CA2547212A1 - Peroxisome proliferator activated receptor modulators - Google Patents

Peroxisome proliferator activated receptor modulators Download PDF

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CA2547212A1
CA2547212A1 CA002547212A CA2547212A CA2547212A1 CA 2547212 A1 CA2547212 A1 CA 2547212A1 CA 002547212 A CA002547212 A CA 002547212A CA 2547212 A CA2547212 A CA 2547212A CA 2547212 A1 CA2547212 A1 CA 2547212A1
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Prior art keywords
methyl
phenoxy
compound
hydrogen
propionic acid
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CA002547212A
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French (fr)
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Emily Jane Canada
Lynn Stacy Gossett
Nathan Bryan Mantelo
Qing Shi
Minmin Wang
Alan M. Warshawsky
Yanping Xu
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Eli Lilly and Co
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Eli Lilly And Company
Emily Jane Canada
Lynn Stacy Gossett
Nathan Bryan Mantelo
Qing Shi
Minmin Wang
Alan M. Warshawsky
Yanping Xu
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Application filed by Eli Lilly And Company, Emily Jane Canada, Lynn Stacy Gossett, Nathan Bryan Mantelo, Qing Shi, Minmin Wang, Alan M. Warshawsky, Yanping Xu filed Critical Eli Lilly And Company
Publication of CA2547212A1 publication Critical patent/CA2547212A1/en
Abandoned legal-status Critical Current

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Abstract

The present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt, solvate hydrate or stereoisomer thereof, which is useful in treating or preventing disorders mediated by a peroxisome proliferator activated receptor (PPAR) such as syndrome X, type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, arteriosclerosis, and other disorders related to syndrome X and cardiovascular diseases.

Description

PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR MODULATORS
FIELD OF THE INVENTION
The present invention relates to compounds of peroxisome proliferator activated receptor (PPAR) agonists, more specifically compounds of PPAR gamma-delta dual agonists, which are useful for the treatment and/or prevention of disorders modulated by a PPAR agonist.
BACKGROUND OF THE INVENTION
The peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor gene family that are activated by fatty acids and fatty acid metabolites. The PPARs belong to the subset of nuclear receptors that function as heterodimers with the 9-cis retinoic acid receptor (RXR). Three subtypes, which are designated as PPARoc, PPAR~y and PPARB are found in species ranging from ~enopus to humans.
PPARoe is the main subtype in the liver and has facilitated analysis of the mechanism by which peroxisome proliferators exert their pleiotropic effects.
PPARoc is activated by a number of medium and long-chain fatty acids, and it is involved in stimulating (3-oxidation of fatty acids. PPARoc is also involved with the activity of fibrates and fatty acids in rodents and humans. Fibric acid derivatives such as clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil, produce a substantial reduction in plasma triglycerides along with moderate reduction in low-density lipoprotein (LDL) cholesterol, and they are used particularly for the treatment of hypertriglyceridemia.
PPARyis the main subtype in adipose tissue and involved in activating the program of adipocyte differentiation. PPARy is not involved in stimulating peroxisome proliferation in the Liver. There are two isomers of PPARy:PPARyI and PPARy2, which differ only in that PPAR~(2, contains an additional 28 amino acids present at the amino terminus. The DNA sequences for the PPARy receptors are described in Elbrecht, et al., BBRC 224;431-437 (1996). Although peroxisome proliferators, including the fibrates and fatty acids, activate the transcriptional activity of PPAR's, only prostaglandin Jz derivatives have been identified as natural ligands for PPAR~y, which also binds the anti-diabetic agents thiazolidinediones with high affinity. The physiological functions of PPARa and PPAR~y in lipid and carbohydrate metabolism were uncovered once it was recognized that they were the receptors for the fibrate and glitazone drugs, respectively.
PPARa and PPARy receptors have been implicated in diabetes mellitus, cardiovascular disease, obesity, and gastrointestinal disease, such as inflammatory bowel disease and other inflammation related illnesses. Such inflammation related illnesses include, but are not limited to Alzheimer's disease, Crohn's disease, rheumatoid arthritis, psoriasis, and ischemia reprofusion injury.
By contrast, PPARB (also referred to as PPAR(3 and NUCl) is not reported to be receptor for any known class of drug molecules, and its role in mammalian physiology has remained undefined. The human nuclear receptor gene PPARB (hPPARB) has been cloned from a human osteosarcoma cell cDNA library and is fully described in A.
Schmidt et al., Molecular Ewdocrinolo~y, 6:1634-1641 (1992).
Diabetes is a disease in which a mammal's ability to regulate glucose levels in the blood is impaired because the mammal has a reduced ability to convert glucose to glycogen for storage in muscle and liver cells. In Type I diabetes, this reduced ability to store glucose is caused by reduced insulin production. "Type II
Diabetes" or "non-insulin dependent diabetes mellitus" (NIDDM) is the form of diabetes, which is due to a profound resistance to insulin stimulating or regulatory effect on glucose and lipid metabolism in the main insulin-sensitive tissues, muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. When these cells become desensitized to insulin, the body tries to compensate by producing abnormally high levels of insulin and hyperinsulemia results. Hyperinsulemia is associated with hypertension and elevated body weight. Since insulin is involved in promoting the cellular uptake of glucose, amino acids and triglycerides from the blood by insulin sensitive cells, insulin insensitivity can result in elevated levels of triglycerides and LDL (known as the "bad"
cholesterol) which are risk factors in cardiovascular diseases. The constellation of symptoms which includes hyperinsulemia combined with hypertension, elevated body weight, elevated triglycerides and elevated LDL is known as Syndrome X.
Hyperlipidemia is a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. These lipids S do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins. One form of hyperlipidemia is hypercholesterolemia, characterized by the existence of elevated LDL
cholesterol levels.
The initial treatment fox hypercholesterolemia is often a diet low in fat and cholesterol coupled with appropriate physical exercise. Drug intervention is initiated if LDL-lowering goals are not rnet by diet and exercise alone. It is desirable to lower elevated levels of LDL cholesterol and increase levels of HDL cholesterol. Generally, it has been found that increased levels of HDL are associated with lower risk for coronary heart disease (CHD). See Gordon, et al., Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N.
Englaiad J. Med., 325, 373- 3$1 (1991); and Kannel, et al., Ahn. Internal Med., 90, $5-9I
(1979). An example of an HDL raising agent is nicotinic acid, but the quantities needed to achieve HDL elevation are associated with undesirable effects, such as flushing.
There are several treatments currently available for treating diabetes mellitus but these treatments still remain unsatisfactory and have limitations. While physical exercise and reduction in dietary intake of calories will improve the diabetic condition, compliance with this approach can be poor because of sedentary lifestyles and excess food consumption, in particular high fat-containing food. Therefore, treatment with hypoglycemics, such as sulfonylureas (e.g., chlorpropamide, tolbutamide, tolazamide and acetohexamide) and biguanides (e.g. phenformin and metformin) are often necessary as the disease progresses. Sulfonylureas stimulate the (3 cells of the pancreas to secrete more insulin as the disease progresses. However, the response of the (3 cells eventually fails and treatment with insulin injections is necessary.
In addition, both sulfonyluxea treatment and insulin injection have the life threatening side effect of hypoglycemic coma, and thus patients using these treatments must carefully control dosage.
It has been well established that improved glycemic control in patients with diabetes (Type I and Type II) is accompanied by decreased microvasclular complications (DCCT and UKPDS). Due to difficulty in maintaining adequate glycemic control over time in patients with Type II diabetes, the use of insulin sensitizers in the therapy of Type II diabetes is growing. There is also a growing body of evidence that PPARy agonist, insulin sensitizer, may have benefits in the treatment of Type II diabetes beyond their effects in improving glycemic control.
In the last decade a class of compounds known as thiazolidinediones (TZD) (e.g. U.S. Pat. Nos. 5,089,514; 4,342,771; 4,367,234; 4,340,605; and 5,306,726) have emerged as effective antidiabetic agents that have been shown to increase the sensitivity of insulin sensitive tissues, such as skeletal muscle, liver and adipose, to insulin. Increasing insulin sensitivity rather than the amount of insulin in the blood reduces the likelihood of hypoglycemic coma. Although thiazolidinediones have been shown to increase insulin sensitivity by binding to PPAR~y receptors, this treatment also produces unwanted side effects such as weight gain and edema and, for troglitazone, liver toxicity. Recently, the compounds that are not TZDs have also been reported as PPAR
modulators.
Adams et al. (WO 97/28115, WO 97/28135 and US Patent No. 5,895,051) discloses acetylphenols, which are useful as antiobesity and antidiabetic compounds.
Leibowitz et al. (WO 97/28149) discloses compounds which are PPAR~
agonists and useful for treating cardiovascular diseases and related conditions.
Brooks et al. (WO 02/100813) discloses compounds of PPAR modulators that are useful for treating type II diabetes and other PPAR-mediated diseases and conditions.
In view of the above, an objective of the present invention is to provide new pharmaceutical agents which modulate PPAR receptors to prevent, treat and/or alleviate these diseases or conditions while reducing and or eliminating one or more of the unwanted side effects associated with the current treatments.
SUMMARY OF THE INVENTION
The present invention relates to a compound of novel peroxisome proliferator activated receptor (PPAR) agonist having a structural formula I, (R ) (R2)r _ -'~ I y Q
D X Da \ O
\ R3 R4 I
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
A
is: a) aryl, 5 b) a 5- to i0-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) C3-C8 cycloalkyl, d) aliphatic group, or e) heterocyclyl, wherein aryl, heteroaryl, cycloalkyl, heterocyclyl~and aliphatic group being optionally substituted with one or more groups independently selected from Rg;
Da and Db are each independently:
a bond or -[C(R°)(Rd)]", wherein R° and Rd are each independently hydrogen, C1-C6 alkyl or aryl;
Q is: -C(O)ORS or Rsa ;
~0 X is: NR6C[O]p, NR6S(O)2, C [O]p,NR6, S(O)2NR6 or NR7;
Y is: a bond, CHZ, S or O;
A~---De X --~ is:

~R8a) R8a 9 ~Rs)9 ~ D
a N-Da ~ or ~Rs)9 N
O
O
n and r are each independently: 1, 2, 3 or 4;
q is: 1, 2, 3, 4 or 5;
p is: 1 or 2;
Rl and R2 are each independently: hydrogen, C1-C6 alkyl, halo or haloalkyl;
R3 and R4 are each independently:
hydrogen, halo, Cl-C6 alkyl, Cl-C6 alkoxy or aryloxy;
R3 and R4 are together a 3- to 6- membered carbocyclyl or heterocyclyl;
RS is: hydrogen, Cl-C6 alkyl or aminoalkyl;
R5A 1S: carboxamide, sulfonamide, acylsulfonamide, tetrazole, O
i s ° °
° ° \ NH
° S NH oNH ~N~
\\, O N~ C O
__~_ O
O H
O N OH ~N~
° NH ~ NH
N
N~ ' H O
O O
R6 is each independently:
hydrogen, C1-C12 alkyl, arylalkyl, C3-C8 cycloalkyl, or (CH2)"C(O)aryl, wherein alkyl, arylalkyl and cycloalkyl group being optionally substituted with one or more groups independently selected from R8;
R7 is: hydrogen, acyl, or sulfonyl;
R8 and Rsa are each independently:
hydrogen, C~-C6 alkyl, C1-C6 alkoxy, nitro, cyano, halo, haloalkyl, haloalkyloxy, aryl, heteroaryl, benzyl, aryloxy, SR9, S [O]pR9 or C[O]PRg; and R9 is: hydrogen, C1-C6 alkyl, or C3-C$ cycloalkyl.
The compounds of the present invention are useful in the treatment and/or prevention of diseases or condition relates to hyperglycemia, dyslipidemia, Type II
diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component.
In one embodiment, the present invention also relates to a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable carrier.
Within the scope of this invention also include a pharmaceutical composition containing additional therapeutic agent as well as a compound of the present invention, or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable carrier.
In another embodiment, the present invention relates to a method of modulating a PPAR by contacting the receptor with a compound of the present invention, and a pharmaceutically acceptable salt, solvate or hydrate thereof.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are directed to peroxisome proliferator activated receptor (PPAR) agonists, more specifically compounds of PPARy/8 dual agonists, which are useful for the treatment and/or prevention of disorders modulated by a PPAR, such as Type II diabetes, hyperglycemia, dyslipidemia, Type I
diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other related diseases.
An embodiment of the present invention is a compound of novel peroxisome proliferator activated receptor (PPAR) agonists having a structural formula I, (Rl)r (R2)r D X D \
\ R3 R4 I
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
A
is: a) aryl, b) a 5- to 10-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) C3-C8 cycloalkyl, d) aliphatic group, or e) heterocyclyl, wherein aryl, heteroaryl, cycloalkyl, heterocyclyl and aliphatic group being optionally substituted with one or more groups independently selected from R8;
Da and Db are each independently:
a bond or -[C(RC)(Rd)]", wherein R° and Rd are each independently hydrogen, Cl-C6 alkyl or aryl;
Q is: -C(O)ORS or Rsa ;
X is: NR6C[O]p, NR6S(O)~, C[O]p,NR6, S(O)2NR6 or NR7;
5 Y is: a bond, CHZ, S or O;
~A -De X--~ is:
(R8a) R8a 9 (R8)9 r ~ D
\ ~ a N-Da ~ or (R8)y \ , N
O
O
n and r are each independently: 1, 2, 3 or 4;
q is: 1, 2, 3, 4 or 5;
10 p is: 1 or 2;
Rl and R2 are each independently: hydrogen, Cz-C6 alkyl, halo or haloalkyl;
R3 and R4 are each independently:
hydrogen, .
halo, C1-C6 alkyl, C1-C6 alkoxy or arylox y;
R3 and R4 are together a 3- to 6- membered carbocyclyl or heterocyclyl;
RS is: hydrogen, Ci-C6 alkyl or aminoalkyl;
RSA is: carboxamide, sulfonamide, acylsulfonamide, tetrazole, O
~ O
HN I ~ ' NH ~ ~NH ~N NH
S O ' O~N~N ~ O O
__~._ O
O H O
O N OH ~N~
NH ~ NH
N O
N~ ' H O
O O
R6 is each independently:
hydrogen, C1-Ci2 alkyl, arylalkyl, C3-C8 cycloalkyl, or (CH2)"C(O)aryl, wherein alkyl, arylalkyl and cycloalkyl group being optionally substituted with one or more groups independently selected from R8;
R7 is: hydrogen, acyl, or sulfonyl;
R8 and R8a are each independently:
hydrogen, CI-C6 alkyl, C~-C6 alkoxy, vitro, cyano, halo, haloalkyl, halaalkyloxy, aryl, heteroaryl, benzyl, aryloxy, SR9, S[~~pR9 Or C[O]pR9; and Rg is: hydrogen, Cl-C6 alkyl, or C3-Cg cycloalkyl.
The compound as recited above, wherein aryl or heteroaryl are selected from the group consisting of phenyl, naphthyl, indolyl, isaindolyl, benzaimidazolyl, quinolinyl, isoquinolinyl, pyridyl, benzothiophenyl and benzofuranyl.
A preferred embodiment of the present inventian is a compound having a structural formula II, (R8)q (R~),. ~R2)r Db X --Da _ , ~ _ \ D \ R3 R4 II
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
qis 1,2,3,4,or5.
The compound as recited above in formula TI, wherein R8 is disubtituted in 2 and 4 positions, ar trisubstituted in 2, 4, and 6 positions of phenyl ring relative to -Db-.

Another preferred embodiment of the present invention is a compound having a structural formula III, (R )i (R )a R Y
\ R6 R~ / ~ / ~ OH
N \ O \ R3 R4 O Ra III
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y is: O or CH2;
RI is: hydrogen, halo or C1-C4 alkyl;
R2, R3 and R4, R6, R° and Rd are each independently: hydrogen or C1-Cø
alkyl;
(R$)1 and (R8)2 are each independently:
hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitro, C1-C6 alkyl, C~-C6 alkoxy or SR9;
R6 is: hydrogen or Cl-C4 alkyl; and R9 is: hydrogen or C~-C4 alkyl or Cs-C6 cycloalkyl.
Yet another preferred embodiment of the present invention is the compound having a structural formula IV, R' R2 HC O
(RS)i (R8)2 3 \ R6 R~ / / O OH
I
/ N \ ~ \ ~ CHs v O Ra IV
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R' and R2 are each independently: hydrogen, halo or C1-C4 alkyl;
R~, Ra and R6 are each independently: hydrogen or methyl; and (R8)1 and (R8)2 are each independently:
hydrogen, F, Cl, Br, OMe, CFs, OCFs, SCHs, NO~, cyano, methyl, ethyl, isobutyl, isopropyl or tert-butyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula V, (R8)1 (R8)Z O
\ H / ( / ~ ~OH
/ N \ O \ CHs O
V
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Rl and R2 are each independently: hydrogen, methyl, ethyl or fluoro; and (R8)1 and (Rg)2 are each independently:
hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, N02, cyano, methyl, ethyl, isobutyl, isopropyl or tart-butyl.
Yet more preferred embodiment of the present invention is the compound having a structural formula VI, F
OH
N \
O
O
VI
or a pharmaceutically acceptable salt or stereoisomer thereof.
Yet another preferred embodiment of the present invention is the compound having a structural formula VII, R~ Ra s R \ R6 ~ ~ O OH
/ N \ ~ \ ~ CH3 O
O
VII
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R1 and R2 are each independently: hydrogen, halo or C1-C4 alkyl;
R6 is: hydrogen or Cl-C~ alkyl;
R8 is: hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy or SR9; and 5 R9 is: hydrogen or Cl-C4 alkyl or C3-C6 cycloalkyl.
The compound as recited above in formula VII, wherein Rl, R2 and R6 are each independently hydrogen or methyl; and R8 is hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, N02, methyl, ethyl, isobutyl, isopropyl or tef°t-butyl.
Yet another preferred embodiment of the present invention is the 10 compound having a structural formula VIII, (Rs)q - R8 (R~)r (R2)r _.
\ ~ . ~~ Q
E -~~-~- \ ~ . \ ~ Rs Ra O
VIII
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
q is 1, 2, 3 or 4; and 15 E is S, O or NRl° wherein Rl° is hydrogen or Cl-C4 alkyl.
Yet another preferred embodiment of the present invention is the compound having a structural formula Ice, (R8)i RZ O
-- R8 R' Y
(R8)2 R6 ~ ~ ~ ~ OH
N \ O \ R R
E
O Ra IX
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y is: O or CH2;
E is: S, O, NH or NCH3, NCH~CH3;
Rl is: hydrogen, Cl-C4 alkyl, halo or haloalkyl;

R2, R3 and R4, R6, R° and Rd are each independently: hydrogen or C1-C4 alkyl;
(Rs)1 and (R8)2 are each independently: hydrogen, halo, haloalkyl, haloalkyloxy, cyano, vitro, Cl-C6 alkyl or Cl-C6 alkoxy; and R$ is: hydrogen or C1-C4 alkyl.
Yet another preferred embodiment of the present invention is the compound having a structural formula X, (Rg) i s R ~ ~ OH
N \ I \ I

Rio 0 X
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Rl and R2 are each independently: hydrogen, halo or C1-C4 alkyl;
(R8)I is: hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, NO2, cyano, vitro, methyl, ethyl, isobutyl, isopropyl or tart-butyl;
R8 is: hydrogen, methyl, ethyl or propyl; and R'° is: hydrogen, methyl or ethyl.
Yet another preferred embodiment of the present invention is the compound having a structural formula XI, (R8) i Rl RZ H3C O
s R ~ ~ ~ OH
N I N \ I \ I CHs O
Rio 0 XI
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R' and RZ are each independently: hydrogen, halo or Cl-C4 alkyl;

(R8)1 is: hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, N02, cyano, nitro, methyl, ethyl, isobutyl, isopropyl or tent-butyl;
R8 is: hydrogen, methyl, ethyl or propyl; and Rl° is: hydrogen, methyl or ethyl.
Yet more preferred embodiment of the present invention is the compound having a structural formula XII, OH
H
N N
I

XII
or a pharmaceutically acceptable salt.
Yet another preferred embodiment of the present invention is the compound having a structural formula XIII, (R8y Rl R2 O

R6 R~ / / Y OH
S ~ N ~ ~ ~ ~ Rs Ra O
O Ra XIII
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y is: O or CH2;
Rl is: hydrogen, C~-C4 alkyl, halo or haloalkyl;
R2, R3, R4, R6, R° and Rd are each independently: hydrogen or C1-C4 alkyl;
R8 are each independently: hydrogen or Cl-C4 alkyl; and (Rg)1 is: hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitroCl-C6 alkyl or C~-C6 alkoxy.

The compound as recited above in formula XIII, wherein Y is O or CH2;
RI is hydrogen, methyl, F, Br or Cl; R' is hydrogen, methyl or ethyl; R3, R~, R6, R$, R°
and Rd are each independently hydrogen or methyl; and (R8)1 is hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, N02, cyano, vitro, methyl, ethyl, isobutyl, isopropyl or tert-butyl.
Yet another preferred embodiment of the present invention is the compound having a structural formula XIV, Cl I N ~ I ~ I
s O
O
XIV
or a pharmaceutically acceptable salt.
Yet more preferred embodiment of the present invention is the compound having a structural formula XV, OH
H
N O

Xv or a pharmaceutically acceptable salt.

Yet another preferred embodiment of the present invention is the compound having a structural formula XVI, R~
~Rs)g R~ R6 / / Y OH
I
I ~N ~ ~ ~ ~ Rs R4 (C)n o Rd O
XVI
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein nisl,2,3,or4.
The compound as recited above in formula XVI, wherein Y is O or CH2;
R~, RZ, R3, Rø R° and Rd are each independently hydrogen or C~-C4 alkyl; n is 1 or 2; R6 is hydrogen, C1-C6 alkyl or arylaikyl; and Rg is hydrogen, Cl-C6 alkoxy, halo or haloalkyl.
Yet another preferred embodiment of the present invention is the compound having a structural formula XVII, (R8a)s O (Rl)r (R2)r (Rg)9 \ O wr Y R4 O
~.

XVII
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R8a is hydrogen, Cl-C4 alkyl or aryl; and s is 1, 2, 3, 4, 5 or 6.

Yet another preferred embodiment of the present invention is the compound having a structural formula XVIII, RSa ~R ) N R

O ~ ~ O CH3 O

XVIII
5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
RZ is: hydrogen or Cl-C4 alkyl, R8 is: hydrogen, Cl-C6 alkyl, C1-C6 alkoxy, halo, haloalkyl or haloalkyloxy;
R8a is: hydrogen, methyl, or phenyl; and q is: 1 or 2.
10 Yet another preferred embodiment of the present invention is the compound having a structural formula XIX, ~R8~9 ~R~ )r (RZ~r \ R7 Y Q
R° ~ R°
. / N \ ~ \ ~ Rs Ra O
Ra Ra XIX
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
15 The compound as recited above in formula XIX, wherein Q is COOH; R7 is hydrogen, mathanesulfonyl or acetyl; and R° and Ra are each hydrogen.

Yet more preferred embodiment of the present invention is the compound selected from the group consisting of:
No Structure Name 1 F F F CH3 H c o 2-(4-{ 3-[(2-Chloro-4-c~ / / 03 off trifluoromethyl benzoylamino) cH3 methyl]-5-fluoro o phenoxy } -2-methyl phenoxy)-2-methyl ro ionic acid 2 ci F cH3 0 3-[4-(3-{ [(5-Chloro--- 1 H-indole-2-/ ~ H ~ I ~ I v \oH carbonyl)-amino]-methyl }-5-fluoro-o phenoxy)-2-methyl-phenyl]-propi onic acid 3 F F F CH3 0 ~,-(4-{3-Fluoro-5-[1-cH3 ~ ~ °3C off (2-methyl-4-trifluoromethyl-cH3 benzoylamino)-o cH3 ethyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid (isomer 1) 4 ci cH3 CH3 H c O ~-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2,-carbonyl)-amino]-o methyl } -5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-ro ionic acid ~~ Chiral F CH3 O ( R )-3-[4-(3-{ 1-[(5-_. cH3 Chloro-1,3-dimethyl-oN 1H-indole-2-carbonyl)-amino]_ o ethyl } -5-fluoro-cH3 o cH3 phenoxy)-2-methyl-phenyl]-propionic acid No Structure Name 6 F F CHa o 3-(2-Ethyl-4-{ 3-F fluoro-5-[(2-methyl-cH3 , / off 4-trifluoromethyl-F
benzoylamino)-o methyl]-phenoxy }-o phenyl)-propionic acid '7 F F CH3 cH3 H o 0 2-(4-{3-[(2-Fluoro-4-F / I / I o3 off trifluoromethyl-F benzoylamino)-H
/ N ~ o \ CHa methyl]-5-methyl-phenoxy } -2-methyl-o phenoxy)-2-methyl-ro ionic acid 8 ci cH3 cH3 0 ( R )-2-[4-(3-{ [(5_ cH3 / / 03~ off Chloro-1,3-dimethyl-1 H-indole-2-oH3 carbonyl)-amino]-I I methyl }-5-rnethyl-cH3 ~ phenoxy)-2-methyl-phenoxy]-2-methyl-ro ionic acid 9 F 3-[4-(3-Fluoro-5-_ F cH3 0 ( [(5-duoro-3-methyl-eH3 ~ ~ OH 1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-o methyl-phenyl]-propionic acid F 2-[4-(3-Fluoro-5-_ F cH3 H o o { [(5-fluoro-1,3-cH3 / / 03 off dimethyl-lI3-indole 2-carbonyl-amino]
N N ~ o ~ CH3 methyl }-phenoxy)-2 H3C o methyl-phenoxy]-2-methyl-propionic acid No Structure Name I I ~ ( R ) -3-[4-(3-{ I-[(5-chirai Fluoro-I,3-dimethyl-CH3 CH3 CH IH-indole-2-p carbonyl)-amino]-i ethyl } -5-methyl-H3p \ ~ \ ~ pH phenoxy)-2-methyi-O H ~ ~ phenyl]-propionic acid 12 F F CH3 p 2-Methyl-2-(2-eH3 .~ / o3c off methyl-4-{3-[(2,-H methyl-4-t~ '~ I o ~. I pH3 trifluoromethyl-o benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid I3 F ~ ~ F eH3 H c o ~-(4-{ 3-Fluoro-5-[(2-CH3 / / 03 off methyl-4-trifluoromethyl-/ N ~ o ~ pH3 benzoylamino)-o methyl]-phenoxy }-2-methyl-phenoxy)-2-methyl-propionic acid 14 chirai ( R ) -3-[4-(3-Fluoro-F CH3 o S-{ 1-[(S-fluoro-1,3-cH3 / , off dimethyl-1H-indole-H ~ ( 2-carbonyl)-amino]-H ~ o ~ ethyl's-phenoxy)-2-CH O CH methyl-phenyl]-3 3 propionic acid 1S Ci 3-[4-(3-{[(5-Chloro-F CH3 0 1,3-dimethyl-1H-f CH3 ~ ~ off »dol e-2-carbonyl)-H ~ f amino]-methyl}-5 N H ~' p ~ fluoro-phenoxy)-~
H3~ o methyl-phenyl]
ro ionic acid No Structure Name 16 cl 3-[4-(3-{ [(5-Chloro-_ cH3 0 1,3-dimethyl-1H-/ / off indole-2-carbonyl)-amino]-methyl } -N ~ ~ o ~ phenoxy)-2-methyl-H3C o phenyl]-propionic acid 1~ F F CH3 C 3-[2-Ethyl-4-(3-fluoro-5-{ [(5-fluoro-/ cH3 / ~ off 1~3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl } -H3C o phenoxy)-phenyl]-propionic acid 18 F ' C 3-(4-{3-[(2-Chloro-4-trifluoromethyl-CI ~ ~ ~ I off benzoylamino)-methyl]-5-methyl phenoxy}-2.-ethyl 0 phenyl)-propionic acid Also encompassed by the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof.
Also encompassed by the present invention is a pharmaceutical composition comprising: (1) a of compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof;
(2) a second therapeutic agent selected from the group consisting of insulin sensitizers, sulfonylureas~
biguanides, meglitinides, thiazolidinediones, o~.-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, statins, acryl CoA:cholestrol acyltransferase inhibitors, antiobesity compounds antihypercholesterolemic agents, fibrates, vitamins and aspirin;
and (3) optionally a pharmaceutically acceptable carrier.
Also encompassed by the present invention is a method of modulating a peroxisome proliferator activated receptor (PPAR) comprising the step of contacting the receptor with a compound of the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof.
The method recited above, wherein the PPAR is an alpha (oc)-receptor.
The method recited above, wherein the PPAR is a gamma (y)-receptor.
5 The method recited above, wherein the PPAR is a delta (8)-receptor.
The method recited above, wherein the PPAR is a gammaldelta (y/8)-receptor.
The method recited above, wherein the PPAR is an alpha, gamma and delta (ody/b)-receptor.
10 Also encompassed by the present invention is a method for treating and/or preventing a PPAR-y mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of the present invention.
Also encompassed by the present invention is a method for treating and/or preventing a PPAR-8 mediated disease or condition in a mammal comprising the step of 15 administering an effective amount of a compound of the present invention.
Also encompassed by the present invention is a method for treating and/or preventing a PPAR-y/8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of the present invention.
Also encompassed by the present invention is a method for treating and/or 20 preventing a PPAR-ody/8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of the present invention.
Also encompassed by the present invention is a method for lowering blood-glucose in a mammal comprising the step of administering an effective amount of a compound of the present invention.
25 Also encompassed by the present invention is a method of treating and/or preventing disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound. of a compound of the present invention.
Also encompassed by the present invention is a method of treating andlr preventing diabetes mellitus in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of the present invention.
Also encompassed by the present invention is a method of treating and/or preventing cardiovascular disease in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisorner thereof.
Also encompassed by the present invention is a method of treating and/or preventing syndrome X in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
Also encompassed by the present invention is a method of treating and/or preventing disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of the present invention, and an effective amount of second therapeutic agent selected from the group consisting of insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, a-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, ~.5 statins, acryl CoA:cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin.
Also encompassed by the present invention is use of a compound of the present invention and a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, fox the manufacture of a medicament for the treatment of a condition modulated by a PPAR.

The terms used to describe the present invention have the following s meanings unless otherwise indicated.
An "aliphatic group" is non-aromatic consisting solely of carbon and hydrogen and may optionally contain one or mere units of unsaturation, e.g., double-bonds ("alkenyl") and/or triple-bonds ("alkynyl"). An aliphatic group may be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between about 1 and about 12 carbon atoms, more typically between about 1 and about 6 carbon atoms. When cyclic, an aliphatic group typically contains between about 3 and about 10 carbon atoms, more typically between about 3 and about 7 carbon atoms. Aliphatic groups are preferably Cl-C12 straight chained and/or branched alkyl groups (i.e., completely saturated aliphatic groups), more preferably C1-C6 straight chained andlor branched alkyl groups. Examples include, but are not limited to, methyl, ethyl, n-propyl, is~-propyl, n-butyl, sec-butyl, tart-butyl and the like.
The term "alkyl," unless otherwise indicated, refers tv those alkyl groups of a designated number of carbon atoms of either a straight or branched saturated configuration, including substituted alkyl. The term "alkyl" used herein also includes "alkylene group" of either straight or branched saturated configuration, including substituted alkylene. Examples of "alkyl" include, but are not limited to:
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl arid tent-butyl, pentyl, hexyl, isopentyl and the tike. Examples of "alkylene group" is -[C(R°)(Rd)]"- where n is a positive integer, and R° and Rd are independently hydrogen or C1-C6 alkyl. Preferably, n is an integer from about 1 to about 6, and more preferably from about 1 to about 4. A "branched (or substituted) alkylene group" is an alkylene group in which one or more methylene hydrogen atoms are replaced with a substituent, such as methyl, ethyl or the like. Alkyl as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
The term "alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isoprvpenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

The term "alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof.
Examples of alkynyl include ethynyl propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
The term "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and the like. Alkoxy as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above. ' The term "cycloalkyl" refers to a saturated or partially saturated carbocycle containing one or more rings of from 3 to 12 carbon atoms, more typically 3 to 6 carbon atoms. Examples of cycloalkyl includes, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like. Cycloalkyl as defined above may also includes a tricycle, such as adamantyl. Cycloalkyl as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
The term "halo" refers to fluoro, chloro, bromo and iodo.
The term "haloalkyl" is a C1-C~ alkyl group, which is substituted with one or more halo atoms selected from F, Br, Cl and I. Examples of haloalkyl group are trifluoromethyl, CH2CF3 and the like.
The term "haloalkyloxy" represents a C~-C6 haloalkyl group attached through an oxygen bridge, such as OCF3. The "haloalkyloxy" as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
The term "aryl" includes carbocyclic aromatic ring systems (e.g. phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl and anthracenyl) and aromatic ring systems fused to carbocyclic non-aromatic ring systems (e.g., 1,2,3,4-tetrahydronaphthyl). The "aryl" as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
The term "aryloxy" represents an aryl group attached through an oxygen bridge, such as phenoxy (-O-phenyl). The "aryloxy" as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
The term "heteroaryl" group, as used herein, is an aromatic ring system having at least one heteroatom such as nitrogen, sulfur or oxygen and includes monocyclic, bicyclic or tricyclic aromatic ring of S- to 14-carbon atoms containing one ar more heteroatoms selected from O, N, or S. The heteroaryl as defined above alsa includes heteroaryl fused with another heteroaryl, aryl fused with heteroaryl or aryl fused with heterocyclyl as defined herein. The "heteroaryl" may also be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
Examples of heteroaryl are, but are not limited to: furanyl, thienyl (also referred to as "thiophenyl"), thiazolyl, imidazolyl, indolyl, isoindolyl, isooxazolyl, oxazoyl, pyrazolyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, pyrimidinyl and purinyl, cinnolinyl, benzofuranyl, benzoimidazolyl, benzothienyl (or benzothiophenyl), benzotriazolyl, benzoxazolyl, quinolinyl, isoxazolyl, isoquinolinyl 1,4 benzodioxan, or 2,3-dihydrobenzofuranyl and the like.
The term "heterocyclyl" refers to a non-aromatic ring which contains one or more heteroatoms selected from O, N or S, which includes a monocyclic, bicyclic or tricyclic ring of 5- to 14-carbon atoms containing one or more heteroatoms selected from O, N or S. The "heterocyclyl" as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
Examples of heterocyclyl include, but are not limited to, morpholine, piperidine, piperazine, pyrrolidine, and thiomorpholine.
The term "carbocyclyl" (also referred as "nonaromatic carbocyclic ring") refers to a saturated or partially saturated nonaromatic carbocyclic ring.
Examples of carbocyclyl are, but are not limited to, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.
An "arylalkyl" as used herein is an aryl substituent that is linked to a compound by an alkyl group having from one to six carbon atoms (e.g., CI-C6 alkyl-aryl).
The "arylalkyl" as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The "acyl" represent an "alkyl-C(=O)- " group. Preferred acyl group are those in which the alkyl group is lower alkyl, such Cl-C6 alkyl. Example of "acyl" is acetyl.
A "sulfonyl" is represent an "alkyl-S(O)2 " group Preferred sulfonyl 5 group are those in which the alkyl group is lower alkyl, such Ci-C6 alkyl.
Example of "sulfonyl" is mathanesulfonyl, ethansulfonyl and the like.
The "aminoalkyl" as used herein contains both a basic amino group (NH2) and an alkyl group as defined above.
The term R5A (or acid bioisosteres) as used herein includes, but are not 10 limited to, carboxamide, sulfonamide, acylsulfonamide, tetrazole or the following moiety.
O
O O O
v ' NH
HN N S O~ '' ~ N \\
O~N~. ~ O O
__~_ O
O H O
O N OH ',~N~
NH
N_~~ , N O
H , I O
O O
Carboxamide, sulfonamide, acylsulfonamide and tetrazole may be optionally substituted with one or more suitable substituents selected from haloalkyl, aryl, heteroaryl, and Cl-C~
alkyl. The heteroalkyl, aryl, heteroaryl and alkyl may further optionally substituted with 15 one or more substituents selected from the list provided for R8. The examples of RSA are, but not limited to, hydroxamic acid, acyl cyanamide, tetrazoles, sulfinylazole, sulfonylazole, 3-hydroxyisoxazole, hydroxythiadiazole, sulphonate and acylsulfonamide.
The term "active ingredient" means the compounds generically described by Formula I as well as the salts, solvates and prodrugs of such compounds.
20 The term "pharmaceutically acceptable" means that the carrier, diluents, excipients and salt must be compatible with the other ingredients of the composition, and not deleterious to the recipient thereof. Pharmaceutical compositions of the present invention are prepared by procedures known in the art using well-known and readily available ingredients.

"Preventing" refers to reducing the likelihood that the recipient will incur or develop any of the pathological conditions described herein.
"Treating" refers to mediating a disease and/or condition, and preventing and/or mitigating its further progression or ameliorating the symptoms associated with the disease or condition.
"Pharmaceutically-effective amount" means that amount of a compound of the present invention, or of its salt, solvate, hydrate or prodrug thereof that will elicit the biological or medical response of a tissue, system or mammal. Such an amount can be administered prophylactically to a patient thought to be susceptible to development of a disease or condition. Such amount when administered prophylactically to a patient can also be effective to prevent or lessen the severity of the mediated condition.
Such an amount is intended to include an amount, which is sufficient to modulate a PPAR
receptor such as a PPARa, PPARy, PPARB or PPARy/8 receptor to mediate a disease or condition. Conditions mediated by PPAR receptors include, for example, diabetes mellitus, cardiovascular disease, Syndrome X, obesity and gastrointestinal disease.
Additional conditions associated with the modulation of a PPAR xeceptor include inflammation related conditions, which include, for example, IBD (inflammatory bowel disease), rheumatoid arthritis, psoriasis, Alzheimer's disease, Chrohn's disease and ischemia reprofusion injury (stroke and miocardial infarction).
A "mammal" is an individual animal that is a member of the taxonomic class Mammalia. The class Mammalia includes humans, monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice, rats and the like.
Administration to a human is most preferred. A human to whom the compounds and compositions of the present invention are administered has a disease or condition in which control blood glucose levels are not adequately controlled without medical intervention, but wherein there is endogenous insulin present in the human's blood. Non-insulin dependent diabetes mellitus (N~DM) is a chronic disease or condition characterized by the presence of insulin in the blood, even at levels above normal, but resistance or lack of sensitivity to insulin action at the tissues.
Those skilled in the art will recognize that sterocenters exist in compound of the present invention. Accordingly, the present invention includes all possible stereoisomers and geometric isomers of the presently claimed compounds including racemic compounds and the optically active isomers.
The compounds of the present invention contain one or more chiral centers and exist in different optically active forms. When compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example by formation of diastereoisomeric salts which may be separated by crystallization; formation of IO diastereoisomeric derivatives or complexes which may be separated by crystallization and gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent such as enzymatic esterification; and gas-liquid or liquid chromatography in a chiral environment such as on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent. See also Steroclzemzstry of Carbon Compounds by E.L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
When a compound of the present invention has more than one chiral substituents, it may exist in diastereoisomeric forms. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of compounds of formula I and mixtures thereof.
Certain compounds of the present invention may exist in different stable conformational forms, which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of compounds of formula I and mixtures thereof.
Certain compound of the present invention may exist in zwitterionic form, and the present invention includes each zwitterionic form of compounds of formula I and mixtures thereof.
Certain compounds of the present invention and their salts may exist in more than one crystal form. Polymorphs of compounds of formula I form part of the present invention and may be prepared by crystallization of a compound of formula I
under different conditions, such as using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and various modes of cooling ranging from very fast to very slow cooling during crystallization.
Polymorphs may also be obtained by heating or melting a compound of formula I followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR
spectroscopy, IR spectroscopy, differential scanning calcirimetry, powder X-ray diffraction or other available techniques.
Certain compounds of the present invention and their salts may exist in more than one crystal form, which includes each crystal form and mixtures thereof.
Certain compounds of the present invention and their salts may also exist in the form of solvates, for example hydrates, and thus the present invention includes each solvate and mixtures thereof.
"Pharmaceutically-acceptable salt" refers to salts of the compounds of formula I, which are substantially non-toxic to mammals. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral, organic acid: an organic base or inorganic base.
Such salts are known as base addition salts, respectively. It should be recognized that the particular counterion forming a part of any salt of the present invention is not of a critical nature so long as the salt as a whole is pharmaceutically acceptable and the counterion does not contribute undesired qualities to the salt as a whole.
By virtue of its acidic moiety, a compound of the present invention forms salts with pharmaceutically acceptable bases. Some examples of base addition salts include metal salts such as aluminum; alkali metal salts such as lithium, sodium or potassium; and alkaline earth metal salts such as calcium, magnesium, ammonium, or substituted ammonium salts. Examples of substituted ammonium salts include, for instance, those with lower alkylamines such as trimethylamine and triethylamine;
hydroxyalkylamines such as 2.-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine; cycloalkylamines such as bicyclohexylamine or dibenzylpiperidine, N-benzyl-(3-phenethylamine, dehydroabietylamine, N,N'-bisdehydro-abietylamine, glucamine, N-piperazine methylglucamine; bases of the pyridine type such as pyridine, collidine, quinine or quinoline; and salts of basic amino acids such as lysine and arginine.
Examples of inorganic bases include, without limitation, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
Compounds of the present invention, which are substituted with a basic group, may exist as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, 1S sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g.
(+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.
The compounds of the present invention (or salt or prodrug, etc.) may also form a solvate with water (e.g., hydrate) or an organic solvent, and the present invention encompasses any solvate, hydrate or any mixtures thereof.
The compounds of present invention, which bind to and activate the PPARs, lower one or more of glucose, insulin, triglycerides, fatty acids andlor cholesterol, and are therefore useful for the treatment andlor prevention of hyperglycemia, dyslipidemia and in particular Type II diabetes as well as other diseases including syndrome X, Type I diabetes, hypertriglyceridemia, insulin resistance, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, heart failure, coagauIopathy, hypertension, and cardiovascular diseases, especially arteriosclerosis. In addition, these compounds are indicated to be useful for the regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia and anorexia nervosa.

The compounds and compositions of the present invention are also useful s to treat acute or transient disorders in insulin sensitivity, which sometimes occurs following a surgery, trauma, myocardial infarction and the like. The compounds and compositions of the present invention are also useful for lowering serum triglyceride 5 levels. Elevated triglyceride level, whether caused by genetic predisposition or by a high fat diet, is a risk factor for the development of heart disease, stroke, and circulatory system disorders and diseases. The physician of ordinary skill will know how to identify humans who can benefit from administration of the compounds and compositions of the present invention.
10 The present invention further provides a method for the treatment and/or prophylaxis of hyperglycemia in a human or.non-human mammal which comprises administering an effective, non-toxic amount of a compound of formula I, or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycemic human or non-human mammal in need 15 thereof.
The compounds of the present invention are useful as therapeutic substances in preventing or treating Syndrome X, diabetes mellitus and related endocrine and cardiovascular disorders and diseases in human or non-human animals.
The present invention also relates to the use of a compound of formula I as 20 described above for the manufacture of a medicament for treating a PPARy or PPAR~
mediated condition, separately or in combination.
A therapeutically effective amount of a compound of the present invention can be used for the preparation of a medicament useful for treating Syndrome X, diabetes, treating obesity, lowering tryglyceride levels, raising the plasma level of high density 25 lipoprotein, and for treating, preventing or reducing the risk of developing arteriosclerosis, and for preventing or reducing the risk of having a first or subsequent atherosclerotic disease event in mammals, particularly in humans. In general, a therapeutically effective amount of a compound of formula I of the present invention typically reduces serum glucose levels, more specifically HbAlc, of a patient by about 30 0.7% or more; typically reduces serum triglyceride levels of a patient by about 20% or more; and increases serum HDL levels in a patient. Preferably, HDL levels can be increased by about 30% or more.
Additionally, an effective amount of a compound of the present invention and a therapeutically effective amount of one or more active agents selected from antihyperlipidemic agent, plasma HDL-raising agents, antihypercholesterolemic agents, fibrates, vitamins, aspirin, insulin secretogogues, insulin and the like can be used together for the preparation of a medicament useful for the above described treatments.
Advantageously, compositions containing the compound of the present invention or their salts may be provided in dosage unit form, preferably each dosage unit containing from about 1 to about 500 mg. It is understood that the amount of the compounds or compounds of the present invention that will be administered is determined by a physician considering of all the relevant circumstances.
Syndrome X includes pre-diabetic insulin resistance syndrome and the resulting complications thereof, insulin resistance, non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity, coagulopathy, hypertension and other complications associated with diabetes. The methods and treatments mentioned herein include the above and encompass the treatment and/or prophylaxis of any one of or any combination of the following: pre-diabetic insulin resistance syndrome, the resulting complications thereof, insulin resistance, Type II or non-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity and the complications associated with diabetes including cardiovascular disease, especially arteriosclerosis.
The compositions are formulated and administered in the same general manner as detailed herein. The compounds of the present invention may be used effectively alone or in combination with one or more additional active agents depending on the desired target therapy. Combination therapy includes administration of a single pharmaceutical dosage composition, which contains a compound of the present invention and one or more additional active agents, as well as administration of a compound of the present invention and each active agent in its own separate pharmaceutical dosage. For example, a compound of the present invention or thereof and an insulin secretogogue such as biguanides, meglitinides, thiazolidinediones, sulfonylureas, insulin or oc-glucosidose inhibitors can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosages. Where separate dosages are used, a compound of the present invention and one or more additional active agents can be administered at essentially the same time, i.e,, concurrently or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
An example of combination treatment or prevention of arteriosclerosis may involve administration of a compound of the present invention or salts thereof in combination with one or more of second active therapeutic agents:
antihyperlipidemic agents; plasma HDL-raising agents; antihypercholesterolemic agents, fibrates, vitamins, aspirin and the like. As noted above, the compounds of the present invention can be administered in combination with more than one additional active agent.
Another example of combination therapy can be seen in treating diabetes and related disorders wherein the compounds of the present invention or salts thereof can be effectively used in combination with second active therapeutic, such as sulfonylureas, biguanides, meglitinides, thiazolidinediones, oc-glucosidase inhibitors, other insulin secretogogues, insulin as well as the active agents discussed above for treating arteriosclerosis.
The examples of second therapeutic agents are insulin sensitizers, PPARy agonists, glitazones, troglitazone, pioglitazone, englitazone, MCC-555, 13RL 49653, biguanides, metformin, phenformin, insulin, insulin minetics, sufonylureas, tolbutamide, glipizide, alpha-glucosidase inhibitors, acarbose, cholesterol lowering agent, HMG-CoA reductase inhibitors, lovastatin, simvastatin, pravastatin, fluvastatin, atrovastatin, rivastatin, other statins, sequestrates, cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran, nicotinyl alcohol, nicotinic acid:
a nicotinic acid salt, PPARoc agonists, fenofibric acid derivatives, gemfibrozil, clofibrate, fenofibrate, benzafibrate, inhibitors of cholesterol absorption, beta-sitosterol, acryl CoA:cholesterol acyltransferase inhibitors, melinamide, probucol, PPARB
agonists, antiobesity compounds, fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide YS inhibitors, (33 adrenergic receptor agonists, and ileal bile acid transporter inhibitors.

The compounds of the present invention and their pharmaceutically acceptable salt, solvate or hydrate thereof have valuable pharmacological properties and can be used in pharmaceutical compositions containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with one or more pharmaceutically acceptable excipients.
Excipients are inert substances such as, without limitation carriers, diluents, fillers, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, wetting agents, binders, disintegrating agents, encapsulating material and other conventional adjuvants.
Proper excipient is dependent upon the route of administration chosen.
Pharmaceutical compositions typically contain from about 1 to about 99 weight percent of the active ingredient, which is a compound of the present invention.
Preferably, the pharmaceutical formulation is in unit dosage form. A "unit dosage form" is a physically discrete unit containing a unit dose suitable for administration in human subjects or other mammals. For example, a unit dosage form can be a capsule or tablet, or a number of capsules or tablets. A "unit dose"
is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more pharmaceutically acceptable excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
The dosage regimen utilizing the compounds of the present invention is selected by one of ordinary skill in the medical or veterinary arts considering various factors, such as without limitation, the species, age, weight, sex, medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed, and the like.
Preferably, the compounds of the present invention are administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or more times per day. Where delivery is via transdermal forms, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of the i present invention include, for example, oral, eye drop, rectal, transmucosal, topical or intestinal administration; parenteral delivery (bolus or infusion), including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraven-tricular, intravenous, intraperitoneal, intranasal, or intraocular injections. The compounds of the present invention can also be administered in a targeted drug delivery system, such as in a liposome coated with endothelial cell-specific antibody.
For oral administration, the compounds of the present invention can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present invention to be Formulated as tablets, pills, powders, sachets, granules, dragees, capsules, liquids, elixirs, tinctures, gels, emulsions, syrups, slurries, suspensions and the like, for oral ingestion by.a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
For oral administration in the form of a tablet or capsule, the active ingredient may be combined with an oral, non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate, calcium phosphate, calcium sulfate, sodium carbonate, mannitol, sorbitol, and the like; together with, optionally, disintegrating agents, such as, without limitation, cross-linked polyvinyl pyrrolidone, maize, starch; methyl cellulose, agar, bentonite, xanthan gum, alginic acid: or a salt thereof such as sodium alginate, and the like; and, optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethyl-cellulose, polyethylene glycol, waxes, and the like;
and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid: sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Solid forms include powders, tablets and capsules. A solid carrier can be one or more substances, which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
In powders, the carrier is a finely divided solid, which is in admixture with 5 the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar 10 or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile liquids include suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, 15 such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose 20 solution or in a suitable oil.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may 25 be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in 30 admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
All formulations for oral administration should be in dosages suitable for such administration. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.
For parental administration, the compounds of the present invention or salts thereof can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Formulations for injection may be presented in unit dosage form, such as in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that each syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against any contamination. The carrier can be solvent or dispersion medium containing, for example, water, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being.preferred in humans.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
The active compounds can also be administered intranasally as, for example, liquid drops or spray.
For buccal administration, the compositions may take the form of tablets or lozenges Formulated in a conventional manner.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the~form of a dry powder inhaler, or an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
Pharmaceutical compositions of the present invention can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, lyophilized solid or paste, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing for example up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration.
Binding and Cotransfection Studies The in vitro potency of compounds in modulating PPARy, PPARa, and PPAR~ receptors are determined by the procedures detailed below. DNA-dependent binding (ABCD binding) is carried out using Scintillation Proximity Assay (SPA) technology with PPAR receptors. Tritium-labeled PPARoc arid PPARy agonists are used as radioligands for generating displacement curves and ICSO values with compounds of the present invention. Cotransfection assays axe carned out in CV-1 cells. The reporter plasmid contains an acylCoA oxidase (AOX) PPRE and TK promoter upstream of the luciferase reporter cDNA. Appropriate PPARs and RXRcc are constitutively expressed using plasmids containing the CMV promoter. Since for PPARa and PPAR~i, interference by endogenous PPAR~y in CV-1 cells is an issue, in order to eliminate such interference, a GAL4 chimeric system is used in which the DNA binding domain of the transfected PPAR is xeplaced by that of GAL4, and the GAL4 response element is utilized in place of the AO~ PPRE. Receptor activation by compounds of the present invention is determined relative to PPARoc agonist and PPARy agonist reference molecules to obtain percent efficacies. EC50 values are determined by computer fit to a concentration-response curve. A typical range for concentration determination is from 1nM to IO~,M. For binding or cotransfectian studies with receptors other than PPARs, similar assays are carried out using appropriate ligands, receptors, reporter constructs and etc. for that particular receptor. In some cases, a single high concentration of agonist (10 ~,M) was used.
These studies are carried out to evaluate the ability of compounds of the present invention to bind to and/or activate various nuclear transcription factors, particularly huPPARa ("hu" indicates "human"), huPPARy and huPPARB. These studies provide in-vitro data concerning efficacy and selectivity of compounds of the present invention. Furthermore, binding and cotransfection data for compounds of the present invention are compared with corresponding data for reference compounds that act on either huPPARoc or huPPAR~y. The typical range of concentration for binding is from 1nM to 10~M. The concentration of test compound required to effect 50% maximal activation of PPARoc (ICSOOC) and PPAR~y (ICSOy) is determined.
The compounds of the present invention, in general, have ICSO or ECSO in the range of about 1nM to about 1000 nM for either PPAR alpha, gamma or delta, preferably below about 50 nM for PPAR delta and below about 500 nM for PPAR
gamma.
Evaluation of Tri~lyceride and Cholesterol Level in HuapoAI Trans~enic Mice Five to six week old male mice, transgenic for human apoAl [C57B116-tgn(apoal)lrub, Jackson Laboratory, Bar Harbor, ME] are housed five per cage (10"x20"x8" with aspen chip bedding) with food (Purina 5001) and water available at all times. After an acclimation period of 2 weeks, animals are individually identified by ear notches, weighed and assigned to groups based on body weight. Beginning the following morning, mice are dosed daily by oral gavage for 7 days using a 20 gauges, 11/a" curved disposable feeding needle. Treatments are test compounds (30 mg/kg), a positive control (fenofibrate, 100 mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/ 0.25%
Tween80 (w/v); 0.2 ml/mouse]. Prior to termination on day 7, mice are weighed and dosed. Three hours after dosing, animals are anesthetized by inhalation of isoflurane (2-4%) and blood obtained via cardiac puncture (0.7-1.0 ml). Whole blood is transferred to serum separator tubes (Vacutainer SST), chilled on ice and permitted to clot. Serum is obtained after centrifugation at 4°C and frozen until analysis for triglycerides, total cholesterol, compound levels and serum lipoprotein profile by fast protein liquid chromatography (FPLC) coupled to an inline detection system. After sacrifice by cervical dislocation, the liver, heart and epididymal fat pads are excised and weighed.
The animals dosed with vehicle have average triglycerides values of about 60 to 80 mg/dl, which are reduced by the positive control fenofibrate (33-58 mg/dl with a mean reduction of 37%). The animals dosed with vehicle have average total serum cholesterol values of about 140 to 180 mg/dl, which are increased by fenofibrate (about 190 to 280 mg/dl with a mean elevation of 41%). When subject to FPLC analysis, pooled sera from vehicle-treated hu apoAI transgenic mice have a high-density lipoprotein cholesterol (HDLG) peak area, which ranges from 47v-sec to 62v-sec.
Fenofibrate increases the amount of HDLe (68-96v-sec with a mean percent increase of 48%).
Test compounds evaluated in terms of percent increase in the area under the curve.
Representative compounds of the present invention are tested using the above methods or substantially similar methods.
Evaluation of Glucose Levels in db/db Mice Five week old male diabetic (db/db) mice [C57B1Ks/j-m +l+ Lepr(db), Jackson Laboratory, Bar Harbor, ME] or lean littermates (db+) are housed 6 per cage (10"x20"x8" with aspen chip bedding) with food (Purina 5015) and water available at all times. After an acclimation period of 2 weeks, animals are individually identified by ear notches, weighed and bled via the tail vein for determination of initial glucose levels.
Blood is collected (100 ~,I) from unfasted animals by wrapping each mouse in a towel, cutting the tip of the tail with a scalpel, and milking blood from the tail into a heparinized capillary tube balanced on the edge of the bench. Sample is discharged into a heparinized microtainer with gel separator (VWR) and retained on ice. Plasma is obtained after centrifugation at 4°C and glucose is measured immediately: Remaining plasma is frozen 5 until the completion of the experiment, and glucose and triglycerides are assayed in all samples. Animals are grouped based on initial glucose levels and body weights.
Beginning the following morning, mice are dosed daily by oral gavage for 7 days using a 20 gauge, 11/a" curved disposable feeding needle. Treatments are test compounds (30 mglkg), a positive control agent (30 mg/kg) or vehicle [1%
carboxymethylcellulose 10 (w/v)/0.25% Tween80 (w/v); 0.3 ml/mouse]. On day 7, mice are weighed and bled (tail vein) for about 3 hours after dosing. Twenty-four hours after the 7'h dose (i.e., day 8), animals are bled again (tail vein). Samples obtained from conscious animals on days 0, 7 and 8 are assayed for glucose. After 24 hour bleed, animals are weighed and dosed for the final time. Three hours after dosing on day 8, animals are anesthetized by inhalation 15 of isoflurane, and blood obtained is via cardiac puncture (0.5-0.7 ml).
Whole blood is transferred to serum separator tubes, chilled on ice and permitted to clot.
Serum is obtained after centrifugation at 4°C and frozen until analysis for compound levels. After sacrifice by cervical dislocation, the liver, heart and epididymal fat pads are excised and weighed.
20 The animals dosed with vehicle have average triglycerides values of about 170 to 230 mg/dl, which are reduced by the positive PPARy control (about 70 to mg/dl with a mean reduction of 50%). Male db/db mice are hyperglycemic (average glucose of about 680 to 730 mg/dl on the 7th day of treatment), while lean animals have average glucose levels between about 290 and 230 mg/dl. Treatment with the positive 25 control agent reduces glucose significantly (about 350 to 550 mg/dl with a mean decrease towards normalization of 56%).
Glucose is measured colorimetrically by using commercially purchased reagents (Sigma #3 25-500). According to the manufacturers, the procedures are modified from published work (McGowan et al. Clin Chem, 20:470-5 (1974) and Keston, A.
30 Specific colorimetric enzymatic analytical reagents for glucose. Abstract of papers 129th Meeting ACS, 31C (1956).); and depend on the release of a mole of hydrogen peroxide for each mole of analyte coupled with a color reaction first described by Trinder (Trinder, P. Anr2 Clifz Biochem, 6:24 (1969)). The absorbance of the dye produced is linearly related to the analyte in the sample. The assays are further modified for use in a 96 well format. Standards (Sigma #339-11, Sigma #16-11, and Sigma #CC0534 for glucose, triglycerides and total cholesterol, respectively), quality control plasma (Sigma # A2034), and samples (~ or 5 p.l/well) are measured in duplicate using 200 p.l of reagent. An additional aliquot of sample, pipetted to a third well and diluted in 200 ~.l water, provided a blank for each specimen. Plates are incubated at room temperature (18, 15, and 10 minutes for glucose, triglycerides and total cholesterol, respectively) on a plate shaker and absorbance read at 500 nm (glucose and total cholesterol) or 540 nm (triglycerides) on a plate reader. Sample absorbance is compared to a standard curve (100-800, 10-500, and 100-400 mg/dl for glucose, triglycerides and total cholesterol, respectively).
Values for the quality control sample are consistently within the expected range and the coefficient of variation for samples is below 10%. All samples from an experiment are assayed at the same time to minimize inter-assay variability.
Serum lipoproteins are separated and cholesterol is quantitated with an in-line detection system. Sample is applied to a Superose~ 6 HR 10/30-size exclusion column (Amersham Pharmacia Biotech) and eluted with phosphate buffered saline-EDTA
at 0.5 ml/min. Cholesterol reagent (Ruche Diagnostics Chol/HP 704036) at 0.16 ml/min is mixed with the column effluent through a T-connection, and the mixture is passed through a 15 m x 0.5 mm id knitted tubing reactor immersed in a 37°C
water bath. The colored product produced in the presence of cholesterol is monitored in the flow stream at 505 nm, and the analog voltage from the monitor is converted to a digital signal for collection and analysis. The change in voltage corresponding to change in cholesterol concentration is plotted against time, and the area under the curve corresponding to the elution of VLDL, LDL and HDL is calculated (Perkin Elmer Turbochrome software).
The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, which may further illustrate details for the preparation of the compounds of the present invention. The compounds illustrated in the schemes and examples axe, however, not to be constmed as forming the only genus that is considered as the present invention.

General Reaction Scheme The compounds of the present invention, in general, may be prepared according to the Reaction Schemes shown below.
Reaction Scheme 1 (Rl)r (RZ)r A OH + H- X' I ( y COORS
\ O
O \ R3 R4 [X' = NH, HN(CHZ)"CHR]
(Rl)r EDC/HOBT/DIEA/ O (R2)r THF (or DMF) A X' I y COORS
or HATU/DIEA/ O \ ~ R R

(Rl )r LiOH O (Ra)r A X' I Y COOH
dioxane/H2O \ O
\ R3 R4 As shown in Reaction Scheme l, treatment of carboxylic acid 1 and amine 2 with EDC and HOBT or HATU in the presence of DIEA provides ester 3.
Hydrolysis of ester under LiOH, dioxane and H20 provides final acid 4.

Reaction Scheme 2:
(Rl)r c (R2~r r' COORS .
A OH + H N \

O Ra \ R3 R4 S
(Rl~r EDC/HOBT/DIEAI (RZ~r R°
THF (or DMF) A N I O COORS
O
or HATU/DIEA/ y a \ Rs Ra (Rl~r R6I/NaH/DMF R R~ I (R ) O COORS
A N \
\ ~ R3 R4 O Ra (Rl~r R6 (R2)r LiOH A N R° ( O COOH
dioxane/H20 \ O /' \ Rs Ra O Ra Similar to Reaction Scheme 1, treatment of carboxylic acid 1 and amine 5 with EDC and HOST or HATU in the presence of DIEA provides ester 6 as shown in Reaction Scheme 2. Alkylation of 6 gives compound 7, which then undergoes a hydrolysis to provide final acid 8.

Reaction Scheme 3 (Rl)r R (R2)r COORS
A H + c ' ~ O
HzN \ O ~ /~
O \ R~ Rø
Ra (R')r ' NaBH CNlNaOAeI
R° ~ COORS
HOAcfMeOH A N \ ~ O
O
\ ~ Rs R4 Ra 9 (R1!r MSC~/'~.'E,AICH~CI R7 (R2~r COORS
or (CH3C0)20 A N ~,, ~ O
O
route a ~ ~ g-s C ) Ra 10 {R~ ~r (R~)r LiOH A N RG ~ ~ O COON
O
~~X~er~o .~ 1 R~ R4 Ra Alternative route (b) (Rl)r (R2)r g R° I O COORS
\

Ra 9 \ R3 R4 (R1)r (R2)r LiOH A N R° \ I O COOH
dioxane/H2O ~ O
\ Rs R4 route (b) Ra 5 As shown in Reaction Scheme 3, treatment of aldehyde 1 and amine 5 with NaBH3CN in the presence of NaOAc and HOAc provides amine 9. Mesylation or acylation of amine 9 gives sulfonamide or amide 10. Hydrolysis of ester under LiOH, dioxane and H2O provides final acid 11. Alternatively as shown in route (b), amine 9 undergoes a hydrolysis to provide final acid 12.

Reaction Scheme 4 NBSlCCl4 ~ \ ~Br \
/ O~
/ O~ benzoyl peroxide O

~R1)r ~RZ)r O COORS
o ~ I R~4 DMF/KzC03 \Rl )r R8 (RZ)r \ ~ ( O COORS LiOH
\
O I %~ dioxane/H20 \ R3 R4 ~h'1)r 8 ( R _ \RZ)r \ I O COOH
/ N \ O
\ R3 R4 As shown in Reaction Scheme 4, bromination of 13 gives bromide 14.
Treatment of bromide 14 with the amine 15 under the basic condition provides lactam 5 16, which then undergoes a hydrolysis to provide final acid 17.

Reaction Scheme 5 (Rl)r (Rz)r O-pT Fluorobenzonitrile (Rz)r N- ~ I O-PT
H-O /' I KF-Alumina \
\ O
1g [PT-protecting group] 19 \
(Rl)r (Ri)r KOH O (Rz)r ~ O (Rz)r O-PT I O~H
H20z- HO \ O \ ~ HO \ 21 i (R )r (R1)r O _ (Rz)r O (Rz)r O~H ~ ~ I _ O\ /COORS
PT-O \ ~ PT-O ~\
O \ ~ 3 4 22 O \ ~ 23 R R
(R1)r O (Rz)r 5 oxalyl chloride O COOR
HO \ ~ ~ MeClz O ~ R'-24 \
(R1)r ~ ~ (Rz)r 5 OA -Db NHR6 O\ /COOR
Cl \ O ~ ~ I R3~Ra \
(R1)r O ~ (Rz)r O~ COORS
U Db-N \ O ~/\
R~~
R6 26 \
(R')r O ~ (Rz)r O\ /COOH
l -,1 Db-N \ O

R6 27 \

As shown in Reaction Scheme 5, a protected phenol 18 is reacted with fluorobenzonitrile in the presence of KF-alumina in an appropriate solvent to give the protected phenoxybenzonitrile 19. The nitrile is hydrolyzed in a suitable condition, such as in the presence of aqueous base and hydrogen peroxide to produce the acid 20. The protecting group (PT), such as benzyl group, is removed to give 21. The acid is then protected with a suitable protecting group, such as benzyl group to give 22, which is then reacted with a suitable ester-protected haloalkyl, such as ethylbromoacetate to give compound 23. The protecting group is removed, and the acid 24 is reacted with a chlorinating agent, such as oxalyl chloride to produce compound 25. The acid chloride compound is then reacted with an amine, such as benzylamine or cyclohexylamine in a suitable solvent, such as dichloromethane with a suitable base, such as triethylamine to give the amide ester compound 26. The ester is cleaved using aqueous base to give the final acid compound 27.

Reaction Scheme 6 (R1)r (R2)r Fluorobenzonitrile (Ra)r halo _ N- halo H- O \ ~ KF-Alumina \ O
29 \
28 (halo=F, Br, C1, I) (RI)r (R1)r KOH , O (RZ)r O (R2)r halo ~ I halo HO \ O ~~ I PT-O \ O
z z 30 \ 31 \
[PT-protecting group]
(RI)r methyl acrylate O ~ (RZ)r COORS
H2, Pd(OAc)2 PT-O \ 32 O \ ~ _ (R1)r O (RZ)r oxalyl chloride COORS
HO \ v MeCl2 33 O \
(R1)r O (R2)r ~A -Db-NHR6 COORS
Cl \ O ' 34 \
(R')r O ~ (R2)r COORS
CA~--Db -N \ O
Rg 35 \
(R1)r O ~ (R~')r COON
A~--Db-N \ O
l R6 36 \
As shown in Reaction Scheme 6, a halophenol 28 is reacted with fluorobenzonitrile in the presence of KF-alumina in an appropriate solvent to give the halophenoxybenzonitrile 29. The nitrile is hydrolyzed in a suitable condition, such as in aqueous base and hydrogen peroxide to produce the acid 30. The acid is protected with a suitable protecting group, such as benzyl group to give 31, which is then reacted in a palladium catalyzed Heck reaction with methyl acrylate to give the intermediate 32.
Compound 32 is reduced under standard hydrogenation condition to give the acid 5 compound 33. The acid is reacted with a chlorinating agent, such as oxalyl chloride to produce compound 34. The acid chloride compound is reacted with an amine, such as benzylamine or cyclohexylamine in a suitable solvent, such as dichloromethane with a suitable base, such as triethylamine to give the amide ester 35. The ester is cleaved using aqueous base to give the final acid product 36.
Reaction Scheme 7 O oxalyl chloride Ka O T~Kb- ~ H
'-J K OH ~ 1 39 R6 O ~
K '~ -Kb T LiBH4 ~Ka ~ b -K T

Q and T are each independently: aryl or alkyl;
15 R6: as defined in the specification;
Ka: a bond, C1-Clo alkylene or cycloalkyl; and Kb: Cl-Clo alkylene or cycloalkyl.
As shown in Reaction Scheme 7, the acid 37 is dissolved in a suitable 20 solvent, such as dichloromethane, and treated with a chlorinating agent such as oxalyl chloride. The acid chloride 38 is then added to the amine 39 in a suitable solvent, such as dichloromethane, with a base such as triethylamine. The resulting amide 40 is then reduced using a reducing agent, such as lithium borohydride with trimethylsilyl chloride in a suitable solvent, such a tetrahydrofuran to give the final amine compound 41.

In the Schemes, Procedures and Examples below, various reagent symbols and abbreviations have the following meanings.
ACN Acetonitrile BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl Boc t-butoxycarbonyl CBZ benzyloxycarbonyl DCM dichloromethane DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate ' D1PEA diisopropylethylamine DMAP 4-dimethylamino pyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide eq (equiv) equivalents) ESI-MS electron spray ion-mass spectroscopy Et ethyl EtOAc ethyl acetate h hours HOAc acetic acid HPLC high performance liquid chromatography HRMS high resolution mass LRMS low resolution mass LAH lithium aluminum hydride Me methyl Ms methanesulfonyl NBS N-bromosuccinimide Pdz(dba)3 tris(dibenzylideneacetone) dipalladium(0) Ph phenyl Pr propyl rt (r.t.) room temperature TBAI tetrabutylammonium iodide TBS tertbutyldimethylsilyl TFA trifluoroacetic acid TEA triethylamine THF tetrahydrofuran TLC thin-layer chromatography Preparation of Intermediates Intermediate 1 5-Fluoro-3-methyl-1H-indole-2-carboxylic acid OH
N O
Step A
5-Fluoro-3-methyl-1H-indole-2-carboxylic acid ethyl ester 4-Fluoroaniline (2.5 g, 22.5 mmol) is added to a solution of hydrochloric acid (5.5 mL in 9.6 mL water) and cooled to -5 °C. A solution of sodium nitrite is added dropwise (1.7 g, 24.7 mmol in 2 mL water). After the addition, reaction is stirred for 15 minutes at 0 °C, then pH is adjusted to 3-4 with sodium acetate (2.0 g, 24.3 mmol). In a separate flask, a solution of potassium hydroxide (1.4 g, 24.7 mmol in 2 mL
water) is added to a solution of ethyl-2-ethylacetoacetate (3.9 g, 24.7 mmol) in ethanol (20 mL) at 0 °C followed by 28 g of ice. The diazonium solution is added immediately to the alkaline solution. The pH is adjusted to 5-6 with sodium acetate and stirred for 3 hours at 0 °C. Additional water is added and extracted 3 times with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure giving an oily residue. Oily residue is dissolved in a few mL ethanol and added dropwise at 78 °C to a solution of HCl in dioxane (50 mL, 4N) and HCl in ethanol (30 mL, 1N). After the addition, reaction is heated at 78 °C for approximately 2-3 hours. The reaction is cooled, then solution is concentrated under reduced pressure, water added, and extracted 3 times with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting slurry is triturated with a minimum of dichloromethane and filtered providing pure title compound (1.38 g).
Recrystallization of the mother liquor material (hexane) provided additional pure product (0.68 g, 4l %
overall). GC/MS: M~+ 221; 1HNMR (400 MHz, CDC13).

Ste~B
5-Fluoro-3-methyl-1H-indole-2-carboxylic acid Compound of Step A (1.3~ g, 6.24 mmol) is dissolved in dioxane (130 mL) and lithium hydroxide hydrate (3.9 g, 93.5 mmol), dissolved in water (65 mL), is added. Mixture is stirred at rt overnight under nitrogen, then acidified with 5 N HCI.
Water is added and extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.76 g, 63%). Mass (ES): 192 (M-H+); 1H NMR (400 MHz, CDC13).
Intermediate 2 5-Fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid OH
N -O
St_ ep A
5-Fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid ethyl ester To a suspension of 60% sodium hydride (162 mg, 4.1 mmol) in dry DMF
(10 mL), cooled to 0 °C under nitrogen, is added dropwise the compound from Step A of Example 1 (600 mg, 2.7 mmol), dissolved in DMF (2 mL). The mixture is stirred at 0 °C
for 45 minutes, then iodomethane (0.26 mL, 4.1 mmol) is added dropwise. Bath is removed after 1 hour and stirring is continued overnight. Reaction is quenched with ice water and a precipitate formed, which is filtered and dried providing title compound (600.
mg, 94%) that is utilized without further purification. GC/MS: M~+ 235; 1HNMR
(400 MHz, CDC13).
Step B
5-Fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid The title compound is prepared according to Step B of Intermediate 1, utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid ethyl ester. Mass (ES-): 206 (M-H+); 1H NMR (400 MHz, CDC13).

Intermediate 3 t 5-Chloro-3-methyl-1H-indole-2-carboxylic acid CI ~ OH
N O
The title compound is prepared according to Intermediate 1 utilizing 4-chloroaniline and ethyl-2-ethylacetoacetate. Mass (ES-): 208 (M-H+); 1H NMR
(400 MHz, CDCl3).
Intermediate 4 5-Chloro-1,3-dimethyl-1H-indole-2-carboxylic acid cl ~ \ off N -O
The title compound is prepared according to Intermediate 2 utilizing 5-chloro-3-methyl-1H-indole-2-carboxylic acid ethyl ester (Intermediate 3, Step A) and iodomethane. Mass (ES-): 222 (M-H+); 1H NMR (400 MHz, CDCl3).
Intermediate 5 3-Methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid F F
F ~ OH
~~ N~~--~C
The title compound is prepared according to Intermediate 1 utilizing 4-trifluormethylaniline and ethyl-2-ethylacetoacetate. Mass (ES-): 242 (M-H+);
'H NMR
(400 MHz, CDC13).

Tntermediate 6 Z,3-Dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid F F
F ~ ~ \ OH
/ N v0 The title compound is prepared according to Intermediate 2 utilizing 1,3-5 dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (Intermediate 5, Step A) and iodomethane. Mass (ES-): 256 (M-H+); 1H NMR (400 MHz, CDC13).
Intermediate 7 5-Chloro-3-propyl-1H-indole-2-carboxylic acid OH

The title compound is prepared according to Intermediate 1 utilizing 4-chloroaniline and ethyl-2-n-butylacetoacetate. Mass (ES-): 236 (M-Hue); rH NMR
(400 MHz, CDC13).
Intermediate 8 15 5-Chloro-1-methyl-3-propyl-1H-indole-2-carboxylic acid cl The title compound is prepared according to Intermediate 2 utilizing 5-chloro-3-propyl-1H-indole-2-carboxylic acid ethyl ester (Intermediate 7, Step A) and iodomethane. Mass (ES-): 250 (M-Ht); 1H NMR (400 MHz, CDC13).

Intermediate 9 t 1-Ethyl-S-fluoro-3-methyl-1H-indole-2-carboxylic acid The title compound is prepared according to Intermediate 2 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid ethyl ester (Intermediate 1, Step A) and iodoethane. Mass (ES-): 250 (M-H+); 1H NMR (400 MHz, CDC13).
Intermediate 10 2-Methyl-4-trifluoromethyl-benzoic acid OH
The compound ofN,N,N,N,-tetramethylethylenediamine (19.8 mL, 131.9 mmol) is added to dry THF (120 mL) under nitrogen and cooled to -78 °C
with a dry ice acetone bath. Sec-butyl lithium (94 mL, 131.9 mmol, 1.4 M in cyclohexane) is added dropwise keeping the temperature between -78 °C to -70 °C with overhead stirring.
1S Suspension is stiiTed 15 minutes, then 4-trifluoromethyl-benzoic acid (11.4 g, 59.8 mmol) dissolved in 70 mL THF is added dropwise within the above temperature range and allowed to warm to -50 °C to -40 °C. Stirring is continued for 2 hours within that temperature range. Mixture is cooled to -78 °C and iodomethane (14.9 mL, 239.2 mmol) is added in 2-3 minutes. Bath is removed after 10 minutes and the reaction is stirred overnight. Reaction is quenched with water, extracted with ether, and the aqueous layer acidified with 5N HCI. Acidified solution is extracted with ether, washed with brine, dried over sodium sulfate and concentrated under reduced pressure.
Purification by flash chromatography, eluting with 10 % EtOAc in hexane then 25 % EtOAc in hexane provides the title compound (2.4 g, 20 %). Mass (ES-): 203 IHNMR (400 MHz, CDCl3).

Intermediate 11 2-Bromo-4-trifluoromethyl-benzoic acid O
Anhydrous copper (II) bromide (1.34 g, 6.0 mmol) and t-butyl nitrite (90%) (0.86 g, 7.5 mmol) are added to dry acetonitrile (20 mL) under nitrogen and the reaction is heated to 65 °C. 2-Amino-4-trifluoromethyl-benzoic acid (1.03 g, 5.0 mmol) is added in 3 portions and stirred for 15 minutes. Reaction is cooled and 5 N
HCl is added, extracted with ether, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography, eluting with 15 % EtOAc in hexane then 25 % EtOAc in hexane provides the title compound (0.80 g, 60 %). Mass (ES-): 267; 1HNMR (400 MHz, CDC13).
Intermediate 12 2-Chloro-4-trifluoromethyl-benzoic acid OH
O
The title compound is prepared according to Intermediate 11 utilizing 2-amino-4-trifluoromethyl-benzoic acid and copper (II) chloride. Mass (ES-): 223 (M-H+);
1H NMR (400 MHz, CDCl3).

Intermediate 13 2-Methyl-4-trifluoromethoxybenzoic acid F\ /F
FO \
OH
O
The title compound is prepared according to Intermediate 10 utilizing 4-trifluoromethoxy-benzoic acid. Mass (ES-): 219 (M-H+); 1H NMR (400 MHz, CDCl3).
Intermediate 14 5-Chloro-benzo[b]thiophene-2-carboxylic acid CI \ O
/ S O
The title compound is prepared according to Intermediate 1, Step B, utilizing 5-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester. Mass (ES-): 211 (M-H+); 1H NMR (400 MHz, CDCl3).
Intermediate 15 7-Bromo-1H-indole-2-carboxylic acid \ \ O
N
H
Br The title compound is prepared according to Intermediate 1, Step B, utilizing 7-bromo-1H-indole-2-carboxylic acid ethyl ester. Mass (ES-): 238 (M-H+); 1H
NMR (400 MHz, CDCl3).

Intermediate 16 3-{4-[3-(1-Amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester \
H2N / O \
Step A
3-[4-(3-Bromo-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester The compounds of 3,5-dibromotoluene (13.5 g, 54.0 mmol), 3-(2-ethyl-4-hydroxy-phenyl)-propionic acid ethyl ester (3.0 g, 13.5 mmol) (Intermediate 59), cesium carbonate (5.27 g, 16.2 mmol), copper (I) chloride (0.67 g, 6.7 mmol), and 2,2,6,6-tetramethyl-3,5-heptanedione (0.62 g, 3.4 mmol) are added to 1-methyl-2-pyrrolidinone (35 ml) and heated overnight at 120 °C under nitrogen. After cooling, HCl acid (50 mL, 1N) is added to quench the reaction. Additional water is added and extracted 3 times with ethyl ether, washed with brine, dried over sodium sulfate and concentrated under reduced pressure.
Purification by flash chromatography, eluting with 5 % EtOAc in hexane then 10 %
EtOAc in hexane provides the title compound (2.7 g, 51 %). MS(ES+): 410 (M+NH~+);
1HNMR (400 MHz, CDCl3).
Step B
3-[4-(3-Acetyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester The compound from Step A (2.7 g, 6.9 mmol), is dissolved in toluene (85 mL), and tributyl(1-ethoxyvinyl)tin (2.56 mL, 7.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.48 g, 0.69 mmol) are added.
The solution is degassed and heated at 100 °C under nitrogen for 5 hours.
After the reaction is cool, HCl acid (40 mL, 1N) is added and stirred for 1 hour. Reaction mixture is filtered through Celite and washed with EtOAc. Organic layer is separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Oil is dissolved in ethyl ether (300 mL) and an aqueous solution of KF (200 mL, 0.1N) is added.
Mixture is stirred overnight. Precipitate is removed by filtration, washed with ethyl ether, and the organic layer removed. The water layer is extracted twice with ethyl ether, then the ethers layers are combined, washed with brine, dried over sodium sulfate and r concentrated under reduced pressure. Purification by flash chromatography, eluting with 5 % EtOAc in hexane then 10 % EtOAc in hexane provides the title compound (1.3 g, 52 %). MS(ES+): 372 (M+NH4+); 1HNMR (400 MHz, CDCl3).
5 Step C
3-{2-Ethyl-4-[3-(1-hydroxy-ethyl)-5-methyl-phenoxy]-phenyl}-propionic acid ethyl ester (R)-2-methyl-CBS-oxazaborolidine (0.34 mL, 0.36 mmol, 1N in toluene) is dissolved in dry toluene (3.5 mL) and borane-N,N diethylaniline complex (O.b4 mL, 3.6 mmol) is added. Flask is immersed in a water bath and the compound from Step B
(1.3 g, 10 3.6 mmol) is dissolved in toluene (9.0 mL) and is added dropwise to the solution keeping the temperature between 19 °C and 23 °C. Reaction is stirred 45 minutes under nitrogen.
Reaction is quenched with methanol (1.2 mL), followed by 1N HCl (2.2 mL) and stirred for 15 minutes. Aqueous layer is separated, extracted twice with ethyl acetate. Organic layers are combined, washed with brine, dried over sodium sulfate and concentrated under 15 reduced pressure. Purification by flash chromatography, eluting with 10 %
EtOAc in hexane then 20 % EtOAc in hexane provides the title compound (1.1 g, 85 %).
MS(ES+):, 374 (M+NH4+); 1HNMR (400 MHz, CDC13).
step D
3-{4-[3-(1-Azido-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester 20 Compound from Step C (1.1 g, 3.1 mmol) and diphenylphosphoryl azide (0.81 mL, 3.8 mmol) are dissolved in toluene (10.0 mL), cooled to 0 °C, and DBU is added dropwise. Reaction is stirred 2 hours under nitrogen at 0 °C, then at rt overnight.
Azidotrimethylsilane (0.41 mL, 3.1 mmol) and tetrabutylammonium fluoride (1M
in THF, 3.1 mL, 3.1 mmol) are added to the solution and heated at 40 °C
for 8 hours.
25 Solvent is removed under reduced pressure. Purification by flash chromatography, eluting with 10 % EtOAc in hexane then 15 % EtOAc in hexane provides the title compound (0.93 g, 78 %). MS(ES+): 399 (M+NH4+);1HNMR (400 MHz, CDCl3).

Ste~E
3-{4-[3-(1-Amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester Compound from Step D (0.93 g, 2.3 mmol) and triphenylphosphine (0.96 g, 3.8 mmol) are stirred overnight in THF (20 mL) and water (2 mL). Solvent is removed under reduced pressure with bath at rt, extracted into ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by SCX
column, eluting with 10 % ammonia (2.0 M in methanol) in dichloromethane provides the title compound (0.93 g, 78 %). MS(ES+): 399 (M+NH4+); 1HNMR (400 MHz, CDC13).
Intermediate 17 2-[4-(3-Aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester \
H2N / O \
Step A
2-[4-(3-Cyano-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester The compounds of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (4.5 g, 18.9 mmol) (WO 20030721) 3-cyanophenylboronic acid (5.5 g, 37.8 mmol), dried copper (II) acetate (6.8 g, 37.8 mmol), and dried molecular sieve (11.3 g) are added to dichloromethane (225 ml). Pyridine (15.3 mL, 189.0 mmol) is added dropwise at rt. Reaction is stirred overnight with a drying tube in place.
Reaction mixture is filtered through Celite and washed with dichloromethane. Filtrate is concentrated under reduced pressure. Purification by flash chromatography, eluting with 10 % EtQAc in hexane then 15 % EtOAc in hexane provides the title compound (3.0 g, 47 %). MS(ES+): 340 (M+H+); 1HNMR (400 MHz, CDCl3).
step B
2-[4-(3-Aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester Compound from Step A (3.0 g, 8.9 mmol) is reacted overnight in a Parr shaker with 5 % Pd/C (0.3 g) in glacial acetic acid (422 mL) at rt with 40 psi hydrogen.
Reaction mixture is filtered, most of acetic acid removed under reduced pressure with rt bath. Ethyl acetate is added to oily residue. Solution is washed with diluted sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure providing the title compound (2.8 g, 92 %) that is utilized without purification.
MS(ES+): 343 (M+H+); iHNMR (400 MHz, CDCl3).
Intermediate 18 2-[4-(4-Aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester H2N ~ \ /
/ \
O
The title compound is prepared according to Intermediate 17 utilizing 4-cyanophenylboronic acid and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (WO 2003072102)., Mass (ES+): 366 (M+Na+); 1H NMR (400 MHz, CDCl3).
Intermediate 19 2-[4-(3-Aminomethyl-4-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester \ /~° o HaN / O \
2-[4-(3-Cyano-4-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (240. mg, 0.68 mmol) (Intermediate 51) is reacted overnight in a Parr shaker with Raney nickel (0.2 g) in ammonia (2N solution in methyl alcohol, 50 mL) at 40 °C with 60 psi hydrogen. Reaction mixture is filtered and concentrated under reduced pressure with rt bath providing the title compound (245 g, quantitative) that is utilized without purification. MS(ES+): 358 (M+H+); 1HNMR (400 MHz, CDCl3).

Intermediate 20 2-[4-(3-Aminomethyl-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester \ /
HzN / O \
The title compound is prepared according to Intermediate 19 utilizing 2-[4-(3-cyano-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 55). Mass (ES+): 358 (M+H+);'H NMR (400 MHz, CDCl3).
Intermediate 21 2-[4-(5-Aminomethyl-2-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester \ /
H2N / O \
The title compound is prepared according to Intermediate 19 utilizing 2-[4-(5-cyano-2-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 54). Mass (ES+): 358 (M+H+);'H NMR (400 MHz, CDC13).
Intermediate 22 2-[4-(3-Aminomethyl-4-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester \ / ( O
HzN / O \
The title compound is prepared according to Intermediate 19 utilizing 2-[4-(3-cyano-4-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 53). Mass (ES+): 362 (M+H+);'H NMR (400 MHz, CDCI3).

Intermediate 23 3-{4-[3-(1-Amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester F O
\ /
HEN / O \
The title compound is prepared according to Intermediate 16 utilizing 1,3-dibromo-5-fluoro-benzene and 3-(2-ethyl-4-hydroxy-phenyl)-propionic acid ethyl ester (Intermediate 59). Mass (ES+): 360 (M+H+);1H NMR (400 MHz, CDCl3).
Intermediate 24 3-{4-[3-(1-Amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester \ / I o/
HaN / O \
The title compound is prepared according to Intermediate 16, Steps A, C, D, and E utilizing 3'-bromoacetophenone and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Chem.Soe.Per7~i~z Trans.l; 4; 1990; 1041-1045). Mass (ES+): 314 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 25 3-{4-[3-(1-Amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester The title compound is prepared according to Intermediate 16 utilizing l,3-dibromo-5-fluoro-benzene and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.ClZefzz.Soc.Perkiz2 Trans.l; 4; 1990; 1041-1045). Mass (ES+): 332 (M+H+); 1H
NMR (400 MHz, CDC13).
Intermediate 26 5 3-{4-[3-(1-Amino-ethyl)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester \ / I o/
HaN / O \
The title compound is prepared according to Intermediate 16 utilizing 3,5-dibromotoluene and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester 10 (J.Clzem.Soc.Perkirz Trans.l; 4; 1990; 1041-1045). Mass (ES+): 32~ (M+H+);

(400 MHz, CDC13).
Intermediate 27 3-[4-(3-Aminomethyl-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester F O
\ /
HzN / O \
The title compound is prepared according to Intermediate 33 utilizing 3,5-difluorobenzonitrile and 3-(2-ethyl-4-hydroxy-phenyl)-propionic acid ethyl ester (Intermediate 59). Mass (ES+): 360 (M+H+);'H NMR (400 MHz, CDC13).

Intermediate 28 3-{4-[2-(2-Amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester 3-{ 4-[2-(2-tert-Butoxycarbonylamino-ethyl)-phenoxy]-2-methyl-phenyl }-propionic acid ethyl ester (600 mg, 1.4 mmol) (Intermediate 56) is dissolved in dioxane (5 mL) and cooled with an ice bath. Cooled HCl in dioxane (30 mL, 4N) is added and reaction is stirred for 1.5 hours, and then concentrated under reduced pressure. Oil is' purified through an SCX column eluting with 10 % ammonia (2N in methanol) in dichloromethane providing the. title compound (390 mg, 85 %). Mass (ES+): 328 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 29 2-{4-[3-(2-Amino-ethyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester i The title compound is prepared according to Intermediate 28 utilizing 2-{ 4-[3-(2-tert-butoxycarbonylamino-ethyl)-phenoxy]-2-methyl-phenoxy } -2-methyl-propionic acid ethyl ester (Intermediate 58). Mass (ES+): 358 (M+H+);'H NMR
(400 MHz, CDC13).

Intermediate 30 2-Ethyl-4-trifluoromethyl-benzoic acid H
2-Methyl-4-trifluoromethyl-benzoic acid (0.10 g, 0.49 mmol) is dissolved in THF (8 ml), and the solution is cooled to -78 °C. LDA (2.0 M in heptane/THF/ethylbenzene, 0.55 mL, 1.1 mmol) is added. The mixture is warmed to -35 °C. After the dark purple color disappeared, the mixture is cooled back to -78 °C and LDA (2.0 M in heptane/THF/ethylbenzene, 0.55 mL, 1.1 mmol) is added, stirred at -35 °C for 1h. The reaction mixture is cooled back to -78 °C and MeI
(0.15 ml, 2.4 mmol) is added, warmed to RT and stirred overnight. The mixture is concentrated, acidified with 5M HCI, extracted with EtOAc, washed with brine, dried over Na2SO4. Removal of solvents give a residue (0.20 g) as a mixture of 56 % the title compound and 44 % of the starting material. This mixture is used without isolation and the purification is done after peptide coupling. Mass (ES-): 217 (M-H+); 1HNMR (400 MHz, CDCl3).
Intermediate 31 2-Phenoxy-4-trifluoromethyl-benzoic acid F F
\ O
F
/ OH
O
A mixture of 2-fluoro-4-(trifluoromethyl) benzoic acid (2.50 g, 12 mmol), phenol (2.26 g, 24 mmol) and CsZC03 (11.73g, 36 mmol) in DMF (20 ml) is heated at 100°C under N2 overnight. The mixture is cooled to RT, quenched with HZO, acidified with 5 M HCI, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated. Purification by reversed phase HPLC provides the title compound.
Mass (ES-): 281.3 (M-H+);1HNMR (400 MHz, CDCl3).
Intermediate 32 2-Phenoxy-4-trifluoromethyl-benzaldehyde I\
F F
\ O
F
/ H
O
A mixture of 2-fluoro-4-(trifluoromethyl)benzaldehyde (4.97g, 26 mmol), phenol (2.64g, 28 mmol) and Cs2CO3 ( 16.94g, 26 mmol) in DMF (20 ml) is heated at 85 °C under N2 overnight. The reaction mixture is cooled to RT. Water is added, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated.
Purification by chromatography, eluting with 5% EtOAc in hexane then 15% EtOAc in hexane provides the title compound (5.30g). Mass (ES-): 265.3 (M-H+); 1HNMR
(400 MHz, CDCl3).
Intermediate 33 3-[4-(3-Aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester O
of H2N / o \
Step A
3-[4-(3-Cyano-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester A mixture of 3-fluorobenzonitrile (4.82 ml, 45 mmol), 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Chen~.Soc.Per-kin Trans.l; 4;
1990; 1041-1045) (8.74g, 45 mmol) and Cs2C03 (29.32g, 90 mmol) in DMF (60 ml) is heated at 100 °C under NZ overnight. The reaction mixture is cooled to RT, quenched with ice-H20, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated.
Purification by chromatography, eluting with 10% EtOAc in hexane then 15%
EtOAc in hexane provides the title compound (8.56g). MS: (ES+) 296.1 (M+H+); 1H NMR
(400 MHz, CDCl3).
Step B
3-[4-(3-Aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The compound from Step A (6.16g, 2lmmol) is dissolved in HOAc (75 ml). 5% Pd/C (0.62g) is added. The mixture is hydrogenated at RT under 40 - 60 Psi overnight. The reaction mixture is filtered, concentrated, dissolved in EtOAc, washed with dilute NaHC03 and brine, dried over Na2S04, filtered and concentrated again to provide the title compound (5.97g). MS: (ES+) 300.2 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 34 3-{4-[3-(1-Amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester F O
O~
HN

St_ ep A
3-[4-(3-Bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The title compound is prepared as described in Intermediate 16, Step A
utilizing 1,3-Dibromo-5-fluoro-benzene and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Chem.Soc.Perkin Trans.l; 4; 1990; 1041-1045). MS: (ES+) (M+NH4+); 1H NMR (400 MHz, CDCl3).

Step B

3-[4-(3-Acetyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The title compound is prepared as described in Intermediate 16, Step B
utilizing the compound Step A above. MS:(ES+) 331(M+H+); iH NMR (400 MHz, 5 CDC13).
Step C
3-{4-[3-Fluoro-5-(1-hydroxyamino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester The compound from Step B (0.54 g, 1.64 mmol) is dissolved in EtOH (8 10 ml). NH20H~HC1 (0.llg, 1.64 mmol), NaOAc (0.27g, 3.28 mmol) and HZO are added, heated under reflux for lh. The reaction mixture is concentrated. Water is added, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated again to provide the title compound (0.56g). MS: (ES+) 346.2 (M+H+); 1H NMR
(400 MHz, CDC13).
15 . Step D
3-{4-[3-(1-Amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester The compound from Step C (0.568, 1.62 mmol) is dissolved in a mixture of MeOH (9.0 ml), AcOH (9.0 ml) and H20 (4.4 ml). Zn dust (0.42g, 6.49 mmol) is 20 added, stirred at RT for 6 h. The reaction mixture is filtered, concentrated. The residue is dissolved in EtOAc, washed with dilute NaHC03, brine, dried over Na2S04, filtered and concentrated again to provide the title compound (0.53g). MS: (ES+) 332.1 (M+H+); IH
NMR (400 MHz, CDC13).
25 Intermediate 35 [4-(3-Aminomethyl-phenoxy)-2-methyl-phenoxy]-acetic acid methyl ester O
/ / ~~O/
H2N \ ~ \
O

The title compound is prepared according to the procedure described in Intermediate 33 utilizing 3-fluoro-benzonitrile and (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester. MS:(ES+) 302.1 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 36 3-[4-(3-Aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester F O
/ ~ / ~ O/
H2N \ O \
The title compound is prepared according to the procedure described in Intermediate 33 utilizing 3,5-difluoro-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.C7zem.Soc.Pez-kin TrazZS.l; 4; 1990; 1041-1045). MS:
(ES+) 318.2 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 37 3-[4-(2-Aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester O
/ / ~ O/
\ O \

The title compound is prepared according to the procedure described in Intermediate 33 utilizing 2-fluoro-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Chenz.Soc.Perkizz Trans.l; 4; 1990; 1041-1045).
MS:
(ES+) 300.12 (M+H+); 1H NMR (400 MHz, CDCl3).

Intermediate 38 3-[4-(3-Aminomethyl-5-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester F F
F O
/ I / I O/
H2N \ O \
The title compound is prepared according to the procedure described in Intermediate 33 utilizing 3-fluoro-5-trifluoromethyl-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Clzezyz.Soc.Per-kin Trafzs.l; 4;
1990; 1041-1045). MS: (ES+) 368.1 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 39 3-[4-(5-Aminomethyl-2-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester F O
F
/ F/
H2N \ I \ I
O
The title compound is prepared according to the procedure described in Intermediate 33 utilizing 3-fluoro-4-trifluoromethyl-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Clzem.Soc.Perkizz Trans.l; 4;
1990; 1041-1045). MS: (ES+) 368.1 (M+H+); 1H NMR (400 MHz, CDC13).
Intermediate 40 3-[4-(3-Aminomethyl-4-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester F F O
F / / I O~
H2N \ I \
O

Step A
3-[4-(3-Cyano-4-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The title compound is prepared according to the procedure described in Intermediate 33, Step A, utilizing 5-fluoro-2-trifluoromethyl-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Chefn.Soc.Perkin Trans.l; 4;
1990; 1041-1045). MS: (ES+) 363.9.1 (M+H+); IH NMR (400 MHz, CDC13).
Step B
3-[4-(3-Aminomethyl-4-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The compound from Step A (0.35 g, 0.96 mmol) is dissolved in 2 M NH3 in MeOH (50 ml). Raney Nickel (0.2,g) is added. The mixture is hydrogenated at 40 °C
under 60 Psi overnight. The reaction mixture is filtered and concentrated to provide the crude title compound (0.44g). MS: (ES+) 36.06 (M+H+).
Intermediate 41 2-{4-[3-(1-Amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester O
/ O O~
hi O
The title compound is prepared according to the procedure described in Intermediate 34 utilizing 1,3-dibromo-5-fluoro-benzene and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (WO 2003072102). MS: (ES+) 376.2 (M+H+); 1H NMR (400 MHz, CDCl3).

Intermediate 42 s 3-[4-(3-Aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-2,2-dimethyl-propionic acid methyl ester F
/ ~ / ~ O/
H2N \ O \ , ' The title compound is prepared according to the procedure described in Intermediate 33 utilizing 3,5-difluoro-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (Intermediate 60). MS: (ESA) 346.2 (M+H+); 1H
NMR (400 MHz, CDC13).
Intermediate 43 3-{4-[3-(1-Amino-propyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester F O
/ ~ / ( O/
H2N \ O \
Step A
3-[4-(3-Fluoro-5-propionyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The title compound is prepared according to the procedure described in Intermediate 33, Step A utilizing 3,5-difluoropropiophenone and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Chem.Soc.Perkin Tra~zs.l; 4; 1990; 1041-1045).
MS: (ES+) 345.2 (M+H+); 1H NMR (400 MHz, CDCl3).
Step B
3-{4-[3-Fluoro-5-(1-hydroxyamino-propyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester The title compound is prepared according to the procedure described in Intermediate 34, Step C utilizing the compound from Step A. MS: (ES''~) 360.2 (M+H+);
1H NMR (400 MHz, CDC13).
Step C
5 3-{4-[3-(1-Amino-propyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester The title compound is prepared according to the procedure described in Intermediate 34, Step D utilizing the compound from Step B. MS: (ES+) 346.3 (M+H+);
1H NMR (400 MHz, CDC13).
Intermediate 44 3-{4-[3-(1-Amino-propyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester O
/ O/
H2N \
O
The title compound is prepared according to the procedure described in Intermediate 16 utilizing 3-[4-(3-fluoro-5-propionyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 43, Step A). Chiral HPLC tR = 6.532 min (LC
column: CHIRALPAK AD; 4.6 x 250 mm; 100% MeOH with 0.2 % DMEA; flow rate:
1.0 mllmin); 1H NMR (400 MHz, CDC13).
Intermediate 45 3-[4-(3-Aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester O
\ / O/
H2N / O \

Step A
s 3-[4-(3-Bromo-5-cyano-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The title compound is prepared according to the procedure described in Intermediate 16, Step A utilizing 3,5-dibromo-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J. Chena. Soc. Perki~z Trari.s. 1, 4, 1990, 1041-1045).
MS: (ES+) 393.2 (M+NH4+);1H NMR (400 MHz, CDCl3).
St_ ep B
3-[4-(3-Cyano-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The compound from Step A above (0.60 g, 1.6 mmol) is dissolved in DMF
( 10 ml). Trimethylboroxine (0.22 ml, 1.6 mmol), (Ph3P)4Pd (0.18 g, 0.16 mmol) and K2C03 (0.66 g) are added. The reaction mixture is heated at 115 °C
under N2 overnight.
The reaction mixture is filtered through Celite, washed with EtOAc. The filtrate is concentrated. The residue is purified by chromatography, eluting with 10%
EtOAc in hexane then 15% EtOAc in hexane providing the title compound (0.40 g). MS:
(ES3a7.s (M+NH4+); 1H NMR (400 MHz, CDCl3).
Step C
3-[4-(3-Aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The title compound is prepared according to the procedure described in Intermediate 33, Step B utilizing the compound from Step B above. The crude product is purified by SCX column eluting with 10 % 2M NH3 in MeOH /CH2Cla. MS: (ES+) 314.5 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 46 3-[4-(3-Aminomethyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester O
\ /) o H2N / O \
The title compound is prepared according to the procedure described in Intermediate 45 utilizing 3,5-dibromo-benzonitrile and 3-(2-ethyl-4-hydroxy-phenyl)-propionic acid ethyl ester (Intermediate 59). MS: (ES+) 342.5 (M+H+); 1H NMR
(400 MHz, CDCl3).
Intermediate 47 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester F
O C02Et I~ \I
-o Step A
2-[4-(3-cyano-5-flurorphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester F
\ / I O C02Et NC O
3,5-difluorobenzonitrile (1.286 g, 9.24 mmol) is added to a suspension of KFlAl203 (5.0 g, 40% KF), 18-crown-6 (220 mg, 0.84 mmol) and compound (a) from Intermediate 55, Step A (2.0 g, 8.4 mmol) in CH3CN (150 mL, HPLC grade). The mixture is warmed to reflux. After 2 h, the reaction is allowed to reach r.t., filtered trough Celite and washed with EtOAc/brine. The organic layer is dried, filtered and concentrated, and the crude residue is flash chromatographed on Si02 (5-10%
EtOAc/hexanes), affording 1.95 g of the title compound (65%, white solid).
Step B
2-[4-(3-methylamino-5-flurorphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester F
O C02Et Ij ~I
-o PdIC (140 mg, 10% Pd on activated C, 0.027 mmol) is added to a solution of compound obtained from Step A (1.70 g, 4.927 mmol) in glacial AcOH (200 mL). The mixture is stirred at r.t. under H2 atmosphere (40 psi) overnight (c.a. 14 h) and filtered trough Celite (CHaCl2 washings). The AcOH is neutralized with NaHCO3, and the mixture partitioned between CHZC12 and HBO. The organic layer is dried, filtered and concentrated. The crude residue is flash chromatographed on Si02 (0.2%
ethyldimethylamine, 30% iPrOH, 70% hexane) to afford about 1.35 g of the title compound (79%, colorless oil).
Intermediate 48 [3-(3-Aminomethyl-5-fluoro-phenoxy)-phenyl]-acetic acid methyl ester F
/ ~ O
H2N / O \ O~
The title compound is prepared according to the procedure described in Intermediate 33 utilizing 3,5- difluoro-benzonitrile and (3-hydroxy-phenyl)-acetic acid methyl ester (WO 2003072102). MS: (ES+) 290.3 (M+H+); 1H NMR (400 MHz, CDCl3).
Intermediate 49 2-[4-(3-Aminomethyl-phenoxy)-phenoxy]-2-methyl-propionic acid ethyl ester O
\ /
H2N ~ /
O
The title compound is prepared according to the procedure described in Intermediate 40 utilizing 3-fluorobenzonitrile and 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (WO 2002081454) except that the reaction is carried out at rt and 500 Psi for Step B. MS: (ES+) 330.3 (M+H+);'H NMR (400 MHz, CDCl3).

Intermediate 50 3-Methyl-5-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid F F
F I ~ ~ OH
O
Step A
1-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-ethanone A solution of 2-fluoro-5-trifluoromethyl acetophenone (3.0 g, 14.5 mmol) in dry DMF (20 mL) was treated with sodium thiomethoxide (1.22 g, 17.4 mmol) and the reaction was stirred for 2 hours at rt under NZ. The reaction was quenched with 1 N HCl (10 mL), diluted with Et20 and then extracted twice with water. The organic layer was dried (Na2S04) and the solvent removed irz vacuo to afford crude product that was absorbed on silica gel and then column purified using 5l1 hexanes/acetone to afford 2.88 g (85%) of the product. Rf = 0.57 (1/1 hexanes/acetone). 1H NMR (400 MHz, CDCl3) b 8.05 (s, 1H), 7.69 (d, 1H, J= 8.31 Hz), 7.42 (d, 1H, J= 8.80 Hz), 2.68 (s, 3H), 2.48 (s, 3H).
Step B
3-Methyl-5-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid A mixture of 1-(2-methylsulfanyl-5-trifluoromethyl-phenyl)-ethanone (made above) (2.06 g, 8.79 mmol) and bromoacetic acid (7.33 g, 52.8 mmol) in acetic acid (20 mL) was heated to reflux and stirred for 20 hours under N2. The reaction was cooled and water was added to form a slurry. The slurry was filtered and the solids rinsed with water to afford 1.59 g (69%) of the product after drying in a vacuum oven at 45 °C.
Rf = 0.18' (1/1 hexanes/acetone). 'H NMR (400 MHz, CDC13). MS (ES-) m/.z mass calcd for CI1H702SF3 260, found 259 (M - 1, 100%).

Intermediate 51 2-[4-(3-cyano-4-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester O C02Et I~ ~I
NC ~O
St_epA
5 2-[4-(3-cyano-4-nitrophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester 02N ~ / O C02Et I~
NC v ~O
A mixture of 9.6 g (58 mmol) of 2,5-difluorobenzonitrile, 13.8 g (58 mmol) of 2-(4-hydroxy-2-methylphenoxy)-2-methylpropionic acid ethyl ester (WO
2003072102), 34.5 g of 40% w/w potassium fluoride-alumina, 1.56 g ( 5.8 mmol) of 18-10 crown-6 in CH3CN is refluxed under argon atmosphere. After 1 hour, the reaction mixture is cooled to rt, partitioned between equal parts of ether and water, and shalced vigorously. The aqueous layer and alumina sediments are separated and the resulting organic phase is washed once with a saturated potassium chloride solution. The organic phase is dried over MgSO4, and concentrated in vacuo. The crude is used in the next step 15 without further purification. About 19.6 g of 2-[4-(3-cyano-4-nitrophenoxy)-methylphenoxy]-2-methylpropionic acid ethyl ester are obtained.
St~ e~B
2-[4-(4-amino-3-cyanophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester H2N ~ / O CO2Et I, NC ~O
20 A mixture of 7 g (18.2 mmol) of 2-[4-(3-cyano-4-nitrophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester, 700 mg of Pd(C) 10% in 50 ml of EtOH is hydrogenated for two hours at rt. The mixture is filtered over celite and washed with EtOH. The solvent is evaporated to give 6.4 g of the title compound, which is used for the next step without further purification.

Step C
2-[4-(4-bromo-3-cyanophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester gr O C02Et I, ~I
NC -O
To a mixture of 2.5 ml (21.2 mmol) of 'BuONO and 3.79 g (17 mmol) of CuBr2 in acetonitrile at 65°C under argon atmosphere is added 5 g (14.1 mmol) of 2-[4-(4-amino-3-cyanophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester in 10 ml of acetonitrile. After the addition is washed, the reaction is stirred at the same temperature for 15 min. The reaction is allowed to reach rt, and HCl (2N) is added. The mixture is extracted with ether (3x20 ml). The organic phase is washed with HCl (2N), dried over MgS04 and concentrated to give 5.8 g of the title compound, which is used for the next step without further purification.
Ste~D
2-[4-(3-cyano-4-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester A sealed tube is charged with 3 g (7.2 mmol) of 2-[4-(4-bromo-3-cyanophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester, 80 mg (0.35 mmol) of Pd(OAc)2 , 192 mg (0.7 mmol) of P(o-tolyl)3, 1.1 ml (7.9 mmol) Sn(CH3)4 and 3 ml of Et3N in 5 ml of DMF and is heated at 115°C under argon atmosphere overnight.
To the mixture, HCl (2N) is added (lOml), and the mixture is extracted with ether (3x50 ml). The organic phase is dried over MgS04 and concentrated. The desired product is purificated by silica gel chromatogaphy using hexane/ethyl acetate 15:1 as eluent to obtain 680 mg (27°Io) of the title compound. MS Data (Ion Trap): mlz 353.8 [M+H] as base peak, m/z 376.1 [M+Na] and m/z 511.7.
Intermediate 52 2-{4-[3-(3-amino-propyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester O~C02Et H2N ~ I
O

Step A
2-[4-(3-formilphenoxy)-2-methylphenoxy]-2-methypropionic acid ethyl ester O C02Et OHC ~ O
A sealed tube is charged with Pd(OAc)Z (36 mg, 0.14 nunol), 2-(ditertbutylphosphino)biphenyl (76 mg, 0.4 mmol) and K3PO4 (3.56 g, 14 mmol).
The tube is evacuated and back-filled with argon and fitted with a rubber septum.
Toluene (10 ml) followed by 3-bromo benzaldehyde ( 0.81 ml, 7 mmol) and 2-(4-hydroxy-2-methylphenoxy)-2-methylpropionic acid ethyl ester (WO 2003072102) (2 g, 8.4 mmol) in toluene (10 ml) are added via syringe. The tube is sealed under argon and stirred at 110 °C for two days. The mixture is diluted with 30 ml of diethyl ether, filtered through a pad of celite and concentrated to leave a crude oil. The resulting oil is purified by flash chromatogaphy on silica gel using 10:1 hexanes/ethyl acetate as eluent to obtain 900 mg of the title compound.
St~ ep B
2-{4-[3-(2-cyanovinyl)-phenoxy]-2-methylphenoxy}-2-methypropionic acid ethyl ester O C02Et NC " ~~ V ~O
Z:E mixture To a solution of diethyl-(cyanomethyl)-phosphonate (0.466 ml, 2.63mmol) in THF (5 ml) at -78°C is added dropwise tBuOK (2.63 ml, 2.63 mmol) under a nitrogen blanket. The solution is stirred for 30 min., and 2-[4-(3-formilphenoxy)-2-methylphenoxy]-2-methypropionic acid ethyl ester (900 mg, 2.63 mmol) in THF
(l0 ml) is added slowly at the same temperature. The mixture is stirred at -78°C for another 30 min. and then warmed to 0°C, quenched with 25% NH4Cl (aq), extracted with EtOAc, washed with brine, dried over MgS04, filtered and concentrated. Purification:
silica gel chromatogaphy. Eluent 12:1 hexanes/ethyl acetate affords 825 mg of a mixture 70:30 of E/Z isomers of the title compound.

Step C
2-{4-[3-(3-amino-propyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester A mixture of 2-{4-[3-(2-cyanovinyl)-phenoxy]-2-methylphenoxy}-2-methypropionic acid ethyl ester (700 mg, 1.9 mmol) and 70 mg of Pd(C) 10% in lOml of EtOH is hydrogenated one hour at rt. Then, it is filtered over celite and washed with EtOH. The solvent is evaporated, and the crude is purified using silica gel chromatogaphy, 25:1 hexane/ethyl acetate as eluent to give 460 mg of the title compound.
MS Data (Ion Trap): m/z 390 [M+Na] as base peak, m/z 368 [M+H], m/z 294 and 254 (in positive mode).
Intermediate 53 2-[4-(3-cyano-4-fluorophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester F O C02Et NC ~O
St_ ep A
1-bromo-2,5-difluoro-4-nitrobenzene F

Br F
To a solution of 2-bromo-1,4-difluorobenzene (10 g, 51.8 mmol) in 40 ml of sulfuric acid at 0°C is added dropwise 35 ml of nitric acid while maintaining an internal temperature below 20°C. The mixture is then poured into ice and extracted with ether (3x100 ml). The organic phase is washed with NaHC03 (3 times), dried over MgS04 and evaporated. The crude is purificated by silica gel chromatogaphy (hexane/acetone 10:1) to afford 11.25 g of the title compound.

St_ ep B
2,5-difluoro-4-nitrobenzonitrile F
02N ( CN
F
A mixture of 1-bromo-2,5-difluoro-4-nitrobenzene (5g, 21 mmol) and 2.44 g (27 mmol) of CuCN in 20 ml of DMF is heated at 160°C in a sealed tube, under argon atmosphere overnight . The mixture is washed with 50 ml of water and NH4OH
(3x20 ml) and then extracted with CH2C12 (3 x 100m1). The organic phase is dried over MgS04 and evaporated to give 3.8 g of the title compound, which is used in next step without further purification.
Step C
2-[4-(5-cyano-4-fluoro-2-nitrophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester F ~ N02 / O C02Et I, ~I
NC ~O
A mixture of 2,5-difluoro-4-nitrobenzonitrile (1.6 g, 8.7 mmol), 2.1 g (8.7 mmol) of 2-(4-hydroxy-2-methylphenoxy)-2-methylpropionic acid ethyl ester (WO
2003072102), 5.25 g of 40% w/w potassium fluoride-alumina, 230 mg ( 0.87 mmol) of 18-crown-6 in CH3CN is refluxed under argon atmosphere. After 1 hour, the mixture is cooled to rt, partitioned between equal parts of ether and water, and shaked vigorously.
The aqueous layer and alumina sediments are separated, and the resulting organic phase is washed once with a saturated potassium chloride solution. The organic phase is dried over MgS04, and concentrated in vacuo. The crude is purificated by silica gel chromatogaphy (hexane/ethyl acetate 15:1 ) to yield 2,4 g of the title compound.

Step D
2-[4-2-amino-5-cyano-4-fluorophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester NH2 O C02Et I, ~I
NC v -O
5 . A mixture of 2-[4-(5-cyano-4-fluoro-2-nitrophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester (1.5 g, 3.7 mmol), 150 mg of Pd(c) 10% in 30 ml of EtOH is hydrogenated overnight at rt. Then, it is filtered over celite and washed with EtOH. The solvet is evaporated to give 1.4 g of the title compound, which is used for the next step without further purification.
10 Step E
2-[4-(3-cyano-4-fluorophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester To a solution of 2-[4-(2-amino-5-cyano-4-fluorophenoxy)-2 methylphenoxy]-2-methylpropionic acid ethyl ester (1.4 g, 3.7 mmol) in a mixture of 80m1 THF/ 8 ml water is added 2.91 ml (52.6 mmol) of H3P02 , catalytic amount of Cu20 15 and a solution of 312 mg (4.5 mmol) of NaN02 in 3 ml of water. After stirring at rt overnight , the mixture is diluted with an aqueous NaHCO3 solution and extracted with ethyl acetate (3x100 ml). he combined organic extracts are washed with aqueous NH4Cl, dried over MgS04 and evaporated to dryness. Purification by silica gel chromatogaphy (hexane/ethyl acetate 10:1 ) provides about 479 mg of the title compound. MS
Data: (ion 20 trap/ESI +): m/z 380.1 [M+Na] as base peak and m/z 358.1 [M+Hl.
Intermediate 54 2-[4-(5-cyano-2-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester / I O C02Et NC ~O

Step A
z 3-fluoro-4-methyl-5-nitrobenzonitrile 02N I w NC ~ F
Add potassium nitrate (4.51 g, 44.54 mmol) in three or four portions to 3-fluoro-4-methylbenzonitrile (6.02 g, 44.54 mmol) in concentrated H2S04 (50 ml) at 0°C and stir.
Stir the deep orange solution for 2 hours at 0°C and then for 1 hour at rt. Add the mixture over 800 ml of ice and extract with 150 ml of AcOEt. Allow the mixture to warm at rt and separate the organic layer. Extract again the aqueous layer with 100 ml of AcOEt.
Combine the organic extracts and washed with water (50 ml) and brine (50 ml).
Dry the organic layer over magnesium sulfate, filter, and concentrate under reduced pressure to give the crude product (7.64 g,.93% yield). Although the product can be used without further purification, flash chromatogapy can be performed in silica using hexane:ethyl acetate ( 10:1 ) as eluent.
St_ ep B
2-[4-(5-cyano-4-vitro-2-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester 02N ~ / O C02Et NC -O
Prepare a solution of 3-fluoro-4-methyl-5-nitrobenzonitrile (2.85 g, 15.49 mmol) and ethyl 2,2,-dimethyl-2-(3'-methyl-4'-hydroxy)phenyloxyacetate (WO
2003072102) (3.69 g, 15.49 mmol) in 150 ml of acetonitrile, and add 7.12 g of potassium fluoride (40% in alumina) and 18-crown-6 ether (409 mg, 1.55 mmol) and heat to reflux for 2 hours. Cool the mixture at rt, and add equal parts of water and diethyl ether (80 ml + 80 ml). Separate the aqueous layer and the alumina sediments and wash the organic layer with water (20 ml) and brine (20 ml). Dry the organic layer with sodium sulfate, filter and concentrate under reduced pressure to give the crude product (5.77 g, 94 %), which can be used without further purification.

Step C
2-[4-(5-cyano-4-amino-2-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester H N O C02Et /
NC ~O
~ Prepare a solution of compound obtained from Step B (5.08 g, 12.76 mmol) in 150 ml of ethanol and add a slurry of 508 mg of Pd/C ( 10%) in 20 ml of ethanol. Close the flask with a septum, purge it several times with H2 and stir it overnight under positive pressure of H2. Afterward, filter the slurry through a short pad of celite and evaporate the solution under reduced pressure to give the crude product (4.60 g, 98%), which can be used without further purification.
St~ ep D
2-[4-(5-cyano-2-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester Add 30 ml of HCl (2N) to a solution of Step C (2.07 g, 5.63 mmol) in 100 ml of THF-AcOH (9:1) and stir for 5 min. Add 1.7 ml of H20~ (3%) and then add a solution of sodium nitrite (388 mg, 5.63 mmol) in water (2m1). Stir the mixture at 0°C for 30 min and then at rt for 2 hours. Wash the mixture with saturated solution of sodium bicarbonate for several times until the aqueous layer reaches pH 9. Separate the organic layer and wash it with water and then brine. Dry the organic layer with magnesium sulfate, filter and evaporate the solvent under reduce pressure to give the crude product (1.69 g, 85%). Purify the product by flash chromatogaphy in silica using hexane-ethyl acetate (6:1) as solvent. Mass spectrum (m/e): 354 (M+1) Intermediate 55 2-[4-(3-cyano-5-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester O CO2Et / \
NC O

Step A
2-[4-(3-cyano-5-nitrophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester / O C02Et ~~C03 I ~ / I O\sCO~Et NC ~ N02 HO \ DMF, 95°C NC ~ O
(a) A mixture of 3,5-dinitrobenzonitrile (3.65 g, 1 x.90 mmol), compound (a) (WO 2003072102) (3 g, 12.60 mmol) and I~2C03 (2.1 g, 15.194 mmol) in DMF (40 mL, HPLC grade) is stirred at 95 °C. After 12 h, the mixture is poured into brine, and extracted with EtOAc. The organic layer is dried, filtered and concentrated, and the crude obtained is flash chromatographed on SiOz (10 % EtOAc/hexanes) affording 5.54 g of the arylether (94%, white solid).
Step B
2-[4-(3-cyano-5-aminophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester O C02Et NC O
Pd/C (600 mg, 10% Pd on activated C, 0.564 mmol) is added to a solution of the nitro compound from Step B (4.3 g, 11.20 mmol) in EtOH (50 mL, HPLC
grade).
The reaction mixture is stirred at r.t. for 2 h under H2 atmosphere (1 atm).
The mixture is filtered trough Celite (EtOAc washings), and the solvent is removed in rotatory evaporator. The product purified by flash chromatography on Si02 (l0-30%
EtOAc/hexanes) to afford 3.94 g of the amino compound (99%, colorless oil).
Step C
2-[4-(3-cyano-5-iodophenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester I
O C02Et / w NC O
Ter-BuONO (1.5 mL, 12.61 mmol) is added to a 0°C cooled solution of the arylamine from Step B (400 mg, 1.13 mmol) and IZ (1.72 g, 6.77 mmol) in (18 mL, HPLC grade). The mixture is allowed to reach r.t., poured into brine, and extracted with TBME. The organic layer is dried, filtered and concentrated.
The resulting crude is flash chromatographed on Si02 (3% EtOAc/hexanes) to afford 416 mg of the title compound (79%, white solid).
Step D
2-[4-(3-cyano-5-methylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester Me4Sn (292 mg, 1.631 mmol) is added to a solution of the iodide from Step C (380 mg, 0.8172 rnmol) and Pd(PPh3)4 (95 mg, 0.08172 mmol) in DMF (12 mL, anhydrous). The mixture is warmed to 120 °C and stirred at that temperature for 90 min.
It is allowed to reach r.t., filtered trough Celite and washed with EtOAc/brine. The organic layer is dried, filtered and concentrated. The crude residue is flash chromatographed on Si02 (3-5% EtOAc/hexanes) to afford 270 mg of the title compound (94%, colorless oil).
Intermediate 56 / I C02Et O
NHBoc Step A
3-methyl-4-bromobenzyloxyphenol OBn Br Benzyl bromide (3 mL, 25.2 mmol) is added to a suspension of 3-methyl-4-bromophenol (4.7 g, 25.13 mmol) and K2C03 (3.5 g, 25.32 mmol) in CH3CN (40 mL, HPLC grade), and the mixture is stirred at r.t. for 16 h. It is acidified with diluted HCI
(1M) and partitioned between EtOAc and HaO. The organic layer is dried, filtered and concentrated. The product is purified by flash chromatography on SiOa (1-2%
EtOAc/hexanes) to afford about 6.5 g of the benzylated phenol (93%, white solid).
Step B
Bn0 CO Et 5 Ethyl acrylate (12 mL, 114.7 mmol) is added to a solution of 3-methyl-4-bromobenzyloxyphenol (6.5 g, 23.465 mmol), palladium acetate (560 mg, 2.494 mmol), P(o-tol)3 (1.5 g, 4.928 mmol) and DIPEA (12 mL, 68.89 mmol) in EtCN (120 mL, HPLC
grade). The mixture is warmed to 95°C and stirred at that temperature for 60 h. It is allowed to reach r.t., filtered trough Celite and partitioned between EtOAc and HBO. The 10 organic layer is dried, filtered and concentrated, and the resulting crude is flash chromatographed on SiO2 (2-3~% EtOAc/hexanes) to afford 6.55 g of the Heck product (94%, white solid).
Step C
HO
C02Et 15 Palladium (1.2 g, 10% on activated carbon, 1.127 mmol) is added to a solution of the benzyloxyphenol (6.5 g, 21.96 mmol) in EtOH ( 120 mL), and the reaction mixture is stirred under HZ atmosphere (H~ balloon) overnight (c.a. 14 h). The reaction mixture is filtered trough Celite, and the solvent is removed in a rotatory evaporator. The crude residue is flash chromatographed on Si02 (5-10-15% EtOAc/hexanes) to afford 20 4.20 g of the title compound (92%, white solid).
Step D
/ I CO2Et O
CHO
A mixture of 2-fluorobenzaldehyde (2.35 g, 18.934 mmol), the compound obtained from Step C (3.5 g, 16.827 mmol) and I~ZC03 (1.35 g, 9.76 mmol) in anhydrous 25 DMF (30 mL) is warmed to 140°C, and the mixture is stirred at that temperature for 2 h.

It is allowed to reach r.t. and poured into brine. The organic layer is diluted with EtOAc, washed with brine and water, and then dried, filtered and concentrated. The resulting crude residue is flash chromatographed on Si02 (3-5% EtOAc/hexanes) to afford 2.38 g of the substitution product (45%, colorless oil).
Step E
/ I C02Et O

Nitromethane (1 mL, 18.46 mmol) is added to a suspension of aldehyde compound obtained from Step D (560 mg, 1.795 mmol) and ammonium acetate (500 mg, 6.486 mmol) in AcOH (glacial, 12 mL), and the mixture is warmed to 115°C. After 5 h, it is allowed to reach r.t., and then neutralized with NaHCO3 (s) and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated to give a crude residue that is flash chromatographed on Si02 (3% EtOAc/hexanes) affording 395g of the condensation product (62%, colorless oil).
St, ep F
/ I C02Et O
NHBoc Palladium (100 mg, 10% on activated carbon, 0.094 mmol) is added to a solution of the nitroalkene obtained from Step E (400 mg, 1.1267 mmol) in EtOH
(15 mL) and concentrated HCl (1 mL). The mixture is stirred under HZ atmosphere (H2 balloon) overnight (c.a. 14 h) and filtered trough Celite. The solvent is removed in a rotatory evaporator. The crude residue is dissolved in CH2C12 (20 mL) and Boc~O (1 g), and Et3N (1.5 mL) are added. The mixture is stirred at r.t. for 2 h, diluted with CH2C12 and washed with HCl (3% aqueous solution). The organic layer is dried, filtered and concentrated to give a crude that is flash chromatographed on Si02 (5%
EtOAc/hexanes) r to afford 302 mg of the title compound (63%, colorless oil).
Intermediate 57 2-[4-(3-amino-5-flurorphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester F
o\ /CO2Et H2N ~ O
Step A
2-[4-(3-vitro-5-flurorphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester F
o\/C02Et 02N ~ O \
The compound of 3,5-difluoronitrobenzene (1.477 g, 9.28 mmol) is added to a suspension of compound (a) from Intermediate 55, Step A (2 g, 8.4 mmol), I~F (4.5 g, 40% in A1203) and 18-crown-6 (210 mg, 0.8 mmol) in CH3CN (40 mL). The mixture is warmed to reflux and stirred for 4 h. It is allowed to reach r.t,. and partitioned between EtOAc and brine. The organic layer is dried, filtered and concentrated to give a crude residue that is flash chromatographed on Si02 (3-5% EtOAc/hexanes) to afford 2.4 g of the coupling product (76%, colorless oil).
Step B
2-[4-(3-amino-5-flurorphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester Palladium on carbon (300 mg, 10% Pd on activated C, 0.282 mmol) is added to a solution of vitro compound obtained from Step A (2.4 g, 6.366 mmol) in MeOH (80 mL). The mixture is stirred at r.t. for 2 h under H2 atmosphere (balloon), and filtered trough Celite (EtOAc washings). The solvent is removed in rotary evaporator, and the product is purified by flash chromatography on SiO2 (10%
EtOAc/hexanes) to afford 2.0 g of title compound (90%, colorless oil).

Intermediate 58 \ O~~COZEt \ ) ~ j~\/
BocN O
St_ ep A
O~~COZEt \ ~ I /
OHC ~O
The compound (a) from Intermediate 55, Step A (1.6 g, 6.722 mmol) and boronic aldehyde (2 g, 13.35 mmol) are added to a suspension of Cu(OAc)2 (2.45 g, 13.488 mmol) in a mixture of pyridine (5.4 mL) and CH2C12 (40 mL). The mixture is stirred at r.t. under air atmosphere in the presence of sieves for 36 h. It is filtered through Celite (CH2Cl2 washings) and partitioned between CHZCl2 and diluted HCl (3%
aqueous solution). The organic layer is dried, filtered and concentrated to give a crude residue that is flash chromatographed on Si02 (5-10% EtOAc/hexanes) affording 0.525 mg of unreacted starting compound (a) and 700 mg of the coupling product (30%, colorless oil).
Step B
/ ~ \ O/' /C02Et \ \ ~ O
OZN
Nitromethane (4 mL, 73.84 mmol) is added to a suspension of aldehyde obtained from Step A (1.3 g, 3.8 mmol) and ammonium acetate (1.2 g, 15.566 mmol) in AcOH (glacial, 15 mL), and the mixture is warmed to 17 0°C. After 4 h 30 min., it is allowed to reach r.t., neutralized with NaHC03 (s) and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated to give a crude residue that is flash chromatographed on Si02 (10% EtOAc/hexanes) affording 980 mg of the title compound (67%, colorless oil).

St__ ep C
O_ 'C02Et H2N ~ O
Palladium (100 mg, 10% on activated carbon, 0.094 mmol) is added to a solution of the nitroalkene obtained from Step B (1.0 g, 2.597 mmol) in a mixture of MeOH (25 mL) and concentrated HCl (1 mL). The mixture is stirred under HZ
atmosphere (H2 balloon) overnight (c.a. 14 h) and filtered trough Celite. The solvent is removed in a rotatory evaporator. The crude residue is flash chromatographed on Si02 (10-20-30% iPrOH, 0.2% DIPEA/hexanes) to afford 200 mg of the title compound (22%, colorless oil).
. Ste D
O/' /COZEt BocN O
Boc20 (165 mg, 0.7575 mmol) and Et3N (0.25 mL, 1.82 mmol) are added to a solution of the amine obtained from Step C (180 mg, 0.606 mmol) in CH2C12 (12 mL). The mixture is stirred at r.t. for 15 min_, diluted with CH2C12 and extracted with HCl (3% aqueous solution). The organic layer is dried, filtered and concentrated to give a crude residue that is flash chromatographed on Si02 (10-20% EtOAc/hexanes) affording 140 mg of the title compound (58%, colorless oil).
v Intermediate 59 3-(2-ethyl-4-hydroxy-phenyl)-propionic acid ethyl ester O
~O
HO
Step A: Benzyl protection of 3-eth~phenol The 3-ethyl phenol (244g, 2.0 mol, 1.0 eq) and benzyl bromide (350.6 g, 2.05 mol, 1.025 eq.) are stirred in a 5-liter flask with 1.0 Liter DMF. A
15°C bath is applied to keep the reaction temperature at 20-25°C. The potassium carbonate (359.6g, 2.6 mol, 1.3 eq) is added with 350 ml DMF, and the mixture is stirred over night (14 hours) at 20-25°C. Tert-butyl methyl ether (MTBE, 650 ml) is added to the mixture. The solids in the mixture are filtered over a Hyflo pad, and are washed with 650 ml MTBE.
The filtrate is washed with a solution 1150 ml 0.35 N HCl. The aqueous layer is back extracted with 500 ml MTBE, and the combined organic layers are washed with 500 ml water and then with 500 ml saturated NaCl solution. The organic layer is dried over magnesium sulfate, and then filtered and evaporated at 40°C on a rotary evaporator to afford about 424 g light yellow fluid oil.
Step B: N-Bromination The starting material (420g, 1.98 mol uncorr., 1 eq) and 1800 ml of acetonitrile are added to a 5L flask and stirred under nitrogen atmosphere.
The N-bromosuccinimide (341.8 g, 1.92 mol, 0.97 eq) is added in four to five portions over 15-20 minutes. A 15°C water bath is applied to the flask to keep the temperature at less than 40°C. The NBS is rinsed into flask with 200 ml ACN. The reaction is stirred for 2 h, over which time the temperature decreased from 37°C to 20°C. The mixture is transferred to a rotary evaporator and evaporated to a mushy oil (app. 900 g).
To this oil is added 2000 ml of MTBE, and the mixture is transferred to a separatory funnel. This is washed once with 750 ml of 1N HCl, once with 750m1 of 0.3 N HCI, and once with ml of saturated NaCl solution. The organic layer is dried over MgS04, and then evaporated on a 40°C bath in vacuo to afford about 567.8 g of light orange oil.

Step C: Form lation The starting material oil (509.2g, 1.75 mol, 1 eq) is dissolved in 1.0 L of THF and dried over night over 4 A molecular sieves. The solution is filtered into a 12-L
4 neck flask, and rinsed in with 3.0 L THF. Under nitrogen atmosphere, the mixture is cooled to -70 to -72°C. n-Butyl Lithium, 2.5M in hexane (800m1, 2.0 mol, 1.15 eq) are added slowly over 1 hour 40 minutes while keeping the temperature below -68°C. The reaction is then stirred for 5 minutes, and then dry DMF (1L, 12.9 mol, 7.37 eq) is. added as quickly as possible, while keeping the temperature below -48°C. The cooling is removed, and the reaction is warmed to -14°C. A solution of 1 N HCl (3.0 L) is added over 3 minutes. The mixture is transferred to a separatory flask and then extracted with 4L diethyl ether, and then with 3.5L diethyl ether. The combined ether layers are washed with a solution of 1L 1N HCI, 1L saturated NaCI solution and 2 L saturated NaCI
solution. The ether solution is dried over 500 g magnesium sulfate and then filtered, washed with ether, and evaporated on 40°C bath to a constant weight to afford about 417.4 g brown oil (99.4% weight yield).
Step D: Homer-Emmons To a 12 flask fitted with a heating mantle, nitrogen atmosphere, and a stirrer is added 4 L ethanol (2B-3). The potassium carbonate (679.1 g, 4.01 mol, 3.15 equivalents), the aldehyde (375 g, 1.56 mol, 1 equiv.), and triethylphosphonoacetate (454.7 g, 2.03 mol, 1.3 eq) are added to the 12L flask, and then rinsed in with a total of 900 ml ethanol. The reaction is heated to reflux over 30 min., and then refluxed for 2h and 15 min., and then allowed to cool to rt. The mixture is filtered to remove the potassium salts, and the filtrate is evaporated to 1270 g to remove most of the ethanol.
The oil is transferred to a separatory flask and added ~t-L ethyl acetate and washed with 5L
0.6 N HCI. The aqueous layer is back extracted with 4L O.1N HCI, and then with saturated NaCI solution. The organic layer is dried over magnesium sulfate, filtered, and then evaporated to a dark brown oil on a 40 bath to afford about 565 g.
Step E: Hydro~enation The starting material oil, 1000g (Then. 2.62 mol from HEW), is dissolved in 4L ethyl acetate and added to a 3-gallon autoclave. About 250 g (42% water wet) of 10% palladium on carbon is added. The mixture is hydrogenated at 50 psi hydrogen pressure at 50°C. After the reaction is completed, the mixture is cooled to 20-25°C and held under 50 psi hydrogen pressure over night. The catalyst is filtered and washed with 1.5 L ethyl acetate. The solution is evaporated on 40°C bath to yield about 732.2 g of the crude final compound.
The final compound is purified as described below. A 5 kg Biotage Flash Chromatography column is pre-conditioned with lOL of 95:5 heptane:ethyl acetate.
About 250 g of crude final product (120 wt% yield from Step 4 SM, GC 70%) is loaded on the column with 250 ml 10:1 heptane:ethyl acetate. The column is eluted with 20L of 95:5 heptane:ethyl acetate (4 L fractions) prior to impurities being eluted;
then with 20 L
of 95:5 heptane:ethyl acetate (2 L fractions). Fractions are analyzed by TLC
(silica; 4:1 heptane:ethyl acetate) and/or by GC. At this point, the fractions contained <95% pure product. The elution is continued with 40 L of 80:20 heptane:ethyl acetate, with 4 L
fractions being taken. The fractions containing the final product of <95%
purity (by GC) are combined and evaporated to a clear oil (colorless to light yellow).
(131.48, 52.5%
weight recovery, 63.1 % yield from Step D, starting material of aldehyde) Intermediate 60 3-(4-Hydroxy-phenyl)-2,2-dimethyl-propionic acid methyl ester / ~ O/
HO
Step A
2-Methyl-4-anisaldehyde A mixture of 2,3-dimethylanisole (508, 0.37 mol), Cu2+ sulfate pentahydrate (90 g, 0.36 mol), and potassium peroxydisulfate (301 g, 1.11 mol) in acetonitrile/water (1:1, 2.6 L) is stirred vigorously and heated to reflux for 30 minutes.
The reaction is cooled to rt and extracted with CHZCh (4L) and washed with water (2L).
The layers are separated, and the aqueous layer is again extracted with CH~C12. The organic layers are combined and concentrated to afford about 55 g 0100%) product, which is taken on as is. 1H-NMR (DMSO-d6): 10.05 (s, 1H), 7.78 (m, 1H), 6.95 (m, 1H), 6.88 (s, 1H), 3.84 (s, 3H), 2.6 (s, 3H).
Step B
4-Methoxy-2-methylbenzyl alcohol NaBH4 (14.82 g, 0.39 mol) is added to a solution of the compound from Step A (55 g, 0.37 mol) in EtOH (800 mL). The reaction is quenched with water (3L), acidified with 5N HCI, and extracted with Et20. The organics are separated and concentrated. The crude product is purified by Biotage 75L (Hexane:EtOAc, 9:1) to afford about 17.35 g (30%). 1H-NMR (CDCI3): 7.22 (m, 1H), 6.7 (m, 2H), 4.64 (s, 2H), 3.8 (s, 3H), 2.4 (s, 3H).
Step C
Acetic acid 4-methoxy-2-methyl-benzyl ester A solution of compound from Step B (17.35 g, 0.114 mol) in CHZC12 (900 mL) is cooled 0°C, and TEA (23.3 mL, 0.167 mol) and acetyl chloride (9.3 mL, 0.131 mol) are added. The reaction is stirred for 1 h and then quenched with 1N HCI, washed with aq. NaHC03, brine, dried (Na2S04), and concentrated to afford an oil (22.14 g, 100%). 1H-NMR (CDCl3): 7.24 (m, 1H), 6.73 (m, 2H), 5.08 (s, 2H), 3.8 (s, 3H), 2.33 (s, 3H), 2.08 (s, 3H).
Step D
3-(4-Methoxy-2-methyl-phenyl)-2,2-dimethyl-propionic acid methyl ester The compound from Step C (22.14 g, 0.114 mol) is dissolved in CH2C12 and treated with 1-methoxy-1-trimethylsiloxy-2-methyl-1-propene (53.3 g, 0.306 mol) and Mg(C104)2 (2.58 g, 0.012 mol). The reaction is stirred overnight at rt.
Upon completion, the reaction is washed with water, brine, and dried with Na2S04.
The crude product is purified (Biotage 75M (Hexane:EtOAc, 9:1 ~ 8:2)) to obtain about 18.7 g (70%). 1H-NMR (CDC13): 6.97 (d, 1H), 6.7 (m, 2H), 3.8 (s, 3H), 3.64 (s, 3H), 2.85 (s, 2H), 2.3 (s, 3H), 1.2 (s, 6H).
Step E
3-(4-Hydroxy-phenyl)-2,2-dimethyl-propionic acid methyl ester BBr3 (1M in CH2CI2, 79 ml) is cooled to 0°C, and the compound from Step D (9.35 g, 0.0395 mol) is added dropwise over 10 minutes. After stirring for 1 h at 0°C, the reaction is quenched with 1:1 MeOH: CH2C12. The organics are concentrated, and the resulting oil is run through a plug of silica gel with Hexane:EtOAc (8:2).
Fractions 1,2 are concentrated and about 7.5 g (85%) of the desired compound are isolated. 1H-NMR (CDCI3): 6.87 (d, 1H), 6.6 (m, 2H), 4.9 (bs, 1H), 3.64 (s, 3H), 2.82 (s, 2H), 2.22 (s, 3H), 1.2 (s, 6H).
Intermediate 61 3-[4-(3-Aminomethyl-5-chloro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester / ( / ~ Oi H2N \ ~ \
The title compound is prepared according to the procedure described in Intermediate 33 utilizing 3-chloro-5-fluoro-benzonitrile and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (J.Claem..Soc.Perkin Tran.s_1; 4; 1990;
1041-1045).
MS: (ES+) 334 (M+H+); 1H NMR (400 MHz, CDC13).
Example 1 General Procedures for Couplin ag nd H
Step A-Coupling Step Acid (1.0 eq), amine (1.0-1.5 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydochloride (1.2-1.5 eq), 1-hydroxybenzotriazole hydrate (1,.2-1.5 eq), and N,N-diisopropylethylamine (1.0 eq) are stirred overnight under nitrogen at rt in dry THF or dry DMF. Water is added, extracted with ethyl acetate, washed with HCI, then saturated sodium bicarbonate, followed by brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography, eluting with 10-15 % EtOAc in hexane then 25 % EtOAc in hexane provides the intermediate ester shown in the above general procedure.
Step B-Hydrolysis Step Compound from Step A (1 eq) is hydrolyzed in dioxane/water (2:1 v/v, ~0.02M) with lithium hydroxide hydrate (7-13 eq). Reaction is stirred at rt overnight under nitrogen, and then acidified with 5 N HCI. Water is added, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the final acid.
Example 2 3-(2-Ethyl-4-{3-fluoro-5-[1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenyl)-propionic acid F O
v ~OH
N O \
O
Step A
3-(2-Ethyl-4-{ 3-fluoro-5-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenyl)-propionic acid ethyl ester 2-Methyl-4-trifluoromethyl-benzoic acid (41.3 mg, 0.20 mmol), 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester (Intermediate 23) (80.0 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydochloride (46.5 mg, 0.24mmo1), 1-hydroxybenzotriazole hydrate (32.8 mg, 0.24 mmol), and N,N diisopropylethylamine (0.035 mL, 0.2,0 mmol) are stirred overnight under nitrogen at rt in dry THF (8 mL). Water is added, extracted with ethyl acetate, washed with 1 N HCI, then saturated sodium bicarbonate, followed by brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography, eluting with 15 % EtOAc in hexane then 25 % EtOAc in hexane provides the title compound (84.1 mg, 76 %). MS(ES+): 546 (M+H+); 1HNMR (400 MHz, CDC13) Step B
3-(2-Ethyl-4-{ 3-fluoro-5-[ l -(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenyl)-propionic acid Compound of Step A (84.1 mg, 0.15 mrnol) is dissolved in dioxane (6 mL) and lithium hydroxide hydrate (85 mg, 2.02 mmol), dissolved in water(3 mL), is added.
Reaction is stirred at rt overnight under nitrogen, then acidified with 5 N
HCI. Water is added, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (66.4- mg, 84 %). Exact mass calculated for C28HZ8F4N04 (M+H+) 518.1954, found 518.1956; 1NMR (400 MHz, CDC13).
Example 3 2-(4-{ 3-[(2,4-Bis-trifluoromethyl-benzoylamino)-methyl]-phenoxy} -2-methyl-phenoxy)-2-methyl-propionic acid F OsC
\ ~~F / / OH
F I / F N \ I \ I CHs O
O
The title compound is prepared according to Example 1 utilizing 2,4-bis-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for Ca7H24F6N05 (M+H+): 556.1559, found 556.1561; 1H NMR (400 MHz, CDCl3).
Example 4 2-(4-{ 3-[(2,4-Dimethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid I \ / I / I O OH
/ N \ O \ CHs O
The title compound is prepared according to Example 1 utilizing 2,4-dimethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C2~H3oN05 (M+H+):
448.2240, found 448.21 l 8; 1H NMR (400 MHz, CDC13).

Example 5 2-Methyl-2-(4-{ 3-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-phenoxy)-propionic acid O
F F HsC
F \ / ~ / ~ O OH
\ O ~ CH3 I
O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 2-[4-(3-aminornethyl-phenoxy)-phenoxy]-2-methyl-propionic acid (Intermediate 49). Exact mass calcd for C~~HZSF3NO5 (M+H+): 488.1685, found 488.1674; 1H NMR (400 MHz, CDC13).
Example 6 2-Methyl-2,-(4-{ 3-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-phenoxy)-propionic acid O

/ ( / ( O OH
N \ O \ CHI
The title compound is prepared according to Example 1 utilizing 4-trifluoromethyl-benzoic acid and 2,-[4-(3-aminomethyl-phenoxy)-phenoxy]-2-methyl-propionic acid (Intermediate 49). Exact mass calcd for C25HasFsNOs (M+H+):
474.1588, found 474.1505; 1H NMR (400 MHz, CDC13).

Example 7 2-Methyl-2-(2-methyl-4-{ 3-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid H / / ~ O OH
N \ ~ O \ CH3 The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C27H27F3NOs (M+H+): 502.1841, found 502.1844; 1H NMR (400 MHz, CDC13).
Example 8 2-{4-[3-(Isopropoxycarbonylamino-methyl)-phenoxy]-2-methyl-phenoxy} -2-methyl-propionic acid O
\ / O OH
O N ~ / \
O
O
The title compound is prepared according to the general procedures described in Example 140 utilizing isopropyl chloroformate and 2-[4-(3-aminomethylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester (Intermediate 17). Mass (ES+): 402.3 (M+H+).

Example 9 2-Methyl-2-(2-methyl-4- { 3-[(2-methyl-4-trifluoromethoxy-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid F F O HsC
\ / / I O OH
H
F / N \ O \ CHs O
step A
2-Methyl-2-(2-methyl-4-{ 3-[(2-methyl-4-trifluoromethoxy-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid ethyl ester The compound of 2-methyl-4-trifluoromethoxy-benzoic acid (30.0 mg, 0.14 mmol) (Intermediatel3), 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17) (47Ø mg, 0.14 mmol), 0-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (62.0 mg, 0.16 mmol), and N,N diisopropylethylamine (0.023 mL, 0.14 mmol) are stirred overnight under nitrogen at rt in DCM (3 mL) and dry DMF (0.5 mL). Water is added, and the mixture is extracted with ethyl acetate. The mixture is washed with 1 N HCl and saturated sodium bicarbonate and brine, and then dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography, eluting with 15 % EtOAc in hexane and then 25 % EtOAc in hexane provides the title compound (41 mg, 55 %). MS(ES+): 546 (M+H+); 1HNMR (400 MHz, CDCl3).
St-ep B
2-Methyl-2-(2-methyl-4-{3-[(2-methyl-4-trifluoromethoxy-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid Compound of Step A (41.0 mg, 0.075 mmol) is dissolved in dioxane (4 mL) and lithium hydroxide hydrate (62.0 mg, 1.5 mmol), dissolved in water (2 mL), is added. Reaction is stirred at rt overnight under nitrogen, and then acidified with 5 N HCI.
Water is added and the mixture is extracted with EtOAc, which is washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (35.0 mg, 90 %). Exact mass calcd for C27H27F3NO6 (M+H+): 518_ 1790, found 518.1797; 1H NMR (400 MHz, CDC13).

Example 10 2-(4-{ 3-[(4-Methoxy-2-methyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-methyl-propionic acid O \ / / 3 OH
I / N \ I \ I ~H3 O
O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-methoxy-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C~7H3pNO6 (M+H+): 464.2073, found 464.2082; 1H NMR (400 MHz, CDC13).
Example 17 2-(4- { 3-[(3,4-Dimethyl-benzoylamino)-methyl]-phenoxy } -2-methyl-phenoxy)-2-methyl-propionic acid \ / I / I ~ OH
H
/ N \ O \ CHs O
The title compound is prepared according to Example 1 utilizing 3,4-dimethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C~,7H3oN05 (M+H+):
448.2124, found 448.2126; 1H NMR (400 MHz, CDCl3).

Example 12 2-(4-{ 3-[(2,4-Dichloro-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid CI \ CI / ~ / ~ O OH
/ N \ O \ CH3 I
O
The title compound is prepared according to Example 1 utilizing 2,4-dichloro-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C25Haa.ClaNOS
(M+H+): 488.1032, found 488.1041;1H NMR (400 MHz, CDCl3).
Example 13 2-(4-{ 3-[(4-Ethyl-benzoylamino)-methyl]-phenoxy } -2-methyl-phenoxy)-2-methyl-propionic acid \ / / ~OH
N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 4-ethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for Ca7H3oN05 (M+H+):
448.2124, found 448.2099; 1H NMR (400 MHz, CDCl3).

Example 14 2-(4-{ 3-[(2-Fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy } -2-methyl phenoxy)-2-methyl-propionic acid \ F / / 03 OH
N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C26H~,4FqNOs (M+H+): 506.1591, found 506.1581; 1H NMR (400 MHz, CDCl3).
Example 15 2-Methyl-2-(2-methyl-4- { 3-[(2-methyl-benzoylamino)-methyl]-phenoxy } -phenoxy) propionic acid \ CH3 / / 03 OH
/ N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 2-methyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for CZ6H28NO5 (M+H+):
434.1967, found 434.1954; IH NMR (400 MHz, CDC13).

Example 16 2-Methyl-2-(2-methyl-4-{ 3-[(2-nitro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid F F O+ CH3 O

NCO / ~ / ~ O OH
/ N \ O \ CHs O
The title compound is prepared according to Example 1 utilizing 2-nitro-4-triflouromethyl-benzoic acid (US Pat. No. 4,868,833) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for C26H24F3N207 (M+H+): 533.1536, found 533.1518; 1H NMR
(400 MHz, CDC13).
Example 17 2-(4-{ 3-[(4-Acetyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid H3C ~ \ H / ~ / ~ ' O OH
/ N \ ~ \ CHa O
The title compound is prepared according to Example 1 utilizing 4-acetyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C~7H2gN06 (M+H+):
462.1897, found 462.1917; 1H NMR (400 MHz, CDC13).

Example 18 2-Methyl-2-[2-methyl-4-(3-{ [2-(4-trifluoromethyl-phenyl)-acetylamino]-methyl }-phenoxy)-phenoxy]-propionic acid CH3 ~ C O

/ / OH

O
F F ~ / O
F
The title compound is prepared according to Example 1 utilizing (4-trifluoromethyl-phenyl)-acetic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C27H~7F3N05 (M+H+): 502.1841, found 502.1832; IH NMR (400 MHz, CDC13).
Example 19 2-Methyl-2-[2-methyl-4-(3-{ [methyl-(2-methyl-4-trifluoromethoxy-benzoyl)-amino]-methyl}-phenoxy)-phenoxy]-propionic acid F

~OH

O
The ethyl ester of the title compound is prepared according to Intermediate 2, Step A by utilizing 2-ethyl-2-(2-methyl-4-{3-[(2-methyl-4-trifluoromethoxy-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid ethyl ester (Example 9, Step A), and is then hydrolyzed according to Example 9, Step B, providing the title compound.
Exact mass calcd for C28H29F3NO6 (M+H+): 532.1947, found 532.1921; 1H NMR (400 MHz, CDCl3).

Example 20 3-(2-Methyl-4-{ 3-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-phenyl)-propionic acid CH3 / ~ / ~ OH
H
/ N \ O \
O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C26Ha5F3N0ø (M+H+): 472.1736, found 472.1744; 1H NMR (400 MHz, CDCl3).
Example 21 2-(4-{ 3-[(2-Methoxy-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid \ O~CH3 / / 03 OH
/ N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 2-methoxy-4-trifluoromethyl-benzoic acid (J.Af~i.Chem.Soc.; 73; 1951; 2375) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C27Ha7FsN06 (M+H+): 518.1790, found 518.1788;'H NMR (400 MHz, CDC13).

Example 22 2-(4-{ 3-[(2-Chloro-4-fluoro-benzoylamino)-methyl]-phenoxy }-2-methyl-phenoxy)-methyl-propionic acid F \ CI / / 03 OH
/ N \ ~ \ ( CHa O
O
The title compound is prepared according to Example 1 utilizing 2-chloro-4-fluoro-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C25HzaC1FN05 (M+H+): 472.1327, found 472.1322; 1H NMR (400 MHz, CDC13).
Example 23 2-(4-{ 3-[(3-Fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-2-methyl-phenoxy)-2-methyl-propionic acid \ / / 03 OH
F
N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 3-fluoro-4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for Cz6H24F4N05 (M+H+): 506.1591, found 506.1593; 1H NMR (400 MHz, CDCl3).

Example 24 i 2-(4-{ 3-[(2,3-Dimethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid \ CH3 / / 03 OH
N \ ~ \ ~ CHs O
O
The title compound is prepared according to Example 1 utilizing 2,3-dimethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C27H3oNO5 (M+H~):
448.2124, found 448.2111;1H NMR (400 MHz, CDC13).
Example 25 2-Methyl-2-(2-methyl-4-{ 3-[(2-methylsulfanyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid F \ S~CH3 / ~ / ~ O OH
H
/ N \ O \ CHs O
The title compound is prepared according to Example 1 utilizing 2-methylsulfanyl-4-trifluoromethyl-benzoic acid (WO 9902489) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for C~7HZ~F3NOSS (M+H+): 534.1562, found 534.1542; 1H NMR
(400 MHz, CDCl3).

Example 26 2-(4-{ 3-[(2-Methanesulfinyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-methyl-phenoxy)-2-methyl-propionic acid CH3, O

/ / ~OH

NH \ ~ \ ~ CH3 ~O
The compound of 2-methyl-2-(2-methyl-4-{3-[(2-methylsulfanyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid (61.7 mg, 0.12mmo1) (Example 25) is dissolved in chloroform (5 mL), cooled in an ice bath, and solid 3-chloroperoxybenzoic acid (77 %) (24.7 mg, 0.11mmol) is added. Solution is stirred for 15 minutes and quenched with water and then extracted with dichloromethane.
The solution is washed with sodium bicarbonate, brine, and then dried with sodium sulfate and concentrated under reduced pressure providing the title compound (18.6 mg, 30 %) without further purification. Exact mass calcd for C27H27F3NO6S (M+H+):
550.1511, found 550.1490; 1H NMR (400 MHz, CDC13).
Example 27 2-(4-{ 3-[(4-Isobutyl-benzoylamino)-methyl]-phenoxy } -2-methyl-phenoxy)-2-methyl propionic acid HsC \ / / O OH
H
CH3 ~ / N \ ( \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 4-isobutyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C29H34N05 (M+H+):
476.2437, found 476.2437; 1H NMR (400 MHz, CDC13).

Example 28 2-(4-{ 3-[(4-Isopropyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid H3C \ / / ~OH
I / N \ I \ I CH3 O
O
The title compound is prepared according to Example 1 utilizing 4-isopropyl-benzoic acid and 2-(4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for CZ8H32N05 (M+H+):
462.2299, found 462.2280; 1H NMR (400 MHz, CDC13).
Example 29 2-(4-{ 3-((2-Bromo-4-methyl-benzoylamino)-methyl]-phenoxy }-2-methyl-phenoxy)-methyl-propionic acid H3C \ Br / I / I O OH
H
/ N \ O \ CHa O
The title compound is prepared according to Example 1 utilizing 2-bromo-4-methyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C26H27BrN05 (M+H+):
512.1073, found 512.1069; IH NMR (400 MHz, CDCl3).

Example 30 2-[4-(3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid / / O OH
N ~ N \ ( \ ~ CHs O
O
The title compound is prepared according to Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C27Ha6C1NZO5 (M+H+): 493.1530, found 493.1547; 1H NMR (400 MHz, CDC13).
Example 31 3-(4-{ 3-[(2-Methoxy-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenyl)-propionic acid \ O~CH3 / ~ / ~ OH
H
/ N \ O \
O
The title compound is prepared according to Example 1 utilizing 2-methoxy-4-trifluoromethyl-benzoic acid (J.Am. Chem.Soe.; 73; 1951; 2375) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33 ).
Exact mass calcd for C26HZSF3N05 (M+H+): 488.1685, found 488.1680;'H NMR (400 MHz, CDCl3).

Example 32 3-(4-{ 3-[(2-Fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-2-methyl-phenyl)-propionic acid F ~ \ F / ~ / ~ OH
H
/ N \ O \
O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for (M+H+): 476.1485, found 476.1503;1H NMR (400 MHz, CDC13).
Example 33 2-Methyl-2-(2-methyl-4-{ 4-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid F F
CH3 / O \
H O
/ N \ ~ ~ / O
I
O O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 2-[4-(4-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 18). Exact mass calcd for C27H27F3N05 (M+H+): 502.1841, found 502.1832; IH NMR (400 MHz, CDC13).

Example 34 2-[4-(3-{ [(3-Chloro-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid \ C~ / ~ / ~ O OH
N N \ O \ CHs O
The title compound is prepared according to Example 1 utilizing 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid and 2-[4-(3-aminomethyl-phenoxy)-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C25HZSC1F3N205 (M+H+): 52.3.1248, found 523.1247; 1H NMR (400 MHz, CDC13).
Example 35 2-[4-(3-{ [( 1 H-Indole-2-carbonyl)-amino]-methyl } -phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid CH3 ~ O

N / / O OH
N \ ~ O \ ~ CH3 I
O
The title compound is prepared according to Example 1 utilizing 1H-indole-2-carboxylic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C27H27N20s (M+H+): 459.1290, found 459.1918; 1H NMR (400 MHz, CDCI3).

Example 36 z 3-[4-(3-{ [(5-Chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid ~ OOH
N \ \
O
O
The title compound is prepared according to Example 1 utilizing 5-chloro-benzo[b]thiophene-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for Cz6HasC1NO4S (M+H+): 480.1036, found 480.1016; 1H NMR (400 MHz, CDC13).
Example 37 3-[4-(3-{ [(5-Fluoro-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2-methyl-phenyl]-propionic acid OOH
N~N \ O \
'IO
The title compound is prepared according to Example 1 utilizing 5-fluoro-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C26HaaFNaO4 (M+H+): 447.1720, found 447.1720; 1H NMR (400 MHz, CDCl3).

Example 38 3-[2-Methyl-4-(3-{ [(5-trifluoromethoxy-1 H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-phenyl]-propionic acid F
F~~---F

/ / ~ ~OH
~I ~I
O
O
The title compound is prepared according to Example 1 utilizing 5-trifluoromethoxy-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2,-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C27H24F3N205 (M+H+): 513.1637, found 513.1647; iH NMR (400 MHz, CDC13).
Example 39 3-[2-Methyl-4-(3-{ [(5-methyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-phenyl]-propionic acid / / a ~OH
NI N ~ I O ~
I
O
The title compound is prepared according to Example 1 utilizing 5-rnethyl-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for Ca7HZ~N~04 (M+H+):
443.1971, found 443.1966; 1H NMR (400 MHz, CDC13).

Example 40 3-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid / / ~ ~OH
I N ~
if O
O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for Cz7HzsC1N04S (M+H+): 494.1193, found 494.1189;1H NMR (400 MHz, CDCl3).
Example 41 2-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid CI

I N ~ I O ~ I CH3 I
O
The title compound is prepared according to Example 9 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and 2-[4-(3-aminomethyl-phenoxy)-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for CZ8H27C1NOSS (M+H+): 524.1298, found 524.1304; 1H NMR (400 MHz, CDCl3).

Example 42 3 3-[2-Methyl-4-(3-{[(naphthalene-2-carbonyl)-amino]-methyl}-phenoxy)-phenyl]-propionic acid \ \ / / ~ ~OH
/ / N \ I \
O
O
The title compound is prepared according to Example 1 utilizing naphthalene-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C2gHz6N04 (M+H+):
440.1862, found 440.1873; 1H NMR (400 MHz, CDCl3).
Example 43 3-[4-(3-{ [(5-Cyano-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid N

/ / ~ ~OH
NI N \ I O \
I
O
The title compound is prepared according to Example 1 utilizing 5-cyano-3-methyl-1H-indole-2-carboxylic acid (J. Med. Chenv. 1997, 40 (18), 2843-2857) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C2gH~6N3O4 (M+H+): 468.1923, found 468.1903; 1H NMR
(400 MHz, CDC13).

Example 44 3-[4-(3-{ [(5-Cyano-1-methyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid ~OH
NI N \ I O \
HsC O
The title compound is prepared according to Example 1 utilizing 5-cyano-1-methyl-1H-indole-2-carboxylic acid (J. Med. Clzem. 1997, 40 (18), 2843-2857) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C~,gH2gN3O4 (M+H+): 468.1923, found 468.1903; 1H NMR
(400 MHz, CDC13).
Example 45 3-[4-(3-{ [(4-Chloro-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid CI

~OH
I N \ ~ \
N ~ O
O
The title compound is prepared according to Example 1 utilizing 4-chloro-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C26Ha4C1N2O4 (M+H+): 463.1425, found 463.1399;'H NMR (400 MHz, CDCl3).

Example 46 3-[4-(3-{ [(5-Chloro-3-phenyl-1 H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-methyl-phenyl]-propionic acid CI

~OH
NI N \ I O \
I
O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-phenyl-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C32H28C1NZO4 (M+H+): 539.1738, found 539.1736; 1H NMR (400 MHz, CDC13).
Example 47 3-[4-(3-{ [(5-Cyano-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid ( H ~ I ~ I OH
N II N \ O \
O
The title compound is prepared according to Example 9 utilizing 5-cyano-1H-indole-2-carboxylic acid (J. Med. Chenz. 1997, 40 (18), 2843-2857) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C27HZ4N3O4 (M+H+): 454.1767, found 454.1743; 1H NMR (400 MHz, CDC13).

Example 48 2-(4-{ 3-Fluoro-5-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-methyl-phenoxy)-2-methyl-propionic acid F \ CH3 / / 03C OH
/ N \ ~ \ ~ CHs O
O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47).
Exact mass calcd for C27H26F4NOs (M+H+): 520.1747, found 520.1747; IH NMR (400 MHz, CDC13).
Example 49 3-[4-(3-{ [(6-Chloro-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid CI \ / ~ / ~ / ~ ~~OH
H
\ O \
O
The title compound is prepared according to Example 1 utilizing 6-chloro-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C26Ha4C1N2O4 (M+H+): 463.1425, found 463.1427;'H NMR (400 MHz, CDC13).

Example 50 3-[4-(3-{ [(5-Chloro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2-methyl-phenyl]-propionic acid CI

~OH
NI N \ I o \ I
I
O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 3) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C27HZgCIN~,O4 (M+H+): 477.1581, found 477.1584; 1H NMR (400 MHz, CDC13).
Example 51 3-[2-Methyl-4-(3-{ [(3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-phenoxy) phenyl]-propionic acid ~OH
S I N \ I O \
I
O
The title compound is prepared according to Example 1 utilizing 3-methyl-benzo[b]thiophene-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C27H~6NO4S
(M+H+): 460.1582, found 460.1578; 1H NMR (400 MHz, CDCl3).

Example 52 i 3-[4-(3-{ [(Benzo[b]thiophene-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]
propionic acid / / ~ OOH
SI N ~ I ~
O
O
The title compound is prepared according to Example 1 utilizing benzo[b]thiophene-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C2gH24NO4S
(M+H+): 446.1439, found 446.1439; 1H NMR (400 MHz, CDC13).
Example 53 3-(2-Methyl-4-{ 3-[(4,4,4-trifluoro-butyrylamino)-methyl]-phenoxy }-phenyl)-propionic acid F F / / ~ OOH
F N ~ I o ~
I
O
The title compound is prepared according to Example 1 utilizing 4,4,4-trifluoro-butyric acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C21H23F3N~4 (M+H+):
410.1579, found 410.1586; 1H NMR (400 MHz, CDCl3).

Example 54 3-(4-{ 3-Fluoro-5-[(2.-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-methyl-phenyl)-propionic acid F I ~ H ~ I ~ I ~~OH
N \ \
O
O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C26H24F4NO4 (M+H+): 490.1641, found 490.1653; 1H NMR (400 MHz, CDCl3).
Example 55 3-[4-(3-{ [(5-Chloro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid CI

N N \ I O \
O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 3) and 3-[4-(3-aminomethyl-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C27HzsCIFN2O4 (M+H+): 495.1487, found 495.1487;'H NMR (400 MHz, CDCl3).

Example 56 i 3-[4-(3-Fluoro-5-{ [(3-methyl-5-trifluoromethyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid F
F F

N \ I \
N ~ O
O
The title compound is prepared according to Example 1 utilizing 3-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 5) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36).
Exact mass calcd for C2$H25F4N2O4 (M+H+): 529.1750, found 529.1757;'H NMR (400 MHz, CDC13).
Example 57 3-[2-Methyl-4-(3-{ [(3-methyl-5-trifluoromethyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-phenyl]-propionic acid F
F
F

N \ I \
N ~ O
H
O
The title compound is prepared according to Example 1 utilizing 3-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 5) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C2gH26F3N?O4 (M+H+): 517.1844, found 511.1834;'H NMR (400 MHz, CDCl3).

Example 58 3-[4-(3-{ [(5-Fluoro-3-methyl-1 H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-methyl-phenyl]-propionic acid F

N ~ I ~
O
H
O
The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic. acid methyl ester (Intermediate 33).
Exact mass calcd for C27H26FNZO4 (M+H+): 461.1877, found 461.1873; 1H NMR (400 MHz, CDCl3).
Example 59 3-[4-(3-Fluoro-5-{ [(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy) 2-methyl-phenyl]-propionic acid F

~ I o ~
H
O
The title compound is prepared according to Example 1 utilizing 3-methyl-5-trifluoro-1H-indole-2-carboxylic acid (Intermediate 1) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C~7H25FZN204 (M+H+): 479.1782, found 479.1787; 1H NMR (400 MHz, CDC13).

Example 60 t 3-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid CI

\ ~ \ ~ _ S ~ O
O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C27H2~.C1FN04S (M+H+): 512.1099, found 512.1160; 1H NMR (400 MHz, CDCl3).
Example 61 2,-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-5-fluoro phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid CI

S ~ N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47).
Exact mass calcd for C28H26C1FNOSS (M+H+): 542.1204, found 542.1190;'H NMR
(400 MHz, CDC13~.

Example 62 2-{4-[3-(5-Chloro-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid CI
F O
\ ~ ~ o / \
O
, o Step A
4-chloro-2-methylbenzoic acid methyl ester 4-Chloro-2-methylbenzoic acid (3.4 g, 20.0 mmol) is dissolved in a solution of methanol (25 ml) and dichloromethane (200 ml) and tetramethylsilyl diazomethane (15 mL, 30.0 mmol, 2M in hexane) is added dropwise keeping the temperature near rt with some cooling. Reaction is stirred overnight at rt under nitrogen. Water is added, the organic layer is separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure providing the title compound with no purification (3.3 g, 90 %).
GCIMS: M~+ 184; 1HNMR (400 MHz, CDCl3).
St_ ep B
2-Bromomethyl-4-chloro-benzoic acid methyl ester The compound from Step A (1.0 g, 5.4 mmol), N-bromosuccinimide (1.1 g, 6.0 mmol), and benzoylperoxide (catalytic amount) are refluxed overnight in carbon tetrachloride (10 mL) under nitrogen. Upon cooling the solid is removed by filtration and the filtrate is concentrated under reduced pressure. Ether is added, and the mixture is washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The remaining solid is triturated with hexane and collected by filtration providing the title compound (0.65 g, 45 %). GC/MS: M~+ 263/264; ~HNMR (400 MHz, CDCl3).
Step C
2-{ 4-[3-(5-Chloro-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester Compound from Step B (76 mg, 0.29mmol), 2-[4-(3-aminomethyl-5-s fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47) (120 mg, 0.33 mmol), and potassium carbonate (92 mg, 0.66 mmol) are dissolved in dry DMF (10 mL) and stirred at rt overnight under nitrogen. Water is added to the reaction, and the mixture is extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography, eluting with 10 % EtOAc in hexane then 25 % EtOAc in hexane provides the title compound (38 g, 26 %). MS(ES~): 512 (M+H+); IHNMR (400 MHz, CDCl3) Step D
2-{ 4-[ 3-(5-Chloro-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-5-fluoro-phenoxy]-2-rnethyl-phenoxy } -2-methyl-propionic acid Compound of Step C (38 mg, 0.074 mmol) is dissolved in dioxane (4 mL) and lithium hydroxide hydrate (40 mg, 0.95 mmol), dissolved in water (2 mL), is added.
Mixture is stirred at rt overnight under nitrogen, and then acidified with 5 N
HCI. Water is added, and the mixture is extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (36.8 mg, quantitative). Exact mass calculated for C26HzaC1FNO5 (M+H+) 484.1327, found 484.1345; 1H NMR (400 MHz, CDCl3).
Example 63 3-(4-{ 3-Fluoro-5-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-methyl-phenyl)-propionic acid F ~ \ F / ~ / ~ OH
/ N \ O \
O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C~SH2~F
SN04 (M+H+): 494.1391, found 494.1379;'H NMR (400 MHz, CDC13).

Example 64 3-(4-{ 3-Fluoro-5-[(2-methoxy-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-methyl-phenyl)-propionic acid F ~ \ O / ~ / ~ OH
H
/ N \ O \
O
The title compound is prepared according to Example 1 utilizing 2-methoxy-4-trifluoromethyl-benzoic acid ( J.Anz.Clzern.Soe.; 73; 1951; 2375) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C26H24F4NO5 (M+H+): 506.1591, found 506.1568; 1H NMR (400 MHz, CDCl3).
Example 65 3-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid CI
_ F CH3 O

N~N \ ~ O \

The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 3-[4-(3-aminomethyl-5-flu~ro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C28H27C1FN~04 (M+H+): 509.1643, found 509.1619; 1H NMR (400 MHz, CDCl3).

Example 66 r 2-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid CI
_ F CH3 O

N \ ~ O \ ~ CH3 The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C29Ha9C1FN205 (M+H+): 539.1749, found 539.1733; 1H
NMR
(400 MHz, CDCl3).
Example 67 2-{ 4-[3-Fluoro-5-( 1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-phenoxy]-2-methyl-phenoxy }-2-methyl-propionic acid F O
\ / o 0 O
O
The title compound is prepared according to Example 62, Steps C and D, utilizing 2-bromomethyl-benzoic acid and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C26HzsFN05 (M+H+): 450.1717, found 450. 7 699; 'H NMR (400 MHz, CDCl3).

Example 68 3-[4-(3-Fluoro-5-{ [(5-fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}
phenoxy)-2-methyl-phenyl]-propionic acid F

N ~ I ~
N ~ O
O
The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1 H-indole-2-carboxylic acid (Intermediate 2) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C28H27F2N2Oø (M+H+): 493.1939, found 493.1932; 1H NMR (400 MHz, CDCl3).
Example 69 2-[4-(3-Fluoro-5-{ [(5-fluoro-1,3-dimethyl-1 H=indole-2-carbonyl)-amino]-methyl }
phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F

-' H3C

N~N ~ I O ~ I CH3 HaC O
The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1 H-indole-2-carboxylic acid (Intermediate 2) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C29H~9F2NZO5 (M+H+): 523.2045, found 523.2038; 1H
NMR
(400 MHz, CDCl3).

Example 70 i 3-[4-(3-{ [(7-Bromo-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]
propionic acid OH
Br N N \ O \
H
O
The title compound is prepared according to Example 1 utilizing 7-bromo-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C26HZdBrN2O4 (M+H+): 507.0919, found 507.0929; 1H NMR (400 MHz, CDCl3).
Example 71 2-(4-{ 3-[(2-Fluoro-4-trifluoromethyl-benzoylamino)-methyl]-4-methyl-phenoxy}-methyl-phenoxy)-2-methyl-propionic acid F / F H3C / / p OH
\ ~ N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-4-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 19). Exact mass calcd for Ca7H26F aNOs (M+H+): 520.1747, found 520.1730; 1H NMR (400 MHz, CDCl3).

Example 72 3-[4-(3-{ [(1,3-Dimethyl-5-trifluoromethyl-1 H-indole-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid F
F
F
_ F CH3 O

N I N \ I O \

The title compound is prepared according to Example 1 utilizing 1,3-dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 6) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C29Hz7F 4N204 (M+H+): 543.1907, found 543.1883; 1H NMR (400 MHz, CDCl3).
Example 73 2-[4-(3-{ [(1,3-Dimethyl-5-trifluoromethyl-1H-indole-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F
F F
_ F CH3 O

N I N \ I O \ ( CH3 HsC O
The title compound is prepared according to Example 1 utilizing 1,3-dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 6) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C30H29FaN2~5 (M+H+): 573.2012, found 573.2009; 1H NMR (400 MHz, CDCl3).

Example 74 2-[4-(3-{ [(5-Chloro-1,3-dimethyl-1 H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2 methyl-phenoxy]-2-methyl-propionic acid .'_" H3C

I N \ I O \ I CH3 l HsC O
The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for C29HsoC1N2O$ (M+H+): 521.1854, found 521.1843; 1H NMR
(400 MHz, CDCl3).
Example 75 3-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2 methyl-phenyl]-propionic acid CI

( CH3 / / OH
~N \ I \
N O
HsC O
The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propion'ic acid methyl ester (Intermediate 33).
Exact mass calcd for C28H28C1N204 (M+H+): 491.1737, found 491.1731; 1H NMR (400 MHz, CDC13).

Example 76 2-Methyl-2-(2-methyl-4-{ 3-methyl-5-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid F \ CH3 / / 03C OH
/ N \ ~ \ ~ CHs O
O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 2-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 20).
Exact mass calcd for C28H29F3N05 (M+H+): 516.1998, found 516.2005; 1H NMR (400 MHz, CDCl3).
Example 77 2-(4-{ 3-[(2-Fluoro-4-trifluoromethyl-benzoylamino)-methyl]-5-methyl-phenoxy}-methyl-phenoxy)-2-methyl-propionic acid F ~ \ F H / ~ / ( O OH
/ N \ O \ CHs O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 20). Exact mass calcd for CZ~H26F4N05 (M+H+): 520.1747, found 520.1774;'H NMR (400 MHz, CDC13).

Example 78 3-[4-(3-{ [(5-Fluoro-1,3-dimethyl-1 H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2 methyl-phenyl]-propionic acid F
_ CH3 O

~OH
N I N \ I O \

The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C2gH28FN2O4 (M+H+): 475.2033, found 475.2019;'H NMR (400 MHz, DMSO-D6).
Example 79 2-[4-(3-{ [(5-Fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2 methyl-phenoxy]-2-methyl-propionic acid F

CH3 ~ I / I O OH
I N \ O \ CH3 N

The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxyl acid (Intermediate 2 ) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for C29HsoFN20s (M+H+): 505.2139, found 505.2147;'H NMR (400 MHz, CDCl3).

Example 80 2-(4-{ 3-[3-(2-Fluoro-4-trifluoromethyl-benzoylamino)-propyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid \ / / 3 OH
F
/ N \ ~ \ ~ CHs O
O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 2-{4-[3-(3-amino-propyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 52). Exact mass calcd for CZ$H28F4N05 (M+H+): 534.1904, found 534.1890; IH NMR (400 MHz, CDC13).
10_ Example 81 2-[4-(3-{ [(1,3-Dimethyl-5-trifluoromethyl-1H-indole-2-carbonyl)-amino]-methyl}-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F

N \ ~ O \ ~ CHs N

The title compound is prepared according to Example 1 utilizing 1,3-dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 6) and 2-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 20). Exact mass calcd for C3~H3~F3N205 (M+H+): 569.2263, found 569.2264;1H NMR (400 MHz, CDCl3).

Example 82 2-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl }-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid CH3 . / / ~ O OH
N \ ~ O \ CH3 N

The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 2-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 20). Exact mass calcd for C3oH32C1N2O5 (M+H+): 535.200, found 535.1976; 1H NMR
(400 MHz, CDCI~).
Example 83 2-[4-(3-{ [(1,3-Dimethyl-5-trifluoromethyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F
F
F
_ CH3 O

N \ ~ O \ ~ CH3 The title compound is prepared according to Example 1 utilizing l ,3-dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 6) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C3oH~oCF3N~05 (M+H+): 555.2107, found 555.2088; 1H NMR (400 MHz, CDC13).

Example 84 3-[4-(3-{ [(1,3-Dimethyl-5-trifluoromethyl-1H-indole-2-carbonyl)-amino]-methyl}
phenoxy)-2-methyl-phenyl]-propionic acid F
F F
_ CH3 O

/ / a ~OH
N I N \ I O \
HsC O
The title compound is prepared according to Example 1 utilizing 1,3-dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 6) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C29H~gF3NZO4 (M+H+): 525.2001, found 525.1984; 1H NMR
(400 MHz, CDCl3).
Example 85 2-[4-(3-{ [(5-Fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F

~N \ O \ CHs N
The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for CZgH28FN2O5 (M+H+): 491.1982, found 491.1995;'H NMR (400 MHz, CDCl3).
i Example 86 2-[4-(3-Fluoro-5-{ [(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F

-' H C

N ~ N \ ~ \ ~ CH3 H O
O
The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 2-[4-(3-aminomethyl-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C28H27FZN205 (M+H+): 509.1879, found 509.1888; 1H
NMR
(400 MHz, CDCl3).
Example 87 2-(4-{ 5-[(2-Fluoro-4-trifluoromethyl-benzoylamino)-methyl]-2-methyl-phenoxy }

methyl-phenoxy)-2-methyl-propionic acid F \ F / CH3 / 03C OH
/ N \ ~ \ ~ CH3 O
O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoro-benzoic acid and 2-[4-(5-aminomethyl-2-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 21 ). Exact mass calcd for C27H26F4N~5 (M+H+): 520.1747, found 520.1730; 1H NMR (400 MHz, CDCl3).

Example 88 2-(4-{4-Fluoro-3-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid F F CHs O

F \ F F / I / I O OH
H
/ N \ O \ CHs O
The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoro-benzoic acid and 2-[4-(3-aminomethyl-4-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 22). Exact mass calcd for C26H~3FSN05 (M+H+): 524.1496, found 524.1494; 1H NMR (400 MHz, CDCl3).
Example 89 3-[4-(3-{ [(3-Chloro-1H-indole-6-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid C~ CHs O
\ H / I / I v ~OH
I / N \ \
H a ~ O
O
The title compound is prepared according to Example 1 utilizing 3-chloro-1H-indole-6-carboxylic acid (WO 9900128) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C26H~4C1NZO4 (M+H+): 463.1420, found 463.1425; 1H NMR (400 MHz, CDCl3).

Example 90 3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenyl]-propionic acid, isomer 1 CH3 O Chiral N \ ~ ~ ~OH
N~
I

The methyl ester of the title compound is prepared according to Example 1, Step A utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and (R, S)-3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 34). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example 1, Step B
utilizing the pure ester enamtiomer. Exact mass calcd for C29H29F2NZOa (M+H+):
507.2095, found 507.20.96; 1H NMR (400 MHz, CDCl3).
Example 91 3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-1,3-dimethyl-1 H-indole-2-carbonyl)-amino]-ethyl }-phenoxy)-2-methyl-phenyl]-propionic acid, isomer 2 CH3 O Chiral V ~OH
N \
The methyl ester of the title compound is prepared according to Example l, Step A utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid ( Intermediate 2) and (R, S)-3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 34). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example l, Step B
utilizing the pure ester enamtiomer. Exact mass calcd for C29H~9F2NZO4 (M+H+):
507.2095, found 507.2096; 1H NMR (400 MHz, CDCl3).

Example 92 3-[4-(3-{ [(1,3-Dimethyl-5-trifluoromethyl-1H-indole-2-carbonyl)-amino]-methyl}-5-fluoro-phenoxy)-2-methyl-phenyl]-2,2-dimethyl-propionic acid F HsC

/ / ~ ~OH
\ ~ \ ~ CH3 N~ ~ O

The title compound is prepared according to Example 1 utilizing 1,3-dimethyl-5-trifluoromethyl-1H-indole-2-carboxylic acid (Intermediate 6) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-2,2-dimethyl-propionic acid methyl ester (Intermediate 42). Exact mass calcd for C3lHsiFaNzCa (M+H+): 571.2220, found 571.2208; 1H NMR (400 MHz, CDCl3).
Example 93 2-(4-{ 3-Fluoro-5-[1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-methyl-phenoxy)-2-methyl-propionic acid, isomer 1 F / ~ CH H / ~ / ~ O OH
\ N \ O \ CHs The methyl ester of the title compound is prepared according to Example 1, Step A utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and (R, S)-2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid methyl ester (Intermediate 41). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example 1, Step B
utilizing the pure ester enamtiomer. Exact mass calcd for C2sH28F4N05 (M+H+):
534.1904, found 534.1887; 1H NMR (400 MHz, CDCl3).

Example 94 2-(4-{ 3-Fluoro-5-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-2-methyl-phenoxy)-2-methyl-propionic acid, isomer 2 \ I N \ I \ I CHs _O

The methyl ester of the title compound is prepared according to Example 1, Step A utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and (R, S)-2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid methyl ester (Intermediate 41). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example 1, Step B
utilizing the pure ester enamtiomer. Exact mass calcd for CZ8H28F4NO5 (M+H+):
534.1904, found 534.1884; 1H NMR (400 MHz, CDC13).
Example 95 2-Methyl-2-(2-methyl-4-{ 3-methyl-5-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid F \ H / I / I O OH
I / N \ O \ CH3 I
O
The title compound is prepared according to Example 1 utilizing 4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 20). Exact mass calcd for Ca7H27F3N05 (M+H+): 502.1841, found 502.1841; 1H NMR (400 MHz, CDCI3).

Example 96 2-Methyl-2-[2-methyl-4-(3-methyl-5-{ [methyl-(4-trifluoromethyl-benzoyl)-amino]-methyl}-phenoxy)-phenoxy]-propionic acid F \ CH3 / / 03 OH
/ N \ ~ \ ~ CHs O
O
The title compound is prepared according to Intermediate 2, Steps A and B, utilizing 2-methyl-2-(2-methyl-4-{3-methyl-5-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid ethyl ester (Example 95, Step A).
Exact mass calcd for C28H29F3NO5 (M+H+): 516.1998, found 516.1990; 1H NMR (400 MHz, DMSO-D6).
Example 97 3-(2-Ethyl-4-{ 3-fluoro-5-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenyl)-propionic acid F F F O
F ~ \ F / ~ / ~ OH
H
/ N \ O \
O
The title compound is prepared according to Example 1 utilizing 2-fluoro-5-trifluoromethyl-benzoic acid and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 27). Exact mass calcd for C26HasFsN04 (M+H+): 508.1547, found 508.1534; 1H NMR (400 MHz, CDCl3).

Example 98 3-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid I H ~ I ~ ( V ~OH
N II N \ O \
HsC O
The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 27).
Exact mass calcd for C~9H29C1FN2Oø (M+H+): 523.1800, found 523.1776; 1H NMR (400 MHz, CDCl3).
Example 99 3-[2-Ethyl-4-(3-fluoro-5-{ [(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-phenyl]-propionic acid F CHs F O

~ ~ ~OH
NI N \ I O \
H I
O
The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Example 1) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 27). Exact mass calcd for C~gH27F~N2O4 (M+H+): 493.1939, found 493.1942; 1H NMR (400 MHz, CDC13).

Example 100 (R)-3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenyl]-propionic acid Chiral ~ OOH
N \I \I
N ~ v ~O

The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and (R)-3-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 24). Exact mass calcd for C29H3oC1N2O4 (M+H+): 505.1894, found 505.1909; 1H NMR (400 MHz, CDC13).
Example 101 (R)-3-[4-(3-{ 1-[(5-Fluoro-1,3-dimethyl-1 H-indole-2-carbonyl)-amino]-ethyl }-phenoxy)-2-methyl-phenyl]-propionic acid Chiral .-- CH3 ~ OOH
N~ ~ ~O

The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and (R)-3-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 24). Exact mass calcd for C29H3oFNZO4 (M+H+): 489.2189, found 489.2190; 1H NMR (400 MHz, CDCl3).

Example 102 i (R)-3-[4-(3-{ 1-[(5-Fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenyl]-propionic acid Chiral ~ OOH
N~ ~ ~O
H

The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and (R)-3-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 24). Exact mass calcd for C2gH~gFN2O4 (M+H+~): 475.2021, found 475.2033;1H NMR (400 MHz, CDCI3).
Example 103 2-[4-(3-Fluoro-5-{ 1-[(3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-ethyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid, isomer 1 OOH
N \ ~ \ ~ CH3 S ~ v 'O

The ethyl ester of the title compound is prepared according to Example 1 Step A utilizing 3-methyl-benzo[b]thiophene-2-carboxylic acid and (R, S)-2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 41). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example 1, Step B utilizing the pure ester enamtiomer. Exact mass calcd for C2gH29FNO5S (M+H+): 522.1750, found 522.1749;'H
NMR (400 MHz, CDCl3).

Example 104 2-[4-(3-Fluoro-5-{ 1-[(3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid, isomer 2 OOH
N \ ~ \ ~ CH3 S ~ v ~O

The ethyl ester,of the title compound is prepared according to General Procedure, Step A as described in Example 1 by utilizing 3-methyl-benzo[b]thiophene-2-carboxylic acid and (R, S)-2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 41). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example 1, Step B utilizing the pure ester enamtiomer. Exact mass calcd for C29H29~o5s (M+H+): 522.1750, found 522.1749; 1H NMR (400 MHz, CDCl3).
Example 105 2-[4-(3-Fluoro-5-{ 1-[(5-fluoro-1,3-dimethyl-1 H-indole-2-carbonyl)-amino]-ethyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid, isomer 1 OOH
N ~ \ ~ CHs I I
CHI O
The ethyl ester of the title compound is prepared according to Example l, Step A utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and (R, S)-2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 41). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example 1, Step B utilizing the pure ester enamtiomer. Exact mass calcd for C3oH3oFzNz~s (M+H+):, found; 1H NMR (400 MHz, CDCl3).

Example 106 2-[4-(3-Fluoro-5-{ 1-[(5-fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid, isomer 2 OOH
\ ~ \ ~ CH3 N ~ v ~O

The ethyl ester of the title compound is prepared according to Example 1, Step A utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2,) and (R, S)-2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 41). Chiral chromatography is used to separate the ester enamtiomers. The title compound is then prepared according to Example 1, Step B utilizing the pure ester enamtiomer. Exact mass calcd .for C3oHsoFaNaOs (M+H+):
found; 1H NMR (400 MHz, CDC13).
Example 107 3-(2-Methyl-4-{ 2-[2-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy } -phenyl)-propionic acid F ~ ~ V ~OH
F
F \ CH3 O \
N
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 3-{4-[2-(2-amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (Intermediate 28). Exact mass calcd for C~7H27F3N04 (M+H+): 486.1892, found 486.1893;'H NMR (400 MHz, CDC13).

Example 108 3-[4-(2-{ 2-[(5-Fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl }-phenoxy)-methyl-phenyl]-propionic acid F /
~OH
CH3 \
O
H
H N I \
O /
The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 3-{4-[2-(2-amino-ethyl)-phenoxy]-2-methyl-phenyl }-propionic acid ethyl ester (Intermediate 28). Exact mass calcd for C28HZ8FN2O4 (M+H+): 475.2033, found 475.2015; 1H NMR (400 MHz, CDC13).
Example 109 3-[4-(2-{ 2-[(5-Chloro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl }-phenoxy)-methyl-phenyl]-propionic acid / I OH
CH3 O \
N
H ~ \
O I/
The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 3) and 3-{4-[2-(2-amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (Intermediate 28). Exact mass calcd for C28H2gC1N204 (M+H+): 491.1737, found 491.1724; 1H NMR (400 MHz, CDC13).

Example 110 i [3-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-5-fluoro-phenoxy)-phenyl]-acetic acid CI F
_-- CH3 / 1 N \ ( ~ ~ OH
O O

The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid ( Intermediate 4) and [3-(3-aminomethyl-5-fluoro-phenoxy)-phenyl]-acetic acid methyl ester (Intermediate 48). Exact mass calcd for C26H23C1FN2O4 (M+H+): 481.1330, found 481.1327;1H NMR (400 MHz, CDC13).
Example 111 [3-(3-Fluoro-5-{ [(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-phenyl]-acetic acid F F
..- CH3 O
\ / ~ N \ ~ \ ~
O v v ~OH
O
The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and [3-(3-aminomethyl-5-fluoro-phenoxy)-phenyl]-acetic acid methyl (Intermediate 48). Exact mass calcd for ~-25H21F2N2~4 (M+H+): 451.1469, found 451.1478; 1H NMR (400 MHz, DMSO-D6).

Example 112 [3-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-phenyl]-acetic acid CI F

/ ~ ( OH
I O \ O
S-O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and [3-(3-aminomethyl-5-fluoro-phenoxy)-phenyl]-acetic acid methyl ester (Intermediate 48). Exact mass calcd for C25H20C1~~4S (M+H+): 484.0786, found 484.0778; 1H NMR (400 MHz, CDC13).
Example 113 (3-{ 3-Fluoro-5-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenyl)-acetic acid F F F

OH
F ~ I N ~ I ~
O O
O
The title compound is prepared according to Example 1 utilizing 3-methyl-5-trifluoromethyl-benzoic acid (Intermediate 10) and [3-(3-aminomethyl-5-fluoro-phenoxy)-phenyl]-acetic acid methyl ester (Intermediate 48). Exact mass calcd for C24H2oF4N04 (M+H+): 462.1332, found 462.1328; IH NMR (400 MHz, DMSO-D6).

Example 114 2-[4-(3-{ [( 1-Ethyl-5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl } -5-fluoro phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ..--- CH3 O9C
\ I \ I CH3 N 1'r O
The title compound is prepared according to Example 1 utilizing 1-ethyl-5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 9) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid (Intermediate 47).
Exact mass calcd for C3oH31F2N2O5 (M+H+): 537.2201, found 537.2215; 1H NMR (400 MHz, CDCl3).
Example 115 3-[4-(3-{ [(1-Ethyl-5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid N \I \I
N~ ~ ~O
O

The title compound is prepared according to Example 1 utilizing 1-ethyl-5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 9) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36).
Exact mass calcd for C29H29F2N2O4 (M+H+): 507.2095, found 507.2096;1H NMR (400 MHz, DMSO-D6).

Example 116 (R)-3-[4-(3-{ 1-[(5-Chloro-3-propyl-1H-indole-2-carbonyl)-amino]-ethyl }-phenoxy)-2-methyl-phenyl]-propionic acid Chiral CI ~H3 CH3 O
~ OOH
~O

The title compound is prepared according to Example 1 utilizing 5-chloro-3-propyl-1H-indole-2-carboxylic acid,(Intermediate 7) and (R)-3-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenyl }-propionic acid methyl ester (Intermediate 24).
Exact mass calcd for CsoH32C1N204 (M+H+): 519.2051, found 519.2038; 1H NMR (400 MHz, CDCl3).
Example 117 3-[4-(3-{ [(5-Chloro-3-propyl-1H-indole-2-carbonyl)-amino]-methyl}-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid ~ OOH
~I ~I
O
The title compound is prepared according to Example 1 utilizing 5-chloro-3-propyl-1H-indole-2-carboxylic acid (Intermediate 7) and 3-[4-(3-aminomethyl-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 36). Exact mass calcd for C29HZgC1)lN2Oq (M+H+): 523.1800, found 523.1810; 1H NMR (400 MHz, CDCl3).

Example 118 (R)-3-(2-Ethyl-4-{ 3-fluoro-5-[ 1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenyl)-propionic acid F F F CH3 O Chiral F
F ~ ~ ~ ~ ~ ~ OH
\ N \ _ \
O

The title compound is prepared according to Example 1 utilizing 2-fluoro-5-trifluoromethyl-benzoic acid and (R)-3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester (Intermediate 23). Exact mass calcd for Ca7H2sFsNC4 (M+H+): 522.1703, found 522.1686; 1H NMR (400 MHz, CDC13).
Example 119 (R)-3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid Chiral Ci F CH3 O

H ~ ~ ~ ( ~\OH
N II N \ O \
HsC O CH3 The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and (R)-3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl }-propionic acid ethyl ester (Intermediate 23).
Exact mass calcd for C3oH31C1FN2O4 (M+H+): 537.1956, found 537.1956;1H NMR
(400 MHz, DMSO-D6).

Example 120 (R)-3-[4-(3-{ 1-[(5-Chloro-1-methyl-3-propyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenyl]-propionic acid Chiral ~ OOH
\ ~ \
~O

The title compound is prepared according to Example 1 utilizing 5-chloro-1-methyl-3-propyl-1H-indole-2-carboxylic acid (Intermediate 8) and (R)-3-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 24).
Exact mass calcd for C31H34C1NZO4 (M+H+): 533.2207, found 533.2197; 1H NMR
(400 MHz, DMSO-D6).
Example 121 (R)-3-[2-Ethyl-4-(3-fluoro-5-{ 1-[(5-fluoro-1,3-dimethyl-l H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-phenyl]-propionic acid Chiral w OH
N \ O \
H C -.

The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and (R)-3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester (Intermediate 23).
Exact mass calcd for C3pH31FZN2O4 (M+H+): 521.2252, found 521.2236; 1H NMR
(400 MHz, DMSO-D6).

Example 122 i (R)-3-[2-Ethyl-4-(3-fluoro-5-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-phenyl]-propionic acid Chiral H ~ I ~ I OOH
N II N \ O \
H

The title compound is prepared according to Example 1 utilizing 3-methyl-5-fluoro-1H-indole-2-carboxylic acid (Intermediate 1) and (R)-3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester (Intermediate 23)_ Exact mass calcd for C29H29F2N2~4 (M+H+): 507.2095, found 507.2087; 1H NMR 01.00 MHz, DMSO-D6).
Example 123 (R)-3-[2-Ethyl-4-(3-fluoro-5-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-phenyl]-propionic acid CI F CHs o Chiral ~OH
SI N \ I O \
I

The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and (R)-3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl }-propionic acid ethyl ester (Intermediate 23). Exact mass calcd for C29H28C1FNO4S (M+H+): 540.1412, found 540.1439; 1H NMR (400 MHz, DMSO-D6).

Example 124 (R)-3-[4-(3-{ 1-[(5-Fluoro-1,3-dimethyl-1 H-indole-2-carbonyl)-amino]-ethyl }-5-methyl phenoxy)-2-methyl-phenyl]-propionic acid Chiral F

w ~ ~ ~ OH
N \ O \
HC~

The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and (R)-3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 26). Exact mass calcd for C3oH32FN2O4 (M+H+): 518.1954, found 518.1956; 1H NMR
(400 MHz, DMSO-D6).
Example 125 (R)-3-[4-(3-{ 1-[(5-Fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid Chiral F

~ OOH
N~ O \
H
O CHs The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-IH-indole-2-carboxylic acid (Intermediate 1) and (R)-3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 26).
Exact mass calcd for C29H30~2~4 (M+H+): 489.2190, found 489.2169; j~I NMR (400 MHz, DMSO-D6).

Example 126 i (R)-3-[4-(3-{ 1-[(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-ethyl }-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid Chiral CI

w OH
\ O \
O CHs The title compound is prepared according to Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and (R)-3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-methyl-phenyl }-propionic acid methyl ester (Intermediate' 26).
Exact mass calcd for C29H29C1NO4S (M+H+): 522.1506, found 522.1501; 1H NMR
(400 MHz, DMSO-D6).
ExamRle 127 (R)-3-(2-Methyl-4-{ 3-methyl-5-[1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenyl)-propionic acid Chiral ~ OOH
N \ I O \

The title compound is prepared according to Example 1 utilizing 2-methyl-5-trifluoromethyl-benzoic acid (Intermediate 10) and (R)-3-{4-[3-(l-amino-ethyl)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 26). Exact mass calcd for C2gH~9F3NO4 (M+H+): 500.2049, found 500.2016;'H NMR (400 MHz, CDCl3).

Example 128 (R)-3-[2-Ethyl-4-(3-{ 1-[(5-fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl} -5-methyl-phenoxy)-phenyl]-propionic acid Chiral F
_ CH3 CH3 O

H ~ ( ~ ~ ~ \OH
N II N \ O \
HsC O CH3 The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2 ) and (R)-3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid methyl ester (Intermediate 16).
Exact mass calcd for C31H34~2~4 (M+H+): 517.2502, found 517.2493; IH NMR (400 MHz, CDC13).
Example 129 (R)-3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid Chiral CI

w OH
N \ O \
HC

The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and (R)-3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid (Intermediate 16).
Exact mass calcd for C31H34C1NaO4 (M+H+): 533.2207, found 533.2222;'H NMR (400 MHz, CDCl3).

Example 130 3-[2-Ethyl-4-(3-fluoro-5-{ [(5-fluoro-1,3-dimethyl-1 H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-phenyl]-propionic acid H ~ ~ ~ ~ ~ OOH
N II N \ O \
HsC O
The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester (Intermediate 27). Exact mass calcd for C29H29F2N2~4 (M+H+): 507.2095, found 507.2101;'H NMR (4.00 MHz, CDCl3).
Example 131 (R)-3-[2-Ethyl-4-(3-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-methyl-phenoxy)-phenyl]-propionic acid Chiral F

H ~ ~ ~ ~ ~ OOH
N II N \ O \
H

The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and (R)-3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid (Intermediate 16). Exact mass calcd for C3pH32~2~4 (M+H+): 503.2346, found 503.2351;'H NMR (400 MHz, CDCl3).

Example 132 3-(2-Ethyl-4-{ 3-methyl-5-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]
phenoxy}-phenyl)-propionic acid F
F ~ I ~ I ~ I ~ ~OH
\ N \ \
O
O
The title compound is prepared according to Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 46). Exact mass calcd for C28H29F3NO4 (M+H+): 500.2049, found 500.2048; 1H NMR (400 MHz, CDCl3).
Example 133 3-[2-Ethyl-4-(3-{ [(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-methyl }-5-methyl-phenoxy)-phenyl]-propionic acid v ~OH
N I N \ I O \
H
O
The title compound is prepared according to Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 3-[4-(3-aminomethyl-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 46).
Exact mass calcd for C29H30~2~4 (M+H+): 489.2190, found 489.2174; 1H NMR (400 MHz, DMSO-D6).

Example 134 3-[2-Ethyl-4-(3-{ [(5-fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-methyl-phenoxy)-phenyl]-propionic acid ~ OOH
NI N ~ I \
I O
HaC O
The title compound is prepared according to Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2 ) and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 46).
Exact mass calcd for C3pH32~2~4 (M+H+): 503.2643, found 503.2326; iH NMR (400 MHz, DMSO-D6).
Example 135 (R,S)-2-[4-(3-Fluoro-5-{ 1-[methyl-(4-trifluoromethyl-benzoyl)-amino]-ethyl}-phenaxy)-2-methyl-phenoxy]-2-methyl-propionic acid F ~ CH3 / I / I O OH
I I
/ N \ O \ CHs The ethyl ester of the title compound is prepared according to Example 1 Step A utilizing 4-trifluoromethyl-benzoic and (R, S)-2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (Intermediate 41). The ester is then reacted with sodium hydride according to Intermediate 2, Step A, followed by hydrolysis according to Example 1 Step B providing the title compound.
Exact mass calcd for C~8H~8F4N05 (M+H+): 534.1904, found 534.1910;'H NMR (400 MHz, DMSO-D6).

A
Example 136 2.-[4-(3-Fluoro-5-{ 1-[methyl-(4-trifluoromethyl-benzoyl)-amino]-ethyl}-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid, isomer 1 F \ CH3 / / 3 OH
/ N \ ~ \ ~ CH3 _O

The title compound is prepared utilizing (R,S)-2-[4-(3-Fluoro-5-{ 1-[methyl-(4-trifluoromethyl-benzoyl)-amino]-ethyl }-phenoxy)-2-methyl-phenoxy]-methyl-propionic acid ethyl ester (Example 135). Chiral chromatography is used to separate the enamtiomers as the esters. The title compound is then prepared according to Example 1, Step B utilizing the pure ester enamtiomer. Exact mass calcd for CZgH28F4N05 (M+H+): 534.1904, found 534.1890; 1H NMR (400 MHz, DMSO-D6).
Example 137 2,-[4-(3-Fluoro-5-{ 1-[methyl-(4-trifluoromethyl-benzoyl)-amino]-ethyl}-phenoxy)-2 methyl-phenoxy]-2-methyl-propionic acid, isomer 2 F ~ \ CH3 / ~ / ~ OOH
I
/ N \ O \ CHs The title compound is prepared utilizing (R,S)-2-[4-(3-Fluoro-5-{ 1-[methyl-(4-trifluoromethyl-benzoyl)-amino]-ethyl }-phenoxy)-2-methyl-phenoxy]-methyl-propionic acid ethyl ester (Example 135). Chiral chromatography is used to separate the enamtiomers as the esters. The title compound is then prepared according to Example 1, Step B utilizing the pure ester enamtiomer. Exact mass calcd for CZaHasFaN05 (M+H+): 534.1904, found 534.1899;'H NMR (400 MHz, DMSO-D6).

Example 138 2-(4-{ 3-[2-(2-Fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy } -2-methyl-phenoxy)-2-methyl-propionic acid F
\ O \ CH3 / ~ /
O ~~~

The title compound is prepared according to Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 2-{4-[3-(2-amino-ethyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 29). Exact mass calcd for C27H26F4NOs (M+NH4+): 537.2013, found 537.2028; 1H NMR (400 MHz, DMSO-D6).
Example 139 3-(2-Methyl-4-{ 3-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenyl)-propionic acid F O
F F ~ \ H / ~ / ~ OOH
N \ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 4-trifluoromethyl-benzoic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C25H23NO4F3 (M+H+): 458.1579; Found: 458.1574; 1H NMR
(400 MHz, CDCl3).

Ex am, lp a 140 2-Methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid F O
F \ / / O OH
FI/ N \I \I
O , O
The compound of 2-[4-(3-Aminomethylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester (Intermediatel7) (53 mg, 0.15 mmol) in CH2C12 (1.5 mL) is treated sequentially at RT with N-methyl morpholine (26 mL, 0.24 mmol) and 4-trifluromethylbenzoyl chloride (36 mL, 0.24 mmol). After 16 h, tris(2-aminoethyl)amine resin (250 mg, 4.4 mmolN/g) is added. The mixture is stirred for 3 h, filtered, and concentrated. The residue is diluted in THF (0.5 mL) and MeOH (1 mL) and then treated with 2N NaOH (0.5 mL). The mixture is heated at 52 °C for 2 h, cooled, and concentrated. The residue is diluted with CH2C12 (1 mL) and 5 N HCl (0.8 mL) and passed through a ChemElute solid phase extraction cartridge (CH2C12 eluent).
The crude product was purified by mass-directed HPLC to give the title compound (41 mg, 56%):
MS: (ES+) 488.2 (M+H+) Example 141 2-Methyl-2-[2-methyl-4-(3-{ [methyl-(4-trifluoromethyl-benzoyl)-amino]-methyl }
phenoxy)-phenoxy]-propionic acid F O
F F \ I / / O OH
I/ N \I \
O
O

S tep A
2-Methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenoxy)-propionic acid ethyl ester The title compound is prepared according to the general procedures described in Example 1, Step A utilizing 4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). MS: (ES+) 516.3 (M+H+); IH NMR (400 MHz, CDC13).
Step B
2-Methyl-2-[2-methyl-4-(3-{ [methyl-(4-trifluoromethyl-benzoyl)-amino]-methyl}-phenoxy)-phenoxy]-propionic acid ethyl ester To NaH (0.0090g, 0.22mmo1) in dry DMF (1m1) is added the compound of Step A above (0.0800g, 0.16mmo1) in dry DMF (1 ml) at rt. The mixture is stirred for 20 min, cooled to 0-5°C, and then~MeI (0.02 ml, 0.38mmo1) in dry DMF (1 ml) is added. The mixture is stirred at 0-5°C for 2h, and then rt overnight. The mixture is acidified with 1M
HCI and diluted with EtOAc, which is then washed with brine, dried over Na2S04, filtered and concentrated. Purification by chromatography by eluting with 20 %
EtOAc in hexane, and 30 % EtOAc in hexane provides the title compound (0.02g) as well as methyl ester side product (0.04g) and a mixture of the ethyl ester and methyl ester (0.01g). For the title compound: MS: (ES+) 530.3 (M+H+); 1H NMR (400 MHz, CDCl3).
For the methyl ester: MS: (ES+) 516.3 (M+H+);1H NMR (400 MHz, CDC13).
Step C
2-Methyl-2-[2-methyl-4-(3-{ [methyl-(4-trifluoromethyl-benzoyl)-amino]-methyl }-phenoxy)-phenoxy]-propionic acid The title compound and the methyl ester from Step B above are combined (0.07g) and dissolved in dioxane (4 ml). LiOH~H~O (O.l Og, 2.4 mmol) in H20 (2 ml) is added and stirred at rt overnight. The mixture is acidified with 1M HCI and concentrated.
MS: (ES+) 502.3 (M+H+);1H NMR (400 MHz, CDC13).

Example 142 2-Methyl-2-[2-methyl-4-(3-{ [propyl-(4-trifluoromethyl-benzoyl)-amino]-methyl }-phenoxy)-phenoxy]-propionic acid F \ / / O OH
F I / N \ I \
O
O
The title compound is prepared according to Example 141 utilizing 2-methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-phenoxy)-propionic acid ethyl ester (Example 141, Step A) and 1-iodo-propane.
MS:
(ES+) 530.4 (M+H~); 1H NMR (400 MHz, CDC13).
Example 143 2-[4-(3-{ [(Biphenyl-4-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid I
\ I \ / I / I ~ OH
H
/ N \ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing biphenyl-4-carboxylic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid (Intermediate 17). Exact mass calcd for C31H3oN~s (M+H+): 496.2124, found 496.2114; ~HNMR (400 MHz, CDCl3).

Example 144 3-(4-{ 3-[(4-tert-Butyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenyl)-propionic acid O
/ I / ~ ~ OOH
N \ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 4-tert-butyl-benzoic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C28H32NO4 (M+H+): 446.2331, found 446.2358; IHNMR (400 MHz, CDC13).
Example 145 2-Methyl-2-(2-methyl-4-{ 3-[(2,4,6-trimethyl-benzoylamino)-methyl]-phenoxy }-phenoxy)-propionic acid O
\ / / O OH
/ N \ ~ \
O
O
The title compound is prepared according to the general procedures described in Example lutilizing 2,4,6-trimethyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for C28H32NO5 (M+H+): 462.2280, found 462.2295; 1HNMR (400 MHz, CDCl3).

Example 146 2-(4-{ 3-[(4-Chloro-2-methyl-benzoylamino)-methyl]-phenoxy }-2-methyl-phenoxy)-methyl-propionic acid O
CI \ / / O OH
~ N \ I \
O
O
The title compound is prepared according to the general procedures described in Example lutilizing 4-chloro-2-methyl-benzoic acid and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C26H27NOSCl (M+H+): 468.1578, found 468.1585; 1HNMR (400 MHz, CDC13).
Example 147 2-Methyl-2-(2-methyl-4-{ 3-[(2-phenoxy-4-trifluoromethyl-benzoylamino)-methyl]
phenoxy}-phenoxy)-propionic acid \
O
F r I I ~OH
N \ O \
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-phenoxy-4-trifluoromethyl-benzoic acid (Intermediate 31) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C32H29NO6F3 (M+H+):
580.1947, found 580.1931; 1HNMR (400 MHz, CDC13).

Example 148 r 2-(4-{ 3-[(2-Ethyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-2-methyl-phenoxy)-2-methyl-propionic acid FF O
F \ / / O OH
/ N \ I \
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-ethyl-4-trifluoromethyl-benzoic acid (Intermediate 30) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C28H2gNO5F3 (M+H+): 516.1998, found 516.2004; 1HNMR (400 MHz, CDC13).
Example 149 2-Methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzylamino)-methyl]-phenoxy}-phenoxy)-propionic acid; compound with trifluoro-acetic acid F F O
F \ / / O OH
I/ N \I \I
O

Step A
2-Methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzylamino)-methyl]-phenoxy}-phenoxy)-propionic acid ethyl ester The compound of 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17) (0.34 g, 0.99 mmol) is dissolved in MeOH (10 ml), and NaOAc (0.32g, 4.0 mmol) is added. The mixture is stirred at 0 °C.
The compound of 4-(trifluoromethyl)benzaldehyde (0.12 ml, 0.89 mmol) is added and then stirred at 0 °C for 15 min. NaBH3CN (0.09 g, 1.5 mmol) is added followed by a few drops of HOAe. The mixture is stirred at 0 °C for 1.5h and then concentrated. The residue is partitioned in EtOAc and water. The EtOAc layer is separated, washed with brine, dried over Na2S04, filtered and concentrated. Purification by chromatography, eluting with 2% MeOH in CH2Cl2 provides the title compound (0.35g). MS: (ES+) 502.3 (M+H+); 1H NMR (400 MHz, CDCl3).
Step B
2-Methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzylamino)-methyl]-phenoxy}
phenoxy)-propionic acid; compound with trifluoro-acetic acid The title compound is prepared according to the general procedures described in Example 1, Step B utilizing the compound from Step A above and purified by reversed HPLC. Exact mass calcd for C2gHa7NO4F3 (M+H+): 474.1892, found 474.1877; 1HNMR (400 MHz, CDCl3).
Example 150 2-[4-(3-{ [Acetyl-(4-trifluoromethyl-benzyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F F ~ O
F ~ O ~ ~ O OH
~ !
N \ O \
Step A
2-[4-(3-{ [Acetyl-(4-trifluoromethyl-benzyl)-amino]-methyl }-phenoxy)-2-methyl phenoxy]-2-methyl-propionic acid ethyl ester The compound of 2-methyl-2-(2-methyl-4-{3-[(4-trifluoromethyl-benzylamino)-methyl]-phenoxy}-phenoxy)-propionic acid ethyl ester (Example 149, Step A, 0.10 g, 0.20 mmol) is mixed with (CH3C0)20 (1.5 ml) and stirred at rt for 1.5h. The mixture is concentrated at 35 °C under vacuum. The residue is dissolved in EtOAc, washed with 1M HCI, diluted NaHC03 and brine, dried over Na2SO4, filtered and concentrated. Purification by chromatography by eluting with 15% EtOAc in hexane and 25 % EtOAc in hexane provides the title compound (0.08g). MS: (ES+) 544.3 (M+H+);
1H NMR (400 MHz, CDCl3).

Step B
s 2-[4-(3-{ [Acetyl-(4-trifluoromethyl-benzyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid The title compound is prepared according to the general procedures described in Example 1, Step B, utilizing the compound of Step A above. Exact mass calcd for C28H29NOSF3 (M+H+): 516.1998, found 516.2004; 1HNMR (400 MHz, CDC13).
Example 151 2-[4-(3-{ [Methanesulfonyl-(4-trifluoromethyl-benzyl)-amino]-methyl}-phenoxy)-methyl-phenoxy]-2-methyl-propionic acid F F O
F \ O og~ / / O OH
I/ N \I \I
O
Step A
2-[4-(3-{ [Methanesulfonyl-(4-trifluoromethyl-benzyl)-amino]-methyl}-phenoxy)-methyl-phenoxy]-2-methyl-propionic acid ethyl ester The compound of 2-methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzylamino)-methyl]-phenoxy}-phenoxy)-propionic acid ethyl ester (Example 149, Step A, 0.13 g, 0.26 mmol) is dissolved in CHZC12 (5 ml), and Et3N (0.05 ml, 0.39 mmol) is added. The mixture is cooled to 0 °C, and MsCI (0.04 ml, 0.31mmo1) is added, which is then stirred at 0 °C to rt for 4h. The mixture is diluted with CHZCl2, washed with 1MHC1, diluted NaHC03 and brine, dried over Na2S04, filtered and concentrated.
Purification by chromatography, eluting with 15% EtOAc in hexane, then 25 % EtOAc in hexane provides the title compound (0.llg). MS: (ES+) 597.2 (M+NH4+);'H NMR (400 MHz, CDCl3).
Step B
(2-[4-(3-{ [Methanesulfonyl-(4-trifluoromethyl-benzyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid The title compound is prepared according to the general procedures described in Example 1, Step B utilizing the compound of Step A above. Exact mass calcd for C27H32N2O6F3 (M+NH4+): 569.1933, found 569.1926; iHNMR (400 MHz, CDCl3).
Example 152 2-(4-{3-[(2-Bromo-5-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid F F
F O
\ / / O
I I -oH
\ \
O
Br O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-bromo-5-trifluoromethyl-benzoic acid (Tetrahedron Lett., Vo1.37, No.l6, pp. 2767-2770, 1996) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for ~26H24NO5F3Br (M+H+): 566.0790, found 566.0787; 1HNMR (400 MHz, CDCl3).
Example 153 2-(4-{3-[(2-Bromo-5-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid FF O
F \ / / O OH
I/ N \I \I
O
Br O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-bromo-4-trifluoromethyl-benzoic acid (Intermediate 11) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). The final product is purified by reversed HPLC.
MS: (ES+) 566 / 568 (M+H+).

Example 154 P
2-[4-(3-{ [Acetyl-(2-phenoxy-4-trifluoromethyl-benzyl)-amino]-methyl }-phenoxy)-2 methyl-phenoxy]-2-methyl-propionic acid F O
\ O / ~ O OH
/ N \ O \
\ O
I/
The title compound is prepared according to Example 150 utilizing 2-Phenoxy-4-trifluoromethyl-benzaldehyde (Intermediate 32) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for C34H33NO6F3 (M+H+): 608.2260, found 608.2253; 1HNMR (400 MHz, CDCl3).
Example 155 2-[4-(3-{ [Methanesulfonyl-(2-phenoxy-4-trifluoromethyl-benzyl)-amino]-methyl }
phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F O
\ O~~g ~ / / O
~OH
/ N \ I \
O
O
I/
The title compound is prepared according to Example 151 utilizing 2-phenoxy-4-trifluoromethyl-benzaldehyde (Intermediate 32) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17).
Exact mass calcd for C33H36NZO7F3s (M+NHø+): 661.2195, found 661.2197; 1HNMR
(400 MHz, CDC13).

Example 156 3-[4-(3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]
propionic acid CI
O
OH
N II N \ O \
H
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 3-[4-(3-Aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C26H24N2CaCl (M+H+): 463.1425, found 463.1402; 1HNMR (400 MHz, DMSO-D6).
Example 157 3-[4-(3-{ [(5-Chloro-1-methyl-1 H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-methyl-phenyl]-propionic acid CI
O
OH
N II N \ O \
O
~ The title compound is prepared according to the general procedures described in Example I utilizing 5-chloro-1-methyl-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C27H26N204C1 (M+H+): 477.1581, found 477.1598; 1HNMR
(400 MHz, CDC13).

Example 158 3-[4-(3-{ [(5-Bromo-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]
propionic acid Br O
H ~ ~ ~ ~ OH
N II N \ O \
H
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-bromo-1H-indole-2-carboxylic acid and 3-[4-(3-Aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C26H24N2~O4Br (M+H+): 507.0919, found 507.0909; 1HNMR
(400 MHz, DMSO-D6).
Example 159 3-[4-(3-{ [(5-Methoxy-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl phenyl]-propionic acid O
H ~ ~ ~ ~ OH
N II N \ O \
H
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-methoxy-1H-indole-2-carboxylic acid and 3-[4-(3-Aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C27H27NaOs (M+H+): 459.1920, found 459.1918; ~HNMR (400 MHz, CDCl3).

Example 160 3-[2-Methyl-4-(3-{ [(3-methyl-benzofuran-2-carbonyl)-amino]-methyl }-phenoxy)-phenyl]-propionic acid O
OOH
O II N \ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 3-methyl-benzofuran-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C27H26N05 (M+H+): 444.1811, found 444.1791; 1HNMR (400 MHz, CDC13).
Example 161 3-[4-(3-{ [(5-Chloro-3-methyl-benzofuran-2-carbonyl)-amino]-methyl }-phenoxy)-methyl-phenyl]-propionic acid CI
O
OH
O II N \ O \
O
The title compound is prepared according to the general procedures described in Example lutilizing 5-chloro-3-methyl-benzofuran-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C27HZSNOsCI (M+H+): 478.1421, found 478.1398; 1HNMR
(400 MHz, CDCl3).

Example 162 2-(4-{ 3-[(2-Chloro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-2-methyl-phenoxy)-2-methyl-propionic acid FF O
/ CI / / O
\ I N I I OH
\ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-chloro-4-trifluoromethyl-benzoic acid (Intermediate 12) and 2-[4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 17). Exact mass calcd for C26H24NOSF3C1 (M+H+):
522.1295, found 522.1310; 1HNMR (400 MHz, CDC13).
Example 163 3-(4-{ 3-[(2-Chloro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-2-methyl phenyl)-propionic acid FF O
/ CI / / OH
\ I N \ I \ I _ O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-chloro-4-trifluoromethyl-benzoic acid (Intermediate 12) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionie acid methyl ester (Intermediate 33). Exact mass calcd for C25HZZN04F3C1 (M+H+): 492.11 ~9, found 492.1202; 1HNMR (400 MHz, CDCl3).

Example 164 3-[4-(3-{ [(5,6-Dichloro-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid CI
O
CI / / OH
\ ~ \
O
O
The title.compound is prepared according to the general procedures described in Example 1 utilizing 5,6-dichloro-1H-indole-2-carboxylic acid (WO
9935130) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). Exact mass calcd for C26HzsN20aCla (M+H+): 497.1035, found 497.1043; 1HNMR (400 MHz, CD30D).
Example 165 3-[4-(3-{ [(1H-Benzoimidazole-2,-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid O
i ~ ~ ~ ~ ~ OOH
N N \ O \
H
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 1H-benzoimidazole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).
Exact mass calcd for C25H2~N3O4 (M+H+): 430.1767, found 430.1772; ~HNMR (400 MHz, DMSO-D6).

Example l66 (2-Methyl-4-{ 3-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-phenoxy)-acetic acid O
CI / / OOH
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-chloro-4-trifluoromethyl-benzoic acid (Intermediate 12) and [4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-acetic acid methyl ester (Intermediate 35). Exact mass calcd for C25HZSNOsFs (M+H+): 474.1528, found 474.1549; 'HNMR (400 MHz, CDCl3).
Example 167 [4-(3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenoxy]-acetic acid CI
_ O
O' ~
_OH
H
N II N \ O \
H
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1 H-indole-2-carboxylic acid and [4-(3-aminomethyl-phenoxy)-2-methyl-phenoxy]-acetic acid methyl ester (Intermediate 35).
MS: (ES+) 465.1 (M+H+);'H NMR (400 MHz, DMSO-D6). .

Example 168 2-[4-(3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino]-methyl }-5-fluoro-phenoxy)-2-methyl phenoxy]-2-methyl-propionic acid CI
F O
O OH
~I ~I
H O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass.calcd for C27H25N205FC1 (M+H+): 511.1436, found 511.1447; 1HNMR (400 MHz, CDCl3).
Example 169 2-(4-{ 3-[(2-Chloro-4-trifluoromethyl-benzoylamino)-methyl]-5-fluoro-phenoxy }-methyl-phenoxy)-2-methyl-propionic acid F F F O
CI / / O OH
~ I N ~ I ~
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-chloro-4-trifluoromethyl-benzoic acid (Intermediate 12) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C26H23NOSF4Cl (M+H+):
540.1201, f~und 540.1218; 'HNMR (400 MHz, CDCI3).

Example 170 2-(4-{ 3-Fluoro-5-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-methyl-phenoxy)-2-methyl-propionic acid F F F O
F ~ F ~ ~ O OH
\ I N \ i \
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C26Ha3NOsFs (M+H+): 524.1496, found 524.1512; 1HNMR (400 MHz, CDC13).
Example 171 3-[4-(3-{ [(1H-Indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]-propionic acid O
H ~ I ~ I OH
N II N \ O \
H
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-phenoxy)-.2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33). The final product is purified by reversed HPLC. Exact mass calcd for C26H~SN2O4 (M+H+):
429.1814, found 429.1843; 1HNMR (400 MHz, DMSO-D6).

' Example 172 3-[4-(3- { [(5-Chloro-1 H-indole-2-carbonyl)-amino]-methyl } -5-flu oro-phenox y)-2-methyl-phenyl]-propionic acid CI
F O
H ~ ~ ~ ~ OH
N II N \ ~ \
H
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and [4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-acetic acid methyl ester (Intermediate 36). Exact mass .calcd for C26H23N2O4FCl (M+H+): 481.1330, found 481.1357; 1HNMR (400 MHz, DMSO-D6).
Exam lp a 173 3-[4-(2-{ [(5-Chloro-1H-indole-2-carbonyl)-amino]-methyl }-phenoxy)-2-methyl-phenyl]
propionic acid CI
O
OH
H
N N \
H O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 3-[4-(2-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 37).
Exact mass calcd for C26H2aNz04Cl (M+H+): 463.1424, found 463.1437; ~HNMR (400 MHz, DMSO-D6).

Example 174 3-[4-(3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino]-methyl }-5-trifluoromethyl-phenoxy) 2-methyl-phenyl]-propionic acid CI F F
F O
OH
N N \I \I
H O
O
The title compound is prepwed according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-5-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 38). Exact mass calcd for C27H23N2O4C1F3 (M+H+): 531.1298, found 531.1312; 1HNMR (400 MHz, DMSO-D6).
Example 175 3-[4-(5-{ [(5-Chloro-1 H-indole-2-carbonyl)-amino]-methyl }-2-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid CI
F F O
F~ OH
N \I \I
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 3-[4-(5-aminomethyl-2-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 39). Exact mass calcd for CZ~H23N204C1F3 (M+H+): 531.1298, found 531.1285; 1HNMR (400 MHz, CDCl3).

Example 176 3-[4-(3-{ 1-[(5-Chloro-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-methyl phenyl]-propionic acid O
/ I ~ ~oH
H
N \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 34). Exact mass .calcd for C2gH24N2~4C1 (M+H+): 495.1487, found 495.1471; 1HNMR (400 MHz, CDC13).
The pure enantiomers are separated by chiral chromatography at the ester stage and hydrolyzed separately to provide isomer 1 (R configuration) and isomer 2 (S
configuration). Isomer 1: Exact mass calcd for C~6H24N204C1 (M+H+): 495.1487, found 495.1466; ~HNMR (400 MHz, CDCl3). Isomer 2: Exact mass calcd for C26H24N2O4C1 (M+H+): 495.1487, found 495.1465; 1HNMR (400 MHz, CDC13).
Example 177 2-(4-{ 3-Fluoro-5-[(2-methoxy-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-methyl-phenoxy)-2-methyl-propionic acid FF I F O
F / O / / O
~OH
\ ~ N \ ~ \
_O
O
2.0 The title compound is prepared according to the general procedures described in Example 1 utilizing ~.-methoxy-4-trifluoromethyl-benzoic acid (J.Ana.Chenz.Soc.; 73; 1951; 2375) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C~~H26N06F~ (M+H+): 536.1696, found 536.1706; 1HNMR (400 MHz, CDC13).
Example 778 2-[4-(3-{[(5-Chloro-1-methyl-1H-indole-2-carbonyl)-amino]-methyl}-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid F O
OH
N \ O \
O
CI
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1-methyl-1H-indole-2-carboxylic acid and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C28H27N2OSFCl (M+H+): 525.1592, found 525.1592; IHNMR (400 MHz, CDC13).
Example 179 3-[4-(3-{ [(5-Chloro-1H-indole-2-carbonyl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid CI
O
OH
N II N \ O \
H
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1H-indole-2-carboxylic acid and 3-[4-(3-aminomethyl-4-trifluoromethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 40). Exact mass calcd for Ca7H23NZO4C1F3 (M+H+): 531.1298, found 531.1307; 1HNMR (400 MHz, DMSO-D6).

Example 180 2-[4-(3-Fluoro-5-{[(3-methyl benzo[b]thiophene-2-carbonyl)-amino]-methyl}-phenoxy) 2-methyl-phenoxy]-2-methyl-propionic acid F O
O
~OH
g N \
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 3-methyl-benzo[b]thiophene-2-carboxylic acid and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C~8H27NO~FS (M+H+): 508.1594, found 508.1588; 1HNMR (400 MHz,' CDC13).
Example 181 2-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-methyl-amino]-methyl }-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid CI
F O
O
\ ~ ~OH
O
O
The title compound is prepared according to the procedure described in Example 141 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass calcd for C3oH29N2O5FCl (M-H+):
551.1749, found 551.1747; IHNMR (400 MHz, CDCI3).

Example 182 2-[4-(3-Fluoro-5-{ 1-[(3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid -. O
/ ~ H ~ o ~OH
S N O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 3-methyl-benzo[b]thiophene-2-carboxylic acid and 2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 41). Exact mass calcd for C29Hz9NOsFS (M+H+): 522.1750, found 522.1741; 1HNMR (400 MHz, CDCl3).
Example 183 2-(4-{ 3-Fluoro-5-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-2-methyl-phenoxy)-2-methyl-propionic acid O
O
~OH
H
N \
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 2-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (Intermediate 41). Exact mass calcd for C28H28NOSF4 (M+H+):
534.1904, found 534.1885; 1HNMR (400 MHz, CDCl3).

Example 184 2-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid CI
O
H / / O OH
~I ~I
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and 2-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 20). Exact mass calcd for C29H29C1NOSS (M+H+):
538.1455, found 538.1454; 1HNMR (400 MHz, CDC13).
Example 185 3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-3-methyl-1 H-indole-2-carbonyl)-amino]-ethyl }-phenoxy) 2-methyl-phenyl]-propionic acid F
O
I / I off O
H I
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 34). Exact mass calcd for C2sH26F2N2Oa (M+H+): 493.1939, found 493.1950; 1HNMR (400 MHz, CDC13).

Example 186 3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}
phenoxy)-2-methyl-phenyl]-propionic acid F
O
OH
I H I
N O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2 ) and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 34). Exact mass calcd for C29H29FaN2O4 (M+H+): 507.2095, found 507.2097; 1HNMR (400 MHz, CDC13).
Example 187 3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro phenoxy)-2-methyl-phenyl]-propionic acid CI
O
I ~ ~oH
H
N \
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 34). Exact mass calcd for (M+H+): 523.1800, found 523.1782; 1HNMR (400 MHz, CDCl3).

Example 188 s ( R ) -3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-phenoxy)-2-methyl-phenyl]-propionic acid F
O
( ~ OH
H I
H O
The title compound is prepared according to the procedure described in Example 176 from 3-[4-(3-{1-[(5-fluoro-3-methyl-1H-indole-~-carbonyl)-amino]-ethyl}-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Example 185).
Exact mass calcd for C28H27F2N2O4 (M+H+): 493.1939, found 493.1946; IHNMR (400 MHz, CDCl3).
Example 189 ( S )-3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}
phenoxy)-2-methyl-phenyl]-propionic acid F
F O
off N \ \I
O
O -The title compound is prepared according to the procedure described in Example 176 from 3-[4-(3-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Example 185).
Exact mass calcd for C28H27FZN2O4 (M+H+): 493.1939, found 493.1930; 1HNMR (400 MHz, CDCl3).

Example 190 ( R )-3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro phenoxy)-2-methyl-phenyl]-propionic acid CI
O
~ ~oH
H
N \
O
The title compound is prepared according to the procedure described in Example 176 from 3-[4-(3-{ 1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Example 187).
Exact mass calcd for C29H~9C1FN2O4 (M+H+): 523.1800, found 523.1789; 1HNMR
(400 MHz, CDCl3).
Example 191 ( S )-3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro phenoxy)-2-methyl-phenyl]-propionic acid CI
F O
~ OOH
N _ \ O \
O -The title compound is prepared according to the procedure described in Example 176 from 3-[4-(3-{ 1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Example 187).
Exact mass calcd for C29H29C1FN~O4 (M+H+): 523.7 800, found 523.1794; ~HNMR
(400 MHz, CDC13).

Example 192 3-(4-{ 3-Fluoro-5-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }

methyl-phenyl)-2,2-dimethyl-propionic acid F F F O
F ~ ( H ~ ~ ~ ~ OH
\ N \ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenyl]-2,2-dimethyl-propionic acid methyl ester (Intermediate 42). Exact mass calcd for C2gHZ8N04F4 (M+H+): 518.1954, found 518.1943; 1HNMR (400 MHz, CDC13).
Example 193 3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-propyl}-phenoxy)-2-methyl-phenyl]-propionic acid F
F O
OH
N II N \ O \
H
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 3-{4-[3-(1-amino-propyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 43). Exact mass calcd for C29Ha9F2N2O4 (M+H+): 507.2095, found 507.2085; 1HNMR (400 MHz, CDC13).

Example 194 3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-propyl}-5-fluoro phenoxy)-2-methyl-phenyl]-propionic acid O
I ~ ~oH
H
N
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 3-{4-[3-(1-amino-propyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 44). Exact mass calcd for C3oH3iC1FN20~
(M+H+): 537.1956, found 537.1942; 1HNMR (400 MHz, CDCl3).
Example 195 3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-3-methyl-1H-indole-2-carbonyl)-amino]-propyl}
phenoxy)-2-methyl-phenyl]-propionic acid F
F O
I ~ ~ OH
N N ~ I ~
~O
H
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 3-{4-[3-(1-amino-propyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 44). Exact mass calcd for C29H29F2N2~4 (M+H+): 507.2095, found 507.2083; ~HNMR (400 MHz, CDCI3).

Example 196 3-[4-(3-Fluoro-5-{ 1-[(5-fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-propyl}-phenoxy)-2-methyl-phenyl]-propionic acid F
O
OOH
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2) and 3- f 4-[3-(1-amino-propyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 44). Exact mass calcd for C3pH31F2N2~4 (M+H+): 521.2252, found 521.2243; 1HNMR (400 MHz; CDCI3).
Example 197 3-(4-{ 3-[ 1-(2-Fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-2-methyl-phenyl)-propionic acid F F O
F ~ ~ ~ OH
N ~ ~ ~
-O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 3-{4-[3-(l-amino-ethyl)-phenoxy]-2-methyl-phenyl }-propionic acid methyl ester (Intermediate 24).
Exact mass calcd for CZ~H23NO4F4 (M+H+): 490.1641, found 490.1625; 1HNMR (400 MHz, CDC13).

Example 198 3-(4- { 3-[ 1-(2-Methoxy-4-trifluoromethyl-benzoyl amino)-ethyl]-phenoxy } -2-methyl-phenyl)-propionic acid F ~ ~ O
~ ~OH
N \ O \
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-methoxy-4-trifluoromethyl-benzoic acid (J.Am.Chem.Soc.; 73; 1951; 2375) and 3-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenyl }-propionic acid methyl ester (Intermediate 24). Exact mass calcd for C27H27NOSF3 (M+H+): 502.1841, found 502.1827; ~HNMR (400 MHz, CDC13).
Example 199 3-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl }-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid C) O
H ~ ( ~ ~ OH
N II N \ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4-) and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 45). Exact mass calcd for CZ~H3oC1N~04 (M+H+): 505.1894, found 505.1882; 1HNMR (400 MHz, CDC13).

Example 200 3-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid CI
O
I H ~ I ~ I off S II N \ O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 45). Exaet .mass calcd for CZ8H27C1N04S (M+H+): 508.1349, found 508.1346; 1HNMR (400 MHz, CDC13).
Example 201 3-(4-{ 3-[(2-Fluoro-4-trifluoromethyl-benzoylamino)-methyl]-5-methyl-phenoxy}-methyl-phenyl)-propionic acid F F O
F ~ F ~ ~ OH
~ I N \ I \
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 45). Exact mass calcd for C26Ha4FaNO4 (M+H+): 490. l 64l , found 490.1645; ~ HNMR (400 MHz, CDCl3).

Example 202 3-(2-Ethyl-4-{ 3-fluoro-5-[(2-methyl-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenyl)-propionic acid F
OH
\ O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-methyl-4-trifluoromethyl-benzoic acid (Intermediate 10) and 3-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 27). Exact mass calcd for C27H26NO4F4 (M+H+): 504.179, found 504.1791; 1HNMR (400 MHz, CDCl3).
Example 203 3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid CI
O
i I v ~OH
N O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (Intermediate 26). Exact mass calcd for C30H3~C1N2O4 (M+H+): 519.2051, found 519.2045; 1HNMR (400 MHz, CDC13).

Example 204 2-{4-[3-Fluoro-5-(2-fluoro-4-trifluoromethyl-benzoylamino)-phenoxy]-2-methyl phenoxy}-2-methyl-propionic acid F O
F O / I / O
I ~OH
\ N \ O \
FF I /
F
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 2-[4-(3-amino-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (Intermediate 47). Exact mass~calcd for CZSHzIFsNOs (M+H+): 510.1340, found 510.1328; 1HNMR (400 MHz, CDC13).
Example 205 3-[4-(3-{ 1-[(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-ethyl }-5-methyl phenoxy)-2-ethyl-phenyl]-propionic acid a / I ~ ~oH
H
N
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and 3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl }-propionic acid ethyl ester (Intermediate 16). Exact mass calcd for C3oH3~CIN~4S (M+H+): 536.1662, found 536.1648; 1HNMR (400 MHz, CDCl3).

Example 206 3-(2-Ethyl-4- { 3-[ 1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-5-methyl-phenoxy}-phenyl)-propionic acid O
'oH
O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 2-fluoro-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester (Intermediate 16). Exact mass calcd for C2gH~8F4N04 (M+H+): 518.1954, found 518.1937; IHNMR
(400 MHz, CDCl3).
Example 207 3-[4-(3-{ [(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid CI
O
/ ~ H ~ ~ ~ ~ OH
N N \ O \
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and -[4-(3-aminomethyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 46). Exact mass calcd for C3oH32C1N204 (M+H+):
519.2051, found 519.2032; 1HNMR (400 MHz, CDC13).

Ex ampl a 208 3-[4-(3-{ [(5-Chloro-3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-methyl }-5-methyl phenoxy)-2-ethyl-phenyl]-propionic acid CI
.- O
H ~ ~ OH
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylic acid and -[4-(3-aminomethyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester (Intermediate 46). Exact mass.calcd for C29H29C1N04S (M+H+): 522.1506, found 522.1502; 1HNMR (400 MHz, CDCl3).
Example 209 3-[4-(3-{ [(5-Fluoro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl }-5-methyl phenoxy)-2-methyl-phenyl]-propionic acid F
-- O
OH
O
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-fluoro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 2 ) and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 45). Exact mass calcd for C29H3oFNzO4 (M+H+): 489.2190, found 489.2188; 1HNMR (400 MHz, CDCl3).

Example 210 3-[4-(3-{ [(5-Fluoro-3-methyl-1H-indole-~-carbonyl)-amino]-methyl }-5-methyl phenoxy)-2-methyl-phenyl]-propionic acid F
O
OH
N \ \
N O
H
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 5-fluoro-3-methyl-1H-indole-2-carboxylic acid (Intermediate 1) and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 45). Exact mass calcd for C~gH~,gFN2O4 (M+H+): 475.2033, found 475.2020;1HNMR (400 MHz, CDCl3).
Example 211 3-[2-Methyl-4-(3-( [(3-methyl-5-trifluoromethyl-benzo[b]thiophene-2-carbonyl)-amino]
methyl}-phenoxy)-phenyl]-propionic acid F
F F
O
H ~ ~ ~ ~ OH
S II N / O \
O
The title compound is prepared according to the general procedures described in Example 1 utilizing 3-methyl-5-trifluoromethyl-benzo[b]thiophene-carboxylic acid (Intermediate 50) and 3-[4-(3-aminomethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 33).

Example 212 2-Methyl-2-(2-methyl-4-{ 3-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]
phenoxy}-phenoxy)-propionic acid O
\ / O ON
ISI ~ N / \
O O
The title compound is prepared according to the general procedures described in Example 140 utilizing 4-trifluoromethylbenzenesulfonyl chloride and 2-[4-(3-aminomethylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester (Intermediate 17). Mass (ES+): 522.2 (M+H+).
Example 213 2-{4-[3-(Isopropoxycarbonylamino-methyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid O
\ / O
~OH
O N ~ / \
O
O
The title compound is prepared according to the general procedures described in Example 140 utilizing isopropyl chloroformate and 2-[4-(3-aminomethylphenoxy)-2-methylphenoxy]-2-methylpropionic acid ethyl ester (Intermediate 17). Mass (ES+): 402.3 (M+H+) Example 214 {2-Methyl-4-[3-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenoxy}acetic acid H O
\ N
U ~ \ O \ ~ O O
OH
Step A
3-(4-Benzyloxy-3-methylphenoxy)benzonitrile \\
/ ~ O \ / O
A mixture of 4-benzyloxy-3-methylphenol (2.19 g, 10.2 mmol) (prepared substantially the similar way as described in W0972321.6), 3-fluorobenzonitrile (1.09 mL, 10.2 mmol), 18-Crown-6 (0.27 g, 1.02 mmol) and 37% potassium fluoride-alumina (3.8 g) (prepared substantially the similar way as described in Tet Lett, 32, 7207, (1997)) is stirred in DMSO (25 mL) at 145 °C for about 8 h. The reaction is diluted in 400 mI.
ether, and the insoluble material is filtered away. The filtrate is washed with brine (3 x 200 mL), dried with Na2SO4 and concentrated to give the title compound as a dark oil (3.1 g, 96%). MS (ES) tnl2 314 (M-1).
Step B
3-(4-Benzyloxy-3-methylphenoxy)benzoic acid O
HO
\ O \ / O
\ /
A solution of 3-(4-benzyloxy-3-methylphenoxy)benzonitrile (3.1 g, 9.8 mmol) in methanol (7 mL) and ethanol (10 mL) is treated with I~OH pellets (11.0 g, 196.0 mmol). To this slurry is added 30% H2O2, and the mixture is heated to 100 °C for 2 h. After cooling, the solution is treated with SN NaOH (30 mL), ether (30mL), and acidified to pH 1 with conc. HC1 (20 mL). The residue is diluted with EtOAc (100 mL) and washed with brine. The organic layer is dried with NaZS04 and concentrated to give the title compound as a tan solid (3.17 g, 96%). MS (ES) jnle 335 (M+1).
Step C
3-(4-Hydroxy-3-methylphenoxy)benzoic acid O
HO
~ OH
To a solution of 3-(4-benzyloxy-3-methylphenoxy)benzoic acid (3.15 g (9.42 mmol) dissolved in THF (10 mL) and EtOH (50 mL) is treated with 5% Pd/C
(0.60 g) and H2 gas (1 atm) for about 16 h. The catalyst is filtered away, and the filtrate is concentrated and redissolved in MeCl2 (100 mL). The mixture is washed with brine, dried with Na2S04 and concentrated to give the title compound as a yellow solid (2.17 g, 94%). MS (ES) mle 243 (M-1).
Step D
3-(4-Hydroxy-3-methylphenoxy)benzoic acid benzyl ester O
O
O ~ ~ OH
A mixture of 3-(4-hydroxy-3-methylphenoxy)benzoic acid (2.13 g, 8.72 mmol), benzyl bromide (1.35 mL, 11.3 mmol) and cesium carbonate (1.42 g, 4.36 mmol) in DMF (8 mL) is stirred at RT for 16 h. The reaction is concentrated, and the residue is taken up in EtOAc (100 mL), which is then washed with brine, dried with Na2S04, concentrated and purified (radial chromatography, 4 mm plate, 5:95 to 25:75 EtOAc:hex) to give the title compound as a yellow solid (1.70 g, 58%). MS (ES) fnle 333 (M-1).

Step E
3-(4-Ethoxycarbonylmethoxy-3-methylphenoxy)benzoic acid benzyl ester O

o-~
A mixture of 3-(4-hydroxy-3-methylphenoxy)benzoic acid benzyl ester (0.85 g, 2.54 mmol), ethylbromoacetate (0.65 mL, 5.08 mmol) and cesium carbonate (1.65 g, 5.08 mmol) in DMF (6 mL) is stirred at RT for 2 h. The reaction is concentrated, and the residue is taken up in EtOAc (100 mL), which is then washed with brine, dried with NaZS04, concentrated and purified (radial chromatography, 2 mm plate, 5:95 to 15:85 EtOAc:hex) to give the title compound as a colorless oil (0.82 g, 76%).
MS (ES) rule 438 (M+NH4).
Step F
3-(4-Ethoxycarbonylmethoxy-3-methylphenoxy)benzoic acid O
HO
~ O ~ ~ O O
O
A mixture of 3-(4-ethoxycarbonylmethoxy-3-methylphenoxy)benzoic acid benzyl ester (0.80 g, 1.90 mmol) in EtOH (200 mL) is treated with 5% Pd/C
(0.19 g) and H2 gas (60 psi) at RT for about 4.5 h. The catalyst is filtered, and the filtrate is concentrated to give the title compound as a white solid (0.61 g, 96%). MS
(ES) rule 348 (M+NH4).

Step G
t [4-(3-Chlorocarbonylphenoxy)-2-methylphenoxy]acetic acid ethyl ester O
CI
O ~ ~ O O
O
To a solution of 3-(4-ethoxycarbonylmethoxy-3-methylphenoxy)benzoic acid (0.61 g, 1.84 mmol) in MeCl2 (30 rnL) is added oxalyl chloride (0.95 mL, 11.1 mmol) and one drop of I~MF. The solution is stirred for 4 h at RT and concentrated to give the title compound as a pale yellow oil (0.61 g, 95%), which is used directly in the next step.
Step H-I
{2-Methyl-4-[3-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenoxy}acetic acid A solution of 4-trifluoromethylbenzylamine (0.031 mL, 0.24 mmol) and Et3N (0.033 mL, 0.24 mmol) in MeCl2 (1 mL) is treated with [4-(3-chlorocarbonyl-phenoxy)-2-methylphenoxy]acetic acid ethyl ester (0.040 g, 0.11 mrnol) in 1 mL
MeCl2.
The reaction is stirred at RT for 2.5 h and concentrated. The residue is treated with EtOH
(1 mL), THF (0.5 mL) and 2N NaOH (0.30 mL, 0.60 mmol) and heated at 50 °C for 16 h.
After cooling, the reaction is concentrated and diluted with 20 mL MeCl2 and 20 mL
water and acidified to pH 1 using 1N HCI. The organic layer is washed with brine and concentrated. The crude residue is purified using mass-directed reverse phase HPLC to give the title compound as a white solid (0.013 g, 25%. MS (ES) rule 460 (M+1).
Examples 215 to 219 are prepared in the substantially the similar way as described in Example 214.

Example 215 [4-(3-Diphenethylcarbamoylphenoxy)-2-methylphenoxy]acetic acid O

O ~ ~ O O
OH
The title compound is prepared by using diphenethylamine, which is prepared substantially the similar way' as described in Example 258, Steps A
and B. MS
(ES) mle 510 (M+1).
Example 216 [4-(3-{[2-(4-Methoxyphenyl)ethyl]phenethylcarbamoyl}phenoxy)-2-methylphenoxy]
acetic acid O

O / ~ O O

The title compound is prepared by using [2-(4-methoxyphenyl)ethyl]
phenethylamine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 540 (M+1).

Example 217 a {4-[3-(Benzylphenethylcarbamoyl)phenoxy]-2-methylphenoxy}acetic acid O

O
OH
The title compound is prepared by using commercially available benzylphenethylamine. MS (ES) rile 496 (M+1).
Example 21S
{4-[3-(4-Methoxybenzylcarbamoyl)phenoxy]-2-methylphenoxy}acetic acid H O
O / ~ N CH3 H3C ~ / O /
OH
The title compound is prepared by using commercially available 4-methoxybenzylamine. MS (ES) mle 422 (M+1).
Exam Ip a 219 [4-(3-Hexylcarbamoylphenoxy)-2-methylphenoxy]acetic acid H O
N CHs ~ O / ~ O O

OH
The title compound is prepared by using commercially available n-hexylamine. MS (ES) fnle 3~6 (M+1).
Example 220 to 254 are prepared substantially the similar way as described in Example 214 except that ethyl 2-bromoisobutyrate is used in Example 214, Step E.

Example 220 2-[4-(3-Diphenethylcarbamoylphenoxy)-2-methylphenoxy]-2-methylpropionic acid /
O

/ O / ~ OCHO
/

The title compound is prepared by using diphenythylamine, which is prepared substantially the similar way as described in Example 258, Steps A
andL B. MS
(ES) mle 538 (M+1).
Example 221 2-[4-(3-{ [2-(4-Methoxyphenyl)ethyl]phenethylcarbamoyl }phenoxy)-2-methyphenoxy]-2-methylpropionic acid O
N CHs O / ~ O CH

The title compound is prepared by using [2-(4-methoxyphenyl)ethyl]
phenethylamine which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 554 (M+1).

Example 222 2-{ 4-[3-(Benzylphenethylcarbamoyl)phenoxy]-2-methylphenoxy } -2-methylpropionic acid O
N CHs / O / ~ pCHO

The title compound is prepared by using the commercially available benzylphenethylamine. MS (ES) mle 524 (M+1).
Example 223 2-Methyl-2-{ 2-methyl-4-[3-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenoxy }
propionic acid O

O / ~ pCH

The title compound is prepared by using the commercially available 4-trifluoromethylbenzylamine. MS (ES) n~le 488 (M+1).
Example 224 2-{ 4-[3-(4-Methoxybenzylcarbamoyl)phenoxy]-2-methylphenoxy } -2-methylpropionic acid, H O
O / ~ N CH3 H3C ' ~ / O / ~ O CH O

The title compound is prepared by using the commercially available 4-methoxybenzylamine. MS (ES) mle 450 (M+1).

Example 225 2-[4-(3-Hexylcarbamoylphenoxy)-2-methylphenoxy]-2-methylpropionic acid H O

O / ~ OCH

The title compound is prepared by using the commercially available n-hexylamine. MS (ES) mle 414 (M+1).
Example 226 2-{ 4-[3-(3,5-Bistrifluoromethylbenzylcarbamoyl)phenoxy]-2-methylphenoxy }-2-methylpropionic acid F
F F H O

F ~ / O ~ ~ OCH
F

The title compound is prepared by using the commercially available 3,5-trifluoromethylbenzylamine. MS (ES) nz/e 556 (M+1).
Example 227 2-[4-(3-{ [2-(3,4-Dimethoxyphenyl)ethyl]hexylcarbamoyl }phenoxy)-2-methylphenoxy]
2-methylpropionic acid ~/
O

O / ~ OCH

The title compound is prepared by using [2-(3,4-dimethoxyphenyl) ethyl]hexylamine which may be prepared essentially as described in Example 258, Steps A and B. MS (ES) mle 578 (M+1).
Example 228 2-[4-(3-{ [2-(3,4-Dimethoxyphenyl)ethyl]heptylcarbamoyl }phenoxy)-2-methylphenoxy]
2-methylpropionic acid O
N CHs O / ~ O
HsC H3C~OH
The title compound is prepared by using [2-(3,4-dimethoxyphenyl)ethyl]
heptylamine which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 592 (M+1).
Example 229 2-[4-(3-{ [2-(3,5-Bistrifluoromethylphenyl)ethyl]phenethylcarbamoyl }phenoxy)-methylphenoxy]-2-methylpropionic acid O
N CHs F F / ~ O / ~ OCH
F

F F
F
The title compound is prepared by using [2-(3,5-bistrifluoromethylphenyl) ethyl]phenethylamine which is prepared substantially the similar way described in Example 258, Steps A and B. MS (ES) fnle 674 (M+1).

Example 230 2-Methyl-2-[2-methyl-4-(3-{ phenethyl-[2-(4-trifluoromethylphenyl)ethyl]carbamoyl }
phenoxy)phenoxy]propionic acid O
N CHs O ~ ~ OCH

F
F
The title compound is prepared by using [2-(4-trifluoromethylphenyl) ethyl]phenethylamine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) hale 606 (M+1).
Example 231 2-{ 4-[3-(6-Methoxy-3,4-dihydro-1 H-isoquinoline-2-carbonyl)phenoxy]-2 methylphenoxy}-2-methylpropionic acid O
H3C ~ ~ N CH3 O
O / ~ OCHO

The title compound is prepared by using 6-methoxy-1,2,3,4-tetrahydoisoquinoline which is prepared substantially the similar way as described in JACS, 56, 1769-1771 (1934). MS (ES) fnle 476 (M+1).

Example 232 2-Methyl-2-{ 2-methyl-4-[3-( 1-methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl )phenoxy]
phenoxy}propionic acid O

CH3 ~ ~ O / ~ O CH O

The title compound is prepared by using 1-methyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in J.
CIZem. Soc. Perkin Trans.l, 9, 955-977 (2001). MS (ES) mle 460 (M+1).
Example 233 2-{4-[3-(6,7-Dichloro-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]-2-methylphenoxy}-2-methylpropionic acid O
N CH3.
CI
O ~ ~ OCH
CI

The title compound is prepared by using 6,7-dichloro-1,2,3,4-tetrahydoisoquinoline, which is prepared substantially the similar way as described in Tet.
Lett., 21, 1393-1396 (1980). MS (ES) rile 515 (M+1).

Example 234 2-Methyl-2-{ 2-methyl-4-[3-( 1-phenyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl)phenoxy]
phenoxy}propionic acid / \
\ / O

/ \ O / \ O_ CH30 H3C~OH
The title compound is prepared by using 1-phenyl-1,2,3,4-tetrahydroisoquinolin, which is prepared substantially the similar way as described in Chem. Ber., 91, 1133-1138 (1958). MS (ES)mle 522 (M+1).
Example 235 2-Methyl-2-{2-methyl-4-[3-(1-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]
phenoxy}propionic acid \ / O
N CHa / \ O / \ OCHO

The title compound is prepared by using 1-methyl-1,2,3,4 tetrahydroisoquinoline, which is prepared substantially the similar way as described in J.
Chem. Soc..Perkifz TrarZS.l, 9, 955-977 (2001). MS (ES) mle 460 (M+1).

Example 236 2-{ 4-[3-(3,4-Dihydro-1 H-isoquinoline-2-carbonyl)phenoxy]-2-methylphenoxy } -methylpropionic acid O
o v N CH3 ~ OCHO

The title compound is prepared by using the commercially available 1,2,3,4-tetrahydroisoquinoline. MS (ES) rile 446 (M+1).
Example 237 2-Methyl-2-(2-methyl-4-{ 3-[2-(4-trifluoromethylphenyl)ethylcarbamoyl]
phenoxy}phenoxy)propionic acid H O

_ ~ ~ O ~ ~ OCHO
F ~ ~ H ~ H

F
F
The title compound is prepared by using the commercially available 4-trifluoromethylphenethylamine. MS (ES) mle 502 (M+1).
Exam Ip a 238 2-Methyl-2-(2-methyl-4-{ 3-[2-(3-trifluoromethylphenyl)ethylcarbamoyl]phenoxy}
phenoxy) propionic acid H O

FF ~ ~ o I ~
F \ / H3C OH
The title compound is prepared by using the commercially available 3-trifluoromethylphenethylamine. MS (ES) mle 502 (M+1).

Example 239 2-Methyl-2-[2-methyl-4-(3-{ methyl-[2-(3-trifluoromethylphenyl)ethyl]carbamoyl }
phenoxy) phenoxy]propionic acid _ / ~ O / ~ OCHO
F \ / H ~ H

F
F
The title compound is prepared by using methyl [2-(4-trifluoromethylphenyl) ethyl]amine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) role 516 (M+1).
Example 240 2-{4-[3-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]-2 methylphenoxy}-2-methylpropionic acid O
H3C, ~ ~ N CH3 O
O ~ ~ O~O
~O

The title compound is prepared by using 6,7-dimethoxy-1,2,3,4-tetrahydoisoquinoline, which is prepared substantially the similar way as described in JAGS, 56, 1769-1771 (1934), MS (ES) male 506 (M+1).

Example 241 2-Methyl-2-(2-methyl-4-{ 3-[methyl-(4-trifluoromethylbenzyl)carbamoyl]phenoxy]
phenoxy)propionic acid F F S \ N CH3 F ~ ~ \ O ~ \ OCH

The title compound is prepared by using methyl(4-trifluoromethylbenzyl)amine which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 502 (M+1 ).
Example 242 2-Methyl-2-{2-methyl-4-[3-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]phenoxy]propionic acid O
F F ~ \ 'N CHI
F ~ \ O ~ \ O
H3C~OH
The title compound is prepared by using 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in WO 9850364. MS (ES) rule 515 (M+1).

Example 243 2-{4-[3-(6-Methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]-2 methylphenoxy}-2-methylpropionic acid O
HaCc ~ ~ N CH3 O
O / ~ OCHO

The title compound is prepared by using 6-methoxy-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in JACS, 56, 1769-1771 (1934). MS (ES) vile 476 (M+1).
Example 244 2-Methyl-2-{2-methyl-4-[3-(1-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]
phenoxy}propionic acid O

CH3 ~ ~ O ~ ~ O CH O

The title compound is prepared by using 1-methyl-1,2,3,4 tetrahydroisoquinoline, which is prepared substantially the similar way as described in J.
Chenn. Soc. Perkiia Tf-ans.l, 9, 955-977 (2001). MS (ES) nzle 460 (M+1).

Example 245 z 2-{4-[3-(6,7-Dichloro-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]-2 methylphenoxy}-2-methylpropionic acid O
/ \ N CH3 CI
/ \ O / \ OCHO
CI
HOC OH
The title compound is prepared by using 6,7-dichloro-1,2,3,4-tetrahydoisoquinoline, which is prepared substantially the similar way as described in Tet.
Lett., 21, 1393-1396 (1980). MS (ES) rile 515 (M+1).
Example 246 2-Methyl-2-{2-methyl-4-[3-(1-phenyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]
phenoxy}propionic acid / \
\ / O
N CHa / \ O / \ OCHO

The title compound is prepared by using 1-phenyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in Chem. Ber-., 91, 1133-1138 (1958). MS (ES) mle 522 (M+1).

Example 247 2-Methyl-2-{ 2-methyl-4-[3-( 1-methyl-3,4-dihydro-1 H-isoquinoline-2 carbonyl)phenoxy]phenoxy}propionic acid O
N CHs ~ OCHp The title compound is prepared by using 1-methyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in J.
Chena. Soc. Perkin Trans.l, 9, 955-977 (2001). MS (ES) snle 460 (M+1).
Example 248 2-{4-[3-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)phenoxy]-2-methylphenoxy}-2-methylpropionic acid O

~ O ~ ~ OCHO

The title compound is prepared by using the commercially available 1,2,3,4-tetrahydroisoquinoline. MS (ES) mle 446 (M+1).

Example 249 2-Methyl-2-(2-methyl-4-{ 3-[2-(4-trifluoromethylphenyl)ethylcarbamoyl]phenoxy}
phenoxy)propionic acid H O

_ I ~ O I ~ pCHO
F \ I H ~ H

F
The title compound is prepared by using the commercially available 4-trifluoromethylphenethylamine. MS (ES) rule 502 (M+1).
Example 250 2-Methyl-2-(2-methyl-4- { 3-[2-(3-trifluoromethylphenyl)ethylcarbamoyl]phenoxy }
phenoxy)propionic acid H O

FF _ I ~ ~ I ~ ocH
F ~ I

The title compound is prepared by using the commercially available 3-trifluoromethylphenethylamine. MS (ES) mle 502 (M+1).

Example 251 2-Methyl-2-[2-methyl-4-(3-{ methyl-[2-(4-trifluoromethylphenyl)ethyl]carbamoyl }
phenoxy)phenoxy]propionic acid N CHs O ~ ~ OCHO

F
F
The title compound is prepared by using methyl(4-trifluoromethylphenyl) ethylamine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 516 (M+1).
Example 252 2-Methyl-2-[2-methyl-4-(3-{methyl-[2-(3-trifluoromethylphenyl)ethyl]carbamoyl}
phenoxy)phenoxy]propionic acid N CHs F F ~ ~ O ~ ~ OCHp F ~ ~ H ~ H

The title compound is prepared by using methyl(3-trifluoromethylphenyl) ethylamine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 516 (M+1).

Example 253 2-{4-[3-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]-2 methylphenoxy}-2-methylpropionic acid O
H3C ~ \ N CH3 O
\ O ~ \ OCH
O

The title compound is prepared by using 6,7-dimethoxy-1,2,3,4-tetrahydoisoquinoline, which is prepared substantially the similar way as described in JAGS, 56, 1769-1771 (1934). MS (ES) mle 506 (M+1).
Example 254 2-Methyl-2-(2-methyl-4-{3-[methyl-(4-trifluoromethylbenzyl)carbamoyl]phenoxy}
phenoxy)propionic acid F F I \ N CH3 ~/ / \ o / \ o The title compound is prepared by using methyl(4-trifluoromethylbenzyl)amine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) fnle 502 (M+1).

Example 255 2-Methyl-2-{4-[4-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenoxy}propionic acid / \ o / \ ocH
N

\ /
F
F
F
The title compound is prepared by using the commercially available 4-trifluoromethylbenzylamine and following the procedure described in Example except that the synthesis begins with Example 214, Step C using the commercially available 4-(4-hydoxyphenoxy)benzoic acid and ethyl 2-bromoisobutyrate in Example 214, Step E. MS (ES) nrle 474 (M+1).
Examples 256 to 257 are prepared as described in Example 214 except that 2-fluorobenzonitrile is used in Example 214, Step A and ethyl 2-bromoisobutyrate is used in Example 214, Step E.
Example 256 2-Methyl-2-{ 4-[2-(6-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl)phenoxy]phenoxy}propionic acid F
F F
~N
O
/ \ O / \ OCHO

The title compound is prepared by using 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in WO 950364. MS (ES) m/e 500 (M+1).

Example 257 s 2-Methyl-2-{4-[2-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenoxy}propionic acid F
F F
/
H
N
O
O / ~ OCHO

The title compound is prepared by using the commercially available 4-trifluoromethylbenzylamine. MS (ES) rile 474 (M+1).
Example 258 Phenethyl[2-(4-trifluoromethylphenyl)ethyl]amine FF
F ~ / N
V
Step A
N-Phenethyl-2-(4-trifluoromethylphenyl)acetamide FF
F ~ / N
O
U
To a solution of 4-trifluoromethylphenylacetic acid (3.0 g, 14.7 mmol) in MeCl2 (30 mL) is added oxalyl chloride (7.6 mL, 88.2 mmol) with 3 drops of DMF, and the mixture is stirred at RT for 5 h. The reaction is concentrated, and the crude acid chloride is redissolved in MeCl2 (15 mL) and added dropwise to an ice bath cooled solution of phenethylamine (2.3 mL, 18.4 mmol) and Et3N (4.1 mL, 30 mmol) in MeCl2 (15 mL). The reaction is stirred at RT for about 16 h and diluted with 50 mL
MeCl2 and 100 mL water, which is then acidified to pH 1 using 1N HCI. The organic layer is washed with brine, dried with Na2S04, concentrated, and purified (radial chromatography, 4 mm plate, 15:85 to 25:75 EtOAc:hex) to give the title compound as a pale yellow solid (2.57 g, 56% over 2 steps). MS (ES) mle 308 (M+1).
Step B
Phenethyl[2-(4-trifluoromethylphenyl)ethyl]amine FF
F \ / ~N
U
To a mixture of lithium borohydride (0.73 g, 33.5 mmol) and trimethylsilyl chloride (8.1 mL, 64.4 mmol) in THF (15 mL) is added a solution of N-phenethyl-2-(4-trifluoromethylphenyl)acetamide (2.54 g, 6.77 mmol) in THF (15 mL). The reaction is stirred for about 56 h (40 h RT, 16 h at 50 °C). After cooling, the reaction is treated slowly with 20 mL MeOH and concentrated. The residue is taken up in MeCl2 (150 ml) and washed with water (100 mL), and then treated with 5N NaOH to bring the pH
to about 12. The organic layer is washed with water, dried with Na2S04, and concentrated to give the title compound as a yellow oil. MS(ES) nz/e 294 (M+1).
Example 259 3-{2-Methyl-4-[3-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenyl}propionic acid H O
F F / ~ N
F ~ / \ O ~ ~ O O
OH

Step A
3-(4-Bromo-3-methylphenoxy)benzonitrile N~
~ O ~ ~ Br This compound is prepared following the procedure of Example 214, Step A except that commercially available 4-bromo-3-methylphenol is used. MS (ES) rile 306 (M+NH4).
Step B
3-(4-Bromo-3-methylphenoxy)benzoic acid HOOC
O ~ /, Br This compound is prepared as described in Example 214, Step B. MS (ES) m1e 305 (M-1).
Step C
3-(4-Bromo-3-methylphenoxy)benzoic acid benzyl ester O
O
a ~ O ~, Br This compound is prepared as described in Example 214, Step D. MS (ES) mle 397 (M+1).

Steps D-E
3-[4-(2-Methoxycarbonylethyl)-3-methylphenoxy]benzoic acid O
HO
O ~ / O
O-The compound of 3-(4-bromo-3-methylphenoxy)benzoic acid benzyl ester (10.4 g, 26.1 mmol) in proprionitrile (200 mL) is treated with DIPEA (10.5 mL, 60.3 mmol). The mixture is degassed (3x vacuum/N2 purge), and methyl acrylate (11 mL, 120 mmol) is added. The mixture is degassed (1x), and tri-o-tolylphosphine (3.65 g, 12.0 mmol) and Pd(OAc)2 are added. The 'mixture is degassed (2x), heated at 110 °C for 2.5 h, cooled, filtered, and concentrated. The crude product is purified (silica gel chromatography, hex:EtOAc 100:0 to 80:20) to give 3-[4-(2-methoxycarbonylvinyl)-3-methylphenoxy]benzoic acid benzyl ester as a yellow oil (9.76 g).
The oily material is dissolved in MeOH (200 mL) and treated with 5%
Pd/C (1.25 g) and H2 gas (60 psi) at RT overnight. The mixture is filtered and concentrated. The product mixture is purified (silica gel chromatography, hex:EtOAc:HOAc 3:1:0 to 1:1:0.02) to give 3-[4-(2-methoxycarbonylvinyl)-3-methylphenoxy]benzoic acid. This material is dissolved in MeOH (125 mL) and treated with 5% PdIC (5 g) and HZ gas (60 psi) at RT 16 h. The mixture is filtered and concentrated. The crude product is purified (silica gel chromatography, hex:EtOAc:HOAc 3:1:0 to 1:1:0.02) to give the title compound (1.8 g, 22%). MS
(ES) mle 313 (M-1).

Step F
3-[4-(3-Chlorocarbonylphenoxy)-2-methylphenyl]propionic acid methyl ester O
CI
("1-O ~ ~ O
O-The title compound is prepared according to the procedure described in Example 214, Step G.
Steps G-H
3-{2-Methyl-4-[3-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenyl}propionic acid The title compound is prepared according to the procedure described in Example 214, Steps H-I. MS(ES) mle 458 (M+1).
Examples 260 and 281 are prepared substantially the similar way as described in Example 259.
Example 260 3-[4-(3-Cyclohexylcarbamoylphenoxy)-2-methylphenyl]propionic acid O ~ ~ O
V
OH
The title compound is prepared by using the commercially available cyclohexylamine. MS (ES) mle 382 (M+1).

Example 261 3-[4-(3-Benzylcarbamoylphenoxy)-2-methylphenyl]propionic acid H O
\ N CH3 / \ O / \ O
OH
The title compound is prepared by using the commercially available benzylamine. MS (ES) n~le 390 (M+1).
Example 262 3-[2-Methyl-4-(3-phenethylcarbamoylphenoxy)phenyl]propionic acid H O
N CHs / \ O / \ O
\ / ~' ~°
OH
The title compound is prepared by using commercially available phenethylamine. MS (ES) rrzle 404 (M+1).
Example 263 3-[2-Methyl-4-(3-phenethylcarbamoylphenoxy)phenyl]propionic acid O

V / \ O / \ O
OH
The title compound is prepared by using commercially available 4-trifluoromethylbenzylamine. MS (ES) mle 458 (M+1).

Example 264 3-{4-[3-(4-Methoxybenzylcarbamoyl)phenoxy]-2-methylphenyl}propionic acid H O
O ~ ~ N CH3 HC ~ ~ O ~ ~ O

OH
The title compound is prepared by using commercially available 4-methoxybenzylamine. MS (ES) rule 420 (M+1).
Exam lp a 265 3-(4-~ 3-[(Biphenyl-3-ylmethyl)carbamoyl]phenoxy}-2-methylphenyl)propionic acid H O

O ~ ~ O
~J
OH
The title compound is prepared by using commercially available biphenyl-3-ylmethylamine. MS (ES) mle 466 (M+1).
Example 266 3-{4-[3-(Benzylphenethylcarbamoyl)phenoxy]-2-methylphenyl}propionic acid O

_ ~ ~ O ~ ~ O
H
The title compound is prepared by using commercially available benzylphenethylamine. MS (ES) rule 494 (M+1).

Example 267 3-(4-(3-Diphenethylcarbamoylphenoxy)-2-methylphenyl]propionic acid O

O / ~ O
/
OH
The title compound is prepared by using diphenethylamine, which is prepared substantially the similar way as described in Example 258, Steps A
and B. MS
(ES) rule 508 (M+1).
Example 268 3-[4-(3-{ [2-(3,4-Dimethoxyphenyl)ethyl]hexylcarbamoyl }phenoxy)-2-methylphenyl]
propionic acid O
O

O
N CHs 0 ~ ~ 0 OH
The title compound is prepared by using [2-(3,4-dimethoxyphenyl) ethyl]heptylamine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) rule 548 (M+1).

Example 269 C
3-[4-(3-{ [2-(3,5-Bis-trifluoromethylphenyl)ethyl]phenethylcarbamoyl}phenoxy)-methylphenyl]propionic acid \ /
O

F F / \ O / \ O
F \ / OH
F F
F
The title compound is prepared by using [2-(3,5-bistrifluoromethylphenyl)ethyl] phenethylamine which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) m~e 644 (M+1).
Example 270 3-[2-Methyl-4-(3-{phenethyl[2-(4-trifluoromethylphenyl)ethyl]carbamoyl}phenoxy) phenyl] propionic acid \ /
O

/ \ O / ~ O
F \ / OH
F ~( F
The title compound is. prepared by using [2-(4-trifluoromethylphenyl)ethyl] phenethylamine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) m~e 576 (M+1).

Example 271 3-{2-Methyl-4-[3-(4-trifluoromethoxybenzylcarbamoyl)phenoxy]phenyl}propionic acid F H O
F-~ ~ ~ N CH3 FO~ ~ ~ O ~ ~ O
OH
The title compound is prepared by using the commercially available 4-trifluoromethoxybenzylamine. MS (ES) rule 474 (M+1).
Example 272 3-(2-Methyl-4-{ 3-[2-(4-trifluoromethylphenyl)ethylcarbamoyl]phenoxy}phenyl)propionic acid H O

O ~ ~ O
OH
F
F
F
The title compound is prepared by using the commercially available 4-trifluoromethylphenethylamine. MS (ES) mle 472 (M+1).
Example 273 3-(2-Methyl-4-{3-[1-(4-trifluoromethylphenyl)ethylcarbamoyl]phenoxy}phenyl) propionic acid H O
F F ~ \ N CH3 F CH3~ ~ O / ~ O
a OH
The title compound is prepared by using 1-(4-trifluoromethylphenyl)ethylamine, which is prepared substantially the similar way as described in J. Med. Chefn., 10, 873-840 (1967). MS (ES) nzle 472 (M+1).

Exam lp a 274 3-[2-Methyl-4-(3-{methyl-[2-(4-trifluoromethylphenyl)ethyl]carbamoyl }phenoxy) phenyl]propionic acid N CHs O / ~ O
F OH
F
F
The title compound is prepared by using methyl(4-trifluoromethylphenyl) ethylamine, which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 486 (M+1).
Example 275 3-{ 2-Methyl-4-[3-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)phenoxy]
phenylpropionic acid O
F F ~ ~ 'N CH3 F ~ ~ ~ ~ ~ O
OH
The title compound is prepared by using 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in WO 9850364. MS (ES) f~2/e 617 (M+1).

Example 276 3-(2-Methyl-4-{ 3-[3-(3-trifluoromethylphenyl)piperidine-1-carbonyl]phenoxy}phenyl) propionic acid O
~N CH3 F F ~ ~ O ~ ~ O
F \ / OH
The title compound is prepared by using 3-(3-trifluoromethylphenyl)piperidine, which is prepared substantially the similar way as described in J. Med. Clzem., 30, 2169-2174 (1987). MS (ES) rule 512 (M+1).
Example 277 3-(2-Methyl-4-{3-[2-(3-trifluoromethylphenyl)ethylcarbamoyl]phenoxy}phenyl) propionic acid H O
N CHa F F ~O ~ \ O
F \ / OH
The title compound is prepared by using the commercially available 3-trifluoromethylphenethylamine. MS (ES) Tnle 472 (M+1).
Example 278 3-(4- { 3-[Cyclopropyl-(3-trifluoromethylbenzyl)carbamoyl]phenoxy } -2-methylphenyl) propionic acid O

F ~ ~ O ~ ~ O
F
F OH

The title compound is prepared by using cyclopropyl(3-trifluoromethylbenzyl)amine which is prepared substantially the similar way as described in Example 258, Steps A and B. MS (ES) mle 498 (M+1).
Example 279 3-[4-(3-{ Benzyl-[2-oxo-2-(4-trifluoromethylphenyl)ethyl]carbamoyl } phenoxy)-methylphenyl]propionic acid / \ O

O / \ O / \ O
OH
F
F F
The title compound is prepared by using 2-benzylamino-1-(4-trifluoromethylphenyl)ethanone which is prepared substantially the similar way as described in Example 258, Step A. MS (ES) nzle 576 (M+1).
Example 280 3-{ 4-[3-(6-Methoxy-3,4-dihydro-1 H-isoquinoline-2-carbonyl)phenoxy]-2-methylphenyl}propionic acid O
H3C' / \ N CH3 O / \ O / \ O
OH
The title compound is prepared by using 6-methoxy-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in JACS, 56, 1769-1771 (1934). MS (ES) mle 446 (M+1).

Example 281 3-{ 2-Methyl-4-[3-( 1-methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl)phenoxy]
phenyl}propionic acid O

CH3 ~ ~ O / ~ O
a OH
The title compound is prepared by using 1-methyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in J.
Chem. Soc. Perkin Trans.l, 9, 955-977 (2001). MS (ES) mle 430 (M+1).
Examples 282 to 292 are prepared according to the procedure described in Example 259 except that 3-fluoro-2-methylbenzonitrile is used in Example 259, Step A.
The compound of 3-fluoro-2-methylbenzonitrile is prepared substantially the similar way as described in US 6,063,789 Example 282 3-{2-Methyl-4-[2-methyl-3-(4-trifluoromethoxybenzylcarbamoyl)phenoxy]phenyl}
propionic acid F H O
F-~ ~ ~ N CH3 CH3 FO~
O O
U
OH
The title compound is prepared by using the commercially available trifluoromethoxybenzylamine. MS (ES) nzle 488 (M+1).

Example 283 3-(2-Methyl-4-{ 2-methyl-3-[2-(4-trifluoromethylphenyl)ethylcarbamoyl]phenoxy }
phenyl)propionic acid H O

O ~ ~ O
F OH
F
F
The title compound is prepared by using the commercially available 4-trifluorornethylphenethylamine. MS (ES) rile 486 (M+1).
Example 284 3-[4-(3-Benzylcarbamoyl-2-methylphenoxy)-2-methylphenyl]propionic acid H O

O ~ ~ O
OH
The title compound is prepared by using the commercially available benzylamine. MS (ES) mle 404 (M+1).
Example 285 3-{ 2-Methyl-4-[2-methyl-3-(4-trifluoromethylbenzylcarbamoyl)phenoxy]phenyl }
propionic acid O
F F ~ ~ N CH3 CH3 F V ~ ~ O ~ ~ O
v OH
The title compound is prepared by using the commercially available 4-trifluoromethylbenzylamine. MS (ES) mle 472 (M+1).

Example 286 3-[2-Methyl-4-(2-methyl-3-phenethylcarbamoylphenoxy)phenyl]propionic acid H O

_ ~ ~ O ~ ~ O
H
The title compound is prepared by using the commercially available phenethylamine. MS (ES) mle 418 (M+1).
Example 287 3-{4-[3-(4-Methoxybenzylcarbamoyl)-2-methylphenoxy]-2-methylphenyl}propionic acid H O
H3C0 ~ ~ N CH3 CH3 ~ O ~ ~ O
U
OH
The title compound is prepared by using the commercially available 4-methoxybenzylamine. MS (ES) mle 434 (M+1).
Example 288 3-[2-Methyl-4-(2-methyl-3-{methyl-[2-(4-trifluoromethylphenyl)ethyl]carbamoyl}
phenoxy)phenyl]propionic acid H3C, O

O ~ ~ O
H
F
F
F
The title compound is prepared by using methyl(4-trifluoromethylphenyl) ethylamine which is prepared substantially the similar way as described in Example 2~8, Steps A and B. MS (ES) rile 500 (M+1).

Example 289 3-{4-[3-(6,7-Dichloro-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-methylphenoxy]-methylphenyl}propionic acid CI

O ~ ~ O
OH
The title compound is prepared by using 6,7-dichloro-1,2,3,4-tetrahydoisoquinoline which is prepared substantially the similar way as described in Tet.
Lett., 21, 1393-1396 (1980). MS (ES) mle 499 (M+1).
Example 290 3-{ 2-Methyl-4-[2-methyl-3-(3-methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl)phenoxy]
phenyl}propionic acid O
'N CH3 CH3 O ~ ~ O
~J
OH
The title compound is prepared by using 3-methyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in J.
Chet~a. Soc. Perkis2 Tras2s.l, 9, 955-977 (2001). MS (ES) hale 444 (M+1).

Example 291 3-[4-(3-Diphenethylcarbamoyl-2-methylphenoxy)-2-methylphenyl]propionic acid O

/ \ O ~ \ O
\ / V ~ H
The title compound is prepared by using diphenethylamine, which is prepared substantially the similar way as described in Example 258, Steps A
and B. MS
(ES) mle 522 (M+1 ).
Example 292 3-{2-Methyl-4--[2-methyl-3-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl) phenoxy]phenyl}propionic acid O
F F / \ N CH3 CH3 F / \ O / \ O
a OH
The title compound is prepared by using 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, which is prepared substantially the similar way as described in WO 9850364. MS (ES) rule 498 (M+1).

Example 293 z 3-[4-(3-Chloro-S-{ [(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2-methyl-phenyl]-propionic acid CI
_ CI CH3 O

~~OH
N I N \ I O \
I
O
The title compound is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid (Intermediate 4) and 3-[4-(3-aminomethyl-5-chloro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (Intermediate 61). Exact mass calcd for C2gH27C12N2O4 (M+H+): 525.1348, found 525.1332; 1H NMR (400 MHz, DMSO-D6).
Example 294 3-(2-Ethyl-4-{ 3-[(2-methoxy-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}
phenyl)-propionic acid F F I O
F ~ I O I \ ~ I OH
H
\ N ~ O \
O
Step A
3-[4-(3-Cyano-phenoxy)-2-ethyl-phenyl]-propionic acid methyl ester O
Oi NC ~ O
A mixture of 3-bromobenzonitrile (1.3 g, 7.2 mmol), 3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester (0.5 g, 2.4 mmol), copper (I) chloride (0.12 g, 1.2 mmol), cesium carbonate (1.6 g, 4.8 mmol), and 2,2,6,6-tetramethyl-3,5-heptanedione (0.12 mL, 0.6 mmol) in NMP (10 mL) is purged with nitrogen. The reaction is heated to 120 °C and stirred overnight. The reaction is cooled to room temperature and filtered through celite. The filtrate is quenched with 1N
aqueous HCl and extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered and the solvent is removed. The crude product is purified by silica gel column chromatography using 4l1 HexaneslEthyl acetate to elute the pure product. The solvent is removed to afford about 0.375 g (50%) of desired product. 'H NMR
(400 MHz, CDCl3); MS (ES+) m/z mass calcd for C19H19NO3 309, found 310 (M + 1).
Step B
3-[4-(3-Aminomethyl-phenoxy)-2-ethyl-phenyl]-propionic acid methyl ester O
( O
H2N ~ \
O
A solution of 3-[4-(3-cyano-phenoxy)-2-ethyl-phenyl]-propionic acid methyl ester (0.38 g, 1.2 mmol) and 5% palladium on carbon (40 mg) in acetic acid (50 mL) is purged with hydrogen (60 psi). The reaction stirred at room temperature overnight. The reaction is filtered through celite and the filtrate is concentrated to one-quarter volume. The solution is quenched with saturate aqueous sodium bicarbonate solution. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered and the solvent is removed to afford about 0.28 g (74%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES''~) nz/z mass calcd for C19H23N~3 313, found 314 (M + l, 100°70).
Step C
3-(2-Ethyl-4-{ 3-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-phenyl)-propionic acid methyl ester F F O
/ \ / ~~O
\ I N I / O \
i O
A solution of 3-[4-(3-aminomethyl-phenoxy)-2-ethyl-phenyl]-propionic acid methyl ester (0.28 g, 0.9 mmol), 2-fluoro-4-(trifluoromethyl)benzoic acid (0.22 g, 1.07 mmol), 1-hydroxybenzotriazole hydrate (0.15 g, 1.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g, 1.07 mmol) and N,N-diisopropylethylamine (0.16 rnL, 0.9 mmol) is is combined in THF (10 mL). The reaction stirred overnight at room temperature. The reaction is quenched with aqueous HCl and extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered and the solvent is removed. The crude is purified by silica gel column chromatography using 4/1 (Hexanes/Ethyl acetate) to elute the pure product.
The solvent is removed to afford about 0.24 g (53%) of desired product. 1H NMR
(400 MHz, CDCl3); MS (ES+) m/,z mass calcd for C27HasFaNO4 503, found 504 (M + l, 100%).
Step D
3-(2-Ethyl-4-{ 3-[(2-methoxy-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }

phenyl)-propionic acid A solution of 3-(2-ethyl-4-{3-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenyl)-propionic acid methyl ester (0.24 g, 0.5 mmol) in methanol (10 mL) is treated with SN aqueous sodium hydroxide (0.9 mL). The reaction is heated to reflux and stirred for 1 hour. The reaction is quenched with 1N aqueous HCl and extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford about 0.2 g (83%) of desired product. 'H
NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C27H26F3N05 501, found 502 (M
+ 1, 100%).
Example 295 3-(2-Ethyl-4-{ 3-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy } -phenyl)-propionic acid FF O
OH
l~~ N
O
O
A solution of 3-(2-ethyl-4-{ 3-[(2-fluoro-4-trifluoromethyl-benzoylamino)-methyl]-phenoxy}-phenyl)-propionic acid methyl ester (0.81 g, 7 .6 mmol) in dioxane (10 mL) is treated with 1N aqueous lithium hydroxide (16 mL). The reaction is stirred overnight at room temperature. The reaction is quenched with 1N aqueous HCl and extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford about 0.65 g (82%) of desired product. 1H
NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C26H23F4NO4 489, found 490 (M
+ 1, 100%).
Example 296 (R)-3-(2-Ethyl-4-{ 3-[ 1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-phenyl)-propionic acid FF ~ O
F
F / \ / OOH
\ ~ N ~ / \
_O
O
Step A
(R)-3-(2-Ethyl-4-{ 3-[1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}
phenyl)-propionie acid ethyl ester FF O
F / ~ F H ~ \ / ~ O
/ O \
IO
The procedure from Example 294, Step C is utilized with (R)-3-{4-[3-(1-amino-ethyl)-phenoxy]-2-ethyl-phenyl }-propionic acid ethyl ester to afford about 0.43 g (80%) of desired product. 1H NMR (400 MHz, CDC13); MS (ES+) fnlz mass calcd for ~29H29F4N~4 531, found 532 (M + 1, 100%).
Step B
(R)-3-(2-Ethyl-4-{ 3-[ 1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }
phenyl)-propionic acid The procedure from Example 295 is utilized with (R)-3-(2-ethyl-4-{3-[1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenyl)-propionic acid ethyl ester to afford about 0.23 g (57%) of desired product. 1H NMR (400 MHz, CDC13); MS
(ES+) ~r~/z mass calcd for Ca7H25F4N0ø 503, found 504 (M + 1, 100%).
Example 297 (R)-3-(4-{3-Fluoro-5-[1-(2-methyl-4-trifluoromethyl-benzoylanuno)-ethyl]-phenoxy}-2-methyl-phenyl)-propionic acid F F F O
F / ~ H ( \ / I ~ OOH
\ N / O \
O
Step A
(R)-3-(4-{ 3-FluOro-5-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-2-methyl-phenyl)-propionic acid methyl ester F F F O
F / I H I \ / I O
\ N / O \
O
The procedure from Example 294, Step C is utilized with 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl }-propionic acid methyl ester and 2-methyl-4-trifluoromethyl-benzoic acid to afford about 0.12 g (50%) of desired product.
1H NMR (400 MHz, CDCl3); MS (ES+) nz/z mass calcd for C28H27F4NO4 517, found (M + 1, 100%).
Step B
(R)-3-(4-{ 3-Fluoro-5-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-2-methyl-phenyl)-propionic acid The procedure from Example 295 is utilized with (R)-3-(4-{3-fluoro-5-[1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy } -2-methyl-phenyl)-propionic acid methyl ester to afford about 0.01 g (87%) of desired product. 'H NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C~~Hz5F4N04 503, found 504 (M + l , 100%).

Example 298 (R)-3-(4-{ 3-Fluoro-5-[1-(2-chloro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2-methyl-phenyl)-propionic acid FF F O
F / I CI H I ~ / I OH
\ N / O \
O
Step A
(R)-3-(4-{ 3-Fluoro-5-[1-(2-chloro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2 methyl-phenyl)-propionic acid methyl ester F F F O
F / I CI H I \ / I Oi \ N / \
O
O
The procedure from Example 294, Step C is utilized with 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl } -propionic acid methyl ester and 2-chloro-4-trifluoromethyl-benzoic acid to afford ab~ut 0.13 g (54%) of desired product.
IH NMR (400 MHz, CDC13); MS (ES+) rnlz mass calcd for C27H2aC1F4N~4 537, found 538 (M + 1, 100%).
Step B
(R)-3-(4-{3-Fluoro-5-[1-(2-chloro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2-methyl-phenyl)-propionic acid The procedure from Example 295 is utilized with (R)-3-(4-{3-fluoro-5-[1-(2-chloro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2-methyl-phenyl)-propionic acid methyl ester to afford about 0.01 g (84%) of desired product. 'H NMR (400 MHz, CDC13); MS (ES+) rnlz mass calcd for C~6H22CIF4N04 523, found 524 (M + 1, 100%).

Exam lp a 299 (R)-3-(4-{ 3-Fluoro-5-[ 1-(2-methoxy-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }
2-methyl-phenyl)-propionic acid F F I F O
F ~ ~ O H ~ \ / ~ OH
\ N
O
O
Std (R)-3-(4-{ 3-Fluoro-5-[ 1-(2-methoxy-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-2-methyl-phenyl)-propionic acid methyl ester FF I F O
F \ ~ O N ~ \
O \
O
The procedure from Example 2.94, Step C is utilized with 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester and 2-methoxy-4-trifluoromethyl-benzoic acid to afford about 0.12 g (51 %) of desired product.
1H NMR (400 MHz, CDCl3); MS (ES+) f~zlz mass calcd for C2gH27F4NO5 533, found (M + l, 100%).
Step B
(R)-3-(4-{3-Fluoro-5-[1-(2-methoxy-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2-methyl-phenyl)-propionic acid The procedure from Example 295 is utilized with (R)-3-(4-{3-fluoro-5-[1-(2-methoxy-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy } -2-methyl-phenyl)-propionic acid methyl ester to afford about 0.11 g (94%) of desired product.

(400 MHz, CDCl3); MS (ES+) m/z mass calcd for C27HZSFaN05 5 7 9, found 520 (M
+ 1, 100%).

Example 300 3-(4-{ 3-[(2-Chloro-4-trifluoromethyl-benzoylamino)-methyl]-5-methyl-phenoxy}-methyl-phenyl)-propionic acid F F O
F / I CI H I ~ / I OH
\ N / O \
O
Step A
3-(4-{ 3-[(2-Chloro-4-trifluoromethyl-benzoylamino)-methyl]-5-methyl-phenoxy}-methyl-phenyl)-propionic acid methyl ester FF O
F / I CI H I \ / I O/
\ N / O \
O
The procedure from Example 294, Step C is utilized with 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester and chloro-4-trifluoromethyl-benzoic acid to afford about 0.23 g (42%) of desired product.
1H NMR (400 MHz, CDCl3); MS (ES+) nilz mass calcd for C27HasC1F3N04 519, found 520 (M + 1, 100%).
Step B
3-(4-{3-[(2-Chloro-4-trifluoromethyl-benzoylamino)-methyl]-5-methyl-phenoxy}-2-methyl-phenyl)-propionic acid The procedure from Example 295 is utilized with 3-(4-{3-[(2-chloro-4-trifluoromethyl-benzoylamino)-methyl]-5-methyl-phenoxy}-2-methyl-phenyl)-propionic acid methyl ester to afford about 0.2 g (93%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES''-) m/z mass calcd for C26Hasc1F3NO4 505, found 506 (M + 1, 100%).

Example 301 s 3-(2-Ethyl-4-{ 3-fluoro-5-[ 1-(2-methoxy-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenyl)-propionic acid F F F O
F ~ ~ O~ ~ ~ ~ ~ OH
H
\ N
O
O
The title compound is prepared according to Example 2 by using 2-methoxy-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 143 mg (81 %). 'H
NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for CZ8H27O$NF4 533, found 534 (M + l, 100%).
Example 302 3-(4-{ 3-[ 1-(2,4-Bis-hifluoromethyl-benzoylamino)-ethyl] -5-fluoro-phenoxy } -2-ethyl-OH
The title compound is prepared according to Example 2 by using 2,4-bis-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 38 mg (90%). 'H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H24O4NF7 571, found 572 (M + 7 , 100%).
phenyl)-propionic acid Exam lp a 303 3-(2-Ethyl-4-{ 3-methyl-5-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]
phenoxy}-phenyl)-propionic acid FF O
F / I / I / I OOH
\ N \ O \
O
The title compound is prepared according to Example 131 by using 2-methyl-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 83 mg (70%). 1H NMR
(400 MHz, CDC13); MS (ES+) rn/z mass calcd for C29H30~aNF3 513, found 514 (M + l, 100%).
Exam l~ a 304 3-(2-Ethyl-4-{ 3-[ 1-(2-methoxy-4-trifluoromethyl-benzoylamino)-ethyl]-5-methyl-phenoxy}-phenyl)-propionic acid FF O
OMe F / / / OOH
\ I N \ I ~
.O
O
The title compound is prepared according to Example 131 by using 2-methoxy-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl }-propionic acid ethyl ester to afford about 232 mg (82%). 1H NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C29H3oO5NF3 529, found 530 (M + 1, 100%).

Example 305 3-(4-{ 3-[(2-Chloro-4-trifluoromethyl-benzoylamino)-methyl]-5-methyl-phenoxy }

ethyl-phenyl)-propionic acid FF O
CI
F / / / ~pH
\ I N ~ I \
O
O
The title compound is prepared according to Example 132 by using 2-chloro-4-trifluoromethyl-benzoic acid and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester to afford about 217 mg (60%~. 1H NMR
(400 MHz, CDCl3); MS (ES+) m/z mass calcd for C27Has0aNF3Cl 519, found 520 and 522 (M
+ 1 and M + 3, 100%).
Example 306 3-(2-Ethyl-4-{ 3-[(2-methoxy-4-trifluoromethyl-benzoyl amino)-methyl]-5-methyl phenoxy}-phenyl)-propionic acid FF O
F / I OMe / I / I OH
\ N \ O \
O
The title compound is prepared according to Example 1 32 by using 2-methoxy-4-trifluoromethyl-benzoic acid and 3-[4-(3-aminomethyl-5-methyl-phenoxy)-2-ethyl-phenyl]-propionic acid ethyl ester to afford about 115 mg (79%)_ 1H NMR
(400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H2gO5NF3 515, found ~ 16 (M + 1, 100%).

Example 307 3-(4-{ 3-[ 1-(2-Chloro-4-trifluoromethyl-benzoylamino)-ethyl]-5-methyl-phenoxy }-2-ethyl-phenyl)-propionic acid F F O
F ~ ~ CI H ~ ~ ~ ~ ON
\ N \ O \
O
The title compound is prepared according to Example 131 by using 2-chloro-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 67 mg (33%). 1H NMR
(400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H2704NF3Cl 533, found 534 and 536 (M
+ 1 and M + 3, 100%).
Example 308 3-(4-{ 3-[ 1-(2-Chloro-4-trifluoromethyl-benzoylamino)-ethyl]-5-methyl-phenoxy } -2-methyl-phenyl)-propionic acid FF O
F ~ ~ CI ~ ~ ~ ~ OH
H
\ N \ O \
O
~ The title compound is prepared according to Example 124 by using 2-chloro-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 132 mg (80%). iH
NMR
(400 MHz, CDCl3); MS (ES+) m!z mass calcd for C27H2504NF3Cl 519, found 520 and (M + 1 and M + 3, 100%).

Example 309 3-(4- { 3-[ 1-(2-Chloro-4-trifluoromethyl-benzoyl amino)-ethyl]-phenoxy } -2-methyl-phenyl)-propionic acid FF O
F ~ ~ C~ H ~ ~ ~ ~ OH
\ N \ O \
O
The title compound is prepared according to Example 100 by using 2-chloro-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 638 mg (69%). 1H NMR (400 MHz, CDCl3); MS (ESA) m/z mass calcd for C26HasCaNFsCI SOS, found 506 and 508 (M +

and M + 3, 100%).
Example 310 3-(4-{ 3-[ 1-(2-Chloro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-2-methyl-phenyl)-propionic acid F F O
F ~ ~ F H ~ ~ ~ ~ OH
\ N \ O \
O
The title compound is prepared according to Example 100 by using 2-fluoro-4-trifluoromethyl-benzoic acid and 3-(4-{3-[1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2-methyl-phenyl)-propionic acid to afford about 662 mg (74%). 1H NMR (400 MHz, CDCl3); MS (ES+) ~rr./z mass calcd for C26H230aNF4 489, found 490 (M + 1, 100%).

Exam lp a 311 3-(2-Methyl-4-{ 3-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-phenyl)-propionic acid FF O
F / / / \/~OH
\
.O
O
The title compound is prepared according to Example 100 by using 2-methyl-4-trifluoromethyl-benzoic acid and 3-(4-{3-[1-(2-fluoro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2-methyl-phenyl)-propionic acid to afford about 486 mg (55%). 'H NMR (400 MHz, CDC13); MS (ES+) f~z/z mass calcd for C27Ha6O4NF3 485, found 486 (M + 1, 100%).
Example 312 3-(4-{ 3-[ 1-(2-Chloro-4-trifluoromethyl-benzoylamino)-ethyl]-5-fluoro-phenoxy }-2-ethyl-phenyl)-propionic acid F F F O
F / I CI H / ~ / ~ OH
\ N \ O \
O
The title compound is prepared according to Example 2 by using 2-chloro-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl }-propionic acid ethyl ester to afford about 166 mg (28%). IH NMR (400 MHz, CDCl3); MS (ES+) rrnz mass calcd for C27Hza04NFaC1537, found 538 and 540 (M +

and M + 3, 100%).

Example 313 3-(4-{ 3-[1-(2-Chloro-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-2-ethyl-phenyl) propionic acid F F O
CI
F / / / OOH
I N ~ I ~
.O
O
The title compound is prepared according to Example 296 by using 2-chloro-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 456 mg (86%). 1H NMR (400 MHz, CDC13); MS (ES+) nilz mass calcd for C27H2504NF3C1519, found 520 and 522 (M +

and M + 3, 100%).
Example 314 3-(2-Ethyl-4-{ 3-[ 1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy } -phenyl)-propionic acid F F ~ O
F / / / OOH
I N ~ I ~
.O
O
The title compound is prepared according to Example 296 by using 2-methyl-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 401 mg (79%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H2804NF3 499, found 500 (M + 1, 100%).

Example 315 3-(2-Ethyl-4-{ 3-[1-(2-methoxy-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}
phenyl)-propionic acid FF O
OMe F ~ ~ ~ ~ ~ ~ ~ OOH
\ N \ O \
O
The title compound is prepared according to Example 296 by using 2-methyl-4-trifluoromethyl-benzoic acid and 3-{4-[3-(1-amino-ethyl)-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 450 mg (~6%). 1H NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for CZ8H2805NF3 515, found 516 (M + 1, 100%).
Example 316 3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-cwbonyl)-amino]-ethyl}-5-fluoro phenoxy)-2-ethyl-phenyl]-propionic acid CI
F O
OH
I ~ ~ ~o \i o -The title compound is prepared according to Example 2 by using 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl }-propionic acid ethyl ester to afford about 76 mg (100%). 'H
NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C3oH3o04N2FC1536, found 537 and 539 (M + 1 and M + 3, 100%).

Example 317 r 3-[4-(3-{ 1-[(5-Chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl }-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid CI
F O
~ ~OH
N ~ N \ ~ O \
I
O
The title compound is prepared according to Example 2 by using 5-chloro-1,3-dimethyl-1H-indole-2-carboxylic acid and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford 2.48 g (45%). 1H
NMR
(400 MHz, CDCl3); MS (ES+) m/z mass calcd for C3oH3oOQ.N2FC1536, found 537 and (M + 1 and M + 3, 100%).
Example 318 3-[4-(3-{ 1-[(5-Chloro-3-methyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid C~
F O
I ~ I off N \ \
.O, The title compound is prepared according to Example 2 by using 5-chloro-3-methyl-1H-indole-2-carboxylic acid and 3-{4-[3-(1-amino-ethyl)-5-fluoro-phenoxy]-2-ethyl-phenyl}-propionic acid ethyl ester to afford about 240 mg (40%). 'H NMR
(400 MHz, CDC13); MS (ES+) m/z mass calcd for C2gH2804N2FCl 522, found 523 and 525 (M
+ 1 and M + 3, 100%).

Example 319 2-(4-{ 3-Fluoro-5-[(4-trifluoromethyl-benzoylamino)-methyl]-phenoxy }-2-methyl phenoxy)-2-methyl-propionic acid FF F O
O
F ~ ~ ~ ~ ~ ~ OH
\ N \ O \
O
The title compound is prepared according to Example 48 by using 4-trifluoromethyl-benzoic acid and 2-[4-(3-aminomethyl-5-fluoro-phenoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester to afford about 111 mg (93%). 1H
NMR
(400 MHz, CDCl3); MS (ES+) m/z mass calcd for C26H23~SNF4 505, found 506 (M +
1, 100%).
Example 320 3-[4-(3-Chloro-5-{ [(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl }
phenoxy)-2-methyl-phenyl]-propionic acid CI

N \ ~ \ ( U
OOH
~O
O
Preparation of Intermediate 3-[4-(3-Aminomethyl-5-chloro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester \ /
H2N ~ \
O
Step A
3-[4-(3-Chloro-5-cyano-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester The compounds of 3-chloro-5-fluoro-benzonitrile (2.0 g, 134.9 mmol), 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (2.7 g, 13.5 mmol) (J.Chem.Soc.Perkin Trans.l; 4; 1990; 1041-1045) and cesium carbonate (~.4 g, 25.7 mmol) are added to dimethylformamide (20 ml) and heated overnight at 85 °C under nitrogen. After cooling, water is added and extracted 3 times with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure.
Purification by flash chromatography, eluting with 10 % EtOAc in hexane then EtOAc in hexane provides the title compound (2.8 g, 65 %). MS(ES+): 347 (M+NH4+);
1HNMR (400 MHz, CDC13).
step B
3-[4-(3-Aminomethyl-5-chloro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester Compound obtained from Step A (208Ø mg, 0.7 mmol) is reacted with platinum oxide (41.0 mg) in methanol (100 mL) and acetic acid (0.5 mL) at room temperature with 60 psi hydrogen for abut 3 hours in a Parr shaker. Reaction mixture is filtered and concentrated under reduced pressure with rt bath. Purification by SCX
column, eluting with 10 % ammonia (2.0 M in methanol) in dichloromethane affords the title compound (81.0 mg, 38%) that is utilized without purification. MS(ES+):

(M+H+); 1HNMR (400 MHz, CDC13).
The final compound of 3-[4-(3-chloro-5-{[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-methyl}-phenoxy)-2-methyl-phenyl]-propionic acid is prepared according to Example 1 utilizing 5-chloro-1,3-dimethyl-l H-indole-carboxylic acid (Intermediate 4) and 3-[4-(3-aminomethyl-5-chloro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester. Exact mass calcd for C2gH26C12N2O4 (M+H+):
525.1348, found 525.1332; 1H NMR (400 MHz, CDC13).
Example 321 2-Methyl-2-(2-methyl-4-{ 3-[1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenoxy)-propionic acid FF O
O
OH
\ N \ O \
O

Preparation of intermediate 2-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester \ / ~ O o-~
H2N / O \
2-{ 4-[3-( 1-Tert-butoxycarbonylamino-ethyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.5 g, 21.9 mmol) is dissolved in 4M HCl in dioxane (80 mL) with an ice bath in place. Bath is removed in 20 minutes and the reaction is stirred for about 1 hour. The reaction is concentrated under reduced pressure which providees the HCl salt of the title compound (0.42 g, 92%). MS(ES+): 376 (M+H+);1HNMR (400 MHz, CDC13).
The title compound of 2-methyl-2-(2-methyl-4-{3-[1-(2-methyl-4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy}-phenoxy)-propionic acid is prepared according to Example 1 by using 4-trifluoromethyl-benzoic acid (Example 10) and 2-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester. 1H
NMR (400 MHz, CDC13); MS (ES+) f~2/z mass calcd for CZ8H2$ F3 N OS 516.1998, found 516.1987 (M + 1, 100%).
Example 322 2-Methyl-2-(2-methyl-4- { 3-[ 1-(4-trifluoromethyl-benzoylamino)-ethyl]-phenoxy }-phenoxy)-propionie acid F F O
F / ~ H ~ ~ / ~ O OH
\ N \ O \
O
The title compound is prepared according to Example 321 by using 4-trifluoromethyl-benzoic acid and 2-{4-[3-(1-amino-ethyl)-phenoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester to afford about 48 mg (64%). 1H NMR (400 MHz, CDC13); MS (ES+) rnlz mass calcd for C27H26OSNF3 501, found 502 (M + 1, 100%).

Claims (45)

1. A compound having a formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

~ is: a) aryl, b) a 5- to 10-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) C3-C8 cycloalkyl, d) aliphatic group, or e) heterocyclyl, wherein aryl, heteroaryl, cycloalkyl, heterocyclyl and aliphatic group being optionally substituted with one or more groups independently selected from R8;
D a and D b are each independently:
a bond or -[C(R c)(R d)]n, wherein R c and R d are each independently hydrogen, C1-C6 alkyl or aryl;
Q is: -C(O)OR5 or R5A;
X is: NR6C[O]p, NR6S(O)2, C[O]p,NR6, S(O)2NR6 or NR7;

Y is: a bond, CH2, S or O;
n and r are each independently: 1, 2, 3 or 4;
q is: 1,2,3,4 or 5;
p is: 1 or 2;
R1 and R2 are each independently: hydrogen, C1-C6 alkyl, halo or haloalkyl;
R3 and R4 are each independently:
hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy or aryloxy;
R3 and R4 are together a 3- to 6- membered carbocyclyl or heterocyclyl;
R5 is: hydrogen, C1-C6 alkyl or aminoalkyl;
R5A is: carboxamide, sulfonamide, acylsulfonamide, tetrazole, R6 is each independently:
hydrogen, C1-C12 alkyl, arylalkyl, C3-C8 cycloalkyl, or (CH2)n C(O)aryl, wherein alkyl, arylalkyl and cycloalkyl group being optionally substituted with one or more groups independently selected from R8;
R7 is: hydrogen, acyl, or sulfonyl;
R8 and R8a are each independently:
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, halo, haloalkyl, haloalkyloxy, aryl, heteroaryl, benzyl, aryloxy, SR9, S[O]p R9 or C[O]p R9; and R9 is: hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl.
2. The compound of Claim 1, wherein aryl or heteroaryl are selected from the group consisting of phenyl, naphthyl, indolyl, isoindolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, pyridyl, benzothiophenyl and benzofuranyl.
3. The compound of Claim 2, wherein the compound having a structural formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
q is 1, 2, 3, 4, or 5.
4. The compound of Claim 3, wherein R8 is disubtituted in 2 and 4 positions, or trisubstituted in 2, 4, and 6 positions of phenyl ring relative to -D b-.
5. The compound of Claim 3, wherein the compound having a structural formula III, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y is: O or CH2;
R1 is: hydrogen, halo or C1-C4 alkyl;
R2, R3 and R4, R6, R c and R d are each independently: hydrogen or C1-C4 alkyl;
(R8)1 and (R8)2 are each independently: hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy or SR9;
R6 is: hydrogen or C1-C4 alkyl; and R9 is: hydrogen or C1-C4 alkyl or C3-C6 cycloalkyl
6. The compound of Claim 5, wherein the compound having a structural formula IV, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R1 and R2 are each independently: hydrogen, halo or C1-C4 alkyl;
R c, R d and R6 are each independently: hydrogen or methyl; and (R8)1 and (R8)2 are each independently:
hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, NO2, cyano, methyl, ethyl, isobutyl, isopropyl or tert-butyl.
7. The compound of Claim 6, wherein the compound having a structural formula V, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R1 and R2 are each independently: hydrogen, methyl, ethyl or fluoro; and (R8)1 and (R8)2 are each independently:
hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, NO2, cyano, methyl, ethyl, isobutyl, isopropyl or tert-butyl.
8. The compound of Claim 7, wherein the compound having a structural formula VI, or a pharmaceutically acceptable salt or stereoisomer thereof.
9. The compound of Claim 3, wherein the compound having a structural formula VII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R1 and R2 are each independently: hydrogen, halo or C1-C4 alkyl;
R6 is: hydrogen or C1-C4 alkyl;
R8 is: hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy or SR9; and R9 is: hydrogen or C1-C4 alkyl or C3-C6 cycloalkyl.
10. The compound of Claim 9, wherein R1, R2 and R6 are each independently hydrogen or methyl; and R8 is hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, NO2, methyl, ethyl, isobutyl, isopropyl or tert-butyl.
11. The compound of Claim 1, wherein the compound having a structural formula VIII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
q is 1, 2, 3 or 4; and E is S, O or NR10 wherein R10 is hydrogen or C1-C4 alkyl.
12. The compound of Claim 11, wherein the compound having a structural formula IX, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y is: O or CH2;
E is: S, O, NH or NCH3, NCH2CH3;
R1 is: hydrogen, C1-C4 alkyl, halo or haloalkyl;
R2, R3 and R4, R6, R c and R d are each independently: hydrogen or C1-C4 alkyl;
(R8)1 and (R8)2 are each independently: hydrogen, halo, haloalkyl, haloalkyloxy, cyano, nitro, C1-C6 alkyl or C1-C6 alkoxy; and R8 is: hydrogen or C1-C4 alkyl.
13. The compound of Claim 12, wherein the compound having a structural formula X, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R1 and R2 are each independently: hydrogen, halo or C1-C4 alkyl;
(R8)1 is: hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, NO2, cyano, nitro, methyl, ethyl, isobutyl, isopropyl or tert-butyl;
R8 is: hydrogen, methyl, ethyl or propyl; and R10 is: hydrogen, methyl or ethyl.
14. The compound of Claim 12, wherein the compound having a structural formula XI, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R1 and R2 are each independently: hydrogen, halo or C1-C4 alkyl;
(R8)1 is: hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, NO2, cyano, nitro, methyl, ethyl, isobutyl, isopropyl or tert-butyl;
R8 is: hydrogen, methyl, ethyl or propyl; and R10 is: hydrogen, methyl or ethyl.
15. The compound of Claim 12, wherein the compound having a structural formula XII, or a pharmaceutically acceptable salt.
16. The compound of Claim 12, wherein the compound having a structural formula XIII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y is: O or CH2;
R1 is: hydrogen, C1-C4 alkyl, halo or haloalkyl;
R2, R3, R4, R6, R c and R d are each independently: hydrogen or C1-C4 alkyl;
R8 are each independently: hydrogen or C1-C4 alkyl; and (R8)1 is: hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitroC1-C6 alkyl or C1-C6 alkoxy.
17. The compound of Claim 16, wherein Y is O or CH2; R1 is hydrogen, methyl, F, Br or Cl; R2 is hydrogen, methyl or ethyl; R3, R4, R6, R8, R c and R d are each independently hydrogen or methyl; and (R8)1 is hydrogen, F, Cl, Br, OMe, CF3, OCF3, SCH3, NO2, cyano, nitro, methyl, ethyl, isobutyl, isopropyl or ter-t-butyl.
18. The compound of Claim 15, wherein the compound having a structural formula XIV, or a pharmaceutically acceptable salt.
19. The compound of Claim 15, wherein the compound having a structural formula XV, or a pharmaceutically acceptable salt.
20. The compound of Claim 1, wherein the compound having a structural formula XVI, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
n is 1, 2, 3, or 4.
21. The compound of Claim 20, wherein Y is O or CH2; R1, R2, R3, R4 R c and R d are each independently hydrogen or C1-C4 alkyl; n is 1 or 2; R8 is hydrogen, C1-C6 alkyl or arylalkyl; and R8 is hydrogen, C1-C6 alkoxy, halo or haloalkyl.
22. The compound of Claim 1, wherein the compound having a structural formula XVII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R8a is hydrogen, C1-C4 alkyl or aryl; and s is 1, 2, 3, 4, 5 or 6.
23. The compound of Claim 22, wherein the compound having a structural formula XVIII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R2 is: hydrogen or C1-C4 alkyl, R8 is: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, haloalkyl or haloalkyloxy;
R8a is: hydrogen, methyl, or phenyl; and q is: 1 or 2.
24. The compound of Claim 1, wherein the compound having a structural formula XIX, or a pharmaceutically acceptable salt or stereoisomer thereof.
25. The compound of Claim 24, wherein Q is COOH; R7 is hydrogen, mathanesulfonyl or acetyl; and R c and R d are each hydrogen.
26. A compound selected from the group consisting of:
27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claims 1-26 or a pharmaceutically acceptable salt.
28. A pharmaceutical composition comprising:
(1) a compound of Claims 1-26, or a pharmaceutically acceptable salt;
(2) a second therapeutic agent selected from the group consisting of:
insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, .alpha.-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, statins, acryl CoA:cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin; and (3) optionally a pharmaceutically acceptable carrier.
29. A method of modulating a peroxisome proliferator activated receptor (PPAR) comprising the step of contacting the receptor with a compound of Claims 1-26, or a pharmaceutically acceptable salt.
30. The method of Claim 29, wherein the PPAR is an alpha (.alpha.)-receptor.
31. The method of Claim 29, wherein the PPAR is a gamma (.gamma.)-receptor.
32. The method of Claim 29, wherein the PPAR is a delta (.delta.)-receptor.
33. The method of Claim 29, wherein the PPAR is a gamma/delta (.gamma./.delta.)-receptor.
34. The method of Claim 29, wherein the PPAR is an alpha/gamma/delta (.alpha./.gamma./.delta.)-receptor.
35. A method for treating a PPAR-.gamma. mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 1-26.
36. A method for treating a PPAR-.delta. mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 1-26.
37. A method for treating a PPAR-.gamma./.delta. mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 1-26.
38. A method for treating a PPAR-.alpha./.gamma./.delta. mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 1-26.
39. A method for lowering blood-glucose in a mammal comprising the step of administering an effective amount of a compound of Claims 1-26.
40. A method of treating disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I
diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of Claims 1-26.
41. A method of treating diabetes mellitus in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of Claims 1-26.
42. A method of treating cardiovascular disease in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of Claims 1-26, or a pharmaceutically acceptable salt.
43. A method of treating syndrome X in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of Claims 1-26, or a pharmaceutically acceptable salt.
44. A method of treating disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I
diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of Claims 1-26 and an effective amount of second therapeutic agent selected from the group consisting of: insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, .alpha.-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, statins, acryl CoA:cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin.
45. Use of a compound of Claims 1-26 and a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of a condition modulated by a PPAR.
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