Urea and carbamate compounds, compositions comprising the same and their use as pharmaceuticals

Abstract

There is provided a compound having the Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. A pharmaceutical composition comprising the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient is also provided. The compound or pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition comprising the same, can be used for the treatment or prevention of a condition, a disease or a disorder.

Description

UREA AND CARBAMATE COMPOUNDS, COMPOSITIONS COMPRISING THE SAME AND THEIR USE AS PHARMACEUTICALS RELATED APPLICATIONS

[0001] The present application claims priority under applicable law to United States provisional application No. 63 / 736,952, filed on December 20, 2024, United States provisional application No. 63 / 794,755, filed on April 25, 2025, and United States provisional application No. 63 / 925,872, filed on November 26, 2025, the contents of which are incorporated herein by reference in their entirety and for all purposes.TECHNICAL FIELD

[0002] The technical field generally relates to compounds, pharmaceutical compositions containing the compounds and their uses as Glucose-dependent Insulinotropic Polypeptide Receptor (Gl PR) antagonists.BACKGROUND

[0003] Glucose-dependent insulinotropic polypeptide (GIP, formerly called gastric inhibitory polypeptide) is a 42-amino acid peptide secreted from K-cells in the proximal small intestine in response to food ingestion. GIP is a member of the incretin family of peptides and enhances glucose-dependent insulin secretion. GIP is also known to promote fat storage in adipose tissue and also influences bone metabolism (see Baggio & Drucker Gastroenterology 2007, 132,2131; Hansen et al. Br J Pharmacol. 2016, 173, 826.; Holst et al. J Clin Endocrinol Metab. 2020,105, 2710).

[0004] The GIP receptor (GIPR) is a class B1 G protein-coupled receptor (GPCR) of the glucagon subfamily and is characterized by an extracellular domain at the N-terminus, seven transmembrane domains and an intracellular domain at the C-terminus (see Zhao et al. Nat. Commun. 2022, 72, 1057). GIPR is expressed in various tissues, including the gut, adipose tissue, the pancreas, the vasculature and the brain (see Hammoud et al. Nat. Rev. Endocrinol.2023, 18, 201). The extracellular domain serves to recognize its natural peptide agonist GIP, which results in a conformational change from inactive to active, triggering an increase in cAMP production mediated by Gas.

[0005] GIPR knockout mice are resistant to high fat diet-induced weight gain and have been shown to have improved insulin sensitivity and lipid profiles (see Yamada et al. Diabetes 2006, 55, S86 and Miyawaki et al. Nature Med. 2002, 8, 738). This observation has been translated to humans, where it has been observed that heterozygous loss of function of GIPR results in lower obesity risk and overall BMI (see Akbari et al. Science 2021, 373, 6550). Pre-clinicalpharmacological translation of these effects have been observed using small molecules, peptides and antibodies with antagonistic activities (see Nakamura et al. Diabetes Metab. Syndr. Obes.2021, 14, 1095; Yang et al. Mol. Metab. 2022, 66, 101638; Killion et al. Sci. Transl. Med. 2018, 10, eaat3392). Furthermore, synergy has been demonstrated between GIPR modulators and GLP-1 agonists to lead to superior weight loss (see Lu etal. Cell Rep. Med. 2021, 2, 100263).

[0006] There is thus a need for the discovery of GIPR antagonist molecules and their use in the treatment of metabolic diseases and obesity, either as single agents or in combination with other incretin modulators.SUMMARY

[0007] According to one aspect, the present technology relates to a compound of Formula I:or a pharmaceutical acceptable salt, solvate, or prodrug thereof, wherein:X is -NR2or -O-;R1and R2are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, linear or branched C1-C6alkyl, C3-Cscycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -OR3, -NR4, -NHC(=O)R5, -S(=O)2-NR6R6’, wherein the linear or branched C1-C6alkyl, C3-Cscycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more halogens, -OR3, -NR4R4’, -NHC(=O)R5, or -S(=O)2-NR6R6’; R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R4and R4’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R5is selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R6and R6’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, Ce-C aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogen;is selected from the group consisting of 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-Cscycloalkyl are optionally substituted with one or more of halogens or -CF3;whereinis selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl.

[0008] According to another aspect, the present technology relates to a compound of Formula II:or a pharmaceutical acceptable salt, solvate, or prodrug thereof, wherein:is selected from the group consisting of 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-Cscycloalkyl are optionally substituted with one or more of halogens or -CF3;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the Ce-C aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogen;whereinis selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl; andis 6- to 14-membered heterocycloalkyl optionally substituted with a fused C₆aryl.

[0009] According to another aspect, the present technology relates to a compound of Formula III:or a pharmaceutical acceptable salt, solvate, or prodrug thereof, wherein:is selected from the group consisting of 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-Cscycloalkyl are optionally substituted with one or more of halogens or -CF3;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, Ce-C aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;is selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;is C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=; andR7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl; and R3is as defined above.

[0010] According to another aspect, the present technology relates to a compound of Formula IV:or a pharmaceutical acceptable salt, solvate, or prodrug thereof, wherein:is a 5-membered heteroaryl optionally substituted with one or more of halogen, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -CF3 or -OR3;R3 is selected from the group consisting of a linear, branched C1-C6alkyl, Ce-C aryl and 5- to 10-membered heteroaryl, wherein the C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens; andwhereinis selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl.

[0011] The present technology also relates to any examples and embodiments of these compounds as further described herein.

[0012] In another aspect, the present technology further relates to pharmaceuticals compositions comprising a compound as herein defined together with a pharmaceutically acceptable carrier, diluent or excipient.

[0013] In a further aspect, this technology also relates to uses and methods for the treatment or prevention of a condition, a disease or a disorder for which modulating the glucose-dependent insulinotropic polypeptide receptor (GIPR) is indicated.

[0014] In a further aspect, this technology also relates to uses and methods for the treatment or prevention of a condition, a disease or a disorder selected from metabolic diseases and obesity.

[0015] In a further aspect, this technology also relates to uses and methods for the treatment or prevention of selected from diabetes (e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes), idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onsetT2DM (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, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0016] Additional objects and features of the present compounds, compositions, methods and uses will become more apparent upon reading of the following non-restrictive description of exemplary embodiments and examples section, which should not be interpreted as limiting the scope of the invention.BRIEF DESCRIPTION OF THE FIGURE

[0017] Figure 1 shows a perspective view of a crystal structure of Compounder 104(lsomer 1), determined by single crystal X-ray diffraction, confirming the absolute stereochemistry of Compound 104(lsomer 1).DETAILED DESCRIPTION

[0018] All technical and scientific terms and expressions used herein have the same definitions as those commonly understood by a person skilled in the art to which the present technologypertains. The definition of some terms and expressions used is nevertheless provided below. To the extent the definitions of terms in the publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification will control. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter disclosed.General Definitions

[0019] Chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a carbon atom, as drawn seems to include an incomplete valency, then the valency is assumed to be satisfied by one or more hydrogen atoms even though these are not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

[0020] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that, the singular forms "a", "an", and "the" include plural forms as well, unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the context clearly dictates otherwise. Furthermore, to the extent that the terms “including”, "includes", "having", "has", "with", or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising”.

[0021] The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about" meaning within an acceptable error range for the particular value should be assumed.

[0022] As used herein, the terms "compounds”, "compounds herein described", "compounds of the present application", “compounds as defined herein” and equivalent expressions refer to compounds described in the present application, e.g. those encompassed by structural Formulae I, II, III and IV, or by Formulae la, lb, Ila, lib, He, lid, He and Ilf, optionally with reference to any ofthe applicable embodiments, and also includes exemplary compounds, such as Compounds 1 to 157, as well as their pharmaceutically acceptable salts, solvates, and prodrugs when applicable. When a zwitterionic form is possible, the compound may be drawn as its neutral form for practical purposes, but the compound is understood to also include its zwitterionic form. Embodiments herein may also exclude one or more of the compounds. Compounds may be identified either by their chemical structure or their chemical name. In a case where the chemical structure and chemical name would conflict, the chemical structure will prevail.

[0023] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure when applicable; for example, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description. The therapeutic compound unless otherwise noted, also encompasses all possible tautomeric forms of the illustrated compound, if any. The term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature. Examples of isotopes that may be incorporated into the present compounds include, but are not limited to,2H (D),3H (T),11C,13C,14C,15N,18O,17O, any one of the isotopes of sulfur, etc. The compound may also exist in unsolvated forms as well as solvated forms, including hydrated forms. The compound may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0024] Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer and may also be enantiomerically enriched. " Enantiomerically enriched" means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high-pressure liquid chromatography (HPLC) on chiral support and the formation and crystallization of chiral salts or be prepared by asymmetric syntheses.

[0025] The expression "pharmaceutically acceptable salt" refers to those salts of the compounds of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base-addition salts).

[0026] The term “solvate” refers to a physical association of one of the present compounds with one or more solvent molecules, including water and non-aqueous solvent molecules. This physical association may include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. The term “solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, without limitation, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, iso-propanolates, 1 -butanolates, 2-butanolate, and solvates of other physiologically acceptable solvents, such as the Class 3 solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Accordingly, the compound as herein described also includes each of its solvates and mixtures thereof.

[0027] The expression "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds formed by the process of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective fortheir intended use. " Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant description.

[0028] Abbreviations may also be used throughout the application, unless otherwise noted, such abbreviations are intended to have the meaning generally understood by the field. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Sue (succinimide). For more certainty, additional definitions of specific abbreviations are also included in the introduction of the Examples section.

[0029] The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix " Cx-Cy" or " Cx-y" where x is the minimum and y is the maximum number of carbon atoms in the substituent. However, when the prefix “Cx-Cy” or " Cx-y" is associated with a group incorporatingone or more heteroatom(s) by definition (e.g. heterocycloalkyl, heteroaryl, etc), then x and y define respectively the minimum and maximum number of atoms in the cycle, including carbon atoms as well as heteroatom(s).

[0030] The term "alkyl" as used herein, refers to a saturated, straight- or branched-chain hydrocarbon radical typically containing from 1 to 20 carbon atoms. For example, " Ci-Cs alkyl" contains from one to eight carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals and the like.

[0031] The term "alkenyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms. For example, "C2-8 alkenyl" contains from two to eight carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.

[0032] The term "alkynyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms. For example, " C2-8 alkynyl" contains from two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl and the like.

[0033] The terms “cycloalkyl”, “alicyclic”, “carbocycle”, “carbocyclic” and equivalent expressions refer to a group comprising a saturated or partially unsaturated (non-aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems, having from three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, bicyclo[1,1,1]pentane, spiro[3.3]heptane and the like. The term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups. The term “Cs-Cncycloalkyl” refers to a cycloalkyl group having from 3 to the indicated “n” number of carbon atoms in the ring structure. Unless the number of carbons is otherwise specified, “lower cycloalkyl” groups as herein used, have at least 3 and equal or less than 8 carbon atoms in their ring structure.

[0034] As used herein, the term "heteroatom" includes but is not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0035] As used herein, the terms "heterocycle", "heterocycloalkyl", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a chemically stable 3- to 7-membered monocyclic or 7-14-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure and any of the ring atoms can be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, 1,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolizinyl, quinuclidinyl, hexamethyleneimine, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, and the like. Heterocyclic groups also include groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, benzodioxole,tetrahydroquinolinyl,H , N or H, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “Cs-nheterocycloalkyl” refers to a heterocycloalkyl group having from 3 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0036] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0037] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", "aryloxy", or "aryloxyalkyl", refers to aromatic groups having 4n+2 conjugated ir(pi) electrons, wherein n is an integer from 1 to 3, in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of six to 15 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present description, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracyl and the like, which may bear one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyl include, but are not limited to, benzyl, phenethyl, and the like. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthimidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “Ce-naryl” refers to an aryl group having from 6 to the indicated “n” number of atoms in the ring structure.

[0038] The term "heteroaryl", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refers to aromatic groups having 4n+2 conjugated π(pi) electrons, wherein n is an integer from 1 to 3 (e.g. having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array); and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" includes but is not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. A heteroaryl may be a single ring, or two or more fused rings. The term "heteroaryl", as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g. pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2-c]pyridinyl), pyrazolopyridinyl (e.g. pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g. imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinyl carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. Heteroarylgroups include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like. For instance, the term “Cs-nheteroaryl” refers to a heteroaryl group having from 5 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0039] As described herein, compounds of the present description may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under the present description are preferably those that result in the formation of chemically stable or chemically feasible compounds. The term "chemically stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0040] The term “halo” designates a halogen atom, i.e. a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0041] The term "optionally substituted" refers to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to F, Cl, Br, I, OH, CO2H, alkoxy, oxo, thiooxo, NO2, CN, CF3, NH2, NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl, NHheterocyclic, dialkylamino, diarylamino, diheteroarylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocyclic, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(O)cycloalkyl, C(O)aryl, C(O) heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O) NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OCO2aryl, OCO2heteroaryl, OCO2heterocycloalkyl, OC(O)NH2, OC(O)NHalkyl, OC(O)NHalkenyl, OC(O) NHalkynyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O) NHheteroaryl, OC(O)NHheterocycloalkyl, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl, NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO2alkyl, NHCO2alkenyl,NHCO2alkynyl, NHCO2cycloalkyl, NHCO2aryl, NHCO2heteroaryl, NHCO2heterocycloalkyl, NHC(O)NH2, NHC(O)NHalkyl, NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl, NHC(O)NHheteroaryl, NHC(O)NHheterocycloalkyl, NHC(S)NH2, NHC(S)NHalkyl, NHC(S)NHalkenyl, NHC(S)NHalkynyl, NHC(S)NHcycloalkyl, NHC(S)NHaryl, NHC(S)NHheteroaryl, NHC(S)NHheterocycloalkyl, NHC(NH)NH2, NHC(NH)NHalkyl, NHC(NH)NHalkenyl, NHC(NH)NHalkenyl, NHC(NH)NHcycloalkyl, NHC(NH)NHaryl, NHC(NH)NHheteroaryl, NHC(NH)NHheterocycloalkyl, NHC(NH)alkyl, NHC(NH)alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl, NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl, C(NH)NHalkenyl, C(NH)NHalkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl, C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)2alkyl, S(O)2alkenyl, S(O)2alkynyl, S(O)2cycloalkyl, S(O)2aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO2NHalkyl, SO2NHalkenyl, SO2NHalkynyl, SO2NHcycloalkyl, SO2NHaryl, SO2NHheteroaryl, SO2NHheterocycloalkyl, NHSO2alkyl, NHSO2alkenyl, NHSO2alkynyl, NHSO2cycloalkyl, NHSO2aryl, NHSO2heteroaryl, NHSO2heterocycloalkyl, CH2NH2, CH2CN, CH2F, CH2OH, CH2OCH3, C(CH3)2OH, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocyclic, phenyl, phenol, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, or methylthiomethyl.Compounds

[0042] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. As such, the following embodiments are present alone or in combination if applicable.

[0043] The present compounds present a linear core structure to which is attached defined substituents to achieve the product’s beneficial activity. Examples of compounds as defined herein are illustrated by general Formula I:or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:X is -NR2or-0-;R1and R2are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, linear or branched C1-C6alkyl, C3-Cscycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -OR3, -NR4, -NHC(=O)R5, -S(=O)2-NR6R6’, wherein the linear or branched C1-C6alkyl, C3-Cscycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more halogens, -OR3, -NR4R4’, -NHC(=O)R5, or -S(=O)2-NR6R6’; R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R4and R4’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R5is selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R6and R6’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;is selected from the group consisting of 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with one or more of halogens or -CF3;is B1, B2, B3, B4, B5, B6, B7, B8, B9or B10:whereinis selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl.

[0044] In some examples of the present compounds, X is -NR2or -O-;R1and R2are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, linear or branched C1-C6alkyl, C3-Cscycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -OR3, -NR4, -NHC(=O)R5, -S(=O)2-NR6R6’ wherein the linear or branched C1-C6alkyl, C3-Cscycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more halogens or -OR3;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R4and R4’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R5is selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R6and R6’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;is selected from the group consisting of 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-Cscycloalkyl are optionally substituted with one or more of halogens or -CF3;whereinis selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl; n is between 0 and 5; p is between 0 and 5; Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=, with 0, 1, 2 or 3 of Y1'8being -N=; R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; and R8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl.

[0045] In other examples,wherein p is between 0 and 5, and R7is independently selected from the group consisting of halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3selected from the group consisting of -H, -CF3and linear or branched C1-C6alkyl.

[0046] In some examples, R7is independently selected from the group consisting of -Cl, -F, -CF3, -OCH3, -CH3, -CH2CH3, -CH2CH2CH3and -CH(CH3)2.wherein R9is independently selected from the group consisting of halogen, -CF3, -OCF3, -SCF3, -OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, and wherein R3is selected from the group consisting of -H, -CF3 and linear or branched C1-C6alkyl.

[0048] In some examples, R9is independently selected from the group consisting of -Cl, -F, -CF3, -OCF3, -SCF3, -OCH3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, optionally substituted with one or more -CF3.

[0049] In some examples, the compound is of Formula la:wherein R1, R2,and are as defined above.

[0050] In other examples, R1and R2are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and Ce-C aryl, optionally substituted with one or more -Cl, -F, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl or C6-C14aryl.

[0051] In some examples, R1and R2are independently selected from the group consisting of -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CF2CH3, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl,

[0054] In some examples, the compound is of Formula lb:(lb),are as defined above.

[0055] In some examples, R1is selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl and C6-C14aryl, optionally substituted with one or more -Cl, -F, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl or Ce-C aryl.

[0056] In other examples, R1is selected from the group consisting of -H, -CH3, phenyl, and -CH2CF2CH3.

[0059] In some examples, the compound is of Formula II:or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:is selected from the group consisting of 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-Cscycloalkyl are optionally substituted with one or more of halogens or -CF3;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, Ce-C aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;( C )wherein ' is selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; and R8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl; andNIis 6- to 14-membered heterocycloalkyl optionally substituted with a fused C₆aryl.R9is independently selected from the group consisting of halogen, -CF3, -OCF3, -SCF3, -OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, and wherein R3is selected from the group consisting of -H, -CF3 and linear or branched C1-C6alkyl.

[0061] In other examples,is B1, B2, B3, B4, B5, B6, B7, B8, B9or B10:o oZEwherein p is between 0 and 5, and R7is independently selected from the group consisting of halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3selected from the group consisting of -H, -CF3 and linear or branched C1-C6alkyl.

[0062] In some examples, the compound is of Formula IIa, IIb, IIc, IId, IIe or IIf:wherein q is between 1 and 2; X1is -CH2- or-O-; andand are as defined above.

[0063] In some examples, the compound of formula Ila isas defined above.

[0066] In some examples, the compound is of Formula III:or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:is selected from the group consisting of 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-Cscycloalkyl are optionally substituted with one or more of halogens or -CF3;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;is selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;is C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=; andR7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl; and R3is as defined above.R9is independently selected from the group consisting of halogen, -CHF2, -CF3, -OCF3, -SCF3, -OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, and wherein R3is selected from the group consisting of -H, -CF3 and linear or branched C1-C6alkyl.wherein p is between 0 and 2;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from the group consisting of -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl; and R3is selected from the group consisting of -H, -CF3, a linear or branched C1-C6alkyl.

[0071] In some examples, the compound is of Formula IV:or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:is a 5-membered heteroaryl optionally substituted with one or more of halogen, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -CF3 or -OR3;R3is selected from the group consisting of a linear, branched C1-C8alkyl, C6-C10aryl and 5- to 10- membered heteroaryl, wherein the C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens; and( C )wherein ' is selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl., wherein R9is independently selected from the group consisting of halogen, -CF3, -OCF3, -SCF3, -OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, and wherein R3is selected from the group consisting of -H, -CF3 and linear or branched C1-C6alkyl.

[0073] In some examples,B

[0074] In other examples, is B1, B2, B3, B4, B5, B6, B7, B8, B9or B10:R7OB9isB10is P or P, wherein p is between 0 and 5, and R7is independently selected from the group consisting of halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3selected from the group consisting of -H, -CF3 and linear or branched C1-Cealkyl.

[0077] Exemplary compounds as defined herein include each single compound described in the present application, including Compounds 1 to 157 in Table 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0078] Table 1: Compounds 1 to 157'X..kH.t ’• 1 ¥ K Il...1.. XI 1.. II...'' ” < X l.x^." T ~1 r.0.,0 C Compound 1 Compound 2c i i i B L i 1 J. N..' L i "[i x.. ~ H I ' I 11 1. OH 11 0 0 Compound 3 Compound 41. 1. 1. 1 a...“ „ -,f:i< Xl L 1 N - 1 J. CH ■ o ' n 0 O Compound 5 Compound 6j - o' Y k X X N... X I. 1 '1, N.~ H' 1 S 1 " I. H 1 ' T " I X..~ X 1. OH ~ X OH IT0 0 Compound 7 Compound 81... / i■' "t 1. A ' - x: i u u~ N NX r N. Y... ■ ~ N N- yT|"" Xlr<> H X...1 y OH 0 0 Compound 9 Compound 10 / / ,i...... o 1... w' I L.ci I K--N'NY C. L. A 1 it...H 1" V--p. 'K 7 T T "1..Lron XX. OH O " IT 0 Compound 11 Compound 121. YX L. A,k U.... 'XtX A 1 11..B: x T: a ' j i:"" XX. OH IX. OH I 0TCompound 13 Compound 14<-oI Y. flX I JI J. N,. X 1 A,.. N...B 1 J' 1 1 B X 11~ X.. X.r. OH " XJ... OH 0 0 Compound 15 Compound 16.1' T I I 1 B.... '■ i: 1 1 j. a...... ■«N' r T i....., ■. »Nr 1 1.... x Il _ 1 y OH.. Il....l.r.. OH 0 o Compound 17 Compound 18A..1..' 1 k I 1 B....1. “k 1 I > N•wnr. (:i. RC N 'N ' y -Q" T,":NL. A. OH~rI.....r. OH 0 0 Compound 19 Compound 20 J.. A' T I. £ X B... " TI °. ri..HNr T 3... «'N1 T 1.1...1.r. OH I.1.. y OH 0 o Compound 21 Compound 22 i. r?, L... -N O,.1 1 N 2. N 1 r' 3 V., -. O o. A..k 1, B......N N 'r Y ■'■'1” <> LA / A;:11o 1.,1.....L J... OHv5.1 O r.. y H 0 0 Compound 23 Compound 241, H.nJ. V. i R.. ' T I. I,1., K' «'Nr T:i.Norr:iI1...1.rOH ~ VY<>" 0 0 Compound 25 Compound 26,1...o.., J..|1? I H 11 L 1HA MrV''i AMAyYA11o " o AAO5:Il JL OH ■ ■ OH 0 ■ r 0 Compound 27 Compound 280A''LA AI A!l A i « N N i' LN N y V Y - N- N 1 yHT.j _H0 Uk / Y,F JL -J- y, OH IA, OH 0 0 Compound 29 Compound 30\,4 -N 0HXn" A / AM NV A....K. £NJL j KT...:1_Hi S A.' ULOH.. C...1 y OH 0 0 Compound 31 Compound 32. v. _.. I 1. 1' « U I I...... <>1 ("" " X I 1 o„vr T 0 0 Compound 33 Compound 34f 2 H" X Ji 1 iN N V" Y Y 0 ” 1 0 I..,. 1 X OHH0 I J. X■ •••• OH 0 Compound 35 Compound 361.1’, Tk A L. A 1,,N-. N, " 'I 1 A.. '..~ HNY X II.11o L,1..." Y 1 y CH U.,0"0 0 Compound 37 Compound 381.. X x 1.8.....-- N - crY Y i: i x i «..-N- " O' Y " X" '■ L J...h0 X... ^IX OH I. <1.. OH 0 0 Compound 39 Compound 40x^..' XL. x 1 a N... 1. A. 1..8,, N.~ H ° Y X IX.. " » ■0X 1 1..'' 11. OH. I.l..r. OH Y0 o Compound 41 Compound 42ojl, X J-.. N. N...... 1 k L i 1rN NN O r, O]v 0r T i... " <> UUI I OH *.... F - J- O 0 Compound 43 Compound 44 \ \-X / yr N l' o I '• / S^NX0"'YNYN- 11? 1rHo L.,... - N' OTy, X o k X o I0.. IrOH 0 Compound 45 Compound 46..k....ll? 1 H" X l. A... II...N- -o'r."0k IXV-H0 Lk....,f I. I OH 0 r 0 Compound 47 Compound 481, 1..’ 'll L 1Hk II. A J.. K.. N.' C ' X. ■" i L.1 ~ k0r r:i.- - N... Xr.on ~ r i OH X0 0 Compound 49 Compound 50Compound 59 Compound 60Compound 61 Compound 62Compound 63 Compound 64Compound 65 Compound 66■ — \ H<N"- " ■?.NX V¥X..3'-CHHN ' 0 H\ ';0xr;XCompound 75 Compound 76■ — H. H _ 0 / \ N. zzOH <N--(zA.. ’^" OH V'X. ■.... X--. TX N ' V— V’” o 0 0HN'""?O HN ' " 01 1[ fCompound 77 Compound 78■ — \ H / \ N... Z, ■■ — •. H / \ N.... "N A 1-. % ''N 'Z'A •: A-., z1 ° • N- / "-OH 0 -- A z< OH HN ' "'0 HN' ---zzA A X0S''VNOCompound 79 Compound 80H Hi N.... / N.N ■' ’V, A A-- / ’■■■AXN'' A. A.... / '--.;. 0 -- 1 OH o --zzo. OH UN' ":?0 HN:() ’A 1 oS'' '''NAN N-N— — / Compound 81 Compound 82Compound 91 Compound 92Compound 93 Compound 94Compound 95 Compound 96Compound 97 Compound 98f H / "" X H, N... VyNIfoL-"UN ’ "'0 [ | xA0, A1oi <F0H4 F7Compound 99 Compound 100HHN^O \\HNX o L^VX OH T0lAsAFF FCompound 101 Compound 102I \ Hx xSV xv. o HN^ X) ° || 1 H jNl Yu)0A OH [T il F °HClr x<FJ TFAF FCompound 103 Compound 104Sh'A j-A,..HN^ X)HN X^O v'Oxxr \\ T o Y \sN=y__A "FCompound 105 Compound 106Compound 108Compound 110 Compound 111 Compound 112Compound 115 Compound 116Compound 117Compound 119Compound 121Compound 123 Compound 124Compound 125 Compound 126Compound 127 Compound 128Compound 129 / X H00H■ A O ° '^^O onY yFAFk?FCompound 137 Compound 138 / "" I H / X H jA rn o r^hn\ x)0 V / 'xXrQHHNO o O \ II o / \ F<FFCompound 139 Compound 140 / "" I HWNU x °HN^. 0 \A A nJ U^J-°H / A<AF FFCompound 141 Compound 142 / X H / \ Hn °A n^ °0H7 n o °A n^ o0HA r FCompound 143 Compound 144AM HHN JAA o \A A ° W0u. 0HNAO ''X^0H0o Y yt °yF-" X F FFCompound 145 Compound 146 / I HNnNY1AHN, A0\A / OH M A / N n A, ML ° ^^CXyOH 4 FF0 Compound 147 Compound 148 i N-l / A A1HN A 0 o Il T M L A^ XA / OH0 1 ° Compound 149 Compound 150AM H AM Hn A oHNA M 0 A \A A ° M0 0AOH<5ClCompound 151 Compound 152

[0079] Examples of preferred compounds include, namely, Compounds 1-56, 58-67, 70-72, 74-78 and 80-83 as defined herein, or a salt, solvate and / or prodrug thereof.

[0080] Other examples of preferred compounds include, namely, Compounds 1, 2, 38, 39, 52, 53, 54, 67 and 80, or Compounds 1, 2, 4, 5, 7 to 19, 32, 33, 35, 38, 39, 41, 42, 44, 46 to 50, 52 to 59, 62, 63, 66, 67, 69, 72, 75 to 78, 80, 83 to 94, 96 to 105, and 108 to 157 as defined herein, or a salt, solvate and / or prodrug thereof.

[0081] Alternatively, the present compound is selected from Compounds 1, 2, 4, 5, 7 to 12, 17 to 19, 32, 35, 38, 39, 41, 42, 46 to 50, 52 to 56, 58, 59, 62, 63, 67, 72, 75, 77, 78, 80, 84, 86 to 94,96 to 100 and 102 to 104, or Compounds 1, 2, 4, 5, 7 to 12, 17 to 19, 32, 35, 38, 39, 41, 42, 46 to 50, 52 to 59, 62, 63, 67, 72, 75, 77, 78, 80, 84 to 94, 96 to 105, 108 to 146, 150, 153, 154, and 157of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or preferably any one of Compounds 1, 4, 8, 38, 39, 41, 42, 46, 48 to 50, 52 to 54, 56, 59, 75, 91, 92, 96, and 104, or any one of Compounds 1, 4, 8, 38, 39, 41, 42, 46, 48, 50, 52, 53, 54, 56, 65, 72, 75, 77, 78, 80, 84, 91, 92, 93, 96, 98, 100, 103, 104, 109, 111, 114, 115, 116, 117, 119, 121, 122, 123, 125, 126, 127, 131, 136, 142, and 144, of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0082] It is understood that any of the above compounds may be in any amorphous, crystalline or polymorphic form, including any salt or solvate form, or a mixture thereof. The compounds of the present description may be further modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0083] These compounds may be prepared by conventional chemical synthesis, such as those exemplified in the Schemes and Examples of the present disclosure. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.Methods, Uses, Formulations and Administration

[0084] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disease, disorder, or symptom thereof, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0085] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in theabsence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0086] According to one embodiment, the condition, disease or disorder is characterized by dysregulation of the glucose-dependent insulinotropic polypeptide receptor (GIPR).

[0087] For example, the condition, disease or disorder is selected from metabolic diseases and obesity.

[0088] In one embodiment, the condition, disease or condition to be treated is a GIPR-related condition, disease, or disorder. The GIPR-related condition, disease, or disorder includes one selected from diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), 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, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0089] The term "patient or subject" as used herein refers to an animal such as a mammal. A subject may therefore refer to, for example, mice, rats, dogs, cats, horses, cows, pigs, guinea pigs, primates including humans and the like. Preferably the subject is a human.

[0090] The present description therefore further relates to a method of treating or preventing metabolic diseases or diabetes in a subject, such as a human subject. The method comprises administering a therapeutically effective amount of a GIPR antagonist, such as a compound as defined herein, to a subject in need of such treatment.

[0091] In another embodiment, the present description further relates to a method of treating or preventing a condition, a disease, or a disorder for which modulation of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is indicated. The method comprises administering a therapeutically effective amount of a GIPR antagonist, such as a compound as defined herein, to a subject in need of such treatment.

[0092] In another embodiment, the present description further relates to a method of treating or preventing a condition, a disease, or a disorder for use in the treatment or prevention of a condition, a disease or a disorder selected from diabetes (e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes), idiopathic T1D (Type 1b), 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-Williand 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, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug). The method comprises administering a therapeutically effective amount of a GIPR antagonist, such as a compound as defined herein, to a subject in need of such treatment.

[0093] In certain embodiments, the present description provides a method of treating a disorder (as described herein) in a subject, comprising administering to the subject identified as in need thereof, GIPR antagonist, such as a compound of the present description. The identification of those patients who are in need of treatment for the disorders described above is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients which are at risk of developing the above disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the subject patient. A clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination, medical / family history, and genetic determination.

[0094] A method of assessing the efficacy of a treatment in a subject includes determining the pre-treatment symptoms of a disorder by methods well known in the art and then administering a therapeutically effective amount of a compound of the present description, to the subject. After an appropriate period of time following the administration of the compound (e.g., 1 week, 2 weeks, one month, six months), the symptoms of the disorder are determined again. The modulation (e.g., decrease) of symptoms and / or of a biomarker of the disorder indicates efficacy of the treatment. The symptoms and / or biomarker of the disorder may be determined periodically throughout treatment. For example, the symptoms and / or biomarker of the disorder may be checked every few days, weeks or months to assess the further efficacy of the treatment. A decrease in symptoms and / or biomarker of the disorder indicates that the treatment is efficacious.

[0095] In some embodiments, the therapeutically effective amount of a GIPR antagonist, such as a compound as defined herein, can be administered to a patient alone or in a composition, admixed with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0096] The expression "pharmaceutically acceptable carrier, adjuvant, or vehicle" and equivalent expressions, refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0097] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0098] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, surfactants, sweetening, flavoring, and perfuming agents.

[0099] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0100] Injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0101] In order to prolong the effect of a provided compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled.

[0102] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0103] Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the present description with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0105] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0106] The composition can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may alsocomprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0107] Dosage forms for topical or transdermal administration of a compound of the present description include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of the present description. Additionally, the description contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0108] Pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0109] Pharmaceutically acceptable compositions provided herein may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0110] The amount of compound that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration. Provided compositions may be formulated such that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0111] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the symptoms associated with the proliferative disease or disorder.The amount of a provided compound in the composition will also depend upon the particular compound in the composition.

[0112] Compounds or compositions described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the symptoms as contemplated herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Provided compounds are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0113] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, provided compounds may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0114] It will be understood that the total daily usage of the compounds and compositions of the present description will be decided by the attending physician within the scope of sound medical judgment. The total daily inhibiting dose of the compound of the present description administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg / kg body weight or more usually from 0.1 to 25 mg / kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In one embodiment, treatment regimens according to the present description comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of the present description per day in single or multiple doses.

[0115] Depending upon the condition, disease or disorder to be treated, additional therapeutic agents may also be present in the compositions of this disclosure or administered separately as part of a dosage regimen, e.g. an additional incretin modulator. Non-limiting examples of additional therapeutic agents which could be used in combination with the present compounds include: semaglutide, liraglutide, danuglipron or orforglipron.

[0116] The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.EXAMPLES

[0117] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention.General Methods:

[0118] The Examples set forth herein below provide syntheses and experimental results obtained for certain exemplary compounds. As it is well known to a person skilled in the art, reactions are performed in an inert atmosphere (nitrogen or argon) where necessary to protect reaction components from air and moisture. Temperatures are given in degrees Celsius (°C). Solution percentages and ratios express a volume-to-volume relationship, unless otherwise stated. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art.

[0119] All chemicals were of the highest purity and commercially available ones were used without further purification. Purification by column chromatography was performed with silica gel on CombiFlash and Teledyne-Isco with solvent mixtures specified for each compound where applicable. Purification by preparative HPLC were performed on Agilent system with an elution phase of methanol, water and 0.1% formic acid, NH4HCO3, or others when specified. NMR spectra were recorded using Varian or Bruker 300 MHz or 400 MHz spectrometer. Chemical shifts are reported as parts per million and referenced according to the residual solvent peak and coupling constants (J) are reported in hertz (Hz). LCMS data were acquired on a Shimadzu LCMS-2020 (or LCMS-2050) with electrospray ionization in positive / negative ion detection mode with 20ADXR pump(or40ADXR pump), SIL-20ACXR autosampler(or SIL-40ACXR autosampler), LCMS 2020 MS detector(or LCMS 2050 MS detector), Alltech ELSD 3300HP detector(or Shimadzu ELSD-LT III detector), (CTO-40C column oven and SPD-M40 PDA detector) or (CTO-20AC column oven and SPD-M20A PDA detector) or (CTO-40S column oven and SPD-M40 PDA detector), Shim pack Scepter C18-120 columns, (Kinetex EVO C18 columns or XSelect HSS T3 columns or HALO 90A C18 columns or HALO 160A PCS C18 columns or HALO 120A ELV C18columns or Luna Omega PS C18 columns), acetonitrile / water gradients, and either trifluoroacetic acid, formic acid, or ammonium bicarbonate modifiers.. All new compounds have been characterized by1H NMR, LCMS and / or HRMS.

[0120] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, stabilities, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors resulting from variations in experiments, testing measurements, statistical analyses and such.

[0121] Abbreviations:Ac AcetylAq. AqueousBoc tert-butyloxycarbonylbpy 2,2'-BipyridylBSA Bovin serum albumin°C Degrees CelsiuscAMP Cyclic adenosine monophosphoateCbz BenzyloxycarbonylCone. Concentratedd Doubletdd Doublet of doubletsdt Doublets of tripletsdba DibenzylideneacetoneDBU 1,8-Diazabicyclo[5.4.0]undec-7-eneDCC N,N'-DicyclohexylcarbodiimideDCM DichloromethaneDIBAL-H Diisobutylaluminum hydrideDIC N,N'-DiisopropylcarbodiimideDIEA N,N-DiisopropylethylamineDMA / V, / V-DimethylacetamideDMAc / V, / V-DimethylacetamideDMAP 4-(Dimethylamino)pyridinedme 1,2-DimethoxyethaneDMF DimethylformamideDMSO Dimethylsulfoxidedppf 1,1'-Ferrocenediyl-bis(diphenylphosphine)dtbpy 4,4'-Di-tert-butyl-2,2'-dipyridylδ Chemical shiftEA Ethyl acetateEC50 Drug concentration that gives 50% of EmaxEC80 Drug concentration that gives 80% of EmaxEDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Equiv. Equivalent(s)Emax Maximal signal obtained by an appropriate agonistES ElectrosprayEu-cAMP Europium-labeled antibody paired with a cAMP analogFA Formic acidGIP Glucose-dependent insulinotropic polypeptideGIPR Glucose-dependent insulinotropic polypeptide receptor HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphateHBSS Hanks Buffered Salt SolutionHEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)HFIP HexafluoroisopropanolHCI Hydrochloric acidHOBt 1 -HydroxybenzotriazoleHz HertzIBMX 3-isobutyl-1 -methylxanthineIC50 Half maximal inhibitory concentrationI nt Intermediate(Ir[dF(CF3)ppy]2- [4,4'-Bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro- (dtbpy))PF62-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III)hexafluorophosphateJ Coupling constantλex Excitation wavelengthλem Emission wavelengthLCMS Liquid chromatography coupled with mass spectrometry m Multipletmg Milligramsmin MinutesmL MillilitermM Millimolar (mmol / L)mmol MillimolesMeCN AcetonitrileMs MethanesulfonylMTBE Methyl tert-butyl etherm / z Mass to charge rationm NanometersNMM N-methylmorpholine1H NMR Proton nuclear magnetic resonancePd / C Palladium on carbonPd(OH)2 / C Palladium hydroxide on carbonPE Petroleum etherppm Parts per millionPrep-HPLC Preparative high-performance liquid chromatography Prep-SFC Preparative supercritical-fluid chromatography q Quartetrpm Revolutions per minuteRT Room temperatures SingletSPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl SPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1, T-biphenyl)]palladium(ll) methanesulfonate t TripletTBAI Tetrabutylammonium iodideTEA TriethylamineTf TrifluoromethanesulfonylTFA Trifluoroacetic acidTHF TetrahydrofuranTMS TrimethylsilylTR-FRET Time-resolved fluorescence energy transferµL MicroliterUV UltravioletVol. VolumeWt% Weight percentXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneExample 1: General Procedures:

[0122] All compounds as herein defined were prepared according to methods as indicated below. Characterization data by mass spectrometry and NMR are provided for each of the examples when available. The compounds are tested in the assays described in Example 3.

[0123] Synthetic route 1 (Scheme 1):Scheme 1

[0124] If isocyanates (Int-T) are not commercially available, they were prepared by reacting appropriate aryl / heteroaryl amines with triphosgene. Eastern portion amines (Jnt-2) were then coupled with an appropriately protected amino acid (Jnt-3) to form amides lnt-4. Deprotection of both the Boc group and terminal tert-butyl group were accomplished in a single operation with HCI, then final Examples were obtained by condensing with the isocyanates (Jnt-1).

[0125] Alternatively, compounds as defined herein can be obtained by other reaction sequences such as synthetic route 2 (Scheme 2):Scheme 2

[0126] Free amino acids (Int-6) were condensed with isocyanates (Int-1) to yield ureas / carbamates (Int-7) which were coupled with Int-2 to yield amides (Int-8). Deprotection then afforded the final Examples.

[0127] In some circumstances, compounds as defined herein can be obtained according to synthetic route 3 (Scheme 3):lnt-7

[0128] Free acids (Int-7) were coupled with boronic acid / ester-containing aryl / heteroaryl amines (Int-9) to yield Int-10, which were then subjected to Suzuki coupling conditions with an appropriate aryl / heteroaryl halide to yield the desired compounds.

[0129] In other cases, Examples can be prepared as defined by synthetic route 4 (Scheme 4):

[0130] Free acids Int-7 were coupled with Int-12 to yield halide-containing amides (Int-13) which were then subjected to Suzuki coupling conditions with an appropriate aryl / heteroaryl boronic acid / ester to yield Int-15. Deprotection then afforded the final Examples.

[0131] Some compounds can also be prepared according to synthetic route 5 (Scheme 5):Scheme 5

[0132] Amines (Int-2) were condensed with acyl halide (Int-16) to yield amides (Int-17) which were deprotected then condensed with isocyanates to yield carbamates (Int-19). Deprotection then afforded the other final Examples.

[0133] Additionally, compounds as defined herein can be obtained according to synthetic route 6 (Scheme 6):Scheme 6

[0134] Amines (Int-2) were condensed with free acids (Int-20) to yield amides (Int-18) which were condensed with isocyanates to yield carbamates (Int-19). Deprotection then afforded the final Examples.Example 2: Synthetic procedures(i) (R)-4 '-(2-(3-(4-isopropylphenyl)-1-methylureido)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 1(a))NMM, THFScheme 7

[0135] Step 1: To a stirred solution of tert-butyl 4'-amino-[1, T-biphenyl]-4-carboxylate (500 mg, 1.9 mmol, 1 equiv) and N-(tert-butoxycarbonyl)-N-methyl-D-alanine (490 mg, 2.4 mmol, 1.3 equiv) in DCM (6 mL) was added EDCI (580 mg, 3.7 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1h and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE I EA (4:1) to afford tert-butyl (R)-4'-(2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-[1,1'-biphenyl]-4-carboxylate (800 mg, 95% yield, 80% purity) as a brown semi-solid. LCMS (ES, m / z): 455.3 [M+H]+.

[0136] Step 2: tert-butyl (R)-4'-(2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-[1, T-biphenyl]-4-carboxylate (800 mg, 1.760 mmol, 1 equiv) in a solution of HCI (4 M) in dioxane (10 mL) was stirred at 40 °C for 3 hours. The resulting mixture was concentrated under reduced pressure. This resulted in (R)-4'-(2-(methylamino)propanamido)-[1, T-biphenyl]-4-carboxylic acid (350 mg, 67% yield, 85% purity) as a light brown solid. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): 299.2 [M+H]+.

[0137] Step 3: To a stirred solution of (R)-4'-(2-(methylamino)propanamido)-[1,1'-biphenyl]-4-carboxylic acid (200 mg, 0.670 mmol, 1 equiv) and 1-isocyanato-4-isopropylbenzene (140 mg, 0.87 mmol, 1.30 equiv) in THF (2 mL) was added NMM (90 mg, 0.89 mmol, 1.33 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with water (3 x 2 mL) and acetonitrile (3 x 2 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 20% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in (R)-4'-(2-(3-(4-isopropylphenyl)-1-methylureido)propanamido)-[1,1'-biphenyl]-4-carboxylic acid (41.8 mg, 14% yield, 97.5% purity) as an off-white solid.Compound 1(a):O

[0138] LCMS (ES, m / z): 460.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.93 (s, 1H), 10.05 (s, 1H), 8.34 (s, 1H), 8.07 - 7.96 (m, 2H), 7.86 - 7.67 (m, 6H), 7.48 - 7.35 (m, 2H), 7.18 -7.06 (m, 2H), 5.07-4.93 (m, 1H), 3.00 (s, 3H), 2.89-2.77 (m, 1H), 1.39 (d, J= 7.2 Hz, 3H), 1.18 (d, J= 6.8 Hz, 6H).(ii) 4 '-(2-(3-(4-isopropylphenyl)-1-methylureido)acetamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 2) - Prepared using Scheme 1.o

[0139] LCMS (ES, m / z): 446.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.07 (s, 1H), 8.36 (s, 1H), 8.15 - 7.92 (m, 2H), 7.83 - 7.65 (m, 6H), 7.47 - 7.37 (m, 2H), 7.16 - 7.06 (m, 2H), 4.28 -4.02 (s, 2H), 3.00 (s, 3H), 2.90 -2.80 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).(Hi) (R)-3-(4-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl) propanoic acid (Compound 67(a)) - Prepared using Scheme 1.

[0140] LCMS (ES, m / z): 424.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.87 (s, 1H), 8.14 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 4.47 - 4.42 (m, 1H), 3.68 - 3.59 (m, 1 H), 3.54 - 3.45 (m, 1 H), 2.86 - 2.72 (m, 4H), 2.26 - 1.83 (m, 5H), 1.17 (d, J = 8.0 Hz, 6H).(i v) (R)-4 '-(1-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-[1, 1 '-bi phenyl]- 4-carboxylic acid (Compound 52(a)) - Prepared using Scheme 1.

[0141] LCMS (ES, m / z): 486.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.02 (s, 1H), 8.47 (s, 1H), 8.04 - 7.95 (m, 2H), 7.85 - 7.62 (m, 6H), 7.42 - 7.33 (m, 2H), 7.15 - 7.03 (m, 2H), 4.98 - 4.84 (m, 1H), 4.04 - 3.89 (m, 1H), 3.42 (t, J = 12.0 Hz, 1H), 2.93 -2.68 (m, 1H), 2.26 -2.10 (m, 1H), 1.81 - 1.56 (m, 3H), 1.53 - 1.32 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H).(v) (R)-4 '-(4-((4-isopropylphenyl)carbamoyl)morpholine-3-carboxamido)-[1, 1 '-bi phenyl]-4-carboxylic acid (Compound 53(a)) - Prepared using Scheme 1.

[0142] LCMS (ES, m / z): 488.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.90 (s, 1H), 10.15 (s, 1H), 8.54 (s, 1H), 8.04 - 7.97 (m, 2H), 7.84 - 7.69 (m, 6H), 7.43 - 7.33 (m, 2H), 7.15 - 7.06 (m, 2H), 4.70 - 4.65 (m, 1 H), 4.39 - 4.32 (m, 1 H), 4.00 - 3.88 (m, 1 H), 3.86 - 3.72 (m, 2H), 3.71 -3.58 (m, 1H), 3.54 - 3.45 (m, 1H), 2.88 -2.77 (m, 1H), 1.18 (d, J= 6.8 Hz, 6H).(vi) (R)-4'-(1-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)-[1, 1 '-bi phenyl]-4-carboxylic acid (Compound 54(a)) - Prepared using Scheme 1.

[0143] LCMS (ES, m / z): 500.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.90 (s, 1H), 10.06 (s, 1H), 8.25 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.82 - 7.68 (m, 6H), 7.40 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.88-4.71 (m, 1 H), 4.03 - 3.90 (m, 1H), 3.36-3.35 (m, 1H), 2.88 -2.76 (m, 1H), 2.41 - 2.23 (m, 1H), 1.96 - 1.66 (m, 4H), 1.54 - 1.40 (m, 1H), 1.39 - 1.25 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H).(vii) (R)-4'-(1-((5-isopropylthiazol-2-yl)carbamoyl)pyrrolidine-2-carboxamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 80(a))Scheme 8

[0144] Step 1: To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-D-proline (5 g, 14.820 mmol, 1 equiv) and HATU (6.75 g, 17.785 mmol, 1.2 equiv) in DMF (50 mL) were added tert-butyl 4'-amino-[1,1'-biphenyl]-4-carboxylate (4 g, 14.820 mmol, 1 equiv) and NMM (4.5 g, 44.460 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was poured into water (200 mL). The precipitated solids were collected by filtration and washed with MeCN (3 x 200 mL). This resulted in (9H-fluoren-9-yl)methyl (R)-2-((4-(tert-butoxycarbonyl)-[1,1'-biphenyl]-4-yl)carbamoyl)pyrrolidine-1 -carboxylate (6 g, 68.77%yield, 95%purity) as an off-white solid. LCMS (ES, m / z): 588.3 [M+H]+.

[0145] Step 2: To a stirred solution of (9H-fluoren-9-yl)methyl (R)-2-((4'-(tert-butoxycarbonyl)-[1,1'-biphenyl]-4-yl)carbamoyl)pyrrolidine-1-carboxylate (3 g, 5.096 mmol, 1 equiv) in DMF (30 mL) were added Piperidine (9 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (300 mL). The precipitated solids were collected by filtration and washed with MeCN (3x30 mL). This resulted in tert-butyl (R)-4'-(pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-carboxylate (1.4 g, 74.97%yield, 95%purity) as an off-white solid. LCMS (ES, m / z): 367.2 [M+H]+.

[0146] Step 3: A solution of 5-isopropylthiazol-2-amine (2 g, 14.063 mmol, 1.0 equiv) and CDI (2.74 g, 16.876 mmol, 1.2 equiv) in DCM (20 mL) was stirred at room temperature for 1h. Theprecipitated solids were collected by filtration and washed with DCM (3 x2 mL). This resulted in N-(5-isopropylthiazol-2-yl)-1H-imidazole-1-carboxamide (3.2 g, 91% purity) as an off-white solid. LCMS (ES, m / z): 237.1.0 [M+H]+.

[0147] Step 4: To a stirred solution of tert-butyl (R)-4'-(pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-carboxylate (781 mg, 2.133 mmol, 0.8 equiv) and N-(5-isopropylthiazol-2-yl)-1H-imidazole-1-carboxamide (630 mg, 2.666 mmol, 1.0 equiv) in DMF (8 mL) were added TEA (809 mg, 7.998 mmol, 3.0 equiv) at room temperature. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): 535.0 [M+H]+.

[0148] Step 5: tert-butyl (R)-4'-(1-((5-isopropylthiazol-2-yl) carbamoyl) pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-carboxylate (1.4 g, 2.618 mmol, 1.0 equiv) in a solution of HCI in dioxane (4M, 14 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ACN (8 mL). This resulted in (R)-4'-(1-((5-isopropylthiazol-2-yl) carbamoyl) pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (579.0 mg, 46.21 %yield, 97.3%purity) as an off-white solid.Compound 80(a):

[0149] LCMS (ES, m / z): 479.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 610.26 (s, 1H), 8.06-7.92 (m, 2H), 7.82-7.69 (m, 6H), 7.15 (s, 1H), 4.63-4.50 (m, 1H), 3.75-3.51 (m, 2H), 3.11 -2.97 (m, 1H), 2.32 -2.19 (m, 1H), 2.06- 1.84 (m, 3H), 1.23 (d, J= 6.8 Hz, 6H).(viii) 4'-(2-(3-(4-isopropylphenyl)-1-methylureido)butanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 8) - Prepared using Scheme 1.

[0150] LCMS (ES, m / z): 474.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 10.11 (s, 1H), 8.34 (s, 1H), 8.06 - 7.93 (m, 2H), 7.83 - 7.65 (m, 6H), 7.46 - 7.37 (m, 2H), 7.17 - 7.07 (m, 2H), 4.89 - 4.79 (m, 1H), 3.02 (s, 3H), 2.89 - 2.76 (m, 1H), 2.03 - 1.88 (m, 1H), 1.83 - 1.67 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H).(ix) 4'-(2-(3-(4-isopropylphenyl)-1-methylureido)-3-methylbutanamido)-[1,1'-biphenyl]-4-carboxylic acid (Compound 9) - Prepared using Scheme 1.

[0151] LCMS (ES, m / z): 488.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 10.29 (s, 1H), 8.32 (s, 1H), 8.04 - 7.97 (m, 2H), 7.81 - 7.68 (m, 6H), 7.46 - 7.37 (m, 2H), 7.15 - 7.09 (m, 2H), 4.59 (d, J= 10.8 Hz, 1H), 3.08 (s, 3H), 2.83 (p, J = 6.8 Hz, 1 H), 2.30 - 2.20 (m, 1H), 1.18 (d, J = 6.9 Hz, 6H), 0.93 (dd, J = 26.4, 6.5 Hz, 6H).(x) 4 '-(2-cyclopentyl-2-(3-(4-isopropylphenyl)~ 1 -methylureido)acetamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 10) - Prepared using Scheme 1.

[0152] LCMS (ES, m / z): 514.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.93 (s, 1H), 10.25 (s, 1H), 8.31 (s, 1H), 8.06 - 7.91 (m, 2H), 7.84 - 7.75 (m, 4H), 7.75 - 7.68 (m, 2H), 7.47 - 7.36 (m,2H), 7.18 - 7.05 (m, 2H), 4.74 - 4.63 (m, 1H), 3.09 (s, 3H), 2.87 - 2.73 (m, 1H), 3.50 - 2.48(m, 1H), 1.74 - 1.46 (m, 6H), 1.43 - 1.33 (m, 1H), 1.33 - 1.21 (m, 1H), 1.18 (d, J= 7.1 Hz, 6H). (xi) 4 '-(2-cyclohexyl-2-(3-(4-isopropylphenyl)- 1 -methylureido)acetamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 11) - Prepared using Scheme 1.o

[0153] LCMS (ES, m / z): 528.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 10.31 (s, 1H), 8.29 (s, 1H), 8.01 (d, J= 8.0 Hz, 2H), 7.84 - 7.67 (m, 6H), 7.41 (d, J= 8.2 Hz, 2H), 7.12 (d, J= 8.2 Hz, 2H), 4.70 (d, J= 10.8 Hz, 1H), 3.08 (s, 3H), 2.89 -2.76 (m, 1H), 2.05 - 1.89 (m, 1H), 1.78 - 1.68 (m, 2H), 1.67 - 1.52 (m, 3H), 1.27 - 1.10 (m, 10H), 1.05 - 0.89 (m, 1H).(xii) 4'-(2-(3-(4-isopropylphenyl)-1-methylureido)-3-phenylpropanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 12) - Prepared using Scheme 1.o

[0154] LCMS (ES, m / z): 536.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.91 (s, 1H), 10.17 (s, 1H), 8.23 (s, 1H), 8.12 - 7.92 (m, 2H), 7.88 - 7.57 (m, 6H), 7.32 (m, 6H), 7.24 - 7.14 (m, 1H), 7.08 (d, J = 8.6 Hz, 2H), 5.29 - 5.23 (m, 1H), 3.29 (d, J = 5.7 Hz, 1H), 3.14 - 2.93 (m, 4H), 2.81 -2.76 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).(xiii) 4 '-(3-cyclohexyl-2-(3-(4-isopropylphenyl)- 1 -methylureido)propanamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 13) - Prepared using Scheme 1.

[0155] LCMS (ES, m / z): 542.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.93 (s, 1 H), 10.08 (s, 1 H), 8.32 (s, 1 H), 8.06 - 7.92 (m, 2H), 7.85 - 7.67 (m, 6H), 7.48 - 7.34 (m, 2H), 7.18 - 6.97 (m, 2H), 5.06 - 5.00 (m, 1 H), 3.00 (s, 3H), 2.81 (m, 1 H), 1.82 (d, J = 12.4 Hz, 1 H), 1.77 - 1.54 (m, 6H), 1.18 (d, J= 7.0 Hz, 10H), 0.98 - 0.93 (m, 2H).(xiv) 4'-(2-(1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 14) - Prepared using Scheme 1.

[0156] LCMS (ES, m / z): 502.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.93 (s, 1 H), 10.07 (s, 1 H), 8.63 (s, 1 H), 8.11 - 7.93 (m, 2H), 7.86 - 7.66 (m, 6H), 7.66 - 7.54 (m, 2H), 7.33 - 7.17 (m, 2H), 5.06 - 4.91 (m, 1 H), 3.01 (s, 3H), 1.51 - 1.32 (m, 3H).(xv) 4'-(2-(3-(benzo[d][1,3]dioxol-5-yl)-1-methylureido)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 15) - Prepared using Scheme 1.

[0157] LCMS (ES, m / z): 462.1 [M+H]+.11 H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1 H), 10.04 (s, 1 H), 8.31 (s, 1 H), 8.09 - 7.91 (m, 2H), 7.91 - 7.61 (m, 6H), 7.20 (d, J = 2.2 Hz, 1 H), 7.04 - 6.88 (m, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 5.95 (s, 2H), 5.05 - 4.88 (m, 1 H), 2.98 (s, 3H), 1.50 - 1.30 (m, 3H).(xvi) 4'-(2-(1-methyl-3-(naphthalen-2-yl)ureido)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 16) - Prepared using Scheme 1.o

[0158] LCMS (ES, m / z): 468.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 10.09 (s, 1H), 8.65 (s, 1H), 8.10 (d, J= 2.0 Hz, 1H), 8.04-7.97 (m, 2H), 7.86-7.67 (m, 10H), 7.42-7.39 (m, 2H), 5.05-4.99 (m, 1H), 3.07 (s, 3H), 1.46-1.41 (m, 3H).(xvii) 4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)acetamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 38) - Prepared using Scheme 2.o

[0159] LCMS (ES, m / z): 433.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.93 (s, 1H), 10.29 (s, 1 H), 9.88 - 9.79 (m, 1 H), 8.07 - 7.97 (m, 2H), 7.82 - 7.77 (m, 2H), 7.74 (s, 4H), 7.40 (d, J = 8.4 Hz, 2H), 7.21 - 7.09 (m, 2H), 4.73 (s, 2H), 2.90 - 2.77 (m, 1H), 1.2 (d, J= 6.8 Hz, 6H).(xviii) 4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 39) - Prepared using Scheme 2.o

[0160] LCMS (ES, m / z): 447.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 10.29 (s, 1H), 9.80 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.86 - 7.62 (m, 6H), 7.38 (d, J = 8.4 Hz, 2H), 7.19 - 7.03 (m, 2H), 5.18 - 5.06 (m, 1H), 2.89 - 2.77 (m, 1H), 1.59 - 1.41 (m, 3H), 1.21 - 1.07 (m, 6H).(xix) (S)-4 '-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 39(a)) - Prepared using Scheme 2.o

[0161] LCMS (ES, m / z): 446.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.93 (s, 1H), 10.30 (s, 1H), 9.79 (s, 1H), 8.06 - 7.96 (m, 2H), 7.87 - 7.69 (m, 6H), 7.44 - 7.35 (m, 2H), 7.21 - 7.09 (m, 2H), 5.15 - 5.04 (m, 1H), 2.89 - 2.78 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H).(xx) (R)-4 '-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 39(b)) - Prepared using Scheme 2.o

[0162] LCMS (ES, m / z): 447.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.93 (s, 1H), 10.30 (s, 1 H), 9.80 (s, 1 H), 8.04 - 7.97 (m, 2H), 7.82 - 7.78 (m, 2H), 7.75 (s, 4H), 7.38 (d, J = 8.4 Hz, 2H), 7.19 - 7.11 (m, 2H), 5.12 (q, J = 6.8 Hz, 1H), 2.82 (p, J = 6.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.17 (d, J= 6.8 Hz, 6H).(xxi) 4'-(2-(3-(4-isopropylphenyl)-1-methylureido)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 1) - Prepared using Scheme 1.o

[0163] LCMS (ES, m / z): 459.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 10.05 (s, 1H), 8.33 (s, 1H), 8.06 - 7.92 (m, 2H), 7.85 - 7.63 (m, 6H), 7.46 - 7.36 (m, 2H), 7.19 - 7.03 (m,2H), 5.12 - 4.96(m, 1 H), 3.00 (s, 3H), 2.89 - 2.74 (m, 1 H), 1.38 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 6H).(xxii) (R)-4 '-(2-((4-isopropylphenyl)carbamoyl)-2-azabicyclo[3.1.1 ]heptane-3-carboxamido)-[1,1 '-biphenyl]-4-carboxylic acid (Compound 56(a)) - Prepared using Scheme 2.

[0164] LCMS (ES, m / z): 498.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 10.14 - 10.05 (m, 1 H), 8.45 - 8.38 (m, 1 H), 7.99 (s, 2H), 7.81 - 7.65 (m, 6H), 7.41 - 7.35 (m, 2H), 7.11 - 7.06 (m, 2H), 4.80 - 4.63 (m, 2H), 2.86 - 2.76 (m, 1 H), 2.48-2.41 (m, 2H), 2.35 - 2.31 (m, 2H), 2.28 - 2.23 (m, 1 H), 1.90 - 1.80 (m, 1 H), 1.50 - 1.40 (m, 1 H), 1.21 - 1.14 (m, 6H).(xxiii) (R)-4-(3-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo [1.1.1]pentan-1-yl)benzoic acid (Compound 72(a))Scheme 9

[0165] Preparation of ((4-isopropylphenyl)carbamoyl)-D-proline: To a stirred solution of D-proline (7.0 g, 60.80 mmol, 1.0 equiv) in THF (150 mL) was added NMM (6.2 g, 61.29 mmol, 1.0 equiv) and 1-isocyanato-4-isopropylbenzene (8 g, 49.62 mmol, 0.8 equiv) dropwise at 0°C. The reaction was stirred at room temperature for 1 h. The resulting mixture was poured into water (100 mL) and basified to pH 8 with Na2CO3solid. The aqueous layer was washed with MTBE (3 x 200 mL). The aqueous layer was acidified to pH 2 with cone. HCI then stirred at room temperature for 30 min. The precipitate was collected by filtration and washed with MTBE (3 x 50 mL). This resulted in (2R)-1-[(4-isopropylphenyl) carbamoyl] pyrrolidine-2-carboxylic acid (9.5 g, 57% yield, 90% purity) as an off-white solid. LCMS (ES, m / z): 277.1 [M+H]+.

[0166] Step 1: To a stirred solution of 3-((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentane-1-carboxylic acid (20.0 g, 88.0 mmol, 1.00 equiv), DCC (27.2 g, 132 mmol, 1.50 equiv) and DMAP (1.08 g, 8.80 mmol, 0.1 equiv) in DCM (200 mL) was added 2-hydroxyisoindoline-1, 3-dione (17.2 g, 106 mmol, 1.20 equiv) at room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 5 mL). The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluted with PE I EA (60:40) to afford 1,3-dioxoisoindolin-2-yl 3-((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentane- 1 -carboxylate (4.0 g, 95% purity) as a light-yellow solid. LCMS (ES, m / z): 373.1 [M+H]+.

[0167] Step 2: To a flask under nitrogen atmosphere were added 1,3-dioxoisoindolin-2-yl 3-((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentane- 1 -carboxylate (4.00 g, 10.7 mmol, 1.00 equiv) and methyl 4-iodobenzoate (4.22 g, 16.1 mmol, 1.50 equiv), 5-methoxypicolinimidamide hydrochloride (324 mg, 2.14 mmol, 0.200 equiv), TBAI (3.97 g, 10.7 mmol, 1.00 equiv), NiCl2(DME) (756 mg, 2.15 mmol, 0.200 equiv), Zn (7.02 g, 107 mmol, 10.0 equiv) and DMAc (40 mL), followed by TFA (2 mL) at room temperature. The reaction was stirred at room temperature for 2 h. The resulting mixture was filtered and, the filter cake was washed with EtOAc (3x5 mL). The filtrate was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (80:20) to afford methyl 4-(3-((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentan-1-yl) benzoate (200 mg, 95% purity) as an off-white solid. LCMS (ES, m / z): 318.0 [M+H]+.

[0168] Step 3: A solution of methyl 4-(3-((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentan-1-yl) benzoate (230 mg, 0.725 mmol, 1 equiv) in 4M HCI in 1,4-dioxane (3 mL) was stirred at roomtemperature for 1 h. The resulting mixture was concentrated under reduced pressure and the crude product was used in the next step without purification. LCMS (ES, m / z): 218.0 [M+H]+.

[0169] Step 4: To a stirred solution of ((4-isopropylphenyl) carbamoyl)-D-proline (345 mg, 1.25 mmol, 1.20 equiv) and EDCI (322 mg, 2.07 mmol, 2.00 equiv) in DMF (2.5 mL) were added methyl 4-(3-aminobicyclo [1.1.1] pentan-1-yl) benzoate (230 mg, 1.06 mmol, 1.00 equiv) at room temperature. The reaction was stirred at room temperature for 1 h, then the resulting mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (1 x 10 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE I EA (60:40) to afford methyl (R)-4-(3-(1 -((4-isopropylphenyl) carbamoyl) pyrrolidine-2-carboxamido) bicyclo [1.1.1] pentan-1-yl) benzoate (150 mg, 95% purity) as an off-white solid. LCMS (ES, m / z): 476.1 [M+H]+.

[0170] Step 5: To a stirred solution of methyl (R)-4-(3-(1 -((4-isopropylphenyl) carbamoyl) pyrrolidine-2-carboxamido) bicyclo [1.1.1] pentan-1 -yl) benzoate (120 mg, 0.252 mmol, 1.0 equiv) in MeOH (1 mL) and H2O (1 mL) was added LiOH (60.0 mg, 2.51 mmol, 10.0 equiv) at room temperature. The reaction was stirred at room temperature for 2 h. The resulting mixture was directly purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 100% gradient in 10 min; detector, UV 254 nm (13% ACN). This resulted in (R)-4-(3-(1-((4-isopropylphenyl) carbamoyl) pyrrolidine-2-carboxamido) bicyclo [1.1.1] pentan-1-yl) benzoic acid (34.0 mg, 99.9% purity) as an off-white solid.Compound 72(a):

[0171] LCMS (ES, m / z): 462.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ (ppm) δ 8.66 – 8.09 (m, 2H), 7.87 - 7.73 (m, 2H), 7.48 - 7.34 (m, 2H), 7.17 - 6.96 (m, 4H), 4.33 - 4.21 (m, 1H), 3.68 -3.54 (m, 1H), 3.48 - 3.37 (m, 1H), 2.89 - 2.74 (m, 1H), 2.21 (s, 6H), 2.12 - 1.98 (m, 1H), 1.97 -1.78 (m, 3H), 1.18 (d, J= 6.8 Hz, 6H).(xxiv) 2-(6-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 75(a)), 2-(6-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-(S)-spiro[3.3]heptan-2-yl)acetic acid (Compound 75(a,a)), and 2-(6-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-(R)-spiro[3.3]heptan-2-yl)acetic acid (Compound 75(a,b))Scheme 10

[0172] Preparation of ((4-isopropylphenyl)carbamoyl)-D-proline: To a stirred solution of D-proline (7.0 g, 60.80 mmol, 1.0 equiv) in THF (150 mL) was added NMM (6.2 g, 61.29 mmol, 1.0 equiv) and 1-isocyanato-4-isopropylbenzene (8 g, 49.62 mmol, 0.8 equiv) dropwise at 0°C. The reaction was stirred at room temperature for 1 h. The resulting mixture was poured into water (100 mL) and basified to pH 8 with Na2CO3solid. The aqueous layer was washed with MTBE (3 x 200 mL). The aqueous layer was acidified to pH 2 with concentrated HCI, then stirred at room temperature for 30 min. The precipitate was collected by filtration and washed with MTBE (3 x 50 mL). This resulted in (2R)-1-[(4-isopropylphenyl) carbamoyl] pyrrolidine-2-carboxylic acid (9.5 g, 57% yield, 90% purity) as an off-white solid. LCMS (ES, m / z): 277.1 [M+H]+.

[0173] Step 1: To a solution of LiCI (0.90 g, 21 mmol, 2.4 equiv) in THF (18 mL) was added triethyl phosphonoacetate (2.0 g, 8.9 mmol, 1.0 equiv) at room temperature. After 10 min, DBU (1.49 g,9.77 mmol, 1.10 equiv) was added dropwise at room temperature and the mixture was stirred at room temperature for an additional 30 min. To the above mixture was added tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate (2.0 g, 8.9 mmol, 1.0 equiv) in THF (18 mL) dropwise and the reaction was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE I EA (3:1) to afford ethyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-ylidene)acetate (2.19 g, 842% yield, 100% purity) as a white solid. LCMS (ES, m / z): 296.4 [M+H]+.

[0174] Step 2: To a solution of ethyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-ylidene)acetate (1.0 g, 3.4 mmol, 1.0 equiv) in MeOH (30 mL) was added Pd / C (0.70 g, 0.66 mmol, 0.19 equiv) in portions at room temperature. The reaction was stirred at room temperature for 2 h under an atmosphere of hydrogen. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford ethyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetate (0.83 g) as a yellow oil. LCMS (ES, m / z): 298.4 [M+H]+.

[0175] Step 3: To a solution of ethyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetate (0.70 g, 2.4 mmol, 1.0 equiv) in DCM (4 mL) was added a solution of 4M HCI in 1,4-dioxane (7 mL) at room temperature. The reaction was stirred at room temperature for 2 h, then concentrated under reduced pressure. The crude product was used directly in the next step without purification. LCMS (ES, m / z): 198.3 [M+H]+.

[0176] Step 4: To a stirred mixture of ((4-isopropylphenyl)carbamoyl)-D-proline (280 mg, 1.01 mmol, 1.00 equiv) and EDCI (204 mg, 1.318 mmol, 1.30 equiv) in DCM (2 mL) were added HOBT (273 mg, 2.03 mmol, 2.00 equiv), ethyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (800 mg, 4.06 mmol, 4.00 equiv) and NMM (512 mg, 5.07 mmol, 5.00 equiv) at room temperature. The reaction was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and the residue purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in ethyl (R)-2-(6-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (400 mg, 87% yield, 87.3% purity) as a white solid. LCMS (ES, m / z): 456.6 [M+H]+.

[0177] Step 5: To a solution of ethyl (R)-2-(6-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (220 mg, 0.483 mmol, 1.00 equiv) in MeOH (2 mL) and H2O (0.4 mL) was added LiOH (41 mg, 1.8 mmol, 3.6 equiv) at room temperature. The reaction was stirred at 50 °C for 3 h. Then, the resulting mixture was neutralized to pH 6 with HCI(aq. 4M) and the desired product extracted with EtOAc (3 x 3 mL). The combined organic layer was dried over anhydrous Na2SO4and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 20% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in (R)-2-(6-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (43 mg, 26% yield, 99.9% purity) as a white solid.Compound 75(a):

[0178] LCMS (ES, m / z): 428.5 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 11.90 (s, 1H), 8.03 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.38 (d, J= 8.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.21 (d, J= 4.8, 1H), 4.02 - 3.95 (m, 1H), 3.56 (s, 1H), 3.40 - 3.04(m, 1H), 2.81 - 2.75 (m, 1H), 2.40 - 2.18 (m, 1H), 2.27 - 2.19 (m, 3H), 2.16 - 2.09 (m, 2H), 2.01 - 1.95 (m, 2H), 1.88 - 1.85 (m, 5H), 1.81 -1.57 (m, 2H), 1.18 (d, J= 6.8 Hz, 6H).OH OH Chiral-HPLCCompound 75(a) Compound 75(a,a)Scheme 11

[0179] (R)-2-(6-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 75(a))(43 mg) was separated by Prep-Chiral-HPLC using the following conditions (Column: CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hex(0.2% FA), Mobile Phase B: MeOH: DCM=1:1--HPLC; Flow rate: 20 mL / min; Gradient (B%): 15% B to 15% B in 45min; Wave Length: 220 / 254 nm; Peak 1 (Compound 75(a)(lsomer 2)) (min): 38.28; Peak 2 (Compound 75(a) (Isomer 1)) (min): 43.10; Sample Solvent: MEOH: DCM=1: 1--HPLC; Injection Volume: 0.9 mL; Number of runs:2) to afford isomer 1 of Compound 75(a) (9.1 mg, 99.7%purity) as a white solid and isomer 2 of Compound 75(a) (9.2 mg, 99.8% purity) as a white solid.Compound 75(a)(lsomer 1):

[0180] The stereochemistry of isomer 1 was not confirmed but corresponds to one of Compound 75(a,a) and Compound 75(a,b). Peak 2: retention time: 43.10 min. LCMS (ES, m / z): 428.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.96 (s, 1H), 8.04 (s, 1H), 7.95 (d, J= 8.0 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.13 - 7.06 (m, 2H), 4.21 -4.15 (m, 1H), 4.02 - 3.99 (m, 1H), 3.57 - 3.43 (m, 1H), 3.40 - 3.22 (m, 1 H), 2.81 -2.65 (m, 1 H), 2.47 - 2.36 (m, 1 H), 2.34 - 2.23 (m, 3H), 2.21 - 2.07 (m, 2H), 2.02 - 1.98 (m, 2H), 1.91 - 1.76 (m, 5H), 1.66 - 1.58 (m, 2H), 1.18 (d, J= 6.8 Hz, 6H).Compound 75(a)(lsomer 2):

[0181] The stereochemistry of isomer 2 was not confirmed but corresponds to the other of Compound 75(a,a) and Compound 75(a,b). Peak 1: retention time: 38.28 min. LCMS (ES, m / z): 428.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.97 (s, 1H), 8.04 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.21 - 4.15 (m, 1H), 4.07 - 3.96 (m, 1H), 3.57 - 3.52 (m, 1 H), 3.40 - 3.22 (m, 1 H), 2.95 -2.87 (m, 3H), 2.55 - 2.46 (m, 1 H), 2.28 -2.19 (m, 2H), 2.21 - 2.08 (m, 2H), 2.01 - 1.98 (m, 2H), 1.93 - 1.82 (m, 3H), 1.78 - 1.72 (m, 1H), 1.66 - 1.58 (m, 2H), 1.17 (d, J= 6.8 Hz, 6H).(xxv) (1R, 2R)-2-(4-((R)~ 1 -((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopropane-1-carboxylic acid (Compound 77(a)), (1 S,2S)-2-(4-((R)~ 1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopropane-1-carboxylic acid (Compound 77(b)), (1S,2R)-2-(4-((R)-1-((4- isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopropane-1-carboxylic acid (Compound 77(c)), and (1 R,2S)-2-(4-((R)-1 -((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopropane-1-carboxylic acid (Compound 77(d)) - Prepared using Scheme 4.

[0182] The structure of Compounds 77(a), 77(b), 77(c) and 77(d) are as follows:Compound 77(a) Compound 77(b)Compound 77(c) Compound 77(d)

[0183] Potassium [2-(ethoxycarbonyl)cyclopropyl]trifluoro-1 -borate was used instead on the corresponding boronic ester. The resulting racemic mixture was separated by Prep-chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.2% TFA)-HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 40% B to 40% in 8min; Wavelength: 220 / 254 nm; Peak 1 (Isomer 3): retention time: 4.61 min; Peak 2 (Isomer 4): retention time: 5.01 min; Peak 3 (Isomer 1):retention time: 6.36 min; Peak 4 (Isomer 2): retention time: 6.82 min; Sample Solvent: MeOH: DCM=1: 1-HPLC; Injection Volume: 0.4 mL; Number Of Runs: 10).Compound 77(lsomer 1):

[0184] The cyclopropane stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 77(a), 77(b), 77(c) or 77 (d). Peak 3: retention time: 6.36 min; LCMS (ES, m / z): 436.2[M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.26 (s, 1H), 9.92 (s, 1H), 8.17 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.43- 7.35 (m, 2H), 7.17-6.99 (m, 4H), 4.48 -4.44 (m, 1H), 3.62 (d, J = 11.0 Hz, 1H), 3.55 - 3.47 (m, 1H), 2.87 - 2.79 (m, 1H), 2.36 (s, 1H), 2.15 (d, J = 7.4 Hz, 1H), 2.06 - 1.86 (m, 3H), 1.78- 1.70 (m, 1H), 1.36 - 1.27 (m, 1H), 1.32 - 1.27 (m, 1H), 1.17 (d, J = 7.2 Hz, 6H).Compound 77(lsomer 2):

[0185] The cyclopropane stereochemistry of Isomer 2 was not assigned but corresponds to another of Compounds 77(a), 77(b), 77(c) or 77 (d). Peak 4: retention time: 6.82 min; LCMS (ES, m / z): 436.2[M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.25 (s, 1H), 9.92 (s, 1H), 8.17 (s, 1H), 7.63 - 7.46 (m, 2H), 7.46 - 7.34 (m, 2H), 7.14 - 7.03 (m, 4H), 4.48 - 4.44 (m, 1H), 3.68 - 3.61 (m, 1H), 3.51 (t, J = 7.0 Hz, 1H), 2.87 - 2.79 (m, 1H), 2.32 (d, J = 4.0 Hz, 1H), 2.20 - 2.13 (m, 1H), 2.05 - 1.87 (m, 3H), 1.78 - 1.70 (m, 1H), 1.52 - 1.38 (m, 1H), 1.38 - 1.25 (m, 1H), 1.17 (d, J = 7.2 Hz, 6H).Compound 77(lsomer 3):

[0186] The cyclopropane stereochemistry of Isomer 3 was arbitrary not assigned but corresponds to another of Compounds 77(a), 77(b), 77(c) or 77 (d). Peak 1: retention time: 4.61 min; LCMS (ES, m / z): 436.2[M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.24 (s, 1H), 9.92 (s, 1H), 8.17 (s, 1H), 7.58 - 7.45 (m, 2H), 7.45 - 7.32 (m, 2H), 7.22 - 7.02 (m, 4H), 4.44 (m, 1 H), 3.68 - 3.61 (m, 1 H), 3.55 - 3.47 (m, 1H), 2.87 - 2.79 (m, 1H), 2.39 - 2.29 (m, 1H), 2.21 - 2.10 (m, 1H), 2.10 - 1.86 (m, 3H), 1.78- 1.70 (m, 1H), 1.44 - 1.33 (m, 1H), 1.32 - 1.27 (m, 1H), 1.17 (d, J = 7.2 Hz, 6H).Compound 77(lsomer 4):

[0187] The cyclopropane stereochemistry of Isomer 4 was not assigned but corresponds to the other of Compounds 77(a), 77(b), 77(c) or 77 (d). Peak 2: retention time: 5.01 min; LCMS (ES, m / z): 436.2[M+H]+.1H NMR (400 MHz, DMSO-d6) 5 12.24 (s, 1H), 9.92 (s, 1H), 8.17 (s, 1H), 7.63 - 7.44 (m, 2H), 7.44 - 7.32 (m, 2H), 7.20 - 7.01 (m, 4H), 4.48 - 4.44 (m, 1H), 3.68 - 3.61 (m, 1H), 3.55 - 3.47 (m, 1H), 2.87 - 2.79 (m, 1H), 2.35 - 2.28 (m, 1H), 2.20 - 2.13 (m, 1H), 2.05 -1.89 (m, 3H), 1.78 - 1.70 (m, 1H), 1.36 - 1.27 (m, 1H), 1.32 - 1.27 (m, 1H), 1.17 (d, J = 7.2 Hz, 6H).(xxvi) 2-((1S,2R)-2-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopropyl)acetic acid (Compound 78(a)) and 2-((1 R,2S)-2-(4-((R)-1 - ((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopropyl)acetic acid (Compound 78(b))1) LiOH, MeOH, H2O 2) Chiral-HPLCScheme 12

[0188] Step 1: To a stirred solution of ethyl hydrogen malonate (1.15 g, 8.705 mmol, 1 equiv) and 2-(4-bromophenyl)acetaldehyde (1.99 g, 9.998 mmol, 1.15 equiv) in NMM (1.21 mL, 11.963 mmol, 1.37 equiv) at room temperature. The resulting mixture was stirred at 80°C for 4h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with DCM (3 x 50mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (9:1) to afford ethyl (3E)-4-(4-bromophenyl)but-3-enoate (1.1 g, 47 %yield, 90%purity) as a light-yellow oil. LCMS (ES, m / z): 269.1 [M+H]+.

[0189] Step 2: To a stirred solution of ZnEt2 (12.26 mL, 12.261 mmol, 3 equiv) in DCM (30 mL) were added CH2I2 (6.57 g, 24.522 mmol, 6 equiv) at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 30min under nitrogen atmosphere. To the above mixture was added TFA (1.40 g, 12.261 mmol, 3 equiv) dropwise at -78°C. The resulting mixture was stirred at -78°C for an additional 30 min. To the above mixture was added ethyl (3E)-4-(4-bromophenyl)but-3-enoate (1.10 g, 4.087 mmol, 1 equiv) dropwise at-78°C. The resulting mixture was stirred at room temperature for an additional 3 days. The reaction was quenched with sat. NaHCOs (aq.) at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (9:1) to afford ethyl 2-(2-(4-bromophenyl)cyclopropyl)acetate (880 mg, 76%yield, 80%purity) as a yellow oil. LCMS (ES, m / z): 283.1 [M+H]+.

[0190] Step 3: To a stirred solution of ethyl 2-(2-(4-bromophenyl)cyclopropyl)acetate (700 mg, 2.472 mmol, 1 equiv) and BocNH2 (868 mg, 7.409 mmol, 3.00 equiv) in dioxane (10 mL) were added BrettPhos Pd G3 (337 mg, 0.372 mmol, 0.15 equiv), BrettPhos (200 mg, 0.373 mmol, 0.15 equiv) and K3PO4 (1580 mg, 7.444 mmol, 3.01 equiv) at room temperature. The resulting mixture was stirred at 100°C for 1h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford ethyl 2-(2-(4-((tert-butoxycarbonyl)amino)phenyl)cyclopropyl)acetate (750 mg, 95%yield, 90%purity) as a white solid. LCMS (ES, m / z): 319.4 [M+H]+.

[0191] Step 4: To a stirred solution of ethyl 2-(2-(4-((tert-butoxycarbonyl)amino)phenyl) cyclopropyl)acetate (700 mg, 2.192 mmol, 1 equiv) in a solution of HCI in 1,4-dioxane (4.0 M, 10 mL) at room temperature. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in ethyl 2-(2-(4-aminophenyl)cyclopropyl)acetate (450 mg) as a white solid. LCMS (ES, m / z): 219.2 [M+H]+.

[0192] Step 5: The resulting diastereomer mixture was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient (B%): 30% B to 30% B in 25 min% B; Wave Length: 220 / 254 nm; Peak 1 (Isomer 1): retention time: 15.04 min; Peak 2 (Isomer 2): retention time: 20.37 min; Sample Solvent: MeOH: DCM=1:1--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 7).Compound 78(lsomer 1):

[0193] The cyclopropane stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 78(a) and 78(b). Peak 1: retention time: 15.04 min. LCMS (ES, m / z): 449.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.12 (s, 1H), 9.87 (s, 1H), 8.16 (s, 1 H), 7.58 - 7.46 (m, 2H), 7.45 - 7.32 (m, 2H), 7.14 - 7.04 (m, 2H), 7.04 - 6.89 (m, 2H), 4.50 - 4.37 (m, 1H), 3.73 -3.56 (m, 1 H), 3.57 - 3.46 (m, 1 H), 2.90 - 2.73 (m, 1 H), 2.34 - 2.23 (m, 2H), 2.23 - 2.09 (m, 1 H), 2.11 - 1.83 (m, 3H), 1.77 - 1.64 (m, 1H), 1.29 - 1.07 (m, 7H), 0.94 - 0.83 (m, 1H), 0.82 - 0.67 (m, 1H).Compound 78(lsomer 2):

[0194] The cyclopropane stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 78(a) and 78(b). Peak 2: retention time: 20.37 min. LCMS (ES, m / z): 449.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.08 (s, 1H), 9.87 (s, 1H), 8.16 (s, 1H), 7.56 -7.45 (m, 2H), 7.45 - 7.33 (m, 2H), 7.15 - 7.07 (m, 2H), 7.05 - 6.94 (m, 2H), 4.51 - 4.38 (m, 1H), 3.73 -3.59 (m, 1 H), 3.58 - 3.45 (m, 1 H), 2.89 - 2.73 (m, 1 H), 2.36 - 2.25 (m, 2H), 2.23 - 2.09 (m, 1 H), 2.10 - 1.82 (m, 3H), 1.77 - 1.64 (m, 1H), 1.28 - 1.06 (m, 7H), 0.93 - 0.83 (m, 1H), 0.82 - 0.68 (m, 1H).(xxvii) 4'-((1R, 3R,4S)-2-((4-isopropylphenyl)carbamoyl)-2-azabicyclo[2.2.1 ]heptane-3-carboxamido)-[1,1 '-biphenyl]-4-carboxylic acid (Compound 55(a)) - Prepared using Scheme 1.

[0195] LCMS (ES, m / z): 497 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 10.02 (s, 1H), 8.33 (s, 1H), 8.04 - 7.97 (m, 2H), 7.82 - 7.67 (m, 6H), 7.44 - 7.38 (m, 2H), 7.13 - 7.04 (m, 2H), 4.55 (s, 1H), 4.41 (d, J= 3.6 Hz, 1H), 2.87 - 2.76 (m, 2H), 1.87 - 1.79 (m, 1H), 1.75 - 1.63 (m, 2H), 1.57 -1.44 (m, 3H), 1.17 (d, J= 6.8 Hz, 6H).(xxviii) 4 '-(2-cyclopropyl-2-(3-(4-isopropylphenyl)-1-methylureido)acetamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 5) - Prepared using Scheme 1.

[0196] For the amine deprotection and ester hydrolysis step, trifluoroacetic acid in dichloromethane was used instead of HCI.O

[0197] LCMS (ES, m / z): 486.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) 6 12.80 (s, 1H), 10.06 (s, 1H), 8.34 (s, 1H), 8.04 - 7.97 (m, 2H), 7.82 - 7.62 (m, 6H), 7.43 - 7.36 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 4.07 (d, J = 10.0 Hz, 1H), 3.23 (s, 3H), 2.92 - 2.78 (m, 1H), 1.33 (d, J = 5.2 Hz, 1H), 1.17 (d, J = 6.8 Hz, 6H), 0.78 (p, J = 4.4 Hz, 1 H), 0.71 - 0.58 (m, 2H), 0.32 - 0.23 (m, 1 H).(xxix) 4'-(2-(3-(4-isopropylphenyl)-1-methylureido)-2-phenylacetamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 7) - Prepared using Scheme 1.o

[0198] LCMS (ES, m / z): 522.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.47 (s, 1H), 8.42 (s, 1H), 8.04 - 7.96 (m, 2H), 7.85 - 7.66 (m, 6H), 7.53 - 7.25 (m, 7H), 7.17 - 7.09 (m, 2H), 6.24 (s, 1H), 2.89 - 2.78 (m, 4H), 1.18 (d, J = 6.8 Hz, 6H).(xxx) 4'-(2-(1-cyclopropyl-3-(4-isopropylphenyl)ureido)propanamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 4) - Prepared using Scheme 1.

[0199] For the amine deprotection and ester hydrolysis step, trifluoroacetic acid in dichloromethane was used instead of HCI.O

[0200] LCMS (ES, m / z): 486.3[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.84 (s, 1 H), 8.33 (s, 1 H), 8.03 - 7.97 (m, 2H), 7.82 - 7.75 (m, 2H), 7.71 (s, 4H), 7.49 - 7.43 (m, 2H), 7.16 - 7.10 (m, 2H), 4.75 - 4.67 (m,1H), 2.86 - 2.78 (m, 1H), 2.69-2.68 (m, 1H), 1.52 (d, J = 8.0 Hz, 3H), 1.18 (d, J = 8.0 Hz, 6H), 1.07 - 0.96 (m, 3H), 0.80-0.77 (m, 1H).(xxxi) (R)-3-fluoro-4'-(2-(3-(4-isopropylphenyl)-1-methylureido)propanamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 17(a)) - Prepared using Scheme 4.

[0201] The Suzuki coupling using lnt-14 was performed with the corresponding carboxylic acid and did not require the saponification step.O

[0202] LCMS (ES, m / z): 478.2 [M +H]+.1H NMR (300 MHz, DMSO-d₆) δ 13.20 (s,1H), 10.09 (s, 1H), 8.34 (s, 1H), 7.93-7.88 (m, 1H), 7.78-7.74 (m, 4H), 7.64 -7.58 (m, 2H), 7.42-7.39 (m, 2H), 7.13-7.09 (m, 2H), 5.01-4.93 (m, 1H), 3.00 (s, 3H), 2.84-2.77 (m, 1H), 1.38 (d, J = 7.2 Hz, 3H), 1.18 (d, J= 6.8 Hz, 6H).(xxxii) (R)-4 '-(2-(3-(4-isopropylphenyl)-1-methylureido)propanamido)-3-methoxy-[1, 1 biphenyl]-4-carboxylic acid (Compound 18(a)) - Prepared using Scheme 1.

[0203] Methyl 4'-amino-3-methoxy-[1,1'-biphenyl]-4-carboxylate (lnt-2) was used instead of the corresponding tert-butyl ester and was hydrolyzed prior to the amine deprotection using LiOH in a MeOH / H2O mixture. Synthesis of lnt-2 was prepared following this 1-step procedure: To a solution of 4-bromoaniline (5 g, 29.066 mmol, 1 equiv) in dioxane (43 mL) was added Pd(dppf)Cl2(2.13 g, 2.907 mmol, 0.1 equiv), K2CO3(12.05 g, 87.198 mmol, 3 equiv), 3-methoxy-4-(methoxycarbonyl)phenylboronic acid (6.10 g, 29.066 mmol, 1 equiv) and H2O (7 mL) at room temperature. The final reaction mixture reacts at 80°C for 1h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:1) to afford methyl 4'-amino-3-methoxy-[1,1'-biphenyl]-4-carboxylate (3.6 g, 48.14%yield, 95.1%purity) as a white solid. LCMS (ES, m / z): 258.1 [M+H]+.O

[0204] LCMS (ES, m / z): 490.2[M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 10.05 (s, 1H), 8.33 (s, 1H), 7.80 - 7.70 (m, 5H), 7.42 (d, J= 8.2 Hz, 2H), 7.36 -7.25 (m, 2H), 7.11 (d, J = 8.2 Hz, 2H), 5.03 - 4.98 (m, 1 H), 3.93 (s, 3H), 3.00 (s, 3H), 2.87 -2.76 (m, 1 H), 1.38 (d, J = 8.0 Hz, 3H), 1.18 (d, J = 6.8 Hz, 6H).(xxxiii) (R)-5-(4-(2-(3-(4-isopropylphenyl)-1-methylureido)propanamido)phenyl)-6-methylpicolinic acid (Compound 19(a)) - Prepared using Scheme 1.

[0205] lnt-2 was prepared according to the procedure described in WO2024214038.o

[0206] LCMS (ES, m / z): 475.6 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.34 (s, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.80 - 7.72 (m, 3H), 7.59- 7.30 (m, 4H), 7.15 - 7.09 (m, 2H), 4.98 -4.72 (m, 1H), 3.45 -3.25 (m, 3H), 3.00 -2.88 (m, 3H), 2.83-2.74 (m, 1H), 1.39 (d, J= 6.8 Hz, 3H), 1.18 - 1.16 (m, 6H).(xxxiv) (R)-4-(4-(2-(3-(4-isopropylphenyl)-1-methylureido)propanamido) phenyl) butanoic acid (Compound 35(a)) - Prepared using Scheme 1.

[0207] Methyl 4-bromobenzenebutanoate (Jnt-2) was used instead of the corresponding tertbutyl ester and lnt-4 was hydrolyzed using LiOH in a MeOH / H2O mixture following the amine deprotection.

[0208] LCMS (ES, m / z):426.3[M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 9.81 (s, 1H), 8.31 (s, 1H), 7.56 - 7.48 (m, 2H), 7.44 - 7.36 (m, 2H), 7.11 (d, J = 8.4 Hz, 4H), 4.94 (d, J = 7.2 Hz, 1H), 2.91 (s, 3H), 2.88 - 2.79 (m, 1H), 2.59 - 2.53 (m, 2H), 2.20 (d, J = 7.6 Hz, 2H), 1.77 (d, J = 7.2 Hz, 2H), 1.35 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 6H).(xxxv) (R)-4-(6-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)pyridin-3-yl) benzoic acid (Compound 41(a)) - Prepared using Scheme 5.OH

[0209] LCMS (ES, m / z): 448.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 6 10.87 (s, 1H), 9.82 (s, 1H), 8.85 - 8.76 (m, 1H), 8.24 - 8.16 (m, 2H), 8.06 - 8.02 (m, 2H), 7.89 - 7.85 (m, 2H), 7.39 -7.33 (m, 2H), 7.17- 7.11 (m, 2H), 5.22 (s, 1H), 2.88 -2.79 (m, 1H), 1.52 - 1.45 (m, 3H), 1.17 (d, J = 6.8 Hz, 6H).(xxxvi)(R)-4-(6-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)pyridin-3-yl)-3-methylbenzoic acid (Compound 42(a)) - Prepared using Scheme 5.

[0210] Methyl 4-(6-aminopyridin-3-yl)-3-methylbenzoate (Jnt-2) was used instead of the corresponding tert-butyl ester and lnt-17 was hydrolyzed using LiOH in a MeOH / H2O mixture prior to the carbamate formation. Synthesis of lnt-2 was prepared following this 1-step procedure: To a stirred solution of methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3017.3 mg, 10.932 mmol, 1 equiv) and 5-bromopyridin-2-amine (2799.8 mg, 16.183 mmol, 1.48 equiv) in dioxane (30 mL) and H2O (3 mL) were added Pd(dppf)Cl2 (1779.6 mg, 2.181 mmol, 0.20 equiv) and K2CO3(4493.9 mg, 32.564 mmol, 2.98 equiv) at room temperature. The resulting mixture was stirred at 80°C for 1h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc(3 x 15mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:3) to afford methyl 4-(6-aminopyridin-3-yl)-3-methylbenzoate (2120 mg, 80.04%yield, 96.0%purity) as a Brown yellow solid. LCMS (ES, m / z): 243.2[M+H]+.OH

[0211] LCMS (ES, m / z): 462.2 [M+H]+;1H NMR (400 MHz, DMSO-d₆) δ 12.96 (s, 1H), 10.83 (s, 1H), 9.81 (s, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.17 (d, J= 8.8 Hz, 1H), 7.95 - 7.78 (m, 3H), 7.48 -7.32 (m, 3H) 7.25 - 7.05 (m, 2H), 5.22 (q, J = 6.8 Hz, 1 H), 2.93 - 2.77 (m, 1 H), 2.33 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H).(xxxvii) (R)-4'-(1-((4-isopropylphenyl)carbamoyl)azetidine-2-carboxamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 58(a)) - Prepared using Scheme 2.

[0212] Phenyl (4-isopropylphenyl)carbamate was used instead of the corresponding isocyanate. Also, the amide formation was performed using the carboxylic acid of lnt-2 and did not require the ester hydrolysis step.

[0213] LCMS (ES, m / z):458.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 8.55 (s, 1H), 8.07 - 7.92 (m, 2H), 7.79 - 7.65 (m, 6H), 7.45 - 7.39 (m, 2H), 7.15 - 7.09 (m, 2H), 4.88 -4.80 (m, 1H), 4.10 - 3.91 (m, 2H), 2.86 - 2.77 (m, 1H), 2.48 -2.43 (m, 1H), 2.31 -2.21 (m, 1H), 1.17 (d, J= 6.8 Hz, 6H).(xxxviii) 4'-((2R,3aS,6aS)-1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta [b]pyrrole-2-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (Compound 59(a)) and 4'- ((2S,3aR,6aR)-1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)-[1, T-biphenyl]-4-carboxylic acid (Compound 59(b))Scheme 13

[0214] Step 1: To a stirred solution of rac-benzyl (2R,3aR,6aR)-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride (450 mg, 1.597 mmol, 1 equiv) in THF (5 mL) was added NMM (210 mg, 2.076 mmol, 1.30 equiv) and 1-isocyanato-4-isopropylbenzene (270 mg, 1.675 mmol, 1.05 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SZ 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: ETCH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 20% Bto20% in 17min% B; Wave Length: 220 / 254 nm; Peak: retention time: 8.16 min; Peak 2: retention: 9.35 min; Sample Solvent: MeOH: DCM=1: 1-HPLC; Injection Volume: 0.4 mL; Number Of Runs: 12) to afford the first eluting peak as Step 1-lsomer 1 (260 mg) as an off-white oil and the second eluting peak as Step 1-lsomer 2 (260 mg) as an off-white oil. LCMS (ES, m / z): 407.1 [M+H]+. Step 1-lsomer 1 is one of as benzyl (2S,3aS,6aS)-1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxylate or benzyl (2R,3aR,6aR)-1-((4-isopropylphenyl) carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxylate while Step-1-Isomer 2 is the other.

[0215] Step 2: To a stirred solution of Step 1-lsomer 2 (Peak 2) (260 mg, 0.640 mmol, 1 equiv.) in MeOH (12 mL) was added Pd / C (260 mg, 0.2443 mmol, 0.382 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in the carboxylic acid (200 mg) as a white solid. LCMS (ES, m / z): 317.1 [M+H]+.

[0216] Step 3: To a stirred solution of the carboxylic acid from step 2 (180 mg, 0.569 mmol, 1 equiv) in DMF (3 mL) were added EDCI (180 mg, 1.159 mmol, 2.04 equiv) and tert-butyl 4'-amino-[1,1'-biphenyl]-4-carboxylate (270 mg, 1.002 mmol, 1.76 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase,MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the step 3 intermediate (130 mg) as a white solid. LCMS (ES, m / z): 568.4 [M+H]+.

[0217] Step 4: The step 3 intermediate (120 mg, 0.211 mmol, 1 equiv) in a solution of HCI in dioxane (4M, 4 mL) was stirred at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in isomer 1 of Compound 59 (39.6 mg, 99.4%purity) as a white solid. Isomer 1 corresponds to one of Compounds 59(a) or 59(b).Compound 59(isomer 1):

[0218] LCMS (ES, m / z): 512.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 12.92 (s, 1H), 10.16 (s, 1H), 8.03- 7.98 (m, 2H), 7.92 (s, 1H), 7.81 - 7.69 (m, 6H), 7.43 - 7.39 (m, 2H), 7.12 -7.07 (m, 2H), 4.59-4.55 (m, 1H), 4.42-4.41 (m, 1H), 2.87-2.75 (m, 2H), 2.45 -2.35 (m, 1H), 2.19 -2.05 (m, 1H), 1.95- 1.67 (m, 4H), 1.57- 1.45 (m, 2H), 1.17 (d, J= 6.8 Hz, 6H).Compound 59(isomer 2):

[0219] Isomer 2 of Compound 59 was prepared following the same procedure as for Isomer 1, but using peak 1 from step 1. Isomer 2 corresponds to the other of Compounds 59(a) or 59(b).

[0220] LCMS (ES, m / z): 512 [M+H]+1H NMR (300 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.14 (s, 1H), 8.05- 7.96 (m, 2H), 7.90 (s, 1H), 7.83 - 7.66 (m, 6H), 7.46 - 7.36 (m, 2H), 7.14 -7.06 (m, 2H), 4.57 (dd, J = 9.1, 5.5 Hz, 1H), 4.42-4.40 (m, 1H), 2.82-2.78 (m, 2H), 2.47 - 2.33 (m, 1H), 2.12 (t, J = 6.4 Hz, 1H), 1.95- 1.65 (m, 4H), 1.59- 1.48 (m, 2H), 1.17 (d, J = 6.9 Hz, 6H).(xxxix) (R)-3-fluoro-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)-[1,1'-biphenyl]-4-carboxylic acid (Compound 48(a)) – Prepared using Scheme 6.

[0221] tert-butyl 4'-amino-3-fluoro-[1,1'-biphenyl]-4-carboxylate (Jnt-2) was prepared using a similar procedure to the one described in WO2024214038.OH

[0222] LCMS (ES, m / z): 464.4[M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 10.32 (s, 1 H), 9.80 (s, 1 H), 7.97 - 7.85 (m, 1 H), 7.84 - 7.71 (m, 4H), 7.70 - 7.54 (m, 2H), 7.46 - 7.34 (m, 2H), 7.23 - 7.10 (m, 2H), 5.18 - 5.07 (m, 1H), 2.92 - 2.76 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H).(xl) (R)-4 '-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)-3-methoxy-[1, 1 biphenyl]-4-carboxylic acid (Compound 46(a)) - Prepared using Scheme 6.Methyl 4'-amino-3-methoxy[1,1'-biphenyl]-4-carboxylate (Jnt-2) was used instead of the corresponding tert-butyl ester and was hydrolyzed using LiOH in a MeOH / H2O mixture prior to the carbamate formation with the isocyanate. Methyl 4'-amino-3-methoxy[1,1'-biphenyl]-4-carboxylate was prepared following this procedure: To a solution of 4-bromoaniline (5 g, 29.066 mmol, 1 equiv) in dioxane (43 mL) was added Pd(dppf)Cl2(2.13 g, 2.907 mmol, 0.1 equiv), K2CO3(12.05 g, 87.198 mmol, 3 equiv), 3-methoxy-4-(methoxycarbonyl)phenylboronic acid (6.10 g, 29.066 mmol, 1 equiv) and H2O (7 mL) at room temperature. The final reaction mixture reacts at 80°C for 1h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:1) to afford methyl 4'-amino-3-methoxy-[1,1'-biphenyl]-4-carboxylate (3.6 g, 48% yield, 95.1 %purity) as a white solid. LCMS (ES, m / z): 258.1 [M+H]+.OH

[0223] LCMS (ES, m / z): 399.2[M+H]+;1H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 10.07 (s, 1H), 9.78 (s, 1H), 7.54 - 7.47 (m, 2H), 7.43 - 7.30 (m, 2H), 7.20 - 7.10 (m, 4H), 5.08 - 5.03 (m, 1 H), 2.84 - 2.74 (m, 3H), 2.50 - 2.47(m, 2H), 1.46 – 1.44(m, 3H), 1.23 – 1.15(m, 6H).(xli) (R)-3-fluoro-4'-(1-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 62(a)) - Prepared using Scheme 1.

[0224] Methyl 4'-amino-3-fluoro[1, T-biphenyl]-4-carboxylate (lnt-2) was used instead of the corresponding tert-butyl ester and was hydrolyzed using LiOH in a MeOH / H2O mixture prior to the amine deprotection.H NOH

[0225] LCMS (ES, m / z): 518.3 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ (ppm) 13.18 (s, 1 H), 10.11 (s, 1 H), 8.27 (s, 1 H), 7.92 - 7.88 (m, 1 H), 7.80 - 7.70 (m, 4H), 7.65 - 7.57 (m, 2H), 7.43 -7.34 (m, 2H), 7.14 - 7.06 (m, 2H), 4.81 - 4.71 (m, 1 H), 3.97 (d, J = 15.6 Hz, 1 H), 3.23 - 3.22 (m, 1 H), 2.88 - 2.76 (m, 1 H), 2.38 - 2.27 (m, 1 H), 1.91-1.81 (m, 1 H), 1.84 - 1.66 (m, 3H), 1.54 - 1.40 (m, 1 H), 1.37 - 1.22 (m, 2H), 1.20 - 1.13 (m, 6H).(xlii) (R)-5-(4-(1-((4-isopropylphenyl)carbamoyl)azepane-2-carboxamido)phenyl)-6-methylpicolinic acid (Compound 63(a)) - Prepared using Scheme 1.

[0226] terf-Butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (Jnt-2) was prepared according to the scheme described in patent application WO2024214038.H N NOH

[0227] LCMS (ES, m / z): 515.3 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 12.96 (s, 1 H), 10.10 (s, 1 H), 8.27 (s, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.79 - 7.70 (m, 3H), 7.45 - 7.35 (m, 4H), 7.15 - 7.07 (m, 2H), 4.75 - 4.79 (m, 1 H), 3.97 (d, J = 15.6 Hz, 1 H), 3.36 (s, 3H), 2.79 - 2.88 (m, 1 H), 2.37-2.30 (m, 1 H), 1.92-1.88 (m, 1 H), 1.85 - 1.68 (m, 3H), 1.47 (d, J = 12.0 Hz, 1 H), 1.39 - 1.11 (m, 9H).(xliii) (R)-4 '-(2-(3-(4-(tert-butyl)phenyl)-1-methylureido)propanamido)-3-methoxy-[1, 1 biphenyl]-4-carboxylic acid (Compound 84(a)) - Prepared using Scheme 1.

[0228] Methyl 4'-amino-3-methoxy-[1,1'-biphenyl]-4-carboxylate (Jnt-2) was used instead of the corresponding tert-butyl ester and was hydrolyzed prior to the amine deprotection using LiOH in a MeOH / H2O mixture.O

[0229] LCMS (ES, m / z): 504.3 [M +H]+.1H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 10.05 (s, 1 H), 8.34 (s, 1 H), 7.82 - 7.65 (m, 5H), 7.45 - 7.39 (m, 2H), 7.34 - 7.22 (m, 4H), 4.98 (q, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.00 (s, 3H), 1.38 (d, J= 7.2 Hz, 3H), 1.26 (s, 9H).(xliv) (R)-4 '-(1-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)-3-methoxy-[1,1 '-biphenyl]-4-carboxylic acid (Compound 86(a)) - Prepared using Scheme 1.

[0230] methyl 4'-amino-3-methoxy-[1,1'-biphenyl]-4-carboxylate (Jnt-2) was used instead of the corresponding tert-butyl ester and was hydrolyzed prior to the amine deprotection using LiOH in a MeOH / H2O mixture.

[0231] LCMS (ES, m / z): 516.2 [M +H]+;1H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H), 10.08 (s, 1H), 8.49 (s, 1H), 7.76-7.68 (m, 5H), 7.39-7.25 (m, 4H), 7.15-7.08 (m, 2H), 4.93-4.89 (m, 1H), 4.09-4.01 (m, 1H), 3.96 (s, 3H), 3.41- 3.38(m, 1H), 2.84-2.78 (m, 1H), 2.19-2.16 (m, 1H), 1.76-1.63 (m, 3H), 1.51-1.33 (m, 2H), 1.23-1.16 (m, 6H).(xlv) (R)-4'-(4-((4-isopropylphenyl)carbamoyl)morpholine-3-carboxamido)-3-methoxy-[1,1 '-biphenyl]-4-carboxylic acid (Compound 87(a)) - Prepared using Scheme 1.

[0232] LCMS (ES, m / z): 518.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.14 (s, 1 H), 8.54 (s, 1 H), 7.81 - 7.65 (m, 5H), 7.47 - 7.25 (m, 4H), 7.20 - 7.07 (m, 2H), 4.76 - 4.62 (m, 1 H), 4.43 - 4.29 (m, 1 H), 3.93 (s, 4H), 3.87 - 3.72 (m, 2H), 3.72 - 3.58 (m, 1 H), 3.58 - 3.43 (m, 1H), 2.91 -2.74 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).(xlvi) (R)-3-fluoro-4'-(1-((5-isopropylthiazol-2-yl)carbamoyl)pyrrolidine-2-carboxamido)- [1,1 '-biphenyl]-4-carboxylic acid (Compound 88(a)) - Prepared using a similar procedure as Example 7.

[0233] LCMS (ES, m / z): 496.5[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.01 -7.89 (m, 1 H), 7.88 - 7.71 (m, 4H), 7.70 - 7.58 (m, 2H), 7.02 (s, 1 H), 4.53 - 4.47 (m, 1 H), 3.68 - 3.60 (m, 1H), 3.59 - 3.49 (m, 1H), 3.09 -2.98 (m, 1H), 2.30 -2.13 (m, 1H), 2.05 - 1.88 (m, 3H), 1.23 (d, J = 6.8 Hz, 6H).(xlvii) (R)-4'-(1-((5-isopropyl-4-methylthiazol-2-yl)carbamoyl)pyrrolidine-2-carboxamido)- [1,1 '-biphenyl]-4-carboxylic acid (Compound 89(a)) - Prepared using a similar procedure as Example 7.

[0234] LCMS (ES, m / z): 493.3 [M +H]+.1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.03 -7.97 (m, 2H), 7.82 - 7.70 (m, 6H), 4.54 - 4.45 (m, 1 H), 3.67 - 3.58 (m, 1 H), 3.57 - 3.47 (m, 1 H), 3.16 - 3.06 (m, 1H), 2.26 - 2.18 (m, 1H), 2.13 (s, 3H), 2.03 - 1.87 (m, 3H), 1.22 - 1.11 (m, 6H).(xlviii) (R)-4 '-(1-((4, 5, 6, 7-tetrahydrobenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine-2-carboxamido)-[1,1 '-biphenyl]-4-carboxylic acid (Compound 90(a)) - Prepared using a similar procedure as Example 7.

[0235] LCMS (ES, m / z): 491.2 [M+H]+.1H N MR (400 MHz, DMSO-d6) δ 8.03 – 7.97 (m, 2H), 7.82 - 7.70 (m, 6H), 4.59-4.53 (m, 1 H), 3.66-3.53 (m, 4H), 2.62 - 2.53 (m, 2H), 2.27 - 2.19 (m, 1H), 2.03 - 1.93 (m, 3H), 1.83-1.66 (m, 4H).(xlix) (R)-4 '-(1-(benzo[d]thiazol-2-ylcarbamoyl)pyrrolidine-2-carboxamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 91(a)) - Prepared using a similar procedure as Example 7.

[0236] 2-isocyanatobenzo[d]thiazole was prepared from triphosgene and used instead of N-(benzo[d]thiazol-2-yl)-1H-imidazole-1 -carboxamide.

[0237] LCMS (ES, m / z): 487.1[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.05-7.94 (m, 2H), 7.86 - 7.72 (m, 8H), 7.62-7.59 (m, 1H), 7.40 - 7.35 (m, 1H), 7.24 - 7.19 (m, 1H), 4.57-4.51 (m, 1H), 3.77 - 3.62 (m, 2H), 2.26-2.21 (m, 1H), 2.02-1.98 (m, 3H).(I) 2-(6-((R)-1-((3-(difluoromethoxy)-4-isopropylphenyl) carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 92(a)(a)) or 2-(6-((R)-1-((3-(difluoromethoxy)-4-isopropylphenyl) carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 92(a)(b))Pd(OH)2 / C, MeOH K2CO3, DMFCompound 92(a)(a) Compound 92(a)(b)Scheme 14Step 1: To a stirred solution of 2-bromo-5-nitrophenol (10 g, 45.870 mmol, 1 equiv) in DMF (100 mL) was added K2CO3(19 g, 137 mmol, 3.00 equiv) and sodium 2-chloro-2,2-difluoroacetate (14 g, 92 mmol, 2.01 equiv) at room temperature. The resulting mixture was stirred at room 100 °C for overnight under nitrogen atmosphere. The resulting mixture was poured into water (200 mL) and the desired product extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (20:1) to afford 1-bromo-2-(difluoromethoxy)-4-nitrobenzene (8.9 g, 82% yield, 80% purity) as a light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.17 – 8.10 (m, 1H), 8.08 – 7.99 (m, 2H), 7.76 – 7.25 (m, 1H).Step 2: To a stirred solution of 1-bromo-2-(difluoromethoxy)-4-nitrobenzene (9.0 g, 33.6 mmol, 1 equiv) in H2O (20 mL) and 1,4-Dioxane (100 mL) was added K2CO3(14 g, 101 mmol, 3.02 equiv), Pd(dppf)Cl2(5 g, 6.8 mmol, 0.20 equiv) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6 g, 35.7 mmol, 1.06 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was poured into water (200 mL) and the desired product extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (20:1) to afford 2-(difluoromethoxy)-4-nitro-1-(prop-1-en-2-yl) benzene (5.5 g, 71% yield, 80% purity) as a light yellow oil. LCMS (ES, m / z): 230.2 [M+H]+.Step 3: To a stirred solution of 2-(difluoromethoxy)-4-nitro-1-(prop-1-en-2-yl) benzene (5.3 g, 23.1 mmol, 1 equiv) in MeOH (60 mL) was added Pd(OH)2 / C (120 mg, 0.171 mmol, 0.01 equiv, 20%) at room temperature. The resulting mixture was stirred at room temperature for 1 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (10:1) to afford 3-(difluoromethoxy)-4-isopropylaniline (3 g, 64% yield, 95% purity) as a light yellow oil. LCMS (ES, m / z): 202.2 [M+H]+. Step 4: To a stirred solution of 3-(difluoromethoxy)-4-isopropylaniline (300 mg, 1.491 mmol, 1 equiv) in THF (3 mL) was added GDI (320 mg, 1.97 mmol, 1.32 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product (380 mg) was used in the next step without further purification.Step 5: To a stirred solution of N-(3-(difluoromethoxy)-4-isopropylphenyl)-1H-imidazole-1-carboxamide (100 mg, 0.339 mmol, 1 equiv) in THF (2 mL) was added K2CO3(140 mg, 1.01 mmol, 2.99 equiv) and the Isomer 1 of tert-butyl 2-(6-((R)-pyrrolidine-2-carboxamido) spiro[3.3] heptan-2-yl)acetate (preparation described with Compound 57(a)(lsomer 1)) (150 mg, 0.465 mmol, 1.37 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:1) to afford the Isomer 1 of tert-butyl 2-(6-((R)-1-((3-(difluoromethoxy)-4-isopropylphenyl) carbamoyl) pyrrolidine-2-carboxamido) spiro [3.3] heptan-2-yl)acetate (70 mg, 38% yield, 80% purity) as a colorless oil. LCMS (ES, m / z): 550.3 [M+HJ+.Step 6: To a stirred solution of Isomer 1 of tert-butyl 2-(6-((R)-1-((3-(difluoromethoxy)-4-isopropylphenyl) carbamoyl) pyrrolidine-2-carboxamido) spiro[3.3] heptan-2-yl)acetate (60 mg, 0.11 mmol, 1 equiv) in HFIP (1.9 mL) was added TFA (0.1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This provided the Isomer 1 of 2-(6-((R)-1-((3-(difluoromethoxy)-4-isopropylphenyl) carbamoyl) pyrrolidine-2-carboxamido) spiro [3.3] heptan-2-yl) acetic acid (45.0 mg, 84% yield, 99.6% purity) as an off-white solid.Compound 92(a)(lsomer 1)LCMS (ES, m / z):494.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) 5 11.94 (s, 1 H), 8.27 (s, 1 H), 8.05 - 7.95 (m, 1H), 7.47-7.42 (m, 1H), 7.36-7.30 (m, 1H), 7.25-7.17 (m, 1H), 7.06-6.85 (m, 1H), 4.25 - 4.18 (m, 1H), 4.06 - 3.95 (m, 1H), 3.63 - 3.53 (m, 1H), 3.44 - 3.39 (m, 1H), 3.18 - 3.07 (m, 1H), 2.45 -2.35 (m, 1H), 2.34 -2.24 (m, 3H), 2.20 -2.08 (m, 2H), 2.06 - 1.97 (m, 2H), 1.93 - 1.83 (m, 4H), 1.81 - 1.73 (m, 1H), 1.72 - 1.60 (m, 2H), 1.20 - 0.88 (m, 6H).f / f) 4'- ((1R,2R,5S)-3-((5-isopropylthiazol-2-yl)carbamoyl)-3-azabicyclo[3.1.0] hexane-2-carboxamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 93(a)) - Prepared using Scheme 1.

[0238] Following the initial step, the tert-butyl carbamate was selectively cleaved using TMS-CI in MeOH prior to the urea formation using the imidazole-1-carboxamide instead of the corresponding isocyanate. Finally, the tert-butyl ester was hydrolyzed using HCI in 1,4-dioxane.

[0239] LCMS (ES, m / z): 491.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.78 - 7.69 (m, 6H), 7.00 (s, 1 H), 4.61 (s, 1 H), 3.86 - 3.76 (m, 1 H), 3.70 - 3.60 (m, 1 H), 3.06 - 2.96 (m, 1 H), 1.71 (s, 2H), 1.22 (d, J = 6.8 Hz, 6H). 0.82 - 0.76 (m, 1 H), 0.32 - 0.25 (m, 1H).(Hi) 4'-((1S, 2R, 5R)-3-((5-isopropylthiazol-2-yl)carbamoyl)-3-azabicyclo[3.1.0] hexane-2-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (Compound 93(b)) - Prepared using Scheme 1 following the same protocol modifications as Example 60.

[0240] LCMS (ES, m / z): 491.1.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.03 -7.98 (m, 2H), 7.81 - 7.72 (m, 6H), 7.02 (s, 1 H), 4.53 (d, J = 5.2 Hz, 1 H), 3.85 (d, J = 9.8 Hz, 1 H), 3.64 - 3.58 (m, 1H), 3.06 - 2.96 (m, 1H), 2.01 - 1.94 (m, 1H), 1.81 - 1.73 (m, 1H), 1.22 (d, J = 6.8 Hz, 6H), 0.78- 0.75 (m, 1H), 0.67 - 0.58 (m, 1H).(liii) (R)-4 '-(1-((5-cyclopropylthiazol-2-yl)carbamoyl)pyrrolidine-2-carboxamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 94(a)) - Prepared using a similar procedure as Example 7.

[0241] LCMS (ES, m / z): 477.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.24 (s, 1H), 8.04 - 7.96 (m, 2H), 7.85 - 7.67 (m, 6H), 6.64 (s, 1H), 4.58 - 4.48 (m, 1H), 3.70 - 3.51 (m, 2H), 2.68-2.58 (m, 1H), 2.29 -2.18 (m, 1H), 2.06 - 1.86 (m, 3H), 0.90 - 0.70 (m, 4H).(iiv) (1 S,4s)-4-(4-((R)-2-(3-(4-isopropylphenyl)-1 -methylureido) propanamido)phenyl)cyclohexane-1 -carboxylic acid (Compound 32(a)) and (1R,4r)-4-(4-((R)-2-(3-(4-isopropylphenyl)-1-methylureido)propanamido) phenyl)cyclohexane-1-carboxylic acid (Compound 32(b)) - Prepared using Scheme 1Scheme 15

[0242] Step 1: To a stirred solution of 4-bromoaniline (2.6 g, 15.114 mmol, 1 equiv) and ethyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclohex- 3-ene- 1 -carboxylate (5.21 g, 18.590 mmol, 1.23 equiv) in dioxane (30 mL) and H2O (6 mL) was added Pd(dppf)Cl2(2.54 g, 3.476 mmol, 0.23 equiv) and K2CO3(5.20 g, 37.634 mmol, 2.49 equiv) at room temperature. The resulting mixture was stirred at 80°C for 3h under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with H2O (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (5:1) to afford ethyl 4-(4- aminophenyl) cyclohex-3-ene-1 -carboxylate (1.2 g, 32%yield, 99%purity) as a yellow oil. LCMS (ES, m / z): 246.1 [M+H]+

[0243] Step 2: To a stirred solution of ethyl 4-(4-aminophenyl)cyclohex-3-ene-1-carboxylate (750 mg, 3.057 mmol, 1 equiv) in EA (25 mL) was added Pd / C (120 mg, 1.128 mmol, 0.37 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (3x50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (9:1) to afford ethyl 4-(4-aminophenyl) cyclohexane- 1-carboxylate (600 mg, 79%yield, 95%purity) as an off-white solid. LCMS (ES, m / z): 248.2 [M+H]+

[0244] Step 3: To a stirred solution of ethyl 4-(4-aminophenyl)cyclohexane-1-carboxylate (600 mg, 2.426 mmol, 1 equiv) and (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (493 mg, 2.426 mmol, 1.00 equiv) in DCM (6 mL) was added EDCI (606 mg, 3.904 mmol, 1.61 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3h. The reactionwas quenched with water at room temperature. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with water (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford ethyl 4-{4-[(2R)- 2-[(tert-butoxycarbonyl)(methyl)amino]propanamido]phenyl}cyclohexane-1 -carboxylate (700 mg, 67%yield, 98%purity) as a yellow oil. LCMS (ES, m / z): 433.3 [M+H]+

[0245] Step 4: To a solution of 4-{4-[(2R)-2-[(tert-butoxycarbonyl) (methyl)amino] propanamido] phenyl] cyclohexane- 1 -carboxylate (500 mg, 1.156 mmol, 1 equiv) in EtOH (10 mL) and H2O (3 mL) was added LiOH (553 mg, 23.090 mmol, 19.98 equiv) at 0°C. The resulting mixture was stirred at room temperature for 3h. The mixture was acidified to pH 4 with HCI (5 M). The aqueous layer was extracted with EtOAC (3x100 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 20 mL / min; Gradient (B%): 65% B to 75% B in 10 min; Wave Length: 254 / 220 nm) to afford two peaks.

[0246] The first eluting peak (Peak 1: retention time: 12.5 min) was identified as Isomer 1 of the step 3 intermediate (stereochemistry was not assigned (110 mg) (LCMS (ES, m / z): 433.3 [M+H]+) and the second eluting peak (Peak 2: retention time: 13.6 min) was identified as Isomer 2 of the step 3 intermediate (stereochemistry was not assigned (95 mg) (LCMS (ES, m / z): 433.3 [M+H]+)Scheme 16Compound 32(lsomer 1):

[0247] Step 1: Isomer 1 of the step 3 intermediate (Peak 1: retention time: 12.5 min) (40 mg, 0.092 mmol, 1 equiv) in a solution of HCI in 1,4-dioxane (4.0 M) (2 mL) was stirred at roomtemperature for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): 305.2 [M+H]+

[0248] Step 2: To a stirred solution of 4-{4-[(2R)-2-(methylamino)propanamido] phenyl} cyclohexane-1 -carboxylic acid from the previous step (60 mg, 0.197 mmol, 1 equiv) in THF (6 mL) was added NMM (60 mg, 0.593 mmol, 3.01 equiv) and 1-isocyanato-4-isopropylbenzene (30 mg, 0.186 mmol, 0.94 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was poured into water (10 mL), extracted with EtOAc (3 x10mL). The combined organic layers were washed with water (1x50 mL) and brine(1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in Isomer 1 of Compound 32 (32.9 mg 73% yield, 99.3%purity) as an off-white solid.

[0249] The cyclohexyl stereochemistry of Isomer 1 of Compound 32 was not assigned but corresponds to one of Compounds 32(a) or 32(b): LCMS (ES, m / z): 466.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.79 (s, 1H), 8.30 (s, 1H), 7.59 - 7.30 (m, 4H), 7.10 (d, J = 8.4 Hz, 4H), 4.98 - 4.88 (m, 1H), 2.96 (s, 3H), 2.86 - 2.77 (m, 1H), 2.68-2.62 (m, 2H), 2.09 (d, J = 7.2 Hz, 2H), 1.68- 1.46 (m, 6H), 1.34 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 6H).Compound 32(lsomer 2):

[0250] Step 1: Isomer 2 of the step 3 intermediate (Peak 2: retention time: 13.6 min) (60 mg, 0.148 mmol, 1 equiv) in a solution of HCI in 1,4-dioxane (4.0 M) (2 mL) was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): 305.2 [M+H]+

[0251] Step 2: To a stirred solution of the 4-{4-[(2R)-2-(methylamino) propanamido] phenyl} cyclohexane-1 -carboxylic acid isomer from the previous step(60 mg, 0.197 mmol, 1 equiv) in THF (6 mL) was added NMM (60 mg, 0.593 mmol, 3.01 equiv) and 1-isocyanato-4-isopropylbenzene (30 mg, 0.186 mmol, 0.94 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1x10 mL) and brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Theresidue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in Isomer 2 of Compound 32 (37.7 mg, 95%purity) as an off-white solid.

[0252] The cyclohexyl stereochemistry of Isomer 2 of Compound 32 was not assigned but corresponds to the other of Compounds 32(a) or 32(b): LCMS (ES, m / z): 466.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.80 (s, 1H), 8.31 (s, 1 H), 7.55 - 7.46 (m, 2H), 7.44 - 7.37 (m, 2H), 7.13 - 7.05 (m, 4H), 4.98 - 4.89 (m, 1H), 2.96 (s, 3H), 2.86 - 2.77 (m,1H), 2.63 - 2.55 (m, 2H), 2.12 - 2.01 (m, 2H), 1.71 - 1.47 (m, 6H), 1.34 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 6H).(Iv) (R)-4'-(2-((4-isopropylphenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 96(a)) - Prepared using Scheme 1.

[0253] LCMS (ES, m / z): 534.25 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 10.67 (s, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 8.02 - 7.94 (m, 2H), 7.79 - 7.63 (m, 7H), 7.45 - 7.39 (m, 2H), 7.30 - 7.23 (m, 3H), 7.15 - 7.09 (m, 2H), 5.80 (s, 1H), 4.15 - 4.07 (m, 1H), 3.79 - 3.71 (m, 1H), 3.25 - 3.20 (m, 1H), 2.97 -2.89 (m, 1H), 2.86 - 2.78 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H).(Ivi) (1R,4r)-4-(6-((R)-2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)pyridin-3-yl)cyclohexane-1-carboxylic acid (Compound 50(a)) - Prepared using Scheme 5.

[0254] frans-4-(6-Aminopyridin-3-yl)cyclohexanecarboxylic acid ethyl ester was used instead of the corresponding tert-butyl ester and was prepared following the following procedure:Scheme 17

[0255] Step 1: A mixture of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1 -carboxylate (2.13 g, 7.603 mmol, 1.51 equiv), 5-bromopyridin-2-amine (0.87 g, 5.029 mmol, 1.00 equiv), Pd(dppf)Cl2(0.82 g, 1.121 mmol, 0.22 equiv) and K2CO3(1.75 g, 12.662 mmol, 2.52 equiv) in dioxane (10 mL) and H2O (2 mL) was stirred at 80 °C for 1h under nitrogen atmosphere. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:9) to afford ethyl 4-(6-aminopyridin-3-yl)cyclohex-3-ene-1-carboxylate (0.91 g, 73%yield, 95%purity) as a white solid. LCMS (ES, m / z): 247.1 [M+H]+.

[0256] Step 2: To a stirred solution of ethyl 4-(6-aminopyridin-3-yl)cyclohex-3-ene-1 -carboxylate (910 mg, 3.695 mmol, 1 equiv) in MeOH (10 mL) was added Pd / C (90mg) at room temperature. The resulting mixture was stirred at room temperature for overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 70% gradient in 20 min; detector, UV 254 nm to afford the racemic product as a yellow oil. The racemic product was further separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient (B%): 15% B to 15% B in 12 min% B; Wave Length: 220 / 254 nm; Peak 1: retention time: 8.35 min; Peak 2: retention time: 10.65 min; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.25 mL; Number Of Runs: 20) to afford the first eluting peak as Step 2-lsomer 1 (360 mg, 39.24%yield, 95%purity) as a white solid and the second eluting peak as Step 2-lsomer 2 (140 mg, 15%yield, 95%purity) as a white solid. LCMS (ES, m / z): 249.2[M+H]+. One of step 2-Isomer 1 and 2 is ethyl (1r,4r)-4-(6-aminopyridin-3-yl)cyclohexane-1 -carboxylate and the other of step 2-lsomer 1 and 2 is ethyl (1s,4s)-4-(6-aminopyridin-3-yl)cyclohexane-1 -carboxylate.oNMM, DMAP, THF

[0257] Step 1: To a stirred solution of as Step 2-lsomer 1 (Peak 1: retention time: 8.35 min) (345 mg, 1.389 mmol, 1 equiv) and DIEA (517 mg, 4.000 mmol, 2.88 equiv) in DCM (17 mL) was added (R)-1-chloro-1-oxopropan-2-yl acetate (258 mg, 1.714 mmol, 1.23 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was diluted with water (30 mL), extracted with DCM (4 x 30 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (3:1) to afford an intermediate (400 mg, 83% yield, 90% purity) as a yellow oil. LCMS (ES, m / z): 363.2[M+H]+.

[0258] Step 2: A solution of the previous intermediate (375 mg, 1.035 mmol, 1 equiv) in EtOH (25 mL) and H2O (12.5 mL) was added and LiOH (212 mg, 8.852 mmol, 8.55 equiv). The resulting mixture was stirred at room temperature overnight. The resulting mixture was directly purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 20% gradient in 20 min; detector, UV 254 nm to afford the carboxylic acid (150 mg, 50% yield, 90% purity) as a white solid. LCMS (ES, m / z): 293.2[M+H]+.

[0259] Step 3: To a stirred solution of the carboxylic acid from step 2 (140 mg, 0.479 mmol, 1 equiv) and NMM (300 mg, 2.966 mmol, 6.19 equiv)in THF (9 mL) were added 1-isocyanato-4-isopropylbenzene (160 mg, 0.993 mmol, 2.07 equiv) and DMAP (70 mg, 0.573 mmol, 1.20 equiv) at 0 degree C, and then the resulting solution was stirred at room temperature for additional 1.5h.The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 30 min; detector, UV 254 nm to afford 30 mg of crude product, and then the crude product was further purified by Prep-HPLC with the following conditions, Column: XBridge Prep OBD C18 Column30*150 mm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 5% B to 5% B in 2 min, 26% B to 46% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.1 to afford Isomer 1 of Compound 50, which is likely Compound 50(a) ((1 R,4r)-4-(6-((R)-2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)pyridin-3-yl)cyclohexane-1-carboxylic acid) (10.3 mg, 5% yield, 98.9% purity) as a white solid.Compound 50(lsomer 1):

[0260] LCMS (ES, m / z): 454.3[M+H]+;1H NMR (400 MHz, DMSO-d6) 6 12.15 (s, 1H), 10.55 (s, 1H), 9.77 (s, 1H), 8.21 - 8.17(m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.40-7.34 (m, 2H), 7.19 - 7.12 (m, 2H), 5.61 - 5.15 (m, 1H), 2.84 -2.78 (m, 1H), 2.65 -2.57 (m, 3H), 2.18-2.09 (m, 2H), 1.81 - 1.34 (m, 8H), 1.32 - 1.09 (m, 6H).(Mi) (1S, 3S)-3-(4-((R)~ 1 -((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentane-1-carboxylic acid (Compound 97(a)), and (1 R,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentane-1-carboxylic acid (Compound 97(b)) - Prepared using Scheme 2.B' 0 6 0 Tf2O, DIEA,toLTf0o 1) Pd / C, H,rEA Pd(dppf)CI2, K2CO3102) Chiral-HPLC dioxane, H20Scheme 19

[0261] Step 1: To a stirred solution of methyl 3-oxocyclopentane-1 -carboxylate (5 g, 35.173 mmol, 1 equiv) and DIEA (18.2 g, 140.816 mmol, 4.00 equiv) in toluene (100 mL) was added Tf20 (24.8 g, 87.903 mmol, 2.50 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2h under nitrogen atmosphere before the reaction was quenched with water (200 mL) and the desired product extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated underreduced pressure and the residue was purified by silica gel column chromatography, eluted with PE I EA (12:1) to afford methyl 3-(trifluoromethanesulfonyloxy)cyclopent-2-ene-1 -carboxylate (6 g, 62% yield, 95% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 66.12-6.09(m, 1H), 3.64 (s, 3H), 3.42-3.38 (m, 1H), 2.75-2.28 (m, 2H), 2.35-2.27 (m, 1H), 2.19-2.15 (m, 1H)

[0262] Step 2: To a stirred solution of methyl 3-(trifluoromethanesulfonyloxy)cyclopent-2-ene-1-carboxylate (2 g, 7.294 mmol, 1 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.76 g, 8.023 mmol, 1.1 equiv) in dioxane (20 mL) and H2O (4 mL) were added Pd(dppf)Cl2(1.19 g, 1.459 mmol, 0.2 equiv) and K2CO3(3.02 g, 21.882 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 1h under nitrogen atmosphere before the reaction was quenched with water (50 mL), and the product extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, and filtered The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE I EA (5:1) to afford methyl 3-(4-aminophenyl)cyclopent-2-ene-1-carboxylate (1.5 g, 95% yield, 94% purity) as a yellow solid. LCMS (ES, m / z): 218.1 [M+H]+

[0263] Step 3: To a solution of methyl 3-(4-aminophenyl)cyclopent-2-ene-1-carboxylate (1 g, 4.603 mmol, 1 equiv) in EA (10 mL) was added Pd / C (100 mg) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 1 h under an atmosphere of hydrogen. The resulting mixture was filtered, the filter cake was washed with EA (3x10 mL) and the filtrate concentrated under reduced pressure to afford 1 g of methyl trans-3-(4-aminophenyl)cyclopentane-1 -carboxylate. The racemic mixture was separated by Prep-Chiral-HPLC using the following conditions (Column: CHIRALPAK IB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient (B%): 20% B to 20% B in 15 min% B; Wave Length: 220 / 254 nm; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.3 mL; Number Of Runs: 28) to afford the first eluting peak (retention time: 9.69 min) (Step 3 intermediate isomer 1) (400 mg, 44.04%yield, 98%purity), and the second eluting peak (retention time: 10.09 min) (Step 3 intermediate isomer 2) (400 mg, 44.04%yield, 98%purity) as a yellow solid. LCMS (ES, m / z):220.1 [M+H]+.Compound 97(a) Compound 97(b)

[0264] Compound 97(isomer 1) was prepared using Step 3 intermediate isomer 1 (Peak 1, stereochemistry not assigned) (Jnt-2) instead of the corresponding tert-butyl ester. Consequently, LiOH in a MeOH / H2O mixture was used instead of acidic conditions for the ester hydrolysis step of lnt-8. Compound 97(isomer 1) corresponds to one of Compounds 97(a) or 97(b).Compound 97(isomer 1):

[0265] LCMS (ES, m / z): 464.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 67.45-7.26 (m, 4H), 7.06-6.91 (m, 4H), 4.14-4.13 (m, 1H), 3.45-3.38 (m, 1H), 3.15-3.10 (m, 1H), 2.81-2.74 (m, 2H), 2.51-2.43 (m, 1H), 2.21-2.08 (m, 1H), 2.05-1.86(m, 3H), 1.87-1.59 (m, 5H), 1.57-1.51 (m, 1H), 1.17 (d, J =6.8 Hz, 6H).

[0266] Compound 97(isomer 2) was prepared using Step 3 intermediate isomer 2 (Peak 2, stereochemistry not assigned) (Jnt-2) instead of the corresponding tert-butyl ester. Consequently, LiOH in a MeOH / H2O mixture was used instead of acidic conditions for the ester hydrolysis step of lnt-8. Compound 97(isomer 2) corresponds to the other of Compounds 97(a) or 97(b).Compound 97(isomer2):

[0267] LCMS (ES, m / z): 464.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) 69.12 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 4.91-4.86(m, 1 H), 3.71 - 3.70 (m, 1 H), 3.45 - 3.41 (m, 1 H), 2.93 - 2.89 (m, 1 H), 2.78 - 2.74 (m, 1 H), 2.59 - 2.55 (m, 1H), 2.18 - 1.88 (m, 8H), 1.74 - 1.69 (m, 1H), 1.52 - 1.40 (m, 1H), 1.14 (d, J = 6.8 Hz, 6H).(Iviii) (R)-4-(3-(1-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)bicyclo [1.1.1] pentan-1 -yl)benzoic acid (Compound 98(a)) - Prepared using Scheme 1.

[0268] Methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was used instead of the corresponding tert-butyl ester and was prepared as described in Example 24. The methyl ester was hydrolyzed using LiOH in a MeOH / H2O mixture prior to the amine deprotection and the urea formation.

[0269] LCMS (ES, m / z): 476.3 [M +H]+.1H NMR (400 MHz, DMSO-d6) 612.82 (s, 1H), 8.41 (d, J = 41.0 Hz, 2H), 7.92 -7.85 (m, 2H), 7.42 - 7.31 (m, 4H), 7.10 (d, J= 8.6 Hz, 2H), 4.78-4.74 (m, 1H), 3.96 (d, J = 13.3 Hz, 1H), 3.16 (d, J= 12.2 Hz, 1H), 2.82 (d, J = 6.9 Hz, 1H), 2.29 (s, 6H), 2.12 (d, J= 13.1 Hz, 1H), 1.57 (d, J= 32.4 Hz, 3H), 1.36-1.33 (m, 2H), 1.18 (d, J = 6.9 Hz, 6H).(lix) (R)-4-(3-(2-(3-(4-isopropylphenyl)- 1 -methylureido)-2-phenylacetamido) bicyclo[1.1.1] pentan-1 -yljbenzoic acid (Compound 99(a)) - Prepared using Scheme 1.

[0270] Methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was used instead of the corresponding tert-butyl ester and was prepared as described in Example 24. The methyl ester was hydrolyzed using LiOH in a MeOH / H2O mixture prior to the amine deprotection and the urea formation.

[0271] LCMS (ES, m / z): 563.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 8.90 (s, 1H), 8.32 (s, 1H), 7.93 - 7.85 (m, 2H), 7.46 - 7.38 (m, 4H), 7.38 - 7.30 (m, 3H), 7.27-7.20 (m, 2H), 7.17 - 7.09 (m, 2H), 6.03 (s, 1H), 2.89 - 2.78 (m, 4H), 2.38 - 2.28 (m, 6H), 1.22-1.15 (m, 6H).(lx) (R)-4-(3-(1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (Compound 100(a))Scheme 20

[0272] Step 1: A mixture of (2R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (495 mg, 2.300 mmol, 1.00 equiv), methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate (500 mg, 2.301 mmol, 1.00 equiv), EDCI (429 mg, 2.763 mmol, 1.20 equiv) and NMM (700 mg, 6.920 mmol, 3.01 equiv) in DCM (5 mL) was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and the product extracted with EtOAc (3 x 10mL). The combined organic layers were dried over anhydrous Na2SO4and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (R)-2-((3-(4-(methoxycarbonyl)phenyl)bicyclo[1.1.1]pentan-1- yl)carbamoyl)pyrrolidine-1 -carboxylate (700 mg, 73% yield, 90% purity) as a white solid. LCMS (ES, m / z):415.2 [M+H]+.

[0273] Step 2: To a solution of 4M HCI in 1,4-dioxane (10 mL) was added tert-butyl (R)-2-((3-(4- (methoxycarbonyl)phenyl)bicyclo[1.1.1]pentan-1-yl)carbamoyl)pyrrolidine-1 -carboxylate (700 mg, 1.687 mmol, 1.0 equiv) at room temperature. After stirring for 2 h, the mixture was concentrated under reduced pressure. This resulted in methyl (R)-4-(3-(pyrrolidine-2- carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoate (560 mg, 93.8%purity) as an off-white solid. LCMS (ES, m / z):315.2 [M+H]+.

[0274] Step 3: To a stirred solution of N-(4-cyclopropyl-3-(trifluoromethyl)phenyl)-1H-imidazole- 1-carboxamide (150 mg, 0.508 mmol, 1 equiv) in DMF (5 mL) were added methyl (R)-4-(3- (pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoate (160 mg, 0.509 mmol, 1equiv) and triethylamine (150 mg, 1.482 mmol, 2.92 equiv) dropwise at room temperature. The reaction was stirred at room temperature for 1 h, then the resulting mixture was poured into water. The desired product was extracted with EtOAc (3 x20 mL) and the combined organic layers were washed with water (3 x 20 mL) and brine (3 x 20 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to affordmethyl (R)-4-(3-(1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo [1.1.1]pentan-1-yl)benzoate (90 mg, 93%purity) as a white solid. LCMS (ES, m / z): 542.2 [M+H]+.

[0275] Step 4: To a stirred solution of methyl (R)-4-(3-(1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoate (90 mg, 0.166 mmol, 1 equiv) in MeOH (2 mL) and H2O (1 mL) was added LiOH (12 mg, 0.501 mmol, 3.02 equiv) in portions at room temperature. The reaction was stirred at room temperature for 2 h before the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (R)-4-(3-(1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (11.5 mg, 99.4% purity) as a white solid.Compound 100(a):

[0276] LCMS (ES, m / z): 340.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.52 (s, 1 H), 8.45 (s, 1 H), 7.96 - 7.90 (m, 1 H), 7.90 - 7.83 (m, 2H), 7.71 - 7.66 (m, 1 H), 7.35 - 7.30 (m, 2H), 7.05 (d, J = 8.6 Hz, 1 H), 4.27 - 4.20 (m, 1 H), 3.62 - 3.54 (m, 1 H), 3.47 - 3.39 (m, 1 H), 2.26 (s, 6H), 2.11 - 1.98 (m, 2H), 1.95 - 1.76 (m, 3H), 0.98 - 0.92 (m, 2H), 0.74 - 0.68 (m, 2H). (Ixi) 4-(( 1 R, 3S)-3-((R)-1-((4-isopropylphenyl) carbamoyl)pyrrolidine-2-carboxamido)cyclopentyl)benzoic acid (Compound 102(a)), 4-((1S,3R)-3-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido) cyclopentyl)benzoic acid (Compound 102(b)), 4-((1S,3S)-3-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)cyclopentyl) benzoic acid (Compound 102(c)), and 4-((1R,3R)-3-((R)-1-((4-isopropylphenyl) carbamoyl)pyrrolidine-2-carboxamido)cyclopentyl)benzoic acid (Compound 102(d))CHIRAL-HPLCOHScheme 21

[0277] Step 1: Into a solution of tert-butyl N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-yl]carbamate (1.22 g, 3.946 mmol, 1.20 equiv) and tert-butyl 4-iodobenzoate (1 g, 3.288 mmol, 1.00 equiv) Dioxane (20 mL) and H2O (4 mL) was added Pd(dppf)Cl2(480.00 g, 0.658 mmol, 0.2 equiv), K2CO3(1.36 g, 9.864 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE I EA (5:1) to afford tert- butyl 4-{3-[(tert-butoxycarbonyl)amino]cyclopent-1-en-1-yljbenzoate (1 g, 85% yield, 90% purity) as a yellow green oil. LCMS (ES, m / z): 360.2 [M +H]+.

[0278] Step 2: Into a solution tert-butyl 4-{3-[(tert-butoxycarbonyl)amino]cyclopent-1-en-1-yljbenzoate (1 g, 2.782 mmol, 1 equiv) in ethyl acetate (30 mL) were added Pd / C (500.32 mg,4.702 mmol, 1.69 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3x30mL). The filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4-{3-[(tert-butoxycarbonyl)amino]cyclopentyl}benzoate (900 mg, 90% yield, 90% purity) as an off-white solid. LCMS (ES, m / z): 362.2 [M +H]+.

[0279] Step 3: Into a 40 mL vial were added tert-butyl 4-{3-[(tert-butoxycarbonyl)amino] cyclopentyljbenzoate (900 mg, 2.490 mmol, 1 equiv) and a solution of HCI in 1,4-dioxane (4.0 M) (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under vacuum. This resulted in 4-(3-aminocyclopentyl)benzoic acid (500 mg, 98%yield, 85%purity) as a off-white solid. LCMS (ES, m / z): 206.1 [M +H]+.

[0280] Step 4: Into a 40mL vial were added 4-(3-aminocyclopentyl)benzoic acid (500 mg, 2.436 mmol, 1 equiv) and (2R)-1-[(4-isopropylphenyl)carbamoyl]pyrrolidine-2-carboxylic acid (807.78 mg, 2.923 mmol, 1.2 equiv), EDCI (756.34 mg, 4.872 mmol, 2 equiv), NMM (492.79 mg, 4.872 mmol, 2 equiv), DMF (15 mL) at room temperature. The resulting mixture was stirred at room temperature for 2h. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3x50mL). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-{3-[(2R)-1-[(4-isopropylphenyl)carbamoyl]pyrrolidine-2-amido]cyclopentyl}benzoic acid (150 mg, 13.28%yield, 90%purity) as an off-white solid. LCMS (ES, m / z): 464.2 [M +H]+.

[0281] Step 5: The mixture (150 mg) was separated by chiral-Prep-HPLC with following condition Column: Column: CHIRAL Cellulose-SC 2*25 cm, 5 pm; Mobile Phase A: Hex(0.2% FA)-HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient (B%): 25% B to 25% B in 50 min% B; Wave Length: 220 / 254 nm; Peak 1: retention time: 19.23 min; Peak 2: retention time: 23.12 min; Peak 3: retention time: 34.81 min; Peak 1: retention time: 44.05 min; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 5; Single injection run time(min): 0.75 to afford Peak 1 (24.4 mg, 16.27%yield, 99.4%purity) as a white solid, Peak 2 (21.5 mg, 14.33%yield, 99.9%purity) as a white solid, Peak 3 (5.2 mg, 3.47%yield, 98.1%purity) as a white solid and Peak 4 (9.7 mg, 6.47%yield, 98.5%purity) as a white solid. The stereochemistry of all four examples was arbitrary assigned.Compound 102(isomer 1):

[0282] The stereochemistry of Isomer 1 was not assigned but corresponds to the one of Compounds 102(a), 102(b), 102(c), or 102(d) - Peak 1: retention time: 19.23 min. LCMS (ES, m / z): 464.2 [M +H]+.1H NMR (300 MHz, DMSO-d6) 6 12.74 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J = 11.7, 7.8 Hz, 3H), 7.39 (dd, J = 8.3, 3.1 Hz, 4H), 7.09 (d, J = 8.3 Hz, 2H), 4.28 (dd, J = 8.2, 3.3 Hz, 1H), 4.23 -4.09 (m, 1H), 3.64 - 3.53 (m, 1H), 3.48 - 3.36 (m, 1H), 3.17 -2.99 (m, 1H), 2.88 - 2.75 (m, 1H), 2.33 (dd, J = 12.9, 6.8 Hz, 1H), 2.12 - 1.77 (m, 6H), 1.71 (d, J = 19.2 Hz, 2H), 1.58 - 1.45 (m, 1H), 1.24 - 1.11 (m, 6H).Compound 102(lsomer 2):

[0283] The stereochemistry of Isomer 2 was not assigned but corresponds to another of Compounds 102(a), 102(b), 102(c), or 102(d) - Peak 2: retention time: 23.12 min. LCMS (ES, m / z): 464.2 [M +H]+.1H NMR (400 MHz, DMSO-d6) 6 12.71 (s, 1H), 8.08 - 7.82 (m, 4H), 7.42 -7.32 (m, 4H), 7.12 - 7.06 (m, 2H), 4.32 - 4.17 (m, 2H), 3.65 - 3.55 (m, 1H), 3.49 - 3.39 (m, 1H), 3.26 (d, J = 8.6 Hz, 1H), 2.87 - 2.77 (m, 1H), 2.17 - 2.00 (m, 3H), 1.98 - 1.76 (m, 5H), 1.64 -1.50 (m, 2H), 1.18 (d, J = 6.9 Hz, 6H).Compound 102(lsomer 3):

[0284] The stereochemistry of Isomer 3 was not assigned but corresponds to the another of Compounds 102(a), 102(b), 102(c), or 102(d) - Peak 3: retention time: 34.81 min. LCMS (ES, m / z): 464.2 [M +H]+.1H NMR (400 MHz, DMSO-d6) 6 12.71 (s, 1H), 8.08 - 7.82 (m, 4H), 7.42 -7.32 (m, 4H), 7.12 - 7.06 (m, 2H), 4.32 - 4.17 (m, 2H), 3.65 - 3.55 (m, 1H), 3.49 - 3.39 (m, 1H), 3.26 (d, J = 8.6 Hz, 1H), 2.87 - 2.77 (m, 1H), 2.17 - 2.00 (m, 3H), 1.98 - 1.76 (m, 5H), 1.64 - I.50 (m, 2H), 1.18 (d, J = 6.9 Hz, 6H).Compound 102(isomer 4):

[0285] The stereochemistry of Isomer 4 was not assigned but corresponds to the other of Compounds 102(a), 102(b), 102(c), or 102(d) - Peak 4: retention time: 44.05 min. LCMS (ES, m / z): 464.2 [M +H]+.1H NMR (300 MHz, DMSO-d6) 6 12.74 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J = II.7, 7.8 Hz, 3H), 7.39 (dd, J = 8.3, 3.1 Hz, 4H), 7.09 (d, J = 8.3 Hz, 2H), 4.28 (dd, J = 8.2, 3.3 Hz, 1H), 4.23 -4.09 (m, 1H), 3.64 - 3.53 (m, 1H), 3.48 - 3.36 (m, 1H), 3.17 -2.99 (m, 1H), 2.88 - 2.75 (m, 1H), 2.33 (dd, J = 12.9, 6.8 Hz, 1H), 2.12 - 1.77 (m, 6H), 1.71 (d, J = 19.2 Hz, 2H), 1.58 - 1.45 (m, 1H), 1.24 - 1.11 (m, 6H).(Ixii) (R)-4-(3-(2-(3-(4-cyclopropyl-3-(trifluoromethyl)phenyl)-1-methylureido) propanamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (Compound 103(a)) - Prepared using Scheme 1.N-(4-cyclopropyl-3-(trifluoromethyl)phenyl)-1H-imidazole-1-carboxamide (lnt-1) was used instead of the corresponding isocyanate. Also, TFA in HFIP was used for the tert-butyl ester hydrolysis instead of HCI in 1,4-dioxane.

[0286] LCMS (ES, m / z): 516.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 612.78 (s, 1 H), 8.57 - 8.53 (m, 2H), 7.96 - 7.93 (m, 1 H), 7.91 - 7.86 (m, 2H), 7.72 - 7.67 (m, 1 H), 7.37 - 7.33 (m, 2H), 7.06 (d, J= 8.6 Hz, 1H), 4.79 (q, J= 7.1 Hz, 1H), 2.87 (s, 3H), 2.29 (s, 6H), 2.11-1.98 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H), 0.99 - 0.93 (m, 2H), 0.76 - 0.69 (m, 2H).(Ixiii) 2-(6-((R)-1-((4-cyclopropyl-3-(trifluoromethyl)phenyl) carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl) acetic acid (Compound 104(lsomer 1)) and 2-(6-((R)-1-((4-cyclopropyl-3-(trifluoromethyl)phenyl) carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic (Compound 104(lsomer 2))S2a) CbzCI, NEt3BiCl3DCM MeCN / H2O b) SFC S3Pd(dppf)CI2, K2CO3, 1,4-dioxane / H2OS6OHScheme 22Step 1: To a stirred suspension of LiCI (65.5 g, 1.55 mol, 2.4 equiv) in THF (1.6 L) was added tert-butyl 2-(diethoxyphosphoryl)acetate (162.4 g, 643.8 mmol, 1 equiv) at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0 °C then DBU (215.6 g, 1.416 mol, 2.2 equiv) and a solution of ferf-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate (145 g, 644 mmol, 1 equiv) in THF (400 mL) were added. The resulting mixture was removed from cooling, stirred overnight, diluted with DCM, concentrated, and purified by silica gel column chromatography (eluting with 9:1 PE / EA) to afford terf-butyl 2-(6-((ferf-butoxycarbonyl)amino)spiro[3.3]heptan-2-ylidene)acetate (170 g, 82% yield).1H NMR (400 MHz, CD3OD) 5 5.52 - 5.43 (m, 1H), 3.97 -3.82 (m, 1H), 3.17-2.72 (m, 4H), 2.42-2.32 (m, 2H), 2.04- 1.93 (m, 2H), 1.51 - 1.35 (m, 18H).Step 2: To a stirred solution of tert-butyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-ylidene)acetate (170 g, 526 mmol, 1 equiv) in MeOH (2 L) was added Pd / C (10 wt%, 10 g, 9.4 mmol, 0.02 equiv) at room temperature. The resulting mixture was stirred overnight under hydrogen atmosphere and filtered. The filter cake was rinsed with MeOH (3 x 20 mL). The filtrate was concentrated to afford tert-butyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetate (170 g, 99% yield).1H NMR (300 MHz, CD3OD) 53.96 - 3.78 (m, 1H), 2.56 -2.36 (m, 2H), 2.32 -2.16 (m, 4H), 2.14 -2.03 (m, 1H), 1.96 - 1.64 (m, 4H), 1.44 (d, J = 3.0 Hz, 18H). Step 3: To a stirred solution of tert-butyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetate (95.0 g, 292 mmol, 1 equiv) in MeCN (1 L) and water (20 mL) was added bismuth(lll) chloride (92.1 g, 292 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight and filtered. The filter cake was rinsed with MeCN (3 x 30 mL). The filtrate was concentrated to afford crude tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate. The crude material was used in the subsequent step without further purification. LCMS (ES, m / z): 226.2 [M+H]+.Step 4: To a stirred solution of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (65.7 g, 292 mmol, 1 equiv) in DCM (700 mL) and TEA (88.6 g, 875 mmol, 3 equiv) was added CbzCI (74.6 g, 438 mmol, 1.5 equiv) at 0 °C. The resulting mixture was removed from cooling, stirred for 3 h then quenched with water. Th organic layer was collected and concentrated, and the residue purified by silica gel column chromatography (eluting with 85:15 PE / EA) followed by chiral preparative SFC (column: Lux 5 pm Cellulose-3 5*25 cm, 5 pm; mobile phase: 60:20:20 CO2 / MeCN / MeOH; flow rate: 100 mL / min; wavelength monitored: 220 nm) to afford, in order of elution, Isomer 1 (retention time: 4.5 min) (55 g, 46% yield) and Isomer 2 (retention time: 6.5 min) (53 g, 42% yield) of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate. The absolute stereochemistry of Isomer 1 and Isomer 2 (one being tert-butyl (R)-2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate and the other being tert-butyl (S)-2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate) were not directly determined, but can be deduced from the single crystal X-ray diffraction analysis of Compound 104(lsomer 1). Results indicates that Isomer 1 is tert-butyl (R)-2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate and Isomer 2 is tert-butyl (S)-2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate). LCMS (ES, m / z): 304.1 [M+H]+.Step 5: To a stirred solution of Isomer 1 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate (43 g, 120 mmol, 1 equiv) in MeOH (500 mL) was added Pd / C (10 wt%, 2.5 g, 2.3 mmol, 0.02 equiv) at room temperature. Theresulting mixture was stirred for 3 h under hydrogen atmosphere and filtered. The filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated to afford Isomer 1 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (21.1 g, 78% yield). LCMS (ES, m / z): 226.2 [M+H]+.Step 6: A solution of 4-bromo-3-(trifluoromethyl)aniline (270 g, 1125 mmol, 1.0 equiv), cyclopropylboronic acid (289.9 g, 3375 mmol, 3.0 equiv), Pd(dppf)Cl2*CH2Cl2 (45.93 g, 56.24 mmol, 0.05 equiv) and K2CO3(310.9 g, 2250 mmol, 2.0 equiv) in 1,4-dioxane (3 L) and H2O (500 mL) was stirred at 80°C for 4h under nitrogen atmosphere. The resulting mixture was diluted with water (3 L) and the desired product extracted with EtOAc (3 x 3L). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (19:1) to afford 4-cyclopropyl-3-(trifluoromethyl)aniline (189 g, 84% yield, 97% purity) as a reddish brown oil. LCMS (ES, m / z): 202.1 [M+H]+.Step 7: To a stirred solution of 4-cyclopropyl-3-(trifluoromethyl)aniline (23.0 g, 114 mmol, 1.0 equiv) in acetonitrile (230 mL) were added pyridine (13.0 g, 171 mmol, 1.5 equiv) and phenyl carbonochloridate (20.0 g, 126 mmol, 1.1 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1h. To the above mixture was added D-proline (17.0 g, 148 mmol, 1.0 equiv) and DIEA (44.0 g, 340 mmol, 3.0 equiv) in portions at 0°C. The resulting mixture was stirred at 40°C overnight. To the above mixture was added methanesulfonic acid (33 g) and water (600 mL) and ((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)-D-proline (115 mg) at room temperature. The resulting mixture was stirred at room temperature for additional 1h. The precipitated solids were collected by filtration and washed with water (3 x 30 mL). This resulted in ((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)-D-proline (20 g, 99% purity) as an off-white solid. LCMS (ES, m / z): 343.1 [M+H]+.Step 8: To a stirred solution of Isomer 1 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (26.33 g, 116.9 mmol, 1 equiv) in DCM (400 mL) were added EDCI (54.42 g, 350.6 mmol, 3 equiv) and DCM (400 mL) at room temperature. To the above mixture was added ((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)-D-proline (40 g, 116.850 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE I EA (6:4) to afford Isomer 1 of tert-butyl 2-(6-((R)-1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (50 g, 78% yield, 95% purity) as an off-white solid. LCMS (ES, m / z): 550.0 [M+H]+.Step 9: A solution of Isomer 1 of tert-butyl 2-(6-((R)-1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (50 g, 90.969 mmol, 1 equiv) in TFA (50 mL) and HFIP (500 mL) was stirred at room temperature for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 100% gradient in 10 min; detector, UV 254 nm (40% ACN). The purified product was re-crystallized from n-hexane / ethyl acetate (1:1 100 mL) to afford the Isomer 1 of 2-(6-((R)-1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (21.272 g, 47% yield, 99% purity) as an off-white solid. LCMS (ES, m / z) 494.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 611.93 (s, 1H), 8.40 (s, 1H), 7.97 (d, J = 8.0 Hz, 1 H), 7.94 - 7.90 (m, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 4.25 - 4.18 (m, 1H), 4.08 - 3.95 (m, 1H), 3.61 - 3.53 (m, 1H), 3.48 - 4.37 (m, 1H), 2.47 - 2.35 (m, 1H), 2.34 -2.21 (m, 3H), 2.20 -2.08 (m, 2H), 2.07 - 1.97 (m, 3H), 1.94 - 1.82 (m, 4H), 1.82 - 1.73 (m, 1H), 1.72 - 1.59 (m, 2H), 0.99 - 0.91 (m, 2H), 0.76 - 0.67 (m, 2H).Referring to FIG. 1, crystals of Compound 104(lsomer 1) generated from a methanol / isopropyl ether (1 / 34) mixture, were selected for single crystal X-ray diffraction analysis. Results indicate that the absolute stereochemistry of Compound 104(a)(lsomer 1) is as represented in FIG. 1. From this data, the stereochemistry of similar compounds sharing the same Isomer 1 intermediate (or the opposite enantiomer thereof) can also be deduced.F- FCompound 104(lsomer 2) was prepared following the procedure shown in Scheme 21 using Isomer 2 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate instead of Isomer 1 in step 5.Knowing the absolute stereochemistry of Compound 104(lsomer 1), the absolute stereochemistry can be deduced for Compound 104(lsomer 2). LCMS (ES, m / z): 494.2 [M+H]+;1 H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 8.42 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.91(d, J = 2.0Hz, 1H), 7.67 (d, J = 10.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.21-4.18 (m, 1H), 4.01 -3.99 (m, 1H), 3.55 - 3.43 (m, 1 H), 339 - 3.33 (m, 1 H), 2.49 - 2.39 (m, 1 H), 2.37-2.24 (m, 3H), 2.25 - 2.08 (m, 2H), 2.03 - 1.98 (m, 3H), 1.93- 1.70 (m, 5H), 1.68 - 1.59 (m, 2H), 0.95 - 0.93 (m, 2H), 0.71 - 0.68 (m, 2H). (Ixiv) (R)-5-(4-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)phenyl-6-methylpicolinic acid (Compound 49(a)) - Prepared using Scheme 6.

[0287] lnt-2 was prepared according to the procedure described in WO2024214038.

[0288] LCMS (ES, m / z): 462 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 10.32 (s, 1H), 9.81 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.80 - 7.72 (m, 3H), 7.45 - 7.34 (m, 4H), 7.19 - 7.12 (m, 2H), 5.15 -5.07 (m, 1H), 2.86 - 2.77 (m, 1H), 1.50 (d, J= 6.8 Hz, 3H), 1.17 (d, J= 7.2 Hz, 6H).(Ixv) (R)-3-(4-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)phenyl) propanoic acid (Compound 47(a)) - Prepared using Scheme 6.OH

[0289] LCMS (ES, m / z): 399.2[M+H]+;1H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 10.07 (s, 1H), 9.78 (s, 1H), 7.54 - 7.47 (m, 2H), 7.43 - 7.30 (m, 2H), 7.20 - 7.10 (m, 4H), 5.08 - 5.03 (m, 1 H), 2.84 - 2.74 (m, 3H), 2.50 - 2.47(m, 2H), 1.46 – 1.44(m, 3H), 1.23 – 1.15(m, 6H).(Ixvi) (R)-2-(3-(4-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)bicyclo[1.1.1]pentan-1-yl)acetic acid (Compound 110(a))DIC, DMAP, Ni(dme)Cl2, pyridine-2-carboximidimide, DCM Zn, TFA, DMATMSCN, TBAFMeCN S6Compound 110(a)Scheme 23

[0290] Step 1: To a stirred solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1 -carboxylic acid (5.00 g, 29.4 mmol, 1 equiv) and / V-hydroxyphthalimide (5.27 g, 32.3 mmol, 1.1 equiv) in DCM (50 mL) were added DIC (7.42 g, 58.8 mmol, 2 equiv) and DMAP (360 mg, 2.94 mmol, 0.1equiv) at 0 °C. The resulting mixture was removed from cooling, stirred for 2 h, and filtered. The filter cake was rinsed with DCM (3 x 5 mL). The filtrate was concentrated to afford crude 1-(1,3-dioxoisoindolin-2-yl) 3-methyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (10.5 g). The crude material was used in the next step without further purification. LCMS (ES, m / z): 316.1 [M+H]+.

[0291] Step 2: A solution of Ni(dme)Cl2 (397 mg, 3.06 mmol, 0.4 equiv) and pyridine-2-carboximidamide (371 mg, 3.06 mmol, 0.4 equiv) in DMAc (20 mL) was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture were added 1-(1,3-dioxoisoindolin-2-yl) 3-methyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (9.49 g, 30.1 mmol, 3.9 equiv), / V-(4-iodophenyl)acetamide (2.00 g, 7.66 mmol, 1 equiv), Zn (7.51 g, 115 mmol, 15 equiv), and TFA (437 mg, 3.83 mmol, 0.5 equiv). The resulting mixture was stirred for 1 h and filtered. The filter cake was rinsed with EtOAc (3 x 10 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluting with 9:1 PE / EA) to afford methyl 3-(4-acetamidophenyl)bicyclo[1.1.1]pentane-1-carboxylate (1.20 g, 60% yield). LCMS (ES, m / z): 260.0 [M+H]+.

[0292] Step 3: A solution of methyl 3-(4-acetamidophenyl)bicyclo[1.1.1]pentane-1 -carboxylate (1.20 g, 4.63 mmol, 1 equiv) in aq. NaOH (4 M, 2 mL) and MeOH (10 mL) was stirred at 50 °C for 1 h, acidified to pH 4 with 2 M aq. HCI, and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with water (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford crude 3-(4-acetamidophenyl)bicyclo[1.1.1]pentane-1 -carboxylic acid (950 mg). The crude material was used in the next step without further purification. LCMS (ES, m / z): 246.0 [M+H]+.

[0293] Step 4: A solution of 3-(4-acetamidophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid (700 mg, 2.85 mmol, 1 equiv) and GDI (597 mg, 3.68 mmol, 1.3 equiv) in DCM (7 mL) was stirred at room temperature for 1 h and concentrated. To this residue was added dropwise a solution of NaBH4 (211 mg, 5.58 mmol, 2 equiv) in THF (7 mL) and water (0.5 mL) at 0 °C. The resulting mixture was removed from cooling, stirred for 1 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 0% to 100% MeCN / water over 10 min; detector: UV 254 nm) to afford / V-(4-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)acetamide (400 mg, 61% yield). LCMS (ES, m / z): 232.0 [M+H]+.

[0294] Step 5: To a stirred solution of / V-(4-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)acetamide (370 mg, 1.60 mmol, 1 equiv) in DCM (4 mL) were added MS2O (833 mg, 4.78 mmol, 3 equiv) and TEA (480 mg, 4.74 mmol, 3 equiv) at 0 °C. The resulting mixture was removed from cooling, stirred for 1 h, diluted with sat. aq. NaHCCh, poured into water (50 mL),and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with water (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford crude (3-(4-acetamidophenyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (730 mg). The crude material was used in the next step without further purification. LCMS (ES, m / z): 310.0 [M+H]+.

[0295] Step 6: To a stirred solution of (3-(4-acetamidophenyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (630 mg, 2.04 mmol, 1 equiv) in MeCN (0.5 mL) were added TMSCN (604 mg, 6.09 mmol, 3 equiv) and TBAF (2.66 g, 10.2 mmol, 5 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 2 h, poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 3:2 PE / EA) to afford / V-(4-(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)acetamide (160 mg, 33% yield). LCMS (ES, m / z): 241.0 [M+H]+.

[0296] Step 7: To a stirred solution of / V-(4-(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)acetamide (140 mg, 0.583 mmol, 1 equiv) in MeOH (1 mL) was added TMSCI (22 mg, 0.203 mmol, 0.35 equiv) at room temperature. The resulting mixture was stirred at 70 °C for 1 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 0% to 100% MeCN / water over 10 min; detector: UV 254 nm) to afford methyl 2-(3-(4-aminophenyl)bicyclo[1.1.1]pentan-1-yl)acetate (15 mg, 11% yield). LCMS (ES, m / z): 232.0 [M+H]+.

[0297] Step 8: To a stirred solution of methyl 2-(3-(4-aminophenyl)bicyclo[1.1.1]pentan-1-yl)acetate (15 mg, 0.065 mmol, 1 equiv) and (2R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxylic acid (see procedure xxiii) (20 mg, 0.072 mmol, 1.1 equiv) in DCM (0.5 mL) was added EDCI (15 mg, 0.097 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 1 h, concentrated, and purified by silica gel column chromatography (eluting with 3:2 PE / EA) to afford methyl (R)-2-(3-(4-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)bicyclo[1.1.1]pentan-1-yl)acetate (28 mg, 88% yield). LCMS (ES, m / z): 490.1 [M+H]+.

[0298] Step 9: A solution of methyl (R)-2-(3-(4-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)bicyclo[1.1.1]pentan-1-yl)acetate (23 mg, 0.047 mmol, 1 equiv) and LiOH (5.0 mg, 0.21 mmol, 4.4 equiv) in MeOH (0.5 mL) and water (0.1 mL) was stirred at room temperature for 2 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 0% to 100% MeCN / water over 10 min; detector: UV 254 nm) toafford (R)-2-(3-(4-(1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)bicyclo[1.1.1]pentan-1-yl)acetic acid (10 mg, 45% yield).Compound 110(a):

[0299] LCMS (ES, m / z): 476.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 10.44 (s, 1H), 8.60 (s, 1 H), 7.64 - 7.47 (m, 2H), 7.46 - 7.35 (m, 2H), 7.14 - 6.99 (m, 4H), 4.68-4.56 (m, 1 H), 3.74 - 3.60 (m, 1H), 3.50 - 3.43 (m, 1H), 2.86 - 2.74 (m, 1H), 2.19 (s, 2H), 2.18 - 2.12 (m, 1H), 2.06 - 1.96 (m, 1H), 1.94- 1.81 (m, 8H), 1.16 (d, J = 6.9 Hz, 6H).(Ixvii) (R)-2-(6-(1-((4-isopropylphenyl)carbamoyl)piperidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 85(a)(a) and 85(a)(b)) -Prepared using Scheme 1.

[0300] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate was used as lnt-2, and (R)-1-((benzyloxy)carbonyl)piperidine-2-carboxylic acid was used as lnt-3. The following modification to the procedure was applied: since lnt-4 in this case contained both a Cbz group and a Boc group, it was transformed into Int-5 over 2 steps (hydrogenolytic removal of the Cbz group with Pd / C and H2 gas in EtOAc followed by acidic removal of the Boc group in HFIP / TFA). terf-Butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate was synthesized from terf-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate in 3 steps: (a) olefination with terf-butyl 2-(diethoxyphosphoryl)acetate in the presence of LiCI and DBU; (b) hydrogenolysis of the resulting alkene with H₂ over Pd / C in MeOH; (c) cleavage of the Boc group with HCI in dioxane / DCM.

[0301] The stereoisomers were separated at the final step using chiral prep-HPLC (column: CHIRALPAK IB, 2*25 cm, 5 pm; mobile phase: 90:5:5 hexanes / DCM / MeOH with 0.18% FA; flow rate: 20 mL / min; run length: 23 min; wavelengths monitored: 220, 254 nM).Compound 85(a)(a) Compound 85(a)(b)Compound 85(a)(lsomer 1):

[0302] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 85(a)(a) and 85(a)(b). Peak 1: retention time: 21.3 min. LCMS (ES, m / z): 441.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.33 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.45 - 7.30 (m, 2H), 7.16 - 7.00 (m, 2H), 4.70-4.69 (m, 1H), 4.09-4.07 (m, 1H), 3.96-3.89 (m, 1H), 3.14-3.09 (m, 1H), 2.83-2.80 (m, 1H), 2.45-2.37 (m, 1H), 2.36-2.20 (m, 4H), 2.20 -2.02 (m, 3H), 1.99 - 1.85 (m, 2H), 1.75 - 1.40 (m, 5H), 1.37- 1.23 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H).Compound 85(b)(lsomer 2):

[0303] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 85(a)(a) and 85(a)(b). Peak 2: retention time: 23.2 min. LCMS (ES, m / z): 441.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.9 - 11.5 (m, 1H), 8.34 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.13 - 7.06 (m, 2H), 4.73 - 4.66 (m, 1H), 4.13 - 4.02 (m, 1H), 3.97 -3.89 (m, 1H), 3.15 -3.03 (m, 1H), 2.86-2.75 (m, 1H), 2.46-2.35 (m, 1H), 2.33 -2.24 (m, 3H), 2.22 - 2.01 (m, 4H), 1.98 - 1.85 (m, 1H), 1.74 - 1.60 (m, 1H), 1.58 - 1.45 (m, 5H), 1.41 - 1.22 (m, 2H), 1.18 (d, J = 6.8 Hz, 6H).(Ixviii) (R)-4-(3-(2-(((4-isopropylphenyl)carbamoyl)oxy)-2-phenylacetamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (Compound 111(a)) - Prepared using Scheme 5.

[0304] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, tert-butyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was used as lnt-2, and (R)-2-chloro-2-oxo-1-phenylethyl acetate was used as lnt-16. The following modifications to the procedure were applied: (a) DIEA was used instead of pyridine in the reaction between lnt-2 and lnt-16; (b) HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized following steps 1 to 3 of Scheme 9, with the following modifications: (a) DIC was used instead ofDCC in step 1; (a) terf-butyl 4-iodobenzoate was used instead of methyl 4-iodobenzoate in step 2; (c) pyridine-2-carboximidamide hydrochloride was used instead of 5-methoxypicolinimidamide hydrochloride in step 2; (d) TMSCI in MeOH / f-BuOH was used instead of HCI in dioxane in step 3.H O YA> oHN O OH

[0305] LCMS (ES, m / z): 486.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.90 (s, 1H), 9.81 (s, 1H), 8.98 (s, 1H), 7.88 (d, J = 8.0Hz, 2H), 7.52 (d, J = 6.8Hz, 2H), 7.43-7.32 (m, 7H), 7.16 (d, J = 8.4Hz, 2H), 5.82 (s, 1H), 2.86-2.79 (m, 1H), 2.25 (s, 6H), 1.17 (d, J = 6.8Hz, 6H).(Ixix) (R)-4-(3-(1-((4-isopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (Compound 112(a)) - Prepared using Scheme 19.

[0306] Compound 112(a) was synthesized according to Scheme 19 with the following modification: / V-(4-isopropyl-3-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide was used instead of / V-(4-cyclopropyl-3-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide in step 3. N-(4-lsopropyl-3-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide was synthesized in 3 steps: (a) cross-coupling of 4-bromo-3-(trifluoromethyl)aniline and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane catalyzed by Pd(dppf)Cl2; (b) hydrogenolysis of the resulting alkene over Pd / C in MeOH; (c) coupling of the resulting arylamine with GDI. Methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was synthesized according to Scheme 9.HrN0FF

[0307] LCMS (ES, m / z): 530.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.50 (d, J = 16.0 Hz, 2H), 7.94 - 7.73 (m, 4H), 7.50 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 4.30 - 4.23 (m, 1H), 3.65 -3.54 (m, 1H), 3.50-3.39 (m, 1H), 3.22 - 3.10 (m, 1H), 2.26 (s, 6H), 2.12 -2.01 (m, 1H) 1.96-1.81 (m, 3H), 1.21 (d, J = 6.8 Hz, 6H).(Ixx) (R)-4-(3-(1-((4-isopropyl-3-(trifluoromethyl)phenyl)carbamoyl)piperidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (Compound 113(a)) - Prepared using Scheme 1.

[0308] 4-lsocyanato-1-isopropyl-2-(trifluoromethyl)benzene was used as lnt-1, methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was used as lnt-2, and (R)-1-(terf-butoxycarbonyl)piperidine-2-carboxylic acid was used as lnt-3. The following modification to the procedure was applied: since lnt-4 in this case contained both a methyl ester and a Boc group, it was transformed into lnt-5 over 2 steps (hydrolysis of the ester with NaOH in MeOH / water followed by hydrolysis of the Boc group in HCI / dioxane). Methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was synthesized according to Scheme 9.

[0309] LCMS (ES, m / z): 544.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.80 (s, 1H), 8.70 (s, 1 H), 8.51 (s, 1 H), 7.88 (d, J = 8.2 Hz, 3H), 7.78 - 7.69 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.77 (d, J = 5.2 Hz, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.15 (d, J = 8.4Hz, 2H), 2.29 (s, 6H), 2.18 -2.09 (m, 1H), 1.76-1.62 (m, 3H), 1.56- 1.27 (m, 2H), 1.21 (d, J = 6.8 Hz, 6H).(Ixxi) (R)-4-(3-(1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)piperidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (Compound 114(a)) - Prepared using Scheme 1.

[0310] 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was used as lnt-1, methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was used as lnt-2, and (R)-1-(terf-butoxycarbonyl)piperidine-2-carboxylic acid was used as lnt-3. The following modification to the procedure was applied: since lnt-4 in this case contained both a methyl ester and a Boc group, it was transformed into lnt-5 over 2 steps (hydrolysis of the ester with NaOH in MeOH / waterfollowed by hydrolysis of the Boc group in HCI / dioxane). Methyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was synthesized according to Scheme 9.

[0311] LCMS (ES, m / z): 542.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.75 (s, 1H), 8.69 (s, 1H), 8.52 (s, 1H), 7.94- 7.85 (m, 3H), 7.67 (d, J = 2.4 Hz, 1H), 7.38- 7.31 (m, 2H), 7.05 (d, J = 8.8 Hz, 1H), 4.80-4.72 (m, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.12 (d, J = 12.0 Hz, 1H), 2.30 (s, 6H), 2.14 (d, J = 13.2 Hz, 1H), 2.06-1.99 (m, 1H), 1.64-1.53 (m, 3H), 1.42-1.18 (m, 2H), 1.00 - 0.90 (m, 2H), 0.76- 0.68 (m, 2H).(Ixxii) 4-((1S,3s)~ and 4-((1R,3r)-3-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)cyclobutyl)benzoic acid (Compounds 109(a)(a) and 109(a)(b)) - Prepared using Scheme 2.

[0312] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, tert-butyl 4-(3-aminocyclobutyl)benzoate was used as lnt-2, and D-proline was used as lnt-6. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final deprotection step, lnt-2 was synthesized by following steps 1 to 3 of Scheme 9, with the following modifications: (a) 3-((terf-butoxycarbonyl)amino)cyclobutane-1 -carboxylic acid was used instead of 3-((terf-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid; (b) DIG was used instead of DCC in step 1; (b) Mn was used instead of Zn and pyridine-2-carboximidamide hydrochloride was used instead of 5-methoxypicolinimidamide hydrochloride in step 2; (c) trichlorobismuthane in MeCN / water was used instead of HCI / dioxane in step 3.

[0313] The stereoisomers were separated at the final step using chiral prep-HPLC (column: CHIRAL ART Cellulose-SZ, 2*25 cm, 5 pm; mobile phase: 70:15:15 hexanes / DCM / MeOH with 0.14% FA; flow rate: 20 mL / min; run length: 13 min; wavelengths monitored: 220, 254 nM).Compound 109(a)(a) Compound 109(a)(b)Compound 109(a)(lsomer 1):

[0314] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 109(a)(a) and 109(a)(b). Peak 1: retention time: 9.2 min. LCMS (ES, m / z): 450.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.79 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.08 (s, 1H), 7.95 - 7.83 (m, 2H), 7.50-7.30 (m, 4H), 7.18-7.03 (m, 2H), 4.30-4.27 (m, 2H), 3.63-3.57 (m, 2H), 3.46-3.40 (m, 1H), 2.83-2.80 (m, 1H), 2.50-2.41 (m, 4H), 2.10-2.06 (m, 1H), 2.02 - 1.77 (m, 3H), 1.17 (d, J = 6.8 Hz, 6H).Compound 109(a)(lsomer 2):

[0315] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 109(a)(a) and 109(a)(b). Peak 2: retention time: 11.3 min. LCMS (ES, m / z) 450.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 12.85 (s, 1H), 8.20 - 8.04 (m, 2H), 8.04 - 7.81 (m, 2H), 7.48 - 7.30 (m, 4H), 7.20 -6.97 (m, 2H), 4.33 -4.17 (m, 2H), 3.64 - 3.55 (m, 1H), 3.43-3.39 (m, 1H), 3.20-3.18 (m, 1H), 2.83-2.79 (m, 1H), 2.61-2.52 (m, 2H), 2.17 - 1.99 (m, 3H), 1.92-1.81 (m, 2H), 1.85 - 1.74 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).(Ixxiii) (R)-2-(4-(3-(1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)phenyl)acetic acid (Compound 105(a)) - Prepared using Scheme 9.

[0316] Compound 105(a) was prepared following the procedure shown in Scheme 9, with the following modifications: (a) tert-butyl 2-(4-iodophenyl)acetate was used instead of methyl 4-iodobenzoate in step 2; (d) Ni(bpy)Ch was used instead of Ni(dme)Cl2 in step 2; (c) TMSCI was used instead of TBAI, TFA, and 5-methoxypicolinimidamide hydrochloride in step 2; (e) TMSCI in MeOH was used instead of HCI in dioxane in step 3 (the terf-butyl ester is transformed into a methyl ester at this step, along with Boc removal); (f) ((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)-D-proline was used instead of ((4-isopropylphenyl)carbamoyl)-D-proline in step 4; (g) DCM was used instead of DMF in step 4. ((4-Cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)-D-proline was synthesized in 2 steps from 4-cyclopropyl-3-(trifluoromethyl)aniline: (a) treatment of the arylamine with triphosgene and NaHCOs in DCM / water; (b) treatment of the resulting isocyanate with D-proline and NMM in THF.HrNHN o'y-FFF

[0317] LCMS (ES, m / z): 542.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 69.09 (s, 1H), 8.90 (s, 1H), 8.02 - 7.92 (m, 1H), 7.72 - 7.65 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.04 -6.96 (m, 3H), 4.43-4.35 (m, 1H), 3.70 - 3.57 (m, 1H), 3.43 - 3.38 (m, 1H), 3.18 (s, 2H), 2.10-2.05(m, 2H), 2.02 (s, 6H), 1.94 - 1.75 (m, 3H), 0.99 - 0.89 (m, 2H), 0.74 - 0.64 (m, 2H).(Ixxiv) 2-(6-((R)-1-((3-methyl-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 57(a)) - Prepared using Scheme 2.

[0318] 4-lsocyanato-2-methyl-1-(trifluoromethyl)benzene was used as lnt-1, terf-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate was used as lnt-2, and D-proline was used as lnt-6. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final deprotection step. terf-Butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate was synthesized from tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate in 3 steps: (a) olefination with terf-butyl 2-(diethoxyphosphoryl)acetate in the presence of LiCI and DBU; (b) hydrogenolysis of the resulting alkene with H₂ over Pd / C in MeOH; (c) cleavage of the Boc group with HCI in dioxane / DCM.HrNo

[0319] LCMS (ES, m / z): 468.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.99 (s, 1H), 8.48 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.61 - 7.46 (m, 3H), 4.28 - 4.16 (m, 1H), 4.10 - 3.92 (m, 1H), 3.65 - 3.52 (m, 1 H), 3.51 - 3.39 (m, 1 H), 2.37 (d, J = 2.0 Hz, 4H), 2.26 (d, J = 7.6 Hz, 3H), 2.22 - 2.08 (m, 2H), 2.07- 1.94 (m, 2H), 1.93 - 1.82 (m, 5H), 1.81 - 1.62 (m, 2H).(Ixxv) 2-(6-((R)-1-((3-methyl-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 57(a)(a) or57(a)(b))Compound 57(a)(a) Compound 57(a)(b)Scheme 24

[0320] Step 1: To a stirred suspension of LiCI (65.5 g, 1.55 mol, 2.4 equiv) in THF (1.6 L) was added terf-butyl 2-(diethoxyphosphoryl)acetate (162.4 g, 643.8 mmol, 1 equiv) at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0 °C and DBU (215.6 g, 1.416 mol, 2.2 equiv) and a solution of tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate (145 g, 644 mmol, 1 equiv) in THF (400 mL) were added. The resulting mixture was removed from cooling, stirred overnight, diluted with DCM, concentrated, and purified by silica gel column chromatography (eluting with 9:1 PE / EA) to afford terf-butyl 2-(6-((terf-butoxycarbonyl)amino)spiro[3.3]heptan-2-ylidene)acetate (170 g, 82% yield).1H NMR (400 MHz, CD3OD) 5 5.52 - 5.43 (m, 1H), 3.97 - 3.82 (m, 1H), 3.17 - 2.72 (m, 4H), 2.42 - 2.32 (m, 2H), 2.04 - 1.93 (m, 2H), 1.51 - 1.35 (m, 18H).

[0321] Step 2: To a stirred solution of tert-butyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-ylidene)acetate (170 g, 526 mmol, 1 equiv) in MeOH (2 L) was added Pd / C (10 wt%, 10 g, 9.4 mmol, 0.02 equiv) at room temperature. The resulting mixture was stirred overnight under hydrogen atmosphere and filtered. The filter cake was rinsed with MeOH (3 x 20 mL). The filtrate was concentrated to afford tert-butyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetate (170 g, 99% yield).1H NMR (300 MHz, CD3OD) 5 3.96 - 3.78 (m, 1H), 2.56 - 2.36 (m, 2H), 2.32 - 2.16 (m, 4H), 2.14 - 2.03 (m, 1H), 1.96 - 1.64 (m, 4H), 1.44 (d, J = 3.0 Hz, 18H).

[0322] Step 3: To a stirred solution of tert-butyl 2-(6-((tert-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetate (95.0 g, 292 mmol, 1 equiv) in MeCN (1 L) and water (20 mL) was added bismuth(lll) chloride (92.1 g, 292 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight and filtered. The filter cake was rinsed with MeCN (3 x 30 mL). The filtrate was concentrated to afford crude tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate. The crude material was used in the subsequent step without further purification. LCMS (ES, m / z): 226.2 [M+H]+.

[0323] Step 4: To a stirred solution of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (65.7 g, 292 mmol, 1 equiv) in DCM (700 mL) and TEA (88.6 g, 875 mmol, 3 equiv) was added CbzCI (74.6 g, 438 mmol, 1.5 equiv) at 0 °C. The resulting mixture was removed from cooling, stirred for 3 h, diluted with water, concentrated, and purified by silica gel column chromatography (eluting with 85:15 PE / EA) followed by chiral prep-SFC (column: Lux 5 pm Cellulose-3 5*25 cm, 5 pm; mobile phase: 60:20:20 CO2 / MeCN / MeOH; flow rate: 100 mL / min; wavelength monitored: 220 nm) to afford, in order of elution, Isomer 1 (retention time: 4.5 min) (55 g, 46% yield) and Isomer 2 (retention time: 6.5 min) (53 g, 42% yield) of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate. The absolute stereochemistry of Isomer 1 and Isomer 2 were not determined, but one is tert-butyl (R)-2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate and the other is tert-butyl (S)-2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate. LCMS (ES, m / z): 304.1 [M+H]+.

[0324] Step 5: To a stirred solution of Isomer 1 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate (43 g, 120 mmol, 1 equiv) in MeOH (500 mL) was added Pd / C (10 wt%, 2.5 g, 2.3 mmol, 0.02 equiv) at room temperature. Theresulting mixture was stirred for 3 h under hydrogen atmosphere and filtered. The filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated to afford Isomer 1 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (21.1 g, 78% yield). LCMS (ES, m / z): 226.2 [M+H]+.

[0325] Step 6: To a stirred solution of (2F?)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (1.00 g, 4.01 mmol, 1 equiv) in DCM (12.5 mL) were added Isomer 1 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (1.00 g, 4.44 mmol, 1.1 equiv) and EDCI (925 mg, 5.96 mmol, 1.5 equiv) at room temperature. The resulting solution was stirred for 1 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 40% to 60% MeCN / water over 20 min; detector: UV 254 nm) to afford Isomer 1 of benzyl (2F?)-2-((6-(2-(tert-butoxy)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.20 g, 66% yield). LCMS (ES, m / z): 457.2 [M+H]+.

[0326] Step 7: To a solution of Isomer 1 of benzyl (2F?)-2-((6-(2-(te / t-butoxy)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamoyl)pyrrolidine-1 -carboxylate (1.00 g, 2.19 mmol, 1 equiv) in MeOH (20 mL) was added Pd / C (10 wt%, 1.00 g, 0.943 mmol, 0.4 equiv) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h under hydrogen atmosphere and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to afford crude Isomer 1 of tert-butyl 2-(6-((F?)-pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (670 mg). The crude material was used directly in the next step without further purification. LCMS (ES, m / z): 323.2 [M+H]+.

[0327] Step 8: To a stirred solution of Isomer 1 of tert-butyl 2-(6-((F?)-pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (73 mg, 0.23 mmol, 0.8 equiv) and NMM (86 mg, 0.85 mmol, 3 equiv) in THF (0.5 mL) was added / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1 -carboxamide (synthesized in 1 step from 3-methyl-4-(trifluoromethyl)aniline and GDI) (76 mg, 0.28 mmol, 1 equiv) portionwise at room temperature. The resulting mixture was stirred for 1 h, poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford crude Isomer 1 of tert-butyl 2-(6-((?)-1-((3-methyl-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (130 mg). The crude material was used directly in the next step without further purification. LCMS (ES, m / z): 524.0 [M+H]+.

[0328] Step 9: A solution of Isomer 1 of tert-butyl 2-(6-((?)-1-((3-methyl-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (120 mg, 0.229 mmol, 1 equiv) in HFIP (2 mL) and TFA (0.1 mL) was stirred at room temperature for1 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 0% to 100% MeCN / 0.05% aq. TFA over 10 min; detector: UV 254 nm) to afford Isomer 1 of 2-(6-((R)-1-((3-methyl-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 57(a)(lsomer 1)) (16.8 mg, 16% yield).Compound 57(a)(lsomer 1):

[0329] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 57(a)(a) and 57(a)(b). Peak 1: retention time: 4.5 min (step 4). LCMS (ES, m / z): 468.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.93 (s, 1 H), 8.46 (s, 1 H), 7.98 (d, J = 7.7 Hz, 1 H), 7.70 - 7.44 (m, 3H), 4.35 - 4.18 (m, 1H), 4.11 - 3.95 (m, 1H), 3.67 - 3.54 (m, 1H), 3.52 - 3.41 (m, 1H), 2.45 -2.40 (m, 1H), 2.40 -2.34 (m, 3H), 2.34 - 2.24 (m, 3H), 2.21 -2.09 (m, 2H), 2.09 - 1.97 (m, 2H), 1.95 - 1.83 (m, 4H), 1.83 - 1.73 (m, 1H), 1.73 - 1.58 (m, 2H).(Ixxvi) 2-((1 R,3R)~, 2-((1 S,3S)~, 2-((1R,3S)-, and 2-((1S,3R)-3-(4-((R)-1-((4- isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compounds 115(a)(a), 115(a)(b), 115(a)(c), and 115(a)(d))Scheme 25

[0330] Step 1: To a stirred solution of D-proline (7.00 g, 60.8 mmol, 1.2 equiv) in THF (150 mL) were added NMM (6.20 g, 61.3 mmol, 1.2 equiv) and 1-isocyanato-4-isopropylbenzene (8.00 g, 49.6 mmol, 1 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h, poured into water (100 mL), and basified to pH 8 with solid Na2CO3. The organic layer was removed and the aqueous layer was washed with MTBE (3x200 mL), acidified to pH 2 with cone.HCI, and stirred at room temperature for 30 min. The precipitated solids were collected by filtration and rinsed with MTBE (3 x 50 mL) to provide (2R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxylic acid (9.50 g, 57% yield). LCMS (ES, m / z): 277.1 [M+H]+.

[0331] Step 2: To a stirred solution of ethyl 2-(3-oxocyclopentyl)acetate (3.00 g, 17.6 mmol, 1 equiv) in DCM (20 mL) was added 2,6-dimethylpyridine (5.70 g, 53.2 mmol, 3 equiv) dropwise at 0 °C. After stirring at 0 °C for 30 min, Tf20 (14.9 g, 52.9 mmol, 3 equiv) was added dropwise. The resulting mixture was removed from cooling, stirred overnight, concentrated, and purified by silica gel column chromatography (eluting with 10:1 PE / EA) to afford ethyl 2-(3-(trifluoromethanesulfonyloxy)cyclopent-2-en-1-yl)acetate (5.0 g, 94% yield). LCMS (ES, m / z): 303.0 [M+H]+.

[0332] Step 3: To a stirred suspension of ethyl 2-(3-(trifluoromethanesulfonyloxy)cyclopent-2-en- 1-yl)acetate (5.0 g, 16.5 mmol, 1 equiv) and K2CO3(6.86 g, 49.6 mmol, 3 equiv) in dioxane (50 mL) were added Pd(dppf)Cl2(2.66 g, 3.64 mmol, 0.2 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.99 g, 18.2 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere, poured into water (20mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 5:1 PE / EA) to afford ethyl 2-(3-(4-aminophenyl)cyclopent-2-en-1-yl)acetate (1.0 g, 25% yield). LCMS (ES, m / z): 246.1 [M+H]+.

[0333] Step 4: To a stirred solution of ethyl 2-(3-(4-aminophenyl)cyclopent-2-en-1-yl)acetate (1.30 g, 5.30 mmol, 1 equiv) in EA (20 mL) was added Pd / C (10 wt%, 1.13 g, 1.06 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred overnight under hydrogen atmosphere and filtered. The filter cake was rinsed with EtOAc (7 x 6 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluting with 1:1 PE / EA) to afford ethyl 2-(3-(4-aminophenyl)cyclopentyl)acetate (1.0 g, 76% yield). LCMS (ES, m / z): 248.2 [M+H]+.

[0334] Step 5: To a stirred solution of (2R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxylic acid (1.10 g, 3.98 mmol, 1 equiv) and EDCI (1.28 g, 8.24 mmol, 2.1 equiv) in DCM (10 mL) was added ethyl 2-(3-(4-aminophenyl)cyclopentyl)acetate (1.10 g, 4.447 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for 1 h and purified directly by silica gel column chromatography (eluting with 1: 1 PE / EA) to afford a mixture of four stereoisomers of ethyl 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate. LCMS (ES, m / z): 421.1 [M+H]+. The mixture of stereoisomers was purified by chiral prep-SFC (column: CHIRALPAK ID, 3*25 cm, 5 pm; mobilephase: 1:1 CO2 / EtOH; flow rate: 80 mL / min; wavelength monitored: 220 nm) to afford, in order of elution: a mixture of two stereoisomers of ethyl 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate (Et- 115(a)(lsomer 1) and Et-115(a)(lsomer 2)) (RT = 5.8 min) (500 mg, 25% yield); an isolated stereoisomer of ethyl 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate (Et-115(a)(lsomer 3)) (RT = 7.6 min) (100 mg, 5% yield); and another isolated stereoisomer of ethyl 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate (Et- 115(a)(lsomer 4)) (RT = 13.5 min) (400 mg, 20% yield). Each of Et-115(a)(lsomer 1), Et-115(a)(lsomer 2), Et-115(a)(lsomer 3), and Et-115(a)(lsomer 4) is one of ethyl 2-((1 S,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate, ethyl 2-((1R,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate, ethyl 2-((1 S,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate, and ethyl 2-((1R,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetate.

[0335] Step 6: To a stirred solution of Et-115(a)(lsomer 1) and Et-115(a)(lsomer 2) (100 mg, 0.20 mmol, 1 equiv) in EtOH (2 mL) and water (0.4 mL) was added LiOH (17 mg, 0.71 mmol, 3.6 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 1 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 10% to 20% MeCN / water over 10 min; detector: UV 254 nm) to give a mixture of two stereoisomers of 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid. The mixture of stereoisomers was purified by chiral prep-HPLC (column: CHIRAL ART Cellulose-SZ, 2*25 cm, 5 pm; mobile phase: 80:10:10 hexanes / DCM / MeOH with 0.16% FA; flow rate: 20 mL / min; run length: 13 min; wavelengths monitored: 220, 254 nm) to afford, in order of elution, an isolated stereoisomer of 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(lsomer 1)) (2.8 mg, 3% yield) and another isolated stereoisomer of 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(lsomer 2)) (8.6 mg, 9% yield). Each of Compound 115(a)(lsomer 1) and Compound 115(a)(lsomer 2) is one of 2-((1R,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(a)), 2-((1S,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(b)), 2-((1R,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(c)), and 2-((1S,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(d)).Compound 115(a)(lsomer 1):

[0336] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 115(a)(a), 115(a)(b), 115(a)(c), and 115(a)(d). Peak 1 (step 5): retention time: 5.8 min; peak 1 (step 6): retention time: 8.5 min. LCMS (ES, m / z): 478.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.00 (br. s, 1H), 9.89 (s, 1H), 8.16 (s, 1H), 7.52 - 7.47 (m, 2H), 7.42 - 7.37 (m, 2H), 7.19 - 7.13 (m, 2H), 7.11 - 7.06 (m, 2H), 4.46 -4.42 (m, 1H), 3.67 - 3.58 (m, 1H), 3.54 - 3.45 (m, 1H), 3.03 - 2.92 (m, 1H), 2.85 -2.75 (m, 1H), 2.32 -2.27 (m, 3H), 2.19 -2.08 (m, 2H), 2.06 - 1.85 (m, 5H), 1.64 - 1.51 (m, 1H), 1.46 - 1.35 (m, 1H), 1.28 - 1.19 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).Compound 115(a)(lsomer 2):

[0337] The stereochemistry of Isomer 2 was not assigned but corresponds to one of Compounds 115(a)(a), 115(a)(b), 115(a)(c), and 115(a)(d). Peak 1 (step 5): retention time: 5.8 min; peak 2 (step 6): retention time: 11.7 min. LCMS (ES, m / z): 478.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.97 (br. s, 1H), 9.88 (s, 1H), 8.16 (s, 1H), 7.53 - 7.47 (m, 2H), 7.43 - 7.37 (m, 2H), 7.19 -7.13 (m, 2H), 7.13 - 7.06 (m, 2H), 4.47 - 4.41 (m, 1H), 3.68 - 3.58 (m, 1H), 3.55 - 3.44 (m, 1H), 3.03 - 2.92 (m, 1H), 2.85 - 2.75 (m, 1H), 2.32 - 2.26 (m, 3H), 2.22 - 2.09 (m, 2H), 2.06 - 1.82 (m, 5H), 1.64- 1.50 (m, 1H), 1.46 - 1.34 (m, 1H), 1.29 - 1.19 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).

[0338] Step 7: To a stirred solution of Et-115(a)(lsomer 3) (100 mg, 0.20 mmol, 1 equiv) in EtOH (2 mL) and water (0.4 mL) was added LiOH (17 mg, 0.71 mmol, 3.6 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 10% to 20% MeCN / water over 10 min; detector: UV 254 nm) to afford a stereoisomer of 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(lsomer 3)) (10.2 mg, 11% yield). Compound 115(a)(lsomer 3) is one of 2-((1R,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(a)), 2-((1S,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(b)), 2-((1R,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(c)), and 2-((1S,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(d)).Compound 115(a)(lsomer 3):

[0339] The stereochemistry of Isomer 3 was not assigned but corresponds to one of Compounds 115(a)(a), 115(a)(b), 115(a)(c), and 115(a)(d). Peak 2 (step 5): retention time: 7.6 min. LCMS (ES, m / z): 478.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.05 (br. s, 1H), 9.90 (s, 1H), 8.17 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.43 - 7.36 (m, 2H), 7.19 - 7.12 (m, 2H), 7.11 - 7.05 (m, 2H), 4.47 - 4.41 (m, 1 H), 3.69 - 3.59 (m, 1 H), 3.54 - 3.45 (m, 1 H), 3.00 - 2.92 (m, 1 H), 2.86 - 2.75 (m, 1 H), 2.48 - 2.37 (m, 1H), 2.32 - 2.23 (m, 3H), 2.21 - 2.07 (m, 2H), 2.08 - 1.83 (m, 4H), 1.82 - 1.64 (m, 1H), 1.63- 1.46 (m, 1H), 1.46 - 1.34 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).

[0340] Step 8: To a stirred solution of Et-115(a)(lsomer4) (100 mg, 0.20 mmol, 1 equiv) in EtOH (2 mL) and water (0.4 mL) was added LiOH (17 mg, 0.71 mmol, 3.6 equiv) at room temperature. The resulting mixture was stirred at 50 °C overnight, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 10% to 20% MeCN / water over 10 min; detector: UV 254 nm to afford a stereoisomer of 2-(3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(lsomer 4)) (7.2 mg, 7% yield). Compound 115(a)(lsomer 4) is one of 2-((1R,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(a)), 2-((1S,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(b)), 2-((1R,3S)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(c)), and 2-((1S,3R)-3-(4-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compound 115(a)(d)).Compound 115(a)(lsomer 4):

[0341] The stereochemistry of Isomer 4 was not assigned but corresponds to one of Compounds 115(a)(a), 115(a)(b), 115(a)(c), and 115(a)(d). Peak 3 (step 5): retention time: 13.5 min. LCMS (ES, m / z): 478.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.96 (br. s, 1H), 9.89 (s, 1H), 8.17 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.19 - 7.12 (m, 2H), 7.12 - 7.03 (m, 2H), 4.50 - 4.36 (m, 1H), 3.70 - 3.59 (m, 1H), 3.55 - 3.44 (m, 1H), 3.11 - 2.90 (m, 1H), 2.86 - 2.74 (m, 1H), 2.48 -2.25 (m, 4H), 2.21 -2.08 (m, 2H), 2.06 - 1.84 (m, 5H), 1.80 - 1.52 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H).(Ixxvii) (R)-4'-(1-((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (Compound 101(a)) - Prepared using Scheme 8.Compound 101(a) was prepared following the procedure shown in Scheme 8, with the following modification: 5-(trifluoromethyl)thiazol-2-amine was used instead of 5-isopropylthiazol-2-amine.

[0342] LCMS (ES, m / z): 550.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.60 (br, 1H), 10.25 (s, 1H), 8.04 - 7.96 (m, 3H), 7.82 - 7.69 (m, 6H), 4.60 - 4.45 (m, 1H), 3.75 - 3.53 (m, 2H), 2.32 -2.20 (m, 1H), 2.01 - 1.91 (m, 3H).(Ixxviii) (R)-2-(6-(1-((4-cyclopentyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 116(a)(a) or 116(a)(b)) -Prepared using Scheme 23.Compound 116(a)(lsomer 2) was prepared following the procedure shown in Scheme 23, with the following modifications: (a) Isomer 2 of terf-butyl 2-(6- (((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5; (b) 1-cyclopentyl-4-isocyanato-2-(trifluoromethyl)benzene was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide in step 8; (c) HCI in dioxane was used instead of TFA in HFIP in step 9. 1-Cyclopentyl-4-isocyanato-2-(trifluoromethyl)benzene was synthesized in 3 steps: (a) Suzuki-Miyaura cross-coupling of 4-bromo-3-(trifluoromethyl)aniline and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane catalyzed by Pd(dppf)Cl2; (b) hydrogenation of the resulting alkene with H2 gas over Pd / C; (c) formation of the isocyanate using triphosgene.Compound 116(a)(a) Compound 116(a)(b)Compound 116(a)(lsomer 2):

[0343] The stereochemistry of Isomer 2 was not assigned but corresponds to one of Compounds 116(a)(a) and 116(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 522.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.89 (s, 1H), 8.41 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.47 (d, J = 8.8 Hz, 1H), 4.25 - 4.19 (m, 1H), 4.08 - 3.95 (m, 1H), 3.68 - 3.53 (m, 1H), 3.47 - 3.37 (m, 1H), 3.33 - 3.11 (m, 1H), 2.46 - 2.35 (m, 1H), 2.34- 2.22 (m, 3H), 2.21 - 1.73 (m, 13H), 1.72 - 1.49 (m, 6H).(Ixxix) (R)-2-(6-(1-((4-cyclobutyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compound 117(a)(a) or 117(a)(b)) -Prepared using Scheme 23.Compound 117(a)(lsomer 2) was prepared following the procedure shown in Scheme 23, with the following modifications: (a) Isomer 2 of terf-butyl 2-(6- (((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5; (b) / V-(4-cyclobutyl-3-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1 -carboxamide in step 8. / \ / -(4-Cyclobutyl-3-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide was synthesized in 4 steps: (a) acetylation of 4-bromo-3-(trifluoromethyl)aniline with AC2O; (b) cross-couping of the resulting bromide with 2-cyclobutyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane catalyzed by (Ir[dF(CF3)ppy]2(dtbpy))PF6and Ni(dme)Cl2 with morpholine and dtbpy in DMF under blue LED light; (c) hydrolysis of the acetyl group with HCI in MeOH / water; (d) coupling of the resulting amine with GDI.Compound 117(a)(a) Compound 117(a)(b)Compound 117(a)(lsomer 2):

[0344] The stereochemistry of Isomer 2 was not assigned but corresponds to one of Compounds 117(a)(a) and 117(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 508.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.96 (s, 1H), 8.44 (s, 1H), 7.99 (d, J = 7.6 Hz, 1 H), 7.90 (d, J = 2.3 Hz, 1 H), 7.80 - 7.75 (m, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 4.23 - 4.20 (m, 1 H), 4.02 - 3.98 (m, 1 H), 3.73 - 3.70 (m, 1 H), 3.58 - 3.55 (m, 1 H), 3.42 - 3.35 (m, 1 H), 2.49 - 2.39 (m, 1H), 2.34 -2.11 (m, 9H), 2.11-1.78 (m, 9H), 1.71-1.62 (m, 2H).(Ixxx) (R)-4 '-(1-((5-isopropylthiazol-2-yl)carbamoyl)pyrrolidine-2-carboxamido)-2-methyl-[1, 1 '-biphenyl]-4-carboxylic acid (Compound 108(a)) - Prepared using Scheme 8.

[0345] Compound 108(a) was prepared following the procedure shown in Scheme 8, with the following modifications: (a) ((benzyloxy)carbonyl)-D-proline was used instead of (((9 / 7-fluoren-9-yl)methoxy)carbonyl)-D-proline and tert-butyl 4'-amino-2-methyl-[1,1'-biphenyl]-4-carboxylate was used instead of tert-butyl 4'-amino-[1,1'-biphenyl]-4-carboxylate in step 1; (b) the deprotection in step 2 was performed using H2 gas and Pd / C in EtOAc instead of piperidine in DMF; (c) TFA in HFIP was used instead of HCI in dioxane for the final deprotection step. tert-Butyl 4'-amino-2-methyl-[1,1'-biphenyl]-4-carboxylate was synthesized in 1 step via the Pd(dppf)Cl2-catalyzed cross-coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and tert-butyl 4-bromo-3-methylbenzoate.

[0346] LCMS (ES, m / z): 493.1 [M+H]+.1H N MR (400 MHz, DMSO-d6) 5 10.16 (s, 1H), 7.90-7.65 (m, 4H), 7.37 - 7.24 (m, 3H), 7.02 (s, 1 H), 4.51-4.49 (m, 1 H), 3.69 - 3.59 (m, 1 H), 3.58 - 3.51 (m, 1 H), 3.08 - 3.00 (m, 1 H), 2.32 - 2.29 (m, 4H), 1.96 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H).(Ixxxi) 2-(6-((R)-1-((4-isopropyl-3-methylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 118(a)(a) and 118(a)(b)) -Prepared using Scheme 23.Isomer 1 and Isomer 2 of Compound 118(a) were prepared following the procedure shown in Scheme 23, with the following modification: / V-(4-isopropyl-3-methylphenyl)-1 / 7-imidazole-1-carboxamide was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / - / -imidazole- 1-carboxamide in step 8. The following modifications were additionally applied only for Isomer 2 of Compound 118(a): (a) Isomer 2 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5; (b) TEA in DMF was used instead of NMM in THF in step 8. / V-(4-lsopropyl-3-methylphenyl)-1 / 7-imidazole-1-carboxamide was synthesized in one step by reacting 4-isopropyl-3-methylaniline with GDI.Compound 118(a)(a) Compound 118(a)(b)Compound 118(a)(lsomer 1):

[0347] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 118(a)(a) and 118(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 442.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.95 (s, 1 H), 8.01 - 7.91 (m, 2H), 7.29 - 7.21 (m, 2H), 7.11 - 7.03 (m, 1H), 4.25 - 4.14 (m, 1H), 4.11 - 3.94 (m, 1H), 3.61 - 3.50 (m, 1H), 3.47 -3.37 (m, 1H), 3.10 - 2.92 (m, 1H), 2.45 - 2.35 (m, 1H), 2.35 - 2.24 (m, 3H), 2.23 (s, 3H), 2.20 -2.06 (m, 2H), 2.06 - 1.96 (m, 2H), 1.94 - 1.81 (m, 4H), 1.81 - 1.73 (m, 1H), 1.73 - 1.59 (m, 2H), 1.15 (d, J = 6.8 Hz, 6H).Compound 118(a)(lsomer 2):

[0348] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 118(a)(a) and 118(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 442.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.94 (s, 1H), 7.94-7.92 (m, 2H), 7.29-7.22 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 4.22 -4.17 (m, 1H), 4.05-3.97 (m, 1H), 3.59-3.52 (m, 1H), 3.44-3.36 (m, 1H), 3.05-2.97 (m, 1H), 2.44-2.36 (m, 1H), 2.33-2.21 (m, 6H), 2.20-2.07 (m, 2H), 2.05-1.75 (m, 7H), 1.72-1.60 (m, 2H), 1.15 (d, J = 6.8 Hz, 6H).(Ixxxii) 2-(6-((R)-1-((4-isopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 119(a)(a) and 119(a)(b)) - Prepared using Scheme 23.Isomer 1 and Isomer 2 of Compound 119(a) were prepared following the procedure shown in Scheme 23, with the following modification: / V-(4-isopropyl-3-(trifluoromethyl)phenyl)-1 / 7-imidazole-1 -carboxamide was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1 -carboxamide in step 8. The following modification was additionally applied only for Isomer 2 of Compound 119(a): Isomer 2 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5. / V-(4-lsopropyl-3-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide was synthesized in 2 steps: (a) hydrogenation of 4-(prop-1-en-2-yl)-3-(trifluoromethyl)aniline with H2over Pd / C; (b) reaction of the resulting amine with GDI.Compound 119(a)(a) Compound 119(a)(b)Compound 119(a)(lsomer 1):

[0349] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 119(a)(a) and 119(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 496.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.93 (br, 1H), 8.28 (s, 1H), 7.98-7.96 (m, 1H), 7.42-7.41 (m, 1H), 7.22-7.14 (m, 2H), 4.22-4.19 (m, 1H), 4.02-3.99 (m, 1H), 3.58-3.53 (m, 1H), 3.41-3.39 (m, 1H), 3.09-3.05 (m, 1H), 2.40-2.38 (m, 1H), 2.29-2.25 (m, 3H), 2.18-2.13 (m, 2H),2.06-2.00 (m, 2H), 1.91-1.87 (m, 4H), 1.86-1.84(m, 1H), 1.72-1.63(m, 2H), 1.18(d, J = 6.8 Hz, 6H).Compound 119(a)(lsomer 2):

[0350] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 119(a)(a) and 119(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 496.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.95 (s, 1H), 8.42 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.25 -4.18 (m, 1H), 4.08 - 3.96 (m, 1H), 3.63 - 3.54 (m, 1H), 3.47 - 3.39 (m, 1H), 3.20 - 3.09 (m, 1H), 2.45 - 2.36 (m, 1 H), 2.35 - 2.23 (m, 3H), 2.20 - 1.98 (m, 4H), 1.97 - 1.73 (m, 5H), 1.72 - 1.59 (m, 2H), 1.21 (d, J = 6.8 Hz, 6H).(Ixxxiii) 4-(6-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)benzoic acid (Compounds 120(a)(a) and 120(a)(b)) -Prepared using Scheme 9.

[0351] Compounds 120(a)(a) and 120(a)(b) were prepared following the procedure shown in Scheme 9, with the following modifications: (a) 6-((terf-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylic acid was used instead of 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1; (b) DIC was used instead of DCC in step 1; (c) tert-butyl 4-iodobenzoate was used instead of methyl 4-iodobenzoate in step 2; (d) TMSCI was used instead of TBAI, TFA, and 5-methoxypicolinimidamide hydrochloride in step 2; (e) BiCh in MeCN / water was used instead of HCI in dioxane in step 3; (f) HCI in dioxane was used instead of LiOH in MeOH / water for the final deprotection step.

[0352] The stereoisomers were separated at the final step using chiral prep-HPLC (column: Lux Cellulose-4, 2.12*25 cm, 5 pm; mobile phase: 80:10:10 hexanes / EtOH / MeOH with 0.16% FA; flow rate: 20 mL / min; run length: 23 min; wavelengths monitored: 220, 254 nM).Compound 120(a)(a) Compound 120(a)(b)Compound 120(a)(lsomer 1):

[0353] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 120(a) (a) and 120(a) (b). Peak 1: retention time: 17.6 min. LCMS (ES, m / z): 490.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.79 (s, 1 H), 8.07 (s, 1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.89 - 7.82 (m, 2H), 7.43 - 7.36 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.13 - 7.06 (m, 2H), 4.26 - 4.19 (m, 1H), 4.15 - 4.01 (m, 1H), 3.62 - 3.53 (m, 1H), 3.51 - 3.39 (m, 2H), 2.89 - 2.74 (m, 1H), 2.49 - 2.39 (m, 2H), 2.34 - 2.25 (m, 1H), 2.20 - 2.13 (m, 1H), 2.14 - 2.00 (m, 4H), 1.97 - 1.74 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H).Compound 120(a)(lsomer 2):

[0354] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 120(a)(a) and 120(a)(b). Peak 2: retention time: 20.7 min. LCMS (ES, m / z) 490.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.81 (s, 1H), 8.11 - 7.97 (m, 2H), 7.89 - 7.82 (m, 2H), 7.43 - 7.35 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.13 - 7.05 (m, 2H), 4.2 - 4.19 (m, 1H), 4.16 - 4.00 (m, 1H), 3.63 - 3.52 (m, 1H), 3.50 - 3.38 (m, 2H), 2.88 -2.72 (m, 1H), 2.48 -2.26 (m, 3H), 2.21 - 1.98 (m, 5H), 1.97 - 1.74 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H).(Ixxxiv) (R)-4 '-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)-2-methyl-[1, 1 biphenyl]-4-carboxylic acid (Compound 121(a)) - Prepared using Scheme 5.

[0355] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, terf-butyl 4'-amino-2-methyl-[1, T-biphenyl]-4-carboxylate was used as lnt-2, and (R)-1-chloro-1-oxopropan-2-yl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized in 1 step via the Pd(dppf)Cl2-catalyzed cross-coupling of terf-butyl 4-bromo-3-methylbenzoate and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0356] LCMS (ES, m / z): 461.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.89 (s, 1H), 10.28 (s, 1 H), 9.80 (s, 1 H), 7.87 (s, 1 H), 7.83 - 7.77 (m, 1 H), 7.75 - 7.68 (m, 2H), 7.42 - 7.27 (m, 5H), 7.20- 7.11 (m, 2H), 5.11 (q, J = 6.8 Hz, 1H), 2.87 - 2.75 (m, 1H), 2.30 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H).(Ixxxv) (R)-4-(6-(2-(((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)oxy)propanamido)pyridin-3-yl)-3-methylbenzoic acid (Compound 122(a)) - Prepared using Scheme 5.

[0357] 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was used as lnt-1, tert-butyl 4-(6-aminopyridin-3-yl)-3-methylbenzoate was used as lnt-2, and (F?)-1-chloro-1-oxopropan-2-yl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized in 1 step via the Pd(dppf)Cl2-catalyzed cross-coupling of tert-butyl 4-bromo-3-methylbenzoate and 5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine.

[0358] LCMS (ES, m / z): 528.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 12.95 (s, 1H), 10.89 (s, 1H), 10.19 (s, 1H), 8.38 (d, J = 2.4 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.92 - 7.81 (m, 4H), 7.57 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 5.24 (d, J = 6.8 Hz, 1H), 2.32 (s, 3H), 2.09-1.98(m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.01 - 0.93 (m, 2H), 0.77 - 0.70 (m, 2H). (Ixxxvi) (R)-4 '-(2-(((4-isopropylphenyl)carbamoyl)oxy)-2-phenylacetamido)-[1, 1 biphenyl]-4-carboxylic acid (Compound 123(a)) - Prepared using Scheme 5.

[0359] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, tert-butyl 4'-amino-[1,1'-biphenyl]-4-carboxylate was used as lnt-2, and (F?)-2-chloro-2-oxo-1-phenylethyl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized in 1 step via the Pd(dppf)Cl2-catalyzed cross-coupling of tert-butyl 4-bromobenzoate and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0360] LCMS (ES, m / z): 509.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.95 (s, 1H), 10.59 (s, 1H), 9.93 (s, 1H), 8.04 - 7.96 (m, 2H), 7.82 - 7.69 (m, 6H), 7.67 - 7.60 (m, 2H), 7.50 - 7.35 (m, 5H), 7.20 -7.12 (m, 2H), 6.06 (s, 1H), 2.89-2.76 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).(Ixxxvii) (R)-4-(3-(2-(((4-isopropylphenyl)carbamoyl)oxy)-2-phenylacetamido)bicyclo[1.1.1]pentan-1-yl)-3-methylbenzoic acid (Compound 124(a)) -Prepared using Scheme 5.

[0361] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, tert-butyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)-3-methylbenzoate was used as lnt-2, and (F?)-2-chloro-2-oxo-1-phenylethyl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized following steps 1 to 3 of Scheme 9, with the following modifications to step 2: (a) terf-butyl 4-bromo-3-methylbenzoatewas used instead of methyl 4-iodobenzoate; (b) Ni(bpy)Ch used instead of Ni(dme)Cl2; (c) TMSCI was used instead of TBAI, TFA, and 5-methoxypicolinimidamide hydrochloride.

[0362] LCMS (ES, m / z): 513.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 69.82 (s, 1H), 8.99 (s, 1H), 7.70-7.67 (m, 2H), 7.59-7.51 (m, 2H), 7.44-7.38 (m, 5H), 7.19-7.12 (m, 3H), 5.83 (s, 1H), 2.88-2.77 (m, 1H), 2.68(s, 6H), 2.37 (s, 3H), 1.17 (d, J = 6.8 Hz, 6H).(Ixxxviii) (R)-4'-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)-2'-methyl-[1, 1 biphenyl]-4-carboxylic acid (Compound 125(a)) - Prepared using Scheme 5.

[0363] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, terf-butyl 4'-amino-2'-methyl-[1,1'-biphenyl]-4-carboxylate was used as lnt-2, and (R)-1-chloro-1-oxopropan-2-yl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized in 1 step via the Pd(dppf)Cl2-catalyzed cross-coupling of terf-butyl 4-iodobenzoate and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0364] LCMS (ES, m / z): 461.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 12.92 (s, 1H), 10.18 (s, 1 H), 9.79 (s, 1 H), 8.03 - 7.96 (m, 2H), 7.59 (d, J = 2.2 Hz, 1 H), 7.57 - 7.50 (m, 1 H), 7.49 - 7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.18 - 7.12 (m, 2H), 5.10 (q, J = 6.7 Hz, 1H), 2.88 -2.77 (m, 1H), 2.24 (s, 3H), 1.49 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.9 Hz, 6H). (Ixxxix) (R)-3-isopropyl-4-( 6-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)pyridin-3-yl)benzoic acid (Compound 126(a)) - Prepared using Scheme 5.

[0365] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, terf-butyl 4-(6-aminopyridin-3-yl)-3-isopropylbenzoate was used as lnt-2, and (R)-1 -chloro- 1-oxopropan-2-yl acetate was used as Int-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized in 2 steps: (a) DMAP-catalyzed terf-butyl protection of 4-bromo-3-isopropylbenzoic acid with Boc2O in t-BuOH; (b) Pd(dppf)Cl2-catalyzed cross-coupling of the resulting ester with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine.

[0366] LCMS (ES, m / z): 490.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 13.04 (s, 1H), 10.85 (s, 1H), 9.84 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.43 - 7.35 (m, 2H), 7.32 (d, J = 8.0 Hz, 1 H), 7.20 - 7.10 (m, 2H), 5.22 (d, J = 6.8 Hz, 1H), 3.04-2.95 (m, 1H), 2.87 -2.78 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.28 - 1.04 (m, 12H).(xc) 2-(6-((R)-1-((4-cyclopentylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 127(a)(a) and 127(a)(b)) -Prepared using Scheme 23.Isomer 1 and Isomer 2 of Compound 127(a) were prepared following the procedure shown in Scheme 23, with the following modification: / V-(4-cyclopentylphenyl)-1 / 7-imidazole-1-carboxamide was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / - / -imidazole- 1-carboxamide in step 8. The following modification was additionally applied only for Isomer 2 of Compound 127(a): Isomer 2 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5. / V-(4-Cyclopentylphenyl)-1 / 7-imidazole-1-carboxamide was synthesized in 1 step by reacting 4-cyclopentylaniline with GDI.Compound 127(a)(a) Compound 127(a)(b)Compound 127(a)(lsomer 1):

[0367] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 127(a)(a) and 127(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z):454.3 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 11.95 (s, 1H), 8.06 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.29 - 4.14 (m, 1H), 4.12 - 3.91 (m, 1H), 3.67 - 3.49 (m, 1 H), 3.45 - 3.40 (m, 1 H), 2.98 - 2.79 (m, 1 H), 2.47 - 2.34 (m, 1 H), 2.33 - 2.22 (m, 3H), 2.22 - 2.06 (m, 2H), 2.05 - 1.81 (m, 8H), 1.81 - 1.58 (m, 7H), 1.57 - 1.40 (m, 2H). Compound 127(a)(lsomer 2):

[0368] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 127(a)(a) and 127(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 454.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.07 (s, 1 H), 7.98 (d, J = 7.6 Hz, 1 H), 7.49 - 7.29 (m, 2H), 7.17 - 7.03 (m, 2H), 4.25 - 4.15 (m, 1H), 4.10 - 3.90 (m, 1H), 3.60 -3.50 (m, 1 H), 3.48 - 3.39 (m, 1 H), 2.94 - 2.82 (m, 1 H), 2.45 - 2.34 (m, 1 H), 2.34 - 2.20 (m, 3H), 2.19 - 2.07 (m, 2H), 2.05 - 1.90 (m, 5H), 1.89 - 1.81 (m, 3H), 1.80 - 1.70 (m, 3H), 1.69 - 1.56 (m, 4H), 1.52 - 1.40 (m, 2H).(xci) 2-(6-((R)-1-((3,5-difluoro-4-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 128(a)(a) and 128(a)(b)) -Prepared using Scheme 23.Isomer 1 and Isomer 2 of Compound 128(a) were prepared following the procedure shown in Scheme 23, with the following modification: 1,3-difluoro-5-isocyanato-2-(trifluoromethyl)benzene was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide in step 8. The following modification was additionally applied only for Isomer 2 of Compound 128(a): Isomer 2 of terf-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5. 1,3-Difluoro-5-isocyanato-2-(trifluoromethyl)benzene was synthesized in 1 step by reacting 3,5-difluoro-4-(trifluoromethyl)aniline with triphosgene.Compound 128(a)(a) Compound 128(a)(b)Compound 128(a)(lsomer 1):

[0369] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 128(a)(a) and 128(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 490.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.92 (s, 1H), 8.96 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 13.8 Hz, 2H), 4.27- 4.16 (m, 1H), 4.07- 3.94 (m, 1H), 3.63-3.53 (m, 1H), 3.53 - 3.41 (m, 1H), 2.45 - 2.35 (m, 1H), 2.35 - 2.23 (m, 3H), 2.20 - 1.99 (m, 4H), 1.94 - 1.82 (m, 4H), 1.82 - 1.60 (m, 3H).Compound 128(a)(lsomer 2):

[0370] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 128(a)(a) and 128(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 490.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 12.87 (s, 1H), 9.00 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.53-7.51 (m, 2H), 4.23-4.21 (m, 1H), 4.02-4.00 (m, 1H), 3.59-3.56 (m, 1H), 3.46-3.34 (m, 1H), 2.51-2.38 (m, 1H), 2.30-2.25 (m, 3H), 2.16-1.94 (m, 4H), 1.92-1.80 (m, 5H), 1.71-1.60 (m, 2H).(xcii) 2-(6-((R)-1-((4-ethylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 129(a)(a) and 129(a)(b)) - Prepared using Scheme 23.Isomer 1 and Isomer 2 of Compound 129(a) were prepared following the procedure shown in Scheme 23, with the following modifications to step 8: (a) / V-(4-ethylphenyl)-1 / - / -imidazole- 1-carboxamide was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / - / -imidazole- 1-carboxamide; (b) TEA was used instead of NMM; (c) DMF was used instead of THF. The following modification was additionally applied only for Isomer 2 of Compound 129(a): Isomer 2 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5. / V-(4-ethylphenyl)-1 / 7-imidazole-1-carboxamide was synthesized in 1 step by reacting 4-ethylaniline with GDI.Compound 129(a)(a) Compound 129(a)(b)Compound 129(a)(lsomer 1):

[0371] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 129(a)(a) and 129(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 414.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 67.46 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.78 (s, 1H), 4.49 - 4.41 (m, 1H), 4.24 - 4.11 (m, 1H), 3.60 - 3.44 (m, 2H), 2.66 - 2.58 (m, 2H), 2.56 - 2.47 (m, 1H), 2.46 - 2.37 (m, 2H), 2.36 - 2.27 (m, 2H), 2.25 -2.15 (m, 2H), 2.12 - 1.92 (m, 5H), 1.88 - 1.81 (m, 1H), 1.73 - 1.65 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H).Compound 129(a)(lsomer 2):

[0372] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 129(a)(a) and 129(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 414.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.07 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.20- 4.18 (m, 1H), 4.05-3.95 (m, 1H), 3.57-3.55 (m, 1H), 3.42-3.38 (m, 1H), 2.57-2.55 (m, 2H), 2.43-2.37(m, 1H), 2.30-2.19 (m, 3H), 2.18-2.09 (m, 2H), 2.03-1.97 (m, 2H), 1.92 -1.74 (m, 5H), 1.69-1.61 (m, 2H), 1.14 (t, J = 7.6 Hz, 3H).(xciii) 2-(6-((R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 130(a)(a) and 130(a)(b)) -Prepared using Scheme 23.Isomer 1 and Isomer 2 of Compound 130(a) were prepared following the procedure shown in Scheme 23. The following modification was applied for Isomer 1 of Compound 130(a): 2-fluoro-4-isocyanato-1 -isopropylbenzene was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1 -carboxamide in step 8. The following modifications were applied for Isomer 2 of Compound 130(a): (a) Isomer 2 of tert- butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5; (b) / \ / -(3-fluoro-4-isopropylphenyl)-1 / 7-imidazole-1 -carboxamide was used instead of / V-(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1 -carboxamide in step 8. 2-Fluoro-4-isocyanato-1 -isopropylbenzene was synthesized in 1 step by reacting 3-fluoro-4-isopropylaniline with triphosgene. / \ / -(3-Fluoro-4-isopropylphenyl)-1 / 7-imidazole-1-carboxamide was synthesized in 1 step by reacting 3-fluoro-4-isopropylaniline with GDI.Compound 130(a)(a) Compound 130(a)(b)Compound 130(a)(lsomer 1):

[0373] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 130(a)(a) and 130(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z) 446.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.94 (s, 1H), 8.26 (s, 1H), 8.05 - 7.87 (m, 1H), 7.44 - 7.35 (m, 1H), 7.25 - 7.12 (m, 2H), 4.24 - 4.16 (m, 1H), 4.07 - 3.94 (m, 1H), 3.63 - 3.51 (m, 1H), 3.45 - 3.36 (m, 1H), 3.13 - 3.01 (m, 1H), 2.45 -2.35 (m, 1H), 2.35 -2.24 (m, 3H), 2.20 - 2.06 (m, 2H), 2.05 - 1.97 (m, 2H), 1.94 - 1.82 (m, 4H), 1.82 - 1.74 (m, 1H), 1.72 - 1.58 (m, 2H), 1.18 (d, J = 6.8 Hz, 6H).Compound 130(a)(lsomer 2):

[0374] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 130(a)(a) and 130(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 446.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.94 (s, 1H), 8.27 (s, 1H), 7.97 - 7.95 (m, 1H), 7.41 - 7.40 (m, 1H), 7.24 - 7.14 (m, 2H), 4.21 - 4.20 (m, 1H), 4.02 - 3.99 (m, 1 H), 3.99 - 3.40 (m, 1 H), 3.40 - 3.38 (m, 1 H), 3.08 - 3.06 (m, 1 H), 2.38 - 2.29 (m, 1 H), 2.31 -2.24 (m, 3H), 2.15 -2.13 (m, 2H), 2.02 - 1.99 (m, 2H), 1.94 - 1.78 (m, 5H), 1.70 - 1.62 (m, 2H), 1.18 - 1.16 (m, 6H).(xciv) 2-(6-((R)-2-(((4-isopropylphenyl)carbamoyl)oxy)-2-phenylacetamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 131(a)(a) and 131(a)(b)) -Prepared using Scheme 5.

[0375] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate was used as lnt-2, and (R)-2-chloro-2-oxo-1-phenylethyl acetate was used as lnt-16. The following modification to the procedure was applied: (a) HFIP / TFA was used instead of HCI in the final ester hydrolysis step. terf-Butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate was synthesized from tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate in 3 steps: (a) olefination with terf-butyl 2-(diethoxyphosphoryl)acetate in the presence of LiCI and DBU; (b) hydrogenolysis of the resulting alkene with H₂ over Pd / C in MeOH; (c) cleavage of the Boc group with HCI in dioxane / DCM.

[0376] The stereoisomers were separated at the final step using chiral prep-HPLC (column: CHIRALPAK IG, 2*25 cm, 5 pm; mobile phase: 80:10:10 hexanes / DCM / MeOH with 0.16% FA; flow rate: 20 mL / min; run length: 20 min; wavelengths monitored: 220, 254 nM).Compound 131(a)(a) Compound 131(a)(b)Compound 131(a)(lsomer 1):

[0377] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 131(a)(a) and 131(a)(b). Peak 1: retention time: 11.1 min. LCMS (ES, m / z): 465.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 9.77 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.59 - 7.45 (m, 2H), 7.45 -7.29 (m, 5H), 7.22 - 7.08 (m, 2H), 5.80 (s, 1 H), 4.02 - 3.98 (m, 1 H), 2.82 - 2.75 (m, 1 H), 2.39 -2.35 (m, 1H), 2.26 (t, J = 5.2 Hz, 3H), 2.16 - 2.10 (m, 2H), 2.00 - 1.95 (m, 1H), 1.95 - 1.76 (m, 2H), 1.66 - 1.60 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H).Compound 131(a)(lsomer 2):

[0378] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 131 (a) (a) and 131 (a)(b). Peak 2: retention time: 15.7 min. LCMS (ES, m / z) 465.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 9.77 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.59 - 7.44 (m, 2H), 7.45 - 7.28 (m, 5H), 7.22 - 7.08 (m, 2H), 5.80 (s, 1H), 4.02 - 3.98 (m, 1H), 2.82 - 2.73 (m, 1H), 2.39 -2.35 (m, 1H), 2.26 (t, J = 5.2 Hz, 3H), 2.16 - 2.12 (m, 2H), 2.00 - 1.93 (m, 1H), 1.95 - 1.78 (m, 2H), 1.66 - 1.62 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H).(xcv) 3-(6-((R)-1-((4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)propanoic acid (Compounds 132(a)(a) and 132(a)(b)) -Prepared using Scheme 9.

[0379] Compounds 132(a)(a) and 132(a)(b) were prepared following steps 3 to 5 of Scheme 9, with the following modification: ethyl 3-(6-((terf-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)propanoate was used instead of methyl 4-(3-((terf-butoxycarbonyl)amino)bicyclo[1.1.1]pentan- 1-yl) benzoate. Ethyl 3-(6-((terf-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)propanoate was synthesized from 6-((terf-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylic acid in 3 steps: (a) one-pot reduction of the carboxylic acid to an aldehyde by submitting the starting material to GDI followed by DIBAL-H; (b) formation of an ethyl enoate by condensing the aldehyde with ethyl 2-(triphenyl-A5-phosphaneylidene)acetate; (c) hydrogenation of the alkene with H₂ gas over Pd / C in MeOH.

[0380] The stereoisomers were separated at the final step using chiral prep-HPLC (column: CHIRALPAK IF, 2*25 cm, 5 pm; mobile phase: 80:10:10 hexanes / DCM / EtOH with 0.16% FA; flow rate: 20 mL / min; run length: 15 min; wavelengths monitored: 220, 254 nM).Compound 132(a)(a) Compound 132(a)(b) Compound 132(a)(lsomer 1):

[0381] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 132(a)(a) and 132(a)(b). Peak 1: retention time: 11.2 min. LCMS (ES, m / z): 442.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.96 (s, 1H), 8.05 (s, 1H), 7.99 - 7.93 (m, 1H), 7.41 - 7.36 (m, 2H), 7.12 - 7.06 (m, 2H), 4.24 - 4.16 (m, 1H), 4.06 - 3.95 (m, 1H), 3.63 - 3.52 (m, 1H), 3.44 -3.39 (m, 1H), 2.85 -2.76 (m, 1H), 2.31 - 2.24 (m, 1H), 2.14 - 1.97 (m, 7H), 1.94 - 1.82 (m, 4H), 1.80 - 1.74 (m, 1H), 1.62 - 1.49 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H).Compound 132(a)(lsomer 2):

[0382] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 132(a)(a) and 132(a)(b). Peak 2: retention time: 13.1 min. LCMS (ES, m / z): 442.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.06 - 11.84 (m, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.16 - 7.04 (m, 2H), 4.25 - 4.19 (m, 1H), 4.04 - 3.95 (m, 1H), 3.61 -3.53 (m, 1 H), 3.44 -3.36 (m, 1 H), 2.86-2.74 (m, 1 H), 2.35-2.23 (m, 1 H), 2.16 - 1.92 (m, 7H), 1.90- 1.81 (m, 4H), 1.81 - 1.73 (m, 1H), 1.64- 1.49 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H).(xcvi) 2-(6-((2RS,3aRS, 6aRS)-1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 133(a)(a) and 133(a)(b))Scheme 26

[0383] Step 1: To a stirred solution of Isomer 1 of 1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (see Scheme 13;using the first-eluting peak from step 1) (120 mg, 0.379 mmol, 1 equiv) in DCM (3 mL) were added EDCI (71 mg, 0.46 mmol, 1.2 equiv) and Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (see Scheme 23) (103 mg, 0.457 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1 h, concentrated, and purified by silica gel column chromatography (eluting with 1:1 PE / EA) to afford Isomer 1,2 of tert-butyl 2-(6-(1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (130 mg, 65% yield). LCMS (ES, m / z): 524.3 [M+H]+.

[0384] Step 2: A solution of Isomer 1,2 of tert-butyl 2-(6-(1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (120 mg, 0.229 mmol, 1 equiv) in HFIP (1.9 mL) and TFA (0.1 mL) was stirred at room temperature for 1 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 10% to 50% MeCN / water over 10 min; detector, UV 254 nm) to afford Isomer 1,2 of 2-(6-(1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (32.6 mg, 30% yield).Compound 133(lsomer 1,2):

[0385] The stereochemistry of Isomer 1,2 was not assigned but corresponds to one of Compounds 133(a)(a), 133(a)(b), 133(b)(a), and 133(b)(b). Peak 1: retention time: 8.16 min (step 1 of Scheme 13); peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 468.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.96 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.41 - 7.36 (m, 2H), 7.13 - 7.07 (m, 2H), 4.36 - 4.27 (m, 2H), 4.07 - 3.96 (m, 1H), 2.82 - 2.77 (m, 1H), 2.73 - 2.64 (m, 1H), 2.45 - 2.36 (m, 1H), 2.35 - 2.22 (m, 4H), 2.20 - 2.10 (m, 2H), 2.08 -1.98 (m, 2H), 1.93 - 1.84 (m, 2H), 1.81 - 1.60 (m, 6H), 1.49 - 1.34 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H).

[0386] Step 3: To a stirred solution of Isomer 2 of 1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (see Scheme 13; using the second-eluting peak from step 1) (120 mg, 0.379 mmol, 1 equiv) in DCM (1.2 mL) were added EDCI (146 mg, 0.940 mmol, 2.5 equiv) and Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (see Scheme 23) (103 mg, 0.457 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1 h, poured into water (30 mL), and extracted with DCM (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 2:1 PE / EA) to afford Isomer 2,2 of tert-butyl 2-(6-(1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (130 mg, 65% yield). LCMS (ES, m / z): 524.3 [M+H]+.

[0387] Step 4: A solution of Isomer 2,2 of tert-butyl 2-(6-(1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (100 mg, 0.191 mmol, 1 equiv) in HFIP (0.95 mL) and TFA (0.05 mL) was stirred at room temperature for 3 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 10% to 50% MeCN / water over 10 min; detector, UV 254 nm) to afford Isomer 2,2 of 2-(6-(1-((4-isopropylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (34.7 mg, 39% yield).Compound 133(lsomer 2,2):

[0388] The stereochemistry of Isomer 2,2 was not assigned but corresponds to one of Compounds 133(a)(a), 133(a)(b), 133(b)(a), and 133(b)(b). Peak 2: retention time: 9.35 min (step 1 of Scheme 13); peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 468.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.93 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.41 - 7.35 (m, 2H), 7.12 - 7.07 (m, 2H), 4.36 - 4.27 (m, 2H), 4.08 - 3.97 (m, 1H), 2.86 - 2.77 (m, 1 H), 2.71 - 2.63 (m, 1 H), 2.45 - 2.35 (m, 1 H), 2.34 - 2.25 (m, 3H), 2.24 - 2.09 (m, 3H), 2.08 -1.97 (m, 2H), 1.95 - 1.79 (m, 3H), 1.76 - 1.61 (m, 5H), 1.50 - 1.33 (m, 2H), 1.18 (d, J = 6.8 Hz, 6H).(xcvii) 2-(6-((R)-2-(((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)oxy)-2-phenylacetamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 134(a)(a) and 134(a)(b)) -Prepared using Scheme 5.

[0389] 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was used as lnt-1, Isomer 1 and Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (see Scheme 23) were used, respectively, as lnt-2, and (F?)-2-chloro-2-oxo-1 -phenylethyl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step. 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was synthesized in 1 step by reacting 4-cyclopropyl-3-(trifluoromethyl)aniline with triphosgene.Compound 134(a)(a) Compound 134(a)(b)Compound 134(a)(lsomer 1):

[0390] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 134(a)(a) and 134(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 531.2 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 10.14 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.52 - 7.43 (m, 2H), 7.43 - 7.31 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 5.80 (s, 1H), 4.09 - 3.92 (m, 1H), 2.44 - 2.30 (m, 1H), 2.30 - 2.22 (m, 3H), 2.21 - 2.10 (m, 2H), 2.09 - 1.94 (m, 2H), 1.94 - 1.75 (m, 2H), 1.74 - 1.58 (m, 2H), 1.04 - 0.89 (m, 2H), 0.83 -0.63 (m, 2H).Compound 134(a)(lsomer 2):

[0391] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 134(a)(a) and 134(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 531.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 511.94 (s, 1H), 10.13 (s, 1H), 8.47 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.49-7.36 (m, 5H), 7.11 (d, J = 8.4 Hz, 1H), 5.81 (s, 1H), 4.06-3.97 (m, 1H), 2.39-2.34 (m, 2H), 2.28-2.24 (m, 2H), 2.17-1.92 (m, 5H), 1.77-1.59 (m, 3H), 0.98-0.95 (m, 2H), 0.75-0.72 (m, 2H).(xcviii) (R)-4-(3-(2-(((4-isopropylphenyl)carbamoyl)oxy)propanamido)bicyclo[1.1.1]pentan-1-yl)benzoic acid (Compound 135(a)) - Prepared using Scheme 5.

[0392] 1-lsocyanato-4-isopropylbenzene was used as lnt-1, tert-butyl 4-(3-aminobicyclo[1.1.1]pentan-1-yl)benzoate was used as lnt-2, and (R)-1 -chloro- 1-oxopropan-2-yl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized following steps1 to 3 of Scheme 9, with the following modifications: (a) DIC was used instead of DCC in step 1; (a) tert-butyl 4-iodobenzoate was used instead of methyl 4-iodobenzoate in step 2; (c) pyridine-2-carboximidamide hydrochloride was used instead of 5-methoxypicolinimidamide hydrochloride in step 2; (d) TMSCI in MeOH / f-BuOH was used instead of HCI in dioxane in step 3.

[0393] LCMS (ES, m / z): 437.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.83 (s, 1H), 9.66 (s, 1H), 8.68 (s, 1H), 7.92 - 7.85 (m, 2H), 7.41 - 7.32 (m, 4H), 7.19 - 7.11 (m, 2H), 4.95 - 4.86 (m, 1H), 2.88 -2.75 (m, 1H), 2.30 (s, 6H), 1.37 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H).(xcix) (R)-4'-(2-(((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)oxy)propanamido)-[1,1 '-biphenyl]-4-carboxylic acid (Compound 136(a)) - Prepared using Scheme 5.

[0394] 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was used as lnt-1, tert-butyl 4'-amino-[1,1'-biphenyl]-4-carboxylate was used as lnt-2, and (R)-1 -chloro- 1-oxopropan-2-yl acetate was used as lnt-16. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final ester hydrolysis step, lnt-2 was synthesized in 1 step via the Pd(dppf)Cl2-catalyzed cross-coupling of tert-butyl 4-bromobenzoate and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.H

[0395] LCMS (ES, m / z): 513.1 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 12.98 - 12.89 (m, 1H), 10.36 - 10.33 (m, 1H), 10.20 - 10.16 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 2.0 Hz, 1H), 7.81 - 7.71 (m, 6H), 7.58 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.13 (d, J = 6.8 Hz, 1H), 2.05 -2.00 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 0.99 - 0.94 (m, 2H), 0.80 - 0.70 (m, 2H).(c) 2-(6-((R)-1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)piperidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 138(a)(a) and 138(a)(b)) -Prepared using Scheme 23.Isomer 1 and Isomer 2 of Compound 138(a) were prepared following the procedure shown in Scheme 23, with the following modifications: (a) (R)-1-((benzyloxy)carbonyl)piperidine-2-carboxylic acid was used instead of (2R)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid in step 6; (b) 1-cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was used instead of / \ / -(3-methyl-4-(trifluoromethyl)phenyl)-1 / 7-imidazole-1-carboxamide in step 8; (c) DCM was used instead of THF in step 8. The following modification was additionally applied only for Isomer 1 of Compound 138(a): ethyl acetate was used instead of methanol in step 7. The following modification was additionally applied only for Isomer 2 of Compound 128(a): Isomer 2 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate was used instead of Isomer 1 in step 5. 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was synthesized in 1 step by reacting 4-cyclopropyl-3-(trifluoromethyl)aniline with triphosgene.Compound 138(a)(a) Compound 138(a)(b)Compound 138(a)(lsomer 1):

[0396] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 138(a)(a) and 138(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z) 508.3 [M+H]+.1H NMR (400 MHz, MeOH-d4) 67.74 (d, J = 2.4 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.86-4.80 (m, 1H), 4.24-4.14 (m, J = 8.0 Hz, 1H), 3.94 - 3.89 (m, 1H), 3.32 - 3.21 (m, 1H), 2.58 - 2.52 (m, 2H), 2.51 - 2.37 (m, 2H), 2.40 - 2.22 (m, 2H), 2.25 - 2.17 (m, 1H), 2.16 - 2.10 (m, 2H), 2.03 - 1.93 (m, 2H), 1.89 - 1.70 (m, 1H), 1.60 - 1.40 (m, 4H), 1.39 -1.25 (m, 2H), 1.05 - 0.94 (m, 2H), 0.79 - 0.70 (m, 2H).Compound 138(a)(lsomer 2):

[0397] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 138(a)(a) and 138(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 508.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.68 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.73-4.69 (m, 1H), 4.11-4.05 (m, 1H), 3.96-3.91 (m, 1H), 3.12-3.04 (m, 1H), 2.45-2.36 (m, 1H), 2.34-2.23 (m, 3H), 2.20-2.07 (m, 3H), 2.05-1.83 (m, 4H), 1.73-1.45 (m, 5H), 1.40-1.20 (m, 2H), 0.96 -0.93 (m, 2H), 0.72-0.69 (m, 2H).(ci) 2-((1S,2R)- and 2-((1 R,2S)-2-(4-((R)-1-((4-cyclopropyl-3- (trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopropyl)acetic acid - Prepared using Scheme 12.

[0398] The following modifications to Scheme 12 were applied: (a) ((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)-D-proline was used instead of ((4-isopropylphenyl)carbamoyl)-D-proline in step 3; (b) EDCI in DCM was used instead of HATU and NMM in DMF in step 3. ((4-Cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)-D-proline was synthesized in 2 steps from 4-cyclopropyl-3-(trifluoromethyl)aniline: (a) treatment of the arylamine with triphosgene and NaHCCfe in DCM / water; (b) treatment of the resulting isocyanate with D-proline and NMM in THF.

[0399] The stereoisomers were separated at the final step using chiral prep-HPLC (column: CHIRAL ART Amylose-SA, 2*25 cm, 5 pm; mobile phase: 75:12.5:12.5 hexanes / DCM / EtOH with 0.15% FA; flow rate: 20 mL / min; run length: 11 min; wavelengths monitored: 220, 254 nM).Compound 139(a)(a) Compound 139(a)(b)Compound 139(a)(lsomer 1):

[0400] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 139(a) (a) and 139(a) (b). Peak 1: retention time: 7.7 min. LCMS (ES, m / z): 516.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 9.94 (d, J = 12.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 2.5 Hz,1 H), 7.72 - 7.62 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.10 - 6.95 (m, 3H), 4.50 -4.42 (m, 1H), 3.70 - 3.60 (m, 1H), 3.55 - 3.35 (m, 1H), 2.35 - 2.25 (m, 2H), 2.20 - 2.10 (m, 1H), 2.08 - 1.83 (m, 4H), 1.72 - 1.65 (m, 1H), 1.28 - 1.14 (m, 1H), 0.92 - 0.90 (m, 2H), 0.87 - 0.77 (m, 2H), 0.75 -0.67 (m, 2H).Compound 139(a)(lsomer 2):

[0401] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 139(a)(a) and 139(a)(b). Peak 2: retention time: 9.9 min. LCMS (ES, m / z): 516.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 67.80 (d, J = 12.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.06 - 7.02 (m, 3H), 4.59 - 4.53 (m, 1H), 3.77 - 3.71 (m, 1H), 3.63 - 3.55 (m, 1H), 2.67 - 2.61 (m, 1H), 2.35 - 2.04 (m, 6H), 1.76 - 1.69 (m, 1H), 1.45 - 1.27 (m, 1H), 1.03 -0.71 (m, 6H).(cii) 2-(6-((R)-1-((4-cyclopropyl-3-fluorophenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 140(a)(a) and 140(a)(b)) -Prepared using Scheme 2.

[0402] 1-Cyclopropyl-2-fluoro-4-isocyanatobenzene was used as lnt-1, Isomer 1 and Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (see Scheme 23) were used, respectively, as lnt-2, and D-proline was used as lnt-6. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final deprotection step. 1-Cyclopropyl-2-fluoro-4-isocyanatobenzene was synthesized in 1 step by reacting 4-cyclopropyl-3-fluoroaniline with triphosgene.Compound 140(a)(a) Compound 140(a)(b)Compound 140(a)(lsomer 1):

[0403] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 140(a)(a) and 140(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 444.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.89 (s, 1H), 8.25 (s, 1H), 7.97 (d, J = 7.6 Hz,1H), 7.45- 7.37 (m, 1H), 7.21- 7.14 (m, 1H), 6.88- 6.80 (m, 1H), 4.23- 4.16 (m, 1H), 4.08- 3.94 (m, 1 H), 3.60- 3.50 (m, 1 H), 3.45 - 3.37 (m, 1 H), 2.46 -2.34 (m, 1 H), 2.34 - 2.22 (m, 3H), 2.21 -2.08 (m, 2H), 2.06 - 1.95 (m, 2H), 1.95 - 1.81 (m, 5H),1.80 - 1.72 (m, 1H), 1.72 - 1.59 (m, 2H),0.94 - 0.85 (m, 2H), 0.68 - 0.59 (m, 2H).Compound 140(a)(lsomer 2):

[0404] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 140(a)(a) and 140(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 444.3 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 11.96 (s, 1H), 8.26 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.48- 7.36 (m, 1H), 7.23 - 7.13 (m, 1H), 6.89-6.80 (m, 1H), 4.24 -4.15 (m, 1H), 4.11 - 3.92 (m, 1H), 3.62 - 3.49 (m, 1H), 3.47 - 3.35 (m, 1H), 2.49 - 2.32 (m, 1H), 2.32 -2.22 (m, 3H), 2.20 -2.07 (m, 2H), 2.07 - 1.87 (m, 7H), 1.87 - 1.57 (m, 3H), 0.95 - 0.78 (m, 2H), 0.69 - 0.58 (m, 2H).(ciii) 2-(6-((R)-1-((4-cyclopropyl-3-(trifluoromethoxy)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 141(a)(a) and 141(a)(b)) -Prepared using Scheme 2.

[0405] 1-Cyclopropyl-4-isocyanato-2-(trifluoromethoxy)benzene was used as lnt-1, Isomer 1 and Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (see Scheme 23) were used, respectively, as lnt-2, and D-proline was used as lnt-6. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final deprotection step. 1-Cyclopropyl-4-isocyanato-2-(trifluoromethoxy)benzene was synthesized in 2 steps: (a) Suzuki-Miyaura crosscoupling of 4-bromo-3-(trifluoromethoxy)aniline and cyclopropylboronic acid catalyzed by Pd(dppf)Cl2; (b) reaction of the resulting amine with triphosgene.Compound 141(a)(a) Compound 141(a)(b)Compound 141(a)(lsomer 1):

[0406] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 141(a)(a) and 141(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 510.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.35 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.69 - 7.63 (m, 1H), 7.43 - 7.36 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.27 - 4.15 (m, 1H), 4.08 - 3.95 (m, 1H), 3.61 - 3.52 (m, 1H), 3.45 - 3.37 (m, 1H), 2.45 - 2.34 (m, 1H), 2.34 - 2.23 (m, 3H), 2.22 - 2.06 (m, 2H), 2.06 - 1.94 (m, 3H), 1.93 - 1.82 (m, 4H), 1.82 - 1.56 (m, 3H), 0.99 -0.89 (m, 2H), 0.70 - 0.60 (m, 2H).Compound 141(a)(lsomer 2):

[0407] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 141(a)(a) and 141(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 510.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.96 (s, 1H), 8.36 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.40 (d, J = 8.8, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.21-4.19 (m, 1H), 4.02-3.98 (m, 1H), 3.57-3.52 (m, 1H), 3.43-3.39 (m, 1H), 2.44-2.38 (m, 1H), 2.31-2.23 (m, 3H), 2.18-2.10 (m, 2H), 2.06-1.82 (m, 7H), 1.79-1.73 (m, 1H), 1.71-1.59 (m, 2H), 0.93-0.91 (m, 2H), 0.66-0.64 (m, 2H).(civ) 2-(6-((R)-1-((4-cyclopropyl-3-(difluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 137(a)(a) and 137(a)(b)) -Prepared using Scheme 2.

[0408] 1-Cyclopropyl-2-(difluoromethyl)-4-isocyanatobenzene was used as lnt-1, Isomer 1 and Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (see Scheme 23) were used, respectively, as lnt-2, and D-proline was used as lnt-6. The following modification to the procedure was applied: HFIP / TFA was used instead of HCI in the final deprotection step. 1-Cyclopropyl-2-(difluoromethyl)-4-isocyanatobenzene was synthesized in 3 steps: (a) Suzuki-Miyaura crosscoupling of 1-bromo-2-(difluoromethyl)-4-nitrobenzene and cyclopropylboronic acid catalyzed by Pd(dppf)Cl2; (b) reduction of the nitro group to an amine using iron and NH4CI in EtOH / water; (c) reaction of the resulting amine with triphosgene.Compound 137(a)(a) Compound 137(a)(b)Compound 137(a)(lsomer 1):

[0409] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 137(a)(a) and 137(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 476.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.29 (s, 1 H), 7.96 (d, J = 7.6 Hz, 1 H), 7.76 - 7.71 (m, 1H), 7.58 - 7.51 (m, 1H), 7.30 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.24- 4.16 (m, 1H), 4.08 -3.94 (m, 1 H), 3.61 - 3.52 (m, 1 H), 3.46 - 3.35 (m, 1 H), 2.46 - 2.34 (m, 1 H), 2.34 - 2.23 (m, 3H), 2.21 - 2.08 (m, 2H), 2.08 - 1.96 (m, 3H), 1.94 - 1.81 (m, 4H), 1.81 - 1.72 (m, 1H), 1.72 - 1.58 (m, 2H), 0.96 - 0.85 (m, 2H), 0.69 - 0.60 (m, 2H).Compound 137(a)(lsomer 2):

[0410] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 137(a)(a) and 137(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 476.2 [M+H]+.1H NMR (400 MHz, MeOH-d4) 67.64 (d, J = 2.4 Hz, 1H), 7.51 -7.44 (m, 1H), 7.28 -6.99 (m, 2H), 4.32 - 4.40 (m, 1H), 4.22 -4.11 (m, 1H), 3.72 - 3.64 (m, 1H), 3.57 - 3.49 (m, 1H), 2.59 - 2.42 (m, 2H), 2.41 - 2.33 (m, 2H), 2.32 - 2.10 (m, 4H), 2.09 - 1.89 (m, 6H), 1.83- 1.69 (m, 2H), 1.04 - 0.93 (m, 2H), 0.74 - 0.64 (m, 2H).(cv) 2-((1R,3R)~, 2-((1S,3S)~, 2-((1R,3S)-, and 2-((1 S,3R)-,3-(4-((R)-1-((4-cyclopropyl-3-(trifluoromethyl)phenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclopentyl)acetic acid (Compounds 142(a)(a), 142(a)(b), 142(a)(c), and 142(a)(d)) - Prepared using Scheme 2.

[0411] 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was used as lnt-1, ethyl 2-(3-(4-aminophenyl)cyclopentyl)acetate (see Scheme 24) was used as lnt-2, and D-proline was used as lnt-6. The following modification to the procedure was applied: LiOH in MeOH / water was used instead of HCI in the final deprotection step. 1-Cyclopropyl-4-isocyanato-2-(trifluoromethyl)benzene was synthesized in 1 step by reacting 4-cyclopropyl-3-(trifluoromethyl)aniline with triphosgene.

[0412] The mixture of four stereoisomers was separated at the final step using chiral prep-HPLC (column: CHIRALPAK IG, 3*25 cm, 5 pm; mobile phase: 70:15:15 hexanes / DCM / EtOH with 0.14% FA; flow rate: 40 mL / min; run length: 18 min; wavelengths monitored: 220, 254 nM) to afford two mixtures of two stereoisomers each: a mixture of Isomers 1 and 2 of Compound 142(a) (retention time: 8.1 min) and a mixture of Isomers 3 and 4 of Compound 142(a) (retention time: 12.6 min). The mixture of Isomers 1 and 2 of Compound 142(a) was further separated using chiral prep-HPLC (column: CHIRALPAK IK, 3*25 cm, 5 pm; mobile phase: 85:7.5:7.5hexanes / DCM / EtOH with 0.17% FA; flow rate: 40 mL / min; run length: 26 min; wavelengths monitored: 220, 254 nM) to afford, in order of elution, Isomer 1 and Isomer 2 of Compound 142(a). The mixture of Isomers 3 and 4 of Compound 142(a) was further separated using chiral prep-HPLC (column: CHIRALPAK IE, 2*25 cm, 5 pm; mobile phase: 75:12.5:12.5 hexanes / DCM / MeOH with 0.17% FA; flow rate: 20 mL / min; run length: 28 min; wavelengths monitored: 220, 254 nM) to afford, in order of elution, Isomer 3 and Isomer 4 of Compound 142(a).Compound 142(a)(c) Compound 142(a)(d) Compound 142(a)(lsomer 1):

[0413] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 142(a)(a), 142(a)(b), 142(a)(c), and 142(a)(d). Peak 1 (separation 1): retention time: 8.1 min; peak 1 (separation 2): retention time: 21.0 min. LCMS (ES, m / z): 544.3 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 11.65 (s, 1 H), 9.91 (s, 1 H), 8.53 (s, 1 H), 7.95 - 7.92 (m, 1 H), 7.70 - 7.65 (m, 1 H), 7.52 - 7.48 (m, 2H), 7.17 - 7.13 (m, 2H), 7.06 - 7.01 (m, 1H), 4.47 - 4.42 (m, 1H), 3.67 - 3.60 (m, 1H), 3.53 - 3.48 (m, 1H), 3.10 - 3.03 (m, 1H), 2.47 -2.40 (m, 1H), 2.30 -2.26 (m, 2H), 2.23 - 2.15 (m, 1H), 2.05 - 1.89 (m, 6H), 1.79 - 1.67 (m, 2H), 1.59 - 1.49 (m, 1H), 1.30 - 1.23 (m, 1 H), 0.97 - 0.92 (m, 2H), 0.73 - 0.69 (m, 2H).Compound 142(a)(lsomer 2):

[0414] The stereochemistry of Isomer 2 was not assigned but corresponds to one of Compounds 142(a)(a), 142(a)(b), 142(a)(c), and 142(a)(d). Peak 1 (separation 1): retention time: 8.1 min; peak 2 (separation 2): retention time: 23.9 min. LCMS (ES, m / z): 544.2 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 12.01 (s, 1H), 9.91 (s, 1H), 8.53 (s, 1H), 7.97 - 7.92 (m, 1H), 7.68 - 7.65 (m, 1H), 7.53 - 7.47 (m, 2H), 7.21 - 7.13 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 4.47 - 4.40 (m, 1H), 3.68 - 3.59 (m, 1 H), 3.55 - 3.46 (m, 1 H), 3.04 - 2.92 (m, 1 H), 2.37 - 2.24 (m, 3H), 2.22 - 2.08 (m, 2H), 2.06 - 1.82 (m, 6H), 1.65 - 1.52 (m, 1H), 1.48 - 1.33 (m, 1H), 1.27 - 1.13 (m, 1H), 0.99 - 0.90 (m, 2H), 0.79- 0.67 (m, 2H).Compound 142(a)(lsomer 3):

[0415] The stereochemistry of Isomer 3 was not assigned but corresponds to one of Compounds 142(a)(a), 142(a)(b), 142(a)(c), and 142(a)(d). Peak 2 (separation 1): retention time: 12.6 min; peak 1 (separation 2): retention time: 19.2 min. LCMS (ES, m / z): 544.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.66 (s, 1 H), 9.92 (s, 1 H), 8.53 (s, 1 H), 7.95 - 7.92 (m, 1 H), 7.70 - 7.66 (m, 1H), 7.51 - 7.48 (m, 2H), 7.17 - 7.13 (m, 2H), 7.05 - 7.02 (m, 1H), 4.46 - 4.42 (m, 1H), 3.66 - 3.60 (m, 1H), 3.55 - 3.49 (m, 1H), 3.10 - 3.04 (m, 1H), 2.45 -2.40 (m, 1H), 2.29 -2.26 (m, 2H), 2.20 - 2.13 (m, 1H), 2.06 - 1.91 (m, 6H), 1.78 - 1.67 (m, 2H), 1.56 - 1.48 (m, 1H), 1.30 - 1.23 (m, 1 H), 0.97 - 0.92 (m, 2H), 0.73 - 0.68 (m, 2H).Compound 142(a)(lsomer 4):

[0416] The stereochemistry of Isomer 4 was not assigned but corresponds to one of Compounds 142(a)(a), 142(a)(b), 142(a)(c), and 142(a)(d). Peak 2 (separation 1): retention time: 12.6 min; peak 2 (separation 2): retention time: 24.4 min. LCMS (ES, m / z): 544.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 12.04 (s, 1 H), 9.91 (s, 1 H), 8.53 (s, 1 H), 7.95 - 7.92 (m, 1 H), 7.70 - 7.65 (m, 1H), 7.53 - 7.48 (m, 2H), 7.19 - 7.14 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 4.47 -4.42 (m, 1H), 3.66 - 3.61 (m, 1H), 3.55 - 3.47 (m, 1H), 3.03 - 2.93 (m, 1H), 2.35 - 2.27 (m, 3H), 2.22 - 2.10 (m, 2H), 2.04 - 1.89 (m, 6H), 1.62 - 1.52 (m, 1H), 1.45 - 1.36 (m, 1H), 1.25 - 1.16 (m, 1H), 0.98 -0.91 (m, 2H), 0.74 - 0.68 (m, 2H).(cvi) 2-(6-((R)-1-((3-chloro-4-cyclopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 143(a)(a) and 143(a)(b)) -Prepared using Scheme 2.

[0417] 2-Chloro-1-cyclopropyl-4-isocyanatobenzene was used as lnt-1, Isomer 1 and Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (see Scheme 23) were used, respectively, as lnt-2, and D-proline was used as lnt-6. The following modification to the procedure was applied:HFIP / TFA was used instead of HCI in the final deprotection step. 2-Chloro-1-cyclopropyl-4-isocyanatobenzene was synthesized in 2 steps: (a) Suzuki-Miyaura cross-coupling of 4-bromo-3-chloroaniline and cyclopropylboronic acid catalyzed by Pd(dppf)Cl2; (b) reaction of the resulting amine with triphosgene.Compound 143(a)(a) Compound 143(a)(b)Compound 143(a)(lsomer 1):

[0418] The stereochemistry of Isomer 1 was not assigned but corresponds to one of Compounds 143(a)(a) and 143(a)(b). Peak 1: retention time: 4.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 459.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.86 (s, 1H), 8.25 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.36 - 7.32 (m, 1H), 6.90 (d, J = 8.8 Hz, 1 H), 4.22 - 4.17 (m, 1H), 4.05 - 3.96 (m, 1 H), 3.59 - 3.51 (m, 1 H), 3.44 - 3.66 (m, 1 H), 2.44 - 2.36 (m, 1 H), 2.36 - 2.25 (m, 3H), 2.20 -2.08 (m, 2H), 2.07 - 1.98 (m, 3H), 1.93 - 1.82 (m, 4H), 1.81 - 1.73 (m, 1H), 1.71 - 1.60 (m, 2H), 0.97 - 0.90 (m, 2H), 0.65 - 0.60 (m, 2H).Compound 143(a)(lsomer 2):

[0419] The stereochemistry of Isomer 2 was not assigned but corresponds to the other of Compounds 143(a)(a) and 143(a)(b). Peak 2: retention time: 6.5 min (step 4 of Scheme 23). LCMS (ES, m / z): 460.2 [M+H]+.1H NMR (400 MHz, MeOH-d4) 68.26 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.41 - 7.28 (m, 1H), 6.90 (d, J = 8.6 Hz, 1H), 4.25 - 4.14 (m, 1H), 4.11 - 3.94 (m, 1H), 3.60 - 3.53 (m, 1H), 3.43-3.40 (m, 1H), 2.46 -2.36 (m, 1H), 2.34 - 2.23 (m, 3H), 2.22 - 2.07 (m, 2H), 2.07 - 1.97 (m, 3H), 1.95 - 1.79 (m, 4H), 1.79 - 1.72 (m, 1H), 1.72 -1.60 (m, 2H), 0.97 - 0.90 (m, 2H), 0.65 - 0.57 (m, 2H).(cvii) 2-(6-((R)-1-((3,5-difluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetic acid (Compounds 144(a)(a) and 144(a)(b))Isomer 2Isomer 1 Compound 144(a)(a) Compound 144(a)(b)Compound 144(a)(a) Compound 144(a)(b)Scheme 27

[0420] Step 1: To a stirred solution of Isomer 2 of tert-butyl 2-(6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptan-2-yl)acetate (see Scheme 23) (45 g, 130 mmol, 1 equiv) in MeOH (500 mL) was added Pd / C (10 wt%, 3.0 g, 2.8 mmol, 0.02 equiv) at room temperature. The resulting mixture was stirred for 3 h under hydrogen atmosphere and filtered. The filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated to afford Isomer 2 of terf-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (21.3 g, 76% yield). LCMS (ES, m / z): 226.2 [M+H]+.

[0421] Step 2: To a stirred solution of (2R)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (1.00 g, 4.01 mmol, 1 equiv) in DCM (12.5 mL) were added Isomer 2 of tert-butyl 2-(6-aminospiro[3.3]heptan-2-yl)acetate (1.00 g, 4.44 mmol, 1.1 equiv) and EDCI (925 mg, 5.96 mmol, 1.5 equiv) at room temperature. The resulting solution was stirred for 1 h, concentrated, and purified by reversed-phase flash chromatography (column: C18; mobile phase: gradient of 40% to 60% MeCN / water over 20 min; detector: UV 254 nm) to afford Isomer 2 of benzyl (2R)-2-((6-(2-(tert-butoxy)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (1.2 g, 66% yield). LCMS (ES, m / z): 457.2 [M+H]+.

[0422] Step 3: To a solution of Isomer 2 of benzyl (2R)-2-((6-(2-(tert-butoxy)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamoyl)pyrrolidine-1 -carboxylate (1.0 g, 2.2 mmol, 1 equiv) in MeOH (20 mL) was added Pd / C (10 wt%, 100 mg, 0.094 mmol, 0.04 equiv) at room temperature. The reaction mixture was stirred for 1 h under hydrogen atmosphere and filtered, rinsing with methanol. The filtrate was concentrated to afford crude Isomer 2 of tert-butyl 2-(6-((R)-pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (680 mg). The crude material was used directly in step 9 without further purification. LCMS (ES, m / z): 323.2 [M+H]+.

[0423] Step 4: To a stirred solution of 4-bromo-3,5-difluoroaniline (2.0 g, 9.6 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.2 g, 19 mmol, 2 equiv) in dioxane (20 mL) and water (4 mL) were added Pd(dppf)CI2*CH2Cl2 (1.6 g, 2.0 mmol, 0.20 equiv) and K2CO3(4.0 g, 29 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere, diluted with water (50 mL), and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed-phase flash chromatography (C18; mobile phase: gradient of 10% to 50% MeCN / water over 10 min; detector, UV 254 nm) to afford 3,5-difluoro-4-(prop-1-en-2-yl)aniline (860 mg, 53% yield). LCMS (ES, m / z): 170.1 [M+H]+.

[0424] Step 5: To a stirred solution of 3,5-difluoro-4-(prop-1-en-2-yl)aniline (800 mg, 4.73 mmol, 1 equiv) in MeOH (10 mL) was added Pd(OH)2 / C (20 wt%, 80 mg, 0.11 mmol, 0.02 equiv) atroom temperature. The resulting mixture was stirred for 1 h under hydrogen atmosphere and filtered, rinsing with methanol. The filtrate was concentrated under reduced pressure to afford crude 3,5-difluoro-4-isopropylaniline (615 mg). The crude material was used directly in the subsequent step without further purification. LCMS (ES, m / z): 172.1 [M+H]+.

[0425] Step 6: A solution of 3,5-difluoro-4-isopropylaniline (200 mg, 1.2 mmol, 1 equiv) and GDI (200 mg, 1.2 mmol, 1 equiv) in DCM (4 mL) was stirred at room temperature for 1 h and concentrated to afford crude / V-(3,5-difluoro-4-isopropylphenyl)-1 / 7-imidazole-1-carboxamide (300 mg). The crude material was used directly in steps 7 and 9 without further purification. LCMS (ES, m / z): 266.2 [M+H]+.

[0426] Step 7: To a stirred solution of / V-(3,5-difluoro-4-isopropylphenyl)-1 / 7-imidazole-1-carboxamide (120 mg, 0.452 mmol, 1 equiv) in DMF (1.5 mL) were added TEA (135 mg, 1.33 mmol, 2.9 equiv) and Isomer 1 of tert-butyl 2-(6-((?)-pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (see Scheme 23) (156 mg, 0.484 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred for 1 h, concentrated, and purified by silica gel column chromatography (eluting with 2:1 PE / EA) to afford Isomer 1 of tert-butyl 2-(6-((F?)-1-((3,5-difluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (186 mg, 79% yield). LCMS (ES, m / z): 520.3 [M+H]+.

[0427] Step 8: A solution of Isomer 1 of tert-butyl 2-(6-((F?)-1-((3,5-difluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)spiro[3.3]heptan-2-yl)acetate (170 mg, 0.327 mmol, 1 equiv) in TFA (0.05 mL) and HFIP (2.5 mL) was stirred at room temperature for 2 h, concentrated, and purified by reversed-phase flash chromatography (C18; mobile phase: gradient of 0% to 100% MeCN / water over 10 min; detector: UV 254 nm) to afford Isomer 1 of ...

Claims

Claims1. A compound of Formula (I):(I)or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:X is -NR2or -O-;R1and R2are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10- membered heteroaryl, optionally substituted with one or more halogens, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10- membered heteroaryl, -OR3, -NR4, -NHC(=O)R5, -S(=O)2-NR6R6’, wherein the linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more halogens, -OR3, - NR4R4’, -NHC(=O)R5, or -S(=O)2-NR6R6’;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, Ce- Cwaryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R4and R4’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R5is selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R6and R6’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogen;is selected from the group consisting of 4- to 14-membered heterocycloalkyl, Ce- C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with one or more of halogens or -CF3;is B1, B2, B3, B4, B5, B6, B7, B8, B9or B10, wherein:whereinis selected from the group consisting of C3-C8cycloalkyl, 5- to 10- membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or-N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched Ci- Cealkyl.

2. The compound of claim 1, wherein:X is -NR2or -O-;R1and R2are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl and 5- to 10- membered heteroaryl, optionally substituted with one or more halogens, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10- membered heteroaryl, -OR3, -NR4, -NHC(=O)R5, -S(=O)2-NR6R6’ wherein the linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more halogens or -OR3; R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, Ce- Cwaryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R4and R4’are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R5is selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;R6and R6’ are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the C6-C14aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;(A)' is selected from the group consisting of 4- to 14-membered heterocycloalkyl, Ce- C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, C6-C14aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with one or more of halogens or -CF3;whereinis selected from the group consisting of C3-C8cycloalkyl, 5- to 10- membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=, with 0, 1, 2 or 3 of Y1'8being -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1- Cealkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl.

3. The compound of claim 1 or 2, whereinis B1, B2, B3, B4, B5, B6, B7, B8, B9or B10, wherein:wherein p is between 0 and 5, andR7is independently selected from the group consisting of halogen, -CHF2, -CF3, -OR3and linear or branched C1-C6alkyl, with R3selected from the group consisting of -H, -CF3and linear or branched C1-C6alkyl.

4. The compound of claim 3, wherein R7is independently selected from the group consisting of -Cl, -F, -CF3, -OCH3, -CH3, -CH2CH3, -CH2CH2CH3and -CH(CH3)2.The compound of any one of claims 1 to 4, whereinR9is independently selected from the group consisting of halogen, -CF3, -OCF3, -SCF3, - OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, andwherein R3is selected from the group consisting of -H, -CF3 and linear or branched Ci- Cealkyl.

6. The compound of claim 5, wherein R9is independently selected from the group consisting of -Cl, -F, -CF3, -OCF3, -SCF3, -OCH3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, optionally substituted with one or more -CF3.

7. The compound of any one of claims 1 to 6, wherein the compound is of Formula la, or a pharmaceutical acceptable salt, solvate, or prodrug thereof:wherein R1,R2, and are as defined in any one of claims 1 to 6.

8. The compound of claim 7, wherein R1and R2are independently selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and C6-C14aryl, optionally substituted with one or more -Cl, -F, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl or C6-C14aryl.

9. The compound of claim 7, wherein R1and R2are independently selected from the group consisting of -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CF2CH3, cyclopropyl, cyclopentyl,Ni Ncyclohexyl, phenyl, pyridinyl,10. The compound of any one of claims 7 to 9, wherein12. The compound of any one of claims 1 to 6, wherein the compound is of Formula lb, or a pharmaceutical acceptable salt, solvate, or prodrug thereof:

13. The compound of claim 12, wherein R1is selected from the group consisting of -H, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl and Ce- C aryl, optionally substituted with one or more -Cl, -F, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl or C6-C14aryl.

14. The compound of claim 13, wherein R1is selected from the group consisting of -H, -CH3, phenyl, and -CH2CF2CH3.15.

16. The compound of any one of claims 12 to 15, wherein7. A compound of Formula (II):or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:is selected from the group consisting of 4- to 14-membered heterocycloalkyl, C6- C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with one or more of halogens or -CF3;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, Ce-C aryl and 5- to 10-membered heteroaryl, wherein the Ce-C aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogen;( C )wherein' is selected from the group consisting of C3-C8cycloalkyl, 5- to 10- membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1- Cealkyl; andis 6- to 14-membered heterocycloalkyl optionally substituted with a fused C₆aryl.

18. The compound of claim 17, whereinR9is independently selected from the group consisting of halogen, -CF3, -OCF3, -SCF3, - OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, andwherein R3is selected from the group consisting of -H, -CF3 and linear or branched Ci- Cealkyl.

19. The compound of claim 17 or 18, whereinis B1, B2, B3, B4, B5, B6, B7, B8, B9or B10, wherein:R7OB3isandwherein p is between 0 and 5, andR7is independently selected from the group consisting of halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3selected from the group consisting of -H, -CF3 and linear or branched C1-C6alkyl.

20. The compound of any one of claims 17 to 19, wherein the compound is of Formula Ila, lib, He, lid, He or Ilf, or a pharmaceutical acceptable salt, solvate, or prodrug thereof:wherein q is between 1 and 2;X1is -CH2- or -O-; andare as defined in any one of claims 17 to 19.

21. The compound of claim 20, wherein the compound of formula Ila ispharmaceutical acceptable salt, solvate, or prodrug thereof.

22. The compound of claim 20 or 21, wherein24. A compound of Formula (III):or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:is selected from the group consisting of 4- to 14-membered heterocycloalkyl, Ce- C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more linear or branched C1-C6alkyl, halogen, -CF3, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CH2CF3, -OR3, or -SR3, wherein the linear or branched C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with one or more of halogens or -CF3;R3is selected from the group consisting of -H, -CF3, linear or branched C1-C6alkyl, Ce-C aryl and 5- to 10-membered heteroaryl, wherein the Ce-C aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens;is E1, E2E3, E4, E5or E6, wherein:is selected from the group consisting of C3-C8cycloalkyl, 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl;is C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=; andR7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1-Cealkyl; andR3is as defined above.R9is independently selected from the group consisting of halogen, -CHCF2, -CF3, -OCF3, -SCF3, -OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14- membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, andwherein R3is selected from the group consisting of -H, -CF3 and linear or branched Ci- Cealkyl.

7. The compound of any one of claims 24 to 26, whereinis E1, E2, E3, E4, E5or E6, wherein:wherein p is between 0 and 2;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or -N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched C1- Cealkyl; andR3is selected from the group consisting of -H, -CF3, a linear or branched C1-C6alkyl.28.or29. A compound of Formula (IV):or a pharmaceutical acceptable salt, solvate, or prodrug thereof,wherein:is a 5-membered heteroaryl optionally substituted with one or more of halogen, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce- Cwaryl, 5- to 10-membered heteroaryl, -CH2CF3, -CF3 or -OR3;R3 is selected from the group consisting of a linear, branched C1-C6alkyl, C6-C14aryl and 5- to 10-membered heteroaryl, wherein the Ce-C aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more halogens; andis B1, B2, B3, B4, B5, B6, B7, B8, B9or B10, wherein:whereinis selected from the group consisting of C3-C8cycloalkyl, 5- to IQ-membered heteroaryl and 4- to 14-membered heterocycloalkyl;n is between 0 and 5;p is between 0 and 5;Y1, Y2, Y3, Y4, Y5, Y6, Y7and Y8are independently -CR7= or-N=;R7is independently selected from -H, halogen, -CF3, -OR3and linear or branched Ci- Cealkyl, with R3as defined above; andR8and R8’ are independently selected from -H, halogen and linear or branched C1-C6alkyl.The compound of claim 29,wherein R9is independently selected from the group consisting of halogen, -CF3, -OCF3, -SCF3, -OR3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, Ce-C aryl and 5- to 10-membered heteroaryl, optionally substituted with one or more halogens, -CF3, linear or branched C1-C6alkyl, C3-C8cycloalkyl, 4- to 14- membered heterocycloalkyl, Ce-C aryl, 5- to 10-membered heteroaryl, andwhere in R3is selected from the group consisting of -H, -CF3 and linear or branched Ci- Cealkyl.( A )The compound of claim 30, wherein' isBThe compound of any one of claims 29 to 31, whereinis B1, B2, B3, B4, B5, B6, B7, B8, B9or B10, wherein:wherein p is between 0 and 5, andR7is independently selected from the group consisting of halogen, -CF3, -OR3and linear or branched C1-C6alkyl, with R3selected from the group consisting of -H, -CF3 and linear or branched C1-C6alkyl.OH 33. The compound of claim 32, wherein34. The compound of claim 32 or 33, wherein35. A compound, which is one of Compounds 1 to 157 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

36. The compound of claim 35, which is Compound 1, 2, 4, 5, 7 to 19, 32, 33, 35, 38, 39, 41, 42, 44, 46 to 50, 52 to 59, 62, 63, 66, 67, 69, 72, 75 to 78, 80, 83 to 94, 96 to 105, and 108 to 157 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

37. The compound of claim 35, which is one of Compounds 1, 2, 4, 5, 7 to 12, 17 to 19, 32, 35, 38, 39, 41, 42, 46 to 50, 52 to 59, 62, 63, 67, 72, 75, 77, 78, 80, 84 to 94, 96 to 105, 108 to 146, 150, 153, 154, and 157 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

38. The compound of claim 35, which is one of Compounds 1, 4, 8, 38, 39, 41, 42, 46, 48, 50, 52, 53, 54, 56, 65, 72, 75, 77, 78, 80, 84, 91, 92, 93, 96, 98, 100, 103, 104, 109, 111, 114, 115, 116, 117, 119, 121, 122, 123, 125, 126, 127, 131, 136, 142, and 144 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is in the form of a racemate or any enantiomer thereof.

40. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier, diluent or excipient.

41. Use of a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the preparation of a pharmaceuticalcomposition for the treatment or prevention of a condition, a disease or a disorder for which modulating the glucose-dependent insulinotropic polypeptide receptor (GIPR) is indicated.

42. Use of a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a condition, a disease or a disorder selected from metabolic diseases and obesity.

43. Use of a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a condition, a disease or a disorder selected from diabetes (e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes), idiopathic T1D (Type 1b), 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, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

44. Use of a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of a condition, a disease or a disorder for which modulating the glucose-dependent insulinotropic polypeptide receptor (GIPR) is indicated.

45. Use of a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of a condition, a disease or a disorder selected from metabolic diseases and obesity.

46. Use of a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament for the treatment or prevention of a condition, a disease or a disorder selected from diabetes (e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes), idiopathic T1D (Type 1b), 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, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

47. A method for treating or preventing a disorder for which modulation of the glucosedependent insulinotropic polypeptide receptor (GIPR) is indicated comprising administering to a patient in need thereof a compound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

48. A method for treating or preventing a condition, a disease or a disorder selected from metabolic diseases and obesity comprising administering to a patient in need thereof acompound as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

49. A method for treating or preventing a condition, a disease or a disorder comprising administering to a patient in need thereof a compound as defined in any one of claims 1 to 39, or a pharmaceutical acceptable salt, solvate, or prodrug thereof, wherein the condition, disease or disorder is selected from diabetes (e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes), idiopathic T1D (Type 1b), 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, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

50. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment or prevention of a condition, a disease, or a disorder for which modulation of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is indicated.

51. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment or prevention of a condition, a disease or a disorder selected from metabolic diseases and obesity.

52. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment or prevention of a condition, a disease or a disorder selected from diabetes (e.g. Type 1 diabetes mellitus (T 1 D), Type 2 diabetes mellitus (T2DM), including pre-diabetes), idiopathic T1D (Type 1b), 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 [includinghyperlipidemia, 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, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

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