Alkylphenyl substituted compounds, compositions and methods of use

Abstract

The present disclosure provides compounds that are useful for the treatment of conditions mediated by GIPR. Also provided are pharmaceutical compositions containing such compounds, and methods of treatment using such compounds.

Description

Alkylphenyl Substituted Compounds, Compositions and Methods of UseCross Reference to Related Applications

[0001] The present application claims the benefit of priority to U. S. Application No. 63 / 718,119, filed November 8, 2024, U. S. Application No. 63 / 725,708, filed November 27, 2024, U. S.Application No. 63 / 737,877, filed December 23, 2024, U. S. Application No. 63 / 787,567, filed April 11, 2025, U. S. Application No. 63 / 787,634, filed April 11, 2025, U. S. Application No. 63 / 822,696, filed June 12, 2025, U. S. Application No. 63 / 855,793, filed August 1, 2025, U. S. Application No. 63 / 878,642, filed September 9, 2025, and U. S. Application No. 63 / 890,989, filed September 30, 2025, the entire contents of each of which are incorporated by reference herein for all purposes.Field of Invention

[0002] The present disclosure provides compounds that modulate GIPR and are therefore useful for the treatment of conditions, diseases and / or disorders mediated by GIPR. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such. Background

[0003] People are typically classified as obese when their body mass index (BMI) — a person's weight divided by the square of the person's height — is over 30 kg / m2; the range 25-30 kg / m2is defined as overweight. Obesity is a major cause of disability and is correlated with various diseases and conditions particularly cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, and certain types of cancer and osteoarthritis.

[0004] Obesity is a leading preventable cause of death worldwide, with increasing rates in adults and children. In 2022, over 1 billion people were obese worldwide (879 million adults and 159 million children), representing more than a double of adult cases (and four times higher than cases among children) registered in 1990. Obesity is more common in women than in men. The World Health Organization and medical societies, e.g. the American MedicalAssociation classify obesity as a disease.

[0005] The GBD [Global Burden of Disease] investigators found an increase in the burden of elevated BMI, with high BMI accounting for 4.0 million deaths in 2015, more than two-thirds of which were caused by cardiovascular disease (CVD),16 even after accounting for smoking and ill health. Furthermore, a large proportion of both BMI-related deaths (41%) and BMI-related disability-adjusted life-years (34%) were caused by CVD among individuals with obesity.Circulation 2021 143:e984-el010.

[0006] Obesity is also a risk factor for several major cancers, including post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancer. Excessbody fat results in an approximately 17% increased risk of cancer-specific mortality. Cancers 2023, 15,485.

[0007] Moreover, the trends in obesity prevalence in the United States and around the world highlight the significant impact that obesity will continue to have on CVD incidence, cancer, Type 2 diabetes and other associated disease / conditions.

[0008] Recently GLP-1 agents have had considerable success in the treatment of obesity. Yet, many individuals on GLP-1 therapy experience adverse side effects including diarrhea, nausea and vomiting. In addition, GLP-1 agents may not sufficiently reduce fat body mass vs. lean body mass which may be aided through the role of GIPR signaling on fat cells. Further, GLP-1 agents’ action on weight loss may diminish with time.

[0009] Glucose-dependent insulinotropic polypeptide (GIP) is a single 42-amino acid peptide secreted from K-cells in the small intestine (duodenum and jejunum). Human GIP is derived from the processing of proGIP, 153-amino acid precursor that is encoded by a gene localized to chromosome 17q (Inagaki et al., Endocrinol 1989; 3:1014-1021; Fehmann et al. Endocr Rev. 1995; 16:390-410). GIP was formerly called gastric inhibitory polypeptide.

[0010] GIP secretion is induced by food ingestion. GIP has a number of physiological effects in tissues, including promotion of fat storage in adipocytes and promotion of pancreatic islet-cell function and glucose-dependent insulin secretion. GIP and glucagon like polypeptide-I (GLP-1) are known insulinotropic factors ("incretins"). Intact GIP is rapidly degraded by DPPIV to an inactive form. The insulinotropic effect of GIP is lost in type 2 diabetic patients while GLP-1 's incretin effect remains intact (Nauck et al. J. Cline. Invest. 1993; 91:301-307).

[0011] The GIP receptor (GIPR) is a member of the secretin-glucagon family of class B G-protein coupled receptors (GPCRs) having an extracellular N-terminus, seven transmembrane domains and an intracellular C-terminus. The N-terminal extracellular domains of this family of receptors are usually glycosylated and form the recognition and binding domain of the receptor. GIPR is highly expressed in a number of tissues, including the pancreas, gut, adipose tissue, heart, pituitary, adrenal cortex, and brain (Usdin et al., Endocrinology. 1993, 133:2861-2870). Human GIPR comprises 466 amino acids and is encoded by a gene located on chromosome 19ql3.3 (Gremlich et al., Diabetes. 1995; 44:1202-8; Volz et al., FEBS Lett. 1995, 373:23-29). Studies have suggested that alternative mRNA splicing results in the production of GIP receptor variants of differing lengths in human, rat and mouse.

[0012] GIPR knockout mice (Gipr_l_) are resistant to high fat diet-induced weight gain and have improved insulin sensitivity and lipid profiles. (Yamada et al., Diabetes. 2006, 55: S86; Miyawaki et al. Nature Med. 2002, 8:738-742). In addition, a novel small molecule GIPRantagonist SKL- 14959 prevents obesity and insulin resistance. (Diabetologia 2008, 51: S373, 44th EASD Annual meeting poster). SKL- 14959 polypeptide suppressed body weight gain in Mice (“Gastric inhibitory polypeptide receptor antagonist, SKL- 14959, suppressed body weight gain on diet-induced obesity mice” T. Nakamura et al. Obesity Science and Practice Jan 2018.

[0013] There have been additional efforts to discover GIPR agents to aid weight loss. Expert Opinion on Drug Discovery 2023, VOL. 18, NO. 6, 659-669. GIPR antagonist small molecules have been disclosed e.g., W02009 / 148004; EP1283058. WO2024 / 214038 and WO2025 / 224599 also disclose GIPR antagonist small molecules.

[0014] Separately, W02006 / 104826 discloses glucagon receptor substituted aryl and heteroaryl derivatives as antagonists for the treatment of diabetes and related conditions.

[0015] Accordingly, these links to obesity and insulin resistance imply GIPR modulation is a useful approach for therapeutic intervention. While GLP- 1 agents have been beneficial in treating some obese patients, given the prevalence of obesity in modem society and its adverse health effects there is a continuing need for new agents (e.g., GIPR antagonists) that are useful for the treatment of obesity.Summary

[0016] The present invention relates to compounds of Formula (I), as described herein including stereochemical isomeric forms thereof and pharmaceutically acceptable salts thereof, which are useful as GIPR antagonists and / or treating or preventing GIPR mediated conditions and diseases.

[0017] More specifically, in some embodiments, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof:1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:A is absent, -(Co-C4)alkyl-C(0)OR2, OR2, or H wherein the -N(H)S(O)2-CH3 is optionally substituted with one to three halogens;R2is H or (Ci-Ce)alkyl;X is -W3-L-W4-, wherein L is absent, -C(O)-N(H)-, or -N(H)-C(O)-, wherein W3is bonded to A and W4is bonded to W;W3is absent, phenyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 membered heteroaryl, or a 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, said phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, and a 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with hydroxy, halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C7)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein when W is absent and W1is a ring system, W4optionally shares one atom with W1in a spiro linkage;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -*C(O)-N(H)-, -*N(H)-C(O)-, or -*N(H)S(0)2-, wherein the represents the point of attachment of W to X;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (C5-Ce)cycloalkyl ring fused to a phenyl ring;wherein each of said (C3-C?)cycloalkyl, (C5-Ce)cycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, (Ci-C4)alkoxy, or trifluoromethyl, or is optionally mono-substituted with phenyl, or are spiro linked to a cyclopropyl or oxetanyl;wherein Y is (Ci-Ce)alkyl, phenyl or (C3-C?)cycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;)NH-, -*O-C(O)-NH-, -*C(O)-O-, -wherein the (Ci-C3)alkyl is optionally substituted with (Ci-C3)alkyl, halo, (Ci-C3)alkoxy or (Ci-C3)alkoxy(Ci-C3)alkyl and the represents the point of attachment to W1;Z is 5 to 7 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, C3-C6 cycloalkyl, 5-10 membered bridged cycloalkyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl or phenyl fused to a 5 to 7 membered cycloalkyl, wherein said 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl and phenyl fused to a 5 to 7 membered heterocycloalkyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;each R3is independently (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, phenyl, mono-, di- or tri-halo(Ci-C4)alkyl, -SCF3, -OCF3, -OCHF2, (C3-C7)cycloalkyl, said (C3-C7)cycloalkyl optionally substituted independently with 1 or 2 (Ci-C4)alkyl, or mono-, di- or tri-halo(Ci-C4)alkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W4-W-W1-W2-Z is not

[0018] Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0019] Also provided herein is a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising:a first compound, said first compound being a compound of Formula I or a pharmaceutically acceptable salt of said compound;a second compound, said second compound being a GLP-1 inhibitor, a GCGR agonist or a GIPR agonist; anda pharmaceutically acceptable excipient.

[0020] Also provided herein is a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising:a first compound, said first compound being a compound of Formula I or a pharmaceutically acceptable salt of said compound;a second compound, said second compound being a GLP-1 inhibitor; anda third compound, said third compound being a GCGR agonist or a GIPR agonist; and a pharmaceutically acceptable excipient.

[0021] Also provided herein is a kit comprising:a. a first compound, said first compound being a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient in a first unit dosage form;b. a second compound, said second compound being a GLP-1 inhibitor, a GCGR agonistor a GIPR agonist and a pharmaceutically acceptable excipient in a second unit dosage form; and c. means for containing said first and second dosage formswherein the amounts of first and second compounds result in a therapeutic effect.

[0022] Also provided herein is a kit wherein said second compound is a GLP-1 inhibitor.

[0023] Further provided herein are methods of modulating GIPR activity; and / or methods of treating a GIPR-mediated disease or disorder in a subject in need thereof, wherein each of these methods independently comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or administering an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0024] Also provided is a method of treating a condition chosen from Type 2 diabetes, elevated glucose levels, elevated insulin levels, dyslipidemia, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, Type 1 diabetes, obesity, conditions exacerbated by obesity, pancreatitis, cirrhosis and Turner’s & Cushing’s syndrome comprising administering to the subject an effective amount of the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0025] Also provided herein is a method of treating a disease or condition chosen from Type 2 diabetes, elevated glucose levels, elevated insulin levels, dyslipidemia, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, Type 1 diabetes and obesity, conditions exacerbated by obesity, pancreatitis, cirrhosis and Turner’s & Cushing’s syndrome comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition thereof; and

[0026] a second compound, said second compound being a GLP-1 inhibitor or a GCGR agonist.

[0027] Also provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. In some embodiments the compound is for use in treating disease or disorder mediated by GIPR.

[0028] Also provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a GIPR-mediated disease or disorder.Brief Description of the Drawings

[0029] Figure 1 shows the percent of body weight change from baseline in hGIPR mice on a high fat diet (HFD) over twenty-two (22) days. The data shown is mean and the error bars show the standard error of the mean (SEM). * = p <0.0332, **** = p <0.0001 compared with vehicle treated mice.

[0030] Figure 2 shows the cumulative food intake per hGIPR mouse on a high fat diet (HFD) over twenty-two (22) days. The data shown is mean (g) and the error bars show the standard error of the mean (SEM). * = p <0.0032, ** = p <0.0021.Detailed Description

[0031] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.

[0032] “Alkyl” means a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms. The term “(Ci-C6)alkyl” refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, s- butyl, / -butyl, pentyl, and hexyl, and the like.

[0033] When the term “alkyl” is used in combination with other substituent groups, such as “halo(Ci-C4)alkyl”, “aryl(Ci-C4)alkyl”, or “ (Ci-C4)alkoxy(Ci-C4)alkyl”, the term “alkyl” is intended to encompass a divalent straight or brane hed-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety. The term “halo (C1-C4) alkyl” is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branched-chain carbon radical. Examples of “halo(Ci-C4)alkyl” groups useful in the present invention include, but are not limited to, mono-, di- or tri-halo(Ci-C4)alkyl-, or, CF3 (trifluoromethyl), CCI3 (trichloromethyl), 1,1 -difluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Examples of “aryl(Ci-C4)alkyl” or “phenyl(Ci-C4)alkyl” groups useful in the present invention include, but are not limited to, benzyl and phenethyl. Examples of “(Ci-C4)alkoxy(Ci-C4)alkyl” groups useful in the present invention include, but are not limited to, methoxymethyl, methoxyethyl, methoxyisopropyl, ethoxymethyl, ethoxyethyl, ethoxyisopropyl, isopropoxymethyl, isopropoxyethyl, isopropoxyisopropyl, t- butoxymethyl, / -butoxy ethyl, and t-butoxyisopropyl.

[0034] “Alkenyl” means a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms and at least one carbon-carbon double bond. The term “(Ci-C6)alkenyl” refers to an alkenyl moiety containing from 1 to 6 carbon atoms. Exemplary alkenyls include, but are not limited to, ethenyl, / 7-propenyl, isopropenyl, n -butenyl, isobutenyl, -butenyl, / -butenyl, pentenyl, and hexenyl, and the like.

[0035] “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, 11-. iso-, or / e / v-butoxy, and the like. The term “(Ci-C4)alkoxy” refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.

[0036] As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. For example, the term (C3-C8)cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms. Exemplary “(C3-C8)cycloalkyl” groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0037] As used herein, “heterocycloalkyl” represents a group or moiety comprising a nonaromatic, monocyclic radical, which is saturated or partially unsaturated and includes one, two or three heteroatoms selected independently from oxygen, sulfur, and nitrogen. For example, the term “4- to 6-membered heterocycloalkyl” refers to a heterocycloalkyl group containing 4, 5, or 6 ring atoms, which includes for example, one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. Illustrative examples of 4- to 6- membered heterocycloalkyl groups useful in the present invention include, but are not limited to azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3 -oxathiol any 1, 1,3-oxathianyl, 1,3-dithianyl, 1,4- oxathiolanyl, 1,4-oxathianyl, and 1,4-dithianyl. An example of a partially unsaturated heterocycloalkyl is a heterocycloalkenyl group.

[0038] As used herein, “amino” refers to primary, secondary and tertiary nitrogen containing groups.

[0039] “Halo” means fluoro, chloro, bromo, or iodo; in one embodiment the halo is fluoro or chloro.

[0040] As used herein (unless otherwise specified), “aryl” refers to a monocyclic aromatic ring having 5-8 carbon atoms that complies with Huckel’s Rule. As used herein, “arylene” refers to a bivalent aryl group. Examples of “aryl” groups are phenyl, naphthyl, indenyl, dihydroindenyl, anthracenyl, phenanthrenyl, and the like.

[0041] “Heteroaryl” as used herein (unless otherwise specified) refers to a group or moiety comprising an aromatic monocyclic ring containing 5 to 8 ring atoms. Illustrative examples of monocyclic and bicyclic groups including a heteroaryl group useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl,imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 5-membered “heteroaryl” groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl. Examples of 6-membered “heteroaryl” groups include oxo-pyridyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl. For the avoidance of doubt, heteroaryl includes those heteroaryl groups that are substituted with an oxo group, where a tautomer retains aromaticity, for example oxo-pyridyl.

[0042] “Oxo” means an =(O) group where the oxygen is bound to any atom and “carbonyl” means a > C(O) or > C=O or C=O group.

[0043] In some embodiments, terms ending in “yl” represent a monovalent group. In some embodiments, terms ending in “yl” represent a bivalent group, or a multivalent group. For example, when G is an alkyl group or cycloalkyl group in R-G, G is monovalent. When G is an alkyl group or cycloalkyl group in R-G-R*, G is bivalent. When G is an alkyl group or cycloalkyl group in R-G(Y)-R*, G is multivalent.

[0044] “Mammal” as used herein means domesticated animals (such as dogs, cats, and horses), and humans. In one embodiment, mammal is a human, male or female.

[0045] It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms withoutdenoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridyl” means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl, and so forth.

[0046] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. In some embodiments, due to the acidic nature of the compounds of this invention the pharmaceutically acceptable salts form with base addition salts, such as salts formed with Na+or K+ions.

[0047] Generally pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toliienesulfonic acid, salicylic acid, and the like. Generallypharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0048] It is understood that the pharmaceutically acceptable salts are non-toxic. For a review on suitable salts, see Handbook of Pharmaceutical Salts. Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Additional information on suitable pharmaceutically acceptable salts can be found in Remington The Science and Practice of Pharmacy, 23rd ed., Elsevier Science, 2020, which is incorporated herein by reference.

[0049] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocycloalkyl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is substituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with alkyl.

[0050] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0051] The phrase “pharmaceutically acceptable excipient” (includes pharmaceutically acceptable carriers, stabilizers and the like) as described herein, used herein means a

[0052] “Treating” or “treatment” of a disease includes:(1) preventing the disease, e.g., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;(2) inhibiting the disease, e.g., arresting or reducing the development or extent of the disease or its clinical symptoms; or(3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms.Thus, prevent, preventing, and the like can refer to the prevention of the disease or condition in the patient. For example, if an individual at risk of contracting a condition / disease is treated with the methods of the present disclosure and does not later contract the condition / disease, then the disease has been prevented, at least over a period of time, in that individual.

[0053] A “therapeutically effective amount” means the amount of a compound of Formula (I) (or any of the embodiments thereof described herein), or combination thereof, that when administered to a mammal for treating a disease, is sufficient to treat the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0054] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another, or “diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. Thus, the compounds of the present invention can exist in the form of various stereoisomers, R and S isomers, depending upon the presence of asymmetric carbon atoms. As used herein, they may be referred to as the “R configuration' or “S configuration” or the like. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active, optically enriched, optically pure, or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Those skilled in the art are familiar with methods for determining absolute stereochemistry e.g., X-Ray powder diffraction. Stereoisomers may also be obtained by stereoselective synthesis into their compounding pure enantiomers by forming a diastereomeric salt with an optically pure chiral base or acid (e.g., 1-phenyl-ethylamine or tartaric acid) and separating the diastereomers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers.

[0055] Certain compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt thereof may exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this disclosure.

[0056] Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as heteroaryl, heterocyclyl are substituted, they include all the positional isomers.

[0057] The compounds described herein include hydrates and solvates of the compounds or pharmaceutically acceptable salts thereof. The term solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl / -butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and the like.

[0058] The term hydrate is employed when the solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g., D2O. d-acetone, d-DMSO. The solvates and / or hydrates preferably exist in crystalline form. A classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0059] The present disclosure also includes prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt thereof. The term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) (or any of the embodiments thereof described herein) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups, however, regenerate original functional groups in vivo or by routine manipulation.Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein)include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., A-dimethylami nocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt thereof are also within the scope of this disclosure.

[0060] Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. The compounds of the invention may also exist as complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and / or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0061] The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins.

[0062] The present disclosure also includes polymorphic forms (amorphous as well as crystalline). The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”). The term “crystalline” refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Suchmaterials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (“melting point”).

[0063] Certain compounds of the present invention or combination agents 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 temperatures; 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 present invention followed by gradual 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 other techniques.

[0064] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms. Thus, the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,160,170,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0065] For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure. In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32. Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0066] Also included within the scope of the invention are metabolites of compounds of Formula I, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include(i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH3 -> -CH2OH):(ii) where the compound of Formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);(iii) where the compound of Formula I contains a tertiary amino group, a secondary amino derivative thereof (-NRR -> -NHR or -NHR);(iv) where the compound of Formula I contains a secondary amino group, a primary derivative thereof (-NHR -> -NH2);(v) where the compound of Formula I contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and(vi) where the compound of Formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH).

[0067] The present invention may be understood by reference to the following detailed description of exemplary aspects / embodiments of the invention and the examples included herein.

[0068] In some embodiments, disclosed herein is a compound of Formula (A) or a pharmaceutically acceptable salt thereof:whereinA is -C(O)OR2;R2is H or (Ci-Ce)alkyl;X is -W3-W4-;W3is absent, phenyl, or a 5 to 6 membered heteroaryl, said heteroaryl having 1 to 2 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C7)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, (Cs-Ce) aryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -N(H)-C(O)-, or -N(H)S(O2)-;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (Cs-Cejcycloalkyl ring fused to a phenyl ring;wherein each of said 3 to 6 membered cycloalkyl ring, (C3-C7)cycloalkyl, (C5-Ce)cycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci- C4)alkyl, halo, or trifluoromethyl, or is optionally mono-substituted with phenyl;wherein Y is (Ci-Ce)alkyl, phenyl or (C3-C7)cycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;W2is -C(O)-N(H)-, -NH-C(O)NH-, -O-C(O)-NH-, -C(O)-O-, -S(O)2-, -S(O)2-N(H)- or -S(O)2- C(H)2-, -N(R4)-C(O)NH-;R3is (Ci-Ce)alkyl, or halo, -SCF3, -OCF3, (C3-C7)cycloalkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W-W1-W2is not

[0069] In some embodiments, disclosed herein is a compound of Formula (B) or a pharmaceutically acceptable salt thereof:whereinA is -C(O)OR2or -CH2-C(O)OR2;R2is H or (Ci-Ce)alkyl;X is -W3-W4-;W3is absent, phenyl, or a 5 to 6 membered heteroaryl, said heteroaryl having 1 to 2 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C7)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C7)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, (Cs-Ce) aryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -N(H)-C(O)-, or -N(H)S(O2)-;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (Cs-Cejcycloalkyl ring fused to a phenyl ring;wherein each of said 3 to 6 membered cycloalkyl ring, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, or trifluoromethyl, or is optionally mono-substituted with phenyl;wherein Y is (Ci-Ce)alkyl, phenyl or (C3-C?)cycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;W2is -C(O)-N(H)-, -NH-C(O)NH-, -O-C(O)-NH-, -C(0)-0-, -S(0)2-, -S(O)2-N(H)- or -S(O)2-C(H)2-, -N(R4)-C(O)NH-;R3is (Ci-Ce)alkyl, halo, -SCF3, -OCF3, (C3-C7)cycloalkyl, or (C3-C7)cycloalkyl substituted with 1 or 2 (Ci-C4)alkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W-W1-W2is not

[0070] In some embodiments, disclosed herein is a compound of Formula (C) or a pharmaceutically acceptable salt thereof:wherein:A is absent or -(Ci-C4)alkyl-C(O)OR2;R2is H or (Ci-Ce)alkyl;X is -W3-W4-;W3is absent, phenyl, or a 5 to 6 membered heteroaryl, said heteroaryl having 1 to 2 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C7)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C7)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -N(H)-C(O)-, or -N(H)S(O)2-;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (Cs-Cejcycloalkyl ring fused to a phenyl ring;wherein each of said 3 to 6 membered cycloalkyl ring, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, or trifluoromethyl, or is optionally mono-substituted with phenyl;wherein Y is (Ci-Ce)alkyl, phenyl or (C3-C?)cycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;W2is -C(O)-N(H)-, -NH-C(O)NH-, -O-C(O)-NH-, -C(0)-0-, -S(0)2-, -S(O)2-N(H)- or -S(O)2-C(H)2-, -N(R4)-C(O)NH-;Z is phenyl, pyridinyl, 5-10 membered bridged cycloalkyl, or phenyl fused to a 5 to 7 membered heterocycloalkyl, wherein said 5 to 7 membered heterocycloalkyl has 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur; X is -W3-W4-;W3is absent, phenyl, or a 5 to 6 membered heteroaryl, said heteroaryl having 1 to 2 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C?)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -N(H)-C(O)-, or -N(H)S(O)2-;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C?)cycloalkyl, (C5-Ce)cycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (Cs-Cvjcycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (Cs-Cejcycloalkyl ring fused to a phenyl ring;wherein each of said 3 to 6 membered cycloalkyl ring, (Cs-Cvjcycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, or trifluoromethyl, or is optionally mono-substituted with phenyl;wherein Y is (Ci-Ce)alkyl, phenyl or (Cs-Cvjcycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;W2is -C(O)-N(H)-, -NH-C(O)NH-, -O-C(O)-NH-, -C(O)-O-, -S(O)2-, -S(O)2-N(H)- or -S(O)2-C(H)2-, -N(R4)-C(O)NH-;Z is phenyl, pyridinyl, 5-10 membered bridged cycloalkyl, or phenyl fused to a 5 to 7 membered heterocycloalkyl, wherein said 5 to 7 membered heterocycloalkyl has 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;each R3is independently (Ci-Ce)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl, -SCF3, -OCF3, or (C3-C?)cycloalkyl, said (C3-C?)cycloalkyl optionally substituted independently with 1 or 2 (Ci-C4)alkyl, or mono-, di- or tri-halo(Ci-C4)alkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W-W1-W2is not

[0071] In some embodiments, disclosed herein is a compound of Formula (D) or a pharmaceutically acceptable salt thereof:wherein:A is absent or -(Co-C4)alkyl-C(0)OR2;R2is H or (Ci-Ce)alkyl;X is -W3-W4-, wherein W3is bonded to A and W4is bonded to W;W3is absent, phenyl, phenyl fused to a 5 to 6 membered heteroaryl, or a 5 to 6 membered heteroaryl, said phenyl fused to a 5 to 6 membered heteroaryl and heteroaryl having 1 to 2 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with hydroxy, halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C?)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -N(H)-C(O)-, or -N(H)S(O)2-, wherein the X-W-W1is X-N(H)-C(O)-W1orX-N(H)S(O)2- W1;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C7)cycloalkyl, (C5-C6)cycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (Cs-Cvjcycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (Cs-Cejcycloalkyl ring fused to a phenyl ring;wherein each of said 3 to 6 membered cycloalkyl ring, (Cs-Cvjcycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, (Ci-C4)alkoxy, or trifluoromethyl, or is optionally mono-substituted with phenyl;wherein Y is (Ci-Ce)alkyl, phenyl or (Cs-Cvjcycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;alkyl-, -*NH-C(O)NH-, -*O-C(O)-NH-, -*C(O)-O-, -*S(O)2-, -*S(O)2-N(H)- or -*S(O)2-C(H)2-, -*N(R4)-C(O)NH-, wherein the represents the point of attachment to W1;Z is 5 to 7 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, pyridinyl, C3-C6 cycloalkyl, 5-10 membered bridged cycloalkyl, phenyl fused to a 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl or phenyl fused to a 5 to 7 membered cycloalkyl, wherein said 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, phenyl fused to a 5 to 6 membered heteroaryl, and 5 to 7 membered heterocycloalkyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;each R3is independently (Ci-Ce)alkyl, halo, phenyl, mono-, di- or tri-halo(Ci-C4)alkyl, -SCF3, -OCF3, -OCHF2, or (C3-C7)cycloalkyl, said (C3-C7)cycloalkyl optionally substituted independently with 1 or 2 (Ci-C4)alkyl, or mono-, di- or tri-halo(Ci-C4)alkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W4-W-W1-W2-Z is not

[0072] In some embodiments, disclosed herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:A is absent, H optionally substituted with one to three halogens, -(Co-C4)alkyl-C(0)OR2or, OR2;R2is H or (Ci-Ce)alkyl;X is -W3-L-W4-, wherein L is absent, -C(O)-N(H)-, or -N(H)-C(O)-, wherein W3is bonded to A and W4is bonded to W;W3is absent, phenyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 memberedheteroaryl, or a 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, said phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, and heteroaryl having 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with hydroxy, halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C7)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -*C(O)-N(H)-, -*N(H)-C(O)-, or -N(H)S(O)2-, wherein the X-W-W1is X-N(H)-C(O)-W!orX-N(H)S(O)2- W1, and wherein the represents the point of attachment to W;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen,oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (C5-Ce)cycloalkyl ring fused to a phenyl ring;wherein each of said 3 to 6 membered cycloalkyl ring, (C3-C?)cycloalkyl, (C5-Ce)cycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, (Ci-C4)alkoxy, or trifluoromethyl, or is optionally mono-substituted with phenyl, or is substituted with a spiro linked cyclopropyl;wherein Y is (Ci-Ce)alkyl, phenyl or (C3-C?)cycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;NH-, -*O-C(O)-NH-, -*C(O)-O-, -wherein the (Ci-C3)alkyl is optionally substituted with (Ci-C3)alkyl, halo, (Ci-C3)alkoxy or (Ci-C3)alkoxy(Ci-C3)alkyl and the represents the point of attachment to W1;Z is 5 to 7 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, C3-C6 cycloalkyl, 5-10 membered bridged cycloalkyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl or phenyl fused to a 5 to 7 membered cycloalkyl, wherein said 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl and 5 to 7 membered heterocycloalkyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;each R3is independently (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, phenyl, mono-, di- or tri-halo(Ci-C4)alkyl, -SCF3, -OCF3, -OCHF2, (C3-C?)cycloalkyl, said (C3-C?)cycloalkyl optionally substituted independently with 1 or 2 (Ci-C4)alkyl, or mono-, di- or tri-halo(Ci-C4)alkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W4-W-W1-W2-Z is not

[0073] In some embodiments, compound of Formula (I) or a pharmaceutically acceptable salt thereof:A is absent, -(Co-C4)alkyl-C(0)OR2, OR2, or H wherein the -N(H)S(O)2-CH3 is optionally substituted with one to three halogens;R2is H or (Ci-Ce)alkyl;X is -W3-L-W4-, wherein L is absent, -C(O)-N(H)-, or -N(H)-C(O)-, wherein W3is bonded to A and W4is bonded to W;W3is absent, phenyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 membered heteroaryl, or a 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, said phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, and a 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with hydroxy, halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C7)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7membered heteroaryl; wherein said 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein when W is absent and W1is a ring system, W4optionally shares one atom with W1in a spiro linkage;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -*C(O)-N(H)-, -*N(H)-C(O)-, or -*N(H)S(O)2-, wherein the represents the point of attachment of W to X;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (Cs-Cejcycloalkyl ring fused to a phenyl ring;wherein each of said (C3-C?)cycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, (Ci-C4)alkoxy, or trifluoromethyl, or is optionally mono-substituted with phenyl, or are spiro linked to a cyclopropyl or oxetanyl;wherein Y is (Ci-Ce)alkyl, phenyl or (C3-C7)cycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;H-, -*O-C(O)-NH-, -*C(O)-O-, -wherein the (Ci-C3)alkyl is optionally substituted with (Ci-C3)alkyl, halo, (Ci-C3)alkoxy or (Ci-C3)alkoxy(Ci-C3)alkyl and the represents the point of attachment to W1;Z is 5 to 7 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, C3-Ce cycloalkyl, 5-10 membered bridged cycloalkyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl or phenyl fused to a 5 to 7 membered cycloalkyl, wherein said 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl and phenyl fused to a 5 to 7 membered heterocycloalkyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;each R3is independently (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, phenyl, mono-, di- or tri-halo(Ci-C4)alkyl, -SCF3, -OCF3, -OCHF2, (C3-C7)cycloalkyl, said (C3-C7)cycloalkyl optionally substituted independently with 1 or 2 (Ci-C4)alkyl, or mono-, di- or tri-halo(Ci-C4)alkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W4-W-W1-W2-Z is not

[0074] In some embodiments, A is absent, -(Co-C4)alkyl-C(0)OR2, or -(Ci-C4)alkyl-C(O)OR2.

[0075] In some embodiments, A is absent, H optionally substituted with one to three halogens, -(Co-C4)alkyl-C(0)OR2or, OR2. In some embodiments, A is absent. In someembodiments, A is H optionally substituted with one to three halogens. In some embodiments, A is -(Co-C4)alkyl-C(0)OR2or, OR2. In some embodiments, A is OR2. In some embodiments, A is OH or OCH3. In some embodiments, A is -C(O)OH. In some embodiments, A is -CH2-C(O)OH.

[0076] In some embodiments, W2is -*C(O)-N(H)-, -*C(O)-N(H)-(Ci-C3)alkyl-,-*NH-C(O)NH-, -*O-C(O)-NH-, -*C(O)-O-, -*S(O)2-, -*S(O)2-N(H)-, -*S(O)2-C(H)2-, or -*N(R4)-C(O)NH-, wherein the (Ci-C3)alkyl is optionally substituted with (Ci-C3)alkyl, halo, (Ci-C3)alkoxy or (Ci-C3)alkoxy(Ci-C3)alkyl and the represents the point of attachment to W1. In some embodiments, W2is -*C(O)-N(H)-. In some embodiments, W2is -*C(O)-N(H)-(Ci-C3)alkyl-, wherein the (Ci-C3)alkyl is optionally substituted with (Ci-C3)alkyl, halo, (Ci-C3)alkoxy or (Ci-C3)alkoxy(Ci-C3)alkyl. In some embodiments, W2is -*NH-C(O)NH-,-*O-C(O)-NH-, -*C(O)-O-.

[0077] In some embodiments, A is absent or -(Co-C4)alkyl-C(0)OR2; W3is phenyl; W4is phenyl; and wherein W3and W4are each independently optionally mono-, di-, or tri-substituted independently with halo,(Ci-C4)alkyl or (Ci-C4)alkoxy.

[0078] In some embodiments, A is absent or -(Co-C4)alkyl-C(0)OR2; W3is a 5 to 6 membered heteroaryl; and W4is phenyl; and wherein W3and W4are each independently optionally mono-, di-, or tri-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

[0079] In some embodiments, A is absent or -(Co-C4)alkyl-C(0)OR2; W3is absent; and W4is a 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl having 1 to 4 heteroatoms selected independently from nitrogen, sulfur and oxygen; and wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

[0080] In some embodiments, A is absent or -(Co-C4)alkyl-C(0)OR2; W3is phenyl; W4is phenyl fused to a 5 to 7 membered heteroaryl having 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen; and wherein W3and W4are each independently optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

[0081] In some embodiments, A is absent or -(Co-C4)alkyl-C(0)OR2; W3is phenyl; and W4is a 5 to 6 membered heteroaryl having 1 to 4 heteroatoms selected independently from nitrogen, sulfur and oxygen; and wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

[0082] In some embodiments, Z is phenyl. In some embodiments, Z is isopropylphenyl. In some embodiments, Z is 3-fluoro-4-isopropylphenyl. In some embodiments, Z is pyridinyl.

[0083] In some embodiments,some embodiments,some embodiments,some embodiments,

[0084] In some embodiments, W is absent, -*C(O)-N(H)-, -*N(H)-C(O)-, or -*N(H)S(O)2-, wherein the represents the point of attachment of W to X. In some embodiments, W is absent, -C(O)-N(H)-, -N(H)-C(O)-, or -N(H)S(O)2-, wherein the X-W-W1is X-W-W1, X-C(O)-N(H)-W1, orX-N(H)S(O)2- W1. In some embodiments, W is -N(H)-C(O)-, wherein the X-W-W1is X-N(H)-C(O)-W1. In some embodiments, W is -N(H)S(O)2- wherein the X-W-W1is X-N(H)S(O)2- W1. In some embodiments, W is absent.

[0085] In some embodiments, each R3is independently (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, phenyl, mono-, di- or tri-halo(Ci-C4)alkyl, -SCF3, -OCF3, -OCHF2, (C3-C7)cycloalkyl, said (C3-C7)cycloalkyl optionally substituted independently with 1 or 2 (Ci-C4)alkyl, or mono-, di- or tri-halo(Ci-C4)alkyl. In some embodiments, R3is halo and n is 1 or 2. In some embodiments, R3is (Ci-C3)alkyl and n is 1. In some embodiments, each R3is independently (Ci-C4)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl and n is 1, 2 or 3.

[0086] In some embodiments, W2is -*C(O)-N(H)-, wherein the represents the point of attachment to W1.

[0087] In some embodiments, W1is pyrrolidinyl. In some embodiments, W1is -C(R10)(R11)- and R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring. In some embodiments, W1is -C(R10)(R11)- and R10is (Ci-C4)alkyl and R11is H. In some embodiments, W1is cyclopentyl. In some embodiments, W1is cyclohexyl. In some embodiments, W1is cyclohexenyl. In some embodiments, W1is azetidinyl. In some embodiments, W1is piperidinyl. In some embodiments, W1is a 4 to 8 membered bridged heterocyclic. In some embodiments, W1is azabicyclo[2.1.1]hexanyl.

[0088] In some embodiments,each optionally substituted, for example with one or two methyl groups or with a spiro linked cyclopropyl group. In further embodiment, W is absent.

[0089] In some embodiments, W1is azetidinyl. In some embodiments, W1is azetidinyl and W is absent.

[0090] In some embodiments,embodiments,some embodiments, W1is imidazolinyl. In some embodiments, W1is pyrazolinyl.

[0091] In some embodiments, W3is unsubstituted. In some embodiments, W3is mono substituted with fluoro. In some embodiments, W3is optionally mono-, di-, or tri-substituted independently with hydroxy, halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

[0092] In some embodiments, W4is unsubstituted. In some embodiments, W4is mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

[0093] In some embodiments, W is absent and W1is a ring system, and W4is linked to W1through a bond between one atom in each ring system. In some embodiments, W is absent and W1is a ring system, and W4shares one atom with W1in a spiro linkage.

[0094] In some embodiments, A is -C(O)OH or -CH2-C(O)OR2; W3is phenyl; W is -N(H)-C(O)-, wherein the X-W-W1is X-NCITl-C -W1; W2is -*C(O)-N(H)-; R3is (Ci-C3)alkyl; n is 1; and W3is optionally mono-substituted with fluoro or methyl. In some embodiments, W1is cyclopentyl. In some embodiments, W1is cyclohexyl. In some embodiments, W1is cyclohexenyl. In some embodiments, W1is azetidinyl. In some embodiments, W1ispiperidinyl. In some embodiments, W1is a 4 to 8 membered bridged heterocyclic. In some embodiments, W1is azabicyclo[2.1.1]hexanyl. In some embodiments, W-W1-W2issome embodiments, W1is imidazolinyl. In some embodiments, W1is pyrazolinyl. In some embodiments, W1is cyclopentyl. In some embodiments, W1is cyclohexyl. In some embodiments, W1is cyclohexenyl. In some embodiments, W1is azetidinyl. In some embodiments, W1is piperidinyl. In some embodiments, W1is a 4 to 8 membered bridged heterocyclic. In some embodiments, W-W1-W2is azabicyclo[2.1.1]hexanyl. In someembodiments,absent. In some embodiments, W-W1-W2iswherein the X-W-W1is X-N(H)-C(O)-W1. In some embodiments, W1is imidazolinyl. In some embodiments, W1is pyrazolinyl.

[0095] In some embodiments,*S(O)2-N(H)- or -*S(O)2-C(H)2- or -*N(R4)-C(O)NH-, wherein the represents the point of attachment to W1. In some embodiments, W2is -*NH-C(O)NH-. In some embodiments, W2is -*O-C(O)-NH-. In some embodiments, W2is -*C(O)-O-. In some embodiments, W2is -*S(O)2-. In some embodiments, W2is - *S(O)2-N(H)-. In some embodiments, W2is -*S(O)2-C(H)2-. In some embodiments, W2is -*N(R4)-C(O)NH-. The in the W2group represents the point of attachment to W1.

[0096] In some embodiments, W is -N(H)-C(O)-, wherein the X-W-W1is X-N(H)-C(O)-W1.

[0097] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

[0098] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

[0099] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

[0100] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

[0101] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

[0102] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

[0103] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is astereocenter in an R configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

[0104] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

[0105] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

[0106] In some embodiments, W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

[0107] In some embodiments, W1is -CH(Y)- and the carbon bonded to (Y) is a stereocenter in an S configuration.

[0108] In some embodiments, W1is -CH(Y)- and the carbon bonded to (Y) is a stereocenter in an R configuration.

[0109] In some embodiments,absent, and the C1carbon is a stereocenter in an R configuration.

[0110] In some embodiments,the C1carbon is a stereocenter in an S configuration.

[0111] In some embodiments, when an R3carbon that is bonded to the phenyl ring is a stereocenter the R3stereocenter carbon is in an R configuration.

[0112] In some embodiments, when an R3carbon that is bonded to the phenyl ring is a stereocenter the R3stereocenter carbon is in an S configuration.

[0113] In some embodiments, A is (Co-C4)alkyl-C(0)OR2;R2is H or (Ci-Ce)alkyl; W3is phenyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy; W4is pyridinyl optionally mono- or di-substituted independentlywith halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;absent; W2is -*C(O)NH-, wherein the represents the point of attachment to W1; Z is phenyl or pyridinyl; R3is (Ci-Ce)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl or (C3-C7)cycloalkyl; and n is 1 or 2.In further embodiments,the C1carbon is a stereocenter in an R configuration. In further embodiments, W3is phenyl optionally mono-substituted independently with halo or (Ci-C4)alkyl; W4is pyridinyl optionally mono-substituted independently with halo or (Ci-C4)alkyl; Z is phenyl or pyridinyl; R3is (Ci-Ce)alkyl, halo or mono-, di- or tri-halo(Ci-C4)alkyl; and n is 1 or 2.

[0114] In some embodiments, A is (Co-C4)alkyl-C(0)OR2; R2is H or (Ci-Ce)alkyl; W3is phenyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy; W4is pyridinyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;absent; W2is -*C(O)NH-, wherein the represents the point of attachment to W1; Z is phenyl fused to a 5 to 7 memberedheterocycloalkyl; R3is (Ci-Ce)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl or (C3-C7)cycloalkyl; and n is 1 or 2. In further embodiments, W2is bonded to the Z phenyl.

[0115] In some embodiments, A is (Co-C4)alkyl-C(0)OR2; R2is H or (Ci-Ce)alkyl;W3is pyridyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy; W4is phenyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkylor (Ci-C4)alkoxy;absent; W2is -*C(O)NH-, wherein the represents the point of attachment to W1; Z is phenyl or pyridinyl; R3is (Ci-Ce)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl or (C3-C7)cycloalkyl; and n is 1 or 2.

[0116] In some embodiments, A is -C(O)OR2,or absent; R2is H; W3is phenyl, pyridinyl or 1H-[l,2,3]triazolo[4,5-Zdpyridin-5-yl optionally mono- or di-substituted independently with (Ci-C3)alkyl or halo; W4is phenyl or pyridinyl optionally mono- or di-substituted independently with (Ci-C4)alkyl or halo; W-W1-W2iswherein W1is optionally mono- or di-substituted with methyl; and W is absent; W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl, pyridinylhalo; and n is 1 or 2. In a further embodiment A is -C(O)OR2; R2is H; W3is phenyl or pyridinyl optionally mono- or disubstituted independently with (Ci-C3)alkyl, fluoro or chloro; W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro;wherein W1is optionally mono- or di-substituted with methyl; and W is absent; W2is -*C(O)NH-, wherein the represents the pointof attachment to W1; Z is phenyl,alkyl, fluoro or chloro; andn is 1 or 2. In alternative further embodiment, A is absent; W3is l / / -[l,2,3]triazolo[4,5- / ?] py ridi n-5-y 1; W4is phenyl or pyridinyl optionally mono- or di-substituted independently withfluoro or chloro;wherein W1is optionally mono- or di-substituted with methyl; and W is absent; W2is -*C(O)NH-, wherein the1 represents the point of attachment to W, Z is phenyl,C4)alkyl, fluoro or chloro; and n is 1 or 2.

[0117] In some embodiments, A is -C(O)OR2,or absent; R2is H; W3is phenyl, pyridinyl or 1H-[l,2,3]triazolo[4,5-Zdpyridin-5-yl optionally mono- or di-substituted independently with (Ci-C3)alkyl or halo; W4is phenyl or pyridinyl optionally mono- or di-substituted independently with(Ci-C4)alkyl or halo;absent or - *NHC(O)-, wherein the represents the point of attachment to X; W1is optionally mono- or di-substituted with methyl; W2is -*C(O)NH-, wherein the represents the point of attachmentto W1; Z is phenyl, pyridinyl,halo; and n is 1 or 2. In a further embodiment, A is C(O)OR2; R2is H; W3is phenyl or pyridinyl optionally mono- or disubstituted independently with (Ci-C3)alkyl, fluoro or chloro; W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro; W-W1-W2isabsent; W1is optionally mono- or di-substituted with methyl; W2is -*C(O)NH-, wherein the represents the point of attachment toW1; Z is phenyl,alkyl, fluoro or chloro; and n is 1 or 2. Inalternative further embodiment, A is C(O)OR2; R2is H; W3is phenyl or pyridinyl optionally mono- or di-substituted independently with (Ci-C3)alkyl, fluoro or chloro; W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro; W-W1-W2iswherein the represents the point of attachment to X; W1is optionally mono- or di-substituted with methyl; W2is -*C(O)NH-, wherein the represents the point of attachment to W1; Z is phenyl,alkyl, fluoro or chloro; and n is 1 or 2.

[0118] In a further alternative embodiment, A is absent; W3isl / / -[l,2,3]triazolo[4,5-&]pyridin-5-yl; W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro orchloro;absent;W1is optionally mono- or di-substituted with methyl; W2is -*C(O)NH-, wherein therepresents the point of attachment to W1; Z is phenyl,alkyl, fluoro or chloro; and n is 1 or 2.

[0119] In a further alternative embodiment, A is absent W3isl / / -[l,2,3]triazolo[4,5-&]pyridin-5-yl; W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro orchloro;wherein the represents the point of attachment to X; W1is optionally mono- or di-substituted withmethyl; W2is -*C(O)NH-, wherein the represents the point of attachment to W1; Z is phenyl,alkyl, fluoro or chloro; and n is 1 or 2.

[0120] In some embodiments, the compound of Formula (I) is a compound as recited in the Examples and Tables herein, or racemic mixtures thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound disclosed herein:

[0121] Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the examples below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. In particular, it is noted that the compounds prepared according to these Examples may be modified further to provide new Examples within the scope of this invention. In addition, it will be evident from the detailed descriptions given in the Experimental section that the modes of preparation employed extend further than the procedures described herein. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2005, and “March’s Advanced Organic Chemistry: Reactions Mechanisms and Structure”, 8thEd., Ed.: Smith, M. B., John Wiley & Sons, New York: 2019, the entire contents of which are hereby incorporated by reference.

[0122] The starting materials are generally available from commercial sources such as Merck Sigma- Aldrich Inc. and Enamine Ltd. Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser 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 Supplements (also available via the Beilstein online database).

[0123] As an initial note, in the preparation of compounds of the present invention, it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in intermediates). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparative methods and can be readily determined by one of ordinary skill in the art. The use of such protection / deprotection methods is also withinthe ordinary skill 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 and Greene’s Protective Groups inorganic Synthesis, John Wiley & Sons, New York 2006.

[0124] For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the Formula I compound.

[0125] General Method I

[0126] General Method I describes a method for the formation of urea derivatives represented by structural formula 1-2. In the scheme, A, W, W1, X, Z, and R3are each as defined herein.Although W1is shown as a pyrrolidine structure, one skilled in the art will appreciate that this motif may be replaced with other nitrogenous W1structures to afford the corresponding products.

[0127] In Step 1, an amine represented by NH2ZR3is treated with a one-carbon dielectrophile equivalent such as phosgene, triphosgene, or carbonyldiimidazole (CDI), in a polar aprotic solvent such as DCM or DMF, in the presence of an organic base such as N, N-diisopropylethylamine (DIEA) or 4-dimethylaminopyridine (DMAP). The reaction may be conducted at a temperature of -10 °C-60 °C, typically at 0 °C-room temperature, and preferably at 0 °C for reactions mediated by phosgene or triphosgene, and at room temperature for those utilizing CDI. After about 1-2 hours at the preferred temperature, the amine 1-1 is introduced, and the mixture is stirred for up to 24 hours at a temperature of 0-70 °C. Preferably, the reaction is conducted at room temperature for about 2 hours. The product of the reaction is a urea derivative, 1-2. In Step 2, for examples where A represents a carboxylic ester functionality such as CH2CO2Me or CO2Me, a saponification may be conducted to produce the corresponding carboxylic acid. This transformation is well known in the art and may be performed with a hydroxide base such as lithium or sodium hydroxide in a polar protic solvent system such as water / THF or water / methanol / THF, within a temperature range of 0 °C- 100 °C, typically within a range of 0-60 °C, and preferably at room temperature. When conducted at room temperature,the reaction is generally complete within 2-4 hours and affords a carboxylic acid. Alternatively, and especially when A represents a tert-butyl ester, the ester may be cleaved under acidic conditions which are well known in the art. An example set of conditions for acid catalyzed hydrolysis of a methyl or ethyl ester include treatment with 6 M HC1 at 60 °C for 4-24 hours. An example set of conditions for tert-butyl ester cleavage include treatment with 1-4 M HC1 in dioxane, at temperatures ranging from 0 °C-60 °C, preferably around room temperature, for 1-18 hours.

[0128] General Method II

[0129] General Method II refers to a synthetic sequence for the preparation of biaryl carboxylic acid derivatives represented by structural formulas II-4. In the scheme, Q and Q' are I, Br, Cl, B(OH)2, or B(OR)2, where R is alkyl, with the proviso that when Q is a halide, Q' must be a boronate, and vice-versa; the remaining variables are as defined elsewhere herein. Although the accompanying scheme depicts a pyrrolidine structure, one skilled in the art will appreciate that the structure may instead be replaced with other nitrogenous W1structures to afford the corresponding products. It will further be appreciated that the sequence order of reactions may be rearranged to-afford the same result. For example, one may conduct the sequence as illustrated, or one may first perform a Suzuki coupling on II-l or an A-protected variant, followed by subsequent A-deprotection and reaction with R3ZNCO to afford II-4. In Step 1, an amine represented by II-l is treated with an isocyanate (R3ZNCO), in a polar aprotic solvent such as DCM or 1,4-dioxane, in the presence of an organic base such as triethylamine (TEA) or DIEA, to afford the urea II-2. This reaction typically proceeds within 1-2 hours at room temperature, although certain substrates such as weakly nucleophilic amines may require extended reaction times of up to 24 hours and / or elevated temperatures of up to around 80 °C. In Step 2, a Suzuki-Miyaura cross coupling reaction is performed between structures II-2 and II- 3 to afford II-4.This type of reaction is well known to those skilled in the art and can be conducted under a variety of conditions. Example conditions include mediation by the catalyst Pd(dppf)Cl2, in the presence of K3PO4, in a solvent system of THF and water or 1,4-dioxane and water, at a temperature of 25 °C-120 °C, preferably 60-110 °C, and more preferably at 60-90 °C (Suzuki review: Kader, D. A. et al. J. Organomet. Chem. 2025, 1030, 123569). When conducted at the preferred temperature, the Suzuki reaction is typically complete within 1-8 hours and mayalternatively be run overnight. In Step 3, for examples of II-4 where A represents carboxylic ester functionality such as CH2CO2R or CO2R, the ester may be cleaved according to methods described previously to produce the corresponding carboxylic acid.

[0130] General Method III

[0131] General Method III refers to a synthetic sequence for the preparation of compounds of structural formula III-5. In the scheme, P is a urethane protecting group such as Boc; P' is H or P, and the remaining variables are as defined elsewhere herein. It will be appreciated by one skilled in the art that the piperidine ring in the scheme may be replaced with other nitrogenous W1structures to afford the corresponding products. It will further be appreciated that the sequence of reactions need not necessarily be run in the order depicted. In Step 1, A- protected amino acid derivative III-l undergoes amidation with amine III-2 (prepared as described herein). There are many ways to conduct amidation reactions with amino acid derivatives, including through treatment with a coupling reagent such as HATU, or with a carbodiimide such as EDCI, or with a uranium salt such as TCFH, or via an acyl chloride or active ester, in apolar aprotic solvent such as DCM, THF, acetonitrile, or DMF, in the presence of an organic base such as TEA, DIEA, NMI, or DBU, with or without racemization suppressing additives such as HOAt or HOBt (Amidation reviews: Valeur, E and Bradley, M. Chem. Soc. Rev. 2009, 38, 606; Humphrey, J. M. and Chamberlin, A. R. Chem. Rev. 1997, 97, 2243). Amidation may be conducted at temperatures ranging from -10 °C to about 80 °C, and is typically begun at 0 °C proceeded by warming to room temperature or more for 1-24 hours. The product of the reaction is represented by III-3. In Step 2, Cleavage of the protecting group P’ from HI-3 according to well-known procedures affords the amine III-4. For example, if P’ is Boc, the cleavage is commonly achieved with a strong acid such as HC1 or TFA in any number of suitable polar aprotic solvents such as DCM, 1,4-dioxane, ethyl acetate, or HFIP at ambient temperature. When P is Cbz, the group may be cleaved by hydrogenation or by strongly acidic conditions. (Greene’s Protective Groups in Organic Synthesis, 5th Edition', Wiley, 2014.) In Step 3, the amine III-4 is treated with a commercial isocyanate (R3ZNCO) in a polar aprotic solvent such as DCM or acetonitrile, in the presence of an organic base such as TEA or DIEA, to afford III-5. The typical reaction is begun at 0 °C and is warmed to room temperature for about 2 hours, with sluggish substrates such as sterically hindered or electron deficient amines potentially requiring higher temperatures and / orextended reaction times. In cases where the requisite isocyanate is not commercially available, it may be prepared in situ via the well-known Curtius rearrangement. In this reaction, a carboxylic acid (R3ZCO2H) undergoes reaction with diphenylphosphoryl azide (DPPA) in an inert solvent such as toluene in the presence of an organic base such as TEA to form an isocyanate in situ. The Curtius reaction can be run between room temperature and 160 °C, preferably between 60 °C- 100 °C, and typically around 80 °C, for a period of 1-24 hours, typically around 2 h. Addition of amine III-4 to the in situ-formed isocyanate affords III-5. In Step 4, for examples of III-5 where A represents carboxylic ester functionality such as CH2CO2R or CO2R, the ester may be cleaved according to methods described herein to produce the corresponding carboxylic acid.

[0132] General Method IV

[0133] General Method IV describes a synthetic sequence for the preparation of compounds represented by structural formula IV-5. In the scheme, P = H or Boc; R = H or tert- Butyl; and all other variables are as described herein. It will be appreciated by one skilled in the art that the azepine ring depicted in the scheme may be replaced other nitrogenous W1structures to afford the corresponding products, and that the sequence of reactions need not necessarily be run in the order depicted. In Step 1, V-Boc derivative IV-1, undergoes an amidation reaction (previously described) with amine IV-2 (prepared as described herein), to afford IV-3. In Step 2, the V-Boc and tert-butyl ester groups are cleaved under strongly acidic conditions as described previously to afford IV-4. In Step 3, IV-4 is treated with an isocyanate, R3ZNCO as described herein to afford the compound IV-5.

[0134] General Method V-V-5 (P' = P)V-6 (P' = H)

[0135] General Method V describes a synthetic sequence for the preparation of compounds represented by structural formula V-7. In the scheme, Br may be Br, Cl, or I; Q is CO2H, CO2Pth, or B(OH)2; R is H or alkyl; P is a urethane protecting group such as Boc; P' is P or H; and all other variables are as defined herein. It will be appreciated by one skilled in the art that thepyrrolidine ring depicted in the scheme may be replaced with other nitrogenous W1structures to afford the corresponding products. Likewise, the Boc group in the scheme may be replaced with other urethane protecting groups and paired with suitable deprotection protocols well known in the art to similar effect. It will be further appreciated that the sequence of transformations need not necessarily be run in the same order as depicted in the scheme. In Step 1, a Suzuki-Miyaura cross coupling reaction (previously described) is performed between two aryl components, represented by a halo species (V-l) and a boronic acid or boronic ester species (V-2), to afford the biaryl species V-3. It will be appreciated by one skilled in the art that the coupling species may be reversed such that V-l is the boronate species, and V-2 is the halide species. In Step 2, V-3 is subjected to a photocatalytic decarboxylative coupling reaction with an V-protected amino acid derivative represented by V-4 (Q = CO2H or B(0H)2). This reaction is accomplished with dual-catalytic system utilizing NiBr2*Bipy and Ir[dF(CF3)ppy]2(dtbpy))PF6in the presence of an inorganic base such as cesium carbonate in a polar aprotic solvent, preferably DMF, under blue light irradiation at a wavelength of around 450 nM, preferably at 450 nM. The reaction may be conducted from 0 °C-80 °C, preferably room temperature, for a period of up to 24 hours. The product of the reaction is represented by V-5. Alternatively, V-3 may be subjected to a photocatalytic decarboxylative coupling reaction with an V-protected amino acid derivative represented by V-4 (Q = CO2Pth). This reaction is mediated by the photocatalyst 1,3-Dicyano-2,4,5,6-tetrakis(diphenylamino)-benzene (4-DPAIPN) in a polar aprotic solvent such as acetonitrile in the presence of TFA at a temperature of -10 °C-60 °C, preferably 0 °C to room temperature, under blue light irradiation of around 405 nM, preferably at 405 nM, for 1-24 hours, preferrably 12-18 hours, to afford V-5. In Step 3, the urethane protecting group is cleaved using any of a variety of conditions known to those skilled in the art. For example, the V-Boc group can be cleaved under acidic conditions as described herein. The product of Step 3 is an amine, V-6. In Step 4, V-6 is reacted with an isocyanate, R3ZNCO, as described previously to afford V-7.In Step 5, If A includes ester functionality, the ester may be hydrolyzed under acidic conditions or saponified under basic conditions to afford the corresponding carboxylic acid. Each set of conditions is well known to those skilled in the art and was described previously.

[0136] General Method VI

[0137] General Method VI refers to a synthetic sequence for the preparation of compounds represented by structural formula VI-5. In the scheme, A, W1, W3, W4, R3and Z are as defined elsewhere herein. Although the scheme depicts W1as a cyclopentyl ring, one skilled in the art will appreciate that this ring may be replaced with alternative W1structures to afford the corresponding products. It will be further appreciated that the sequence of transformations need not necessarily be run in the same order as depicted in the scheme. In Step 1, an amidation reaction is conducted between a dicarboxylic acid, represented by VI-1, and an amino component (VI-2). Amidation of carboxylic acids is well known to those skilled in the art and can be accomplished by a variety of methods such as through mediation by acid chlorides, or active esters, or through treatment with propanephosphonic acid cyclic anhydride (T3P). For example, VI-1 may be combined with VI-2 and T3P in an aprotic solvent such as EtOAc, DMF, or pyridine, in the presence of an organic base such as pyridine or triethylamine. The reaction may be run from -10 °C to 100 °C, typically from 0 °C to 70 °C. Preferably, the reaction mixture is cooled to 0 °C for the addition of the T3P, and is then warmed to room temperature where it is held for up to 24 hours, typically around 2 hours. The product of the reaction is an amide, represented by VI-3. In Step 2, a second T3P coupling is performed between VI-3 and amine component VI-4 to afford the bis-amide structure VI-5. In Step 3, for examples where A possesses ester functionality, the ester group may be hydrolyzed in the presence of strong acid or saponified with a hydroxide base according to methods generally known in the art, and as described herein. For example, if the ester is is tert-butyl, one would select acidic conditions. If R is methyl or ethyl, one may select either acidic or basic conditions for the transformation.

[0138] General Method VIIVH Step 1 VII-3 Step 2 VII-4

[0139] General Method VII describes a synthetic sequence for the preparation of of reaction intermediates represented by structural formula VII-4. In the scheme, P is H or a urethane protecting group such as Boc; R is H or alkyl; Br may be Br, Cl, or I; and W3, W4, and A as as described herein. One skilled in the art will recognize that the sequence of steps may be ordered differently than that presented in the scheme. In Step 1, a boronic acid or boronic ester derivative represented by VII-1 is subjected to a Suzuki cross-coupling reaction (described previously) with a halo component, VII-2, to afford the species VII-3 or VII-4. One skilled in the art will recognize that the cross -coupling partners can generally be reversed in this reaction such that VII-1 is the halo component, and VII-2 is the boronate component. In Step 2, if VII-3 possessesa urethane protecting group, the group may be removed using conditions well known in the art. For example, if P is Boc, it may be cleaved under acidic conditions as described herein to afford VII-4.

[0140] General Method VIIIwj AR' H2N W3R3ZNCO- ►HO CO2H „aStep 1Step 2VIII-1

[0141] General Method VIII refers to a synthetic sequence for the preparation of compounds represented by structural formula VIII-3. In the Scheme, R' represents alkyl group configurations defined herein under W1, and the remaining variables are also as defined herein. It will be appreciated by one skilled in the art that the sequence of transformations need not necessarily be run in the same order as depicted in the scheme. In Step 1, a lactic acid derivative represented by VIII-1 undergoes amidation (described herein) with the amine NH2W4W3A (prepared as described herein) to afford the amide product VIII-2. In Step 2, a solution of VIII-2 and an organic amine such as TEA in a polar aprotic solvent such ac DCM is treated dropwise with an isocyanate (R3ZNCO). The reaction can be run at a temperature of 0 °C to 80 °C, typically 0 °C-60 °C. Preferred conditions include addition of the isocyanate at 0 °C followed by warming to room temperature for 2-8 hours.

[0142] General Method IXIX-7 (P' = H)

[0143] General Method IX refers to a synthetic sequence for the preparation of compounds represented by structural formula IX-8. In the scheme, Br may be Br, Cl, or I; P is a urethane protecting group such as Boc; P' is H or P; R is H or alkyl; and the remaining variables are as defined elsewhere herein. In Step 1, an amidation reaction (described previously) is conducted between IX-1 and IX-2 to afford IX-3. In step 2, an intramolecular Mitsunobu dehydration isperformed on IX-3 to afford IX-4. In this reaction, a mixture of IX-3 and triphenylphosphine in a polar aprotic solvent such as THF is treated with a dialkyl azodicarboxylate such as DIAD or DEAD. This reaction can be run between -10 °C and 80 °C. Typically, the DIAD or DEAD is introduced at 0 °C, and the mixture is then warmed to room temperature for 2-24 hours, preferably from 2-6 h. In Step 3, a Suzuki-Miyaura cross coupling reaction (previously described) is conducted between IX-4 and IX-5 to afford IX-6. One skilled in the art will recognize that the Suzuki coupling partners can generally be reversed, such that IX-4 may represent the boronate and IX-5 may represent the halide. In Step 4, the urethane protecting group is removed using well-known methods to afford IX-7. For example, if P’ is Boc, it may be removed under acidic conditions as described previously. In Step 4, reaction with a commercial isocyanate or one prepared in situ via the Curtius rearrangement as previously described affords the urea derivative IX-8. For examples where A is a carboxylic ester, the ester may be saponified or hydrolyzed via methods described herein to afford the corresponding carboxylic acid.Pharmaceutical Dosages, Compositions and Formulations

[0144] The compounds or pharmaceutical compositions described herein that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, the condition of the individual patient, the site of delivery of the compound or pharmaceutical composition, the method of administration and other factors known to practitioners. The compounds or pharmaceutical compositions can be prepared according to the description of preparation described herein.

[0145] A therapeutically effective amount can be the amount of a compound or pharmaceutical composition or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered. A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment and can be ascertainable by one skilled in the art using known techniques.

[0146] One of ordinary skill in the art would understand that the amount, duration, and frequency of administration of a pharmaceutical composition or compound described herein to a subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the patient, the grade or level of a specific disease or condition of the patient, the additional therapeutics the subject is being or has been administered, and the like.

[0147] Pharmaceutical compositions or compounds of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations. The one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks, or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days or less than 1 day after the first administration. The one or more administrations can occur more than once per day, more than once per week, or more than once per month. The compounds or pharmaceutical compositions can be administered to the subject in need thereof in cycles of 21 days, 14 days, 10 days, 7 days, 4 days, or daily over a period of one to seven days.

[0148] In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg / kg patient body weight per day, which can be administered in single or multiple doses. In one embodiment, the dosage level will be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, about 0.1 to about 250 mg / kg per day, about 0.1 to about 50 mg / kg per day or about 0.5 to about 100 mg / kg per day. In addition, the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.

[0149] These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian Subjects to be treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention is dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding Such an active compound for the treatment of sensitivity in individuals.

[0150] Thus, one of skill in the art would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.

[0151] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The compounds of the invention may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Parenteral administration and administered parenterally as used herein includes modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0152] Also provided, in some embodiments, is a pharmaceutical composition comprising the compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0153] A pharmaceutically acceptable excipient includes pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. Each excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable excipients include: (1) monosaccharides, disaccharides, and othercarbohydrates including glucose, sucrose; lactose; mannose, trehalose, sorbitol or dextrins and (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide, aluminum hydroxide phosphate, citrate, and other organic acids; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as semm albumin; hydrophilic polymers; amino acids; chelating agents such as EDTA; salt-forming counter-ions such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycol and other non-toxic compatible substances employed in pharmaceutical formulations.

[0154] Examples of excipients and their use may be found in Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0155] Methods for formulation of pharmaceutical compositions can include formulating any of the compounds described herein with one or more inert, pharmaceutically acceptable excipients (including carriers) to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. This formulation can be an aqueous solution. Alternatively, the compositions described herein can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions.

[0156] The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0157] The pharmaceutical compositions described herein can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution, or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion.

[0158] For parenteral administration, the compounds can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently nontoxic, and non-therapeutic. A vehicle can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0159] The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. Thus, in some preferred embodiments, the active ingredient(s) is administered in a pharmaceutical composition which is an immediate release oral dosage form, preferably but not necessarily including an enteric coating. In some preferred embodiments, the active ingredients(s) are administered in a pharmaceutical composition which is an extended-release oral dosage form, preferably but not necessarily including an enteric coating. In further preferred embodiments, the active ingredients are administered in a pharmaceutical composition which contains both an immediate release dose and an extended-release dose or pulsed release dose of the first agent preferably but not necessarily also including an enteric coating. Such dual release dosage forms achieve release of an initial dose of active ingredient, followed late in time by another pulsed release, or by a sustained release dose. Methodologies for preparing such dual release dosage forms are well known in the art.

[0160] In some embodiments, the active ingredients are formulated into a controlled release matrix tablet, which contains one or more polymeric matrix materials that promote the sustained, delayed or pulsed release profile. Non-limiting examples of such polymeric matrix materials include cellulosic materials as described above, and carbomers, for example those sold by Lubrizol Corporation under the name Carbopol®, for example Carbopol® 71G NF, Carbopol® 97 IP NF and Carbopol® 974P NF polymers.

[0161] Some preferred examples of extended-release compositions suitable for use in the methods and compositions of the invention include, for example and not limitation, extended-release compositions found in nifedipine formulations such as Adalat CC®, Procardia® XL, Afeditab® CR and Nifedical® XL; and in diltiazem formulations such as Cardizem® CD, Cardizem® LA, Cardizem® SR, Cartia® XT and Dilacor® XR.Combinations

[0162] Compounds of the present disclosure may be used in methods of treating in combination with one or more other combination agents (e.g., one, two, or three other drugs) that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful. In some embodiments, the combination of the drugs together is safer or more effective than either drug alone. In some embodiments, the compound disclosed herein and the one or more combination agents have complementary activities that do not adversely affect each other. Such molecules can be present in combination in amounts that are effective for the purpose intended. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, in some embodiments, the agents are administered together in a single pharmaceutical composition in unit dosage form.

[0163] Examples of combination agents are GLP-1 drugs. Any GLP-1 inhibitor can be used as the second agent in combination with a compound of the present invention. A "GLP-1 receptor agonist" refers to compounds having GLP-1 receptor activity. Such exemplary compounds include exendins, exendin analogs, exendin agonists, GLP-1 (7-37), GLP-1 (7-37) analogs, GLP-1(7-37) agonists, and the like. The GLP-1 receptor agonist compounds may optionally be amidated.

[0164] The term "exendin" includes naturally occurring (or synthetic versions of naturally occurring) exendin peptides that are found in the salivary secretions of the Gila monster.Exendins of particular interest include exendin-3 and exendin-4. The exendins, exendin analogs, and exendin. agonists for use in the methods described herein may optionally be amidated, and may also be in an acid form, pharmaceutically acceptable salt form, or any other physiologically active form of the molecule.

[0165] The combination of a GLP-1 and a GIPR antagonist may achieve the effect of simultaneously improving insulin resistance and reducing excessive fat accumulation (obesity), while lowering blood glucose, and also interfering with lipid metabolism. In this regard, theGLP-1 part may be used to improve glucose tolerance, reduce appetite, lower blood glucose and reduce body weight; whereas the GIPR antagonist compound may be used to reduce the further accumulation of fat, impact reduction in fat mass vs. lean body mass, and improve liver function. The fat reduction effect of the GIPR antagonist and the weight loss effect of the GLP-1 may be used synergistically to treat the non-alcoholic fatty liver disease / non-alcoholic steatohepatitis. This disclosure provides a drug that will benefit patients who have one or more diseases of nonalcoholic fatty liver disease / nonalcoholic steatohepatitis, type 2 diabetes and obesity.

[0166] In one embodiment, the GLP-1 receptor agonist is selected from the group consisting of exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, efpeglenatide, taspoglutide. danuglipron, orforglipron, lotiglipron, PF-06954522, HM15211, L Y3298176, Medi-0382, NN-9924, TTP-054, TTP-273, CT-996, ECC5004, XW004, XW014, MDR-001, ZT002, KN-056, GL0034, GSBR-1290, noiiglutide, RGT-075, TTP-273, HRS-7535, GMA-105, TG103, GZR-18, GX-G6, ecnoglutide, PB-119, QLG2065, beinaglutide, those described in WG2018109607, those described in WO2019239319 (PCT / IB 2019 / 054867 filed June 11, 2019), and those described in WO2019239371 (PCT / IB2019 / 054961 filed June 13, 2019). In some embodiments, liraglutide is a preferred GLP-1 receptor agonist. Each of the molecules recited above, while depicted in a list, are intended to be recited as individual molecules useful in a combination with the compounds of this invention.

[0167] In one embodiment, the molar ratio of a GLP-1 receptor agonist to a GIPR antagonist is from about 1: 1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1: 10, 1: 1 to 1:5, and 1: 1. In one embodiment, the molar ratio of a GIPR antagonist to a GLP-1 receptor agonist is from about 1:1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, and 1:1 to 1:5.

[0168] Also examples of combination agents are GIPR agonists, which can act as functional GIPR antagonists. Combination therapy with GIPR agonists and antagonists can contribute to additional efficacy in GIPR inhibition. Exemplary GIPR agonist molecules are described in WO2018181864, WO2014192284 and WG2022076503.

[0169] In one embodiment, provided herein is a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising:a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound;a second compound, said second compound being a GLP-1 inhibitor, a GCGR agonist or a GIPR agonist; and a pharmaceutically acceptable excipient.

[0170] In one embodiment, provided herein is a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising:a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound;a second compound, said second compound being a GLP-1 inhibitor; anda third compound, said third compound being a GCGR agonist or a GIPR agonist; anda pharmaceutically acceptable excipient.

[0171] In one embodiment, the therapeutically effective amounts of the GLP-1 receptor agonist and the GIPR antagonist are administered to the subject simultaneously.

[0172] In one embodiment, the therapeutically effective amounts of the GLP-1 receptor agonist and the GIPR antagonist are administered to the subject sequentially.

[0173] Any GCGR agonist can be used as the second agent in combination with a compound of the present invention. The combination of a GCGR agonist and a GIPR antagonist may achieve the effect of simultaneously improving insulin resistance and reducing excessive fat accumulation (obesity), while lowering blood glucose, and also interfering with lipid metabolism. Examples of GCGR agonists include antibodies disclosed in US11,845,802.

[0174] In one embodiment, the molar ratio of a GCGR receptor agonist to a GIPR antagonist is from about 1: 1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1: 10, 1: 1 to 1:5, and 1: 1. In one embodiment, the molar ratio of a GIPR antagonist to a GCGR receptor agonist is from about 1:1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, and 1:1 to 1:5.

[0175] In one embodiment, the therapeutically effective amounts of the GCGR receptor agonist and the GIPR antagonist are administered to the subject simultaneously.

[0176] In one embodiment, the therapeutically effective amounts of the GCGR receptor agonist and the GIPR antagonist are administered to the subject sequentially.

[0177] The addition of a third hormone to incretin-based therapies, glucagon GCGR agonism has been shown to significantly increase energy expenditure. Thus, the GCGR agonist can be used in combination with the GIPR antagonist and the GLP-1 receptor agonist (GIPR / GLP-1R / GCGR triple agents)_in triple therapy. Examples of triple therapy agents include NN9423 (NovoNordisk) and Lilly’s LY3437943. [Expert Opinion on Drug Discovery 2023, VOL. 18, NO. 6, 659-669.

[0178] Due to the compounds of the invention action on metabolic diseases the compounds may also be beneficially used in combination with other agents such as anti-diabetic agents.

[0179] Suitable anti-diabetic agents include insulin, metformin, GLP-1 receptor agonists (described herein above), SGL T2 inhibitors, monoacylglycerol Oacyltransferase inhibitors,phosphodiesterase (PDE)-IO inhibitors, AMPK activators [e.g., ETC-1002 (bempedoic acid)], sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinides, a-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688), an azglucoside hydrolase inhibitor (e.g., acarbose), a-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPARy agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), PPAR a / y agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP- 297, L-796449, LR-90, MK-0767 and SB-219994), protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors [e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S. et al., Drug Discovery Today, 12(9 / 10), 373-381 (2007)], SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (OPP-IV) inhibitors (e.g., those in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, glucokinase activators (GKa) such as those described in WG2010103437, WG2010103438, WG2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g., GSK1362885), VPAC2 receptor agonists, glucagon receptor modulators such as those described in Demong, D. E. et al., Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described in WG2010140092, WO2010128425, WG2010128414, WG2010106457, Jones, R. M. et al., Annual Reports in Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J. C., Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high-affinity nicotinic acid receptor (HM74A) activators, and SGL T1 inhibitors, such asGSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611.

[0180] Due to the compounds of the invention action on metabolic diseases the compounds may also be beneficially used in combination with other agents. Other combination agents includeamylin, NPY2 receptor agents, cannabinoid receptor agents, serotonin receptor agents and MC4R receptor agents which are useful for the treatment of obesity.

[0181] In addition, other agents such as lipid modulating agents (HMG-CoA reductase inhibitors such as atorvastatin, pravastatin, pitavastatin, lovastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin) are useful as combination agents.

[0182] Due to the compounds of the invention action on metabolic diseases the compounds may also be beneficially used in combination with other cardiovascular agents such as antihypertensive agents. Any anti-hypertensive agent can be used as the second agent in such combinations. Such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples include calcium channel blockers (amlodipine besylate), ACE- inhibitors, angiotensin II receptor antagonists, beta-adrenergic receptor blockers, alpha-adrenergic receptor blockers, peripheral vasodilators and diuretics.

[0183] Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active agent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. In some embodiments, combination therapy includes therapies in which the compound of the present disclosure and one or more other drugs are administered separately, and in some cases, the two or more agents are administered on different, overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. In some embodiments, the combination agent is a drug for reduction of symptoms of obesity.

[0184] As the present invention has an aspect that relates to the treatment of the disease / conditions described herein with a combination of active ingredients which may be administered jointly, the invention also relates to combining separate pharmaceutical compositions in a single dosage form, such as (but not limited to) a single tablet or capsule, a bilayer or multilayer tablet or capsule, or through the use of segregated components or compartments within a tablet or capsule.

[0185] Since the present invention has an aspect that relates to the treatment of the disease / conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceuticalcompositions in kit form. The kit comprises two, or more, separate pharmaceutical compositions: a compound of Formula I a prodrug thereof or a salt of such compound or prodrug and a second compound as described above. The kit comprises a means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0186] In some embodiments, provided herein is a kit comprising:a. a first compound, said first compound being a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient in a first unit dosage form;b. a second compound, said second compound being a GLP-1 inhibitor, a GCGR agonist or a GIPR agonist and a pharmaceutically acceptable excipient in a second unit dosage form; andc. means for containing said first and second dosage formswherein the amounts of first and second compounds result in a therapeutic effect.

[0187] In some embodiments, the second compound is a GLP-1 inhibitor.

[0188] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0189] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen on which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday,... etc. SecondWeek, Monday, Tuesday,... etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered microchip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and / or reminds one when the next dose is to be taken.

[0190] The compounds, pharmaceutical compositions, and methods of the present disclosure can be useful for treating a subject such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a nondomesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig, a horse, a goat, a sheep, or a rabbit. In preferred embodiments, compounds, pharmaceutical compositions, and methods of the present disclosure are used for treating a human; male or female.

[0191] The present invention further comprises use of a compound of Formula I for use as a medicament (Such as a unit dosage tablet or unit dosage capsule). In another embodiment, the present invention comprises the use of a compound of Formula I for the manufacture of a medicament (such as a unit dosage tablet or unit dosage capsule) to treat one or more of the conditions discussed herein.

[0192] In practicing the methods described herein, therapeutically effective amounts of the compounds or pharmaceutical compositions described herein can be administered to a subject in need thereof, often for treating and / or preventing a condition or progression thereof. The compounds of this invention and pharmaceutical compositions thereof can affect the physiology of the subject, such as the metabolic system, the immune system, inflammatory response, or other physiologic affect. In addition, the compounds of this invention and pharmaceutical compositions thereof can affect the neuronal (nervous system) based on the incretins role in addictive behavior, Alzheimer’s and Parkinson’s. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.

[0193] The Formula I compounds of this invention, their prodrugs and the salts of such compounds and prodrugs (including combinations thereof) are all adapted to therapeutic use as agents that mediate the GIPR in mammals, particularly humans e.g., males, females. For example, these compounds act as GIPR receptor antagonists and thus are useful for the treatment of the various conditions (e.g., those described herein) in which such action is implicated.

[0194] Given the positive correlation between mediation of the GIPR receptor with the number of physiological effects in tissues - including promotion of fat storage in adipocytes, promotion of pancreatic islet cell function and beta-cell survival, glucose-dependent insulin secretion, and that GIPR is highly expressed in a number of tissues (including the pancreas, gut, adipose tissue, heart, pituitary, adrenal cortex, and brain) (Usdin et al., Endocrinology. 1993, 133:2861-2870), GIPR antagonists are useful for the treatment of glucose metabolism (e.g. Type 2 diabetes, elevated glucose levels, elevated insulin levels, dyslipidemia, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, Type 1 diabetes, obesity and conditions exacerbated by obesity), pancreatitis, cirrhosis and Turner’s & Cushing’s syndrome.

[0195] Preferred disease / conditions include obesity and type II diabetes. An especially preferred disease / condition is obesity.

[0196] Through the compounds of this invention capacity to treat obesity they also have a treatment impact on cardiovascular diseases, including coronary artery disease, myocardial infarction, heart failure, stroke, venous thromboembolic disease, and pulmonary hypertension. Circulation 2021 143:e984-el010.

[0197] Through the compounds of this invention capacity to treat obesity they also have a treatment impact on cancer including post-menopausal breast, colorectal, endometrial, esophageal, pancreatic, renal, liver, stomach, gallbladder, ovarian, thyroid, multiple myeloma, and meningioma. Other cancers associated with obesity include cancers of the mouth, pharynx and larynx, prostate, and male breast, as well as diffuse large B-cell lymphoma. A high risk associated with obesity is shown for three of the most challenging cancers to treat — pancreatic, esophageal, and gallbladder — as well as the two most prevalent malignancies — breast and colorectal cancer. Cancers 2023, 15,485

[0198] Through the compounds of this invention capacity to treat obesity they also have a treatment impact on obstructive sleep apnea, and associated conditions.

[0199] Through the compounds of this invention capacity to treat obesity they also have a treatment impact on osteoarthritis and associated disease / conditions.

[0200] Further the compounds of this invention can be used to treat any GIPR-related condition, disease, or disorder including the following: diabetes [e.g. Type 1 diabetes mellitus (T1 D), Type2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, depression, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addition to alcohol, nicotine, and / or drug).EXAMPLES

[0201] As can be appreciated by the skilled artisan, the representative examples (below) are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described in the examples may be performed in an alternate sequence or order to give the desired compounds. The disclosure further encompasses “intermediate” compounds, including structures produced from the synthetic procedures described, whether isolated or generated in-situ and not isolated, prior to obtaining the finally desired compound. These intermediates are included in the scope of this disclosure. Exemplary embodiments of such intermediate compounds are set forth in the Examples below.

[0202] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). The starting materials and the intermediates, and the final products of a reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0203] The chemical names may be generated using the ChemDraw Professional, for example ChemDraw Professional Version 22.2.0.3348, 23.0.1.11 or 23.1.1.3. Other software naming programs such as Marvin JS 21.19.0 software naming programs may also be used.

[0204] The following abbreviations may be used in throughout the text: AIBN = azobisisobutyronitrile, BINAP = 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, Boc = tertbutyloxycarbonyl, BSA = Bovine Serum Albumin, bpy or bipy = bipyridine, BTMG = 2-tert-Butyl-l,l,3,3-tetramethylguanidine, cAMP = Cyclic adenosine monophosphate, Cbz = (benzyloxycarbonyl, CDI = carbonyldiimidazole, DMA = Dimethylacetamide, DMSO = dimethyl sulfoxide, ex = excitation; em = emission, LCMS = liquid chromatography-mass spectrometry, ESI = Electrospray Ionization, M+H = a unit higher than the monoisotopic mass of the uncharged molecule, HPLC = High pressure liquid chromatography, Prep-HPLC = preparatory scale HPLC, AcOH = acetic acid, ACN or MeCN = acetonitrile, PE = petroleumether, EA or EtOAc = ethyl acetate, EDCI = l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dtbbpy = 4,4'-Di-tert-butyl-2,2'-dipyridyl, DBU = l,8-diazabicyclo[5.4.0]undec-7-ene, DEA = diethanolamine, DEAD = diethylazodicarboxylate, DIAD = Diisopropyl azodicarboxylate, DIEA = N, N-diisopropylethylamine, DMAP = 4-Dimethylaminopyridine, DME = dimethyl ether, DMSO = dimethyl sulfoxide, DMF = N, N-dimethylacetamide, DCM = dichloromethane, DPPA = diphenylphosphoryl azide, dppf = l,l'-Bis(diphenylphosphino)ferrocene, EtOH = ethanol, FA = formic acid, MeOH = methanol, MtBE / MTBE = methyl tert-butyl ether, TEA or EtsN = triethylamine, TFA = trifluoroacetic acid, GOI = genes of interest, HATU = hexafluorophosphate azabenzotriazole tetramethyl uronium, HFIP = hexafluoroisopropanol, HMDS = hexamethyldisilazane, HC1 = hydrochloric acid, HBSS = Hanks’ Balanced Salt Solution, HEPES = 4- (2-hy droxy ethyl)- 1 -piperazineethane sulfonic acid, HO At = l-hydroxy-7-azabenzotriazole, HOBt = 1 -hydroxybenzotriazole, SFC = Supercritical fluid chromatography, TCFH = N, N, N’, N’ -tetramethylchloroformamidinium hexafluorophosphate, THF = tetrahydrofuran, TLC = thin layer chromatography, TMG = tetramethylguanidine, T3P = propanephosphonic acid cyclic anhydride, Oac = acetate, m-CPBA = meta-chloroperoxybenzoic acid, NiBr2*Bipy = (2, 2 ’-bipyridine) nickel (II) dibromide, NMM = N-methylmorpholine, NMI = 1 -Methylimidazole, POCE = Phosphoryl chloride, py = pyridine, Pd / C = palladium on carbon, HTRF - Homogeneous Time-Resolved Fluorescence, IB MX = Isobutylmethylxanthine, RT = retention time, h = hour, hrs = hours, aq. = aqueous, min. = minute, sat. = saturated, equiv = equivalent, e.e. = enantiomeric excess, UV = ultraviolet, 4-CZIPN = tetrakis(9H-carbazol-9-yl)benzene-l,4-dicarbonitrile, 4-DPAIPN = l,3-Dicyano-2,4,5,6-tetrakis(diphenylamino)-benzene, XPhos Pd G3 = 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate, Ir[dF(CF3)ppy]2(dtbpy))PF6 = ([4,4'-BA(l,l-dimethylethyl)-2,2'-bipyridine-Al, Al [3,5-difhioro-2-[5-(trifhioromethyl)-2-pyridinyl-A]phenyl-C]Iridium(III) hexafluorophosphate); GIP = Gastric inhibitory polypeptide or glucosedependent insulinotropic polypeptide; GIPR = Gastric inhibitory polypeptide receptor; GIPR = Gastric inhibitory polypeptide receptor and / or glucose-dependent insulinotropic polypeptide receptor.Compound Examples

[0205] The following compounds are provided as examples of this invention.Synthesis and Characterization Examples

[0206] For certain compounds disclosed herein the absolute stereochemistry has not been independently confirmed. Thus, in some instances, the absolute stereo configurations of one or more chiral centers are arbitrarily assigned (e.g., stereochemistry of one chiral center is knownand remaining chiral centers arbitrarily assigned). Accordingly, the enantiomers or diastereomers are identified by their respective properties, for example, retention times on a prep chiral HPLC, chiral SFC, NMR shift or optical rotation or its biological activities (e.g., as described further in the Examples). Thus, should the stereochemistry assigned to any compound or compounds ultimately be proven incorrect, then the analytical data (e.g., prep chiral HPLC, chiral SFC, NMR shift or optical rotation or biological activity) associated with each compound is determinative of the actual identity of the compound. In addition, in light of such corrected stereochemical designation appropriate adjustments to the stereochemistry identification contained in the description, examples, tables and claims should be adjusted as needed by one skilled in the art.

[0207] Chiral analytical separation methods (e.g., supercritical fluid chromatography (SFC), and high performance liquid chromatography (HPLC)) used in the following synthetic examples are summarized in Table A below. These methods were used to identify a single compound / stereoisomer from a mixture of chiral compounds based on a peak retention time.TABLE AProcedures for Preparing Intermediate Compounds Used in the Examples

[0208] Preparation of methyl 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0209] Step 1: methyl 4-(6-chloro-5-fluoropyridin-3-yl)benzoate

[0210] A solution of 5-bromo-2-chloro-3-fluoropyridine (10 g, 47.5 mmol) and 4-(methoxycarbonyl)phenylboronic acid (8.55 g, 47.5 mmol), K3PO4 (30.3 g, 143 mmol) and Pd(dppf)Cl2 (3.48 g, 4.75 mmol) in THF (30 mL) and H2O (7.5 mL) was stirred at 60°C for 2 hours under nitrogen atmosphere. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel columnchromatography, eluted with PE / EA (6:1) to afford methyl 4-(6-chloro-5-fluoropyridin-3-yl)benzoate (5.6 g, 44%) as a white solid. LCMS (ESI) [M+H]+: 266.0.

[0211] Step 2: tert-butyl 2-(3-fluoro-5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)pyrrolidine-l-carboxylate

[0212] A solution of methyl 4-(6-chloro-5-fluoropyridin-3-yl)benzoate (5.6 g, 21.1 mmol), CS2CO3 (20.4 g, 63.2 mmol), tetrakis(9 / / -carbazol-9-yl)benzene-l,4-dicarbonitrile (416 mg, 0.527 mmol) and NiBr2-bipy (790 mg, 2.11 mmol) in DMF (16 mL) was treated with (tert-butoxycarbonyl)proline (6.81 g, 31.6 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under irradiation at 450 nm with blue LEDs for 24 hours. Upon completion, the resulting mixture was diluted with H2O (8 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl 2-(3-fluoro-5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)pyrrolidine-l-carboxylate (2.00 g, 24%) as a brown oil. LCMS (ESI) [M+H]+: 401.2.

[0213] Step 3: methyl 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0214] A solution of tert-butyl 2-(3-fluoro-5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)pyrrolidine- 1 -carboxylate (2.00 g, 5.00 mmol) in hydrochloric acid (8 mL, 32 mmol, 4.0 M in 1,4-dioxane) was stirred at room temperature for 2 hours under nitrogen atmosphere. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: water (0.1% formic acid); mobile phase B: MeCN; gradient (B%): 0% to 100% over 30min; detector: UV 254 nm) to afford methyl 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate (1.05 g, 70%) as a yellow green solid. LCMS (ESI) [M+H]+: 301.1.

[0215] Preparation of 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoic acid

[0216] To a mixture of methyl 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate (1.00 g, 3.33 mmol) in THF (20 mL) were added LiOH monohydrate (420 mg, 1.00 mmol) and H2O (10 mL). The resulting mixture was stirred at room temperature for 2 hours under an atmosphere of nitrogen. Upon completion, the mixture was acidified to pH 3 with HC1 (1 M in water) and the resulting mixture concentrated under reduced pressure. The crude residue was directly purified by reversed phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), mobile phase B: MeCN; Gradient (B%): 0 to 100% in 25 min; detector: UV 254 nm) to afford 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (750 mg, 79%) as an off-white solid. UCMS [M+H]+: 286.1

[0217] Preparation of 5-(4-(3,3-dimethylazetidine-2-carboxamido)phenyl)-6-methylpicolinic acid

[0218] Step 1: methyl 3, 3-dimethyl-2-(picolinamido)butanoate

[0219] A solution of picolinic acid (20.3 g, 165 mmol), TCFH (77.3 g, 275 mmol), NMI (56.5 g, 689 mmol) and methyl 2-amino-3,3-dimethylbutanoate (20.0 g, 138 mmol) in ACN (100 mL) was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford methyl 3,3-dimethyl-2-(pyridin-2-ylformamido)butanoate (20 g, 58%) as a yellow oil. UCMS (ESI) [M+H]+: 251.3.

[0220] Step 2: methyl 3, 3 -dimethyl- l-picolinoylazetidine-2-carboxylate

[0221] A solution of methyl 3,3-dimethyl-2-(pyridin-2-ylformamido)butanoate (5.0 g, 20.0 mmol), Pd(OAc)2 (224.2 mg, 1.0 mmol) and PhI(OAc)2 (16.18 g, 49.9 mmol) in acetic acid (1 mL) and toluene (50 mL) was stirred at 110°C for 1 hour under an atmosphere of nitrogen. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford methyl 3,3-dimethyl-l-(pyridine-2-carbonyl)azetidine-2-carboxylate (4.0 g, 80%) as a yellow oil. LCMS (ESI) [M+H]+: 249.2.

[0222] Step 3: 3,3-dimethyl-l-picolinoylazetidine-2-carboxylic acid

[0223] To a solution of methyl 3,3-dimethyl-l-(pyridine-2-carbonyl)azetidine-2-carboxylate (4.0 g, 16.1 mmol) in MeOH (20 mL) and THF (20 mL) was added lithium hydroxide monohydrate (6.76 g, 161 mmol) in H2O (10 mL) at room temperature. The resulting mixture was stirred at 80°C for 1 day. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), mobile phase B: MeCN; Gradient (B%): 0 to 100% in 25 min; detector: UV 254 nm) to afford 3, 3 -dimethyl- 1-picolinoylazetidine-2-carboxylic acid (3.20 g, 85%) as a white solid. LCMS (ESI) [M+H]+:130.1.

[0225] To a mixture of methyl 6-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinate (2.63 g, 9.50 mmol), 4-bromoaniline (1.63 g, 9.50 mmol) and Pd(dppf)Cl2 (695 mg, 0.950 mmol) in THF (50 mL) was added a solution of K3PO4 (5.04 g, 23.8 mmol) in H2O (10 mL).The mixture was stirred at 60°C for 2 hours under an atmosphere of nitrogen. Upon completion, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with H2O (2 x 30 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (8:1) to afford methyl 5-(4-aminophenyl)-6-methylpicolinate (1.43 g, 32%) as a white solid. LCMS (ESI) [M+H]+: 243.

[0226] Step 5: methyl 5-(4-(3,3-dimethyl-l-picolinoylazetidine-2-carboxamido)phenyl)-6-methylpicolinate

[0227] A solution of methyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (1.21 g, 5.0 mmol), TCFH (2.72 g, 10.0 mmol), NMI (2.6 g, 30.0 mmol) and 3, 3 -dimethyl- 1-picolinoylazetidine-2-carboxylic acid (1.17 g, 5 mmol) in ACN (80 mL) was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford methyl 5 -(4- (3, 3 -dimethyl- 1-picolinoylazetidine-2-carboxamido)phenyl)-6-methylpicolinate (1.2 g, 52%) as a yellow solid. LCMS (ESI) [M+H]+: 459.2.

[0229] To a solution of methyl 5-(4-(3,3-dimethyl-l-picolinoylazetidine-2-carboxamido)phenyl)-6-methylpicolinate (1.2 g, 2.62 mmol) in MeOH (20 mL) and THF (20 mL) was added lithium hydroxide monohydrate (550 mg, 13.1 mmol) in H2O (10 mL) at room temperature. The resulting mixture was stirred at 50°C for 1 hour. Upon completion, the mixture was acidified to pH 6 with HC1 (IM aq.). The resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), mobile phase B: MeCN; Gradient (B%): 0 to 100% in 25 min; detector: UV 254 nm) to afford 5-(4-(3,3-dimethylazetidine-2-carboxamido)phenyl)-6-methylpicolinic acid (750 mg, 84%) as a white solid. LCMS (ESI) [M+H]+: 340.1.

[0230] Preparation of 4'-(3,3-dimethylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid

[0232] To a mixture of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (2.49 g, 9.50 mmol), 4-bromoaniline (1.63 g, 9.50 mmol) and Pd(dppf)Cl2 (695 mg, 0.950 mmol) in THF (20 mL) was added solution of K3PO4 (5.04 g, 23.8 mmol) in H2O (10 mL) under nitrogen atmosphere. The mixture was stirred at 60°C for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (8:1) to afford methyl 4'-amino-[l, T-biphenyl] -4-carboxylate (1.68 g, 78%) as a white solid. LCMS (ESI) [M+H]+: 228.

[0233] Step 2: methyl 4'-(3,3-dimethyl-l-picolinoylazetidine-2-carboxamido)-[l,l ’-biphenyl] -4-carboxylate

[0234] A solution of methyl 4'-amino-[l,l'-biphenyl]-4-carboxylate (1.14 g, 5.0 mmol), TCFH (2.72 g, 10.0 mmol), NMI (2.6 g, 30.0 mmol) and 3,3-dimethyl-l-picolinoylazetidine-2-carboxylic acid (1.17 g, 5 mmol) in ACN (30 mL) was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford methyl 4'-(3,3-dimethyl-l-picolinoylazetidine-2-carboxamido)-[l, T-biphenyl] -4-carboxylate (1.37 g, 50%) as a yellow solid. LCMS (ESI) [M+H]+: 444.1.

[0235] Step 3: 4'-(3,3-dimethylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid

[0236] To a solution of methyl 4'-(3,3-dimethyl-l-picolinoylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (1.37 g, 3.09 mmol) in MeOH (20 mL) and THF (20 mL) was added lithium hydroxide monohydrate (651 mg, 15.5 mmol) in H2O (10 mL) at room temperature. The resulting mixture was stirred at 50°C for 1 hour. Upon completion, the mixture was acidified to pH 6 with HC1 (IM aq.) and then concentrated under reduced pressure. The crude residue was directly purified by reversed phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), mobile phase B: MeCN; Gradient (B%): 0 to 100% in 25 min; detector: UV 254 nm) to afford 4'-(3,3-dimethylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (785 mg, 78%) as a white solid. LCMS (ESI) [M+H]+: 325.1.

[0237] Preparation of tert-butyl 4-(6-chloropyridin-3-yl)benzoate

[0239] To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (28.9 g, 95.0 mmol), 5-bromo-2-chloropyridine (18.3 g, 95.0 mmol) and Pd(dppf)Cl2 (6.95 g, 9.50 mmol) in THF (200 mL) was added solution of K3PO4 (50.4 g, 238 mmol) in H2O (40 mL) under nitrogen atmosphere. The mixture was stirred at 60°C for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (8:1) to afford tertbutyl 4-(6-chloropyridin-3-yl)benzoate (16.9 g, 61%) as a white solid. LCMS (ESI) [M+H]+: 290.

[0240] Preparation of tert-butyl 4-(6-chloropyridin-3-yl)benzoate

[0241] To a mixture of methyl tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (28.9 g, 95.0 mmol), 5-bromo-2-chloro-3-fluoropyridine (20.0 g, 95.0 mmol) and Pd(dppf)Cl2 (6.95 g, 9.50 mmol) in THF (200 mL) was added a solution of K3PO4 (50.4 g, 238 mol) in H2O (40 mL) under nitrogen atmosphere. The mixture was stirred at 60°C for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (8:1) to afford tert-butyl 4-(6-chloropyridin-3-yl)benzoate (18.5 g, 63%) as a white solid. LCMS (ESI) [M+H]+: 308.Example 1: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add (Compound la) and (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2- yl)pyridin-3-yl)benzoic add (Compound lb)

[0242] Step 1: 2-(5-bromopyridin-2-yl)-N-(4-isopropylphenyl)pyrrolidine-1-carboxamide

[0243] A solution of 5-bromo-2-(pyrrolidin-2-yl)pyridine (1.0 g, 4.40 mmol), l-isocyanato-4- isopropylbenzene (1.42 g, 8.81 mmol) and TEA (1.34 g, 13.21 mmol) in DCM (10 mL) were stirred at 25 °C for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2), to afford 2-(5-bromopyridin-2-yl)-N-(4-isopropylphenyl)pyrrolidine-l- carboxamide (800 mg, 47% yield) as a yellow solid. LCMS (ESI) [M+H]+: 388.0 / 390.0

[0244] Step 2: methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3- yl)benzoate

[0245] A solution of 2-(5-bromopyridin-2-yl)-N-(4-isopropylphenyl)pyrrolidine-l-carboxamide (200 mg, 0.52 mmol), 4-(methoxycarbonyl)phenylboronic acid (92.7 mg, 0.52 mmol), Pd(dppf)Cl2 (37.7 mg, 0.052 mmol) and K3PO4 (328 mg, 1.55 mmol) in THF (2 mL) and H2O (0.2 mL) were stirred at 80°C for 1 hour under nitrogen atmosphere. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1), to afford methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (150 mg, 66% yield) as a yellow oil. LCMS (ESI) [M+H]+: 444.2

[0246] Step 3: 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0247] A solution of methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (80 mg, 0.180 mmol) and LiOH (8.6 mg, 0.36 mmol) in THF (1 mL) and H2O (1 mL) was stirred at 25 °C for 1 hour. Upon completion, the mixture was acidified to pH = 2 with HC1 (1 M in water). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase, FA (0.1%) in H2O / ACN, 10% to 60% gradient in 10 min; detector, UV 254 nm) to yield 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (50 mg, 64% yield) as a white solid. LCMS (ESI) [M+H]+: 430.2

[0248] Step 4: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add (Compound la) and (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add (Compound lb)

[0249] 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (40 mg, 0.093 mmol) was separated by prep-Chiral-HPLC (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 206 / 246 nm; RT1 (min): 7.61; RT2 (min): 15.22) to afford (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (Compound la) (1stpeak, 13.8 mg, 34% yield; Method A, Peak 1, 1.24 min) and (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (Compound lb) (2ndpeak, 13.2 mg, 33% yield; Method A, Peak 2, 2.47 min).Example 2: (S)-2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic add (Compound 2a) and (R)-2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic add (Compound 2b)

[0250] Step 1: methyl 2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetate

[0251] A solution of 2-(5-bromopyridin-2-yl)-N-(4-isopropylphenyl)pyrrolidine-l-carboxamide (200 mg, 0.52 mmol), 4-(2-methoxy-2-oxoethyl)phenylboronic acid (99.9 mg, 0.52 mmol), Pd(dppf)Cl2 (37.7 mg, 0.052 mmol) and K3PO4 (328 mg, 1.55 mmol) in THF (2 mL) H2O (0.2 mL) was stirred at 80°C for 1 hour under nitrogen atmosphere. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1), to afford methyl 2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetate (150 mg, 63% yield) as a yellow oil. LCMS (ESI) [M+H]+: 458.2.

[0252] Step 2: 2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic add

[0253] A solution of methyl 2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetate (100 mg, 0.22 mmol) and LiOH (10.5 mg, 0.44 mmol) in THF (1 mL) and H2O (1 mL) was stirred at 25 °C for 1 hour. Upon completion, the mixture was acidified to pH = 2 with HC1 (1 M in water). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (lOmL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase, FA (0.1%) in H2O / ACN, 10% to 60% gradient in 10 min; detector, UV 254 nm) to yield 2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic acid (50 mg, 51% yield) as a white solid. LCMS (ESI) [M+H]+: 444.2.

[0254] Step 3: (S)-2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic add and (R)-2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic add

[0255] 2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic acid (40 mg, 0.090 mmol) was separated by prep-Chiral-HPLC (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 206 / 246 nm; RT1 (min): 7.61; RT2 (min): 15.22) to afford (S)-2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl) acetic acid (Compound 2a) (1stpeak, 16.4 mg, 42% yield; Method B, Peak 1, 0.59 min) and (R)-2-(4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)phenyl)acetic acid(Compound 2b) (2ndpeak, 14.7 mg, 38% yield; Method B, Peak 2, 0.94 min).Example 6: (R)-4'-(2-((4-isopropylphenyl)carbamoyl)pyrrolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add

[0256] Step 1: tert-butyl (R)-2-((4-isopropylphenyl)carbamoyl)pyrrolidine-l -carboxylate

[0257] To a mixture of (tert-butoxycarbonyl)-D-proline (1.00 g, 4.6 mmol) and 4-isopropylaniline (691 mg, 5.1 mmol) in ACN (12 mL) were added N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (1.56 g, 5.6 mmol) and 1 -methyl- l / 7-imidazole (1.14 g, 13.9 mmol). The resulting mixture was stirred atroom temperature for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3); Mobile Phase B: MeCN; Gradient: 0% to 100% B in 20 min; detector, UV 254 nm) to give tert-butyl (7?)-2-((4-isopropylphenyl)carbamoyl)pyrrolidine-l -carboxylate (1.1 g, 71% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 333

[0258] Step 2: (R )- V-(4-isopropy 1 phenyl )pyrrolidine-2-carboxamide

[0259] To a mixture of tert-butyl (7?)-2-((4-isopropylphenyl)carbamoyl)pyrrolidine- 1 -carboxylate (1.05 g, 3.2 mmol) in dioxane (2 mL) was added HC1 (40 mmol, 10 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the mixture was concentrated under reduced pressure to give (7?)-A-(4-isopropylphenyl)pyrrolidine-2-carboxamide (820 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 233

[0260] Step 3: methyl (lf)-4'-(2-((4-isopropylphenyl)carbamoyl)pyrrolidine-l-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylate

[0261] To a solution of methyl 4'-amino-[l, T-biphenyl]-4-carboxylate (147 mg, 0.6 mmol) in THF (5 mL) was added DIEA (417 mg, 3.2 mmol) and triphosgene (77 mg, 0.3 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0°C and (7?)-A-(4-isopropylphenyl)pyrrolidine-2-carboxamide (150 mg, 0.6 mmol) was added. The mixture was warmed to room temperature and stirred for an additional 2 hours. Upon completion, the resulting mixture was diluted with water (8 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel columnchromatography, eluted with PE / EA (2:3) to afford methyl (7?)-4'-(2-((4-isopropylphenyl)carbamoyl)pyrrolidine- 1 -carboxamide)- [1,1 '-biphenyl] -4-carboxylate ( 180 mg, 57% yield) as a yellow solid. LCMS (ESI) [M+H]+: 486

[0262] Step 4: (lf)-4'-(2-((4-isopropylphenyl)carbamoyl)pyrrolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add

[0263] To a solution of methyl (7?)-4'-(2-((4-isopropylphenyl)carbamoyl)pyrrolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylate (100 mg, 0.2 mmol) in THF (1.5 mL) was added a solution of LiOH monohydrate (26 mg, 0.6 mmol) and H2O (1.5 mL). The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was acidified to pH 3 with HC1 (1 M) and then concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 36% to 61% B in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 11.37) to afford (7?)-4'-(2-((4-isopropylphenyl)carbamoyl)pyrrolidine- 1 -carboxamide)- [1,1 '-biphenyl] -4-carboxylic acid (44.0 mg Compound 6) as an off-white solid.Example 7: (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[1,1 ' -biphenyl] -4-carboxylic acid

[0264] Step 1: methyl 4'-((tert-butoxycarbonyl)amino)-3-fluoro-[l,l'-biphenyl]-4-carboxylatez=\ OHHNA,FBoc H / =< OBr~ A \HN' — ' b Pd(dppf)CI2, K2CO3, dioxane / H2O, 90 °C Boc

[0265] To a mixture of methyl 4-bromo-2-fluorobenzoate (20.0 g, 85.8 mmol) and (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (30.5 g, 129 mmol) in dioxane (300 mL) were addedH2O (75 mL), K2CO3 (35.6 g, 258 mmol) and Pd(dppf)Cl2*CH2C12 (7.01 g, 8.5 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated at 90°C for 1 hour. Upon completion, the mixture was allowed to cool down to room temperature and was then filtered. The filter cake was washed with DCM (3 x 350 mL). The combined filtrates were concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl 4'-(( / e / 7-butoxycarbonyl)amino)-3-fluoro-[l,l'-biphenyl]-4-carboxylate (23.0 g, 78% yield) as a yellow solid. LCMS (ESI) [M+H]+: 346

[0266] Step 2: methyl 4'-amino-3-fluoro-[l,l'-biphenyl]-4-carboxylate

[0267] To a mixture of methyl 4'-((tert-butoxycarbonyl)amino)-3-fluoro-[l,l'-biphenyl]-4-carboxylate (10.0 g, 29.0 mmol) in dioxane (30 mL) was added HC1 (600 mmol, 150 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl 4'-amino-3-fluoro-[l, T-biphenyl]-4-carboxylate (7.00 g, crude) as a white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 246

[0268] Step 3: tert-butyl (S)-2-((3'-fluoro-4'-(methoxycarbonyl)-[l,l'-biphenyl]-4-yl)carbamoyl)piperidine- 1 -carboxylateBoc

[0269] A solution of (5)-l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (200 mg, 0.9 mmol), methyl 4'-amino-3-fluoro-[l, T-biphenyl]-4-carboxylate (214 mg, 0.9 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (293 mg, 1.0 mmol) and 1 -methyl- 1 / 7-imidazole (215 mg, 2.6 mmol) in ACN (6 mL) was stirred for 2 hours at room temperature. Upon completion, the reaction mixture was directly purified by reverse phase flash chromatography (conditions: column, Cl 8 silica gel; mobile phase A, Water (10 mmol / L NH4HCO3), mobile phase B: MeCN; Gradient (B%): 0% to 100% B in 20 min; detector, UV 254 nm) to yield tert-butyl (S)-2-((3'-fhioro-4'-(methoxycarbonyl)-[l,l'-biphenyl]-4-yl)carbamoyl)piperidine- 1 -carboxylate (160 mg, 40% yield) as a white solid. LCMS (ESI) [M+H]+: 457

[0270] Step 4: methyl (S)-3-fluoro-4'-(piperidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate

[0271] To a solution of tert-butyl (S)-2-((3'-fluoro-4'-(methoxycarbonyl)-[l, T-biphenyl]-4-yl)carbamoyl)piperidine- 1 -carboxylate (140 mg, 0.3 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to afford methyl (S)-3-fhioro-4'-(piperidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (100 mg, crude) as a white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 357

[0272] Step 5: methyl (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylate

[0273] To a solution of methyl (S)-3-fhioro-4'-(piperidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (90 mg, 0.2 mmol) in DCM (3 mL) was added triethylamine (25 mg, 0.2 mmol) and l-isocyanato-4-isopropylbenzene (41 mg, 0.2 mmol) sequentially at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% B in 20 min; detector, UV 254 nm) to yield methyl (5)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate (80 mg, 61% yield) as a white solid. LCMS (ESI) [M+H]+: 518

[0274] Step 6: (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)- [1,1 ' -biphenyl]-4-carboxylic add

[0275] To a solution of methyl (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate (78 mg, 0.1 mmol) in THF (2 mL) was added a solution of LiOH monohydrate (11 mg, 0.4 mmol) in H2O (2 mL) and at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the mixture was acidified to pH 5 with aqueous HC1 (2 M) at 0°C and then was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient (B%): 57% to 75% B in 12 min; Wave Length: 254 nm / 220 nm; RT1 (min): 13.55) to afford (5)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (26.3 mg, Compound 7; Method C, Peak 1, 2.11 min - analyzed against Compound 8) as a white solid.Example 8: (7f)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[1,1 ' -biphenyl]-4-carboxylic add

[0276] Step 1: tert-butyl (R)-2-((3'-fluoro-4'-(methoxycarbonyl)-[l,l'-biphenyl]-4-yl)carbamoyl)piperidine- 1 -carboxylateBoc

[0277] A solution of (R)-l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (200 mg, 0.8 mmol), methyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (224 mg, 0.9 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (256 mg, 0.9 mmol) and 1 -methyl- IH-imidazole (358 mg, 4.3 mmol) in ACN (6 mL) was stirred for 2 hours at room temperature. Upon completion, the mixture was concentrated under reducedpressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% B in 20 min; detector, UV 254 nm) to give tert-butyl (7?)-2-((3'-fluoro-4'- (methoxycarbonyl)- [1,1 '-biphenyl] -4-yl)carbamoyl)piperidine- 1 -carboxylate ( 180 mg, 45% yield) as a white solid. LCMS (ESI) [M+H]+: 457

[0278] Step 2: methyl (lf)-3-fluoro-4'-(piperidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate

[0279] To a solution of tert-butyl (7?)-2-((3'-fhioro-4'-(methoxycarbonyl)-[l, T-biphenyl]-4-yl)carbamoyl)piperidine-l -carboxylate (160 mg, 0.3 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to afford methyl (7?)-3-fhioro-4'-(piperidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (120 mg, crude) as a white solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 357

[0280] Step 3: methyl (lf)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)- [1,1' -biphenyl] -4-carboxylate

[0281] To a solution of methyl (7?)-3-fhioro-4'-(piperidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate (100 mg, 0.2 mmol) in DCM (3 mL) were added triethylamine (51 mg, 0.5 mmol) and l-isocyanato-4-isopropylbenzene (41 mg, 0.2 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (10 mmol / LNH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% B in 20 min; detector, UV 254 nm) to give methyl (7?)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate (90 mg, 68% yield) as a white solid. LCMS (ESI) [M+H]+: 518

[0282] Step 4: (lf)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0283] To a solution of methyl (7?)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (88 mg, 0.1 mmol) in THF (2 mL) was added a solution of LiOH monohydrate (4 mg, 0.1 mmol) in H2O (2 mL) at 0°C under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the mixture was acidified to pH 5 with aqueous HC1 (2 M) at 0°C. The resulting solution was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 45% B to 55% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 11.4) to afford (7?)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[l,r-biphenyl]-4-carboxylic acid (26.6 mg, Compound 8; Method C, Peak 2, 3.82 min - analyzed against Compound 7) as a white solid.Example 9: (lf)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0284] Step 1: tert-butyl (lf)-2-((3'-fluoro-4'-(methoxycarbonyl)-[l,l'-biphenyl]-4-yl)carbamoyl)-2-methylazetidine-l-carboxylateboc

[0285] A solution of methyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (200 mg, 0.8 mmol), (7?)-l-(ter / -butoxycarbonyl)-2-methylazetidine-2-carboxylic acid (175 mg, 0.8 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (343 mg, 1.2 mmol) and 1 -methyl- 1 / / -imidazole (201 mg, 2.4 mmol) in ACN (6 mL) was stirred for 2 hours at room temperature. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, Cl 8 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% in 20 min; detector, UV 254 nm) to yield tert-butyl (7?)-2-((3'-fhioro-4'-(methoxycarbonyl)-[l,r-biphenyl]-4-yl)carbamoyl)-2-methylazetidine-l-carboxylate (310 mg, 85% yield) as a white solid. LCMS (ESI) [M+H]+: 443

[0286] Step 2: methyl (lf)-3-fluoro-4'-(2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate

[0287] To a mixture of tert-butyl (7?)-2-((3'-fluoro-4'-(methoxycarbonyl)-[l,r-biphenyl]-4-yl)carbamoyl)-2-methylazetidine-l -carboxylate (200 mg, 0.4 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to give methyl (7?)-3-fhioro-4'-(2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate (150 mg, crude) as a light yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 343

[0288] Step 3: methyl (lf)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate

[0289] To a solution of methyl (7?)-3-fluoro-4'-(2-methylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (100 mg, 0.1 mmol) in DCM (3 mL) were added triethylamine (15 mg, 0.1 mmol) and l-isocyanato-4-isopropylbenzene (47 mg, 0.1 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl (7?)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (140 mg, 95% yield) as a white solid. LCMS (ESI) [M+H]+: 504

[0290] Step 4: (R)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)- [1,1 ' -biphenyl]-4-carboxylic add

[0291] To a solution of methyl (7?)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (120 mg, 0.3 mmol) in THF (3 mL) was added a solution of LiOH monohydrate (30 mg, 0.9 mmol) in H2O (3 mL) at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the mixture was acidified to pH 5 with aqueous HC1 (2 M) at 0°C and then was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 48% to 69% B in 10 min; Wave Length: 254 nm / 220 nm; RTl(min): 10.52) to afford (7?)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (45.7 mg, Compound 9; Method D, Peak 1, 3.17 min - analyzed against Compound 10) as a white solid.Example 10: (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0292] Step 1: tert-butyl (S)-2-((3'-fluoro-4'-(methoxycarbonyl)-[l,l'-biphenyl]-4-yl)carbamoyl)-2-methylazetidine-l-carboxylateBoo

[0293] A solution of methyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (120 mg, 0.5 mmol), (5)-l-(tert-butoxycarbonyl)-2-methylazetidine-2-carboxylic acid (211 mg, 1.0 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (206 mg, 0.7 mmol) and 1 -methyl- 1 H-imidazole (402 mg, 4.9 mmol) in ACN (6 mL) was stirred for 2 hours at room temperature. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, Cl 8 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% in 20 min; detector, UV 254 nm) to give tert-butyl (S)-2-((3'-fhioro-4'-(methoxycarbonyl)-[l,r-biphenyl]-4-yl)carbamoyl)-2-methylazetidine-l-carboxylate (100 mg, 46% yield) as a yellow solid. LCMS (ESI) [M+H]+: 443

[0294] Step 2: methyl (S)-3-fluoro-4'-(2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate

[0295] To a mixture of tert-butyl (S)-2-((3'-fluoro-4'-(methoxycarbonyl)-[l, T-biphenyl]-4-yl)carbamoyl)-2-methylazetidine-l -carboxylate (100 mg, 0.2 mmol) in dioxane (0.6 mL) was added HC1 (12 mmol, 3 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to give methyl (S)-3-fhioro-4'-(2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate (90 mg, crude) as a light yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 343

[0296] Step 3: methyl (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate

[0297] To a solution of methyl (S)-3-fluoro-4'-(2-methylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (90 mg, 0.3 mmol) in DCM (3 mL) was added triethylamine (27 mg, 0.3 mmol) and l-isocyanato-4-isopropylbenzene (42 mg, 0.3 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, Cl 8 silica gel; mobile phase A: water (0.1% formic acid), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% in 20 min; detector, UV 254 nm) to give methyl (5)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylate (100 mg, 76% yield) as white solid. LCMS (ESI) [M+H]+: 504

[0298] Step 4: (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0299] To a solution of methyl (5)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylate (88 mg, 0.2 mmol) inTHF (3 mL) were added a solution of LiOH monohydrate (22 mg, 0.6 mmol) in H2O (3 mL) at 0°C under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the mixture was acidified to pH 5 with aqueous HC1 (2 M) at 0°C and then was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions (Column: Xbridge Phenyl OBD Column, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 39% B to 59% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.2) to afford (5)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylicacid (41.4 mg, Compound 10; Method D, Peak 2, 3.51 min - analyzed against Compound 9) as a white solid.Example 11: (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)-[1,1 ' -biphenyl]-4-carboxylic add

[0300] Step 1: tert-butyl (S)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,l'-biphenyl]-4-yl)carbamoyl)azepane- 1 -carboxylate

[0301] A solution of (5)-l-(tert-butoxycarbonyl)azepane-2-carboxylic acid (169 mg, 0.7 mmol), tert-butyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (200 mg, 0.7 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (293 mg, 1.0 mmol) and 1 -methyl- l / 7-imidazole (171 mg, 2.1 mmol) in ACN (6 mL) was stirred for 2 hours at room temperature. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, Cl 8 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector, UV 254 nm) to yield tert-butyl (S)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,r-biphenyl]-4-yl)carbamoyl)azepane-l-carboxylate (180 mg, 62% yield) as a white solid. LCMS (ESI) [M+H]+: 513

[0302] Step 2: (S)-4'-(azepane-2-carboxamido)-3-fluoro-[ 1,1 '-biphenyl ]-4-carboxylic acid

[0303] To a solution of tert-butyl ( )-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,r-biphenyl]-4-yl)carbamoyl)azepane-l -carboxylate (200 mg, 0.4 mmol) in dioxane (1 mL) was added HC1 in (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to give (5)-4'-(azepane-2-carboxamido)-3-fluoro-[l,r-biphenyl]-4-carboxylic acid (150 mg, crude) as a light yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 357

[0304] Step 3: (S)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)- [1,1' -biphenyl] -4-carboxylic acid

[0305] To a mixture of (S)-4'-(azepane-2-carboxamido)-3-fluoro-[l, T-biphenyl]-4-carboxylic acid (100 mg, 0.2 mmol) in DCM (4 mL) were added triethylamine (28 mg, 0.2 mmol) and 1-isocyanato-4-isopropylbenzene (45 mg, 0.2 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xbridge Phenyl OBD Column, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 41% B to 57% B in 15 min; Wave Length: 254 nm / 220 nm; RTl(min): 12.2) to afford (5)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)-[l,r-biphenyl]-4-carboxylic acid (18.2 mg, Compound 11; Method C, Peak 1, 1.65 min - analyzed against Compound 12) as a white solid.>Example 12: (lf)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)-[1,1' -biphenyl] -4-carboxylic acid

[0306] Step 1: tert-butyl (lf)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,l'-biphenyl]-4-yl)carbamoyl)azepane- 1 -carboxylate

[0307] A solution of (7?)-l-(tert-butoxycarbonyl)azepane-2-carboxylic acid (169 mg, 0.7 mmol), tert-butyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (200 mg, 0.7 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (293 mg,1.0 mmol) and 1 -methyl- IH-imidazole (171 mg, 2.1 mmol) in ACN (6 mL) was stirred for 2 hours at room temperature. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector, UV 254 nm) to give tert-butyl (7?)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,r-biphenyl]-4-yl)carbamoyl)azepane-l-carboxylate (150 mg, 42% yield) as a yellow solid. LCMS (ESI) [M+H]+: 513

[0308] Step 2: (lf)-4'-(azepane-2-carboxamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic add

[0309] To a mixture of tert-butyl (7?)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,r-biphenyl]-4-yl)carbamoyl)azepane-l -carboxylate (150 mg, 0.3 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to give (7?)-4'-(azepane-2-carboxamido)-3-fluoro-[l,r-biphenyl]-4-carboxylic acid (120 mg, crude) as a light yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 357.

[0310] Step 3: (lf)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)-[1,1' -biphenyl] -4-carboxylic acid

[0311] To a mixture of (7?)-4'-(azepane-2-carboxamido)-3-fluoro-[l, T-biphenyl]-4-carboxylic acid (110 mg, 0.3 mmol) in DCM (6 mL) were added triethylamine (31 mg, 0.3 mmol) and 1-isocyanato-4-isopropylbenzene (50 mg, 0.3 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xbridge Phenyl OBD Column, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient (B%): 40% B to 60% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.6) to afford (7?)-3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)-[l, T-biphenyl]-4-carboxylic acid (25.6 mg, Compound 12; Method C, Peak 2, 2.70 min - analyzed against Compound 11) as a white solid.Example 13: 3-fluoro-4'-((lS,2S)-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add and 3-fluoro-4'-((llf,21f)-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add

[0312] Step 1: (tr«ns)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,l'-biphenyl]-4-yl)carbamoyl)cyclopentane- 1 -carboxylic acid

[0313] To a mixture of (tra / 7 )-cyclopentane-l,2-dicarboxylic acid (300 mg, 1.9 mmol) and tertbutyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (545 mg, 1.9 mmol) in ACN (6 mL) were added A-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (639 mg, 2.3 mmol) and 1 -methyl- l / 7-imidazole (467 mg, 5.7 mmol). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (tra / 7 )-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l, T-biphenyl]-4-yl)carbamoyl)cyclopentane-l -carboxylic acid (350 mg, 43% yield) as a white solid. LCMS (ESI) [M+H]+: 428

[0314] Step 2: tert-butyl 3-fluoro-4'-((tr«ns)-2-((4-isopropylphenyl)carbamoyl)cyclopentane-1 -carboxamido)- [1,1' -biphenyl] -4-carboxylate

[0315] To a mixture of (t )-2-((4'-(n? -butoxycarbonyl)-3'-fluoro-[l, T-biphenyl]-4-yl)carbamoyl)cyclopentane-l -carboxylic acid (330 mg, 0.8 mmol) and 4-isopropylaniline (52 mg, 0.4 mmol) in ACN (8 mL) were added A-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (217 mg, 0.8 mmol) and 1 -methyl- 1 / / -imidazole (190 mg, 2.3 mmol). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl 3-fhioro-4'-((tra 7 )-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l -carboxamide)- [1,1'-biphenyl] -4-carboxylate (200 mg, 48% yield) as a white solid. LCMS (ESI) [M+H]+: 545 Step 3: 3-fluoro-4'-((tr«ns)-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l-carboxamido)-[1,1' -biphenyl] -4-carboxylic acid

[0316] To a mixture of tert-butyl 3-fluoro-4'-((tratzs,)-2-((4-isopropylphenyl)carbamoyl)cyclopentane- 1 -carboxamide)- [ 1, 1 '-biphenyl] -4-carboxylate (150 mg, 0.3 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred overnight. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector, UV 254 nm) to afford 3-fhioro-4'-(( / )-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (36 mg, 27% yield) as a white solid. LCMS (ESI) [M+H]+: 489

[0317] Step 3: 3-fluoro-4'-((lS,2S)-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add and 3-fluoro-4'-((llf,21f)-2-((4-isopropylphenyl)carbamoyl)cyclopentane- 1 -carboxamido)- [1,1 ' -biphenyl] -4-carboxylic acid

[0318] 3-fluoro-4'-((rra / 75)-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (34 mg) was separated by Prep-Chiral-SFC (conditions: Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (10 mM NH3); Flow rate: 100 mL / min; Gradient (B%): isocratic 40% B; Column Temperature (°C): 35; BackPressure (bar): 100; Wave Length: 254 nm; RT1 (min): 3.92; RT2 (min): 5.5) to afford first peak (Compound 13a) 3-fluoro-4'-((15,25)-2-((4-isopropylphenyl)carbamoyl)cyclopentane- 1 -carboxamide)- [ 1, 1 '-biphenyl] -4-carboxylic acid (14.3 mg; Method E, Peak 1, 1.30 min) as a yellow solid and second peak (Compound 13b) 3-fhioro-4'-((lR,2R)-2-((4-isopropylphenyl)carbamoyl)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (12.1 mg; Method E, Peak 2, 1.49 min) as a yellow solid.Example 14: (S)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)-l-methylureido)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylic acid

[0319] Step 1: tert-butyl (S)-4' -(2-((tert- butoxycarbonyl )( methyl )ami no )-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylate

[0320] To a mixture of A-(tert-butoxycarbonyl)-A-methyl-L-valine (161 mg, 0.7 mmol) and tertbutyl 4'-amino-3 -fluoro- [l,l'-biphenyl]-4-carboxylate (200 mg, 0.7 mmol) in EtOAc (2 mL) was added pyridine (6 mL) and propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (664 mg, 2.0 mmol). The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: water (0.1% formic acid), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% in 20 min; detector, UV 254 nm) to give tert-butyl (5)-4'-(2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-3-fluoro-[l, T-biphenyl]-4-carboxylate (230 mg, 66% yield) as a white solid. LCMS (ESI) [M+H]+: 501

[0321] Step 2: (S)-3-fluoro-4'-(3-methyl-2-(methylamino)butanamido)-[l,l'-biphenyl]-4-carboxylic add

[0322] To a mixture of tert-butyl (5)-4'-(2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-3-fluoro-[l,r-biphenyl]-4-carboxylate (150 mg, 0.3 mmol) in dioxane (0.6 mL) was added HC1 (12 mmol, 3 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 6 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to give (S)-3-fhioro-4'-(3-methyl-2-(methylamino)butanamido)-[l, T-biphenyl]-4-carboxylic acid (120 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 345

[0323] Step 3: (S)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)-l-methylureido)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylic acid

[0324] To a mixture of (S)-3-fhioro-4'-(3-methyl-2-(methylamino)butanamido)-[l, l'-biphenyl]-4-carboxylic acid (100 mg, 0.3 mmol) in DCM (4 mL) were added triethylamine (29 mg, 0.3 mmol) and l-isocyanato-4-isopropylbenzene (46 mg, 0.3 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction wasquenched with ice water at 0°C and the resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 42% B to 60% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.2) to afford (S)-3-fhioro-4'-(2-(3-(4-isopropylphenyl)-l-methylureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid (31.0 mg, Compound 14;Method F, Peak 2, 2.77 min - analyzed against Compound 15) as a white solid.Example 15: (lf)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)-l-methylureido)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylic acid

[0325] Step 1: tert-butyl (lf)-4'-(2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylate

[0326] To a mixture of W(tert-butoxycarbonyl)W-methyl-D-valine (200 mg, 0.9 mmol) and tertbutyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (298 mg, 1.0 mmol) in EtOAc (3 mL) was added pyridine (9 mL) and propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (3.30 g, 5.2 mmol) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN: Gradient (B%): 0% to 100% in 25 min; detector, UV 254 nm) to give tert-butyl (7?)-4'-(2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylate (150 mg, 35% yield) as a yellow solid. LCMS (ESI) [M+H]+: 501

[0327] Step 2: (lf)-3-fluoro-4'-(3-methyl-2-(methylamino)butanamido)-[l,l'-biphenyl]-4-carboxylic add

[0328] To a mixture of tert-butyl (7?)-4'-(2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-3-fluoro-[l,r-biphenyl]-4-carboxylate (150 mg, 0.3 mmol) in dioxane (0.6 mL) was added HC1 (12 mmol, 3 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 6 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to give (7?)-3-fhioro-4'-(3-methyl-2-(methylamino)butanamido)-[l, T-biphenyl]-4-carboxylic acid (120 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 345

[0329] Step 3: (lf)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)-l-methylureido)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylic acid

[0330] To a mixture of (7?)-3-fhioro-4'-(3-methyl-2-(methylamino)butanamido)-[l, l'-biphenyl]-4-carboxylic acid (110 mg, 0.3 mmol) in DCM (5 mL) were added triethylamine (32 mg, 0.3 mmol) and l-isocyanato-4-isopropylbenzene (52 mg, 0.3 mmol) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xbridge Phenyl OBD Column, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 40% B to 60% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.6) to afford (7?)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)-l-methylureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid (31.2 mg, Compound 15;Method F, Peak 1, 2.66 min - analyzed against Compound 14) as a white solid.Example 16: 3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-3,3-dimethylazetidine-2-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0331] Step 1: tert-butyl 2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,l'-biphenyl]-4-yl)carbamoyl)-3,3-dimethylazetidine-l -carboxylateBoc

[0332] A solution of l-(tert-butoxycarbonyl)-3,3-dimethylazetidine-2-carboxylic acid (90 mg, 0.3 mmol), tert-butyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (118 mg, 0.4 mmol), 1-methyl-l H-imidazole (161 mg, 1.9 mmol) and A-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (115 mg, 0.4 mmol) in ACN (3 mL) was stirred at room temperature for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector, UV 300 nm) to give tert-butyl 2- ((4'- (tert-butoxycarbonyl)-3'-fluoro- [1,1 '-biphenyl] -4-yl)carbamoyl)-3,3 -dimethylazetidine- 1 -carboxylate (100 mg, 51% yield) as a white solid. LCMS (ESI) [M+H]+: 499

[0333] Step 2: 4'-(3,3-dimethylazetidine-2-carboxamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic add

[0334] To a solution of tert-butyl 2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,r-biphenyl]-4-yl)carbamoyl)-3,3-dimethylazetidine-l-carboxylate (90 mg, 0.2 mmol) in dioxane (0.6 mL) was added HC1 (12 mmol, 3 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred overnight. Upon completion, the resulting mixture was concentrated under reduced pressure to give 4'-(3,3-dimethylazetidine-2-carboxamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic acid (100 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 343

[0335] Step 3: 3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-3,3-dimethylazetidine-2-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0336] To a mixture of 4'-(3,3-dimethylazetidine-2-carboxamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic acid (90 mg, 0.2 mmol) in DCM (3 mL) were added triethylamine (36 mg, 0.3 mmol) and l-isocyanato-4-isopropylbenzene (45 mg, 0.2 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 42% to 60% B in 12 min; Wave Length: 254 nm / 220 nm; RT1 (min): 12.50) to afford 3-fluoro-4'-(l-((4-isopropylphenyl)carbamoyl)-3,3-dimethylazetidine-2-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (31 mg, 25% yield, Compound 16) as a white solid.Example 17: 3-fluoro-4'-(( l / ?.2 / ?)-2-((4-isopropylphenyl)carbanioyl)cyclohexane-l-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0337] Step 1: (lR,21f)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,l'-biphenyl]-4-yl)carbamoyl)cyclohexane-l-carboxylic add

[0338] To a mixture of (17?,27?)-cyclohexane-l,2-dicarboxylic acid (200 mg, 1.1 mmol) and tertbutyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (300 mg, 1.0 mmol) in EtOAc (3 mL) was added pyridine (9 mL) and propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (2.20 g, 3.4 mmol) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reducedpressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (17?,27?)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l, T-biphenyl]-4-yl)carbamoyl)cyclohexane-l -carboxylic acid (200 mg, 39% yield) as a yellow solid. LCMS (ESI) [M+H]+: 442

[0339] Step 2: tert-butyl 3-fluoro-4'-((llf,21f)-2-((4-isopropylphenyl)carbamoyl)cyclohexane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylate

[0340] To a mixture of (17?,27?)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l, T-biphenyl]-4-yl)carbamoyl)cyclohexane-l -carboxylic acid (180 mg, 0.4 mmol) and 4-isopropylaniline (110 mg, 0.8 mmol) in EtOAc (2 mL) was added pyridine (6 mL) and propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (778 mg, 1.2 mmol) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector, UV 300 nm) to give tert-butyl 3-fluoro-4'-((17?,27?)-2-((4-isopropylphenyl)carbamoyl)cyclohexane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylate (150 mg, 65% yield) as a white solid. LCMS (ESI) [M+H]+: 559

[0341] Step 3: 3-fluoro-4'-((llf,21f)-2-((4-isopropylphenyl)carbamoyl)cyclohexane-l-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0342] To a mixture of tert-butyl 3-fluoro-4'-((17?,27?)-2-((4-isopropylphenyl)carbamoyl)cyclohexane-l -carboxamide)- [l,l'-biphenyl]-4-carboxylate (80 mg, 0.1 mmol) in dioxane (0.6 mL) was added HC1 (12 mmol, 3 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residuewas purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 46% to 64% B in 12 min; Wave Length: 254 nm / 220 nm; RT1 (min): 14.43) to afford 3-fluoro-4'-(( 17?,27?)-2-((4-isopropylphenyl)carbamoyl)cyclohexane- 1 -carboxamide)- [1,1'-biphenyl]-4-carboxylic acid (26.7 mg, Compound 17; Method E, Peak 2, 1.49 min - analyzed against Compound 18) as a white solid.Example 18: 3-fluoro-4'-((lS,2S)-2-((4-isopropylphenyl)carbamoyl)cydohexane-l-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0343] Step 1: (lS,2S)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,l'-biphenyl]-4-yl)carbamoyl)cyclohexane-l-carboxylic add

[0344] To a mixture of (15,25)-cyclohexane-l,2-dicarboxylic acid (200 mg, 1.2 mmol) and tertbutyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (413 mg, 1.4 mmol) in EtOAc (3 mL) was added pyridine (9 mL) and propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (1.91 g, 6.0 mmol) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (2:3) to afford (15,25)-2-((4'-(tert-butoxycarbonyl)-3'-fluoro-[l,r-biphenyl]-4-yl)carbamoyl)cyclohexane-l -carboxylic acid (220 mg, 43% yield) as a yellow solid. LCMS (ESI) [M+H]+: 442

[0345] Step 2: tert-butyl 3-fluoro-4'-((lS,2S)-2-((4-isopropylphenyl)carbamoyl)cydohexane- 1 -carboxamido)- [1,1' -biphenyl] -4-carboxylate

[0346] To a mixture of (lS,2S)-2-((4'-(tert-butoxycarbonyl)-3'-fhioro-[l,l'-biphenyl]-4-yl)carbamoyl)cyclohexane-l -carboxylic acid (220 mg, 0.5 mmol) and 4-isopropylaniline (1.27 g, 2.0 mmol) in EtOAc (3 mL) was added pyridine (9 mL) and propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (793 mg, 2.5 mmol) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector, UV 254 nm) to yield tert-butyl 3-fhioro-4'-((lS,2S)-2-((4-isopropylphenyl)carbamoyl)cyclohexane-l-carboxamido)-[1,1 '-biphenyl] -4-carboxylate (160 mg, 58% yield) as a white solid. LCMS (ESI) [M+H]+: 559

[0347] Step 3: 3-fluoro-4'-((lS,2S)-2-((4-isopropylphenyl)carbamoyl)cyclohexane-l-carboxamido)- [1,1 ' -biphenyl]-4-carboxylic add

[0348] To a mixture of tert-butyl 3-fluoro-4'-((15,25)-2-((4-isopropylphenyl)carbamoyl)cyclohexane- 1 -carboxamide)- [1,1 '-biphenyl] -4-carboxylate ( 100 mg, 0.2 mmol) in dioxane (0.6 mL) was added HC1 (12 mmol, 3 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 45% to 65% B in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 12.40) to afford 3-fhioro-4'-((lS,2S)-2-((4-isopropylphenyl)carbamoyl)cyclohexane-l-carboxamido)-[l,r-biphenyl]-4-carboxylic acid (33.5 mg, Compound 18; Method E, Peak 1, 1.25 min - analyzed against Compound 17) as an off-white solid.Example 19: 3-fluoro-4' -(1 -(3-(4-isopropylphenyl)- 1 -methylureido)cyclopentane- 1 -carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0349] Step 1: tert-butyl 4'-(l-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxamido)-3-fluoro-[ 1,1 ' -biphenyl] -4-carboxylate

[0350] To a mixture of l-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxylic acid (239 mg, 1.0 mmol) in THF (7 mL) were added DIEA (270 mg, 2.1 mmol), tert-butyl 4'-amino-3-fluoro-[l,l'-biphenyl]-4-carboxylate (300 mg, 1.0 mmol) and HATU (437 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 4 days. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4'-(l-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxamido)-3-fluoro-[l,r-biphenyl]-4-carboxylate (300 mg, 58% yield) as a yellow solid. LCMS (ESI) [M+H]+: 499

[0351] Step 2: 4'-(l-aminocyclopentane-l-carboxamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic add

[0352] To a mixture of tert-butyl 4'-(l-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxamido)-3-fluoro-[l, T-biphenyl]-4-carboxylate (300 mg, 0.6 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to yield 4'-(l-aminocyclopentane-l-carboxamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic acid (220 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) [M+H]+: 343

[0353] Step 3: 3-fluoro-4'-(l-(methylamino)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid

[0354] To a mixture of 4'-(1-aminocyclopentane-1-carboxamido)-3-fluoro-[ I, l'-biphenyl]-4-carboxylic acid (200 mg, 0.6 mmol) in DMF (6 mL) were added K2CO3 (242 mg, 1.8 mmol) and methyl iodide (83 mg, 0.6 mmol). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was diluted with H2O (8 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (2:3) to afford 3-fhioro-4'-(l-(methylamino)cyclopentane- l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (150 mg, 72% yield) as a yellow solid. LCMS (ESI) [M+H]+: 357

[0355] Step 4: 3-fluoro-4'-(l-(3-(4-isopropylphenyl)-l-methylurddo)cyclopentane-l-carboxamido)-[ 1,1 ' -biphenyl]-4-carboxylic add

[0356] To a mixture of 3-fhioro-4'-(l-(methylamino)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (100 mg, 0.3 mmol) in DCM (3 mL) were added triethylamine (28 mg, 0.3 mmol) and l-isocyanato-4-isopropylbenzene (45 mg, 0.3 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 41% B to 58% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.8) to afford 3-fluoro-4'-(l-(3-(4-isopropylphenyl)-l-methylureido)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (35.2 mg, 24% yield, Compound 19) as a white solid.Example 20: 4-(6-((S)-l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add, 4-(6-((R)-l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add, 4-(6-((S)-l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoicacid and 4-(6-((R)-l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0357] Synthesis of 4-[(lS)-2,2-dimethylcyclopropyl]aniline and 4-[(lR)-2,2-dimethylcyclopropyl]aniline

[0358] Step 1: 4-methyl-N'-(propan-2-ylidene)benzenesulfonohydrazide

[0359] A solution of 4-toluenesulfonyl hydrazide (2.0 g, 10.7 mmol) in acetone (20 mL) was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure to give 4-methyl-N'-(propan-2-ylidene)benzenesulfonohydrazide (2.2 g, crude) as a yellow solid which was used in the next step without further purification. LCMS (ESI) [M+H]+: 227.

[0360] Step 2: 4-(2,2-dimethylcyclopropyl)aniline

[0361] A solution of 4-methyl-N'-(propan-2-ylidene)benzenesulfonohydrazide (2.0 g, 8.8 mmol), 4-vinylaniline (2.1 g, 17.6 mmol), (tetraphenylporphinato)cobalt (300 mg, 0.4 mmol) and CS2CO3 (4.3 g, 13.2 mmol) in 1,4-dioxane (20 mL) was stirred at 90°C for 12 hours under nitrogen atmosphere. Upon completion, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-(2,2-dimethylcyclopropyl)aniline (300 mg, 21.0% yield) as a white solid. LCMS (ESI) [M+H]+: 162.

[0362] Step 3: 4-[(lS)-2,2-dimethylcyclopropyl]aniline and 4-[(lR)-2,2-dimethylcyclopropyl]aniline

[0363] 4-(2,2-dimethylcyclopropyl)aniline (4.0 g) was separated by Prep Chiral HPLC (conditions: Column: CHIRALPAK-IK, 3*25 mm, 5 pm; Mobile Phase A: Hex (0.1% DEA), Mobile Phase B: IPA; Flow rate: 70 mL / min; Gradient (B%): isocratic 2% B) to yield (S)-4-(2,2-dimethylcyclopropyl)aniline (Peak 1, 1.4 g, 36% yield) and (R)-4-(2,2-dimethylcyclopropyl)aniline (Peak 2, 1.2 g, 30% yield ). LCMS (ESI) [M+H]+: 162

[0364] Step 4: methyl 4-(6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0365] A solution of 5-bromo-2-(pyrrolidin-2-yl)pyridine (400 mg, 1.76 mmol), 4-(methoxycarbonyl)phenylboronic acid (380 mg, 2.1 mmol), Pd(dppf)Cl2 (129 mg, 0.18 mmol) and K3PO4 (1.12 g, 5.28 mmol) in THF (4 mL) and H2O (0.4 mL) was stirred at 80°C for 1 hour under nitrogen atmosphere. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (3 / 1) to afford methyl 4-(6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate (350 mg, 70% yield) as a yellow solid. LCMS (ESI) [M+H]+: 283.1

[0366] Step 5: methyl 4-(6-(l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0367] A solution of methyl 4-(6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate (150 mg, 0.53 mmol), 4-[(lS)-2,2-dimethylcyclopropyl]aniline (Peak 1, 343 mg, 2.12 mmol), CDI (345 mg, 2.12 mmol) and triethylamine (215 mg, 2.12 mmol) in DMF (2 mL) was stirred at 40°C for 1 hour. Upon completion, the resulting mixture cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with H2O (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford methyl 4-(6-(l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 40% yield) as a yellow solid. LCMS (ESI) [M+H]+: 470.2

[0368] Step 6: 4-(6-(l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0369] A solution of methyl 4-(6-(l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 0.21 mmol) and LiOH monohydrate (10.2 mg, 0.43 mmol) in THF (1 mL) and H2O (1 mL) was stirred at room temperature for 1 hour. Upon completion, the mixture was acidified to pH 2 with HC1 (2 M). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Gradient (B%): 10% to 50% in 10 min; detector, UV 254 nm) to yield 4-(6-(l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (50 mg, 51% yield) as a white solid. LCMS (ESI) [M+H]+: 456.2

[0370] Step 7: 4-(6-((S)-l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add and 4-(6-((R)-l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0371] 4-(6-(l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (40 mg, 0.088 mmol) was separated by prep-Chiral-HPLC (Column:CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 250 / 260 nm; RT1 (min): 9.2; RT2 (min): 14.2) to afford (Compound 20a) 4-(6-((S)-l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (1stpeak, 14.7 mg, 36% yield; Method G, Peak 1, 1.10 min) and (Compound 20b) 4-(6-((R)-l-((4-((S)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (2ndpeak, 13.7 mg, 34% yield; Method G, Peak 2, 2.60 min).

[0372] Step 8: methyl 4-(6-(l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0373] A solution of methyl 4-(6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate (150 mg, 0.53 mmol), 4-[(lR)-2,2-dimethylcyclopropyl]aniline (Peak 2, 343 mg, 2.12 mmol), CDI (345 mg, 2.12 mmol) and triethylamine (215 mg, 2.12 mmol) in DMF (2 mL) was stirred at 40°C for 1 hour. Upon completion, the resulting mixture was diluted with EtOAc (30 mL). The organic layer was washed with H2O (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford methyl 4-(6-(l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 40% yield) as a yellow solid. LCMS (ESI) [M+H]+: 470.2

[0374] Step 9: 4-(6-(l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0375] A solution of methyl 4-(6-(l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 0.21 mmol) and LiOH monohydrate (10.2 mg, 0.43 mmol) in THF (1 mL) and H2O (1 mL) was stirred at room temperature for 1 hour. The mixture was acidified to pH 2 with HC1 (2 M). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 10% to 50% in 10 min; detector, UV 254 nm) to give 4-(6-(l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (50 mg, 51% yield) as a white solid. LCMS (ESI) [M+H]+: 456.2

[0376] Step 10: 4-(6-((S)-l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin- 2-yl)pyridin-3-yl)benzoic acid and 4-(6-((R)-l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid

[0377] 4-(6-(l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (40 mg, 0.088 mmol) was separated by prep-Chiral-HPLC (Column:CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 250 / 260 nm; RT1 (min): 9.2; RT2 (min): 20) to afford (Compound 20c) 4-(6-((S)-l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (1stpeak, 16.4 mg, 41% yield; Method G, Peak 1, 1.08 min) and (Compound 20d) 4-(6-((R)-l-((4-((R)-2,2-dimethylcyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (2ndpeak, 15.8 mg, 39% yield; Method G, Peak 2, 2.20 min).Example 22: (R)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)ureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid

[0378] Step 1: tert-butyl (R)-4'-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-fluoro-[ 1,1 ' -biphenyl] -4-carboxylate

[0379] A solution of tert-butyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (150 mg, 0.5 mmol), (tert-butoxycarbonyl)-D-valine (170 mg, 0.8 mmol), 1 -methyl- IH-imidazole (129 mg, 1.5 mmol) and A-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (220 mg, 0.8 mmol) in ACN (6 mL) was stirred at room temperature for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (7?)-4'-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-fluoro-[l,r-biphenyl]-4-carboxylate (120 mg, 47% yield) as a light yellow solid. LCMS [M+H]+: 487

[0380] Step 2: (lf)-4'-(2-amino-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic acid

[0381] To a mixture of tert-butyl (7?)-4'-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylate (115 mg, 0.2 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure to give (7?)-4'-(2-amino-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic acid (100 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS [M+H]+: 331

[0382] Step 3: (lf)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)ureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid

[0383] To a mixture of (7?)-4'-(2-amino-3-methylbutanamido)-3-fluoro-[l, T-biphenyl]-4-carboxylic acid (50 mg, 0.1 mmol) in DCM (2 mL) were added triethylamine (45 mg, 0.4 mmol)and l-isocyanato-4-isopropylbenzene (24 mg, 0.1 mmol) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xbridge Phenyl OBD Column, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 38% B to 58% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 9.18) to afford (7?)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)ureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid (25.9 mg, Compound 22; Method E, Peak 1, 1.40 min - analyzed against Compound 23) as a white solid.Example 23: (S)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)ureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic add

[0384] Step 1: te / 7-butvl (S)-4'-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-

[0385] A solution of tert-butyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (150 mg, 0.5 mmol), (tert-butoxycarbonyl)-L-valine (170 mg, 0.8 mmol), I -methyl- 1 / / -imidazole (129 mg, 1.5 mmol) and A-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (220 mg, 0.8 mmol) in ACN (6 mL) was stirred at room temperature for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (5)-4'-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-fluoro-[l,r-biphenyl]-4-carboxylate (125 mg, 49% yield) as a light yellow solid. LCMS [M+H]+: 487

[0386] Step 2: (S)-4'-(2-amino-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic add

[0387] To a mixture of tert-butyl (5)-4'-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylate (120 mg, 0.2 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure to yield (5)-4'-(2-amino-3-methylbutanamido)-3-fluoro-[l,r-biphenyl]-4-carboxylic acid (110 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS [M+H]+: 331

[0388] Step 3: (S)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)ureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid

[0389] To a mixture of (5)-4'-(2-amino-3-methylbutanamido)-3-fluoro-[l,l'-biphenyl]-4-carboxylic acid (100 mg, 0.3 mmol) in DCM (4.5 mL) were added triethylamine (92 mg, 0.9 mmol) and l-isocyanato-4-isopropylbenzene (49 mg, 0.3 mmol). The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xbridge Phenyl OBD Column, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 38% B to 58% B in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 9.22) to afford (S)-3-fhioro-4'-(2-(3-(4-isopropylphenyl)ureido)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid (22.8 mg, Compound 23; Method E, Peak 2, 1.59 min - analyzed against Compound 22) as a white solid.Example 25: 4'-(2-((4-isopropylphenyl)carbamoyl)pyrazolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add

[0390] Step 1: tert-butyl 2-((4'-(tert-butoxycarbonyl)-[ 1,1 '-biphenyl ]-4-yl)carbamoyl)pyrazolidine-l-carboxylat

[0391] To a mixture of bis (trichloromethyl) carbonate (68 mg, 0.2 mmol) in DCM (6 mL) were added tert-butyl pyrazolidine- 1 -carboxylate (100 mg, 0.5 mmol) and DIEA (225 mg, 1.7 mmol) at 0°C. After 30 minutes, tert-butyl pyrazolidine- 1 -carboxylate (312 mg, 1.1 mmol) was added in portions. The resulting mixture was warmed to room temperature and stirred for an additional 30 minutes. Upon completion, the reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% gradient in 25 min; detector, UV 200 nm) to give tert-butyl 2-((4'-(tert-butoxycarbonyl)-[l,l'-biphenyl]-4-yl)carbamoyl)pyrazolidine-l -carboxylate (110 mg, 40% yield) as an off-white solid. LCMS (ESI) [M+H]+: 468

[0392] Step 2: 4'-(pyrazolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add

[0393] To a mixture of tert-butyl 2-((4'-(tert-butoxycarbonyl)-[l,l'-biphenyl]-4-yl)carbamoyl)pyrazolidine-l -carboxylate (100 mg, 0.2 mmol) in dioxane (1 mL) was added HC1 (20 mmol, 5 mL, 4 M in dioxane) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 12 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to give 4'-(pyrazolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (80 mg, crude) as a white solid. LCMS (ESI) [M+H]+: 312

[0394] Step 3: 4'-(2-((4-isopropylphenyl)carbamoyl)pyrazolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic add

[0395] To a mixture of 4'- (pyrazolidine-1 -carboxamide)- [l,l'-biphenyl]-4-carboxy lie acid (78 mg, 0.2 mmol) in DCM (3.5 mL) were added triethylamine (45 mg, 0.4 mmol) and 1-isocyanato-4-isopropylbenzene (39 mg, 0.2 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 43% to 64% B in 12 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.88) to afford 4'-(2-((4-isopropylphenyl)carbamoyl)pyrazolidine-l-carboxamido)-[l,l'-biphenyl]-4-carboxylic acid (26.3 mg, 24% yield, Compound 25) as a white solid.Example 29: (S)-3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add & (R)-3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0396] Step 1: methyl 3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0397] A solution of 2-(5-bromopyridin-2-yl)-N-(4-isopropylphenyl)pyrrolidine-l-carboxamide (100 mg, 0.26 mmol), methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (87.8 mg, 0.34 mmol), Pd(dppf)Cl2 (18.8 mg, 0.026 mmol), K3PO4 (164 mg, 0.77 mmol) in THF (2 mL) and H2O (0.2 mL) was stirred at 80°C for 2 hours under nitrogen atmosphere. Upon completion,the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (80 mg, 70% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 444.2

[0398] Step 2: 3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0399] A solution of methyl 3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (75 mg, 0.163 mmol) and LiOH monohydrate (68.0 mg, 1.63 mmol) in MeOH (3 mL) and H2O (2 mL) was stirred at room temperature for 2 hours. Upon completion, the mixture was acidified to pH=4 with cone. HC1 acid and then concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% FA), Mobile phase B: MeCN, Gradient (B%): 25% to 80% in 25 min; detector: UV 254 nm) to afford 3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (70 mg, 96% yield) as a white solid. LCMS (ESI) [M+H]+: 430.2

[0400] Step 3: (S)-3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add & (R)-3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0401] 3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (70 mg) was separate by Prep-Chiral-HPLC (conditions: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min;Gradient (B%): isocratic 30% B; Wave Length: 230 / 240 nm; RT1 (min): 8.1; RT2 (min): 11.4) to give (Compound 29a) (S)-3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (1stpeak, 18.0 mg, 26% yield; Method K, Peak 1, 1.00 min) as a white solid and(Compound 29b) (R)-3-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (2ndpeak, 14.9 mg, 21 yield; Method K, Peak 2, 1.43 min) as a white solid.Example 30: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic add & (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic add

[0402] Step 1: tert-butyl 2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-2-methylazetidine- 1 -carboxylate

[0403] A solution of methyl 4-(6-chloropyridin-3-yl)benzoate (900 mg, 3.63 mmol), CS2CO3 (1.78 g, 5.45 mmol), tetrakis(9H-carbazol-9-yl)benzene-l,4-dicarbonitrile (71.7 mg, 0.091 mmol) and NiBr2*bipy (136 mg, 0.363 mmol) in DMF (10 mL) was treated with l-(tert-butoxycarbonyl)-2-methylazetidine-2-carboxylic acid (1.17 g, 5.45 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred and irradiated with 450 nm blue LEDs for 24 hours. The precipitated solids were collected by filtration and the filter cake was washed with DMF (2 x 2 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 22% to 50% in 16 min; detector: UV 254 nm) to afford tert-butyl 2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-2-methylazetidine-l -carboxylate (66 mg, 4.8% yield) as a greenish solid. LCMS (ESI) [M+H]+: 383.5

[0404] Step 2: methyl 4-(6-(2-methylazetidin-2-yl)pyridin-3-yl)benzoate

[0405] A solution of tert-butyl 2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-2-methylazetidine- 1 -carboxylate (60 mg, 0.157 mmol) in DCM (2 mL) was treated with TFA (2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (Conditions: column, C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 20% to 30% in 10 min; detector: UV 254 nm) to afford methyl 4-(6-(2-methylazetidin-2-yl)pyridin-3-yl)benzoate (35 mg, 79% yield) as a white solid. LCMS (ESI) [M+H]+: 283.3

[0406] Step 3: methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoate

[0407] A solution of l-isocyanato-4-isopropylbenzene (25.7 mg, 0.159 mmol) and methyl 4-(6-(2-methylazetidin-2-yl)pyridin-3-yl)benzoate (30 mg, 0.106 mmol) in THF (4 mL) was treated with NMM (32.2 mg, 0.318 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 43% to 56% in 24 min; detector, UV 254 nm) to afford methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoate (30 mg, 64% yield) as a white solid. LCMS (ESI) [M+H]+: 444.6

[0408] Step 4: 4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic add

[0409] A solution of methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoate (30 mg, 0.068 mmol) and LiOH monohydrate (14.0 mg, 0.34 mmol) in MeOH (1 mL) and H2O (1 mL) at room temperature under nitrogen atmosphere. The resultingmixture was stirred at 50°C for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 26% to 39% in 14 min; detector: UV 254 nm) to afford 4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic acid (15 mg, 52% yield) as a white solid. LCMS (ESI) [M+H]+: 430.5

[0410] Step 5: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic add & (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic add

[0411] 4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic acid (14 mg, 0.033 mmol) was separated by prep Chiral-HPLC (conditions: Column: CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 248 / 205 nm; RT1 (min): 10.6; RT2 (min): 14) to give (Compound 30a) (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic acid (1stpeak, 3 mg, 21% yield; Method K, Peak 1, 1.17 min) as a white solid and (Compound 30b) (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)-2-methylazetidin-2-yl)pyridin-3-yl)benzoic acid (2ndpeak, 3.3 mg, 24% yield; Method K, Peak 2, 1.51 min) as a white solid.Example 31: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic add & (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic add

[0412] Step 1: methyl 4-(6-chloropyridin-3-yl)benzoate

[0413] A solution of 4-(methoxycarbonyl)phenylboronic acid (10.0 g, 55.6 mmol) and 5-bromo-2-chloropyridine (10.69 g, 55.6 mmol) in THF (40 mL) and H2O (10 mL) was treated with Pd(dppf)Cl2 (4.07 g, 5.6 mmol) and K3PO4 (35.38 g, 166.7 mmol) at room temperature under nitrogen atmosphere. The reaction was heated at 60°C for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 4- (6-chloropyridin-3-yl)benzoate (6.0 g, 44% yield) as a white solid. LCMS (ESI) [M+H]+: 248.6 Step 2: tert-butyl 2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)piperidine-l-carboxylate,

[0414] A solution of methyl 4-(6-chloropyridin-3-yl)benzoate (1.0 g, 4.04 mmol), CS2CO3 (1.97 g, 6.06 mmol), NiBr2*bipy (0.15 g, 0.404 mmol) and tetrakis(9H-carbazol-9-yl)benzene-l,4-dicarbonitrile (0.08 g, 0.101 mmol) in DMF (10 mL) was treated with l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1.39 g, 6.06 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred and irradiated with 450 nm blue LEDs for 24 hours. Upon completion, the precipitated solids were collected by filtration and the filter cake was washed with DMF (2 x 2 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 40% to 60% in 20 min; detector: UV 254 nm) to afford tert-butyl 2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)piperidine-l -carboxylate (140 mg, 8.8% yield) as a greenish solid. LCMS (ESI) [M+H]+: 397.4

[0415] Step 3: methyl 4-(6-(piperidin-2-yl)pyridin-3-yl)benzoate

[0416] A solution of tert-butyl 2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)piperidine-l-carboxylate (130 mg, 0.33 mmol) in DCM (2 mL) was treated with TFA (2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 18% to 28% in 10 min; detector: UV 254 nm) to afford methyl 4-(6-(piperidin-2-yl)pyridin-3-yl)benzoate (80 mg, 82% yield) as a white solid. LCMS (ESI) [M+H]+: 297.3

[0417] Step 4: methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoate

[0418] A solution of l-isocyanato-4-isopropylbenzene (57.1 mg, 0.35 mmol) and methyl 4-(6-(piperidin-2-yl)pyridin-3-yl)benzoate (70 mg, 0.24 mmol) in THF (4 mL) was treated with NMM (71.7 mg, 0.71 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 30% to 60% in 20 min; detector: UV 254 nm) to afford methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoate (70 mg, 65% yield) as a white solid. LCMS (ESI) [M+H]+: 458.5

[0419] Step 5: 4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic add

[0420] A solution of methyl 4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoate (70 mg, 0.153 mmol) and LiOH monohydrate (32.0 mg, 0.765 mmol) in MeOH (4 mL) and H2O (2 mL) at room temperature under nitrogen atmosphere. The reaction was stirred at 50°C for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 30% to 50% in 20 min; detector: UV 254 nm) to afford 4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic acid (60 mg, 88% yield) as a white solid. LCMS (ESI) [M+H]+: 444.5

[0421] Step 6: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic add & (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic add

[0422] 4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic acid (60 mg, 88% yield) was separated by prep Chiral-HPLC (conditions: Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 20% B; Wave Length: 240 / 250 nm; RT1 (min): 10; RT2 (min): 14.8) to give (Compound 31a) (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic acid (1stpeak, 23.3 mg, 39% yield; Method L, Peak 1, 1.19 min) as a white solid and (Compound 31b) (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)piperidin-2-yl)pyridin-3-yl)benzoic acid (2ndpeak, 22.0 mg, 37% yield; Method L, Peak 2, 1.71 min) as a white solid.Example 32: (S)-4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add & (R)-4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0423] Step 1: 3-fluoro-4-(prop-l-en-2-yl)aniline

[0424] 4-Bromo-3-fluoroaniline (2.0 g, 10.53 mmol), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-1,3,2-dioxaborolane (3.54 g, 21.05 mmol), Pd(dppf)Cl2 (0.86 g, 1.052 mmol) and potassium phosphate tribasic (6.70 g, 31.58 mmol) were dissolved in tetrahydrofuran (8 mL) and water (0.8 mL) at room temperature under a nitrogen atmosphere. The resulting solution was stirred at 80°C for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel chromatography, eluted with (dichloromethane: methanol =15:1) to give 3-fluoro-4-(prop-l-en-2-yl)aniline (1.3 g, 82% yield) as a grey oil. LCMS (ESI) [M+H]+: 152.2

[0425] Step 2: 3-fluoro-4-isopropylaniline

[0426] To a solution of 3-fluoro-4-(prop-l-en-2-yl)aniline (1.3 g, 8.60 mmol) in tetrahydrofuran (10 mL) was added Pd / C (10 wt%, 1.83 g, 17.2 mmol) under nitrogen atmosphere. The reaction system was degassed under vacuum and purged with H2 gas. The mixture was hydrogenated under H2 balloon at 25 °C for 3 hours. Upon completion, the reaction filtered over celite. The filter cake was washed with methanol (20 mL). The corresponding filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography, elutedwith (petroleum ether / ethyl acetate =35:1) to afford 3-fluoro-4-isopropylaniline (1.1 g, 84% yield) as a grey oil. LCMS (ESI) [M+H]+: 154.1

[0427] Step 3: methyl 4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0428] A mixture of 3-fluoro-4-isopropylaniline (369 mg, 2.41 mmol), CDI (488 mg, 3.01 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 10 minutes. Then, methyl 4-[6-(pyrrolidin-2-yl)pyridin-3-yl]benzoate (170 mg, 0.602 mmol) was added. The resulting mixture was stirred for an additional 1 hour. Upon completion, the mixture was poured into water and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase chromatography (conditions: column: C18 silica gel; Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient (B%): 25% to 100% in 30 min; Detector: 254 nm) to afford methyl 4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (120 mg, 43% yield) as alight yellow solid. LCMS (ESI) [M+H]+: 462.2

[0429] Step 4: 4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0430] A mixture of methyl 4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 0.217 mmol), LiOH monohydrate (46 mg, 1.09 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was stirred at room temperature for 1 hour. Upon completion, the mixture was directly purified by reversed-phase chromatography (conditions: column: C18 silica gel; Mobile Phase A: Water (0.1% PA), Mobile Phase B: acetonitrile; Gradient (B%): 25% to 100% in 30 min, Detector: 254 nm) to afford 4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (60 mg, 62% yield) as a light grey solid. LCMS (ESI) [M+H]+: 448.2

[0431] Step 5: (S)-4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin- 3-yl)benzoic add & (R)-4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0432] 4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (60 mg) was separated by prep Chiral-HPLC (conditions: Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 pm; Mobile Phase A: MTBE (0.1% FA), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 10% B; Wave Length: 246 / 204 nm; RT1 (min): 5.73; RT2 (min): 7.86) to afford (Compound 32a) (S)-4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (1stpeak, 10.5 mg, 13% yield; Method J, Peak 1, 0.58 min) as a white solid and (Compound 32b) (R)-4-(6-(l-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (2ndpeak, 11.2 mg, 14% yield; Method J, Peak 2, 0.82 min) as a white solid.Example 37: (S)-4-(6-(l-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic add & (R)-4-(6-(l-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic add

[0433] Step 1: methyl 4-(6-(l-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoate

[0434] A mixture of methyl 4-[5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl]benzoate (200 mg, 0.67 mmol), CDI (540 mg, 3.33 mmol) and triethylamine (337 mg, 3.33 mmol) in DMF (5 mL) were stirred at 60°C. After 30 minutes, 4-chloro-3-(trifhioromethyl)aniline (391 mg, 2.00 mmol) was added and the resulting mixture was stirred at 60°C for an additional 1 hour. Upon completion, the mixture was allowed to cool down to room temperature and was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 20% to 70% in 10 min; detector: UV 254 nm) to afford methyl 4-(6-(l-((4-chloro-3-(trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoate (100 mg, crude) as a yellow oil. LCMS (ESI) [M+H]+: 522.1

[0435] Step 2: 4-(6-(l-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic add

[0436] A solution of methyl 4-(6-(l-((4-chloro-3-(trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoate (100 mg, 0.192 mmol) and LiOH monohydrate (40.3 mg, 0.96 mmol) in THF (1 mL) and H2O (0.2 mL) was stirred at 50°C for 2 hours. Upon completion, the mixture was allowed to cool down to room temperature and the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (3 x 5 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% LA), Mobile Phase B: MeCN; Gradient (B%): 10% to 60% in 20 min; detector: UV 254 nm) to afford 4-(6-(l-((4-chloro-3-(trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic acid (80 mg, 82% yield) as a yellow solid. LCMS (ESI) [M+H]+: 508.1

[0437] Step 3: (S)-4-(6-(l-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)- 5-fluoropyridin-3-yl)benzoic acid & (R)-4-(6-(l-((4-chloro-3- (trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic acid

[0438] 4-(6-(l-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin- 3-yl)benzoic acid (80 mg, 0.158 mmol) was separated by prep Chiral-HPLC (conditions:Column: CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 10% B; Wave Length: 253 / 286 nm; RT1 (min): 17.11; RT2 (min): 26.84) to afford (Compound 37a) (S)-4-(6-(l-((4-chloro-3- (trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic acid (1stpeak, 29.4 mg, 37% yield; Method O, Peak 1, 1.84 min) as a white solid and (Compound 37b) (R)-4- (6-(l-((4-chloro-3-(trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic acid (2ndpeak, 27.8 mg, 35% yield; Method O, Peak 2, 2.85 min) as a white solid.Example 38: (S)-4-(5-fluoro-6-(l-((3-fluoro-4- (trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid & (R)-4-(5-fluoro-6-(l-((3-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid

[0439] Step 1: methyl 4-(5-fluoro-6-(l-((3-fluoro-4- (trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0440] A solution of 3-fluoro-4-(trifluoromethyl)aniline (358 mg, 2.00 mmol), CDI (324 mg, 2.00 mmol) in DMF (2 mL) was treated with EtsN (202 mg, 2.00 mmol) followed by the dropwise addition of methyl 4-[5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl]benzoate (120 mg, 0.400 mmol). The resulting mixture was stirred at 70°C for 2 hours. Upon completion, the mixture was cooled to room temperature and was directly purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 25% to 100% in 25 min; detector: UV 254 nm) to afford methyl 4-(5-fluoro-6-(l-((3-fhioro-4-(trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 50% yield) as a light yellow oil. LCMS (ESI) [M+H]+: 506.1

[0441] Step 2: 4-(5-fluoro-6-(l-((3-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0442] To a solution of methyl 4-(5-fluoro-6-(l-((3-fluoro-4-(trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 0.198 mmol) in MeOH (2 mL) and H2O (2 mL) was added LiOH monohydrate (83.0 mg, 1.98 mmol). The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was acidified to pH=4 with cone. HC1 acid and then concentrated under reduced pressure. The crude residue was directly purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: Water (0.1% FA), Mobile Phase B: MeCN; Gradient (B%): 15% to 50% in 25 min; detector: UV 254 nm) to afford 4-(5-fluoro-6-(l-((3-fluoro-4-(trifhioromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (75 mg, 77% yield) as a white solid. LCMS (ESI) [M+H]+: 492.1

[0443] Step 3: (S)-4-(5-fluoro-6-(l-((3-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add & (R)-4-(5-fluoro-6-(l-((3-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0444] 4-(5-fluoro-6-(l-((3-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (75 mg) was separated by Prep-Chiral HPLC (conditions: Column:CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 20% B; Wave Length: 250 / 284 nm; RT1 (min): 6.43; RT2 (min): 8.55) to give (Compound 38a) (S)-4-(5-fluoro-6-(l-((3-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (1stpeak, 28.6 mg, 38% yield; Method P, Peak 1, 0.80 min) as a white solid and (Compound 38b) (R)-4-(5-fluoro-6-(l-((3-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (2ndpeak, 28.2 mg, 38% yield; Method P, Peak 2, 1.03 min) as a white solid.Example 40: (S)-5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2-methylbenzoic add & (R)-5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2-methylbenzoic add

[0445] Step 1: methyl 5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)- 2-methylbenzoate

[0446] 2-(5-bromopyridin-2-yl)-N-(4-isopropylphenyl)pyrrolidine-l-carboxamide (100 mg, 0.26 mmol), (3-(methoxycarbonyl)-4-methylphenyl)boronic acid (125 mg, 0.6 mmol), Pd(dppf)Cl2 (21.0 mg, 0.026 mmol) and potassium phosphate tribasic (164 mg, 0.77 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). The mixture was stirred at 80°C for 1 hour under nitrogen atmosphere. Upon completion, the mixture was concentrated under reduced pressure.The crude residue was purified by silica gel chromatography, eluted with (Petroleum ether / Ethyl acetate =15:1) to give methyl 5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2- yl)pyridin-3-yl)-2-methylbenzoate (95 mg, 81% yield) as a yellow solid. LCMS (ESI) [M+H]+: 458.6

[0447] Step 2: 5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2- methylbenzoic add

[0448] A mixture of methyl 5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3- yl)-2-methylbenzoate (90 mg, 0.20 mmol), lithium hydroxide monohydrate (42.0 mg, 0.99 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) was stirred at room temperature for 1 hour. Upon completion, the mixture was directly purified by reversed-phase column chromatography (conditions: column: C18 Silica gel; Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient (B%): 0% to 100% in 25 min; detector: 254 nm) to afford 5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2-methylbenzoic acid (80 mg, 87% yield) as an off-white solid. LCMS (ESI) [M+H]+: 444.6

[0449] Step 3: (S)-5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2- methylbenzoic add & (R)-5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3- yl)-2-methylbenzoic add

[0450] 5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2-methylbenzoic acid (80 mg, 0.180 mmol) was separated by Prep-CHIRAL HPLC (conditions: Column:CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 237 / 254 nm; RT1 (min): 77.2; RT2 (min): 91.2) to afford (Compound 40a) (S)-5-(6-(l-((4- isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2-methylbenzoic acid (1stpeak, 31.1 mg, 39% yield; Method K, Peak 1, 0.91 min) as a white solid and (Compound 40b) (R)-5-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)-2-methylbenzoic acid (2ndpeak, 30.0 mg, 38% yield; Method K, Peak 2, 1.79 min) as a white solid. LCMS (ESI) [M+H]+: 444.6Example 44: (S)-4-(5-fluoro-6-(l-((4-(l-(trifluoromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add and (7f)-4-(5-fluoro-6-(l-((4-(l-(trifluoromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0451] Step 1: methyl 4-(5-fluoro-6-(l-((4-(l- (trifluoromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0452] A mixture of ditrichloromethyl carbonate (40 mg, 0.1 mmol) and 4-[l-(trifluoromethyl)cyclopropyl]aniline (67 mg, 0.3 mmol) in THF (2 mL) was stirred at 0°C for 5 minutes under nitrogen atmosphere. Then, methyl 4-(5-fhioro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate (100 mg, 0.3 mmol) was added dropwise. The resulting mixture was warmed to room temperature and was allowed to stir for an additional 1 hour. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 4-(5-fluoro-6-(l-((4-(l-(trifhioromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (140 mg, 79% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 528

[0453] Step 2: 4-(5-fluoro-6-(l-((4-(l-(trifluoromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0454] To a stirred mixture of methyl 4-(5-fluoro-6-(l-((4-(l-(trifluoromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (125 mg, 0.2 mmol) in H2O (0.5 mL) and THF (2 mL) was added LiOH monohydrate (50.4 mg, 1.2 mmol) in portions at room temperature. After 16 hours, the mixture was acidified to pH 6 with 1 M HC1 (aq). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: water (0.1% formic acid), Mobile Phase B: MeCN; Gradient (B%): 10% to 40% in 20 min; detector: UV 254 nm) to afford 4-(5-fluoro-6-(l-((4-(l-(trifhioromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (85 mg, 69% yield) as a white solid. LCMS (ESI) [M+H]+: 514

[0455] Step 3: (S)-4-(5-fluoro-6-(l-((4-(l-(trifluoromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add and (R)-4-(5-fluoro-6-(l-((4-(l-(trifluoromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0456] 4-(5-fhioro-6-(l-((4-(l-(trifhioromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (83 mg) was purified by Prep-Chiral-HPLC (conditions: Column: CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% formic acid), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 248 / 286 nm; RT1 (min): 6.42; RT2 (min): 10.44) to afford first peak (S)-4-(5-fluoro-6-(l-((4-(l-(trifhioromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (25.3 mg, Compound 44a; Method K, Peak 1, 0.82 min) as a white solid and second peak (R)-4-(5-fhioro-6-(l-((4-(l-(trifhioromethyl)cyclopropyl)phenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (25.1 mg, Compound 44b; Method K, Peak 2, 1.29 min) as a white solid.Example 45: (S)-4-(5-fluoro6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add and (lf)-4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0457] Step 1: 2-fluoro-4-(prop-l-en-2-yl)aniline

[0458] To a mixture of 4-bromo-2-fluoroaniline (2.0 g, 10.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.12 g, 12.6 mmol) and Pd(dppf)Cl2 (0.77 g, 1.0 mmol) in dioxane (20 mL) and H2O (4 mL) was added K3PO4 (6.7 g, 31.5 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 hours. Upon completion, the reaction was allowed to cool down to room temperature and was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford 2-fluoro-4-(prop-l-en-2-yl)aniline (1.2 g, 75% yield) as a light purple oil. LCMS (ESI) [M+H]+: 152

[0459] Step 2: 2-fluoro-4-isopropylaniline

[0460] To a solution of 2-fluoro-4-(prop-l-en-2-yl)aniline (600 mg, 3.9 mmol) in MeOH (6 mL) was added Pd / C (84 mg, 0.08 mmol, 10 wt%) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. Upon completion, the resulting mixture was filtered over celite. The filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure to afford 2-fluoro-4-isopropylaniline (550 mg, crude) as a light purple oil, which was used in the next step directly without further purification. LCMS (ESI) [M+H]+: 154

[0461] Step 3: methyl 4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate

[0462] To a mixture of ditrichloromethyl carbonate (60 mg, 0.2 mmol) in THF (2 mL) was added 2-fluoro-4-isopropylaniline (77 mg, 0.5 mmol) and DIEA (323 mg, 2.5 mmol) dropwise at 0°C under nitrogen atmosphere. After 10 minutes, methyl 4-(5-fhioro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoate (150 mg, 0.5 mmol) in THF (2 mL) was added dropwise over 2 minutes. The resulting mixture was warmed to room temperature and stirred for an additional 1 hour. Upon completion, the reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl 4- (5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (120 mg, 50% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 480

[0463] Step 4: 4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0464] To a mixture of methyl 4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoate (120 mg, 0.2 mmol) in H2O (0.5 mL) and THF (2 mL) was added LiOH monohydrate (50.4 mg, 1.2 mmol) in portions at room temperature. After 16 hours, the mixture was acidified to pH 6 with 1 M HC1 (aq). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-(5-fhioro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (90 mg, 77% yield) as a white solid. LCMS (ESI) [M+H]+: 466

[0465] Step 5: (S)-4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add and (R)-4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0466] 4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (90 mg) was purified by prep Chiral-HPLC (conditions: Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% formic acid), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30% B; Wave Length: 240 / 250 nm; RT1 (min): 11.8; RT2 (min): 13.8) to afford first peak (5)-4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (39.6 mg, Compound 45a;Method A, Peak 1, 1.17 min) as a white solid and second peak (R)-4-(5-fluoro-6-(l-((2-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (36.5 mg, Compound 45b;Method A, Peak 2, 1.48 min) as a white solid.Example 46: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic add and (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic add

[0467] Step 1: tert-butyl 2-(5-chloro-3-methylpyridin-2-yl)pyrrolidine-l -carboxylate[lr(dF(Me)ppy)2(dtbbpy)]PF6, NiBr2(dtbbpy),, TMG, dioxane, DMA, blue LED,460nm

[0468] To a mixture of 2-bromo-5-chloro-3-methylpyridine (500 mg, 2.4 mmol), l-(tert-butoxycarbonyl)pyrrolidin-2-ylboronic acid (781 mg, 3.6 mmol), [Ir(dF(Me)ppy)2(dtbbpy)]PF6 (61 mg, 61 pmol), A, A, M, W-tetramethylguanidine (836 mg, 7.2 mmol) and [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (117 mg, 0.2 mmol) in dioxane (8 mL) was added N, N-dimethylacetamide (2 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours with irradiation by 460 nm blue light. Upon completion, the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford tert-butyl 2-(5-chloro-3-methylpyridin-2-yl)pyrrolidine-l-carboxylate (280 mg, 39% yield) as a light yellow oil. LCMS [M+H]+: 297

[0469] Step 2: tert-butyl 2-(5-(4-(tert-butoxycarbonyl)phenyl)-3-methylpyridin-2-yl)pyrrolidine- 1 -carboxylate

[0470] A solution of tert-butyl 2-(5-chloro-3-methylpyridin-2-yl)pyrrolidine-l-carboxylate (270 mg, 0.9 mmol), K3PO4 (579 mg, 2.7 mmol), Xphos Pd G3 (77 mg, 91 pmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzoate (332 mg, 1.0 mmol) in dioxane (4 mL) and H2O (1 mL) was stirred at 80°C for 2 hours under nitrogen atmosphere. The reaction was allowed to cool down to room temperature and was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford tert-butyl 2-(5-(4-(tert-butoxycarbonyl)phenyl)-3-methylpyridin-2-yl)pyrrolidine-l -carboxylate (200 mg, 50% yield) as a light yellow solid. LCMS [M+H]+: 439

[0471] Step 3: 4-[5-methyl-6-(pyrrolidin-2-yl)pyridin-3-yl]benzoic acid

[0472] A solution of tert-butyl 2-(5-(4-(tert-butoxycarbonyl)phenyl)-3-methylpyridin-2-yl)pyrrolidine-l -carboxylate (190 mg, 0.4 mmol) in 4.0 M HC1 in 1,4-dioxane (2 mL) was stirredat room temperature for 4 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to afford 4-[5-methyl-6-(pyrrolidin-2-yl)pyridin-3-yl]benzoic acid (120 mg, crude), which was used directly in the next step without further purification LCMS [M+H]+: 283

[0473] Step 4: 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic acid

[0474] A solution of 4-[5-methyl-6-(pyrrolidin-2-yl)pyridin-3-yl]benzoic acid (110 mg, 0.3 mmol) and l-isocyanato-4-isopropylbenzene (62 mg, 0.3 mmol) in DCM (2 mL) was stirred at room temperature for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A water (0.1% formic acid), Mobile phase B: MeCN; Gradient (B%): 30% to 80% in 20 min; detector, UV 254 nm) to afford 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic acid (90 mg, 52% yield) as an off-white solid. LCMS [M+H]+: 444

[0475] Step 5: (S)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic acid and (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic acid

[0476] 4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic acid (90 mg, 0.2 mmol) was purified by prep-Chiral-HPLC (conditions: Column: CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% formic acid), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 20% B; Wave Length: 262 / 236 nm; RT1 (min): 14.2; RT2 (min): 17) to afford first peak (5)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic acid (32.1 mg, Compound 46a; Method K, Peak 1, 0.96 min) as an off-white solid and second peak (R)-4-(6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-5-methylpyridin-3-yl)benzoic acid (31.0 mg, Compound 46b, Method K, Peak 2, 1.22 min) as a white solid.Example 47: (S)-4'-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic add

[0477] Step 1: tert-butyl (S)-2-(4'-(tert-butoxycarbonyl)-[l,l'-biphenyl]-4-yl)pyrrolidine-l-carboxylate

[0478] A mixture of tert-butyl (5)-2-(4-bromophenyl)pyrrolidine-l -carboxylate (293 mg, 0.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (395 mg, 1.3 mmol), Xphos Pd G3 (77 mg, 92 pmol) and K3PO4 (585 mg, 2.7 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 80°C for 2 hours under nitrogen atmosphere. Upon completion, the mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford tert-butyl (5)-2-(4'-(tert-butoxycarbonyl)-[ 1, l'-biphenyl]-4-yl)pyrrolidine-l -carboxylate (310 mg, 79% yield) as a white solid. LCMS [M+H]+: 424

[0479] Step 2: (S)-4'-(pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic add

[0480] A solution of tert-butyl ( )-2-(4'-(tert-butoxycarbonyl)-[l,r-biphenyl]-4-yl)pyrrolidine-l-carboxylate (300 mg, 0.7 mmol) in 4 M HC1 in dioxane (10 mL) was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure to afford (5)-4'-(pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic acid (180 mg, crude) as a white solid, which was used directly in the next step without further purification. LCMS [M+H]+: 268

[0481] Step 3: (S)-4'-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic acid

[0482] To a stirred solution of ( )-4'-(pyrrolidin-2-yl)-[l, T-biphenyl]-4-carboxylic acid (80 mg, 0.3 mmol) and TEA (151 mg, 1.4 mmol) in DCM (1 mL) was added l-isocyanato-4-isopropylbenzene (48 mg, 0.3 mmol) in portions at 0°C. The resulting mixture was warmed to room temperature and stirred for an additional 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was directly purified by prep Prep-HPLC (conditions; Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 48% to 68% in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.57) to afford (5)-4'-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic acid (36.0 mg, Compound 47; Method I; Peak 1, 1.51 min - analyzed against Compound 48) as a white solid.Example 48: (R)-4'-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic add

[0483] Step 1: tert-butyl (R)-2-(4'-(tert-butoxycarbonyl)-[ l,l'-biphenyl]-4-yl)pyrrolidine-l-carboxylate

[0484] A mixture of tert-butyl (27?)-2-(4-bromophenyl)pyrrolidine-l-carboxylate (300 mg, 1.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (279 mg, 1.0 mmol), Pd(dppf)Cl2 (67 mg, 0.1 mmol) and K3PO4 (585 mg, 2.7 mmol) in dioxane (3 mL) and H2O (0.6 mL) was stirred at 80°C for 2 hours under nitrogen atmosphere. Upon completion, the mixture was allowed to cool down to room temperature and was diluted with water. The resulting mixturewas extracted with EtOAc (3 x 100 mL). the combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford tert-butyl (7?)-2-(4'-(tert-butoxycarbonyl)-[l,l'-biphenyl]-4-yl)pyrrolidine-l-carboxylate (330 mg, 84% yield) as a white solid. LCMS (ESI) [M+H]+: 424

[0485] Step 2: (R)-4'-(pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic add

[0486] A mixture of tert-butyl (7?)-2-(4'-(tert-butoxycarbonyl)-[l,l'-biphenyl]-4-yl)pyrrolidine-l -carboxylate (330 mg, 0.7 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 6 hours. Upon completion, the resulting mixture was concentrated under reduced pressure to afford (7?)-4'-(pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic acid (200 mg, crude) as a white solid, which was used directly in the next step without further purification. LCMS (ESI) [M+H]+: 268

[0487] Step 3: (R)-4'-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic add

[0488] A mixture of (7?)-4'-(pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic acid (80 mg, 0.3 mmol), TEA (90 mg, 0.9 mmol) and l-isocyanato-4-isopropylbenzene (48 mg, 0.3 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 49% to 69% in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.25) to afford (7?)-4'-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)-[l,l'-biphenyl]-4-carboxylic acid (35.6 mg, Compound 48; Method I; Peak 2, 1.93 min - analyzed against Compound 47) as a white solid.Example 49: (S)-4-(5-fluoro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)p yridin-3-yl)benzoic add and (lf)-4-(5-fluoro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl) pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0489] Step 1: 3-methyl-4-(prop-l-en-2-yl)aniline

[0490] A solution of 4-bromo-3-methylaniline (1.00 g, 5.3 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.81 g, 10.7 mmol), Pd(dppf)Cl2 (390 mg, 0.5 mmol), K3PO4 (3.42 g, 16.1 mmol) and H2O (1 mL) in dioxane (10 mL) was stirred at 80°C for 2 hours under nitrogen atmosphere. Upon completion, the mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filter cake was washed with DCM (3 x 15 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-methyl-4-(prop-l-en-2-yl)aniline (600 mg, 75% yield) as a yellow oil. LCMS [M+H]+: 148

[0491] Step 2: 4-isopropyl-3-methylaniline

[0492] To a mixture of 3-methyl-4-(prop-l-en-2-yl)aniline (590 mg, 4.0 mmol) in MeOH (10 mL) was added Pd / C (426 mg, 10 wt%) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. Upon completion, the resulting mixture was filtered over celite. The filter cake was washed with MeOH (3 x 15 mL). The resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-isopropyl-3-methylaniline (450 mg, 75% yield) as a yellow oil. LCMS [M+H]+: 150

[0493] Step 3: 4-(5-fluoro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid

[0494] To a mixture of 4-isopropyl-3-methylaniline (80 mg, 0.5 mmol) in DCM (5 mL) were added with DIEA (346 mg, 2.7 mmol) and ditrichloromethyl carbonate (80 mg, 0.3 mmol) dropwise at 0°C under nitrogen atmosphere. After 30 minutes, the reaction was warmed to room temperature and 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (153 mg, 0.5 mmol) was added dropwise over 2 minutes. The resulting mixture was stirred for additional 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 7 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10:1) to afford 4-(5-fluoro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (80 mg, 32% yield) as a yellow solid. LCMS [M+H]+: 462

[0495] Step 4: (S)-4-(5-fluoro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid and (R)-4-(5-fluoro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid

[0496] 4-(5-fhioro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (78 mg) was separated by Prep-Chiral HPLC (conditions: Column:CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hexane (0.1% formic acid), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 25% B; Wave Length: 247 / 210 nm; RT1 (min): 6.79; RT2 (min): 15.15) to afford first peak (S)-4-(5-fhioro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (20.5 mg, Compound 49a;Method P, Peak 1, 1.53 min) as a white solid and second peak (R)-4-(5-fluoro-6-(l-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (26.3 mg, Compound 49b;Method P, Peak 2, 2.77 min) as a white solid.Example 51: (7f)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[1,1' -biphenyl] -4-carboxylic acid

[0497] Step 1: tert-butyl (7f)-3-fluoro-4'-(2-hydroxy-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylate

[0498] A solution of (7?)-2-hydroxy-3-methylbutanoic acid (150 mg, 1.3 mmol), tert-butyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (365 mg, 1.3 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (356 mg, 1.3 mmol) and 1 -methyl- l / 7-imidazole (521 mg, 6.4 mmol) in ACN (5 mL) was stirred for 2 hours at room temperature. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector, UV 254 nm) to afford tert-butyl (7?)-3-fluoro-4'-(2-hydroxy-3-methylbutanamido)-[l, T-biphenyl]-4-carboxylate (140 mg, 28% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 388

[0499] Step 2: tert-butyl (7f)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylate

[0500] To a mixture of tert-butyl (7?)-3-fluoro-4'-(2-hydroxy-3-methylbutanamido)-[l, T-biphenyl] -4-carboxylate (130 mg, 0.3 mmol) in DCM (6 mL) were added TEA (85 mg, 0.8mmol) and l-isocyanato-4-isopropylbenzene (81 mg, 0.5 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl (t )-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylate (100 mg, 54% yield) as a white solid. LCMS (ESI) [M+H]+: 549

[0501] Step 3: (R)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylic acid

[0502] To a mixture of tert-butyl (7?)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylate (100 mg, 0.2 mmol) in dioxane (1 mL) was added 4M HC1 in 1,4-dioxane (5 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 41% to 62% in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 9.87) to afford (7?)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[l, T-biphenyl]-4-carboxylic acid (35.4 mg, Compound 51; Method E, Peak 1, 1.27 min - analyzed against Compound 52) as a white solid.Example 52: (S)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[1,1' -biphenyl] -4-carboxylic acid

[0503] Step 1: tert-butyl (S)-3-fluoro-4'-(2-hydroxy-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylate

[0504] A solution of (5)-2-hydroxy-3-methylbutanoic acid (150 mg, 1.3 mmol), tert-butyl 4'-amino-3-fluoro-[l,r-biphenyl]-4-carboxylate (365 mg, 1.3 mmol), N-(chloro(dimethylamino)methylene)-A-methylmethanaminium hexafluorophosphate(V) (356 mg, 1.3 mmol) and 1 -methyl- 1 H-imidazole (521 mg, 6.4 mmol) in ACN (5 mL) was stirred for 2 hours at room temperature. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Gradient (B%): 5% to 95% in 25 min; detector: UV 254 nm) to afford tert-butyl (S)-3-fhioro-4'-(2-hydroxy-3-methylbutanamido)-[l, T-biphenyl]-4-carboxylate (145 mg, 28% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 388

[0505] Step 2: tert-butyl (S)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylate

[0506] To a mixture of tert-butyl (S)-3-fhioro-4'-(2-hydroxy-3-methylbutanamido)-[l, T-biphenyl]-4-carboxylate (135 mg, 0.3 mmol) in DCM (6 mL) were added TEA (88 mg, 0.9 mmol) and l-isocyanato-4-isopropylbenzene (84 mg, 0.5 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SO4h, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl (. S')-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylate (100 mg, 54% yield) as a white solid. LCMS (ESI) [M+H]+: 549

[0507] Step 3: (S)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)- [1,1' -biphenyl] -4-carboxylic acid

[0508] To a mixture of tert-butyl (5)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[l, T-biphenyl]-4-carboxylate (110 mg, 0.2 mmol) in dioxane (1 mL) was added 4M HC1 in 1,4-dioxane (5 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 41% to 62% in 15 min; Wave Length: 254 nm / 220 nm; RT1 (min): 9.6) to afford (S)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)-3-methylbutanamido)-[l,l'-biphenyl]-4-carboxylic acid (36.8 mg, Compound 52; Method E, Peak 2, 1.35 min - analyzed against Compound 51) as a white solid.Example 53: 3-fluoro-4'-(l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l-carboxamido)- [1,1' -biphenyl] -4-carboxylic acid

[0509] Step 1: l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l-carboxylic acid

[0510] To a mixture of 1 -hydroxycyclopentane- 1 -carboxylic acid (300 mg, 2.3 mmol) in DCM (8 mL) were added TEA (700 mg, 6.9 mmol) and l-isocyanato-4-isopropylbenzene (743 mg, 4.6 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l -carboxylic acid (180 mg, 27% yield) as a yellow solid. LCMS (ESI) [M+H]+: 292

[0511] Step 2: tert-butyl 3-fluoro-4'-(l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l-carboxamido)- [1,1' -biphenyl] -4-carboxylate

[0512] To a mixture of l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l-carboxylic acid (170 mg, 0.6 mmol) and tert-butyl 4'-amino-3-fluoro-[l, T-biphenyl]-4-carboxylate (168 mg, 0.6 mmol) in EtOAc (2 mL) was added pyridine (6 mL) and propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (1.11 g, 1.7 mmol) dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: water (0.1% formic acid), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% in 20 min; detector, UV 254 nm. This resulted in tert-butyl 3-fluoro-4'-(l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l-carboxamido)-[l,l'-biphenyl]-4-carboxylate (60 mg, 18% yield) as a yellow oil. LCMS (ESI) [M+H]+: 561

[0513] Step 3: 3-fluoro-4'-(l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l-carboxamido)- [1,1' -biphenyl] -4-carboxylic acid

[0514] To a mixture of tert-butyl 3-fluoro-4'-(l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane- 1 -carboxamide)- [ 1, 1 '-biphenyl] -4-carboxylate (58 mg, 0.1 mmol) in dioxane (0.5 mL) was added 4M HC1 in 1,4-dioxane (2.5 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (conditions: Column: Xselect CSH Prep C18, 30*150 mm 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 54% to72% in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 10.65) to afford 3-fluoro-4'-(l-(((4-isopropylphenyl)carbamoyl)oxy)cyclopentane-l-carboxamido)-[l,r-biphenyl]-4-carboxylic acid (10.4 mg, 20% yield) as a white solid.Example 54A: A synthetic route to (S)-4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add and (R)-4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0515] Step 1: 4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0516] To a mixture of 4-(5-fluoro-6-(pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (125 mg, 0.4 mmol) in DCM (5 mL) were added TEA (88 mg, 0.9 mmol) and l-isocyanato-4-isopropylbenzene (84 mg, 0.5 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with ice water at 0°C. The resulting mixture was extracted with EtOAc (3 x 7 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (conditions: column: C18 silica gel; mobile phase A: water (0.1% formic acid), Mobile Phase B: MeCN; Gradient (B%): 0% to 100% in 20 min; detector: UV 254 nm) to afford 4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (38 mg, 19% yield) as a yellow solid. LCMS [M+H]+: 448

[0517] Step 2: (S)-4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid and (R)-4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic add

[0518] 4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (99 mg) was separated by Prep-Chiral HPLC (conditions: Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: MTBE (0.1% FA), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 10% B; Wave Length: 274 / 202 nm; RT1 (min): 7.21; RT2 (min): 10.22) to afford first peak (Compound 54a; Method U, Peak 1, 0.82 min) (5)-4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (36.5 mg) as a white solid and second (Compound 54b; Method U, Peak 2, 1.20 min) (R)-4-(5-fluoro-6-(l-((4-isopropylphenyl)carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid (35.1 mg) as an off-white solid.Example 54B-1: An alternative synthetic route for (S)-4-(5-fluoro-6-(l-((4-isopropylphenyl) carbamoyl)pyrrolidin-2-yl)pyridin-3-yl)benzoic acid

[0519] Step 1: tert-butyl (2S,4R)-2-(3-fluoro-5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-4-hydroxypyrrolidine- 1 -carboxylate

[0520] A mixture of methyl 4-(6-chloro-5-fluoropyridin-3-yl)benzoate (500 mg, 1.88 mmol), (2S,4R)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (653 mg, 2.82 mmol), dichloronickel* 1,2-dimethoxyethane (41.4 mg, 0.19 mmol), 4,4'-dimethoxy-2,2'-bipyridine (48.8 mg, 0.23 mmol), N"-tert-butyl-N, N, N', N'-tetramethylguanidine (484 mg, 2.82 mmol), Ir[dF(CF3)ppy]2(dtbpy))PF6 (42.2 mg, 0.038 mmol) and 2, 3-dihydro-lH-isoindole- 1,3-dione (277 mg, 1.88 mmol) in DMSO (8 mL) was stirred at 25°C under nitrogen atmosphere. The resulting mixture was stirred and irradiated with 450 nm blue LEDs for 24 hours. Upon completion, the mixture was directly purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase A: H2O, Mobile Phase B: MeCN (0.1% FA); Gradient (B%): 10% to 50% in 10 min; detector, UV 254 nm) to afford tert-butyl (2S,4R)-2-(3-fluoro-5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-4-hydroxypyrrolidine-l-carboxylate (450 mg, 57% yield) as a brown oil. LCMS (ESI) [M+H]+: 417.1Step 2: tert-butyl (2S,4R)-2-(3-fluoro-5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-4-((phenoxycarbonothioyl)oxy)pyrrolidine-l-carboxylate

[0521] To a stirred solution of tert-butyl (2S,4R)-2-(3-fluoro-5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-4-hydroxypyrrolidine-l-carboxylate (400 mg, 0.96 mmol) and DMAP (235 mg, 1.92 mmol) in MeCN (4 mL) was added phenyl chloromethanethioate (199 mg, 1.15 mmol) in portions at 0°C. The resulting mixture was warm...

Claims

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:A is absent, -(Co-C4)alkyl-C(0)OR2, OR2, or H wherein the -N(H)S(O)2-CH3 is optionally substituted with one to three halogens;R2is H or (Ci-Ce)alkyl;X is -W3-L-W4-, wherein L is absent, -C(O)-N(H)-, or -N(H)-C(O)-, wherein W3is bonded to A and W4is bonded to W;W3is absent, phenyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 membered heteroaryl, or a 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, said phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, and a 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen;wherein W3is optionally mono-, di-, or tri-substituted independently with hydroxy, halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is absent, phenyl, 5 to 6 membered heteroaryl, phenyl fused to a (C3-C?)cycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl, or a phenyl fused to a 5 to 7 membered heteroaryl; wherein said 5 to 6 membered heteroaryl, phenyl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a (C3-C?)cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl and phenyl fused to a 5 to 7 membered heteroaryl have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;wherein when W is absent and W1is a ring system, W4optionally shares one atom with W1in a spiro linkage;wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W is absent, -*C(O)-N(H)-, -*N(H)-C(O)-, or -*N(H)S(O)2-, wherein the represents the point of attachment of W to X;W1is -CH(Y)-, -C(R10)(R11)-, (C3-C7)cycloalkyl, (C5-C6)cycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl;wherein adjacent ring atoms of each of said (Cs-Cvjcycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocyclo alkenyl are bonded to W and W2;wherein each of said 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;wherein R10and R11are each independently H or (Ci-C4)alkyl; or R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring; or R10and R11can be taken together with the carbon to which they are attached to form a (Cs-Cejcycloalkyl ring fused to a phenyl ring;wherein each of said (Cs-Cvjcycloalkyl, (Cs-Cejcycloalkyl ring fused to a phenyl ring, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 membered heterocycloalkenyl is optionally mono- or di- substituted independently with (Ci-C4)alkyl, halo, (Ci-C4)alkoxy, or trifluoromethyl, or is optionally mono-substituted with phenyl, or are spiro linked to a cyclopropyl or oxetanyl;wherein Y is (Ci-Ce)alkyl, phenyl or (Cs-Cvjcycloalkyl) each optionally mono-substituted with phenyl or trifluoromethyl;-*O-C(O)-NH-, -*C(O)-wherein the (Ci-C3)alkyl is optionally substituted with (Ci-C3)alkyl, halo, (Ci-C3)alkoxy or (Ci-C3)alkoxy(Ci-C3)alkyl and the represents the point of attachment to W1;Z is 5 to 7 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, C3-Ce cycloalkyl, 5-10 membered bridged cycloalkyl, phenyl fused to a 5 to 6 membered heteroaryl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, a 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl, phenyl fused to a 5 to 7 membered heterocycloalkyl or phenyl fused to a 5 to 7 membered cycloalkyl, wherein said 5 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, phenyl fused to a 5 to 6 membered heteroaryl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered cycloalkyl, 5 to 6 membered heteroaryl fused to a 5 to 7 membered heterocycloalkyl and phenyl fused to a 5 to 7 membered heterocycloalkyl have 1 to 3 heteroatoms selected independently from nitrogen, oxygen and sulfur;each R3is independently (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo, phenyl, mono-, di- or tri-halo(Ci- C4)alkyl, -SCF3, -OCF3, -OCHF2, (C3-C?)cycloalkyl, said (C3-C?)cycloalkyl optionally substituted independently with 1 or 2 (Ci-C4)alkyl, or mono-, di- or tri-halo(Ci-C4)alkyl;R4is (Ci-C4)alkyl or phenyl; andn is 0, 1, 2, or 3;with the proviso that W4-W-W1-W2-Z is not2. The compound of claim 1, wherein A is absent or -(Co-C4)alkyl-C(0)OR2; W3is phenyl; W4is phenyl; and wherein W3and W4are each independently optionally mono-, di-, or trisubstituted independently with halo,(Ci-C4)alkyl or (Ci-C4)alkoxy.

3. The compound of claim 1, wherein A is absent or -(Co-C4)alkyl-C(0)OR2; W3is a 5 to 6 membered heteroaryl; and W4is phenyl; and wherein W3and W4are each independently optionally mono-, di-, or tri-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

4. The compound of claim 1, wherein A is absent or -(Co-C4)alkyl-C(0)OR2; W3is absent; and W4is a 5 to 6 membered heteroaryl fused to a 5 to 6 membered heteroaryl having 1 to 4 heteroatoms selected independently from nitrogen, sulfur and oxygen; and wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

5. The compound of claim 1, wherein A is absent or -(Co-C4)alkyl-C(0)OR2; W3is phenyl; W4is phenyl fused to a 5 to 7 membered heteroaryl having 1 to 3 heteroatoms selected independently from nitrogen, sulfur and oxygen; and wherein W3and W4are each independently optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

6. The compound of claim 1, wherein A is absent or -(Co-C4)alkyl-C(0)OR2; W3is phenyl; and W4is a 5 to 6 membered heteroaryl having 1 to 4 heteroatoms selected independently from nitrogen, sulfur and oxygen; and wherein W4is optionally mono-, di-, or tri-substituted independently with halo, oxo, (Ci-C4)alkyl or (Ci-C4)alkoxy.

7. The compound of any one of claims 2 to 6, wherein Z is phenyl.

8. The compound of any one of claims 2 to 6, wherein Z is pyridinyl.The compound of any one of claims 2 to 6, wherein10. The compound of any one of claims 2 to 6, wherein11. The compound of any one of claims 2 to 10, wherein W is -N(H)-C(O)-, wherein the X- W-W1is X-NfTTl-C -W1.

12. The compound of any one of claims 2 to 10, wherein W is -N(H)S(O)2-, wherein the X-W-W1is X-N(H)-S(O)2-W1.

13. The compound of any one of claims 2 to 10, wherein W is absent.

14. The compound of any one of claims 2 to 13, wherein R3is (Ci-C3)alkyl and n is 1.

15. The compound of any one of claims 2 to 14, wherein W2is -*C(O)-N(H)-.

16. The compound of any one of claims 2 to 15, wherein W1is pyrrolidinyl.

17. The compound of any one of claims 2 to 15, wherein W1is -C(R10)(R11)- and R10and R11are taken together with the carbon to which they are attached to form a 3 to 6 membered cycloalkyl ring.

18. The compound of any one of claims 2 to 15, wherein W1is -C(R10)(R11)- and R10is (Ci- C4)alkyl and R11is H.

19. The compound of any one of claims 2 to 15, wherein W1is cyclopentyl.

20. The compound of any one of claims 2 to 15, wherein W1is cyclohexyl.

21. The compound of any one of claims 2 to 15, wherein W1is cyclohexenyl.

22. The compound of any one of claims 2 to 15, wherein W1is azetidinyl.

23. The compound of any one of claims 2 to 15, wherein W1is piperidinyl.

24. The compound of any one of claims 2 to 15, wherein W1is a 4 to 8 membered bridged heterocyclic.

25. The compound of any one of claims 2 to 15, wherein W1is azabicyclo[2.1.1]hexanyl.

26. The compound of any one of claims 2 to 15, wherein W-W1-W2is28. The compound of any one of claims 2 to 15, wherein W1is imidazolinyl.

29. The compound of any one of claims 2 to 15, wherein W1is pyrazolinyl.

30. The compound of any one of claims 2 to 29, wherein W3is mono substituted with fluoro.

31. The compound of claim 1, wherein A is absent or -(Co-C4)alkyl-C(0)OR2; W3is phenyl; W is -N(H)-C(O)-, wherein the X-W-W1is X-NCffl-C -W1; W2is -*C(O)-N(H)-; R3is (Ci- Cs)alkyl; n is 1; and W3is optionally mono- substituted with fluoro or methyl.

32. The compound of claim 31, wherein Z is phenyl.

33. The compound of claim 31, wherein Z is pyridinyl.

34. The compound of claim 31, wherein35. The compound of claim 31, wherein36. The compound of claim 31, wherein W1is cyclopentyl.

37. The compound of claim 31, wherein W1is cyclohexyl.

38. The compound of claim 31, wherein W1is cyclohexenyl.

39. The compound of claim 31, wherein W1is azetidinyl.

40. The compound of claim 31, wherein W1is piperidinyl.

41. The compound of claim 31, wherein W1is a 4 to 8 membered bridged heterocyclic.

42. The compound of claim 31, wherein W1is azabicyclo[2.1.1]hexanyl.

43. The compound of claim 31, wherein W-W1-W2is44. The compound of claim 1, wherein W1is imidazolinyl.

45. The compound of claim 1, wherein W1is pyrazolinyl.

46. The compound of claim 1, wherein W1is cyclopentyl.

47. The compound of claim 1, wherein W1is cyclohexyl.

48. The compound of claim 1, wherein W1is cyclohexenyl.

49. The compound of claim 1, wherein W1is azetidinyl.

50. The compound of claim 1, wherein W1is piperidinyl.

51. The compound of claim 1, wherein W1is a 4 to 8 membered bridged heterocyclic.

52. The compound of claim 1, wherein W1is azabicyclo[2.1.1]hexanyl.

53. The compound of claim 1, wherein W-W1-W2isabsent.

54. The compound of claim 1, wherein W-W1-W2iswherein the X-W-W1is X-N(H)-C(O)-W1.

55. The compound of claim 1, wherein W2is -*NH-C(O)NH-, -*O-C(O)-NH-, -*C(O)-O-, -*S(O)2-, -*S(O)2-N(H)- or -*S(O)2-C(H)2- or -*N(R4)-C(O)NH-, wherein the represents the point of attachment to W1.

56. The compound of claim 55, wherein W2is -*NH-C(O)NH-.

57. The compound of claim 55, wherein W2is -*O-C(O)-NH-.

58. The compound of claim 55, wherein59. The compound of claim 55, wherein60. The compound of claim 55, wherein61. The compound of claim 55, wherein62. The compound of claim 55, wherein W2is -*N(R4)-C(O)NH-.

63. The compound of any one of claims 55 to 62, wherein W is -N(H)-C(O)-, wherein the X-W-W1is X-NfTTl-C -W1.

64. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

65. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

66. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

67. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

68. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

69. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

70. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

71. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

72. The compound of any one of claims 1-10, wherein W1is (C3-C?)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an R configuration.

73. The compound of any one of claims 1-10, wherein W1is (C3-C7)cycloalkyl, 4 to 7 membered heterocyclic, 4 to 8 membered bridged heterocyclic, or 4 to 7 memberedheterocycloalkenyl having the formula, wherein W is absent, X is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration; and wherein W2is bonded to a W1ring carbon and said W1ring carbon is a stereocenter in an S configuration.

74. The compound of claim 1, wherein W1is -CH(Y)- and the carbon bonded to (Y) is a stereocenter in an S configuration.

75. The compound of claim 1, wherein W1is -CH(Y)- and the carbon bonded to (Y) is a stereocenter in an R configuration.

76. The compound of claim 26, whereinabsent, and the C1carbon is a stereocenter in an R configuration.

77. The compound of claim 26, whereinthe C1carbon is a stereocenter in an S configuration.

78. The compound of claim 1, wherein when an R3carbon that is bonded to a phenyl ring is a stereocenter the R3stereocenter carbon is in an R configuration.

79. The compound of claim 1, wherein when an R3carbon that is bonded to a phenyl ring is a stereocenter the R3stereocenter carbon is in an S configuration.

80. A pharmaceutical composition comprising a therapeutically effective amount of a compound and / or a pharmaceutically acceptable salt of any one of claims 1 to 79 and a pharmaceutically acceptable excipient.

81. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising:a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound;a second compound, said second compound being a GLP-1 inhibitor, a GCGR agonist or a GIPRagonist; anda pharmaceutically acceptable excipient.

82. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising:a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound;a second compound, said second compound being a GLP-1 inhibitor; anda third compound, said third compound being a GCGR agonist or a GIPR agonist; and a pharmaceutically acceptable excipient.

83. A kit comprising:a. a first compound, said first compound being a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable excipient in a first unit dosage form;b. a second compound, said second compound being a GLP-1 inhibitor, a GCGR agonist or a GIPR agonist and a pharmaceutically acceptable excipient in a second unit dosage form; andc. means for containing said first and second dosage formswherein the amounts of first and second compounds result in a therapeutic effect.

84. A kit as recited in claim 83, wherein said second compound is a GLP-1 inhibitor.

85. A method of modulating GIPR activity, the method comprising administering an effective amount of a compound of any one of claims 1 to 79, or a pharmaceutical composition of claim 80.

86. A method of treating, preventing or ameliorating a GIPR-mediated disease or condition in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of claims 1 to 79, or a pharmaceutical composition of claim 80.

87. The method of claim 86, wherein the disease is chosen from Type II diabetes, elevated glucose levels, elevated insulin levels, dyslipidemia, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, Type 1 diabetes, obesity, conditions exacerbated by obesity, pancreatitis, cirrhosis and Turner’s & Cushing’s syndrome.

88. A method of treating a disease or condition selected from Type 2 diabetes, elevated glucose levels, elevated insulin levels, dyslipidemia, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, Type 1 diabetes, obesity, conditions exacerbated by obesity, pancreatitis, cirrhosis and Turner’s & Cushing’s syndrome, comprisingadministering to the subject an effective amount of a compound of any one of claims 1 to 79, or a pharmaceutical composition of claim 80.

89. The method of claim 88, wherein the condition is obesity.

90. The method of claim 88, wherein the condition is type II diabetes.

91. A method of treating a disease or condition chosen from Type 2 diabetes, elevated glucose levels, elevated insulin levels, dyslipidemia, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria, metabolic acidosis, Type 1 diabetes, obesity, conditions exacerbated by obesity, pancreatitis, cirrhosis and Turner’s & Cushing’s syndrome, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 79 or a pharmaceutical composition thereof; anda second compound, said second compound being a GLP-1 inhibitor, a GCGR agonist or a GIPR agonist.

92. The method of claim 91, wherein the second compound is a GLP-1 inhibitor.

93. The method of claim 91, wherein the condition is obesity.

94. A compound selected from (R)-4'-(l-((2,2-difhiorobenzo[d][l,3]dioxol-5-yl)carbamoyl)-3,3-dimethylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylic acid, and pharmaceutically acceptable salts thereof.

95. A compound selected from (R)-2-(5-(lH-[l,2,3]triazolo[4,5-b]pyridin-5-yl)-3-fhioropyridin-2-yl)-N-(2,2-difluoro-[l,3]dioxolo[4,5-b]pyridin-6-yl)pyrrolidine-l-carboxamide, and pharmaceutically acceptable salts thereof.

96. A compound selected from (R)-4'-(3,3-dimethyl-l-((4-(trifluoromethyl)phenyl)carbamoyl)azetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylic acid, and pharmaceutically acceptable salts thereof.

97. A compound selected from (R)-2-(5-(l / / -[l,2,3]triazolo[4,5-&]pyridin-5-yl)-3-fhioropyridin-2-yl)-A-(2,2-difhiorobenzoM[l,3]dioxol-5-yl)pyrrolidine-l-carboxamide, and pharmaceutically acceptable salts thereof.

98. A compound selected from (R)-A2-(4-(l / / -[l,2,3]triazolo[4,5-&]pyridin-5-yl)phenyl)-A1-(4-isopropylphenyl)-3,3-dimethylazetidine-l,2-dicarboxamide, and pharmaceutically acceptable salts thereof.

99. A compound selected from (R)-4'-(l-((4-isopropylphenyl)carbamoyl)-3,3-dimethylazetidine-2-carboxamido)-[l, T-biphenyl]-4-carboxylic acid, and pharmaceutically acceptable salts thereof.

100. A compound selected from 4-(6-((2S,3S)-l-((2,2-difluorobenzo[d][l,3]dioxol-5- yl)carbamoyl)-3-methylpyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic acid, and pharmaceutically acceptable salts thereof.

101. A compound selected from (5)-5-(4-(l-((4-isopropylphenyl)carbamoyl)-3,3- dimethylazetidine-2-carboxamido)phenyl)-6-methylpicolinic acid, and pharmaceutically acceptable salts thereof.

102. A compound selected from (R)-4-(6-(l-((2,2-difluorobenzo[d][l,3]dioxol-5- yl)carbamoyl)pyrrolidin-2-yl)-5-fluoropyridin-3-yl)benzoic acid, and pharmaceutically acceptable salts thereof.

103. A compound selected fromor a pharmaceutically acceptable salt thereof.

104. A compound having the structurepharmaceutically acceptable salt thereof.

105. A compound having the structure, or a pharmaceutically acceptable salt thereof.

106. The compound of claim 1, whereinA is (C0-C4)alkyl-C(O)OR2;R2is H or (Ci-Ce)alkyl;W3is phenyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is pyridinyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W-W1-W2isW2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl or pyridinyl;R3is (Ci-Ce)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl or (C3-C?)cycloalkyl; and n is 1 or 2.

107. The compound of claim 106, whereinthe C1carbon is a stereocenter in an R configuration.

108. The compound of claim 106, whereinW3is phenyl optionally mono-substituted independently with halo or (Ci-C4)alkyl; W4is pyridinyl optionally mono-substituted independently with halo or (Ci-C4)alkyl; Z is phenyl or pyridinyl;R3is (Ci-Ce)alkyl, halo or mono-, di- or tri-halo(Ci-C4)alkyl; andn is 1 or 2.

109. The compound of claim 1, whereinA is (Co-C4)alkyl-C(0)OR2;R2is H or (Ci-Ce)alkyl;W3is phenyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is pyridinyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W-W1-W2isabsent;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl fused to a 5 to 7 membered heterocycloalkyl;R3is (Ci-Ce)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl or (C3-C?)cycloalkyl; and n is 1 or 2.

110. The compound of claim 109, wherein W2is bonded to the Z phenyl.

111. The compound of claim 1, whereinA is (Co-C4)alkyl-C(0)OR2;R2is H or (Ci-Ce)alkyl;W3is pyridyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W4is phenyl optionally mono- or di-substituted independently with halo, (Ci-C4)alkyl or (Ci-C4)alkoxy;W-W1-W2isabsent;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl or pyridinyl;R3is (Ci-Ce)alkyl, halo, mono-, di- or tri-halo(Ci-C4)alkyl or (C3-C7)cycloalkyl; and n is 1 or 2.

112. The compound of claim 1, whereinA is -C(O)OR2,or absent;R2is H;W3is phenyl, pyridinyl or l / / -[l,2,3]triazolo[4,5-&]pyridin-5-yl optionally mono- or di- substituted independently with (Ci-C3)alkyl or halo;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with (Ci- C4) alkyl or halo;W-W1-W2iswherein W1is optionally mono- or di- substituted with methyl; and W is absent;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl, pyridinylR3is (Ci-C4)alkyl or halo; andn is 1 or 2.

113. The compound of claim 112, whereinA is -C(O)OR2;R2is H;W3is phenyl or pyridinyl optionally mono- or di-substituted independently with (Ci- Cs)alkyl, fluoro or chloro;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro;W-W1-W2iswherein W1is optionally mono- or di- substituted with methyl; and W is absent;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl,R3is (Ci-C4)alkyl, fluoro or chloro; andn is 1 or 2.

114. The compound of claim 112, whereinA is absent;W3is 1 A / -[ 1,2,3] triazolo[4,5- / ?]pyridin-5-yl;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro;W-W1-W2iswherein W1is optionally mono- or di- substituted with methyl; and W is absent;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;n is 1 or 2.

115. The compound of claim 1, whereinA is -C(O)OR2,or absent;R2is H;W3is phenyl, pyridinyl or l / / -[l,2,3]triazolo[4,5-&]pyridin-5-yl optionally mono- or di- substituted independently with (Ci-C3)alkyl or halo;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with (Ci- C4) alkyl or halo;W-W1-W2isW is absent or -*NHC(O)-, wherein the represents the point of attachment to X; W1is optionally mono- or di-substituted with methyl;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl, pyridinyl,R3is (Ci-C4)alkyl or halo; andn is 1 or 2.

116. The compound of claim 115, whereinA is C(O)OR2;R2is H;W3is phenyl or pyridinyl optionally mono- or di-substituted independently with (Ci- Cs)alkyl, fluoro or chloro;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro;W-W1-W2isW is absent;W1is optionally mono- or di-substituted with methyl;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl,R3is (Ci-C4)alkyl, fluoro or chloro; andn is 1 or 2.

117. The compound of claim 115, whereinA is C(O)OR2;R2is H;W3is phenyl or pyridinyl optionally mono- or di-substituted independently with (Ci- Cs)alkyl, fluoro or chloro;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro;W-W1-W2isW is -*NHC(O)-, wherein the represents the point of attachment to X;W1is optionally mono- or di-substituted with methyl;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl,R3is (Ci-C4)alkyl, fluoro or chloro; andn is 1 or 2.

118. The compound of claim 115, whereinA is absent;W3is I A / -[ 1,2,3]triazolo[4,5- / ?]pyridin-5-yl;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro;W-W1-W2isW is absent;W1is optionally mono- or di-substituted with methyl;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl,R3is (Ci-C4)alkyl, fluoro or chloro; andn is 1 or 2.

119. The compound of claim 115, whereinA is absent;W3is 1 A / -[ 1,2,3]triazolo[4,5- / ?]pyridin-5-yl;W4is phenyl or pyridinyl optionally mono- or di-substituted independently with fluoro or chloro;W-W1-W2isW is -*NHC(O)-, wherein the represents the point of attachment to X;W1is optionally mono- or di-substituted with methyl;W2is -*C(O)NH-, wherein the represents the point of attachment to W1;Z is phenyl,R3is (Ci-C4)alkyl, fluoro or chloro; andn is 1 or 2.

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