OA16506A

OA16506A - Glucagon receptor modulator.

Info

Publication number: OA16506A
Application number: OA1201300322
Authority: OA
Inventors: Gary Erik Aspnes; Mary Theresa Didiuk; Kevin James Filipski; Angel Guzman-Perez; Esther Cheng Yin LEE; Jeffrey Allen Pfefferkorn; Benjamin Dawson STEVENS; Meihua Mike Tu
Original assignee: Pfizer Inc.
Priority date: 2011-02-08
Filing date: 2012-01-25
Publication date: 2015-10-21

Abstract

The present invention provides a compound of Formula (I)

Description

The présent invention relates to compounds that are antagonists, mixed agonists/antagonists, partial agonists, négative allosteric modulators or inverse agonists of the glucagon receptor, pharmaceutical compositions comprising the compounds, and the uses of the compounds or compositions.

BACKGROUND

Diabètes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which resuit in the failure to maintain appropriate blood glucose levels. Two major forms of diabètes are recognized. Type I diabètes, or insulin-dependent diabètes mellitus (IDDMT1 DM), is the resuit of an absolute deficiency of insulin. Type II diabètes, or noninsulin dépendent diabètes mellitus (NIDDMT2DM), often occurs with normal, or even elevated levels of insulin and appears to be the resuit of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM T2DM with médication is essentiel; otherwise it can progress into β-cell failure and insulin dependence.

Glucagon is a twenty nine amino acid peptide which is secreted from the a cells of the pancréas into the hepatic portai vein thereby exposing the liver to higher levels of this hormone than non-hepatic tissues. Plasma glucagon levels decrease in response to hyperglycémie, hyperinsulinemia, elevated plasma non-esterified fatty acid levels and somatostatin whereas glucagon sécrétion is increased in response to hypoglycémie end eleveted plesme emino ecid levels. Glucagon, through activation of its receptor, is a potent activator of hepatic glucose production by activating glycogenolysis and gluconeogenesis.

The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors. Other closely related G-protein coupled receptors include glucagon-like peptide-1 receptor (GLP-1), glucagon-like peptide-2 receptor (GLP2) and gastric inhibitory polypeptide receptor. The glucagon receptor is encoded by the GCGR gene in humans and these receptors are mainly expressed in the liver with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal glands, pancréas, cérébral cortex and gastrointestinal tract. Stimulation of the glucagon receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP.

Reports hâve indicated that an uncommon missense mutation in the GCGR gene is correlated with diabètes mellitus type 2 and one reported inactivating mutation of the glucagon receptor in humans causes résistance to glucagon and is associated with pancreatic a-cell hyperplasia, nesidioblastosis, hyperglucagonemia and pancreatic neuroendocrine tumors. In rodent studies with GCGR knockout mice and mice treated with GCGR antisense oligonucleotides the mice exhibited improved fasting glucose, glucose tolérance and pancreatic β-cell function. In both healthy control animais and animal models of type 1 and type 2 diabètes, removal of circulating glucagon with sélective and spécifie antibodies has resulted in a réduction of the glycémie level. More specifically, treatment of both mice and cynomolgus monkeys with GCGRantagonizing antibodies (mAb B and mAb Ac) has been shown to improve glycémie control without causing hypoglycémie. Recent mice studies hâve further shown that antagonism of the glucagon receptor results in improved glucose homeostasis through a mechanism which requires a functional GLP-1 receptor. Antagonism of the glucagon receptor resulted in compensatory overproduction of GLP-1, likely from the pancreatic α-cells, and this may play an important rôle in intraislet régulation and maintenance of β-cell function.

A promising area of diabètes research învolves the use of small molécule antagonists, mixed agonists/antagonists, partial agonists, négative allosteric modulators or inverse agonists of the glucagon receptor to lower the level of circulating glucagon and thereby lower the glycémie level. Therapeutically, it is antîcipated that inactivation of the glucagon receptor would be an effective strategy for lowering blood glucose by reducing hepatic glucose output and normalizing glucose stimulated insulin sécrétion. Consequently, a glucagon antagonist, mixed agonist/antagonist, partial agonist, négative allosteric modulator or or inverse agonist may provide therapeutic treatmentfor NIDDM T2DM and associated complications, inter alia, hyperglycémie, dyslipidemia, insulin résistance syndrome, hyperinsulinemia, hypertension, and obesity.

Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM T2DM (Moller, D. E., New drug targets for Type 2 diabètes and the metabolic syndrome Nature 414; 821-827, (2001)): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance sécrétion of insulin by acting on the pancreatic betacells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a spécifie receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lîpid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anémia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.

Ideally, an effective new treatment for NIDDM T2DM would meet the following criteria: (a) it would not hâve significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are

independent from the actions of insuiin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

A number of publications hâve appeared which disclose non-peptide compounds which act at the glucagon receptor. For example, WO 03/048109, WO 2004/002480, WO 2005/123668, WO 2005/118542, WO 2006/086488, WO 2006/102067, WO 2007/106181, WO 2007/114855, WO 2007/120270, WO 2007/123581 and Kurukulasuriya et al. Bioorganic & Médicinal Chemistry Letters, 2004, 14(9), 2047-2050 each disclose non-peptide compounds that act as glucagon receptor antagonists. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabètes, partîcularly NIDDM.

Brief Description of the Drawings

Figure 1 provides the powder X-ray diffraction for the exemplified compound as noted.

SUMMARY OF THE INVENTION

The présent invention provides compounds of Formula I that act as glucagon receptor modulators, in particular, glucagon antagonists; therefore, may be used in the treatment of diseases mediated by such antagonism (e.g., diseases related to Type 2 diabètes, and diabetesrelated and obesity-related co-morbidities). A first embodiment of the présent invention are compounds of Formula I

R² or a pharmaceutically acceptable sait thereof, wherein R¹ is a 5 membered heteroaryl group attached through either a carbon or nitrogen atom and which is optionally fused to a (C4C7)cycloalkyl, phenyl or 6 membered heteroaryl; wherein the optionally fused 5 membered heteroaryl is optionally substituted with one to four substituents each independently selected from halo, -S(O)2-(CrC3)alkyl, -S-(Ci-C3)alkyl, hydroxy, -C(O)NR^aR^b, (C3-Cs)cycloalkyl, cyano, phenyl which is optionally substituted with one to three halo, cyano, (Ci-C₃)alkyl or (C_rC₃) alkoxy, 6 membered heteroaryl which is optionally substituted with one to three halo, cyano, (CrC₃)alkyl or (CrCy alkoxy, (CrCeJalkyl optionally substituted with one to three fluoro, or (C_rC_e)alkoxy optionally substituted with one to three fluoro; R^a and R^b are each independently H or (Ct-C3)alkyl; R² is H or methyl; R³ is tetrazolyl, -CH2-tetrazolyl, -(CH₂)₂SO₃H or -(CH₂)₂CO₂H, -CH₂CHFCO₂H or -CH₂CHOHCO₂H;

A¹, A², A³ and A⁴ are each independently CR⁴ or N, with the proviso that no more than two of A¹, A², A³ and A⁴ are N; R⁴ at each occurrence is independently H, halo, cyano, (CrCsJalkyl optionally substituted with one to three fluoro, or (CrC₃)alkoxy optionally substituted with one to three fluoro;

L is -X-CH(R⁵)- or -CH(R^S)-X-; X is CH_2l O or NH; R⁵ is (CrCeJalkyl which is optionally substituted with one to three fluoro, hydroxy or methoxy; (C₃-C₇)cycloalkyl which is optionally substituted with one to two (CrCaJalkyl which are optionally substituted with one to three fluoro and wherein one to two carbons of the (C₃-C₇)cycloalkyl can be replaced with a NH, N(Ci-C₃)alkyl, O or S; or (C₃-C₇)cycloalkyl-(C_rC_e)alkyl wherein the (C₃-C₇)cycloalkyl group of said (C₃C₇)cycloalkyl-(Ci-C_e)alkyl is optionally substituted with one to two (CpC^alkyl which are optionally substituted with one to three fluoro; B¹, B², B³ and B⁴ are each independently CR⁶ or N, with the proviso that no more than two of B¹, B², B³ and B⁴ are N; and R^e at each occurrence is independently H, halo, (CrC₃)alkyl optionally substituted with one to three fluoro, or (Ci-C₃)alkoxy optionally substituted with one to three fluoro.

A second embodiment of the présent invention is the compound of the first embodiment or a pharmaceutically acceptable sait thereof, wherein R¹ is a 5 membered heteroaryl attached through a nitrogen atom to the carbon between A¹ and A⁴ of the ring containing A¹, A², A³ and A⁴; R² is hydrogen; and R³ is -(CH₂)₂CO₂H.

A third embodiment of the présent invention is the compound of the first or second embodiments or a pharmaceutically acceptable sait thereof, wherein X is O. A fourth embodiment of the présent invention is the compound of the first or second embodiments or a pharmaceutically acceptable sait thereof, wherein X is NH. A fifth embodiment of the présent invention is the compound of the first or second embodiments or a pharmaceutically acceptable sait thereof, wherein X is CH₂.

A sixth embodiment of the présent invention is the compound of the third or fourth embodiments or a pharmaceutically acceptable sait thereof wherein R² is hydrogen; R³ is (CH2)₂CO₂H; L is -X-CH(R⁵)- ; A¹, A², A³ and A⁴ are each independently CR⁴; or A* is N and A¹, A²and A³ are each CR⁴; or A¹ and A⁴ are each N and A² and A³ are each CR⁴; or A² and A⁴ are each N and A’ and A³ are each CR⁴; R⁴ at each occurrence is independently H or methyl; B¹, B², B³ and B⁴ are each CR⁶; or B’ is N and B², B³ and B⁴ are each CR⁶; or B² and B³ are each N and B¹ and B⁴ are each CR⁶; or B’ and B⁴ are each N and B² and B³ are each CR⁶; and R⁶ at each occurrence is H.

A seventh embodiment of the présent invention is the compound of the third embodiment or a pharmaceutically acceptable sait thereof wherein R² is hydrogen; R³ is -(CH₂)₂CO2H; L is -XCH(R⁵)- ; A¹, A², A³ and A⁴ are each CR⁴; or A⁴ is N and A¹, A² and A³ are each CR⁴; or A¹ and A⁴are each N and A² and A³ are each CR⁴; or A² and A⁴ are each N and A¹ and A³ are each CR⁴; R⁴at each occurrence is independently H or methyl; B¹, B², B³ and B⁴ are each CR⁶; and R⁶ at each occurrence is independently H or methyl.

An eighth embodiment of the présent invention is the compound of the fourth embodiment or a pharmaceutically acceptable sait thereof wherein R² is hydrogen; R³ is -(CH₂)2CO_aH; L is CH(R^S)-X- ; A⁴ is N and A¹, A² and A³ are each CR⁴; or A¹ and A⁴ are each N and A² and A³ are

K each CR⁴; or A^z and A⁴ are each N and A¹ and A³ ara each CR⁴; R⁴ at each occurrence is independently H or methyl; B¹, B², B and B⁴ are each CR , and R^s at each occurrence is independently H or methyl.

A ninth embodiment of the présent invention rs the compound of the fourth embodiment or a pharmaceutically acceptable sait thereof wherein R² is hydrogen; R³ is ~(CH₂)₂CO₂H; L is CH(R^S)-X- ; A¹, A², A³ and A⁴ are each independently CR⁴; R⁴ at each occurrence is independently H or methyl; one of B¹, B², B³ and B⁴ is N and the others are each CR^e; and R⁶ at each occurrence is independently H or methyl.

A tenth embodiment of the présent invention is the compound of the sixth through ninth embodiments or a pharmaceutically acceptable sait thereof wherein R⁶ is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.

An eleventh embodiment of the présent invention is the compound of the tenth embodiment or a pharmaceutically acceptable sait thereof wherein R¹ is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro.

A twelth embodiment of the présent invention is the compound of the first embodiment or a pharmaceutically acceptable sait thereof wherein R¹ is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro; L is -X-CHR⁵-; X is O; and R⁵ is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.

A thirteenth embodiment of the présent invention is the compound of the first embodiment or a pharmaceutically acceptable sait thereof wherein R¹ is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro; L is CHR⁵-X-; X is NH; and R⁵ is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.

A fourteenth embodiment of the présent invention is the compound of the twelth or thirteenth embodiments or a pharmaceutically acceptable sait thereof wherein R¹ is 4trifluoromethylpyrazol-1-yl or 4-trifluoromethylimidazol-1-yl.

A fifteenth embodiment of the présent invention is a compound selected from the group consisting of:

(+/-)-3-(4-(1 -(3-methyl-4-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)phenylamino)butyl) benzamido)propanoic acid; (+/-)-3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1yl)phenyl)butoxy)benzamido)propanoic acid; (+/-)-3-(6-(1 -(4-(4-(trifluoromethyl)-1H-pyrazol-1 yl)phenoxy)butyl) nicotinamido)propanoic acid;

(+/-)-3-(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenyl)pentan-2yl)banzamido)propanoic acid; (+/-)-3-(4-(1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridine-3ylamino)butyl) benzamido)propanoic acid; (R)-3-(4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1yl)pyridine-3-ylamino)butyl)benzamido)propanoic acid; (S)-3-(4-(1 -(6-(4-(trifluoromethyl)-1Hpyrazol-1-yl)pyridine-3-ylamino)butyl) benzamido)propanoic acid; (+/—)-3-(4-(cyclopentyl(6-(4(trifluoromathyl)-1H-imidazol-1-yl)pyridine-3-ylamino)mathyl)benzamido)propanoicacid; (+/-)-3-(4(1 -(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)yridine-3-ylamino)butyl)benzamido)propanoic acid; (R)-3(4-(1 -(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyridine-3-ylamino)butyl) benzamidojpropanoic acid;

(S)-3-(4-(1-(6-(4-(trifluoromethyl)-1 H-imidazol-1-yl) yridine-3-ylamino)butyl) benzamidojpropanoic acid; (+/-)-3-(4-(1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenylamino) butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenylamino)butyl) benzamidojpropanoic acid; (R)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl) phenylamino)butyl)benzamido)propanoic acid; (S)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1Hpyrazol-1 -yl)phenylamino)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(4-(trifluoromethyl)-1Himidazol-1-yl)phenylamino) butyl)benzamido)propanoic acid; (R)-3-(4-(1-(4-(4-(trifluoromethyl)-1 Himidazol-1 -yl)phenylamino)butyl) benzamidojpropanoic acid; (S)-3-(4-(1 -(4-(4-(trifluoromethyl)-1Himidazol-1-yl)phenylamino) butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(4-(trifluoromethyl)1 H-imidazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(4-(methylthio)-1Hpyrazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(3-tert-butyl-1 H-pyrazol-1 yl)phenoxy)butyl) benzamidojpropanoic actd; (+/-)- 3-(4-(1-(4-(4-chloro-3-methyl-1 H-pyrazol-1 yl)phenoxy)butyl) benzamidojpropanoic acid; (+/-J-3-(4-(1-(4-(4-chloro-1 H-pyrazol-1-yljphenoxy) butyljbenzamidojpropanoic acid; (+/-)-3-(4-(1 -(4-(4-ethyl-3-methyl-1 H-pyrazol-1 yljphenoxyjbutyljbenzamidojpropanoic acid; (+/-)-3-(4-(1-(4-(3,5-diethyl-1H-pyrazol-1yljphenoxyjbutylj benzamidojpropanoic acid; (+/-)-3-(4-(1 -(4-(4-methyl-1H-pyrazol-1yljphenoxyjbutyljbenzamidojpropanoic acid; (+/-)- 3-(4-(1-(4-(3-isopropyl-1H-pyrazol-1yljphenoxyjbutyljbenzamidojpropanoicacid; (+/-)-3-(4-(1-(4-(4-fluoro-1 H-pyrazol-1yljphenoxyjbutyljbenzamidojpropanoic acid; (+/-)-3-(4-(1 -(4-(3-methyl-1H-pyrazol-1yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 -(4-(2H-1,2,3-triazol-2-yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(3-butyl-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 -(4-(5-ethoxy-3-methyl-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid; (+/)-3-(4-(1 -(4-(5-methoxy-3-methyl-1 H-pyrazol-1 -yljphenoxy) butyl)benzamido)propanoic acid; (+/-)-

3-(4-(1-(4-(4-butyl-1 H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(2cyano-3,4,5-trimethyl-1H-pyrrol-1-yl)phenoxy)butyl) benzamidojpropanoic acid; (+/-)-3-(4-(1-(4-(3cyano-2,4-dimethyl-1 H-pyrrol-1 -yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 -(4-(2-cyano-3-methyl-1 H-pyrrol-1 -yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-

3-(6-(1 -(4-(3-propyl-1H-pyrazol-1-yl)phenoxy)butyl) nicotinamido)propanoic acid; (+/-)-3-(4-(1 -(4(3,4-dimethyl-1H-pyrazol-1-yl) phenoxy)butyl)benzamïdo)propanoic acid; (+/-)-3-(4-(1 -(4-(1/7pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1H-imidazo[1,2-b]pyrazol1-yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1 -(4-(3-ethyl-1 H-pyrazol-1 yl)phenoxy) butyl) benzamido)propanoic acid; (+/-)- 3-(4-(1-(4-(4-chloro-5-methyl-1H-imidazol-1yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 -(4-(4,5-diethyl-1 H-imldazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4(1 -(4-(3,5-dimethyl-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(3methyl-1H-1,2,4-triazol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1 H-1,2,4triazol-1-yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(2-butyl-1H-imidazol-1yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(4,5-dimethyl-1H-imîdazol-1yl)phenoxy) butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1-propyl-1 H-pyrazol-4yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1 H-pyrazol-3yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(3,5-dimethylisoxazol-4yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(1 -methyl-3-(trifluoromethyl)-1 Hpyrazol-5-yl)phenoxy) butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1-methyl-1 H-pyrazol-4yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(1,5-dimethyl-1 H-pyrazol-4yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)- 3-(4-(1-(4-(1 H-pyrazol-4-yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1 -methyl-1 H-pyrazol-5-yl) phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1,3,5-trimethyl-1H-pyrazol-4yl)phenoxy)butyl)benzamido)propanoicacid; (+/-)-3-(4-(1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)butyl) benzamido)propanoic acid; (R)-3-(4-(1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid; (S)-3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenoxy)butyl) benzamido)propanorc acid; (+/-)-3-(4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridine-3ylamino)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(4-fluoro-1H-pyrazol-1yl)phenylamino)butyl)benzamido)propanoic acid; (+/-)-3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenyl)butylamino) nicotinamido)propanoic acid; (+/-)-3-(4-(2-cyclopropyl-1 -(4-(4(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl) benzamido)propanoic acid; (+/-)-3-(4(cyclopentyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy) methyl)benzamido)propanoic acid; (R)-

3-(4-(cyclopentyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)methyl)benzamido) propanoic acid; (S)-3-(4-(cyclopentyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy) methyl)benzamido)propanoic acid; (+/-)-3-(4-(cyclobutyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)methyl)benzamido)propanoic acid; (+/-)- 3-(4-(1 -(4-(3-(trifluoromethyl)-1H-pyrazol-1yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(3,3-dimethyl-1-(4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(4-methyl-3(trifluoromethyl)-l H-pyrazol-1-yl) phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(316506 (trifIuoromethyl)-1 H-1,2,4-triazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(3methyl-4-(trifluoromethyl)-1H-pyrazoM -yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 (4-(2-methyl-4-(trifluoromethyl)-1 H-imidazol-1-yl)phenoxy) butyljbenzamido) propanoic acid; (+/-)-

3-(4-(cyclopropyl(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)methyl)benzamido)propanoic acid; (+/-)-3-(4-(2-methyl-1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)propyl)benzamido) propanoic acid; (+/-)-3-(4-(1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phanoxy)propyl) benzamido) propanoic acid; (+/-)-3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1 H-imidazol-1yl)phenyl)butoxy)benzamido)propanoic acid; (+/-)-3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(3,5-dimethyl-4-(4(trifluoromethyl)-lH-pyrazol-1 -yl)phenoxy)butyl) benzamido) propanoic acid; (S)-3-(4-(1-(3,5dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl) phenoxy)butyl)benzamido)propanoic acid; (R)-3-(4(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl) phenoxy) butyl) benzamido) propanoic acid; (+/-)-3-(4-(1-(5-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridine-2-yloxy)butyl) benzamido)propanoic acid; (+/-) -3- (4-(1- (6- (4- (trifluoromethyl)-1 H-pyrazol-1 -yl) pyridine-3yloxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl) pyridine-3-yloxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 -(4-(4-cyano-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 -(4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)butyl)benzamido) propanoic acid; (+/)-3-(4-(1-(4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(4methyl-1H-1,2,3-triazol-1-yl)phenylamino)butyl)benzamido)propanoic acid; (+/-)-3-(2-(3-methyl-1 (4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)butylamino)pyrimidine-5-carboxamido) propanoic acid; (+/-)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl) pyridine-3-ylamino)methyl) benzamidojpropanoic acid; (R)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridine-3ylamino)methyl)benzamido)propanoic acid; (S)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-pyrazol1-yl) pyridine-3-ylamino)methyl)benzamido)propanoic acid; (R)-3-(4-(cyclopentyl(6-(4(trifluoromethyl)-l H-imidazol-1 -yl)pyridin-3-ylamino)methyl) benzamidojpropanoic acid; (S)-3-(4(cyclopentyl (6- (4- (tnfluoromethyl)-1 H-imidazol-1 -yl) pyridin-3-ylamino) methyl) benzamido) propanoic acid; (+/-)-3-(2-(cyclohexyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridine-3-yl)methylamino) nicotinamido) propanoic acid; (-+/—)-3-(4-(3,3-dimethyl-1 -(6-(4-(trÎfJuoromethyI)-1 H-imidazol-1 -yl) pyridine-3-ylamino)butyl) benzamidojpropanoic acid; (+/-)-3-(4-(cyclohexyl(6-(4-(trifluoromethyl)1 H-pyrazol-1 -yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid; (+/-)-3-(6-(3-methyl-1 -(5methyl-6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-ylamino)butyl) nicotinamido)propanoic acid; (R)-3-(4-(1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenylamino)butyl) benzamido)propanoic acid; and (S)-3-(4-( 1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenylamino)butyl) benzamidojpropanoic acid;

or a pharmaceutically acceptable sait thereof.

A sixteenth embodiment of the présent invention is a compound selected from the group consisting of:

(+/-)-3-(4-(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1/-/-pyrazol-1 -yl) phenoxy)butyl) benzamido)propanoic acid; (S)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl) phenoxy)butyl) benzamido)propanoic acid; (R)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1Hpyrazol-1-yl) phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3ylamino)methyl)benzamido)propanoic acid; (R)- 3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1Himidazol-1 -yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid; and (S)-3-(4-(cyclopentyl(6-(4(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid; or a pharmaceutically acceptable sait thereof.

A seventeenth embodiment of the présent invention is the compound (-)-3-(4-(1-(3,5άΐπΊθΙ1^Ι-4-(4-(ύϊΐΙυοΓθΠΊθίΙ^Ι)-1Η-ρνΓ3ζοΙ-1-νΙ)ρΐΊθηοχν)ΡυΐγΙ)Ρθηζ3ΓΤΊΐΡο) propanoic acid or a pharmaceutically acceptable sait thereof. An eighteenth embodiment of the présent invention is the crystalline form of the compound of the seventeenth embodiment with the powder X-ray diffraction spectrum substantially as shown in Figure 1.

Preferred R¹ groups include optionally substituted pyrazolyl, imidazolyl and indazolyl. Preferred embodiments of the ring containing A¹, A², A³ and A⁴ include phenyl, methyl substituted phenyl, dimethyl-substituted phenyl, pyridinyl, pyrimidinyl and pyrazinyl. Preferred embodiments of the ring containing B¹, B², B³ and B⁴ include phenyl, pyridinyl, pyrimidinyl and pyrazinyl. A preferred embodiment of R³ is -(CH2)2CO₂H.

Another embodiment of the présent invention is the compound of formula I according to the first embodiment or a pharmaceutically acceptable sait thereof with the exception that R⁵ Is (C₃C₇)cycloalkyl which can be further substituted with one to three fluoro. Yet another embodiment of the présent invention is the compound of formula I according to the first embodiment or a pharmaceutically acceptable sait thereof with the exception that R¹ is a 5 membered heteroaryl which can be fused to another 5 membered heteroaryl. Yet another embodiment of the présent invention are the compounds as set forth in Examples 105-193.

Another aspect of the présent invention is a pharmaceutical composition that comprises (1) a compound of the présent invention, and (2) a pharmaceutically acceptable excipient, diluent, or carrier. Preferably, the composition comprises a therapeutically effective amount of a compound of the présent invention. The composition may also contain at least one additional pharmaceutical agent (described herein). Preferred agents include anti-obesity agents and/or anti-diabetic agents (described herein below).

In yet another aspect of the présent invention is a method for treating a disease, condition, or disorder mediated by glucagon, in particular, deactivation of the glucagon receptor, in a mammal that includes the step of administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the présent Invention, or a pharmaceutical composition thereof.

Diseases, disorders, or conditions mediated by glucagon include Type II diabètes, hyperglycemia, metabolic syndrome, impaired glucose tolérance, glucosuria, cataracte, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslididemia, hypertension, hyperinsulinemia, and insulin résistance syndrome. Preferred diseases, disorders, or conditions include Type II diabètes, hyperglycemia, impaired glucose tolérance, obesity, and insulin résistance syndrome. More preferred are Type II diabètes, hyperglycemia, and obesity. Most preferred is Type II diabètes.

In yet another aspect of the présent invention is a method of reducing the level of blood glucose in a mammal, preferably a human, which includes the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the présent invention, or a pharmaceutical composition thereof.

Compounds of the présent invention may be administered in combination with other pharmaceutical agents (in particular, anti-obesity and anti-diabetic agents described herein below). The combination therapy may be administered as (a) a single pharmaceutical composition which comprises a compound of the présent invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the présent invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions may be administered simultaneously or sequentially and In any order.

Définitions

As used herein, the term “alkyl refers to a hydrocarbon radical of the general formula C_nH_2n+1. The alkane radical may be straight or branched. For example, the term “(Ci-C₆)alkyr refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2methylbutyl, 3-methylbutyl, neopentyl, 3,3-dlmethylpropyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, alkylsulfonyl, and alkylthio group hâve the same définition as above. When indicated as being optionally substituted, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).

The term “cycloalkyl refers to nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the carbocyclic ring is generally a 3- to 8-membered ring. For example, (C₃-C₇) cycloalkyl include groups such as

cyclopropyt, cyclobutyl, cyctopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, norbornyl (bicyclo[2,2.1]heptyl) and the like. In certain embodiments one or more of the carbon atoms in a cycloalkyl may be replaced with a heteroatom as specified, such as with an O, S, NH or N-alkyl.

The phrase “5 membered heteroaryl or 6 membered heteroaryl means a radical of a 5 or 6 membered heteroaromatic ring, respectively. The heteroaromatic ring can contain 1 to 4 heteroatoms selected from N, O and S. 5 to 6 membered heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. Preferred 5 to 6 membered heteroaryl groups include pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl. The heteroaryl group may be fused to another ring when specified. For example, a 5 membered heteroaryl such as a pyrazole may be fused with a phenyl to provide an indazole.

The phrase therapeutically effective amount means an amount of a compound of the présent invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) atténuâtes, améliorâtes, or éliminâtes one or more symptoms of the particular disease, condition, or disorder, or (ïii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

The term “animal refers to humans (male or female), companion animais (e.g., dogs, cats and horses), food-source animais, zoo animais, marine animais, birds and other similar animal species. Edible animais refers to food-source animais such as cows, pigs, sheep and poultry.

The phrase “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingrédients comprising a formulation, and/or the mammal being treated therewith.

The terms “treating, treat, or “treatment' embrace both preventative, i.e., prophylactic, and palliative treatment.

The terms “modulated or modulating, or modulate(s), as used herein, unless otherwise indicated, refers to the changes in activity of the glucagon receptor as a resuit of action of the compounds of the présent invention.

The terms “mediated or “mediating or “mediate(s), as used herein, unless otherwise indicated, refers to the treatment or prévention the particular disease, condition, or disorder, (ii) atténuation, amelioration, or élimination of one or more symptoms of the particular disease, condition, or disorder, or (iii) prévention or delay of the onset of one or more symptoms of the particular disease, condition, or disorder described herein, by modulation of glucagon.

The term “compounds of the présent invention (unless specifically identified otherwise) refer to compounds of Formula I and any pharmaceutically acceptable salts of the compounds, as well as, ail stereoisomers (including diastereoisomers and enantiomers), tautomers, conformational isomers, and isotopically labeled compounds. Hydrates and solvatés of the compounds of the présent invention are considered compositions of the présent invention, wherein the compound is in association with water or solvent, respectively.

DETAILED DESCRIPTION

Compounds of the présent invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fiesar and Mary Fieser, Reagents for Organic Synthesis. v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie. 4, Aufl. ed. Springer-Verlag, Berlin, including suppléments (also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the présent invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although spécifie starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of dérivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modifîed in light of this disclosure using conventional chemistry well known to those skilled in the art.

In the préparation of compounds of the présent invention, protection of remote functionality (e.g,, primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of tha remote functionality and the conditions of the préparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, fbutoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl-protecting groups (O-Pg) include for example, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991.

Reaction Scheme I outlines the general procedures that can be used to provide compounds of the présent invention of Formula I.

Reaction Scheme I

BSB³ O *'L— ,A⁴-A³ B¹-B² 0-R IV

A />-1? ______________

R¹^À¹-A²

V

A’-M

Vil

A*A³ + C —L'

Lg'-'A’-A²

VI

III hydrolysls

R²

R³'-NH couple and deprotect if necessary

Reaction Scheme I provides a general route which can be employed to préparé compounds of Formula I. More spécifie details of the transformations depicted are provided in Reaction Schemes ll-VII below. It is to be understood that the reaction schemes are illustrative and are not to be construed as a limitation in any manner. In step one of Reaction Scheme I the compound R’-M of Formula VII and the compound of Formula VI are coupled. In the compound of Formula VII, R¹ is a 5 membered optionally fused and optionally substituted heteroaryl group. The group M can represent either hydrogen when attached to nitrogen in the heteroaryl group R¹ or an appropriate métal species when attached to a carbon in the heteroaryl group R¹. When M is a métal attached to a carbon in the group R¹ the coupling reaction can be carried out using a palladium catalyzed coupling reaction. When M represents hydrogen attached to nitrogen in the heteroaryl R¹ group the nucleophilic displacement reaction to form the compound of Formula V can be carried out in an appropriate solvent in the presence of a base. In the compound of Formula VI Lg is an appropriate leaving group, such as a halide or triflate. The compound of Formula V can then be reacted with the compound of Formula IV to provide the compound of Formula III. In the compound of Formula V L'represents a precursor group which is, along with R in the compound of Formula IV is converted into the linker L in the compound of Formula III. The compound of Formula III can then be hydrolyzed to provide the free acid of Formula II which can then be subjected to an amide coupling reaction with the amine R³ R²NH, followed by deprotection if necessary to provide the compound of Formula I. The group R³ in the amine R³ R²NH can represent either R³ itself or a protected version of R³ which can be subsequently deprotected to provide R³.

Reaction Scheme II outlines another general procedure that can be used to provide compounds of the présent invention having Formula I.

Reaction Scheme II

R¹-H

Lg

hydrolysle Α⁴:Α³ BL-B³ ,P % —^L—4 ~~\ rI-'A’-A² Θ’-B² OH

II

R²

R³'-NH AtA³ B⁴.-B³ O

tf necessary ₍ R²

The ester compound of Formula III may be formed by reaction of an appropriate heteroaryl compound R^H or a metallated heteroaryl compound R¹-M with the compound of Formula Ilia. The reaction with R’-H can be employed when the hydrogen depicted in R’-H is attached to nitrogen in the R¹ heteroaryl group. The reaction can be carried out in an appropriate solvent such as dimethyl sulfoxide and a base such as potassium carbonate in the presence of copper(l) iodide. The reaction between the compound of Formula Ilia and R'-M can be carried out by a palladium catalysed coupling reaction, Preferably, the reaction is carried out between the boronate ester R¹M (where M is B(OR')2 and R' is H or lower alkyl or both R's together form an appropriate cyclic group) and the compound of Formula Ilia (wherein Lg is OSOaCFs, Cl, Br or I) using a suitable palladium catalyst, a suitable phosphine ligand and a suitable base in the presence of a suitable solvent at a température of typically from room température up to around reflux (or at températures above the boiling point of the solvent e.g. 120 °C using microwave conditions).

A suitable palladium catalyst is tris(dibenzylideneacetone)dipalladium, bis (dibenzylideneacetone) palladium, palladium acetate or (1,r-bis(diphenylphosphino) ferrocene) dichloropalladium. A suitable phosphine ligand is tricyclohexylphosphine, triphenylphosphine or 2dicyclohexylphosphino-2',6’-dimethoxylbiphenyl. A suitable base is sodium carbonate, potassium carbonate, potassium phosphate or sodium hydrogen carbonate and solvents are DME, 1,4dioxane or THF/water.

Alternative^, the cross coupling may be carried out between the trimethyl stannane of general Formula F^-M (wherein M is SnMe₃) and the compound of Formula Ilia using a suitable catalyst, such as tetrakis(triphenylphosphine)palladium, an optional copper (I) source, such as copper (I) chloride, a suitable base, such as césium fluoride, and a suitable solvent, such as N,Ndimethylformamide, at a température of typically around Θ0 °C to 120 °C. Further alternative methods using metallated compounds R’-M (where M is MgX' or ZnX' and X’ is a halide) with the dérivative Ilia using a suitable palladium catalyst, a suitable phosphine base, an optional copper (I) source, and a suitable base in the presence of a suitable solvent at a température of typically around reflux, can also be employed.

Suitable palladium catalysts are tris(dibenzylideneacetone)dipalladium, bis(dibenzylîdene acetone)palladium, palladium acetate or (1,T-bÎs(diphenylphosphino) ferrocene) dichloropalladium. Suitable phosphine bases are tricyclohexylphosphine or 2-dicyclohexylphosphino-2',6’dimethoxylbiphenyl. A suitable copper (I) source is copper (I) chloride. Suitable bases are potassium carbonate or sodium hydrogen carbonate. Suitable solvents are DME, 1,4-dioxane or THF/water.

The compound of Formula III then undergoes hydrolysis to provide the compound of Formula II. Depending on which R group is présent in the ester of Formula III, appropriate acid or base catalyzed hydrolysis can be carried out to provide the corresponding free acid in the compound of Formula II. For example, when R represents methyl, hydrolysis is typically carried out with aqueous sodium hydroxide or lithium hydroxide in a mixture of methanol and tetrahydrofuran at a température from room température up to 80 °C for 15 minutes to 24 hours.

Conversion of the compound of Formula II to provide the compound of Formula I can be carried out using standard amide coupling conditions. Amide coupling is carried out using standard literature conditions. The acid of Formula II can be converted to the corresponsing acid chloride using a suitable chlorinating agent, such as oxalyl chloride or thionyl chloride, in a suitable solvent, such as dichloromethane or toluene, optionally in the presence of catalytic DMF, at a suitable température, typically of between 0 °C and room température. The acid chloride can then be reacted with the amine of generic formula R³-NH₂ in the presence of a base, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as dichloromethane or toluene, at a température of between 0 °C and room température. R³ can represent either R³ itself or a protected version of R³ which can be subsequently deprotected to provide R³. Alternatively, the acid of Formula II can be converted to a suitable activated species with a coupling agent, such as EDCI.HCl, HBTU, HATU, PyBop, DCC, or CDI, in a suitable solvent, such as dichloromethane, acetonitrile or DMF. In the presence of EDCI.HCl, HOBT îs typically added. EDCI is 1-ethyl-3-(3dimethylaminopropyl)carbodiimide; HBTU is O-Benzotriazole-N,N,N’,N'-tetramethyluronium hexafluorophosphate; HATU is 0-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; PyBop is Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate: DCC is dicyclohexylcarbodiimide; CDI is Ν,Ν'-carbonyldiimidazole and HOBT is 1-hydroxy benzotriazole. A suitable base, such as triethylamine or diisopropylethylamine, is also used and the reaction is typically carried out at room température. In the instance where R³' represents a protected version of R³, subséquent deprotection can then be carried out by methods known in the art to provide R³. For example, when R³ is an ester, appropriate acid or base catalyzed hydrolysis can be carried out to provide the corresponding free acid in the compound of Formula I.

Réaction Scheme III outlines the general procedures one could use to provide compounds of the présent invention having Formula la. The compounds of Formula la are of Formula I wherein L is -C(R⁵)-X-, X is NH and R^z is H.

Reaction Scheme III

R⁵M Va'

réduction

B⁴--B³ p

A⁴: A³ H N—<\ z)—\ hydrolysis < />—< B¹-B² b-R -------R¹ A’-A² R⁵

Ilia b+b³ O a^4;A³ hn—4 i)—

C />—-< b¹-b² oh rI^À’-A² R⁵ r³'-nh² couple and deprotect if necessary

B⁴.-B³ o

A⁴; A³ HN—4

C B¹-B² HN-R³ rKÀ'-A² R⁵la

The nitrile of Formula Va is reacted with an appropriate Grignard reagent R^s-M wherein M represents a magnésium halide such as magnésium chloride or magnésium bromide. The reaction is carried out in an appropriate solvent such as tetrahydrofuran or a mixture of tetrahydrofuran and 10 diethyl ether. The reaction is typically carried out at 0 °C to 100 °C and microwave irradiation of the reaction mixture is preferred. Upon completion of the Grignard reaction the reaction mixture is then subjected to réduction using an appropriate reducing agent such as sodium borohydride in an appropriate solvent such as methanol to provide the amine compound of Formula IVa. The compound of Formula IVa is then converted to the compound of Formula la as previously 15 described for Reaction Scheme II.

Reaction Scheme IV provides the préparation of compounds where L is -XCHR⁵- and X is NH as depicted.

Réaction Scheme IV

A .A

J* ')~NO₂

R¹<A¹-A² | réduction A⁴: A³

F />-NH2 R¹ a¹-a² _|Vb

Η B⁴-B³ Ο ^a> A4

Ο Β¹-Β^ζ O-R IVb’ ^r b) R⁵-M IVb ~

lllb

A

R³ B⁴--B³ O

H, M ^lw

O B'B² O-R

X_, -_____.

hydrolysis

R³’-NH² couple and deprotect il necessary

R⁵ B⁴--B³ ,O a⁴ a3 A4

C- 4— NH B¹'B² HN-R³R’ À¹-A² lb

The amine of Formula IVb can be prepared by réduction, such as by hydrogénation, of the corresponding nitro dérivative. The amine of Formula IVb can be converted to the compound of Formula lllb by two methods. The first method involves reaction of the amine with the aldéhyde of Formula IVb’ followed by alkylation of the resulting aldimine with an appropriate alkylating reagent R^s-M of Formula IVb. The reaction of the amine of Formula IVb with the aldéhyde of Formula IVb' to provide the corresponding aldimine is carried out in an appropriate solvent, such as toluene, typically in the presence of molecular sieves, at a température from room température up to 100 °C for a period of 1 to 24 hours. The reaction mixture containing the aldimine can be filtered and concentrated. The resulting residue can then be redissolved in a solvent appropriate for the alkylation reaction, such as tetrahydrofuran. Typically, an appropriate metallated alkylating agent, such as a Grignard reagent R⁵-M of Formula IVb where M represents a métal such as a magnésium halide is employed. The alkylation reaction can be carried out at a température of 0 °C to 60 °C for a period of 1 to 24 hours to provide the compound of Formula lllb. When R⁵-M represents a Grignard reagent addition of zinc chloride to the reaction mixture may be désirable to increase the yield of the compound of Formula lllb (see Ishihara, K. et al.; JA CS, 2006, 128, 9998.

Alternatively, the compound of Formula lllb can be prepared by reaction of an amine of Formula IVb and a ketone of Formula IVb’” followed by réduction of the resulting imine. The reaction can be carried out under typical reductive amination conditions to provide the compound of Formula lllb. For example, the amine of Formula IVb and ketone IVb’ in an appropriate solvent such as dimethoxyethane and in the presence of molecular sieves and para-toluene sulfonic acid can be reacted at room température up to 120 °C (sealed tube) for 1 to 24 hours. The reaction mixture can then be allowed to cool to room température and be treated with an appropriate reducing agent, such as sodium cyanoborohydride in methanol, and in the presence of acetic acid for 1 to 24 hours to provide the compound of Formula lllb.

The compound of Formula lllb can be hydrolyzed to provide the free acid compound of Formula llb by methods as previously described for the préparation of the compound of Formula lia in Reaction Scheme II. The free acid compound of Formula llb can then undergoe amide coupling conditions followed by deprotection if necessary to provide the compound of Formula lb as previously described for the conversion of the compound of Formula lia to Formula la in Reaction Scheme II.

Reaction Scheme V outlines the general procedures that can be used to provide compounds of the présent invention having Formula le. The compounds of Formula le are of Formula I wherein L is -X-C(R⁵)-, X is O and R² is H.

Reaction Scheme V

A⁴:A³

X —OH

R ^{A A} IVc’

H B⁴-B³ O R⁵-M R® B*-B³O }——t 71 * )

O B¹-B² O- R ^Vc HO B¹'B²O-R

VcIVc

R5 b⁴--B³o

A⁴:A³ )—(\ fl-# hydrolysis

C /)—O B¹~8² o-R----------r’Xa¹-a^z ile ’ R³ B⁴--B³ O

R³-NH² A⁴:A³ )---(x à-couple and deprotect ,,--¼, .2 θ ^B ~^B Η N-R³ if necessary R ^A le

The compound of Formula IVc is prepared by reaction of an aldéhyde of Formula Vc with an appropriate metallated alkylating compound R⁵-M (Vc‘). Typically, R⁵-M is a Grignard reagent in which M represents a magnésium halide, such as magnésium chloride or magnésium bromide. The reaction is carried out in an appropriate solvent, such as tetrahydrofuran, at a température from about -78 °C to room température for a period of 15 minutes to 24 hours to provide the alcohol of Formula IVc. The alcohol IVc is then coupled with the phénol of Formula IVc’ using phenolic ether Mitsunobu reaction conditions (see e.g Mitsunobu, O.; Synthesis, 1981, 1; Lepore,

S.D. et al. J. Org. Chem, 2003, 68(21), 8261-8263) to provide the compound of Formula lllc. This reaction is typically carried out in an appropriate solvent such as tetrahydrofuran in the presence of an appropriate coupling reagent such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and a phosphine ligand such as triphenylphosphine. The reaction is typically run at a température from about 0 °C to room température for 1 to 24 hours. The compound lllc can then be hydrolyzed to the compound of Formula Ile followed by amide

formation and deprotection, as necessary, to provide the compound of Formula le as previously described for the corresponding steps in Reaction Scheme II.

Reaction Scheme VI outlines the general procedures that can be used to provide compounds of the présent invention having Formula Id. The compounds of Formula Id are of

Formula I wherein L is -C(R^S)-X-, X is O and R² is H.

Reaction Scheme VI

R^s-M

Vd'

IVd

B⁴.-B³ O HO-<\

B’-B² 0-R

IVd’ hydrolysis lld

R³'-NH²

B⁴.-B³ O ,A⁴:A³ couple and deprotect /2 bs ^B θ* ^hn_r3 if necessary R ^A’^A R

Id

The compound of Formula Id is prepared in an analogous manner to the préparation of the compound of Formula le in Réaction Scheme V by substituting the compounds of Formula Vd, Vd', 10 IVd, IVd’, llld and lld for the compounds Vc, Vc', IVc, IVc', lllc and Ile as previously described.

Reaction Scheme VII outlines the general procedures one could use to provide compounds of the présent invention having Formula la. The compounds of Formula la are of Formula I wherein R¹ is in the para position, L is -X-C(R⁵)', X is CH₂ and R² is H.

Reaction Scheme VII

Ph₃Br

FP'-NH²couple deprotect

P hydrogenats

NH-R³’ ^F

The phosphomium bromide compound of Formula Vile may be treated with an appropriate base and then reacted with the ketone dérivative of Formula Vile’ to provide the olefinic compound of Formula Vie. The compound of Formula Vile is typically treated with a base such as lithium bis(trimethylsilyl)amide (LHMDS) in an appropriate solvent such as toluene at -78 °C up to room température. Other bases that can be employed include lithium amides such as lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethyl piperidide (LiTMP) or lithium diethyl amide as well as alkyl lithiums such as methyl lithium or n-butyl lithium.

The compound of Formula Vie can then be reacted with the heteroaryl compound R¹-M (Vie’ wherein M is hydrogen when attached to nitrogen or an appropriate métal when attached to carbon). When M is a métal attached to a carbon in the heteroaryl represented by R¹ the reaction is typically a palladium catalyzed coupling reaction, as was described previously for the first step in Reaction Scheme II to provide the compound of Formula Ve. When M is hydrogen attached to nitrogen in the heteroaryl R¹, the nucleophilic substitution reaction is typically carried out in an appropriate solvent in the presence of a base. The compound of Formula Ve is then subjected to hydrolysis, typically in methanol and tetrahydrofuran using sodium hydroxide as base at 0 “C to room température for a period of 1 to 24 hours to provide the frae acid of formula IVe. The frea acid of Formula IVe can then be reacted with the amine R³-NH₂ using the amide coupling conditions previously described for Reaction Scheme II to provide the compound of Formula II le. The compound of Formula II le is then subjected to hydrogénation to reduce the olefinic moiety and provide the compound of Formula Ile. The hydrogénation is typically carried out in the presence of an appropriate hydrogénation catalyst, such as 10% palladium on carbon (Pd/C), in an appropriate solvent such as methanol at a température from room température up to 50 °C. Hydrogénation apparatus such as the ThalesNano H-Cube® hydrogenator (ThalesNano, Budapest, Hungary) with a 10% Pd/C cartridge can ba employed for this step. The compound of Formula Ile can then be deprotected as necessary and as previously described for Reaction Scheme II to provide the compound of Formula le.

Reaction Scheme VIII outlines another general procedure that can be used to provide compounds of the présent invention having Formula le. The compounds of Formula le are of Formula I wherein L is -X-C(R⁵)-, X is O and R² is H.

Reaction Scheme VIII

R® ₈4_îB3 q r5 _B4_;S3 Q

A^4;A³ )—(\ ))—hydrolysis ^a4;A3 ) (\ jt /)—O B¹-B^z HN-R³’ --------* > -v^-O B¹-B^a HN-R³

R Va¹-A² R Va¹-A² lllf le

The compound of Formula Vf in which Lg is an appropriate halide, preferably iodide, and R³ represents a protected R³ group (such as an ester of an appropriate R³ carboxylic acid group) can be treated with magnésium in an appropriate solvent to provide the corresponding Grignard reagent. The Grignard reagent can then be reacted with the aldéhyde R^S-CHO to provide the compound of Formula IVf. The compound of Formula IVf can undergoe Mitsunobu coupling with the compound of Formula IVc’ as previously described for Réaction Scheme V to provide the compound of Formula lllf. Deprotection of the compound of Formula lllf, for example by hydrolysis of an ester as previously described, then provides the compound of Formula le.

The compounds of the présent invention may be isolated and used per se, or when possible, in the form of its pharmaceutically acceptable sait. The term “salts refers to înorganic and organic salts of a compound of the présent invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound with a suitable organic or înorganic acid or base and isolatîng the sait thus formed. Représentative salts include the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stéarate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryisulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnésium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tétraméthylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., Berge, et al., J. Pharm. Sci.. 66, 1-19(1977).

The compounds of the présent invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. Unless specified otherwise, it is intended that ail stereoisomeric forms of the compounds of the présent invention as well as mixtures thereof, including racemic mixtures, form part of the présent invention. In addition, the présent invention embraces ali géométrie and positional isomers. For example, if a compound of the présent invention incorporâtes a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical différences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the présent invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column. Alternatively, the spécifie stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.

It is also possible that the intermediates and compounds of the présent invention may exist in different tautomeric forms, and ail such forms are embraced within the scope of the invention. The term tautomer” or “tautomeric form refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A spécifie example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding électrons. For example, the pyrimidonr ring of this invention may also exist in its hydroxy pyrimidine form. Both such forms are included in the compounds of Formula I.

Certain compounds of the présent 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 séparation of different conformers.

The présent invention also embraces isotopically-labeled compounds of the présent invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0,¹⁷0,^1BO, ³¹P, ³²P, 35_S1 18_F( 123(, 12S| _and 36_C| _{Γθ8ρθ(ΐ1}(_νθ(_γ#

Certain isotopically-labeled compounds of the présent invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ^1SO, ¹³N, ¹¹C, and ¹⁸F are useful for positron émission tomography (PET) studies to examine substrate occupancy. Isotopically labeled compounds of the présent invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Certain compounds of the présent invention may exist in more than one crystal form (generally referred to as polymorphs). Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different températures; and/or various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound of the présent invention followed by graduai or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

Compounds of the présent invention are useful for treating diseases, conditions and/or disorders modulated by glucagon; therefore, another embodiment of the présent invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the présent invention and a pharmaceutically acceptable excipient, diluent or carrier. The compounds of the présent invention (including the compositions and processes used therein) may also be used in the manufacture of a médicament for the therapeutic applications described herein.

A typical formulation is prepared by mixing a compound of the présent invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobie materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will dépend upon the means and purpose for which the compound of the présent invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, éthanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an élégant présentation of the drug (i.e., a compound of the présent invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., médicament).

The formulations may be prepared using conventional dissolution and mixing procedures.

For example, the bulk drug substance (i.e., compound of the présent invention or stabilized form of the compound (e.g., complex with a cyclodextrin dérivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the présent invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an élégant and easily handleable product.

The pharmaceutical compositions also include solvatés and hydrates of the compounds of Formula I. The term solvaté refers to a molecular complex of a compound represented by Formula I (including pharmaceutically acceptable salts thereof) with one or more solvent molécules. Such solvent molécules are those commonly used in the pharmaceutical art, which are known to be Innocuous to the récipient, e.g., water, éthanol, ethylene glycol, and the like, The term “hydrate refers to the complex where the solvent moiecule is water. The solvatés and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvatés in the préparation of more désirable solvatés, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and the like.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materiais such as bottles (plastic and glass), sachets, ampoules, plastic bags, métal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that descrîbes the contents of the container. The label may also include appropriate warnings.

The présent invention further provides a method of treating diseases, conditions and/or disorders modulated by glucagon in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the présent invention or a pharmaceutical composition comprising an effective amount of a compound of the présent invention and a pharmaceutically acceptable excipient, diluent, or carrier. The method is particularly useful for treating diseases, conditions and/or disorders that benefit from the modulation of glucagon which include: eating disorders (e.g., binge eating disorder, anorexia, bulimia, weight loss or control and obesîty), prévention of obesity and insulin résistance.

One aspect of the présent invention is the treatment of obesity, and obesity-related disorders (e.g., overweight, weight gain, or weight maintenance).

Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimâtes the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m^a). Overweight is typically defined as a BMI of 25-29.9 kg/m^z, and obesity is typically defined as a BMI of 30 kg/m². See, e.g., National Heart,

Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998).

Another aspect of the présent invention is for the treatment or delaying the progression or onset of diabètes or diabetes-related disorders including Type 1 (insulin-dependent diabètes mellitus, also referred to as ‘'IDDM) and Type 2 (noninsulin-dependent diabètes mellitus, also referred to as NIDDM) diabètes, impaired glucose tolérance, insulin résistance, hyperglycemia, and diabetic complications (such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).

Yet another aspect of the présent invention is the treatment of diabètes- or obesity-related co-morbidities, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin résistance, diabètes (e.g., Type 2 diabètes), weight gain, coronary artery disease and heart failure. For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P.Z., et al., The Metabolic Syndrome: Perhaps an Etiologie Mystery but Far From a Myth - Where Does the International Diabètes Fédération Stand?, Diabètes & Endocrinology, 7(2), (2005); and Alberti, K.G., et al., The Metabolic Syndrome - A New Worldwide Définition,” Lancet, 366,1059-62 (2005). Preferably, administration of the compounds of the présent invention provides a statistically significant (p<0.05) réduction in at least one cardiovascular disease risk factor, such as lowering of plasma leptin, C-reactive protein (CRP) and/or cholestérol, as compared to a vehicle control containing no drug. The administration of compounds of the présent invention may also provide a statistically significant (p<0.05) réduction in glucose sérum levels.

In yet another aspect of the présent invention, the condition treated is impaired glucose tolérance, hyperglycemia, diabetic complications such as sugar cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardlomyopathy, anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertrîglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischémie reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and ovarian cancer.

The présent invention also relates to therapeutic methods for treating the above described conditions in a mammal, including a human, wherein a compound of Formula I of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the

therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will dépend upon the compound of formula (I) of this invention being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the conditions.

In general, an effective dosage for the compounds of the présent invention is in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 5 mg/kg/day of active compound in single or divided doses. However, some variability in the general dosage range may be required depending upon the âge and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like. The détermination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure. Practitioners will appreciate that “kg refers to the weight of the patient measured in kilograms.

The compounds or compositions of this invention may be administered in single (e.g., once daily) or multiple doses or via constant infusion. The compounds of this invention may also be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, stérile aqueous solutions and various organic solvents.

The compounds or compositions of the présent invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally and parenterally, (e.g., intravenously, subcutaneously or intramedullary). Further, the pharmaceutical compositions of this invention may be administered intranasally, as a suppository, or using a flash formulation, i.e., allowing the médication to dissolve in the mouth without the need to use water.

It is also noted that the compounds of the présent invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the présent invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the présent invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, antihyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a diacylglycérol O-acyltransferase 1 (DGAT-1) inhibitor, a phosphodiesterase (PDEJ-10 inhibitor, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone and troglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) agonist (e.g., exendin-3 and exendin-4), a protein tyrosine phosphatase-1 B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug DiscovervTodav. 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol), adîpeptidyl peptidase IV (DPP-IV) inhibitor (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin), an SGLT1 inhibitor, an SGLT2 inhibitor (e.g. dapagliflozin, remogliflozin, sergliflozin and AVE2268), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, and a VPAC2 receptor agonist. Preferred anti-diabetic agents for the combination aspects are metformin, SGLT2 inhibitors (e.g. dapagliflozin, remogliflozin, sergliflozin and AVE2268) and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin). Preferred combinations include the instant compounds of Formula I with metformin and a DPP-IV inhibitor or with metformin and an SGLT2 inhibitor.

Suitable anti-obesity agents include 11β-hydroxy steroid dehydrogenase-1 (1 Ιβ-HSD type 1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5 antagonists), PYY₃._3e(including analogs thereof), thyromimetic agents, déhydroépiandrostérone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide), opioid antagonist, orexin antagonist, and the like.

Preferred anti-obesity agents for use in the combination aspects of the présent invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541-47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1 H-indol-3ylmethyl)-5-oxo-1 -phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropylacetamide described in PCT Publication No. WO 2005/116034 or US Publication No. 20050267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US

6,818,658), iipase inhibitor (e.g., Cetilistat), PYY₃.₃6(as used herein ΡΥΥ₃._3Θ includes analogs, such as peglated ΡΥΥ₃.3β e.g., those described in US Publication 2006/0178501), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide (Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine. Preferably, compounds of the présent invention and combination thérapies are administered in conjunction with exercise and a sensible d jet.

AI! of the above recited U.S. patents and publications are incorporated herein by reference. Embodiments of the présent invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the spécifie details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

EXAMPLES

Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientifîc (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England).

General Experimental Procedures

NMR spectra were recorded on a Varian Unity™ 400 (available from Varian Inc,, Palo Alto, CA) at room température at 400 MHz for proton. Chemical shifts are expressed in parts per million (δ) relative to residual solvent as an internai reference. The peak shapes are denoted as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; 2s, two singlets. Atmospheric pressure chemical ionization mass spectra (APCI) were obtained on a Fisons™ Platform II Spectrometer (carrier gas: acetonitrile: available from Micromass Ltd, Manchester, UK). Chemical ionization mass spectra (Cl) were obtained on a Hewlett-Packard™ 5989 instrument (ammonia ionization, PBMS: available from Hewlett-Packard Company, Palo Alto, CA). Electrospray ionization mass spectra (ES) were obtained on a Waters™ ZMD instrument (carrier gas: acetonitrile: available from Waters Corp., Milford, MA). High resolution mass spectra (HRMS) were obtained on an Agilent™ Model 6210 using time of flight method. Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for ^3SCI/³⁷CI-containing ions and 1:1 for ⁷⁹Br/^s,Br-containing ions) and the intensity of only the lower mass ion is given. In some cases only représentative ¹H NMR peaks are given. Optical rotations were determined on a PerkinElmer™ 241 polarimeter (available from PerkinElmer Inc., Wellesley, MA) using the sodium D line (λ = 589 nm) atthe indicated température and are reported as follows [α]ο'^θπιρ, concentration (c = g/100 ml), and solvent.

Column chromatography was performed with either Baker™ silica gel (40 μπτ, J.T. Baker, Phillipsburg, NJ) or Silica Gel 50 (EM Sciences™, Gibbstown, NJ) in glass columns or in Flash 40

Biotage™ columns (ISC, Inc., Shelton, CT) or Biotage™ SNAP cartridga KPsil or Redisep Rf silica (from Teledyne™ Isco™) under low nitrogen pressure. Chiral SFC (supercritical fluid chromatography) was performed on the chiral columns as specified.

Certain solvents and reagents may be referred to using common abbreviations such as DCM for dichloromethane, DMF for dimethylformamide, EtOH for éthanol, EtOAc for ethyl acetate, and MeOH for methanoi, for example.

Préparation of Starting Materials and Intermediates

The foilowing starting materials are available from the corresponding sources: (Z)-A/-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-A/-methylmethanaminium hexafluorophosphate-Anichem LLC (North Brunswick, NJ, USA); 4-phenyl-1H-pyrazole Anichem LLC (North Brunswick, NJ, USA); tert-butyl 3-(tert-butylamino)propanoate - Aurora Fine Chemicals LLC (San Diego, CA, USA); 2,4,5,6-tetrahydrocyclopenta[c]pyrazole - Ambinter (Paris, France); methyl 6-formylnicotinate - Ark Pharm Inc. (Libertyville, IL, USA); 4-(trifluoromethyl)-1Hpyrazole - Anichem LLC (North Brunswick, NJ, USA); 4-(trifluoromethyl)-1/-/-imidazole - Ark Pharm Inc. (Libertyville, IL, USA); 4-methyl-3-(trifluoromethyl)-1H-pyrazole - ASDI Inc. (Newark, DE, USA); 3-methyl-4-(trlfluoromethyl)-1H-pyrazole - Accel Pharmtech LLC (East Brunswick, NJ, USA); 3-(trifluoromethyl)-1H-1,2,4-triazole - Beta Pharma Inc. (Branford, CT, USA); 2-methyl-4(trifluoromethyl)-IH-imidazole-APAC Pharmaceutical LLC (Columbia, MA, USA); ethyl 2chloropyrimidine-5-carboxylate - Ark Pharm Inc. (Libertyville, IL, USA); 2-cyc!opropylacetaldehydeAnichem LLC (North Brunswick, NJ, USA); 4-chloro-3-methyl-1H-pyrazole-Oakwood Products, Inc. (West Columbia, SC, USA); 2-(1H-pyrazol-4-yl)pyridine - Oakwood Products, Inc. (West Columbia, SC, USA); and

4-ethyl-3-methyl-1H-pyrazole-Aces Pharma, Inc. (Branford, CT, USA).

Préparation of Intermediates

Intermediate (1k (4-(4-(trifluoromethyl)-1 H-pvrazol-1 -yl)phenyl)methanol

A mixture of (4-iodophenyl)methanol (1030 mg, 4.41 mmol), 4-(trifluoromethyl)-1H-pyrazole (600 mg, 4.41 mmol), copper(l) iodide (168 mg, 0.882 mmol), frans-4-hydroxy-L-proline (231 mg,

1.76 mmol) and césium carbonate (2900 mg, 8.82 mmol) in dimethylsulfoxide (7.5 mL) was heated to 85°C for 20 hours. The mixture was diluted with water and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 - 45% ethyl acetate in heptane), gave (4-(4-(trifluoromethyl)-1 /7pyrazol-1-yl)phenyl)methanol. ¹H NMR (400 MHz, CDCI₃, δ): 8.16 (s, 1 H), 7.89 (s, 1 H), 7.65 (d, J = 8.39 Hz, 2 H), 7.47 (d, J = 8.39 Hz, 2 H), 4.74 (d, J = 5.66 Hz, 2 H), 1.85 (t, J = 5.86 Hz, 1 H). Intermediate (2): 4-(4-(trifluoromethyl)-1H-pvrazol-1-vl)benzaldehvde

(2)

A mixture of Intermediate (1) (230 mg, 0.95 mmol), dimethylsulfoxide (1.35 mL) and triethylamine (0.662 mL, 4.75 mmol) in dichloromethane (3.5 mL) was cooled to 0°C. Sulfur trioxide pyridine complex (0.454 g, 2.85 mmol) was added in portions and the mixture stirred at 0°C for 2 hours. The reaction was diluted with ethyl acetate, washed with saturated ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated to give 4-(4-(trifluoromethyl)-1H-pyrazol1-yl)benzaldehyde. ¹H NMR (400 MHz, CDCI₃, δ): 10.04 (s, 1 H), 8.29 (s, 1 H), 7.99 - 8.05 (m, 2 H), 7.95 (s, 1 H), 7.87 - 7.92 (m, 2 H).

Intermediate (3): 1 -(2-methyl-4-nitroDhenyl)-4-(trifluoromethvlM H-imidazole

A mixture of 4-(trifluoromethyl)-1H-imidazole (198 mg, 1.46 mmol), 1-fluoro-2-methyl-4nitrobenzene (216 mg, 1.53 mmol) and potassium carbonate (402 mg, 2.91 mmol) in acetonitrile (1.5 mL) was heated to 85°C for 24 hours. The mixture was diluted with water and saturated ammonium chloride and was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 50% ethyl acetate in heptane), gave 1-(2-methyl-4-nitrophenyl)-4-(trifluoromethyl)-1H-imidazole. ¹H NMR (500 MHz, CDCI₃, δ): 8.30 (d, J = 2.44 Hz, 1 H), 8.21 - 8.25 (m, 1 H), 7.70 (s, 1 H), 7.45 -

7.49 (m, 2 H), 2.38 (s, 3 H).

Intermediate (4): 3-methvl-4-(4-(trifluoromethvn-1/7-imidazol-1-vnbenzenamine

A mixture of Intermediate (3) (325 mg, 1.20 mmol) and 10 wt% palladium on carbon (40 mg) in éthanol (6 mL) was pressurized to 48 psi hydrogen and agitated for 6 hours. The mixture was filtered through celite, rinsing with ethyl acetate and methanol. The filtrate was concentrated to give 3-methyl-4-(4-(trifluoromethyl)-1H-imidazol-1-yl) benzenamine. ¹H NMR (500 MHz, CDCI₃,

δ): 7.56 (s, 1 Η), 7.32 (s, 1 Η), 7.01 (d, J = 8.54 Hz, 1 H), 6.62 (d, J = 2.68 Hz, 1 H), 6.57 (dd, J =

8.29, 2.44 Hz, 1 H), 3.85 (br. s., 2 H), 2.08 (s, 3 H). MS (M+1): 242.3.

Intermediate (5): Ethyl 4-butvrvlbenzoate

At -40°C, isopropylmagnesium chloride lithium chloride (15.3 mL, 1.3 M in THF, 19.9 mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5000 mg, 18,11 mmol) in tetrahydrofuran (30 mL). The solution was stirred at -40°C for 40 minutes. Butyraldéhyde (1830 mg, 25.4 mmol) was added. The mixture was allowed to warm to room température over 3 hours. The reaction was quenched with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give ethyl 4(l-hydroxybutyl)benzoate. ¹H NMR (400 MHz, CDCI₃, δ): 8.02 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 4.83 - 4.66 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.86 (d, J = 3.7 Hz, 1 H), 1.83 -1.61 (m, 2H), 1.51-1.42 (m, 1 H), 1.39 (t, J = 7.2 Hz, 3H), 1.36 - 1.23 (m, 1 H), 0.94 (t, J = 7.6 Hz, 3H).

A mixture of the crude alcohol (1.0 g, 4,5 mmol) in dichloromethane (16.7 mL), dimethylsulfoxide (4.79 mL) and triethylamine (2.28 g, 22.5 mmol) was cooled to 0°C. Sulfur trioxide pyridine complex (2.15 g, 13.5 mmol) was added in portions and the mixture stirred at 0°C for 1 hour. The reaction was then allowed to warm to room température and stir for 2 hours. The reaction was quenched with brine and diluted with dichloromethane. The layers were separated and the aqueous was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 30% ethyl acetate in heptane) gave ethyl 4-butyrylbenzoate. ’H NMR (400 MHz, CDCI₃, δ): 8.05 8.17 (m, 2 H), 8.04-7.92 (m, 2 H), 4.40 (q, J = 7.15 Hz, 2 H), 2.96 (t, J = 7.22 Hz, 2 H), 1.86-1.69 (m, 2 H), 1.40 (t, J = 7.12 Hz, 3 H), 1.00 (t, J = 7.22 Hz, 3 H).

Intermediate (6): 6-(4-(trifluoromethvl)-1H-imidazol-1 -vl)pvridin-3-amine

A mixture of 4-(trifluoromethyl)-1H-imidazole (2000 mg, 14,70 mmol), 2-chloro-5nitropyridine (2330 mg, 14,70 mmol), and potassium carbonate (4060 mg, 29.4 mmol) in acetonitrile (14.7 mL) was heated at 85°C overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in éthanol (20 mL) and ethyl acetate (15 mL). 10 wt% Palladium on carbon (500 mg) was added to the solution. The mixture was pressurized to 50 psi hydrogen and was shaken for 5 hours. The reaction was filtered through celite, rinsing with methanol. The filtrate was concentrated to give 6(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-amine. ’H NMR (400 MHz, COCI₃, δ): 8.15 (s, 1 H),

7.93 (d, J= 2.73 Hz, 1 H), 7.85 (s, 1 H), 7.20 - 7.15 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.13 - 2.30 (m, 2 H). MS (M+HCO2): 273.0.

Intermediate (7A): (Z)-/V-(3-(dimethylaminoÎ-2-(trifluoromethvl)allvlidene)-/V-methvlmethanaminium hexafluoroDhosDhatefV)

Phosphoryl chloride (18.0 mL, 200 mmol), was added in an addition funnel over 30 minutes to anhydrous dimethylformamide (40.0 mL) at 0°C. After completion of the addition, the light pink solution was warmed to room termperature and 3,3,3-trifluoropropionic acid (8.90 mL, 101 mmol) was added dropwise over 10 minutes. The solution was then warmed to 55°C and stirred for 4 hours at 55°C. The bright yellow solution was cooled to room température and slowly added over 30 minutes to a 0°C solution of sodium hexafluorophosphate (19.0 g, 110 mmol) in water (250 mL) while maintaining the internai température below 10°C. The yellow precipitate was collected by vacuum filtration and washed with ice cold water (3X150 mL). The yellow solid was dried in vacuo and then azeotrophed with toluene two times and dried again in vacuo to provide (Z)-M-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-N-methylmethanaminium hexafluorophosphate(V) as a yellow solid (22.0 g, 64%). ’H NMR (400 MHz, CD₃CN, δ): 7.72 (s, 2 H), 3.41 (s, 6 H), 3.23 (d, J = 1.4 Hz, 6 H).

Intermediate (7B): 1-(4-bromo-2,6-dimethvlphenvl)hvdrazine hydrochloride ^Η·^ΝΛ^^8Γ h₂n

HCl ⁷

In a 3L 3-neck round bottom flask equîpped with a mechanical stirrer was added concentrated hydrochloric acid (125 mL) and water (250 mL). 4-Bromo-2,6-dimethylbenzenamine (100 g, 500 mmol) was added slowly at 0°C. Stîrring was continued for an additional 15 minutes, resulting in a thick white slurry. A freshly prepared solution of sodium nitrite (34.5 g, 500 mmol) in water (100 mL) was added to the slurry dropwise maintaining the internai température below 5°C.

After stirring for 30 minutes, a deep orange solution was formed. Tin(ll) chloride dehydrate (282 g, 1250 mmol) in 1:1 concentrated hydrochloric acid:water (300 mL) was added dropwise while maintaining the internai température between 0-5°C. The resulting mixture was stirred at 0°C for 1 hour and then warmed to room température and stirred for 15 hours. The reaction mixture was filtered and washed with diethyl ether. The solid was slowly added to an aqueous 10 M solution of sodium hydroxide (1L) between 0-10°C and extracted with ethyl acetate (3X 800 mL). The organic layer was washed with brine twice, dried over anhydrous sodium sulfate, and concentrated to give 1-(4-bromo-2,6-dimethylphenyl)hydrazine (76.0 g, 353 mmol). The hydrazine was dissolved in ethyl acetate (800 mL) to which hydrochloric acid/methanol (88.2 mL) was added. The mixture was stirred for 25 minutes. The reaction was filtered, washed with ethyl acetate until the solid is white. The white solid was dried in vacuo to afford 1-(4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (80.0 g, 64%). ’H NMR (400 MHz, DMSO-d6, δ): 9.71 (s, 3 H), 7.32 (s, 2 H), 6.78 (s, 1 H), 2.37 (s, 6 H).

Intermediate (7): 1-(4-bromo-2.6-dimethvlphenvl)-4-(trifluoromethvl)-1H-pvrazole

(Z)-A/-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-A/-methyl methanaminium hexafluorophosphate (3000 mg, 8.819 mmol) and 1-(4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (2480 mg, 9.84 mmol) were suspended in tetrahydrofuran. The suspension was cooled to 0°C. Sodium methoxide (551 mg, 9.7 mmol) was added as a solid in one portion. The ice bath was removed and the mixture warmed to room température and stirred for 48 hours. Trifluoroacetic acid (3 mL) was then added at room température. The reaction was heated to 80°C for 5 hours, diluted with ethyl acetate and washed with saturated sodium bicarbonate twice. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 - 20% ethyl acetate in heptane), gave 1-(4-bromo-2,6-dimethylphenyl)-

4-(trifluoromethyl)-1H-pyrazole as an oil. ’H NMR (400 MHz, CDCI₃, δ): 7.93 (s, 1 H), 7.71 (s, 1 H),

7.31 (s, 2 H), 1.99 (s, 6 H).

Intermediate (8): 3,5-dimethyl-4-(4-itrifluoromethvl)-1 H-pyrazol-1 -vDbenzenamine

NH₂ (8)

A vial containing Intermediate (7) (1200 mg, 3.76 mmol), copper(l) lodide (143 mg, 0.75 mmol), frans-4-hydroxy-L-proline (197 mg, 1.50 mmol) and potassium carbonate (1570 mg, 11.3 mmol) was purged with nitrogen. Dimethylsulfoxide (7.5 mL) was added followed by ammonia (3.73 mL, ~28% aqueous). The vial was sealed and heated to 75°C for 20 hours. The reaction was cooled to room température, diluted with water, and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 3,5dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl) benzenamine. ’H NMR (400 MHz, CDCI₃, δ): 7.84 (s, 1 H), 7.65 (s, 1 H), 6.37 (s, 2 H), 3.82 - 3.47 (br s, 2 H), 1.85 (s, 6 H). MS (M+H+CH₃CN): 297.2.

Intermediate (9): i+/-)-methvl 4-f1-hvdroxy-3-methvlbutyl)benzoate

mL) was cooled to 0°C. Isobutylmagnesium chloride (4.75 mL, 2M in THF) was then added dropwise over 15 minutes. The reaction was stirrad at 0°C for 1 hour. The ice bath was removed and the reaction was allowed to warm to room température and stir for 1 hour. The reaction was quenched by carefully adding 1N HCl. The reaction was diluted with water and diethylether and the layers were separated. The aqueous was extracted three more times with diethyl ether. The combined organics were dried over magnésium sulfate, filtered, and concentrated. Purification by column chromatography (0-40% ethyl acetate in heptane) gave (+/-)-methyl 4-(1-hydroxy-3methylbutyl)benzoate (404.6 mg, 19%) as a clear, coloriess oil. ¹H NMR (400 MHz, CDCI₃, δ): 7.99 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 4.79 (br. s., 1 H), 3.89 (s, 3H), 1.94 (d, J = 2.73,1 H),

1.65 - 1.78 (m, 2H), 1.42 -1.52 (m, 1H), 0.91 - 0.97 (m, 6H).

Intermediate (10): methyl 4-f3-methylbutanovl)benzoate

cooled to 0°C. Pyridinium chlorochromate (785 mg, 3.64 mmol) was added. The ice bath was removed and the reaction was allowed to warm to room température and stir for 48 hours. The reaction was diluted with dichloromethane and magnésium sulfate was added. This mixture was

stirred for 10 minutes and was then filtered and concentrated. Purification by column chromatography (0 - 30% ethyl acetate in heptane) gave methyl 4-(3-methylbutanoyl)benzoate (363.7 mg, 91%) as a clear, colorless oil. ’H NMR (400 MHz, CDCIg, δ): Θ.07 - 8.13 (m, 2H), 7.95 8.00 (m, 2H), 3.93 (s, 3H), 2.82 - 2.86 (m, 2H), 2.28 (dt, J = 13.4, 6.8 Hz, 1H), 0.99 (d, 6H).

Intermediate (111: 4-fluoro-1-(4-nitroDhenvl)-1H-Dvrazole

F (11)

To a solution of 4-fluoro-1H-pyrazole (250 mg, 2.90 mmol) and potassium carbonate (803 mg, 5.81 mmol) in acetonitrile (3 mL) was added 4-fluoronitrobenzene (430 mg, 3.05 mmol). The resulting mixture was stirred at 70°C for 2 hours. The reaction was then filtered and concentrated. Purification by column chromatography gave 4-fluoro-1-(4-nitrophenyl)-1H-pyrazole (400 mg, 67%). ’H NMR (400 MHz, CDCI₃, δ): 8.34 (d, 2H), 7.91 (d, 1 H), 7.81 (d, 2H), 7.67 (d, 1H). Intermediate (12): 4-(4-fluoro-1H-Dvrazol-1-vl)aniline

F (12)

A mixture of Intermediate (11) (200 mg, 0.965 mmol) and 10 wt% palladium on carbon (100 mg) in éthanol (10 mL) was pressurized to 15 psi hydrogen and stirred at 35°C overnight. The reaction was filtered and concentrated. Purification by column chromatography gave 4-(4-fluoro1 H-pyrazol-1-yl)aniline (150 mg, 88%). ’HNMR (400 MHz, CDCi₃, δ): 7.65 (d, 1H), 7.50 (d, 1H),

7.37 (d, 2H), 6.72 (d, 2H), 3.76 (br s, 2H).

Intermediate (13): 4-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)benzonitrile

To a 0°C solution of 4-(trifluoromethyl)-1H-pyrazole (1 g, 7 mmol) in N.N dimethylformamide (10 mL) was added 60 wt% sodium hydride (132 mg, 3.31 mmol). The mixture was stirred at 0^qC for 30 minutes. 4-fluorobenzonitrile (979 mg, 8.08 mmol) was added and the reaction was heated to 80°C overnight. Saturated ammonium chloride was added and the mixture extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 4-(4-(trifluoromethyl)-1H-pyrazol-1-

yl)benzonitrile (1.2 g, 72%). Ή NMR (400 MHz, CD₃OD, δ): 8.84 (s, 1H), 7.96 (s, 1 H), 7.95 (d, 2H),

7.78 (d, 2H).

Intermediate (14): (+/--)-3-methvÎ-1-(4-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)Dhenvl)butan-1-amine

A microwave vial was charged with Intermediate (13) (300 mg, 1.26 mmol) and tetrahydrofuran (5 mL). Isobutylmagnesium bromide (1.90 mL, 2M in THF, 3.80 mmol) was added. The resulting mixture was heated to 100°C under microwave irratiation for 1 hour, The mixture was carefully added to a solution of sodium borohydride (95.7 mg, 2.53 mmol) in methanol (5 mL) at room température. After stirring for 5 minutes, the reaction was concentrated to dryness. Purification by column chromatography gave (+/-)-3-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1yl)phenyl)butan-1 -amine (250 mg, 67%). ¹H NMR (400 MHz, CD₃OD, δ): 8.69 (s, 1H), 7.91 (s, 1H),

7.76 (d, 2H), 7.46 (d, 2H), 4.09 - 4.05 (m, 1 H), 1.67 - 1.60 (m, 2H), 1.37-1.34 (m, 1 H), 0.86 (d, 3H), 0.82 (d, 3H).

Intermediate (15): (+/-)-tert-butyl 3-(N-tert-butvl-4-(1-hvdroxv-3-methvlbutvl) benzamidojproDanoate

To a -20°C solution of Intermediate 30 (1.28 g, 4.26 mmol) in tetrahydrofuran (20 mL) was added isobutylmagnesium bromide (2.13 mL, 2M in THF, 4.26 mmol), The reaction mixture was warmed to room température and stirred for 5 hours. Saturated ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)tert-butyl 3-(A/-tert-butyl-4-(1-hydroxy-3-methylbutyl)benzamido)propanoate (400mg, 24%). ’H NMR (400 MHz, CD₃OD, δ): 7.45 - 7.43 (m, 2H), 7.35 - 7.33 (m, 2H), 4.73 (m, 1 H), 3.62 - 3.58 (m, 2H), 2.48-2.45 (m, 2H), 1.72-1.67 (m, 2H), 1.57 (s, 9H), 1.50-1.47 (m, 1H), 1.36 (s, 9H), 0.97-0.96 (m,6H).

Intermediate (16): (+/-)-methyl 4-(2-cvcloDroDyl-1-hvdroxvethvl)benzoate

(16)

To a -40 C solution of methyl 4-iodobenzoate (0.39 g, 1.5 mmol) in tetrahydrofuran (7.5 mL) was added isopropylmagnesium chloride-lithium chloride (1.5 mL, 1.3 M in THF, 1.95 mmol) dropwise. After stirring for 30 minutes at -40°C, 2-cyclopropylacetaldehyde (190 mg, 2.26 mmol) was added dropwise. The resulting mixture was then stirred at room température for 1 hour. The reaction mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The layers were separated and the aqueous was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)-methyl 4-(2-cyclopropyl-1hydroxyethyl)benzoate (150 mg, 45%). ’HNMR (400MHz, CDCI₃, δ): 7.89 (d, 2H), 7.32 (d, 2H), 4.75 - 4.72 (m, 1 H), 3.79 (s, 3H), 1.60 - 1.51 (m, 2H), 0.60 - 0.51 (m, 1 H), 0.49 - 0.25 (m, 2H), 0.07- -0.12 (m, 2H).

Intermediate (17): (+/-)-tert-butvl 3-(A/-terf-butvl-4-(1-hvdroxv-2-methylDropyl) benzamidolpropanoate

OH (17)

To a -20°C solution of Intermediate (30) (100 mg, 0.3 mmol) in tetrahydrofuran (1 mL) was added isopropylmagnesium bromide (0.45 mL, 1M in THF, 0.45 mmol). The reaction mixture was stirred for 5 hours at room température. Saturated ammonium chloride was then added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)tert-butyl 3-(A/-tert-butyl-4-(1-hydroxy-2-methylpropyl)benzamido)propanoate (45 mg, 40%). ¹H NMR (400 MHz, CDCI₃, δ): 7.26 - 7.32 (m, 4H), 4.39 - 4.41 (m, 1 H), 3.53 - 3.57 (m, 2H), 2.37 2.41 (m, 2H), 1.93-1.95 (m, 1H), 1.53 (s, 9H), 1.34 (s, 9H), 0.97 (m, 3H), 0.79 (m, 3H). Intermediate (18): 1-azido-4-nitrobenzene

A solution of sodium nitrite (761 mg, 11 mmol) in water (5 mL) was added dropwise to a

0°C solution of 4-nitroaniline (508 mg, 3.68 mmol) in trifluoroacetic acid (5 mL). After stirring for 10 minutes, a solution of sodium azide (1.55 g, 23.9 mmol) was added slowly. The resulting yellow suspension was stirred at room température for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-azido-4-nitrobenzene (600mg, 99%).

¹H NMR (400 MHz, CDCI₃, δ): 8.16-8.19 (m, 2H), 7.05 - 7.09 (m, 2H).

Intermediate (19): (+/-)-methvl 4-(cvcloDropyl(hvdroxv)methvl)benzoate

The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclopropanecarbaldehyde. ¹H NMR (400 MHz, CDCI₃, δ): 7.96 (d, J = 6.8 Hz, 2 H),

7.43 (d, J = 8.4 Hz, 2 H), 4.00 (d, J = 8.4 Hz, 1 H), 3.85 (s, 3H), 1.19-1.12 (m, 1 H), 0.59 - 0.52 (m, 2 H), 0.43-0.34 (m, 2 H).

Intermediate (20): (+/-)-methvl 4-(1-hvdroxybutvl)benzoate

A solution of methyl 4-formylbenzoate (2.092 g, 12.74 mmol) in tetrahydrofuran (50 mL) was cooled to 0°C. To this solution was added n-propylmagnesium bromide (6.4 mL, 2.0M in THF) dropwise over 20 minutes. The reaction was stirred at 0°C for 2 hours. The reaction was then quenched by addition of saturated ammonium chloride. This mixture was extracted with ethyl acetate twice. The organics were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography (0 - 40% ethyl acetate in heptanes) gave (+/-)-methyl 4-(1hydroxybutyl)benzoate (1.252 g, 47%) as a colorless oil, ¹H NMR (400 MHz, CDCI₃, δ): 7.97 - 8.02 (m, 2H), 7.40 (d, J = 8.4 Hz, 2H), 4.74 (dd, J = 7.8, 5.7 Hz, 1 H), 3.90 (s, 3H), 1.61 -1.82 (m, 2H), 1.23-1.49 (m, 2H), 0.92 (t, J = 7.32 Hz, 3H).

Intermediate (21): methyl 4-butyrylbenzoate

(10) using Intermediate (20). ’H NMR (400 MHz, CDCI₃, δ): 8.08 - 8.13 (m, 2H), 7.97 - 8.01 (m,

2H), 3.94 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H), 1.77 (m, 2H), 1.00 (t, J = 7.41 Hz, 3H).

Intermediate (21) (256.1 mg, 1.242 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3.0 mL). 1N NaOH (3.73 mL) was added and the reaction was heated to 50°C for 3 hours, The reaction was then cooled to room température and concentrated. The crude residue was taken up in water and acidified to pH = 5 with 1N HCl. A white precipitate formed. The solids were filtered off and dried under vacuum to give 4-butyrylbenzoic acid (155.4 mg, 65%) as a white solid. ¹H NMR (400 MHz, CDCI_3t δ): 8.16 - 8.21 (m, 2H), 8.01 - 8.05 (m, 2H), 2.98 (t, J = 7.2 Hz, 2H), 1.78 (m, 2H). 1.01 (t, J =7.41 Hz, 3H).

added to a solution of Intermediate (22) (154 mg, 0.801 mmol), methyl 3-aminopropanoate hydrochloride (90.8 mg, 0.881 mmol), 1-hydroxy-7-azabenzotriazole (109 mg, 0.801 mmol), and triethylamine (120 pL, 0.86 mmol) in dichloromethane (8.0 mL). The reaction was stirred at room température for 19 hours. The reaction was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnésium sulfate, filtered, and concentrated. Purification by column chromatography (5 - 60% ethyl acetate in heptane) gave methyl 3-(4butyrylbenzamido)propanoate (124.1 mg, 56%) as a white solid. ’H NMR (400 MHz, CDCI₃, δ): 7.99 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 6.89 (br. s., 1 H), 3.69 - 3.77 (m, 5H), 2.95 (t, J =

7.2 Hz, 2H), 2.66 (t, J = 5.8 Hz, 2H), 1.71 -1.82 (m, 2H), 1.00 (t, J = 7.43 Hz, 3H). MS (M+1):

278.2.

Intermediate (24): 5-iodo-2-(4-phenyl-1H-Dvrazol-1-vDpyridine

A mixture of 2-fluoro-5-iodopyridine (368.3 mg, 1.652 mmol), 4-phenyl-1H-pyrazole (238.2 mg, 1.652 mmol), and potassium carbonate (457 mg, 3.30 mmol) in N,N-dimethylformamide (3.30 mL) was heated to 85°C for 21 hours. The reaction was then concentrated and the crude residue diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were dried over magnésium sulfate, filtered, and concentrated to give 5-iodo-2-(4-phenyl-1 H-pyrazol-1-yOpyridine (537.2 mg, 94%) as a white solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.76 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.09 (dd, J = 8.7,

2.2 Hz, 1H), 8.01 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.55 - 7.61 (m, 2H), 7.36 - 7.43 (m, 2H), 7.25 -

7.31 (m, 1H). MS (M+1): 348.0.

Intermediate (25): 6-f4-Dhenvl-1H-Dvrazol-1-yl)pyridin-3-amine

A reaction vial was oven-dried and cooled under nitrogen. To this vial was added Intermediate (24) (100.9 mg, 0.291 mmol), copper(l) iodide (11.0 mg, 0.058 mmol), trans-4hydroxy-L-proline (15.2 mg, 0.116 mmol), potassium carbonate (122 mg, 0.873 mmol), and dimethylsulfoxide (0.58 mL). The vial was capped,evacuated, and back-filled with nitrogen 4 times. Ammonium hydroxide (28 wt%, 0.29 mL) was then added. The reaction was heated to 80°C for 18 hours. The reaction was then cooled to room température and diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were washed once with brine, dried over magnésium sulfate, filtered, and concentrated. Purification by column chromatography (5 - 60% ethyl acetate in heptane) gave 6(4-phenyl-1 H-pyrazol-1 -yl)pyridin-3-amine (42.1 mg, 61%) as a pale yellow solid, ¹H NMR (400 MHz, CDCh, δ): 8.66 (s, 1 H), 7.95 (s, 1H), 7.89 (d, J = 2.9 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1H), 7.54 -

7.60 (m, 2H), 7.34 - 7.41 (m, 2H), 7.21 - 7.27 (m, 1H), 7.14 (dd, J = 8.7, 2.8 Hz, 1H), 3.69 (br. s., 2H). MS (M+1): 237.2.

Intermediate (26): 3.5-dimethvl-4~ (4-(trifluoromethylM 1 H-pyrazol-1 -yl) phénol

A microwave vial was charged with tris(dibenzylideneacetone)dipalladium(0) (75.9 mg, 0.13 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (22.1 mg, 0.051 mmol), and potassium

hydroxide (113 mg, 1.92 mmol). The vial was capped, evacuated, and back-filled with nitrogen three times. A solution of Intermediate (7) (204 mg, 0.64 mmol) in 1,4-dioxane (0.38 mL) was added, followed by degassed water (0.38 mL). The reaction was heated at 100°C for 2.5 hours. The reaction was quenched with 1 N HCl and extracted three times with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-15% ethyl acetate in heptane) provided 3,5-dimethyl-4-(4-(trifluoromethyl)-(1Hpyrazol-1-yl)phenol (120 mg, 73%) as a white solid. ’H NMR (400 MHz, CDCI₃₁ δ): 7.94 (s, 1H),

7.72 (s, 1H), 6.50 (s, 2H), 1.92 (s, 6H). MS (M+1): 257.

Alternatively, intermediate (26) can be prepared as follows. To a flask containing Intermediate (7) (15.0 g, 47.0 mmol) in 1,4-dioxane (28.1 mL) and degassed water (28.1 mL), was added tris(dibenzylideneacetone)dîpalladium{0) (557 mg, 0.94 mmol), 2-di-tert-butylphosphino2',4',6'-triisopropylbiphenyl (1.6 g, 3.76 mmol), and potassium hydroxide (3.3 g, 141.0 mmol). The reaction was purged with nitrogen and then heated at 95 °C for 1 hour. The reaction was quenched with 1 N HCl and extracted three times with ethyl acetate.The organics were dried over sodium sulfate, filtered and concentrated. The crude material was filtered through a plug of silica (5-10% ethyl acetate in heptane). The concentrated material was then triturated three times with heptanes to provide 3,5-dimethyl-4-(4-(trifluoromethyl)-(1 H-pyrazol-1-yl)phenol (11 g, 91%) as a white solid. ’H NMR (400 MHz, CDCI₃, δ): 7.94 (s, 1H), 7.72 (s, 1 H), 6.50 (s, 2H), 1.92 (s, 6H). MS (M+H): 257.

Intermediate (27): (+/-)-methyl 4-(1-(4-iodophenoxy)butyl)benzoate

O

Diisopropyl azodicarboxylate (880 pL, 4.47 mmol) was added to a room température solution of Intermediate (20) (929 mg, 4.46 mmol), 4-iodophenol (987 mg, 4.49 mmol), and triphenylphosphine (1.17 g, 4.46 mmol) in tetrahydrofuran (22 mL). The reaction was stirred at room température overnight. The reaction was then diluted with diethylether (30 mL). The mixture was washed successively with 1N NaOH and saturated ammonium chloride. The organic layer was dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)-methyl 4-(1-(4-iodophenoxy)butyl)benzoate (1.38 g, 75%) as a colorless oil. ’H NMR (400 MHz, CDCIa, δ): 7.95 - 8.00 (m, 2H), 7.39 - 7.45 (m, 2H), 7.32 -7.38 (m, 2H), 6.52 - 6.59 (m,

2H), 5.03-5.10 (m, 1 H), 3.88 (s, 3H), 1.89-2.01 (m, 1H), 1.70-1.82 (m, 1H), 1.33-1.52 (m,

2H), 0.89-0.95 (m, 3H).

Intermediate (28): Préparation of 1-(4-methoxvphenvl)-4-(trifluoromethvlM/-/-pyrazole

(Z)-/V-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-/V-methyl methanaminium hexafluorophosphate (4.46 g, 13.1 mmol) and 4-methoxyphenyl hydrazine hydrochloride (2.55 g,

14.6 mmol) were suspended in tetrahydrofuran (50 mL) and cooled to 0°C. Sodium methoxide (820 mg, 14 mmol) was added as a solid in one portion. The mixture was stirred at 0°C for 10 minutes. The ice bath was removed and the mixture was stirred at room température for 1 hour. The mixture was cooled again to 0°C and trifluoroacetic acid (3 mL) was added. The ice bath was removed and the mixture heated to reflux. After 18 hours at reflux, the reaction was cooled to room température and diluted with ethyl acetate (50 mL). The mixture was washed successively with saturated sodium bicarbonate until the washings were basic. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnésium sulfate, filtered and concentrated. The crude material was passed through a plug of silica gel (100 g), eluting with dichloromethane (600 mL). The filtrate was concentrated to give 1(4-methoxyphenyl)-4-(trifluoromethyl)-1H-pyrazole (2.7 g, 85%). ’H NMR (400 MHz, CDCI₃₁ δ): 8.06 (s, 1 H), 7.85 (s, 1 H), 7.53 - 7.59 (m, 2H), 6.94 - 7.00 (m, 2H), 3.84 (s, 3H).

Intermediate (29): 4-(4-ftrifluoromethvl)-1 H-pyrazol-1-vDphenol

Intermediate (28) (2.63 g, 10.9 mmol) was dissolved in dichloromethane (50 mL). The solution was cooled to -78°C. Boron tribromide (2.0 mL, 21 mmol) was added dropwise over 10 minutes. Following the addition, the mixture was allowed to gradually warm to room température and stir overnight. The resulting clear red solution was cooled to 0°C and additional boron tribromide (1 mL) was added. The ice bath was removed and the solution stirred at room température. After 6 hours the solution was cooled to 0°C and quenched by slow addition of anhydrous methanol (15 mL). The resulting mixture was washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over

magnésium sulfate, filtered and concentrated to give 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (2.46 g, 99%). Ή NMR (400 MHz, CDCI₃, δ): 8.04 (s, 1H), 7.86 (s, 1 H), 7.45-7.51 (m, 2H), 6.856.92 (m, 2H), 5.65-5.85 (br s, 1H).

Intermediate (30): tert-butyl 3-(Mtert-butyl-4-formylbenzamido)propanoate

O O x+C x^C (30)

N,N-dimethylformamide (25 pL) was added to a room température suspension of 4carboxybenzaldehyde (2.0 g, 13 mmol) and oxalyl chloride (1.14 mL, 13.3 mmol) in dichloromethane (50 mL). The reaction was stirred at room température 30 minutes, then heated to reflux for 5 hours. The reaction mixture was concentrated. A solution of tert-butyl 3-(tertbutylamino)propanoate (2.68 g, 13.3 mmol) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (50 mL) was added to the crude acid chloride. The mixture was stirred at room température overnight. The reaction was washed with water, then brine. The organic layer was dried over magnésium sulfate, filtered and concentrated to give tert-butyl 3-(N-tert-butyl-4formylbenzamido)propanoate (4.47 g, 100% ). ¹H NMR (400 MHz, CDCI₃, δ): 10.01 (s, 1H), 7.867.91 (m, 2H), 7.45-7.49 (m, 2H), 3.46-3.54 (m, 2H), 2.34-2.41 (m, 2H), 1.52 (s, 9H), 1.31 (s, 9H).

Intermediate (31): ethyl 4-(cycloDentanecarbonvl)benzoate

At -40°C, isopropylmagnesium chloride lithium chloride (13.9 mL, 1.3 M in THF) was added dropwise to a solution of ethyl 4-iodobenzoate (4971 mg, 18.01 mmol) in tetrahydrofuran (30 mL). The solution was stirred at -40°C for 50 minutes. Copper(l) iodide (1.03 g, 5.4 mmol) was added. The mixture was allowed to warm to -15°C and stir for 8 minutes. The solution was cooled back to 40°C and cyclopentanecarbonyl chloride (3580 mg, 27.0 mmol) was added dropwise. The mixture was allowed to gradually warm to 0°C over 3 hours. The mixture was quenched with 1 N HCl (20 mL) and diluted with ethyl acetate. The mixture was stirred at room température for 5min. A white precipitate formed. The mixture was filtered through celite and the filtrate transferred to a separatory tunnel. The layers were separated. The aqueous was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-20% ethyl acetate in heptane) gave ethyl

4-(cyclopentanecarbonyl)benzoate as an oil. ¹H NMR (400 MHz, CDCI₃, δ): 8.13 - 8.08 (m, 2 H), 8.02-7.97 (m, 2 H), 4.39 (q, J = 7.22 Hz, 2 H), 3.77-3.65 (m, 1 H), 1.99-1.79 (m, 4 H), 1.77-

1.60 (m, 4 H), 1.40 (t, J = 7.22 Hz, 3 H).

Intermediate (32): 6-(4-(trifluoromethvl)-1H-Dyrazol-1 -vl)Dyridin-3-amine

The title compound was prepared by a method analogous to that described for Intermediate (6) using 4-(trifluoromethyl)-1H-pyrazole. ’H NMR (400 MHz, CDCI₃, δ): 8.68 (s, 1H), 7.86 (d, J =

2.73 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J= 8.58 Hz, 1 H), 7.13 (dd, J= 8.68, 2.83 Hz, 1H), 3.77 (br. s, 2H). MS (M+1): 229.1.

Intermediate (33): (+/-)-1-(4-bromophenvl)-3-methylbutan-1-ol

4-bromo-iodobenzene (1.42 g, 5.00 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -40°C. A solution of isopropylmagnesium chloride lithium chloride (5 mL, 1.3 M in THF) was added dropwise over 5 minutes. The mixture was stirred at -40°C for 30 minutes, then 3methylbutanal (0.81 mL, 7.5 mmol) was added. The reaction was allowed to warm to room température and stir for 1 hour. The reaction was then quenched by addition of saturated ammonium chloride (10 mL) and water (40 mL). The mixture was diluted with ethyl acetate (50 mL), and the layers were separated. The organics were washed with water (50 mL) and brine (25 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/-)-1-(4-bromophenyl)-3-methylbutan-1-ol (958 mg, 79%) as a clear oil. ’H NMR (400 MHz, CDCI₃, δ): 7.47 - 7.41 (m, 2H), 7.22 - 7.17 (m, 2H), 4.68 (dd, J =

8.1,5.4 Hz, 1H), 1.97 (br.s, 1H), 1.71 -1.61 (m, 2H), 1.49-1.39 (m, 1 H). 0.94-0.90 (m, 6H).

Intermediate (34): (+/-)-methyl 4-(1-(4-bromophenvl)-3-methvlbutoxv)benzoate

(34)

Methyl 4-hydroxybenzoate (609 mg, 4,00 mmol), 1-(4-bromophenyl)-3-methylbutan-1-ol (1.95 g, 8.00 mmol) and triphenylphosphine (2.10 g, 8.00 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.58 mL, 8.00 mmol) was added. The resulting solution was stirred at room température overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with 0.1 M HCl (3 x 100 mL) and brine. The organics were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave (+/-)-methyl 4-(1-(4-bromophenyl)-3-methylbutoxy) benzoate (1.4 g, 93%) as a clear oil. ¹H NMR (400 MHz, CDCI₃, δ): 7.89 - 7.83 (m, 2H), 7.46 - 7.40 (m, 2H), 7.21 - 7.16 (m, 2H), 6.83 -

6.78 (m, 2H), 5.16 (dd, J =9, 4.7 Hz, 1 H), 3.83 (s, 3H), 1.99 - 1.91 (m, 1 H), 1.88 - 1.75 (m, 1 H),

1.58 - 1.51 (m, 1 H), 0.97 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H).

Intermediate (35): (+/-)-1-(5-bromoDvridin-2-vl)butan-1-ol

OH (35)

2,5-Dibromopyridine (1.08 g, 4.6 mmol) was azeotroped with toluene several times, then dissolved in anhydrous toluene (12 mL) under a nitrogen atmosphère. The resulting solution was cooled to -78°C and n-butyl lithium (2.4 mL, 2.1 M in hexane, 5.0 mmol) was added dropwise, maintaining an internai température below -70°C. The resulting orange solution was stirred for 30 minutes at -78°C, then butyraldéhyde was added. The resulting solution was stirred for 30 minutes at -78°C then quenched by addition of saturated ammonium chloride. The resulting mixture was warmed to room température and diluted with ethyl acetate (25 mL) and water (25 mL). The layers were separated. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/-)1-(5-bromopyridin-2-yl)butan-1-ol (738 mg, 70%) as a clear oil. ¹H NMR (400 MHz,CDCI₃, δ): 8.57 (d, J = 2.3 Hz, 1 H), 7.77 (dd, J = 8.3, 2.2 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 4.72-4.66 (m, 1 H), 3.58 (d, J = 5.7Hz, 1 H), 1.79-1.57 (m, 2H), 1.47-1.35 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). Intermediate (36): (+/-l-5-bromo-2-(1-(4-iodoDhenoxy)butvl)Dvridine

Intermediate (35) (738 mg, 3.21 mmol), 4-iodophenol (1.06 g, 4.81 mmol) and triphenylphosphina (1.68 g, 6.41 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylata (1.34 mL, 6.41 mmol) was added. The resulting solution was allowed to stir at room température overnight. The reaction was heated to 50°C and allowed to stir for 24 hours. The reaction was concentrated. Purification by column chromatography (0-100% ethyl acetate in heptane) gave (+/-)-5-bromo-2-(1-(4-iodophenoxy)butyl)pyridine (540 mg, 39%) as a clear oil. ¹H NMR (400 MHz, CDCI₃, δ): 8.61 (d, J = 2.3 Hz, 1 H), 7.73 (dd, J = 8.4, 2.3 Hz, 1 H), 7.48 - 7.42 (m, 2H), 7.22 (d, J = 8.4 Hz, 1 H), 6.62-6.56 (m, 2H), 5.13 (dd, J = 8.1,4.8 Hz, 1H), 1.99-1.81 (m, 2H), 1.57 - 1.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). MS (M+1 ): 432.0.

Intermediate (37): (+/-)-methvl 4-(cvclopentvl(hvdroxv)methvl)benzoaÎe

The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclopentanecarbaldehyde. ¹H NMR (400 MHz, CDCI₃, δ): 8.005 (m, 2H), 7.413 (m, 2H), 4.50 (m, 1H), 3.90 (s, 3H), 2.25-2.15 (m, 1 H), 1.87-1.71 (m, 2H), 1.70 -1.49 (m, 6H), 1.47 - 1.43 (m, 1H), 1.30-1.11 (m, 1H).

Concentrated sulfuric acid (5.5 mL) was added to water (20 mL) and cooled to 0°C. Intermediate (32) (500 mg, 2.19 mmol) was added, followed by the dropwise addition of a solution of sodium nitrite (133 mg, 1,93 mmol) in water (1.5 mL). The reaction was stirred at 0°C for 30 minutes. The reaction was then poured into a boiling mixture of water (29 mL) and concentrated sulfuric acid (2.6 mL) and stirred for 30 minutes. The reaction was cooled to room température, poured onto ice, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6 -(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ol (220 mg, 44%). ¹H NMR (400 MHz, CD₃OD, δ): 8.71 (s, 1 H), 7.89 (m, 1H), 7.84 (s, 1H), 7.71 (m, 1H), 7.27 - 7.24 (m, 1H).

Intermediate (39): 1-bsnzyl-1H-Dvrazol-4-ol

OH (39) 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dïoxaborolan-2-yl)-1H-pyrazole (2.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (18 mL) and cooled to 0°C. 2N NaOH (7.03 mL, 14.06 mmol) and 30% peroxide (14.07 mL) were added and the reaction was stirred at room température for 45 minutes. The reaction was acidified to pH = 2 by addition of 2N HCl and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 1-benzyl-1H-pyrazol-4-ol (1.54 g) as a yellow solid. ¹H NMR (400 MHz, CDCI₃, δ): 7.25-7.21 (m, 3H), 7.08 - 7.07 (m, 3H), 6.91 (s, 1H), 5.06 (s, 2H).

Intermediate (40): 1-benzvl-4-methoxv-1H-pvrazole

/ (40)

To a mixture of Intermediate (39) (588 mg, 3.38 mmol) and césium carbonate (1540 mg,

4.73 mmol) in /V,/V-dimethylformamide (14.7 mL) was added iodomethane (672 mg, 4.73 mmol). The reaction mixture was stirred at room température for 1 hour. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-benzyl-4-methoxy-1H-pyrazole (0.586 g, 92%) as a yellow oil. ’HNMR (400 MHz, CDCI₃, δ): 7.29-7.22 (m, 3H), 7.19 (s, 1H), 7.14 (m, 2H), 6.95 (s, 1 H), 5.13 (s, 2H), 3.64 (s, 3H).

Intermediate (41): 4-methoxv-1H-pyrazole

O / (41)

Intermediate (40) (586 mg, 3.11 mmol) was dissolved in methanol (70 mL) and 1N HCl (7.78 mL). Palladium hydroxide on carbon (0.734 g, 4.83 mmol) was added. The mixture was pressurized to 50 psi hydrogen and agitated at room température overnight. The reaction mixture was filtered through celite and the filtrate concentrated to give 4-methoxy-1H-pyrazole (110 mg, 36%) as a yellow oil. ’H NMR (400 MHz, CD₃OD, δ): 7.64 (br s, 2H), 3.64 (s, 3H).

Intermediate (42): (+/-)-methvl 4-(1-hvdroxv-3,3-dimethylbutvl)benzoate

To a -40°C solution of methyl 4-iodobenzoate (1 g, 4 mmol) in tetrahydrofuran (10 mL) was

added isopropylmagnesium chloride lithium chloride (3.82 mL, 1.3 M in THF, 4.98 mmol). The mixture was stirred at -40°C for 30 minutes. 3,3-Dimethylbutanal (573 mg, 2.86 mmol) was added. The reaction was stirred at room température for 4 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)-methyl 4-(1-hydroxy-3,3dimethylbutyl)benzoate (640 mg, 95%). ¹H NMR (400 MHz, CDCI₃, δ): 7.93 (d, 2H), 7.34 (d, 2H), 4.81-4.84 (m, 1H), 3.84 (s, 3H), 1.70-1.61 (m, 1H), 1.53-1.49 (m, 1H), 0.94 (s, 9H).

Intermediate (43): methyl 4-(3.3-dimethvlbutanoyl)benzoate

To a 0°C solution of Intermediate (42) (0.300 g, 1.27 mmol) in tetrahydrofuran (10 mL) was added trifluoroacetic acid (261 mL, 2.29 mmol) followed by 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2benziodoxol-3-(1H)-one (862 mg, 2.03 mmol), The reaction was stirred at room température for 2 hours. The reaction mixture was quenched by addition of 1M sodium hydrosulfite (10 mL) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave methyl 4-(3,3dimethylbutanoyl)benzoate (220 mg, 74%). ¹H NMR (400 MHz, CDCI₃, δ): 8.04 (d, 2H), 7.90 (d,

2H), 3.88 (s, 3H), 2.82 (s, 2H), 0.99 (s, 9H).

Intermediate (44): methyl 4-(cvclohexanecarbonvl)benzoate

(44)

Magnésium turnings (324 mg, 13.5 mmol) were suspended in tetrahydrofuran (20 mL). A crystal of iodine was added. Bromocyclohexane (2.00 g, 12.26 mmol) was added dropwise. The mixture was refluxed for 2 hours. The mixture was then added to a -5°C solution of methyl 4(methoxy(methyl)carbamoyl) benzoate (456 mg, 2.04 mmol) In tetrahydrofuran (5 mL). The réaction was stirred 1 hour, maintaining an internai température below 0°C. The reaction was

quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 4-(cyclohexanecarbonyl)benzoate (160 mg, 32%), ’H NMR (400 MHz, CDCI₃, δ): 8.10 - 8.12 (m, 2H), 7.96 - 7.98 (m, 2H), 3.94 (s, 3H), 3.22 - 3.25 (m, 1 H), 1.90 - 1.82 (m, 4H), 1.76 -

1.72 (m, 1 H), 1.25 — 1.50 (m, 5H).

Intermediate (45): (+/-)-methvl 4-(cvclobutvl(hydroxv)methvl)benzoate

(45)

The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclobutanecarbaldehyde. ’H NMR (400 MHz, CDCI₃₁ δ): 7.93-8.00 (m, 2H), 7.35-

7.39 (m, 2H), 4.64 (m, 1 H), 3.90 (s, 3H), 2.57 - 2.65 (m, 1 H), 1.95 - 2.08 (m, 2H), 1.80 - 1.91 (m, 4H).

intermediate (46): (+/-)-tert-butvl 3-(A/-tert-butvl-4-(1-hvdroxypropvl)benzamido) propanoate

The title compound was prepared by a method analogous to that described for Intermediate (17), using ethylmagnesium bromide. ’H NMR (400 MHz, CDCI₃, δ): 7.29-7.35 (m, 4H), 4.59-

4.62 (m, 1H), 3.53-3.57 (m, 2H), 2.37-2.41 (m, 2H), 1.71-1.83 (m, 2H), 1.53 (s, 9H), 1.34 (s, 9H), 0.87-0.91 (m, 3H).

Intermediate (47): 4-(4-methvl-1H-1.2.3-triazol-1-vl)aniline

A solution of 1 -azido-4-nitrobenzene (0.500 g, 3.05 mmol) and 3-bromoprop-1-yne (1.45 g,

12.2 mmol) in toluene (3 mL) was heated to 60°C for 24 hours in a sealed tube. Additional 3bromoprop-1-yne (1.45 g, 12.2 mmol) was added and the solution stirred at 60°C overnight. The reaction mixture was concentrated to an orange solid. The crude residue was dissolved in éthanol (100 mL). 10 wt% Palladium on carbon (150 mg) was added and the mixture was pressurized to 50 psi hydrogen and stirred for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was slurried in ethyl acetate. The mixture was filtered, and the solid dried under vacuum to give 4-(4-methyl-1H-1,2,3-triazol-1 -yl)aniline (300 mg). ’HNMR (400MHz, CD₃OD, δ): 8.37 (s, 1 H). 8.03 (m, 2H), 7.58 (m, 2H), 2.44 (s, 3H).

Intermediate (48): (+/-)-fert-butvl 3-(A/-tert-butvl-4-f1-hvdroxvbutvl)benzamido) propanoate

OH (48)

The title compound was prepared by a method analogous to that described for Intermediate (17) using n-propylmagnesium bromide. ¹H NMR (400 MHz, CDCI₃, δ): 7.33 (m, 4H), 4.69 (m, 1H),

3.55 (m, 2H), 2.41 (m, 2H), 1.77 (m, 4H), 1.52 (s, 9H), 1.42 (s, 9H), 0.90 (m, 3H).

Intermediate (49): (+/-)-methvl 4-(1-(5-Îodopvridin-2-vloxv)butvl)benzoate

(27) using 2-hydroxy-5-iodopyridine. ¹H NMR (400 MHz, CDCI₃, δ): 8.19 (d, J = 2.5 Hz, 1 H), 7.99 -

7.94 (m, 2H), 7.73 (dd, J = 8.7, 2.4 Hz, 1 H), 7.44 - 7.39 (m, 2H), 6.61 (d, J = 8.6 Hz, 1 H), 6.00 (dd, J = 7.8, 5.7 Hz, 1H), 3.87 (s, 3H), 2.03-1.92 (m, 1H), 1.85-1.74 (m, 1H), 1.49-1.27 (m, 2H), 0.92 (t, J = 7.41 Hz, 3H). MS (M+1): 412.1.

Intermediate (50): 6-(4-(trifluoromethvll-1H-imidazol-1-vl)ovridin-3-ol

The title compound was prepared by a method analogous to that described for Intermediate (38) using Intermediate (6). Ή NMR (400 MHz, CD₃OD, δ): 8.71 (s, 1H), 7.89 (d, 1H), 7.84 (s, 1H),

7.71 (m, 1 H), 7.27-7.24 (m, 1H).

Intermediate (51): 1-(4-nitrophenvl)-4-(trifluoromethvl)-1H-pvrazole

no₂ (51)

The title compound was prepared by a method analogous to that described for Intermediate (3), using 1-fluoro-4-nitrobenzene and 4-(trifluoromethyl)-1H-pyrazole. ¹H NMR (400 MHz, CDCI₃, δ): 8.38 (m, 1H), 8.30 (m, 1H), 7.97 (s, 2H), 7.90 (m, 2H).

Intermediate (52): 4-f4-(trifluoromethvl)-1 H-pyrazol-1 -vllaniline

The title compound was prepared by a method analogous to that described for Intermediate (4) using Intermediate (51). ¹H NMR (400 MHz, CDCI₃, δ): 8.03 (m, 1H), 7.85 (s, 1H), 7.43 (dt, J =

9.0, 2.9 Hz, 2H), 6.75 (dt, J = 9.0, 3.1 Hz, 2H).

Intermediate (53): 1 -(4-nitrophenvl)-4-(trifluoromethvl)-1H-imidazole

The title compound was prepared by a method analogous to that described for Intermediate (3) using 1 -fluoro-4-nitrobenzene. The crude product was recrystallized from toluene and minimal ethyl acetate to afford the product as a white powder. MS (M+1): 257.0.

Intermediate (54): 4-f4-(trifluoromethvl)-1 H-imidazol-1 -vllaniline

NH₂ (54)

A solution of Intermediate (53) (3.02 g, 11.7 mmol) and di-tert-butyl dicarbonate (4.05 mL,

17.6 mmol) in éthanol (117 mL) was passed through an H-Cube reactor (50°C, 50bar, 1 mL/mîn, 10% Pd/C cartridge). The reaction mixture was concentrated and the crude oil was heated at 40°C overnight. The crude oil was then treated with trifluoroacetic acid (8.7mL) in dicholoromethane (15.6mL). The mixture was stirred for 30min whereupon the reaction mixture was concentrated and the residual trifluoroacetic acid was removed via a toluene azeotrope. Purification via column chromatography (0-70% ethyl acetate in heptane) gave 4-[4-(trifluoromethyl)-1H-imidazol-1-

yl]aniline (1.23 g, 46%) as a solid. ¹H NMR (400 MHz, CD₃OD, δ): 8.15 (s, 1H), 8.02 (m, 1H), 7.48 (dd, J = 8.8, 2.9 Hz, 2H), 7.10 (dd, J = 8.6, 2.9 Hz, 2H). Intermediate (55): 4-(2H-indazol-2-vl) phénol

4-Bromophenol (2.00 g, 11.6 mmol) was combined with 1H-indazole (1.64 g, 13.9 mmol), copper(l) iodide (110 mg, 0.578 mmol), potassium phosphate (5.15 g, 24.3 mmol), transdimethylcyclohexane-1,2-diamine (0.365 mL, 2.31 mmol), and toluene (10 mL). The reaction was refluxed for 21 hours, then cooled to room température and partitloned between ethyl acetate and water/ammonium hydroxide. The organic layer was washed with 0.5 N HCl and brine, dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography (0 - 40% ethyl acetate in heptane) gave 4-(2H-indazol-2-yl)phenol (0.479 g, 20%) as a tan solid. ¹H NMR (400 MHz, (CD₃)₂SO, δ): 9.84 (s, 1H), 8.90 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.22 - 7.33 (m, 1 H), 7.03 - 7.12 (m, 1 H), 6.94 (d, J = Θ.Θ Hz, 2H). MS (M+1): 211.2.

Intermediate (56): (R)-ethvl 4-(1-hydroxvbutvl)benzoate

A mixture of Intermediate (5) (30.0 g, 140 mmol) and [/V-[(1R,2R)-2-(amino-K/V)-1,2diphenylethyl]-4-methylbenzenesulfonamidato-KA/]chloro[(1,2,3,4,5,6-r))-1,3,5'trimethylbenzene]ruthénium (2.12 g, 3.40 mmol) was suspended in a 5:2 azetropic mixture of formic acid and triethylamine (68.1 mL). The mixture was stirred at ambient température for 12 hours. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with concentrated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was dissolved in dichloromethane (1.0 L) and silacycle SiThiol (90 g) was added. The mixture was slurried for twelve hours at ambient température. The crude mixture was filtered and concentrated in vacuo to give primarily (R)-ethyl 4-(1 hydroxybutyl)benzoate (30.0 g, 100%). ¹H NMR (400 MHz, CDCI₃, δ): 7.98 (d, J = 8.4 Hz, 2H),

7.38 (d, J = 8.0 Hz, 2H), 4.71 (dd, J = 7.4, 5.7 Hz, 1 H), 4.34 (q, J = 7.0 Hz, 2H), 1.58 -1.81 (m, 2H), 1.29 -1.48 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). Chiral HPLC: Chiralpak AD-H, 4.6 mm x 25 cm; SFC Mobile Phase 80:20 CO^Methanol, 2.5 mL/min, Rétention time: 3.13 min (R-ent, 92.9%), 3.41 min (S-ent, 7.1%), 86% ee. The (R)-enantiomer was further resolved by chiral SFC to give optically pure (R)-ethyl 4-(1-hydroxybutyl) benzoate. Column: Chiralpak AD-H.

Dimensions: 21 x 250mm. Mobile Phase: 80/20 COs/methanol. Flow Rate: 65mL/min. Modifier:

none. Rétention time: 2.91 min.

Intermediate (57) : ethvi 4-(3-methvlbutanovl)benzoate

Step A: (4-/-)-ethvl 4-(1-hvdroxv-3-methvlbutvl)benzoate

To a solution of ethyl 4-iodobenzoate (20 g, 72 mmol) in tetrahydrofuran (200 mL) at -40 °C was added isopropylmagnesium chloride lithium chloride (62 mL, 80 mmol, 1.3 M in THF) dropwise, maintaining the internai température below -30 °C. The mixture was stirred for 30 minutes and 3-methylbutanal (8.68 g, 101 mmol) was then added dropwise, maintaining the internai température below -35 °C. Following the addition, the reaction was allowed to stir for 15 minutes at -35 °C and was then allowed to warm to room température. The reaction was quenched with 1 N aqueous hydrochloric acid (400 mL), and the mixture was extracted with ethyl acetate (2 x 200 mL). The organics were washed with brine (200 mL) and water (200 mL), dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-hydroxy-3-methylbutyl)benzoate (16 g, 93%) as an oil. ¹H NMR (400 MHz, CDCl_a, C): 7.95 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 4.73 - 4.76 (m, 1 H), 4.28 - 4.33 (m, 2 H), 1.60 - 1.71 (m, 2 H), 1.41 -1.46 (m, 1 H), 1.31 -1.39 (m, 3 H), 0.87 0.92 (m, 6 H).

Step B: ethyl 4-(3-methylbutanoyl)benzoate

A mixture of ethyl 4-(1-hydroxy-3-methylbutyl)benzoate (15 g, 63 mmol), dichloromethane (150 mL), dimethylsuifoxide (198 g, 2540 mmol), and triethylamine (32 g, 317 mmol) was cooled to 0 °C. Sulfur trioxide pyridine complex (30 g, 190 mmol) was added in portions, maintaining the internai température below 50 °C. The mixture was stirred at 0 ’C for 1 hour. The reaction was then allowed to warm to room température and stir for 36 hours. The reaction was diluted with brine (300 mL) and extracted with methyl tert-butyiether (2 x 500 mL). The combined organics were washed with 1 N aqueous hydrochloric acid (500 mL), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(3methylbutanoyljbenzoate (12 g, 80%) as a white solid. ’H NMR (400 MHz, CDCI_a, δ): 8.11 (dd, J= 1.6, 6.8 Hz, 2 H), 7.98 (d, J = 6.8 Hz, 2 H), 4.40 (q, J = 7.2 Hz, 2 H), 2.85 (d, J = 6.8 Hz, 2 H), 2.24 - 2.34 (m, 1 H),

1.39 - 1.43 (t, J = 7.2 Hz, 3 H), 1.50 (d, J = 6.8 Hz, 6 H).

Intermediate ( 58): methyl 3-(4-(3-methylbutanovl)benzamido)propanoate

To a solution of Intermediate (57) (12 g, 51 mmol) in methanol (80 mL) was added 2 N aqueous sodium hydroxide (80 mL, 160 mmol). The réaction was stirred at room température for 40 minutes. The methanol was then removed in vacuo and the residue was extracted with dichloromethane. The aqueous phase was acidified to pH = 4 with 3 N aqueous hydrochloric acid and extracted with ethyl acetate (2 x 200 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 4-(3-methylbutanoyl)benzoic acid (9.5 g, 86%) as a white solid. ’H NMR (400 MHz, CDCI₃, δ): 8.13 (d, J = 8.4 Hz, 2 H), 7.96 (d, J = 8.0 Hz. 2 H). 2.81 (d, J = 6.8 Hz, 2 H), 2.19 - 2.29 (m, 1 H), 0.96 (d, J = 6.8 Hz, 6 H).

Step B: methyl 3-(4-(3-methvlbuÎanovl)benzamido)proDanoate

To a solution of 4-(3-methylbutanoyl)benzoic acid (9,5 g, 46 mmol) tn N,N-dimethylformamide (80 mL) was added 0-(7-Azabenzotriazol-1-yl)-A/,/V,N',/V’--tetramethyluronium hexafluorophosphate (26.3 g, 69.1 mmol) at 0 °C. The mixture was stirred for 40 minutes. Methyl 3-aminopropanoate hydrochloride (7.72 g,

55.3 mmol) and triethylamine (23.3 g, 230 mmol) were added and the réaction was allowed to warm to room température and stir for 16 hours. The reaction mixture was extracted with ethyl acetate (3 x). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 3-(4-(3-methylbutanoyl)benzamido)propanoate (10 g, 77%) as a pale yellow solid. ’H NMR (400 MHz, CDCI₃₁ δ): 7.98 (d, J = 8.0 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 6.91 (s, 1 H),

3.72 -3.76 (m, 5 H), 2.84 (d, J = 6.0 Hz, 2 H), 2.66 - 2.69 (t, J = 6.0 Hz, 2 H), 2.23 - 2.33 (m, 1 H), 0.99 (d, J = 6.4 Hz, 6 H).

Intermediate (59) : ethyl 4-(cvclobutanecarbonvl)benzoate

Step A: f+/-)-ethvl 4-(cyclobutvl(hvdroxy)methvl)benzoate

The title compound was prepared by a method analogous to that described for Intermediate (16), using ethyl 4-iodobenzoate and cyclobutanecarbaldehyde. ¹H NMR (400 MHz, CDCl₃, δ): 7.93 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 4.58 (d, J = 8.0 Hz. 1 H), 4.29 (q, J = 6.8 Hz, 2 H), 2.50 - 2.58 (m, 1 H), 1.70 - 2.02 (m, 6 H), 1.34 (t, J = 7.2 Hz, 3 H).

Step B: ethvl 4-(cvclobutanecarbonvl)benzoate

Trifluoroacetic acid (613 mg, 5.38 mmol) was added dropwise to a 0’C solution of ethyl 4(cyclobutyl(hydroxy)methyl)benzoate (700 mg, 3 mmol) In dichloromethane (10 mL). Then Dess-Martln periodinane (2.03 g, 4.78 mmol) was added and the reaction was warmed to room température and stirred for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(cyclobutanecarbonyl)benzoate (540 mg, 78%) as an oil. ¹H NMR (400 MHz, CDCI₃₁ δ): 8.04 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 8.4 Hz, 2 H), 4.33 (q, J = 7.2 Hz, 2 H), 3.90- 3.99 (m, 1 H), 2.20 - 2.40 (m, 4 H), 2.00 - 2.09 (m, 1 H), 1.81 - 1.90 (m, 1 H), 1.34 (t, J = 7.2 Hz, 3 H).

Intermediate (60): ethvl 4-(2-cvclopropvlacetvl)benzoate

The title compound was prepared by a method analogous to that described for Intermediate (59), using 2-cyclopropylacetaldehyde. ¹H NMR (400 MHz, C0CI_3l δ): 8.15 (d, J = 7.2 Hz, 2 H), 8.01 (d, J = 7.2 Hz, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 2.94 (d, J = 6.8 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H), 1.10-1.22 (m, 1 H), 0.59 - 0.68 (m, 2 H), 0.21 - 0.26 (m, 2 H).

Intermediate (61): 3-methvl-4-(4-(trifluoromethvl)-1H-pyrazol-1-vl)Dhenol

Step A: 1-(4-methoxy-2-methvlphenvl)-4-ftrifluoromethvl)-1/-/-pyrazole

To a mixture of 1-bromo-4-methoxy-2-methylbenzene (1.5 g, 7.5 mmol) in /V.N-dimethylformamide (15 mL) was added 4-(trifluoromethyl)-1H-pyrazole (1.12 g, 8.21 mmol), copper(ll) oxide (107 mg, 0.746 mmol), and césium carbonate (4.86 g, 14.9 mmol). The mixture was heated in a microwave to 120 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave 1-(4-methoxy-2-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (550 mg, 29%) as a white solid. ¹H NMR (400 MHz, CDCIa, δ): 7.81 (s, 1 H), 7.74 (s, 1 H), 7.16 (m, 1 H), 6.74 (m, 2 H), 3.77 (s, 3 H), 2.10 (s, 3 H). Step B: 3-methvl-4-(4-(trifluoromethvl)-1H-pvrazol-1-vl)phenol

To a 0 °C solution of 1-(4-methoxy-2-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (400 mg, 2 mmol) in dichloromethane (5 mL) was added boron tribromide (1 g, 6 mmol). The mixture was allowed to warm to room température and stir overnight. The reaction was quenched with methanol (2 mL), diluted with water (10 mL), and extracted with dichloromethane (3x10 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give 3-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (390 mg, 99%) as a brown solid. ¹H NMR (400 MHz, CDCI₃₁ δ): 7.83 (s. 1 H), 7.74 (s, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 5.57 (s, 1 H), 2.05 (s, 3 H).

Intermediate (62k methyl 4-butvryl-3-fluorobenzoate

O

Step A: (+/-)-1 -(4-bromo-2-fluoroDhenvl)butan-1 -ol

Br

OH

To a -78 °C solution of 4-bromo-2-fluorobenzaldehyde (600 mg, 3 mmol) in tetrahydrofuran (10 mL) was added n-propylmagnesium chloride (2.22 mL, 4.43 mmol) dropwise over 20 minutes. The réaction was warmed to 0 °C and stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3 x), dried over sodium sulfate, filtered, and concentrated. Purification by preparatory thin layer chromatography gave (+/-)-1-(4-bromo-2-fluorophenyl)butan-1-ol (440 mg, 60%) as a coloriées oil. ’H NMR (400 MHz, CDCI₃₁ δ): 7.26 - 7.30 (m, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 4.90 (t, J = 5.6 Hz, 1 H), 1.53 - 1.79 (m, 2 H), 1.30 - 1.45 (m, 2 H), 0.85 (s, J = 5.6 Hz, 3 H).

Step B: 1-(4-bromo-2-fluorophenvi)butan-1-one

Br

O

Trifluoroacetic acid (366 mL, 3.21 mmol) was added dropwise to a 0 °C solution of 1-(4-bromo-2fluorophenyl)butan-1-ol (440 mg, 1.8 mmol) in dichloromethane (10 mL). Added Dess-Martin periodinane (1.21 g, 2.85 mmol) and let reaction warm to room température and stir for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 1-(4-bromo-2-fluorophenyl)butan-1-one (330 mg, 75%) as a colorless oil. 'H NMR (400 MHz, CDCI₃, δ): 7.65 - 7.69 (m, 1 H), 7.32 - 7.45 (m, 2 H), 2.83-2.87 (m, 2 H), 1.62 - 1.71 (m, 2 H), 0.90 (m, 3 H).

Step C: methyl 4-butvrvl-3-fluorobenzoate

A mixture of 1-(4-bromo-2-fluorophenyl)butan-1-one (300 mg, 11.8 mmol), (1,1bis(diphenylphosphino)ferrocene) dichloropalladium (258 mg, 0.367 mmol), and diisopropylethylamine (790 mg, 6.1 mmol) in methanol (20 mL) was pressurized to 50 psi of carbon monoxide. The reaction was heated to 80 °C and stirred for 10 hours. The reaction was cooled to room température and filtered through Celite.

The filtrate was concentrated and purified by flash column chromatography to give methyl 4-butyryl-357 fluorobenzoate (260 mg, 87%) as a pale yellow solid. H NMR (400 MHz, CDCI₃, 6): 7.81 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.73 (d, 1 H), 3.88 (s, 3 H), 2.88-2.92 (m, 2 H), 1.64 - 1.73 (m, 2 H), 0.92 (t, J = 7.6 Hz, 3 H).

Intermediate (63V. methyl 4-butvrvl-3-methvlbenzoate

Step A; (+/-)-methvl 4-(1 -hvdroxvbutvl)-3-methvlbenzoate

The title compound was prepared by a method analogous to that described for intermediate (16), using methyl 4-iodo-3-methylbenzoate and butyraldéhyde. ¹H NMR (400 MHz, CDCI₃, δ): 7.87 (d, J = 8.4 Hz, 1 H), 7.81 (s, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 4.98 (q, J = 4.4 Hz, 1 H), 3.90 (s, 3 H), 2.37 (s, 3 H), 1.63 -

1.72 (m, 2 H), 1.50 - 1.54 (m, 1 H), 1.39 - 1.43 (m, 1 H), 0.98 (t, J = 7.6 Hz, 3 H).

Step B: methyl 4-butvrvl-3-methvÎbenzoate

To a solution of (+/-)-methyl 4-(1-hydroxybutyi)-3-methylbenzoate (0.8 g, 4 mmol) in dichloromethane (15 mL) was added manganèse dioxide (3.13 g, 36.0 mmol). The reaction was stirred at 30 °C overnight. TLC showed starting material remained and the reaction was heated to reflux for 5 hours. The reaction was cooled to room température and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography to give methyl 4-butyryl-3-methylbenzoate (290 mg) as an oil. ’H NMR (400 MHz, CDCI₃₁ δ): 7.90 (d, J = 7.6 Hz, 2 H), 7.59 (d, J = 7.6 Hz, 1 H), 3.93 (s, 3 H), 2.86 (t, J = 7.6 Hz, 2 H), 2.49 (s, 3 H), 1.69 -1.78 (m, 2 H), 0.99 (t, J = 7.6 Hz, 3 H).

Intermediate (64): 2-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)pvrimidÎn-5-amine

Step A: 5-nltro-2-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)pvrimidine

To a solution of 2-chloro-5-nitropyrimidine (1.5 g, 9.4 mmol) and 4-{trifluoromethyl)-1H-pyrazole (1.41 g, 10.3 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.60 g, 18.8 mmol). The reaction was heated to 80 °C and stirred overnight. The reaction was concentrated and the residue was diluted with water and extracted with ethyl acetate (2 x 40 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography

gave 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.5 g, 62%) as a yellow solid. Ή NMR (400

MHZ, CDCI₃₁ δ): 9.48 (s, 2 H), 8.92 (s, 1 H), 8.05 (s, 1 H).

Step B: 2-(4-ftrifluoromethvl)-1H-Pvrazol-1-vl)pvrimidin-5-amine

Glacial acetic acid (2.78 g, 46.3 mmol) was slowly added to a solution of 5-nitro-2-(4(triftuoromethyl)-l H-pyrazol-1-yl)pyrimidine (1.5 g, 5.8 mmol) and Iron powder (1.94 g, 34.7 mmol) in methanol (30 mL). The reaction was stirred at room température for 3 hours. The réaction was then diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was neutralized with saturated aqueous potassium carbonate. The organic layer was separated and washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrlmidin-5-amine (850 mg, 64%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.68 (s, 1 H), 8.16 (s, 2 H), 7.87 (s, 1 H), 3.82 (s. 2 H).

Intermediate (65): ethyl 4-(3,3-dimethvlcvclobutanecarbonvl)benzoate

O

To a 0 °C solution of 3,3-dÎmethylcyclobutanecarboxylic acid (1.35 g, 10.5 mmol) in dichloromethane (10 mL) was slowly added oxalyl chloride (4.01 g, 31.6 mmol) and 1 drop of N.M-dlmethylformamide. The reaction was warmed to room température and stirred for 2 hours. The réaction was concentrated in vacuo to give crude 3,3-dimethylcyciobutanecarbonylchloride (1.54 g) as a yellow oil.

To a -40 °C solution of ethyl 4-iodobenzoate (2.30 g, 8.30 mmol) in tetrahydrofuran (20 mL) was added isopropylmagnesium chloride·lithium chloride (7.1 mL, 1.3 M in THF, 9,2 mmol) dropwise. The mixture was stirred for 1 hour at -40 °C. Copper(l) iodide (476 mg, 2.50 mmol) was then added and the reaction was allowed to warm to -10 C and stirfor 20 minutes. The solution was cooled again to -40 °C and a solution of the previously prepared 3,3-dimethytcyclobutanecarbonylchloride (1.54 g, 10.5 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was allowed to warm to 0 °C and stir for 2 hours. The reaction was quenched with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (3x15 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (1.80 g, 83%) as a pale yellow solid. ¹H NMR (400 MHz, CDCI₃, ô): 8.15 (d, J = 8.4 Hz, 2 H), 7.98 (d, J = 8.4 Hz, 2 H), 4.20 - 4.47 (m, 2 H), 3.89 - 3.98 (m, 1 H), 2.22 - 2.27 (m, 2 H), 2.09 - 2.15 (m, 2 H), 1.45 (t, J = 7.2 Hz, 3 H), 1.32 (s, 3 H), 1.13 (s, 3 H).

Intermediate (66): 4-(2H-indazol-2-vl)-3-methvlphenol

HO

Step A: 2-(4-methcxv-2-methvlDhenvl)-2H-indazole

A mixture of 4-methoxy-2-methylani1lne (1.37 g, 10.0 mmol) and 2-nitrobenzaldehyde (1.51 g, 10.0 mmol) in tetrahydrofuran (30 mL) was stirred at reflux for 4 hours. The reaction was concentrated. To the residue was added triethyl phosphite (10 mL) and the mixture was stirred at reflux for 40 hours. The reaction was concentrated and purification by flash column chromatography gave 2-(4-methoxy-2-methylphenyl)-2Hindazole (1.5 g, 63%) as a white solid. ¹H NMR (400 MHz, CDCI₃, Ô): 8.05 (s, 1 H), 7.80 (d, J = 8.8 Hz, 1 H),

7.74 (d, J= 8.8 Hz, 1 H), 7.31-7.35 (m, 2 H), 7.12-7.16 (m, 1 H), 6.82-6.88 (m, 2 H), 3.87 (s, 3 H), 2.20 (s, 3 H).

Step B: 4-(2H-indazol-2-vl)-3-methvlDhenol

A solution of 2-(4-methoxy-2-methylphenyl)-2H-indazole (500 mg, 2.1 mmol) in dichloromethane (10 mL) was cooled to -78 °C. Added boron tribromide (2.6 g, 10.5 mmol) and reaction was stirred at -78 °C for 1 hour. Réaction was warmed to room température are stirred overnight. The reaction was diluted with methanol and water, and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 4-(2H-indazol-2-yl)-3methylphenol (350 mg, 74%) as a yellow solid. ’H NMR (400 MHz, DMSO-d_e, δ): 9.82 (s, 1 H), 8.51 (s, 1 H),

7.76 (d, J = 8.4 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.25 - 7.30 (m, 2 H), 7.07 - 7.11 (m, 1 H), 6.80 (d, J = 2.4 Hz, 1 H), 6.75 (dd, J = 8.4, 2.4 Hz, 1 H), 2.06 (s, 3 H).

Intermediate (67): 2-methvl-4-(4-('trifluoromethvD-1H-Dvrazol-1-vl)benzonitrile

N

To a solution of 4-(trifluoromethyl)-1H-pyrazole (1.0 g, 7.0 mmol) and 4-fluoro-2-methylbenzonitrile (1.16 g, 8.50 mmol) in acetonitrile (8 mL) was slowly added potassium carbonate (1.96 g, 14.2 mmol) at room température. The reaction was heated to 80 “C and stirred overnight. The reaction was cooled to room température and poured into water. The layers were separated and the aqueous was extracted with ethyl acetate (3x15 mL). The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol1-yl)benzonitrile (710 mg, 40%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.26 (s, 1 H), 7.94 (s, 1 H),

7.72 - 7.74 (m, 2 H), 7.61 - 7.64 (m, 1 H), 2.64 (s, 3 H).

Intermediate (68) : (+/-)-ethvl 4-(cvcloDentvl(hvdroxv)methvl)benzoate

O

OH

The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclopentanecarbaldehyde and ethyl 4-iodobenzoate. ’H NMR (400 MHz, CDCI₃₁ δ): 8.01 (d, J = 8.4 Hz, 2 H), 7.40 - 7.44 (m, 2 H), 4.49 (d, J = 8.0 Hz, 1 H), 4.39 (q, J = 7.2 Hz, 2 H), 2.19 - 2.21 (m, 1 H), 1.82 - 1.87 (m, 2 H), 1.41 -1.67 (m, 6 H), 1.39 (t, J = 7.2 Hz, 3 H).

Intermediate (69) : 6-(4-chloro-1H-imidazol-1-vl)pyridin-3-amine

CI /^N

Step A: 4-chloro-1/-/-imidazole

HN

Cl

To a solution of 1H-imidazole (10.0 g, 0.15 mol) in chloroform (100 mL) was slowly added a solution of chlorine (2.08 g, 0.0294 mol) in chloroform (18.6 mL). The reaction was cooled to 0 ’C, then left stirring overnight, gradually warming to room température. Aqueous sodium bisulfite was added and the layers were separated. The aqueous was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-10% methanol / dichloromethane) gave 4-chloro-1/7-imidazo!e (400 mg) as a light yellow solid. ¹H NMR (400

MHz, CD₃OD, δ): 7.58 (s, 1 H), 7.05 (s, 1 H).

Step B: 2-(4-chloro-1/-/-imidazol-1-vl)-5-nitropyridine

/

Ό

A vial was charged with 4-chloro-1H-imidazole (450 mg, 4.4 mmol), 2-chloro-5-nitropyridine (1.04 g,

6.58 mmol), potassium carbonate (1.21 g, 8.78 mmol), and acetonitrile (10 mL), The vial was capped and heated to 80 ’C for 2 hours. The reaction was cooled to room température and poured into water (20 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-(4-chloro-1Himidazol-1-yl)-5-nitropyridine (675 mg, 68%) as a white solid. ¹H NMR (400 MHz, CD₃OD, δ): 9.35 (d, J =

2.4 Hz, 1 H), 8.78 (dd, J = 9.0, 2.6 Hz, 1 H), 8.64 (d, J = 1.6 Hz, 1 H), 8.05 (d, J = 1.6 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 1 H).

Step C: 6-(4-chloro-1H-imidazol-1-vl)Dvridin-3-amine

A vial was charged with 2-(4-chloro-1H-imidazol-1-yi)-5-nitropyridine (675 mg, 3.01 mmol), tin(ll) chloride dihydrate (2.03 g, 9.02 mmol), and methanol (10 mL). The vial was sealed and heated to 90 ’C and stirred for 16 hours. The reaction was cooled to room température and concentrated. The residue was taken up in water (20 mL) and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 6-(4-chloro-1/7-imidazol-1-yl)pyridin-3amine (380 mg, 65%) as a light yellow solid. ¹H NMR (400 MHz, CD₃OD, δ): 8.20 (d, J = 1.6 Hz, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.21 (dd, J = 8.8, 2.8 Hz, 1 H). Intermediate (70): 1-brQmo-3,3-dimethvlbutan-2-one

O

To a solution of 3,3-dimethylbutan-2-one (18 g, 180 mmol) in dichloromethane (400 mL) and methanol (160 mL) was added tetrabutylammonium tribromide (95.3 g, 198mmol). The reaction mixture was stirred at room température for 2 h. The solution was concentrated under reduced pressure and the residue dissolved in methyl f-butyl ether (250 mL). The solution was washed with 1N aqueous HCI (250 mL * 3) and brine (250 mL*2), Theorganiclayer was dried overanhydrous Na₂SO4 and concentrated under reduced pressureto give crude 1-bromo-3,3-dimethylbutan-2-one (28 g) as a colorless oil which was used without further purification. ¹H NMR (400 MHz, CDCI₃) δ 4.17 (s, 2 H), 1.23 (s, 9 H).

Intermediate (71): 4-tert-butvl-1 H-imidazole

A solution of intermediate (70) (3 g, 20 mmol) in formamide (15 mL) was heated to 160 °C for 5 h. The mixture was poured into 10% aqueous sodium bicarbomate (30 mL). The solution was extracted with dichloromethane (30 mL * 2). The combined organic layers were washed with 10% aqueous potassium carbonate, brine, dried over Na_zSO₄ and concentrated under reduced pressure to give 4-tert-butyl-1Hrmidazole (1.1 g) as a brown oil. ¹H NMR (400 MHz, CDCI₃) δ 7.57 (s, 1 H), 6.76 (s, 1 H), 1.31 (s, 9 H). Intermediate (72): 2-(4-tert-butvl-1 H-imidazol-1 -vD-S-nitropyridine

To a solution 2-bromo-5-nitropyridine (2.2 g, 10 mmol) in acetonitrile (15 mL) was added Intermediate (71) (1.5 g, 12 mmol) and potassium carbonate (3 g, 20 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL * 3). The organic layer was dried over anhydrous Na_zSO₄ and concentrated under reduced pressure. Purification by silica gel chromatography gave 2-(4-tert-butyl-1 H-imidazol-1-yl)-5-nitropyridine (1.4 g) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) δ 9.23 (d, J=2.8 Hz, 1H), 8.53 (dd, J=9.2, 2.8 Hz, 1H), 8.33 (s, 1H), 7.39 (d, J=9.2 Hz, 1 H), 7.19 (s, 1 H), 1.28 (S, 9H).

Intermediate (73): 6-(4-tert-butvl-1 H-imidazol-1 -vl)Dvridin-3-amine

To a solution of Intermediate (72) (1.2 g, 4.9 mmol) in éthanol (40 mL) was added 10% Pd/C (500 mg). The mixture was stirred under a 40 psi hydrogen atmosphère for 24 h. The mixture was filtered and concentrated to give 6-(4-tert-butyl-1 H-imidazol-1 -yl)pyridin-3-amine (1.1 g) as a yellow solid which was used without further purification. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1 H), 7.93 (d, J=2.8 Hz, 1H), 7.42-7.40 (m, 2H), 7.28 (d, J=2.4 Hz, 1 H), 1.38 (s, 9H).

Intermediate (74): 4-isoDroDvl-1H-imidazote

A solution of 1-bromo-3-methylbutan-2-one (15 g, 9.1 mmol) in formamide (60 mL) was refluxed for 4 h. The mixture was poured into 10% aqueous sodium bicarbonate (30 mL) and adjusted to pH=9.5. The solution was extracted with dichloromethane (30 mL*2). The combined organic layers were washed with 10%

aqueous potassium carbonate, brine, dried over Na₂SO₄₁ and concentrated under reduced pressure to give

4-isopropyl-1H-imidazole (5.5 g) as a brown oii. ¹H NMR (400 MHz, CDCI₃) δ 7.51 (s, 1H), 6.70 (s, 1H),

2.92-2.85 (m, 1H), 1.22 (d, 6H).

Intermediate (75): 2-(4-lsoDroDvl-1 H-imidazol-1 -vl)-5-nitropvridine

To a solution 2-chloro-5-nltropyridine (1 g, 9.1 mmol) in acetonitrile (15 mL) was added Intermediate (74) (1.3 g, 8.3 mmol) and potassium carbonate (2.27 g, 16.4 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL *3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification by silica gel chromatography gave 2-(4-isopropyl-1 H-imidazol-1 -yl)-5-nitropyridine (860 mg) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) δ 9.23 (d. J=2.4 Hz, 1 H), 8.53 (dd, J=9.2, 2.8 Hz, 1 H), 8.35 (d, J=0.8 Hz, 1 H), 7.39 (d, J=9.2 Hz, 1H), 7.31 (s, 1H), 2.94-2.87 (m, 1H), 1.27 (d, J=6.8 Hz, 6H).

Intermediate (76): 6-(4-isoproovl-1 H-imidazol-1-vl)pyridin-3-amine

To a solution of Intermediate (75) (800 mg, 3.44 mmol) in methanol (20 mL) was added 10% Pd/C (400 mg). The mixture was stirred under a 40 psi hydrogen atmosphère 12 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give 6-(4-isopropyl-1H-imidazol-1-yl)pyridin-3-amine (600 mg) as a yellow solid which was used without further purification. ¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=1.2 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.22-7.26 (m, 2H), 7.10 (dd, J=8.4, 2.8 Hz, 1H), 2.83-2.76 (m, 1H), 1.18 (d, J=7.2 Hz, 6H).

Intermediate (77): (+/-)-ethvl 4-(1-(4-bromoohenoxv)butvl)benzoate

O

To a 0 °C solution of 4-bromophenol (1.87 g, 1.08 mmol), ethyl 4-(1-hydroxybutyl)benzoate (2 g, 0.9 mmol) and triphenylphosphine (2.83 g, 1.08 mmol) in THF (20 mL) was added DIAD (2.18 g, 1.08 mmol). The resulting mixture was stirred at 30 °C ovemight. The reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (3*25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (+/-)ethyl 4-(1-(4-bromophenoxy)butyl)benzoate (2.3 g, 67.7 %) as a yellow oil. ’HNMR (400MHz, CDCI₃) δ 8.00 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.25 (d, J=8.8Hz, 2H), 6.67 (d, J=8.8Hz, 2H), 5.08 (m, 1H), 4.35 (q,

J=7.2Hz, 2H), 1.98-1.94 (m, 1 H). 1.80-1.74 (m, 1H), 1.52-1.50 {m, 1H), 1.43-1.39 (m, 1H), 1.37 (t, J=7.2Hz,

3H), 0.94 (t, J=7.2Hz, 3H).

Intermediate (78): 4-phenvl-1/-/-imidazoie

A solution of 2-bromo-1-phenylethanone (5.56 g, 30.38 mmol) in formamide (35.4 ml, 1.04 mol) was stirred at 185 °C for 3 h. After cooling to room température, the reaction was washed with satured aqueous sodium chloride (100 mL) and extracted with ethyl acetate (100 mL*4). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-phenyl-1H-imidazole (4.6 g) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) δ 8.23 (d, J=13.6 Hz, 1H), 7.72-7.75 (m, 3H), 7.34-7.42 (m 2H), 7.26-7.29 (m, 1H).

Intermediate (79): 2-bromo-5-methoxv-1.3-dimethylbenzene

To a 0 °C solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.98 mmol) in DMF (10.0 mL) was added iodomethane (1.41 g, 9.96 mmol) and potassium carbonate (1.37 g, 9.96 mmol). The mixture was stirred for 5 h at room température. The mixture was poured into water and extracted with ethyl acetate (15 ml*3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 2-bromo-5-methoxy-1,3-dlmethylbenzene (1.00 g) as a yellow oil. ¹H NMR (400 MHz, CDCI₃) δ 6.57 (s, 2H), 3.69 (s, 3H), 2.31 (s, 6H).

Intermediate (80): 4-ohloro-1 -(4-meÎhoxv-2,6-dimethvlphenvl)-1 H-pvrazole

To a -78 °C solution of Intermediate (79) (500 mg, 2.34 mmol) in THF (10 mL) was added n-BuLi (0.98 mLof a 2.5M solution in hexanes, 2.45 mmol). The reaction mixture was stirred for 30 min at-78 °C. Di-f-butyl diazene-1,2-dicarboxylate (565 mg, 2.45 mmol) was added in one portion. The reaction mixture was allowed to warm to room température and stirred for 30 min. A solution of 2-chloromalonaldehyde (260 mg, 2.45 mmol) In THF (2.0 mL) was added dropwise at 0 °C. 4M HCl in dioxane (10 mL) was added. The reaction mixture was stirred at reflux overnight. Saturated aqueous NaHCO_a was added to bring the aqueous layer to pH=7. The mixture was extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give compound 4-chloro-1-(4-methoxy-2,6-dimethylphenyl)-1H-pyrazole (100 mg) as a pale yellow oil. ¹H NMR (400 MHz, CDCI₃) δ 7.57 (s, 1H), 7.35 (s, 1H), 6.57 (s, 2H), 3.74 (s, 3H), 1.92 (s, 6H).

Intermediate (81): 4-(4-chlpro-1H-Pvrazol-1 -vl)-3.5-dimethvlphenol

To a -10 °C solution of Intermediate (80) (850 mg, 3.60 mmol) in dichloromethane (15.0 mL) was added boron tribromide (2.72 mg, 10.8 mmol). The reaction mixture was allowed to warm to room température and stirred overnglht. The resulting mixture was quenched by addition of methanoi and concentrated under reduced pressure to give 4-(4-chloro-1 H-pyrazol-1 -yl)-3,5-dimethylphenol (795 mg) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 7.83 (d, J=0.4 Hz, 1H), 7.72 (d, J=0.4Hz, 1H), 6.60 (s,2H), 1.94 (s, 6H). Intermediate (82): 1-f2.6-dimethvl-4-niÎroDhenvl)-4-(trifluoromethvl)-1H-imidazole

To a 0 °C solution of 2,6-dimethyl-4-nitrophenol (3 g, 17.9 mmol) and pyridine (4,25 g, 53.7 mmol) In dichloromethane (30 mL) was slowly added triflic anhydride (7.6 g, 26.8 mmol). The solution was stirred at room température for 2 h. The mixture was concentrated poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give crude 2,6-dimethyl-4-nitrophenyl trifluoromethanesulfonate (5.5 g) as a yellow solid.

To a 0 °C solution of 4-(trifluoromethyl)-1H-imidazole (1.82 g, 13.4 mmol) in DMF (20 mL) was added sodium hydride (0.81 g, 20.1 mmol). The mixture was stirred at room température for 1 h. The crude 2,6-dimethyl-4nitrophenyl trifluoromethanesulfonate prepared above (4.0 g, 13.4 mmol) was added. The mixture was stirred at 80 °C for 12 h. The reaction was diluted with water and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 1-(2,6-dimethyl-4-nitrophenyl)-4-(trifluoromethyl)1H-imidazole (805 mg, 21%) as a colorless solid. ¹H NMR (400 MHz, CDCI₃) 0 8.01 (s, 2 H), 7.47 (s, 1 H), 7.23 (s, 1 H), 2.11 (s, 6 H).

Intermediate (83): 3.5-dimethv!-4-(4-(trifluoromethvl)-1 H-imidazol-1 -vDphenol

To a solution of Intermediate (82) (470 mg, 1.65 mmol) in éthanol (40 mL) was added 10% Pd/C (150 mg). The mixture was stirred under a 40psi hydrogen atmosphère at 15 ”0 for 24 h. The mixture was filtered and concentrated under reduced pressure. The residue was added to a solution of concentrated H₂SO₄ (5.5 mL) in water (20 mL) and cooled to 0 °C. A solution of sodium nitrite (146 mg, 2.12 mmol) in water (2 mL) was added dropwise. The mixture was stirred for at 0 °C 30 min. The reaction was poured into a boiling mixture of concentrated H₂SO₄ (2.9 mL) and water (26 mL) and refluxed for 2 h. The reaction mixture was then cooled to room température and slowly added into ice water. The mixture was extracted with ethyl acetate (30 mL x

3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and then concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 3,5-dimethyl4-(4-(trifluoromethyl)-1H-imïdazol-1-yl)phenol (330 mg) as a yellow solid. ’H NMR (400 MHz, CD₃OD) δ 7.80 (s, 1 H), 7.68 (s, 1 H), 6.64 (s, 2 H), 2.03 (s, 6 H).

Intermediate (84): 6-(4-phenvl-1H-pyrazol-1-vl)pvridin-3-ol

HO

Intermediate 25 (400 mg, 1.69 mmol) was added to a 0 °C solution of concentrated H₂SO₄ (5.5 ml) in water (20 ml). A solution of sodium nitrite (128.5 mg, 1.86 mmol) in water (1.5 ml) was added dropwise. The reaction was stirred at 0 °C for 1 h. The reaction mixture was poured into a boiling mixture of water (29 ml) and concentrated H₂SO₄ (2.6 ml) and refluxed for 1h. The mixture was cooled, poured into ice water and extracted with ethyl acetate (3 x 25 ml).The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to afford

6-(4-phenyl-1H-pyrazol-1-yl)pyridln-3-ol (200 mg) as an orange solid. ’H NMR (400 MHz, CDCI₃) 58.75 (s, 1H), 8.14 (d, J=2.8 Hz, 1 H), 7.99 (s, 1H), 7.93 (d, J=8.8Hz, 1 H), 7.59 (d, J=7.6Hz, 2H), 7.38-7.42 (m, 3H), 7.26-7.29 (m, 1H).

Intermediate (85): tert-butyl 4-tert-butvl-1H-pyrazole-1-carboxylate

A mixture of pyrazole (40 g, 0.5Θ7 mol) and 2-chloro-2-methylpropane (81.7 g, 0.881 mol) were heated at 220 °C for 6h in an autoclave. The reaction mixture was cooled to room température and adjusted to ~pH 9 with saturated aqueous NaHCO₃. The mixture was extracted with dichloromethane (200 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated to dryness, providing a 50 g of mixture, consitsting mostly of 4-tert-butyl-1H-pyrazole and 1,4-di-fert-butyl-1H-pyrazole. 500 mg of this crude mixture was dissolved in THF (8 mL). The solution was cooled to 0 ’C. LiHMDS (6 mL of a 1M solution in THF, 6.0 mmol) was added. The mixture was stirred at 0 °C for 45 min. Di-t-butyldicarbonate (967 mg, 4.43 mmol) was added. The resulting mixture was stirred at room température overnight. The reaction was quenched by addition of 1N aqueous HCl and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by silica gel chromatography to give tert-butyl 4-tert-butyl-1H-pyrazole-1-carboxylate (120 mg) as a yellow solid. ’H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.63 (S, 1 H), 1.64 (s, 9H), 1.26 (S, 9H).

Intermediate (86): 4-fert-butvl-IH-pyrazole

To a solution of Intermediate (85) (120 mg, 0.535 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (64 mg, 1.6 mmol). The mixture was stirred at romm température overnight. Saturated aqueous NaHCO₃ was added and the mixture extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give 4-tert-butyl-lH-pyrazole (80 mg) as a yellow solid. ’HNMR (400 MHz, CDCI₃) δ 11.98 (br s, 1 H), 7.47 (br s, 2H), 1.20 (s, 9H).

Intermediate (87): 6-i4-fert-butvl-1H-pvrazol-1-yl)pyridin-3-amine

To a solution of 4-fert-butyl-1H-pyrazole (300 mg, 2,41 mmol) and 2-bromo-5-nitropyridine in acetonitrile (15 mL) was added potassium carbonate (833 mg, 6.04 mmol). The mixture was stirred at reflux overnight. The mixture was diluted with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄₁ and concentrated to give 350 mg yellow solid. The solid was dissolved in éthanol (10 mL). 10 wt% Pd/C (30 mg) was added. The mixture was stirred overnight at 30 °C under a 40 psi hydrogen atmosphère. The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography to give 6-(4-tert-butyl-1H-pyrazol-1-yl)pyridin-3-amine (140 mg) as a yellow solid. ’H NMR (400 MHz, CD₃OD) δ 8.04 (s, 1 H), 7.72 (d, J=2.4 Hz,1 H), 7.43-7.47 (m, 2H), 7.09 (dd, J=8.8, 2.8 Hz, 2H), 1.19 (s, 9H).

Intermediate (88): 4-(5-chloro-2H-indazol-2-vl)phenol

HO.

Cl

4-(5-chloro-2H-indazol-2-yl)phenol was prepared using a method analogous to that described for Intermediate (Q10), starting from 4-methoxyanrline and 5-chloro-2-nrtrobenzaldehyde. Yellow solid. ’HNMR (400MHz Methanol-^) δ 8.60 (d, J=1.6Hz, 1 H), 7.71-7.75 (m, 3H), 7.65 (d, J=9.2Hz, 1 H), 7.27 (dd, J=9.2, 2.0 Hz, 1 H), 6.95 (d, J=8.8Hz, 2H).

Intermediate (89): 3-methvl-1-(6-(4-(trifluoromethvl)-1 H-pyrazol-1-vl)Dvridin-3-vl)butan-1-ol

OH

Step A: S-chloro-N-methoxy-N-methylnicotinamide

Το a solution of 6-chloronicotinic acid (2.0 g, 12.7 mmol) in DMF (20 mL) was added TBTU ( 6.11 g, 19.0 mmol), di-iso-propylethylamine (4.9 g, 38.1 mmol), and N-methoxymethylamine hydrochloride (1.48 g, 15.2 mmol). The réaction mixture was stirred at 25 °C overnight, The reaction solution was poured into brine (40 mL) and extracted with ethyl acetate (40 mL*2). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gai chromatography to give 6-chloro-N-methoxyN-methylnicotinamide (2.3g) as an oil. ’H NMR (400 MHz, CDCI₃) δ 8.70 (d, J = 2.0 Hz, 1H), 7.95 (dd, J =

2.4, 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 3.49 (s, 3H), 3.32 (s, 3H).

Step B: 1-(6-chloropvridln-3-vl)-3-methvlbutan-1-one

To a 0 °C solution of 6-chloro-N-methoxy-N-methylnicotinamide (2 g, 10 mmol) in THF (30 mL) was added the feo-butymagnesium bromide (15 mL of a 1.33M solution in THF, 20 mmol), The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched by addition of aqueous NH₄CI (30 mL) and extracted with ethyl acetate (30 mL*2). The organic layer was washed with brine (50 mL) and water (50 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure, The crude residue was purified by silica gel chromatography to give 1-(6-chloropyridin-3-yl)-3-methylbutan-1-one (1,8 g) as a colorless solid. ’H NMR (400 MHz, CDCh) δ 8.85 (d, J=2.0 Hz, 1H). 8.12 (dd, J=2.4, 8.4 Hz, 1 H), 7.37 (d, J=8.0 Hz, 1H), 2.75 (d, J= 6.8 Hz, 2H), 2.26-2.19 (m, 1H), 0.94 (d, J= 6.8 Hz, 6H).

Step C: 3-methvl-1 -(6-(4-(trifluoromethyl)-1 H-pyrazoM -vl)pyridin-3-vl)butan-1 -one

To a solution of 1-(6-chloropyridin-3-yl)-3-methylbutan-1-one (1.0 g, 5.1 mmol) and 4-(trifluoromethyl)-1Hpyrazole (766 mg, 5.62 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (2.12 g, 15.3 mmol). The mixture was stirred at 50 °C for 6 h. The réaction mixture was poured into brine (30 mL) and extracted with ethyl acetate (30 mL*2). The combined organic layers were dried over anhydrous Na₂SO₄₁filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)butan-1 -one (1.4 g) as a colorless solid. ’H NMR (400 MHz, CDCI₃) δ 8.92 (d, J=2.0 Hz, 1H), 8.85 (s, 1 H), 8.33 (dd, J=2.0, 8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 2.79 (d, J=6.8 Hz, 2H), 2.31-2.21 (m, 1 H), 0.96 (d, J=6.8 Hz, 6H). Step D: 3-methvl-1-(6-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)pvrldin-3-vl)butan-1-ol

To a 0 °C solution of 3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)butan-1 -one (1.4 g, 4.7 mmol) in methanol (20 mL) was added sodium borohydride (367 mg, 9.4 mmol). The resulting mixture was stirred at 20 °C for 1 hour. Water was added and the mixture was extracted with ethyl acetate (40mL). The organic layer was dried over anhydrous Na_zS0₄₁ filtered, and concentrated to give 3-methyl-1 -(6-(4(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-ol (1.4 g) as a colorless solid. ¹H NMR (400 MHz, CDCI₃) δ 8.78 (s, 1 H), 8.32 (d, J = 2.0 Hz, 1 H), 7.91 (d. J = 8.4 Hz, 1 H), 7.Θ2-7.79 (m, 2H), 4.82-4.77 (m, 1H), 1.83 (S, 1H), 1.75-1.64 (m, 2H), 1.47-1.43 (m,1 H), 0.88-0.92 (m, 6H).

Intermediate (90): methyl 6-ffôrt-butoxvcarbonvlamino)nicotinate

Di-t-butyldicarbonate (5.0 g, 23 mmol) was added to a room température suspension of methyl 6aminonlcotinate (2.65g, 17.4 mmol) and A/,N-dimethylaminopyridine (109 mg, 0.86 mmol) in 40 mL acetonitrile. The resulting orange mixture was stirred at room température overnight. The suspension was filtered. The solid was washed with acetonitrile and air dried to give 2.64g methyl 6-(tertbutoxycarbonylamino)nicotinate as a colorless solid. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give an additional 1,50g methyl 6-(tertbutoxycarbonylamino)nicotinate. ¹H NMR (400 MHz, CDCi₃) δ 8.89-8.92 (m, 1H), 8.49-8.59 (brs, 1H), 8.24 (dd, J=8.0, 2.3Hz, 1H), 8.04 (d, J=8.0 Hz), 3.89 (s, 3H), 1.54 (s, 9H).

Intermediate (91): (E)-N-(2-cycloDroDvl-3-(dimethvlamino)allylidene)-A/-methylmethanamlnium hexafluorophosDhateiV)

(E)-N-(2-cyclopropyl-3-(dÎmethylamino)allylidene)-/V-methylmethanaminium hexafluorophosphate(V) was prepared using a method analogous to that described for the préparation of Intermediate (7A), starting from

2-cyclopropylacetic acid. Yellow solid. ’H NMR (400MHz, DMSO-d_e) δ7.38 (s, 2H), 3.42 (s, 6H), 3.25 (s, 6H), 1.80-1.78 (m, 1 H), 0.89-0.85 (m, 2H), 0.47-0.43 (m, 2H).

Intermediate (92): 1-(4-bromo-2.6-dlmethvlDhenvl)-4-cvclODroDvl-1H-Dvrazole

1-(4-bromo-2,6-dimethylphenyl)-4-cyclopropyl-1H-pyrazole was prepared using a method analogous to that described for the préparation of Intermediate (7), starting from Intermediate (7B) and Intermediate (91). Brown oil. ’H NMR (400MHz, CDCI₃) δ 7.42 (s, 1H), 7.19 (s, 2H), 7.10 (s, 1H), 1.91 (s, 6H), 1.72-1.67 (m, 1H), 0.85-0.80 (m, 2H), 0.52-0.48 (m, 2H).

Intermediate (93): 4-(4-cvcloDroDvl-1H-Dvrazol-1-vi)-3.5-dimethvlphenol

A^-cyclopropyl-IH-pyrazol-l-ylJ-S.S-diniethylpheriol was prepared using a method analogous to that described for Intermediate (26), starting from Intermediate (92). Yellow solid. ¹H NMR (400 MHz, CDCI₃) δ

7.55 (br, 1H), 7.42 (s, 1H), 7.10 (s, 1H), 6.30 (s, 1H), 1.79 (s, 6H), 1.71-1.67 (m, 1 H), 0.85-0.80 (m, 2H),

0.52-0.48 (m, 2H).

Intermediate (94): 1-(4-bromo-2.6-dimethvlphenvl)-4-(trifluoromethyl)-1H-1.2,3-Îriazole

4-bromo-2,6-dimethylaniline (302 mg, 1.51 mmol) was suspended in 4 mL 18% aqueous HCl. The mixture was cooled to 0 ’C. A solution of sodium nitrite (125 mg, 1.81 mmol) in 500 pL water was added dropwise over 5 min. During addition, the suspension begins to clear, giving a yelfow solution. The solution was stirred at 0 °C 1 h. A solution of sodium acetate (2.50 g , 30.5 mmol) and sodium azide (201 mg, 3.1 mmol) in 5 mL water was added dropwise. The mixture was stirred at 0 ’C for 30 min and then warmed to room température. The mixture was extracted with 3x20 mL ethyl acetate. The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure, without heating, to give 520 mg brown oil. The residue was dissolved in 15 mL éthanol in a heavy walled sealable glass tube. The solution was cooled to -78 °C. 3,3,3-trifluoromethylpropyne was bubbled through the solution for 5 min. A solution of copper (I) iodide (14 mg, 0.074 mmol) and sodium ascorbate (30 mg, 0.15 mmol) in 500 pL water was added. The reaction vessel was sealed and allowed to warm to room température. After 15h at, the réaction mixture was cooled to -78^eC. The vessel was opened at this température and then allowed to warm to room température. The reaction mixture was concentrated to give 1-(4-bromo-2,6-dimethylphenyl)-4-(trifluoromethyl)-1H-1,2,3triazole (447mg) as a pale yellow solid. Recrystallization from heptane gave fine, colorless needles. ¹H NMR (400 MHz, CDCIg) δ 7.89-7.92 (m, 1H), 7.38 (S, 2H), 1.98 (s, 6H).

Intermediate (95): 3.5-dimethvl-4-(4-(trifluoromethvl)-1H-1.2.3-triazol-1-vl)Dhenol

3,5-dimethyl-4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenol was prepared using a method analogous to that described for Intermediate (26), starting from Intermediate (94). Colorless solid. ¹H NMR (400 MHz, CDCIg) δ 7.87-7.90 (m, 1H), 6.65 (s, 2H), 5.09 (s, 1H), 1.93 (S, 6H).

Intermediate (96): ethyl 3-(4-(1-hydroxybutyllbenzamidolpropanoate

Ο

Step (A): 4-f1-hvdroxybutvl)benzoic acid

The alcohol corresponding to intermediate 5 (1.0 g, 4.5 mmoi) was charged with tetrahydrofuran (10.0 mL), water (10.0 mL), and methanol (10.0 mL). Lithium hydroxide monohydrate (944 mg, 22.5 mmol) was then added. The suspension was stirred at room température for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 1.4 g of crude material. Purification by silica gel flash chromatography (0-30% ethyl acetate in heptane) afforded 4-(1-hydroxybutyl)benzoic acid (730 mg, 83% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 8.09 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.79 (dd, J = 7.6, 5.5 Hz, 1 H), 1.86-1.75 (m, 1 H), 1.75-1.64 (m, 1 H), 1.52-1.24 (m, 2H), 0.95 (t, J =

7.4 Hz, 3H).

Step (B): ethvl 3-(4-(1-hydroxybutyllbenzamidolpropanoate

N,/V-dimethylformamide (8.60 mL) was added to a vial containing 4-(1-hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O-(7azabenzotriazol-1-yl)-/V,N,N',/V'-tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Dlisopropylethylamine (1,12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0 - 50% ethyl acetate in heptane) afforded ethyl

3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. ’H NMR (400 MHz, CDCI₃) δ

7.73 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 6.84 (br.s., 1H), 4.74 (t, J = 6.5 Hz, 1 H), 4.23-4.07 (m, 2H),

3.72 (q, J = 5.9 Hz, 2H), 2.64 (t, J = 5.9 Hz, 2H), 1.85-1.72 (m, 1 H), 1.72-1.58 {m, 1 H), 1.52-1.37 (m, 1 H), 1.37-1.30 (m, 1 H), 1.28 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H). MS (M+1) 294.3.

Intermediate (97): 5-methvl-6-(4-(trifluoromethvl)-1H-pyrazol-1 -vl)Dvridln-3-ol

OH

Step (A): 5-bromo-3-methvl-2-(4-(trifluoromeÎhvl)-1H-pvrazol-1 -vfipyridine

A flask was charged with 5-bromo-2-chloro-3-methylpyridine (250 mg, 1.21 mmol), 4(trifiuoromethyi)-l H-pyrazole (165 mg, 1.21 mmol), potassium carbonate (512 mg, 3.63 mmol), and anhydrous dimethylformamide (1.21 mL). The reaction was heated at 85 to 130 °C for 36 h. The reaction was concentrated to give 690 mg of crude material. Purification by silica gel flash chromatography (0 - 5% ethyl acetate in heptane) afforded 5-bromo-3-methyl-2-(4-(trifluoromethyl)-lH-pyrazol-1-yl)pyridine (containing approximately 30% starting material) was carried forth to the next reaction, MS (M+1) 308.1. Step (B): 5-meÎhvl-6-(4-(tri1luoromethvl)-1 H-pyrazol-1 -vl)pyridin-3-ol

To a flask containing 5-bromo-3-methyl-2-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridine (55.0 mg, 0.180 mmol) in 1,4-dioxane (0.100 mL) and degassed water (0.100 mL), was added tris(dibenzylideneacetone)dipailadium(0) (21.3 mg, 0.0360 mmol), 2-di-tert-butyiphosphino-2',4',6‘triisopropylbiphenyl (6.10 mg, 0.014 mmol), and potassium hydroxide (31.9 mg, 0.0540 mmol). The reaction was purged with nitrogen and then heated at 100 °C for 2 hour. The reaction was quenched with 1 N HCl and extracted three times with ethyl acetate.The organics were dried over sodium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (0 - 25% ethyl acetate in heptane) afforded impure 5-methyl-6-(4-(trifluoromethyl)-lH-pyrazol-1-yl)pyridin-3-ol (containing approximately 30% impurity as a solid. MS (M+H): 244.2.

Intermediate (98): ethvl 3-(4-(cvclobutyl(hvdroxv)methyl)benzamido)proDanoate

Step (A): cvclobutanecarbaldehyde

Aflask was charged with oxalyl chloride (1.12 mL, 12.8 mmol) and anhydrous methylene chloride (21.0 mL). The solution was cooled to -78 °C and dimethylsulfoxide (1.82 mL, 25.5 mL) was added dropwise and the reaction was stirred for 30 min. at -78 °C. A solution of cyclobutylmethanol (1.10 mL, 11.6 mmol) in methylene chloride (8.0 mL) was added dropwise and the reaction was aged for 1 h atthe same température. Triethylamine (8.20 mL, 58.0 mL) was then added dropwise and the reaction was warmed to room température and aged for 18 h. The reaction was quenched with water and extracted three times with methylene chloride. The combined organic layers were dried over magnésium sulfate, filtered, and concentrated to give cyclobutanecarbaldehyde (2.00 g) as a crude oil containing approximately 1.0 g triethylamine. ’H NMR (400 MHz, CDCIg) δ 9.73 (d, J = 2.0 Hz, 1H), 3.18 (s, 1H), 2.34-2.22 (m, 2H), 2.22-

2.11 (m,2H), 2.11-1.99 (m, 1H), 1.99-1.84 (m, 1H).

Step (B): ethvl 4-(cvclobutvl(hvdroxv)methvl)benzoate

To a solution of ethyl 4-lodobenzoate (1.45 mL, 8.69 mmol) In anhydrous tetrahydrofuran (14.5 mL) at -40 °C was added isopropyl magnésium chloride lithium chloride complex (8.0 mL, 10.4 mmol) dropwise. The resulting brown solution was stirred for 40 min at -40 °C. The crude cyclobutanecarbaldehyde (1.8 g, approximately 10.5 mmol pure) was added and the reaction was warmed to room température and stirred for 18 h. The reaction is then quenched with 1 N hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 2.0 g of crude material. Purification by silica gel flash chromatography (0 - 20% ethyl acetate In heptane) afforded ethyl 4(cyclobutyl(hydroxy) methyl)benzoate (1.05 g) as an oil. ’H NMR (400 MHz, CDCI₃) δ 8.01 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 4.64 (d, J = 7.6 Hz, 1H), 4.47-4.25 (m, 2H), 2.73-2.47 (m, 1 H). 2.13-1.94 (m, 2H), 1.95-1.70 (m, 4H), 1.55 (br. s„ 1H), 1.38 (t, J = 7.0 Hz, 3H).

Step (C): 4-(cyclobutvl(hvdroxv)methyl)benzoic acid

To a flask containing ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (530 mg, 2.26 mmol) was added tetrahydrofuran (5.60 mL), water (5.60 mL), and methanol (5.60 mL). Lithium hydroxide monohydrate (475 mg, 11.3 mmol) was then added. The suspension was stirred at room température for 18 hours. The reaction was quanched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 490 mg of crude material. Purification by silica gel flash chromatography (0 - 20% ethyl acetate in heptane) afforded 4(cyclobutyl(hydroxy)methyl)benzoic acid (360 mg, 77%) as a white solid. ’H NMR (400 MHz, CDCI₃) δ 8.07

(d, J = 8.2 Hz, 2H), 7.43 (dd, J = 8.0, 1.0 Hz, 2H), 4.67 (d, J = 7.6 Hz, 1 H), 2.62 (d, J = 8.0 Hz, 1 H), 2.09-1.98 (m, 2H), 1.91-1.80 (m, 4H). MS (M-1 ): 205.2.

Step (D): ethyl 3-(4-(cvclobutvl(hvdroxv)methyl)benzamido)propanoaÎe

Λ/,Ν-dimethylformamide (9.00 mL) was added to a vial containing 4(cyclobutyt(hydroxy)methyl)benzoic acid (370 mg, 1.79 mmol), ethyl 3-aminopropanoate hydrochloride (551 mg, 3.59 mmol) and 0-(7-azabenzotriazol-1-yl)-AI,A/,N',N'-tetramethyluronium hexafluorophosphate (1.36 g,

3.59 mmol). Diisopropylethylamine (1.56 mL, 8.97 mmol) was then added. The reaction was stirred for 1.5 h, and was then concentrated. Purification by column chromatography (0 - 50% ethyl acetate In heptane) afforded ethyl 3-(4-(cyclobutyl(hydroxy)methyl)benzamido)propanoate (570 mg, 100% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 7.73 (d, J = 8.2 Hz, 2H). 7.38 (d, J = 8.2 Hz, 2H), 4.63 (d, J = 7.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.72 (q, J = 6.0 Hz, 2H), 2.64 (t, J = 5.9 Hz, 2H), 2.61-2.54 (m, 1 H), 2.08-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H). MS (M+1): 306.3.

Intermediate (99): ethyl 4-(3.3-dimethvlcvclobutanecarbonvl)benzoate

Step (A) - 3.3-dimethvlcvclobutanecarbonvl chloride

3,3-Dimethyl-cyclobutanecarboxylic acid (Parkway Scientific, New York, NY, USA) (500 mg, 3.90 mmol) was dissolved in dichloromethane (3 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room température for 4 h before concentrating in vacuo to provide 3,3dimethylcyclobutanecarbonyl chloride which was carried on without purification. ¹H NMR (400 MHz, CDCI₃) δ 3.49 (quin, J=8.9 Hz, 1 H) 2.27 - 2.15 (m, 2 H) 2.14 - 2.06 (m, 2 H) 1.18 (s, 3 H) 1.12 (s, 3 H).

Step (B): ethyl 4-(3,3-dimethvlcyclobutanecarbonvl)benzoate

In a 3-neck flask at -30 °C (monitored with thermalcouple) containing ethyl 4-iodobenzoate (25.0 g, 89.0 mmol) in anhydrous tetrahydrofuran (148 mL) was added isopropylmagnesium chloride (51.0 mL, 20.4 mmol) dropwise over 30 min. and then stirred at the same température for another 105 min. Copper iodide (5.07 g, 26,6 mmol) was then added quickly in one portion. The mixture was brought to -20 °C for 25 min. to ensure the solid has dissolved. The réaction is then brought back to -40 “C. 3,3-dimethylcyclobutane carbonyl chloride (15.6 g, 106 mmol) was then added over 5 min. the reaction was then warmed to 0 °C over 4 h. The mixture was then diluted with 1 N HCl and extracted three times with ethyl acetate. The combined organic layers were then washed two times with brine and then dried over sodium sulfate, filtered, and concentrated to provide 26.6 g of crude brown oil. Purification by silica gel flash chromatography twice (0 - 5% ethyl acetate in heptane) afforded ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (17.2 g, 74% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 4.40 {q, J = 7.2 Hz, 2H), 3.89 (quin, J = 8.8 Hz, 1 H), 2.27 - 2.14 (m, 2H), 2.12 - 2.02 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.27 (s, 3H), 1.08 (s, 3H). MS (M+1): 261.2.

Intermediate (100): ethyl 4-((3.3-dimethyÎcvclobutyl)(hydroxv)methvl)benzoate

To a flask containing Intermediate (99) (350 mg, 1.34 mmol) was added anhydrous methanol (6.70 mL). The solution was cooled to 0 °C and sodium borohydride (152 mg, 4.00 mmol) was added.' After 20 min., the reaction was quenched with saturated aqueous ammonium chloride and extracted three fîmes with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 420 mg of crude material. Purification by silica gel flash chromatography (0-15% ethyl acetate in heptane) afforded impure ethyl 4-((3,3-dimethylcyclobutyl)(hydroxy)methyl)benzoate (260 mg, 73.8%) as a solid. ¹H NMR (400 MHz, CDCI₃) δ 8.00 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 4.60 (d, J = 7.8 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 2.61 -2.39 (m, 1 H), 1.89-1.71 (m, 2H), 1.66-1.51 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H),

1.11 (s, 3H), 1.07 (s, 3H).

Intermediate (101): ethvl 3-(4-(3₁3-dimethvlcvclobutanecarbonvl)benzamido)proDanoate

o

Step (A): 4-(3.3-dimethvlcvc1obutanecarbonvl)benzoic acid

To a flask containing Intermediate (99) (3.00 g, 12.0 mmol) was added anhydrous tetrahydrofuran (28.8 mL), methanol (28.8 mL), and 1 N sodium hydroxîde (28.8 mL, 28.8 mmol). After 1 h, the reaction was concentrated to a white solid. The solid was the redissolved in 700 mL of water. With vigorous stirring, 1 N HCl (29.0 mL) was added dropwise and the suspension was stirred for 30 min. at room température. The solid was then collected with a Buchner funnel and the solid was washed two times with water. The solid was then azeotrophed with toluene to give 4-(3,3-dimethylcyclobutanecarbonyl) benzoic acid (2.15 g, 92% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 8.21 - 8.15 (m, 2H), 8.01- 7.94 (m, 2H), 3.91 (quin, J =

8.9 Hz, 1H), 2.28 - 2.17 (m, 2H), 2.15 - 2.04 (m, 2H), 1.28 (s. 3H), 1.09 (s, 3H). MS (M-1 ): 231.4.

Step (B): ethvl 3-(4-(3.3-dimethvlcvclobutanecarbonyi)benzamido)propanoate

Tetrahydrofuran (138 mL) was added to a vial containing 4-(3,3dimethylcyclobutanecarbonyl)benzoic acid (3.20 g, 14.0 mmol), ethyl 3-aminopropanoate hydrochloride (3.17 g, 20.7 mmol) and 1,2,3-benzotriazol-1-ol monohydrate (2.22 g, 14.5 mmol). Triethylamine (9.11 mL, 4.75 mmol) was then added. The réaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-35% ethyl acetate in heptane) afforded impure ethyl 3-(4-(3,3dimethylcyclobutanecarbonyl)benzamido)propanoate (4.22 g, approximately 8.90 mmol pure) as an oil. MS (M+1) 332.2.

Intermediate (102): ethvl 3-(4-((3.3-dimeÎhvlcvclobutvl)(hvdroxv)methvl)benzamido) propanoate

To a flask containing ethyl 3-(4-(3,3-dimethylcyclobutanecarbonyl)benzamido) propanoate (1.21 g, approximately 2.55 mmol pure) was added anhydrous methanol (18.3 mL). The solution was cooled to 0 °C and sodium borohydrlde (414 mg, 11.0 mmol) was added. After 15 min., the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 1.10 g of crude material. Purification by silica gel flash chromatography (0 - 50% ethyl acetate in heptane) afforded impure ethyl 3-(4-((3,3dimethylcyclobutyl)(hydroxy)methyl)benzamido)propanoate (750 mg, approximately 1.8 mmol pure) as an oil. MS (M+1): 334.3.

Intermediate (103): 3-methoxv-5-methvl-4-(4-(triÎluoromethvl)-1H-Dvrazol-1-vl)phenol

MeO

Step (A): 1-(2-methoxv-6-methvlphenyl)-4-(trifluoromethy|)-1 H-pyrazole

Intermediate 7A (1.77 g, 5.20 mmol) and 1-(2-methoxy-6-methylphenyl)hydrazlne hydrochloride (Shanghai Chempartner Co. Ltd.) (1.00 g, 5.20 mmol) were suspended In tetrahydrofuran (20.8 mL). The suspension was cooled to 0 °C. Sodium methoxide (325 mg, 5.72 mmol) was added as a solid in one portion. The ice bath was removed and the mixture warmed to room température and stirred for 18 hours. Trifluoroacetic acid (1.77 mL) was then added at room température. The reaction was heated to 80°C for 5 hours, diluted with ethyl acetate and washed with saturated sodium bicarbonate twice. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-10% ethyl acetate in heptane), gave 1-(2-methoxy-6-methylphenyl)-4-(trifluoromethyl)-1 H-pyrazole (810 mg, 61%) as a solid. ’HNMR (400 MHz, CDCI₃) δ 7.93 (S, 1 H), 7.81 - 7.71 (m, 1 H), 7.33 (t, J = 8.1 Hz, 1 H), 6.96 - 6.81 (m, 2H), 3.76 (S, 3H), 2.07 (s, 3H). MS (M+1): 257.2.

Step (B): 3-methoxv-5-methyl-4-(4-(trifluoromethvl)-1 H-pyrazol-1 -vl) phénol

To a flask containing 1-(2-methoxy-6-methylphenyl)-4-(trifluoromethyl)-1 H-pyrazole (75.0 mg, 0.290 mmol) was added di-p-methoxobis(1,5-cyclooctadiene)diiridium(l) (2.00 mg, 0.003 mmol), bis(pinacolato)diboron (75.2 mg, 0.290 mmol), 4,4’dl-tert-butyl-2,2'-dipyridyl (1.60 mg, 0.006 mmol) and degassed methyl tert-butyl ether (1.50 mL). The resulting red solution was heated to 80 °C for 18 h and then at room température for 3 d. The reaction was concentrated. Acetone (0.980 mL) was added to provide a homogenous solution folfowed by an aqueous solution of oxone (180 mg, 0.290 mmol), 0.98 mL of water) dropwise over 2 min. The reaction was stirred at room température for 18 h. The reaction was then quenched with aqueous sodium bisulfate and extracted three times with methylene chloride. The combined organic layers were washed with brine and water. The organic layer was then dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0 - 25% ethyl acetate in heptane), gave

3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenol (26.0 mg, 33%) as a solid. ’H NMR (400

MHz, CDCI3) δ 7.93 (s, 1H), 7.75 - 7.70 (m, 1H), 6.27 (dd, J = 15.8, 2.5 Hz, 2H), 3.68 (s, 3H), 1.96 (s, 3H).

MS (M+1): 273.2.

Intermediate (104): ethvl 4-(3,3-difluorocvclobutanecarbonvl)benzoate

Step (A): 3.3-difluorocvclobutanecarbonvl chloride

3,3-Difluorocyclobutanecarboxylic acid (Parkway Scientific, New York, NY, USA) (531 mg, 3.90 mmol) was dissolved in dichloromethane (3.00 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room température for 4 h before concentrating in vacuo to provide 3,3difluorocyclobutanecarbonyl chloride (ca. 50% pure), which was carried on without purification. Step (B): ethvl 4-(3.3-difluorocvclobutanecarbonvl)benzoate

In a 3-neck flask at -30 °C containing ethyl 4-iodobenzoate (600 mg, 2.17 mmol) in anhydrous tetrahydrofuran (6.00 mL) was added isopropylmagnesium chloride lithium chloride complex (1.84 mL, 2.39 mmol) dropwise and then stirred at the same température for another 40 min. Copper iodide (124 mg, 0.650 mmol) was then added quickly in one portion. The mixture was broughtto -15 °C for 20 min. to ensure the solid has dissolved. The reaction is then brought back to -40 ’C. Crude 3,3-dîfiuorocyclobutanecarbonyl chloride (470 mg, 1.50 mmol pure) was then added and the reaction was then warmed to 0 °C over 1 h and then stirred at room température for 18 h. The mixture was then diluted with 1 N HCl and extracted three times with ethyl acetate. The combined organic layers were then washed with brine and then dried over sodium sulfate, filtered, and concentrated to provide 680 mg of crude oil. Purification by silica gel flash chromatography (0-10% ethyl acetate in heptane) afforded impure ethyl 4-(3,3difluorocyclobutanecarbonyl)benzoate (130 mg, approximately 0.24 mmol pure) as a solid. ’H NMR (400 MHz, CDCI3) δ 8.09 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 9.2 Hz, 2H), 4.39 (q, J = 7.4 Hz, 2H), 3.34-3.15 (m, 1H), 3.12-2.78 (m, 4H), 1.40 (t, J = 7.4 Hz, 3H).

intermediate (105): 2-(4-ftrifluoromethvl)-1 H-pyrazol-1 -yl)pyrimidin-5-ol

OH

Step (A): 5-bromo-2-(4-(trifluoromethvl)-1 H-pyrazol-1 -vPpyrimidine

To a mixture of 5-bromo-2-chloropyrimidine (4.32 g, 21.5 mmol), 4-(trifluoromethyl)-1H-pyrazole (2.92 g, 21.5 mmol), and dried potassium carbonate (8.90 g, 64.4 mmol) was added anhydrous dimethylformamide (31.5 mL). The resulting suspension was heated at 85 °C for 4 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 12.4 g of crude yellow solid. The crude material was put through a plug of silica eluting with 15% ethyl acetate in heptanes to give 5-bromo-2-(4-(trifluoromethyl)-1 H-

pyrazol-1 -yljpyrimidine (6.2 g, 99%) as a solid. Ή NMR (400 MHz, CDCh) δ 8.87 (s, 1 H). 8.83 (s, 2H), 8.02 (s, 1H).

Step (Bk 5-(4.4,5,5-tetramethvl-1.3.2-dioxaborolan-2-vl)-2-(4-(trifluoromethyl)-1 H-pvrazol-1 -vDpyrimidine

To a flask containing 5-bromo-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidina (2.90 g, 9.9 mmol) was added bis(dipinacolato)borane (3.00 g, 11.9 mmol), potassium acetate (2.90 g, 29.7 mmol), and 1,1’bis(diphenylphosphino)ferrocenepalladium(ll)dichlorlde (366 mg, 0.500 mmol). After purging with nitrogen, anhydrous dimethylforamide (12.4 mL) was added. The reaction was heated at 80 °C. After 2h, the reaction was cooled to room température and partitioned between ethyl acetate and brine. The mixture was filtered through celite and eluted with ethyl acetate. The filtrate was washed twice with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 5.30 g of crude material. Purification by siiica gel flash chromatography (0 - 50% ethyl acetate in heptane) afforded 5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (3.22 g, 96% yield) as a yellow solid. ’H NMR (400 MHz, CDCh) δ 9.05 (s, 2H), 9.00-8.89 (m, 1H), 8.02 (s, 1H), 1.38 (s, 12H).

Step (Ck 2-(4-(trifluoromethvl)-1H-pvrazol-l-vl)pyrimidin-5-ol

To a flask containing 5-(4,4,5,5-tetramBthyl-1,3,2-dioxaborolan-2-yl)-2-(4-(trlfluoromethyl)-1 Hpyrazol-1-yl)pyrimidine (3.20 g, 9.40 mmol) was added methanol (72.4 mL) and 50% aqueous hydrogen peroxide (1.71 mL). After 2 h, the reaction was carefully concentrated and the solid was dissolved in diethyl ether and washed twice with water then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 880 mg of crude solid. The brown solid was suspended in water and filtered through a Buchner tunnel and washed with ethyl acetate to give a white solid (580 mg). The above aqueous layer was also filtered through a Buchner funnel to provide 926 mg of white solid. The combined batches provided pure 2-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyrimidin-5-ol (1.50 g, 69%) as a white solid. ¹H NMR (400 MHz, CDCh) □: 8.79 (s, 1H), 8.43 (s, 2H), 7.96 (s, 1H). MS (M+1) 231.1.

Intermediate (106): 2-(4-(tfifiuoromethvl)-1 H-pyrazol-1 -vl)pyrimidin-5-amine

Step (A): 5-nitro-2-(4-(trifluoromethvl)-1 H-pyrazol-1-vDpyrimidine

A round bottom flask was charged with 2-chloro-5-nitropyrimidine (2.50 g, 15.7 mmol), 4(trifluoromethyl)-l H-pyrazole (2.35 g, 17.2 mmol), K₂CO₃ (4.33 g, 31.3 mmol) and acetonitrile (39 mL). The reaction was heated at 80 °C for 2 hours. Potassium carbonate filtered off with a büchner funnel and acetonitrile removed under reduced pressure. The crude material was dissolved in ethyl acetate and transferred to a separatory funnel. Organics washed with water (3X), with brine (1X), dried over sodium sulfate, filtered and concentrated to afford the raw material. Purification by siiica gel flash chromatography (ethyl acetate / heptane) provide 5-nitro-2-(4-(trifluoromethyl)-1 Hpyrazol-1-yl)pyrimidine (1.95 g, 49%) as a yellow solid. MS (M+1): 259.2.

Step (B): 2-f4-(trifluoromethvl)-1 H-pvrazol-1-vl)pyrimidin-5-amine

A Parr Shaker bottle was charged with Pd/C (10% wet; degussa type; 300 mg) and the 5nitro-2-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pynmidine (1.18 g, 4.55 mmol) in ethyl acetate (91 mL). Shaked at 40 psi of H_a (g) for 8 hours. Crude mixture filtered through celite and concentrated under reduced pressure to afford 2-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyrimidin-5-amine (1.78 g, 98%) as an orange solid. ¹H NMR (400 MHz, DMSO-d6) δ 5.85 (s, 2 H) 8.15 (s, 1 H) 8.18 (s, 2 H) 8.95 (s, 1 H); MS (M+1): 230.2.

Intermediate (107): 6-(4-phenyl-1H-imidazol-1-vl)pyridin-3-amine

Step A: 5-iodo-2-(4-phenvl-1H-lmldazol-1-vl)pyridlne

The title compound was prepared by a method analogous to that described for Intermediate (24), using 4-phenyl-1H-imidazo!e. ¹H NMR (400 MHz, CDCI₃, δ): 8.69 (d, J = 2.1 Hz, 1 H), 8.40 (s, 1 H), 8.11 (dd, J = 8.5, 2.2 Hz, 1 H), 7.89 (s, 1 H), 7.85 (d, J = 7.2 Hz, 2 H), 7.41 (t, J = 7.7 Hz, 2 H), 7.22 - 7.32 (m, 2 H). MS (M+1) 348.1.

Step B: 6-(4-Dhenyl-1H-[midazol-1-yl)pyridin-3-amine

The title compound was prepared by a method analogous to that described for Intermediate (25), using 5-iodo-2-(4-phenyl-1H-imidazol-1-yl)pyridine. ¹H NMR (400 MHz, CDCI₃, δ): 8.20 (s, 1 H), 7.94 (d, J = 2.7 Hz, 1 H), 7.79 - 7.87 (m, 3 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.22 - 7.28 (m, 1 H), 7.16 - 7.21 (m, 1 H), 7.08 -

7.12 (m, 1 H), 3.72 (br. s., 2 H). MS (M+1) 237.3.

Intermediate (108): 6-(4-chloro-3-methvl-1H-pyrazol-1-vl)ovridin-3-amine

The title compound was prepared by a method analogous to that described for Intermediate (107), using 4-chloro-3-methyl-1H-pyrazole. ’H NMR (400 MHz, CDCI₃, δ): 8.28 (s, 1 H), 7.82 (d, J = 2.9 Hz, 1 H),

7.62 - 7.66 (m, 1 H), 7.07 - 7.11 (m, 1 H), 3.68 (br. s., 2 H), 2.30 (s, 3 H). MS (M+1) 209.2.

Intermediate (109): 6-(4-(pyridin-2-vl)-1 H-pyrazol-1 -vl)pyridin-3-amine

The title compound was prepared by a method analogous to that described for Intermediate (107) using 2-(1H-pyrazol-4-yl)pyridine. ¹H NMR (400 MHz, CDCI₃, δ): 8.88 - 8.90 (m, 1 H), 8.56 - 8.59 (m, 1 H), 8.19 (s, 1 H), 7.88 (d, J = 2.7 Hz, 1 H), 7.77 (d, J = 8.6 Hz, 1 H), 7.62-7.68 (m, 1 H), 7.50-7.55 (m, 1 H), 7.08 - 7.14 (m, 2 H), 3.73 (br. s., 2 H). MS (M+1) 238.3.

Intermediate (110): 6-(4-ethvl-3-methvl-1H-Dvrazol-1-vl)Dvridin-3-amine

The title compound was prepared by a method analogous to that described for Intermediate (107), using 4-ethyl-3-methyl-1H-pyrazole. ¹H NMR (400 MHz, CDCI₃₍ Ô): 8.07 (s, 1 H), 7.82 (d, J = 2.3 Hz, 1 H),

7.65 (d, J = 8.6 Hz, 1 H), 7.08 (dd, J = 8.7, 2.8 Hz, 1 H), 3.56 (br. s., 2 H), 2.44 (q, J = 7.6 Hz, 2 H), 2.26 (s, 3 H), 1.20 (t, J = 7.5 Hz, 3 H). MS (M+1) 203.3.

Intermediate (111): 3.5-dlmethvl-4-(4-(tntluoromethvl)-1H-Dvrazol-1-vl)benzonitrile

A microwave vial was charged with Intermediate (7) (1.00 g, 3.10 mmol), zinc cyanide (199 mg, 1.69 mmol), zinc acetate (22.9 mg, 0.125 mmol), zinc dust (8.2 mg, 0.13 mmol), bis(dibenzylideneacetone)palladium(0) (17.8 mg, 0.0310 mmol), and 1,1’bis(diphenylphosphîno)ferrocene (52.6 mg, 0.0940 mmol). The solids were purged with dry nitrogen, and then dissolved in /V,A/-dimethylformamide (3.13 mL) and water (0.31 mL). The reaction was sealed and heated to 100 °C for 3 hours. The mixture was cooled to room température, quenched by addition of sat. aq ammonium chloride, and extracted with ethyl acetate (3 x). The combined organics were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate ! heptane) gave

3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile. ’H NMR (400 MHz, CDCI₃, δ): 8.00 (S, 1H), 7.77 (s, 1H), 7.50 (s, 2H), 2.09 (s, 6H). MS (M+1): 266.1.

Intermediate (112): 3.5-dimethvl-4-(4-(trifluoromethvl)-1H-Dyrazol-1-vl)benzaldehvde

A solution of Intermediate (111) (250 mg, 0.943 mmol) in tetrahydrofuran (8.57 mL) was cooled to -78 °C. Diisobutylaluminum hydride (1.5 M in toluene, 1.57 mL, 2.36 mmol) was added dropwise. After 2 hours, the reaction was warmed to 0 °C. After 30 minutes, the mixture was quenched by addition of sat. aq ammonium chloride, allowed to warm to room température, and extracted with ethyl acetate (3 x). The combined organics were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography

(ethyl acetate/ heptane) gave 3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde. ’H

NMR (400 MHz, CDCI₃, δ): 10.04 (s, 1 H), 8.00 (s, 1 H), 7.79 (s, 1 H), 7.70 (s, 2 H), 2.13 (s, 6 H). MS (M+1): 269.2.

Intermedaite (113): (4-/-)-/V-(3.5-dimethvl-4-(4-(trifluoromethvl)-1rt-pyrazol-1-vl)benzvlidene)-2methvlpropane-2-sulfinamide

To a solution of Intermediate (112) (526 mg, 1.96 mmol) and (+/-)-2-methyl-2propanesulfinamide (245 mg, 1.96 mmol) in dichloromethane (19.6 mL) was added titanium(IV) ethoxide (0.822 mL, 3.92 mmol). Reaction was refluxed for 1 hour then cooled to room température. Methanol (2 mL) was added followed by sat. aq sodium bicarbonate (1 mL). The resulting slurry was stirred for 1 hour, then concentrated under reduced pressure. After diluting with ethyl acetate (40 mL), the slurry was dried (Na₂SO₄) and filtered through celite (ethyl acetate eluent). The filtrate was concentrated under reduced pressure to provide (+/-)-N-(3,5-dimethyl-4(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzylidene)-2-methylpropane-2-sulfinamide. ’H NMR (400 MHz, CDCIg, δ): 8.59 (s, 1 H). 7.99 (s, 1 H), 7.78 (s, 1 H), 7.66 (s, 2 H), 2.10 (s, 6 H), 1.30 (s, 9 H).

Intermedaite (114): (+/-)-N-(1-(3,5-dimethvl-4-(4-(trifluoromeÎhvl)-1H-pvrazol-1-vl)Dhenvl)-3-methvlbutvl)-2methyl propane-2-sulfinamÎde

A suspension of Intermediate (113) (186 mg, 0.501 mmol) in tetrahydrofuran (5.01 mL) was cooled to -78 °C. Isobutyllithium (1.7 M in heptane, 0.353 mL, 0.600 mmol) was added dropwise. After 2 hours, additional isobutyllithium (1.7 M in heptane, 0.353 mL, 0.600 mmol) was added. After 1 hour, the solution was quenched at -78 °C by addition of sat. aq ammonium chloride (6 mL). The resulting slurry was allowed to warm to room température. The mixture was diluted with 20 mL sat. aq ammonium chloride then extracted with ethyl acetate (3 x 25 mL). The combined

organics were dried (NaaSCU) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) gave (+/-)-N-(1-(3,5dimethyl-4-(4-(trifluoromθthyl)-1H-pyrazol·1-yl)phθnyl)-3-methylbutyl)-2-mθthylpropanθ-2sulfinamide. ¹H NMR (400 MHz, CDCI₃₁ δ): 7.94 (s, 1 H), 7.75 (s, 1 H), 7.12 (s, 2 H), 4.37 (t, J =

7.4 Hz, 1 H), 2.03 (s, 6 H), 1.89 -1.79 (m, 1 H), 1.68 - 1.45 (m, 4 H), 1.24 (s, 9 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H). MS (M+1): 430.5.

Intermediate (115): (+/-)-1 -i3.5-dimethyl-4-(4-(trifluorometh vl)-1 H-pyrazol-1 -vl)phenvl)-3-methvlbutan-1 amine hydrochloride

To a solution of Intermediate (114) (226 mg, 0.525 mmol) in methanol (2.62 mL) was added hydrogen chloride (4 M in dioxane, 0.524 mL, 2.10 mmol) dropwise. The reaction was concentrated under reduced pressure to provide (+/-)-1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 Hpyrazol-1-yl)phenyl)-3-methylbutan-1-amine hydrochloride. ¹H NMR (400 MHz, CD₃OD, δ): 8.33 (s, 1 H), 8.08 (s, 1 H), 7.32 (s, 2 H), 4.35 (dd, J= 9.8, 5.9 Hz, 1 H), 2.06 (s, 6 H), 1.99 -1.87 (m, 1 H), 1.84 -1.74 (m, 1 H), 1.50 - 1.37 (m, 1 H), 0.99 (d, J = 6.4 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H).

Intermediate (116): methvl (+/-)-6-((1-(3.5-dimethvl-4-(4-ftrifluoromethvl)-1 H-pyrazol-1-yl)phenyl)-3methvlbutvl)amlno)nlcotinate

To a mixture of Intermediate (115) (190 mg, 0.525 mmol) and potassium carbonate (296 mg, 2.10 mmol) in Λ/,/V-dimethylformamide (1.05 mL) was added methyl 6-fluoronicotinate (88.1 mg, 0.551 mmol). The reaction was heated to 85 °C. After 19 h, the reaction was cooled to room température, diluted with water (25 mL), and extracted with ethyl acetate (3 x 25 mL). The combined organics were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) gave methyl (+/-)-6-((1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)-3-

methylbutyl)amino)nicotinate. Ή NMR (400 MHz, CDCI₃₁ δ): 8.67 (d, J = 1.8 Hz, 1 H), 8.03 (dd, J = 8.8, 2.0 Hz, 1 H), 7.94 (s, 1 H), 7.74 (s, 1 H), 7.12 (s, 2 H), 6.33 (d, J = 9.0 Hz, 1 H), 4.67 - 4.61 (m, 1 H), 3.88 (s, 3 H), 2.01 (s, 6 H), 1.89 -1.71 (m, 2 H), 1.71 -1.61 (m, 1 H), 1.02 (d, J = 6.4 Hz,

H), 0.98 (d, J = 6.4 Hz, 3 H). MS (M+1): 461.5.

Intermediate (117): (+/-)-6-((1-(3.5-dimethvl-4-(4-(trifluoromethvl)-1 H-pvrazol-1-vl)phenvt)-3methvlbutvl)amlno)nlcotlnic acid

To a solution of Intermediate (116) (197 mg, 0,428 mmol) in tetrahydrofuran (2.14 mL) and methanol (2.14 mL) was added 1 N aq sodium hydroxide (2.14 mL, 2.14 mmol). After 22 h, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 3.5. The mixture was diluted with sat. aq sodium chloride (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure to provide (+/-)-6-((1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)-3methylbutyl)amino)nicotinic acid. ’H NMR (400 MHz, CDCI₃, δ): 8.71 (s, 1 H), 8.16 (d, J = 9.0 Hz, 1 H), 7.94 (s, 1 H), 7.75 (s, 1 H), 7.14 (s, 2 H), 6.40 (d, J = 9.2 Hz, 1 H), 4.55 - 4.48 (m, 1 H), 2.02 (s, 6 H), 1.99-1.91 (m, 1 H), 1.89-1.77 (m, 1 H), 1.71 -1.60(m, 1 H), 1.03 (d,J = 6.6 Hz, 3 H), 0.98 (d, J= 6,6 Hz, 3 H). MS (M+1): 447.5.

Intermediate (118): ethvl (fî)-3-(6-((1-i3.5-dimethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1-vl)phenvl)-3meÎhylbutvl)amlno)nlcotinamido)DroDanoate and Intermedaite (119): ethvl (S)-3-(6-((1-(3,5-dlmethvl-4-(4(ίηίΙυοΓθΠΊΒίΐΊνΙ)-1Η-ονΓ3ζοΙ-1-νΙ)ρΐΊΒηνΙ)-3-Γη6ίΐΊνΙΡυίνΙ) amino)nicotinamido)Dropanoate

To a mixture of Intermediate (117) (183 mg, 0.410 mmol), β-alanine ethyl ester hydrochloride (99.4 mg, 0.615), and 1-hydroxy-7-azabenzotriazole (69.0 mg, 0.492 mmol) in

dichloromethane (4.10 mL) was added triethylamine (0.172 mL, 1.23 mmol) followed by Λ/-(3dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (95.8 mg, 0.492 mmol). After 20 hours, additional β-alanine ethyl ester hydrochloride (99.4 mg, 0.615), 1-hydroxy-7-azabenzotriazole (69.0 mg, 0.492 mmol), triethylamine (0.172 mL, 1.23 mmol), /V-(3-dimethylaminopropyl)-/Vethylcarbodiimide hydrochloride (95.8 mg, 0.492 mmol), and dichloromethane (2.10 mL) were added. After 7 hours, the mixture was diluted with dichloromethane (20 mL) and washed with water (3 x 20 mL) and sat. aq sodium chloride (20 mL). The organic layer was dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) followed by SFC (Chiralpak OD-H column, 10 mm x 250 mm, 15% 2-propanol / carbon dioxide eluent) gave ethyl (R)-3-(6-((1-(3,5-dimethyl-4-(4(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)-3-methylbutyl)amino)nicotinamido) propanoate (SFC rétention time 4.54 min) and ethyl (S)-3-(6-((1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenyl)-3-methylbutyl)amino)nicotinamido) propanoate (SFC rétention time 6.94 min). ’H NMR (400 MHz, CDCIa, δ): 8.49 (d, J = 1.6 Hz, 1 H), 7.92 (s, 1 H), 7.77 (dd, J = 8.8, 2.3 Hz, 1 H), 7.74 (s, 1 H), 7.09 (s, 2 H), 6.71 (t, J = 5.9 Hz, 1 H), 6.24 (d, J = 8.8 Hz, 1 H), 5.55 (br. s., 1 H), 4.68 (d, J = 6.4 Hz, 1 H), 4.16 (q, J = 7.0 Hz, 2 H), 3.67 (q, J « 5.9 Hz, 2 H), 2.60 (t, J = 5.9 Hz, 2 H), 1.98 (s, 6 H), 1.80 -1.67 (m, 2 H), 1.67 - 1.56 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.99 (d, J = 6.2 Hz, 3 H), 0.96 (d, J = 6.2 Hz, 3 H). MS (M+1): 546.4.

An asymmetric synthesis of ethyl (H)-3-(6-((1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenyl)-3-methylbutyl)amino)nicotinamido) propanoate may also be achieved by utilizing (S)-(-)-2-methyl-2-propanesulfinamide and Intermediate (112), analogous to that described for the préparation of Intermediate (113). Ethyl (/7)-3-(6-((1-(3,5-dimethyl-4-(4(trifluoromethyl)-lH-pyrazol-1-yl)phenyl)-3-methylbutyl)amino)nicotinamido) propanoate may then be prepared analogous to the racemic route.

Intermediate (120): methyl 4-(tetrahydro-2H-pvran-4-carbonvl)benzoate

O

Step A: To a solution of methyl 4-iodobenzoate (1.21 mL, 7.24 mmol) in THF (12 ml) at -40 °C was added TurboGrignard (1.3 M in THF,6.13 ml, 7.97 mmol) dropwise. The mixture was stirred for approximately 60 minutes whereupon, tetrahydro-2H-pyran-4-carbaldehyde (0.761 ml, 0.724 mmol) was added dropwise. The mixture was stirred for 15 minutes and slowly warmed to rt over 12 hours. The reaction was quenched with HCl (1 N, aq.) and the aq. layer was extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to provide ethyl 4-(hydroxy(tetrahydro-2H-pyran-4yl)methyl)benzoate. Crude mixture used into the next step without any further purification, step B:

A round bottom flask was charged with ethyl 4-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)benzoate (1.9 g, 7.2 mmol), the Dess-Martin reagent (3.66 g, 8.63 mmol) and DCM (15 mL). The reaction was stirred at room température overnight. Reaction diluted with DCM and solid filtered off. The mother liquor concentrated and loaded onto a silica gel column. Purification by silica gel flash chromatography (ethyl acetate ! DCM) provide methyl 4-(tetrahydro-2H-pyran-4-carbonyl)benzoate (290 mg, mmol) as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 1.75 - 1.96 (m, 4 H) 3.45 - 3.62 (m, 3 H) 3.97 (s, 3 H) 4.07 (dt, J=11.88, 3.25 Hz, 2 H) 7.98 - 8.02 (m, 2 H) 8.12 - 8.17 (m, 2 H); MS (M1):246.8.

Intermediate (121): (±)-methvl 4-((tetrahvdro-2H-pvran-4-vl)((6-(4-(trifiuoromethyl)-1 H-pyrazol-1 -vBovridin-3vl)amino)methvl)benzoate cf₃

A round bottom flask was charged with methyl 4-(tetrahydro-2H-pyran-4-carbonyl)benzoate (150 mg, 572 mmol),6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-amine (130 mg, 572 mmol) and MeOH (1.2 mL). Decaborane reagent (26.4 mg, 229 mmol) was added in one portion and the reaction stirred over the week-end. The reaction mixture was quenched with HCl solution (1 N, aq.) and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate / heptane) provide (±)-methyl 4-((tetrahydro-2H-pyran-4-yl)((6-(4-(trifluoromethyl)1 H-pyrazol-1-yl)pyridin-3-yl)amino)methyl)benzoate (206 mg, 78%) as a colorless gum. MS (M+1):

461.3.

Intermediate (122): ethyl 3-(4-pivalovlbenzamido)oropanoate:

o

Step A: A round bottom flask was charged with the ethyl 4-iodobenzoate (10 g, 36 mmol) and THF (45 mL). Solution cooled down to 0 °C. Turbo Grignard 1.3 M in THF (30.6 mL, 39.8 mmol) was then added in one portion and the reaction stirred for 30 minutes at 0 °C. Pivaloyl chloride (5.35 mL, 43.5 mmol) was then charged in a second flask in THF (10 mL) and the preformed anion transferred via canula to the acyl chloride. The reaction was then slowly warmed to room température and stirred overnight. The reaction was quenched with ammonium chloride solution (sat. aq.) and extracted with ethyl acetate (2X), washed with brine (1X), dried over sodium sulfate, filtered and concentrated to provide ethyl 4-pivaloylbenzoate as a crude yellow gum (8.50 g). Used without further purification. ¹H NMR (400 MHz, CDCI₃) δ 1.30 - 1.36 (m, 9 H) 1.42 (t, J=7.04 Hz, 3 H) 4.40 (q, J=7.24 Hz, 2 H) 7.61 - 7.69 (m, 2 H) 8.04 - 8.12 (m, 2 H); MS (M): 234.

Step B: A round bottom flask was charged with ethyl 4-pivaloylbenzoate (7.67 g, 32.7 mmol), THF (100 mL) and MeOH (100 mL). Sodium hydroxide 1N, aq. (65.5 mL, 65.5 mmol) was then added in one portion. Reaction stirred at 40 °C for 1 hour. Organic solvent removed under reduced pressure and water (150 mL) added to the flask. Acidification with HCl 1N aq. to ca. pH 1 followed by filtration of the solid formed over a büchner funnel provide 4-pivaloylbenzoic acid as a light yellow solid (9.25 g). ¹H NMR (400 MHz, DMSO-d₆) δ 1.25 -1.27 (m, 9 H) 7.70 - 7.74 (m, 2 H) 7.97 - 8.01 (m, 2 H) 13.00 (br. s., 1 H); MS (M-1): 205.3.

Step C: A round bottom flask was charged with 4-pivaloylbenzoic acid (7.67 g, 37.2 mmol), ethyl

3-aminopropanoate hydrochloride (6.86 g, 44.6 mmol), HOAT (5.57 g, 40.9 mmol), DCM (93 mL) and TEA (7.80 mL, 55.8 mmol). EDC hydrochloride (7.92 g, 40.9 mmol) was then added in one portion and the reaction allowed to stir at room température for 2 hours. DCM added to the reaction mixture and organics washed with an ammonium chloride solution (sat.aq.; 1X), water (2X), brine (1X), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate / heptane) provide ethyl 3-(4-pivaloylbenzamido)propanoate as a yellow oil (4.25 g, 37.4%; over 3 steps). ¹H NMR (400 MHz, CDCI₃) δ 1.26 (m, J=7.02, 7.02 Hz, 3 H) 1.32 (s, 9 H) 2.63 (t, J=5.95 Hz, 2 H) 3.72 (m, J=6.05, 6.05, 6.05 Hz, 2 H) 4.16 (m, J=7.22, 7.22, 7.22 Hz, 2 H) 6.92 (br. s., 1 H) 7.64 - 7.68 (m, 2 H) 7.75 - 7.79 (m, 2 H); MS (M+1): 306.3.

Intermediate (123) (±)-ethvl 3-(4-f2.2-dimethvl-1-f(6-(4-(trifluoromethvl)-1H-pyrazol-1-vl)DvridÎn-3vl)amino)Dropyl)benzamido)proDanoate

A round bottom flask was charged with Intermediate (32) (1.12 g, 4,91 mmol), ethyl 3-(4pivaloylbenzamido)propanoate (1.50 g, 4.91 mmol), decaborane (309 mg, 2.46 mmol) and MeOH (12 mL). Reaction mixture stirred overnight at room température. The mixture was quenched with

1N HCl and extracted with EtOAc (2X). The combined organic layers were washed with brine (1X), dried over Na₂SO₄₁ filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate / heptane) provide (+)-ethyl

3-(4-(2,2-dîmethyl-1 -((6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)amino)propyl) benzamido)propanoate as an orange gum (1.97 g, 77.5%). ¹H NMR (400 MHz, CDCI₃) δ 1.05 (s, 9 H) 1.27 (t, J=7.12 Hz, 3 H) 2.59 - 2.67 (m, 2 H) 3.72 (q, J=6.18 Hz, 2 H) 4.12 - 4.21 (m, 3 H) 6.83 (t, J=5.95 Hz, 1 H) 6.90 (dd, J=8.78, 2.34 Hz, 1 H) 7.37 (d, J=8.00 Hz, 2 H) 7.65 (d, J=8.78 Hz, 1 H) 7.71 (d, J=8.58 Hz, 2 H) 7.76 (br. s., 1 H) 7.79 (s, 1 H) 8.67 (s, 1 H); MS (M+1): 518.4.

Intermediate (124) (±)-ethvl 3-i4-(2.2-dimethvl-1-((6-(4-(trifluoromethvl)-1 Η·ίπΊΪά3ζοΙ-1-νΙ)ρντίΰίη-3vl)amino)propvl)benzamido)propanoate

A round bottom flask was charged with Intermediate (6) (747 mg, 3.28 mmol), 3-(4pivaloylbenzamidojpropanoate (1.00 g, 3.28 mmol), decaborane (206 mg, 1.64 mmol) and MeOH (8 mL). Reaction mixture stirred ovemight at room température. The mixture was quenched with 1N HCl and extracted with EtOAc (2X). The combined organic layers were washed with brine (1X). dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate / DCM) provide (±)-ethyl 3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1 Himidazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoate as an orange oil. ¹H NMR (400 MHz, DMSOd_e) δ 0.99 (s, 9 H) 1.16 (m, J=6.83, 6.83 Hz, 3 H) 2.54 (t, J=6.93 Hz, 2 H) 3.42 - 3.50 (m, 2 H) 4.00 - 4.08 (m, 2 H) 4.34 (d, J=8.39 Hz, 1 H) 6.55 (d, J=8.39 Hz, 1 H) 7.11 (dd, J=8.88, 2.83 Hz, 1 H) 7.42 - 7.48 (m, 3 H) 7.71 - 7.77 (m, 2 H) 7.89 (d, J=2.73 Hz, 1 H) 8.26 - 8.30 (m, 1 H) 8.38 (s, 1 H) 8.46 (t, J=5.56 Hz, 1 H); MS (M+1): 518.4.

Intermediate (125): 4-(5-fluoro-indazol-2-vl)-phenol

4-bromophenol (1.27 g, 7.35 mmol) was combined with 5-fluoro-1H-indazo!e (1.000 g, 7.35 mmol), Cul (69.9 mg, 0.367 mmol), KgPO₄ (3.282 g, 15.4 mmol), toluene (15 mL), and dimethylethylenediamlne (0.158 mL, 1.47 mmol). This was refluxed as a mixture for 3 d. The reaction was cooled and partitioned between ethyl acetate and sat. NH₄CI. The aqueous was extracted with ethyl acetate and the combined organics were dried over MgSO₄. Purification by silica gel flash chromatography (ethyl acetate in heptane)

gave 4-(5-fluoro-indazol-2-yl)-phenol (0.114 g) impure with the indazole starting material. Used as is. The other regioisomer was also observed but was separated by chromatography. MS (M+1): 229.2.

Intermediate (126): 4-(6-fluoro-indazol-2-vl)-Dhenol

4-bromophenol (1.27 g, 7.35 mmol) was combined with 6-fluoro-1H-indazole (1.000 g, 7.35 mmol), Cul (69.9 mg, 0.367 mmol), K₃PO₄ (3.282 g, 15.4 mmol), toluene (15 mL), and dimethylethylenediamrne (0.158 mL, 1.47 mmol). This was refluxed as a mixture for 3 d. The reaction was cooied and partitioned between ethyl acetate and sat. NH₄CI. The aqueous was extracted with ethyl acetate and the combined organics were dried over MgSO₄. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave 4-(6fluoro-indazol-2-yl)-phenol (0,129 g, 8%) as a tan sotid. The other regioisomer was also observed but was separated by chromatography. ¹H NMR (400 MHz, DMSO-d_e, δ): 9.86 (s, 1 H) 8.96 (s, 1 H) 7.75 - 7.91 (m, 3 H) 7.41 (d, J = 10.6 Hz, 1 H) 6.99 (td, J = 9.3, 2.2 Hz, 1 H) 6.93 (d, J = 8.8 Hz, 2 H); MS (M+1): 229.2. Intermediate (127): 4-(2H-indazol-2-vl)-3.5-dlmethviDhenol

Step A: (E)-4-((2-(hvdroxvmethvl)Dhenyl)diazenvl)-3,5-dimethvlDhenol

(2-aminophenyl)methanol (4000 mg, 32.48 mmol) was dissolved in water (25 mL) with concentrated HCI (6 N, 7.00 mL, 42.2 mmol) and the solution was cooled in an ice/NaCI bath to -5 °C, afterward sodium nitrite (2420 mg, 39 mmol) in 20 mL of water was added dropwise over 20 minutes. Solids precipitated out. The organic mixture/suspensîon was stirred at -5 °C->0 °C for 25 minutes. 5 mL CH₃CN was added. The solution of 3,5-dimethylphenol (3970 mg, 32.5 mmol) in CH₃CN (10 mL) was mixed with a solution of Na₂CO₃ (13.8 g, 130 mmol) in H₂O (20 mL). The mixed solution was added to the above diazonium solution slowly at -5 °C->0 °C. The mixture was stirred at at -5 °C->0 °C for 2 hours. Brownish solids precipitated out. The mixture was neutralized with conc. HCl (12 N) and diluted with EtOAc. The suspension filtered through colite and washed with EtOAc which was used for extraction. After four extractions, the combine dark brownish organic layers were washed with brine, dried over Na₂SO₄ and concentrated, leading to dark brownish solids. The crude was dissolved in EtOAc and loaded to the column and purified by ISCO (120 g silica gel, EtOAc/Heptane: 0->45%), leading the desired product as orange solids. ’H NMR (400 MHz, DMSO-de) δ ppm 2.42 (s, 6 H) 4.96 (d, J=5.66 Hz, 2 H) 5.14 - 5.25 (m, 1 H) 6.58 (s, 2

H) 7.29 - 7.36 (m, 1 H) 7.41 - 7.50 (m, 2 H) 7.65 (d, J=0.78 Hz, 1 H) 9.92 (s, 1 H). LCMS: m/z =

257.3 [M+HJ.

Step B: 4-(2H-indazol-2-vl)-3.5-dimethvlphenol lodine {3980 mg, 15.7 mmol) was added to the orange solution of (E)-4-((2-(hydroxymethyl)phenyl)diazenyl)-

3,5-dimethylphenol (2680 mg, 10.46 mmol), triphenylphosphine (4110 mg, 15.7 mmol) and imidazole (2140 mg, 31.4 mmol) in tetrahydrofuran (30 mL) at room température. The mixture was stirred for 40 minutes. The solvent was evaporated. The crude was dissolved in EtOAc/MeOH and loaded to the column and purified by ISCO (40 g silica gel, EtOAc/heptane: 0->50%), leading to the desired product as a white/pale yellow solid. ’H NMR (400 MHz, CDCI₃) δ ppm 1.85 (s, 6 H) 6.49 (s, 2 H) 7.07 - 7.21 (m, 1 H) 7.32 - 7.42 (m, 1 H) 7.75 (d, J=8.58 Hz, 1 H) 7.80 (dd, J=8.78, 0.98 Hz, 1 H) 7.96 (d, J=0.78 Hz, 1 H) 7.99 (s, 1 H). LCMS: m/z = 239.2 [M+H],

Intermediate (128): 1-(6-i4-itrifluoromethvl)-1H-Dvrazol-1-vl)pvridin-3-vl)butan-1-ol

OH

Step A: 1-(6-chloroDvridin-3-yl)butan-1-ol

Cl

To a -10 °C solution of 6-chloronicotinaldehyde (553 mg, 3.91 mmol) in 3.5 mL THF was added npropylmagnesium bromide (2.34 mL of a 2.0 M solution in THF, 4.69 mmol). The solution was stirred at -10 °C for 10 min, and was then allowed to warm to room température. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was concentrated. The crude residue was purified by silica gel chromatography to give 1-(6chloropyridin-3-yl)butan-1-ol (400 mg) as a yellow oil. ’H NMR (400 MHz, CDCI₃) δ 8.24-8.31 (m, 1H), 7.617.67 (m, 1H), 7.25-7.30 (m, 1H), 4.68-4.74 (m, 1H), 2.05-2.26 (brs, 1 H), 1.69-1.82 (m, 1H), 1.57-1.68 (m, 1H), 1.19-1.49 (m,2H),0.91 (t,J=7.43Hz, 3H).

Step B: 1-(6-chloropyridln-3-v))butan-1-one 'Cl

To a solution of_1-(6-chloropyridin-3-yl)butan-1-ol (210 mg, 1.13 mmol) in 10 mL dichloromethane was added 2g of silica gel, followed by pyridinium chlorochromate (488 mg, 2.26 mmol) The mixture was stirred at room température 5h. The mixture was filtered through a plug of silica gel, eluting with 100 mL dichloromethane. The eluent was concentrated to give 1-(6-chloropyridin-3-yl)butan-1-one (210 mg). ’H NMR (400 MHz,

CDCI₃) 6 8.88-8.96 (m, 1H), 8.14-8.20 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 2.92 (t, J=7.2 Hz, 2H), 1.70-1.82 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).

Step C: 1-(6-(4-(trifluoromethyl)-1 H-Dvrazol-1-vl)pvridin-3-vl)butan-1-one

A mixture of 4-(trifluoromethyl)pyrazole (116 mg, 0,85 mmol), 1-(6-chloropyridîn-3-yl)butan-l-one (130 mg, 0.71 mmol), and potassium carbonate (294 mg, 2.12 mmol) was stirred 4h at 50 °C. The mixture was cooled to room température and stirred overnight. The mixture was partitloned between ethyl acetate and water. The organic layer was dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (200 mg) as a colorless solid. ¹H NMR (400 MHz, CDCI₃) 5 8.97-8.99 (m. 1H), 8.90-8.91 (m, 1H), 8.39 (dd, J= 8.5,2.4 Hz, 1H), 8.08 (dd, J=8.58, 0.78 Hz, 1H), 7.93 (s, 1H), 2.94 (t, J=7.4 Hz, 2H), 1.74-1.85 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Step D: 1-(6-(4-(trifluoromethvl)-1H-pvrazol-1-vl)pyridin-3-vl)butan-1-ol

1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (140 mg, 0.49 mmol) was dissolved in 5 mL methanol. Sodium borohydride (18.7 mg, 0.494 mmol) was added. The reaction mixture was concentrated and the residue partitioned between water and ethyl acetate. The organic layer was concentrated to give 1(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-ol (140 mg). ’H NMR (400 MHz, CDCI_a) δ 8.84 (s, 1H), 8.34-8.40 (m, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.82-7.90 (m, 2H), 4.75-4.82 (m, 1H), 1.64-1.89 (m, 2H), 1.27-1.53 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Intermediate (129): 2-(4-itrifluoromethvl)-1H-lmidazol-1 -vl)Dvrimidin-5-amine

A mixture of 4-(trifluoromethyl)-1H-imidazole (572 mg, 4.2 mmol) 5-bromo-2-ch!oropyrimidine (813 mg, 4.20 mmol) and potassium carbonate (1740 mg, 12.6 mmol) in DMF (5 mL) was heated at 85 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. A mixture of this crude residue (376 mg), copper(l) iodide (61,1 mg, 0.32 mmol), 4-hydroxy-L-proline (84.1 mg, 0.64 mmol) and potassium carbonate (537 mg, 3.85 mmol) was purged with nitrogen. Dimethyl sulfoxide (2.5 mL) was added followed by ammonium hydroxide (1.40 mL, 28% aqueous solution). The mixture was heated at 75 °C for 20 hours. The mixture was diluted with 1 N HCl and extracted with ethyi acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to the provide 2-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-5-amine. ’H NMR (400 MHz, CDCIg) 3.86 (br s, 2H), 8.13 - 8.15 (m, 1 H), 8.15 (s, 2H), 8.50 (s, 1 H). LCMS: m/z = 230.1 [M+HJ.

Préparation of compounds of Formula I

Example 1 : (+/-) -3-(4- ( 1 -(3-methvl-4- (4- (trifluoromethyl) -1 H-imidazol-1 -yl) phenvlamino)butvl)benzamido)propanoic acid

Step A: i+/-)-methvl-4-(1-(3-methyl-4-(4-(trifluoromethvl)-1H-imidazol-1-

To a solution of Intermediate (21) (24Θ mg, 1.2 mmol) and Intermediate (4) (290 mg, 1.2 mmol) in methanol (12 mL) was added decaborane (44.1 mg, 0.36 mmol) at room température under nitrogen. The resulting solution was stirred at room température overnight. The reaction was concentrated and purification by column chromatography (0 - 35% ethyl acetate in heptane), gave (+/-)-methyl-4-(1 -(3-methyl-4-(4-(trifluoromethyl)-1 H-imÎdazol-1 -yl)phenylamino)butyl)benzoate as a foam. ¹H NMR (500 MHz, CDCl₃, δ): 8.02 (d, J = 8.29 Hz, 2H)_r 7.48 (s, 1 H), 7.42 (d, J = 8.29 Hz, 2H), 7.25 (s, 1 H), 6.90 (d, J = 8.54 Hz, 1 H), 6.41 (m, 1H), 6.34 (m, 1H), 4.40 (m, 2H), 3.91 (s, 3H),

1.98 (s, 3H), 1.72-1.87 (m, 2H), 1.34-1.52 (m, 2H), 0.96 (t, J = 7.32 Hz3H). MS (M+1): 432.4.

Step B: (+/-)-tert-butvl 3-(4-(1-(3-methyl-4-(4-(4-(trifluoromethyl)-1 H-imidazol-1vl)phenvlamino)butvl)benzamido)propanoate

To a solution of (+/-)-methyl-4-(1-(3-methyl-4-(4-(trifluoromethyl)-1 H-imidazol-1 yl)phenylamino)butyl)benzoate (0.100 g, 0.232 mmol) in methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL) was added lithium hydroxide (0.40 g, 9.2 mmol). The reaction was stirred at room température for 60 hours. The mixture was acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated.

To the crude residue was added /V./V-dimethylformamide (2 mL), beta-alanine tert-butyl ester hydrochloride (69.8 mg, 0.384 mmol) and O-^-Azabenzotriazol-l-yO-ty/V./V'./V'tetramethyluronium hexafluorophosphate (146 mg, 0.384 mmol). Diisopropylethylamine (99.3 mg, 0.768 mmol) was then added and the reaction was stirred at room température for 4 hours. The reaction was concentrated and purification by column chromatography (0 - 70% ethyl acetate in heptane), gave (+/-)-tert-butyl 3-(4-(1-(3-methyl-4-(4-(4-(trifluoromethyl)-1H-imidazol-1yl)phenylamino)butyl)benzamido)propanoate (92 mg, 88%). ’H NMR (500 MHz, CDCI₃, δ): 7.73 (d, J = 8.29 Hz, 2H), 7.46 (s, 1 H), 7.39 (d, J = 8.05 Hz, 2H), 7.24 (s, 1 H), 6.99 - 6.93 (m, 1 H), 6.89 -

6.85 (m, 1 H), 6.41 - 6.39 (m, 1 H), 6.34 - 6.30 (m, 1 H), 4.54 - 4.43 (m, 1 H), 4.41 - 4.31 (m, 1 H),

3.70-3.62 (m, 2H), 2.57-2.50 (m, 2H), 1.96 (s, 3H), 1.85-1.70 (m, 2H), 1.45 (s, 9H), 1.431.27 (m, 2H), 0.94 (t, J = 7.44 Hz, 3H). MS (M+1): 545.2.

Step C: (+/-)-3-(4-(1-(3-methyl-4-(4-(trifluoromethvl)-1H-imidazol-1vl)phenvlamino)butvl)benzarnido)propanoic acid

Trifluoroacetic acid (0.4 mL) was added to a solution of (+/-)-tert-butyl 3-(4-(1 -(3-methyl-4(4-(4-(trifluoromethyl)-1H-imîdazol-1-yl)phenylamino)butyl) benzamido)propanoate (58 mg, 0.11 mmol) in dichloromethane (0.6 mL). The mixture was stirred at room température overnight. The reaction was concentrated and successîvely evaporated from dichloromethane, ethyl acetate and toluene, to give (+/-)-3-(4-(1 -(3-methyl-4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenylamino) butyl)benzamido)propanoic acid (10 mg, 16%) as a solid. ’H NMR (400 MHz, CDCI₃, δ): 7.77 -

7.72 (m, 1 H), 7.72 - 7.68 (m, 2H), 7.40 - 7.35 (m, 2H), 7.30 - 7.25 (m, 1 H), 6.90 - 6.84 (m, 2H),

6.40 - 6.36 (m, 1 H), 6.33 - 6.28 (m, 1 H), 4.41 - 4.32 (m, 1 H), 3.82 - 3.67 (m, 2H), 2.75 - 2.66 (m, 2H), 1.97 (s, 3H), 1.89-1.73 (m, 2H), 1.49 - 1.31 (m, 2H), 0.94 (t, J = 7.44 Hz, 3H). MS (M+1):

489.2.

Example 2: (+/-)-3-(4-(3-methvl-1 -(4-(4-(trifluoromethvl)-1H-imidazol-1 -vDphenyl) butoxv)benzamido)propanoic acid

Step A: (+/-)-methvl 4-(3-methvl-1 -(4-(4-(trifluoromethvl)-1 H-imidazol-1 -vl)phenvl)butoxy)benzoate

F

Dimethylsulfoxide (1.5 mL) was added to a screw-top reaction vial charged with Intermediate (34) (128 mg, 0.339 mmol), 4-(trifluoromethyl)imidazole (55 mg, 0.406 mmol), copper(l) iodide (13 mg, 0.068 mmol), quinolin-8-ol (9.9 mg, 0.068 mmol), and potassium carbonate (92 mg, 0.67 mmol). The vial was evacuated and back-filled with nitrogen repeatedly then heated with stirring to 100°C overnight. After 18 hours the reaction was diluted with saturated ammonium chloride (20 mL) and ethyl acetate (20 mL). The phases were separated and the organic layer was washed with water (2 x 20 mL) and brine (5 mL). The organics were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography (0 - 50% ethyl acetate In heptanes) gave (+/—)-methyl 4-(3-methyl-1-(4-(4-(trifluoromethyl)’1H-imidazol-1yl)phenyl)butoxy)benzoate (65 mg, 44%) as a clear oil. ¹H NMR (400 MHz, CDCI₃, δ): 7.94-7,89 (m, 2H), 7.84 (s, 1 H), 7.58 (s, 1 H), 7.53 - 7.48 (m, 2H), 7.40 - 7.36 (m, 2H), 6.89 - 6.84 (m, 2H),

5.31 (dd, J = 9, 4.6 Hz, 1H), 3.86 (s, 3H), 2.04 (m, 1H), 1.96-1.83 (m, 1H), 1.67-1.59 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H). MS (M+1): 433.0.

Step B: (+/-)-4-(3-methvl-1-(4-(4-(trifluoromethvl)-1H-imidazol-1-vl)phenvl)butoxv) benzoicacid

O

Methyl 4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy) benzoate (65 mg, 0.15 mmol) was dissolved in methanol (1.5 mL) and 1M NaOH (0.75 mL) was added at room température. The resulting mixture was stirred overnight. The reaction mixture was diluted with water (10 mL), acidified with 1M HCl (1 mL) and extracted with ethyl acetate (2x10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give (+/-)-4-(3-mθthyl-1-(4-(4-(trifluoromethyl)-1H-imidazol·1-yl)phenyl)butoxy)benzoίc acid (65 mg, 100%) as a gum. ’H NMR (400 MHz, CDCI₃, δ): 7.98 (d, J = 9Hz, 2H), 7.88 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.58 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.33 (dd, J = 9, 4.6

Hz, 1H), 2.05 (m, 1 H), 1.96-1.83 (m, 1 H). 1.67-1.60 (m, 1 H), 1.04 (d, J =6.6 Hz, 3H), 0.99 (d, J-6.6 Hz, 3H). MS (M+1): 419.0.

Step C: (+/-)-methvl 3-(4-(3-methvl-1-(4-(4-(trifluoromethyl)-1H-imldazol-1vD phenyl) butoxv) benzam ido) propanoate

4-(3-Methyl-1-(4-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)phenyl)butoxy)benzoic acid (65 mg, 0.16 mmol), methyl beta-alanine hydrochloride (31 mg, 0.16 mmol), and triethylamine (0.031 mL) were dissolved in dichloromethane (1 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.18 mmol) was added. The solution was stirred at room température for 15 minutes, and 1-hydroxy-7-azabenzotriazole (34 mg, 0.25 mmol) was then added. The resulting yellow solution was stirred ovemight. After 18 hours, the reaction was diluted with ethyl acetate (20 mL) and washed with water (25 mL) and brine (10 mL). The organics were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography (0 - 100% ethyl acetate in heptane) gave (+/-)-methyl 3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1 yl)phenyl)butoxy)benzamido) propanoate (70 mg, 90%). ¹H NMR (400 MHz, CDCI₃, δ): 7.84 (s,

H), 7.67 - 7.62 (m, 2H), 7.58 (s, 1 H), 7.53 - 7.46 (m, 2H), 7.39 - 7.34 (m 2H), 6.89 - 6.84 (m,

2H), 6.72 (t, J = 5.9 Hz, 1 H), 5.29 (dd, J = 8.9, 4.5 Hz, 1 H), 3.72 - 3.65 (m, 5H), 2.63 (m, 2H), 2.03 (m, 1H), 1.95 — 1.83 (m, 1H), 1.65-1.58 (m, 1 H), 1.03 (d,J = 6.6 Hz, 3H), 0.99 (d,J = 6.3 Hz, 3H). MS (M+1): 504.0.

Step D: (+/-)-3-(4-(3-methvl-1-(4-(4-(trifluoromethvl)-1H-imidazol-1-yl)phenvl) butoxy)benzamido)propanoic acid

Methyl 3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl) butoxy)benzamido)propanoate (70 mg, 0.14 mmol) was dissolved in methanol (2 mL) and 1M lithium hydroxide (1 mL) was added. The reaction was stirred at room température for 1 hour. The methanol was removed under reduced pressure and the residue was diluted with water (2 mL). Upon stirring a precipitate forms. The solution was further diluted with water (15 mL) and 1M NaOH (3 mL). The solution was extracted with ether (20 mL). The organics were washed with water (10 mL) and the aqueous layers were combined. The aqueous solution was acidified with 1M HCl to give a cloudy solution. The solution was extracted with ethyl acetate (2x15 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give (+/-)-3-(4-(3-methyl-1(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzamido)propanoic acid (53.1 mg, 78%) as an off-white solid. ’H NMR (400 MHz, CDCI_a, δ): 7.89 (s, 1 H), 7.66 - 7.60 (m, 2H), 7.58 (s, 1H),

7.49 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.97 - 6.92 (m, 2H), 6.77 (t, J = 6 Hz, 1H), 5.29 (dd, J = 9, 4.4 Hz, 1H), 3.73-3.63 (m, 2H), 2.66-2.64 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.83 (m, 1 H), 1.62 (m, 1 H), 1.03 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H). MS (M+1): 490.2. Example 3: (+/-)-3-(6-(1-(4-(4-(trifluoromethvl)-1H-Pvrazol-1-vl)phenoxv)butvl) nicotinamidoloropanoic acid

Step A: (+/-)-5-bromo-2-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxv)butvl) pyridine

Br

Intermediate (36) (216 mg, 0.50 mmol), 4-trifluoromethylpyrazole (68 mg, 0.50 mmol), copper(l) iodide (19 mg, 0.10 mmol), frans-4-hydroxy-L-proline (26.2 mg, 0.20 mmol) and césium carbonate (329 mg, 1.00 mmol) were suspended in dimethylsulfoxide and heated to 85°C with stirring for 18 hours. The reaction was diluted with ethyl acetate (25 mL) and washed with water (2 x 25 mL) and brine (20 mL). The organics were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography (0 - 50% ethyl acetate in heptanes) gave 5bromo-2-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)pyridine (81 mg, 37%) asaclear oil. ’H NMR (400 MHz, CDCI₃, δ): 8.63 (d, J = 2.3 Hz, 1 H), 8.00 (br. s, 1 H), 7.82 (br. s, 1 H), 7.75 (dd, J = 8.4, 2.3 Hz, 1 H), 7.49 - 7.43 (m, 2H), 7.26 (d, overiaps with CHCI₃, 1 H), 6.94 - 6.88 (m, 2H), 5.22 (dd, J = 8.0, 4.9 Hz, 1 H), 2.03 - 1.86 (m, 2H), 1.62-1.38 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

Step B: (+/-)-ethvl 3-(6-(1-(4-(4-(trifluoromethvl)-1H-pyrazol-1-vl)phenoxv)butvl) nicotinamido)propanoate

5-Bromo-2-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)pyridine (81 mg, 0.180 mmol), ethyl 3-aminopropanoate hydrochloride (85 mg, 0,55 mmol), molybdenumhexacarbonyl (50 mg, 0.18 mmol), tri-tert-butylphosphonium tetrafluoroborate (8.4 mg, 0.028 mmol), palladium(ll) acetate (2 mg, 9 pmol), and 1,8-diazabicycloundec-7-ene (150 pL, 1.1 mmol) were placed in a microwave vial and suspended in dry acetonitrile (2 mL). The vial was capped and heated by a Biotage Initiator microwave to 170°C for 2 minutes. The resulting dark amber mixture was filtered through a Γ plug of silica gel, and eluted with ethyl acetate. The residue was concentrated and purification by column chromatography (0 -100% ethyl acetate in heptane) gave (+/-)-ethyl 3-(610 (1-(4-(4-(trrfluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)nicotinamido)propanoate (42 mg, 45%) as a pale amber glass. ¹H NMR (400 MHz, CDCI₃, δ): 8.63 (dd, J = 2.2, 0.9 Hz, 1 H), 8.01 - 7.97 (m, 2H), 7.82 (s, 1 H), 7.48 - 7.40 (m, 3H), 6.94 - 6.85 (m, 3H), 5.30 (dd, J = 7.90, 4.8 Hz, 1 H), 4.15 ( q, J = 7.2 Hz, 2H), 3.74 - 3.68 (m, 2H), 2.65 - 2.60 (m, 2H), 2.05 - 1.87 (m, 2H), 1.63 -1.39 (m, 2H), 1.28-1.23 (m, 3H), 0.96 (t, J = 7.4 Hz, 3H). MS (M+1): 505.4.

Step C: (+/-)-3-(6-(1-(4-(4-(trifluoromethvl)-1 H-pyrazol-1-vl)phenoxv)butvl) nicotinamido)propanoic acid (+/-)-Ethyl 3-(6-(1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)butyl) nicotinamido)propanoate (45 mg, 0.089 mmol) was dissolved in methanol (2 mL). 1 M NaOH (2 mL) was added with stirring at room température. After stirring for 6 hours, 1M HCl (2 mL) was added. The pH was adjusted to approximately 4, using 1M HCl and 1M NaOH. The resulting cloudy solution was extracted with ethyl acetate (2x15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give (+/-)-3-(6-(1 -(4-(4-(trifluoromethyl)-1 Hpyrazol-1-yl)phenoxy)butyl)nicotinamido)propanoic acid (42mg, 100%) as a foamy solid. ’H NMR (400 MHz, CDCI₃, ô): 9.23 (d, J = 1.6 Hz, 1 H), 8.38 (dd, J = 8.2, 2.1 Hz, 1 H), 7.99 (s, 1 H), 7.85 25 7.80 (m, 2H), 7.55 (d, 1 H), 7.49 - 7.42 (m, 2H), 6.92 - 6.85 (m, 2H), 5.31 (dd, J = 7.7,4.8 Hz, 1 H),

3.83 - 3.76 (m, 2H), 2.75 - 2.69 (m, 2H), 2.09 - 1.85 (m, 2H), 1.60 -1.39 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). MS (M+1): 477.3.

Example 4: (+/-)-3-i4-(4-methvl-1-(4-(4-(trifluoromethyl)-1H-ovrazol-1-vl)phenvl) pentan-2vl)benzamido)propanoic acid

Step A: methyl ^(Ι-Μ-όΓοηΊορήθηνΠ-Α-ΓηθΙΙ'ΊνΙρθηΜ-en-2-vl)benzoate

4-Bromobenzyltriphenylphosphonium bromide (2.07 g, 4.40 mmol) was suspended in toluene (4.0 mL) and cooled to 0°C. Lithium bis(trimethylsilyl)amide (4.04 mL, 1.0 M in toluene) was added. The ice bath was removed and the reaction was allowed to warm to room température and stîr for 1 hour. A solution of Intermediate (10) (180 mg, 0.817 mmol) in toluene (0.8 mL) was then added drop-wise, and the reaction was allowed to stîr for 18 hours. The reaction was diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted three times with ethyl acetate. The combined organics were washed twice with 1N HCl and once with brine, then dried over magnésium sulfate, filtered, and concentrated. The crude solid was taken up in heptane and the remaining solids (triphenylphospine oxide) were filtered off. The filtrate was concentrated and purified by column chromatography (0 -10% ethyl acetate in heptane) to give methyl 4-(1-(4bromophenyl)-4-methylpent-1-en-2-yl)benzoate (184.7 mg, 61%) as an approximate 1:1 mixture of E/Z isomers. Ή NMR (400 MHz, CDCI₃, δ): 8.04 - 8.00 (m, 2H), 7.97 - 7.92 (m, 2H), 7.50 - 7.46 (m, 4H), 7.22 - 7.16 (m, 6H), 6.77 - 6.72 (m, 2H), 6.69 (s, 1 H), 6.39 (s, 1 H), 3.92 (s, 3H), 3.90 (s, 3H), 2.58 (d, J = 7.4 Hz, 2H), 2.37 (dd, J = 7.2, 1.2 Hz, 2H), 1.68 - 1.57 (m, 1H), 1.51 (dt, J = 13.5,

6.8 Hz, 1 H), 0.88 (d, J = 6.6 Hz, 6H), 0.78 (d, J = 6.6 Hz, 6H).

Step B: methyl 4-(4-methvl-1-(4-(4-(trifluoromethvlM H-pyrazol-1-yl)phenyl)pent-1-en-2vDbenzoate

An oven-dried and nitrogen-cooled vial was chargad with 4-trifluoromethyl pyrazola (77.0 mg, 0.56 mmol), quinolin-8-ol (10mg, 0.07 mmol), copper(l) iodida (14 mg, 0.073 mmol), and potassium carbonate (140 mg, 1.0 mmol). A solution of methyl 4-(1-(4-bromophenyl)-4-methylpent1-en-2-yl)benzoate (182.7 mg, 0.489 mmol) in dimethylsulfoxide (2.5 mL) was then added. The vial was capped and evacuated and back-filled with nitrogen four times. The reaction was then heated to 90°C for 18 hours. The reaction was cooled to room température and partitioned between saturated ammonium chloride and ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organics were dried over magnésium sulfate, filtered, and concentrated. Column chromatography (0-10% ethyl acetate in heptane) provided methyl 4-(4-methyl-1-(4-(4(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoate (19.8 mg, 9.5%) as an approximate 1:1 mixture of E/Z isomers. ¹H NMR (400 MHz, CDCI₃, δ): 8.20 (s, 1H), 8.06 (s, 1H), 8.05 - 8.01 (m, 2H), 7.98 - 7.93 (m, 2H), 7.91 (s, 1 H), 7.83 (s, 1 H), 7.71 - 7.66 (m, 2H), 7.53 -

7.49 (m, 2H), 7.46 - 7.42 (m, 2H), 7.41 - 7.36 (m, 2H), 7.24 - 7.20 (m, 2H), 7.01 - 6.96 (m, 2H),

6.78 (s, 1 H), 6.49 (s, 1 H), 3.92 (s, 3H), 3.90 (s, 3H), 2.62 (d, J = 7.2 Hz, 2H), 2.41 (dd, J = 7.2, 1.0 Hz, 2H), 1.70 - 1.48 (m, 2H), 0.90 (d, J = 6.6 Hz, 6H), 0.80 (d, J = 6.6 Hz, 6H). MS (M+1): 429.3.

Step C: 4-(4-methvl-1-(4-i4“(trifluoromethvl)-1H-pvrazol-1-vl)phenvl)Dent-1-en-2-vl) benzoic acid

Methyl 4-(4-methyl-1 -(4'(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)pent-1 -en-2-yl)benzoate (19.8 mg, 0.0460 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). 1 N Sodium hydroxide (0.092 mL) was added and the reaction was stirred at room température for 60 hours. The reaction was concentrated. The crude residue was taken up in water and acidified to pH = 2 with 1N HCl. This solution was extracted four times with ethyl acetate, dried over magnésium sulfate, filtered, and concentrated to provide 4-(4-methyl-1-(4-(4'(trifluoromethyl)-1H-

pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoicacid (18.3 mg, 96%) as an approximate 1:1 mixture of E/Z isomers. Ή NMR (400 MHz, CD₃OD, δ): 8.76 (s, 1H), 8.62 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H),

7.98 (s, 1 H), 7.97 - 7.93 (m, 2H), 7.90 (s, 1 H), 7.85 - 7.79 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.54 7.47 (m, 4H), 7.30 - 7.24 (m, 2H), 7.06 - 7.00 (m, 2H), 6.84 (s, 1 H), 6.56 (s, 1 H), 2.70 (d, J = 7.2 Hz, 2H), 2.46 (dd, J= 7.2,1.0 Hz, 2H), 1.63 (dt, J= 13.5, 6.7 Hz, 1H), 1.57-1.46 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H), 0.80 (d, J = 6.6 Hz, 6H).

Step D: (+/-)-methvl 3-(4-(4-methvl-1-(4-(4-(trifluoronnethvl)-1H-pvrazol-1-vl)ohenyl)pentan-2vDbenzamidojpropanoate

To a solution of 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenyl)pent-1-en-2yl)benzoic acid (18.3mg, 0.0440mmol), methyl 3-aminopropanoate hydrochloride (6.70 mg, 0.0480 mmol), 1-hydroxy-7-aza benzotriazole (6.00 mg, 0.0440mmol), and triethylamine (6.6 pL, 0.047 mmol) in dichloromethane (0.5 mL), was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (8.50 mg, 0.0440 mmol). The reaction was stirred at room température for 18 hours. The reaction was diluted with dichloromethane and was washed with water and brine. The organic layer was dried over magnésium sulfate, filtered and concentrated.

This crude material was dissolved in methanol (15 mL) and was cycled through a THALES Nano H-cube (10% Pd/C catalyst cartridge, 50°C, full hydrogen setting, 1mL/min) for 2 hours. The crude réaction was concentrated. Purification by column chromatography (0 - 40% ethyl acetate in heptane) gave methyl 3-{4-(4-methyl-1-(4-(4-(trifluoromethyl)-l H-pyrazol-1 -yl)phenyl)pentan-2yljbenzamido) propanoate (4.2mg, 19%). ’H NMR (400 MHz, CDCI₃, δ): 8.10 (s, 1H), 7.85 (s, 1H),

7.65 - 7.60 (m, 2H), 7.48 - 7.42 (m, 2H), 7.14 - 7.09 (m, 2H), 7.06 - 7.00 (m, 2H), 6.79 - 6.72 (m, 1 H), 3.73 - 3.67 (m, 5H), 3.00 - 2.91 (m, 2H), 2.86 - 2.78 (m, 1 H), 2.66 - 2.61 (m, 2H), 1.67 (m, 1H), 1.52-1.43 (m, 1H), 1.38-1.27 (m, 1 H), 0.82 (dd, J = 6.5, 2.4 Hz, 6H). MS (M+1): 502.4.

Step E: (+/-)-3-(4-(4-methyl-1 -(4-(4-(trifluoromethvl)-1H-ovrazol-1-vl)phenvl)pentan-2vl)benzamido)propanoic acid

Methyl 3-(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pentan-2yl)benzamido)propanoate (4.2 mg, 0.0080 mmol) was dissolved in 1:1 methanol: tetrahydrofuran (0.50 mL). 1N NaOH (0.024 mL) was added and the reaction was stirred at room température for hours. The reaction was concentrated to dryness. The crude residue was taken up in water and acidified to pH = 2 with 1N HCl. This solution was extracted three times with ethyl acetate. The combined organics were dried over magnésium sulfate, filtered, and concentrated to give (+/-)-3(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pentan-2-yl)benzamido)propanoic acid (4.0 mg, 100%), as a white solid. ¹H NMR (400 MHz, CD₃OD, δ): 8.62 (s, 1 H), 7.91 (s, 1H), 7.69 -

7.64 (m, 2H), 7.58-7.53 (m, 2H), 7.22-7.17 (m, 2H), 7.14-7.09 (m, 2H), 3.62-3.55 (m, 2H), 3.09 - 2.96 (m, 2H), 2.90 - 2.81 (m, 1 H), 2.60 (t, J = 6.9 Hz, 2H), 1.78 - 1.68 (m, 1 H), 1.52 (ddd, J = 13.7, 9.2, 4.9 Hz, 1 H), 1.39-1.25 (m, 1H), 0.83 (dd, J = 6.4, 4.7 Hz, 6H). MS (M+1): 488.4.

Example 5: (+/-)-3-(4-(1-f6-(4-(trifluoromethvl)-1/-/-pvrazol-1-vl)pyridine-3vlamino)butvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (32). ’H NMR (400 MHz, CDCI₃, δ): 8.54 (s, 1 H), 7.83 (s, 1 H), 7.81 (d, J = 2.8 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.97 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.06 (t, J =

5.95 Hz, 1 H), 6.98 (dd, J = 8.97, 2.8 Hz, 1 H), 4.37 (t, J = 6.83 Hz, 1 H), 3.71 (m, 2 H), 2.70 (t, J =

5.85 Hz, 2 H), 1.92 - 1.72 (m, 2 H), 1.50 - 1.26 (m, 2 H), 0.93 (t, J = 7.32 Hz, 3 H). MS(M+1):

476.3.

Example 6: 3-(4-(1-(6-(4-itrifluoromethvl)-1H-pvrazol-1-vl)pvridine-3-vlamino)butvl) benzamido)propanoic acid. Isomer 1

The title compound is obtained by resolving racemic 3-(4-(1 -(6-(4-(trifluoromethyl)-1Hpyrazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoic acid Example 5, by chiral SFC.

Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 70/30 COa/methanol. Flow

Rate: 2.5 mL/min. Modifier: none. Rétention time: 4.05 minutes.

Example 7: 3-(4-(1 -(6-(4-(trifluoromethvl)-1 W-pyrazol-1 -vl)oyridine-3-vlamino)butvl) benzamido)propanoic acid. Isomer 2

The title compound is obtained by resolving racemic 3-(4-(1 -(6-(4-(trifluoromethyl)-1Hpyrazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoic acid, the compound of Example 5, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 70/30 COs/methanol. Flow Rate: 2.5 mLJmin. Modifier: none. Rétention time: 6.40 minutes. Example 8: (+/-)-3-(4-(cvclopentyl(6-(4-(trifluoromethvl)-1/-/-imidazol-1 -vl)pvridine-3vlamino)methvl)benzamido)Dropanoic acid

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (31) and Intermediate (6). ¹H NMR (400 MHz, CDCI₃₁ δ): 8.29 (s, 1 H), 7.81 (s, 1 H), 7.76 (d, J = 2.73 Hz, 1 H), 7.69 (d, J = 8.19 Hz, 2 H), 7.37 (d, J = 8.19 Hz, 2 H), 7.09 - 7.05 (m, 1 H), 6.96 - 6.90 (m, 1 H), 6.85 - 6.80 (m, 1 H), 4.14 (d, J = 8.39 Hz, 1 H), 3.73 - 3.66 (m, 2 H), 2.72-2.64 (m, 2 H), 2.24-2.14 (m, 1 H), 2.00-1.88 (m, 1 H), 1.75-1.20 (m, 7 H). MS (M+1): 502.2.

Example 9: (+/-)-3-(4-(1-(6-(4-(trifluoromethvl)-1H-imidazol-1-vl)vridine-3ylamino)butvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (6). Column: Waters Atlantis dC18 4.6x50mm, 5um. Modifier: TFA 0.05%.

Gradient: 95%H₂0 / 5%MeCN linear to 5%H₂0 / 95%MeCN over 4.0min, HOLD at 5%H₂0 !

95%MeCN to 5.0min. Flow: 2.0mL/min. Rétention time: 2.83 min. MS (M+1): 476.4.

Example 10: 3-(4-(1 -i6-(4-(trifluoromethvl)-1 H-imidazol-1 -vl) vridine-3ylamino)butyl)benzamido)propanoic acid. Isomer 1

100

The title compound is obtained by resolving racemic 3-(4-(1 -(6-(4-(trîfluoromethyl)-1Himidazol-1-yl) yridine-3-ylamino)butyl)benzamido)propanoic acid Example 9, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 CO^ethanol. Flow Rate: 2.5 mL/min. Modifier: none. Rétention time: 4.990 minutes.

Example 11: 3-(4-(1-(6-(4-(trifluoromethvl)-1H-imidazol-1-yl) vridine-3vlamino)butvl)benzamido)propanoic acid. Isomer 2

The title compound is obtained by resolving racemic 3-(4-(1-(6-(4-(trifluoromethyl)-1Himidazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoic acid Example 9, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 CCWethanol. Flow Rate: 2.5 mL/min. Modifier: none. Rétention time: 7.410 minutes.

Example 12: (+/-)-3-(4-(1 -(4-(4-(trifluoromethvl)-1 H-Pvrazol-1-vOohenvlamino)

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (5) and Intermediate (52). ¹H NMR (400 MHz, CDCI₃, δ): 7.91 (s, 1H), 7.78 (s, 1 H), 7.67 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.03 - 6.88 (m, 1 H), 6.60-6.42 (m, 2H), 4.33 (t, J = 6.3 Hz, 1H), 3.64 (s, 2H), 2.72-2.54 (m, 2H), 1.87-1.65 (m, 2H), 1.51 - 1.22 (m, 2H), 0.90 (t, J= 7.0 Hz, 3H). MS (M+1): 475.2.

101

Example 13: (+/-)-3-(4-(1 -(3,5-dimethyl-4-(4-(trifluoromethvl)-1 H-pyrazol-1 vl)phenvlamino)butvl)benzamido) propanoic acid

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (8). ¹H NMR (400 MHz, CDCI₃, δ): 7.91 (s, 1 H), 7.72 - 7.61 (m, 3 H), 7.39 (d, J = 8.00 Hz, 2 H), 7.21 - 7.12 (br. t, J = 5.6 Hz, 1 H), 6.49 (s, 2 H), 4.36 (m, 1 H), 3.75 - 3.59 (m, 2 H), 2.71 -2.57 (m, 2H), 1.91 -1.76 (m, 2 H), 1.84 (s, 6 H), 1.40-1.16 (m, 2 H), 0.88 (t, J = 7.32 Hz, 3 H). MS (M+1): 503.2.

Example 14: 3-(4-(1-(3,5-dimethvl-4-(4-(trifluoromethylMH-pyrazol-1 -vl) phenvlamino)butvl)benzamÎdo)propanoic acid. Isomer 1

NH

OH

The title compound is obtained by resolving racemic 3-(4-(1-(3,5-dimethyl-4-(4(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoicacid Example 13, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 75/25 CO2/2propanol. Flow Rate: 2.5 mL/min. Modifier: none. Rétention time: 3.77 minutes.

Example 15: 3-(4-(1-(3,5-dimethvl-4-(4-(trifluoromethvl)-1H-pyrazol-1-vl) phenvlamino)butvl)benzamido)propanoic acid. Isomer 2

NH

OH

The title compound is obtained by resolving racemic 3-(4-(1-(3,5-dimethyl-4-(4(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyi)benzamido)propanoicacid Example 13, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 75/25 00^2propanol. Flow Rate: 2.5 mL/min. Modifier; none. Rétention time: 4.62 minutes.

Example 16: (+/-)-3-(4-(1-(4-(4-(trifluoromethvl)-1H-imidazol-1-vl)phenylamino)

102

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (5) and Intermediate (54). ¹H NMR (400 MHz, CDCI₃, δ): 7.77 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.43 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2H), 7.06 (dt, J = 8.8, 3.5 Hz, 2H), 6.83 (t, J = 6.1 Hz, 1 H), 6.53 (dt, J = 8.8, 3.3 Hz, 2H), 4.38 (t, J = 6.7 Hz, 1 H), 3.73 (q, J = 6.0 Hz, 2H), 2.71 (t, J =

5.8 Hz, 2H), 1.88-1.73 (m, 2H), 1.53 - 1.31 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). MS (M+1 ): 475.2. Example 17: 3-(4-(1-(4-(4-(trifluoromethvl)-1H-imidazol-1-vl)phenvlamino)butvl) benzamidolpropanoic acid. Isomer 1

The title compound is obtained by resolving racemic 3-(4-(1 -(4-(4-(trifluoromethyl)-1 Himidazol-1-yl)phenylamino)butyl)benzamido)propanoic acid Example 16, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10mm x 250mm. Mobile Phase: 70/30 COa/methanol. Flow Rate: 10.0mL/min. Modifier: none. Rétention time: 7.25 minutes.

Example 18: 3-(4-(1-(4-(4-(trifluoromethvl)-1/7-imidazol-1-vl)phenvlamino) butvl)benzamido)propanoic acid, Isomer 2

The title compound is obtained by resolving racemic 3-(4-(1 -(4-(4-(trifluoromethyl)-1 Hίιτ^βζοΙ-Ι-νΟρίΊβηνΙβΓηίηοψυΙνΙ^θηζθίτ^οίρΓορΒηοίο acid Example 16, by chiral SFC. Column:

Chiralpak AD-H. Dimensions: 10mm x 250mm. Mobile Phase: 70/30 COa/methanol. Flow Rate:

10.0mL/min. Modifier: none. Rétention time: 8.80 minutes.

103

Example 19: (+/-)-3-(4-(1-(4-(4-(trifluoromethvl)-1H-lmidazol-1yl)phenoxv)butvl)benzamido)propanoic acid o o

Step A: (+/-)-methvl 4-(1-(4-(4-(trifluoromethvl)-1H-imidazol-1-vl)phenoxv) butvDbenzoate

A mixture of Intermediate (27) (130 mg, 0.32 mmol), 4-(trifluorornethyl)-1H-imidazole (50 mg, 0.37 mmol), quinolin-8-ol (7.0 mg, 0.048 mmol), copper(l) iodide (9.1 mg, 0.048 mmol), and potassium carbonate (90.0 mg, 0.65 mmol) in dimethylsulfoxide (1.5 mL) was stirred under nitrogen at 100°C overnight. The reaction mixture was cooled to ambient température and partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)-methyl 4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzoate (95 mg, 71%). ¹H NMR (400 MHz, CDCI₃, δ): 8.02 - 7.98 (m ,2H), 7.68 (s, 1 H), 7.44 - 7.42 (m, 1 H), 7.41 - 7.37 (m, 2H), 7.18-7.14 (m, 2H), 6.91 -6.86 (m, 2H), 5.18-5.12 (m, 1H), 3.88 (s, 3H), 2.07-1.94 (m, 1H), 1.87-1.75 (m, 1H), 1.60-1.36 (m, 2H), 0.98-0.91 (m, 3H).

Step B: i+/-)-4-i1-(4-(4-(trifluoromethyl)-1H-imidazol-1-vl)ohenoxv)butvl)benzoic acid

Lithium hydroxide (1.0 mL, 1N in water, 1.0 mmol) was added to a room température solution of methyl 4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzoate (95 mg, 0.23 mmol) in tetrahydrofuran (2 mL). The solution was stirred at ambient température for 18 hours, then at reflux for 2 hours. The mixture was cooled to room température and acidified to pH = 2 with 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was dried over magnésium sulfate, filtered and concentrated to give (+/-)-4-(1-(4-(4-(trifluoromethyl)-1H-imidazol16506

104

-yl)phenoxy)butyl)benzoic acid (80 mg, 87%). ¹H NMR (400 MHz, CDCh, δ): 8.09-8.04 (m, 2H),

7.71 (s, 1H), 7.46 — 7.41 (m, 3H), 7.20-7.14 (m, 2H), 6.92-6.87 (m, 2H), 5.20-5.14 (m, 1H), 2.08 -1.95 (m, 1 H), 1.88 - 1.76 (m, 1 H), 1.62-1.36 (m, 2H), 1.01 - 0.92 (m, 3H).

Step C: (+/-)-methvl 3-(4-(1 -(4-(4-(trifluoromethyl)-1 H-imidazol-1-vl)phenoxv)butvl) benzamidolpropanoate

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) was added to a room température solution of (+/-)-4-(1-(4-(4-(trifluoromethyl) -1H-imidazol-1yl)phenoxy)butyl)benzoic acid (80 mg, 0.20 mmol), methyl 3-aminopropanoate hydrochloride (28 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.22 mmol), and triethylamine (31 pL, 0.22 mmol) in dichloromethane (2 mL). The solution was stirred at room température overnight. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water, then brine. The organic layer was dried over magnésium sulfate, filtered and concentrated to give (+/-)-methyl 3(4-(1-(4-(4-(trifluoromethyl)-1 H-imidazol-1-yl)phenoxy)butyl) benzamido)propanoate (89 mg, 90%). Ή NMR (400 MHz, CDCI₃, δ): 7.74 - 7.70 (m, 2H), 7.69 - 7.66 (s, 1 H), 7.44 - 7.41 (m, 1 H), 7.40 -

7.36 (m, 2H), 7.18-7.13 (m, 2H), 6.91 -6.86 (m, 2H), 6.83-6.75 (m, 1H), 5.16-5.12 (m, 1H),

3.72 - 3.66 (m, 5H), 2.66 - 2.60 (m, 2H), 2.06 - 1.93 (m, 1 H), 1.86 - 1.74 (m, 1 H), 1.55-1.35 (m, 2H), 0.99-0.91 (m, 3H).

Step D: (+/-)-3-(4-(1 -(4-(4-(trifluoromethvl)-1 H-imidazol-1 -yDphenoxvlbutvl) benzamidojpropanoic acid

Lithium hydroxide (1.0 mL, 1N in water, 1.0 mmol) was added to a room température solution of (+/-)-methyl 3-(4-(1-(4-(4-(trifluoromethyl)-1 H-imidazol-1yl)phenoxy)butyl)benzamido)propanoate (89 mg, 0.18 mmol) in tetrahydrofuran (2 mL). The solution was stirred at room température 5 hours. The mixture was acidified to pH = 2 with 1N HCl, and extracted with ethyl acetate. The organic layer was dried over magnésium sulfate, filtered and concentrated to give (+/-)-3-(4-(1-(4-(4-(trifluoromethyl)-1 H-imidazol-1yl)phenoxy)butyl)benzamido)propanoic acid (84 mg, 98%). ’H NMR (400 MHz, CDCh, δ): 7.74-

7.68 (m, 3H), 7.45-7.41 (m, 1H), 7.39-7.34 (m, 2H), 7.18-7.12 (m, 2H), 6.91 -6.85 (m, 2H),

6.84 - 6.77 (m, 1 H), 5.17 - 5.11 (m, 1 H), 3.73 - 3.65 (m, 2H), 2.71 - 2.64 (m, 2H), 2.03 - 1.94 (m, 1H), 1.86-1.74 (m, 1H), 1.60-1.35 (m, 2H), 0.99 - 0.91 (m, 3H). MS (M+1): 475.9.

Example 20: (+/-)-3-(4-(1-(4-(4-(methvlthio)-1H-pvrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid

105

Copper iodide (1.31 g, 6.87 mmol), quînolin-8-ol (1.00 g, 6.87 mmol), and potassium carbonate (10.5 g, 76.0 mmol) were combined and pulverized. 78 mg of this mixture was added to 4-(methylthio)-1H-pyrazole (0.400 mmol) in a two dram vial. A solution of Intermediate (27) (123 mg, 0.300 mmol) in dimethylsulfoxide (0.500 mL) was added to the vial under a stream of dry nitrogen. The vial was capped and agitated on an orbital shaker at 120°C for 12 hours. The reaction mixture was concentrated in vacuo.

To the crude residue was added methanoi (2.0 mL), tetrahydrofuran (1.0 mL), and aqueous lithium hydroxide (2.0 M, 2.0 mL). The reaction was agitated on an orbital shaker at 60°C for 12 hours. The reaction mixture was concentrated in vacuo and the remaining crude residue was carefully acidified with 1.0M aqueous hydrochloric acid (5.0 mL). The resulting acidified mixture was concentrated in vacuo.

A mixture of tert-butyl 3-aminopropanoate hydrochloride (12.3 g, 67.7 mmol), 1hydroxybenzotriazole (6.89 g, 45 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (12.9 g, 67.3 mmol) was suspended in tetrahydrofuran (450 mL). A 3.0 mL aliquot of this solution was transferred to the crude acid from the previous transformation. Triethylamine (0.167 mL, 1.20 mmol) was added and the mixture was agitated on an orbital shaker overnight. The reaction mixture was treated with Si-diamine scavenger (ca. 5.0 eq) and was agitated for 12 hours on an orbital shaker. The reaction was filtered through a silica gel plug, washing with tetrahydrofuran (three times). The combined organic filtrate was concentrated in vacuo.

To the crude residue was added dichloromethane (4.0 mL), followed by trifluoroacetic acid (2.0 mL). The reaction was agitated on an orbital shaker for 12 hours. The reaction mixture was concentrated in vacuo. Purification by reversed-phase HPLC on a Waters Sunfire Cie 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(4-(methylthio)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (39.7 mg, 23% over 4 steps). Analytical LCMS: rétention time 3.25 minutes (Atlantis C_)B 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 454.0.

106

Example 21: (+/-)-3-(4-(1-(4-(3-fert-butvl-1H-pvrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 3-tert-butyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci_B 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(3-fert-butyl-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid (50.3 mg, 29% over 4 steps). Analytical LCMS: rétention time 3.71 minutes (Atlantis C_1B 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.0.

Example 22: (+/-)- 3-(4-(1-(4-(4-chloro-3-methvl-1H-pyrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 4-chloro-3-methyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C_1B19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)- 3-(4-(1 -(4-(4-chloro-3-methyl-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid (31.4mg, 18% over 4 steps). Analytical LCMS: rétention time 3.44 minutes (Atlantis Ci_B 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 456.0.

Example 23: (+/-)-3-(4-(1-i4-(4-chloro-1H-pyrazol-1-vl)phenoxv)butvl)benzamido) propanoic acid

107

The title compound was prepared by a method analogous to that described for Example 20 using 4-chloro-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C_1B19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(4-chloro-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (40.1 mg, 24% over 4 steps). Analytical LCMS: rétention time 3.31 minutes (Atlantis Cm 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mUminute); MS (M+1): 441.0.

Example 24: (+/-)-3-(4-(1 -(4-(4-ethvl-3-methvl-1 H-pyrazol-1 -vl)phenoxv)butvl) benzamldo)propanoic acid

NH

OH

The title compound was prepared by a method analogous to that described for Example 20 using 4-ethyl-3-methyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C_1B19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1 -(4-(4-ethyl-3-methyl-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid (15.2 mg, 9% over 4 steps). Analytical LCMS: rétention time 3.19 minutes (Atlantis Cm 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 450.0.

Example 25: (+/-)-3-(4-(1-(4-(3,5-diethvl-1 H-pyrazol-1-vl)phenoxv)butyl) benzamido)propanoic acid

NH

OH

The title compound was prepared by a method analogous to that described for Example 20 using 3,5-diethyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci_B 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1 -(4-(3,5-diethyl-1H-pyrazol-1yl)phenoxy)butyl)benzamido)propanoic acid (24.4 mg, 14.1 %). Analytical LCMS: rétention time

3.31 minutes (Atlantis C_1B 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mUminute); MS (M+1): 464.1.

Exampie 26: (+/-)-3-(4-(1-(4-(4-methyl-1H-pvrazol-1-vl)phenoxy)butvl)benzamido) prooanoic acid

108

The title compound was prepared by a method analogous to that described for Example 20 using 4-methyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Cw 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1 -(4-(4-methyl-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (57.5 mg, 36% over 4 steps). Analytical LCMS: rétention time 3.10 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 422.0.

Example 27: (+/-)- 3-(4-(1-(4-(3-isopropvl-1H-pvrazol-1-vl)phenoxy)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 3-isopropyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C_ie 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)- 3-(4-(1-(4-(3-isopropyl-1H-pyrazol-1yl)phenoxy)butyl)benzamido)propanoic acid (38.6 mg, 23% over 4 steps). Analytical LCMS: rétention time 3.43 minutes (Atlantis C₁₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 450.0.

Example 28: (+/-)-3-(4-(1 -(4-i4-fluoro-1H-pvrazol-1-yl)phenoxv)butvl)benzamido) propanoic acid

109

The title compound was prepared by a method analogous to that described for Example 20 using 4-fluoro-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(4-fluoro-1 H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (34.4 mg, 23% over 4 steps). Analytical LCMS: rétention time 3.25 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 454.0.

Example 29: (+/-)-3-(4-(1-(4-(3-methvl-1H-pvrazoi-1-yl)phenoxv)butyl)benzamido) propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 3-methyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C_1B19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1 -(4-(3-methyl-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid (52 mg, 32% over 4 steps). Analytical LCMS: rétention time 3.02 minutes (Atlantis Cw 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minuta); MS (M+1): 422.0.

Example 30: (+/-)-3-(4-(1-(4-(2H-1.2,3-triazol-2-vl)phenoxv)butvl)benzamido) propanoic acid

OH

Tha title compound was prepared by a method analogous to that described for Example 20 using 2H-1,2,3-triazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1 -(4-(2H-1,2,3-triazol-2-yl)phenoxy)butyl)benzamldo)propanoic acid (18.7 mg, 12% over 4 steps). Analytical LCMS: rétention time 3.07 minutes (Atlantis C₁₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 409.0.

Example 31 : (+/-)-3-(4-(1-(4-(3-butvl-1H-pyrazol-1-vl)phenoxv)butvl)benzamido) propanoic acid

110

The title compound was prepared by a method analogous to that described for Example 20 using 3-butyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(3-butyl-1 H-pyrazol-1-yl)phenoxy)butyl)benzamîdo)propanoic acid (15.3 mg, 9% over 4 steps). Analytical LCMS: rétention time 3.4 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.0.

Example 32: (+/-)-3-(4-(1-(4-(5-ethoxv-3-methvl-1H-pyrazol-1 -vl)phenoxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 5-ethoxy-3-methyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Cia 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(5-ethoxy-3-methyl-1 H-pyrazol-1yl)phenoxy)butyl)benzamido)propanoic acid (33.3 mg, 19 % over 4 steps). Analytical LCMS: rétention time 3.23 minutes (Atlantis C_w 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 466.0.

Example 33: (+/-)-3-(4-(1 -(4-(5-methoxv-3-methvl-1 H-pyrazol-1 -vDphenoxy)butyl) benzamido)propanoic acid

111

The title compound was prepared by a method analogous to that described for Example 20 using 5-methoxy-3-methyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(5-methoxy-3-methyl-1H-pyrazol-1yl)phenoxy)butyl)benzamido)propanoic acid (36.3 mg, 21% over 4 steps). Analytical LCMS: rétention time 3.07 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 452.0.

Example 34: (+/-)-3-(4-(1-(4-(4-butvl-1/-/-imidazol-1-vl)phenoxv)butyl)benzamido) propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 4-butyl-1H-imidazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(4-butyl-1H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (5.9 mg, 3% over 4 steps). Analytical LCMS: rétention time 2.45 minutes (Atlantis C₁₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 464.1.

Example 35: (+/-)-3-(4-(1 -(4-(2-cvano-3,4.5-trimethvl-1 H-pyrrol-1 -vl)phenoxv)butvl) benzamido)propanoÎc acid

The title compound was prepared by a method analogous to that described for Example 20 using 3,4,5-trimethyl-1H-pyrrole-2-carbonitrile. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈ 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1 -(4-(2-cyano-3,4,5-trimethyl-1H-pyrrol-1 yl)phenoxy)butyl) benzamido)propanoic acid (31.9 mg, 18% over 4 steps). Analytical LCMS: rétention time 3.6 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 pM column; 95 % water/acetonitrile linear

112 gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes;

0.05 % trifluoroacetic acid modifier; flow rate 2.0mUminute); MS (M+1): 474.0.

Example 36: (+/-)-3-(4-(1-(4-(3-cvano-2.4-dimethvl-1H-pyrrol-1 -yl) phenoxy) butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 2,4-dimethyl-1H-pyrrole-3-carbonitrile. Purification by reversed-phase HPLC on a Waters Sunfire C_1B 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(3-cyano-2,4-dimethyl-1H-pyrrol-1yl)phenoxy)butyl) benzamido)propanoic acid (19.9 mg, 12% over 4 steps). Analytical LCMS: rétention time 3.4 minutes (Atlantis C_1B 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mUminute); MS (M+1): 460.0.

Example 37: (+/-)-3-(4-(1-(4-(2-cvano-3-methvl-1H-pvrrol-1-vl)phenoxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 3-methyl-1H-pyrrole-2-carbonitrile. Purification by reversed-phase HPLC on a Waters Sunfire Cja 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(2-cyano-3-methyl-1H-pyrrol-1yl)phenoxy)butyl)benzamido)propanoic acid (37.1 mg, 22% over 4 steps). Analytical LCMS: rétention time 3.36 minutes (Atlantis C_1B 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 446.0.

Example 38: (+/-)- 3-(6-(1-(4-(3-propvl-1H-pvrazol-1-yl)phenoxv)butvl) nicotinamidolpropanoic acid

113

The title compound was prepared by a method analogous to that described for Example 20 using 3-propyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C₁₀19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)- 3-(6-(1-(4-(3-propyl-1H-pyrazol-1yl)phenoxy)butyl)nicotinamido)propanoic acid (4.4 mg, 3% over 4 steps). Analytical LCMS: rétention time 3.24 minutes (Atlantis Cj₀ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0ml_/mlnute); MS (M+1): 450.0.

Example 39: (+/-)-3-(4-(1-(4-(3.4-dimethvl-1H-pvrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 3,4-dimethyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C₁₀ 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(3,4-dimethyl-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid (22.8 mg, 14% over 4 steps). Analytical LCMS: rétention time 3.07 minutes (Atlantis C₁₀ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 436.

Example 40: (+/-)-3-(4-(1-(4-(1H-pyrazol-1-yl)phenoxv)butvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₀ 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (46.1 mg,

29% over 4 steps). Analytical LCMS: rétention time 2.93 minutes (Atlantis C_f8 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mLJmïnute);

MS (M+1): 408.0.

Example 41: (+/-)-3-(4-(1 -(4-(1 H-imidazo(1,2-blpvrazoM-vl)phenoxy)butyl) benzamido)propanoic acid

114

The title compound was prepared by a method analogous to that described for Example 20 using 1H-imidazo[1,2-b]pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(1 H-imidazo[1,2-b]pyrazol-1yl)phenoxy)butyl)benzamido)propanoic acid (29.6 mg, 18 % over 4 steps). Analytical LCMS: rétention time 2.74 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes;

0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 447.0.

Example 42: (+/-)-3-(4-(1-(4-(3-ethvl-1H-pvrazol-1-vl)phenoxv)butvl)benzamido) propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 3-ethyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1 -(4-(3-ethyl-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (10.0 mg, 6% over 4 steps). Analytical LCMS: rétention time 3.07 minutes (Atlantis C₁₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate

2.0 mL/minute); MS (M+1): 436.0.

Example 43: (+/-)- 3-(4-(1-(4-(4-chloro-5-methvl-1H-imidazol-1-vl)phenoxy)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20

115

using 4-chloro-5-methyl-1H-imidazole. Purification by reversed-phase HPLC on a Waters Sunfire

Ci819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)- 3-(4-(1 -(4-(4-chloro-5-methyl-1 H-imidazol-1yl)phenoxy)butyl)benzamido)propanoicacid (5.1 mg, 3% over 4 steps). Analytical LCMS: rétention time 2.48 minutes (Atlantis C₁₀ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 456.0.

Example 44: (+/-)-3-(4-(1-(4-Î4.5-diethvl-1H-imidazol-1-vl)phenoxv)butyl) benzamidolpropanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 4,5-diethyl-IH-imidazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci_S 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(4,5-diethyl-1H-imidazol-1yl)phenoxy)butyl)benzamido)propanoic acid (56.1 mg, 32% over 4 steps). Analytical LCMS: rétention time 2.50 minutes (Atlantis C_1B 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/ acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes;

0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.0.

Example 45: (+/-)-3-(4-(1-(4-(3,5-dimethvl-1H-pvrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid

116

The title compound was prepared by a method analogous to that described for Example 20 using 3,5-dimethyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire Cie 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(3,5-dimethyl-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid (42.0 mg, 25% over 4 steps). Analytical LCMS: rétention time 2.97 minutes (Atlantis C_1f} 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 436.0.

Example 46: (+/-)-3-(4-(1-(4-(3-methvl-1 H-1.2.4-triazol-1-vl)phenoxv) butyl) benzamido) propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 3-methyl-1H-1,2,4-triazole. Purification by reversed-phase HPLC on a Waters Sunfire C_ia 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave ¢+/-)-3-(4-(1-(4-(3-methyl-1 H-1,2,4-triazol-1yl)phenoxy)butyl)benzamido)propanoic acid (30.3 mg, 19% over 4 steps). Analytical LCMS; rétention time 2.58 minutes (Atlantis Cw 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 423.0.

Example 47: (+/-)-3-(4-(1-(4-(1 H-1 ^^-triazol-l-vDphenoxvIbutvDbenzamido) propanoicacid

The title compound was prepared by a method analogous to that described for Example 20 using 1H-1,2,4-triazole. Purification by reversed-phase HPLC on a Waters Sunfire C₁₀ 19 x 100 mm, 0.005 mm column eluting with a gradient of water în acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(1 H-1,2,4-triazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (44.2 mg, 28% over 4 steps). Analytical LCMS: rétention time 2.59 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 409.0.

Example 48: (+/-)-3-(4-(1-(4-(2-butvl-1H-imidazol-1-vl)phenoxv)butvl)benzamido) propanoic acid

117

OH

The title compound was prepared by a method analogous to that described for Example 20 using 2-butyl-1H-imidazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈ 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(2-butyl-1H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (82 mg, 47% over 4 steps). Analytlcal LCMS: rétention time 2.36 minutes (Atlantis Ci₈ 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.1.

Example 49: (+/-)-3-(4-(1-(4-(4.5-dimethvl-1H-imidazol-1-yl)phenoxy)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using 4,5-dimethyl-1H-imidazole. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(1-(4-(4,5-dimethyl-1H-imidazol-1yl)phenoxy)butyl)benzamido)propanoic acid (43.1 mg, 26% over 4 steps). Analytical LCMS: rétention time 2.19 minutes (Atlantis C_1s 4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 436.0.

Example 50: (+/-)-3-(4-(1-(4-(1-propyl-1H-pvrazol-4-vl)phenoxv)butvl)benzamido) propanoic acid

To 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (95.2 mg, 0.400 mmol) and PS-PPh₃-Pd (0.170 g, 0.017 mmol) in a microwave vial was added a solution of

Intermediate (27) (123 mg, 0.300 mmol) in dimethoxyethane (3.3 mL), followed by an aqueous

118 solution of potassium carbonate (2.0M, 1.7 mL). The vial was capped and heated to 100°C for 1 hour. The reaction mixture was filtered, the resin was washed with tetrahydrofuran (2 x 1.0 mL), and the combined organic filtrate was concentrated in vacuo.

To the crude residue was added methanol (2.0 mL), tetrahydrofuran (1.0 mL), and aqueous lithium hydroxide (2.0 mL, 2.0M). The reaction was agitated on an orbital shaker at 60°C for 12 hours. The reaction mixture was concentrated in vacuo and the remaining crude residue was carefully acidified with 1.0M aqueous hydrochloric acid (5.0 mL). The resulting acidified mixture was concentrated in vacuo.

A mixture of tert-butyl 3-aminopropanoate hydrochloride (12.3 g, 67.7 mmol), 1hydroxybenzotriazole (6.89 g, 45 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (12.9 g, 67.3 mmol) was suspended in tetrahydrofuran (450 mL). A 3.0 mL aliquot of this solution was transferred to the crude acid from the previous transformation. Triethylamine (0.167 mL, 1.20 mmol) was added and the mixture was agitated on an orbital shaker overnight. The reaction mixture was treated with Si-diamine scavenger (ca. 5.0 eq) and the mixture was agitated for 12 hours on an orbital shaker. The reaction was filtered through a plug of silica gel, rinsing with tetrahydrofuran (3 times). The combined organic filtrate was concentrated in vacuo.

To the crude residue was added dichloromethane (4.0 mL), followed by trifluoroacetic acid (2.0 mL). The reaction was agitated on an orbital shaker for 12 hours at ambient température. The crude reaction mixture was concentrated in vacuo. The crude material was purified by reversed-phase HPLC on a Waters Sunfire C₁₈19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) to give (+/-)-3-(4-(1-(4(1-propyl-1H-pyrazol-4-yl)phenoxy)butyl)benzamido)propanoîc acid (56.1 mg, 33% over 4 steps). Analytical LCMS: rétention time 3.11 minutes (Atlantis Cw 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 450.0.

Example 51 : (+/-)-3-(4-(1-(4-(1H-Pvrazol-3-yl)phenoxv)butvl)benzamido)propanoic acid

119

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈ 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave the desired product (3.8mg, 2% over 4 steps). Analytîcal LCMS: rétention time 2.65 minutes (Atlantis C₁₈ 4.6 x 50mm, 5μΜ column; 95% water/acetonîtrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 408.0.

Example 52: (+/-)-3-(4-(1-i4-Î3.5-dimethylisoxazol-4-vl)phenoxv)butyl)benzamido) propanoic acid

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4(1 -(4-(3,5-dimethylisoxazol-4-yl)phenoxy)butyl)benzamido)propanoic acid (40.3 mg, 24% over 4 steps). Analytîcal LCMS: rétention time 3.14 minutes (Atlantis Cw 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 437.0.

Example 53: (+/-)-3-(4-(1-(4-(1 -methvl“3-(trifluoromethvl)-1/-/-pyrazol-5-vl)phenoxv)

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈ 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4(1-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)butyl)benzamido)propanoic acid (53.5 mg, 30% over 4 steps). Analytîcal LCMS: rétention time 3.42 minutes (Atlantis Ci_B 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 490.0.

Example 54: (+/-)-3-(4-(1-(4-i1-methvl-1H-Dvrazol-4-vl)phenoxv)butvl)benzamido) propanoic acid

120

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4(1 -(4-(1 -methyl-1H-pyrazol-4-yl)phenoxy)butyl)benzamido)propanoic acid (2.5 mg, 2% over 4 steps). Analytical LCMS: rétention time 2.85 minutes (Atlantis Ci₈ 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 422.0.

Example 55: (+/-)-3-(4-(1-(4-(1,5-dimethvl-1H-pvrazol-4-vDphenoxv)butyl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈ 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4(1-(4-(1,5-dimethyl-1H-pyrazol-4-yl)phenoxy)butyl)benzamido)propanoic acid (7.0 mg, 4% over 4 steps). Analytical LCMS: rétention time 2.86 minutes (Atlantis C]₈ 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 436.0.

Example 56: (+/-)- 3-(4-(1-(4-(1 H-pvrazol-4-vl)phenoxv)butvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire Ci₈19 x 100mm, 0.005mm column

121 eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)- 3-(4(1 -(4-(1 H-pyrazol-4-yl)phenoxy)butyl)benzamido)propanoic acid (1.8 mg, 1% over 4 steps). Analytical LCMS: rétention time 2.62 minutes (Atlantis C₁₀ 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 408.0.

Example 57: (+/-)-3-(4-(1-(4-(1-methvl-1H-pyrazol-5-ynphenoxv)butvl)benzamido) oropanoic acid

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C₁₈19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4(1-(4-(1-methyl-1 H-pyrazol-5-yl)phenoxy) butyl)benzamido)propanoic acid (8.1 mg, 5% over 4 steps). Analytical LCMS: rétention time 2.85 minutes (Atlantis Ci_e 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 422.0.

Example 58: (+/-)-3-(4-(1-(4-(1.3.5-trimethvl-1H-pvrazol-4-vl)ph6noxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire Cw 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4(1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenoxy)butyl)benzamido)propanoic acid (21 mg, 12% over 4 steps). Analytical LCMS: rétention time 2.81 minutes (Atlantis Cia 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 450.0.

122

Example 59: (+/-)-3-(4-(1-(4-(4-itrÎfluoromethvl)-1H-Pvrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 19, using 4-(trifluoromethyl)-1H-pyrazole. ¹H NMR (400 MHz, CDCI₃, δ): 8.00-7.97 (m, 1 H), 7.84-

7.80 (m, 1 H), 7.73 - 7.68 (m, 2H), 7.46 - 7.36 (m, 4H), 6.90 - 6.84 (m, 2H), 6.77 - 6.70 (m, 1 H), 5.18-5.11 (m, 1H), 3.74-3.66 (m, 2H), 2.72-2.66 (m, 2H), 2.02-1.93 (m, 1H), 1.85-1.74 (m, 1H), 1.59-1.36 (m, 2H), 0.99-0.91 (m, 3H). MS (M-1 ):474.0.

Example 60: 3-(4-(1-(4-(4-(trifluoromethvl)-1H-pyrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid. Isomer 1

The title compound is obtained by resolving racemic 3-(4-(1 -(4-(4-(trifluoromethyl)-1 Hpyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid Example 59, by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 10mm x 250mm. Mobile Phase: 80/20 COz/methanol. Flow Rate: 10.0 mL/min. Modifier: none. Rétention time: 3.66 minutes.

Example 61: 3-(4-(1-(4-(4-(trifluoromethvl)-1H-pvrazol-1-vl)phenoxv)butvl) benzamido)propanoic acid. Isomer 2

The title compound is obtained by resolving racemic 3-(4-(1-(4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid Example 59, by chiral SFC. Column:

X

123

Chiralcel OJ-H. Dimensions: 10mm x 250mm. Mobile Phase: Θ0/20 CO^methanol. Flow Rate: 10.0 mL/min. Modifier: none. Rétention time: 4.81 minutes.

Example 62: (+/-)-3-(4-(1 -(6-(4-phenvl-1H-pvrazol-1 -yl)pvridine-3-ylamino)butvl) benzamido)propanoic acid

Step A: (+/-)-methvl 3-(4-(1-(6-(4-phenvl-1H-pvrazol-1-vl)pvridine-3vlamino)butvl)benzamido)propanoate

Intermediate (25) (42.1 mg, 0.178 mmol) was dissolved in methanol (0.8 mL). Intermediate (23) (54.4mg, 0.196mmol) was added, followed by decaborane (13.1 mg, 0.107 mmol). The reaction was stirred at room température for 18 hours and was then concentrated. Purification by column chromatography (20 -100% ethyl acetate in heptane) gave (+/-)-methyl 3-(4-(1-(6-(4-phenyl-1Hpyrazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoate (81.3 mg, 92%) as a white solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.61 (s, 1H), 7.90 (s, 1H), 7.76-7.66 (m, 4H), 7.53 (d, J = 7.2 Hz, 2H), 7.42 - 7.31 (m, 4H), 7.26 - 7.19 (m, 1 H), 6.94 (m, 1 H), 6.81 - 6.74 (m, 1 H), 4.41 - 4.34 (m, 1 H),

3.73 - 3.66 (m, 5H), 2.66 - 2.60 (m, 2H), 1.94 - 1.72 (m, 2H), 1.50 - 1.29 (m, 2H), 0.98 - 0.90 (m, 3H). MS (M+1): 498.4.

Step B: (+/-)-3-(4-(1-(6-(4-phenvl-1H-pvrazol-1-vl)pvridine-3-vlamino)butvl) benzamido)propanoic acid

Methyl 3-(4-(1 -(6-(4-phenyl-1 H-pyrazol-1 -yl)pyridine-3-ylamîno)butyl) benzamido)propanoate (82.1 mg, 0.165 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). 1N Sodium hydroxide (0.33 mL) was added and the reaction was stirred at room température for 24 hours. The reaction was then concentrated. The crude residue was taken up in water and acidified with 1N hydrochloric acid to pH = 3. A white precipitate formed. The soltds were filtered off and dried under vacuum to give (+/-)-3-(4-(1-(6-(4-phenyl-1 H-pyrazol-1 yl)pyridine-3-ylamino)butyl)benzamido)propanoicacid (61.6 mg, 77%) as an off-white solid. ¹H NMR (400 MHz, CD₃OD, δ): 8.57 (d, J = 1.0 Hz, 1 H), 7.96 (d, J = 0.8 Hz, 1 H), 7.78 - 7.69 (m, 3H),

7.61 - 7.50 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.38 - 7.31 (m, 2H), 7.24 - 7.16 (m, 1 H), 7.05 (dd, J

= 8.9, 3.0 Hz, 1 H), 4.48 - 4.41 (m, 1 H), 3.63 - 3.55 (m, 2H), 2.60 (t, J = 6.9 Hz, 2H), 1.94-1.69 (m, 2H), 1.58-1.33 (m, 2H), 0.96 (t, J= 7.4 Hz, 3H). MS (M+1): 484.4.

Example 63: (+/-)-3-(4-(1-(4-(4-fluoro-1 H-pyrazol-1-vl)phenvlamino)butvl) benzamidolpropanoic acid

124

The title compound was prepared by a method analogous to that described for Example 62 using Intermediate (12). ¹HNMR (400 MHz, CD₃OD, δ): 7.91 (d, 1H), 7.72 (d, 2H), 7.48 (d, 1H),

7.44 (d, 2H), 7.23 (d, 2H), 6.58 (d, 2H), 4.39 (m, 1 H), 3.59 (m, 2H), 2.60 (m, 2H), 1.84 - 1.80 (m, 1H), 1.74-1.68 (m, 1H), 1.50-1.48 (m, 1H), 1.40-1.35 (m, 1 H), 0.94 (m, 3H). MS (M+1): 425.3. Example 64: (+/-)-3-(6-(3-methvl-1 -(4-(4-(trifluoromethvl)-1H-pyrazol-1 vl)phenyl)butvlamino)nicotinamido)proDanoic acid

Step A: (+/-)-6-(3-methvl-1-(4-(4-(trifluoromethvl)-1H-pvrazol-1-vl)phenvl) butvlaminolnicotinic acid

A microwave reaction vial was charged with Intermediate (14) (180 mg, 0.605 mmol) and isopropanol (5 mL). Methyl 6-chloronicotinate (114 mg, 0.665 mmol) and diisopropylethylamine (313 mg, 2.42 mmol) were added. The resulting mixture was heated to 130°C for 15 hours under microwave irradiation. The mixture was concentrated and the crude residue was purified by column chromatography to give (+/-)-methyl 6-(3-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenyl) butylamino)nicotinate (30 mg).

To a solution of (+/—)-methyl 6-(3-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenyl)butylamino)nicotinate (30 mg, 0.069 mmol) in tetrahydrofuran (3 mL) was added lithium

125 hydroxide (0.103 mL, 2N in water, 0.207 mmol). The mixture was stirred at 50 C overnight. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(3-methyl-1 -(4-(4(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinic acid (25 mg, 87%) as a white solid. MS (M+1): 419.1.

Step B: (+/-)-methvl 3-(6-(3-methvl-1-(4-(4-(trifluoromethvl)-1H-pyrazol-1yl)phenvl)butvlamino)nicotinamÎdo)propanoate

F

To a solution of (+/-)-6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)butylamino)nicotinic acid (50 mg, 0.12 mmol) in /V./V-dimethylformamide (5 mL) was added 0-(7-Azabenzotriazol-1-yl)-A/_IN,N',N'-tetramethyluronium hexafluorophosphate (67.7 mg, 0.178 mmol). The mixture was stirred for 45 minutes. Methyl 3-aminopropionate hydrochloride (24.6 mg, 0.178 mmol) and diisopropylethylamine (61.5 mg, 0.476 mmol) were added. The resulting mixture was stirred at room température for 2 hours. The mixture was diluted with saturated ammonium chloride. The solution was extracted three times with ethyl acetate. The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated to give methyl 3-(6-(3-methyl-1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 83%) as a brown oil. MS (M+1): 504.1. Step C: (+/-)-3-(6-(3-methvl-1-f4-(4-(trifluoromethvl)-1H-pyrazol-1vl)phenvl)butvlamino)nicotinamido)propanoicacid

Methyl 3- (6- (3-methyl-1 - (4-(4- (trifluoromethyl)-1 H-pyrazol-1 -yl) phenyl) butylamÎno)nicotinamido)propanoate (50 mg, 0.099 mmol) was dissolved in water (5 mL) and tetrahydrofuran (5 mL). Lithium hydroxide (0.387 mL, 2N in water, 0.774 mmol) was added. The mixture was stirred at room température for 2 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150x30mm, 5pm; modifier: formic acid 0.225%: gradient: 10 to 80% acetonitrile in water) gave (+/—)-3-(6-(3-methyl-1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)butylamino) nicotinamido)propanoic acid (25 mg, 52%). ¹H NMR (400 MHz, CD₃OD, δ): 8.70 (s, 1 H), 8.40 (s, 1 H), 7.97 (s, 1 H), 7.82 (d, 1 H), 7.74 (d, 2H), 7.53 (d, 2H), 6.59 (d, 1 H), 5.12 - 5.02 (m, 1 H), 3.57 (m, 2H), 2.59 (m, 2H), 1.89-1.69 (m, 2H), 1.68-1.58 (m, 1H), 1.02 (d, 3H), 0.98 (d, 3H). MS (M+1): 490.5.

126

Example 65: (+/-)-3-(4-(2-cyclopropvl-1-(4-(4-(trifluoromethvh-1 H-pvrazol-1vl)phenoxv)ethvl)benzamido)propanoic acid

Step A: (+/-)-methvl 4-(2-cvclopropvl-1-(4-(4-itrifluoromethvl)-1H-pvrazol-1 vl)phenoxv)ethvl)benzoate

To a solution of Intermediate (16) (50.0 mg, 0.227 mmol), Intermediate (29) (62.2 mg, 0.272 mmol) and triphenylphosphine (120 mg, 0.454 mmol) in tetrahydrofuran (0.5 mL) was added diethylazodicarboxylate (79.1 mg, 0.454 mmol). The resulting mixture was stirred at room température overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave (+/-)methyl 4-(2-cyclopropyl-1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)ethyl)benzoate (32 mg,

33%). ’HNMR (400MHz, CDCI₃, δ): 7.95 - 7.93 (m, 3H), 7.79 (s, 1 H), 7.45 - 7.33 (m, 4H), 6.84 (d,

2H), 5.19 (m, 1H), 3.83 (s, 3H), 1.99-1.94 (m, 1 H), 1.64-1.55 (m, 1H), 0.79-0.69 (m, 1 H), 0.46 -0.42 (m, 2H), 0.10--0.10 (m, 2H).

Step B: (+/-)-methvl 3-(4-(2-cvclopropvl-1-(4-(4-(trifluoromethvn-1H-pyrazol-1vl)phenoxv)ethvhbenzamido)propanoate

127

To a mixture of (+/-)-methyl 4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenoxy)ethyl)benzoate (104 mg, 0.242 mmol) in methanol (1.2 mL) and water (0.2 L) was added lithium hydroxide monohydrate (50.08 mg, 1.21 mmol) at room température. The resulting mixture was stirred overnight. The reaction mixture was poured into water and actdified to pH = 6 with 1N hydrochloric acid. The solution was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in Ν,Νdimethylformamide (0.84 mL) and 0-(7-Azabenzotriazol-1-yl)-/V,/V,A/’,A/-tetramethyluronium hexafluorophosphate (95.8 mg, 0.252 mmoljwas added, followed by N-methylmorpholine (50.9 mg, 0.504 mmol). The reaction mixture was stirred for 30 minutes at room température. Methyl 3aminopropionate (23.4 mg, 0.168 mmol) was then added and the reaction was stirred for 48 hours. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)-methyl 3-(4-(2-cyclopropyl-1-(4(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoate (92 mg, 76%). MS (M+Na): 524.1.

Step C: (+/-)-3-(4-(2-cvclopropyl-1 -(4-(4-(trifluoromethvl)-1H-pvrazol-1vl)phenoxv)ethvl)benzamido)propanoic acid

To a mixture of methyl 3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenoxy)ethyl)benzamido)propanoate (92 mg, 0.18 mmol) in methanol (0.9 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (38.4 mg, 0.92 mmol). The resulting mixture was stirred at room température overnight. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to pH = 6. The mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave (+/—)-3-(4-(2-σνοΓορΓορνΙ-1 -(4-(4-(triffuoromethyl)-1/-/-pyrazol-1yl)phenoxy)ethyl)benzamido)propanoic acid (52 mg, 59%). ’HNMR (400 MHz, CD₃OD, δ): 8.47 (s, 1H), 7.82 (s, 1H), 7.70 (d, 2H), 7.50 (d, 2H), 7.42 (d, 2H), 6.92 (d, 2H), 5.34 (m, 1H), 3.53 (m, 2H), 2.48 (m, 2H), 1.98 -1.94 (m, 1 H), 1.60 -1.58 (m, 1 H), 0.75 - 0.77 (m, 1 H), 0.42 -0.33 (m, 2H), 0.08-0.01 (m, 2H). MS (M+Na): 510.3.

Example 66: (+/-)-3-(4-(cvclopentyl(4-f4-ftrifluoromethvl)-1 H-pyrazol-1 -vDohenoxy) methvl)benzamido)propanoic acid

128

The title compound was prepared by a method analogous to that described for Example 65 using Intermediate (37). ¹H NMR (400 MHz, CD₃OD, δ): 8.55 (s, 1 H), 7.92 (s, 1H), 7.78 (d, 2H),

7.57 (d, 2H), 7.51 (d, 2H), 6.99 (d, 2H), 5.15 (d, 1H), 3.64-3.60 (m, 2H), 2.65-2.61 (m, 2H), 2.50-

2.41 (m, 1H), 1.97-1.90 (m, 1H), 1.80-1.38 (m, 7H). MS (M+1): 502.3.

Example 67: 3-(4-(cvclopentyl(4-(4-(trifluoromethyl)-1H-pvrazol-1 vl)phenoxv)methvl)benzamido)propanoic acid. Isomer 1 o o

The title compound is obtained by resolvlng racemic 3-(4-(cyclopentyl(4-(4-(trifluoromethyl)1 H-pyrazol-1-yl)phenoxy) methyl) benzamido) propanoic acid Example 66, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 x 250mm. Mobile Phase: 70/30 COz/2-propanol. Flow Rate: 10.0 mL/min. Modifier: none. Rétention time: 4.24 minutes.

Example 68: 3-(4-(cvclopentvl(4-(4-(trifluoromethvl)-1 H-pyrazol-1 -vDphenoxv) methyllbenzamidolpropanoic acid. Isomer 2 o o

The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(4-(4-(trifluoromethyl)1H-pyrazol-1-yl)phenoxy)methyl)benzamido)propanoic acid Example 66, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 x 250mm. Mobile Phase: 70/30 CO₂/2-propanol. Flow Rate: 10.0 mL/min. Modifier: none. Rétention time: 6.00 minutes.

129

Example 69: (+/-)-3-(4-(cyclobutvl(4-(4-(trifluoromethvl)-1H-pyrazol-1vl)phenoxv)methvl)benzamido)Dropanoic acid

The title compound was prepared by a method analogous to that described for Example 65 using Intermediate (45). ¹H NMR (400 MHz, CD₃OD, δ): 8.56 (s, 1H), 7.92 (s, 1H), 7.77 (d, 2H),

7.58 (d, 2H), 7.48 (d, 2H), 7.01 (d, 2H), 5.27 - 5.25 (m, 1 H), 3.63 - 3.60 (m, 2H), 2.88 - 2.78 (m, 1 H), 2.65 - 2.59 (m, 2H), 2.21 - 2.00 (m, 3H), 2.00 - 1.70 (m, 3H). MS (M+1): 488.5.

Example 70: (+/-)- 3-(4-(1-(4-(3-(trifluoromethvl)-1H-pyrazol-1-vl)phenoxy)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 19 using 3-(trifluoromethyl)-1H-pyrazole. Analytical LCMS: rétention time 3.48 minutes (Waters Atlantis dCi₀4.6 x 50mm, 5pm column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 475.98.

Example 71: (+/-)-3-(4-(3,3-dimethvl-1-(4-(4-(trifiuoromethyl)-1H-pvrazol-1vl)phenoxv)butyl)benzamido)proDanoic acid

The title compound was prepared by a method analogous to that described for Example 65 using Intermediate (42). Ή NMR (400 MHz, CD₃OD, δ): 8.57 (s, 1H), 7.93 (s, 1H), 7.79 (d, 2H),

7.60 (d, 2H), 7.49 (d, 2H), 6.99 (d, 2H), 5.47-5.45 (m, 1H), 3.64-3.60 (m, 2H), 2.65-2.61 (m,

2H), 2.12-2.05 (m, 1 H), 1.66-1.63 (m, 1H), 1.08 (s, 9H). MS (M+1): 504.4.

Example 72: (+/-)-3-(4-(1 -i4-(4-methvl-3-(trifluoromethvl)-1H-pyrazol-1-yl)phenoxv)

130

The title compound was prepared by a method analogous to that described for Example 19 using 4-methyl-3-(trifluoromethyl)-1/7-pyrazole. Analytical LCMS: rétention time 3.63 minutes (Waters Atlantis dCi_B4.6 x 50mm, 5pm column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 489.98.

Example 73: (+/-)-3-(4-(1-(4-(3-(trifluoromethvl)-1/7-1,2,4-triazol-1-vl)phenoxy)

The title compound was prepared by a method analogous to that described for Example 19 using S-ttrifluorômethyO-IH-l^^-triazole. ’H NMR (400 MHz, CD₃OD, δ): 8.99 (s, 1H), 7.76 (d, J =

8.2 Hz, 2H), 7.57 - 7.63 (m, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.99 - 7.05 (m, 2H), 5.35 (dd, J = 7.8,

5.1 Hz, 1 H), 3.55 - 3.62 (m, 2H), 2.59 (t, J = 6.9 Hz, 2H), 1.94 - 2.05 (m, 1 H), 1.76 - 1.87 (m, 1 H), 1.36-1.61 (m, 2H), 0.96 (t, 3H). MS (M+1): 477.1.

Example 74: (+/-)-3-(4-(1-(4-(3-methvl-4-(trifluoromethvl)-1H-pyrazol-1-vl) phenoxv)butyl)benzamido)propanoic acid

131

The title compound was prepared by a method analogous to that described for Example 19 using 3-methyl-4-(trifluoromethyl)-1H-pyrazole. Analytical LCMS: rétention time 3.57 minutes (Waters Atlantis dCie4.6 x 50mm, 5pm column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 490.04.

Example 75: (+/-)-3-(4-(1-(4-(2-methvl-4-(trifluoromethvl)-1 H-imidazol-1vDphenoxv)butvDbenzamido)propanoicacid

The title compound was prepared by a method analogous to that described for Example 19 using 2-methyl-4-(trifluoromethyl)-1H-imidazole. ¹H NMR (400 MHz, CDCI₃, δ): 7.75-7.70 (m, 2H), 7.40 - 7.35 (m, 2H), 7.23 (s, 1 H), 7.11 - 7.05 (m, 2H), 6.93 - 6.85 (m. 3H). 5.16 - 5.11 (m, 1 H), 3.73 - 3.67 (m, 2H), 2.71 - 2.65 (m, 2H), 2.31 (s, 3H), 2.03 - 1.94 (m, 1 H), 1.84-1.74 (m_T1H), 1.58-1.48 (m, 1 H), 1.47-1.37 (m, 1 H), 0.98-0.92 (m, 3H). MS (M+1): 490.3.

Example 76: (+/-Î-3-i4-(cvclopropvl(4-(4-(trifluoromethvl)-1H-pvrazol-1vl)phenoxv)methvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 65 using Intermediate (19). ’H NMR (400 MHz, CDCI₃, δ): 8.00 (s, 1H), 7.83 (s, 1H), 7.73 (m, 2H),

7.44 - 7.42 (m, 4H), 6.89 - 6.87 (m, 2H), 6.77 - 6.76 (m, 1 H), 4.69 - 4.67 (m, 1 H), 3.74 - 3.70 (m, 2H), 2.71 - 2.69 (m, 2H), 1.38 - 1.34 (m, 1 H), 0.73 - 0.68 (m, 1 H), 0.63 - 0.46 (m, 3H). MS (M+1):

474.4, MS (M+23): 496.3.

Example 77: (+/-)-3-(4-(2-methvl-1 -(4-(4-(trifluoromethvl)-1 H-nvrazol-1 vl)phenoxv)propvl)benzamido)propanoic acid

132

Step A: (+/-)-tert-butvl 3-W-tert-butvl-4-(2-methvl-1-(4-(4-(trifluoromethvl)-l/-/-Dvrazol-1vl)phenoxv)propyl)benzamido)propanoate

To a 0 °C solution of Intermediate (17) (120 mg, 0.32 mmol) and Intermediate (29) (103 mg, 0.48 mmol) in toluene (2 mL) was added tributylphosphine (129 mg, 0.64 mmol) followed by 1,1'(azodicarbonyl)dipiperidine (134 mg, 0.64 mmol). The reaction was warmed to ambient température and stirred overnight. Brine (20 mL) was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography gave tert-butyl 3-(/V-tert-butyl-4-(2-methyl-1(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)propyl) benzamidojpropanoate (60 mg, 32%). ’H NMR (400 MHz, CDCI₃₁ δ): 7.93 (s, 1H), 7.75 (s, 1H), 7.37-7.32 (m, 2H), 7.30-7.20 (m, 4H),

6.81 -6.79 (m, 2H), 4.78 (d, 1 H), 3.47-3.43 (m, 2H), 2.31 -2.27 (m, 2H), 2.10 - 2.05 (m, 1H),

1.44 (s, 9H), 1.21 (s, 9H), 0.97 (d, 3H), 0.85 (d, 3H).

Step B: (+/-)-3-(4-(2-methyl-1 -(4-(4-(trifluoromethvl)-1 H-pyrazol-1 -vDphenoxy) propyl)benzamido)propanoic acid

To a room température solution of tert-butyl 3-(N-tert-butyl-4-(2-methyl-1 -(4-(4(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)propyl)benzamido)propanoate (60 mg, 0.10 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.0 mL). The mixture was stirred at room température for 3 hours. The reaction mixture was concentrated and purification by HPLC gave (+/-)-3-(4-(2-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)propyl)benzamido)propanoic acid (11.4 mg, 24%). ’H NMR (400 MHz, CD₃OD, δ): 8.53 (s, 1H), 7.89 (s, 1H), 7.76 (d, 2H), 7.55 (d, 2H), 7.45 (d, 2H), 6.97 (d, 2H), 5.06 (d, 1H), 3.61 -3.58 (m, 2H), 2.62-2.59 (m, 2H), 2.21 2.11 (m, 1H), 1.08 (d, 3H), 0.93 (d, 3H). MS (M+1): 476.4.

Example 78: (+/-)-3-(4-(1 -(4-(4-(trifluoromethvl)-1H-pvrazol-1 -vl)phenoxv)propyl) benzamido)propanoic acid

133

The title compound was prepared by a method analogous to that described for Example 77 using Intermediate (46). ¹H NMR (400 MHz, (CD₃)₂SO, δ): 8.97 (s, 1 H). 8.49-8.47 (m, 1H), 8.11 (s, 1 H), 7.80 - 7.78 (d, 2H), 7.69 - 7.65 (m, 2H), 7.49 - 7.47 (m, 2H), 7.05 - 7.01 (m, 2H), 5.40 -

5.37 (m, 1 H), 3.51 - 3.40 (m, 2H), 2.50 - 2.46 (m, 2H), 2.00 - 1.81 (m, 2H), 0.96 - 0.92 (m, 3H). MS (M+1): 462.5.

Example 79: (+/-)-3-(4-(3-methvl-1 -(4-(4-(trifluoromethvl)-1 H-imidazol-1 vl)phenvl)butoxv)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 19 using Intermediate (41). ¹H NMR (400MHz, CD₃OD, δ): 7.78 - 7.77 (m, 3H), 7.50 - 7.44 (m,4H),

7.39 (s, 1 H), 6.96 - 6.92 (m, 2H), 5.33 - 5.31 (m,1 H), 3.75 (s, 3 H), 3.67 - 3.59 (m, 2H), 2.64 -

2.60 (m, 2H), 2.05-1.95 (m, 1H), 1.87-1.61 (m, 1 H), 1.61-1.41 (m, 2H). 0.98-0.94 (m, 3H). MS (M+1): 438.1.

Example 80: (+/-)-3-(4-(3-methvl-1 -(4-(4-(trifluoromethvl)-1H-pyrazol-1 -vDphenoxv)

The title compound was prepared by a method analogous to that described for Example 77 using Intermediate (15). ¹H NMR (400 MHz, CD₃OD, δ): 8.52 (s, 1H), 7.89 (s, 1H), 7.76 (d, 2H),

7.57 (d, 2H), 7.47 (d, 2H), 6.97 (d, 2H), 5.39 - 5.36 (m, 1 H), 3.61 - 3.57 (m, 2H), 2.62 - 2.58 (m,

2H), 2.00-1.92 (m, 1H), 1.89-1.82 (m, 1 H), 1.63 - 1.57 (m, 1H), 1.02-0.97 (m, 6H). MS (M+1):

490.5.

134

Example 81: 3-(4-(3-methvl-1-(4-(4-itrifluoromethvl)-1H-pvrazol-1-vl)phenoxv) butvl)benzamido)propanoic acid. Isomer 2

The title compound is obtained by resolving racemic 3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)1 H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 80, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 x 250mm. Mobile Phase: 70/30 CO^-propanol.

Flow Rate: 10.0 mL/min. Modifier: none. Rétention time: 3.39 minutes (second peak eluted).

Example 82: (+/-)-3-(4-(1-(3.5-dimethvl-4-(4-(trifluoromethyl)-1H-pvrazol-1 vl)phenoxv)butvl)benzamido)propanoic acid

Step A: (+/-)-ethvi 4-(1-(3.5-dimethyl-4-(4-(trifluoromethvl)-1H-pyrazol-1 -yl)phenoxy)butvl)benzoate

Diisopropyl azodicarboxylate (0.14 mL, 0.67 mmol) was added dropwise to a solution of

135

Intermediate (26) (119.9 mg, 0.47 mmol), ethyl 4-(1-hydroxybutyl) benzoate (98.0 mg, 0.44 mmol), and triphenylphosphine (178 mg, 0.67 mmol) in tetrahydrofuran (4.4 mL). After 18 hours, the reaction was concentrated and purification by column chromatography (0 - 40% ethyl acetate in heptanes) gave (+/-)-ethyl 4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl) benzoate (140 mg, 69%) as an oil. ¹H NMR (400 MHz, CDCI₃, δ): 8.02 (d, J = 8.8 Hz, 2H), 7.88 (s, 1 H), 7.65 (s, 1 H), 7.40 (d, J = 8.2 Hz, 2H), 6.57 (s, 2H), 5.16 (dd, J = 7.9, 5.0 Hz, 1 H), 4.37 (q, J = 7.0 Hz, 2H), 2.06 - 1.91 (m, 1 H), 1.88 (s, 6H), 1.86 -1.74 (m, 1 H), 1.54 -1.41 (m, 2H), 1.38 (t, J =

7.1 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H). MS (M+1): 461.

Step B: (+/-1-4-(·1-(3·5-όίπη6ίΐΊνΙ-4-(4-(ΐΓίίΙυοΓθΐ·ηθΗινΙΜΗ-ρνΓ3ζοΙ-1 -vOphenoxv)butyl)benzoic acid

O

To a vial containing ethyl 4-(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)butyl)benzoate (135 mg, 0.29 mmol) was added water (0.59 mL), tetrahydrofuran (0.591 mL), and methanol (0.59 mL). Lithium hydroxide monohydrate (615.0 mg, 14.6 mmol) was then added. The suspension was stirred at room température for 18 hours. The reaction was concentrated in vacuo. The residue was acidified to pH = 3 with citric acid (5%). The mixture was extracted three times with ethyl acetate, The organics were dried over sodium sulfate, filtered and concentrated to give (+/-)-4-(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenoxy)butyl)benzoic acid (120 mg, 95%) as a white solid. ’H NMR (400 MHz, CDCI₃, δ): 8.07 (d, J = 8.4 Hz, 2H), 7.88 (s, 1 H), 7.65 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J = 8.0, 4.9 Hz, 1 H), 2.04 -1.92 (m, 1 H), 1.89 (s, 6H), 1.87-1.75 (m, 1 H), 1.61 -1.36 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). MS (M+1): 433.

Step C: (+/-)-ethvl 3-i4-(1-(3,5-dimethvl-4-(4-ÎtrïfluoromethvlÎ-1H-pvrazol-1vl) phenoxy) butvl) be nzamido) propanoate

136

Λ/,/V-dimethylforrnamide (1.88 mL) was added to a vial containing 4-(1-(3,5-dimethyl-4-(4(trifluoromethyl)-l H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (122.0 mg, 0.28 mmol), ethyl 3aminopropanoate hydrochloride (86.6 mg, 0.56 mmol) and O-^-azabenzotriazol-l-yO-M,/'/,/^/'^tetramethyluronium hexafluorophosphate (214.0 mg, 0.56 mmol). Diisopropylethylamine (0.25 mL,

1.41 mmol) was then added. After stirring for 4 hours, the reaction was diluted with saturated ammonium chloride and extracted three times with diethyl ether. The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 25% ethyl acetate in heptane) afforded (+/-)-ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenoxy)butyl)benzamido) propanoate (117 mg, 78% yield). ¹H NMR (400 MHz, CDCIa, δ): 7.87 (s, 1 H), 7.73 (d, J = 8.0 Hz, 2H), 7.65 (s, 1 H), 7.39 (d, J = 8.2 Hz, 2H), 6.84 (d, J =

5.9 Hz, 1 H), 6.57 (s, 2H), 5.15 (dd, J = 7.8, 5.1 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2H), 3.71 (q, J = 6.0 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.04 -1.91 (m, 1 H), 1.88 (s, 6H), 1.86 -1.71 (m, 1 H), 1.58 -1.33 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). MS (M+1): 532.

Step D: (+/-)-3-(4-(1 -i3.5-dimethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1vl)phenoxv)butyl)benzamido)propanoic acid

To a flask containing ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1yl)phenoxy)butyl)benzamido)propanoate (117 mg, 0.22 mmol) was added water (0.55 mL), tetrahydrofuran (0.55 mL), and methanol (0.55 mL). Lithium hydroxide monohydrate (508 mg, 12.1 mmol) was then added. The suspension was stirred at room température for 18 hours. The reaction was concentrated and acidified to pH = 3 with citric acid (10%). A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (+/-)-3-(4-(1-(3,5dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (90 mg, 81%) as a white solid. ¹H NMR (400 MHz, CDCI₃, δ): 7.88 (s, 1 H), 7.73 (d, J = 8.2 Hz, 2H), 7.65 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2H), 6.80 (t, J = 5.9 Hz, 1H), 6.56 (s, 2H), 5.16 (dd, J = 7.8, 5.1 Hz, 1H),

3.71 (q, J = 5.9 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.04 - 1.91 (m, 1 H), 1.88 (s, 6H), 1.86 -1.67 (m, 1H), 1.63-1.31 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). MS (M+1): 504.

Example 83: (S)-3-(4-(1-(3.5-dimethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1-vl) phenoxv)butvl)benzamido)propanoic acid

137

The title compound is obtained by resolving racemic 3-(4-(1 -(3,5-dimethyl-4-(4(trifluoromethyl)-l H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 82, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 x 250mm. Mobile Phase: 80/20 COa/2-propanol. Flow Rate: 10.0 mL/min. Modifier: 0.2% isopropylamine. Rétention time:

3.23 minutes.

Alternative^ (S)-3-(4-(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 83 can be prepared by chiral synthesis as follows.

Step A: (S)-ethvl 4-(1 -(3.5-dimethvl-4-(4-(trifluoromethyl)-1H-pyrazol-1-vl)phenoxv)butvl)benzoate

To a solution of Intermediate (56) (4.51 g, 20.3 mmol) and Intermediate (26) (5.2 g, 20.0 mmol) in tetrahydrofuran (100 mL) was added diisopropyl azodicarboxylate (13.1 mL, 30.4 mmol). Tributylphosphine (7.86 mL, 31.5 mmol) was added dropwise at room température, maintaining the internai température below 30 °C. The mixture was stirred at room température for 2 hours. The reaction was then concentrated. The resulting solid was diluted with dichloromethane and hydrochloric acid (1 N). The mixture was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-8% ethyl acetate in heptanes) afforded (S)-ethyl 4-(1-(3,5-dimethyl-4-(4(trifluoromethyl)-lH-pyrazol-1 -yl)phenoxy)butyl) benzoate (6.9 g, 74%) as an oil: ’H NMR (400 MHz, CDCI₃, δ): 8.02 (d, J = 8.8 Hz, 2H), 7.88 (s, 1 H), 7.65 (s, 1 H), 7.40 (d, J = 8.2 Hz, 2H), 6.57 (s, 2H), 5.16 (dd, J = 7.9, 5.0 Hz, 1 H), 4.37 (q, J = 7.0 Hz, 2H), 2.06 - 1.91 (m, 1 H), 1.88 (s, 6H),

1.86 -1.74 (m, 1 H), 1.54 -1.41 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H). MS (M+1): 461.

Step B: fS)-4-(1-(3,5-dimethvl-4-(4-(trifluoromethvl)-1H-pyrazol-1-vl)phenoxv)butyl)benzoic acid

138

To a flask containing (S)-ethyl 4-(1-(3_l5-dimethyl-4-(4-(trifluoromethyl)-1/-/-pyrazol-1yl)phenoxy)butyl)benzoate (11.8 g, 25.6 mmol) was added water (32.0 mL), tetrahydrofuran (32,0 mL), and methanol (32.0 mL). Lithium hydroxide monohydrate (2.15 g, 51.2 mmol) was then added. The suspension was stirred at room température. After 1.5h, another (1.07 g, 25.6 mmol) of lithium hydroxide monohydrate was added. After 2h, the reaction was concentrated. The crude residue was dissolved in water and the solution was acidified to pH = 3 with 1N hydrochloric acid. A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)-4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (11.1 g, 100%) as a white gum. ’H NMR (400 MHz, CDCI₃, δ): 8.07 (d, J = 8.4 Hz, 2H), 7.88 (s, 1 H),

7.65 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J = 8.0, 4.9 Hz, 1H), 2.04-1.92 (m, 1H), 1.89 (s, 6H), 1.87-1.75 (m,1H), 1.61 -1.36 (m, 2H), 0.97(t,J = 7.4 Hz, 3H). MS (M+1): 433.

Step C: (S)-ethyl 3-(4-(1-(3,5-dimethvl-4-(4-(trifluorornethvl)-1A/-pvrazol-1yl)phenoxy)butvl)benzamido)propanoate

A/,N-dimethylformamide (17.6 mL) was added to a vial containing (S)-4-(1-(3,5-dimethyl-4(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoicacid (6.1 g, 14.1 mmol), ethyl 3aminopropanoate hydrochloride (4.33 g, 28.2 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,A/',Ntetramethyluronium hexafluorophosphate (10.7 g, 28.2 mmol). Diisopropylethylamine (12.3 mL, 70.5 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0 - 30% ethyl acetate in heptane) afforded (S)-ethyl 3-(4(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido) propanoate (7.07 g, 94% yield) as a colorless gum. ’H NMR (400 MHz, CDCI₃₁ δ): 7.87 (s, 1 H), 7.73 (d, J = 8.0 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 5.9 Hz, 1H), 6.57 (s, 2H), 5.15 (dd, J = 7.8,

139

5.1 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.71 (q,J = 6.0 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.04 - 1.91 (m, 1 H), 1.88 (s, 6H), 1.86-1.71 (m, 1 H), 1.58 - 1.33 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 0.96 (t, J =

7.4 Hz, 3H). MS (M+1): 532.

Step D: (5)-3-(4-(1-(3.5-dimethvl-4-(4-(trifluoromethvl)-1H-pyrazol-1yl)phenoxv)butvl)benzamido)Dropanoic acid

To aflask containing ethyl (fî)-ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl) -1H-pyrazol1-yl)phenoxy)butyl)benzamido)propanoate (6.95 g, 13.1 mmol) was added water (33.0 mL), tetrahydrofuran (33.0 mL), and methanol (33.0 mL). Lithium hydroxide monohydrate (1.1 g, 26.1 mmol) was then added. The suspension was stirred at room température for 13 hours. The réaction was concentrated. The crude residue was dissolved in water, and the solution was acidified to pH = 4 with 1N hydrochloric acid. A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)1 H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (5.7g, 87%) as a white solid. ¹H NMR (400 MHz, CDCIa, δ): 7.88 (s, 1 H), 7.73 (d, J = 8.2 Hz, 2H), 7.65 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2H),

6.80 (t, J = 5.9 Hz, 1 H), 6.56 (s, 2H), 5.16 (dd, J = 7.8, 5.1 Hz, 1 H), 3.71 (q, J = 5.9 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.04 - 1.91 (m, 1 H), 1.88 (s, 6H), 1.86 - 1.67 (m, 1 H), 1.63-1.31 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). MS (M+1): 504.

Another alternative synthesis of (3)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol1-yl)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 83 is provided by chiral synthesis as follows.

Step A: (ffl-4-(1 -hydroxybutyl)benzoic acid

To a solution of Intermediate (56) (3.25 g, 14.6 mmol), was added water (25.0 mL), tetrahydrofuran (25.0 mL), and methanol (25.0 mL). Lithium hydroxide monohydrate (1.23 g, 29.2 mmol) was then added. The suspension was stirred at room température. After 2.5h, the reaction was concentrated. The crude residue was dissolved in ethyl acetate and the solution was acidified to pH = 3 with 1N hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to give (R)-4-(1 hydroxybutyl)benzoic acid (2.63 g, 93%) as a white solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.09 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.79 (dd, J = 7.6, 5.5 Hz, 1H), 1.86- 1.76 (m, 1 H), 1.76-

1.64 (m, 1 H), 1.54 -1.40 (m, 1 H), 1.40 - 1.27 (m, 1 H), 0.95 (t, J = 7.3 Hz, 3H). MS (M-1 ): 193. Step B: (H)-ethyl 3-(4-(1-hvdroxvbutvl)benzamido)propanoate

140

M,W-dimethylformamide (16.9 mL) was added to a vial containing (fl)-4-(1-hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-amînopropanoate hydrochloride (4.16 g, 27.1 mmol) and O-(7azabenzoÎrÎazol-1-yl)-N,N,N’,N’-tetramethyluroniunn hexafluorophosphate (10.3 g, 27.1 mmol). Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The réaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0 - 50% ethyl acetate in heptane) afforded (R)-ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (3.97 g, 100% yield) as an oil. ¹H NMR (400 MHz, CDCI₃, δ): 7.75 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 6.83 (br. s., 1 H), 4.74 (t, J = 8.2 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2H), 3.73 (q, J = 5.9 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84- 1.62 (m, 2H), 1.49-1.30 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.93 (t, J= 7.3 Hz, 3H). MS (M+1): 294.

Step C: (S)-ethvl 3-(4-(1-(e.S-dimethvl^-^-ftrifluoromethvD-l H-pyrazol-1vl) phenoxy) butvl) benzam ido) pro panoate

To a solution of azeotropically dried (R)-ethyl 3-(4-(1-hydroxybutyl) benzam ido) propan oate (2.6 g, 8.9 mmol) and azodicarboxylic acid dipiperidine (3.8 g, 15.1 mmol) (with toluene) in tetrahydrofuran (49.2 mL) was added tributylphosphine (3.9 mL, 16.0 mmol) dropwise at room température. Intermediate (26) (2.3 g, 8.9 mmol) was then added portionwise. The mixture was stirred at room température for 16 hours. The réaction was diluted with ethyl acetate and then extracted twice with sodium hydroxide (1N), once with water, once with hydrochloric acid (1N), and finally once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptanes) afforded (S)-ethyl 4-(1 (3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl) benzoate (3.53 g, 75%) as colorless gum: ’H NMR (400 MHz, CDCI₃₁ δ): 7.87 (s, 1H), 7.73 (d, J= 8.0 Hz, 2H), 7.65 (s, 1H),

7.39 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 5.9 Hz, 1 H), 6.57 (s, 2H), 5.15 (dd, J = 7.8, 5.1 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2H), 3.71 (q, J = 6.0 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.04 -1.91 (m, 1 H), 1.88 (s, 6H), 1.86 -1.71 (m, 1 H), 1.58- 1.33 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). MS (M+1): 532. Chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6 x 250mm. Mobile Phase: 80/20 COa/ethanol. Flow Rate: 2.5 mL/min. Modifier: None. Rétention time: 3.05 minutes.

141

Step D: (5)-3-(4-(1 -(3,5-dimethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1-yl)phenoxv) butvDbenzamido)propanoic acid

To a flask containing ethyl (S)-ethyl 3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl) -1H-pyrazol1-yl)phenoxy)butyl)benzamido)propanoate (3.5 g, 6.6 mmol) was added tetrahydrofuran (16.5 mL), methanol (16.5 mL), and sodium hydroxide (1N) (16.5 mL, 16.5 mmol). The suspension was stirred at room température for 18 hours, The reaction was concentrated. The crude residue was dissolved in water, and the solution was actdified to pH = 3 with 1N hydrochloric acid. A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)-3(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (2.87 g, 87%) as a white solid. Recrystallization was performed using methyl tert-butyl ether to provide a crystalline compound. The crystalline compound can be characterized by powder X-ray diffraction to provide the spectrum substantially as shown in Figure 1. ¹H NMR (400 MHz, CDCI₃, δ): 7.88 (s, 1 H), 7.73 (d, J = 8.2 Hz, 2H), 7.65 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2H), 6.80 (t, J = 5.9 Hz, 1 H), 6.56 (s, 2H), 5.16 (dd, J = 7.8, 5.1 Hz, 1 H), 3.71 (q, J = 5.9 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.04 -1.91 (m, 1 H), 1.88 (s, 6H), 1.86 -1.67 (m, 1 H), 1.63-1.31 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). MS (M+1): 504. Mp 157-159 °C. [α]₀ = -43.8 (c=1; CHCI₃).

A further synthesis of the compound of Example 83 is provided below.

Step (1): (ffl-methvl 4-(1-hydroxybutvl)benzoate

To a solution of borane diethylaniline complex (20.6 g, 25.2 mL, 126 mmol) in tetrahydrofuran (130 mL) at 20 °C was added (s)-methyl oxazaborilidine (6.3 mL, 6.3 mmol). A solution of ketone (26.0 g, 126 mmol) in tetrahydrofuran (130 mL) was added over 2.5 h. The reaction was stirred 10 min before quenching with methanol (15.3 mL), To the quenched solution was added 1 M HCl (125 mL) and the product was extracted with heptane (2 x 130 mL). The combined organic solution was washed with 1 M HCl (125 mL) and concentrated to a final volume of 250 mL. The solution was cooled to -10 °C the product filtered and washed with cold heptanes to give (R)-methyl 4-(1-hydroxybutyl)benzoate as a white solid (23.3 g, 89% yield). ’H NMR (400 MHz, CDCI₃) ô: 7.99 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.73 (dd, J = 7.4, 5.9 Hz, 1 H), 3.89 (s, 3H), 1.81-1.61 (m, 2H), 1.47-1.26 (m,2H),0.92 (t, J = 7.4 Hz, 3H).

142

Br OH

CF₃ cf₃

Step (1s): 3,5-dimethvl-4-(4-(trifluoromethvl)-1 H-pyrazol-1-vllphenol

To a solution of tha aryl bromide (intermediate 7) (15.3 g, 49 mmol) and potassium hydroxide (9.50 g, 144 mmol) in N-methylpyrrolidone (38 mL) and water (38 mL) was added tris(dibenzylidineacetone)dipalladium (0.44 g, 0.48 mmol) and t-butyl X-Phos (0.41 g, 0.96 mmol). The solution was heated to 90 °C. After 30 min the reaction was cooled to room température and ethyl acetate (75 mL) was added. The solution was acidified with conc. HCl (9 mL). The aq. phase was split and the organic layer washed with a 0.5 M potassium phosphate, tribasic solution (75 mL). The solvent was removed and toluene (75 mL) added. The toluene solution was cooled to 0 °C and filtered to give 3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenol (9.21 g, 75% yield) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) ô: 9.71 (s, 1H), 8.52 (s, 1 H), 8.09 (s, 1H), 6.57 (s, 1H), 1.82 (s, 6H).

Step (2.3.4): (S)-4-(1-(3,5-dimethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1-vl)Dhenoxv)butyl)benzoic acid tromethamine sait.

Step (2): (fî)-methyl 4-i1-(meÎhvlsulfonvloxy)butvl)benzoate:

To a solution of (R)-methyl 4-(1-hydroxybutyl)benzoate, intermediate (26) (10 g, 48 mmol) in methyl f-butyl ether (80 mL) containing triethylamine (6.32 g, 62 mmol) was added methanesulfonyl chloride (6.05 g, 53 mmol) slowly at 20 °C. The solution was filtered to remove triethylamine salts and the solution used in the next step without isolation.

Step (3): (S)-methyt 4-Î1-(3.5-dimethyl-4-(4-(trifluoromethvl)-1H-pvrazol-1vl)phenoxv)butvl)benzoate:

Tp a solution of 3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenol (intermediate 26) (12,6 g, 49 mmol) in 2-methyltetrahydrofuran (70 mL) was added césium carbonate (23.5 g, 72 mmol) and the solution of mesylate from step 2. The reaction was heated to 65 °C for 5 h. The reaction was then cooled to room température and water (80 mL) was added. The aq. layer was split and the organic solution was used in the next step without isolation.

Step (4): (S)-4-(1-i3.5-dÎmethvl-4-(4-(trifluoromethvl)-1 H-pyrazol-1-vl)phenoxv)butvl)benzoic acid

143 tromethamine sait:

To the solution from step 3 was added 5 M sodium hydroxide solution (29 mL, 145 mmol) and methanol (30 mL). The solution was heated to 35 °C for 6 h. After cooling to room température, the solution was acidified with conc. HCl (12.4 mL). The reaction was washed with water (30 mL). The organic solution was concentrated and the residue taken up in acetonitrile (100 mL). A solution of tris(hydroxymethyl)aminomethane (5.82 g , 48 mmol) in water (5 mL) was added slowly. The resulting slurry was cooled to 0 °C. The product was filtered and washed with acetonitrile to give the desired sait as a white solid (20.5 g, 77% yield) ’H NMR (400 MHz, DMSOd6) δ: 8.53 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.74 (s, 2H),

5.38 (dd, J = 7 A, 5.1 Hz, 1 H), 3.37 (s, 6H), 1.94-1.85 (m, 1H), 1.79 (s, 6H), 1.76-1.68 (m, 1H), 1.45-1.29 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H),

Step (5-6): (5)-3-(4-(1-(3,5-dimethvl-4-(4-(trifluoromethvl)-1 H-pyrazol-1yl)phenoxv)butvl)benzamido)propanoic acid:

Step (5): (S)-methvl 3-(4-(1-(3.5-dimethvl-4-(4-(trifluoromethvl)-1 H-pvrazol-1vl)phenoxv)butvl)benzamido)propanoate

To a solution of the tromethamine sait (20 g, 36 mmol) in 2-methyltetrahydrofuran (200 mL) was added β-alanine ethyl ester (7.08 g, 45 mmol), 2-chloro-4,6-dimethoxy-1,3_l5-triazine (8.25 g, 47 mmol) and N-methylmorpholine (7.31 g, 72 mmol). The reaction was stirred at 20 °C for 2 h. The reaction was washed with water (2x72 ml) and the organic solution used in the next step without isolation.

Step (6): (S)-3-(4-(1-(3,5-dimethvl-4-(4-(trifluoromethyl)-1 H-ovrazol-1vl)phenoxv)butyl)benzamido)propanoic acid:

To the solution from step 5 was added methanol (40 mL), water (54 mL) and sodium hydroxide (4.34 g, 108 mmol). The reaction was stirred 1 h at 30 °C. The solution was acidified with conc. HCl (9.33 mL) and the aq. phase split. The organic solution was washed with 1 N HCl (40 mL). The organic phase was concentrated and the residue taken up in acetonitrile (300 mL). The solution was cooled to 0 °C and stirred 5 h. The solid product was filtered and washed with cold acetonitrile, giving the desired compound as a white solid (14.6 g, 80% yield). ¹H NMR (400 MHz, CDCI₃) δ: 7.88 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.38 (d, J = 8.3 Hz, 2H), 6.89 (t, J = 6.2 Hz, 1 H), 6.55 (s, 2H), 5.15 (dd, J = 7.8, 4.6 Hz, 1 H), 3.68 (q, J = 6.2 Hz, 2H), 2.65 (t, J =

144

The final compound was recrystallized from acetonitrile (5 vol). The compound was heated to BO °C and then cooled to 0 °C to provide a purity of 99.01%.

Example 84: (R)-3-(4-(1 -(3,5-dimethvl-4-(4-(trifluoromethvl)-1 H-pyrazol-1 vl)phenoxv)butvl)benzamido)propanoic acid

The title compound is obtained by resolving racemic 3-(4-(1-(3,5-dimethyl-4-(4(trifluoromethyl)-l H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 82, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 x 250mm. Mobile Phase: 80/20 CO2/2-propanol. Flow Rate: 10.0 mL/min. Modifier: 0.2% isopropylamine. Rétention time:

3.65 minutes.

Example 85: (+/-)-3-(4-(1-(5-(4-(trifluoromethvl)-1 H-pyrazol-1-vl)pvridine-2vloxv)butvl)benzamido)oropanoic acid

The title compound was prepared by a method analogous to that described for Example 19 using Intermediate (49) and 4-(trifluoromethyl)-1H-pyrazole. ¹H NMR (400 MHz, CD₃OD, δ): 8.62 (s, 1 H), 8.42 (d, J = 2.3 Hz, 1 H), 8.03 (dd,J = 9.0, 2.9 Hz, 1 H), 7.94 (s, 1 H), 7.76 - 7.72 (m, 2H),

7.49 - 7.44 (m, 2H), 6.99 - 6.93 (m, 1 H), 6.09 (dd, J = 7.9, 5.6 Hz, 1 H), 3.63 - 3.55 (m, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.08 - 1.96 (m, 1 H), 1.90-1.78 (m, 1 H), 1.54 - 1.33 (m, 2H), 0.98 - 0.92 (m, 3H). MS (M+1): 477.3.

Example 86: (+/-)-3-(4-(1 -(6-i4-(trifluoromethvl)-1 H-pvrazol-1 -vl)pyridine-3vloxv)butvl)benzamido)oropanoic acid

145

Step A: (+/-)-methvl 4-(1-(6-(4-(trifluoromethvl)-1H-pvrazol-1-vl)pyridine-3-vloxv)butvl)benzoate

To a 0 °C mixture of Intermediate (20) (150 mg, 0.72 mmol) and Intermediate (38) (110 mg, 0.48 mmol) in tetrahydrofuran (5.0 mL) was added triphenylphosphine (252 mg, 0.96 mmol) followed by diethylazodicarboxylate (167 mg, 0.96 mmol). The mixture was stirred at 40°C overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)-methyl 4-(1 -(6-(4-(trifluoromethyl)-1H-pyrazol-1 -yl)pyridine-3-yloxy)butyl)benzoate (170 mg, 84%). ¹H NMR (400 MHz, CDCI₃, δ): 8.60 (s, 1H), 7.97-7.93 (m, 3H), 7.75 (s, 1H), 7.72 (d, 1H), 7.34 (d, 2H), 7.20-7.17 (m, 1 H), 5.13-5.10 (m,1H), 3.83 (s, 3H), 2.01 -1.95 (m, 1H) , 1.81 - 1.78 (m, 1 H), 1.48-1.47 (m, 1 H), 1.38 - 1.36 (m, 1 H), 0.92 - 0.89 (m, 3H).

Step B: (+/-)-3-(4-(1-(6-(4-(triÎluoromethyl)-1H-pyrazol-1 -vl)pvridine-3vloxy)butvl)benzamido)Dropanoic acid

To a 0 °C solution of methyl 4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3yloxy)butyl)benzoate (170.0 mg, 0.405 mmol) in tetrahydrofuran (3 mL) was added 2N lithium hydroxide (610 pL, 1.22 mmol). The mixture was stirred at 50 °C overnight. The reaction was neutralîzed with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated, to give 164 mg of a coloriess solid. To a solution of 100 mg ofthe crude residue in /V,/V-dimethylformamide (5 mL) was added O-(7-azabenzotriazol-1yl)-/V,/V,A/',W'-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol). The mixture was stirred for 45 minutes and then methyl 3-aminopropionate hydrochloride (51.1 mg, 0.37 mmol) and diisopropylethylamine (128 mg, 0.988 mmol) were added. The resulting mixture was stirred at room température for 2 hours. The mixture was diluted with saturated ammonium chloride, and the

layers were separated. The organic layer was washed with water, dried over sodium sulfate,

146 filtered and concentrated. The crude residue was dissolved in water (5 mL) and tetrahydrofuran (5 mL). 2N lithium hydroxide (330 pL, 0.66 mmol) was added. The mixture was stirred at room température for 2 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150x30mm, 5pm; modifier: formic acid 0.225%; gradient: 47 to 67% acetonitrile in water) gave (+/-)-3-(4-(1-(6-(4(trifluoromethyl)-l H-pyrazol-1-yl)pyridine-3-yloxy)butyl)benzamido)propanoic acid (90 mg) as a colorless solid. ¹H NMR (400 MHz, CD₃OD, 5): 8.71 (s, 1H), 7.98 (m, 1H), 7.84 (s, 1H), 7.71 -7.69 (m, 3H), 7.42 - 7.35 (m, 3H), 5.33 - 5.30 (m, 1 H), 3.53 - 3.50 (m, 2H), 2.54 - 2.51 (m, 2H), 1.97 1.92 (m, 1H), 1.79-1.73 (m, 1H), 1.49-1.38 (m, 1H), 1.37-1.34 (m, 1H), 0.90 (t, 3H). MS (M+1): 477.5.

Example 87: (+/-)-3-(4-(1-(6-(4-(trifluoromethvl)-1H-imidazol-1-vl) pyridine-3vloxv)butvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 86 using Intermediate (50). Ή NMR (400 MHz, CD₃OD, δ): 8.43 (s, 1H), 8.22 (s, 1H), 8.14 (d, 1H),

7.80 - 7.78 (m, 2H), 7.57 - 7.55 (m, 1 H), 7.47 - 7.44 (m, 3H), 5.44 - 5.41 (m, 1 H), 3.61 - 3.57 (m, 2H), 2.62 - 2.58 (m, 2H), 2.06 - 2.03 (m, 1 H), 1.89 - 1.85 (m, 1 H), 1.57 - 1.55(m, 1 H), 1.47-1.43 (m, 1H), 1.00-0.96 (m, 3H). MS (M+1): 477.2.

Example 88: (+/-)-3-(4-(1-(4-(4-cvano-1 H-pyrazol-1-vl)phenoxv)butvl)benzamido) propanoic acid

Step A: 1-(4-methoxvphenvl)-1H-pyrazole

A mixture of (4-methoxyphenyl)hydrazine hydrochloride (8.0 g, 0.046 mol) and 1,1,3,3tetramethoxypropane (8.3 g, 0.05 mol) in éthanol (120 mL) was heated to reflux for 1 hour. The reaction was then cooled to room température and concentrated. The residue was diluted with saturated sodium bicarbonate (50 mL) and ethyl acetate (100 mL). The phases were separated

and the aqueous was extracted with ethyl acetate (2 x 20 mL). The combined organics were

147 washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-(4-methoxyphenyl)-1H-pyrazole (7.7 g, 97%) as a yellow oil, ’H NMR (400 MHz, CDCI₃₁ δ): 7.S2 (m, 1 H), 7.69 (m, 1 H), 7.59 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 6.43 (m, 1H), 3.83 (s, 3H).

Step B: 4-bromo-1-(4-methoxyphenvl)-1H-pvrazole

To a solution of 1-(4-methoxyphenyl)-1H-pyrazole (7.2 g, 0.042 mol) in tetrahydrofuran (100 mL) was added A/-bromosuccinimide (7.3 g, 0.042 mol). The reaction was stirred at room température for 3 hours. The reaction was concentrated and purification by column chromatography gave 4-bromo-1-(4-methoxyphenyl)-1H-pyrazole (8.9 g, 84%) as a white solid. ’H NMR (400MHz, CDCI₃, δ): 7.83 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 6.97 (d,J=8.8 Hz,

2H), 3.84 (s, 3H).

Step C: 1-(4-methoxvphenvl)-1H-pyrazole-4-carbaldehvde

To a -78°C solution of 4-bromo-1-(4-methoxyphenyl)-1H-pyrazole (506mg, 2.0mmol) in anhydrous tetrahydrofuran (20mL) was added n-butyllithium in hexane (0.95mL, 2.4mmol). The réaction was stirred for 2h at -78°C. Ν,Ν-dimethylformamide (292mg, 4mmol) was added and the reaction continued to stir at -78°C for 1 h, then at room température for 2h. The reaction was quenched with saturated ammonium chloride (20mL) and extracted with ethyl acetate (3 x 30mL). The combined organics were washed with brine (30mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-(4-methoxyphenyl)-1H-pyrazole-4carbaldehyde (80mg, 20%) as a yellow oil. ’H NMR (400 MHz, CDCI₃, δ): 9.95 (s, 1H), 8.33 (s, 1 H), 8.13 (s, 1 H), 7.62 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 3.86 (s, 3H).

Step D: 1-(4-methoxyphenvl)-1H-pyrazole-4-carbonitrile

To a mixture of 1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (80 mg, 0.54 mmol) in tetrahydrofuran (3 mL) and ammonium hydroxide (3 mL) was added iodine (138 mg, 0.54 mmol). The reaction was stirred at room température for 5 hours. The reaction was diluted with saturated sodium thiosulphate (5 mL) and extracted with ethyl acetate (3x10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 1 -(4methoxyphenyl)-1H-pyrazole-4-carbonitrile (78 mg, 100%) as a yellow solid. ’H NMR (400 MHz, CDCI₃, δ): 8.19 (s, 1H), 7.96 (s, 1H), 7.56 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 3.86 (s, 3H).

148

Step E: 1-(4-hvdroxvphenvl)-1H-pyrazole-4-carbonitrile

To a solution of 1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (115 mg, 0.575 mmol) in dichloromethane (5 mL) was added boron tribromide (431 mg, 1.73 mmol) at -10°C. The reaction was then warmed to room température and stirred for 16 hours. The reaction was quenched with methanol (0.5 mL) and water (5 mL), and extracted with ethyl acetate (3x15 mL). The combined organics were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated to give 1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (46 mg, 43%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃, δ): 9.09 (s, 1H), 9.12 (s, 1H), 8.27 (s, 1H), 7.62 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H).

Step F: (+/-)-3-(4-(1-(4-(4-cvano-1H-pvrazol-1-vl)phenoxy)butvl)benzamido) propanoic acid

The title compound was prepared by a method analogous to that described for Example 77 using Intermediate (48), 1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile, triphenylphosphine, and diethylazodicarboxylate. Analytîcal LCMS: rétention time 1.310 minutes (Atlantis C₁₈ 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 433.2.

Example 89: (+/-)-3-(4-(1 -(4-(4,5.6.7-tetrahvdro-2H-indazol-2-yl)phenoxv)butvl) benzamido)propanoic acid

Step A: (+/-)-methyl 4-(1-(4-(4,5.6,7-tetrahydro-2H-indazol-2-yl)phenoxv)butvl) benzoate

Intermediate (27) (111 mg, 0.271 mmol) was combined with 4,5,6,7-tetrahydro-2H-indazole (39.4 mg, 0.323 mmol), copper(l) iodide (2.7 mg, 0.014 mmol), potassium carbonate (78.6 mg, 0.569 mmol), frans-dimethylcyclohexane-1,2-diamine (9.0 pL, 0.054 mmol), and toluene (2 mL). The reaction was refluxed for 16 hours, then cooled to room température, and partitioned between

149 ethyl acetate and water/ammonium hydroxide. The organic layer was washed with 0.5N HCl and brine, dried over magnésium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave (+/-)-methyl 4-(1-(4-(4,5,6,7-tetrahydro2H-indazol-2-yl)phenoxy)butyl)benzoate (0.056g, 51%) as a clear oil. ¹H NMR (400 MHz, CDCI₃₁δ): 8.01 (d, J = 8.2 Hz, 2H), 7.35 - 7.48 (m, 5H), 6.84 (d, J = 9.0 Hz, 2H), 5.15 (dd, J = 7.6, 5.1 Hz, 1 H), 3.91 (s, 3 H), 2.74 (t, J = 6.2 Hz, 2H), 2.58 (t, J = 6.1 Hz, 2H), 1.94 - 2.04 (m, 1 H), 1.70-1.90 (m, 5H), 1.37-1.56 (m, 2H), 0.96 (t, 3H). MS (M+1): 405.2.

Step B: (+/-)-3-(4-(1-(4-(4_>5.6.7-tetrahydro-2H-indazol-2-vl)phenoxv)butvl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using methyl 4-(1-(4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy) butyl)benzoate. Column: Waters Atlantis C18 4.6 x 50mm, 5pm; Modifier: TFA 0,05%; Gradient: 95% H₂0 /5% acetonitrile linear to 5% H_a0 / 95% acetonitrile over 4.0 min, hold at 5% H₂0 / 95% acetonitrile to 5.0min. Flow: 2.0 mL / min.; Rétention time: 3.39 minutes. MS (M+1): 462.2.

Example 90: (+/-)-3-(4-(1 -(4-(5.6-dihvdrocvclopentafclpvrazol-2(4H)vl)phenoxv)butvl)benzamido)propanoic acid

Step A: (+/-)-methvl 4-(1-(4-(5.6-dihvdrocvclopenta(clpvrazol-2(4H)-vl)phenoxv)butvl)benzoate

The title compound was prepared by a method analogous to that described for Example 89,

Step A, using 1,4,5,6-tetrahydro-cyclopenta[c]pyrazole hydrochloride. The product obtained was a

4:1 mixture of regioisomers. ¹H NMR (500 MHz, CDCI₃, δ): 8.01 (d, J = 8.1 Hz, 2H), 7.46 - 7.29 (m,

5H), 6.88-6.79 (m, 2H), 5.19-5.11 (m, 1 H), 3.91 (s, 3H), 2.93-2.36 (m, 6H), 2.04-1.94 (m,

1H), 1.87-1.75 (m, 1H), 1.56-1.38 (m, 2H), 0.97 (t,3H). MS (M+1): 391.3.

150

Step B: (+/-)-3-(4-(1-(4-(5,6-dihvdrocyclopentafôlpvrazol-2(4H) vll phenoxy) butvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using methyl 4-(1-(4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)phenoxy)butyl)benzoate. ¹H NMR (400 MHz, CDCI₃₁ δ): 7.72 (d, J = Θ.2 Hz, 2H), 7.45 - 7.30 (m, 5H), 6.90 - 6.76 (m, 3H), 5.13 (dd, J = 7.5, 5.4 Hz, 1 H), 3.76 - 3.64 (m, 2H), 2.94 - 2.73 (m, 2H), 2.73 - 2.35 (m, 6H), 2.10 - 1.93 (m, 1H), 1.8Θ- 1.74 (m, 1H), 1.64-1.36 (m, 2H), 0.96 (t, 3H). MS (M+1): 448.4.

Example 91 : (+/-)-3-(4-(1 -(4-(2H-indazol-2-yl)phenoxv)butvl)benzamido)propanoic acid

Step A: f+/-)-methyl 4-i1-(4-(2H-indazol-2-vl)phenoxv)butvl)benzoate

The title compound was prepared by a method analogous to that described for Intermediate (27), using Intermediate (55). ’H NMR (400 MHz, CDCI₃, δ): 8.26 (s, 1H), 8.03 (d, J= 8.4 Hz, 2H),

7.75 (d, J = 9.0 Hz, 1 H), 7.72 - 7.64 (m, 3H), 7.44 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.4 Hz, 1 H), 7.14-7.05 (m, 1 H), 6.95 (d, J = 9.0 Hz, 2H), 5.21 (dd, J = 7.6, 5.3 Hz, 1H), 3.91 (s, 3H), 2.11 -

1.97 (m, 1 H), 1.91-1.77 (m, 1 H), 1.65 - 1.37 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). MS (M+1 ): 211.2. Step B: (+/-)-3-(4-(1-(4-(2H-indazol-2-vl)phenoxv)butyl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 20 using methyl 4-(1-(4-(2H-indazol-2-yl)phenoxy)butyl)benzoate. Column: Waters Atlantis C18 4.6 x 50mm, 5pm; Modifier: TFA 0.05%; Gradient: 95% H₂0 / 5% acetonitrile linear to 5% H₂0 / 95% acetonitrile over 4.0min, hold at 5% H₂0 / 95% acetonitrile to 5.0min. Flow: 2.0 mL / min.; Rétention time: 3.23 minutes. MS (M+1): 458.2.

Example 92: (+/-)-3-(4-(1 -(4-(4-methvl-1H-1.2,3-triazol-1-vl)phenvlamino)butyl) benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 62 using Intermediate (47) and Intermediate (23). ’HNMR (400 MHz, CD₃OD, δ): 8.0 (s, 1H), 7.76 (d,

2H), 7.48 (d, 2H), 7.37 (d, 2H), 6.65 (d, 2H), 4.47 (m, 1H), 3.62 (m, 2H), 2.63 (m, 2H), 2.36 (s, 3H),

1.89 - 1.84 (m, 1 H), 1.79 - 1.72 (m, 1 H), 1.57 - 1.45 (m, 1 H), 1.44-1.38 (m, 1 H), 1.00 (m, 3H).

151 ο ο

MS (M+1): 422.4.

Example 93: (+/-)-3-(2-(3-methvl-1 -(4-(4-(trifluoromethvl)-1 H-pyrazol-1 vl)phenvl)butvlamino)pvrimidine-5-carboxamido)propanoic acid

Steo A: f+/-)-ethvl 2-(3-methvl-1 -(4-f4-(trifluoromethvlM H-ovrazol-1 vl)phenvl)butvlamino)pyrimidine-5-carboxvlate

A vial was charged with Intermediate (14) (180 mg, 0.605 mmol), éthanol (5 mL), ethyl 2chloropyrimidine-5-carboxylate (115 mg, 0.665 mmol), and diisopropylamine (156 mg, 1.21 mmol). The resulting mixture was heated under microwave irradiation at 100 °C for 20 minutes. The reaction mixture was diluted wîth water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/-)-ethyl 2-(3-methyl-1 -(4-(4-(trifIuoromethyI)-1 H-pyrazol-1 -yljphenyl) butylamino)pyrimidine-5carboxylate (120 mg, 44%). Ή NMR (400 MHz, CDCI₃, δ): 8.80 (s, 2H), 8.13 (s, 1H), 7.88 (s, 1H), 20 7.62 (d, 2H), 7.46 (d, 2H), 5.97 - 5.95 (m, 1 H), 5.29 - 5.22 (m, 1 H), 4.34 - 4.29 (m, 2H), 1.82 -

1.78 (m, 1 H), 1.70 - 1.66 (m, 2H), 1.35 - 1.32 (m, 3H), 0.99 - 0.95 (m, 6H).

152

Step B: (+/-)-3-(2-(3-methvl-1 -(4-(4-(trifluoromethvl)-1 H-pyrazol-1 -vhohenvl) butvlaminoiDvrimidine-5-carboxamido)propanoic acid

To a solution of ethyl 2-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)butylamino)pyrimidine-5-carboxylate (120 mg, 0.268 mmol) in anhydrous tetrahydrofuran (3 mL) was added 1N lithium hydroxide (0.83 mL, 0.83 mmol). The mixture was stirred at 50 °C overnight. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in N./V-dimethylformamide (5 mL). 0-(7-Azabenzotriazol-1-yl)-/V,/V,/V',/Vtetramethyluronium hexafluorophosphate (149 mg, 0.393 mmol) was added. The mixture was stirred for 45 minutes at room température. Methyl 3-aminopropionate hydrochloride (54.3 mg, 0.393 mmol) and diisopropylethylamine (136 mg, 1.05 mmol) were added. The resulting mixture was stirred at room température for 2 hours. The mixture was diluted with aqueous ammonium chloride and ethyl acetate. The layers were separated and the organic layer was washed with water, dried over sodium sulfate, filtered and concentrated.

The residue was dissolved in water (5 mL) and tetrahydrofuran (5 mL). 1N Lithium hydroxide (0.774 mL, 0.774 mmol) was added. The mixture was stirred at room température for 2 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Kromasil Eternity-5-C18 150 x 30mm, 5pm; modifier: formic acid 0.225%; gradient: 36 to 56% acetonitrile in water) gave (+/-)-3-(2-(3-methyl-1-(4-(4-(trifluoromethyl)-1/-Lpyrazol-1yl)phenyl)butylamino)pyrimidine-5-carboxamido)propanoic acid (50 mg). ’H NMR (400 MHz, CD₃OD, δ): 8.70 (s, 1 H), 8.64 (s, 2H), 7.96 (s, 1 H). 7.73 (d, 2H), 7.53 (d, 2H), 5.27 - 5.21 (m, 1H), 3.62-3.53 (m, 2H), 2.68-2.53 (m, 2H), 1.94-1.82 (m, 1H), 1.79-1.68 (m, 1H), 1.68-1.58 (m, 1H), 1.06-0.91 (m, 6H). MS (M+1): 491.4.

Example 94: (+/-)-3-(4-(ονοΙορθηίνΙ(6-(4-(ΐΓΐίΙυοΓθΓΊΊθΐίινΙ)-1/-/-ρνΓ3ζοΙ“1-νΙ) ovridine-3vlamino)methvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (31) and Intermediate (32). ’H NMR (400 MHz, CDCI₃, δ): 8.54 (s, 1 H), 7.82 (s, 1 H), 7.77 (d, J = 2.73 Hz, 1 H), 7.69 (d, J = 8.19 Hz, 2 H), 7.60 (d, J = 8.97 Hz, 1 H), 7.40 (d, J =

8.19 Hz, 2 H), 7.01 -6.95 (m, 1 H), 6.93 (dd, J = 8.88, 2.83 Hz, 1 H), 4.15 (d. J = 8.58 Hz, 1 H), 3.77-3.66 (m, 2 H), 2.76 - 2.65 (m, 2 H), 2.25-2.12 (m, 1 H), 2.00-1.87 (m, 1 H), 1.73-1.16 (m, 7H). MS (M+1): 502.2.

153

Example 95: 3-i4-(cvclopentvl(6-(4-(trifluoromethvl)-1/-/-pyrazol-1 -vl)pvridine-3vlamino)methvl)benzamido)propanoic acid. Isomer 1

The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(6-(4-(trifluoromethyl)1 H-pyrazol-1 -yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, the compound of Example 94, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 80/20 COü/methanol. Flow Rate: 2.5 mL/min. Modifier: 0.2% isopropylamine. Rétention time: 3.49 minutes.

Example 96: 3-(4-(cvclopentvl(6-(4-(trifluoromethvlMH-ovrazol-1-vli pyridine-3vlamino)methvObenzamido)propanoic acid. Isomer 2

The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(6-(4-(trifluoromethyl)1 H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, the compound of Example 94, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 80/20 COa/methanol. Flow Rate: 2.5 mL/min. Modifier: 0.2% isopropylamine. Rétention time: 4.38 minutes.

Example 97: 3-(4-(cvclopentvl(6-(4-(trifluoromethvD-1H-imidazol-1 -vDpyridin-3vlamino)methvl)benzamido)propanoic acid. Isomer 1

The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(6-(4-(trifluoromethyl)1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid, the compound of Example 8, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 CO2/2propanol. Flow Rate: 2.5 mL/min. Modifier: none. Rétention time: 3.92 minutes.

154

Example 98: 3-(4-(cvclopentvl(6-(4-(trifluoromethvh-1H-imidazol-1 -vl)pyridin-3vlamino)methvl)benzamido)proDanoic acid. Isomer 2

The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H5 imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid, the compound of Example 8, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 CO2/2propanol. Flow Rate: 2.5 mL/min. Modifier: none. Rétention time: 4.91 minutes.

Examole 99: (+/-)-3-(2-(ονοΙοίΊθχνΙ(6-(4-(νΐίΙυοΓθΠΊθΐΐΊνΙ)-1 H-imidazol-1 -vhpvridine-3vl)methvlamino)nicotinamido)propanoic acid

Step A: i+Z-Tmethyl 6-(cvclohexvl(4-(4-(trifluoromethyl)-1H-pyrazol-1-vl)phenvl) methvlaminolnicotinate

A round bottom flask equipped with a condenser was charged with Intermediate (2) (230 mg, 0.958 mmol) and 2-methyl-2-propane-sulfinamide (120 mg, 0.958 mmol) in dichloromethane (5 mL). Titanium(IV) ethoxide (437 mg, 1.92 mmol) was added in one portion and the mixture was stirred at reflux for 2 hours. Then methanol (1.5 mL) and saturated sodium bicarbonate (1.5 mL) were added to the reaction. A precipitate formed. The mixture was diluted with ethyl acetate and the slurry was filtered through celite, rinsing with ethyl acetate. The organics were dried over

sodium sulfate, filtered and concentrated to give (E)-/V-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 155 yl)benzylidene)-2-methylpropane-2-sulfinamide (290 mg, 0.845 mmol).

This crude residue was diluted in tetrahydrofuran (3 mL) and cooled to -78 °C. Cyclohexyl magnésium chloride (1.27 mL, 2M in diethyl ether, 2.54 mmol) was then added dropwise. The reaction mixture was warmed to room température and stirred for 3 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was dissolved in methanol (4.2 mL). Hydrogen chloride (4M in dioxane) was added. The mixture was stirred at room température for 3 hours. The reaction was then concentrated. To this crude residue was added W./V-dimethylformamide (1 mL), methyl

6-fluoronicotinate (155 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol). The reaction was heated to 120°C for 2 hours. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 - 45% ethyl acetate in heptane) gave (+/-)-methyl 6-(cyclohexyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenyl)methylamino)nicotinate. ’H NMR (400 MHz, CDCI₃, δ): 8.69 (d, J = 1.56 Hz, 1 H), 8.13 (s, 1 H), 7.93 - 7.82 (m, 2 H), 7.67 - 7.53 (m, 2 H), 7.45 - 7.33 (m, 2 H), 6.16 (d, J = 8.78 Hz, 1 H), 5.67-5.51 (m, 1 H), 4.61-4.41 (m, 1 H), 3.81 (s, 3 H), 1.94-0.98 (m, 11 H). MS (M+1): 459.1.

Step B: (+/-)-tert-butvl 3-(2-icvclohexyl(4-(4-(trifluoromethvl)-1H-pyrazol-1vl)phenyl)methvlamino)nicotinamido)propanoate

Lithium hydroxide (800 mg) was added to a solution of methyl 6-(cyclohexyl (4-(4(trifluoromethyl)-l H-pyrazol-1-yl)phenyl)methylamino)nicotinate (129 mg, 0.281 mmol) in methanol (1.67 mL), tetrahydrofuran (1.67 mL), and water (1.67 mL). The mixture was stirred at room température for 4 hours. The mixture was acidified with 4N hydrochloric acid and extracted with three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated.

To the crude acid was added A/,A/-dimethylformamide (2 mL), tert-butyl 3-aminopropanoate

156 hydrochlorîde (94.1 mg, 0.518 mmol), 0-(7-azabenzotriazol-1-yl)-A/,/\/,/\/',/V'-tetramethyluronium hexafluorophosphate) (197 mg, 0.518 mmol), and diisopropylethylamine (251 pL, 1.44 mmol). The mixture was stirred at room température ovemight and was then concentrated. Purification by column chromatography (0 - 45% ethyl acetate in heptane), gave (+/-)-tert-butyl 3-(2(cyclohexyl(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido) propanoate. ’H NMR (400 MHz, CDCI₃, δ): 8.49 - 8.40 (m, 1 H), 8.12 (s, 1 H), 7.85 (s, 1 H), 7.75 - 7.66 (m, 1 H),

7.59 (d, J = 8.41 Hz, 2H), 7.36 (d, J = 8.41 Hz, 2H), 6.73 - 6.58 (m, 1 H), 6.24 - 6.10 (m, 1 H), 5.58

- 5.41 (m, 1 H), 4.57 - 4.38 (m, 1 H), 3.66 - 3.50 (m, 2H), 2.53 - 2.40 (m, 2H), 2.08 - 0.95 (m, 11 H), 1.41 (s, 9H). MS (M+1): 572.3.

Step C: (+/-)-3-(2-(cyclohexvl(4-(4-(trifluoromethyl)-1H-pvrazol-1 vl)phenvl)methylamino)nicotinamido)propanoic acid

Trifluoroacetic acid (0.30 mL) was added to a solution of tert-butyl 3-(2-(cyclohexyl(6-(4(trifluoromethyl)-1H-pyrazol-1 -yl)pyridine-3-yl)methylamino)nicotinamido)propanoate (30 mg, 0.052 mmol) in dichloromethane (0.4mL). The mixture was stirred at room température for 2 hours. The reaction was concentrated and the residue was co-evaporated with dichloromethane, ethyl acetate and toluene several times, to give (+/-)-3-(2-(cyclohexyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenyl)methylamino)nicotinamido)propanoîcacid, as a solid. ’H NMR (400 MHz, CDCI₃, δ): 9.81 (br. s, 1 H), 8.94 (br. s, 1H), 8.31 - 8.21 (m, 1 H), 8.15 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.58 Hz, 2H), 7.61 - 7.51 (m, 1 H), 7.39 (d, J = 8.39 Hz, 2H), 6.70 - 6.58 (m, 1 H), 4.29 - 4.17 (m, 1 H), 3.69

- 3.53 (m, 2H), 2.76 - 2.65 (m, 2H), 2.00 - 0.91 (m,-11 H). MS (M+1): 516.2.

Example 100: (+/-)-3-(4-(3,3-dimethvl-1-f6-(4-(trifluoromethvl)-1H-imidazol-1-vh pyridine-3ylamino)butvl)benzamido)propanoic acid

Step A: (+/-)-methvl 4-(3,3-dimethvl-1-i6-(4-(tnfluoromethvl)-1H-imidazol-1-vl)pyricline-3vlaminolbutvIÎbenzoate

157

To a solution of Intermediate (43) (220 mg, 0.939 mmol) and Intermediate (6) (214 mg,

0.939 mmol) in methanol (48 mL) was added decaborane (57.3 mg, 0.469 mmol). The mixture was stirred at room température for 48 hours. The reaction mixture was concentrated and purification by préparative TLC gave methyl 4-(3,3-dimethyl-1-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridine5 3-ylamino)butyl) benzoate (50 mg, 12%). ¹H NMR (400 MHz, CDCI₃, δ): 8.03 (s, 1H), 7.94 (d, 2H),

7.71 (m, 2H), 7.32 (d, 2H), 7.01 (d, 1H), 6.78-6.75 (m, 1H), 4.41 -4.34 (m, 1 H), 3.83 (s, 3H),

1.71-1.68 (m, 2H), 0.95 (s, 9H).

Step B: (+/-)-3-(4-(3,3-dimethyl-1 -(6-(4-(trifluoromethvl)-1H-imidazol-1-vl)pyridine-3vlamino)butvl)benzamido)oropanoic acid

To a solution of methyl 4-(3,3-dimethyl-1 -(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridine-3ylamino)butyl)benzoate (50 mg, 0.11 mmol) in tetrahydrofuran (5 mL) was added 2N lithium hydroxide (5 mL, 10 mmol). The reaction mixture was heated to 70°C for 12 hours. The mixture was adjusted to pH = 2 by addition of 1N aqueous hydrochloric acid and the resulting solution extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in /V,A/-dimethylformamide (5 mL). O-(7-Azabenzotriazoll-yO-N.N.N’.N’-tetramethyluronium hexafluorophosphate (70.0 mg, 0.184 mmol) was added and the solution stirred at room température for 30 minutes. Methyl 3-aminopropionate hydrochloride (19.3 mg, 0.138 mmol) was added followed by diisopropylamine (47.6 mg, 0.37 mmol). The resulting mixture was stirred at room température for 1 hour. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (4 mL) and 2N Lithium hydroxide (4 mL, 8 mmol) was added. The mixture was stirred at room température for 1 hour. 1N Aqueous hydrochloric acid was added to adjust the pH = 2 and the solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150 x 30mm, Spm; modifier: formic acid 0.225%; gradient: 39 to 59% acetonitrile in water) gave (+/-)-3(4-(3,3-dimethyl·1-(6-(4-(trifluoromθthyl)-1H-imidazol-1-yl)pyΓidΐnθ-3-ylamino)butyl)benzamido) propanoic acid (22.7 mg, 41%). ¹H NMR (400 MHz, CD₃OD, δ): 8.21 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.65 (d, 2H), 7.36 (d, 2H), 7.26 (d, 1H), 6.94 (m, 1 H), 4.48-4.45 (m, 1H), 3.51 -3.48 (m,

2H), 2.53-2.49 (m, 2H), 1.81-1.75 (m, 1H), 1.58-1.53 (m, 1H), 0.94 (s, 9H). MS (M+1): 504.3.

Example 101 : (+/-)-3-(4-(cvclohexvl(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridine-3vlamino)methvl)benzamido)propanoic acid

15Θ

The title compound was prepared by a method analogous to that described for Example 100 using Intermediate (44) and Intermediate (32). ’HNMR (400 MHz, CD₃OD, δ): 8.64 (s, 1H), 7.86 (s, 1H), 7.74-7.72 (m, 3H), 7.55 (d, 1H), 7.42 (d, 2H), 7.04 (m, 1H), 4.19 (m, 1H), 3.59 (m, 2H), 2.60 (m, 2H), 2.07 - 2.04 (m, 1 H), 1.79-1.66 (m, 4H), 1.43 - 1.40 (m, 1 H), 1.30 - 1.04 (m, 5H). MS (M+1): 516.2.

Example 102: (+/-)-3-(6-(3-methvl-1 -(5-methyl-6-i4-(trifluoromethvn-1 H-pyrazol-1 -vlÎpyridin-3vlamino)butvl)nicotinamido)propanoic acid

Step A: 5-methvl-6-(4-(trifluoromethvl)-1 H-pyrazol-1 -vl)pyridin-3-amine N==\ F

-

H₂N

The title compound was prepared by a method analogous to that described for Intermediate (6) using 4-trifluoromethyl-1H-pyrazole and 2-chloro-3-methyl-5-nitro-pyrîdine. ¹H NMR (400 MHz, CDCIa, δ): 8.21 (s, 1 H), 7.85 (s, 1 H), 7.75 (d, J = 2.4 Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 3.85 (s, 2H), 2.32 (s, 3H).

Step B: methyl 6-(f5-methvl-6-(4-(trifluoromethvl)-1 H-pyrazol-1-vl)pyridin-3vliminolmethvDnicotinate

A mixture of methyl 6-formylnicotinate (251.3 mg, 1.52 mmol) and 5-methyl-6-(420 (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine (369 mg, 1.52 mmol) in toluene (8mL) was heated at reflux under nitrogen overnight. The reaction mixture was concentrated to give methyl 6-((5methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylimino)methyl)nicotinate (592 mg, 100%).

¹H NMR (400 MHz, (CDgbSO, δ): 9.09 (d, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.35-8.30 (m, 2H), 8.20

159

-8.17 (m, 1H), 8.11 (s, 1H), 7.90 (d, 1H), 3.79 (s, 3H), 2.32 (s, 3H).

Step C: (+/-)-methvl 6-(3-mθthvl·1-(5-methvl·6-(4-(trifluoromethvl¾-1H-pvrazol-1-vl¾pvridin-3vlaminoÎbutvDnicotinate

To a 0°C solution of methyl 6-((5-methyl-6-(4-(trifiuoromethyl)-1H-pyrazol-1-yl)pyridin-3ylimino)methyl)nicotinate (592 mg, 1.52 mmol) in anhydrous tetrahydrofuran (8 mL) was added isobutylmagnesium bromide (1.0 mL, 2.0M in THF, 2.0 mmol). The reaction mixture was allowed to warm to room température and stir for 3 hours. Saturated aqueous ammonium chloride (10 mL) was added and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by préparative TLC gave methyl

6-(3-methyl-1-(5-methyl-6-(4-(trifluoromethyl)-1/-/-pyrazol-1-yl)pyridin-3-ylamir)o)butyl)nicotinate (250 mg). ’H NMR (400 MHz, CDCI₃, δ): 9.18-9.17 (m, 1H), 8.26-8.23 (m, 1H), 8.16 (s, 1H),

7.81 (s, 1 H), 7.69 - 7.68 (m, 1 H), 7.40 - 7.38 (m, 1 H), 6.79 - 6.78 (m, 1 H), 4.65 - 4.58 (m, 1 H), 4.00 (s, 3H), 2.27 (s, 3H), 1.78-1.66 (m, 3H), 1.02 (d, 3H), 0.96 (d, 3H).

Step D: (+/-L3-(6-(3-methvl-1-f5-methvl-6-(4-(trifluoromethvl)-1H-pyrazol-1-vl) pyridin-3vlamino)butvl)nicotinamido)propanoic acid

The title compound was prepared by a method analogous to that described for Example 100 step B using methyl 6-(3-methyl-1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3ylamino)butyl)nicotinate. Ή NMR (400 MHz, CD₃OD, δ): 8.91 (d, 1H), 8.32 (s, 1H), 8.14-8.11 (m, 1 H), 7.91 (s, 1 H), 7.65 - 7.64 (d, 1 H), 7.55 - 7.53 (m, 1 H), 6.90 - 6.89 (m, 1 H), 4.63 - 4.60 (m, 1 H), 3.62 -3.59 (m, 2H), 2.63 - 2.59 (m, 2H), 2.08 (s, 3H), 1.81-1.78 (m, 2H), 1.70-1.65 (m, 1H), 1.01 (d, 3H), 0.97 (d, 3H). MS (M+1): 505.3.

Example 103: 3-(4-(1-(4-ί4-(trifluoromθthvlΐ-1/7-Dvrazol·1-vl)phenvlamίnoΐbutvD benzamîdo)propanoic acid. Isomer 1

Step A: 4-(1-(4-Î4-(trifluoromethvh-1H-pvrazol-1-vl)phenvlamino)butvl)benzoic acid

160

The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (5) and Intermediate (52). MS (M-1): 402.0.

Step B; ethyl 3-(4-(1-(4-(4-(trifluoromethvl)-1 H-pyrazol-1-vDphenylaminolbutvl) benzamidolpropanoate, Isomers 1 and 2

To a mixture of ethyl 3-aminopropanoate hydrochloride (418 mg, 2.72 mmol), 4-(1-(4-(4(trifluoromethyl)-lH-pyrazol-1 -yl)phenylamino)butyl) benzoic acid (732 mg, 1.82 mmol), 1hydroxybenzotriazole hydrate (292 mg, 1.91 mmol), and A/,A/-diisopropylethylamine (1.20 mL, 7,26 mmol) in tetrahydrofuran (18.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (557 mg, 2.90 mmol). The mixture was stirred for 48 hours at ambient température. The réaction mixture was concentrated and the crude material was purified by column chromatography (0 -100% ethyl acetate in heptane) to afford racemic ethyl 3-(4-(1-(4-(4(trifluoromethyl) -1 H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoate (684 mg, 85%) as a solid. The racemate was further purified via chiral SFC to afford 300 mg of Isomer 1 and 300 mg of Isomer 2, which were used in conversion to the final enatiopure products. ’H NMR (400 MHz, CDCI₃,ô ): 7.94 (q, J = 0.8 Hz, 1 H), 7.81 (s, 1 H), 7.73 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H),

7.32 (d, J = 9.0 Hz, 2H), 6.84 (t, J = 5.8 Hz, 1 H), 6.53 (d, J = 8.8 Hz, 2H), 4.42 - 4.34 (m, 1 H), 4.31 (d, J =4.7 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.71 (q, J =6.1 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 1.88

- 1.71 (m, 2H), 1.53-1.31 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H). Chiral SFC:

Chiralpak AD-H, 10 x 250mm; Mobile Phase 65:35 COg/methanol, 65mL/min, Rétention time: 3.95min (Isomer 1), 6.81min (Isomer 2).

Step C: 3-(4-(1-(4-(4-itrifluoromethvl)-1H-pvrazol-1-vnphenvlamino)butvl) benzamidoÏpropanoic acid. Isomer 1

Isomer 1 of ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl) phenylamino)butyl)benzamido)propanoate (0.300 g, 0.597 mmol) was dissolved in methanol (8.0 mL) and tetrahydrofuran (4.2 mL) and treated with 2N aqueous lithium hydroxide (4.2 mL, Θ.4

161 mmol). The mixture was stirred at ambient température for 4 hours. The crude reaction mixture was concentrated and the residual solid was dissolved in water and acîdified to pH = 4 with 1 .OM aqueous hydrochloric acid. A brown precipitate formed. The precipitate was collected by filtration, washed with water, and dried in vacuo to afford 3-(4-(1-(4-(4-(trifluoromethyl)-1/7-pyrazol-1yl)phenylamino)butyl)benzamido)propanoic acid, Isomer 1 (0.220 g, 78%) as a solid. ¹H NMR (400 MHz, CDCI3, δ): 7.91 (s, 1 H), 7.78 (s, 1 H), 7.67 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.03 - 6.88 (m, 1 H), 6.60 - 6.42 (m, 2H), 4.33 (t, J = 6.3 Hz, 1 H), 3.64 (s, 2H),

2.72-2.54 (m, 2H), 1.87-1.65 (m, 2H), 1.51-1.22 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H). MS (M+1):

475.2.

Example 104: 3-(4-(1-i4-(4-(trifluoromethvlÎ-1H-pvrazol-1-vhphenvlamino)butvl) benzamidoÏpropanoic acid. Isomer 2

The title compound was prepared by a method analogous to that described for Example 103 using Isomer 2 of ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenylamino)butyl)benzamido)propanoate. ’H NMR (400 MHz, CDCI₃₎ δ): 7.91 (s, 1H), 7.78 (s, 1 H), 7.67 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.03 - 6.88 (m, 1 H), 6.60 - 6.42 (m, 2H), 4.33 (t, J = 6.3 Hz, 1H), 3.64 (s, 2H), 2.72 - 2.54 (m, 2H), 1.87 - 1.65 (m, 2H), 1.51 - 1.22 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H). MS (M+1): 475.2.

Example 105 : f+/-)-3-(4-(3-methvl-1 -(5-methvl-6-(4-itrifluoromethvl)-1 H-pyrazol-1 -vl)pyridin-3vlaminoÎbutvl)benzamido)propanotc acid

The title compound was prepared by a method analogous to that described for Example 62, using Intermediate (58) and 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine (Step Aof Example 102). ’H NMR (400 MHz, CO_aOD, δ): 8.32 (s, 1 H), 7.92 (s, 1 H), 7.77 (dd, J = 2.4, 8.4 Hz, 2 H), 7.65 (d, J =

2.4 Hz, 1 H), 7.48 (dd, J = 2.0, 8.4 Hz, 2 H), 6.91 (s, 1 H), 4.54-4.58 (m, 1 H), 3.61 (t,J = 4.8 Hz, 2 H), 2.60

162

-2.64 (m, 2 H), 2.08 (d, J = 2.0 Hz, 3 H), 1.72-1.86 (m, 2 H), 1.53-1.61 (m, 1 H), 0.97 - 1.04 (m, 6 H).

MS (M+1): 504.3,

Example 106 : (+/-)-3-(4-icvclobutvlf6-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)pyridln-3vlamlno)methvl)benzamido)Dropanoic acid

The title compound was prepared by a method analogous to that described for Example 100, using Intermediate (59) and Intermediate (32). ¹H NMR (400 MHz, CDCI₃, δ): 8.66 (s, 1 H), 7.88 (s, 1 H), 7.76 (d, J = 1.6 Hz, 1 H), 7.75 (S, 2 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.48 (d, J =1.6 Hz, 1 H), 7.47 (s, 1 H), 7.05 (dd, J = 2.8, 8.8 Hz, 1 H), 4.36 (d, J = 8.4 Hz, 1 H), 3.60 (t, J = 6.0 Hz, 2 H), 2.59-2.68 (m, 3 H), 2.24 (s, 1 H), 1.75 -2.00 (m, 5 H). MS (M+1): 510.2.

Example 107: (+/-)-3-f4-(2-cvcloproDvl-1-(6-f4-(trifluoromethvl')-1H-Dvrazol-1-vDDvridin-3vlamino)ethvl)benzamldo)Dropanoic acid

O o

F

The title compound was prepared by a method analogous to that described for Example 100, using Intermediate (60) and Intermediate (32). ’H NMR (400 MHz, CD₃OD, δ): 8.61 (s, 1 H), 7.83 (s, 1 H), 7.70-

7.72 (m, 3 H), 7.54 (d, J = 6.4 Hz, 1 H), 7.46 (d, J = 6.4 Hz, 2 H), 7.01 (d, J = 6.4 Hz, 1 H), 4.48 - 4.52 (m, 1 H), 3.55 (t, J = 6.8 Hz, 2 H), 2.56 (t, J = 6.8 Hz, 2 H), 1.78 - 1.89 (m, 1 H), 1.52 - 1.61 (m, 1 H), 0.67 -0.79 (m, 1 H), 0.31 - 0.49 (m, 2 H), 0.00 - 0.14 (m, 2 H). MS (M+1) 488.4.

Example 108: (+/-)-3-(4-(1-(3-methvl-4-(4-(trifluoromethvl)-1H-pyrazol-1vl)phenoxv)butvl)benzamÎdo)proDanoic acid o O

F

163

The title compound was prepared by a method analogous to that described for Example 86, usina

Intermediate (61). H NMR (400 MHz, CD₃OD, 5): 8.23 (s, 1 H), 7.95 (s, 1 H), 7.79 (d, J = 8.0 Hz. 2 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.8 Hz, 1 H), 7.90 (s, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 5.36 - 5.39 (m, 1 H),

3.61 - 3.64 (m, 2 H), 2.62 - 2.65 (m, 2 H), 2.06 (s, 3 H), 1.98 - 2.05 (m, 1 H), 1.81 - 1.86 (m, 1 H) 1.54 1.58 (m, 1 H), 1.45-1.51 (m, 1 H), 0.97-1.01 (m, 3 H). MS (M+1) 490.4.

Example 109: 3-(3-fluoro-4-(1 -(6-(4-(trifluoromethvh-1H-Pvrazol-1-vl)pyridin-3vlamino)butvObenzamido)proDanoic acid. Isomer 1

Step A: (+/-)-methvl 3-ίΙυοΓθ-4-(1-(6-(4-(1πίΙυοΓθΠΊβΐΐΊνΙΜ/·/-ρνΓ3ΖθΙ-1-νΙ)ονΓί8ίη-3-νΐ8ΓΤΊΐηο)Ρυΐν066ηζο3ΐθ

Decaborane (65.4 mg, 0.535 mmol) was added to a solution of Intermediate (32) (244 mg, 1,07 mmol) and Intermediate (62) (240 mg, 1.07 mmol) in methanol (8 mL). The reaction was heated to 60 ’C for 24 hours. The reaction was cooled to 35 ’C and stirred for another 24 hours. The reaction was concentrated and purified by flash column chromatography to give (+/-)-methyl 3-fluoro-4-(1-(6-(4-(trifluoromethyl)-1Hpyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate (400 mg, 86%) as a yellow oil. ¹H NMR (400 MHz, CDCI_3l δ):

8.55 (s, 1 H), 7.60 - 7.90 (m, 5 H), 7.29 - 7.33 (m, 1 H), 6.86 (dd, J = 8.8, 2.8 Hz, 1 H), 4.64 -4.69 (m, 1 H), 4.16 (d, J = 6.8 Hz, 1 H), 3.83 (s, 3 H), 1.75 - 1.98 (m, 2 H), 1.21 - 1.45 (m, 2 H), 0.90 (t, J = 7.2 Hz, 3 H). Step B: methyl 3-(3-ίΙυοΓθ-4-(1-(6·(4·(ΐΓίίΙυοΓθΠΊ6ΐΐΊνΙ)-1Η-ρνΓ3ζοΙ·1-νΙ)ρνπΰίη-3vlamino)butvl)benzamido)prooanoate, Isomers 1 and 2

N Aqueous lithium hydroxide (15 mL, 30 mmol) was added to (+/-)-methyl 3-fluoro-4-(1 -(6-(4-

164 (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamlno)butyl)benzoate (400 mg, 0.9 mmol) in tetrahydrofuran (15 mL). The reaction was heated to 80 ’C for 12 hours. The reaction was cooled to room température and acidified to pH ~ 2 with 1 N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3x10 mL) and the combined organics were dried over sodium sulfate, filtered, and concentrated to give a yellow solid (380 mg). The solid was taken up in A/₍A/-dimethylformamide (30 mL) and O-(7-azabenzotriazol-1-yl)A/,/V,N',N’-tetramethyluronium hexafluorophosphate (1.86 g, 4.88 mmol) was added. The mixture was stirred at room température for 30 minutes. Methyl 3-aminopropanoate hydrochloride (511 mg, 3.66 mmol) and diisopropylethylamlne (1.26 g, 9.76 mmol) were added, and the reaction was stirred for 1 hour. The reaction was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave racemic methyl 3-(3-fiuoro-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3ylamino)butyl)benzamido)propanoate (450 mg, 96%) as a yellow solid. The racemate was further purified via chiral SFC to afford 180 mg of Isomer 1 and 150 mg of Isomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Gradient: 95% CO₂/ 5% éthanol linear to 60% CO₂/ 40% éthanol over 3.0 minutes. Flow: 4mL/min. Rétention time: 1,44 minutes (Isomer 1), 1.75 minutes (Isomer 2).

Steo C: 3-(3-fluoro-4-(1-(6-(4-(trifluoromethvl)-1rt-Dvrazol-1-vl)Dyridin-3-vlamino)butvl)benzamido)propanoic acid. Isomer 1

To a solution of Isomer 1 of methyl 3-(3-ίΙυοΓθ-4-(1-(6-(4-(ΙπίΙυθΓθΓΠ6ΗψΙ)-1/-/-ρνΓ3ΖθΙ-1-γΙ)ργτίΰίη-3ylamino)butyl)benzamido)propanoate (180 mg, 0.36 mmol) in tetrahydrofuran (8 mL) was added 2 N aqueous lithium hydroxide (B mL, 16 mmol). The reaction was stirred at room température for 1 hour. The reaction mixture was acidified to pH - 2 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (3x5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give 3-(3fluoro-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido) propanoic acid, Isomer 1 (104 mg, 59%) as a white solid. ’H NMR (400 MHz, CD₃OD, δ): 8.57 (s, 1 H), 7.77 (s, 1 H), 7.63 (s, 1 H),

7.50 (d, J = 8.8 Hz, 1 H), 7.43 - 7.46 (m, 2 H), 7.34 - 7.38 (m, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 4.66 (t, J = 6.8 Hz, 1 H), 3.48 (t, J = 6.8 Hz, 2 H), 2.50 (t, J = 6.8 Hz, 2 H), 1.65 - 1.82 (m, 2 H), 1.17 -1.49 (m, 2 H), 0.89 (t, J = 6.8 Hz, 3 H). MS (M+1) 494.2. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Gradient: 95% CO₂ / 5% éthanol linear to 60% CO_a / 40% éthanol over 3.0 minutes. Flow: 4mL/min. Rétention time: 1.74 minutes, 100% ee (Isomer 1).

Example 110 : 3-(3-fluoro-4-(1-(6-i4-(trifluoromethvl)-1H-pyrazol-1-vl)pyridin-3vlamino)butvDbenzamido)propanoic acid. Isomer 2

ΌΗ

The title compound was prepared by a method analogous to that described for Example 109, using

165

Isomer 2 of methyl 3-(3-fluoro-4-(1-(6-(4-(trifIuoromethyl)-1H-pyrazol-1-yl)pyridin-3ylamino)butyl)benzamido)propanoate in Step C. ¹H NMR (400 MHz, CD₃OD, δ): 8.57 (s, 1 H), 7.77 (s, 1 H),

7.63 (s, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.43 - 7.46 (m, 2 H), 7.34 - 7.38 (m, 1 H), 6.94 (d, J = 8.4 Hz. 1 H),

4.66 (t, J = 7.2 Hz, 1 H), 3.48 (t, J = 7.2 Hz, 2 H), 2.50 (t, J = 6.8 Hz, 2 H), 1.67-1.82 (m. 2 H), 1.29 - 1.48 (m, 2 H), 0.89 (t, J = 7.6 Hz, 3 H). MS (M+1) 494.2. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Gradient: 95% CO₂ ! 5% éthanol linear to 60% CO₂140% éthanol over 3.0 minutes. Flow: 4mL/mln. Rétention time: 1.42 minutes, 99% ee (Isomer 2).

Example 111: 3-f3-meÎhvl-4-(1-(6-(4-(trifluoromethvl)-1H-pvrazol-1-vl)pvridin-3vlamino)butvl)benzamido)propanoic acid. Isomer 1

Step A: methvl 3-(3-methvl-4-(1-(6-(4-(trifluoromethvl)-lH-pyrazol-1-vl)pvridin-3vlamlno)butvl)benzamido)proDanoate· isomers 1 and 2

The title compounds were prepared by a method analogous to that described in Steps A - B of Example 109, using Intermediate (63). Purification of racemic methyl 3-(3-methyl-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1yl)pyridin-3-yiamino)butyl)benzamido) propanoate via chiral SFC afforded 140 mg of Isomer 1 and 140 mg of Isomer 2, which were used in conversion to the final enantiopure products. ’H NMR (400 MHz, CDCI₃, δ):

8.60 (s, 1 H), 7.79 (s, 1 H), 7.59 - 7.66 (m, 3 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 6.75 -

6.82 (m, 2 H), 4.56 - 4.61 (m, 1 H), 4.26 (d, J = 4.8 Hz, 1 H), 3.66 - 3.72 (m, 5 H), 2.64 (t, J = 5.8 Hz, 2 H),

2.50 (s, 3 H), 1.73 - 1.78 (m, 2 H), 1.40 - 1.57 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3 H). Chiral SFC: Chiralpak AD2, 30 x 50mm, 3pm. Modifier: none. Mobile Phase: 60/40 COz/ethanol. Flow rate: 80 mL/min. Rétention time: 1.46 minutes (Isomer 1) and 2.13 minutes (Isomer 2).

Step B: 3-f3-methvl-4-(1-(6-(4-(trifluoromethvl)-1H-pvrazol-1-vl)pvridin-3-vlamino)butvl)bBnzamido)propanoic acid. Isomer 1

The title compound was prepared by a method analogous to that described in Step C of Example

166

109, using Isomer 1 of methyl 3-(3-methyl-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3ylamino)butyl)benzamido)propanoate. ¹H NMR (400 MHz, CD_aOD, δ): 8.65 (s, 1 H), 7.86 (s, 1 H), 7.63 (d, J = 2.8 Hz, 2 H), 7.53 - 7.58 (m, 2 H), 7.40 (d, J = 8.0 Hz, 1 H), 6.92 (dd, J = 8.8, 2.8 Hz, 1 H), 4.60 - 4.64 (m, 1 H), 3.58 {t, J = 6.4 Hz, 2 H), 2.59 (t, J = 7.0 Hz, 2 H), 2.52 (s, 3 H), 1.70 - 1.79 (m, 2 H), 1.61 - 1.67 (m, 1 H), 1.46-1.51 (m, 1 H), 0.99 (t, J = 7.2 Hz, 3 H). MS (M+1) 490.1. Chiral SFC: Chiralpak AD-H, 4.6 x 250mm, 5pm. Modifier: 0.05% DEA. Mobile Phase: 75/25 COz/ethanol. Flow rate: 35 mL/min. Rétention time: 3.92 minutes, 99.9% ee (Isomer 1).

Example 112: 3-(3-methvl-4-(1-(6-Î4-(trifluoromethvlM/-/-Dvrazo!-1-vl)Dvridin-3vlamino)butvl)benzamido)Dropanoic acid. Isomer 2

The title compound was prepared by a method analogous to that described for Example 111, using Isomer 2 of methyl 3-(3-methyl-4-(1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridln-3ylamino)butyl)benzamido)propanoate. ¹H NMR (400 MHz, CD_aOD, δ): 8.65 (s, 1 H), 7.86 (s, 1 H), 7.63 (d, J = 2.8 Hz, 2 H), 7.53 -7.58 (m, 2 H), 7.40 (d, J = 8.0 Hz, 1 H), 6.92 (dd, J = 8.8, 2.8 Hz, 1 H), 4.60 - 4.64 (m, 1 H), 3.58 (t, J = 6.4 Hz, 2 H), 2.59 (t, J = 7.0 Hz, 2 H), 2.52 (s, 3 H), 1.70 - 1.79 (m, 2 H), 1.61 - 1.67 (m, 1 H), 1.46 -1.51 (m, 1 H), 0.99 (t, J = 7.2 Hz, 3 H). MS (M+1) 490.1. Chiral SFC: Chiralpak AD-H, 4.6 x 250mm, 5pm. Modifier: 0.05% DEA. Mobile Phase: 75/25 COa/ethanol. Flow rate: 35 mLJmin. Rétention time: 5.38 minutes, 99.7% ee (Isomer 2).

Example 113: 3-(4-(1-(2-(4-itrifluoromethvl)-1H-Pvrazol-1-vl)Dyrimidln-5-vlamlno)butvl)benzamÎdo)propanoic acid. Isomer 1

Step A: methyl 3-(4-(1-(2-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)pvrimidin-5ylamino)butvl)benzamldo)propanoate. Isomer 1 and 2

167

The title compound was prepared by a method analogous to that described in Step A of Example 62, using Intermediate (64). Purification of racemic methyl 3-(4-(1-(2-(4-(trifluoromethyl)-1H-pyrazol-1yl)pyrimidin-5-ylamino)butyl)benzamido)propanoate via chiral SFC afforded 400 mg of Isomer 1 and 420 mg of Isomer 2, which were used in conversion to the final enantiopure products. ’H NMR (400 MHz, CD₃OD, δ):

8.84 (s, 1 H), 8.08 (S, 2 H), 7.99 (s, 1 H), 7.79 (d, J = 8.4 Hz, 2 H), 7.50 (d, J = 8.4 Hz, 2 H), 4.52 (t, J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 3.63 (t, J = 6.8 Hz, 2 H), 2.66 (t, J = 6.8 Hz, 2 H), 1.75 -1.99 (m, 2 H), 1.39 - 1.60 (m, 2 H), 1.00 (t, J = 7.2 Hz, 3 H). Chiral SFC: Chiralpak AD, 50 x 250mm, 10ym. Modifier: 0.05% DEA. Mobile Phase: 70/30 CO/methanol. Flow rate; 200 mL/min. Rétention time: 8.65 minutes (Isomer 1) and

10.5 minutes (Isomer 2).

Step B: 3-(4-(1 -t2-(4-ftrifluoromethvl)-1H-Dyrazol-1-vl)pvrimidin-5-vlamino)butvl)benzamido) propanoic acid. Isomer 1

The title compound was prepared by a method analogous to that described in Step C of Example 109, using Isomer 2 of methyl 3-(4-(1 -(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimÎdin-515 ylamino)butyl)benzamido)propanoate. ¹H NMR (400 MHz, CD₃OD, δ): 8.73 (s, 1 H), 7.97 (s, 2 H), 7.89 (s, 1 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 8.4 Hz, 2 H), 4.40 (t, J = 6.8 Hz, 1 H), 3.50 (t, J = 6.8 Hz, 2 H), 2.52 (t, J = 6.4 Hz, 2 H), 1.67-1.82 (m, 2 H), 1.20 - 1.50 (m, 2 H), 0.87 (t, J = 7.2 Hz, 3 H). MS (M+1) 477.2. Chiral SFC: Chiralpak AD-3, 4.6 x 150mm, 3pm. Modifier: 0.05% DEA. Gradient: 95% CO₂/ 5% methanol linear to 60% CO_Z / 40% methanol over 16.0 minutes. Flow rate: 2.5 mL/min. Rétention time: 7.69 minutes,

99.8% ee (Isomer 1).

Example 114: 3-(4-((3.3-dimethvlcvclobutvl)(6-i4-(trifluoromethvl)-1/-/-pvrazol-1-vl)pyridin-3vlamino)methvl)benzamido)Dropanoic acid. Isomer 1

Step A: (+/-)-ethyl 4-((3.3-dimethvlcvclobutyl)(6-(4-(trifluoromethvl)-1F/-pvrazol-1-vl)Dvridin-325 vlamino)methvl)benzoate

168

The title compound was prepared by a method analogous to that described in Step A of Example 1, using Intermediate (65) and Intermediate (32). ¹H NMR (400 MHz, CDCI₃, 5): 8.54 (s, 1 H), 7.93 (d, J = 8.00 Hz, 2 H), 7.72 (s, 1 H), 7.55-7.60 (m, 2 H), 7.31 (d, J = 8.00 Hz, 2 H), 6.79 (d, J = 8.80 Hz, 1 H), 4.26 5 4.31 (m, 2 H), 4.14 (d, J = 8.80 Hz, 1 H), 2.38-2.43 (m, 1 H), 1.92-1.98 (m, 1 H), 1.50 -1.67 (m, 3 H),

1.30 (t, J = 7.20 Hz, 3 H), 1.06 (s, 3 H), 1.01 (s, 3 H). MS (M+1) 473.2.

Step B: 3-(4-((3.3-dimethylcvclobutvD(6-(4-(trifluoromethvl)-1 H-Pvrazol-1-vl)ovridin-3vlamino)methvl)benzamido)propanoic acid. Isomer 1

The title compound was prepared by a method analogous to that described in Steps B - C of

Example 99, using (+/-)-ethyl 4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3ylamino)methyl)benzoate. Purification of racemic 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1Hpyrazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid via chiral SFC afforded the single enantiomer product. ¹H NMR (400 MHz, CDCI₃, δ): 8.53 (s, 1 H), 7.84 (s, 1 H), 7.80 (d, J = 2.7 Hz, 1 H),

7.68 (d, J = 8.4 Hz, 2 H), 7.61 (d. J = 9.0 Hz, 1 H), 7.38 (d, J = 8.2 Hz, 2 H), 6.98 - 7.05 (m, 1 H), 6.95 (dd, J = 8.9, 2.8 Hz, 1 H), 4.21 (d, J = 9.4 Hz, 1 H), 3.72 (q, J = 5.9 Hz, 2 H), 2.72 (t, J = 5.9 Hz, 2 H), 2.42 - 2.56 (m, 1 H), 1.99 (m, 1 H), 1.53- 1.73 (m, 3 H), 1.11 (s, 3 H), 1.07 (s, 3 H). MS (M+1) 516.1. Chiral SFC: MiniGram-2, 20 x 250mm. Modifier: None. Mobile Phase: 60/40 COz/ethanol. Flow rate: 10.0 mL/min. Rétention time: 2.37 minutes (Isomer 1).

Example 115: 3-(4-((3.3-dimethvlcvctobutvl)(6-(4-(triÎluoromethvb-1H-Pvrazol-1-vi)Dvridin-320 vlamino)methvl)benzamido)propanoic acid. Isomer 2

The title compound was prepared by a method analogous to that described in Steps B - C of Example 99, using (+/-)-ethyl 4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3ylamino)methyl)benzoate. Purification of racemic 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H25 pyrazol-1-yl)pyridin-3-ylamino)methyl) benzamido)propanoic acid via chiral SFC afforded the single enantiomer product. ¹H NMR (400 MHz, CDCI₃, Ô): 8.53 (s, 1 H), 7.84 (s, 1 H), 7.80 (d, J = 2.7 Hz, 1 H),

7.68 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 9.0 Hz. 1 H), 7.38 (d, J = 8.2 Hz, 2 H), 6.98 - 7.05 (m, 1 H), 6.95 (dd, J = 8.9, 2.8 Hz, 1 H), 4.21 (d, J = 9.4 Hz, 1 H), 3.72 (q, J = 5.9 Hz. 2 H), 2.72 (t, J = 5.9 Hz, 2 H), 2.42 - 2.56

169 (ΠΊ, 1 H), 1.99 (m, 1 H), 1.53 - 1.73 (m, 3 H), 1.11 (s, 3 H), 1.07 (s, 3 H). MS (M+1 ) 516.1. Chiral SFC:

MiniGram-2, 20 x 250mm, Modifier: None. Mobile Phase: 60/40 COï/ethanol. Flow rate: 10.0 mUmin.

Rétention time: 4.12 minutes (Isomer 2),

Example 116: 3-(4-(1-(4-(2H-lndazol-2-yl)-3-methvlphenoxv)butyl)benzamido)DroDanoic acid. Isomer 2

ΌΗ

Step A: methvl 3-(4-(1-(4-(2H-indazol-2-vl)-3-methvlphenoxv)butylÎbenzamido)Dropanoate, Isomers 1 and 2

The title compound was prepared by a method analogous to that described in Steps A - C of Example Θ2, using Intermediate (66) in Step A and methyl 3-aminopropanoate hydrochloride in Step C. Racemic methyl 3-(4-(1-(4-(2H-indazol-2-yl)-3-methylphenoxy)butyl)benzamido)propanoate was purified via chiral SFC to afford Isomer 1 and Isomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Berger MultiGram SFC, Mettler Toledo Co Ltd., OD 30 x 250mm, 5pm. Modifier: none. Mobile Phase: 60/40 CO₂/methanol. Flow rate: 50 mLVmin, Rétention time: 6.89 minutes (Isomer 1) and 9.42 minutes (Isomer 2).

Step B: 3-(4-(1-(4-(2H-lndazol-2-vl)-3-methvtphenoxv)butyl)benzamido)propanoic acid, isomer 2

The title compound was prepared by a method analogous to that described in Step D of Example 82, using Isomer 2 of methyl 3-(4-(1 -(4-(2H-indazol-2-yl)-3-methylphenoxy)butyl)benzamido) propanoate. ’H NMR (400 MHz, CD₃OD, 5): 8.25 (S, 1 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 2 H), 7.30 - 7.35 (m, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.09 -7.13 (m, 1 H), 6.92 (d, J = 2.4 Hz, 1 H), 6.83 (dd, J = 8.4, 2.8 Hz, 1 H), 5.37-5.40 (m, 1 H), 3.60 (t, J = 6.4 Hz, 2 H), 2.61 (t, J =

6.8 HZ, 2 H), 1.96 - 2.02 (m, 4 H), 1.80 - 1.86 (m, 1 H), 1.44 - 1.57 (m, 2 H), 1.00 (t, J = 6.4 Hz, 3 H). MS (M+1) 472.3. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Gradient: 95% CO₂ / 5% methanol linear to 60% CO₂ / 40% methanol over 3 minutes. Flow rate: 4 mL/min. Rétention time: 1.94 minutes, 96.1% ee (Isomer 2).

Example 117: 3-(6-(cvclohexvl(2-methvl-4-(4-(trif|uoromethvD-1H-pvrazol-1vDphenvl)methvlamino)nicotinamido)oropanoic acid, Isomer 1

170

Step A: (+/-)-cvciohexvl(2-methvl-4-(4-(trifluoromeÎhvl)-1H-pvrazol-1 -vllphenvllmethanamlne

To a solution of Intermediate (67) (300.0 mg. 1.19 mmol) in tetrahydrofuran (3 mL) was added cyclohexylmagnesium bromide (1.79 mL, 3.58 mmol, 2 M in THF). The reaction vessel was sealed and heated to 120 ’C in a microwave for 20 minutes. The reaction was cooled to 0 ’C and methanol (1 mL) was added, followed by sodium borohydride (90.4 mg, 2.39 mmol). The reaction was stirred at 0 ’C for 10 minutes. The reaction was quenched with water and extracted with ethyl acetate (3x10 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave (+/-)-cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)methanamine (80 mg, 20%) as a brown solid. ¹H NMR (400 MHz, CDCIg, δ): 8.09 (s, 1 H), 7.82 (s, 1 H), 7.41 -7.45 (m, 3 H), 3.87 (d, J = 8.00 Hz, 1 H), 2.34 (s, 3 H), 1.94 - 1.98 (m, 1 H), 0.98 - 1.85 (m, 10 H).

Step B: (+/-)-methyl 6-(cvclohexyl(2-methvi-4-(4-(trifiuoromethvl)-1H-pvrazol-1vl)phenvl)methvlamino)nicotinate

To a solution of (+/-)-ογοΙο6θχνΙ(2-ΠΊθ1ΙινΙ-4-(4-(ΙπΑυοΓθπΓΐθΙΙινΙ)-1Η-ρνίΗζοΙ-1-γΙ)ρΙΐθηνΙ)πΊ6ΐ1ΐ3η3Γηΐηθ (80.0 mg, 0.237 mmol) in N,N-dimethylformamide (3 mL) was added methyl 6-fluoronicotinate (55.2 mg, 0.356 mmol) and potassium carbonate (98.4 mg, 0.712 mmol). The reaction was heated to 110 ’C and stirred overnlght. The reaction was cooled to room température, diluted with water, and extracted with ethyl 20 acetate (3x5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated.

Purification by flash column chromatography gave (+/-)-methyl 6-(cyclohexyl(2-m8thyl-4-(4-(trifluoromethyl)1H-pyrazol-1-yi)phenyl)methylamrno)nicotinat8 (20 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃, δ): 8.63 (s, 1 H), 8.06 (s, 1 H), 7.79 - 7.82 (m, 2 H), 7.43 (s, 1 H), 7.33 - 7.36 (m, 1 H), 7.25 (d, J = 8.4 Hz, 1

171

H), 6.03 (d, J = 8.8 Hz, 1 H), 5.39 (d, J = 6.8 Hz, 1 H), 4.74 (m, 1 H), 3.75 (s, 3 H), 2.49 (s, 3 H), 1.85 - 1.88 (m, 1 H), 1.58 - 1.72 (m, 5 H), 1.05 -1.19 (m, 5 H).

Step C: methyl 3-(6-(cvc!ohexvl(2-meÎhvl-4-(4-(trifluoromethvl)-1H-ovrazol-1-

The title compound was prepared by a method analogous to that described in Steps B - C of Example 82, using (+/-)-methyl 6-(cyclohexyl(2-methyi-4-(4-(trifluoromethyl)-1 H-pyrazol-1yl)phenyl)methylamino)nicotinate rn Step B and methyl 3-aminopropanoate hydrochloride in Step C. Racemlc methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenyl)methylamino)nicotinamido)propanoate was purified by chiral SFC to afford Isomer 1 and Isomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-H, 4.6 x 250 mm, 5 pm. Modifier: 0.05% DEA, Mobile Phase: 60/40 COa/ethanol. Flow: 2.35 mL/min. Rétention time: 5.19 minutes (Isomer 1) and 7.83 minutes (Isomer 2).

Step D: 3-(6-(cvclohexvl(2-methvl-4-(4-(Îrifluoromethvl)-1H-Dvrazol-1yl)Dhenvl)methvlamino)nicotlnamido)DroDanoic acid. Isomer 1

The title compound was prepared by a method analogous to that described in Step D of Example 82, using Isomer 1 of methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methylamino)nicotinamido)propanoate. ’H NMR (400 MHz, CD₃OD, δ): 8.68 (s, 1 H), 8.41 (d, 1 H),

7.95 (s, 1 H), 7.72 - 7.75 (m, 1 H), 7.54 - 7.57 (m, 2 H), 7.45 (d, 1 H), 6.49 (d, 1 H), 5.08 (d, 1 H), 3.55 (t. 2 H), 2.56 - 2.60 (m, 5 H), 2.08 (m, 1 H), 1.68 - 1.79 (m, 4 H), 1.40 -1.50 (m, 1 H), 1.00 -1.35 (m, 5 H). MS (M+1) 530.1. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Mobile Phase: 60/40 COa/2-propanol. Flow: 4 mL/min. Rétention time: 0.78 minutes, 99.7% ee (Isomer 1).

Example 118: 3-(6-(cvclohexvl(2-methyl-4-(4-(trifluoromethvl)-1H-Dvrazol-1vl)Dhenvl)methylamino)nicotinamido)Dropanoic acid. Isomer 2

The title compound was prepared by a method analogous to that described in Step D of Example 82, using Isomer 2 of methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methylamrno)nicotinamido)propanoate. ’H NMR (400 MHz, CD₃OD, δ): 8.68 (s, 1 H), 8.41 (d, 1 H),

172

7.95 (S, 1 H), 7.72 - 7.75 (m, 1 H), 7.54-7.57 (m, 2 H), 7.45 (d, 1 H), 6.49 (d, 1 H), 5.08 (d, 1 H), 3.55 (t, 2

H), 2.56 - 2.60 (m, 5 H), 2.08 (m, 1 H), 1.68 -1.79 (m, 4 H), 1.40 -1.50 (m, 1 H), 1.00 - 1.35 (m, 5 H). MS (M+1) 530.1. Chiral SFC: Chiralpak AD-3,4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Mobile Phase: 60/40 COa/2-propanol. Flow; 4 mLJmin. Rétention time: 1,46 minutes, 100% ee {Isomer 2).

Example 119: (+/-)-3-ί4·((4-(2Η-ίπΡ3ΖθΙ-2-νΙ)ρΚθηοχν)(ονοΙορΒηΐνΙ)ηΒΐΚνβ benzamido)propanoic acid

O O

The title compound was prepared by a method analogous to that described for Example 86, using Intermediate (55) and Intermediate (68), and heating the réaction in toluene to 110 °C for 18 hours in Step A. ’H NMR (400 MHz, CD₃OD, δ): 8.64 (s, 1 H), 7.84 (d, J = 8.4 Hz, 2 H), 7.79 (dd, J = 9.2, 2.8 Hz, 3 H), 7.70 (d, J = 8.8 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 7.10 (d, 2 H),

5.24 (d, J = 7.6 Hz, 1 H), 3.67 (t, J = 6.8 Hz, 2 H), 2.68 (t, J = 6.8 Hz, 2 H), 1.99 - 2.10 (m, 1 H), 1.62 - 1.80 (m, 6 H), 1.49-1.56 (m, 2 H). MS (M+1) 484.4.

Example 120 : 3-(4-(f6-(4-chloro-1H-imidazol-1-vl)pvridin-3-vlaminoïïcyclopentvl) methyl) benzamido)propanoic acid. Isomer 1

Step A: ethvl 4-((6-(4-chloro-lH-imidazol-1-vl)pyridin-3-vlamino)(cvclopentyl)methvl) benzoate

The title compound was prepared by a method analogous to that described in Step A of Example 1, using Intermediate (31) and Intermediate (69). ’H NMR (400 MHz, CD₃OD, δ): 8.11 (d, J = 1.6 Hz, 1 H),

7.97 (d, J = 8.4 Hz, 2 H), 7,80 (d, J = 2.8 Hz, 1 H), 7.59 (d, J = 1.6 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.8 Hz, 1 H), 7.04 (dd, J = 8.8, 2.8 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H), 4.22 (d, J = 8.8 Hz, 1 H), 2.21 -

2.32 (m, 1 H), 2.03 - 2.11 (m, 1 H), 1.68 - 1.78 (m, 3 H), 1.48 - 1.66 (m, 2 H), 1.25 - 1.45 (m, 5 H). Step B: 3-f4-((6-(4-chloro-1H-imidazol-1-vl)Pvridin-3-vlamino)(cvclopentvl)methvl) benzamidoloropanoic acid. Isomer 1

173

The title compound was prepared by a method analogous to that described in Example 65, Steps B

-C, using ethyl 4-((6-(4-chloro-1H-imidazol-1-yl)pyridln-3-ylamino)(cyclopentyl) methyl)benzoate. Racemic

3-(4-((6-(4-chloro-1H-Îmidazol-1 -yl)pyridin-3-yiamino)(cyclopentyl) methyl)benzamido)propanoic acid was resolved by chiral SFC to afford the single enantlomer prouduct. ¹H NMR (400 MHz, CD₃OD, δ): 7.99 (d, J =

1.2 Hz, 1 H), 7.68 (d, J = 2.8 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 1.6 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.14 (d, J = 8.8 Hz, 1 H), 6.92 (dd, J = 8.8, 2.8 Hz, 1 H), 4.09 (d, J = 9.2 Hz, 1 H), 3.50 (t, J = 6.8 Hz, 2 H), 2.50 (t, J = 6.8 Hz, 2 H), 2.11 -2.18 (m, 1 H), 1.91-1.97 (m, 1 H), 1.51 -1.63 (m, 3 H), 1.37-1.43 (m, 2 H), 1.17-1.28 (m, 2 H). MS (M+1) 468.1. Chiral SFC: Chiralcel AD-3,4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Mobile Phase: 40/60 COz/methanol. Flow rate: 3 mL/min. Rétention time: 0.81 minutes, 100% ee (Isomer 1).

Example 121 : (+/-)-3-(4-(2.2.2-trifluoro-1-(6-(4-(trifluoromethvl)-1H-imldazol-1-vl)pyridin-3viamino)ethvl)benzamidoloropanoic acid

Step A: f+/-Î-/V-(1-(4-bromophenvl)-2.2.2-trifluoroethvl)-6-(4-itrifluoromethvl)-1H-imidazol-1-vl)Dvridin-3amine

Br

A solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (253 mg, 1.00 mmol) In dichloromethane (10 mL) was cooled to 0 °C. Added Intermediate (6) (228 mg, 1.00 mmol), titanium(IV) isopropoxide (1.1 g, 4.0 mmol), and diisopropylethylamine (0.7 mL, 4 mmol). The reaction was warmed to 30 °C and stirred for 18 hours. The reaction was cooled to 0 °C and sodium borohydride (80 mg, 2 mmol) was added. The reaction was allowed to warm to 30 ’C and stir for 2 hours. The reaction was concentrated and purification by flash column chromatography gave (+/-)-N-(1 -(4-bromophenyl)-2,2,2-trifluoroethyl)-6-(4-(trifluoromethyl)-1 Himidazol-l-yOpyridin-S-amine (100 mg, 21%) as an oil. ¹H NMR (400 MHz, CDCI₃, 5): 8.09 (s, 1 H), 7.84 (d, J = 2.8 Hz, 1 H), 7.77 (s, 1 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.11 (d, J = 9.2 Hz, 1 H),

6.97 (dd, J = 6.0, 8.8 Hz, 1 H), 4.82 (m, 1 H).

Step B: (+/-)-3-(4-(2.2.2-trifluoro-1-(6-(4-(trifluoromethvlMH-imldazol-1-vDpvrldln-3viaminolethyl)benzamido)propanoic acid

A mixture of (+/-)-N-(1 -(4-bromophenyl)-2,2,2-trifluoroethyl)-6-(4-(trifluoromethyl)-1 H-imidazol-1 yl)pyridin-3-amine (100 mg, 0.2 mmol), ethyl 3-aminopropanoate hydrochloride (90 mg, 0.6 mmol), molybdenum hexacarbonyl (57 mg, 0.21 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (165 mg, 1.07 mmol), palladium(ll) acetate (2.4 mg, 0.01 mmol), and tri-tert-butylphosphine tetrafluoroborate (9.4 mg, 0.03 mmol)

X

174 in acetonitrile (2 mL) was heated to 170 °C for 5 minutes In a microwave. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue (40 mg) was taken up rn tetrahydrofuran (2 mL) and cooled to 0°C. 2 N Aqueous lithium hydroxide (0.4 mL, 0.Θ mmol) was added and the mixture was allowed to warm to room température and stir for 1 hour. The pH was adjusted to 4 with 1 N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2 x 20 mL). The combined organics were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated. Purification by reversedphase HPLC gave (+/-)-3-(4-(2,2,2-trifiuoro-1 -(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyridin-3ylamino)ethyl)benzamido)propanoic acid (12 mg, 31%) as a white solid. ’H NMR (400 MHz, CD_aOD, δ): 8.29 (s, 1 H), 8.08 (s, 1 H), 7.94 (d, J = 2.8 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.38 (d, J = 9.2 Hz, 1 H), 7.23 (dd, J = 2.8, 8.8 Hz, 1 H), 5.40 (m, 1 H), 3.51 (t, J = 6.8 Hz, 2 H), 2.53 (t, J = 6.8 Hz, 2 H). MS (M+1) 502.0.

Example 122:3-(4-((6-(4-tert-butvl-1 H-imidazol-1-vl)pvridin-3-vlaminoKcvclODentvl) methvl)benzamido)propanoic acid

ΌΗ

To a 0 °C solution of Intermediate (68) (5 g, 20 mmol) in anhydrous dichloromethane (30 mL) was added triethylamine (6 g, 60 mmol) and methanesulfonyl chloride (2.54 g, 22 mmol). The solution was stirred at 20 °C for 4 h. The mixture was diluted with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford crude ethyl 4-(cyclopentyl(methylsulfonyloxy)methyl)benzoate (6 g) as a yellow oil.

To a solution of crude ethyl 4-(cyclopentyl(methylsulfonyloxy)methyl)benzoate (1.43g, 4.58 mmol) and Intermediate (73) (900 mg, 3.92 mmol) in acetonitrile (15 mL) was added potassium carbonate (1.15 g, 8.33 mmol). The mixture was stirred at 80 °C for 12 h. The reaction was diluted with water and extracted with ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification by silica gel chromatography gave impure ethyl 4-((6-(4-tert-butyl-1H-imidazol1-yl)pyridin-3-ylamino)(cyclopentyl)methyl)benzoate (250 mg) as a colorless solid, which was dissolved in THF (8 mL). 8 mL 2N aqueous lithium hydroxide was added. The mixture was refluxed for 2 h. The mixture was adjusted to pH 1-2 by addition of 1N aqueous HCl and extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a yellow solid which was dissolved in DMF (5 mL). HATU (425.7 mg, 1.12 mmol) was added. After 30 min methyl 3aminopropanoate hydrochloride (116.13 mg, 0.84 mmol) was added followed by addition of diisopropylethelamine (361.78 mg, 2.8 mmol). The resulting mixture was stirred at room température for 2 h. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give a yellow solid which was dissolved in THF (5 mL). 5 mL 2N aqueous lithium hydroxide was

175 added. The mixture was stirred at 25 °C for 2 h. The mixture was adjusted to pH 1 -2 by addition of 1N aqueous HCl and extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. HPLC purification using a Kromasil Eternity-5-Ci₈ 150 x 30 mm x 5pm column eluting with 23 to 43% acetonitrile in water (0.225% formic acid modifier) gave (+/-)-3(4-((6-(4-tert-butyl-1 H-imidazol-1 -yl)pyridin-3-ylamino)(cyclopentyl)methyl)benzamido)propanoic acid (34 mg) as a colorless solid. ¹H NMR (400 MHz, CD₃OD) δ 8.96 (s, 1H), 8.46-8.50 (m, 1H), 7.84 (d, 4=2.8 Hz, 1H),

7.76 (d, 4=8.0 Hz, 2H), 7.66 (d, 4=1.2 Hz, 1 H), 7.49 (d, 4=8.4 Hz, 2H), 7.39 (d, 4=9.2 Hz, 1 H). 7.07 (dd, 4=8.8, 3.2 Hz, 1H), 4.22 (d, 4=9.2 Hz, 1 H), 3.59-3.63 (m, 2H), 2.60-2.64 {m, 2H), 2.30-2.24 (m, 1H), 2.082.04 (m, 1 H), 1.75-1.65 (m, 3H), 1.55-1.51 (m, 2H), 1.29-1.49 (m, 11 H). MS (M+1) =490.2

Example 123: 3-(4-(cycloDentvl(6-(4-isoDropyl-1 H-imidazol-1-vl)pvridin-3vlamino)methvl)benzamido)propanoic acid

The title compound was prepared using a method analogous to that describe in Example 122, starting from Intermediate (76) and Intermediate (66). Colorless solid. ¹H NMR (400 MHz, CD₃OD) δ 9.23 (d, J= 1.6 Hz,

H), 7.88 (d, J= 2.8Hz, 1H), 7.82 (s, 1H), 7.77 (d, 4=8.4 Hz, 2H), 7.50 (d, 4=8.4 Hz, 2H), 7.44 (d, 4=8.8 Hz, 1H), 7.09 (dd, 4=8.8 Hz, J=3.2 Hz, 1H), 4.24 (d, 4=9.2 Hz, 1H), 3.60-3.64 (m, 2H), 3.12-3.02 (m, 1H), 2.61-

2.65 (m, 2H), 2.48-2.25 (m, 1H), 2.13-2.02 (m, 1H), 1.81-1.62 (m, 3H), 1.59-1.49 (m,2H), 1.48-1.30 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (M+1 ) =476.3.

Example 124: 3-(4-(1 -(4-(2-indazol-2-vl)phenoxv)butvl)benzamldo)propanoic acid. Isomer 1

Step A: (+/-)-3-(4-(1-i4-(2-indazol-2-vl)phenoxy)butvl)benzamldo)propanoic acid

Racemic 3-(4-(1 -(4-(2-indazol-2-yl)phenoxy)butyl)benzamido)propanoîc acid was prepared using a method analogous to that described for Example 86 using Intermediate 55 and ethyl 4-(1-hydroxybutyl)benzoate (prepared as described in préparation of Intermediate 5). ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.78 (d, J =8.4 Hz, 2H), 7.73-7.70 (m, 3H), 7.63 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2H), 7.32-7.28 (m, 1 H), 7.107.01 (m, 3H), 5.39-5.36 (m, 1H), 3.59 (m, 2H), 2.60 (m, 2H), 2.02-1.99 (m, 1H), 1.86-1.83 (m, 1H),1.58-1.45 (m, 2H), 0.98 (t, J = 7.2 Hz , 3H). MS (M+1) =458,2

Step B: 3-(4-(1-(4-(2-indazol-2-vl)phenoxv)butvl)benzamido)propanoic acid. Isomer 1

Racemic 3-(4-(1-(4-(2-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid was resolved by SFC (Column: OJ 300 x 50 mm x 10 pm; Eluent: 60:40 CO₂:methanol; Flow rate: 200 mU/min; Modifier: none) to provide 3I

176 (4-(1 -(4-(2-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid, Isomer 1 (rétention time: 1.38 min) and 3(4-(1-(4-(2-indazol-2-yl)phenoxy)buty))benzamido)propanoicacid, Isomer 2 (rétention time 0.75 min) as colorless solids. Spectral data for isomer 1 : ’H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.78 (d, J =8.4 Hz, 2H), 7.73-7.70 (m, 3H), 7.63 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2H), 7.32-7.28 (m, 1H), 7.10-7.01 (m, 3H), 5.39-5.36 (m, 1H), 3.59 (m, 2H), 2.60 (m, 2H), 2.02-1.99 (m, 1H), 1.86-1.83 (m, 1 H),1.58-1.45 (m, 2H), 0.98 (t, J = 7.2 Hz , 3H). MS (M+1) =458.2

Example 125: 3-(4-(1-(4-i7-methvl-2H-indazol-2-vl)phenoxv)butvDbenzamido) propanoic acid

ΌΗ

A suspension of Intermediate (77) (300 mg, 0.795 mmol), 7-methylindazole (126 mg, 0.954 mmol), copper(l) iodide (7.5 mg, 0.0397 mmol), K₃PO₄ (354 mg, 1.67 mmol) and N,N’-drmethylcyclohexane-1,2-diamine (22.7 mg 0.159 mmol) in toluene (3 mL) was stirred at 48h at 110 °C under a nitrogen atmosphère. The mixture was concentrated and the residue purified by préparative TLC to give 110 mg impure ethyl 4-(l-(4-(7-methyl2H-indazol-2-yl)phenoxy)butyl)benzoate as an oil. This material was dissolved in THF (5 mL). 5 mL aqueous 2N sodium hydroxide was added. The resulting mixture was stirred at 30 °C overnight. The mixture was acidrfied to pH 3 by addition of 1N aqueous HCl. The mixture was extracted with ethyl acetate (3x5 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). HATU (128.3 mg, 1.95 mmol) was added. The mixture was stirred for 20 min. Methyl 3-aminopropanoate hydrochloride (46.8 mg, 0.338 mmol), and diisopropylethylamine (145.4 mg, 1.125 mmol) were added. The resulting mixture was stirred at room température for 30 min. The mixture was poured into water (10 mL) and extracted with ethyl acetate (2x15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in THF (5 mL). 5 mL 2N aqueous lithium hydroxide was added. The resulting mixture was stirred at room température for 1h. The mixture was adjusted to pH 5 by addition of 1N aqueous HCL The mixture was extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Préparative HPLC purification using a Kromasil Eternity-5-C_1B 150 x 30mm x 5 pm column eluting with 52 to 68% acetonitrile in water (0.225% formîc acid modifier) gave 3-(4-(1-(4-(7-methyl-2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid_(19.1 mg) as a colorless solid. ’H NMR (400MHz, CD₃OD) δ 8.46 (s, 1H), 7.76 (d, J=8.4Hz, 2H), 7.68 (d, J=8.8Hz, 2H), 7.45-7.51 (m, 3H), 7.04-6.94 (m, 4H), 5.32-5.35 (m, 1H), 3.57-3.61 (m, 2H), 2.58-2.62 (m, 2H), 2.55 (S, 3H), 2.01-1.97 (m, 1H), 1.84-1.80 (m, 1H), 1.56-1.53 (m, 1H), 1.46-1.42 (m, 1H), 0.96 (t, J=7.2Hz, 3H). MS (M+1) = 472.1.

Example 126:3-(4-(1 •(4-(6-methvl-2H-indazol-2-vnphenoxv)butvl)benzamido) propanoic acid

177

The title compound was prepared using a method analogous to that described for Example 125 using Intermediate (77) and 6-methylindazole. Colorless solid. ¹H NMR (400MHz, CD₃0D) δ 8.47 (d, J=1.2 Hz,

1H), 7.77 (d, J=8.4Hz, 2H), 7.67 (d, J=8.8Hz, 2H), 7.58 (d, J=8.8Hz, 1H), 7.47 (d, J=8.4Hz, 2H), 7.37 (s, 1H),

7.01 (d, J=8.8Hz, 2H), 6.93 (dd, J=8.8, 1.2Hz, 1H), 5.33-5.36 (m, 1 H), 3.56-5.59 (m, 2H), 2.50-2.54 (m, 2H),

2.41 (s, 3H), 2.04-1.96 (m, 1 H), 1.85-1.79 (m, 1 H), 1.60-1.52 (m, 1 H), 1.50-1.42 (m, 1 H), 0.97 (t, J=7.2 Hz, 3H). MS (M+1) = 472.4.

Example 127:3-(4-(1-(4-(4-methvl-2H-indazol-2-vl)phenoxy)butvl)benzamido) propanoic acid

The title compound was prepared using a method analogous to that described for Example 126 using Intermediate (77) and 4-methylindazole. Colorless solid. ¹H NMR (400MHz CD₃OD) δ 8.63 (s, 1H), 7.77 (d, J=8.4Hz, 2H), 7.72 (d, J=8.8Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.43 (d, J=8.8Hz, 1H), 7.20 (dd, J=8.8, 6.8Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 6.84 (d, J=6.8Hz, 1H), 5.35-5.38 (m, 1H), 3.57-3.61 (m, 2H), 2.59-2.62 (m, 2H), 2.54 (s, 3H), 2.02-1.98 (m, 1H), 1.85-1.82 (m, 1H), 1.56-1.55 (m, 1H), 1.48-1.44 (m, 1 H), 0.98 (t, J=7.2Hz,

3H). MS (M+1)=472.1.

Example 128: 3-(4-(1-(4-(5-methv1-2H-indazol-2-yl)phenoxv)butvl)benzamido) propanoic acid

The title compound was prepared using a method analogous to that described in Example 126 using Intermediate (77) and 5-methylindazole. Colorless solid. ’H NMR (400MHz, CD₃OD) δ 8.42 (s, 1H), 7.77 (d,

J=8.4Hz, 2H), 7.67 (d, J=8.8Hz, 2H), 7.44-7.52 (m, 4H), 7.15 (dd, J=8.8, 1.2Hz, 1H), 7.00 (d, J=8.8Hz, 2H),

5.33-5.36 (m, 1H), 3.57-3.60 (m, 2H), 2.53-2.56 (m, 2H), 2.38 (s, 3H), 2.04-1.96 (m, 1H), 1.85-1.78 (m, 1H),

1.61 -1.52 (m, 1 H), 1.50-1.40 (m, 1 H), 0.97 (t, J=7.2Hz, 3H). MS (M+1 )= 472.1.

178

Example 129: 3-(4-(1-f6-f4-Dhenvl-1H-imidazol-1-vl)Dvridln-3-vlaminoÎbutvl) benzamidolpropanoic acid.

Isomer 1

To a solution of Intermediate (78) (3.9 g, 27,1 mmol) 5-nitro-2-chloropyridine (5.15 g. 32.5 mmol) in acetonitrile (30 mL) was added potassium carbonate (7.47 g, 54.2 mmol). The resulting mixture was stirred at 85 °C overnight. The reaction mixture was washed with water (200 ml), and extracted with ethyl acetate (150 mL x 4). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL). 10% Pd/C (800 mg) was added. The mixture was stirred overnight at 35 °C under a 40 psi atmosphère of hydrogen. The reaction mixture was filtered and concentrated under reduced pressure to give a yellow solid. The solid was dissolved In methanol (15 mL). Intermediate (23) (3.52 g, 12.71 mmol) was added followed by decaborane (776.6 mg, 6.35 mmol). The resulting mixture was stirred at 35 °C for 72 h. The reaction was concentrated and purified by silica gel chromatography to give methyl 3-(4-(1-(6-(4-ρΙιβηνΙ-1Η-ΐΓηίά3ζοΙ-1-νΙ)ρνΓίυΐη-3ylamino)butyl)benzamido)propanoate (1.1 g) as a yellow solid. The solid was dissolved in THF (8 mL). 8 mL 2N aqueous lithium hydroxide was added. The mixture was stirred at room température for 2 h. The mixture was acidified to pH 4 with 1 N aqueous HCl, and extracted with ethyl acetate (4 x 100 mL). The combined organic layers were dried over Na₂SO₄ and concentrated. Purification by silica gel chromatography gave racemic 3-(4-(1 -(6-(4-phenyl-1/-/-imidazol-1-yl)pyridin-3-ylamino)butyl) benzamido)propanolc acid as a colorless solid. Resolution of this material by SFC (Column: Chiralcel AD 250 x 30 mm x 20 pm, mobile phase: 45:55 CO₂:methanol, flow rate: 80 mL/min) gave 3-(4-(1-(6-(4-phenyl-1H-imidazol-1-yl)pyridin-3ylamino)butyl)benzamido) propanoic acid, Isomer 1 (rétention time: 2.63 min) and 3-(4-(1-(6-(4-phenyl-1Himidazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid, Isomer 2 (rétention time 0.85 min). Spectral data for isomer 1: ¹H NMR (400MHz, CD₃OD) δ 8.29 (s, 1H), 7.99 (s, 1H), 7.81 (d, J = 2.4 Hz, 1 H), 7.78 (d, J = 5.6 Hz, 4H), 7.49 (d, J = 8.0 Hz, 2H), 7.40-7.35 (m, 3H), 7.26 (t, J = 7.0 Hz, 1H), 7.06 (dd, J = 8.8, 2.0 Hz, 1 H), 4.47 (t, J = 7.0 Hz, 1 H),3.61 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 6.8 Hz, 2H), 1.95-1.86 (m, 1 H), 1.83-1.76 (m, 1 H), 1.59-1.56 (m, 1 H), 1.46-1.39 (m, 1 H), 0.99 (t, J = 7.4 Hz, 3H).MS (M+1 )=484.2.

Example 130 : (+\-)-3-f4-(1-(4-(4-ch!oro-1H-pvrazol-1-vl)-3.5-dimethvlphenoxv)butvl) benzamido)prooanoic acid

179 (+\-)-3-(4-(1-(4-(4-chloro-1 H-pyrazol-1-yl)-3,5-dimethylphenoxy)butyl)benzamido)propanoic acid was prepared using a method analogous to that described in Example 86 starting from Intermediate (81) and ethyl 4-(1-hydroxybutyl)benzoate (prepared as described in préparation of Intermediate 5). Colorless solid. ’H NMR (400 MHz, Methanol-d4) δ 8.50-8.60 (m, 1H), 7.77-7.81 (m, 3H) 7.68 (s, 1H), 7.48 (d, 7=B.0Hz, 2H), 6.70 (s, 2H), 5.35-5.38 (m, 1H), 3.61-3.64 (m, 2H), 2.62-2.68 (m, 2H), 2.00-1.96 (m, 1H), 1.89 (s, 6H), 1.87-

1.79 (m, 1H), 1.57-1.44 (m, 2H), 0.99 (t,7=7.2Hz, 3H). MS (M+23) =492.2.

Example 131 : (+\4-3-(4-(cvclopentvl(3.5-dimethvl-4-(4-(Îrifluoromethvl)-1H-imidazol-1 vl)Phenoxv)methvl)benzamido)oropanoic acid

(+\-)-3-(4-(cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-lH-imidazol-1-yl)phenoxy)methyl) benzamido)propanoïc acid was prepared using a method analogous to that described in Example 86 starting from Intermediate (83) and Intermediate (68). Colorless solid. ’H NMR (400 MHz, CD₃OD) δ 7.74-7.78 (m, 3H), 7.62 (s, 1H), 7.49 (d, 7=8.4 Hz, 2H), 6.73 (s, 2H), 5.15 (d. 7=7.6 Hz, 1H), 3.60-3.63 (m,2H), 2.60-2.64 (m, 2H), 2.42-2.38 (m, 1 H), 1.92 (s, 6H), 1.89-1.87(m, 1H), 1.67-1.54 (m, 5H), 1.47-1.40 (m,2H). MS (M+1) =530.2.

Example 132: (+\-)-3-(6-i1-i6-(4-phenvl-1H-pvrazol-1-vl)pyridin-3-vlamino)butvl) nicotinamido)oropanoic acid o o

(+\-)-3-(6-(1-(6-(4-phenyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino)butyl)nicotinamido)propanoic acid was prepared using a method analogous to that described for Example 102 starting from Intermediate 25 and methyl 6formylnicotinate using n-propylmagnesium chloride in Step C. Colorless solid. ’H NMR (400 MHz, CD₃OD) δ 8.88 (d, 7=1.2 Hz, 1H), 8.54 (s, 1H), 8.23 (d, J=7.6 Hz, 1H), 7.92 (s, 1 H). 7.67-7.63 (m, 2H), 7.55-7.50 (m, 3H), 7.28-7.25 (m 2H), 7.15-7.11 (m 1H), 7.03-7.06 (m, 1H), 4.54-4.58 (m, 1H), 3.52-3.55 (m, 1H), 2.52-2.55 (m, IH), 1.84-1.80 (m, 2H), 1.52-1.37 (m, 2H), 0.90 (t,7=6.8 Hz, 3H). MS (M+1)=485.3.

Example 133: (+\-)-3-(6-(1 -(6-(4-phenvl-1 H-pyrazol-1 -vl)Dvridin-3-vloxv)butvl)benzamido)propanoic acid

180

(+\-)-3-(6-{1-(6-(4-phenyl-1H-pyrazol-1-yl)pyrÎdin-3-yloxy)butyl)benzamido)propanoicacid was prepared using a method analogous to that described in Example 86, starting from Intermediate (20) and Intermediate (84). Colorless solid. ’H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.04 (d, J=2.8 Hz, 1H), 8.02 (s, 1 H), 7.735 7.79 (m, 3H), 7.60 (d, J=7.6Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.43-7.46 (m, 1H), 7.35 (t, J=7.6Hz, 2H), 7.22 (t,

J=7.6Hz, 1H). 5.37-5.40 (m, 1H), 3.57-3.61 (m, 2H), 2.58-2.62 (m, 2H), 2.05-2.02 (m, 1 H), 1.87-1.84 (m, 1H), 1.57-1.55 (m, 1H), 1.47-1.43 (m, 1H), 0.98 (t, J=7.2Hz, 3H). MS (M+1) =485.2.

Example 134: 3-(4-f(3.3-dlmethvlcvclobutvlïï6-(4-ftrifluoromethvlM H-imidazol-1-vDpyridin-3vlamino)methvhbenzamldo)propanoic acid. Isomer 1 and

Example 135: 3-(4-((3.3-dimethvlcvctobutvl)(6-i4-ftrifluoromethv0-1 H-imidazol-1-vl)pyridin-3vlaminolmethvhbenzamldolpropanoic acid. Isomer 2

Step A: methyl 3-(4-((3.3-dimethvÎcvclobutvlïï6-(4-ftrifluoromethvlMH-imidazol-1-vl)pvridln-315 vlaminolmethyObenzamidolpropanoate, Isomer 1 and Isomer 2,

(+\-)-methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3ylamïno)methyl)benzamido)propanoate was prepared using a method analogous to that described in Example 1, using appropriately substituted Intermediates such as Intermediate 6 in Step A and methyl 320 aminopropanoate hydrochloride in Step B. Yellow solid. (+\-)-methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4(trifluoromethyl)-lH-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoate was resolved by SFC (column: Chiralpak AS-H 250 x 4.6 mm x 5pm; mobile phase: 5% to 40% methanol in CO₂; modifier: 0.05% diethylamine; flow rate: 2.35 mL/min) to give methyl 3-(4-((3,3-dimethylcycIobutyl)(6-(4-(trifluoromethyl)-1H-

181 imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoate, Isomer 1 (rétention time: 8.26 min) and methyl

3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-lH-imidazol-1-yl) pyridin-3ylamino)methyl)benzamido)propanoate, Isomer 2 (rétention time: 7.43 min). Step B: 3-(4-((3.3-dimethvlcvclobutvl)(6-(4-(trifluoromethvl)-1H-imidazol-1-vl)pvridin-3vlamino)methyl)benzamido)proDanolc acid, Isomer 1

To a solution of methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3ylamino)methyl)benzamido)propanoate, Isomer 1 (550 mg, 1.10 mmol) in THF (5 mL) was added 2N aqueous lithium hydroxide (5.00 mL, 10 mmol). The reaction mixture was stirred for 1h at room température. The mixture was acidified to pH 3 by addition of 1N aqueous HCl. The mixture was extracted with ethyl acetate (10 mL x 3) The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated to dryness. The crude residue was purified by silica gel chromatography to give 3-(4-((3,3dimethylcyclobutyi)(6-(4-(trifluoromethyl)-lH-imidazol-1-yl)pyridin-3-ylamino)methyl) benzamido)propanoic acid, Isomer 1 (255.8 mg) as an off-white solid. ’H NMR (400 MHz, Methanol-d₄) δ 8.33 (s, 1H), 8.12 (s, 1 H), 7.82-7.76 (m, 3H), 7.48 (d, J=8.40 Hz, 2H), 7.35 (d, J=8.80 Hz, 1 H), 7.04 (d, J=8.80 Hz, 1 H), 4.31 (d, J=8.80 Hz, 1H), 3.62 (t, J=6.80 Hz, 2H), 2.64-2.55 (m, 3H), 2.11-2.03 (m, 1H), 1.77-1.68 (m, 2H), 1.59-1.50 (m, 1H), 1.16 (s, 3H), 1.11 (s, 3H). MS (M+1)=516.1.

Step C: 3-(4-((3.3-dimethvlcvclobutvl)i6-(4-(triÎluoromethvl)-1H-imidazol-1-vl)pvridin-3vlamino)methvl)benzamido)propanoic acid. Isomer 2

To a solution of methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrldin-3ylamino)methyl)benzamido)propanoate, Isomer 2 (550 mg, 1.10mmol) in THF (5 mL) was added 2N aqueous lithium hydroxide (5.00 mL, 10 mmol). The reaction mixture was stirred for 1h at room température. The mixture was acidified to pH 3 by addition of 1N aqueous HCl. The mixture was extracted with ethyl acetate (10 mL x 3) The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated to dryness. The crude residue was purified by silica gel chromatography to give 3-(4-((3,3dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl) benzamido)propanoic acid, Isomer 2 (255.8 mg) as an off-white solid. ’H NMR (400 MHz, Methanol-d₄) δ 8.33 (s, 1H), 8.12 (s, 1H), 7.82-7.76 (m, 3H), 7.48 (d, J=8.40 Hz, 2H), 7.35 (d, J=8.80 Hz, 1H), 7.04 (d, J=8.80 Hz, 1H), 4.31 (d, J=8.80 Hz, 1H), 3.62 (t, J=6.80 Hz, 2H), 2.64-2.55 (m, 3H), 2.11-2.03 (m, 1H), 1.77-1.68 (m, 2H), 1.59-1.50 (m, IH), 1.16 (s, 3H), 1.11 (s, 3H). MS (M+1 )=516.1.

Example 136:3-(4-(1-(6-(4-ίθΠ-δυΐνΙ-1Η-ρνΓ3ΖθΙ-1-νΙ)ρνΓΐόίη-3-νΐ8ππίηο)δυΜ) benzamidolpronanoic acid. Isomer 1 and Example 137:3-(4-(1-(6-(4-tert-butvl-1H-pvrazol-1-vl)pyridin-3vlamino)butvl)benzamido)Dropanoic acid. Isomer 2

ΌΗ

182

Step A: methvl 3-(4-(1-(6-(4-tert-butvl-1H-Dvrazol-1-vnDvridin-3-vlamino)butvl)benzamido)propanoate, Isomer and methyl 3-(4-(1 -(6-(4-tert-butvl-1H-pvrazol-1-vl)Dvridln-3-vlamino)butvl)benzamido)propanoate· Isomer

To a solution of intermediate (87) (1.2 g, 5.5 mmol) and Intermediate (23) (1.54 g, 5.55 mmol) in anhydrous methanol (15 mL) was added decaborane (340 mg, 2.78 mmol). The solution as stirred at 30 °C overnight. The solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (+\-)-methyl 3-(4-(1-(6-(4-tert-butyl-1 H-pyrazol-1-yl)pyridin-3ylamino)butyl)benzamido)propanoate (1.6 g) as a colorless solid. ’H NMR (400 MHz, CD₃OD) δ 8.06 (d, J=0.8 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H),7.68 (d, J=2.8 Hz, 1H), 7.48 (s, 1 H), 7.44-7.47 (m, 3H), 7.01-7.04 (m, 1H), 4.43 (t, 1H), 3.67 (s, 3H), 3.59-3.62 (m, 2H), 2.61-2.65 (m, 2H), 1.95-1.70 (m, 2H), 1.60-1.35 (m, 2H), 1.29 (s, 9H), 0.97 (t, J=7.2 Hz, 3H). (+\-)-methyl 3-(4-(1-(6-(4-tert-butyl-1 H-pyrazol-1-yl)pyridin-3ylamino)butyl)benzamido)propanoate was resolved by SFC (Column: Chiralpak OJ-H 250 x 4.6 mm x 5 pm; mobile phase: 5 to 40% methanol in CO₂; modifier: 0.05% diethylamine; flow rate: 2.35 mL/min) to give methyl 3-(4-(1 -(6-(4-tert-butyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino)butyl)benzamido)propanoate, Isomer 1 (rétention time 6.43 min) and methyl 3-(4-(1 -(6-(4-tert-butyl-1 H-pyrazol-1 -yl)pyridin-3ylamino)butyl)benzamido) propanoate, Isomer 2 (rétention time, 7.37 min).

Step B: 3-(4-(1 -(6-(4-tert-butvl-1H-pvrazol-1-vl)Dvridin-3-ylamino)butyl)benzamÎdo)propanoic acid, Isomer 1 To a solution of methyl 3-(4-(1-(6-(4-tert-butyl-1 H-pyrazol-1-yl)pyridin-3ylamino)butyl)benzamido)propanoate, Isomer 1 (500 mg, 1.05 mmol) in THF (5 mL) was added 2M aqueous lithium hydroxude (5 mL, 10 mmol). The mixture was stirred at room température for 1h. The mixture was neutralized with 1N aqueous HCl and extracted with ethyl acetate (10 mL x 3), The combined organic layer was dried over Na₂SO₄ and concentrated to dryness. The crude residue was purified by silica gel chromatography to give 3-(4-(1 -(6-(4-tert-butyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid, Isomer 1 (261.5 mg) as a colorless solid. ¹H NMR (400 MHz, MeOD): 58.06 (s, 1 H), 7.74 (d, J=8.4 Hz, 1 H),7.68 (d, J=2.8 Hz, 1H), 7.48 (s, 1H), 7.46 (m, 3H), 7.03 (dd, J=8.8 Hz, 1H), 4.43 (t, 1H), 3.61 (t, J=6.8 Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), 1.95-1.70 (m, 2H), 1.60-1.35 (m, 2H), 1.29 (s, 9H). 0.97 (t, J=7.2 Hz, 3H). MS (M+1)=464.2

Step C: 3-(4-(1-(6-(4-tert-butvl-1H-pvrazol-1-vl)pvridin-3-vlamino)butvl)benzamido)propanoic acid, Isomer 2 To a solution of methyl 3-(4-(1-(6-(4-tert-butyl-1H-pyrazol-1-yl)pyridin-3ylamino)butyl)benzamido)propanoate, Isomer 2 (500 mg, 1.05 mmol) in THF (5 mL) was added 2M aqueous lithium hydroxude (5 mL, 10 mmol). The mixture was stirred at room température for 1h. The mixture was neutralized with 1N aqueous HCl and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over Na₂SO₄ and concentrated to dryness. The crude residue was purified by silica gel chromatography to give 3-(4-(1-(6-(4-tert-butyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic

183 acid, Isomer 2 (271.3 mg) as a colorless solid. ’H NMR (400 MHz, MeOD): 68.06 (s, 1H), 7.74 (d, J=8.4 Hz,

H),7.68 (d, J=2.8 Hz, 1H), 7.48 (s, 1H), 7.46 (m, 3H), 7.03 (dd, J=8.8 Hz, 1H), 4.43 (t, 1 H), 3.61 (t, J=6.8

Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), 1.95-1.70 (m, 2H), 1.60-1.35 (m, 2H), 1.29 (s, 9H), 0.97 (t, J=7.2 Hz, 3H). MS (M+1 )=464.2

Example 138: 3-(4-(cvclobutvl(3.5-dimethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1vl)Dhenoxv)methvl)benzamido)propanoic acid. Isomer 1

Step A: methyl 3-(4-(cvclobutvif3.5-dimethvl-4-(4-(trifluoromethvl)-1 H-pyrazol-1 yl)phenoxv)methvl)benzamido)prooanoate· Isomer 1

(+/-)-methyl 3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)methyl)benzamido)propanoate was prepared using a method analogous to that described in Example 65, Steps A-B, starting from Intermediate (26) and Intermediate (45). Resolution of the racemic material by SFC (column: Chiralpak AD-3 50 x 4.6 mm x 3 pm; mobile phase: gradient 5 to 40% methanol in CO₂; modifier: 0.05% diethylamine; flow rate: 2.5 mL/min) gave methyl 3-(4-(cyclobutyl(3,5-dimethyl-4-(4(trifluoromethyl)-l H-pyrazol-1-yl)phenoxy)methyl)benzamido)propanoate, Isomer 1 (rétention time: 5.14 min) and methyl 3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phanoxy)methyl) benzamido)propanoate, Isomer 2 (rétention time: 5.74 min) as colorless solids._Spectral data for Isomer 1 : ’H NMR (400 MHz, CDCI₃) δ 7.80 (s. 1 H), 7.65 (d, J = 8.4 Hz, 2H), 7.58 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H),

6.73 (t, J = 6.0 Hz, 1 H), 6.51 (s, 2H), 4.97 (d, J = 7.2 Hz, 1 H), 3.67-3.63 (m, 5H), 2.71 -2.65 (m, 1 H), 2.58-

2.60 (m, 2H), 2.02-1.91 (m, 3H), 1.91-1.76 (m, 9 H).

Step B: 3-f4-(cvclobutvl(3.5-dimethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1vl)phenoxv)meÎhvl)benzamido)propanoic acid. Isomer 1

To a solution of methyl 3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)methyl)benzamidQ)propanoate, Isomer 1 (450 mg, 0.85 mmol) in THF (4 mL) was added 2N aqueous lithium hydroxide (4mL, 8.0 mmol). The resulting mixture was stirred at 20 °C for 1 h. THF was removed under reduced pressure. The residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (20mL*2). The organic layer was concentrated to give 3-(4-(cyclobutyl(3,5dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)methyl)benzamido)propanolc acid, Isomer 1 (330

184 mg) as a coloriess solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.88 (s, 1H), 7.65 (d, J = 8.0 Hz,

2H), 7.35 (d, J = 8,0 Hz, 2H), 6.61 (s, 2H), 5.15 (d, J = 7.2 Hz, 1 H), 3.50 (t, J = 6.8 Hz, 2H), 2.70-2.67 (m,

H), 2.52 (t, J = 6.8 Hz, 2H), 2.04-1.94 (m, 3H), 1.82-1.72 (m, 9H). MS (M+1 ) = 516.1.

Example 139: (+\-)-3-(4-(1-(4-(7-chtoro-2H-indazol-2-vl)phenoxv)butvl)benzamido) propanoic acid

O o

(+\-)-3-(4-(1-(4-(7-chloro-2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid was prepared using a method analogous to that described in Example 125, starting from Intermediate (77) and 7-chloroindazole. Coloriess solid. ’HNMR (400MHz Methanol-d4) δ 8.67 (s, 1 H), 7.74-7.78 (m, 4H) 7.66 (d, J=8.4Hz, 1 H), 7.49 (d, J=8.4Hz, 2H), 7.33 (d, J=7.2Hz, 1H), 7.01-7.05 (m, 3H), 5.36-5.39 (m, 1H), 3.59 (t, J=6.8Hz, 2H),2.60 (t, J=6.8Hz,2H), 2.02-1.98 (m, 1H), 1.87-1.81 (m, 1H), 1.58-1.53 (m, 1H), 1.50-1.44 (m, 1H), 0.98 (t, J=7.2Hz, 3H). MS (M+1) =492.2.

Example 140: (+V)-3-(4-(1-(4-(5-chloro-2H-lndazol-2-vl)phenoxv)butvl)benzamido)Dropanoic acid

(+\-)-3-(4-(1-(4-(5-chloro-2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid was prepared using a method analogous to that described in Example 82, starting from Intermediate (88) and ethyl 4-(1hydroxybutyijbenzoate (prepared as described in préparation of Intermediate 5). Coloriess solid. ’H NMR (400MHz, Methanol-^) δ 8.56 (s, 1H), 7.77 (d, J=8.4Hz, 2H), 7.70-7.72 (m, 3H), 7.62 (d, J=8.4Hz, 1H), 7.48 (d, J=8.4Hz, 2H), 7.24 (dd, J=9.2, 2.0Hz, 1H), 7.03 (d, J=9.2Hz, 2H), 5.35-5.38 (m, 1H), 3.59 (t, J=6.8Hz, 2H), 2.59 (t, J=6.8Hz, 2H), 2.02-1.98 (m, 1H), 1.86-1.82 (m, 1H), 1.57-1.54 (m, 1H), 1.48-1.44 (m, 1H), 0.97 (t, J=7.2Hz, 3H). MS (M+1) = 492.2.

Example 141: (+\-)-3-(4-(1-(3,5-dimethyl-4-(4-(trifiuoromethvll-1H-imidazol-1vl)phenoxv)butyl)benzamido)proDanoic acid

185

(+\-)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid was prepared using a method analogous to that described in Example 86 starting from Intermediate (83) and ethyl 4-(1-hydroxybutyl)benzoate {prepared as described in préparation of Intermediate 5). Colorless solid.

¹H NMR (400 MHz, CD₃0D) δ 7.78-7.80 (m, 3H), 7.65 (s, 1H), 7.49 (d, J=8.4 Hz, 2 H), 6.76 (s, 2H), 5.36-

5.39 (m, 1H), 3.64 (t, J=6.8 Hz, 1H), 2.65 (t, J=6.8 Hz, 2H), 2.03-1.97 (m, 1H), 1.94 (s, 6H), 1.87-1.79 (m,

H), 1.58-1.43 (m, 2H), 0.99 (t, J=7.2 Hz, 3H). MS (M+1) = 504.2.

Example 142:3-(6-(3-methvl-1-(6-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)pvrïdÎn-3vl)butylamino)nicotinamido)oropanoic acid, Isomer 1 and Example 143:3-(6-(3-methvl-1-(6-(410 (trifluoromethvlM H-pvrazol-1-vl)pvridin-3-vDbutvlamino) nicotlnamido)propanoic acid. Isomer 2

Step A: (+\-)-methvl 6-(tert-butoxvcarbonvl(3-methvl-1-(6-(4-(trifluoromethvl)-1 H-Dvrazol-1-vDpvridin-3vDbutvOaminolnicoÏinate

To aO °C solution of Intermediate (89) (1.40 mg, 4.67 mmol), Intermediate (90) (1.18 mg, 4.67 mmol), and triphenylphosphine (2.05 mg, 7.81 mmol) in THF (20 mL) was added di-/so-propyl azodicarboxylate (1.58 g,

7.8 mmol). The reaction was allowed to warm to 25 °C and stirred overnight. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30mLx 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by siiica gel chromatography to give (+\-)-methyl 6-(tert-butoxycarbonyl(3-methyl-1-(6-(4-(trifluoromethyl) -1 H-pyrazol-1yl)pyridin-3-yl)butyl)amino)nicotinate (1.10g) as an oil. ¹H NMR (400 MHz, CDCI₃) δ 8.95 (d, J=1.6 Hz, 1H), 8.78 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.15 (dd, J=2.0, 8.4 Hz, 1H), 7.95 (dd, J=2.4, 8.8 Hz, 1H), 7.86-7.82 (m,

186

2H), 7.50 (d, J=8.4 Hz, 1 H), 5.95-5.92 (m,1H), 3.87 (s, 3H), 2.27-2.20 (m, 1 H), 1.91-1.84 (m,1 H), 1.57-1.54 (m, 1 H), 1.19 (s, 9H), 0.88 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H).

Step B: (-tA-)-methvl 6-(3-methvl-1 -(6-f4-(trifluoromethvl)-1 H-pyrazol-1 -vl)pvridin-3-vl)butvlamÎno)nicotinate

To aO°C solution of (+\-)-methyl 6-(tert-butoxycarbonyi(3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1yl)pyridin-3-yl)butyl)amino)nicotinate (110 mg, 4.7 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The solution was stirred at 20 °C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous Na_zSO₄, filtered, and concentrated to give (+\-)-methyl 6-(3methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)butylamino)nicotinate (800 mg) as a colorless solid. ’H NMR (400 MHz, CDCI₃) δ 11.11 (d, J=4.0 Hz, 1H ), 8.76 (s, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.36 (d, </=1.6 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.86-7.82 (m, 2H), 6.59 (d, J=9.6 Hz, 1H), 4.54-4.49 (m, 1 H), 3.83 (s, 3H), 2.06-1.97 (m, 1 H), 1.72-1.58 (m, 2H), 0.96 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H).

Step C: methyl 3-(6-f3-rnethvl-1-(6-(4-(Îrifluoromethvl)-1H-Dvrazol-1-vhovridin-3vllbutylaminolnicotlnamidoloropanoate· Isomer 1 and methyl 3-(6-(3-methvl-1-(6-(4-(trifluoromethvl>-1Hpyrazol-1 -vl)pvridin-3-vl)butvlamino)nicotinamido)Dronanoate, Isomer 2

To a solution of (+\-)-methyl 6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3yl)butylamino)nicotinate (800 mg, 1.85 mmol) in methanol (5 mL) was added 2N aqueous sodium hydroxîde (9.2 mL, 18.4 mmol). The resulting mixture was stirred at 20 °C for 2 h. Methanol was removed under reduced pressure and the residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (30mL x 2), The combined organic layers were concentrated under reduced pressure. The resiude was dissolved in DMF (10 mL). HATU (1.36 mg, 3.58 mmol) and W,W-di-iso-propylethylamine (1.15 mg, 8.95 mmol) were added. Methyl 3-aminopropanoate hydrochloride (370 mg, 2.68 mmol) was added. The resulting mixture was stirred at 30 °C for 1 h. The mixture was poured into brine (30 mL) and extracted with ethyl acetate (30mL x 2). The combined organic layers were washed with 1N aqueous HCl (30 mL), dried over anhydrous Na_zSO₄ and concentrated to dryness. The crude residue was purified silica gel

187 chromatography to giva (+\-)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3yl)butylamlno)nicotinamido)propanoate (850mg) as an oil. NMR (400 MHz, CDCI₃) δ 8.75 (s, 1H), 8.37 (d, J=12.0 Hz, 2H), 7.87 (d,J=8.4 Hz, 1 H), 7.80 (S, 1 H), 7.76-7.70 (m, 2H), 6.52 (S, 1H), 6.22 (d, J=8.4 Hz, 1 H). 5.07 (d, J=4.0 Hz, 1 H), 4.86 (d, J=9.2 Hz, 1 H), 3.62-3.58 (m, 5H), 2.54 (t, J=5.6 Hz, 2H), 1.77-1.59 (m, 3H), 1.75-1.63 (m, 2H), 0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H).

(+\-)-methyl 3-(6-(3-methyl-1 -(6-(4-(trif luoromethyl)-1 H-pyrazol-1 -yl)pyridîn-3yl)butylamlno)nicotinamido)propanoate was resolved by SFC (column: Chiralpak AD-3, 50 x 4.6 mm x 3 pm; mobile phase: 40% methanoi in CO₂; modifier; 0.05% diethylamine; flow rate: 4 mL/min) to give methyl 3-(6(3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 1 (450 mg, rétention time: 0.62 min) and methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yljpyridin3-yl)butylamino)nicotinamido)prûpanoate, isomer 2 (400 mg, rétention time: 1.30 min).

Step D: 3-(6-(3-meÎhvl-1-(6-(4-(trifluoromethvÎ)-1H-pvrazol-1-vl)pvridin-3yl)butvlamino)nicotinamido)propanoic acid. Isomer 1

To a solution of methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3yl)butylamino)nicotinamido)propanoate, Isomer 1 (450 mg, 0.89 mmol) in THF (4 mL) was added 2N aqueous lithium hydroxide (4.5 mL, 9.0 mmol). The resulting mixture was stirred at 20 °C for 1hour. Methanoi was removed under reduced pressure. The residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (20mL*2). The organic layer was concentrated to give 3-(6-(3-methyl-1(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoic acid, Isomer 1 (400 mg) as a colorless solid. ¹H NMR (400 MHz, Methanol-d4) δ 8,87 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=1.2 Hz, 1H), 8.10 (dd, J=2.0, 9.2 Hz, 1H), 7.94-7.90 (m, 3H). 7.01 (d, J=9.6 Hz, 1H), 5.00-4.97 (m, 1H), 3.47 (t, J=6.8 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 2H), 0.90-0.95 (m, 6H). MS (M+1)= 491.1. Step E: 3-(6-(3-methyl-1-(6-(4-(trifluoromethvl)-1H-Pvrazol-1-vl)Dvridin-3vl)butylamlno)nicotinamido)propanoic acid, Isomer 2

To a solution of methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3yl)butylamino)nicotinamido)propanoate, Isomer 2 (400 mg, 0.79 mmol) in THF (4 mL) was added 2N aqueous lithium hydroxide (4mL, 8.0 mmol). The resulting mixture was stirred at 20 °C for 1h. Methanoi was removed under reduced pressure. The residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (20mL x 2). The organic layer was concentrated to give 3-(6-(3-methyl-1-(6(4-(trifluoromethyl)-1 H-pyrazol-1-yt)pyridin-3-yl)butylamino)nicotinamido)propanoic acid, Isomer2 (330 mg) as a colorless solid. ’H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=1,2 Hz, 1H),

8.10 (dd, J=2.0, 9.2 Hz, 1H), 7.94-7,90 (m, 3H), 7.01 (d, J=9.6 Hz, 1H), 5.00-4.97 (m, 1H), 3.47 (t, J=6.8 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 2H), 0.90-0.95 (m„ 6H). MS (M+1)=491.1. Example 144: (+\-)-3-(4-(1-(4-(4-cvcloDropvl-1 H-pyrazol-1 -vl)-3.5dimethvlphenoxv)butyl)benzamido)propanoic acid

188

(+\-)-3-(4-(1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)-3,5-dimethylphenoxy)butyl)benzamido) propanoic acid was prepared using a method analogous to that describe for Example 82, starting from Intermediate (93) and ethyl 4-(1-hydroxybutyl) benzoate. Colorless solid. ¹H NMR (400 MHz, CD₃OD) δ 7.75 (d, J=8.0 Hz , 2H),

7.44 (s, J=8.0 Hz, 2H), 7.36 (S, 1 H), 6.64 (s, 2H), 5.33-5.30 (m, 1 H), 3.59 (t, J=6.8 Hz, 2H), 2.63 (t, J=6.8 Hz , 2H), 1.98-1.92 (m, 1H), 1.81 (s, 6H), 1.81-1.72 (m, 2H), 159-1.35 (m, 2H), 096 (t, J=7.6 Hz, 3H), 0.88-0.84 (m, 2H), 0.56-0.52 (m, 2H). MS (M+1 )=476.3.

Example 145:3-(4-(1 -(4-(4-chloro-1H-pvrazoi-1-vl)-3.5-dlmethvlDhenoxv)butvl)benzamido) propanoic acid. Isomer 1

(+\-)-methyl 3-(4-(1-(4-(4-chloro-1 H-pyrazol-1 -yl)-3,5-dimethylphenoxy)butyl)benzamido) propanoate was prepared using a method analogous to that described in Example 82, Steps A-C, using Intermediate (81) in Step A and methyl 3-aminopropanoate hydrochloride in Step C. (+\-)-methyl 3-(4-(1-(4-(4-chîoro-1 H-pyrazol1-yl)-3,5-dimethyiphenoxy)butyl) benzamido)propanoate was resolved by SFC (column: Chiralpak AD-3 50 x

4.6 mm, 3 pm; mobile phase: gradient elution 5% to 40% methanol in CO₂; modifier; 0.05% diethylamine; flow rate: 4 mU/min) to give methyl 3-(4-(1-(4-(4-chloro-1H-pyrazol-1-yl)-3,5dimethylphenoxy)butyl)benzamido)propanoate, Isomer 1 (rétention time: 1.32 min) and methyl 3-(4-(1-(4-(4chloro-1 H-pyrazol-1 -yl)-3,5-dimethylphenoxy)butyl)benzamido) propanoate, Isomer 2 (rétention time: 1.49 min), methyl 3-(4-(1-(4-(4-chloro-1 H-pyrazol-1-yl)-3,5-dimethylphenoxy)butyl) benzamido)propanoate, Isomer 1 (70.0 mg, 0.145 mmol) was dissolved in THF (1.5 mL). 1N aqueous lithium hydroxide (1.50 mL, 1.50) was added. The reaction mixture was stirred for 1 h at room température. The mixture was acidified to pH 3 by addition of 1N aqueous HCl. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3-(4-(1 -(4-(4-chloro-1H-pyrazol-1-yl)-

3,5-dimethylphenoxy)butyl) benzamido)propanoic acid, Isomer 1 (23.9 mg) as an off-white solid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.77-7.81 (m, 3H) 7.68 (s, 1H), 7.48 (d, J=8.0Hz, 2H), 6.70 (s, 2H), 5.35-5.38 (m, 1H), 3.61-3.64 (m, 2H), 2.62-2.68 (m, 2H), 2.00-1.96 (m, 1H), 1.89 (s, 6H), 1.87-1.79 (m, 1H), 1.57-1.44 (m, 2H), 0.99 (t, J=7.2Hz, 3H). MS (M+23) =492.2.

189

Example 146: 3-(4-(cvclohexvl(6-(4-(trifluoromethvl)-1H-pvrazol-1-vl)pyridlne-3vlaminoÎmethvl)benzamido)Dropanoic acid. Isomer 1 and

Example 147: 3-(4-(cvcÎohexvl(6-(4-(trifluoromethyl)-1 H-pvrazol-1 -yl)pyridine-3vlamÎno)methvl)benzamido)oropanoic acid. Isomer 2

(+\-)-3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl) benzamido)propanoic acid (Example 101) was resolved by SFC (Column: Chiralpak AD-H 25 x 4.6 mm; mobile phase: 25% éthanol in CO₂; modifier; 0.2% isopropylamine; flow rate: 2.5 mL/min) to provide 3-(4-(cyclohexyl(6-(4(trifluoromethyl)-l H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 1 (rétention time: 6.93 min) and 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3ylamino)methyl)benzamido) propanoic acid, Isomer 2 (rétention time: 9.58 min) as their isopropylammonium salts. The salts were dissolved in water and the pH adjusted to 3.5 by addition of 1N aqueous HCl. The mixtures were extracted with dichloromethane. The organic layers were dried over MgSO< and concentrated to provide 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1 -yl)pyridine-3ylamino)methyi)benzamido)propanoic acid, Isomer 1 and 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 2. Spectral data for Isomer 1:¹H NMR (400 MHz, CDCI₃) δ 8.58 (s. 1H), 7.77 (s, 1H), 7.65-7.72 (m, 3H), 7.60 (d, J=8.8Hz), 7.32 (d, J=B.2Hz, 2H), 6.82-6.88 (m, 1H), 6.71-6.78 (m, 1H), 4.15 (d, J=6.2Hz, 1 H), 3.65-3.73 (m, 2H), 2.63-2.73 (m, 2H), 1.83-1.93 (m, 1H), 1.59-1.82 (m, 4H), 1.46-1.56 (m, 1H), 0.94-1.28 (m, 6H). MS (M+H)=516.2.

Exemple 148: i+\-)-3-(4-(1-(3.5-dimethvl-4-(4-(trifluoromethvl)-1H-1.2.3-triazol-1-vl)phenoxy) butyl)benzamido)propanoic acid

(+\-)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenoxy)butyl) benzamido)propanoic acid was prepared using a method analogous to that described in Example 82, starting from Intermediate (95). Colorless solid. ¹H NMR (400 MHz, CDCI₃) δ 7.84 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.37 (d, 4=8.4 Hz, 2H), 6.82-6.91 (m, 1H), 6.59 (s, 1H), 5.12-5.20 (m, 1H), 3.64-3.74 (m, 2H), 2.63-2.72 (m, 2H), 1.90-2.01 (m, 1H), 1.84 (s, 6H), 1.71-1.82(m, 1H), 1.34-1.57 (m, 2H), 0.94 (t, J=7.2 Hz, 3H). MS (M+H)=505.0.

190

Example 149: (+/-)-3-(4-(1 -(2-(4-(trifluoromethvl)-1H-pvrazol-1-vl)pvrimidin-5vloxv)butvl)benzamldo)DropanoÎc acid

The title compound was prepared by a method analogous to that described for Example 82- Steps A and D using Intermediate (105) and Intermediate (96). Purification by reversed-phase HPLC on a Waters Sunfire C₁₈ 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave ¢+/-)-3-(4-(1 -(2-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyrimidin-5-yloxy)butyl) benzamido)propanoic acid. Analytical LCMS: rétention time 2.95 minutes (Atlantis C_1S 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0,05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1):

478.2.

Example 150: (+/-)-3-(4-(1-(5-methvl-6-(4-(trifluoromethvl)-1 H-Dvrazol-1-vl)pyridin-3 vloxv) butvl) benzamidoÎDropanolc acid

The title compound was prepared by a method analogous to that described for Example 82- Steps A and D using Intermediate (97) and Intermediate (96). Purification by reversed-phase HPLC on a Waters Sunfire Cj₈ 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-) -3-(4-(1 -(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3yloxy)butyl) benzamidojpropanoic acid. Analytical LCMS: rétention time 3.27 minutes (Atlantis Ci_B 4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1):

491.2.

Example 151: (+/-)-3-(4-(cvclobutvl(3,5-dimethvl-4-(4-(trifluoromethvl)-1H-pyrazol-1 vl)phenoxv)methvl)benzamido)propanoic acid

191

The title compound was prepared by a method analogous to that described for Example 82-Steps A and D using Intermediate (98) and Intermediate (26). Purification by reversed-phase HPLC on a Waters Sunfire C₁₈ 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)-3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyi)-1 H-pyrazol-1 yl)phenoxy)methyl)benzamido)propanoic acid. Analytical LCMS: rétention time 3.46 minutes (Atlantis Cw

4.6 x 50mm, 5μΜ column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 516.2.

Example 152: (+/-)-3-(4-((3,5-dimethvl-4-(4-(trifluoromethvl)-1 H-ovrazol-1-yl)phenoxv)(3.3dimethvIcyclobutvDmethvDbenzamidolpropanoic acid

Step (A): ethvl 4-((3.5-dimethvl-4-(4-(trifluoromethvl)-1H-Pvrazol-1-vl)phenoxv)(3.3dl meth vlcyclobutvl) m ethyl) benzoate

Diisopropyl azodicarboxylate (0.310 mL, 0.730 mmol) was added dropwise to a solution of Intermediate 26 (120 mg, 0.490 mmol), Intermediate (100) (128 mg, 0.490 mmol), and tributylphosphine (0.190 mL, 0.760 mmol) in tetrahydrofuran (2.20 mL). After 18 hours, another 0.5 equiv. of both diisopropyl azodicarboxylate and tributylphosphine were added. After an additional 3 h, the reaction was concentrated. The mixture was diiuted with methylene chloride and acidified with 1 N hydrochloric acid. The mixture was then extracted twice with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 1.00 g of crude material. The crude material was purified by column

192 chromatography (0 - 8% ethyl acetate in heptanes) gave ethyl 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1 Hpyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoate (134 mg, 54%) as an oil. ¹H NMR (400 MHz, CDCI₃) δ 8.00 (d, J = 8.2 Hz, 2H), 7.87 (S, 1 H), 7.64 (s, 1 H), 7.37 (d, J = 8.2 Hz, 2H), 6.57 (s, 2H), 5.01 (d, J = 6.8 Hz, 1 H), 4.36 (q, J = 7.0 Hz, 2H), 2.67 (d, J = 7.0 Hz, 1 H), 1.88 (s, 6H), 1.87-1.74 (m, 3H), 1.69-1.59 (m, 1H), 1.38 (t, J = 7.4 Hz. 3H), 1.14 (s, 3H), 1.10 (s, 3H). MS (M+1): 501.4.

Step (B): 4-((3.5-dimethvl-4-(4-(trifluoromethvl)-1 H-Pvrazol-1-vl)ohenoxv)(3,3dimethvlcvclobutvllmethvl) benzoic acid

To a flask containing ethyl 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3dlmethylcyclobutyl)methyl)benzoate (135 mg, 0.270 mmol) was added anhydrous tetrahydrofuran (0.680 mL), methanol (0.680 mL), water (0.680 mL) and sodium hydroxide (55.7 mg, 1.35 mmol). After 8 h, the reaction was concentrated and dissolved in ethyl acetate and water. 1 N hydrochloric acid was added to pH 3 and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoic acid (110 mg, 86% yield) as an oll. ¹H NMR (400 MHz, CDCI₃) δ 8.06 (d, J = 8.2 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.58 (s, 2H), 5.03 (d, J = 6.8 Hz, 1H), 2.80-2.55 (m, 1H), 2.07-1.72 (m, 9H), 1.67 (dd, J = 8.2, 3.5 Hz. 1H), 1,14 (s, 3H), 1.10 (s, 3H). MS (M+1): 473.5.

Step (C): ethvl 3-(4-((3,5-dimethyl-4-(4-(trifluoromethvl)-1H-Dyrazol-1-vl)phenoxv)(3,3dlmethylcvclobutvl)methvl)benzamido)propanoate

Tetrahydrofuran (1,2 mL) was added to a vial containing 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoic acid (115 mg, 0,240 mmol), ethyl 3aminopropanoate hydrochloride (74.7 mg, 0.490 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',Ntetramethyluronium hexafluorophosphate (185 mg, 0.490 mmol). Diisopropylethylamine (0.210 mL, 1.22 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0 - 50% ethyl acetate in heptane) afforded ethyl 3-(4-((3₁5-dimethyl-4-(4-(trifluoromethyl)1H-pyrazoM-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoate (110 mg, 39% yield) as an oil. ’H NMR (400 MHz, CDCI3) δ 7.87 (s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.64 (s, 1 H), 7.36 (d, J = 8.2 Hz, 2H),

6.81 (t,J = 4.8Hz, 1H),6.57(s, 2H), 5.00 (d, J = 6.8 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2H), 3.71 (q, J = 6.1 Hz,

2H), 2.57 - 2.74 (m, 3H), 1.87-1.92 (m, 7H), 1.80-1.87 (m, 1H), 1.72-1.80 (m, 1H), 1.59 -1.68 (m, 1H), 1.21 -1.35 (m, 3H), 1.13 (S, 3H), 1.10 (S, 3H). MS (M+1): 572.3.

Step (D): (+/-)-3-(4-((3.5-dimethvl-4-(4-(trifluoromethvl)-1 H-pvrazol-1-vl)phenoxv)(3.3dimethvlcvclobutvl)methvl)benzamido)propanoic acid

To a flask containing ethyl 3-(4-((3,5-dimethyl-4-{4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)(3,3dimethylcyclobutyl)methyl)benzamido)propanoate (100 mg, 0.180 mmol) was added water (0.437 mL), tetrahydrofuran (0.437 mL), and methanol (0.437 mL). Sodium hydroxide (36.1 mg, 0.880 mmol) was then added. The suspension was stirred at room température for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 108 mg of crude material. The crude material was azeotrophed three times with toluene and three times with methylene chloride and then dried In vacuo for 18 h to provide (+/-)-3-(4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)(3,3dimethylcyclobutyl)methyl)benzamido)propanoic acid (99.0 mg, 100%) as a solid. ¹H NMR (400 MHz, CDCI₃) δ 7.88 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.65 (s, 1 H), 7.36 (d, J = 8.4 Hz, 2H), 6.76 (t, J = 6.2 Hz, 1 H), 6.56 (S, 2H), 5.01 (d, J = 7.0 Hz, 1 H), 3.72 (q, J = 5.9 Hz, 2H), 2.74 - 2.59 (m, 3H), 1.88 (s, 6H), 1.87- 1.68 (m,

3H), 1.68-1.58 (m, 1H), 1.13 (s, 3H), 1.10 (s, 3H). MS (M+1): 544.3.

Example 153: (+/-)-3-(4-(1 -(3-methoxv-5-methvl-4-(4-(trifluoromethvlM H-pyrazol-1 vl)phenoxv)butvl)benzamido)DroDanoic acid

Step (A): ethvl 3-(4-(1-i3-methoxv-5-methvl-4-(4-(trifluoromethvl)-1 H-ovrazol-1vl) phenoxy) butvl) benzam ido) propanoate

Tetrahydrofuran (0.450 mL) was added to azodicarboxylic acid dipiperidine (34.2 mg, 0.130 mmol), Intermediate (96) (26.0 mg, 0.0900 mmol) and Intermediate (103) (24.2 mg, 0.0900 mmol).

Tributylphosphine (0.035 mL, 0.142 mmol) was added dropwise at room température. Another 0.450 mL of tetrahydrofuran was added. The mixture was stirred at room température for 16 hours. The reaction was diluted with ethyl acetate and then extracted twice with sodium hydroxide (1 N), once with water, once with hydrochloric acid (1 N), and finally once with brine. The organic layer was dried over sodium sulfate filtered,

194 and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptanes) afforded ethyl

3-(4-(1-(3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (39.5 g, 81%) as an oil: ¹H NMR (400 MHz, CDCI₃) δ 7.86 (s, 1 H), 7.74 (d, J = 8.2 Hz, 2H), 7.66 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 6.84 (t, J = 6.0 Hz, 1 H), 6.35 (d, J = 2.5 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 5.16 (dd, J = 7.7, 5.2 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2H), 3.77 - 3.67 (m, 2H), 3.64 (s, 3H), 2.70 - 2.54 (m, 2H), 2.08-1.93 (m, 1 H), 1.91 (s, 3H), 1.87 - 1.72 (m, 1 H), 1.60 -1.36 (m, 2H), 1.36 -1.18 (m, 3H), 0.97 (t, J = 7.4 Hz, 3H). MS (M+1): 548.4.

Step (B): (+/-)-3-(4-(1 -(3-methoxy-5-methvl-4-(4-(trifluoromethvl)-1 H-pyrazol-1vl)ph6noxv)butyl)benzamïdo)propanoic acid

To a flask containing ethyl 3-(4-(1-(3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoate (37.0 mg, 0.0700 mmol) was added tetrahydrofuran (0.170 mL), methanol (0.170 mL), and 1 N sodium hydroxide (0.170 mL, 0.170 mmol) was then added. The suspension was stirred at room température for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 2 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to provide (+/-)-3-(4-(1 -(3-methoxy-5-methyl-4-(4(trifluoromethyl)-l H-pyrazol-1-yl)phenoxy)butyl)benzamido) propanoic acid (26.0 mg, 74%) as a solid. ¹H NMR (400 MHz, CDCI₃) δ 7.87 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 6.88 (t, J = 6.0 Hz, 1H), 6.41 - 6.21 (m, 2H), 5.17 (dd, J = 7.7, 5.2 Hz, 1 H), 3.75 - 3.65 (m, 2H), 3.63 (s, 3H), 2.66 (t, J = 5.9 Hz, 2H), 2.04 - 1.93 (m, 1 H), 1.89 (s, 3H), 1.86 - 1.74 (m, 1 H), 1.62 - 1.35 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). MS (M+1): 520.4.

Example 154: (+/-)-3-(4-((3.3-difluorocvclobutyl)(6-(4-(trifluoromethvl)-1 H-imidazol-1 -yl)pyridin-3vlamino)m8thvl)benzamido)DroDanoic acid

Step (A): ethyl 4-((3.3-difluorocyclobutvl)(6-(4-(trifluoromethvl)-1 H-imidazol-1-vl)pyridin-3ylamino)methyl) benzoate

To a solution of impure Intermediate (104) (72.0 mg, approximately 0.214 mmol pure) and intermediate 6 (61.2 mg, 0.270 mmol) in methanol (0.670 ml) was added decaborane (19.7 mg, 0.160 mmol),

The reaction was stirred for 16 hours at ambient température. The reaction mixture was quenched with

195 aqueous 1 .OM hydrochlorlc acid and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel flash chromatography (0 -50% ethyl acetate in heptane) afforded impure ethyl 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1 Himidazol-1-yl)pyridin-3-ylamino)methyl)benzoate (30.0 mg, approximately 0.050 mmol pure) as a solid. MS (M+1): 481.1.

Step (B): 4-((3.3-difluorocvclobutvl)(6-i4-(trifluoromethvn-1 H-imidazol-1-yl)Dvridin-3-vlamino)methvnbenzoic acid

To a flask containing impure ethyl 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1 H-imidazol-1 yl)pyridln-3-ylamino)methyl)benzoate (35.0 mg, 0.073 mmol) was added tetrahydrofuran (0.180 mL), methanol (0.180 mL), and 1 N sodium hydroxide (0.180 mL, 0.180 mmol) was then added. After 2 h, another 5 equiv. of aqueous sodium hydroxide was added. The suspension was stirred at room température for 18 hours. Another 5 equiv. of aqueous sodium hydroxide was added and the reaction was heated to 50 °C. After 2 h, the reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to provide crude 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyridin-3ylamino)methyl)benzoic acid (24.0 mg). MS (M+1): 453.2.

Step (C): ethvl 3-(4-((3.3-difluorocvclobutvl)(6-(4-(trifluoromethvl)-1 H-imidazol-1-vl)Dvridin-3vlamino) methvhbenzam ido) propanoate

Dimethylformamide (0.270 mL) was added to a vial containing crude 4-((3,3-difluorocyclobutyl)(6-(4(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoic acid (24.0 mg, approximately 0.120 mmol pure), ethyl 3-aminopropanoate hydrochloride (16.3 mg, 0.110 mmol) and O-(7-azabenzotriazol-1-y))Ν,Λ/,Λ/',Ν’-tetramethyluronium hexafluorophosphate (40.3 mg, 0.110 mmol). Diisopropylethylamine (0.046 mL, 0.270 mmol) was then added. The reaction was stirred for 16h, and was then concentrated. Purification by column chromatography (0 - 60% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-difluorocyclobutyl)(6(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyridin-3-ytamino)methyl)benzamido)propanoate (7.00 mg) as an oil. MS (M+1): 552.3.

Step (D): (+Z-)-3-(4-((3.3-difluorocvclobutvl)(6-(4-(trifluoromethvl)-1H-imldazol-1-vlÎDvridln-3vlamino)methvl)benzamido)propanoic acid

To a flask containing 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifiuoromethyl)-1 H-imidazol-1-yl)pyridin-3ylamino)methyl)benzamido)propanoate (7.00 mg, 0.0100 mmol) was added water (0.0650 mL), tetrahydrofuran (0.0650 mL), and methanol (0.0650 mL). Lithium hydroxide monohydrate (27.3 mg, 0.650 mmol) was then added. The suspension was stirred at room température for 2 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (+/-)-3-(4-((3,3difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl) benzamido)propanoic acid (4.5 mg, 70%) of a glass-like material. ¹H NMR (400 MHz, CDCIs) δ 8.36 - 8.34 (m, 1 H), 8.16 - 8.12 (m, 1H), 7.86 (d, J = 2.9 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.58 - 7.51 (m, 2H), 7.39 (dd, J = 8.8, 0.6 Hz, 1 H), 7.10 (dd, J = 8.8, 2.9 Hz, 1 H), 4.48 (d, J = 8.8 Hz, 1 H), 3.63 (t, J = 6.9 Hz, 2H), 2.94 - 2.73 (m, 1 H), 2.64 (t, J = 6.9 Hz, 2H), 2.61 -2.49 (m, 2H), 2.49- 2.33 (m, 2H). MS (M+1): 524.3.

Example 155: 3-(4-((3.3-dlmethvlcvclobutvl)(2-(4-(trifluoromethvl)-1 H-pyrazol-1-vl)pyrimidln-5vloxvlmethyDbenzamidolpropanoic acid. Isomer 1 and

Example 156: 3-(4-((3.3-dimethvlcvclobutvl)(2-(4-(Îrifluoromethvl)-1H-Dvrazol-1-vl)pyrimidin-5vloxv)methvl)benzamido)propanoic acid. Isomer 1

Voh

Step (A): ethyl 3-(4-((3,3-dimethvlcvclobutvl)(2-(4-(trifluoromethvl)-1 H-pyrazol-1 -vl)pyrlmidin-5vIoxylmethylIbenzamidolDropanoate, Isomer 1 and Isomer 2

Azodicarboxylic acid dipiperidine (814 mg, 3.19 mmol) and Intermediate (102) (781 mg, 2.34 mmol) were azeotrophed twice with toluene. To this mixture was added anhydrous tetrahydrofuran (10.6 mL). Tributylphosphine (0.840 mL, 3.41 mmol) was then added dropwise, Intermediate (105) (490 mg, 2.13 mmol) was then added as a solid in one portion. After 18 hours, the reaction was not complété so another 0.5 equiv. of Azodicarboxylic acid dipiperidine and tributylphosphine were added. After another 4 h, the reaction was diluted with ethyl acetate to fully dissolve the solid. The mixture was washed twice with 1.0 M sodium hydroxide, water, 1.0 M hydrochloric acid, and brine. The organic layer was dried over magnésium sulfate, filtered, and concentrated to a viscous oil. Purification by silica gel flash chromatography (0 - 30% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)pyrimidin-5-yloxy)methyl)benzamido)propanoate (520 mg, 45% yield) as a white solid.

197

Isomer 1 is obtained by resolving (+/-)-ethyl 3-(4-((3,3-dimethylcyclobutyi)(2-(4-(trifluoromethyl)-1Hpyrazol-1-yl)pyrimidin-5-yloxy)methyl)benzamido)propanoate by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 21mm x 25cm. Mobile Phase: 70/30 COü/methanol. Flow Rate: 65.0 mL/min. Modifier: none. Rétention time: 2.05 minutes, isomer 1,2.71 minutes, isomer 2. Isomer 1 : ’H NMR (400 MHz, CDCI₃) δ 8.71 (S, 1H), 8.29 (s, 2H), 7.92 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.81 (t, J = 6.2 Hz, 1H), 5.08 (d, J = 7.4 Hz, 1 H), 4.27 - 4.02 (m, 2H), 3.70 (q, J = 6.0 Hz, 2H), 2.85 - 2.66 (m, 1 H), 2.62 (t, J = 5.9 Hz, 2H), 1.96- 1.82 (m, 2H), 1.79- 1.69 (m, 1H), 1.69- 1.59 (m, 1H), 1.30-1.21 (m, 3H), 1.15 (s, 3H), 1,11 (s, 3H). MS (M+1): 546.4. Isomer 2:) ¹H NMR (400 MHz, CDCI_a) δ 8.72 (s, 1H), 8.29 (s, 2H), 7.92 (s, 1 H), 7.74 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.81 (t, J = 6.1 Hz, 1 H), 5.08 (d, J = 7.4 Hz, 1 H), 4.23 - 4.03 (m, 2H), 3.71 (q, J = 6.0 Hz, 2H), 2.84 - 2.67 (m, 1H). 2.62 (t, J = 5.8 Hz, 2H), 1.97 - 1.84 (m, 2H), 1.78 - 1.69 (m, 1H), 1.69-1.58 (m, 1H), 1.31 - 1.22 (m, 3H), 1.15 (s, 3H), 1.11 (s, 3H). MS (M+1): 546.4.

Step_______(B):_______3-(4-((3.3-dimethylcyclobutvlïï2-(4-(trifluoromethvl)-1H-pvrazol-1-vÎ)pyrimldln-5vtoxv)methvl)benzamido)propanoic acid. Isomer 1

The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-dimethylcyclobutyl) (2-(4(trifluoromethyl)-l H-pyrazol-1-yl)pyrimidin-5-yloxy)methyl)benzamido)propanoate, isomer 1 using the conditions in Example 152, Step D. ¹H NMR (400 MHz, CDCI₃) δ 8.71 (s, 1H), 8.29 (s, 2H), 7.92 (s, 1H), 7.80

- 7.68 (m, 2H), 7.42 - 7.31 (m, 2H), 6.74 (t, J = 6.1 Hz, 1 H), 5.08 (d, J = 7.2 Hz, 1 H), 3.72 (q, J = 6.0 Hz, 2H),

2.82 - 2.74 (m, 1 H), 2.71 (t, J = 6.0 Hz, 2H), 1.97 - 1.82 (m, 2H), 1.80 - 1.68 (m, 1H), 1.68 - 1.58 (m, 1H), 1.15 (s, 3H), 1.11 (s, 3H). MS (M+1): 518.2. Chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6 x 250mm. Mobile Phase: 60/40 COa/methanol. Flow Rate: 2.5 mL/min. Modifier: None. Rétention time: 3.80 minutes.

Step (B): 3-(4-((3.3-dimethvlcvclobutyl)(2-(4-itrifluoromethvl)-1 H-pvrazol-1-vl)pvrimidin-5vloxv)methvl)benzamido)prooanoic acid. Isomer 2

The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-dimethylcyclobutyl) (2-(4(trifluoromethyl)-l H-pyrazol-1 -yl)pyrimidin-5-yloxy)methyl)benzamido)propanoate, isomer 2 using the conditions in Example 152, Step D. ¹H NMR (400 MHz, CDCI₃) δ 8.71 (s, 1H), 8.29 (s, 2H), 7.92 (s, 1H), 7.77

- 7.67 (m, 2H), 7.42 - 7.32 (m, 2H), 6.75 (t, J = 6.3 Hz, 1 H), 5.08 (d, J = 7.4 Hz, 1 H), 3-72 (q, J = 6.2 Hz, 2H),

2.82 - 2.73 (m, 1 H), 2.71 (t, J = 6.0 Hz, 2H), 1.96 - 1.83 (m, 2H), 1.80-1.69 (m, 1H), 1.69 -1.58 (m, 1 H), 1.15 (s, 3H), 1.11 (s, 3H). MS (M+1): 518.2. Chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6 x 250mm. Mobile Phase: 60/40 COa/methanol. Flow Rate: 2.5 mL/min. Modifier: None. Rétention time: 5.93 minutes.

Example 157:3-(4-({3.3-dimethvlcvclobutvl)(2-(4-(trifluoromethvl)-1 H-pyrazol-1 -vl)pvrimidln-5vlamino)methvl)benzamido)propanoic acid. Isomer 1 and

Example 158:3-(4-((3.3-dimethvlcyclobutvl)(2-(4-(trifluoromethvl)-1H-pyrazol-1-vl)pvrimidin-5vlamino)methvl)benzamido)proDanoÎc acid. Isomer 2

Step (A): ethvl 3-(4-((3.3-dimethvicvclobutvl)(2-(4-(trifluoromBthvll-1H-Dvrazol-1-vl)pyrimidln-5vlaminolmethyllbenzamidolpropanoate

To a solution of Intermediate (101) (1.19 g, 3.60 mmol) and Intermediate (106) (750 mg, 3.27 mmol) In methanol (10.9 ml) was added decaborane (240 mg, 1.96 mmol). The reaction was stirred for 12 hours at ambient température. The reaction mixture was quenched with aqueous 1.0M hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel flash chromatography (0 - 70% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5ylamino)methyl)benzamido)propanoate (842 mg, 47% yield) as a yellow solid.

(+/-)-ethyl 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyrimidin-5ylamino)methyl)benzamido)propanoate was resolved by chiral SFC (Column: Chiralpak IA. Dimensions: 10mm x 25cm. Mobile Phase: 65/35 COz/methanol. Flow Rate: 10.0 mL/mïn. Modifier: none) to give ethyl 3(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5ylamino)methyl)benzamido)propanoate Isomer 1 (rétention time: 3.42 min) and ethyl 3-(4-((3,3dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-y!amino)methyl)benzamido)propanoate, Isomer 2 (rétention time: 4.55 min). Isomer 1:¹H NMR (400 MHz, CDCIg) δ 8.64 (s, 1 H), 7.97 (s, 2H), 7.88 (s, 1 H), 7.79 - 7.64 (m, 2H), 7.41 - 7.31 (m, 2H), 6.82 (t, J = 5.9 Hz, 1 H), 4.22 (d, J = 9.4 Hz, 1 H), 4.16 (q, J = 7.0 Hz, 2H), 3.80 - 3.64 (m, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.58 - 2.45 (m, 1 H), 2.05-1.97 (m , 1 H), 1.75 - 1.63 (m, 2H), 1.63- 1.55 (m, 1H), 1.26 (t, J = 7.2 Hz. 3H), 1.13 (s, 3H), 1.09 (s, 3H). MS (M+1): 545.4. Isomer 2: ’H NMR (400 MHz, CDCI₃) δ 8.64 (s, 1H), 7.97 (s, 2H), 7.88 (s, 1H), 7.80 - 7.67 (m, 2H), 7.43 - 7.30 (m, 2H),

6.82 (t, J = 6.0 Hz, 1 H), 4.22 (d, J = 9.4 Hz, 1 H), 4.16 (q, J = 12 Hz, 2H). 3.77 - 3.64 (m, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.58 - 2.40 (m, 1 H), 2.05-1.97 (m, 1 H), 1.76 - 1.64 (m, 2H), 1.64 -1.52 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3H), 1.13 (s, 3H), 1.09 (s, 3H). MS (M+1): 545.4.

Step (Βί: 3-(4-f(3.3-dimethvlcvclobutvl)(2-(4-(trifluoromethvl)-1 H-pvrazol-1-vl)pyrimidin-5vlamino)methyl)benzamido)propanoic acid. Isomer 1

199

The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-dimethylcyclobutyl) (2-(4(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-ylamino)methyl)benzamido)propanoate, isomer 1 using the conditions in Example 152, Step D. ¹H NMR (400 MHz, CDCI₃) δ 8.80 - 8.53 (m, 1H), 8.01 (br. s., 2H), 7.89 (br. s., 1H), 7.78 - 7.67 (m, 2H), 7.41 - 7.30 (m, 2H), 6.84 (s, 1H), 4.22 (d, J = 9.4 Hz, 1H), 3.71 (q. J = 4.7 Hz, 2H), 2.70 (t, J = 5.7 Hz, 2H), 2.64 - 2.40 (m, 1 H), 2.12 - 1.90 (m, 1 H), 1.77 -1.47 (m, 3H), 1.12 (s, 3H), 1.08 (s, 3H). MS (M+1): 517.3.

Step (C): 3-(4-((3.3-dimethvicvclobutvlïï2-(4-(trifluoromethvl)-1 H-pvrazol-1-vl)pyrimidin-5vlamino)methvl)benzamido)propanoic acid. Isomer 2

The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-d Imethylcyclobutyl) (2-(4(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-ylamino)methyl)benzamido)propanoate, isomer 2 using the conditions in Example 152, Step D. ¹H NMR (400 MHz, CDCI₃) δ C8.72 - 8.58 (m, 1H), 8.00 (br. s._t 2H), 7.89 (br. s„ 1 H), 7.76 - 7.65 (m, 2H), 7.40 - 7.29 (m, 2H), 6.87 (br. s, 1 H), 4.22 (d, J = 9.4 Hz, 1 H), 3.78 - 3.66 (m, 2H), 2.70 (t, J = 5.5 Hz, 2H), 2.62 - 2.42 (m, 1 H), 2.08 -1.93 (m, 1 H), 1.77 - 1.51 (m, 3H), 1.12 (s, 3H), 1.08 (s, 3H). MS (M+1); 517.3.

Example 159:3-(4-(1-(2-methvl-4-(4-(trifluoromethvl)-1H-ovrazol-1-vl)phenoxv)butvl) benzamidolpropanoic acid o o

A mixture of 4-iodo-2-methylphenol (700 mg, 3.0 mmol), benzyl bromide (563 mg, 3.3 mmol), potassium carbonate (620 mg, 4.5 mmol), and acetonitrile (15 ml) was stirred at the ambient température for three days. The reaction was concentrated in vacuum and theresidue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnésium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 5% to 30% of ethyl acetate in heptane gave the target product as a coloriess solid (950 mg, 98%). ¹H NMR (500 MHz,CDCI₃) δ 7.48 (d, 1 H), 7.38 - 7.45 (m, 5H), 7.33 - 7.37 (m, 1H), 6.66 (d, J = 8.54 Hz, 1H), 5.07 (s, 2H), 2.25 (s, 3H).

Step B: 1 -(4-(benzvloxv)-3-methylphenvl)-4-(trifluoromethvl)-1 H-pyrazole

A mixture of 1-(benzyloxy)-4-iodo-2-methylbenzene (850 mg, 2.6 mmol), 4-(trifluoromethyl)-1H-pyrazole (535

200 mg, 3.9 mmol), copper iodide (100 mg, 0.52 mmol), dimethylglycine (54 mg, 0.52 mmol), potassium carbonate (906 mg, 6.6 mmol), and DMSO (10 ml) was stirred at +120° for 20 hours. The reaction was cooled to the ambient température, diluted with 10 ml of 5% aqueous ammonia and 10 ml of ethyl acetate and vigorously stirred for 20 min. The mixture was extracted with ethyl acetate (2x20 mi). The combined organic extract was washed with brine, dried over anhydrous magnésium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 5% to 30% of ethyl acetate In heptane gave the target product as an oil, which crystailized upon standing to a colorless solid (670 mg, 77%). MS (M+1): 333.1.

Step C: 2-methvl-4-(4-(trifluoromethvl)-1 H-pyrazol-1-yllphenol

HO.

A mixture of 1-(4-(benzyloxy)-3-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (670 mg, 2.0 mmol), 20% palladium hydroxide on activated carbon (50 mg), éthanol (20 ml), and THF (20 ml) was shaken under 40 psi of hydrogen gas at the ambient température for 3 days and at +50° for 1 day, to drive reaction to completion. The reaction was filtered through a pad of Celite and the mother liquor was concentrated to obtain the target product as a colorless solid (420 mg, 86%). MS (M+1): 243.0.

Step D: ethvl 4-i1-(2-methvl-4-(4-(trifluoromethvD-1H-pvrazol-1-vl)Dhenoxv)butvl)benzoate

F

2-Methyl-4-(4-(trlfluoromethyl)-1 H-pyrazol-1 -yl)phenol (200 mg, 0.83 mmol) was combined with ethyl 4-(1 hydroxybutyl)benzoate (see Intermediate 5) (19 mg, 0.87 mmol) and dissolved in anhydrous tetrahydrofuran (5 mL). Triphenylphosphine (347 mg, 1.3 mmol) was added at 0° under stirring followed by 0.83 ml of 1.5 M solution of dlazoethyl azodicarboxylate (1.24 mmol). The reaction was stirred at room température as a yellow solution. At 17 hours, the reaction was concentrated and 10 ml of ethyl acetate and 5 ml of heptanes were added. Solid was filtered off and the mother liquor was loaded on silica gel. Chromatography on a silica gel column (gradient from 5% to 40% of ethyl acetate in heptane) gave the target product as a colorless glass (90 mg, 24%). MS (M+1): 447.2.

Step E: 4-(1-(2-methvl-4-(4-(trifluoromethvll-1 H-pyrazol-1-vl)phenoxv)butvl)benzoic acid

₍ 201

A mixture of ethyl 4-(1-(2-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl) benzoate (90 mg, 0.2 mmol), lithium hdroxide monohydrate (24 mg, 1.0 mmol), methanol (2 ml), THF (3 ml), and water (1 ml) was stirred at +45° for 18 hours. The mixture was concentrated, diluted with 8 ml of water and 2 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate-heptane (1:1), extract was washed with brine, dried over anhydrous magnésium sulfate and concentrated to obtain the target product as a white solid (84 mg, 99%). MS (M+1): 419.2.

Step F: ethyl 3-(4-(1 -(2-meÎhvl-4-(4-(trifluoromethvl)-1H-Pvrazol-1-vl)phenoxv)butvDbenzamldolpropanoats

To a mixture of ethyl 3-aminopropanoate hydrochloride (46 mg, 0.3 mmol), 4-(1-(2-methyl-4-(4(trifluoromethyl)-lH-pyrazol-1 -yl)phenoxy)butyl)benzoic acid (84 mg, 0.2 mmol), HOBt hydrate (34 mg, 0.22 mmol), and DIPEA (0.133 ml, 0.8 mmol), and THF (3 ml) was added EDCI hydrochloride (62 mg, 0.32 mmol) In one portion at the ambient température and the reaction was stirred at the same température for three days. The mixture was diluted with 3 ml of ethyl aceate, 3 ml of heptanes, and washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnésium sulfate, and loaded on siiica gel. Chromatography on a siiica gel column, eluting with a gradient from 10% to 50% of ethyl acetate In heptane gave the target product as a colorless gum (55 mg, 53%).

¹H NMR (500 MHz, CDCI₃) δ DB.01 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 8.29 Hz, 2H), 7.45 (d, J = 2.68 Hz, 1H),

7.40 (d, J = 8.05 Hz, 2H), 7.20 (dd, J = 2.68, 8.78 Hz, 1 H), 6.81 - 6.87 (m, 1 H), 6.61 (d, J = 8.78 Hz, 1 H), 5.21 (dd, J = 5.12, 7.56 Hz, 1H), 4.18 (q, J = 7.16 Hz, 2H),3.73 (q, J = 6.02 Hz, 2H), 2.64 (t, J = 5.85 Hz, 2H), 2.40 (s, 3H), 2.00 - 2.10 (m, 1 H), 1.81 -1.90 (m, 1 H), 1.52 -1.61 (m, 1 H), 1.44 - 1.51 (m, 1 H), 1.28 (t, J = 7.20 Hz, 3H), 0.98 (t, J = 7.44 Hz, 3H). MS (M+1): 518.2.

Step G: 3-(4-(1-(2-methvl-4-(4-(Îrifluoromethvl)-1 H-pvrazol-1-vl)phenoxv)butvl)benzamido)propanoic acid

A mixture of ethyl ethyl 3-(4-(1 -(2-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido)propanoate (55 mg, 0.11 mmol), lithium hdroxide monohydrate (7.2 mg, 0.3 mmol), methanol (2 ml), THF (2 ml), and water (0.3 ml) was stirred at 22° for 3 days. The mixture was concentrated, diluted with 8 ml of water and 0.35 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate, the extract was washed with brine, dried over anhydrous magnésium sulfate and concentrated to obtain 3-(4(1-(2-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl)benzamido)-propanoic acid as a white solid

202 (50 mg, 96%). ’H NMR (500 MHz, CDCI₃) δ 8.00 (s. 1H), 7.84 (s, 1H), 7.73 (d, J = 8.29 Hz, 2H), 7.43 (d, J =

2.68 Hz, 1 H), 7.39 (d, J = 8.29 Hz, 2H), 7.18 (dd, J = 2.68, 8.78 Hz, 1 H), 6.84 - 6.90 (m, 1 H), 6.59 (d, J =

8.78 Hz, 1 H), 5.20 (dd, J = 5.12, 7.56 Hz, 1 H), 3.71 (q, J = 5.94 Hz, 2H), 2.69 (t, J = 5.85 Hz, 2H), 2.39 (s, 3H), 1.99 - 2.09 (m, 1 H), 1.80 - 1.89 (m, 1 H), 1.51-1.61 (m, 1 H), 1.42 - 1.50 (m, 1 H), 0.98 (t, J = 7.32 Hz, 3H). MS (M+1): 490.2.

Example 160: 3-(4-(1-(6-(4-phenvl-1H-pvrazol-1-vl)Dvrïdine-3-vlamino)butvl)benzamido)oropanoic acid, tsomer 1

The title compound is obtained by resolving racemic 3-(4-(1-(6-(4-phenyl-1 H-pyrazol-1-yl)pyridine-3ylamino)butyl)benzamido)propanoic acid Example 62, by chiral SFC. Column: Chiralcel AS-H. Dimensions: 4.6mm x 250mm. Mobile Phase: 60/40 COa/isopropanol. Flow Rate: 2.5 mL/min. Modifier; 0.2% isopropylamine. Rétention time: 5.33 minutes.

Example 161: 3-f4-(1-/6-(4-phenvl-1H-pvrazol-1-vl)pyrÎdine-3-vlamino)butvl)benzamido)prooanoicacid, Isomer 2

The title compound is obtained by resolving racemic 3-(4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridine-3y)amino)butyl)benzamido)propanoic acid Example 62, by chiral SFC. Column: Chiralcel AS-H. Dimensions: 4.6mm x 250mm. Mobile Phase: 60/40 COa/isopropanol. Flow Rate: 2.5 mL/min. Modifier: 0.2% isopropylamine. Rétention time: 6.25 minutes.

Example 162: f+/-)-3-(4-(1-f6-(4-phenyl-1H-imidazo1-1-vl)pvridin-3-vlamino)butvl)benzamido)propanoic acid

203

The title compound was prepared by a method analogous to that described for Example 62, using 6(4-phenyl-1H-imidazol-1-yl)pyridin-3-amine. Column: Waters Atlantis dC10 4.6 x 50mm, 5pm. Modifier: TFA 0.05%. Gradient: 95%H_a0 / 5%MeCN linear to 5%H₂0 / 95%MeCN over 4.0min, Hold at 5%H₂0 / 95%MeCN to 5.0min. Flow: 2.0mL/min. Rétention time: 2.38 min. MS (M+1): 484.0.

Example 163: (+/-)-3-(4-((6-(4-chloro-3-methvl-1H-Dyrazol-1-vl)pvrldln-3vlamino)icyclODentvl)methvl)benzamido)DroDanoic acid

Steo A: f+Z-Vethyl 4-((6-(4-chloro-3-methvl-1H-Dvrazol-1-vl)ovridln-3-vlamino) (cvclooentvl)methvübenzoate

ci

The title compound was prepared by a method analogous to that described in Step A of Example 1, using Intermediate (31) and Intermediate (108). ’H NMR (400 MHz, CDCI₃, C): 8.18 (s, 1 H), 7.96-8.00 (m, 2 H), 7.62 (d, J = 2.7 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.36 - 7.40 (m, 2 H), 6.85 (dd, J = 8.9, 2.8 Hz, 1 H),

4.34 (q, J = 7.0 Hz, 2 H), 4.13 (d, J = 8.4 Hz, 1 H), 2.26 (S, 3 H), 2.13 - 2.22 (m, 1 H), 1.87 - 1.96 (m, 1 H), 1.38-1.72 (m, 6 H), 1.33-1.38 (m, 3 H), 1.22-1.32 (m, 2 H). MS (M+1) 439.3.

Step B: (+/-)-4-((6-(4-chloro-3-methyl-1H-pvrazol-1-vl)Dvridin-3-vlamino)(cvclopentyl) methvObenzolc acid o

Cl

To a solution of (+/-)-ethyl 4-((6-(4-chloro-3-methyl-1 H-pyrazol-1 -yl)pyridin-3ylamino)(cyclopentyl)methyl)benzoate (78.6 mg, 0.179 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added 1 N aqueous sodium hydroxide (0.36 mL, 0.36 mmol). The reaction was heated to 50 °C for 10 minutes. The heat was removed and the reaction was allowed to stir at room température for 1 hour. The reaction was concentrated. The residue was taken up in water and acidified to pH = 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (68.3 mg, 93%) as a white solid. ’H NMR (400 MHz, CD₃OD, 5): 8.19 (s, 1 H), 7.92 - 7.96 (m, 2 H), 7.66 - 7.69 (m, 1 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.42 - 7.45 (m, 1 H), 7.03 (dd, J = 8.9, 2.8 Hz, 1 H), 4.18

! 204 (d, J = 9.2 Hz, 1 H), 2.22 (S, 3 H), 1.98 - 2.07 (m, 1 H), 1.43 -1.74 (m, 6 H), 1.23 - 1.38 (m, 2 H). MS (M+1 )

411.3.

Step C: (+/-)-methvl 3-(4-((6-(4-chloro-3-methyl-1H-pvrazol-1-vl)pyridin-3vlamino) (cvclopentvl) methyl) benzam ido) propanoate

The title compound was prepared by a method analogous to that described in Step C of Example 2, using (+/-)-4-((6-(4-chloro-3-methyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino)(cyclopentyl)methyl)benzoic acid. ’H NMR (400 MHz, CDCI₃, δ): 8.18 (s, 1 H), 7.66 - 7.72 (m, 2 H), 7.61 (d, J = 2.7 Hz, 1 H), 7.49 - 7.54 (m, 1 H), 7.37 (d, J = 8.4 Hz, 2 H), 6.85 (dd, J = 8.8, 2.9 Hz, 1 H), 6.78 (t, J = 6.0 Hz, 1 H), 4.09 - 4.14 (m, 1 H), 3.65-3.73 (m, 5 H), 2.59-2.65 (m, 2 H), 2.25 (s, 3 H), 1.86-1.96 (m, 1 H). 1.35-1.73 (m, 6 H), 1.19-

1.32 (m, 2 H). MS (M+1) 496.4.

Step D: (+/-)-3-(4-((6-(4-chloro-3-methvl-1H-Dvrazol-1-vl)pvrldln-3vlamino)(cvclopentvl)methvl)benzamido)propanoic acid

The title compound was prepared by a method analogous to that described in Step E of Example 4, using (+/-)-methyl 3-(4-({6-(4-chloro-3-methyl-1 H-pyrazol-1 -yl)pyridin-3ylamlno)(cyclopentyl)methyl)benzamido)propanoate. ’H NMR (400 MHz, CD₃OD, δ): 8.19 (s, 1 H), 7.707.75 (m, 2 H), 7.66 (d, J = 2.5 Hz, 1 H), 7.41 - 7.49 (m, 3 H), 7.05 (dd, J = 9.0, 2.9 Hz, 1 H), 4.17 (d, J = 9.2 Hz, 1 H), 3.58 (t, J = 6.9 Hz, 2 H), 2.59 (t, J = 6.9 Hz, 2 H), 2.22 (s, 3 H), 1.97-2.08 (m, 1 H), 1.42-1.75 (m, 5 H), 1.23 - 1.39 (m, 3 H). MS (M+1) 482.4.

Example 164: (+/-)-3-(4-(1-(6-(4-(pvrldin-2-vl)-1H-pvrazol-1-yl)pyridin-3-vlamino)butyl)benzamido)propanoic acid

Step A: (+/-)-ethvl 4-(1-(6-(4-(Dvridin-2-vl)-1/-/-ovrazol-1-vl)Dvridin-3-vlamino)butvl)benzoate

205

To a solution of Intermediate (109) (42.3 mg, 0.178 mmol) In methanol (1.Θ mL) was added glacial acetic acid (20 pL, 0.4 mmol) and Intermediate (5) (43.0 mg, 0.195 mmol). Lastly, added decaborane (13 mg, 0.11 mmol) and let reaction stir at room température for 65 hours. The reaction was concentrated. The crude residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate (3 x) and brine, dried over magnésium sulfate, filtered, and concentrated. Purification by flash column chromatography (10-70% ethyl acetate / heptanes) gave ethyl 4-(1 -(6-(4-(pyridin-2-yl)-1H-pyrazol-1 -yl)pyridin-3ylamino)butyl)benzoate (19.6 mg, 25%). ’H NMR (400 MHz, CDCI_3> δ): 8.82 (s, 1 H), 8.56 (dd, J = 4.9, 1.0 Hz, 1 H), 8.16 (s, 1 H), 8.00 (d, J = 8.2 Hz, 2 H), 7.61 - 7.72 (m, 3 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.39 (d, J =

8.2 Hz, 2 H), 7.10 (ddd, J = 7.5, 5.0, 1.0 Hz. 1 H), 6.88 (dd, J = 8.9, 2.8 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 4.23 (d, J = 5.5 Hz, 1 H), 1.71 - 1.90 (m, 2 H), 1.31-1.54 (m, 5 H), 0.94 (t, J = 7.3 Hz. 3 H). MS (M+1)

442.4.

Step B: (+/-)-3-(4-(1 -i6-(4-(pvridin-2-vl)-1H-pvrazol-1-vl)Dvrldin-3-vlamino)butvl) benzamido)propanoic acid The title compound was prepared by a method analogous to that described for Example 163, Steps B - D, using (+/-)-ethyl 4-(1-(6-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate. Column: Waters Atlantis dC18 4.6 x 50mm, 5pm. Modifier; TFA 0.05%. Gradient: 95%H₂0 / 5%MeCN linear to 5%H₂0 / 95%MeCN over 4.0min, Hold at 5%H₂0 / 95%MeCN to 5.0min. Flow: 2.0mL/min. Rétention time: 2.20 min. MS (M+1): 485.0.

Example 165: (+/-)-3-(A/-methvl-4-(1-(6-(4-phenvl-1H-pvrazol-1-vl)pvridin-3vlamino)butvl)benzamldo)propanoic acid

Step A: (+/-)-ethvl 4-(1-(6-(4-phenvl-1H-pvrazol-1-vl)DvrÎdln-3-vlamino)butvl)benzoate

206

The title compound was prepared by a method analogous to that described in Step A of Example 62, using Intermediate (5). ¹H NMR (400 MHz, CDCI₃, δ): 8,59 (s, 1 H), 7.98 - 8.03 (m, 2 H), 7.90 (s, 1 H), 7.65 - 7.71 (m, 2 H), 7.51 - 7.56 (m, 2 H), 7.32 - 7.43 (m, 4 H), 7.20 - 7.25 (m, 1 H), 6.90 (dd, J = 8.8, 2.9 Hz, 1 H), 4.31 - 4.41 (m, 3 H), 1.73 - 1.90 (m, 2 H), 1.32 - 1.51 (m, 5 H), 0.92 - 0.98 (m, 3 H). MS (M+1) 441.4. Step B: (+/-)-tert-butvl 3-W-methvl-4-(1-(6-(4-phenyl-1H-ovrazol-1-vl)pvridin-3vlamino)butvl)benzamido)DroDanoate

The title compound was prepared by a method analogous to that described in Steps B and C of Example 2, using ethyl 4-(1-(6-(4-phenyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate and tert-butyl 3(methylamino)propanoate. MS (M+1) 554.5.

Step C: (+/-)-3-W-methvl-4-i1-(6-(4-Dhenvl-1H-Dvrazol-1-yl)ovridin-3-vlamino)butvl)benzamido)Dropanoic acid

The title compound was prepared by a method analogous to that described in Step C of Example 1, using (+/—)-tert-butyl 3-(/V-methyl-4-(1-(6-(4-phenyl-1H-pyrazol-1 -yi)pyridin-3ylamino)butyl)benzamido)propanoate. Column: Waters Atlantis dC18 4.6 x 50mm, Spm. Modifier: TFA 0.05%. Gradient: 95%H_a0 / 5%MeCN linear to 5%H₂0 / 95%MeCN over 4.0min, Hold at 5%H₂0 / 95%MeCN to 5.0min. Flow: 2.0mL/min. Rétention time: 3.27 min. MS (M+1): 498.1.

Example 166:3-(4-(1-(6-(4-ethvl-3-methvl-lH-pvrazol-1-vl)pvridin-3-vlamino)butvl) benzamido)propanoic acid. Isomer 1 and

Example 167: 3-(4-(1-Î6-(4-ethvl-3-methvl-1H-pvrazol-1-vÎ)pvridin-3-vlamino)butvl) benzamidoipropanoic acid, Isomer 2 o

o

ΌΗ

207

Racemic 3-(4-(1-(6-(4-ethyl-3-methyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid was prepared by a method analogous to that described for Example 62, using Intermediate (110). ¹H NMR (400 MHz, CD₃OD, δ): 7.95 (s, 1 H), 7.72 - 7.76 (m, 2 H), 7.61 (d, J = 2.5 Hz, 1 H), 7.40 - 7.47 (m, 3 H), 7.08 (dd, J = 8.9, 2.8 Hz, 1 H), 4.41 (t, J = 6.9 Hz, 1 H), 3.58 (t, J = 6.9 Hz, 2 H), 2.60 (t. J = 6.9 Hz, 2 H),

2.44 (q, J = 7.5 Hz, 2 H), 2.20 (s, 3 H), 1.67 - 1.92 (m, 2 H), 1.31 - 1.56 (m, 2 H), 1.18 (t, J = 7.5 Hz, 3 H), 0.95 (t, J = 7.4 Hz, 3 H). MS (M+1) 450.4.

Racemic 3-(4-(1 -(6-(4-ethyl-3-methyl-1 H-pyrazol-1 -yl)pyridtn-3-ylamino)butyl)benzamido)propanoic acid was resolved by chiral SFC to afford the two single enantiomers. Chiral SFC: Chiralcel OJ-H, 10 x 250 mm; Mobile Phase 65:35 COa/methanol, lOml/min, Rétention time: 3.03 minutes (Isomer 1), 5.47 minutes (Isomer 2).

Example 168: (fî)-3-(6-ii1-(3.5-dimethvl-4-(4-(trifluoromethvh-1H-pvrazol-1-vl)phenyl)-3methvlbutvl)amino)nicotinamido)propanoic acid

To a solution of Intermediate (118) (218 mg, 0.400 mmol) in tetrahydrofuran (2.00 mL) and methanol (2.00 mL) was added 1 N aq sodium hydroxide (2.00 mL, 2.00 mmol). After 10 minutes, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 4. The mixture was diluted with sat. aq sodium chloride (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organics were dried (Na₂SO4) and filtered, and the filtrate was concentrated under reduced pressure to provide (R)-3-(6-((1-(3,5-dirnethyl-4-(4-(tnfluoromethyl)1 H-pyrazol-1-yl)phenyl)-3-methylbutyl)amino)nicotinamido)propanoic acid. ¹H NMR (400 MHz, CDCI₃, δ):

9.25 - 9.15 (m, 1 H), 8.25 (s, 1 H), 8.18 (d, J = 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.78 - 7.68 (m, 2 H), 7.11 (s, 2 H), 6.46 (d, J = 9.2 Hz, 1 H), 4.48 - 4.39 (m, 1 H), 3.85 - 3.65 (m, 2 H), 2.64 (t, J = 5.6 Hz, 2 H), 2.10 (s, 1 H), 2.00 (s, 6 H), 1.96 -1.86 (m, 1 H), 1.81 -1.70 (m, 1 H), 1.70 - 1.59 (m, 1 H), 1.02 (d, J = 6.4 Hz, 3 H), 0.96 (d, J = 6.4 Hz, 3 H). MS (M+1): 518.7.

Example 169: (S)-3-(6-i(1-(3.5-dimethvl-4-(4-itrifluoromethvl)-1H-pvrazol-1-yl)phenvO-3methylbutvlÎamino)nicotinamido)propanoic acid

208

The title compound was prepared by a method analogous to that described for Example 168 using Intermediate (119). ’H NMR (400 MHz, CDCI₃, δ): 9.25 - 9.15 (m, 1 H). 8.25 (s, 1 H), 8.18 (d, J = 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.78 - 7.68 (m, 2 H), 7.11 (s, 2 H), 6.46 (d, J = 9.2 Hz, 1 H), 4.48 - 4.39 (m, 1 H), 3.85 - 3.65 (m, 2 H), 2.64 (t, J = 5.6 Hz, 2 H), 2.10 (s, 1 H), 2.00 (s, 6 H), 1.96 -1.86 (m, 1 H), 1.81 -1.70 (m, 1 H), 1.70 - 1.59 (m, 1 H), 1.02 (d, J = 6.4 Hz, 3 H), 0.96 (d, J = 6.4 Hz, 3 H). MS (M+1): 518.7.

Example 170: (3-(6-((cvcloDentvl(3,5-dimethvl-4-(4-(trifluoromethvl)-1 H-pvrazol-1 vl)phenyl)methvl)amino)nicotinamido)propanoic acid. Isomer 1

Step A: (+/-)-N-fcvcloDentvl(3.5-dimethvl-4-(4-(trifluoromethvlï-1H-Dyrazol-1-vl)Dhenvl)methvl)-2meth vlpropane-2-sulf i nam ide

Cyclopentylmagnesîum bromide (2 M in diethyl ether, 3.46 mL, 6.92 mmol) and dimethylzinc (2 M in toluene, 3.89 mL, 7.78 mmol) were allowed to stir for 15 minutes. This solution was then added dropwise to a solution of Intermediate (1003) (1.28 g, 3.46 mmol) in tetrahydrofuran (34.6 mL) at -78 °C. After 5 hours, an additional portion of cyclopentylmagnesîum bromide (2 M in diethyl ether, 0.86 mL, 1.72 mmol) and dimethylzinc (2 M in toluene, 0.95 mL, 1.90 mmol) that had been allowed to mix for 15 minutes was added dropwise to the reaction mixture at 78 °C. After 1 hour, the solution was quenched at -78 °C by addition of sat. aq ammonium chloride (10 mL). The resulting slurry was allowed to warm to room température. The mixture was diluted

X with 120 mL sat. aq ammonium chloride and enough water to dissolve precipitated solids. This

209 solution was then extracted with ethyl acetate (3 x 120 mL). The combined organics were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) gave (+/-)-/V-(cyclopentyl(3,5-dimethyl-4-(4(trifluoromethyt)-lH-pyrazol-1 -yl)phenyl)methyl)-2-methylpropane-2-sulfinamide. ¹H NMR (400 MHz, CDCIa, δ): 7.94 (s, 1 H), 7.75 (s, 1 H), 7.09 (s, 2 H), 4.03 (d, J = 9.2 Hz, 1 H), 2.41 - 2.27 (m, 1 H), 2.02 (s, 6 H), 1.99- 1.87 (m, 1 H), 1.72-1.35 (m, 7 H), 1.23 (s, 9 H), 1.16-1.04 (m, 1 H). MS (M+1): 442.5.

Step B: (+Z-)-cvclopentvl(3.5-dÎmethyl-4-(4-(trifluoromethvl)-1H-Dvrazol-1-vl)phenvl)methanamine hydrochloride

To a solution of (+/-)-W-(cyclopentyi(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methyl)-2-methylpropane-2-sulfinamide (1.184 g, 2.680 mmol) in methanol (13.4 mL) was added hydrogen chloride (4 M in dioxane, 3.35 mL, 13.4 mmol) dropwise. The reaction was concentrated under reduced pressure to provide (+/-)-cyclopentyl(3,5-dimethyl-4-(4(trifluoromethyl)-lH-pyrazol-1-yl)phenyl)methanamine hydrochloride. ’H NMR (400 MHz, CD₃OD, δ): 8.33 (s, 1 H), 8.07 (s, 1 H), 7.31 (s, 2 H), 4.05 (d, J = 10.6 Hz, 1 H), 2.35 - 2.51 (m, 1 H), 2.10 -

1.98 (m, 7H), 1.89-1.39 (m, 6 H), 1.20-1.14 (m, 1 H).

Step C: methyl (+/-)-6-((cvcloDentvl(3.5-dimethvl-4-(4-(trifluoromethvl)-1H-pyrazol-1yl)phenvl)methyl)amino)nicotinate

To a mixture of (+/-)-cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methanamine hydrochloride (1.002 g, 2.680 mmol) and potassium carbonate (1.51 g, 10.7 mmol) in A/,A/-dimethylformamide (5.36 mL) was added methyl 6-fluoronicotinate (472 mg,

2.95 mmol). The reaction was heated to 85 °C. After 15 h, the reaction was cooled to room température, diluted with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The

combined organics were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) gave methyl (+/-)-6-((ονοΙορθηΙνΙ(3₁5^ίΓηθΐίΊνΙ-4-(4-(ΙπίΙυοΓθΓηθ^Ι)-1Η-ρνΓ3ζοΙ-1yl)phenyl)methyl)amino)nicotinate. ¹H NMR (400 MHz, CDCI₃, δ): 8.67 (d, J = 1.6 Hz, 1 H), 7.99 (dd, J = 9.0, 2.0 Hz, 1 H), 7.93 (s, 1 H), 7.75 (s, 1 H), 7.12 (s, 2 H), 6.28 (d, J = 9.0 Hz, 1 H), 4.43 -

4.33 (m, 1 H), 3.87 (s, 3 H), 2.36-2.23 (m, 1 H), 2.04 -1.97 (m, 7 H), 1.77 -1.41 (m, 6 H), 1.37 1.28 (m, 1 H). MS (M+1): 473.2.

Step D: i+/-)-6-i(cyclopentyl(3.5-dlmethvl-4-(4-(trifluoromethvl)-1H-pvrazol-1 vl)phenyl)methvl)amlno)nicotinicacid

CO₂H

To a solution of methyl (+/-)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol1-yl)phenyl)methyl)amino)nicotinate (753 mg, 1.59 mmol) in tetrahydrofuran (7.97 mL) and methanol (7.97 mL) was added 1 N aq sodium hydroxide (7.97 mL, 7.97 mmol). After 16 h, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 4. The mixture was diluted with sat. aq sodium chloride (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure to provide (+/-)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methyl)amino)nicotinic acid. ¹H NMR (400 MHz, CDCI₃, Ô): 8.68 (s, 1 H), 8.14 (d, J = 9.2 Hz, 1 H), 7.94 (s, 1 H), 7.75 (s, 1 H), 7.15 (s, 2 H), 6.39 (d, J = 9.2 Hz, 1 H), 4.28 - 4.18 (m, 1 H), 2.44-2.31 (m, 1 H), 2.12-2.05 (m, 1 H), 2.01 (s, 6 H), 1.78 - 1.40 (m, 6 H), 1.36 - 1.28 (m, 1 H). MS (M+1): 459.5.

Step E: ethvl 3-f6-((cvcloDentvl(3.5-dimethvl-4-(4-(trifluorornethvD-1H-pvrazol-1-vl)Dhenvl) methvl)amino)nicotinamido)proDanoate, Isomer 1 and ethyl 3-(6-((cvclopentvl(3.5-dimethvl-4-(4(trifluoromethvl)-1H-pvrazol-1-vl)phenvl)meÎhvl)amino)nicotÎnamido) propanoate. Isomer 2

211

To a mixture of (+/-)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methyl)amino)nicotinic acid (731 mg, 1.59 mmol), β-alanine ethyl ester hydrochloride (516 mg,

3.19 mmol), and 1-hydroxy-7-azabenzotriazoie (336 mg, 2.39 mmol) in dichloromethane (15.9 mL) was added triethylamine (0.782 mL, 5.58 mmol) followed by N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (465 mg, 2.39 mmol). After 70 hours, the mixture was diluted with dichloromethane (50 mL) and washed with water (3 x 50 mL) and sat. aq sodium chloride (50 mL). The organic layer was dried (Na₂SO₄) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) followed by chiral SFC (Cellulose-2 column, 21 mm x 250 mm,

35% methanol / carbon dioxide eluent) gave ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1Hpyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 1 (SFC rétention time 2.71 min) and ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 2 (SFC rétention time 3.43 min). ’H NMR (400 MHz, CDCIg, δ): 8.45 (d, J = 2.0 Hz. 1 H), 7.91 (s, 1 H), 7.81 - 7.72 (m, 2 H), 7.09 (s, 2 H), 6.84 (t, J = 5.7 Hz,

1 H), 6.41 - 6.27 (m, 1 H), 6.26 (d, J = 9.0 Hz, 1 H), 4.33 (t, J = 7.6 Hz, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 3.65 (q, J = 6.0 Hz, 2 H), 2.59 (t, J = 6.0 Hz, 2 H), 2.33 - 2.19 (m, 1 H), 1.98 (s, 6 H), 1.96 - 1.85 (m, 1 H), 1.74 1.37 (m, 6 H), 1.34-1.21 (m, 4 H). MS (M+1): 558.5.

Step F: 3-(6-(icvclODentvl(3.5-dimethvl-4-(4-(trifluoromethvl)-1/-/-pyrazol-1vl)phenvl)methvl)amino)nicotinamido)Dropanoic acid. Isomer 1 (Example 170)

To a solution of ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 1 (255 mg, 0.457 mmol) in tetrahydrofuran (2.29 mL) and methanol (2.28 mL) was added 1 N aq sodium hydroxide (2.28 mL, 2.28 mmol). After 10 minutes, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq 25 hydrochloric acid was added until the mixture was at pH 3. The mixture was diluted with sat. aq sodium chloride (15 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organics were dried (Na₂SO₄)

212 and filtered, and the filtrate was concentrated under reduced pressure to provide 3-(6-((cyc!opentyl(3,5dimethyl-4-(4-(trifluoromethyl)-lH-pyrazol-1-yi)phenyl)methyl)amino)nicotinamido)propanoic acid, Isomer 1. ¹H NMR (400 MHz, CDCI₃, δ): 9.54 - 9.42 (m, 1 H), 8.58 - 8.48 (m, 1 H), 8.22 (d, J = 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 - 7.72 (m, 2 H), 7.12 (s, 2 H), 6.54 (d, J = 9.4 Hz, 1 H), 4.20 - 4.08 (m, 1 H), 3.81 - 3.64 (m, 2 H),

2.67 (t, J = 5.5 Hz, 2 H), 2.44 - 2.33 (m, 1 H), 2.18 - 2.06 (m, 1 H), 2.01 (s, 6 H), 1.75 - 1.36 (m, 6 H), 1.33 -

1.19 (m, 1 H). MS (M+1): 530.4.

Example 171:3-(6-(fcvclopentvl(3,5-dimethvl-4-(4-(trifluoromethvl)-1H’pvrazol-1vl)Dhenvl)methvhamino)nÎcotinamido)propanoic acid. Isomer 2

The title compound was prepared by a method analogous to that described for Example 170, Step F, using ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 2. ¹H NMR (400 MHz, CDCI₃, δ): 9.54 - 9.42 (m, 1 H), 8.58 - 8.48 (m, 1 H), 8.22 (d, J = 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 - 7.72 (m, 2 H), 7.12 (s, 2 H), 6.54 (d, J = 9.4 Hz, 1 H), 4.20 - 4.08 (m, 1 H), 3.81 - 3.64 (m, 2 H), 2.67 (t, J = 5.5 Hz, 2 H), 2.44 - 2.33 (m, 1 H), 2.18 2.06 (m, 1 H), 2.01 (s, 6 H), 1.75- 1.36 (m, 6 H), 1.33 -1.19 (m, 1 H). MS (M+1): 530.4.

Example 172: Ni4-f4,4,4-trifluoro-1 -tf6-f4-(triÎluoromethvn-1 H-pvrazol-1 -vnDvridin-3-vltamino)butyi1benzoviybeta-alanine. Isomer 1 and

Example 173: N44-f4.4.4-trifluoro-1 -((6-f4-(trifluoromethvlM H-Dvrazol-1-yllpvridin-3-vlÎamino)butvl1benzoyiybeta-alanine. Isomer 2

Step A: f+Z—)~ethvl 4-(4.4.4-trÎfluoro-1-hvdroxvbutvl)benzoate

213

To a solution of the ethyl 4-iodobenzoate (1.21 ml, 7.24 mmol) in tetrahydrofuran (12 ml) at -40 °C was added isopropylmagnesium chloride lithium chloride complex (6.13 ml, 7.97 mmol, 1.3M in tetrahydrofuran) dropwise. The mixture was stirred for approximately 1 hour whereupon the 4,4,4-trifluorobutanal (0.761 ml, 0.724 mmol) was added dropwise. The mixture was stirred at -40 °C for 15 minutes and slowly warmed to ambient température over 12 hours. The reaction was quenched with aqueous 1.0M hydrochloric acid and the aqueous Iayer was extracted with ethyl acetate (3x). The combined organic layers were dried over magnésium sulfate, filtered, and concentrated in vacuo. The alcohol was used without further purification.

Step B: ethyl 4-(4.4.4-trifluorobutanoyl)benzoate

A mixture of (+/-)-ethyl 4-(4,4,4-trifluoro-1-hydroxybutyl)benzoate (2.10 g, 7.60 mmol) in dichloromethane (28 ml), dimethyl sulfoxide (22 ml), and triethylamine (5.29 ml, 38.0 mmol) was cooled to 0 °C. Sulfur trioxide pyridine complex (3.63 g, 22.8 mmol) was added in portions and the mixture stirred at 0 °C for 1 hour, then slowly raised to ambient température over 12 h. The reaction was quenched with water and diluted with diethylether. The aqueous Iayer was extracted with diethylether and the combined organic layers were washed with brine. The combined organic extracts were dried over magnésium sulfate, filtered, and concentrated in vacuo to affording the crude product as a solid that was used without further purification.

Step C: (+/-)-ethvl 4-f4.4,4-trifluoro-1-((6-i4-(trifluoromethvl)-1H-pyrazol-1-vllpyridin-3vllaminolbutvllbenzoate

To a solution of crude ethyl 4-(4,4,4-trifluorobutanoyl)benzoate (0.060 g, 0.22 mmol) and 6-[4(trifluoromethyl)-l H-pyrazol-1 -yl]pyridin-3-amine (0.050 g, 0.22 mmol) in methanol (2.2 ml) was added decaborane (8.0 mg, 0.066 mmol). The reaction was stirred for 12 hours at ambient température. The reaction mixture was quenched with aqueous 1.0M hydrochloric acid and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO_a, 0-100% ethyl acetate in heptane) to yield the product (47g, 42%) as an Oil. ¹H NMR (400 MHz, CDCI₃): δ 8.63 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.75 (d, J =

2.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1 H), 7.38 - 7.45 (m, 2H), 6.96 (dd, J = 8.8, 2.7 Hz, 1H), 4.50 (t, J = 6.2 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 2.07-2.32 (m, 4H), 1.39 (t, J = 7.2 Hz, 3H). MS (M+1): 487.3.

214

Step D: f+/-)-4-f4.4.4-Îrifluoro-1-tf6-f4-ftrifluoromethvl)-1 H-pvrazol-1 -vIlovridin-S-yltaminolbutyllbenzoÏc acid

F

F F

A mixture of (+/-)-ethyl 4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1 H-pyrazol-1-yl]pyridin-3yl}amino)butyl]benzoate (46 mg, 0.095 mmol) in methanol (0.19 ml) and tetrahydrofuran (0.095 ml) was treated with aqueous lithium hydroxide (0.095 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient température for 12 hours. The reaction was concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. The mixture was then concentrated in vacuo a second time, and the crude residue was used directly for further transformations.

Step E: f+/-)-ethvl N-f444.4.4-trifluoro-1-ff6-r4-itrifluoromethvl)-1H-pvrazol-1-vllpyridin-3vlfamlnoibutvribenzovll-beta-alaninate

NH

To s mixture of ethyl 3-aminopropionate hydrochloride (23 mg, 0.19 mmol), (+/-)-4-(4,4,4-trifluoro-1-({6-[4(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzO!c acid (44 mg, 0.096 mmol), hydroxybenzotriazole hydrate (15 mg, 0.096 mmol), and triethylamine (55 ul, 0.39 mmol) in dichloromethane (0.96 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.11 mmol). The mixture was stirred for 2 hours at ambient température. The reaction was diluted with water and the organic layer was separated. The aq. layer was extracted with dichloromethane (2x) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo, The crude material was used without further purification.

Step F: (+) & H-N-f4-r4.4.4-trifluoro-1-({6-f4-(trifluoromethvl)-1H-pvrazol-1-vllpyridin-3vllaminolbutyllbenzovri-beta-alanine

A mixture of crude (+/-)-ethyl N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1 H-pyrazol-1 -yl]pyridin-3yi}amino)butyi]benzoyl}-beta-alaninate (52 mg, 0.093 mmol) was dissolved in methanol (0.20 ml) and tetrahydrofuran (0.10 ml) and treated with aqueous lithium hydroxide (0.093 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient température for 1 hour. The crude reaction mixture was concentrated in vacuo and the residual solid was dissolved in water (0.50 ml) and treated with aqueous 1.0M hydrochloric acid until approximately pH 6 was reached, resulting in the précipitation of racemic N-{4-[4,4,4-trifluoro-1-({6[4-(trifluoromethyl)-1 H-pyrazol-1 -yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alanine as a white gummy solid.

215

I

The two enantiomeric products were separated by chiral SFC Column: Chiralpak AD-H. Dimensions: 21 x

250mm. Mobile Phase: 70/30 CO2/methanol, (peak 1,0.30 g, 22% and peak 2,0.30 g, 22%). Flow Rate: 65mL/min. Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm x 25 cm; SFC Mobile Phase 70:30 CO2/Methanol, 2.5 mL/min, analytical rétention time: 2.97 min (Isomer 1) and 5.15 (Isomer 2). ¹H NMR (400 MHz, CDCIg): δ 8.64 (s, 1H), 7.73 - 7.84 (m, 4H), 7.70 (d, J = 8.8 Hz, 1H), 7.37 - 7.43 (m, 2H), 6.98 (br. dd, J = 8.6, 2.0 Hz, 1H), 6.73 - 6.86 (m, 1H), 4.48 (br. t, J = 6.3 Hz, 1H), 3.73 (br. q, J = 5.9 Hz, 2H), 2.72 (br. t, J =

5.8 Hz, 2H), 2.06 - 2.34 (m, 4H). MS (M+1): 530.3.

Example 174: N-i4-iïr6-(4-cvclopropyl-1 H-pvrazol-1-vl)Dvrldln-3-vnaminoÎ(3.3άϊΓΠ6ΐΐΊνΙονοΙοόυίνΙ)Γη81ΐΊνΙ^θηζονΙ}-όθΐ3-3ΐ3ηίηθ· Isomer 1 and

Example 175: N-f4-f(f6-(4-cvclopropy|-1 H-pvrazol-1-vl)pvrldin-3-yl1amlno)(3.3dimethvIcvclobutvDmethyllbenzovIPbeta-alanine, Isomer 2

Step A: 2-(4-lodo-1 H-pyrazol-1-vh-5-nitropyridine

A mixture of the 4-iodo-1 H-pyrazole (4.59 g, 23.7 mmol) and 2-chloro-5-nitropyridine (3.75 g, 23.7 mmol) in N,/V-dimethylformamide (11.8 ml) was treated with potassium carbonate (3.76 g, 27.2 mmol). The mixture was heated to 80 °C for 12 hours. The reaction mixture was diluted with excess water resulting in the précipitation of a solid that was collected by filtration. Further drying in vacuo afforded the product (7.5 g, 100%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃): δ 9.27 (d, J = 2.3 Hz, 1H), 8.70 (s, 1H), 8.62 (dd, J = 9.0, 2.5 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.80 {s, 1H).

Step B: 2-(4-cvclopropyl-1H-pvrazol-1-vl)-5-nitropyridine

216

A flask was charged with a mixture of the 2-(4-iodo-1 H-pyrazol-1 -yl)-5-nitropyridine (0.600 g, 1.90 mmol), cyclopropylboronic acid (652 mg, 7.59 mmol), palladium acetate (43 mg, 0.19 mmol), tricyclohexylphosphine (112 mg, 0.380 mmol), and tripotassium phosphate (1.41 g, 6.64 mmol) and then equipped with a micro reflux condenser and purged with dry nitrogen. Freshly degassed toluene (10 ml) was added followed by degassed water (0.4 ml) and the mixture was heated to reflux for 12 hours. The reaction mixture was cooled to ambient température, then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3x) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via ISCO MPLC (SIO₂, 0-25% ethyl acetate tn heptane) to yield the product (0.12 g, 28%) as a solid. ’H NMR (400 MHz, CDCI_a): 5 9.24 (d, J = 2.7 Hz, 1H), 8.56 (dd, J = 9.1,2.6 Hz, 1H), 8.32 (s, 1H), 8.08 (d, J = 9.0 Hz, 1 H), 7.62 (s, 1H), 1.79 (tt, J = 8.6, 5.1 Hz, 1 H), 0.97 (ddd, J = 8.2, 6.1,4.3 Hz, 2H), 0.64 (dt, J = 6.3, 4.7 Hz, 2H).

Step C: 6-(4-cvclopropvl-1H-pvrazol-1-vl)pyridin-3-amlne

A solution of 2-(4-cyclopropyl-1 H-pyrazol-1-yl)-5-nitropyridine (2.91 g, 12.7 mmol) in ethyl acetate (250 ml) was passed through an H-Cube reactor equipped with a 10% Pd(OH)2/C cartridge at 50 °C, 50 bar, at 1 ml/min. The solution was concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO₂, ΟΙ 00% ethyl acetate in heptane) to yield the product (964 mg, 38%) as a solid. ’H NMR (400 MHz, CDCI₃): δ 8.12 (s, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.12 (dd, J = 8.7, 2.8 Hz, 1H), 3.70 (br. s., 2H), 1.75 (tt, J = 8.6, 5.3 Hz, 1H), 0.80 (ddd, J = 8.4, 6.3, 4.5 Hz, 1H), 0.59 (dt, J = 5.7, 4.5 Hz, 2H).

Step D: (+/-)-ethyl Nf4-Rf6-(4-cyclopropvl-1H-pvrazol-1-yl)pyridln-3-yllaminoÎ(3.3dimθthvlcvc1obutvl)methvllbenzovll·beta-alaninate

To a solution of Intermediate (101) (964 mg, 4.81 mmol) and 6-(4-cyclopropyl-1 H-pyrazol-1-yl)pyridin-3amine (1.60 g, 4.81 mmol) in methanol (10.9 ml) was added decaborane (235 mg, 1.93 mmol) in a single portion. The mixture was stirred for 12 hours. An additional aliquot of decaborane (235 mg, 1.93 mmol) was added and the mixture stirred a further 4 hours. The reaction mixture was concentrated in vacuo then treated with aqueous 1.0M hydrochloric acid for 12 hours at ambient température. The crude product was concentrated in vacuo and used dïrectly for further transformations.

Step E: (+) & (-)-N-i4-iïr6-(4-cvclopropvl-1H-Pvrazol-1-vl)Dvridin-3-vl1amino)(3,3dimethvlcyclobutvnmethyllbenzovll-beta-alanine

A mixture of crude {+/-)-ethyl N-{4-[{[6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}(3_l3dimethylcyclobutyl)methyl]benzoyl}-beta-alaninate (2.48 g, 4.91 mmol) was dissolved in methanol (4.8 ml) and tetrahydrofuran (2.4 ml) and treated with aqueous 2.0M lithium hydroxide (4.8 ml, 9.6 mmol). The mixture was stirred at ambient température for 12 hours. The reaction was concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. A yellow precipitate formed and was collected by filtration. The two enantiomeric products were separated by chiral SFC Column: Chiralpak ADH. Dimensions: 21 x 250mm. Mobile Phase: 50/50 CO2/methanol, (peak 1,638 mg, 27% and peak 2, 682 g, 29%). Flow Rate: 65mL/min. Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm x 25 cm; SFC Mobile Phase 50:50 C02/Methanol, 2.5 mL/mln, analytical rétention time: 3.90 min (Isomer 2) and 9.30 (Isomer 1). ’H NMR (400 MHz, CDCI₃): δ 8.01 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.84 (dd. J = 8.8, 2.7 Hz, 1H), 4.14 (d, J = 9.4 Hz, 1H). 3.56 -

3.67 (m, 2H), 2.40 - 2.47 (m, 2H), 1.96 (ddd, J = 11.2, 8.0, 3.9 Hz, 1 H), 1.60 - 1.74 (m, 3H), 1.54 (ddd, J = 11.9, 8.4, 3.7 Hz, 1 H), 1.28 - 1.34 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.81 -0.86 (m, 2H), 0.50 - 0.56 (m, 2H) MS (M+1); 488.4.

Example 176: (+/-)-Ν-Γ4·(1 -iï6-(4-cvclopropyl-1 H-pvrazol-1 -vl)pyridin-3-vllamino)butvl)benzovl1-beta-alanine

To a solution of ethyl 4-butyrylbenzoate (121 mg, 0.549 mmol) and 6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-

3-amine (0.110 g, 0.549 mmol) in methanol (1.3 ml) was added decaborane (27 mg, 0.22 mmol). The reaction was stirred for 12 hours at ambient température. The reaction mixture was quenched with aqueous 1.0M hydrochloric acid and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO₂, 0-100% ethyl acetate in heptane) to yield the product (26 mg, 12%) as an oil. ¹H NMR (400 MHz, CDCI₃): δ 8.05 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H). 7.67 (br. s„ 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 6.8 Hz, 1H), 4.37 (q, J = 7.2 Hz, 3H), 1.76 - 1.90 (m, 2H), 1.72 (tt, J = 8.4, 5.1 Hz, 1H),

1.41 -1.52 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H), 0.86 (ddd, J = 8.2, 5.9, 3.9 Hz, 2H), 0.56 (dt, J = 5.9, 4.1 Hz, 2H).

Step B: (+/-)-4-(1-i(6-(4-cyclopropvl-1 H-pvrazol-1-vl)pvridin-3-vl1amino}butvl)benzoic acid

A mixture of (+/-)-ethyl 4-(H[6-(4-cyclopropyl-1 H-pyrazol-1 -yl)pyridin-3-yl]amino}butyl)benzoate (26 mg,

0.064 mmol) was dissolved in methanol (0.13 ml) and tetrahydrofuran (0.070 ml) and treated with aqueous

2.0M lithium hydroxide (64 ul, 0.13 mmol). The mixture was stirred at ambient température for 12 hours.

The réaction was concentrated in vacuo and the residue was acidified with aqueous 1.0M hydrochloric acid.

The crude product was concentrated in vacuo a second time and was used without further purification.

Step C: (+/-)-ethvl N-(4-(1 -ff6-(4-cvcloproovl-1 H-pyrazol-1 -yl)pyridin-3-vllamlnoÎbutvl)benzovll-beta-alaninate

218

To a mixture of ethyl 3-aminopropionate hydrochloride (31 mg, 0.27 mmol), (+/-)-4-(14[6-(4-cyclopropyl-1H10 pyrazol-1-yl)pyrldin-3-yl]amino}butyi)benzoic acid (0.050 g, 0.13 mmol), hydroxybenzotriazole hydrate (0.020 g, 0.13 mmol), and triethylamine (76 ul, 0.55 mmol) in dichloromethane (1.3 ml) was added 1-ethyl-3-(3dimethylaminopropyljcarbodiimide hydrochloride (38.9 g, 201 mmol) (28 mg, 0.15 mmol) at rt. The mixture was stirred for 2 hours at ambient température. The reaction was diluted with water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2x) and the combined organic 15 layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was used without further purification.

Step D: (+/-)-Ν-Γ4-(1 -i(6-(4-cyclopropyl-1 H-pvrazol-1 -vnpyridin-3-vHaminoïbutvllbenzoyll-beÎa-alanine

A mixture of crude (+/-)-ethyl N-[4-(1-{[6-(4-cyclopropyl-1 H-pyrazol-1 -yl)pyridin-3-yl]amino}butyl)benzoyl]beta-alaninate (63 mg, 0.13 mmol) was dissolved in methanol (0.26 ml) and tetrahydrofuran (0.13 ml) and treated with aqueous 2.0M lithium hydroxide (0.13 ml, 0.26 mmol). The mixture was stirred at ambient température for 12 hours. The reaction was concentrated in vacuo. The residue was acidified with aqueous 1.0M hydrochloric acid and concentrated in vacuo a second time. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave the product. Analytical LCMS: rétention time 2.94 minutes (Atlantis C18

4.6 x 50 mm, 5 μΜ column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 448.2.

Example 177: (±)-3-(4-((tetrahvdro-2H-pyran-4-vl)((6-(4-(trifluoromethvl)-1H-Pvrazol-1-vl)nvridin-3vl)amÎno)methvl)benzamido)propanoic acid

The title compound Is obtained by a method analogous to the one described for Example 2 (step B, C and D) using Intermediate (121) as starting material. Filtration of the solid formed after acidification to ca. pH 3 with citric acid (10%, aq.), provide (±)-3-(4-((tetrahydro-2H-pyran-4-yl)((6-(4-(trifluoromethyl)-1H-pyrazol-1yi)pyridin-3-yl)amino)methyl)benzamido) propanoic acid (98.8 mg, 77.9%) as a white solid.¹ H NMR (400 MHz, DMSO-d_e) δ 1.13 (br. s., 1 H) 1.22 - 1.47 (m, 2 H) 1.84 - 1.94 (m, 2 H) 2.43 - 2.48 (m, 2 H) 3.14 - 3.23 (m, 1 H) 3.23 - 3.30 (m, 1 H) 3.38 - 3.47 (m, 2 H) 3.75 - 3.84 (m, 1 H) 3.87 - 3.95 (m, 1 H) 4.32 (t, J=7.83 Hz, 1 H) 6.80 (d, J=8.02 Hz, 1 H) 7.12 (dd, J=8.80, 2.74 Hz, 1 H) 7.45 (d, J=8.22 Hz, 2 H) 7.57 (d, J=8.80 Hz, 1 H) 7.73-7.80 (m, 3 H) 8.09 (s, 1 H) 8.42 (t, J=5.28 Hz, 1 H) 8.84 (s, 1 H) 12.18 (s, 1 H); MS (M+1): 518.4. Example 178: (±)-3-(4-(2.2-dimethvl-1-((6-(4-(trifluoromethvn-1 H-Dvrazol-1-vl)pvridin-3vl)amlno)propy|)benzamido)propanolc acid

A 20 drams vial was charged with methyl (±)-3-(4-(2,2-dimethyl-1 -((6-(4-(trifiuoromethyl)-1 Hpyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoate (92 mg, 0.18 mmol), THF (1.8 mL) and MeOH (1.8 mL). NaOH 1M aq. (0.9 mL) was then added in one portion and the resulting mixture stirred for 30 minutes at room température. Organic solvents removed under reduced pressure and 5 mL of water added to the vial. Under magnetic stirring, citric acid solution (10%, aq.) added dropwise to reach ca. pH 3. The solid formed was recovered with a büchnerfunnel, washed with water and dried under high vacuum to provide (±)-3-(4-(2,2-dimethyl-1 -((6-(4(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido) propanoic acid as a white solid (76.9 mg, 86.0%). ¹H NMR (400 MHz, DMSO-c/_e) δ 0.98 (s, 9 H) 2.44 - 2.48 (m, 2 H) 3.38 3.47 (m, 2 H) 4.33 (d, J=8.22 Hz, 1 H) 6.54 (d, J=8.41 Hz, 1 H) 7.17 (dd, J=8.90, 2.84 Hz, 1 H)

7.44 (d, J=8.22 Hz, 2 H) 7.55 (d, J=9.00 Hz, 1 H) 7.74 (d, J=8.41 Hz, 2 H) 7.84 (d, J=2.54 Hz, 1 H) 8.08 (s, 1 H) 8.44 (t, J=5.28 Hz, 1 H) 8.84 (s, 1 H) 12.18 (br. s., 1 H); MS (M+1): 490.4.

Example 179:3-f4-(2.2-dimethvl-1-(i6-f4-(trifluoromethvl)-1 H-pvrazol-1-vl)Dvridin-3vl)amlno)propvl)benzamido)propanoic acid. Isomer 1 and

i

220

Example 180: 3-(4-(2.2-dimethvi-1-((6-(4-(trlfluoromethvl)-lH-pvrazol-1-vl)ovridin-3-

Intermediate (123) was resolved using préparative SFC (Column: Chiralpak AD-H. Dimensions: 21 mm x 250 cm. Mobile Phase: 65/35 CO2/2-propanol. Flow Rate: 65 mL/min. Modifier: none) to give ethyl 3-(4-(2,2dimethyl-1-((6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridln-3-yl)amino)propyl)benzamido)propanoate, Isomer 1 (Rétention time: 2.87 min) and ethyl 3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3yl)amino)propyl)benzamido)propanoate, Isomer 2 (rétention time 5.10 min). Subséquent saponification of ethyl 3-(4-(2,2-dimethyl-1 -((6-(4-(trifluoromethy!)-1 H-pyrazol-1 -yl)pyridln-3yl)amino)propyl)benzamido)propanoate, Isomers 1 and 2 separately by a method analogous to the one described for Example 178 provided 3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3yl)amino)propyl)benzamido)propanoic acid, Isomer 1 and 3-(4-(2,2-dlmethyl-1-((6-(4-(trifJuoromethyl)-1Hpyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido) propanoic acid, Isomer 2, respectively, as light yellow solids. ¹H NMR (400 MHz, DMSO-c/6) δ 0.98 (s, 9 H) 2.44 - 2.48 (m, 2 H) 3.38 - 3.46 (m, 2 H) 4.33 (d, J=8.19 Hz, 1 H) 6.54 (d, J=8.19 Hz, 1 H) 7.17 (dd, J=8.97, 2.73 Hz, 1 H) 7.44 (d, J=8.39 Hz, 2 H) 7.55 (d, J=8.78 Hz, 1 H) 7.74 (d, J=8.39 Hz, 2 H) 7.84 (d, J=2.73 Hz, 1 H) 8.08 - 8.09 (m, 1 H) 8.44 (t, J=5.46 Hz, 1 H) 8.82 -

8.85 (m, 1 H) 12.20 (br. s., 1 H); MS (M+1): 490.4.

Example 181: (±)-3-(4-(2.2-dimethvl-1-((6-(4-(trifluoromethvl)-1H-imÎdazol-1-vl)pvridin-3vl)amino)propyl)benzamido)propanoic acid

A round bottom flask was charged with Intermediate (124) (33 mg, 64 pmol), Ethanol (1 mL), THF (1 mL). NaOH 1M aq. (0.2 mL) was then added and the reaction mixture was stirred at room température for 30 minutes. Organic solvent removed under reduced pressure and water added to obtain a nice solution. Acidification of the aqueous solution with HCl (1N aq.) to reach ca. pH 4.5 led to a precipitate. The solid formed was recovered over a büchner funnel and washed with plenty of water. The solid was dried under high vacuum overnight to provide (±)-3-(4-(2,2-dimethyl-1-((6(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-yl)amino) propyl)benzamido)propanoic acid as

a white solid (25.7 mg, 82%). ¹H NMR (400 MHz, DMSO-d6) δ 0.98 (s, 9 H) 2.44 - 2.48 (m, 2 H)

221

3.38 - 3.46 (m, 2 H) 4.33 (d, J=8.19 Hz, 1 H) 6.55 (d, J=8.39 Hz, 1 H) 7.11 (dd, J=8.88, 2.83 Hz, 1 H) 7.40 - 7.47 (m, 3 H) 7.74 (d, J=8.39 Hz, 2 H) 7.89 (d, J=2.73 Hz, 1 H) 8.24 - 8.29 (m, 1 H) 8.37 (s, 1 H) 8.44 (t, J=5.46 Hz, 1 H) 12.19 (br. s., 1 H); MS (M+1): 490.4.

Example 182: 3-(442.2-dimethyl-14(644-(trifluoromethvl)-1 H-imidazol-1-vl)pvridin-3vl)amino)propvl)benzamidoÎpropanoic acid. Isomer 1 and

Example 183:3-(4-(2.2-dimethvl-1-((644-(trifluoromethvl)-1H-imldazol-1-vl)pvridin-3· vl)amÎno)propvl)benzamidolpropanoiGacid, Isomer 2

Intermediate (124) was resolved using préparative SFC (Column: Chiralpak AD-H. Dimensions: 21 mm x 250 cm. Mobile Phase: 55/45 COs/ethanol. Flow Rate: 65 mL/min. Modifier: 0.2% isopropylamine) to provide ethyl 3-(4-(2,2-dimethyl-1 -((6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyridin-3yl)amino)propyl)benzamido)propanoate, Isomer 1 (rétention time: 4.77 min) and ethyl 3-(4-(2,2-dimethyl-1((6-(4-(trifluoromethyl)-1 H-imidazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoate, Isomer 2 (rétention time: 6.45 min). Subséquent saponification of ethyl 3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-imidazol1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoate, Isomer 1 and ethyl 3-(4-(2,2-dimethyl-1 -((6-(4(trifluoromethyl)-l H-imidazol-1-yl)pyridin-3-yi)amino)propyl)benzamido)propanoate, Isomer 2 separately by a method analogous to the one described for Example 181 provided 3-(4-(2,2-dimethyl-1 -((6-(4(trifluoromethyl)-l H-imidazol-1-yl)pyridin-3-yl)amino)propyl) benzamido)propanoic acid, Isomer 1 and 3-(4(2,2-dim ethyl-1 -( (6- (4-(trif luorometh yl)-1 H-imidazol-1 -yl)pyridin-3-yl)amino)propyl)benzamido)propanoic acid, Isomer 2, respectively, as white solids. ¹H NMR (400 MHz, DMSO+/6) δ 0.98 (s, 9 H) 2.44 - 2.48 (m, 2 H) 3.38 - 3.46 (m, 2 H) 4.33 (d, J=8.19 Hz, 1 H) 6.55 (d, J=8.39 Hz, 1 H) 7.11 (dd, J=8.88, 2.83 Hz, 1 H) 7.40 7.47 (m, 3 H) 7.74 (d, J=8.39 Hz, 2 H) 7.89 (d, J=2.73 Hz, 1 H) 8.24 - 8.29 (m, 1 H) 8.37 (s, 1 H) 8.44 (t, J=5.46 Hz, 1 H) 12.19 (br. s., 1 H); MS (M+1): 490.4.

Example 184: (+/-)-3-(441-ί3.5-ΡίίΙυοΓο-4444ΓίίΙυοΓθπιβΐΡνΙ-ρνΓ3ΖθΙ-1-νΙ+ρ|·ιθηοχν1-ΡυΐνΙ}-Ρ6ηζονΐ3ηηίηο)propion ic acid

OH

Step A: di-fert-butvl l-(2.6-difluoro-4-methoxyphenvl)hvdrazine-1.2-dicarboxvlate

In an oven-dried, N₂-purged round bottom, 4-bromo-3,5-difluoroanisole (500 mg, 2.24 mmol) was dissolved in anhydrous THF (11 mL) and brought to -78 °C. nBuLi (0.96 mL, 2.44 M in THF, 2.35 mmol) was added over 2 min. This was stirred for 5 min and then a solution di-tert-butyi azodicarboxylate (542 mg, 2.35 mmol) in anhydrous THF (3 mL) in an oven-dried, N₂-purged pear flask was added in one portion via syringe. The reaction was removed from the ice bath and allowed to warm to room température over 30 min. The reaction, a clear solution, was quenched by the addition of aq. sat. NH₄CI. The material was extracted with two portions of ethyl acetate and the combined organics were dried over MgSO₄ and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave di-tert-butyi 1-(2,6-difluoro-4methoxyphenyl)hydrazine-1,2-dicarboxylate (0.868 g, impure with ethyl acetate) as a clear oil. ¹H NMR (400 MHz. CDCI_3i δ): 6.48 (d, J = 10.1 Hz, 2 H) 3.73 - 3.85 (m, 3 H) 1.36 - 1.60 (m, 18 H).

Step B: (2,6-difluoro-4-methoxv-phenvl)-hvdrazine hydrochloride

Di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (616 mg, 1.64 mmol) was heated In 4 M HCl tn dioxane (5 mL, 20 mmol) at reflux. The solution over time became a suspension. At 30 min, the reaction was cooled, diethylether was added, and the solid was collected with a medium frit, washing with diethylether. This gave (2,6-dlfluoro-4-methoxy-phenyl)-hydrazine hydrochloride (0.246 g, 86%) as a tan solid. ¹H NMR (400 MHz, DMSO-d_e, δ): 9.75 (br. s., 3 H) 7.46 (s, 1 H) 6.79 - 6.90 (m, 2 H) 3.78 (s, 3 H).

Step C: 1 -(2.6-difluoro-4-methoxv-phenvl)-4-trifluoromethvl-1H-Dvrazole

(2,6-Difluoro-4-methoxy-phenyl)-hydrazine hydrochloride (244 mg, 1.40 mmol) was combined with Intermediate (7A) (477 mg, 1.40 mmol) and anhydrous tetrahydofuran (5 mL). This suspension was brought to 0 ’C and solid NaOMe (87.6 mg, 1.54 mmol) was added. The reaction was stirred overnight allowing the bath to melt. At 21 h, the reaction was a brown solution with some solid présent. Trifluoroacetic acid (0.48 mL, 6.19 mmol) was added and the reaction refluxed. At 5 h, the reaction was cooled and partitioned between ethyl acetate and sat. NaHCO₃. The aqueous was extracted with ethyl acetate and the combined organics dried over MgSO₄. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave 1-(2,6-difluoro-4-methoxy-phenyl)-4-trifluoromethyl-1H-pyrazole (0.230 g, 59%) as a yellow oil, ¹H NMR (400 MHz, CDCI₃, δ): 7.97 (s, 1 H) 7.89 (s, 1 H) 6.64 (d, J = 9.4 Hz, 2 H) 3.87 (s, 3 H); MS (M+1): 279.2.

223

Step D: 3,5-difluoro-4-(4-trlfluoromethyl-pyrazol-1-vl)-phenol

1-(2_l6-Difluoro-4-methoxy-phenyl)-4-trifluoramethyl-1H-pyrazole (278 mg, 0.999 mmol) was dissolved in dichloromethane (3 mL). Boron tribromide (20.0 mL, 1.0 M in DCM, 20.0 mmol) was added and the reaction was refluxed. At 42 h, the reaction was cooled in an ice bath and slowly quenched with methanol. The combined materials were then concentrated and partitioned between ethyl acetate and sat. NaHCO₃. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO₄. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave 3,5-difluoro-4-(4trifluoromethyl-pyrazoM-yl)-phenol (0.231 g, 88%) as a tan oil that solidiiied upon standing. ’H NMR (400 MHz, CDCI₃, δ): 7.99 (s, 1 H) 7.90 (s, 1 H) 6.50 - 6.60 (m, 2 H); MS (M+1): 265.2.

Step E: (+/-)-441-[3·5-άίίΙυοΓο-444-ΐπ1ΙυοΓθΐ·η6{ήνΙ-ρνΓ3ζοΙ-1-νΙ)-οΐΊ6ηοχν1-ίιιίνΙ)^6ηζοΐΡ acid ethyl ester

S.S-Difluoro^-^-trifluoromethyl-pyrazol-l-yO-phenol (230 mg, 0.871 mmol) was combined with ethyl

4-(1-hydroxybutyl)benzoate (see Intermediate 5) (194 mg, 0.871 mmol) and dissolved in anhydrous tetrahydrofuran (4 mL). Triphenylphosphine (457 mg, 1.74 mmol) was added followed by diazopropyl azodicarboxylate (0.451 mL, 2.18 mmol). This was stirred at room température as a yellow solution. At 17h, the reaction was concentrated. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave impure (+/-)-4-(1 -[3,5-difluoro-4-(4-trifluoronr)ethyl-pyrazol-1-yl)-phenoxy]-butyl}-benzoic acid ethyl ester (0.411 g) as a clear oil. ’H NMR (400 MHz, CDCI₃₁ δ): 8.06 (d, J = 8.2 Hz, 2 H) 7.93 (s, 1 H) 7.82 (s, 1 H)

7.39 (d, J = 8.4 Hz, 2 H) 6.54 (d, J = 9.4 Hz, 2 H) 5.15 (dd, J = 7.6, 5.3 Hz, 1 H) 4.39 (q, J = 7.2 Hz, 2 H) 1.96 -2.10 (m, 1 H) 1.77-1.91 (m, 1 H) 1.19-1.61 (m, 5 H) 0.98 (t, J = 7.3 Hz, 3 H); MS (M+1): 469.3. Step F: (+/-)-3-(441 -f3.5-difluoro-4-(4-trifluoromethvl-Dvrazol-1-vl)-phenoxyl-butvl)-benzovlamino)-propionic acid

The title compound was prepared by a method analogous to that described for Example 20 using (+/-)-4-(1-[3,5-difluoro-4-(4-trifluoromethyl-pyrazol-1-yl)-phenoxy]-butyl}-benzoic acid ethyl ester. Column: Waters Atlantis d C18 4.6 x 50 mm, 5 pm; Modifier: TFA 0,05%; Gradient: 95% H₂O / 5% acetonitrile linear to 5% H₂O / 95% acetonitrile over 4.0 min, hold at 5% H₂O / 95% acetonitrile to 5.0 min. Flow: 2.0 mL / min.; Rétention time: 3.31 minutes. MS (M+1): 512.1.

Example 185: (+/-)-34441-[4454luoro-indazol-2-yl)-Dhenoxvl-butyH-benzov!amino)-proDionic acid

224

The title compound was prepared by a method analogous to that described for Example 184 using

Intermediate (125). Column: Waters Atlantis d C18 4.6 x 50 mm, 5 pm; Modifier: TFA 0.05%; Gradient: 95% H₂O / 5% acetonitrile linear to 5% H₂O / 95% acetonitrile over 4.0 min, hold at 5% H₂O / 95% acetonitrile to

5.0 min. Flow: 2.0 mL / min.; Rétention time: 3.35 minutes. MS (M+1): 476.0.

Example 186: (+/-)-3-(441 -r4-(6-fluoro-indazol-2-vl)-phenoxvl-butvl)-benzoylamino)-propionic acid

Intermediate (126). Column: Waters Atlantis d C18 4.6 x 50 mm, 5 pm; Modifier; TFA 0.05%; Gradient: 95% 10 H₂O / 5% acetonitrile linear to 5% H₂O / 95% acetonitrile over 4.0 min, hold at 5% H₂O / 95% acetonitrile to

5.0 min. Flow: 2.0 mL/ min.; Rétention time: 3.33 minutes. MS (M+1): 476.0.

Example 187: /S)-3-(4-(1-(4-(2H-Îndazol-2-yl)-3.5-dimethvlphenoxv)butvl)benzamido) propanoic acid

The title compound was prepared using a method analogous to that described in Example 83, starting from 15 Intermediate (127). ^TH NMR (400 MHz, CDCI₃) δ ppm 0.95 (t, J = 7.32 Hz, 3 H) 1.35 - 1.59 (m. 2 H) 1.74 -

1.86 (m,1 H) 1.82 (s, 3 H) 1.90 - 2.03 (m, 1 H) 2.55 (t, 4=5.85 Hz, 2 H) 3.55 - 3.67 (m, 2 H) 5.10 - 5.25 (m, 1 H) 6.57 (br. s., 2 H) 7.08 - 7.17 (m, 2 H) 7.31 (ddd, 4=8.73, 6.68, 0.98 Hz. 1 H) 7.37 (d, 4=8.19 Hz, 2 H) 7.67 - 7.78 (m, 4 H) 7.88 (d, J=0.78 Hz, 1 H). LCMS: m/z = 486.2 [M+H].

Example 188: (+\-)-3-(4-(i3.3-dimethylcvclobutvl)i6-(4-(trifluoromethvl)-1H-imidazol-1-vl)pyridin-320 vlamino)methvl)benzamido)propanoic acid

OH

225

The title compound was prepared using a method analogous to that described in Example 62, starting from

Intermediate (101) and Intermediate 6.¹H NMR (400 MHz, CDCI3) δ ppm 1.05 (s, 3 H) 1.08 (s, 3 H) 1.49 1.72 (m, 3 H) 1.90 - 2.01 (m, 1 H) 2.45 (d, J=8.80 Hz, 1 H) 2.62 (m, 2 H) 3.54 - 3.71 (m, 2 H) 4.16 (d, J=9.19

Hz, 1 H) 6.80 (dd, J=8.80, 2.74 Hz, 1 H) 7.07 (d, J=8.80 Hz, 1 H) 7.12 - 7.19 (m, 1 H) 7.32 (d, J=8.22 Hz, 2

H) 7.67 (d, J=8.02 Hz, 2 H) 7.72 (d, J=2.74 Hz, 1 H) 7.82 (s, 1 H) 8.36 (s, 1 H). LCMS: m/z = 516.2 [M+H].

Example 189: (+\-)-3-(4-f1-(4-(2H-indazol-2-vl1-3.5-dimethylphenoxvÎbutvlÎbenzamido) propanoic acid

The title compound was prepared using a method analogous to that described in Example 83, starting from Intermediate (127). ¹H NMR (400 MHz, CDCI3) δ ppm 0.95 (t, J = 7,32 Hz, 3 H) 1.35 - 1.59 (m, 2 H) 1.74 -

1.86 (m,1 H) 1.82 (s, 3 H) 1.90 - 2.03 (m, 1 H) 2.55 (t, J=5.85 Hz, 2 H) 3.55 - 3.67 (m, 2 H) 5.10 - 5.25 (m, 1

H) 6.57 (br. s., 2 H) 7.08 - 7.17 (m, 2 H) 7.31 (ddd, J=8.73, 6.68, 0.98 Hz, 1 H) 7.37 (d, J=8.19 Hz, 2 H) 7.67

- 7.78 (m, 4 H) 7.88 (d, J=0.78 Hz, 1 H). LCMS: m/z = 486.2 [M+H].

Example 190: (+\-T3-(6-(1-(6-(4-(trifluoromethvl)-1 H-pyrazol-1-vl)pvridin-3vl)butvÎamlno)nlcotinamldolpropanoic acid o o

The title compound was prepared using a method analogous to that described for Example 142, starting from

Intermediate (90) and Intermediate (128). ’H NMR (400 MHz, CDCI₃) δ 8.85-9.00 (brs, 1H), 8.80 (s, 1H),

8.40 (d, J=1.95 Hz, 1H), 8.25 (s, 1H), 8.13 (dd, 7=9.7, 2.1 Hz, 1H), 7.96 (d, 7=8.4 Hz, 1H), 7.81-7.87 (m, 2H), 7.50-7.57 (m, 1H), 6.42 (d, 7=9.2 Hz, 1H), 4.47-4.56 (m, 1H), 3.65-3.76 (m, 2H), 2.58-2.64 (m, 2H), 1.77-2.06 (m, 2H), 1.30-1.53 (m, 2H), 0.95 (t, 7=7.4 Hz, 3H). MS (M+H)=477.4.

Example 191:3-(4-((6-(4-chloro-3-methvl-1H-pvrazol-1-vl)pvridin-3-vlaminoïïcvclopentvl) methvlibenzamidolpropanoic acid. Isomer 1 and Example 192:3-(4-((6-(4-chloro-3-methvl-1H-pyrazol-1vl)pvridin-3-vfamino)(cvciopentvl) methvl)benzamido)oropanoic acid. Isomer 2

226

Racemlc ethyl 3-{4-((6-(4-ch!oro-3-methyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)(cyclopentyl) methyl)benzamido)propanoate was prepared using a method analogous to that described in Example 163, Steps A-C, using ethyl 3-aminopropanoate hydrochloride in Step 3. This material was resolved by SFC (column: Chiralcel OD-H 10 x 250 mm; mobile phase: 60/40 COa/methanol; no modifier; flow rate; 10 mL/min) to give ethyl 3-(4-((6-(4-chloro-3-methyl-1 H-pyrazol-1 -yl)pyridin-3ylamino)(cyclopentyl)methyl)benzamido)propanoate, Isomer 1 (rétention time 3.23 min) and ethyl 3-(4-((6-(4chloro-3-methyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino){cyclopentyl)methyl)benzamido)propanoate, Isomer 2 (rétention time 4.54 min).

ethyl 3-{4-((6-(4-chloro-3-methyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino)(cyclopentyl)methyl) benzamidojpropanoate, Isomer 1 and ethyl 3-(4-((6-(4-chloro-3-methyl-1 H-pyrazol-1-yl)pyridin-3ylamino)(cyclopentyl)methyl)benzamido)propanoate, Isomer 2 were saponified seperately using a method analogous to that described in Example X158, Step D, to give 3-(4-((6-(4-chloro-3-methyl-1 H-pyrazol-1 yl)pyridin-3-ylamino)(cyclopentyl)methyl)benzamido) propanoic acid, Isomer 1 and 3-(4-((6-(4-chloro-3methyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)(cyciopentyi)methyl)benzamido)propanoic acid, Isomer 2, respectively.

Spectral data for Isomer 1:¹H NMR (400 MHz, CDCI₃) δ 8.17 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.59-7.64 (m, 1H), 7.50 (d, J=9.2 Hz, 1H), 7.35 ( d, J=8.2 Hz, 2H), 6.81-6.88 (m, 1H), 6.74-6.81 (m, 1H), 4.10 (d, J=8.4 Hz, 1 H), 3.64-3.73 (m, 2H), 2.62-2.72 (m, 2H), 2.25 (s, 3H), 2.10-2.21 (m, 1H), 1.83-1.95 (m, 2H), 1.33-1.72 (m, 4H), 1.15-1.30 (m, 2H). MS (M+H)= 482.3.

Exemple 193: 3-(4-(cvclopentvl(2-(4-(trifluoromethvl)-1H-imidazol-1 -vl)pyrimldin-5vlamino)methvl)benzamido)propanoic acid

The title compound was prepared using a method analogous to that described in Example 163, starting from Intermediate (31) and Intermediate (129). Analytical HPLC: rétention time 2.99 min (Column: Waters Atlantis dC18 4.6x50mm, 5um. Modifier: TFA 0.05%. Gradient: 95%H20 / 5%MeCN linear to 5%H20 / 95%MeCN over 4.0min, HOLD at 5%H20 / 95%MeCN to 5.0min. Flow: 2.0mL/min ). LCMS: m/z = 503.2 [M+H].

Biological data

Glucagon cAMP assay

The Cisbio cAMP détection assay is used to détermine the ability of punitive glucagon antagonist to block glucagon induced cAMP production, Potential glucagon antagonists are re-suspended and diluted in 100% DMSO. Prior to use in the Glucagon cAMP assay 100x DMSO compound stocks are diluted 20x with DMEM-F12 media (Invitrogen) containing either 0.1% or 4% BSA. 2pls of 5x

227 compound stocks are spotted into the appropriate wells of low binding white solid bottom 384 well plates (Corning). 2pls of 5% DMSO or known glucagon antagonist are added to each plate to define the assay window. CH0K1 cells stably transfected with the human glucagon receptor are removed from culture flasks with cell dissociation buffer. Cell pellets are re-suspended, at a 5 concentration of 8.3e⁵ cells/m) in DMEM-F12 with or without 4% BSA and 200uM IBMX. 6pls of cell suspensions are added to the assay plates. Plates are incubated for 20min at room température prior to the addition of a 10OpM challenge dose of glucagon. On a separate plate glucagon dose response curves are run to détermine the ΕΟ_Μ of glucagon. After a 30min room température incubation the reaction is terminated by the addition of lysis buffer containing the 10 cAMP détection reagents. Plates are incubated for an additional 60 min at room température prior to being read on the Perkin Elmer fluorescent plate reader. Raw is converted to nM of cAMP produced based on a cAMP standard curve. Converted data is then analyzed using the Pfizer data analysis program. IC50 values are determined from the generated sigmoidal dose response curves. Kb values are calculated using a modified Cheng-Prusoff équation. N is the number of times the 15 compound was assayed.

TableofcAMP data

Example	N	cAMP (Kb nM)	Example	N	cAMP (Kb nM)
Example 1	4	1500	Example 105	6	455
Example 2	6	5280	Example 106	4	187
Example 3	6	1820	Example 107	2	252
Example 4	10	1270	Example 108	7	224
Example 5	12	242	Example 109	2	1710
Example 6	30	77.3	Example 110	4	97
Example 7	6	760	Example 111	2	2350
Example 8	12	155	Example 112	4	126
Example 9	21	572	Example 113	10	103
Example 10	8	15500	Example 114	8	17
Example 11	8	612	Example 115	6	231
Example 12	9	491	Example 116	4	450
Example 13	16	297	Example 117	4	227
Example 14	10	293	Example 118	2	1020
Example 15	4	1170	Example 119	6	67

228

Example 16	8	717	Example 120	10	65
Example 17	6	419	Example 121	2	764
Example 18	7	3860	Example 122	6	43
Example 19	12	2860	Example 123	4	106
Example 20	6	800	Example 124	12	82
Example 21	6	824	Example 125	4	144
Example 22	4	835	Example 126	4	212
Example 23	6	948	Example 127	3	202
Example 24	4	1030	Example 128	3	268
Example 25	4	1120	Example 129	5	13
Example 26	6	1050	Example 130	2	195
Example 27	4	1080	Example 131	10	247
Example 28	6	1300	Example 132	4	153
Example 29	4	1360	Example 133	8	75
Example 30	6	1410	Example 134	2	876
Example 31	2	1450	Example 135	6	28
Example 32	2	1590	Example 136	4	222
Example 33	4	1560	Example 137	7	27
Example 34	2	1710	Example 138	4	40
Example 35	2	1790	Example 139	4	147
Example 36	2	1820	Example 140	4	154
Example 37	2	1760	Example 141	8	586
Example 38	2	2130	Example 142	2	883
Example 39	4	2460	Example 143	8	179
Example 40	2	2540	Example 144	6	174
Example 41	2	2840	Example 145	10	156
Example 42	2	2810	Example 146	8	21
Example 43	2	2910	Example 147	6	343

229

Example 44	2	3110	Example 148	14	423
Example 45	2	3350	Example 149	4	2250
Example 46	2	6890	Example 150	4	1640
Example 47	2	7810	Example 151	6	227
Example 48	2	8150	Example 152	6	301
Example 49	2	10300	Example 153	6	225
Example 50	4	1560	Example 154	6	629
Example 51	8	1810	Example 155	6	313
Example 52	2	2410	Example 156	6	246
Example 53	4	2610	Example 157	10	18.6
Example 54	2	3530	Example 158	10	155
Example 55	2	3720	Example 159	8	730
Example 56	2	4370	Example 160	6	111
Example 57	4	6100	Example 161	8	9.49
Example 58	2	7300	Example 162	8	55.8
Example 59	14	1390	Example 163	8	42.7
Example 60	13	1270	Example 164	8	52.4
Example 61	14	3250	Example 165	6	305
Example 62	12	32.2	Example 166	5	94.8
Example 63	12	613	Example 167	3	1140
Example 64	14	494	Example 168	8	185
Example 65	6	2880	Example 169	4	1150
Example 66	2	1450	Example 170	6	1300
Example 67	14	526	Example 171	8	150
Example 68	6	1710	Example 172	8	59.9
Example 69	4	1510	Example 173	4	641
Example 70	6	1910	Example 174	4	252
Example 71	2	2120	Example 175	6	10.5

230

Example 72	6	2300	Example 176	8	79.1
Example 73	6	2640	Example 177	4	2340
Example 74	5	4680	Example 178	8	215
Example 75	6	7710	Example 179	4	134
Example 76	2	6130	Example 180	6	45
Example 77	6	2390	Example 181	2	195
Example 78	6	4330	Example 182	8	424
Example 79		4140	Example 183	8	154
Example 80	2	1290	Example 184	4	321
Example 81	10	1830	Example 185	6	175
Example 82	10	388	Example 186	6	192
Example 83	22	164	Example 187	8	167
Example 84	12	3900	Example 188	8	106
Example 85	6	4140	Example 189	2	370
Example 86	4	615	Example 190	8	978
Example 87	2	9390	Example 191	4	11.7
Example 88	2	4740	Example 192	4	88.5
Example 89	6	1420	Example 193	6	84.1
Example 90	4	>2500
Example 91	11	213
Example 92	2	5600
Example 93	4	3840
Example 94	10	57.5
Example 95	10	32.8
Example 96	4	871
Example 97	10	90.8
Example 98	4	1060
Example 99	6	376

231

Example 100	6	226
Example 101	6	79.3
Example 102	4	3540
Example 103	8	1080
Example 104	8	169

Human Glucagon SPA assay

The Glucagon SPA assay is used to détermine the ability of test compounds to block the binding of glucagon-cex to the glucagon receptor. Test compounds are re-suspended and serially diluted in 5 100% DMSO. 1 μΙ of test compound at the desired concentrations is spotted into the appropriate wells of 96 well low binding white clear bottom plate (Corning). 1 μΙ of DMSO is spotted into total binding wells. 1μΙ of a known glucagon antagonist at a concentration of 20μΜ is added to non spécifie binding wells. 0.3-0.75pg of membrane from chem-1 cells stably transfected with the human glucagon receptor (Millipore), 125pM of [^1Z5l]Glucagon-Cex (Perkin Elmer) and 175pg of 10 WGA PVT SPA beads (Perkin Elmer) are added to ail wells of the assay plate. Ail assay ingrédients with the exception of test compounds are re-suspended in the following buffer; 50mM Hepes pH 7.4; 5mM MgCI₂; 1mM CaCI; 5% glycerol and 0.2% BSA. Following a 6-1 Ohr incubation at room température the amount of hot ligand bound to the cell membranes is determined by reading the plates on a Wallac Trilux radioactive émission detector. Data is analyzed using 15 Pfizer’s Data analysis program. IC·» values are then determined from the generated sigmoidal dose response curves. Ki values are calculated using Cheng-Prusoff équation. N is the number of times the compound was assayed.

	Table for SPA Binding d	ata
Example number	N	Binding Ki (nM)	Example number	N	Binding Ki (nM)
Example 97	2	93	Example 147	3	26.7
Example 98	4	1,100	Example 148	7	125
Example 86	2	233	Example 149	2	1050

232

Example 101	2	17	Example 150	2	446
Example 31	1	1331	Example 151	3	20.2
Example 22	2	665	Example 152	3	35.2
Example 28	2	1659	Example 153	3	32.3
Example 53	2	556	Example 154	3	235
Example 105	4	69.8	Example 155	4	94.9
Example 106	3	91.9	Example 156	3	251
Example 107	2	71.6	Example 157	5	5.55
Example 108	4	203	Example 158	5	41
Example 109	2	153	Example 159	4	315
Example 110	3	57.2	Example 160	4	29
Example 111	2	202	Example 161	5	25.7
Example 112	3	143	Example 162	5	47.3
Example 113	4	38.2	Example 163	5	65.9
Example 114	5	7.6	Example 164	5	192
Example 115	4	15.8	Example 165	4	142
Example 116	2	464	Example 166	4	91.5
Example 117	2	183	Example 167	3	414
Example 118	1	297	Example 168	4	27.4
Example 119	4	103	Example 169	2	193
Example 120	5	225	Example 170	2	224
Example 121	1	298	Example 171	4	28
Example 122	4	45.7	Example 172	4	8.18
Example 123	3	88.4	Example 173	2	26.6
Example 124	6	109	Example 174	2	57
Example 125	3	98.2	Example 175	3	28.7
Example 126	3	161	Example 176	4	101

233

Example 127	3	316	Example 177	2	432
Example 128	3	208	Example 178	4	37.4
Example 129	4	29.3	Example 179	4	22.1
Example 130	2	116	Example 180	5	10.3
Example 131	6	51	Example 181	1	87.2
Example 132	3	132	Example 182	4	156
Example 133	5	58	Example 183	4	53.5
Example 134	1	110	Example 184	2	240
Example 135	3	35	Example 185	3	137
Example 136	2	30.2	Example 186	3	175
Example 137	4	20.2	Example 187	5	47.8
Example 138	2	5.75	Example 188	4	42.2
Example 139	3	354	Example 189	2	109
Example 140	3	62.8	Example 190	4	399
Example 141	5	89.5	Example 191	2	29.3
Example 142	2	636	Example 192	2	50.3
Example 143	5	57.4	Example 193	4	44.7
Example 144	4	62.6
Example 145	6	93.2
Example 146	4	9.05

Claims

We Claim:

1. A compound of Formula I /

R² or a pharmaceutically acceptable sait thereof, wherein

R’ is a 5 membered heteroaryl group attached through either a carbon or nitrogen atom and which is optionally fused to a (C4-C₇)cycloalkyl, phenyl or 6 membered heteroaryl; wherein the optionally fused 5 membered heteroaryl is optionally substituted with one to four substituents each independently selected from halo, -S(O)₂-(Ci-C₃)alkyl, -S-(Ci-C₃)alkyl, hydroxy, -C(0)NR^aR^b, (C₃C_s)cycloalkyl, cyano, phenyl which is optionally substituted with one to three halo, cyano, (Cr C₃)alkyl or (Ci-C₃)alkoxy, 6 membered heteroaryl which is optionally substituted with one to three halo, cyano, (C_rC₃)alkyl or (C,-C₃)alkoxy, (C_rCe)alkyl optionally substituted with one to three fluoro, or (CrCe)alkoxy optionally substituted with one to three fluoro;

R^a and R^b are each independently H or (C_rC₃)alkyl;

R² is H or methyl;

R³ is tetrazolyl, -CH₂-tetrazolyl, -(CH₂)_ZSO₃H or -(CH₂)₂CO₂H, -CH_aCHFCO₂H or CH₂CHOHCO₂H;

A’, A², A³ and A⁴ are each independently CR⁴ or N, with the proviso that no more than two of A¹, A², A³ and A⁴ are N;

R⁴ at each occurrence is independently H, halo, cyano, (Ci-C₃)alkyl optionally substituted with one to three fluoro, or (C_rC₃)alkoxy optionally substituted with one to three fluoro;

L is -X-CH(R⁵)- or -CH(R^S)-X-;

X is CH₂, O or NH;

R⁵ is (CrCeJalkyl which is optionally substituted with one to three fluoro, hydroxy or methoxy; (C₃C₇)cycloalkyl which is optionally substituted with one to two (Ci-C₃)alkyl which are optionally substituted with one to three fluoro and wherein one to two carbons of the (C₃-C₇)cycloalkyl can be replaced with a NH, N(Ci-C₃)alkyl, O or S; or (C₃-C₇)cycloalkyl-(Ci-C₆)alkyl wherein the (C₃C₇)cycloalkyl group of said (Ca-C^cycloalkyl-tCrCeJalkyl is optionally substituted with one to two (CrC₃)alkyl which are optionally substituted with one to three fluoro;

B¹, B², B³ and B⁴ are each independently CR⁶ or N, with the proviso that no more than two of B¹,

B², B³ and B⁴ are N; and

R⁶ at each occurrence is independently H, halo, (CvC^alkyl optionally substituted with one to three fluoro, or (CrC₃)alkoxy optionally substituted with one to three fluoro.

235
2. The compound of claim 1 or a pharmaceutically acceptable sait thereof, wherein R¹is a 5 membered heteroaryl attached through a nitrogen atom to the carbon between A¹ and A⁴ of the ring containing A¹, A², A³ and A⁴; R² is hydrogen; and R³ is -(CH₂)₂CO₂H.
3. The compound of claim 1 or 2 or a pharmaceutically acceptable sait thereof, wherein X is O.
4. The compound of claim 1 or 2 or a pharmaceutically acceptable sait thereof, wherein X is NH.
5. The compound of claim 1 or 2 or a pharmaceutically acceptable sait thereof, wherein X is CH₂.
6. The compound of claim 3 or 4 or a pharmaceutically acceptable sait thereof wherein L is -X-CH(R⁵)- ; A¹, A², A³ and A⁴ are each independently CR⁴; or A⁴ is N and A¹, A² and A³ are each CR⁴; or A¹ and A⁴ are each N and A² and A³ are each CR⁴; or A² and A⁴ are each N and A¹and A³ are each CR⁴; R⁴ at each occurrence is independently H or methyl; B¹, B², B³ and B⁴ are each CR^e; or B¹ is N and B², B³ and B⁴ are each CR⁶; or B² and B³ are each N and B¹ and B⁴ are each CR⁸; or B¹ and B⁴ are each N and B² and B³ are each CR⁸; and R⁶ at each occurrence is H.
7. The compound of claim 3 or a pharmaceutically acceptable sait thereof wherein L is -X-CH(R^S)- ; A¹, A², A³ and A⁴ are each CR⁴; or A⁴ is N and A¹, A² and A³ are each CR⁴; or A¹ and A⁴ are each N and A² and A³ are each CR⁴; or A² and A⁴ are each N and A’ and A³ are each CR⁴; R⁴ at each occurrence is independently H or methyl; B¹, B², B³ and B⁴ are each CR⁸; and R⁸ at each occurrence is independently H or methyl.
8. The compound of claim 4 or a pharmaceutically acceptable sait thereof wherein R^zis hydrogen; R³ is -(CH₂)₂CO₂H; L is -CH(R^S)-X- ; A⁴ is N and A¹, A² and A³ are each CR⁴; or A¹and A⁴ are each N and A² and A³ are each CR⁴; or A² and A⁴ are each N and A¹ and A³ are each CR⁴; R⁴ at each occurrence is independently H or methyl; B¹, B², B³ and B⁴ are each CR⁶; and R⁶at each occurrence is independently H or methyl.
9. The compound of claim 4 or a pharmaceutically acceptable sait thereof wherein R^ais hydrogen; R³ is ~(CH₂)₂CO₂H; L is -CH(R⁵)-X- ; A¹, A², A³ and A⁴ are each independently CR⁴;

236

R⁴ at each occurrence is independently H or methyl; one of B¹, B^z, B³ and B⁴ is N and the others are each CR⁶; and R⁶ at each occurrence is independently H or methyl.
10. The compound of claim 6, 7, 8 or 9 or a pharmaceutically acceptable sait thereof wherein R⁵ is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.
11. The compound of claim 10 or a pharmaceutically acceptable sait thereof wherein R¹is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro.
12. The compound of claim 1 or a pharmaceutically acceptable sait thereof wherein R¹is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro; L is -X-CHR⁵-; X is O; and R⁵ is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.
13. The compound of claim 1 or a pharmaceutically acceptable sait thereof wherein R¹is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro; L is -CHR⁵-X-; X is NH; and R^s is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.
14. The compound of claim 12 or 13 or a pharmaceutically acceptable sait thereof wherein R¹ is 4-trifluoromethylpyrazol-1-yl or 4-trifluoromethylimidazol-1-yl.
15. A compound of claim 1 selected from the group consisting of (+/-)-3-(4-(1 -(3-methyl-4-(4-(trifluoromethyl)-1 H-imidazol-1 -yl) phenylamino)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(3-methyl-1 -(4-(4-(trifluoromethyl)-1 H-imidazol-1 -yI)phenyl) butoxy)benzamido) propanoic acid;

(+/-)-3-(6-(1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)butyl) nicotinamido)propanoic acid; (+/-)-3-(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl) pentan-2-yl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(6-(4-(trifIuoromethyl)-1 H-pyrazol-1 -yl)pyridine-3-ylamino)butyl) benzamido) propanoic acid;

237 (R) -3-(4-(1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1-ylJpyridine-3-ylamîno)butylJ benzamido) propanoic acid;

(S) -3-(4-(1-(6-(4-(trifluoromethylJ-1H-pyrazol-1-yl)pyridine-3-ylamino)butyl) benzamido) propanoic acid;

(+/-)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-ylJpyridine-3-ylaminoJmethylJ benzamidojpropanoic acid;

(₊/-)-3-(4-(1-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)yridine-3-ylamino)butyi) benzamido) propanoic acid;

(R) -3-(4-(1 -(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl) yridine-3-ylamino)butyl) benzamido) propanoic acid;

(S) -3-(4-(1 -(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl) yridine-3-ylamino)butyl) benzamidojpropanoic acid;

(+/-)-3-(4-(1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenylamino) butyl)benzamido) propanoic acid; (+/-)-3-(4-(1 -(3,5-dimethyl-4-(4-(trifluoromethylJ-1 H-pyrazol-1 -yl)pheny(amino)butyl) benzamido) propanoic acid;

(R) -3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1 -yl) phenylamino)butyl) benzamido) propanoic acid;

(S) -3-(4-(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl) phenylamino)butyl) benzamidojpropanoic acid;

(+/-)-3-(4-(1 -(4-(4-(triftuoromethyl)-1 H-imidazol-1 -yl)phenylamino) butyl)benzamido) propanoic acid;

(R) -3-(4-(1 -(4-(4-(trifluoromethyl)-1 H-imidazol-1 -yljphenylaminojbutyl) benzamido) propanoic acid;

(S) -3-(4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenylamino) butyl)benzamido) propanoic acid; (+/-)-3-(4-(1 -(4-(4-(trifIuoromethyl)-1 H-imidazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid;

(+/—)-3-(4-(1-(4-(4-(methylthio)-1 H-pyrazol-1-yljphenoxy) butyl) benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(3-tert-buty1-1 H-pyrazol-1 -yl)phenoxy)butyl) benzamidojpropanoic acid;

(+/-)- 3-(4-(1-(4-(4-chloro-3-methyl-1 H-pyrazol-1-yljphenoxy) butyl) benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(4-chloro-1H-pyrazol-1-yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(4-(4-ethyl-3-methyl-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(3,5-diethyl-1H-pyrazol-1-yl)phenoxy)butyl) benzamidojpropanoic acid;

(+/—)-3-(4-(1-(4-(4-methyl-1 H-pyrazol-1 -yljphenoxyjbutyljbenzamidoj propanoic acid;

(+/-)- 3-(4-(1-(4-(3-isopropyl-1H-pyrazol-1-yl)phenoxy)butylJ benzamidojpropanoic acid;

(+/-)-3-(4-(1 -(4-(4-fluoro-1 H-pyrazol-1 -yljphenoxyjbutyljbenzamidoj propanoic acid;

(+/-)-3-(4-(1-(4-(3-methyl-1 H-pyrazol-1-yljphenoxyjbutyljbenzamidoj propanoic acid;

(+/-)-3-(4-(1 -(4-(2H-1,2,3-triazol-2-yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(3-butyl-1 H-pyrazol-1 -yljphenoxyjbutyljbenzamidoj propanoic acid;

(+/-)-3-(4-(1-(4-(5-ethoxy-3-methyl-1 H-pyrazol-1-yljphenoxyjbutyl) benzamidojpropanoic acid;

238 (+/-)-3-(4-(1 -(4-(5-methoxy-3-methyl-1 H-pyrazol-1 -yl)phenoxy)butyl) benzamido)propanoic acid;

(+/—)-3-(4-(1-(4-(4-butyl-1 H-imidazol-1-yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(2-cyano-3,4,5-trimethyl-1 H-pyrrol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(3-cyano-2,4-dimethyl-1 H-pyrrol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(2-cyano-3-methyl-1 H-pyrrol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)- 3-(6-(1-(4-(3-propyl-1 H-pyrazol-1-yl)phenoxy)butyl) nicotinamido)propanoic acid; (+/-)-3-(4-(1 -(4-(3,4-dimethyl-1 H-pyrazol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1 H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1-(4-(1 H-imidazo[1,2-b]pyrazol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1 -(4-(3-ethyl-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)- 3-(4-(1-(4-(4-chloro-5-methyl-1H-imidazol-1-yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(4,5-diethyl-1H-lmidazol-1-yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(3,5-dimethyl-1H-pyrazol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(3-methyl-1H-1,2,4-triazol-1-yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1 H-1,2,4-triazol-1-yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(2-butyl-1 H-imidazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(4-(4,5-dimethyl-1 H-imidazol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(1-propyl-1H-pyrazol-4-yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(1H-pyrazol-3-yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 -(4-(3,5-dimethylisoxazol-4-yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(4-(1-methyl-3-(tritluoromethyl)-1H-pyrazol-5-yl)phenoxy) butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(1 -methyl-1 H-pyrazol-4-yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(4-(1,5-dimethyl-1H-pyrazol-4-yl)phenoxy)butyl) benzamido)propanoic acid (+/-)- 3-(4-(1 -(4-(1 H-pyrazol-4-yl)phenoxy)butyl)benzamîdo) propanoic acid;

(+/-)-3-(4-(1-(4-(1-methyl-1H-pyrazol-5-yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenoxy)butyl)benzamido) propanoic acid; (+/-)-3-(4-(1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl) benzamido)propanoic acid;

(R) -3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl) benzamido)propanoic acid;

(S) -3-(4-(1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(6’(4-phenyl-1H-pyrazol-1-yl)pyridine-3-ylamino)butyl) benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(4-fluoro-1H-pyrazol-1-yl)phenylamino)butyl) benzamido)propanoic acid; (+/-)-3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenyl)butylamino)nicotinamido) propanoic acid;

(+/-)-3-(4-(2-cyclopropyl-1 - (4-(4- (trif I uoromethyi)-1 H-pyrazol-1 -yl)phenoxy)ethyl)benzamido) propanoic acid;

(+/-)-3-(4-(cyclopentyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy) methyl)benzamido) propanoic acid;

(R) -3-(4-(cyclopentyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)methyl)benzamido) propanoic acid;

(S) -3-(4-(cyclopentyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy) mathyl)benzamîdo) propanoic acid;

(+/-)-3-(4-(cyclobutyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)methyl)benzamido) propanoic acid;

(+/-)- 3-(4-(1 -(4-(3-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(3,3-dimethyl-1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)butyl) benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(4-methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy) butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(3-(trifluoromethyl)-1 H-1,2,4-triazol-l-yl)phenoxy) butyl)benzamido)propanoic acid; (+/-)-3-(4-(1-(4-(3-methyl-4-(trifluoromethyl)-1 H-pyrazol-1-yl) phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(2-methyl-4-(trifluoromethyl)-1 H-imidazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(cyclopropyl(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl) phenoxy) methyl)benzamido) propanoic acid;

(+/-)-3-(4-(2-methyl-1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy)propyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)propyl) benzamido) propanoic acid;

(+/-)-3-(4-(3-methyl-1 -(4-(4-(trifIuoromethyl)-1 H-imidazol-1 -yl)phenyl)butoxy)benzamido) propanoic acid;

(+/-)-3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenoxy) butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl) benzamido) propanoic acid;

(S) -3-(4- ( 1 - (3,5-dimethyl-4-(4- (trifluoromethyl) -1 H-pyrazol-1 -yl) phenoxy)butyl)benzamido)propanoicacid;

240 (R)-3-(4-(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 yl)phenoxy)butyl)benzamido)propanoic acid (+/-)-3-(4-(1-{5-(4-(tnfluoromethyl)-1H-pyrazol-1-yl)pyridine-2-yloxy)butyl)benzamÎdo)propanoic acid;

(+/-)-3-(4-(1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridine-3-yloxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1-(6-(4-(trifluoromethyl)-1H-lmidazol-1-yl) pyridine-3-yloxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(4-cyano-1 H-pyrazol-1 -yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(1 -(4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenoxy)butyl) benzamido)propanoic acid;

(+/-)-3-(4-(1-(4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1-(4-(2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoîc acid;

(+/-)-3-(4-(1-(4-(4-methyl-1 H-1,2,3-triazol-1-yl)phenylamino)butyl) benzamido)propanoic acid; (+/-)-3-(2-(3-methyl-1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)butylamino)pyrimidine-5carboxamido)propanoic acid;

(+/-)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl) pyridina-3-ylamino)methyl) benzamido) propanoic acid;

(R) -3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl) benzamido)propanoic acid;

(S) -3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl) pyridine-3-ylamino)methyl) benzamido)propanoic acid;

(R) -3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl) benzamido)propanoic acid;

(S) -3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyndin-3-ylamino)methyl) benzamido)propanoic acid;

(+/-)-3-(2-(cyclohexyl(6-(4-(trifluoromethyl)-1H-innidazol-1-yl)pyridine-3-yl)methylamîno) nicotinamido)propanoic acid;

(+/-)-3-(4-(3,3-dimethyl-1-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl) pyridine-3-ylamino)butyl) benzamidojpropanoic acid;

(+/-)-3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridine-3-ylamino)methyl) benzamidojpropanoic acid (+/-)-3-(6-(3-methyl-1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl) nicotinamido)propanoic acid;

(R) -3-(4-(1-(4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenylamino)butyl) benzamidojpropanoic acid; and (S) -3-(4-(1 -(4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenylamino)butyl) benzamidojpropanoic acid;

241 or a pharmaceutically acceptable sait thereof.
16. A compound of claim 1 selected from the group consisting of (+/-)-3-(4-(1 -(3,S-dimethyl^-^-itrifluoromethyQ-l H-pyrazol-1 -yl) phenoxy)butyl) benzamido)propanoic acid;

(S)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl) benzamîdo)propanoic acid;

(R)-3-(4-(1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl) phenoxy)butyl) benzamido)propanoic acid;

(+/-)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridln-3ylamino)methyl)benzamido)propanoic acid;

(R) - 3-(4-(cyclopantyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3ylamino)methyl)benzamido)propanoic acid; and (S) -3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3ylamîno)methyl)benzamido)propanoicacid;

or a pharmaceutically acceptable sait thereof.
17. A compound selected from the group consisting of (+/-)-3-(4-(3-methyl-1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido) propanoic acid;

(+/-)-3-(4-(cyclobutyl(6-(4-(trifluoromethyi)-1H-pyrazol-1-yl)pyridin-3-ylamino)methyl)benzamido) propanoic acid;

(+/-)-3-(4-(2-cyc!opropyt-1-(6-(4-(trifluoromethyl)-1/-/-pyrazol-1-yl)pyridin-3-ylamino)ethyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(3-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid; (+)-3-(3-fluoro-4-(1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid; (-)-3-(3-fluoro-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid; (+)-3-(3-methyl-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid;

(-)-3-(3-methyl-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylaniino)butyl)benzamido)propanoic acid; (+)-3-(4-(1-(2-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyrifnidin-5-ylamino)butyl)benzamido)propanoic acid; (+)-3-(4-((3,3-dimethylcyc!obutyl)(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)methyl) benzamido)propanoic acid;

(-)-3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)methyl) benzamido)propanoic acid;

3-(4-(1-(4-(2H-indazol-2-yl)-3-methylphenoxy)butyl)benzamido)propanoic acid;

(+)-3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)mBthylamino)nicotinamido) propanoic acid;

242 (-)-3-(6-(cyclohexyl(2-methyl-4-(4-(trÎfluoromethyi)-1H-pyrazol-1-yl)phenyl)methyiamino) nicotinamido)propanoic acid;

(+/-)-3-(4-((4-(2H-indazol-2-yl)phenoxy)(cyclopentyl)methyl)benzamido)propanoic acid;

(+)-3-(4-((6-(4-chloro-1H-imidazol-1-yl)pyridin-3-ylamino)(cyclopentyl)methyl) benzamidojpropanoic acid;

(+/-)-3-(4-(2,2,2-trifluoro-1 -(6-(4-(tritluoromethyl)-1H-imidazol-1-yl)pyrldin-3-ylamino)ethyl)benzamido) propanoic acid;

3-(4-((6-(4-tert-butyl-1 H-imidazol-1 -yl)pyridin-3-ylamino)(cyclopentyl) methyl)benzamido)propanoic acid; 3-(4-(cyclopentyl(6-(4-lsopropyl-1H-Îmidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoicacid; (+)-3-(4-(1 -(4-(2-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid;

3-(4-(1-(4-(7-methyl-2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid;

3-(4-(1-(4-(6-methyl-2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoicacid;

3-(4-(1 -(4-(4-methyl-2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid;

3-(4-(1-(4-(5-methyl-2H-indazo1-2-yl)phenoxy) butyl) benzamidojpropanoic acid;

3-(4-(1-(6-(4-phenyl-1H-imidazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid;

(+\-)-3-(4-(1 -(4-(4-chloro-1 H-pyrazol-1 -yl)-3,5-dimethyIphenoxy)butyl)benzamido)propanoic acid; (+\-)-3-(4-(cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy) methyl) benzamidojpropanoic acid;

(+\-)-3-(6-(1 -(6-(4-phenyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino)butyl)nicotinamido)propanoic acid;

(+\-)-3-(6-(1 -(6-(4-phenyl-1 H-pyrazol-1 -yl) pyridin-3-ytoxy) butyl) benzamido)propanoic acid;

(+)-3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl) benzamidojpropanoic acid;

(-)-3-(4-((3,3-dlmethylcyclobutyl)(6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyridin-3ylamino)methyl)benzamido)propanoic acid;

(+)-3-(4-(1-(6-(4-tert-butyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)butyl) benzamidojpropanoic acid;

(-)-3-(4-(1-(6-(4-tert-butyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid;

(+)-3-(4-(cycIobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)methyl) benzamido) propanoic acid;

(-)-3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)methyl)benzamido) propanoic acid;

(+\-)-3-(4-(1-(4-(7-chloro-2H-indazol-2-yl)phenoxy)butyl)benzamido)propanoic acid;

(+\-) -3-(4-(1 -(4-(5-chloro-2H- i nd azol-2-yi) ph e noxy) butyl)benzamido)propanoicacid;

(+\-)-3-(4-(1-(3,5-dimethyi-4-(4-(trifluoromethyl)-1 H-imidazol-1-yl)phenoxy)birtyl)benzamido)propanoic acid; (+)-3-(6-(3-methy)-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoic acid;

(-)-3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)butylamino) nicotinamido)propanoic acid;

(+\-)-3-(4-(1-(4-(4-cyclopropyl-1 H-pyrazol-1-yl)-3,5-dimethylphenoxy)butyl)benzamido)propanoic acid;

3-(4-(1-(4-(4-chloro-1 H-pyrazol-1-yl)-3,5-dimethylphenoxy)butyl)benzamido) propanoic acid;

(+)-3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido) propanoic acid;

243 (-)-3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridlne-3-ylamino)methyl)benzamido)propanoic acid;

(+\-)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenoxy)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-yloxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(1 -(5-methyl-6-(4-{trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yloxy)butyl)benzamido)propanoic acid; (+/-)-3-(4-(cyclobutyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1yl)phenoxy)methyl)benzamido)propanoic acid;

(+/-)-3-(4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)(3,3dimethylcyclobutyl)methyl)benzamido)propanoic acid;

(+/-)-3-(4-(1-{3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl)benzamido) propanoic acid;

(+/-)-3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3ylamino)methyl)benzamido)propanoic acid;

(+)-3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyrimidin-5yloxy)methyl)benzamido)propanoic acid;

(-)-3-(4-((3₁3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyrimidin-5yloxy) methyl) benzamido) propanoic acid;

(+)-3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyrimidin-5ylamino)methyl)benzamido)propanoic acid;

(-)-3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyrimidin-5ylamino)methyl)benzamido)propanoic acid;

3-(4-(1-(2-methyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)phenoxy)butyl) benzamido)propanoic acid; (+)-3-(4-(1 -(6-(4-phenyl-1 H-pyrazol-1 -yl)pyndine-3-ylamino)butyl)benzamido)propanoic acid;

(-)-3-(4-(1 -(6-(4-phenyl-1 H-pyrazol-1 -yl)pyridlne-3-ylamlno)butyl)benzamido)propanoic acid;

(+/-)-3-(4-(1 - (6-(4-phenyl-1 H-imidazol-1 -yl)pyridin-3-ylamlno)butyl)benzamido)propanoic acid;

(+/-)-3-(4-((6-(4-chloro-3-methyl-1H-pyrazol-1-yl)pyridin-3-ylamino)(cyclopentyl)methyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-(6-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid;

(₊/_).3-(W-methyl-4-(1 -(6-(4-phenyl-1 H-pyrazol-1 -yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid;

(+)-3-(4-(1-(6-(4-ethyl·3-methyl-1H-pyrazol·1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid;

(-)-3-(4-(1-(6-(4-ethyl-3-methyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamïdo) propanoic acid;

(H)-3-(6-((1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-3methylbutyl)amino)nicotinamido)propanoic acid;

(S)-3-(6-((1 -(3,5-dimethyl-4-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)-3methylbutyl)amino)nicotinamido)propanoic acid;

(+)-(3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino) nicotinamidojpropanoic acid;

H-S-te-ftcyclopentyliS.S'dimethyl^-^ritrifluoromethyQ-IH-pyrazol-l-yOphenyOmethylJannÎno) nicotinamido)propanoic acid;

244 (+)-N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1 H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-betaalanine;

(-)-N-(4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1 H-pyrazol-1 -yl]pyridin-3-yl}amino)butyl]benzoyl}-betaalanine;

(+)-Ν-{4-[{[6-(4-ονοΙορΓορνΙ-1Η^ΓθζοΙ-1^Ι)ρνΓΪάίη-3-ν1]αππίηο}(3,3-άίιηθίΐΊνΙονοΚΛυΙνΙ)πΊθΙΙινΙ^θπζονΙ}^θ(θalanine;

(-)-N-{4-[{[6-(4-cyclopropyl-1 H-pyrazol-1-yl)pyridin-3-yl]amino}(3,3-dimethylcyclobutyl)methyl]benzoyl}-betaalanine;

(+/-)-N-[4-(1-([6-(4-cyclopropyl-1 H-pyrazol-1-yl)pyridln-3-yl]amino}butyl)benzoyl]-beta-alanine; (±)-3-(4-((tetrahydro-2H-pyran-4-yl)((6-(4-(trifluoronnethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)amino)methyl) benzamido)propanoic acid;

(±)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1 H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido) propanoic acid;

(+)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-3-yl)amino)propyl) benzamido) propanoic acid;

(-)-3-(4-(2,2-dimethyl-1-((6-(4-(trif!uoromethyl)-1 H-pyrazol-1 -yl)pyridin-3yl)amino)propyl)benzamido)propanoic acid;

(±)-3-(4-(2,2-dimethyl-1 -((6-(4-(trifluoromethyl)-1 H-imidazol-1 -yl) pyridin-3yl)amino)propyl)benzamido)propanoic acid;

(+)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-yl)amino)propyl) benzamido) propanoic acid;

(-)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1 H-imidazol-1-yl)pyridin-3-yl)amino)propyl)benzamido) propanoic acid;

(+/-)-3-(4-(1-[3,5-difluoro-4-(4-trifluoromethyl-pyrazol-1-yl)-phenoxy]-butyi}-benzoylamino)-propÎonïc acid;

(+/-)-3-(4-(1-[4-(5-fluoro-indazol-2-yl)-phenoxy]-butyl}-benzoylamino)-propionic acid;

(+/-)-3-(4-(1-[4-(6-fluoro-indazol-2-yl)-phenoxy]-butyl)-benzoylamino)-propionic acid; (S)-3-(4-(1-(4-(2H-indazol-2-yl)-3,5-dimethylphenoxy)butyl)benzamido) propanoic acid;

(+\-)-3-(4-((3,3-dimethylcyclobutyi)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3ylamino)methyl)benzamido)propanoic acid;

(+\-)-3-(4-(1 -(4-(2H-indazol-2-yl)-3,5-dimethylphenoxy)butyl)benzamido) propanoic acid; (+\-)-3-(6-(1-(6-(4-(tnfluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido) propanoic acid; (+)-3-(4-((6-(4-chloro-3-methyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)(cyclopentyl)methyl) benzamido) propanoic acid;

(-)-3-(4-((6-(4-chloro-3-methyl-1 H-pyrazol-1-yl)pyridin-3-ylamino)(cyclopentyl)methyl) benzamido) propanoic acid; and

3-(4-(cyclopentyl(2-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-5-ylamino)methyl) benzamidojpropanoic acid;

or a pharmaceutically acceptable sait thereof.

245
18. A pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of any one of daims 1 to 17; or a pharmaceutically acceptable sait thereof and (il) a pharmaceutically acceptable excipient, diluent, or carrier.
19. Use of a compound or a pharmaceutically acceptable sait thereof of any one of daims 1 through 17 in the manufacture of a pharmaceutical composition for treating or delaying the progression or onset of Type 2 diabètes and diabètes related disorders in animais
20. Use of a compound of any one of daims 1 through 17; or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable excipient, diluent, or carrier in the manufacture of a pharmaceutical composition for treating or delaying the progression or onset of Type 2 diabètes and diabètes related disorders in animais.
21. The compound of claim 1 that is (S)-3-(4-(1-(3,5-dîmethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1yl) phenoxy)butyl)benzamido)propanoic acid or a pharmaceutically acceptable sait thereof.
22. The compound of claim 1 that is 3-(4-(cyc!opentyl(6-(4-(trifluoromethyl)-1 H-pyrazol-1yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 1, or a pharmaceutically acceptable sait thereof.
23. The compound of daim 1 that is 3-(4-(1-(6-(4-tert-butyl-1H-pyrazol-1-yl)pyridln-3ylamîno)butyl)benzamldo)propanolc acid, Isomer 2, or a pharmaceutically acceptable sait thereof.
24. The compound of claim 1 that is 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1 Hpyrazol-1-yl)pyrimidin-5-yloxy)methyl)benzamido)propanoic acid, Isomer 1, or a pharmaceutically acceptable sait thereof.