。

A mixture of 4-trifluoromethyl-benzyl (R) -3- (3-ethoxycarbonyl-4-methyl-phenyl) -piperidine-1-carboxylate (2.12g, 4.72mmol), potassium carbonate (1.30g, 9.43mmol), methanol (25mL) and water (6mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (150mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.98g (99%) of 4-trifluoromethyl-benzyl (R) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylate as a white solid.

MS(LC-MS)420.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.80(d，1H)，7.67(d，2H)，7.55(brs，2H)，7.32(d，1H)，7.22(d，1H)，5.22(s，2H)，4.17(d，2H)，2.90(brm，2H)，2.72(t，1H)，2.53(s，3H)，2.02(d，1H)，1.82(m，2H)，1.61(m，1H)。

Example 9-1

(R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid

(R) -5- (3-piperidinyl) -2-methylbenzoic acid ethyl ester-D-tartaric acid (example 9; 2.13g, 5.36mmol) was dissolved in 100mL of ethyl acetate and washed with 100mL of saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The resulting oil was taken up in 20mL of dichloromethane and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (2.05g, 10.72mmol) and 4-methyl-2- [4- (trifluoromethyl) phenyl ] -1, 3-thiazole-5-carboxylic acid (1.69g, 5.90mmol) were added. The reaction was stirred at room temperature under nitrogen for 72 hours. The reaction was diluted with 200mL of diethyl ether and washed with water (100mL), saturated aqueous sodium bicarbonate (2X 100mL), 0.5N hydrochloric acid (2X 100mL), water (100mL) and brine (100mL), dried over sodium sulfate and concentrated under reduced pressure to give (R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid ethyl ester (2.62g, 95%) as a clear oil.

MS(LC-MS)517.1(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ8.02(d，2H)，7.75(brs，1H)，7.69(d，2H)，7.19(m，1H)，4.35(q，2H)，3.01(brm，1H)，2.79(brm，1H)，2.55(s，3H)，2.52(s，3H)，2.12(d，1H)，1.92(d，1H)，1.78(q，1H)，1.63(m，2H)，1.38(t，3H)。

A mixture of (R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid ethyl ester (3.31g, 6.41mmol), potassium carbonate (1.77g, 12.82mmol), methanol (25mL) and water (6mL) was heated under reflux for 3 hours, cooled to room temperature and then concentrated under reduced pressure. The resulting residue was taken up in water (150mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.95g (94%) (R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid as a white solid.

MS(LC-MS)489.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.82(brs，1H)，7.79(d，2H)，7.35(m，1H)，7.24(m，1H)，2.84(t，1H)，2.53(s，3H)，2.49(s，3H)，2.07(d，1H)，1.90(m，2H)，1.71(m，2H)。

Examples 9-2 to 9-31 were prepared from similar starting materials using similar procedures as described for examples 9 and 9-1.

Example 9-2

(S) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)489.0(M+H)⁺。

Examples 9 to 3

2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)489.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.82(brs，1H)，7.79(d，2H)，7.35(m，1H)，7.244(m，1H)，2.84(t，1H)，2.53(s，3H)，2.49(s，3H)，2.07(d，1H)，1.90(m，2H)，1.71(m，2H)。

Examples 9 to 4

(S) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

MS(LC-MS)420.0(M+H)⁺。

Examples 9 to 5

3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

MS(LC-MS)420.0(M+H)⁺。

Examples 9 to 6

2-methyl-5- {1- [ (4-trifluoromethoxy-phenyl) -acetyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)422.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 7.80(s, 0.5H), 7.60(s, 0.5H), 7.34-7.09(m, 6H), 4.58(t, 1H), 3.98(dd, 1H), 3.88(d, 0.5H), 3.86(s, 0.5H), 3.74(d, 1H), 3.12(d, 1H), 2.67(m, 1.5H), 2.52(s, 3H), 2.26(t, 0.5H), 1.93(dd, 1H), 1.76(m, 2H), 1.47(m, 1H).

Examples 9 to 7

5- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -2-methyl-benzoic acid

MS(LC-MS)380.3(M+H)⁺。

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 7.47(s, 0.5H), 7.33-7.12(m, 6H), 6.97(d, 0.5H), 4.60(dd, 1H), 4.02(d, 0.5H), 3.90(d, 0.5H), 3.81(d, 0.5H), 3.76(s, 1H), 3.66(d, 0.5H), 3.02(m, 1H), 2.90(m, 1H), 2.67(m, 1.5H), 2.51(d, 3H), 2.03(t, 0.5H), 1.76(m, 3H), 1.45(m, 1H), 1.24(dd, 6H).

Examples 9 to 8

2-methyl-5- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)406.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 7.80(s, 0.5H), 7.66(d, 1H), 7.60(dd, 1H), 7.46(m, 1.5H), 7.33(dd, 0.5H), 7.20(dd, 1H), 7.11(dd, 0.5H), 4.59(t, 1H), 4.01(dd, 1H), 3.95(d, 0.5H), 3.91(s, 1H), 3.81(d, 0.5H), 2.11(m, 1H), 2.73(m, 1.5H), 2.52(d, 3H), 2.26(t, 0.5H), 1.92(dd, 1H), 1.78(m, 2H), 1.51(m, 1H).

Examples 9 to 9

2-methyl-5- {1- [3- (4-trifluoromethyl-phenyl) -acryloyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)418.2(M+H)⁺。

¹HNMR(400MHz，DMSO_d6)δ7.94(m，2H)，7.73(m，3H)，7.58-7.36(m，3H)，7.25(d，1H)，4.52(t，1H)，4.32(t，1H)，3.30(s，3H)，3.19(m，1H)，2.68(m，2H)，1.90(m，1H)，1.74(m，2H)，1.47(m，1H)。

Examples 9 to 10

5- {1- [3- (4-isopropyl-phenyl) -acryloyl ] -piperidin-3-yl } -2-methyl-benzoic acid

MS(LC-MS)392.3(M+H)⁺。

¹H NMR(400MHz，DMSO_d6)δ7.72(d，1H)，7.61(t，2H)，7.45(d，1H)，7.37(m，1H)，7.24(m，4H)，4.52(t，1H)，4.29(t，1H)，3.30(s，3H)，3.16(dt，1H)，2.88(m，1H)，2.68(m，2H)，1.89(brm，1H)，1.73(m，2H)，1.48(brm，1H)，1.18(t，6H)。

Examples 9 to 11

2-methyl-5- {1- [3- (4-trifluoromethyl-phenyl) -propionyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)418.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.77(dd，1H)，7.57(dd，2H)，7.43(dd，2H)，7.31(dd，1H)，7.22(dd，1H)，4.56(d，1H)，3.92(dd，1H)，3.05(m，3H)，2.79(m，1H)，2.67(m，2H)，2.53(s，3H)，2.42(t，1H)，1.95(t，1H)，1.78(m，2H)，1.45(t，1H)。

Examples 9 to 12

5- {1- [3- (4-isopropyl-phenyl) -propionyl ] -piperidin-3-yl } -2-methyl-benzoic acid

MS(LC-MS)394.3(M+H)⁺。

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 7.78(d, 0.5H), 7.70(d, 0.5H), 7.31(dd, 0.5H), 7.21(m, 1.5H), 7.15(m, 5H), 4.58(t, 1H), 3.83(dd, 1H), 3.01(t, 0.5H), 2.90(m, 3H), 2.79(m, 1H), 2.62(m, 1H), 2.54(m, 1H), 2.52(s, 3H), 2.02(t, 0.5H), 1.89(dd, 1H), 1.70(m, 2H), 1.40(m, 1H), 1.21(m, 6H).

Examples 9 to 13

3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester

MS(LC-MS)394.1(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ7.78(brs，1H)，7.24(m，6H)，5.09(s，2H)，4.14(brm，2H)，2.89(m，3H)，2.67(br，1H)，2.53(s，3H)，1.97(m，1H)，1.77(t，1H)，1.72(t，1H)，1.59(m，1H)，1.23(d，6H)。

Examples 9 to 14

(R) -2-methyl-5- [1- (4-trifluoromethyl-benzylcarbamoyl) -piperidin-3-yl ] -benzoic acid

MS(LC-MS)421.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.90(d，1H)，7.58(d，2H)，7.43(d，2H)，7.39(dd，1H)，7.31(dd，1H)，7.22(d，1H)，4.50(s，2H)，4.01(dd，2H)，2.88(m，3H)，2.60(s，3H)，2.04(m，1H)，1.84(m，1H)，1.69(m，2H)，1.25(t，1H)。

Examples 9 to 15

(S) -2-methyl-5- [1- (4-trifluoromethyl-benzylcarbamoyl) -piperidin-3-yl ] -benzoic acid

MS(LC-MS)421.2(M+H)⁺。

Examples 9 to 16

(R) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester

MS(LC-MS)436.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ1.49(br，1H)，1.69(m，2H)，1.94(d，1H)，2.41(s，3H)，2.53(brm，1H)，2.79(m，2H)，3.04(t，2H)，4.07(m，2H)，4.32(brs，2H)，6.95(brs，1H)，7.07(d，1H)，7.31(s，1H)，7.44(brs，2H)，7.58(brs，2H)。

Examples 9 to 17

2-methyl-4- [1- (4-trifluoromethyl-benzoyl) -piperidin-3-yl ] -benzoic acid

MS(LC-MS)392.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.19(d，1H)，7.78(d，2H)，7.62(d，1H)，7.22(m，1H)，7.04(s，1H)，4.67(d，1H)，3.62(dd，1H)，3.20(m，1H)，2.96(q，1H)，2.86(m，1H)，2.55(d，3H)，2.06(d，1H)，1.86(m，1H)，1.75(m，1H)，1.63(m，1H)。

Examples 9 to 18

2-methyl-4- {1- [ (4-trifluoromethyl-phenyl) -acetyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)406.1(M+H)⁺。

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 7.84(dd, 1H), 7.65(dd, 2H), 7.46(t, 2H), 7.18(s, 1H), 6.94(d, 0.5H), 6.84(s, 0.5H), 4.59(dd, 1H), 4.04(d, 0.5H), 3.92(s, 1H), 3.89(d, 0.5H), 3.88(dd, 1H), 3.15(t, 1H), 2.78(t, 0.5H), 2.66(q, 1H), 2.54(d, 3H), 2.25(t, 0.5H), 1.94(dd, 1H), 1.78(m, 2H), 1.53(m, 0.5H), 1.41(m, 0.5H).

Examples 9 to 19

2-methyl-4- {1- [3- (4-trifluoromethyl-phenyl) -acryloyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)418.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ1.67(m，1H)，1.89(m，2H)，2.05(d，1H)，2.57(d，3H)，2.82(m，2H)，3.24(dd，1H)，3.35(t，1H)，4.34(dd，1H)，4.67(d，1H)，7.21(m，2H)，7.32(dd，1H)，7.58(q，1H)，7.65(m，2H)，7.78(d，1H)，7.83(d，1H)。

Examples 9 to 20

2-methyl-4- (1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)489.1(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.15(dd，2H)，7.90(brs，1H)，7.79(d，2H)，7.20(m，2H)，2.84(t，1H)，2.57(s，3H)，2.49(s，3H)，2.07(d，1H)，1.89(q，2H)，1.70(m，2H)。

Examples 9 to 21

3- (4-carboxy-3-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

MS(LC-MS)420.0(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ7.86(d，1H)，7.66(d，2H)，7.54(brs，2H)，7.16(m，2H)，5.22(s，2H)，4.17(m，2H)，2.98(brm，1H)，2.90(m，1H)，2.71(t，1H)，2.56(s，3H)，1.99(d，1H)，1.78(m，2H)，1.61(m，1H)。

Examples 9 to 22

4- [1- (4-isopropyl-benzoyl) -piperidin-3-yl ] -2-methyl-benzoic acid

MS(LC-MS)366.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.89(m，1H)，7.35(s，4H)，7.24(s，1H)，7.04(s，1H)，4.65(m，1H)，3.78(t，1H)，3.18(q，1H)，2.94(m，2H)，2.82(m，1H)，2.55(d，3H)，2.04(d，1H)，2.00-1.60(m，3H)，1.26(m，6H)。

Examples 9 to 23

4- {1- [ (4-isopropyl-phenyl) -acetyl ] -piperidin-3-yl } -2-methyl-benzoic acid

MS(LC-MS)380.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 1.25(m, 6H), 1.49(q, 1H), 1.72(t, 1H), 1.82(t, 1H), 1.94(d, 0.5H), 2.08(t, 0.5H), 2.53(d, 3H), 2.64(t, 0.5H), 2.75(t, 0.5H), 2.91(m, 1H), 3.03(t, 0.5H), 3.09(t, 0.5H), 3.68(d, 0.5H), 3.70(s, 3H), 3.78(d, 0.5H), 3.88(d, 0.5H), 4.02(d, 0.5H), 4.55(d, 0.5H), 4.64(d, 0.5H), 6.77(d, 1H), 7.18(m, 4H), 7.25(d, 1H), 7.86(d, 7.77H), 7.5H).

Examples 9 to 24

4- {1- [3- (4-isopropyl-phenyl) -acryloyl ] -piperidin-3-yl } -2-methyl-benzoic acid

MS(LC-MS)426.3(M+H)⁺。

¹H NMR(400MHz，CD₃OD) δ racemic mixture: 7.89(d, 1H), 7.54(m, 3H), 7.22(m, 4H), 7.11(dd, 1H), 4.66(d, 1H), 4.29(dd, 1H), 3.32(m, 0.5H), 3.19(m, 0.5H), 2.83(m, 3H), 2.58(s, 3H), 2.03(d, 1H), 1.86(m, 3H), 1.63(m, 1H), 1.23(m, 6H).

Examples 9 to 25

3- (4-carboxy-3-methyl-phenyl) -piperidine-1-carboxylic acid 4-isopropyl-benzyl ester

MS(LC-MS)394.1(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ7.85(d，1H)，7.27(d，2H)，7.22(d，2H)，7.13(m，2H)，5.08(s，2H)，4.15(d，2H)，2.89(m，3H)，2.67(m，1H)，2.55(s，3H)，1.97(d，1H)，1.75(m，2H)，1.58(m，1H)，1.23(d，6H)。

Examples 9 to 26

2-methyl-4- {1- [3- (4-trifluoromethyl-phenyl) -propionyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)420.2(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.86(dd，1H)，7.57(m，2H)，7.44(dd，2H)，7.17(m，1H)，7.12(m，1H)，4.57(t，1H)，3.93(dd，1H)，3.24(dd，1H)，3.09(q，1H)，3.01(m，2H)，2.80(m，1H)，2.69(m，1H)，2.56(d，3H)，1.95(t，1H)，1.78(m，2H)，1.46(m，1H)。

Examples 9 to 27

4- {1- [3- (4-isopropyl-phenyl) -propionyl ] -piperidin-3-yl } -2-methyl-benzoic acid

MS(LC-MS)394.3(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.86(t，1H)，7.16(m，5H)，7.07(m，1H)，4.58(dd，1H)，3.84(dd，1H)，3.05-2.61(m，7H)，2.56(d，3H)，2.19(t，1H)，1.89(t，1H)，1.71(m，2H)，1.40(m，1H)，1.28(m，1H)，1.22(d，6H)。

Examples 9 to 28

The isomer of 2-methoxy-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid was obtained from L-tartaric acid

The optically pure starting materials used:

l- (+) -tartaric acid: 5- (3-piperidinyl) -2-methoxybenzoic acid methyl ester-L-tartrate in 97.5% ee.

HPLC analysis: chirobiotic V, 1mL/min, 100% methanol, 0.1% triethylamine, 0.1% acetic acid; rt 6.29 min, 8.53 min.

MS(APCI)504.8(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.16(d，2H)，7.79(d，2H)，7.75(br，1H)，7.47(br，1H)，7.09(d，1H)，3.88(s，3H)，2.82(t，2H)，2.49(s，3H)，2.07(d，1H)，1.88(m，2H)，1.70(m，1H)，1.28(s，1H)。

Examples 9 to 29

The isomer of 2-methoxy-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid was obtained from D-tartaric acid

The optically pure starting materials used:

d- (-) -tartaric acid: 5- (3-piperidinyl) -2-methoxybenzoic acid methyl ester-D-tartrate in 91.8% ee

MS(APCI)504.8(M+H)⁺。

Examples 9 to 30

2-fluoro-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid

MS(LC-MS)493.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.85(br s，1H)，7.79(d，2H)，7.53(br s，1H)，7.15(t，1H)，2.89(t，1H)，2.49(s，3H)，2.08(d，1H)，1.89(m，2H)，1.71(m，1H)。

Examples 9 to 31

3- (3-carboxy-4-fluoro-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

MS(LC-MS)493.0(M+H)⁺。

Example 10

{3- [ 4-methyl-3- (1H-tetrazol-5-yl) -phenyl ] -piperidin-1-yl } - [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl ] -methanone

(R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzoic acid (example 9-1; 1.026g, 2.10mmol) was dissolved in 20mL of dichloromethane and treated with oxalyl chloride (0.22mL, 2.52mmol) and 10mL of dimethylformamide. The mixture was stirred for 1 hour until all solids dissolved. 10mL of THF saturated with ammonia was added slowly. A thick white precipitate formed. The slurry was stirred for 20 minutes, then diluted with ether (100mL), washed with 100mL each of water, 0.2N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was flash chromatographed, eluting with 50% ethyl acetate/hexanes, to give 740mg (72%) of the desired product 2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzamide as a clear oil.

MS(LC-MS)488.6(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ8.02(d，2H)，7.69(d，2H)，7.33(brs，1H)，7.19(brs，2H)，5.85(brs，2H)，3.01(br，2H)，2.79(m，1H)，2.51(s，3H)，2.45(s，3H)，2.08(d，1H)，1.89(m，H)，1.77(q，1H)，1.67(m，1H)。

(R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzamide (230mg, 0.47mmol) was dissolved in pyridine (5mL) and cooled to 0 ℃. Trifluoroacetic anhydride (0.67mL, 4.72mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0 ℃. The reaction was diluted with ether (100mL) and washed with 1N hydrochloric acid (2X 100mL) and saturated sodium bicarbonate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was flash chromatographed, eluting with 33% ethyl acetate/hexanes, to give 262mg (97%) of the desired product 2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzonitrile as a clear oil.

MS(LC-MS)470.0(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.99(d，2H)，7.74(d，2H)，7.46(brs，1H)，7.35(brs，1H)，7.19(m，1H)，2.82(m，1H)，2.53(s，3H)，2.52(s，3H)，2.14(d，1H)，1.97(m，H)，1.78(m，2H)。

(R) -2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -benzonitrile (262mg, 0.56mmol) was dissolved in toluene (5 mL). Trimethyltin azide (230mg, 1.12mmol) was added and the mixture was heated under reflux for 24 hours. The mixture was diluted with ether (100mL) and washed with 0.1N hydrochloric acid (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was flash chromatographed, eluting with 7.5% methanol/chloroform (0.5% ammonium hydroxide modifier). The product fractions were combined and then concentrated under reduced pressure. The resulting oil was taken up in 100mL ethyl acetate and extracted with 0.1N hydrochloric acid (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 132mg (46%) of the desired product {3- [ 4-methyl-3- (1H-tetrazol-5-yl) -phenyl ] -piperidin-1-yl } - [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl ] -methanone as a clear oil.

MS(LC-MS)513.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.79(d，2H)，7.56(brs，1H)，7.39(m，2H)，2.89(t，1H)，2.49(s，3H)，2.44(s，3H)，2.10(d，1H)，1.90(m，2H)，1.72(m，1H)。

Example 11

(S) -2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid

A500 mL Parr bottle was charged with 2.0g of 10% palladium on charcoal (50% water) and covered with 50mL of ethanol. 2-methyl-5-nitroanisole (10.0g, 59.8mmol) is dissolved in 100mL of ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50psi for 3 hours. The catalyst was filtered through a plug of celite. The filter cake was washed with 150mL of ethanol, and the filtrate was concentrated under reduced pressure to obtain 8.05g (98%) of 5-amino-2-methylanisole as a clear oil.

¹H NMR(400MHz，CDCl₃)δ6.90(d，1H)，6.23(m，2H)，3.78(s，3H)，2.11(s，3H)。

5-amino-2-methylanisole (8.05g, 58.7mmol) was dissolved in 244mL water and 8.1mL concentrated sulfuric acid and cooled to 0 ℃. Under stirringNaNO in 61mL of water was added dropwise₂(4.86g, 70.4 mmol). The reaction was stirred at 0 ℃ for 30 minutes. Urea (0.70g, 11.7mmol) was added and stirring was continued for 30 min. The light yellow solution was transferred to a dropping funnel and slowly added to a stirred aqueous solution of potassium iodide (19.48g, 117.4mmol) in 122 mL. After the addition was complete, the solution was stirred at room temperature for 1 hour. The reaction was extracted with ether (3X 300 mL). The organic extracts were combined, washed with 1M sodium thiosulfate (2 × 200mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 9.60g (66%) of 5-iodo-2-methylanisole as a brown oil.

¹H NMR(400MHz，CDCl₃)δ7.19(dd，1H)，7.10(d，1H)，6.86(t，1H)，3.81(s，3H)，2.15(s，3H)。

5-iodo-2-methylanisole (9.60g, 38.70mmol) and diethyl- (3-pyridyl) borane (5.70g, 38.70mmol) were dissolved in 60mL tetrahydrofuran in a 250mL round bottom flask equipped with a magnetic stirrer. Sodium carbonate (8.20g, 77.40mmol) and 30mL of water were added, followed by tetrakis (triphenylphosphine) palladium (0) (0.90g, 0.77mmol) and 15mL of ethanol. The mixture was heated to reflux under nitrogen for 24 hours and then cooled to room temperature. The mixture was diluted with 200mL of water and extracted with ether (2X 200 mL). The organic phases were combined and extracted with 1N hydrochloric acid (3X 150 mL). The acidic extracts were combined and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ether (3 × 150mL), the extracts combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7.71g (99%) of 2-methyl-5- (3-pyridinyl) -anisole as a brown oil.

MS(LC-MS)200.1(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ8.87(s，1H)，8.60(d，1H)，8.03(dd，1H)，7.50(m，1H)，7.25(d，1H)，7.08(d，1H)，7.00(s，1H)，3.92(s，3H)，2.27(s，3H)。

A500 mL hydrogenation vessel was charged with 0.77g of platinum (II) oxide and purged with nitrogen. A solution of 2-methyl-5- (3-pyridyl) -anisole (7.71g, 38.7mmol) in 150mL of acetic acid was added. The suspension was hydrogenated at 45psi for 18 hours. The catalyst was filtered through celite and the filter plug was washed with 200mL of acetic acid. The filtrate was concentrated under reduced pressure. The resulting oil was taken up in 300mL of water and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ethyl acetate (2X 300mL), and the extracts were combined and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The resulting oil was placed in 300mL of hot ethanol. To the ethanol solution was added a 50mL hot ethanol solution of L- (+) -tartaric acid (5.81g, 38.7mmol) and stirred at room temperature for 24 hours to form a white precipitate, which was collected by filtration. The white solid was recrystallized from hot 5% water/ethanol (200mL) to give 4.88g (35%) of 5- (3-piperidinyl) -2-methylanisole-L-tartrate as a white solid. The mother liquors were combined and then concentrated under reduced pressure. The resulting oil was taken up in 500mL of diethyl ether and washed with 300mL of saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was placed in 200mL of hot ethanol. D- (-) -tartaric acid (3.75g, 25.0mmol) in 50mL of hot ethanol was added and stirred at room temperature for 48 hours to form a white precipitate, which was collected by filtration. The white solid was recrystallized from hot 5% water/ethanol (300mL) to give 5.36g (39%) of 5- (3-piperidinyl) -2-methylanisole-D-tartrate as a white solid.

¹H NMR(400MHz，DMSO_d6)δ7.06(d，1H)，6.82(d，1H)，6.71(dd，1H)，3.87(s，2H)，3.77(s，3H)，3.27(m，2H)，2.97(t，1H)，2.86(q，2H)，2.09(s，3H)，1.85(d，2H)，1.69(m，2H)。

3- (3-methoxy-4-methylphenyl) -1H-piperidine-L-tartrate (4.88g, 13.73mmol) was slowly dissolved in hydrobromic acid (50mL) and the resulting mixture was heated at 140 ℃ for 2H. After cooling to room temperature, hydrobromic acid and water were distilled off, the brown oil formed was azeotropically distilled with toluene (3 × 100mL) and dried under high vacuum for 18 h. The resulting tan solid (3- (3-hydroxy-4-methylphenyl) -1H-piperidine hydrobromide (3.74g, 13.73mmol) was dissolved in 25mL of water and 50mL of tetrahydrofuran, sodium bicarbonate (2.31g, 27.46mmol) was added, then dibenzyl dicarbonate (3.93g, 13.73mmol) was added, the reaction was stirred at room temperature for 1 hour, then diluted with 300mL of diethyl ether and washed with 200mL of 0.5N hydrochloric acid, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the resulting oil was flash chromatographed, eluting with 33% ethyl acetate/hexane to give 3.41g (76%) of the desired product benzyl 3- (3-hydroxy-4-methyl-phenyl) -piperidine-1-carboxylate as a clear oil.

MS(LC-MS)324.2(M-H)^-。

¹H NMR(400MHz，CDCl₃)δ7.36(m，5H)，7.05(d，1H)，6.70(dd，1H)，6.63(s，1H)，5.14(m，2H)，4.22(t，2H)，2.79(t，2H)，2.61(m，1H)，2.21(s，3H)，1.97(d，1H)，1.76(m，1H)，1.57(m，2H)。

HPLC analysis: chiralcel OJ, 1mL/min, 40% ethanol/heptane 0.2% diethylamine, rt 10.22 min.

ee＝90.4％。

To a solution of benzyl 3- (3-hydroxy-4-methyl-phenyl) -piperidine-1-carboxylate (2.02g, 6.21mmol) in 15mL dimethylformamide was added cesium carbonate (4.05g, 12.42mmol) and ethyl 2-bromoisobutyrate (3.64mL, 24.83 mmol). The mixture was heated under nitrogen at 60 ℃ with stirring for 18 hours and then cooled to room temperature. The resulting brown suspension was diluted with 300mL of water and extracted with ether (2X 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 20% ethyl acetate/hexane, to give 1.36g (50%) of the desired product, benzyl 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylate, as a clear oil.

MS(LC-MS)462.1(M+Na)⁺。

¹H NMR(400MHz，CDCl₃)δ7.34(m，5H)，7.06(d，1H)，6.73(d，1H)，6.52(s，1H)，5.13(m，2H)，4.22(m，4H)，2.74(q，1H)，2.70(t，1H)，2.57(m，1H)，2.19(s，3H)，1.96(d，1H)，1.76(m，1H)，1.57(d，6H)，1.53(s，2H)，1.22(t，3H)。

A250 mL Parr bottle was charged with 0.27g of 10% palladium on charcoal (50% water) and covered with 20mL of ethanol. Benzyl 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylate (1.36g, 3.09mmol) was dissolved in 50mL of ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50psi for 2 hours. The catalyst was filtered through a plug of celite. The filter cake was washed with 150mL of ethanol and the filtrate was concentrated under reduced pressure. The resulting oil was taken up in 20mL of hot ethanol, to which was added L-tartaric acid (464mg, 3.09mmol) in 10mL of hot ethanol. The solution was stirred at room temperature for 24 hours. The white crystalline precipitate was collected by filtration to yield 805mg (57%) of 2-methyl-2- (2-methyl-5-piperidin-3-yl-phenoxy) -propionic acid ethyl ester L-tartrate as a white crystalline solid.

MS(LC-MS)306.3(M+H)⁺。

¹H NMR(400MHz，DMSO_d6)δ7.11(d，1H)，6.78(d，1H)，6.44(s，1H)，4.16(q，2H)，3.81(s，2H)，3.21(t，2H)，2.78(m，2H)，2.10(s，3H)，1.81(m，2H)，1.69(m，1H)，1.56(m，1H)，1.51(s，6H)，1.14(t，3H)。

HPLC analysis: chiralpak AD, 1mL/min, 5% isopropanol/heptane 0.2% diethylamine, rt 9.75 min.

ee＝100％。

Ethyl 2-methyl-2- (2-methyl-5-piperidin-3-yl-phenoxy) -propionate L-tartrate (155mg, 0.34mmol) was dissolved in 50mL ethyl acetate and washed with 50mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The resulting oil was taken up in 2mL of dichloromethane and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (130mg, 0.68mmol) and 4-methyl-2- [4- (trifluoromethyl) phenyl ] -1, 3-thiazole-5-carboxylic acid (98mg, 0.34mmol) were added. The reaction was stirred at room temperature under nitrogen for 72 hours. The reaction was diluted with 100mL of diethyl ether and washed with water (100mL), 0.5N hydrochloric acid (2X 100mL), saturated aqueous sodium bicarbonate solution (2X 100mL), dried over sodium sulfate and concentrated under reduced pressure to give 2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid ethyl ester (179mg, 91%) as a clear oil.

MS(LC-MS)575.0(M-H)^-。

¹H NMR(400MHz，CD₃)δ8.04(d，2H)，7.70(d，2H)，7.07(d，1H)，6.73(m，1H)，6.52(m，1H)，4.21(m，2H)，2.64(m，1H)，2.53(s，3H)，2.18(s，3H)，2.05(m，1H)，1.81(m，2H)，1.62(m，2H)，1.57(m，6H)，1.21(m，3H)。

A mixture of 2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid ethyl ester (179mg, 0.31mmol), potassium carbonate (86mg, 0.62mmol), methanol (10mL) and water (2mL) was heated under reflux for 3 hours, cooled to room temperature and then concentrated under reduced pressure. The resulting residue was taken up in water (50mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 151mg (89%) of 2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid as a white solid.

MS(LC-MS)547.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.78(d，2H)，7.08(d，1H)，6.79(m，1H)，6.68(m，1H)，2.74(m，1H)，2.47(s，3H)，2.15(s，3H)，2.03(d，1H)，1.91(brm，2H)，1.79(m，2H)，1.54(brs，6H)。

Example 11-1

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

2-methyl-2- (2-methyl-5-piperidin-3-yl-phenoxy) -propionic acid ethyl ester L-tartrate (example 11; 155mg, 0.34mmol) was dissolved in 50mL ethyl acetate and washed with 50mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The resulting oil was taken up in 3mL of toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (92mg, 0.34mmol) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction was subjected to flash chromatography, eluting with 15% ethyl acetate/hexanes to give 157mg (91%) of the desired product, 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.

MS(LC-MS)525.2(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.61(d，2H)，7.46(d，2H)，7.07(d，1H)，6.74(m，1H)，6.52(s，1H)，5.19(s，2H)，4.21(m，2H)，2.73(brm，2H)，2.58(m，1H)，2.19(s，3H)，1.97(d，1H)，1.76(m，2H)，1.58(m，6H)，1.22(m，3H)。

A mixture of 4-trifluoromethyl-benzyl 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylate (156mg, 0.31mmol), potassium carbonate (85mg, 0.62mmol), methanol (10mL) and water (2mL) was heated at reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 139mg (94%) of 4-trifluoromethyl-benzyl 3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylate as a white solid.

MS(LC-MS)478.1(M-H)^-。

¹H NMR(400MHz，CDCl₃)δ7.66(d，2H)，7.54(m，2H)，7.07(d，1H)，6.77(d 1H)，6.67(s，1H)，5.21(s，2H)，4.14(m，2H)，2.88(brm，2H)，2.58(t，1H)，2.17(s，3H)，1.96(d，1H)，1.77(m，2H)，1.62(m，1H)，1.57(s，6H)。

Examples 11-2 and 11-3 were prepared from similar starting materials using similar procedures as described for examples 11 and 11-1.

Example 11-2

(R) -2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid

3- (3-methoxy-4-methylphenyl) -1H-piperidine-D-tartrate (example 11; 5.36g, 15.08mmol) was slowly dissolved in hydrobromic acid (50mL) and the resulting mixture was heated at 140 ℃ for 2H. After cooling to room temperature, hydrobromic acid and water were distilled off, the brown oil formed was azeotropically distilled with toluene (3 × 100mL) and dried under high vacuum for 18 h. The resulting tan solid (3- (3-hydroxy-4-methylphenyl) -1H-piperidine hydrobromide (4.11g, 15.08mmol) was dissolved in 25mL of water and 50mL of tetrahydrofuran, sodium bicarbonate (2.54g, 30.16mmol) was added, then dibenzyl dicarbonate (4.32g, 15.08mmol) was added, the reaction was stirred at room temperature for 1 hour, then diluted with 300mL of diethyl ether and washed with 200mL of 0.5N hydrochloric acid, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the resulting oil was flash chromatographed, eluting with 33% ethyl acetate/hexane to give 3.82g (78%) of the desired product, benzyl 3- (3-hydroxy-4-methyl-phenyl) -piperidine-1-carboxylate, as a clear oil.

MS(LC-MS)324.2(M-H)^-。

HPLC analysis: chiralcel OJ, 1mL/min, 40% ethanol/heptane 0.2% diethylamine, rt 8.55 min.

ee＝85.8％。

To a solution of benzyl 3- (3-hydroxy-4-methyl-phenyl) -piperidine-1-carboxylate (2.24g, 6.88mmol) in 15mL dimethylformamide was added cesium carbonate (4.49g, 13.77mmol) and ethyl 2-bromoisobutyrate (4.04mL, 27.53 mmol). The mixture was heated under nitrogen at 60 ℃ with stirring for 18 hours and then cooled to room temperature. The resulting brown suspension was diluted with 300mL of water and extracted with ether (2X 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 20% ethyl acetate/hexane, to give 1.36g (45%) of the desired product, benzyl 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylate, as a clear oil.

MS(LC-MS)462.1(M+Na)⁺。

A250 mL Parr bottle was charged with 0.27g of 10% palladium on charcoal (50% water) and covered with 20mL of ethanol. Benzyl 3- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylate (1.36g, 3.09mmol) was dissolved in 50mL of ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50psi for 2 hours. The catalyst was filtered through a plug of celite. The filter cake was washed with 150mL of ethanol and the filtrate was concentrated under reduced pressure. The resulting oil was taken up in 20mL of hot ethanol, to which was added D-tartaric acid (464mg, 3.09mmol) in 10mL of hot ethanol. The solution was stirred at room temperature for 24 hours. The white crystalline precipitate was collected by filtration to yield 978mg (69%) of 2-methyl-2- (2-methyl-5-piperidin-3-yl-phenoxy) -propionic acid ethyl ester D-tartrate as a white crystalline solid.

MS(LC-MS)306.3(m+H)⁺。

HPLC analysis: chiralpak AD, 1mL/min, 5% isopropanol/heptane 0.2% diethylamine, rt 8.90 min.

ee＝98％。

2-methyl-2- (2-methyl-5-piperidin-3-yl-phenoxy) -propionic acid ethyl ester D-tartrate was treated in a similar manner to that described in example 11 to give the title compound (R) -2-methyl-2- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid

MS(LC-MS)547.0(M+H)⁺。

Examples 11 to 3

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

The title compound was prepared by the method described in example 11-1 using the starting material prepared in example 11-2.

MS(LC-MS)478.1(M-H)^-。

¹H NMR(400MHz，CDCl₃)δ7.66(d，2H)，7.54(m，2H)，7.07(d，1H)，6.77(d，1H)，6.67(s，1H)，5.21(s，2H)，4.14(m，2H)，2.88(brm，2H)，2.58(t，1H)，2.17(s，3H)，1.96(d，1H)，1.77(m，2H)，1.62(m，1H)，1.57(s，6H)。

Examples 11-4, 11-5 and 11-6 were prepared using similar methods as described for examples 11 and 11-1.

Examples 11 to 4

2-methyl-2- (2-methyl-4- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -propionic acid

MS(LC-MS)547.0(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ8.17(d，2H)，7.78(d，2H)，7.06(m，2H)，6.96(br，1H)，6.73(brm，1H)，2.71(t，1H)，2.48(s，3H)，2.18(brs，3H)，2.02(d，1H)，1.84(m，2H)，1.67(m，1H)，1.54(s，6H)。

Examples 11 to 5

3- [4- (1-carboxy-1-methyl-ethoxy) -3-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

MS(LC-MS)478.0(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ7.66(d，2H)，7.54(m，2H)，7.03(s，1H)，6.94(d，1H)，6.72(d，1H)，5.21(s，2H)，4.14(m，2H)，2.89(brm，2H)，2.57(t，1H)，2.19(s，3H)，1.93(d，1H)，1.79(d，1H)，1.70(q，1H)，1.58(m，1H)，1.55(s，6H)。

Examples 11 to 6

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester and (R) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester

MS(LC-MS)494.3(M-H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.57(br s，2H)，7.43(br s，2H)，7.07(d，1H)，6.75(br s，1H)，6.63(s，1H)，4.34(br s，2H)，4.05(brm，2H)，3.06(t，2H)，2.72(brm，1H)，2.43(brm，1H)，2.18(s，3H)，1.92(d，1H)，1.70(m，1H)，1.61(t，1H)，1.56(m，1H)，1.43(br，1H)。

Example 12

(S) - (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl) -phenoxy) -acetic acid

To a solution of benzyl 3- (3-hydroxy-4-methyl-phenyl) -piperidine-1-carboxylate (example 11; 2.08g, 6.39mmol) in 15mL dimethylformamide was added cesium carbonate (4.17g, 12.78mmol) and ethyl bromoacetate (1.42mL, 12.78 mmol). The mixture was heated under nitrogen at 60 ℃ with stirring for 3 hours and then cooled to room temperature. The resulting brown suspension was diluted with 300mL of water and extracted with ether (2X 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 15% ethyl acetate/hexane, to give 1.42g (54%) of the desired product, benzyl 3- (3-ethoxycarbonylmethoxy-4-methyl-phenyl) -piperidine-1-carboxylate, as a clear oil.

MS(LC-MS)462.1(M+Na)⁺。

¹H NMR(400MHz，CDCl₃)δ7.35(m，5H)，7.09(d，1H)，6.76(d，1H)，6.56(s，1H)，5.14(m，2H)，4.61(s，2H)，4.23(m，2H)，2.78(q，2H)，2.62(m，1H)，2.25(s，3H)，1.98(m，1H)，1.76(m，1H)，1.56(m，3H)，1.29(t，3H)。

To a 250mL Parr bottle was added 0.14g of 10% palladium on charcoal (50% water) and covered with 20mL of ethanol. Benzyl 3- (3-ethoxycarbonylmethoxy-4-methyl-phenyl) -piperidine-1-carboxylate (1.42g, 3.45mmol) was dissolved in 50mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50psi for 2 hours. The catalyst was filtered through a plug of celite. The filter cake was washed with 150mL of ethanol and the filtrate was concentrated under reduced pressure. The resulting oil was taken up in 20mL of hot ethanol, to which was added L-tartaric acid (518mg, 3.45mmol) in 10mL of hot ethanol. The solution was stirred at room temperature for 24 hours. The white crystalline precipitate was collected by filtration to yield 730mg (50%) of (2-methyl-5-piperidin-3-yl-phenoxy) -acetic acid ethyl ester L-tartrate as a white crystalline solid.

MS(LC-MS)278.3(M+H)⁺。

HPLC analysis: chiralpak AD, 1mL/min, 5% isopropanol/heptane 0.2% diethylamine, rt 4.01 min.

ee＝99.3％。

Ethyl (2-methyl-5-piperidin-3-yl-phenoxy) -acetate L-tartrate (147mg, 0.34mmol) was dissolved in 50mL ethyl acetate and washed with 50mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The resulting oil was taken up in 2mL of dichloromethane and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (132mg, 0.69mmol) and 4-methyl-2- [4- (trifluoromethyl) phenyl ] -1, 3-thiazole-5-carboxylic acid (99mg, 0.34mmol) were added. The reaction was stirred at room temperature under nitrogen atmosphere for 24 hours. The reaction was diluted with 100mL of diethyl ether and washed with water (100mL), 0.5N hydrochloric acid (2X 100mL), saturated aqueous sodium bicarbonate solution (2X 100mL), dried over sodium sulfate and concentrated under reduced pressure to give (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl) -phenoxy) -acetic acid ethyl ester (146mg, 76%) as a clear oil.

MS(LC-MS)547.1(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ8.03(d，2H)，7.69(d，2H)，7.10(d，1H)，6.76(brs，1H)，6.57(brs，1H)，4.62(brs，2H)，4.25(q，2H)，2.97(brm，1H)，2.72(m，1H)，2.52(s，3H)，2.25(s，3H)，2.09(m，1H)，1.91(m，1H)，1.70(m，4H)，1.28(t，3H)。

A mixture of (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid ethyl ester (146mg, 0.26mmol), potassium carbonate (71mg, 0.52mmol), methanol (10mL) and water (2mL) was heated under reflux for 3 hours, cooled to room temperature and then concentrated under reduced pressure. The resulting residue was taken up in water (50mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 130mg (94%) of (S) - (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid as a white solid.

MS(LC-MS)450.1(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.78(d，2H)，7.06(m，1H)，6.75(brm，2H)，4.66(brs，2H)，2.76(t，1H)，2.48(s，3H)，2.20(s，3H)，2.04(d，1H)，1.83(m，2H)，1.67(m，1H)。

Example 12-1

(S) -3- (3-carboxymethoxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

Ethyl (2-methyl-5-piperidin-3-yl-phenoxy) -acetate L-tartrate (example 12; 147mg, 0.34mmol) was dissolved in 50mL ethyl acetate and washed with 50mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and then concentrated under reduced pressure. The resulting oil was taken up in 3mL of toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (93mg, 0.34mmol) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction was subjected to flash chromatography, eluting with 15% ethyl acetate/hexanes to give 118mg (74%) of the desired product 4-trifluoromethyl-benzyl 3- (3-ethoxycarbonylmethoxy-4-methyl-phenyl) -piperidine-1-carboxylate as a clear oil.

MS(LC-MS)502.1(M+Na)⁺。

¹H NMR(400MHz，CDCl₃)δ7.61(d，2H)，7.46(d，2H)，7.10(d，1H)，6.76(d，1H)，6.56(s，1H)，5.19(m，2H)，4.62(s，2H)，4.25(m，2H)，2.79(brm，2H)，2.63(m，1H)，2.26(s，3H)，2.02(m，1H)，1.80(m，2H)，1.56(m，4H)，1.28(t，3H)。

A mixture of 4-trifluoromethyl-benzyl 3- (3-ethoxycarbonylmethoxy-4-methyl-phenyl) -piperidine-1-carboxylate (118mg, 0.25mmol), potassium carbonate (68mg, 0.49mmol), methanol (10mL) and water (2mL) was heated under reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 110mg (97%) of 4-trifluoromethyl-benzyl (S) -3- (3-carboxymethoxy-4-methyl-phenyl) -piperidine-1-carboxylate as a white solid.

MS(LC-MS)450.1(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ7.66(d，2H)，7.54(m，2H)，7.06(d，1H)，6.76(d，1H)，6.69(s，1H)，5.21(s，2H)，4.66(s，2H)，4.15(m，2H)，2.88(brm，2H)，2.62(t，1H)，2.21(s，3H)，1.96(d，1H)，1.79(m，1H)，1.69(t，1H)，1.58(m，1H)。

Example 12-2

(R) - (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid

To a solution of benzyl 3- (3-hydroxy-4-methyl-phenyl) -piperidine-1-carboxylate (example 11-2; 2.34g, 7.19mmol) in 15mL dimethylformamide was added cesium carbonate (4.69g, 14.38mmol) and ethyl bromoacetate (1.60mL, 14.38 mmol). The mixture was heated under nitrogen at 60 ℃ with stirring for 3 hours and then cooled to room temperature. The resulting brown suspension was diluted with 300mL of water and extracted with ether (2X 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 15% ethyl acetate/hexane, to give 1.78g (60%) of the desired product, benzyl 3- (3-ethoxycarbonylmethoxy-4-methyl-phenyl) -piperidine-1-carboxylate, as a clear oil.

MS(LC-MS)462.1(M+Na)⁺。

To a 250mL Parr bottle was added 0.18g of 10% palladium on charcoal (50% water) and covered with 20mL of ethanol. Benzyl 3- (3-ethoxycarbonylmethoxy-4-methyl-phenyl) -piperidine-1-carboxylate (1.78g, 4.33mmol) was dissolved in 50mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50psi for 2 hours. The catalyst was filtered through a plug of celite. The filter cake was washed with 150mL of ethanol and the filtrate was concentrated under reduced pressure. The resulting oil was taken up in 20mL of hot ethanol and D-tartaric acid (650mg, 4.33mmol) in 10mL of hot ethanol was added to the solution. The solution was stirred at room temperature for 24 hours. The white crystalline precipitate was collected by filtration to yield 1.014g (55%) of (2-methyl-5-piperidin-3-yl-phenoxy) -acetic acid ethyl ester D-tartrate as a white crystalline solid.

MS(LC-MS)278.3(M+H)⁺。

1HNMR(400MHz，DMSO_d6)δ7.11(d，1H)，6.78(d，1H)，6.44(s，1H)，4.16(q，2H)，3.81(s，2H)，3.21(t，2H)，2.78(m，2H)，2.10(s，3H)，1.81(m，2H)，1.69(m，1H)，1.56(m，1H)，1.51(s，6H)，1.14(t，3H)。

HPLC analysis: chiralpak AD, 1mL/min, 5% isopropanol/heptane 0.2% diethylamine, rt 3.18.

ee＝98.9。

(2-methyl-5-piperidin-3-yl-phenoxy) -acetic acid ethyl ester D-tartrate was treated in a similar manner as described in example 12 to give the title compound (R) - (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid.

MS(LC-MS)450.1(M-H)^-。

Examples 12 to 3

(R) -3- (3-carboxymethoxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

The title compound was prepared in a similar manner to that described in example 12-1 using the starting materials prepared in example 12-2.

MS(LC-MS)450.1(M-H)^-。

Examples 12-4 and 12-5 were prepared in a similar manner to examples 12 and 12-1.

Examples 12 to 4

(2-methyl-4- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenoxy) -acetic acid

MS(LC-MS)519.0(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.78(d，2H)，7.03(br s，2H)，6.74(brm，1H)，4.64(brs，2H)，2.74(t，1H)，2.48(s，3H)，2.22(brs，3H)，2.02(d，1H)，1.84(m，2H)，1.67(m，1H)。

Examples 12 to 5

3- (4-carboxymethoxy-3-methyl-phenyl) -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

MS(LC-MS)450.0(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ7.66(d，2H)，7.54(m，2H)，7.03(s，1H)，6.99(d，1H)，6.73(d，1H)，5.21(s，2H)，4.64(s，2H)，4.15(m，2H)，2.89(brm，2H)，2.58(t，1H)，2.23(s，3H)，1.94(d，1H)，1.79(d，1H)，1.69(q，1H)，1.58(m，1H)。

Example 13

C, C, C-trifluoro-N- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenyl) -methanesulfonamide

2-Nitro-4-bromotoluene (8.74g, 40.46mmol) was dissolved in 75mL of dioxane and 25mL of water, and diethyl- (3-pyridyl) borane (5.95g, 40.46mmol), sodium carbonate (8.58g, 80.91mmol) and tetrakis (triphenylphosphine) palladium (0) (0.94g, 0.81mmol) were added thereto. The mixture was heated to reflux for 18 hours and then cooled to room temperature. The mixture was diluted with 600mL of water and extracted with ether (2X 300 mL). The organic phases were combined and extracted with 0.3N hydrochloric acid (3X 200 mL). The acidic extracts were combined and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ether (2X 300mL), the extracts combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.39g (74%) of 2-nitro-4- (3-pyridyl) toluene as a brown oil.

MS(LC-MS)215.1(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ8.87(d，1H)，8.66(d，1H)，8.20(d，1H)，7.92(d，1H)，7.73(dd，1H)，7.44(m，2H)，2.66(s，3H)。

To a 500mL hydrogenation vessel was added 0.64g of platinum (II) oxide and purged with nitrogen. A solution of 2-nitro-4- (3-pyridyl) toluene (19.57g, 81.10mmol) in 150mL of acetic acid was added. The suspension was hydrogenated at 45psi for 18 hours. The catalyst was filtered through celite and the filter plug was washed with 300mL ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting oil was taken up in 300mL of water and basified with 5N aqueous sodium hydroxide. The basic layer was extracted with ethyl acetate (2X 300mL), the extracts combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5.38g (95%) of 2-amino-4- (3-piperidinyl) toluene as a brown oil.

MS(LC-MS)191.2(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ6.97(d，1H)，6.56(dd，1H)，6.54(d，1H)，3.57(brs，1H)，3.12(dd，2H)，2.61(m，3H)，2.13(s，3H)，1，+95(brs，2H)，1.75(m，1H)，1.57(m，2H)。

2-amino-4- (3-piperidinyl) toluene (1.25g, 6.57mmol) was dissolved in 25mL tetrahydrofuran. 1N sodium hydroxide (13.14mL, 13.14mmol) was added followed by dibenzyl dicarbonate (1.88g, 6.57 mmol). The reaction was stirred at room temperature for 2 hours, then diluted with 200mL of diethyl ether and washed with 200mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 20% ethyl acetate/hexane, to give 1.414g (66%) of the desired product, benzyl 3- (3-amino-4-methyl-phenyl) -piperidine-1-carboxylate, as a clear oil.

MS(LC-MS)325.2(M+H)⁺。

¹H NMR(400MHz，DMSO-d₆)δ7.34(m，5H)，6.81(d，1H)，6.45(s，1H)，6.32(d，1H)，5.06(s，2H)，4.02(m，2H)，2.76(brm，1H)，2.41(t，1H)，1.97(s，3H)，1.82(d，2H)，1.69(d，1H)，1.54(q，1H)，1.44(t，1H)。

Benzyl 3- (3-amino-4-methyl-phenyl) -piperidine-1-carboxylate (470mg, 1.45mmol) was dissolved in 10mL of dichloromethane and cooled to 0 ℃. Triethylamine (0.4mL, 2.90mmol) was added followed by dropwise addition of triflic anhydride (0.24mL, 1.45mmol) and the reaction stirred at 0 ℃ for 0.5 h. The mixture was concentrated under reduced pressure and placed in 50mL of water. The aqueous suspension was acidified with 1N hydrochloric acid and extracted with 50mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was flash chromatographed, eluting with 15% methanol/chloroform (1% ammonium hydroxide modifier). The product fractions were combined and then concentrated under reduced pressure. The resulting oil was taken up in 50mL of water, acidified with 1N hydrochloric acid and extracted with 50mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 403mg (61%) of the desired product, benzyl 3- [ 4-methyl-3- (trifluoro-methanesulfonylamino) -phenyl ] -piperidine-1-carboxylate as a clear oil.

MS(LC-MS)455.1(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ7.35(m，5H)，7.22(d，1H)，7.18(brs，2H)，5.13(s，2H)，4.15(d，2H)，2.89(brm，2H)，2.65(m，1H)，2.32(s，3H)，2.00(d，1H)，1.76(d，1H)，1.69(q，1H)，1.58(t，1H)。

To a 250mL Parr bottle was added 80mg of 10% palladium on charcoal (50% water) and covered with 10mL of ethanol. Benzyl 3- [ 4-methyl-3- (trifluoromethanesulfonylamino) -phenyl ] -piperidine-1-carboxylate (403mg, 0.88mmol) was dissolved in 20mL of ethanol and added to the catalyst suspension. The reaction was hydrogenated at 45psi for 2 hours. Water (50mL) was added to dissolve the white precipitate and the catalyst was filtered through a plug of celite. The filter cake was washed with 200mL 25% water/ethanol and the filtrate was concentrated under reduced pressure to give 275mg (97%) of C, C-trifluoro-N- (2-methyl-5-piperidin-3-yl-phenyl) -methanesulfonamide as a white crystalline solid.

MS(LC-MS)323.2(M+H)⁺。

¹H NMR(400MHz，DMSO-d₆)δ8.58(brs，1H)，8.29(brs，1H)，6.97(s，1H)，6.92(d，1H)，6.56(d，1H)，3.24(m，2H)，2.87(brm，2H)，2.70(t，1H)，2.06(s，3H)，1.83(t，2H)，1.66(m，2H)。

To a 10mL round bottom flask was added C, C, C-trifluoro-N- (2-methyl-5-piperidin-3-yl-phenyl) -methanesulfonamide (64mg, 0.20mmol), 3mL dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (76mg, 0.40mmol) and 4-methyl-2- [4- (trifluoromethyl) phenyl ] -1, 3-thiazole-5-carboxylic acid (57mg, 0.20 mmol). The suspension was stirred at room temperature for 72 hours. The reaction was filtered and the filtrate was flash chromatographed using 10% methanol/chloroform (1% ammonium hydroxide modifier). The product fractions were combined and then concentrated under reduced pressure. The resulting oil was taken up in 50mL of water, acidified with 1N hydrochloric acid and extracted with 50mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 28mg (24%) of C, C-trifluoro-N- (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenyl) -methanesulfonamide as a white solid.

MS(LC-MS)592.0(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.79(d，1H)，7.22(brm，3H)，2.81(t，1H)，2.48(s，3H)，2.31(s，3H)，2.07(d，1H)，1.85(m，2H)，1.69(m，2H)。

Example 13-1

3- [3- (carboxymethyl-amino) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester

Benzyl 3- (3-amino-4-methyl-phenyl) -piperidine-1-carboxylate (example 13; 230mg, 0.71mmol) was dissolved in 5mL dimethylformamide. Cesium carbonate (462mg, 1.42mmol) and ethyl bromoacetate (86 μ L, 0.78mmol) were added and the mixture was stirred at room temperature under nitrogen for 72 hours. Then 86 μ L of ethyl bromoacetate was added and the reaction was stirred for an additional 24 hours. The mixture was diluted with 100mL of water and extracted with ether (2X 50 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was subjected to flash chromatography, eluting with 20% ethyl acetate/hexanes, to give 152mg (52%) of benzyl 3- [3- (ethoxycarbonylmethyl-amino) -4-methyl-phenyl ] -piperidine-1-carboxylate as a clear oil.

MS(LC-MS)411.2(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ7.37(m，5H)，7.03(d，1H)，6.84(brm，1H)，6.78(brm，1H)，5.14(s，2H)，4.22(q，2H)，3.98(s，2H)，2.79(m，2H)，2.63(m，1H)，2.25(s，3H)，1.99(d，1H)，1.83(d，1H)，1.58(m，2H)，1.28(t，3H)。

To a 100mL Parr bottle was added 30mg of 10% palladium on charcoal (50% water) and covered with 10mL of ethanol. Benzyl 3- [3- (ethoxycarbonylmethyl-amino) -4-methyl-phenyl ] -piperidine-1-carboxylate (152mg, 0.37mmol) was dissolved in 10mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 45psi for 2 hours. The catalyst was filtered through a plug of celite. The filter cake was washed with 30mL ethanol and the filtrate was concentrated under reduced pressure to yield 126mg (100%) of (2-methyl-5-piperidin-3-yl-phenylamino) -acetic acid ethyl ester as a clear oil.

MS(LC-MS)277.2(M+H)⁺。

¹H NMR(400MHz，CDCl₃)δ9.80(brs，1H)，9.56(brs，1H)，7.02(d，1H)，6.55(brm，1H)，6.36(brm，1H)，4.22(q，2H)，3.93(s，2H)，3.52(t，2H)，3.13(m，1H)，2.87(m，2H)，2.02(d，1H)，1.98(d，1H)，1.59(m，2H)，1.23(t，3H)。

Ethyl (2-methyl-5-piperidin-3-yl-phenylamino) -acetate (63mg, 0.23mmol) was dissolved in 3mL of toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (93mg, 0.34mmol) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction was subjected to flash chromatography, eluting with 15% ethyl acetate/hexanes, to give 40mg (37%) of the desired product, 4-trifluoromethyl-benzyl 3- [3- (ethoxycarbonylmethyl-amino) -4-methyl-phenyl ] -piperidine-1-carboxylate as a clear oil.

MS(LC-MS)479.1(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.66(d，2H)，7.54(m，2H)，6.94(d，1H)，6.51(d，1H)，6.32(m，1H)，5.21(s，2H)，4.21(m，2H)，3.96(s，2H)，2.91(m，2H)，2.58(t，1H)，2.13(s，3H)，1.97(d，1H)，1.80(d，1H)，1.72(m，1H)，1.58(m，1H)，1.23(m，3H)。

A mixture of 4-trifluoromethyl-benzyl 3- [3- (ethoxycarbonylmethyl-amino) -4-methyl-phenyl ] -piperidine-1-carboxylate (40mg, 0.084mmol), potassium carbonate (23mg, 0.167mmol), methanol (5mL) and water (1mL) was heated under reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 40mg (99%) of 4-trifluoromethyl-benzyl 3- [3- (carboxymethyl-amino) -4-methyl-phenyl ] -piperidine-1-carboxylate as a white solid.

MS(LC-MS)451.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ7.67(d，2H)，7.54(brs，2H)，6.94(d，1H)，6.50(d，1H)，6.35(brs，1H)，5.21(s，2H)，4.15(brm，2H)，3.92(s，2H)，3.92(m，1H)，3.81(m，1H)，2.57(t，1H)，2.13(s，3H)，1.95(d，1H)，1.78(d，1HO，1.72(q，1H)，1.58(t，1H)。

Example 13-2

(2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenylamino) -acetic acid

Ethyl (2-methyl-5-piperidin-3-yl-phenylamino) -acetate (example 13-1; 63mg, 0.23mmol) was dissolved in 2mL of dichloromethane and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (87mg, 0.46mmol) and 4-methyl-2- [4- (trifluoromethyl) phenyl ] -1, 3-thiazole-5-carboxylic acid (65mg, 0.23mmol) were added. The reaction was stirred at room temperature under nitrogen atmosphere for 24 hours. The reaction was subjected to flash chromatography, eluting with 30% ethyl acetate/hexanes, to give 19mg (15%) of the desired product (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenylamino) -acetic acid ethyl ester as a clear oil.

MS(LC-MS)546.0(M+H)⁺。

¹H NMR(400MHz，CD₃OD)δ8.14(d，2H)，7.79(d，2H)，6.91(m，1H)，6.51(m，1H)，6.34(m，1H)，4.19(brm，2H)，3.97(brs，2H)，2.69(m，1H)，2.47(s，3H)，2.13(s，3H)，2.02(d，1H)，1.85(m，2H)，1.64(m，1H)，1.24(brm，3H)。

A mixture of (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenylamino) -acetic acid ethyl ester (19mg, 0.035mmol), potassium carbonate (10mg, 0.07mmol), methanol (5mL) and water (1mL) was heated under reflux for 3 hours, cooled to room temperature and then concentrated under reduced pressure. The resulting residue was taken up in water (50mL), acidified with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 20mg (99%) of (2-methyl-5- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbonyl ] -piperidin-3-yl } -phenylamino) -acetic acid as a white solid.

MS(LC-MS)518.0(M-H)^-。

¹H NMR(400MHz，CD₃OD)δ8.13(d，2H)，7.79(d，2H)，6.97(m，1H)，6.54(m，1H)，6.37(m，1H)，3.91(brs，2H)，2.71(t，1H)，2.69(m，1H)，2.47(s，3H)，2.12(s，3H)，2.03(d，1H)，1.87(m，2H)，1.65(m，1H)。

Claims

1. A compound of formula I

Or a pharmaceutically acceptable salt thereof;

wherein

x is a) -Z or b) -O-C (R)¹R²)-Z；

Z is a) -C (O) OH, b) -C (O) O- (C)₁-C₄) Alkyl, c) -C (O) -NH₂Or d) tetrazolyl;

R¹is a) H or b) methyl;

R²is a) H, b) methyl or c) -O-CH₂-a phenyl group;

w is a) a single bond, b) oxygen, C) -N (H) -, e) - (C₁-C₄) Alkyl-, f) - (C₁-C₄) alkyl-O-, d) -NH- (C₁-C₄) Alkyl-or g) CR⁷R⁸Wherein R is⁷And R⁸Bonded together to form a 3-membered fully saturated carbocyclic ring;

a is

a) Phenyl optionally substituted independently with 1 or 2 substituents selected from: 1) - (C)₁-C₆) Alkyl, 2) -CF₃、3)-OCF₃、4)-(C₁-C₆) Alkoxy, 5) (C₃-C₇) Cycloalkyl, 6) halogen or 7) hydroxy; or

b) Thiazolyl optionally independently substituted with: 1)1 or 2 methyl groups or 2) phenyl optionally independently substituted with 1 or 2 substituents selected from the group consisting of: a) - (C)₁-C₆) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₆) Alkoxy, e) (C)₃-C₇) Cycloalkyl, f) halogen, g) - (C₁-C₄) Alkylthio or h) hydroxy;

with the following conditions:

when W is a single bond, X is-O-C (R)¹R²) -Z, wherein R¹And R²Are each hydrogen, and Z is-C (O) OH or-C (O) O- (C)₁-C₄) Alkyl, then one of F or G must be a) - (C₁-C₄) Alkyl or b) (C)₁-C₄) An alkoxy group.

2. The compound of claim 1, wherein X is-O-C (R) ¹R²)-Z。

3. The compound of claim 2, which is a compound of formula I-A or formula I-C,

wherein R is¹And R²Independently of one another, a) hydrogen or b) methyl;

f and G are independently of each other a) hydrogen or b) methyl; and is

Z is-C (O) OH.

4. The compound of claim 3 wherein W is a) oxygen, b) -N (H) -, C) -N (H) - (C₁-C₄) Alkyl, d) - (C₁-C₄) Alkyl-or e) - (C₁-C₄) alkyl-O-; and a is phenyl optionally substituted with: a) - (C)₁-C₄) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₄) Alkoxy, e) cyclopropyl, f) halogen or g) hydroxy; or

W is a single bond; and a is thiazolyl optionally substituted with: a)1 or 2 methyl groups or b) phenyl optionally substituted with: 1) - (C)₁-C₄) Alkyl, 2) -CF₃、3)-OCF₃、4)-(C₁-C₄) Alkoxy, 5) cyclopropyl, 6) halogen or 7) - (C₁-C₄) An alkylthio group.

5. The compound of claim 1, wherein X is-Z.

6. The compound of claim 5, which is a compound of formula I-B or formula I-D,

Z is a) -C (O) OH, b) -C (O) O- (C)₁-C₄) Alkyl orc)-C(O)NH₂。

7. The compound of claim 6, wherein,

w is a) - (C₁-C₄) Alkyl-or b) - (C₁-C₄) alkyl-O-; and a is phenyl optionally substituted with: a) - (C)₁-C₄) Alkyl, b) -CF₃、c)-OCF₃、d)-(C₁-C₄) Alkoxy, e) cyclopropyl, f) halogen or g) hydroxy; or

W is a single bond; and A is a) thiazolyl optionally substituted with: 1)1 or 2 methyl groups or 2) phenyl optionally substituted with: i) - (C)₁-C₄) Alkyl, ii) -CF₃、iii)-OCF₃、iv)-(C₁-C₄) Alkoxy, v) cyclopropyl or vi) halogen; or b) phenyl optionally substituted with: 1) - (C)₁-C₄) Alkyl, 2) -CF₃、3)-OCF₃、4)-(C₁-C₄) Alkoxy, 5) cyclopropyl, 6) halogen, or 7) - (C₁-C₄) An alkylthio group.

8. The compound of claim 4 selected from:

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 3-trifluoromethyl-benzyl ester;

3- [3- (1-carboxy-1-methyl-ethoxy) -phenyl ] -piperidine-1-carboxylic acid 3-trifluoromethyl-benzyl ester;

(S) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester;

(R) -3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester; and

3- [3- (1-carboxy-1-methyl-ethoxy) -4-methyl-phenyl ] -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester.

9. The compound of claim 7 selected from:

(R) -3- (3-carboxy-4-methyl-phenyl) -piperidine-1-carboxylic acid 2- (4-trifluoromethyl-phenyl) -ethyl ester; and

10. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of: obesity, overweight, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, type I and/or type II diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complications, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, inflammation, osteoporosis, thrombosis, or congestive heart failure.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.