Compounds for treating fibrotic diseases

Abstract

This disclosure provides compounds and pharmaceutically acceptable salts thereof, that inhibit lysophosphatidic acid receptor 1 (LPA1). These compounds are useful, e.g., for treating a disease associated with LPA1 activity. This disclosure also provides compositions containing the same as well as methods of using and making the same.

Description

[0001] Compounds for Treating Fibrotic Diseases

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Application No. 63 / 470,603, filed on June 2, 2024, the contents of which are hereby incorporated by reference.

[0004] TECHNICAL FIELD

[0005] This disclosure relates to the fields of chemistry and biology. More particularly, this disclosure provides compounds and pharmaceutically acceptable salts thereof, that inhibit lysophosphatidic acid receptor 1 (LPA1). These compounds are useful, e.g., for treating a disease associated with LPA1 activity. This disclosure also provides compositions containing the same as well as methods of using and making the same.

[0006] BACKGROUND

[0007] Lysophospholipids (LPAs) are bioactive lipids that regulate various cellular signaling pathways by binding to the 7-transmembrane domain G protein-coupled (GPCR) receptors. The LPAs have long been known as precursors of phospholipid biosynthesis in both eukaryotic and prokaryotic cells, but the LPAs have emerged only recently as signaling molecules that are rapidly produced and released by activated cells, notably platelets, to influence target cells by acting on specific cell-surface receptors. There are currently six identified LPA receptors designated as LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6. These receptors signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi / o, G12 / 13, Gq, and Gs. LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. SUMMARY

[0008] Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the compound of Formula (I) is: or pharmaceutically acceptable salts thereof, wherein:

[0009] RAis hydrogen, C1-C6 alkyl, or C1-C6 alkoxy;

[0010] Ring B is 3-7 membered heterocyclylene or 5-6 membered heteroarylene;

[0011] Ring C is phenylene or 5-6 membered heteroarylene; m is 0 or 1; n is 0, 1, 2, or 3; each R1is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl; or two R1together with the atoms to which they are attached forms a 5-8 membered heterocyclyl or 5-6 membered heteroaryl; each R2is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen;

[0012] R3is selected from:

[0013] (i) hydrogen,

[0014] (ii) C1-C6 alkyl optionally substituted with 1-2 independently selected RE,

[0015] (iii) C6-C10 aryl optionally substituted with hydroxyl,

[0016] (iv) C5-C10 cycloalkyl,

[0017] (v) 5-6 membered heteroaryl optionally substituted with phenyl, and

[0018] (vi) 5-6 membered heterocyclyl optionally substituted with phenyl; each REis independently selected from: (i) hydroxyl;

[0019] (ii) C1-C6 alkoxy,

[0020] (iii) phenyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, and halogen,

[0021] (iv) 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, and

[0022] (v) C3-C10 cycloalkyl;

[0023] Q is selected from:

[0024] (i) C1-C6 hydroxyalkyl,

[0025] (ii) -C(=O)OH,

[0026] (iii) -S(=O)2OH,

[0027] (iv) cyano,

[0028] (v) -S(O)2NRA1RB1,

[0029] (vi) -NRCS(O)2NRA1RB1,

[0030] (vii) -C(=O)C1-C6 alkoxy optionally substituted with C1-C6 alkoxy optionally substituted with -S(=O)2NRCRD; or 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl;

[0031] (viii) -C(=O)C6-C10 aryloxy;

[0032] (ix) -C(=O)-(5-6 membered heterocyclyloxy) optionally substituted with 1-4 substituents selected from C1-C6 alkyl, hydroxyl, and -C(=O)OH,

[0033] (x) -C(=O)NRA2RB2,

[0034] (xi) C1-C6 haloalkyl optionally substituted with hydroxyl,

[0035] (xii) 5-6 membered heteroaryl optionally substituted with hydroxyl, and

[0036] (xiii) -C(=O)NHS(=O)2RF;

[0037] X is selected from -(CH2)XNRGC(=O)O-, -(CH2)XOC(=O)NRG-, -(CH2)XNRG-, or -CH(OH)-;RA1and RB1are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl;

[0038] RA2and RB2are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl or -S(=O)2NH2;

[0039] Rcand RDare independently selected from hydrogen and C1-C6 alkyl;

[0040] RFis selected from:

[0041] (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from:

[0042] (a) hydroxyl, (b) halogen,

[0043] (c) cyano,

[0044] (d) C1-C6 alkoxy,

[0045] (e) 4-6-membered heterocyclyl optionally substituted with C1-C6 alkyl,

[0046] (f) -C(=O)OH,

[0047] (g) -OC(=O)C1-C6 alkyl,

[0048] (h) -S(=O)2Cl-C6 alkyl,

[0049] (i) -C(=O)NRA1RB1,

[0050] (j) -NRCRD,

[0051] (k) -C(=O)C1-C6 aryloxy,

[0052] (l) C3-C6 cycloalkyl optionally substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy, and

[0053] (m) -C(=O)C1-C6 alkoxy optionally substituted with -C(=O)C1-C6 alkyl or -OC(=O)C1-C6 alkyl,

[0054] (ii) C2-C6 alkenyl,

[0055] (iii) C1-C6 haloalkyl,

[0056] (iv) phenyl,

[0057] (v) C3-C6 cycloalkyl optionally substituted with

[0058] (a) C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxyl, -C(=O)OH, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy,

[0059] (b) cyano,

[0060] (c) -C(=O)OH,

[0061] (d) -C(=O)NRCRD, ore

[0062] (e) -C(=O)C1-C6 alkoxy optionally substituted with hydroxyl or -C(=O)C1-C6 alkyl, or

[0063] (f) -NRCRD, and

[0064] (vi) -NRA3RB3;

[0065] RA3and RB3are independently selected from hydrogen and C1-C6 alkyl;

[0066] RGis H or C1-C3 alkyl; and x is 0 or 1. Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, or a pharmaceutical composition as described herein.

[0067] Some embodiments provide a method of treating a fibrotic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0068] Some embodiments provide a method for reducing LPA1 activation in a cell comprising LPA1, the method comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0069] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and the claims.

[0070] Additional Definitions

[0071] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In case of conflict, the present specification, including definitions, will control.

[0072] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0073] The term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent,, solvent, or encapsulating material. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed , Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed. Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0074] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salts not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0075] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0076] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

[0077] As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0078] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease or disorder described herein (e.g., a fibrotic disease), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0079] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0080] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0081] The term "hydroxyl" refers to an -OH radical.

[0082] The term "cyano" refers to a -CN radical.

[0083] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, Zc / 7-butyl, w-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term “alkenyl” refers to an alkyl group having at least one double-bond between constituent carbon atoms. Non-limiting examples include ethenyl, zz-propenyl, zso-propenyl, n- butenyl, ec-butenyl.

[0084] The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0085] The term "hydroxy alkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl.

[0086] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0087] The term “alkoxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected alkoxy.

[0088] The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0089] The term "aryloxy" refers to an -O-aryl radical (e g., phenoxy).

[0090] The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[EEO]butane, bicyclo[2. E0]pentane, bicyclo[E El]pentane, bicyclo[3.E0]hexane, bicyclo[2.E l]hexane, bicyclo[3.2.0]heptane, bicyclo[4.E0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-t / ]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[ ][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[ / >][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more N_| imidazolone (e g., ’ ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). The term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[ 1.1.1 Jpentane, 3 -azabicyclo[3. 1 .0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7 azabi cy cl o [2.2.1 ] heptane, 6-azabicyclo[3.1.1 Jheptane, 7-azabicyclo[4.2.0]octane, 2 azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2 oxabicyclo[2.1.0]pentane, 2-oxabicyclo[ 1.1.1 Jpentane, 3-oxabicyclo[3.1.0]hexane, 5 oxabicyclo[2. 1. l]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2. l]heptane, 6-oxabicyclo[3.1.1 Jheptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4- azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2- oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5- dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyndazine, pyndone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

[0091] The term "heterocyclyloxy" refers to an -O-heterocylyl radical.

[0092] The term “saturated” as used in this context means only single bonds present between constituent atoms.

[0093] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0094] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms

[0095] (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., single ring atom (spiro-fused ring systems) ( r (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,

[0096] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0097] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0098] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

[0099] DETAILED DESCRIPTION

[0100] LPA signaling promotes normal wound healing and collagen deposition, including fibroblast activation, proliferation, and migration. However, increased LPA levels and activation of LPA1 can promote fibrosis, the result of an uncontrolled tissue healing process which leads to excessive accumulation and insufficient resorption of extracellular matrix (ECM) which ultimately results in end-organ failure.

[0101] This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that are antagonists of LPA1. These chemical entities are useful, e.g., for treating a disease in which increased (e.g., excessive) LPA1 activation contributes to the pathology and / or symptoms and / or progression of the disease (e.g., a fibrotic disease in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.

[0102] Formulae (I) Compounds

[0103] Some embodiments provide a compound of Formula (I): or pharmaceutically acceptable salts thereof, wherein:

[0104] RAis hydrogen, C1-C6 alkyl, or C1-C6 alkoxy;

[0105] Ring B is 3-7 membered heterocyclylene or 5-6 membered heteroarylene;

[0106] Ring C is phenylene or 5-6 membered heteroarylene; m is 0 or 1; n is 0, 1, 2, or 3; each R1is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl; or two R1together with the atoms to which they are attached forms a 5-8 membered heterocyclyl or 5-6 membered heteroaryl; each R2is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen;

[0107] R3is selected from:

[0108] (i) hydrogen,

[0109] (ii) C1-C6 alkyl optionally substituted with 1-2 independently selected RE,

[0110] (iii) C6-C10 aryl optionally substituted with hydroxyl,

[0111] (iv) C5-C10 cycloalkyl,

[0112] (v) 5-6 membered heteroaryl optionally substituted with phenyl, and (vi) 5-6 membered heterocyclyl optionally substituted with phenyl; each REis independently selected from:

[0113] (i) hydroxyl;

[0114] (ii) C1-C6 alkoxy,

[0115] (iii) phenyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, and halogen,

[0116] (iv) 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, and

[0117] (v) C3-C10 cycloalkyl;

[0118] Q is selected from:

[0119] (i) C1-C6 hydroxyalkyl,

[0120] (ii) -C(=O)OH,

[0121] (iii) -S(=O)2OH,

[0122] (iv) cyano,

[0123] (v) -S(O)2NRA1RB1,

[0124] (vi) -NRCS(O)2NRA1RB1,

[0125] (vii) -C(=O)C1-C6 alkoxy optionally substituted with C1-C6 alkoxy optionally substituted with -S(=O)2NRCRD; or 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl;

[0126] (viii) -C(=O)C6-C10 aryloxy;

[0127] (ix) -C(=O)-(5-6 membered heterocyclyloxy) optionally substituted with 1-4 substituents selected from C1-C6 alkyl, hydroxyl, and -C(=O)OH,

[0128] (x) -C( O)NRA2RB2,

[0129] (xi) C1-C6 haloalkyl optionally substituted with hydroxyl,

[0130] (xii) 5-6 membered heteroaryl optionally substituted with hydroxyl, and

[0131] (xiii) -C(=O)NHS(=O)2RF;

[0132] X is selected from -(CH2)XNRGC(=O)O-, -(CH2)XOC(=O)NRG-, -(CH2)XNRG-, or -CH(OH)-;RA1and RB1are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl;

[0133] RA2and RB2are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl or -S(=O)2NH2;

[0134] Rcand RDare independently selected from hydrogen and C1-C6 alkyl;

[0135] RFis selected from: (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from:

[0136] (a) hydroxyl,

[0137] (b) halogen,

[0138] (c) cyano,

[0139] (d) C1-C6 alkoxy,

[0140] (e) 4-6-membered heterocyclyl optionally substituted with C1-C6 alkyl,

[0141] (f) -C(=O)OH,

[0142] (g) -OC(=O)C1-C6 alkyl,

[0143] (h) -S(=O)2Cl-C6 alkyl,

[0144] (i) -C(=O)NRA1RB1,

[0145] (j) -NRCRD,

[0146] (k) -C(=O)C1-C6 aryloxy,

[0147] (l) C3-C6 cycloalkyl optionally substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy, and

[0148] (m) -C(=O)C1-C6 alkoxy optionally substituted with -C(=O)C1-C6 alkyl or -OC(=O)C1-C6 alkyl,

[0149] (ii) C2-C6 alkenyl,

[0150] (iii) C1-C6 haloalkyl,

[0151] (iv) phenyl,

[0152] (v) C3-C6 cycloalkyl optionally substituted with

[0153] (a) C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxyl, -C(=O)OH, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy,

[0154] (b) cyano,

[0155] (c) -C(=O)OH,

[0156] (d) -C(=O)NRCRD, ore

[0157] (e) -C(=O)C1-C6 alkoxy optionally substituted with hydroxyl or -C(=O)C1-C6 alkyl, or

[0158] (f) -NRCRD, and

[0159] (vi) -NRA3RB3;

[0160] RA3and RB3are independently selected from hydrogen and C1-C6 alkyl;

[0161] RGis H or C1-C3 alkyl; and x is 0 or 1 .

[0162] In some embodiments, Formula (I) is Formula (I-I): or pharmaceutically acceptable salts thereof, wherein:

[0163] RAis hydrogen, C1-C6 alkyl, or C1-C6 alkoxy;

[0164] Ring B is 3-7 membered heterocyclylene or 5-6 membered heteroarylene;

[0165] Ring C is phenylene or 5-6 membered heteroarylene; m is 0 or 1; n is 0, 1, 2, or 3; each R1is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl; or two R1together with the atoms to which they are attached forms a 5-8 membered heterocyclyl or 5-6 membered heteroaryl; each R2is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen;

[0166] R3is selected from

[0167] (i) hydrogen,

[0168] (ii) C1-C6 alkyl optionally substituted with 1-2 independently selected RE,

[0169] (iii) C6-C10 aryl optionally substituted with hydroxyl,

[0170] (iv) C5-C10 cycloalkyl,

[0171] (v) 5-6 membered heteroaryl optionally substituted with phenyl, and

[0172] (vi) 5-6 membered heterocyclyl optionally substituted with phenyl; each REis independently selected from

[0173] (i) hydroxyl;

[0174] (ii) C1-C6 alkoxy, (iii) phenyl optionally substituted with 1-3 substituents selected from C1 -C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, and halogen,

[0175] (iv) 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, and

[0176] (v) C3-C10 cycloalkyl;

[0177] Q is selected from:

[0178] (i) C1-C6 hydroxyalkyl,

[0179] (ii) -C(=O)OH,

[0180] (iii) -S(=O)2OH,

[0181] (iv) cyano,

[0182] (v) -S(O)2NRA1RB1,

[0183] (vi) -NRCS(O)2NRA1RB1,

[0184] (vii) -C(=O)C1-C6 alkoxy optionally substituted with C1-C6 alkoxy optionally substituted with -S(=O)2NRCRD; or 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl,

[0185] (viii) -C(=O)C6-C10 aryloxy;

[0186] (ix) -C(=O)-(5-6 membered heterocyclyloxy) optionally substituted with 1-4 substituents selected from hydroxyl and -C(=O)OH,

[0187] (x) -C(=O)NRA2RB2,

[0188] (xi) C1-C6 haloalkyl optionally substituted with hydroxyl,

[0189] (xii) 5-6 membered heteroaryl optionally substituted with hydroxyl, and

[0190] (xiii) -C(=O)NHS(=O)2RF;

[0191] RA1and RB1are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl;

[0192] RA2and RB2are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl or -S(=O)2NH2;

[0193] Rcand RDare independently selected from hydrogen and C1-C6 alkyl; and

[0194] RFis selected from:

[0195] (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from

[0196] (ii) hydroxyl,

[0197] (iii) halogen,

[0198] (iv) cyano,

[0199] (v) C1-C6 alkoxy, (vi) 4-6-membered heterocyclyl optionally substituted with C1-C6 alkyl,

[0200] (vii) -C(=O)OH,

[0201] (viii) -OC(=O)C1-C6 alkyl,

[0202] (ix) -S(=O)2C1-C6 alkyl,

[0203] (x) -C(=O)NRA1RB1,

[0204] (xi) -NRCRD,

[0205] (xii) -C(=O)C1-C6 aryloxy,

[0206] (xiii) C3-C6 cycloalkyl optionally substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy,

[0207] (xiv) -C(=O)C1-C6 alkoxy optionally substituted with -O(=O)C1-C6 alkyl,

[0208] (xv) C2-C6 alkenyl,

[0209] (xvi) C1-C6 haloalkyl,

[0210] (xvii) phenyl,

[0211] (xviii) C3-C6 cycloalkyl optionally substituted with

[0212] (a) C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxyl,

[0213] -C(=O)OH, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy,

[0214] (b) cyano,

[0215] (c) -C(=O)OH,

[0216] (d) -C(=O)NRCRD, or

[0217] (e)-C(=O)Cl-C6 alkoxy optionally substituted with hydroxyl or -O(=O)C1-C6 alkyl, or

[0218] (f) -NRCRD

[0219] In some embodiments, RAis hydrogen.

[0220] In some embodiments, RAis C1-C6 alkyl. In some embodiments, RAis methyl.

[0221] In some embodiments, RAis C1-C6 alkoxy. In some embodiments, RAis methoxy.

[0222] In some embodiments, Q is -C(=O)OH. In some embodiments, Q is -S(=O)2OH. In some embodiments, Q is cyano. In some embodiments, Q is C1-C6 hydroxyalkyl. In some embodiments, Q is C1-C3 hydroxyalkyl. In some embodiments, Q is -C(=O)C6-C10 aryloxy. In some embodiments, Q is -S(0)2NRA1RB1. In some embodiments, Q is -NRcS(0)2NRA1RB1. In some embodiments, Q is -C(=O)C1-C6 alkoxy optionally substituted with C1-C6 alkoxy optionally substituted with -S(=O)2NRCRD. In some embodiments, Q is -C(=O)C1-C3 alkoxy optionally substituted with C1 -C6 alkoxy. In some embodiments, Q is -C(=O)C1-C3 alkoxy. In some embodiments, Q is -C(=O)OEt. In some embodiments, Q is C(=O)C1-C6 alkoxy substituted with C1-C6 alkoxy optionally substituted with -S(=O)2NRCRD. In some embodiments, Q is C(=O)C1-C6 alkoxy substituted with C1-C6 alkoxy substituted with -S(=O)2NRCRD. In some embodiments, Q is C(=O)C1-C3 alkoxy substituted with C1-C3 alkoxy substituted with - S(=O)2NRCRD. In some embodiments, Q is C(=O)C1-C6 alkoxy optionally substituted with 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, Q is C(=O)C1-C3 alkoxy substituted with 5-6 membered heterocyclyl optionally substituted with Cl- C6 alkyl. In some embodiments, Q is C(=O)C1-C3 alkoxy substituted with 6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, Q is C(=O)C1-C3 alkoxy substituted with 5 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0223] In some embodiments, Q is -C(=O)-(5-6 membered heterocyclyl oxy) optionally substituted with 1-4 substituents selected from C1-C6 alkyl, hydroxyl, and -C(=O)OH. In some embodiments, Q is -C(=O)-(5 membered heterocyclyloxy) optionally substituted with 1-4 substituents selected from C1-C6 alkyl, hydroxyl, and -C(=O)OH. In some embodiments, Q is - C(=O)-(6 membered heterocyclyloxy) optionally substituted with 1-4 substituents selected from

[0224] C1-C6 alkyl, hydroxyl, and -C(=O)OH. In some embodiments, some embodiments, Q is -C(=O)NRA2RB2. In some embodiments, each of RA2and RB2is hydrogen. In some embodiments, one of RA2and RB2is hydrogen and the other one of RA2and RB2is C1-C6 alkyl optionally substituted with hydroxyl or -S(=O)2NH2. In some embodiments, one of RA2and RB2is hydrogen and the other one of RA2and RB2is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA2and RB2is hydrogen and the other one of RA2and RB2is - CH2CH2OH. In some embodiments, one of RA2and RB2is hydrogen and the other one of RA2and RB2is C1-C6 alkyl substituted with -S(=O)2NH2. In some embodiments, one of RA2and RB2is y\^s°2NH2 hydrogen and the other one of RA2and RB2is . In some embodiments, one of RA2and RB2is hydrogen and the other one of RA2and RB2is unsubstituted C1-C6 alkyl. In some embodiments, each of RA2and RB2is independently selected C1-C6 alkyl optionally substituted with hydroxyl or -S(=O)2NH2. In some embodiments, each of R42and RB2is independently selected unsubstituted C1 -C6 alkyl. In some embodiments, Q is C1 -C6 haloalkyl optionally substituted with hydroxyl.

[0225] In some embodiments, Q is C1-C6 haloalkyl substituted with hydroxyl.

[0226] In some embodiments, Q is unsubstituted C1-C6 haloalkyl.

[0227] In some embodiments, Q is 5-6 membered heteroaryl optionally substituted with hydroxyl.

[0228] In some embodiments, Q is 6 membered heteroaryl optionally substituted with hydroxyl.

[0229] In some embodiments, Q is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0230] In some embodiments, Q is 5 membered heteroaryl optionally substituted with hydroxyl.

[0231] In some embodiments, Q is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.

[0232] In some embodiments,

[0233] In some embodiments,

[0234] In some embodiments, Q is unsubstituted 5-6 membered heteroaryl.

[0235] In some embodiments, Q is -C(=0)NHS(=0)2RF.

[0236] In some embodiments, RFis C2-C6 alkenyl.

[0237] In some embodiments,

[0238] In some embodiments,

[0239] In some embodiments, RFis C1-C6 haloalkyl.

[0240] In some embodiments, RFis -CF3 or CHF2.

[0241] In some embodiments, RFis phenyl.

[0242] In some embodiments, RFis -NRCRD.

[0243] In some embodiments, RFis C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxyl; halogen; cyano; C1-C6 alkoxy; 4-6-membered heterocyclyl optionally substituted with C1-C6 alkyl; -C(=O)OH; -OC(=O)C1-C6 alkyl; -S(=O)2C1-C6 alkyl; - C(=O)NRA1RB1; -NRCRD; -C(=O)C1-C6 aryloxy; C3-C6 cycloalkyl optionally substituted with -C(=O)OH, cyano, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy; or - C(=O)C1-C6 alkoxy optionally substituted with -C(=O)C1-C6 alkyl or -OC(=O)C1-C6 alkyl.

[0244] In some embodiments, RFis C1-C6 alkyl substituted with 1-2 hydroxyl.

[0245] In some embodiments, RFis selected from the group consisting of

[0246] In some embodiments, RFis C1-C6 alkyl substituted with cyano.

[0247] In some embodiments,

[0248] In some embodiments, RFis C1-C6 alkyl substituted with C1-C6 alkoxy.

[0249] In some embodiments, RFis selected from the group consisting of

[0250] In some embodiments, RFis C1-C6 alkyl substituted with 4-6-membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0251] In some embodiments,

[0252] In some embodiments, RFis C1-C6 alkyl substituted with -C(=O)OH.

[0253] In some embodiments, RFis selected from the group consisting of ,

[0254] In some embodiments, RFis C1-C6 alkyl substituted with -OC(=O)C1-C6 alkyl. In some embodiments,

[0255] In some embodiments, RFis C1-C6 alkyl substituted with -S(=O)2C1-C6 alkyl.

[0256] In some embodiments,

[0257] In some embodiments, RFis C1-C6 alkyl substituted with -C(=O)NRA1RB1. o

[0258] In some embodiments, RFis selected from the group consisting of ■^NR^R81

[0259] In some embodiments, RFis C1-C6 alkyl substituted with 1-3 substituents selected from halogen, -C(=O)NRA1RB1, and -C(=O)OH.

[0260] In some embodiments, RFis selected from the group consisting

[0261] In some embodiments, RFis C1-C6 alkyl substituted with NRCRD.

[0262] In some embodiments, RFis C1-C6 alkyl substituted with -C(=O)C1-C6 aryloxy.

[0263] In some embodiments, RFis C1-C6 alkyl substituted with C3-C6 cycloalkyl optionally substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy.

[0264] In some embodiments, RFis C1-C6 alkyl substituted with C3-C4 cycloalkyl substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy. In some embodiments, RFis selected from the group consisting of

[0265] In some embodiments, RFis C1-C6 alkyl substituted with -C(=O)C1-C6 alkoxy optionally substituted with -C(=O)C1-C6 alkyl.

[0266] In some embodiments, RFis C1-C6 alkyl substituted with C(=O)C1-C4 alkoxy substituted with -C(=O)C1-C6 alkyl.

[0267] In some embodiments, RFis C1-C6 alkyl substituted with C(=O)C1-C6 alkoxy.

[0268] In some embodiments, RFis selected from the group consisting of ,

[0269] In some embodiments, RFis C1-C6 alkyl optionally substituted with C(=O)OH. In some embodiments, RFis C1 -C6 alkyl substituted with -C(=O)OH. .

[0270] In some embodiments, RFis unsubstituted C1-C6 alkyl.

[0271] In some embodiments, RFis selected from the group consisting of methyl, ethyl, n- propyl, isopropyl.

[0272] In some embodiments, RFis C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxyl, -C(=O)OH, - C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy; cyano; -C(=O)OH; -C(=O)NRcRD; or -C(=O)Cl- C6 alkoxy optionally substituted with hydroxyl or -C(=O)C1-C6 alkyl.

[0273] In some embodiments, RFis C3-C6 cycloalkyl substituted with Cl -C6 alkyl substituted with 1-2 hydroxyl.

[0274] In some embodiments, RFis C3-C4 cycloalkyl substituted with Cl -C6 alkyl substituted with 1 -2 hydroxyl . In some embodiments, RFis cyclopropyl substituted with C1-C6 alkyl substituted with 1-2 hydroxyl.

[0275] In some embodiments, R is selected from the group consisting of

[0276] In some embodiments, RFis C3-C6 cycloalkyl substituted with C 1-C6 alkyl substituted with -C(=O)OH.

[0277] In some embodiments, RFis C3-C4 cycloalkyl substituted with Cl -C6 alkyl substituted with -C( O)OH.

[0278] In some embodiments, RFis cyclopropyl substituted with C1-C6 alkyl substituted with

[0279] -C(=O)OH.

[0280] In some embodiments,

[0281] In some embodiments, RFis C3-C6 cycloalkyl substituted with C 1-C6 alkyl substituted with -C(=O)NRA1RB1.

[0282] In some embodiments, RFis C3-C4 cycloalkyl substituted with Cl -C6 alkyl substituted with -C(=O)NRA1RB1.

[0283] In some embodiments, RFis cyclopropyl substituted with C1-C6 alkyl substituted with -C(=O)NRA1RB1.

[0284] In some embodiments,

[0285] In some embodiments, RFis C3-C6 cycloalkyl substituted with C 1-C6 alkyl substituted with -C(=O)C1-C6 alkoxy.

[0286] In some embodiments, RFis C3-C4 cycloalkyl substituted with Cl -C6 alkyl substituted with -C(=O)C1-C6 alkoxy.

[0287] In some embodiments, RFis cyclopropyl substituted with C1-C6 alkyl substituted with -C(=O)C1-C6 alkoxy. Y\ n some embodiments, RFis selected from the group consisting ofC02

[0288] IMeand

[0289] In some embodiments, RFis C3-C6 cycloalkyl substituted with cyano.

[0290] In some embodiments, RFis C3-C4 cycloalkyl substituted with cyano.

[0291] X

[0292] In some embodiments, RFisCN.

[0293] In some embodiments, RFis C3-C6 cycloalkyl substituted with -C(=O)OH.

[0294] In some embodiments, RFis C3-C4 cycloalkyl substituted with -C(=O)OH.

[0295] In some embodiments,

[0296] In some embodiments, RFis C3-C6 cycloalkyl substituted with -C(=O)NRcRD.

[0297] In some embodiments, RFis C3-C4 cycloalkyl substituted with -C(=O)NRcRD.

[0298] In some embodiments,

[0299] In some embodiments, RFis C3-C6 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with hydroxyl.

[0300] In some embodiments, RFis C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with hydroxyl.

[0301] In some embodiments,

[0302] In some embodiments, RFis C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy.

[0303] In some embodiments, RFis selected from the group consisting anj

[0304] In some embodiments, RFis C3-C6 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -C(=O)C1-C6 alkyl.

[0305] In some embodiments, RFis C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -C(=O)C1-C6 alkyl. In some embodiments, RFis C3-C6 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -OC(=O)C1-C6 alkyl.

[0306] In some embodiments, RFis C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -OC(=O)C1-C6 alkyl.

[0307] In some embodiments,

[0308] In some embodiments, RFis unsubstituted C3-C6 cycloalkyl.

[0309] In some embodiments, Q is selected from C(=O)OH; -S(=O)2OH; 5-6 membered heteroaryl optionally substituted with hydroxyl; and-C(=O)NHS(=O)2RF. In some embodiments, Q is C(=O)OH or -C(=O)NHS(=O)2RF.

[0310] In some embodiments, each of RA1and RB1is hydrogen.

[0311] In some embodiments, one of RA1and RB1is hydrogen and the other one of RA1and RB1is C1-C6 alkyl optionally substituted with hydroxyl.

[0312] In some embodiments, one of RA1and RB1is hydrogen and the other one of RA1and RB1is C1-C3 alkyl.

[0313] In some embodiments, one of RA1and RB1is hydrogen and the other one of RA1and RB1is methyl.

[0314] In some embodiments, each of RA1and RB1is independently selected C1-C6 alkyl optionally substituted with hydroxyl.

[0315] In some embodiments, each of RA1and RB1is independently selected unsubstituted C 1- C6 alkyl.

[0316] In some embodiments, RFis -NRA3RB3.

[0317] In some embodiments, each of RA3and RB3is hydrogen.

[0318] In some embodiments, one of RA3and RB3is hydrogen and the other one of RA3and

[0319] RB3is C1-C6 alkyl.

[0320] In some embodiments, one of RA3and RB3is hydrogen and the other one of RA3and RB3is C1-C3 alkyl.

[0321] In some embodiments, one of RA3and RB3is hydrogen and the other one of RA3and RB3is methyl.

[0322] In some embodiments, each of RA3and RB3is independently selected C1-C6 alkyl. In some embodiments, each of RA3and RB3is independently selected unsubstituted Cl - C6 alkyl.

[0323] In some embodiments, Ring B is 3-7 membered heterocyclylene.

[0324] In some embodiments, Ring B is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinethionyl, isothiazolidinonyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidindione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, triazinanedionyl, and azaspiro[3.3]heptanyl.

[0325] In some embodiments, Ring B is selected from the group consisting of azetidinyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, and azaspiro[3.3]heptanyl.

[0326] In some embodiments, Ring B is selected from the group consisting of wherein indicates the attachment point to Ring A.

[0327] In some embodiments, Ring B is , wherein indicates the attachment point to Ring A.

[0328] In some embodiments, Ring B is 5-6 membered heteroarylene.

[0329] In some embodiments, Ring B is 5 membered heteroarylene selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.

[0330] In some embodiments, Ring B is 6 membered heteroarylene selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0331] In some embodiments, Ring B is pyridyl.

[0332] In some embodiments, Ring B is

[0333] In some embodiments, Ring C is phenylene.

[0334] In some embodiments, Ring C is 5-6 membered heteroarylene.

[0335] In some embodiments, Ring C is 5 membered heteroarylene selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.

[0336] In some embodiments, Ring C is selected from the group consisting of isoxazolyl, pyrazolyl, triazolyl, thiophenyl, and isothiazolyl.

[0337] In some embodiments, Ring C is selected from the group consisting wherein

[0338] *” indicates the attachment point to Ring B.

[0339] In some embodiments, Ring wherein *” indicates the attachment point to Ring B.

[0340] In some embodiments, Ring , wherein “ ” indicates the attachment point to Ring B. In some embodiments, Ring C is 6 membered heteroarylene selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0341] In some embodiments, Ring C is pyrimidinyl.

[0342] In some embodiments, each R1is an independently selected C1-C6 alkyl.

[0343] In some embodiments, each R2is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen.

[0344] In some embodiments, at least one R2is halogen.

[0345] In some embodiments, at least one R2is chloro.

[0346] In some embodiments, at least one R2is C1-C6 alkyl.

[0347] In some embodiments, at least one R2is methyl.

[0348] In some embodiments, at least one R2is C 1-C6 haloalkyl.

[0349] In some embodiments, at least one R2is C1-C6 alkoxy.

[0350] In some embodiments, at least one R2is methoxy.

[0351] In some embodiments, X is -(CH2)XNRGC(=O)O-. In some embodiments, X is -CH2NHC(=0)0-. In some embodiments, X is -NHC(=O)O-. In some embodiments, X is -N(CH3)C(=O)O-.

[0352] In some embodiments, X is -(CH2)XOC(=O)NRG-. In some embodiments, X is -CH2OC(=O)NH-. In some embodiments, X is -OC(=O)NH-.

[0353] In some embodiments, X is -(CH2)xNRG-. In some embodiments, X is -CH2NH-. In some embodiments, X is -NH-.

[0354] In some embodiments, RGis hydrogen.

[0355] In some embodiments, RGis C1-C3 alkyl. In some embodiments, RGis methyl.

[0356] In some embodiments, x is 0.

[0357] In some embodiments, x is 1.

[0358] In some embodiments, X is -CH(OH)-.

[0359] In some embodiments, R3is hydrogen.

[0360] In some embodiments, R3is C1-C6 alkyl optionally substituted with 1-2 RE.

[0361] In some embodiments, at least one REis hydroxyl.

[0362] In some embodiments, at least one REis C1-C6 alkoxy. In some embodiments, at least one REis phenyl optionally substituted with 1 -3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, or halogen.

[0363] In some embodiments, at least one REis 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0364] In some embodiments, at least one REis C3-C10 cycloalkyl.

[0365] In some embodiments, R3is selected from the group consisting of ** ,

[0366] In some embodiments, R3is , wherein REis phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyalkyl, C1-C63 alkoxy, hydroxyl, cyano, or halogen.

[0367] In some embodiments, R3is , wherein REis phenyl substituted with 1-2 substituents selected from the group consisting of methyl, ethyl, isopropyl, chloro, fluoro, cyano, methoxy, and trifluoromethyl.

[0368] In some embodiments,

[0369] In some embodiments, R3is , wherein REis 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0370] In some embodiments, R3is , wherein REis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0371] In some embodiments, R3is C6-C10 aryl optionally substituted with hydroxyl.

[0372] In some embodiments, R3is phenyl substituted with hydroxyl.

[0373] In some embodiments, R3is C5-C10 cycloalkyl. In some embodiments, R3is 5-6 membered heteroaryl optionally substituted with phenyl.

[0374] In some embodiments, R3is 5 membered heteroaryl optionally substituted with phenyl.

[0375] In some embodiments, R3is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatri azolyl, each optionally substituted with phenyl.

[0376] In some embodiments, R3is pyrazolyl, oxazolyl, or oxadiazolyl, each optionally substituted with phenyl.

[0377] In some embodiments, R3is selected from the group consisting

[0378] In some embodiments, R3is 6 membered heteroaryl optionally substituted with phenyl.

[0379] In some embodiments, R3is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl, each optionally substituted with phenyl.

[0380] In some embodiments, R3is pyridyl optionally substituted with phenyl.

[0381] In some embodiments,

[0382] In some embodiments, R3is unsubstituted 5-6 membered heteroaryl.

[0383] In some embodiments, R3is 5-6 membered heterocyclyl optionally substituted with phenyl.

[0384] In some embodiments, R3is 5 membered heterocyclyl optionally substituted with phenyl.

[0385] In some embodiments, R3is pyrrolidine.

[0386] In some embodiments, R3is 6 membered heterocyclyl optionally substituted with phenyl.

[0387] In some embodiments, R3is dihydro-4H- 1,3 -oxazinyl.

[0388] In some embodiments, R3is unsubstituted 5-6 membered heterocyclyl. In some embodiments, Rcis hydrogen.

[0389] In some embodiments, Rcis C1-C6 alkyl.

[0390] In some embodiments, each of Rcand RDis hydrogen.

[0391] In some embodiments, one of Rcand RDis hydrogen and the other one of Rcand RDis C1-C6 alkyl.

[0392] In some embodiments, each of Rcand RDis independently selected C1-C6 alkyl.

[0393] In some embodiments, RDis C1-C3 alkyl.

[0394] In some embodiments, RDis methyl.

[0395] In some embodiments, m is 0.

[0396] In some embodiments, m is 1.

[0397] In some embodiments, n is 0.

[0398] In some embodiments, n is 1.

[0399] In some embodiments, n is 2.

[0400] In some embodiments, n is 3.

[0401] In some embodiments, Formula (I) is Formula (I-a): or pharmaceutically acceptable salts thereof.

[0402] In some embodiments, Formula (I) is Formula (I-b):

[0403] or pharmaceutically acceptable salts thereof.

[0404] In some embodiments, Formula (I) is Formula (I-c): or pharmaceutically acceptable salts thereof, wherein Z is CH, N, O, or S; V is C or N; and wherein Z is O or S when V is C.

[0405] In some embodiments, Formula (I) is Formula (I-d): or pharmaceutically acceptable salts thereof, wherein Q is -CO2H or -C(=O)NHS(=O)2RF; and Z is O or S.

[0406] In some embodiments, Formula (I) is Formula (I-e):

[0407] or pharmaceutically acceptable salts thereof, wherein Q is -CO2H or -C(=O)NHS(=O)2RF; Z is CH, N, O, or S; V is C or N; and wherein Z is O or S when V is C. In some embodiments, Formula (I) is Formula (I-f): or pharmaceutically acceptable salts thereof, wherein Q is -CO2H or -C(=O)NHS(=O)2RF; Z is CH, N, O, or S; V is C or N; and wherein Z is O or S when V is C.

[0408] Non-Limiting Exemplary Compounds

[0409] In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-31, or a pharmaceutically acceptable salt thereof.

[0410] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof. Table A

[0411]

[0412]

[0413] Pharmaceutical Compositions

[0414] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0415] Methods of Treatment

[0416] Indications

[0417] Provided herein are methods for antagonizing the activation of the lysophosphatidic acid receptor 1 (LPA1). For example, provided herein are LPA1 antagonists useful for treating a fibrotic in a subject.

[0418] Some embodiments provide a method of treating a fibrotic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0419] Some embodiments provide a method of treating a fibrotic disease in a subject previously determined to have a fibrotic disease, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0420] Some embodiments provide a method of treating a fibrotic disease in a subject comprising

[0421] (a) determining that the subject has a fibrotic disease; and

[0422] (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the subject is suspected of having a fibrotic disease.

[0423] In some embodiments, the subject is at risk of developing a fibrotic disease.

[0424] In some embodiments, the fibrotic disease is associated with one or more of the liver, lung, kidney, heart, eyes, skin, pancreas, intestines, or bladder. In some embodiments, the fibrotic disease is associated with cell proliferative disease such as cancer. In some embodiments, the fibrotic disease is associated with nerve injury. In some embodiments, the fibrotic disease is associated with tissue repair.

[0425] In some embodiments, the fibrotic disease comprises liver fibrosis. In some embodiments, the liver fibrosis is associated with, for example, acute hepatitis, chronic hepatitis, liver cirrhosis, alcohol and drug induced liver fibrosis, fatty liver (NAFLD), non-alcoholic steatohepatitis (NASH), viral hepatitis, hepatic blood flow disorder, and / or portal hypertension. In some embodiments, the fibrotic disease is liver fibrosis.

[0426] In some embodiments, the fibrotic disease comprises lung fibrosis. In some embodiments, the lung fibrosis is associated with, for example, idiopathic pulmonary fibrosis, interstitial lung disease (ILD), radiation induced lung injury, and / or acute respiratory distress syndrome (ARDS). In some embodiments, the fibrotic disease is lung fibrosis.

[0427] In some embodiments, the fibrotic disease comprises skin fibrosis. In some embodiments, the skin fibrosis is associated with, for example, scleroderma, keloids, and / or Dupuytren’s contracture. In some embodiments, the fibrotic disease is skin fibrosis.

[0428] In some embodiments, the fibrotic disease comprises kidney fibrosis. In some embodiments, the kidney fibrosis is associated with, for example, chronic kidney disease, Alport syndrome, and / or hypertension. In some embodiments, the fibrotic disease is kidney fibrosis.

[0429] In some embodiments, the fibrotic disease comprises nerve injury. In some embodiments, the nerve injury is associated with, for example, neuropathic pain and / or multiple sclerosis, demyelination, or fetal hydrocephalus. In some embodiments, the fibrotic disease is nerve injury.

[0430] In some embodiments, the fibrotic disease comprises a cell proliferative disorder. In some embodiments, the cell proliferative disorder is, for example, a hematological or solid tumor, including cancer metastases. In some embodiments, the fibrotic disease is a cell proliferative disorder.

[0431] In some embodiments, the fibrotic disease comprises intestinal fibrosis. In some embodiments, the fibrotic disease comprises head and neck fibrosis. In some embodiments, the fibrotic disease comprises bladder fibrosis. In some embodiments, the fibrotic disease comprises biliary cirrhosis. In some embodiments, the fibrotic disease is intestinal fibrosis. In some embodiments, the fibrotic disease is head and neck fibrosis. In some embodiments, the fibrotic disease is bladder fibrosis. In some embodiments, the fibrotic disease is biliary cirrhosis.

[0432] Some embodiments provide a method for reducing LPA1 activation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0433] Some embodiments provide a method for reducing LPA1 activation in a cell comprising LPA1, the method comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting comprises administering to a subject having the cell a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0434] The ability of test compounds to act as LPA1 antagonists may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as LPA1 antagonists can be assayed in vitro, in vivo, or in a cell line.

[0435] Potency of an LPA1 antagonist as provided herein can be determined by EC50 or IC50 values. A compound with a lower EC 50 or IC50 value, as determined under substantially similar conditions, is a more potent antagonist relative to a compound with a higher EC50 or IC50 value.

[0436] When employed as pharmaceuticals, the compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.

[0437] EXAMPLES

[0438] Compound Preparation

[0439] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.

[0440] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[0441] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0442] Synthetic Examples

[0443] Example 1. Preparation of l-[4-[4-[3-methyl-4-[[(lR) -1- phenylethoxyjcarbonylamino] isoxazol-5-yl]-l- piperidyljphenyljcyclopropanesulfonic acid (Compound 89)

[0444] Step 1. Preparation of Ethyl (4-bromophenyl) methanesulfonate To a solution of (4-bromophenyl)methanesulfonyl chloride (2 g, 7.42 mmol, 1 eq) in DCM (20 mL) was added sodium;ethanolate (3.79 g, 11.13 mmol, 20% purity, 1.5 eq at 0°C, The reaction solution was stirred at 0°C for 1 hr. TLC (PE:EA=5:1, Rf=0.3) showed starting material consumed and a new major spot was detected. The residue was dissolved in water (50 mL) and subsequently extracted with CH2CI2 (3 x 50 mL). The CH2CI2 layer was dried (Na2SO4), and evaporated under vacuum. The residue was purified by silical gel column chromatography (PE:EA=5: l) to get ethyl (4-bromophenyl) methanesulfonate (1.8 g, 6.45 mmol, 86.90% yield) as a white solid. ’H NMR (400 MHz, chloroform-d) 5 = 7.59 - 7.53 (m, 2H), 7.34 - 7.29 (m, 2H), 4.31 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H).

[0445] Step 2. Preparation of Ethyl 1 -(4-bromophenyl) cyclopropane sulfonate

[0446] To a solution of ethyl (4-bromophenyl) methanesulfonate (1 g, 3.58 mmol, 1 eq} in THF (30 mL) was added NaHMDS (I M, 10 mL, 2.79 eq) at -40 °C and stirred for 1 hr, then the resulting mixture was added 1, 3, 2-dioxathiolane 2, 2-dioxide(2A) (1.00 g, 8.06 mmol, 2.25 eq) at -40°C and then stirred for 1 hr. TLC (PE / EA=5: 1, Rf=0.4) showed a new spot was detected. The reaction mixture was partitioned between EtOAc (130 mL) and NH4CI (80 mL), washed with brine (90 mL), dried over Na2SC>4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel and eluted with PE / EA=50:l to 5: 1 and evaporated under recuded pressure to give the ethyl 1 -(4-bromophenyl) cyclopropanesulfonate (400 mg, 1.31 mmol, 36.59% yield) as a white solid.

[0447] Step 3. Preparation of 1 -(4-bromophenyl) cyclopropanesulfonic acid

[0448] To a solution of ethyl 1 -(4-bromophenyl) cyclopropanesulfonate (250 mg, 819.17 pmol, 1 eq) in EtOH (5 mL) / H2O (2.5 mL) was added KOH (140 mg, 2.50 mmol, 3.05 eq). The reaction solution was stirred at 50°C for 2 hr. TLC (PE:EA=2: 1, Rf=0.02) showed starting material consumed and a new major spot was detected. LCMS showed desired MS was detected. The pH of the residue was adjusted to 6 by adding AcOH. The reaction mixture was partitioned between EtOAc (20 mL) and water (10 mL), washed with brine (10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was lyophilized to give 1 -(4-bromophenyl) cyclopropanesulfonic acid (100 mg, 353.62 pmol, 43.17% yield, 98% purity) as a brown solid. The crude product was used for next step without further purification. MS m / z: 274.9 ({79Br})[M-H]‘

[0449] Step 4. Preparation of l-[4-[4-[3-methyl-4-[[(lR)-l-phenylethoxy] carbonylamino]isoxazol-5-yl]~ I -piperidyl phenyl ] cyclopropanesulfonic acid

[0450] To a mixture of 1 -(4-bromophenyl) cyclopropanesulfonic acid (100 mg, 360.84 pmol, 1 eq) in dioxane (1 mL) was added RuPhos Pd G3 (100 mg, 119.57 pmol, 3.3 le-1 eq), CS2CO3 (200 mg, 613.84 pmol, 1.70 eq) and [(1R) -1 -phenyl ethyl] N-[3-methyl-5-(4-piperidyl) isoxazol-4- yl]carbamate (160 mg, 485.74 pmol, 1.35 eq), The reaction solution was degassed and purged under N2 for three times, The reaction solution was stirred at 80 °C for 1 hr. LCMS showed desired MS was detected. The pH of the residue was adjusted to 6 by adding AcOH. The residue was purified by Prep-HPLC (column: Shim-pack Cis 150*25*10um;mobile phase: [water (FA) - ACN];B%: 25%-55%, 10 min), After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give l-[4-[4-[3-methyl-

[0451] 4-[[(lR)-l-phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanesulfonic acid (2 mg, 3.81 pmol, 1.05% yield, 100% purity) as a white solid.XH NMR (400 MHz, methanoldi 8 = 7.54 (d, J= 7.6 Hz, 2H), 7.43 - 7.28 (m, 5H), 7.07 - 6.95 (m, 2H), 5.91 - 5.71 (m, 1H), 3.70 (m, 2H), 3.01 - 2.77 (m, 3H), 2.13 (s, 3H), 1.98 (s, 4H), 1.60 - 1.52 (m, 5H), 1.04 - 0.98 (m, 2H). MS m / z: 524.1[M-H]’

[0452] Example 2. Preparation of [(IR)-l-phenylethyl] N- [3-methyl-5-[l-[4-[l-(lH-tetrazol-

[0453] 5-yl) cyclopropyl]phenyl]-4-piperidyl] isoxazol-4-yl]carbamate (Compound 88)

[0454] Step 1. Preparation of l-(4-bromophenyl) cyclopropanecarbonitrile

[0455] To a solution of 2-(4-bromophenyl) acetonitrile (10 g, 51.01 mmol, 1 eq and l-bromo-2- chloro-ethane (10 g, 69.73 mmol, 5.78 mL, 1.37 eq in DMF (200 mL) was added CS2CO3 (50 g, 153.46 mmol, 3.01 eq and benzyl (triethyl) ammonium;chloride (6 g, 26.34 mmol, 5.16e-l eq), The reaction solution was stirred at 110°C for 12 hr. TLC (PE:EA=10:l, Rf=0.52) showed starting material consumed and a new major spot was detected. The reaction mixture was partitioned between H2O (500 mL) and EtOAc (500 mb). The organic phase was separated, washed with sat. NaCl (500 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. l-(4-bromophenyl) cyclopropanecarbonitrile (10 g, 45.03 mmol, 88.28% yield) as a red oil was used for next step without further purification.XH NMR (400 MHz, CDCI3) d (ppm)-. 7.50 - 7.43 (m, 2H), 7.20 - 7.11 (m, 2H), 1.77 - 1.70 (m, 2H), 1.41 - 1.35 (m, 2H).

[0456] Step 2. Preparation of [(lR)-l-phenylethyl] N-[5-[l-[4-(l-cyanocyclopropyl) phenyl]-4- piperidyl]-3-methyl- isoxazol-4-yl] carbamate

[0457] To a solution of [(IR)-l-phenylethyl] N-[3-methyl-5-(4-piperidyl) isoxazol-4- yl]carbamate (200 mg, 607.18 pmol, 1 eq) and l-(4-bromophenyl) cyclopropanecarbonitrile (170 mg, 765.49 pmol, 1.26 eq) in dioxane (5 mL) was added RuPhos Pd G3 (200 mg, 239.13 pmol, 3.94e-l eq and CS2CO3 (400 mg, 1.23 mmol, 2.02 eq), The reaction solution was degassed and purged under N2 for three times, the reaction mixture was stirred at 80°C for 1 hr. LCMS showed desired MS was detected. TLC (PE / EtOAc=3 / l, Rf=0.20) showed one major spot was observed The reaction was extracted with EtOAc (100 mL*3). The combined organic phase was washed with sodium bicarbonate (100 mL*3) and saturated brine (100 mL *2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residual. The crude product was purified by prep-TLC with PE: EtOAc=3: l to give [(lR)-l-phenylethyl]-N-[5-[l-[4-(l- cyanocyclopropyl)phenyl]-4-piperidyl]-3-methyl- isoxazol-4-yl] carbamate (260 mg, 363.01 pmol, 59.79% yield, 65.7% purity) as yellow oil.

[0458] Step 3. Preparation of[(lR)-l -phenylethyl] N-[3-methyl-5-[l-[4-[l-(lH-tetrazol-5-yl) cyclopropyl (phenyl] -4-piperidyl]isoxazol-4-y I (carbamate

[0459] To a solution of [(lR)-l-phenylethyl]-N-[5-[l-[4-(l-cyanocyclopropyl) phenyl]-4- piperidyl]-3-methyl-isoxazol-4-yl]carbamate (200 mg, 425.02 pmol, 1 eq and NH4CI (100 mg, 1.87 mmol, 4.40 eq) inDMSO (2 mL) was added NaNs (217 mg, 3.34 mmol, 7.85 eq), The reaction solution was stirred at 110°C for 2 hr. LCMS showed desired MS was detected. The pH of the reaction solution was adjusted to 9 by adding sat NaHCC . The residue was partitioned between H2O (10 mL) and EtOAc (10*3 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 Cis Ultra 150*50 mm*3 um;mobile phase: [water (0.225%FA) -ACN];B%: 43%-63%, 10 min). After Prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to give [(1R) -1 -phenyl ethyl] N-[3- methyl-5-[l-[4-[l-(lH-tetrazol-5-yl)cyclopropyl]phenyl]-4-piperidyl]isoxazol-4-yl]carbamate

[0460] (10 mg, 19.47 pmol, 4.58% yield, 100% purity) as a white solid.rH NMR (400 MHz, methanoldi d (ppm)'. 7.51-7.30 (m, 4H), 7.30-7.26 (m, 3H), 6.98 (d, J= 8.6 Hz, 2H), 5.84 - 5.73 (m, 1H), 3.72 (d, J= 12.8 Hz, 2H), 2.97 - 2.68 (m, 3H), 2.10 (s, 3H), 1.98 - 1.83 (m, 4H), 1.61 - 1.53 (m, 5H), 1.47 - 1.41 (m, 2H). MS m / z: 512.2[M-H]’.

[0461] Example 3. Preparation of methyl 2-methyl-2-[[l-[4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l- piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoate (Compound 69)

[0462] Step 1. Preparation of methyl 2-[bis [(4-methoxyphenyl)methyl] sulfamoyl]acetate

[0463] To a solution of methyl 2-chlorosulfonylacetate (500.00 mg, 2.90 mmol, 7.45e-l eq) in DCM (15 mL) was added l-(4-methoxyphenyl)-N-[(4- methoxyphenyl)methyl]methanamine (1 g, 3.89 mmol, 1 eq), DIPEA (1.48 g, 11.48 mmol, 2.00 mL, 2.95 eq) at 0°C, the resulting mixture was stirred at 25°C for 12 hr. TLC (PE / EA=3: 1, Rf=0.4) showed a new spot was detected and the l-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine consumed. The reaction mixture was partitioned between DCM (70 mL) and sat.NaHCCh (50 mL), washed with brine (90 mL), dried over Na2SO4, fdtered and evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography and eluted with PE / EA=50: 1 to 3 : 1 to give the methyl 2-[bis[(4-methoxyphenyl)methyl]sulfamoyl]acetate (500 mg, 1.27 mmol, 32.70% yield) as a yellow solid.

[0464] 'H NMR (400 MHz, DMSO-d6) 8 = 7.13 (d, J= 8.8 Hz, 4H), 6.85 (d, J= 8.8 Hz, 4H), 4.33 - 4.27 (m, 2H), 4.24 (s, 4H), 3.72 (s, 6H), 3.69 (s, 3H).

[0465] Step 2. Preparation of methyl2-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-2-methyl- propanoate

[0466] To a solution of methyl 2-[bis[(4-methoxyphenyl) methyl] sulfamoyl]acetate (400 mg, 1.02 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (480.00 mg, 3.47 mmol, 3.42 eq), Mel (684.00 mg, 4.82 mmol, 0.3 mL, 4.74 eq), then the resulting mixture was stirred at 40°C for 48 hr. LCMS showed the desired MS was detected and the methyl 2-[bis[(4-methoxyphenyl) methyl]sulfamoyl]acetate consumed. TLC (PE / EA=3:1, Rf=0.7) showed a new spot was detected and the methyl 2-[bis[(4-methoxyphenyl) methyl]sulfamoyl]acetate consumed. The reaction mixture was partitioned between EtOAc (100 mL) and water (70 mL), washed with brine (60 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (PE / EA=3:1, Rf=0.7) to give the methyl 2-[bis[(4- methoxyphenyl) methyl]sulfamoyl]-2-methyl -propanoate (250 mg, 593.11 pmol, 58.34% yield) as a white solid.

[0467] 'H NMR (400 MHz, chloroform-d) 8 = 7.10 (d, J = 8.6 Hz, 4H), 6.79 (d, J = 8.6 Hz, 4H), 4.29 (s, 4H), 3.79 (s, 9H), 3.78 (s, 6H), 1.75 (s, 6H).

[0468] Step 3. Preparation of methyl 2-methyl-2-siilfamoyl-propanoate

[0469] To a solution of methyl 2- [bis[(4-methoxyphenyl) methyl]sulfamoyl]-2-methyl- propanoate (100 mg, 237.24 pmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL), then the resulting mixture was stirred at 25°C for 1 hr. TLC (PE / EA=3: 1, Rf=0.1, I2) showed a new spot was detected and the methyl 2-[bis[(4-methoxyphenyl) methyl]sulfamoyl]-2-methyl-propanoate consumed. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude methyl 2-methyl-2-sulfamoyl-propanoate (80 mg, crude) as white solid which was used into the step without further purification.

[0470] Step 4. Preparation of methyl 2-methyl-2-[[l-[4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l- piperidyl / phenyl / cyclopropanecarbonyl / sulfamoyl / propanoate

[0471] To a solution of l-[4-[4-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino]isoxazol-5- yl]-l- piperidyl] phenyl]cyclopropane carboxylic acid (80 mg, 163.41 pmol, 1 eq) in DCM (2 mL) was added methyl 2-methyl-2-sulfamoyl-propanoate (70 mg, 386.29 pmol, 2.36 eq), DMAP (50 mg, 409.27 pmol, 2.50 eq) and EDCI (50 mg, 260.82 pmol, 1.60 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and the l-[4-[4- [3- methyl-4-[[(lR)-l-phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl] cyclopropanecarboxylic acid consumed. The reaction mixture was partitioned between EtOAc (70 mL) and water (50 mL), washed with brine (50 mL), dried over Na2SO4, fdtered and evaporated under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC (UniSil 3-100 Ci8 Ultra (150*25 mm*3um) ;mobile phase: [water (FA) -ACN];B%: 47%-77%, 7min) and lyophilized to give the methyl 2-methyl-2-[[l-[4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l- piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoate (5.7 mg, 8.56 pmol, 5.24% yield, 98% purity) as a yellow solid.

[0472] 'H NMR (400 MHz, methanol-d^ 8 = 7.43 - 7.26 (m, 7H), 7.01 (d, J= 8.6 Hz, 2H), 5.80- 5.75 (m, 1H), 3.76-3.73 (m, 2H), 3.70 (s, 3H), 2.98 - 2.86 (m, 1H), 2.82 - 2.71 (m, 2H), 2.11 (s, 3H), 1.97 - 1.85 (m, 4H), 1.64 - 1.55 (m, 9H), 1.53 - 1.50 (m, 2H), 1.20 - 1.17 (m, 2H). MS m / z: 653.2 [M+H]+

[0473] Example 4. Preparation of (R)-l-(3-methoxy-4-(4-(3-methyl-4-(((l-phenylethoxy) carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylic acid (Compound 63)

[0474] Step 1. Preparation of methyl l-(4-hromo-3-methoxyphenyl)cyclopropane-l-carhoxylate

[0475] To a stirred solution of l-(4-bromo-3-methoxyphenyl)cyclopropane-l-carboxylic acid (0.500g, 1.84 mmol) in methanol (O. lmL) added sulfuric acid (0.1 mL,1.84mmol) at 0 °C, stirred for lOminutes, maintained reaction mixture at 70 °C for 8h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was concentrated, diluted with water (15 mL) extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with water (2 x 10 mL), 10% NaHCCh solution (2 x 7 mL) and brine solution (5 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to afford methyl l-(4- bromo-3-methoxyphenyl) cyclopropane-l-carboxylate (0.5 g and 95% Yield ) as a colorless liquid; MS (ES) m / z 287.0 (M+H)+.

[0476] Step 2. Preparation of 5-(l-(2-methoxy-4-(l -(methoxycarbonyl) cyclopropyl)phenyl) piperidin-4-yl)-3-methylisoxazole-4-carboxylic acid

[0477] To a stirred solution of 3-methyl-5-(piperidin-4-yl)-l,2-oxazole-4-carboxylic acid hydrochloride (0.4 g, 1.62 mmol) in dimethylformamide (13.2 m , 170 mmol) were added cesium carbonate (2.11 g, 4 eq., 6.49 mmol), methyl l-(4-bromo-3-methoxyphenyl) cyclopropane-l- carboxylate (509 mg, 1.1 eq., 1.62 mmol) and X-phos (77.3 mg, 0.1 eq., 162 pmol), purged under argon gas for 15 minutes. Finally added Pd2(dba).3 (74.2 mg, 0.05 eq., 81.1 pmol) and heated reaction mixture to 100 °C for 16 hours in sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was cooled to room temperature and fdtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq. layer was acidified with 10% citric acid until pH was acidic, then extracted with ethyl acetate (2 x 100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 5-(l-{4-[l- (methoxycarbonyl)cyclopropyl] phenyl}piperidin-4-yl)-3-methyl-l,2-oxazole-4-carboxylic acid (150 mg, Yield 22%%) as a dark yellow solid; MS (ES) m / z 415.0 (M+1H)+

[0478] Step 3. Preparation of methyl (R)-l-(3-methoxy-4-(4-(3-methyl-4-(((l-phenylethoxy) carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylate

[0479] To a stirred solution of 5-(l-{4-[l-(methoxycarbonyl)cyclopropyl] phenyl }piperidin-4-yl)- 3 -methyl- l,2-oxazole-4-carboxylic acid (0.100 g, 241umol) in toluene (10 mL) were added triethylamine (0.1 mL, 3 eq. ,719 pmol) and ((IR)-l-phenylethan-l-ol (29.5mg, 1 eq. 241 umol) heated reaction mixture to 50 °C, for 20 minutes. Then added DPPA (57.5 pL, 1.1 eq., 265 pmol), heated to 85°C, maintained for 4 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was diluted with water (20 mL) extracted with ethyl acetate (2 x 25mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n- hexane (1% to 28%) to afford methyl (R)-l -(3 -methoxy-4-(4-(3-methyl-4-(((l -phenylethoxy) carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylate (50 mg, Yield:, 39% ) as a pale yellow gum; MS (ES) m / z 533.3 (M+H)+.

[0480] Step 4. Preparation of (R)-l-(3-methoxy-4-(4-(3-methyl-4-(((l -phenyl 'ethoxy) carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylic acid

[0481] To a stirred solution of methyl l-(3-methoxy-4-{4-[3-methyl-4- ({[(1R)-1- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l- carboxylate (50mg, 93.7 umol) in THF (3.0 mL), MeOH (3.0 mL) solution was added lithium(l+) hydrate hydroxide (15.7 mg, 375 umol) in water (3.0 mL) and the mixture was stirred at RT for 18 hours. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was concentrated, diluted with water (10 mL), washed with diethyl ether (2 x 5 mL), pH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on Buchner funnel, solid was washed with water (2 x 5 mL), pentane (2 x 5 mL) and dried under vacuum to get crude product (30 mg). It was purified by Prep HPLC to afford l-(3-methoxy- 4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l- yl} phenyl )cy cl opropane-1 -carboxylic acid as a white solid (lOmg, 20% yield); MS (ES) m / z 520.3 (M+1H)+. LC purity 98.72% @ 254 nm. 'H NMR (400 MHz, DMSO-t / e): 5 12.2 (s, 1H), 8.92 (s, 1H), 7.39-7.30 (m, 5H), 6.85 (d, J= 7.6 Hz, 1H), 6.80 (d, J= 8.4 Hz, 2H), 5.75 (q, J= 6.8 Hz, 1H), 3.78 (s, 3H), 3.38 - 3.35 (m, 2H), 2.84 - 2.82 (m, 1H), 2.58 - 2.56 (m, 2H), 2.04 (s, 3H), 1.85 -1.83 (m, 4H), 1.53 - 1.51 (m, 2H), 1.41 - 1.39 (m, 2H), 1.11 (d, J= 2.8 Hz, 2H).

[0482] Example 5. Preparation of l-(3-methoxy-4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l-carboxylic acid (Compound 46)

[0483] Step 1. Preparation of Methyl l-(4-bromo-3-methoxyphenyl)cyclopropane-l -carboxylate To a stirred solution of 1 -(4-bromo-3-methoxyphenyl)cyclopropane-l -carboxylic acid (1g, 3.69 mmol) in methanol (ImL) added sulfuric acid (217 uL,3.69 mmol) at 0 °C, stirred for lOminutes, maintained reaction mixture at 70 °C for 8h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was concentrated, diluted with water (15 mL) extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with water (2 x 10 mL), 10% NaHCO3 solution (2 x 7 mL) and brine solution (5 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford methyl l-(4- bromo-3-methoxyphenyl)cyclopropane-l -carboxylate (0.8 g and 76% Yield ) as colorless liquid MS (ES) mY 285.0 (M+H)+.

[0484] Step 2. Preparation of 5-(2-{2-methoxy-4-[l-(methoxycarbonyl)cyclopropyl]phenyl}-2- azaspiro[ 3.3 ]heptan-6-yl)-3-methyl-l , 2-oxazole-4-carboxylic acid

[0485] To a stirred solution of 5-{2-azaspiro[3.3]heptan-6-yl}-3-methyl-l,2-oxazole-4-carboxylic acid hydrochloride (350 mg, 1.35 mmol) in dimethylformamide (8.75 mL, 113 mmol) were added Cesium carbonate (1.76 g, 4 eq., 5.41 mmol), methyl l-(4-bromo-3-methoxyphenyl)cyclopropane- 1-carboxylate (386 mg, 1.35 mmol) and X-phos (64.5 mg, 0.1 eq., 135 pmol), purged under argon gas for 15 minutes. Finally added Pd2(dba)3 (61.9 mg, 0.05 eq., 67.6 pmol) and heated reaction mixture to 100 °C for 16 hours inside sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was cooled to room temperature and fdtered through celite, and concentrated then diluted with water (20 mL) and washed with ether, then Aq. layer was acidified with 10% citric acid until pH is acidic, then extracted with ethyl acetate (2 x 20 mL), washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude. The crude product was co-distilled with toluene and given ether and pentane wash to afford 5-(2-{2-methoxy-4-[l- (methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptan-6-yl)-3-methyl-l,2-oxazole-4- carboxylic acid (300 mg, 52%; Yield) as dark yellow solid; MS (ES) m / z 427.2 (M+1H)+.

[0486] Step 3. Preparation of methyl l-(3-methoxy-4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l, 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl}phenyl)cyclopropane-l-carboxylate

[0487] To a solution of 5-(2-{2-methoxy-4-[l-(methoxycarbonyl)cyclopropyl]phenyl}-2- azaspiro[3.3 ]heptan-6-yl)-3 -methyl- l,2-oxazole-4-carboxylic acid (0.3 g, 703 pmol) in toluene (10 mL, 3.26 mmol) were added, triethylamine (196 pL, 2 eq., 1.41 mmol), (IR)-l-phenylethan- l-ol (258 pL, 3 eq., 2.11 mmol) stirred reaction mixture at 50 °C. Then added {[azido(phenoxy)phosphoryl]oxy}benzene (303 pL, 2 eq., 1.41 mmol). The mixture was stirred at 85 °C for 3 h. Reaction was progressed by TLC, rm was diluted with water (20 mL) extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (10 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 50%) to afford methyl l-(3-methoxy-4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l -carboxylate as yellowish liquid ( 120 mg, 31% ;Yield ) MS (ES) m / z 546.0 (M+H)+.

[0488] Step 4. Preparation of l-(3-methoxy-4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l, 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl}phenyl)cyclopropane-l-carboxylic acid

[0489] To a stirred solution of methyl l-(3-methoxy-4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l -carboxylate (120 mg, 220 pmol) in oxolane (2 mL), methanol (2 mL, 156 mmol) solution was added lithium hydrate hydroxide (36.9 mg, 4 eq., 880 pmol) in water (2 mL) and the mixture was stirred at RT for 18 hours. Reaction was progressed by LCMS and TLC, rm was concentrated, diluted with water (10 mL), washed with diethyl ether (2 x 10 mL), PH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on buchnel funnel, solid was washed with water (2 x 10 mL), pentane (2 x 10 mL) and dried under vacuum to get crude, crude was given for prep HPLC Mobile phase(A) : 0.1% Ammonia in water, Mobile phase(B) : Acetonitrile purification to afford l-(3-methoxy-4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl} phenyl )cy cl opropane-1 -carboxylic acid as off white solid (30 mg, 26% ;yield) MS (ES) m / z 532.4 (M+1H)-. LC purity 99.62% @ 240 nm.

[0490] ‘HNMR (400 MHz, DMSO-de): 5 12.02 (s, 1H), 8.86 (S, 7=1H), 7.39 - 7.27 (m, 5H), 6.76 - 6.71 (m, 2H), 6.24 (d, J =8 Hz, 1H), 5.75 (q, J =6.4 Hz, 1H), 3.84 (s, 2H), 3.71 (s, 5H), 3.48 - 3.40 (m, 1H), 2.46 - 2.32 (m, 4H), 2.07 (s, 3H), 1.52 (s, 3H), 1.41 - 1.34 (m, 2H), 1.05 - 1.03 (m, 2H).

[0491] Example 6. Preparation of (R)-l-(4-(3-(3-methyl-4-(((l-phenylethoxy)carbonyl) amino)isoxazol-5-yl)azetidin-l-yl)phenyl)cyclopropane-1 -carboxylic acid (Compound 23)

[0492] Step 1. Preparation of methyl 3-(methylamino) but-2-enoate

[0493] To a mixture of methyl 3-oxobutanoate (25 g, 215.30 mmol, 23.15 mL, 1 eq) in MeOH (300 mL) was added 33% aq. MeNI E (31.57 g, 335.45 mmol, 1.56 eq) dropwise over 30 min at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction solution was concentrated in vacuo at 25 °C to give methyl 3 -(methylamino) but-2-enoate (27.5 g, crude) as a white solid.

[0494] Step 2. Preparation of tert-butyl 3-chlorocarbonylazetidine-l -carboxylate

[0495] To a mixture of l-tert-butoxycarbonylazetidine-3 -carboxylic acid (10 g, 49.70 mmol, 1 eq) and DMF (182 mg, 2.48 mmol, 191 pL, 0.05 eq) in DCM (100 mL) was added oxalyl dichloride (6.31 g, 49.70 mmol, 4.35 mL, 1 eq) at 0 °C dropwise, the mixture was stirred at 25 °C for 16 hr. The mixture was concentrated to dryness in vacuo to give tert-butyl 3-chlorocarbonylazetidine-l - carboxylate (5.1 g, 23.22 mmol, 46.72% yield) as a yellow oil.

[0496] Step 3. Preparation of tert-butyl 3-[(E)-2-methoxycarbonyl-3-(methylamino) but-2- enoyl]azetidine-l -carboxylate

[0497] To a mixture of methyl 3-(methylamino)but-2-enoate (2.5 g, 19.36 mmol, 1 eq) and pyridine (4.90 g, 61.94 mmol, 5.00 mL, 3.2 eq) in THF (30 mL) was added tert-butyl 3- chlorocarbonylazetidine-1 -carboxylate (5.10 g, 23.23 mmol, 1.2 eq) drop-wise at O °C, the mixture was stirred at 25 °C for 16 hr. The mixture was poured into H2O (30 mL), the resulting mixture was extracted with EtOAc (40 mL*3). The combined organic layer was dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to give tert-butyl 3-[(E)-2-methoxycarbonyl-3-(methylamino) but-2- enoyl] azetidine-l-carboxylate (1.5 g, 4.80 mmol, 24.81% yield) as a yellow oil.

[0498] Step 4. Preparation of methyl 5-(l-tert-butoxycarbonylazetidin-3-yl)-3-methyl-isoxazole- 4-carboxylate

[0499] To a mixture of tert-butyl 3-[(E)-2-methoxycarbonyl-3-(methylamino) but-2-enoyl] azetidine- 1 -carboxylate (1.3 g, 4.16 mmol, 1 eq) in HOAc (5 mL) was added NH2OH HCI (347 mg, 4.99 mmol, 1.2 eq). The mixture was stirred at 60 °C for 0.5 hr. The mixture was concentrated, the residue was dissolved in EtOAc (10 mL), treated with sat. NaHCOa until pH 8, and extracted with EtOAc (10 mL*3). The combined organic layer was dried over Na2SO4, fdtered and concentrated in vacuo. The residue was purified by reversed-phase MPLC (0.1 % FA condition) to give methyl 5-(l-tert-butoxycarbonylazetidin-3-yl)-3-methyl- isoxazole-4-carboxylate (585 mg, 1.97 mmol, 47.44% yield) as yellow oil.

[0500] Step 5. Preparation of 5-(l-tert-butoxycarbonylazetidin-3-yl)-3-methyl-isoxazole-4- carboxylic acid

[0501] To a mixture of methyl 5-(l-tert-butoxycarbonylazetidin-3-yl)-3-methyl-isoxazole- 4- carboxylate (585 mg, 1.97 mmol, 1 eq) in MeOH (15 mL) and H2O (1.5 mL) was added LiOH (118 mg, 4.94 mmol, 2.5 eq). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was cooled to rt, treated with HC1 (1 M) until pH 6, and extracted with EtOAc (5 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 5-(l-tert- butoxycarbonylazetidin-3-yl)-3-methyl-isoxazole-4- carboxylic acid (480 mg, crude) as a yellow solid.

[0502] Step 6. Preparation of tert-butyl 3-[3-methyl-4-[[(lR)-l-phenylethoxy] carbonylamino] isoxazol-5-yl] azetidine- 1 -carboxylate

[0503] To a mixture of 5-(l-tert-butoxycarbonylazetidin-3-yl) -3-methyl-isoxazole-4- carboxylic acid (250 mg, 886 pmol, 1 eq) and (1R) -1 -phenyl ethanol (325 mg, 2.66 mmol, 321 pL, 3 eq) in toluene (3 mL) were added DPPA (268 mg, 974 pmol, 211 pL, 1.1 eq) and TEA (179 mg, 1.77 mmol, 247 pL, 2 eq). The mixture was stirred at 80 °C for 4 hr under N2 atmosphere. The mixture was concentrated. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to give tert-butyl 3-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]azetidine-l-carboxylate (185 mg, 460.82 pmol, 52.03% yield) as a colorless oil.

[0504] Step 7. Preparation of [(1R)-1 -phenylethyl] N-[5-(azetidin-3-yl)-3-methyl- isoxazol-4-yl] carbamate

[0505] To a mixture of tert-butyl 3-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino] isoxazol- 5-yl]azetidine-l -carboxylate (150 mg, 373.64 pmol, 1 eq) in i-PrOH (5 mL) was added HCl / di oxane (4 M, 1 mL). The mixture was stirred at 25 °C for 17 hr. The mixture was concentrated. The residue was purified by reversed-phase MPLC (0.1 % FA condition), followed by lyophilization to give [(lR)-l-phenylethyl] N-[5-(azetidin-3-yl)-3-methyl-isoxazol-4- yl]carbamate (112 mg, 372 pmol, 99.47% yield) as a colorless oil.

[0506] Step 8. Preparation of methyl l-[4-[3-[3-methyl-4-[[(lR)-l-phenylethoxy] carbonylamino]isoxazol-5-yl] azetidin-l-yl] phenyl] cyclopropanecarboxylate

[0507] To a mixture of [(1R)-1 -phenylethyl] N-[5-(azetidin-3-yl)-3-methyl-isoxazol-4-yl] carbamate (72 mg, 239 umol, 1 eq) in DCM (5 mL) were added Cu(OAc)2 (88 mg, 478 umol, 2 eq), TEA(48 mg, 478 umol, 67 uL, 2 eq), and [4-(l-methoxy carbonylcyclopropyl)phenyl]boronic acid (105.14 mg, 477.87 umol, 2 eq). The mixture was stirred at 20 °C for 18 hr under O2 atmosphere. The mixture was filtered, the filtrate was concentrated. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate= 3:1) to give methyl l-[4-[3-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl] azetidin-l-yl]phenyl]cyclopropanecarboxylate (41 mg, 86 umol, 36 % yield) as a yellow oil.

[0508] Step 9. Preparation of l-[4-[3-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino] isoxazol-5-ylJazetidin-l-ylJphenylJcyclopropanecarboxylic acid

[0509] To a mixture of methyl l-[4-[3-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino] isoxazol-5-yl]azetidin-l-yl]phenyl]cyclopropanecarboxylate (41 mg, 86 umol, 1 eq) in THF (5 mL) and H2O (1 mL) was added LiOH (6 mg, 259 umol, 3 eq). The mixture was stirred at 25 °C for 16 hr and at reflux for 32 hr. The reaction mixture was cooled to rt, treated with 1 N HC1 until pH 6, and extracted with EtOAc (10 mL*3). The combined organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(0.225%FA)-ACN]; B%: 40%-70%,10min) to give l-[4-[3-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino] isoxazol-5-yl]azetidin-l- yl]phenyl]cyclopropanecarboxylic acid (7.1 mg, 13.85 umol, 16.06% yield, 90% purity) as an off- white solid. [M+H]+= 462.2. 'HNMR (400 MHz, MeOD-d4) 8 = 7.49 - 7.26 (m, 5H), 7.17 (d, J = 8.4 Hz, 2H), 6.40 (d, J = 8.4 Hz, 2H), 5.81 - 5.67 (m, 1H), 4.15 - 3.97 (m, 3H), 3.96 - 3.85 (m, 2H), 2.13 (s, 3H), 1.59 - 1.46 (m, 5H), 1.15 - 1.08 (m, 2H). Example 7. Preparation of (R)-l-(4-(l-(3-methyl-4-(((l- phenylethoxy)carbonyl)amino) isoxazol-5-yl)piperidin-4-yl)phenyl)cyclopropane-l- carboxylic acid (Compound 8)

[0510] Step 1. Preparation of tert-butyl 4-(p-tolylsulfonylhydrazono)piperidine- 1 -carboxylate

[0511] To a mixture of 4-methylbenzenesulfonohydrazide (10.84 g, 58.22 mmol, 1 eq) in MeOH (100 mL) was added tert-butyl 4-oxopiperidine-l -carboxylate (11 .6 g, 58.22 mmol, 1 eq) at 25 °C under N2. The mixture was stirred at 25 °C for 16 hr. The mixture was filtered, the filter cake was dried in vacuo to give tert-butyl 4-(p-tolylsulfonylhydrazono) piperidine- 1 -carboxylate (17 g, crude) as an off-white solid.

[0512] Step 2. Preparation of tert-butyl 4- [4-(l -ethoxy carbonylcyclopropyl)phenyl] piperidine- 1- carboxylate

[0513] To a mixture of tert-butyl 4-(p-tolylsulfonylhydrazono) piperidine- 1 -carboxylate (5 g, 13.61 mmol, 1 eq) and in dioxane (50 mL) were added CS2CO3 (13.30 g, 40.83 mmol, 3 eq) and ethyl l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (2.5 g, 7.91 mmol, 0.58 eq). The mixture was stirred at 110 °C for 3 hr. Then tert-butyl 4-(p- tolylsulfonylhydrazono) piperidine- 1 -carboxylate (5.00 g, 13.61 mmol, 1 eq) was added, the mixture was stirred at 110 °C for 32 hr. The mixture was poured into water (50 mL), the resulting mixture was extracted with EtOAc (50 mL*3). The combined organic was dried over Na2SCU, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 10: 1) to give tert-butyl 4-[4-(l- ethoxycarbonylcyclopropyl)phenyl]piperidine-l -carboxylate (2.3 g, 6.16 mmol, 45.25% yield) as a yellow oil. Step 3. Preparation of ethyl l-[4-(4-piperidyl) phenyl] cyclopropanecarboxylate

[0514] To a mixture of tert-butyl 4-[4-(l-ethoxycarbonylcyclopropyl)phenyl] piperidine-1- carboxylate (2.3 g, 6.16 mmol, 1 eq) in DCM (9 mL) was added TFA (3 mL). The mixture was stirred at 20 °C for 3.5 hr. The mixture was concentrated to dryness in vacuo, and the residue was re-dissolved in DCM (30 mL). K2CO3 (10 g) was added, and the resulting mixture was stirred at 25 °C for 0.5 h before being filtered, and the filtrate was concentrated to give ethyl l-[4-(4- piperidyl) phenyl] cyclopropanecarboxylate (1.6 g, crude) as a yellow solid.

[0515] Step 4. Preparation of ethyl l-[4-[l-(4-carbamoyl-3-methyl-isoxazol-5-yl) -4-piperidyl] phenyl / cyclopropanecarboxylate

[0516] Amixture of ethyl l-[4-(4-piperidyl)phenyl]cyclopropanecarboxylate (500 mg, 1.83 mmol, 1 eq), 5-chloro-3-methyl-isoxazole-4-carboxylic acid (295.47 mg, 1.83 mmol, 1 eq) and TEA (925.40 mg, 9.15 mmol, 1.27 mL, 5 eq) in DMF (10 mL) was stirred at 40 °C for 16 hr. The mixture was cooled to rt before the addition of HATU (835 mg, 2.19 mmol, 1.2 eq). The resulting mixture was stirred at 25 °C for 10 min before being treated with NH4Q (196 mg, 3.66 mmol, 2 eq), and the stirring was continued at 25 °C for 1 hr. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc (5 mL), followed by filtration, the filter cake was dried in vacuo to give ethyl l-[4-[l-(4-carbamoyl-3-methyl-isoxazol-5-yl)-4- piperidyl]phenyl]cyclopropanecarboxylate (260 mg, 654 pmol, 35.76% yield) as a white solid.

[0517] Step 5. Preparation of ethyl l-[4-[l-[3-methyl-4-[[(lR)-l-phenylethoxy] carbonylamino ]isoxazol-5-yl ] -4-piperidyl ] phenyl] cyclopropanecarboxylate

[0518] To a mixture of ethyl l-[4-[l-(4-carbamoyl-3-methyl-isoxazol- 5-yl)-4-piperidyl] phenyl]cyclopropanecarboxylate (180 mg, 453 pmol, 1 eq) in toluene (5 mL) were added bis(trifluoroacetoxy)iodo]benzene (390 mg, 905.74 pmol, 2 eq) and pyridine (107 mg, 1.36 mmol, 110 pL, 3 eq). The mixture was stirred at 30 °C for 1 hr under N2 atmosphere. Then (1R) -1- phenylethanol (277 mg, 2.26 mmol, 274 pL, 5 eq) was added, and the stirring was continued at 70 °C for 2 hr. The mixture was poured into water (10 mL), the resulting mixture was extracted with EtOAc (10 mL*3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to give ethyl l-[4-[l-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-4-piperidyl] phenyl]cyclopropanecarboxylate (45 mg, 86.94 pmol, 19.20% yield) as a yellow oil.

[0519] Step 6. Preparation of l-[4-[l-[3-methyl-4-[[(lR)-l-phenylethoxy] carbonylamino ]isoxazol-5-yl -4-piperidyl phenyl ] cyclopropanecarboxylic acid

[0520] To a mixture of ethyl l-[4-[l-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino] isoxazol-5-yl]-4-piperidyl]phenyl] cyclopropanecarboxylate (45 mg, 87 pmol, 1 eq) in THF (5 mL) and H2O (1 mL) was added LiOH (6 mg, 261 pmol, 3 eq). The mixture was stirred at 65 °C for 64 hr. HC1 aqueous solution (1 M, 3 mL) was added into the mixture, the mixture was extracted with EtOAc (10 mL*3). The combined organic was dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (0.225%FA) -ACN]; B%: 42%-72%, 10 min), followed by lyophilization to give l-[4-[l-[3-methyl-4-[[(lR)-l-phenylethoxy] carbonylamino]isoxazol-5-yl]-4- piperidyl]phenyl]cyclopropanecarboxylic acid (11.5 mg, 23.26 pmol, 26.75% yield, 99% purity) as an off-white solid. [M+H+] = 490.3. (400 MHz, CD3OD) 8 = 7.44 - 7.19 (m, 7H), 7.17 - 7.05 (m, 2H), 5.87 - 5.70 (m, 1H), 4.15 - 3.95 (m, 2H), 3.10 - 2.90 (m, 2H), 2.77 - 2.56 (m, 1H), 2.03 (s, 3H), 1.81 - 1.41 (m, 9H), 1.20 - 1.05 (m, 2H).

[0521] Example 8. Preparation of !-(4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l-carboxylic acid (Compound 54)

[0522] Step 1. Preparation of tert-butyl 6-(3-ethoxy-3-oxopropanoyl)-2-azaspiro[3.3]heptane-2- carboxylate

[0523] To a stirred solution of 2-[(tert-butoxy)carbonyl]-2-azaspiro[3.3]heptane-6-carboxylic acid (2 g, 8.29 mmol) in Acetonitrile (50 mL) was added 2-(lH-imidazole-2-carbonyl)-lH-imidazole (2.02 g, 1 .5 eq., 12.4 mmol) at rt. The reaction mixture was stirred at rt for 16 hours. To a solution potassium 3 -ethoxy-3 -oxopropanoate (3.1 g, 2.2 eq., 18.2 mmol) in Acetonitrile (50 mL) were added triethylamine (3.49 mL, 3 eq., 24.9 mmol) and magnesium(2+) dichloride (1.74 g, 2.2 eq., 18.2 mmol),N,N-dimethylpyridin-4-amine (203 mg, 0.2 eq., 1.66 mmol) at 0 °C and stirred at rt for 8 hours, after that above solution (CDI mixture solution) was added to reaction mixture at 0 °C and stirred at 70 °C for 6 hours. Reaction was progressed by TLC & LCMS. Reaction mixture was quenched with Imol / L hydrochloric acid (50 mL) under ice cooling, extracted with ethyl acetate (2 x 150 mL). The combined organic layer was washed with water (2 x 100 mL), sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 20%) to afford tert-butyl 6- (3-ethoxy-3-oxopropanoyl)-2-azaspiro[3.3]heptane-2-carboxylate as viscous liquid (2.4 g, 93% yield); MS (ES) m / z 256.1 (M+1H)+, -56 De-BOC mass was observed.

[0524] Step 2. Preparation of (Z)-N-hydroxyethanecarbonimidoyl chloride

[0525] To a solution of (E)-N-ethylidenehydroxylamine (3 g, 50.8 mmol) in N,N- dimethylformamide (60.0 mL) was added 1 -chloropyrrolidine-2, 5-dione (7.46 g, 1.1 eq., 55.9 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 3 hr. The reaction mass was diluted with water (80 mL) and extracted with diethyl ether (2 x 100 mL), combined organic layer was washed with brine solution dried over sodium sulfate and concentrated to afford 2-methylbut-2-ene ( Yield: 2.8 g, 59%).

[0526] Step 3. Preparation of tert-butyl 4-[4-(ethoxycarbonyl)-3-methyl-l,2-oxazol-5-yl] piperidine-l-carboxylate

[0527] To a solution of tert-butyl 6-(3-ethoxy-3-oxopropanoyl)-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 3.21 mmol) in ethanol (20 mL) and THF (20 mL) was added Sodium ethoxide (21% solution in ethanol) 21%w / w 21%v / v (6.08 mL, 5 eq., 16.1 mmol) was added at 0 °C, maintained for 30 minutes, then added (Z)-N-hydroxyethanecarbonimidoyl chloride (2.4 g, 8 eq., 25.7 mmol) and the resulting mixture was stirred at room temperature for 16 hr. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was diluted with water (80 mL) extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (2 x 50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated to get crude. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 10%) to afford tert-butyl 6-[4-(ethoxycarbonyl)-3-methyl-l ,2- oxazol-5-yl]-2-azaspiro[3.3]heptane-2-carboxylate as yellowish liquid ( Yield; 550 mg, 49% ) MS (ES) m / z 351 (M+H)+. but m / z 295.1 (-56 De-Boc mass is observed.).

[0528] Step 4. Preparation of 5-{2-[(tert-butoxy)carbonyl]-2-azaspiro[3.3]heptan-6-yl}-3- methyl-1, 2-oxazole-4-carboxylic acid

[0529] To a solution of tert-butyl 6-[4-(ethoxycarbonyl)-3-methyl-l,2-oxazol-5-yl]-2- azaspiro[3.3]heptane-2-carboxylate (550 mg, 1.57 mmol) in methanol (10 mL) was added sodium hydroxide (188 mg, 3 eq., 4.71 mmol) in water (6 mL) at room temperature, and stirred at the same temperature for 2 hours. Reaction was progressed by LCMS and TLC, rm was concentrated, diluted with water (20 mL), PH was adjusted with IN HCL up to 3 to 4, white solid was precipitated, extracted with DCM (2 x 30 ml), washed with water (2 x 15 mL), and dried under vacuum to afford 5-{2-[(tert-butoxy)carbonyl]-2-azaspiro[3.3]heptan-6-yl}-3-methyl-l,2- oxazole-4-carboxylic acid as gummy liquid, ( Yield: 450 mg, 89% ); MS (ES) m / z 321.2 (M-H)’.

[0530] Step 5. Preparation of 5-{2-azaspiro [3.3]heptan-6-yl}-3-methyl-l,2-oxazole-4-carboxylic acid hydrochloride

[0531] To a stirred solution of 5-{2-[(tert-butoxy)carbonyl]-2-azaspiro[3.3]heptan-6-yl}-3- methyl-l,2-oxazole-4-carboxylic acid (410 mg, 1.27 mmol) in dichloromethane (20 mL) were added Dioxane in HCL (4 mL, 8 eq., 10.2 mmol) at 0 °C, and stirred reaction mixture at room temperature for 12 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated, washed with pentane, dried under vacuum to obtain 5-{2-azaspiro[3.3]heptan-6-yl}-3-methyl-l,2-oxazole-4-carboxylic acid hydrochloride ( Yield: 275 mg, 84% ) as white solid, MS (ES) m / z 221.1 (M+H)+.

[0532] Step 6. Preparation of 5-(2-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl}-2- azaspiro[ 3.3 ]heptan-6-yl)-3-methyl-l , 2-oxazole-4-carboxylic acid

[0533] To a stirred solution of 5-{2-azaspiro[3.3]heptan-6-yl }-3-methyl-l,2-oxazole-4-carboxylic acid hydrochloride (275 mg, 1.06 mmol) in dimethylformamide (15 mL, 194 mmol) were added Cesium carbonate (1.39 g, 4 eq., 4.25 mmol), methyl l-(4-bromophenyl)cyclopropane-l- carboxylate (325 mg, 1.2 eq., 1.28 mmol) and X-phos (50.7 mg, 0.1 eq., 106 pmol), purged under argon gas for 15 minutes. Finally added Pd2(dba)3 (48.7 mg, 0.05 eq., 53.1 pmol) and heated reaction mixture to 100 °C for 16 hours inside sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq. layer was acidified with 10% citric acid until pH is acidic, then extracted with ethyl acetate (2 x 100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 5-(2-{4-[l- (methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptan-6-yl)-3-methyl-l,2-oxazole-4- carboxylic acid ( Yield: 325 mg, 77 %) as dark yellow solid; MS (ES) m / z 397.2 (M+1H)+.

[0534] Step 7. Preparation of methyl l-(4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l, 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl}phenyl)cyclopropane-l-carboxylate

[0535] {[azido(phenoxy)phosphoryl]oxy}benzene (163 pL, 2 eq., 757 pmol) and triethylamine (105 pL, 2 eq., 757 pmol) were added to a solution of 5-(2-{4-[l- (methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptan-6-yl)-3-methyl-l,2-oxazole-4- carboxylic acid (150 mg, 378 pmol) at 50 °C. The mixture was stirred at 50 °C for 30 minutes, then added (1R)-1 -phenyl ethan-l-ol (139 mg, 3 eq., 1.14 mmol). The mixture was stirred at 80 °C for 3 h. Reaction was progressed by TLC, rm was diluted with water (20 mL) extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 50%) to afford methyl l-(4-{6-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l -carboxylate (30 mg, 58.2 pmol) as pale yellow solid (30 mg, 16% yield); MS (ES) m,'z 516.3 (M+H)+.

[0536] Step 8. Preparation of l-(4-{6-[3- ethyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)-l,2- oxazol-5-yl]-2-azaspiro[ 3.3 ]heptan-2-yl}phenyl)cyclopropane-l -carboxylic acid

[0537] To a solution of methyl l-(4-{6-[3-methyl-4-({ [(lR)-l-phenylethoxy]carbonyl}amino)- l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropane-l-carboxylate (32 mg, 62.1 pmol) in oxolane (4.00 mL), methanol (4.00 mL) was added lithium(l+) hydrate hydroxide (13 mg, 5 eq., 310 pmol) in water (4.00 mL) at room temperature and stirred at the same temperature for 18 hours. Reaction was progressed by LCMS and TLC, rm was concentrated, diluted with water (20 mL), PH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on Buchner funnel, solid was washed with water (2 x 25 mL), pentane (2 x 25 mL) and dried under vacuum to afford 1 -(4-{6-[3-methyl-4-({[(lR)-l -phenylethoxy]carbonyl}amino)-l ,2- oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropane-l-carboxylic acid as white solid. (Yield: 15 mg, 48%) MS (ES) m / z 502.4 (M+H)+.

[0538] ‘HNMR (400 MHz, DMSO-de): 8 12.1 (s, 1H), 8.87 (s, 1H), 7.37-7.28 (m, 5H), 7.08 (d, J = 8.4 Hz, 2H, 6.30 (d, J= 8.4 Hz, 2H), 5.72 (t, J = 6.8 Hz, 1H), 3.81 (s, 2H ), 3.67 (s, 2H ), 3.47- 3.29 (m, 1H), 2.48-2.37 ( m, 4H ), 2.02 (s, 3H ), 1.49 (s, 3H ), 1.35 (s, 2H ), 1.00 (s, 2H ).

[0539] Example 9. Preparation of l-(4-((2S,4S)-2-methyl-4-(3-methyl-4-((((R) -1- phenylethoxy)carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l- carboxylic acid (Compound 10) & l-(4-((2R,4R)-2-methyl-4-(3-methyl-4-((((R)-l- phenylethoxy) carbonyl)amino)isoxazol-5-yI)piperidin-l-yl)phenyl)cyclopropane-l- carboxylic acid (Compound 21)

[0540] Step 1. Preparation of 1 -(tert-butyl) 4-methyl 2- ethylpiperidine-l,4-dicarboxylate

[0541] To a mixture of methyl 2-methylpiperidine-4-carboxylate (6.5 g, 33.56 mmol, 1 eq, HC1) in DCM (100 mL) were added TEA (10.19 g, 100.69 mmol, 14.01 mL, 3 eq) and BOC2O (10.99 g, 50.34 mmol, 11.57 mL, 1.5 eq), the mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether) to give 1 -(tert- butyl) 4-methyl 2-methylpiperidine-l,4-dicarboxylate (6.9 g, 26.81 mmol, 79.89% yield) as a yellow oil.

[0542] Step 2. Preparation of l-tert-butoxycarbonyl-2-methyl-piperidine-4-carboxylic acid

[0543] To a mixture of Oi-tert-butyl CL-methyl 2-methylpiperidine-l,4-dicarboxylate (6.8 g, 26.43 mmol, 1 eq) in THF (70 mL) and H2O (35 mL) was added LiOH (2.53 g, 105.70 mmol, 4 eq), the mixture was stirred at 25 °C for 16 hr. The mixture was concentrated in vacuo to remove THF, diluted with EtOAc (40 mL) and H2O (40 mL), treated with HC1 (1 M) aqueous solution until pH 5, and extracted with EtOAc (40 mL*3). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give l-tert-butoxycarbonyl-2-methyl-piperidine-4- carboxylic acid (5.75 g, 23.63 mmol, 89.43% yield) as a yellow solid.

[0544] Step 3. Preparation of tert-butyl 4-chlorocarbonyl-2-methyl-piperidine-l-carboxylate

[0545] To a mixture of l-tert-butoxycarbonyl-2-methyl-piperidine-4-carboxylic acid (2 g, 8.22 mmol, 1 eq) and DMF (60.00 mg, 820.86 pmol, 63.16 pL, 0.1 eq) in DCM (40 mL) was added (COC1)2 (1.57 g, 12.33 mmol, 1.08 mL, 1.5 eq) drop-wise at 0 °C, and the resulting mixture was stirred at 25 °C for 2 hr. The mixture was concentrated to give tert-butyl 4-chlorocarbonyl-2- methyl-piperidine-1 -carboxylate (4 g, crude) as a yellow oil.

[0546] Step 4. Preparation of tert-butyl 4-[(E)-2-methoxycarbonyl-3-(methylamino) but-2-enoyl]- 2-methyl-piperidine-l -carboxylate

[0547] To a mixture of methyl (Z)-3-(methylamino)but-2-enoate (1.18 g, 9.17 mmol, 1.2 eq) and pyridine (1.81 g, 22.92 mmol, 1.85 mL, 3 eq) in THF (20 mL) was added tert-butyl 4- chlorocarbonyl-2-methyl-piperidine-l-carboxylate (2 g, 7.64 mmol, 1 eq) drop-wise, and the resulting mixture was stirred at 25 °C for 17 hr. The mixture was poured into water (40 mL) and extracted with EtOAc (40 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether) to give tertbutyl 4-[(E)-2-methoxycarbonyl-3-(methylamino) but-2-enoyl]-2-methyl-piperidine-l- carboxylate (2 g, 5.64 mmol, 36.92% yield) as a yellow oil.

[0548] Step 5. Preparation of methyl 5-(l-tert-butoxycarbonyl-2-methyl-4-piperidyl) -3-methyl- isoxazole-4-carboxylate

[0549] To a mixture of tert-butyl 4-[(E)-2-methoxycarbonyl-3-(methylamino) but-2-enoyl] -2- methyl-piperidine-1 -carboxylate (2 g, 5.64 mmol, 1 eq) in MeOH (20 mL) was added aq.hydroxylamine (1.12 g, 16.93 mmol, 50% purity, 3 eq). The mixture was stirred at 60 °C for 2 hr. The mixture was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether) to give methyl 5-(l-tert-butoxycarbonyl-2-methyl-4-piperidyl) -3-methyLisoxazole-4-carboxylate (760 mg, 2.25 mmol, 39.80% yield) as a yellow oil.

[0550] Step 6. Preparation of methyl 3-methyl-5-(2-methyl-4-piperidyl) isoxazole-4-carboxylate HCl salt

[0551] To a mixture of methyl 5-(l-tert-butoxycarbonyl-2-methyl-4-piperidyl) -3-methyl- isoxazole-4-carboxylate (710 mg, 2.10 mmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (4 M, 5 mL), and the resulting mixture was stirred at 25 °C for 1 hr. The mixture was concentrated to give methyl 3-methyl-5-(2-methyl-4-piperidyl)isoxazole-4-carboxylate (520 mg, 1.89 mmol, 90.21% yield, HCl) as a white solid.

[0552] Step 7. Preparation of methyl 5- [l-[4-(l -ethoxycarbonylcyclopropyl) phenyl] -2-methyl-4- piperidyl]-3-methyl-isoxazole-4-carboxylate

[0553] To a mixture of methyl 3-methyl-5-(2-methyl-4-piperidyl) isoxazole-4-carboxylate (500 mg, 1.82 mmol, 1 eq, HCl) in dioxane (10 mL) were added CS2CO3 (1.78 g, 5.46 mmol, 3 eq), RuPhos Pd G3 (152.21 mg, 181.99 pmol, 0.1 eq) and ethyl l-(4- bromophenyl)cyclopropanecarboxylate (979.58 mg, 3.64 mmol, 2 eq) under N2, the mixture was stirred at 110 °C for 16 hr. The mixture was cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether) to give methyl 5-[l-[4-(l-ethoxycarbonylcyclopropyl)phenyl]-2- methyl-4-piperidyl]-3-methyl-isoxazole-4-carboxylate (420 mg, 984.75 pmol, 54.11% yield) as a yellow oil.

[0554] Step 8. Preparation of 5-[l-[4-(l -ethoxy carbonylcyclopropyl) phenyl] -2-methyl- 4- piperidyl ]-3-methyl-isoxazole-4-carboxylic acid

[0555] To a mixture of methyl 5-[l-[4-(l -ethoxy carbonylcyclopropyl) phenyl]-2-methyl- 4- piperidyl]-3-methyl-isoxazole-4-carboxylate (350 mg, 820.62 pmol, 1 eq) in THF (5 mL) and H2O (2.5 mL) was added LiOH (39.31 mg, 1.64 mmol, 2 eq), the mixture was stirred at 25 °C for 17 hr. HCl aqueous solution (IM) was added to adjust pH to 4, the resulting mixture was extracted with EtOAc (10 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 5-[l-[4-(l-ethoxy carbonylcyclopropyl) phenyl]-2- methyl-4-piperidyl]-3-methyl- isoxazole-4- carboxylic acid (270 mg, crude) as a yellow solid.

[0556] Step 9. Preparation of l-[4-[4-[4-(l-hydroxy-4-phenyl-butyl)-3-methyl- isoxazol-5-yl]-l- piperidyl / phenyl / cyclopropanecarboxylic acid

[0557] To a mixture of 5-[l-[4-(l-ethoxycarbonylcyclopropyl) phenyl]-2-methyl-4-piperidyl] -3- methyl-isoxazole-4-carboxylic acid (250.00 mg, 606.09 pmol, 1 eq) and (1R) -1 -phenylethanol (222.13 mg, 1.82 mmol, 219.93 pL, 3 eq) in toluene (4 mL) were added DPPA (250.20 mg, 909.14 pmol, 197.00 pL, 1 .5 eq) and TEA (122.66 mg, 1.21 mmol, 168.72 pL, 2 eq), and the mixture was stirred at 80 °C for 1 hr. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether) to give ethyl l-[4-[2-methyl-4-[3- methyl-4-[[(lR) - 1 -phenylethoxy] carbonylamino] isoxazol-5-yl]-l-piperidyl] phenyl] cyclopropanecarboxylate (120 mg, 225.72 pmol, 37.24% yield) as a yellow oil.

[0558] Step 10. Preparation of l-[4-[(2S,4S)-2-methyl-4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino ]isoxazol-5-yl ]-l -piperidyl Jphenyl cyclopropanecarboxylic acid and l-[ 4- [(2R, 4R)-2-methyl-4-[3-methyl-4-[[( I R)-l -phenylethoxy] carbonylamino] isoxazol-5-yl ]-l- piperidyl] phenyl] cyclopropanecarboxylic acid

[0559] To a mixture of ethyl l-[4-[2-methyl-4-[3-methyl-4-[[(lR) -1 -phenyl ethoxy] carbonylamino] isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarboxylate (110 mg, 206.91 pmol, 1 eq) in THF (2 mL), EtOH (1 mL) and H2O (1 mL) was added LiOH (24.78 mg, 1.03 mmol, 5 eq). The mixture was stirred at 60 °C for 3 hr. HC1 aqueous solution (IM) was added to adjust pH to 5, the resulting mixture was extracted with EtOAc (10 mL*3). The combined organic layer was dried over Na2SC>4, fdtered and concentrated in vacuo. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 12%-42%, 10 min) to give the off-white solid which was further separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, lOum); mobile phase: [0.1%NH3H2O in MEOH]; B%: 30%-30%, 3.5 min) to successively give l-[4-[(2S,4S)-2-methyl-4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarboxylic acid (12.56 mg, 24.94 pmol, 12.05% yield, 100% purity) and l-[4-[(2R,4R)-2-methyl-4-[3-methyl-4- [[(1R)-1 -phenylethoxy] carbonylamino] isoxazol-5-yl]-l-piperidyl]phenyl] cyclopropanecarboxylic acid (13.1 mg, 26.01 umol, 12.57% yield, 100% purity), both off-white solids. The absolute configurations of the two chiral centers on the piperidine ring were unknown, and the relative configuration was cis. l-[4-[(2S,4S)-2-methyl-4-[3-methyl-4-[[(lR)-l-phenylethoxy]carbonylamino]isoxazol-5- yl]-l-piperidyl]phenyl]cyclopropanecarboxylic acid (Compound 10): 'H NMR (400 MHz, MeOD-d4) 8 = 7.48 - 7.26 (m, 7H), 7.14 (d, J = 8.3 Hz, 2H), 5.84 - 5.73 (m, 1H), 3.23 - 3.10 (m, 1H), 3.06 - 2.90 (m, 2H), 2.85 - 2.75 (m, 1H), 2.11 (s, 3H), 2.05 - 1.87 (m, 3H), 1.74 - 1.63 (m, 1H), 1.61 - 1.51 (m, 5H), 1.21 - 1.12 (m, 2H), 0.89 (d, J = 6.1 Hz, 3H). [M+H]+= 504.2. l-[4-[(2R,4R)-2-methyl-4-[3-methyl-4-[[(lR)-l -phenyl ethoxy]carbonylamino]isoxazol- 5-yl]- l-piperidyl]phenyl]cyclopropanecarboxylic acid (Compound 21):JH NMR (400 MHz, MeOD-d4) 5 = 7.50 - 7.22 (m, 7H), 7.14 (d, J = 8.3 Hz, 2H), 5.86 - 5.68 (m, 1H), 3.21 - 3.10 (m, 1H), 3.06 - 2.90 (m, 2H), 2.85 - 2.75 (m, 1H), 2.11 (s, 3H), 2.03 - 1.86 (m, 3H), 1.77 - 1.63 (m, 1H), 1.62 - 1.52 (m, 5H), 1.18 - 1.13 (m, 2H), 0.90 (d, J = 5.7 Hz, 3H). [M+H+] = 504.2.

[0560] Example 10. Preparation of l-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l-carboxylic acid (Compound 33)

[0561] Step 1. Preparation of methyl !-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy ] carbonyl }amino)-l, 2-oxazol-5-yl ]-2-azaspiro[ 3.3 ]heptan-2- yl}phenyl)cyclopropane-l-carboxylate

[0562] To a solution of 5-(2-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl}-2- azaspiro[3.3 ]heptan-6-yl)-3 -methyl- l,2-oxazole-4-carboxylic acid (0.3 g, 757 pmol) in toluene (15 mb) were added triethylamine (211 pL, 2 eq., 1.51 mmol), (lR)-l-(2-methylphenyl)ethan-l- ol (309 mg, 3 eq., 2.27 mmol) stirred reaction mixture at 50 °C. Then added {[azido(phenoxy)phosphoryl]oxy (benzene (196 pL, 1.2 eq., 908 pmol). The mixture was stirred at 85 °C for 3 h. Reaction was progressed by TLC, rm was diluted with water (20 mL) extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 50%) to afford methyl l-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy]carbonyl (amino)- l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l -carboxylate as yellowish liquid (Yield; 280 mg, 70% ) MS (ES) m z 530.3 (M+H)+.

[0563] Step 2. Preparation of l-(4-{6-[3-methyl-4-({[(lR)-l-(2-methylphenyl)ethoxy carbonyl}amino)-l , 2-oxazol-5-yl]-2-azaspiro[ 3.3 ]heptan-2-yl}phenyl)cyclopropane-l -carboxylic acid

[0564] To a solution of methyl l-(4-{6-[3-methyl-4-({ [(lR)-l-(2-methylphenyl) ethoxy] carbonyl } amino)- 1 ,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl }phenyl)cyclopropane- 1 - carboxylate (280 mg, 529 pmol) in oxolane (4.00 mL), methanol (4.00 mL) was added lithium(l+) hydrate hydroxide (111 mg, 5 eq., 2.64 mmol) in water (4.00 mL) at room temperature and stirred at the same temperature for 18 hours. Reaction was progressed by LCMS and TLC, reaction mas was concentrated, diluted with water (20 mL), PH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on Buchner funnel, solid was washed with water (2 x 25 mL), pentane (2 x 25 mL) and dried under vacuum to afford l-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropane-l -carboxylic acid (Yield:40 mg, 15%) as white solid. (Yield: 15 mg, 15%) MS (ES) m / z 516.3 (M+H)+.

[0565] ‘H NMR (400 MHz, DMSO-de): 5 12.01 (s, 1H), 8.87 (s, 1H), 7.39 (d, J = 6.4 Hz, 1H), 7.21-7.15 (m, 3H), 7.06 (d, J= 8.4 Hz, 2H), 6.29 (d, J= 8.8 Hz, 2H), 5.88-5.83 (m, 1H), 3.80 (s, 2H), 3.65 (s, 2H), 3.44-3.31 (m, 1H), 2.48-2.38 (m, 4H ), 2.35 (s, 3H ), 2.05 (s, 3H ), 1.47 (d, J = 5.6 Hz, 3H), 1.32 (d, .7= 2.8 Hz, 2H), 0.96 (d, .7= 1.6 Hz, 2H).

[0566] Example 11. Preparation of l-(4-{4-[5-chloro-3-({[(lR)-l-phenylethoxy]carbonyl} amino)thiophen-2-yI]piperidin-l-yl}phenyl)cyclopropane-l-carboxylic acid (Compound 92) Step 1. Preparation of tert-butyl 4-(5-chloro-3-(ethoxycarbonyl) thiophen-2-yl) piperidine- 1-carboxylate

[0567] To a stirred solution of tert-butyl 4-[3-(ethoxycarbonyl) thiophen-2-yl] piperidine-1- carboxylate (0.2 g, 0.29 mmol) in DMF (2 mL) was added NCS (177 mg, 1.18 mmol) at rt in sealed tube. The reaction mixture was stirred at rt for 3 hours. The progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the reaction mixture was quenched with ice (20 mL), extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 20%) to afford tert-butyl 4-[5-chl oro-3 - (ethoxy carbonyl)thiophen-2-yl] piperidine- 1 -carboxylate as a viscous liquid (125 mg, 57% yield); MS (ES) m / z 274.1 (M+1H)+ (-100 mass, boc cleavage mass was observed in LCMS).!H NMR (400 MHz, CDC13): 8 7.20 (s, 1H), 4.28 (q, J= 7.2 Hz, 2H), 4.14 - 4.11 (m, 2H), 3.93 - 3.87 (m, 1H), 2.81 - 2.61 (m, 2H), 1.50 - 1.47 (m, 2H), 1.49 (s, 9H), 1.35 (t, J= 7.0 Hz, 3H).

[0568] Step 2. Preparation of 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-chlorothiophene- 3- carboxylic acid

[0569] To a solution of tert-butyl 4-[5-chloro-3-(ethoxy carbonyl )thiophen-2-yl] piperidine- 1- carboxylate (200 mg, 0.535 mmol) in methanol (20 mL) was added sodium hydroxide (64.2 mg, 1.6 mmol) in water (5 mL) at room temperature and stirred at the same temperature for 18 hours. Progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, it was concentrated, diluted with water (50 mL), pH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, fdtered on buchnel funnel, solid was washed with water (2 x 15 mL), pentane (2 x 20 mL) and dried under vacuum to afford 2-{l-[(tert-butoxy)carbonyl]piperidin- 4-yl}-5-chlorothiophene-3 -carboxylic acid as a pale yellow solid (160 mg, 86% yield); MS (ES) m / z 246.1 (M+H)+. (-100 mass was observed by LCMS).

[0570] Step 3. Preparation of 5-chloro-2-(piperidin-4-yl)thiophene-3-carboxylic acid hydrochloride

[0571] To a solution of 2-{ l-[(tert-butoxy)carbonyl]piperidin-4-yl}-5-chlorothiophene- 3- carboxylic acid (0.18 g, 0.52 mmol) in Dichloromethane (20 mL) was added 4 M HC1 in Dioxane (2.6 mL, 10.4 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 8 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated to afford 2-(piperidin-4-yl) thiophene-3-carboxylic acid hydrochloride as a pale yellow solid (147 mg, crude). MS (ES) m / z 245.8 (M+1H)+. (Free amine mass).

[0572] Step 4. Preparation of 5-chloro-2-(l-(4-(l-(methoxycarbonyl) cyclopropyl)phenyl) piperidin-4-yl)thiophene-3-carboxylic acid

[0573] To a stirred solution of 5-chloro-2-(piperidin-4-yl)thiophene-3-carboxylic acid hydrochloride (90 mg, 0.31 mmol) and methyl l-(4-bromophenyl) cyclopropane- 1 -carboxylate (89.5 mg, 0.35 mmol) in DMF (8 m ) under N2 atm, was added CS2CO3 (312 mg, 0.95 mmol) then purged with N2 gas 3 mins, then added dicyclohexyl[2',4',6'-tris(propan-2-yl)-[l,r-biphenyl]-2- yl]phosphane (15.2 mg, 0.032 mmol), tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (14.6 mg, 0.016 mmol) and the mixture was stirred at 100 °C for 8 hours in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, it was cooled to rt and filtered through celite, and concentrated then diluted with water and washed with diethyl ether (2 x 25 mL), then aq. layer was acidified with citric acid pH-5 then extracted with ethyl acetate (2 x 50 mL), washed with water (25 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 5-chloro-2-(l-{4-[l- (methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)thiophene-3-carboxylic acid as a pale brown gum (130 mg, crude); MS (ES) m / z 420.1 (M+H)+.

[0574] Step 5. Preparation of methyl (R)-l-(4-(4-(5-chloro-3-(((l-phenylethoxy) carbonyl)amino)thiophen-2-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylate

[0575] To a solution of diphenylphosphinoyl azide (0.123 mL, 0.572 mmol) and TEA (0.08 mL, 0.572 mmol) were added to a solution of 5-chloro-2-(l-{4-[l-(methoxycarbonyl) cyclopropyl] phenyl }piperidin-4-yl)thiophene-3- carboxylic acid (200 mg, 0.476 mmol) in Toluene (15 mL) at 50 °C. The mixture was stirred at 50 °C for 30 minutes, then added (1R)-1 -phenyl ethan-l-ol (0.235 mL, 1.91 mmol). The mixture was stirred at 90 °C for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, it was diluted with water (30 mL) extracted with ethyl acetate (2 x 75 mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 20%) to afford methyl l-(4-{4-[5-chloro-3-({[(lR)-l- phenylethoxy]carbonyl}amino) thiophen-2-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylate as a pale yellow gum (120 mg, 46% yield); MS (ES) m / z 539.2 (M+H)+. Step 6. Preparation of (R)-l-(4-(4-(5-chloro-3-(((l-phenylethoxy)carbonyl)amino) thiophen-2-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylic acid

[0576] To a solution of methyl l-(4-{4-[5-chloro-3-({[(lR)-l-phenylethoxy]carbonyl} amino)thiophen-2-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylate (100 mg, 0.185 mmol) in THF (7 mb) and methanol (7 mL) was added lithium(l+) hydrate hydroxide (31.1 mg, 0.74 mmol) in water (4 mL) at room temperature, and stirred at the same temperature for 18 hours. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, it was concentrated, diluted with water (10 mL), pH was adjusted with 10% Aq. citric acid up to 3 to 4, then extracted with ethyl acetate (2 x 25 mL), washed with water (20 mL), brine solution (10 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product, it was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 70%) to afford 1 -(4-{4-[5-chl oro-3- ({[(lR)-l-phenylethoxy]carbonyl}amino)thiophen-2-yl]piperidin-l- yl}phenyl)cyclopropane-l -carboxylic acid as an off white solid (55 mg, 56% yield); MS (ES) m / z 525.1 (M+H)1. 'H NMR (400 MHz, DMSO-tfc): 8 12.12 (s, 1H), 9.35 (s, 1H), 7.37 - 7.22 (m, 5H), 7.13 - 7.05 (m, 3H), 6.84 (d, J= 8.8 Hz, 2H), 5.74 (q, J= 6.8 Hz, 1H), 3.68 - 3.67 (m, 2H), 3.30 - 3.15 (m, 1H), 2.65 - 2.60 (m, 2H), 1.96 - 1.86 (m, 2H), 1.54 - 1.46 (m, 5H), 1.37 (d, J= 4.0 Hz, 2H), 1.04 (d, .7= 3.6 Hz, 2H).

[0577] Example 12. Preparation of (R)-l-(4-(4-(4-methoxy-2-(((l-phenylethoxy)carbonyl) amino)phenyl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylic acid (Compound 19)

[0578] Step 1. Preparation of tert-butyl 4-(2-amino-4-methoxy-phenyl)-3, 6-dihydro-2H-pyridine- 1-carboxylate

[0579] To a mixture of 2-bromo-5-methoxy-aniline (1.30 g, 6.43 mmol, 1 eq) and tert-butyl 4-(4, 4, 5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-3, 6-dihydro-2H-pyridine-l-carboxylate (1.99 g, 6.43 mmol, 1 eq) in DMF (20 mL) were added 2 M aq. NaOH (6.43 mL, 12.86 mmol, 2 eq) and Pd(dppf)Ch (471 mg, 643 umol, 0.1 eq), the mixture was stirred at 15 °C for 1 hr under N2. H2O (50 mL) was added, and the resulting mixture was extracted with EtOAc (50 mL*3), the combined organic phase was washed by NaCl saturated solution (30 mL*3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether) to give tertbutyl 4-(2-amino-4-methoxy-phenyl)-3, 6-dihydro-2H-pyridine-l -carboxylate (1.7 g, 5.59 mmol, 86.80% yield) as a yellow oil.

[0580] Step 2. Preparation of 4-(2-amino-4-methoxy-phenyl) iperidine-l-carboxylate

[0581] To a mixture of tert-butyl 4-(2-amino-4-methoxy-phenyl)-3,6-dihydro-2H-pyridine- 1- carboxylate (1.7 g, 5.59 mmol, 1 eq) in MeOH (20 mL) was added Pd / C (500 mg, 5% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred at 40 °C for 36 hr under H2 (15 Psi). The mixture was filtered, the filtrate was concentrated to give 4-(2-amino-4-methoxy-phenyl) iperidine-l-carboxylate (1.41 g, crude) as a black oil.

[0582] Step 3. Preparation of tert-butyl 4-[4-methoxy-2-(phenoxycarbonylamino) phenyl] piperidine-I-carboxylate

[0583] To a mixture of tert-butyl 4-(2-amino-4-methoxy-phenyl) iperidine-l-carboxylate (1.4 g, 4.57 mmol, 1 eq) in DCM (20 mL) were added pyridine (723 mg, 9.14 mmol, 737.60 uL, 2 eq) and phenyl carbonochloridate (1.07 g, 6.85 mmol, 859 uL, 1.5 eq), the mixture was stirred at 15 °C for 1 hr. The mixture was poured into water (10 mL) and extracted with EtOAc (40 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether) to give tert-butyl 4-[4-methoxy-2- (phenoxycarbonylamino)phenyl]piperidine-l -carboxylate (1.6 g, 3.75 mmol, 82.10% yield) as a yellow oil.

[0584] Step 4. Preparation of tert-butyl 4- [4-methoxy-2-[[(lR)-l -phenylethoxy] carbonylamino] phenyl / piperidine-l-carboxylate

[0585] To a mixture of tert-butyl 4-[4-methoxy-2-(phenoxycarbonylamino)phenyl]piperidine- 1- carboxylate (1.33 g, 3.11 mmol, 1 eq) in DMF (5 mL) was added NaH (187 mg, 4.67 mmol, 60% purity, 1.5 eq) batch-wise, the mixture was stirred at 0 °C for 0.5 hr, then (1R)-1 -phenylethanol (0.38 g, 3.11 mmol, 376 uL, 1 eq) was added drop-wise at 15 °C, the mixture was stirred at 15 °C for 0.5 hr. The mixture was poured into NH4CI saturated solution (40 mL) and extracted with EtOAc (40 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether) to afford tert-butyl 4-[4- methoxy-2-[[(lR)-l-phenylethoxy] carbonylamino]phenyl]piperidine-l -carboxylate (780 mg, 1.72 mmol, 55.17% yield) as a pink oil.

[0586] Step 5. Preparation of [(1R)-1 -phenylethyl] N-[5-methoxy-2-(4-piperidyl) phenyl] carbamate

[0587] To a mixture of tert-butyl 4-[4-methoxy-2-[[(lR)-l-phenylethoxy]carbonylamino] phenyl]piperidine-l -carboxylate (780 mg, 1.72 mmol, 1 eq) in i-PrOH (5 mL) was added HCl / di oxane (4 M, 1 mL), the mixture was stirred at 15 °C for 16 hr. The mixture was poured into NaHCCh saturated solution (20 mL), and extracted with EtOAc (40 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give [(1R)-1 -phenylethyl] N- [5-methoxy-2-(4-piperidyl) phenyl] carbamate (524 mg, crude) as a yellow solid.

[0588] Step 6. Preparation of ethyl l-[4-[4-[4-methoxy-2-[[(lR)-l-phenylethoxy] carbonylamino] phenyl] -1 -piperidyl] phenyl] cyclopropanecar boxy late

[0589] To a mixture of [(IR)-l-phenylethyl] N-[5-methoxy-2-(4-piperidyl)phenyl]carbamate (470 mg, 1.33 mmol, 1 eq) and [4-(l -ethoxy carbonylcy cl opropyl)phenyl] boronic acid (621 mg, 2.65 mmol, 2 eq) in DCM (10 mL) were added TEA (269 mg, 2.65 mmol, 369 uL, 2 eq) and Cu(OAc)2 (240.85 mg, 1.33 mmol, 1 eq), and the mixture was stirred at 40 °C for 16 hr under O2 atmosphere. The mixture was filtered, the filtrate was concentrated. The residue was purified by reversed-phase MPLC (0.1 % FA condition) to give ethyl l-[4-[4-[4-methoxy-2-[[(lR)-l -phenylethoxy] carbonylamino] phenyl]- 1 -piperidyl] phenyl] cyclopropanecarboxylate (400 mg, 737.10 umol, 55.59% yield) as a yellow oil.

[0590] Step 7. Preparation of 1 - [4- [4-[4-methoxy-2-[](lR)-l -phenylethoxy] carbonylamino] phenyl]-! -piperidyl] phenyl] cyclopropanecarboxylic acid

[0591] To a mixture of ethyl l-[4-[4-[4-methoxy-2-[[(lR)-l-phenylethoxy] carbonylamino]phenyl]-l-piperidyl]phenyl]cyclopropanecarboxylate (400 mg, 737.10 umol, 1 eq) in THF (5 mL) and H2O (5 mL) was added LiOH (53 mg, 2.21 mmol, 3 eq), the mixture was stirred at 70 °C for 32 hr. HC1 aqueous solution (1 M) was added into the mixture to adjust the pH to 4, the resulting mixture was extracted with EtOAc (40 mL*3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (lOmM NH4HCOs)-ACN]; B%: 27%- 57%, lOmin) and prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(0.225%FA)-ACN]; B%: 35%-65%,10min), followed by lyophilization to give l-[4-[4-[4- methoxy-2-[[(lR)-l-phenylethoxy]carbonyl amino]phenyl]-l-piperidyl] phenyl] cyclopropanecarboxylic acid (93.69 mg, 182.06 umol, 24.70% yield, 100% purity) as a white solid. [M+H]+= 515.21H NMR (400 MHz, MeOD-d4) 5 = 7.47 - 7.37 (m, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 - 7.16 (m, 4H), 6.95 (d, J = 8.8 Hz, 2H), 6.88 - 6.75 (m, 2H), 5.80 (q, J = 6.6 Hz, 1H), 3.74 (s, 3H), 3.73 - 3.61 (m, 2H), 2.83 - 2.65 (m, 2H), 2.64 - 2.52 (m, 1H), 1.84 - 1.69 (m, 4H), 1.60 - 1.51 (m, 5H), 1.19 - 1.11 (m, 2H).

[0592] Example 13. Preparation of (R)-l-(4-(4-(l-methyl-5-(((l- phenylethoxy)carbonyl)amino)-lH-l,2,3-triazol-4-yl)piperidin-l-yl)phenyl)cyclopropane-l- carboxylic acid (Compound 60)

[0593] Step 1. Preparation of tert-butyl 4-(2,2-dibromovmyl)piperidine-l-carboxylate

[0594] To a stirred solution of tetrabromomethane (15.5 g, 2 eq., 46.9 mmol) in di chloromethane (50 mL) was added dropwise a solution of triphenylphosphane (24.6 g, 4 eq., 93.8 mmol) in dichloromethane (50 mL) at 0 °C, and the reaction temperature maintained 20 mins, was added dropwise a solution of tert-butyl 4-formylpiperidine-l -carboxylate (5 g, 23.4 mmol) in dichloromethane (50 mL) at 0 °C, and the mixture was stirred at RT for 12 h. Progress of the reaction was monitored by TLC and LCMS. This solution was diluted with diethyl ether (200 ml), and the precipitate was filtered off. The filtrate was concentrated in vacuo to get crude. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 10%) to afford tert-butyl 4-(2, 2-dibromoethenyl)piperi dine- 1 -carboxylate (4.5 g, 46% yield) as off white solid; MS (ES) m / z 269.0 (M+H)+, (M-100, boc mass cleaved in LCMS).

[0595] 'H NMR (400 MHz, CDCh-d): 8 6.20 (d, J = 9.2 Hz, 1H), 4.05 (s, 2H), 2.76 (t, J = 12.4 Hz, 2H), 2.40 - 2.03 (m, 1H), 1.70 (d, J = 12. 4 Hz, 2H), 1.60 (s, 1H), 1.44 (s, 9H), 1.30 (q, = 3.6 Hz, 2H).

[0596] Step 2. Preparation of tert-butyl 4-(3-ethoxy-3-oxoprop-l-yn-l-yl)piperidine-l- carboxylate

[0597] To a stirred solution of tert-butyl 4-(2,2-dibromoethenyl)piperidine-l -carboxylate (5 g, 13.5 mmol) in THF (100 mL) was added butyllithium (19 mL, 2.1 eq., 28.4 mmol) at -78 °C under a nitrogen atmosphere, and the mixture was stirred at -78 °C for 1 h and at 0 °C for 1 h. ethyl carb onochlori date (4.77 mL, 3.7 eq., 50.1 mmol) in THF ( 50 mL) was added at -78 °C, and the reaction mixture was allowed to room temperature and continued to stir for 8 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the resulting mixture was quenched ice cold water (lOOmL), and extracted with Ethyl acetate (2 x 100 mL). The extract was washed with brine, dried and evaporated. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 15%) to afford tert-butyl 4-(3 -ethoxy-3 -oxoprop- 1- yn-l-yl)piperidine-l -carboxylate (288 mL, 8 l%yield) as pale yellow liquid; MS (ES) m z 182.1 (M+H)+, (M-100, boc mass cleaved in LCMS). rH NMR (400 MHz, CDCh-d): 84.27 - 4.21 (m, 2H), 3.76 - 3.70 (m, 2H), 3.23 - 3.17 (m, 2H), 2.76 - 2.70 (m, 1H), 1.88 - 1.81 (m, 2H), 1.74 - 1.62 (m, 2H), 1.54 (s, 9H), 1.33 - 1.23 (m, 3H).

[0598] Step 3. Preparation of tert-butyl 4-(5-(ethoxycarbonyl)-l-((trimethylsilyl)methyl)-lH- 1, 2, 3-triazol-4-yl)piperidine-l -carboxylate

[0599] To a stirred solution of tert-butyl 4-(3-ethoxy-3-oxoprop-l-yn-l-yl)piperidine-l- carboxylate (1.4 g, 4.98 mmol) in toluene (7.98 mL, 67.5 mmol) was added (azidomethyl)trimethylsilane (2.93 mL, 4 eq., 19.9 mmol), heated to 110 °C for 8hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction mixture was cooled to room temperature and concentrated under reduced pressure. Crude mass was purified by normal silica gel column chromatography using ethyl acetate-hexane (10% to 15%) as eluting solvent to get two major fractions. The regio-chemistry was assigned by the 1H NOE study. One fraction is tert-butyl 4-[5-(ethoxy carbonyl)- l-[(trimethylsilyl)methyl]-lH-l, 2, 3-triazol-4-yl]piperidine-l- carboxylate (1 .2 g, yield 58%) as light yellow liquid and other major fraction gave tert-butyl 4-[4- (ethoxycarbonyl)-l-[(trimethylsilyl)methyl]-lH-l,2,3-triazol-5-yl]piperidine-l-carboxylate (1 g, yield 48%) as white solid; LC-MS (M + H)+ 411.3 (m / e);

[0600] Step 4. Preparation of tert-butyl 4-(5-(ethoxycarbonyl)~ 1 -methyl- 1H-1, 2, 3-triazol-4- yl)piperidine-l -carboxylate

[0601] To a stirred solution of tert-butyl 4-[5-(ethoxycarbonyl)-l-[(trimethylsilyl)methyl]-lH-

[0602] 1.2.3 -triazol-4-yl]piperi dine- 1 -carboxylate (2.2 g, 5.36 mmol) in tetrahydrofuran (34.4 mL, 422 mmol) were added water (193 mg, 2 eq., 10.7 mmol) and TBAF IM solution in THF (1.68 g, 1.2 eq., 6.43 mmol) at 0°C, maintained at same temperature for Ihour. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was concentrated under reduced pressure to yield crude residue. Residue was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 25%) to afford tert-butyl 4-[5-(ethoxycarbonyl)-l-methyl-lH-

[0603] 1.2.3 -triazol-4-yl]piperi dine- 1 -carboxylate (666 mg, 36% yield) as yellow gummy solid; MS (ES) m / z 339 (M+H)1but deboc mass MS (ES) m / z 283.2 (M-56)1was observed in LCMS.

[0604] 'H NMR (400 MHz, CDCh-d): 5 4.43 (q, J = 6.8 Hz, 2H), 4.29 (s, 3H), 4.26 - 4.24 (m, 2H), 3.34 - 3.36 (m, 1H), 2.88 - 2.82 (m, 2H), 1.92 - 1.79 (m, 4H), 1.54 (s, 9H), 1.40 (t, J = 7.2 Hz, 2H).

[0605] Step 5. Preparation of 4-( 1 -(tert-butoxycarbonyl)piper idin-4-yl)-l -methyl- 1H- 1,2,3 - triazole-5-carboxylic acid

[0606] To a stirred solution of tert-butyl 4-[5-(ethoxycarbonyl)-l-methyl-lH-l,2,3-triazol-4- yl]piperidine-l -carboxylate (0.6 g, 1.77 mmol) in ethanol (5 mL, 171 mmol) was added sodium hydroxide (284 mg, 4 eq., 1.77 mmol) by dissolving in water (5 mL, 278 mmol) at 0 °C, maintained reaction mass at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 1 N HC1 solution and stirred for lOminutes. Product got precipitated, precipitated product was filtered, washed with dichloromethane and dried over sodium sulphate, concentrated to yield crude product 4-{ l-[(tert-butoxy)carbonyl]piperidin-4-yl}- 1 -methyl- 1H-1, 2, 3-triazole-5-carboxylic acid (520 mg, 94% yield) as off white solid; MS (ES) m / z 309.1 (M-1H)+. Step 6. Preparation of l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride

[0607] To a stirred solution of 4-{ l-[(tert-butoxy)carbonyl]piperidin-4-yl}-l-methyl-lH-l,2,3- triazole-5-carboxylic acid (0.6 g, 1.93 mmol) in dichloromethane (20 mb, 312 mmol) were added 1,4-dioxane hydrochloride (1.44 g, 6 eq., 11.6 mmol) at 0 °C, and stirred reaction mixture at room temperature for 12 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated, washed with pentane, dried under vacuum to obtain product l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (450 mg, crude) as white solid; MS (ES) m / z 211.1 (M+H)+.

[0608] Step 7. Preparation of 4-(l-(4-(l-(methoxycarbonyl)cyclopropyl)phenyl)piperidin-4-yl)-l- methyl-lH-1, 2, 3-lriazole-5-carboxylic acid

[0609] To a stirred solution of l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (510 mg, 2.07 mmol) in dimethylformamide (15 mL, 194 mmol) were added Cesium carbonate (2.69 g, 4 eq., 8.27 mmol), methyl l-(4-bromophenyl)cyclopropane-l- carboxylate (633 mg, 1.2 eq., 2.48 mmol) and X-phos (98.6 mg, 0.1 eq., 207 pmol), purged under argon gas for 15 minutes. Finally added Pd2(dba)3 (94.7 mg, 0.05 eq., 103 pmol) and heated reaction mixture to 100 °C for 16 hours inside sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq. layer was acidified with 10% citric acid until pH is acidic, then extracted with ethyl acetate (2 x 100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 4-(l-{4-[l- (methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-l-methyl-lH-l,2,3-triazole-5-carboxylic acid (452 mg, yield 56%) as brown solid; MS (ES) m / z 385.2 (M+1H)+.

[0610] Step 8. Preparation of methyl (R)-l-(4-(4-(l-methyl-5-(((l-phenylethoxy)carbonyl)amino)- 1H-1,2, 3-triazol-4-yl)piperidin-l-yl)phenyl)cyclopropane-l -carboxylate

[0611] To a stirred solution of 4-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)- 1 -methyl- 1H-1, 2, 3-triazole-5-carboxylic acid (0.2 g, 520 pmol) in toluene (5 mL) were added triethylamine (79.5 pL, 1.1 eq., 572 pmol) and (IR)-l-phenylethan-l-ol (254 mg, 4 eq., 2.08 mmol), heated reaction mixture to 50°C, for 20 minutes. Then added DPPA (124 pL, 1.1 eq., 572 pmol), heated to 85°C, maintained for 3 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was diluted with water (20 mL) extracted with ethyl acetate (2 x 25mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (41% to 70%) to afford methyl l-(4-{4-[l-methyl-5-({[(lR)-l- phenylethoxy]carbonyl }amino)- 1 H- 1 ,2,3 -triazol-4-yl]piperidin- 1 -yl }phenyl)cyclopropane- 1 - carboxylate (108 mg, Yield 41%); MS (ES) m / z 504.3 (M+H)+.

[0612] Step 9. Preparation of (R)-l-(4-(4-(l-methyl-5-(((l-phenylethoxy)carbonyl)amino)-lH- 1, 2, 3-triazol-4-yl)piperidin-l-yl)phenyl)cyclopropane-l -carboxylic acid

[0613] To a stirred solution of methyl l-(4-{4-[l-methyl-5-({[(lR)-l- phenylethoxy]carbonyl ) amino)- 1H- 1 ,2,3 -triazol-4-yl]piperidin- 1 -yl }phenyl)cyclopropane- 1 - carboxylate (0.1 g, 199 pmol) in tetrahydrofuran (1.96 mL, 24 mmol) and methanol (1.96 mL, 48.3 mmol) was added LiOH.H2O (33.3 mg, 4 eq., 794 pmol) in water (1.96 mL, 109 mmol) at 0°C, stirred for 10 minutes. Finally maintained reaction at room temperature for 16hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for lOminutes. Product was precipitated, filtered and washed with pentane(10 mL) to yield product l-(4-{4-[l-methyl-5-({[(lR)-l-phenylethoxy]carbonyl}amino)-lH-l,2,3-triazol-4- yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylic acid (55 mg, crude) as off white solid; MS (ES) m / z 430.3 (M+1H)+. rH NMR (400 MHz, DMSO-de): 5 7.89 (s, 1H), 7.81 (d, . / - 7.6 Hz, 1H), 7.51 (d, J= 7.6 Hz, 1H), 7.41 (d, J= 7.6 Hz, 1H), 5.15 (s, 2H), 4.05 (s, 3H), 3.60 (m, 2H), 3.31 (s, 2H), 3.11 (d, J = 5.6 Hz, 2H), 2.79 (s, 3H), 2.77 - 2.68 (m, 1H), 2.06 (t, J= 10 Hz, 2H), 1.86 - 1.80 (m, 2H), 1.79 - 1.68 (m, 2H),1.43 (s, 2H), 0.76 (t, J= 6 Hz, 3H).

[0614] Example 14. Preparation of l-(4-{4-[5-({[(lR)-l-(2- chlorophenyl)ethoxy]carbonyl}amino)-l-methyl-lH-l,2,3-triazol-4-yl]piperidin-l- yl}phenyl)cyclopropane-l-carboxylic acid (Compound 27)

[0615] Step 1. Preparation of tert-butyl 4-(2,2-dibromovinyl)piperidine-l -carboxylate

[0616] To a stirred solution of tetrabromomethane (15.5 g, 2 eq., 46.9 mmol) in di chloromethane (50 mL) was added dropwise a solution of triphenylphosphane (24.6 g, 4 eq., 93.8 mmol) in dichloromethane (50 mL) at 0 °C, and the same temperature was maintained for 20 min, then dropwise addition of a solution of tert-butyl 4-formylpiperidine-l -carboxylate (5 g, 23.4 mmol) in di chloromethane (50 mL) at 0 °C, and the mixture was stirred at rt for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with diethyl ether (200 ml), and the precipitate was filtered off. The filtrate was concentrated in vacuo to get crude. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 10%) to afford tert-butyl 4-(2,2-dibromoethenyl)piperidine-l- carboxylate (4.5 g, 52% yield) as an off white solid; MS (ES) m / z 269.0 (M+H)+, (M-100, boc mass cleaved in LCMS).

[0617] 1H NMR (400 MHz, CDCh): 8 6.20 (d, J = 9.2 Hz, 1H), 4.05 (s, 2H), 2.76 (t, J = 12.4 Hz, 2H), 2.40 - 2.03 (m, 1H), 1.70 (d, J= 12. 4 Hz, 2H), 1.60 (s, 1H), 1.44 (s, 9H), 1.30 (q, J= 3.6 Hz, 2H).

[0618] Step 2. Preparation of tert-butyl 4-(3-ethoxy-3-oxoprop-l-yn-l-yl)piperidine-l- carboxylate

[0619] To a stirred solution of tert-butyl 4-(2,2-dibromoethenyl)piperidine-l -carboxylate (5 g, 13.5 mmol) in THF (100 mL) was added n-butyl lithium 1.6M solution in hexane (19 mL, 2. 1 eq., 28.4 mmol) at -78°C under nitrogen atmosphere, and the mixture was stirred at -78°C for 1 h and at 0 °C for 1 h. Ethylchloroformate (4.77 mL, 3.7 eq., 50.1 mmol) in THF ( 50 mL) was added at -78°C, and the reaction mixture was allowed to warm up at room temperature and continued to stir for 8 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the resulting mixture was quenched ice cold water (lOOmL), and extracted with ethyl acetate (2 x 50 mL). The extract was washed with brine, dried and evaporated. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 15%) to afford tert-butyl 4-(3 -ethoxy - 3-oxoprop-l-yn-l-yl)piperidine-l-carboxylate (3.2 g, 83% yield) as a yellow liquid; MS (ES) m / z 182.1 (M+H)+, (M-100, boc mass cleaved in LCMS).

[0620] ‘HNMR (400 MHz, CDCh): 84.21 (q, J= 8 Hz, 2H), 3.72 - 3.69 (m, 2H), 3.17 - 3.14 (m, 2H), 2.70- 2.00 (m, 1H), 1.83 - 1.80 (m, 2H), 1.67 - 1.60 (m, 2H), 1.14 (s, 9H), 1.36 - 1.30 (m, 3H).

[0621] Step 3. Preparation of tert-butyl 4-(5-(ethoxycarbonyl)-l-((trimethylsilyl)methyl)-lH-

[0622] 1.2.3-triazol-4-yl)piperidine-l-carboxylate

[0623] To a stirred solution of tert-butyl 4-(3-ethoxy-3-oxoprop-l-yn-l-yl)piperidine-l- carboxylate (0.5 g, 1.78 mmol) in toluene (2.85 mL, 24.1 mmol) was added (azidomethyl)trimethylsilane (919 mg, 4 eq., 7.11 mmol) and the reaction mixture was heated to 110°C for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Crude mass was purified by normal silica gel column chromatography using ethyl acetate-hexane (10% to 15%) as eluting solvent to get two major fractions. The regio-chemistry was assigned by the 'H NOE study. One fraction is tert-butyl 4-[5-(ethoxycarbonyl)-l- [(trimethylsilyl)methyl]-lH-l,2,3-triazol-4-yl]piperidine-l-carboxylate (324 mg, 44% yield) as a light yellow liquid and other major fraction gave tert-butyl 4-[4-(ethoxycarbonyl)-l- [(trimethylsilyl)methyl]-lH-l,2,3-triazol-5-yl]piperidine-l-carboxylate (254 mg, 34% yield) as a white solid; LC-MS (M + H)+411.3 (m / z).

[0624] Step 4. Preparation of tert-butyl 4-(5-(ethoxycarbonyl)-l-methyl-l I-l,2,3-triazol-4- yl)piperidine- 1 -carboxylate

[0625] To a stirred solution of tert-butyl 4-[5-(ethoxycarbonyl)-l-[(trimethylsilyl)methyl]-lH-

[0626] 1.2.3 -triazol-4-yl]piperi dine- 1 -carboxylate (320 mg, 779 pmol) in tetrahydrofuran (7 mL, 86 mmol) were added water (28.1 mg, 2 eq., 1.56 mmol) and tetrabutyl azanium fluoride (245 mg, 1.2 eq., 935 pmol) at 0 °C and same temperature was maintained for Ih. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield crude residue. Residue was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 25%) to afford tert-butyl 4-[5-(ethoxy carbonyl)- 1- methyl-lH-l,2,3-triazol-4-yl]piperidine-l-carboxylate (120 mg, yield 45%) as a yellow gummy solid; MS (ES) m / z 339 (M+H)+ but deboc mass MS (ES) m / z 283.2 (M-56)+was observed in LCMS.

[0627] 1H NMR (400 MHz, CDCh): 84.34 (d, J = 7.2 Hz, 2H), 4.20 (s, 3H), 4.17 - 4.14 (m, 2H), 3.24 - 3.18 (m, 1H), 3.76 (t, J= 13.2 Hz, 2H), 1.85 - 1.79 (m, 4H), 1.40 (s, 9H), 1.32 (d, J= 4 Hz, 3H).

[0628] Step 5. Preparation of 4-(l-(tert-butoxycarbonyl)piperidin-4-yl)-l-methyl-lH-l,2,3- triazole-5-carboxylic acid

[0629] To a stirred solution of tert-butyl 4-[5-(ethoxy carbonyl)-! -methyl- 1H- 1,2, 3 -triazol -4- yl]piperidine-l -carboxylate (120 mg, 355 pmol) in THF (4 mL) was added lithium(l+) hydrate hydroxide (74.4 mg, 5 eq., 1.77 mmol) by dissolving in water (2 mL, 111 mmol) at 0°C and the reaction mixture was stirred at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for 10 minutes. Product got precipitated, precipitated product was filtered, washed with water and pentane. Dried under vacuum to obtain product 4-{ l-[(tert-butoxy)carbonyl]piperidin-4-yl}-l- methyl-lH-l,2,3-triazole-5-carboxylic acid (20 mg, yield 18%) as a white solid; MS (ES) m / z 309.1 (M-1H)+.

[0630] 'H NMR (400 MHz, CDCh): 84.37 (s, 3H), 4.27 - 4.22 (m, 2H), 3.42 - 3.34 (m, 1H), 2.91 - 2. 85 (m, 2H), 2.03 - 1.93 (m, 4H), 1.50 (s, 9H).

[0631] Step 6. Preparation of l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride

[0632] To a stirred solution of 4-{l-[(tert-butoxy)carbonyl]piperidin-4-yl}-l-methyl-lH-l,2,3- triazole-5-carboxylic acid (0.3 g, 967 pmol) in dichloromethane (10 mL, 156 mmol) was added 1,4-dioxane hydrochloride (722 mg, 6 eq., 5.8 mmol) at 0 °C, and stirred reaction mixture at room temperature for 12 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated, washed with pentane, dried under vacuum to obtain product l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (220 mg, yield 92%) as a white solid; MS (ES) m / z 211.1 (M+H)+.

[0633] 1HNMR (400 MHz, CDC13): 8 14.08 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 4.19 (s, 3H), 3.57 (s, 1H), 3.47 - 3.40 (m, 1H), 3.36 - 3.32 (m, 2H), 3.06 - 2.97 (m, 2H), 2.33 - 1.96 (m, 4H).

[0634] Step 7. Preparation of4-(l-(4-(l-(methoxycarbonyl)cyclopropyl)phenyl)piperidin-4-yl)-l- methyl-lH-1,2, 3-triazole-5-carboxylic acid

[0635] To a stirred solution of l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (240 mg, 973 pmol) in dimethylformamide (6 mL, 62 mmol) were added cesium carbonate (1.27 g, 4 eq., 3.89 mmol), methyl l-(4-bromophenyl)cyclopropane-l -carboxylate (298 mg, 1.2 eq., 1.17 mmol) and X-phos (46.4 mg, 0.1 eq., 97.3 pmol) and purged the mixture under argon gas for 15 minutes. Finally added Pd2(dba).3 (44.5 mg, 0.05 eq., 48.6 pmol) and heated reaction mixture to 100 °C for 16 hours in a sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq. layer was acidified with 10% citric acid until pH is acidic (3- 4), then extracted with ethyl acetate (2 x 20 mL), washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 4-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl(piperidin-4-yl)-l-methyl-lH-l,2,3- triazole-5-carboxylic acid (232 mg, yield 62%) as a brown gummy solid; MS (ES) m / z 385.2 (M+1H)+.

[0636] Step 8. Preparation of methyl !-(4-{4-[5-({[(lR)-l-(2- chlorophenyl)ethoxy]carbonyl}amino)-l -methyl- 1H-1, 2, 3-triazol-4-yl ]piperidin-l- yl}phenyl)cyclopropane-l-carboxylate

[0637] To a stirred solution of 4-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl(piperidin-4-yl)- l-methyl-lH-l,2,3-triazole-5-carboxylic acid (230 mg, 598 pmol) in toluene (6 mL, 3.26 mmol) were added, TEA (167 pL, 2 eq., 1.2 mmol) and (lR)-l-(2-chlorophenyl)ethan-l-ol (281 mg, 3 eq., 1.79 mmol) heated reaction mixture to 50 °C for 20minutes. Then added {[azido(phenoxy)phosphoryl]oxy (benzene (329 mg, 2 eq., 1.2 mmol) The mixture was stirred at 85 °C for 4 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was diluted with water (10 mL) extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (2 x 10 mL), brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to got crude. The crude product was taken into next step without purification to afford methyl !-(4-{4-[5-({[(lR)-l - (2-chlorophenyl)ethoxy]carbonyl }amino)- 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl]piperidin- 1 - yl}phenyl)cyclopropane-l -carboxylate (480 mg ) as a yellow liquid; MS (ES) m / z 538.2 (M+H)+.

[0638] Step 9. Preparation of l-(4-{4-[5-({[(lR)-l-(2-chlorophenyl)ethoxy]carbonyl}amino)-l- methyl-lH-l,2,3-triazol-4-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylic acid

[0639] To a stirred solution of methyl !-(4-{4-[5-({ [(lR)-l-(2- chlorophenyl)ethoxy]carbonyl } amino)- 1 -methyl- 1H-1 ,2,3 -triazol-4-yl]piperidin- 1 - yl}phenyl)cyclopropane-l -carboxylate (0.5 g, 9.1 eq., 929 pmol) in oxolane (3 m ), methanol (3 m , 156 mmol) solution was added lithium(l+) hydrate hydroxide (260 mg, 61 eq., 6.2 mmol) in water (3 mb) and the mixture was stirred at rt for 18 hours. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was concentrated, diluted with water (10 mb), washed with diethyl ether (2 x 10 mb), pH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, fdtered on Buchner funnel, solid was washed with water (2 x 10 mL), pentane (2 x 10 mb) and dried under vacuum to get crude, crude was given for prep HPLC Mobile phase(A) : 0.1% Formic Acid in water

[0640] Mobile phase(B) Acetonitrile purification to afford !-(4-{4-[5-({[(lR)-l-(2- chlorophenyl)ethoxy]carbonyl } amino)- 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl]piperidin- 1 - yl}phenyl)cyclopropane-l -carboxylic acid (15 mg, 28% ) as an off white solid; MS (ES) m / z 524.0 (M+1H)+. LC purity 96.84%.

[0641] 'H NMR (400 MHz, DMSO-t / s): 8 12.15 (s, 1H), 9.68 (s, 1H), 7.56 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.38-7.22 (m, 2H), 7.14 (d, J= 8.0 Hz, 2H), 6.86 (d, J= 8.0 Hz, 2H), 6.02 (d, = 8.0 Hz, 1H), 3.71 (t, J= 28.0 Hz, 6H), 1.79 (m, 4H), 1.55 (s, 2H), 1.38 (d, J= 4.0 Hz, 2H), 1.05 (d, J = 4.0 Hz, 2H).

[0642] Prep Conditions: Colum : X-Select C18 (19 mm X 250 mm X 5 mic) Mobile phase(A) :0.1% FA in water Mobile phase(B) : Acetonitrile Flow rate : 19 ml / min

[0643] Example 15. Preparation of (S)-l-(4-(4-(5-(((l-(2-

[0644] (methoxymethyl)phenyl)ethoxy)carbonyl)amino)- 1-methyl- 1H- 1 ,2,3-triazol-4-yl)piperidin- l-yl)phenyl)cyclopropane-l-carboxylic acid (Compound 24)

[0645] Step 1. Preparation of 2 f methoxymethyl) benzaldehyde

[0646] To a solution of l-bromo-2-(methoxymethyl) benzene (2 g, 9.95 mmol, 1 eq) in THF (5 mL) was added n-BuLi (2.5 M, 6 mb, 1.51 eq) at -70 °C, stirred for 1 hr, then the resulting mixture was added DMF (1.90 g, 25.99 mmol, 2.00 mL, 2.61 eq) at -70°C and stirred for 1 hr. TLC (PE / EA=3: 1, Rf=0.5) showed a new spot was detected and the l-bromo-2-(methoxymethyl) benzene consumed. The reaction mixture was quenched by adding sat. NH4CI (30 mL), partitioned between EtOAc (60 mL*3) and water (80 mL), washed with brine (30 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=5 / l to 3 / 1) to give the 2-(methoxymethyl) benzaldehyde (1.2 g, 7.99 mmol, 80.33% yield) as a white solid.1HNMR (400 MHz, chloroform-d) 8 = 10.22 (s, 1H), 7.87 (d, J= 7.5 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.52 - 7.45 (m, 1H), 4.88 (s, 2H), 3.51 - 3.48 (m, 3H).

[0647] Step 2. Preparation of 1 -[2 f methoxymethyl) phenyl J ethanol

[0648] To a solution of 2-(methoxymethyl) benzaldehyde (1.2 g, 7.99 mmol, 1 eq) in THF (20 mL) was added MeMgBr (3 M, 5 mL, 1.88 eq) at 0°C, then the resulting mixture stirred at 25°C for 1 hr. TLC (PE / EA=3:1, Rf=0.3) showed a new spot was detected and 2-(methoxymethyl) benzaldehyde consumed. The reaction mixture was quenched by adding sat. NH4CI (30 mL), partitioned between EtOAc (120 mL) and water (50 mL), washed with brine (70 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1) to give l-[2-(methoxy methyl) phenyl] ethanol (0.8 g, 4.81 mmol, 60.23% yield) as the colourless oil. 'H NMR (400 MHz, chloroform-d) 8 = 7.55 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 1.8, 7.4 Hz, 1H), 7.27 (s, 2H), 5.14 (q, .7= 6.4 Hz, 1H), 4.67 (d, J= 11.3 Hz, 1H), 4.44 (d, J= 11.3 Hz, 1H), 3.41 (s, 3H), 1.55 (d, .7 = 6.5 Hz, 3H).

[0649] Step 3. Preparation of Ethyll-[4-[4-[5-[l-[2-(methoxymethyl)phenyl] ethoxycarbonylamino] -l-methyl-triazol-4-y I] -l-piperidyl]phenyl] cyclopropanecarboxylate

[0650] To a solution of 5-[l-[4-(l-ethoxycarbonylcyclopropyl) phenyl]-4-piperidyl] -3-methyl- triazole- 4-carboxylic acid (200 mg, 501.94 pmol, 1 eq) in toluene (10 mL) was added l-[2- (methoxymethyl) phenyl]ethanol (270 mg, 1.62 mmol, 3.24 eq), TEA(218.10 mg, 2.16 mmol, 0.3 mL, 4.29 eq), DPPA (510.00 mg, 1.85 mmol, 0.4 mL, 3.69 eq) at 0°C, then the resulting mixture was purged with N2 for three times and stirred at 80°C for 12 hr. LCMS showed the desired MS was detected and the 5-[l-[4-(l-ethoxycarbonylcyclopropyl) phenyl]-4-piperidyl]-3- methyl- triazole-4-carboxylic acid consumed. TLC (PE / EA=1 : 1, Rf=0.4) showed a new spot was detected and the 5-[l-[4-(l -ethoxycarbonylcyclopropyl) phenyl]-4-piperidyl]-3-methyl- triazole-4- carboxylic acid consumed. The reaction mixture was partitioned between EtOAc (150 mL) and water (70 mL), washed with brine (80 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash@ Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ethergradient @ 40 mL / min) to give the ethyl l-[4-[4-[5-[l-[2-(methoxymethyl) phenyl]ethoxycarbonylamino] -l-methyl-triazol-4-yl]-l-piperidyl]phenyl] cyclopropanecarboxylate (180 mg, 320.47 pmol, 63.85% yield, 100% purity) as a yellow solid. MS m / z: 562.6 [M+H]+

[0651] Step 4. Preparation of l-[4-[4-[5-[l-[2-(methoxymethyl)phenyl]ethoxy carbonylamino] - l-methyl-triazol-4-yl ]-l-piperidyl I phenyl ] cyclopropanecarboxylic acid

[0652] To a solution of ethyl l-[4-[4-[5-[l-[2-(m ethoxymethyl) phenyl]ethoxy carbonylamino] -1- methyl-triazol-4-yl]-l-piperidyl]phenyl]cyclopropanecarboxylate (150 mg, 267.06 pmol, 1 eq) in EtOH (1 mL) was added LiOH (2 M, 1 mL, 7.49 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and the ethyl l-[4-[4-[5-[l-[2- (methoxymethyl)phenyl]ethoxycarbonylamino]-l-methyl-triazol-4-yl] -1 -piperidyl] phenyl]cyclopropanecarboxylate consumed. The reaction mixture was acidified to pH=6 by adding AcOH. The reaction mixture was purified by prep-HPLC (Phenomenex luna Cis 150*25 mm* 10um;mobile phase: [water (FA) -ACN];gradient:29%-59% B over 10 min) and lyophilized to give the l-[4-[4-[5-[l-[2-(methoxymethyl)phenyl] ethoxy carbonylamino]-l-methyl-triazol-4-yl]-l- piperidyl]phenyl]cyclopropanecarboxylic acid (90 mg, 165.29 pmol, 61.89% yield, 98% purity) as a white solid. MS m / z: 534.4 [M+H]+

[0653] Step 5. Preparation of l-[4-[4-[5-[[(lS)-l- [2-(methoxymethyl)phenyl]ethoxy] carbonylamino ]-l-methyl-triazol-4-yl] -1 -piperidyl] phenyl ] cyclopropanecarboxylic acid l-[4-[4-[5-[l-[2-(methoxymethyl)phenyl]ethoxy carbonylamino]- 1-methyl-tri azol -4-yl]- 1- piperidyl] phenyl] cyclopropanecarboxylic acid(6) (80 mg, 149.92 pmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, lOum); mobile phase: [CCh-i-PrOH (0.1%NH3H2O)]; B%:50%, isocratic elution mode) to give 1 -[4-[4-[5-[[(lR) -l-[2- (methoxymethyl) phenyl]ethoxy] carbonylamino]-l-methyl-triazol-4-yl]-l- piperidyl]phenyl]cyclopropanecarboxylic acid (30.3 mg, 56.78 pmol, 37.88% yield, 100% purity) (Rt=1.880 min, 30.3 mg) as a white solid and 1 -[4-[4-[5-[[(l S) -l-[2-(m ethoxymethyl) phenyl ] ethoxy ] carb onyl ami no] - 1 - m ethyl -tri azol -4-y 1 ] - 1 - piperidyl]phenyl]cyclopropanecarboxylic acid (41.5 mg, 74.66 pmol, 49.80% yield, 96% purity) ) (Rt=2.540 min, 41.5 mg) as a white solid.

[0654] 'H NMR (400 MHz, methanol-d4) 8 = 7.57 (d, J= 1.1 Hz, 1H), 7.41 - 7.34 (m, 3H), 7.23 (d, J= 8.6 Hz, 2H), 6.90 (d, J= 8.4 Hz, 2H), 6.12 - 6.04 (m, 1H), 4.80 - 4.75 (m, 1H), 4.40 (d, J = 11.5 Hz, 1H), 3.79 (s, 3H), 3.63 (d, . / = 12.1 Hz, 2H), 3.36 (s, 3H), 2.70 - 2.60 (m, 3H), 1.90 (s, 4H), 1.58 (s, 3H), 1.48 - 1.44 (m, 2H), 1.02 (d, J= 2.0 Hz, 2H). MS m / z: 534.3 [M+H]+

[0655] Example 16. Preparation of (R)-l-(4-(4-(5-(((l-cyclohexylethoxy)carbonyl)amino)-l- methyl-lH-l,2,3-triazol-4-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylic acid

[0656] (Compound 26)

[0657] Step 1. Preparation of l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride

[0658] To a stirred solution of 4-{ l-[(tert-butoxy)carbonyl]piperidin-4-yl}-l-methyl-lH-l ,2,3- triazole-5-carboxylic acid (490 mg, 1.58 mmol) in dichloromethane (5 mL, 78.1 mmol) were added 1,4-dioxane hydrochloride (1.18 g, 6 eq., 9.47 mmol) at 0 °C, and stirred reaction mixture at room temperature for 12 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated, washed with pentane, dried under vacuum to obtain product l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (Yield: 380 mg, 98% ) as white solid; MS (ES) m / z 211.1 (M+H)+.

[0659] Step 2. Preparation of 4-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)- l-methyl-lH-1,2, 3-triazole-5-carboxylic acid

[0660] To a stirred solution of l-methyl-4-(piperidin-4-yl)-lH-l,2,3-triazole-5-carboxylic acid hydrochloride (410 mg, 1.66 mmol) in dimethylformamide (10 mL, 129 mmol) were added Cesium carbonate (2.17 g, 4 eq., 6.65 mmol), methyl l-(4-bromophenyl)cyclopropane-l - carboxylate (509 mg, 1.2 eq., 1.99 mmol) and X-phos (79.2 mg, 0.1 eq., 166 pmol), purged under argon gas for 15 minutes. Finally added Pd2(dba)s (76.1 mg, 0.05 eq., 83.1 pmol) and heated reaction mixture to 100 °C for 16 hours inside sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq. layer was acidified with 10% citric acid until pH is acidic, then extracted with ethyl acetate (2 x 100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 4-(l-{4-[l- (methoxycarbonyl)cyclopropyl]phenyl }piperidin-4-yl)-l-methyl-lH-l,2,3-triazole-5-carboxylic acid ( yield: 330mg, 52% ) as brown solid; MS (ES) m / z 385.2 (M+1H)+.

[0661] Step 3. Preparation of methyl l-(4-{4-[5-({[(lR)-l-cyclohexylethoxy]carbonyl}amino)-l- methyl-lH-l,2,3-triazol-4-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylate

[0662] To a solution of 4-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-l- methyl-lH-l,2,3-triazole-5-carboxylic acid (150 mg, 390 pmol) in toluene (15 mL) were added triethylamine (109 pL, 2 eq., 780 pmol), (IR)-l-cyclohexylethan-l-ol (150 mg, 3 eq., 1.17 mmol) stirred reaction mixture at 50 °C. Then added { [azido(phenoxy)phosphoryl]oxy}benzene (101 pL, 1.2 eq., 468 pmol). The mixture was stirred at 85 °C for 3 h. Reaction was progressed by TLC, rm was diluted with water (20 mL) extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 50%) to afford methyl l-(4-{4-[5-({[(lR)-l-cyclohexylethoxy]carbonyl}amino)-l-methyl-lH-l,2,3-triazol-4- yl]piperidin-l-yl}phenyl)cyclopropane-l -carboxylate as yellowish liquid ( Yield; 80 mg, 40% ) MS (ES) m / z 510.3 (M+H)+.

[0663] Step 4. Preparation of (R)-l-(4-(4-(5-(((l-cyclohexylethoxy)carbonyl)amino)-l-methyl- 1H-1, 2, 3-triazol-4-yl)piperidin-l-yl)phenyl)cyclopropane-l -carboxylic acid

[0664] To a stirred solution of methyl l-(4-{4-[5-({[(lR)-l-cyclohexylethoxy]carbonyl}amino)- l-methyl-lH-l,2,3-triazol-4-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylate (80 mg, 157 pmol) in oxolane (2 mL), methanol (2 mL, 156 mmol) solution was added lithium(l+) hydrate hydroxide (26.3 mg, 4 eq., 628 pmol) in water (2 mL) and the mixture was stirred at RT for 18 hours. Reaction was progressed by LCMS and TLC, rm was concentrated, diluted with water (20 mL), washed with diethyl ether (2 x 10 mL), PH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on buchnel funnel, solid was washed with water (2 x 10 mL), pentane (2 x 10 mL) and dried under vacuum to afford !-(4-{4-[5-({[(lR)-l- cyclohexylethoxy]carbonyl } amino)- 1 -methyl- 1H- 1 ,2,3-triazol-4-yl]piperidin- 1 - yl}phenyl)cyclopropane-l -carboxylic acid as off white solid (48 mg, 62% yield); MS (ES) m / z 496.4 (M+1H)-. LC purity 99.52% @ 240 nm. 'H NMR (400 MHz, DMSO-de): 8 12.09 (s, 1H), 9.32 (s, 1H), 7.13 (d, J =8.4 Hz, 2H), 6.86 (d, J =8.4 Hz, 2H), 4.63 (q, J= 6.4 Hz, 1H), 3.82 - 3.71 (m, 5H), 2.76 - 2.67 (m, 3H), 1.83 (d, J =3.6 Hz, 4H), 1.79 - 1.64 (m, 4H), 1.46 - 1.43 (m, 1H), 1.39 - 1.33 (m, 2H), 1.24 - 1.09 (m, 7H), 1.04 (d, J =2.8 Hz, 4H).

[0665] Example 17. Preparation of (4-{4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l- carboxylic acid (Compound 87) (R)-l-( 4-( 4-( 3-methyl-4-( (1- phenylethoxy)carbonyl)amino)isoxazol-5-yl)piperidm-l-yl)phenyl)cyclopropane-l-carboxylate

[0666] To a stirred solution of 5-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl }piperidin-4-yl)- 3 -methyl- l,2-oxazole-4-carboxylic acid (770 mg, 1.82 mmol, Example 18, Step 1) in toluene (10 mL) were added triethylamine (278 pL, 1.1 eq., 2 mmol) and (lR)-l-phenylethan-l-ol (660 pL, 3 eq., 5.45 mmol), heated to 50 °C, maintained for 30minutes. Then added DPPA (434 pL, 1.1 eq., 2.01 mmol) and heated reaction mixture to 85 °C, for 4 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was diluted with water (10 mL) extracted with ethyl acetate (2 x 15mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 28%) to afford methyl l-(4-{4-[3- methyl-4-({ [(1R)- 1 -phenylethoxy]carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl} phenyl )cy cl opropane-1 -carboxylate (418 mg, 45% yield); MS (ES) m / z 504.3 (M+H)+.

[0667] Step 2. Preparation of l-(4-{4-[ 3-methyl-4-({[ (lR)-l-phenylethoxy]carbonyl}amino)-l ,2- oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l -carboxylic acid

[0668] To a stirred solution of methyl l-(4-{4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 -yl }phenyl)cyclopropane- 1 - carboxylate (55 mg, 0.11 mmol) in THF (2 mb) and methanol (2 mL) was added Lithium hydroxide Monohydrate (30 mg, 6 eq., 0.7 mmol) by dissolving in water (2 mL) at 0°C, maintained reaction mass at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for 10 minutes. Product got precipitated, precipitated product was filtered, washed with water and pentane. Dried under vacuum to obtain product l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)- l,2-oxazol-5-yl]piperi din- l-yl}phenyl)cyclopropane-l -carboxylic acid (48 mg, 88% yield) as off white solid; MS (ES) m z 490.0 (M+H)+; LC purity: 99.5%

[0669] 1H NMR (400 MHz, DMSO-de): 8 12.10 (s, 1H), 8.90 (s, 1H), 7.37-7.45 (m, 5H), 7.12 (d, J= 8.0 Hz, 2H), 6.83 (d, J= 8.0 Hz, 2H), 5.74-5.69 (q, 1H), 3.65 (d, J = 12.0 Hz, 2H), 2.89-2.85 (m, 2H), 2.69-2.65 (m, 2H), 2.01 (s, 3H), 1.80-1.73 (m, 4H), 1.50-1.48 (d, 7= 8.4 Hz, 3H), 1.37- 1.36 (t, 7= 2.4 Hz, 2H), 1.04-1.01 (t, 7= 2.8 Hz, 2H);

[0670] Example 18. Preparation of (R)-l-(4-(4-(4-(((l-(2- ethylphenyl)ethoxy)carbonyl)amino)-3-methylisoxazol-5-yl)piperidin-l- yl)phenyl)cyclopropane-l-carboxylic acid (Compound 38)

[0671] Step 1. Preparation of 5-(l-(4-(l-(methoxycarbonyl)cyclopropyl)phenyl)piperidin-4-yl)-3- methylisoxazole-4-carboxylic acid

[0672] To a stirred solution of 3-methyl-5-(piperidin-4-yl)-l,2-oxazole-4-carboxylic acid hydrochloride (2 g, 8.11 mmol) in dimethylformamide (30 mL, 387 mmol) were added Cesium carbonate (10.6 g, 4 eq., 32.4 mmol), methyl l-(4-bromophenyl)cyclopropane-l -carboxylate (2.48 g, 1.2 eq., 9.73 mmol) and X-phos (386 mg, 0.1 eq., 811 pmol), purged under argon gas for 15 minutes. Finally added Pd2(dba)3 (371 mg, 0.05 eq., 405 pmol) and heated reaction mixture to 100 °C for 16 hours inside sealed tube. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was cooled to room temperature and filtered through celite, and concentrated then diluted with water (20 mL) and washed with ethyl acetate, then Aq. layer was acidified with 10% citric acid until pH is acidic, then extracted with ethyl acetate (2 x 100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford 5-(l-{4-[l- (methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3-methyl-l,2-oxazole-4-carboxylic acid (2.5 g, 80%) as pale yellow solid; MS (ES) m z 385.2 (M+1H)+.

[0673] Step 2. Preparation of methyl (R)-l-(4-(4-(4-(((l-(2-ethylphenyl)ethoxy)carbonyl)amino)- 3-methylisoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylate

[0674] To a solution of 5-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3- m ethyl- l,2-oxazole-4-carboxylic acid (150 mg, 390 pmol) in toluene (10 mL, 3.26 mmol) were added, TEA(109 pL, 2 eq., 780 pmol), (lR)-l-(2-ethylphenyl)ethan-l-ol (117 mg, 2 eq., 780 pmol) stirred reaction mixture at 50 °C. Then added DIPEA (168 pL, 2 eq., 780 pmol). The mixture was stirred at 85 °C for 3 h. Reaction was progressed by TLC, rm was diluted with water (20 mL) extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (18% to 30%) to afford methyl l-(4-{4-[4-({[(lR)-l-(2- ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol-5-yl]piperidin-l- yl} phenyl )cy cl opropane-1 -carboxylate (76 mg, 36% yield) yellowish liquid. MS (ES) m z ' 532.3 (M+H)+.

[0675] Step 3. Preparation of (R)-l-(4-(4-(4-(((l-(2-ethylphenyl)ethoxy)carbonyl)amino)-3- methylisoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylic acid

[0676] To a stirred solution of methyl !-(4-{4-[4-({[(lR)-l-(2- ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol-5-yl]piperidin-l- yl}phenyl)cycl opropane-1 -carboxylate (70 mg, 132 pmol) in tetrahydrofuran (1.3 mL, 15.9 mmol) and methanol (1.3 mL, 32 mmol) was added UOH.H2O (22.1 mg, 4 eq., 527 pmol) in water (1 .3 mL, 72 mmol) at 0°C, stirred for 10 minutes. Finally maintained reaction at room temperature for 16hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for lOminutes. Product was precipitated. Formed product was filtered, washed with water and pentane. Then dried under vacuum to get product l-(4-{4-[4- ({[(lR)-l-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol-5-yl]piperidin-l- yl}phenyl)cyclopropane-l -carboxylic acid (40 mg, 59%) as white solid; MS (ES) m / z 518.4 (M+1H)+. LCMS Purity 98.14%.

[0677] 'H NMR (400 MHz, DMSO-de): 8 12.08 (s, 1H), 8.87 (s, 1H), 7.45 - 7.35 (m, 4H), 7.21 (d, J= 4 Hz, 2H), 7.51 (d, J= 7.2 Hz, 2H), 5.96 (q, J= 6.4 Hz, 1H), 3.74 - 3.66 (m, 2H), 2.87 (s, 1H), 2.70 - 2.65 (m, 4H), 2.11 (s, 3H), 1.95 - 1.76 (m, 4 H), 1.66 - 1.51 (m, 3H), 1.40 - 1.38 (m, 2H), 1.18 (t, J = 3.6 Hz, 3H), 0.93 - 0.84 (m, 2H).

[0678] Example 19. Preparation of !-(4-{4-[4-({[(lR)-l-(2-chlorophenyl)ethoxy]carbonyl} amino)-3-methyl- l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylic acid (Compound 74)

[0679] Step 1. Preparation of methyl (R)-l-(4-(4-(4-(((l-(2-chlorophenyl)ethoxy)carbonyl) ammo)-3-methyUsoxazol-5-yl)piperidm-l-yl)phenyl)cyclopropane-l -carboxylate

[0680] {[azido(phenoxy)phosphoryl]oxy}benzene (101 pL, 1.2 eq., 468 pmol) and triethylamine (109 pL, 2 eq., 780 pmol) were added to a solution of 5-(l-{4-[l- (methoxycarbonyl)cyclopropyl]phenyl }piperidin-4-yl)-3-methyl-l,2-oxazole-4-carboxylic acid (150 mg, 390 pmol) in Toluene (10 mL) at 50 °C. The mixture was stirred at 50 °C for 30 minutes, then added (lR)-l-(2-chlorophenyl)ethan-l-ol (244 mg, 4 eq., 1 .56 mmol). The mixture was stirred at 90 °C for 8 h. Reaction was progressed by TLC, rm was diluted with water (20 mL) extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with water (2 x 50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 20%) to afford methyl !-(4-{4-[4-({ [(lR)-l-(2- chlorophenyl)ethoxy]carbonyl} amino) -3-methyl-l,2-oxazol-5-yl]piperidin-l- yl}phenyl)cyclopropane-l -carboxylate as off white solid (90 mg, 42% yield);JH NMR (400 MHz, DMSO-de): 5 9.01 (s, 1H), 7.56-7.33 (m, 4H), 7.16 (d, J= 8.0 Hz, 2H), 6.87 (d, J= 8.0 Hz, 2H), 5.99 (q, 1H), 3.70 (m, 2H), 3.53 (s, 3H), 2.90 (m, 1H), 2.68 - 2.65 (m, 2H), 2.04 (s, 3H), 1.81-1.75 (m, 4H), 1.53 - 1.48 (m, 3H), 1.42 (t, J= 2.8 Hz, 2H), 1.12 (t, J= 2.8 Hz, 2H); MS (ES) m z 539.0 (M+H)+; LC purity: 86%.

[0681] Step 2. Preparation of (R)-l-(4-(4-(4-(((l-(2-chlorophenyl)ethoxy)carbonyl)amino) -3- methylisoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l -carboxylic acid

[0682] To a stirred solution of methyl !-(4-{4-[4-({[(lR)-l-(2-chlorophenyl)ethoxy] carbonyl }amino)-3-methyl-l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l -carboxylate (70.0 mg, 130 pmol) in THF (5.0 mL), MeOH (5.0 mL) was added lithium(l+) hydroxide (31.2 mg, 10 eq., 1.30 mmol) in water (5.0 mL) and the mixture was stirred at RT for 12 hours. Reaction was progressed by TLC, The reaction solution was concentrate to remove ethanol and THF, diluted with water (5 mL) and acidified with citric acid solution pH-5, and filtered and dried to get l-(4- {4-[4-({[(lR)-l-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl- l,2-oxazol-5-yl]piperidin- l-yl }phenyl)cyclopropane-l-carboxylic acid as off white solid (37.0 mg, 54% yield); 'H NMR (400 MHz, DMSO-de): 8 12.14 (s, 1H), 9.01 (s, 1H), 7.54 - 7.32 (m, 4H), 7.12 (d, J= 8.0 Hz, 2H), 6.84 (d, J= 8.0 Hz, 2H), 5.96 (q, 1H), 3.68 -3.65 (m, 2H), 2.87 (m, 1H), 2.68 - 2.65 (m, 2H), 2.01 (s, 3H), 1.81 - 1.75 (m, 4H), 1.50-1.45 (m, 3H), 1.36 (t, .7= 2 8 Hz, 2H), 1.03 - 1.02 (t, J= 2.8 Hz, 2H); MS (ES) m / z 525.0 (M+H)+; LC purity: 98%. Example 20. Preparation of (1R)-1 -phenylethyl N-{3-methyl-5-[1-(4-{l-[(prop-2-ene- l-sulfonyl)carbamoyl]cyclopropyl}phenyl)piperidin-4-yl]-l,2-oxazol-4-yl}carbamate (Compound 2)

[0683] Step 1. Preparation of methyl l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy] carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylate

[0684] To a stirred solution of 5-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)- 3 -methyl- l,2-oxazole-4-carboxylic acid (1.4 g, 3.64 mmol) in toluene (20 mb) were added triethylamine (557 pL, 1.1 eq., 4.01 mmol) and (IR)-l-phenylethan-l-ol (1.32 mb, 3 eq., 10.9 mmol) and the reaction mixture was heated at 50 °C for 30 minutes. Then added DPPA (868 pL, 1.1 eq., 4.01 mmol) and the reaction mixture was heated at 85 °C for 4 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was diluted with water (20 mb) extracted with ethyl acetate (2 x 25mL). The combined organic layer was washed with water (2 x 20 mL) and brine solution (20 mb), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (1% to 28%) to afford methyl l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l- yl}phenyl)cyclopropane-l -carboxylate (835 mg, 45% yield) as a gummy solid; MS (ES) m / z 504.3 (M+H)+.

[0685] Step 2. Preparation of l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)-l,2- oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l -carboxylic acid

[0686] To a stirred solution of methyl l-(4-{4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 -yl }phenyl)cyclopropane- 1 - carboxylate (1.1 g, 2.18 mmol) in THF (5 mL) and methanol (5 mL) was added Lithium hydroxide Monohydrate (550 mg, 6 eq., 13.1 mmol) by dissolving in water (5 mL) at 0 °C and the reaction mixture was stirred at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10% citric acid solution and stirred for 10 minutes. Product got precipitated, precipitate was filtered, washed with water and pentane. Dried under vacuum to obtain product l-(4-{4-[3-methyl-4-({ [(lR)-l-phenylethoxy]carbonyl}amino)- l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylic acid (950 mg, 88% yield) as an off white solid; MS (ES) m / z 490.2 (M+1H)+;

[0687] Step 3. Preparation of (1R)-1 -phenyl ethyl N-{3-methyl-5-[l-(4-{l-[(prop-2-ene-l- sulfonyl)carbamoyl]cyclopropyl}phenyl)piperidin-4-yl]-l,2-oxazol-4-yl}carbamate

[0688] To a stirred solution of l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)- l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylic acid (0.2 g, 409 pmol) in dichloromethane (5 mL, 78.1 mmol) were added TEA (113 pL, 2 eq., 817 pmol), EDC.HCL (66.5 mg, 1.5 eq., 613 pmol) and HOBT (82.8 mg, 1.5 eq., 613 pmol) at 0 °C and the reaction mixture was stirred at room temperature for 15 minutes. Finally added prop-2-ene-l -sulfonamide (74.2 mg, 1.5 eq., 613 pmol) and stirred at rt for 16 hours. Progress of the reaction was monitored by TLC & LCMS. After completion of reaction, reaction mass was quenched with water and extracted with DCM (2X20mL), washed with water (2X20mL) ) and brine solution (20 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (75% to 80%) to afford (1R)-1 -phenylethyl N-{3-methyl-5-[l-(4-{ l-[(prop-2-ene-l- sulfonyl)carbamoyl]cyclopropyl}phenyl)piperidin-4-yl]-l,2-oxazol-4-yl}carbamate (148 mg, 61% yield) as a yellow gummy solid.; MS (ES) m / z 593.2 (M+H)+@ 240. Onm.

[0689] 'l l NMR (400 MHz, DMSO-< 5 10.81 (s, 1H), 8.91 (s, 1H), 7.39 - 7.29 (m, 5H), 7.15 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.4 Hz, 2H), 5.76 - 5.69 (m, 2H), 5.38 - 5.28 (m, 2H), 4.09 (d, J = 5.2 Hz, 2H), 3.73 - 3.70 (m, 2H), 2.89 (bs, 1H), 2.73 - 2.66 (m, 2H), 2.03 (s, 3H), 1.85 - 1.74 (m, 4H), 1.51 (d, J= 4.8Hz, 3H), 1.36 (bs, 2H), 1.05 (bs, 2H). Example 21. Preparation of l-[({[l-(4-{4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l- yl}phenyl)cyclopropyl]formamido}sulfonyl)methyl]cyclopropane-l-carboxylic acid

[0690] (Compound 82)

[0691] Step 1. Preparation of methyl !-[({[ l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy] carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropyl]formamido}sulfonyl)methyl] cyclopropane- 1 -carboxylate

[0692] To a stirred solution of l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)- l,2-oxazol-5-yl]piperi din- l-yl}phenyl)cyclopropane-l -carboxylic acid (0.3 g, 613 pmol) in tetrahydrofuran (6 m , 73.7 mmol) were added l-(lH-imidazole-l -carbonyl)- IH-imidazole (99.4 mg, 613 pmol) and DMAP (7.49 mg, 0.1 eq., 61.3 pmol) at rt and the reaction mixture was heated at 70 °C for 2 hours. Then cooled to room temperature and added methyl 1- (sulfamoylmethyl)cyclopropane-l -carboxylate (118 mg, 613 pmol) and DBU (367 pL, 4 eq., 2.45 mmol) at 0 °C and stirred at rt for 16 hours. Progress of the reaction was monitored by TLC & LCMS. After completion of reaction, reaction mass was quenched with ice cold water, extracted with ethyl acetate (2 x 20 m ). The combined organic layer was washed with water (2 x 10 mL), sodium bicarbonate solution (10 mL) and brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by prep HPLC Mobile phase (A) : 0.1% Ammonia in water, Mobile phase(B) : Acetonitrile purification to afford methyl l-[({[l-(4-{4-[3-methyl-4-({[(lR)-l - phenylethoxy] carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)methyl]cyclopropane-l -carboxylate (240 mg, 58%) as a white solid; MS (ES) m z 665.6 (M+1H)+. LC purity 99.72%.

[0693] 1HNMR (400 MHz, DMSO-t / e): 8 10.83 (s, 1H), 8.91 (s, 1H), 7.39-7.29 (m, 5H), 7.16 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.76-5.71 (m, 1H), 3.71 (d, J = 12.0 Hz, 4H), 3.58 (s, 3H), 2.89 (s, 1H), 2.73-2.66 (m, 2H), 2.03 (s, 3H), 1.85-1.71 (m, 4H), 1.51 (d, J = 4.0 Hz, 3H), 1.47 (s, 2H), 1.21 (s, 2H), 1.11-1.04 (m, 4H).

[0694] Step 2. Preparation of l-[({[l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy] carbonyl}amino)-l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropyl]formamido} sulfonyl)methyl ] cyclopropane- 1 -carboxylic acid

[0695] To a stirred solution of methyl l-[({[l-(4-[4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl ) amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)methyl]cyclopropane-l -carboxylate (0.1 g, 1.2 eq., 150 pmol) in methanol (1 mL, 24.7 mmol), tetrahydrofuran (1 mL, 12.3 mmol) solution was added lithium(l+) hydrate hydroxide (41.1 mg, 8 eq., 980 pmol in water (1 mL, 55.5 mmol) and the mixture was stirred at rt for 18 hours. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was concentrated, diluted with water (10 mL), washed with diethyl ether (2 x 10 mL), pH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, fdtered on Buckner funnel, solid was washed with water (2 x 10 mL), pentane (2 x 10 mL) and dried under vacuum to afford crude. The crude was purified by prep HPLC to afford l-[({[l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)-l,2- oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropyl]formamido}sulfonyl)methyl]cyclopropane-l- carboxylic acid (45 mg, 56%) as a white solid; MS (ES) m / z 651.5 (M+1H)+. LC purity 97.10%.

[0696] 'H NMR (400 MHz, DMSO-t / e): 8 8.92 (s, 1H), 7.39-7.30 (m, 6H), 7.07 (d, J = 12.0 Hz, 2H), 6.80 (d, J= 8.0 Hz, 2H), 5.76-5.71 (m, 1H), 3.63 (d, J= 12.0 Hz, 2H), 3.34 (s, 2H), 2.85 (m, 1H), 2.68-2.62 (m, 2H), 2.03 (s, 3H), 1.82-1.75 (m, 4H), 1.52 (d, J= 4.0 Hz, 3H),1.24 (t, J= 8.0 Hz, 2H), 1.03-0.97 (m, 4H), 0.74-0.73 (d, J= 4.0 Hz, 2H). Example 22. Preparation of 3-({[l-(4-{4-[4-({[(lR)-l-(2- ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol-5-yl]piperidin-l- yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoic acid (Compound 37)

[0697] Step 1. Preparation of methyl (R)-l-(4-(4-(4-(((l-(2-ethylphenyl)ethoxy)carbonyl)amino)- 3-methylisoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l-carboxylate

[0698] To a solution of 5-(l-{4-[l-(methoxycarbonyl)cyclopropyl]phenyl }piperidin-4-yl)-3- m ethyl- l,2-oxazole-4-carboxylic acid (0.4 g, 1.04 mmol) in toluene (10 mL, 3.26 mmol) were added, TEA (290 pL, 2 eq., 2.08 mmol), (lR)-l-(2-ethylphenyl)ethan-l-ol (313 mg, 2 eq., 2.08 mmol) and the reaction mixture stirred at 50 °C for Ih. Then added DPPA (448 pL, 2 eq., 2.08 mmol) and the mixture was stirred at 85 °C for 12 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (2 x 20 mL) and brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n-hexane (18% to 30%) to afford methyl l-(4-{4-[4-({[(lR)-l-(2- ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol-5-yl]piperidin-l- yl} phenyl )cy cl opropane-1 -carboxylate (220 mg, 40% yield) as a yellowish liquid. MS (ES) m / z 532.3 (M+H)+.

[0699] Step 2. Preparation of l-(4-{4-[4-({[(lR)-l-(2-ethylphenyl)ethoxy]carbonyl}amino)-3- methyl-1, 2-oxazol-5-yl ]piperidin-l-yl}phenyl)cyclopropane-l -carboxylic acid

[0700] To a stirred solution of methyl !-(4-{4-[4-({[(lR)-l-(2- ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l ,2-oxazol-5-yl]piperi din-1 - yl}phenyl)cyclopropane-l -carboxylate (270 mg, 508 pmol) in tetrahydrofuran (4.91 mb, 60.3 mmol) and methanol (4.91 mL, 121 mmol) was added LiOH.ILO (128 mg, 6 eq., 3.05 mmol) in water (4.91 mL, 272 mmol) at 0 °C and stirred for 10 minutes. Then the reaction mixture was stirred at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10 % citric acid solution and stirred for 10 minutes. Product was precipitated. It was filtered, washed with water and pentane. Then dried under vacuum to get product l-(4-{4-[4-({[(lR)-l-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol-5- yl]piperidin-l-yl}phenyl) cyclopropane- 1 -carboxylic acid (190 mg, 72% yield) as a white solid; MS (ES) m 'z 518.4 (M+1H)+.

[0701] ’H NMR (400 MHz, DMSO- e): 5 12.08 (s, 1H), 8.87 (s, 1H), 7.45 - 7.35 (m, 4H), 7.21 (d, J= 4 Hz, 2H), 7.51 (d, J= 7.2 Hz, 2H), 5.96 (q, J= 6.4 Hz, 1H), 3.74 - 3.66 (m, 2H), 2.87 (s, 1H), 2.70 - 2.65 (m, 4H), 2.11 (s, 3H), 1.95 - 1.76 (m, 4 H), 1.66 - 1.51 (m, 3H), 1.40 - 1.38 (m, 2H), 1.18 (t, J = 3.6 Hz, 3H), 0.93 - 0.84 (m, 2H).

[0702] Step 3. Preparation of methyl 3-({[l-(4-{4-[4-({[(lR)-l-(2- ethylphenyl)ethoxy ] car bony l}amino)-3-methyl-l , 2-oxazol-5-yl lpiperidin-1- yl}phenyl)cyclopropyl]formamido} sulfonyl) propanoate

[0703] To a stirred solution of l-(4-{4-[4-({[(lR)-l-(2-ethylphenyl)ethoxy]carbonyl}amino)-3- methyl-l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropane-l-carboxylic acid (186 mg, 359 pmol) in dichloromethane (5 mL, 78.1 mmol) were added triethylamine (146 pL, 3 eq., 1.08 mmol), EDC.HC1 (115 mg, 3 eq., 1.08 mmol), HOBT (97.1 mg, 2 eq., 719 pmol) and DMAP (4.39 mg, 0.1 eq., 35.9 pmol) at 0 °C and stirred at room temperature for 15 minutes. Finally added methyl 3-sulfamoylpropanoate (120 mg, 2 eq., 719 pmol) and stirred at rt for 16 hours. Progress of the reaction was monitored by TLC & LCMS. After completion of reaction, reaction mass was quenched with ice cold water, extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (2 x 25 mL), sodium bicarbonate solution (15 mL) and brine solution (15 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product which was purified by combiflash MPLC using methanol in DCM (5% to 15%) to afford methyl 3-({[l-(4-{4-[4-({[(lR)-l-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl- l,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoate (210 mg, 87% yield) as a gummy brown solid; MS (ES) nvz 667.1 (M+1H)+.

[0704] Step 4. Preparation of 3-({[l-(4-{4-[4-({[(lR)-l-(2-ethylphenyl)ethoxy]carbonyl}amino)- 3-methyl-l,2-oxazol-5-yl piperidin-l-yl}phenyl)cyclopropyllformamido}sulfonyl)propanoic acid

[0705] To a stirred solution of methyl 3-({[l-(4-{4-[4-({[(lR)-l-(2- ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol-5-yl]piperidin-l-yl}phenyl) cyclopropyl]formamido} sulfonyl )propanoate (0.1 g, 150 pmol) in tetrahydrofuran (2.5 mL, 30.7 mmol) and methanol (2.5 mL, 61.7 mmol) was added LiOEI.EEO (25.2 mg, 4 eq., 0.6 mmol) by dissolving in water (2.5 mL, 139 mmol) at 0 °C and stirred for 10 minutes. Then, the reaction mixture was stirred at room temperature for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was concentrated to get the crude product. Obtained crude was acidified with 10 % citric acid solution and stirred for 10 minutes. Product was precipitated. The precipitate was filtered, washed with water and pentane dried under vacuum to yield crude product. The obtained crude was purified by preparative HPLC using method Mobile Phase (A) :0.1% Formic Acid in water and Mobile Phase (B) : ACN to yield

[0706] 3-({[l-(4-{4-[4-({[(lR)-l-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-l,2-oxazol- 5-yl]piperidin-l-yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoic acid (49 mg, 50% yield) as a white solid; MS (ES) m / z 653.6 (M+1H)+. LCMS Purity 98.20% @ 254.0 nm.

[0707] 1H NMR (400 MHz, DMSO-rfe): 8 12.54 (s, 1H), 10.86 (s, 1H), 8.89 (s, 1H), 7.51 (s, 1H), 7.31 - 6.99 (m, 5H), 6.93 - 6.85 (m, 2H), 5.96 (q, J= 6.4 Hz, 1H), 3.73 -3.66 (m, 2H), 3.54 - 3.49 (m, 2H), 2.89 - 2.87 (m, 1H), 2.76 - 2.67 (m, 2H), 2.66 - 2.56 (m, 2H), 2.08 (s, 3H), 1.85 -1.76 (m, 4H), 1.52 - 1.51 (m, 3H), 1.40 - 1.36 (m, 2H), 1.27 - 1.25 (m, 2H), 1.20 - 1.17 (m, 3H), 1.86 - 1.80 (m, 2H).

[0708] Example 23. Preparation of (1R)-1 -phenylethyl N-(5-{l-[4- (!-{[(!- carbamoylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl)phenyl]piperidin-4-yl}-3-methyl- l,2-oxazol-4-yl)carbamate (Compound 73)

[0709] Step 1. Preparation of methyl l-(([l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy] carbonyl} amino)-l ,2-oxazol-5-yl]piperidin-l-yl}phenyl)cyclopropyl] formami do} sulfonyl) cyclopropane- 1- carboxylate

[0710] To a stirred solution of l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)- l,2-oxazol-5-yl]piperi din- l-yl}phenyl)cyclopropane-l -carboxylic acid (0.3 g, 613 pmol) in tetrahydrofuran (2 mb, 12.3 mmol) were added l-(lH-imidazole-l-carbonyl)-lH-imidazole (149 mg, 1.5 eq., 919 pmol) and DMAP (7.49 mg, 0.1 eq., 61.3 pmol) at room temperature, heated to 70°C for 2hours. Then cooled to room temperature and added methyl 1-sulfamoylcyclopropane- 1-carboxylate (165 mg, 1.5 eq., 919 pmol) and DBU (367 pL, 4 eq., 2.45 mmol) at rt, maintained for 16 hours at RT. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was quenched with 1.0N HC1 solution (5 mL) extracted with ethyl acetate (2 x 25mL). The combined organic layer was washed with water (2 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. The crude product was purified by combiflash MPLC using ethyl acetate in n- hexane (68% to 70%) to afford product methyl l-({[l-(4-{4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)cyclopropane-l -carboxylate (370 mg, 93% Yield) as colorless liquid. MS (ES) m z 651.0 (M+1H)+.

[0711] Step 2. Preparation of (1R)-1 -phenylethyl N-(5-{l-[4-(l-{[(l-carbamoylcyclopropyl) sulfonyl]carbamoyl}cyclopropyl)phenyl]piperidin-4-yl}-3-methyl-l,2-oxazol-4-yl)carbamate

[0712] I l l To a stirred solution of methyl l-({[l-(4-{4-[3-methyl-4-({[(lR)-l - phenylethoxy] carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)cyclopropane-l -carboxylate (0.1 g, 154 pmol) in THF (5 mL) was added Ammonia (15 pL, 4 eq., 615 pmol) and the reaction mixture was stirred 60°C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the resulting mixture was concentrated to get crude product, crude was given for prep HPLC Mobile phase(A) : 0.1% Ammonia in water, Mobile phase(B) : Acetonitrile purification to afford (lR)-l-phenylethyl N-(5-{ l-[4-(l-{[(l-carbamoylcyclopropyl)sulfonyl]carbamoyl] cyclopropyl)phenyl]piperidin-4-yl}-3-methyl-l,2-oxazol-4-yl)carbamate as off white solid (10 mg, 10% : Yield) MS (ES) m / z 636.5 (M+1H)+. LC purity 99.08% @ 254 nm.

[0713] 1H NMR (400 MHz, DMSO-de): 8 10.61 (s, 1H), 8.92 (s, 1H), 7.6 (s, 1H), 7.39 - 7.30 (m, 6H), 7.18 (t, J=10.4 Hz, 2H), 6.93 (t, J=7.6 Hz, 2H), 5.75 (q, J =6A Hz, 1H), 3.72 (d, J = 11.2 Hz, 2H), 2.90 (s, 1H), 2.71 - 2.67 (m, 2H), 2.07 (s, 3H), 1.86 - 1.75 (m, 4H), 1.63 (s, 2H), 1.52 - 1.38 (m, 7H), 1.09 (s, 2H).

[0714] Example 24. Preparation of (lR)-l-phenylethyl N-{5-[l-(4-{l-[(3-hydroxy-2- inethylpropanesulfonyl)carbamoyl]cyclopropyl}phenyl)piperidin-4-yl]-3-methyl-l,2-oxazol- 4-yl}carbamate (Compound 79)

[0715] Step 1. Preparation of methyl 2-methyl-3-sulfamoylpropanoate

[0716] To a solution of methyl 3-(chlorosulfonyl)-2-methylpropanoate (0.5 g, 2.49 mmol) in diethyl ether (10 mL, 96.2 mmol) at 0°C and purged under ammonia for 30 min and stirred at room temperature 1 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, it was filtered and filterate was concentrated under reduced pressure to afford methyl 2- methyl-3-sulfamoylpropanoate as a gummy liquid. (450 mg, 100% : Yield).

[0717] Step 2. Preparation of methyl 2-methyl-3-({[l-(4-{4-[3-methyl-4-({[(lR)-l phenylethoxy] carbonyl} amino)-l,2-oxazol-5-yl]piperidin-l yl}phenyl) cyclopropyl ]f or mamido] sulfonyl) propanoate

[0718] To a stirred solution of l-(4-{4-[3-methyl-4-({[(lR)-l-phenylethoxy]carbonyl}amino)- l,2-oxazol-5-yl]piperi din- l-yl}phenyl)cyclopropane-l -carboxylic acid (0.5 g, 1.02 mmol) in THF (5 mL) were added l-(lH-imidazole-l-carbonyl)-lH-imidazole (248 mg, 1.5 eq., 1.53 mmol) and DMAP (62.4 mg, 0.5 eq., 511 pmol) at 0°C, stirred at 70°C for 2 hr. Reaction mixture was cooled to rt, Finally added methyl 2-methyl-3-sulfamoylpropanoate (204 mg, 1.1 eq., 1.12 mmol) and DBU (610 pL, 4 eq., 4.09 mmol) at 0°C stirred at rt for 16 hours. Progress of the reaction was monitored by TLC & LCMS. After completion of reaction, reaction mass was quenched with ice cold water, extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (2 x 10 mL), sodium bicarbonate solution (10 mL) and brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude product. Crude was given for prep HPLC Mobile phase (A): 0.1% Ammonia in water Mobile phase (B): Acetonitrile to afford methyl 2-methyl-3-({[l-(4-{4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoate as awhite solid (550 mg, 82% Yield); MS (ES) m / z 653.5 (M+H)+.

[0719] Step 3. Preparation of (lR)-l-phenylethyl N-{5-[l-(4-{l-[(3-hydroxy-2- methylpropanesulfonyl)carbamoyl]cyclopropyl}phenyl)piperidin-4-yl]-3-methyl-l,2-oxazol-4- yl}carbamate

[0720] To a stirred solution of methyl 2-methyl-3-({[l-(4-{4-[3-methyl-4-({[(lR)-l- phenylethoxy]carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoate (150 mg, 230 pmol) in tetrahydrofuran (10 mL, 123 mmol) were added LAH (16.1 mg, 2 eq., 460 pmol) at 0°C, allowed to stir at same temperature for 1 hour. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was quenched with water and ethyl acetate and filtered through celite bed and washed with ethyl acetate, dried with sodium sulphate and concentrated to get crude product. Crude was given for prep HPLC Mobile phase (A): 0.1% Ammonia in water Mobile phase (B): Acetonitrile to afford (1R)-1 -phenylethyl N-{5-[l-(4-{ l-[(3-hydroxy-2- methylpropanesulfonyl)carbamoyl]cyclopropyl}phenyl)piperidin-4-yl]-3-methyl-l,2-oxazol-4- yl}carbamate as white solid (25 mg, 17% Yield) ; MS (ES) m z 625.5 (M+H)+,LC purity 99.52% @ 240 nm.

[0721] 'H NMR (400 MHz, DMSO-de): 5 8.93 (s, 1H), 7.39 - 7.07 (m, 5H), 7.31 (d, J =8.4 Hz, 2H), 6.78 (d, .7 =8.4 Hz, 2H), 5.75 (q, J= 6.4 Hz, 1H), 4.41 (d, .7 =6.4 Hz, 1H), 3.62 (d, J= 12 Hz, 2H), 3.28 (d, J= 5.2 Hz, 2H), 3.19 - 3.14 (m, 1H), 2.93 - 2.85 (m, 2H), 2.79 - 2.74 (m, 1H), 2.67 - 2.61 (m, 1H), 2.07 (s, 3H), 1.96 - 1.90 (m, 1H), 1.88 - 1.66 (m, 4H), 1.52 (s, 3H), 1.21 (d, J=3.2 Hz, 2H), 0.90 (d, J =6.4 Hz, 3H), 0.68 (d, J =3.2 Hz, 2H).

[0722] Example 25. Preparation of l-[[l-[4-[4-[l-methyl-5-[[(lR)-l- phenylethoxy]carbonylainino]triazol-4-yl]-l-piperidyl]phenyl]cyclopropanecarbonyl] sulfamoyljcyclopropanecarboxylic acid (Compound 57)

[0723] To a solution of ethyl l-[[l-[4-[4-[l-methyl-5-[[(lR) -1 -phenylethoxy] carbonylamino] triazol-4-yl] -l-piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]cyclopropanecarboxylate (85 mg, 127.86 pmol, 1 eq) in EtOH (2 mL) was added LiOH (2 M, 1 mb, 15.64 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and the tertbutyl 4-(5-propoxy carbonyl- lH-triazol-4-yl) piperidine- 1 -carboxylate consumed. The reaction mixture was acidified to pH=6 by adding AcOH. The reaction mixture was purified by prep-HPLC (Phenomenex luna Cis 150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 29%-59%, lOmin) and lyophilized to give l-[[l-[4-[4-[l-methyl-5-[[(lR) -1- phenylethoxy]carbonylamino]triazol-4-yl] -l-piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl] cyclopropanecarboxylicacid (70 mg, 109.94 pmol, 85.98% yield, 100% purity) as a white solid.

[0724] 'H NMR (400 MHz, methanol-d4) 8 = 7.43 - 7.27 (m, 7H), 7.05 (d, J= 8.6 Hz, 2H), 5.83 (q, J = 6.7 Hz, 1H), 3.85 - 3.80 (m, 3H), 3.77 ( d, J = 12.6 Hz, 2H), 2.85 - 2.69 (m, 3H), 2.00 - 1.88 (m, 4H), 1.88 - 1.84 (m, 2H), 1.67 - 1.63 (m, 2H), 1.62 - 1.52 (m, 5H), 1.24 - 1.16 (m, 2H). MS m / z: 637.4 [M+H]+

[0725] Example 26. Preparation of 2-[[l-[4-[4-[l-methyl-5-[[(lR)-l- phenylethoxy]carbonylamino]triazol-4-yl]-lpiperidyl]phenyl]cyclopropanecarbonyl] sulfamoyl] acetic acid (Compound 58)

[0726] To a solution of methyl 2- [[l-[4-[4-[l-methyl-5- [[(1R) -1 -phenylethoxy]carbonylamino] triazol- 4- yl]- 1- piperidyl] phenyl] cyclopropanecarbonyl] sulfamoyl] acetate (25 mg, 40.02 pmol, 1 eq) in MeOH (2 mb) was added LiOH«H2O (2 M, 0.5 mL, 24.99 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and the methyl 2- [[1- [4-[4-[l-methyl-5-[[(lR) -1 -phenylethoxy] carbonylamino] triazol- 4-yl] - 1 -piperidyl] phenyl] cyclopropanecarbonyl] sulfamoyl] acetate consumed. The reaction mixture was acidified to pH=6 by adding AcOH. The crude product was purified by prep-HPLC (Unisil 3-100 Cis Ultra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 24%-54%, 7min) to give 2-[[l-[4-[4-[l-methyl- 5-[[(lR) -l-phenylethoxy]carbonylamino]triazol-4-yl]-l- piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]acetic acid (2.7 mg, 4.29 pmol, 10.72% yield, 97% purity) as a white solid.

[0727] ‘HNMR (400 MHz, methanol-d4) 8 = 7.41 - 7.25 (m, 7H), 7.01 (d, J= 8.8 Hz, 2H), 5.85- 5.80 (m, 1H), 4.31 (s, 2H), 3.82 (s, 3H), 3.74 (d, J= 12.5 Hz, 2H), 2.83 - 2.71 (m, 3H), 1.98 - 1.86 (m, 4H), 1.65 - 1.55 (m, 5H), 1.22 - 1.16 (m, 2H). MS m / z: 611.2 [M+H]+ Example 27. Preparation of l-[[l-[4-[4-[5-[[(lR)-l-(2- chlorophenyl)ethoxy]carbonylamino]-l-methyl-triazol-4-yl]-l- piperidyllphenyl]cyclopropanecarbonyl]sulfamoyl]cyclopropanecarboxylic acid

[0728] (Compound 39)

[0729] To a solution of ethyl l-[[l-[4-[4-[5-[[(lR)-l-(2-chlorophenyl)ethoxy] carbonylamino]- 1- methyl- triazol-4-yl]-l-piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl] cyclopropanecarboxylate (50 mg, 71.51 pmol, 1 eq) in EtOH (1 mL) was added LiOH (2 M, 0.5 mL, 13.98 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and all of ethyl l-[[l-[4-[4-[5-[[(lR)-l-(2-chlorophenyl)ethoxy]carbonylamino]- l-methyl-triazol-4-yl]-l -piperidyl] phenyl]cyclopropanecarbonyl]sulfamoyl] cyclopropanecarboxylate consumed. The reaction mixture was acidified to pH=6 by adding AcOH, then the resulting mixture was purified by Prep-HPLC (Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:36%-66% B over 10 min) to give 1 -[[ l-[4-[4-[5- [[(lR)-l-(2-chlorophenyl)ethoxy]carbonylamino] -1-methyl- triazol-4-yl]-l -piperidyl] phenyl] cyclopropanecarbonyl]sulfamoyl]cyclopropanecarboxylic acid (15.7 mg, 22.46 pmol, 31.40% yield, 96% purity) as a white solid.

[0730] ‘H NMR (400 MHz, methanol-d4) 8 = 7.59 (d, J= 3.9 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.36 - 7.28 (m, 4H), 7.05 (d, J= 8.7 Hz, 2H), 6.21 - 6.15 (m, 1H), 3.85 (s, 3H), 3.80 (d, J= 12.2 Hz, 2H), 2.88 - 2.76 (m, 3H), 1.98 - 1.90 (m, 4H), 1.88 - 1.84 (m, 2H), 1.66 - 1.63 (m, 2H), 1.62 - 1.57 (m, 3H), 1.57 - 1.54 (m, 2H), 1.22 - 1.18 (m, 2H). MS m / z: 671.2 [M+H]+ Example 28. Preparation of 3-({[l-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoic acid (Compound 31)

[0731] Step 1. Preparation of methyl 3-({[l-(4-{6-[3-methyl-4-({[(lK)-l-(2- methylphenyl)ethoxy ]carbonyl}amino)-l , 2-oxazol-5-yl]-2-azaspiro[ 3.3 ] heptaneyl) phenyl) cyclopropyl Jformamido }sulfonyl)propanoate stirred solution l-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy]carbonyl (amino)- l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl (phenyl) cyclopropane- 1 -carboxylic acid (130 mg, 252 pmol) in DCM (2 mL) were added Tri ethylamine (105 pL, 3 eq., 756 pmol), DMAP (15.4 mg, 0.5 eq., 126 pmol), EDC.HC1 (82.1 mg, 3 eq., 756 pmol) and HOBT (68.1 mg, 2 eq., 504 pmol), stirred at room temperature for 15 minutes. Finally added methyl 3-sulfamoylpropanoate (126 mg, 3 eq., 756 pmol) and stirred at rt for 12 hours. Progress of the reaction was monitored by TLC & LCMS. After completion of reaction, reaction mass was quenched with ice cold water, extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (2 x 10 mL), sodium bicarbonate solution (10 mL) and brine solution (5 mL), dried over anhydrous sodium sulphate, fdtered and evaporated under reduced pressure to get crude product methyl 3-({[l-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy]carbonyl (amino)- l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoate (Crude) as white solid; MS (ES) m / z 665.3 (M+1H) .

[0732] 'H NMR (400 MHz, DMS0-d6): 8 8.88 (s, 1H), 7.42 (d, J = 6.8 Hz, 1H), 7.24 - 7.18 (m, 3H), 7.03 (d, J =8.4 Hz, 2H), 6.28 (d, J= 8.4 Hz, 2H), 5.90 (q, J = 6.8 Hz, 1H), 3.82 (s, 2H), 3.66 (s, 2H), 3.58 (s, 3H), 3.45 - 3.40 (m, 1H), 3.24 - 3.17 (m, 1H), 3.15 - 3.06 (m, 1H), 3.09 - 3.04 (m, 2H), 3.03 - 2.95 (m, 1H), 2.46 (s, 1H), 2.38 (s, 3H), 2.20 - 2.17 (m, 1H), 2.10 (s, 3H), 2.03 - 1.96 (m, 1H), 1.74 - 1.61 (m, 1H), 1.36 (s, 3H), 1.24 (d, J= 3.2 Hz, 2H). 0.71 (d, J=2.4 Hz, 2H).

[0733] Step 2. Preparation of 3-({[l-(4-{6-[3-methyl-4-({[(lR)-l-(2- methylphenyl)ethoxy ]carbonyl}amino)-l , 2-oxazol-5-yl]-2-azaspiro[3.3 ]heptan-2- yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoic acid

[0734] To a stirred solution of methyl 3-({ [l-(4-{6-[3-methyl-4-({ [(lR)-l-(2- methylphenyl)ethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoate (60 mg, 90.3 pmol) in oxolane (2 mL), methanol (2 mL, 156 mmol) solution was added lithium(l+) hydrate hydroxide (15.1 mg, 4 eq., 361 pmol) in water (2 mL) and the mixture was stirred atRT for 18 hours. Reaction was progressed by LCMS and TLC, rm was concentrated, diluted with water (10 mL), washed with diethyl ether (2 x 10 mL), PH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on buchnel funnel, solid was washed with water (2 x 10 mL), pentane (2 x 10 mL) and dried under vacuum to afford 3-({ [l-(4-{6-[3-methyl-4-({ [(lR)-l-(2- methylphenyl)ethoxy]carbonyl}amino)-l,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2- yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoic acid as off white solid (35 mg, 60% yield); MS (ES) m'z 651.3 (M+1H)+. LC purity 98.42% @ 240 nm.

[0735] 'H NMR (400 MHz, DMSO-de): 6 12.55 (s, 1H), 10.72 (s, 1H), 8.87 (s, 1H), 7.42 (d, J =6.4 Hz, 1H), 7.24 - 7.09 (m, 5H), 6.36 (q, J =8.4 Hz, 2H), 5.91 (q, J= 6.4 Hz, 1H), 3.85 (d, J = 7.6 Hz, 2H), 3.70 (d, J= 8.4 Hz, 2H), 3.54 (t, J= 7.2 Hz, 2H), 3.48 - 3.41 (m, 1H), 2.61 (t, J= 6.8 Hz, 2H), 2.47 - 2.39 (m, 4H), 2.33 (s, 3H), 2.07 (s, 3H), 1.58 (s, 3H), 1.34 (s, 2H), 1.02 (s, 2H).

[0736] Example 29. Preparation of 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarbonyl] sulfamoyl] propanoic acid (Compound 1)

[0737] Step 1. Preparation of dimethyl 2-(4-bromo-3-methoxy-phenyl)propanedioate

[0738] To a solution of l-bromo-4-iodo-2-methoxy-benzene(2A) (10 g, 31.96 mmol, 1 eq) and dimethyl propanedioate(2B) (23.00 g, 174.09 mmol, 20 mb, 5.45 eq) in dioxane (200 mL) was added Cui (1.2 g, 6.30 mmol, 1.97e-l eq), pyridine-2-carboxylic acid (1.6 g, 13.00 mmol, 4.07e- 1 eq) and Cs2CO3 (30 g, 92.08 mmol, 2.88 eq), the reaction mixture was stirred at 110°C for 22 hrs. TLC (PE / EtO Ac=2 / 1 , Rf=0.24) showed one major spot was observed. The reaction was extracted with EtOAc (500 mL*3). The combined organic phase was washed with saturated brine (500 mL *2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to afford dimethyl 2-(4-bromo- 3 -methoxy -phenyl) propanedioate(2C) (10 g, 31.53 mmol, 98.67% yield) as yellow oil.

[0739] 'H NMR (400 MHz, chloroform-d) 8 = 7.40 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 1.9, 8.1 Hz, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 3.52 (s, 2H).

[0740] Step 2. Preparation of methyl 2-(4-bromo-3-methoxy-phenyl)acetate

[0741] To a solution of dimethyl 2-(4-bromo-3 -methoxy -phenyl) propanedioate(2C) (7 g, 22.07 mmol, 1 eq) in DMSO (100 mL) was added H2O (3.50 g, 194.28 mmol, 3.5 mL, 8.80 eq) and LiCl (3 g, 70.76 mmol, 1.45 mL, 3.21 eq), the reaction mixture was stirred at 110°C for 12 hr. TLC (PE / EtO Ac=5 / 1, Rf=0.24) showed one major spot was observed. The reaction was extracted with EtOAc (300 mL*3). The combined organic phase was washed with sat. NH4C1 (100 mL*3) and saturated brine (300 mL *2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford methyl 2-(4-bromo-3 -methoxy -phenyl) acetate(2D) (5.4 g, 20.84 mmol, 94.42% yield) as yellow oil.

[0742] 'H NMR (400 MHz, chloroform -d) 5 = 7.40 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 1.8, 8.0 Hz, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 3.52 (s, 2H).

[0743] Step 3. Preparation of methyl l-(4-bromo-3-methoxy-phenyl)cyclopropanecarboxylate

[0744] To a solution of methyl 2-(4-bromo-3 -methoxy-phenyl) acetate(2D) (5.4 g, 20.84 mmol, 1 eq) in THF (100 mL) was added NaHMDS (1 M, 60 mL, 2.88 eq) at -40°C and stirred for 1 hr, then the resulting mixture was added 1, 3, 2-dioxathiolane 2, 2-dioxide(2E) (5.4 g, 43.51 mmol, 2.09 eq) at -40°C and stirred for 1 hr. TLC (PE / EtOAc=10 / l, Rf=0.58) showed one major spot was observed, sat. NH4C1 (10 mL) was added to the solution and keep the temperature from 0°C to 5°C, then the reaction was extracted with EtOAc (20 mL*3). The combined organic phase was washed with saturated brine (20 mL *2), dried over anhydrous Na2SO4, fdtered and concentrated in vacuo to give a residual. The residual was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford methyl l-(4-bromo-3 -methoxy -phenyl) cyclopropanecarboxylate (1.7 g, 5.96 mmol, 28.61% yield) as colorless oil.

[0745] 'H NMR (400 MHz, chloroform-d) 8 = 7.31 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 1.8, 8.4 Hz, 1H), 3.75 (s, 3H), 3.49 (s, 3H), 1.48 - 1.46 (m, 2H), 1.06 - 1.03 (m, 2H).

[0746] Step 4. Preparation of methyl l-]3-methoxy-4-[4-[3-methyl-4-[](lR)-l- phenylethoxy]carbonylamino] isoxazol -5-yl]-l -piperidyl] phenyl] cyclopropane- carboxylate

[0747] To a solution of [(lR)-l-phenylethyl] N-[3-methyl-5-(4-piperidyl) isoxazol-4-yl] carbamate (150 mg, 455.38 pmol, 1 eq) in dioxane (2 mL) was added methyl l-(4-bromo-3- methoxy-phenyl) cyclopropanecarboxylate (240.00 mg, 841.71 pmol, 1.85 eq), Cs2CO3 (450.00 mg, 1.38 mmol, 3.03 eq) and CPHOS Pd G3 (40 mg, 49.61 pmol, 1.09e-l eq), then the resulting mixture was purged with N2 for three times and stirred at 90°C for 12 hr. LCMS showed the desired MS was detected and the [(1R) -1 -phenyl ethyl] N-[3-methyl-5-(4-piperidyl) isoxazol-4- yl]carbamate consumed. TLC (PE / EA=3: 1, Rf=0.3) showed a new spot was detected and the [(1R) -1 -phenylethyl] N-[3-methyl-5-(4-piperidyl) isoxazol-4-yl] carbamate consumed. The reaction mixture was partitioned between EtOAc (80 mL) and water (60 mL), washed with brine (60 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (SiO2, PE: EA = 3 : 1) to give methyl l-[3-methoxy-4-[4- [3-methyl-4- [[(1R) -1 -phenyl ethoxy] carbonylamino] isoxazol-5-yl]-l -piperidyl] phenyl] cyclopropane- carboxylate (130 mg, 168.10 pmol, 36.91% yield, 69% purity) as a white solid. MS m / z: 534.3 [M+H] +

[0748] Step 5. Preparation of l-[3-methoxy- 4-[4-[3-methyl-4- [[(1R) -1- phenylethoxy] carbonylamino] isoxazol-5-yl] -1 -piper idyl] phenyl] cyclopropanecarboxylic acid

[0749] To a solution of methyl l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarboxylate (120 mg, 224.88 pmol, 1 eq) in MeOH (2 mL) was added Li OH (2 M, 1 mL, 8.89 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and the methyl l-[3- methoxy-4-[4-[3-methyl-4-[[(lR) -l-phenylethoxy]carbonylamino]isoxazol-5-yl]-l -piperidyl] phenyl]cyclopropanecarboxylate consumed. The reaction mixture was acidified to pH=6 by adding AcOH, partitioned between EtOAc (60 mL) and water (40 mL), washed with brine (40 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give crude l-[3-methoxy- 4-[4- [3-methyl-4- [[(1R) -l-phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl] cyclopropanecarboxylic acid (100 mg, 192.46 pmol, 85.58% yield) as the yellow oil which was used into the step without further purification. MS m / z: 520.3 [M+H] +

[0750] Step 6. Preparation of methyl 3-][l-[3-methoxy-4-]4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino ]isoxazol-5-yl ] -1 -piperidyl phenyl] cyclopropane carbonyl ] sulfamoyl propanoate

[0751] To a solution of l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarboxylic acid (70 mg, 134.72 pmol, 1 eq) in DCM (3 mL) was added methyl 3-sulfamoylpropanoate (50 mg, 299.07 pmol, 2.22 eq), EDCI (120 mg, 625.97 pmol, 4.65 eq) and DMAP (70 mg, 572.98 pmol, 4.25 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and the l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino] isoxazol-5-yl]-l- piperidyl]phenyl] cyclopropanecarboxylic acid consumed. TLC (PE / EA=1 : 1, Rf=0.3) showed a new spot was detected and the l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1- phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarboxylic acid consumed. The reaction mixture was partitioned between EtOAc (70 mL) and HC1 (0. IN, 40 mL), washed with brine (50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (SiO2, PE: EA = 1 : 1) to give methyl 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino]isoxazol-5-yl] -l-piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoate (45 mg, 63.25 pmol, 46.95% yield, 94% purity) as a white solid. MS m / z: 669.4 [M+H] +.

[0752] Step 7. Preparation of 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR)-l- phenylethoxy]carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarbonyl] sulfamoyl]propanoic acid

[0753] To a solution of methyl 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1 -phenylethoxy] carbonylamino]isoxazol-5-yl]-l-piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoate (40 mg, 59.81 pmol, 1 eq) in MeOH (2 mL) was added LiOH (2 M, 1 mL, 33.44 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the desired MS was detected and the methyl 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -l-phenylethoxy]carbonylamino]isoxazol- 5-yl] -l-piperidyl]phenyl]cyclopropanecarbonyl] sulfamoyl]propanoate consumed. The reaction mixture was acidified to pH=6 by adding AcOH. The reaction mixture was purified by prep-HPLC (Phenomenex luna C18 150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 26%-56%, 10 min) to give the 3-[[l-[3-methoxy-4-[4-[3-methyl-4-[[(lR) -1- phenylethoxy]carbonylamino]isoxazol-5-yl] -l-piperidyl]phenyl] cyclopropanecarbonyl] sulfamoyl] propanoic acid (11.29 mg, 17.24 pmol, 28.83% yield, 100% purity) as a white solid.

[0754] 'H NMR (400 MHz, methanol-d4) 5 = 7.42 - 7.26 (m, 5H), 7.03 - 6.96 (m, 3H), 5.83 - 5.75 (m, 1H), 3.90 (s, 3H), 3.66 (t, J = 7.1 Hz, 2H), 3.49 - 3.42 (m, 2H), 2.91 - 2.82 (m, 1H), 2.73 (t, J = 7.2 Hz, 2H), 2.69 - 2.57 (m, 2H), 2.11 (s, 3H), 2.05 - 1.86 (m, 4H), 1.57 (m, 5H), 1.24 - 1.18 (m, 2H). MS m / z: 655.2 [M+H]+.

[0755] Example 30. Preparation of 2-methyl-2- [ [1 - [4- [4- [3-methyl-4- [ [( 1 R)- 1 - phenylethoxy]carbonylamino]isoxazol-5-yl]-l- piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoic acid (Compound 67)

[0756] To a solution of methyl 2-methyl-2- [[l-[4-[4- [3-methyl -4-[[(lR) -1- phenylethoxy]carbonylamino] isoxazol -5-yl] -1 -piperidyl]phenyl] cyclopropanecarbonyl]sulfamoyl] propanoate (50 mg, 76.60 pmol, 1 eq) in MeOH (2 mL) was added LiOH’IHbO (2 M, 0.5 mL, 13.06 eq), then the resulting mixture was stirred at 25°C for 12 hr. LCMS showed the methyl 2-methyl-2-[[l-[4-[4-[3-methyl-4-[[(lR) -1- phenylethoxy]carbonylamino]isoxazol-5-yl]-l -piperidyl] phenyl]cyclopropanecarbonyl]sulfamoyl]propanoate (50 mg, 76.60 pmol, 1 eq) consumed and desired MS was detected. The reaction mixture was acidified to pH=6 by adding AcOH. The reaction mixture was purified by prep-HPLC (Unisil 3-100 Cis Ultra 150*50 mm*3 unpmobile phase: [water (FA) -ACN];B%: 46%-76%, 7min) to give the 2-methyl-2-[[l-[4-[4-[3-methyl-4- [ [( 1 R) - 1 -phenyl ethoxy ] carb ony 1 amino] i soxazol -5 -y 1 ] - 1 - piperidyl]phenyl]cyclopropanecarbonyl]sulfamoyl]propanoicacid (15.1 mg, 23.64 pmol, 30.86% yield, 100% purity) as a white solid.

[0757] ‘HNMR (400 MHz, methanol-d4) 5 = 7.43 - 7.28 (m, 7H), 7.03 (d, J= 8.4 Hz, 2H), 5.84 - 5.74 (m, 1H), 3.75 (d, J = 12.6 Hz, 2H), 2.99 - 2.90 (m, 1H), 2.85 - 2.72 (m, 2H), 2.11 (s, 3H), 1.95 (m, 4H), 1.58 (s, 9H), 1.56 - 1.53 (m, 2H), 1.24 - 1.17 (m, 2H). MS m / z: 639.2 [M+H]+ Example 31. Preparation of (R)-2,2-dimethyl-3-(N-(l-(4-(4-(3-methyl-4- (((1- phenylethoxy)carbonyl)amino)isoxazol-5-yl)piperidin-l-yl)phenyl)cyclopropane-l- carbonyl)sulfamoyl)propanoic acid (Compound 78)

[0758] To a stirred solution of methyl 2,2-dimethyl-3-({[l-(4-{4-[3- methyl-4-({[(lR)-l- phenylethoxy]carbonyl } amino)- 1 ,2-oxazol-5-yl]piperidin- 1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoate (25 mg, 37.5 umol) in THF (3.0 mL), MeOH (3.0 mL) solution was added lithium(l+) hydrate hydroxide (6.29 mg, 150 umol) in water (3.0 mL) and the mixture was stirred at rt for 18 hours. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was concentrated, diluted with water (10 mL), washed with diethyl ether (2 x 5 mL), pH was adjusted with 10% Aq. citric acid up to 3 to 4, white solid was precipitated, filtered on buchnel funnel, solid was washed with water (2 x 5 mL), pentane (2 x 5 mL) and dried under vacuum to afford 2,2-dimethyl-3-({[l- (4- {4-[3 -methyl -4-({ [(1R)-1 -phenylethoxy]carbonyl} amino)- l,2-oxazol-5-yl]piperi din-1 - yl}phenyl)cyclopropyl]formamido}sulfonyl)propanoic acid as an off white solid (5 mg, 21% yield); MS (ES) m / z 653.5 (M+1H)+. LC purity 99.43% @ 240 nmdH NMR (400 MHz, DMSO- d6) 8 12.54 (s, 1H), 10.88 (s, 1H), 8.92 (s, 1H), 7.39 - 7.30 (m, 5H), 7.16 (d, J= 8.8 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 5.74 (q, J= 6.4 Hz, 1H), 3.72 (d, J= 12.0 Hz, 2H), 3.64 (s, 2H), 2.91 - 2.89 (m,lH), 2.74 - 2.66 (m, 2H), 2.04 (s, 3H), 1.86 - 1.75 (m, 4H), 1.52 (d, J= 5.6 Hz, 3H), 1.39 (s, 2H), 1.23 ( m, 6H), 1.06 (s, 2H).

[0759] Additional Exemplary Compounds of Formula (I)

[0760] Compounds 3-7, 9, 11-18, 20, 22, 25, 28-30, 32, 34-36, 40-45, 47-53, 55, 56, 59, 61, 62, 64-66, 68, 70-72, 75-77, 80, 81, 83-86, 90, 91, and 93-97 were synthesized analogously to compounds 1, 2, 8, 10, 19, 21, 23, 24, 26, 27, 31, 33, 37-39, 46, 54, 57, 58, 60, 63, 67, 69, 73, 74, 78, 79, 82, 87-89, and 92 using modifications within the purview of one having skill in the art.

[0761] Biological Examples

[0762] Ca2+Flux Assay

[0763] Procedure

[0764] B103 cells stably expressing hLPARl were seeded at a density of 1.0 x 103cells per well in clear flat-bottom black 96-well plates and incubated overnight in complete media. The following day, the cells were pre-incubated in serum-free media for 2 hours prior to ensure cellular equilibration. For the loading a calcium-sensitive fluorescent dye, the cells were treated with a concentration of 5 pM Fura-2 AM dye (Sigma, F1225) in Hank’s buffered salt solution (HBSS) supplemented with 20 mM HEPES, 1 M probenecid, and 0.3% fatty-acid-free bovine serum albumin for 40 minutes at room temperature (RT). Test compounds, prepared in DMSO, were then added to each well and incubated for 20 minutes at RT. To induce calcium release, a concentration of 5 pM LPA in HBSS supplemented with 20 mM HEPES, and 0.3% fatty-acid-free bovine serum albumin was introduced. Intracellular calcium mobilization was subsequently quantified by monitoring the fluorescence intensity using the Spark® multimode microplate reader (TEC AN).

[0765] Chemotaxis Assay

[0766] Procedure

[0767] For monitoring the migration of cells, Neuroprobe ChemoTx® System plates (10 mm pore size, 5.7 mm diameter sites; Gaithersburg, MD, USA) were utilized. To induce cell migrations, a concentration of 5 pM LPA or vehicle in DMEM were loaded to the bottom chamber. A total of 15,000 A2058 cells, which were starved for 24 hr following treated with test compounds or vehicle, were then applied to the upper membrane coated with 0.001% fibronectin. The plate was incubated for 4 to 8 hours to allow cell migration. Following incubation, the plate was dissembled, and the migrated cells were visualized by crystal violet staining. The stained area with crystal violet was quantified by measuring the absorbance at 590 nm and the relative percentage of the control was calculated. Bile Salt Export Pump (BSEP) Assay

[0768] A. Test Article

[0769] 1. A stock solution was prepared with the test article (Sponsor compound) in DMSO.

[0770] 2. All final assay solutions of probe substrate, reference inhibitor or test article contain 0.5% (v / v) DMSO (vehicle control).

[0771] 3. Test article concentrations in transport study were specified in the Summary Table of

[0772] Experimental Conditions of this protocol.

[0773] Table 1. Summary of Experimental Conditions:

[0774] B. Materials

[0775] 1. Bovine Serum Albumin (BSA)

[0776] 2. Dimethyl sulfoxide (DMSO)

[0777] 3. BSEP Assay Uptake Buffer (10 mM HEPES-Tris pH 7.4, 0.1 M KN03, 12.5 mM Mg(NOs)2, 50 mM sucrose)

[0778] 4. BSEP Wash Buffer (10 mM Tris-HCl pH 7.4, 0.1 M KNO3, 50 mM sucrose)

[0779] 5. BSEP Blocking Buffer (BSEP Wash Buffer + 0.5 mg / mL BSA)

[0780] 6. 25 mM Mg-ATP solution

[0781] 7. 25 mM AMP solution

[0782] 8. Corning Costar 96-well flat-bottom, untreated, white Assay Plate (Corning Cat. No. 3912)

[0783] 9. Millipore Multi screenurs Filtration Plate, glass fiber FB - 1.0 / 0.65 pm (Cat. No. MSFBN6B10 or glass fiber FC - 1.2 / 0.65 pm (Cat. No. MSFCN6B10)

[0784] 10. Millipore Multi screenurs Vacuum Manifold (Cat. No. MSVMHTS00)

[0785] 11. Probe substrates listed in Table 1

[0786] 12. Reference inhibitors listed in Table 1

[0787] 13. Test articles C. Transport Study for BSEP

[0788] 1. Test system: a. 96-well flat bottom plate containing a suspension of vesicles and a corresponding 96-well glass fiber filtration plate. b. Transport experiments were conducted in the Assay Uptake Buffer. c. Transport experiment was initiated with the addition of Mg- ATP or AMP to appropriate wells. d. Each condition was run in triplicate wells.

[0789] 2. Prepared the 96-well flat-bottom assay plate. a. Incubated the assay plate with the Blocking Buffer for 60 min at 37 °C with orbital shaking at approximately 90 rpm. (NOTE: This is done to prevent nonspecific binding of vesicles to polystyrene assay plate)' . b. After 60 min, completely removed the Blocking Buffer from the assay plate. c. The Assay Uptake Buffer solutions were added to the assay plate wells as follows: i. For probe substrate transport assays, the Assay Uptake Buffer contained vesicles and the probe substrate at the specified concentration. ii. For the reference inhibition assay, the Assay Uptake Buffer contained vesicles, the reference inhibitor and the probe substrate at the specified concentration in Table 1. iii. For the test article assays, Assay Uptake Buffer contained vesicles, the test article and the probe substrate at the specified concentration in Table 1.

[0790] 3. Incubate at 37° C with orbital shaking at approximately 90 rpm for the time period specified in Table 1 of this protocol.

[0791] 4. Using the 25 mM Mg-ATP or AMP stocks, Mg-ATP or AMP was added to test wells of flat bottom assay plate to a final concentration of 5 mM.

[0792] 5. Incubated at 37° C with orbital shaking at approximately 90 rpm for the incubation time specified in Table 1 of this protocol.

[0793] 6. Prepared the 96-well glass fiber filtration plate: a. Incubated the filtration plate with the Blocking Buffer for 2 min at room temperature with under no vacuum. b. Turned on vacuum and allowed Blocking Buffer to fdter through plate. c. With vacuum on, fdter plate was washed with ice cold Wash Buffer.

[0794] 7. At the end of the specified incubation time indicated in Table Is of this protocol, vesicle transport was quenched by adding ice cold Wash Buffer to samples in 96-well assay plate.

[0795] 8. Mixed assay samples (now diluted in Wash Buffer) with pipette and transfered 175 L into the 96-well glass fiber filtration plate to separate vesicles from buffer by applying vacuum.

[0796] 9. Washed filter plate wells with ice cold Wash Buffer.

[0797] 10. Allowed filter plate to dry under vacuum.

[0798] 11. Transfered filters to scintillation sample plate and added 700 pL of scintillation fluid to the above samples.

[0799] 12. Counted the above samples on a 1450 Microbeta (Perkin-Elmer).

[0800] D. Analytical, Data Analysis and Reporting

[0801] 1. The amount of substrate was quantified with radiometric detection on a 1450 Microbeta (Perkin-Elmer).

[0802] 2. For transport study samples run in triplicate, the mean and standard deviation of the replicates were reported.

[0803] 3. For BSEP, the ATP-dependent substrate transport rate (V) in Sf9 vesicles containing the transporter were calculated by subtracting the mean substrate accumulation in vesicles treated with AMP from the substrate accumulation in vesicles treated with ATP:

[0804] ATP-dependent transport rate (pmol / min / mg)

[0805] = ((Vesicular accumulation^? - (Mean vesicular accumulation)AMp) / Incubation time

[0806] 4. Percent inhibition in the presence of the test article or the reference inhibitors was calculated as follows:

[0807] Percent inhibition = 100-(100*(ATP-dependent transport rate)with inhibitor / (ATP- dependent transport rate)vehicie control)

[0808] 5. For vesicle assays, statistical analysis using unpaired t test was performed between transporter-mediated uptake rate or ATP-dependent transport rate of probe substrate with vehicle control and the inhibitor. A p value <0.05 is considered statistically significant. 6. All reported data was based on nominal concentration used unless otherwise stated.

[0809] 7. Data and calculated values were displayed at 3 significant figures with rounding occurring only for final display.

[0810] 8. BSEP % inhibition is at 10 pM of test compound

[0811] 9. BSEP inhibition was determined at BioIVT.

[0812] The following table, Table B, lists the results of exemplary compounds tested in the Ca2+Flux and Chemotsaxis assays as described the foregoing, with the IC50 values listed in ranges according to: Ca2+Assay IC50: D > 3000 nM > C > 200 nM > B > 10 nM > A; Chemotaxis IC50: D > 5000 nM > C > 500 nM > B > 100 nM > A. Liver microsomal stability is percent of parent compound remaining after 30 minutes incubation with mouse (M), rat (R), or human (H) liver microsomes with percent ranges of D < 25% < C < 50% < B < 75% < A. BSEP % inhibition is at 10 pM of test compound, with percent inhibition ranges of A < 25% < B < 50% < C < 75% < D < 100%.

[0813] Table B

[0814] R-l and R-2 are selected reference compounds included for comparison.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or pharmaceutically acceptable salts thereof, wherein:RAis hydrogen, C1-C6 alkyl, or C1-C6 alkoxy;Ring B is 3-7 membered heterocyclylene or 5-6 membered heteroarylene;Ring C is phenylene or 5-6 membered heteroarylene; m is 0 or 1; n is 0, 1, 2, or 3; each R1is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl; or two R1together with the atoms to which they are attached forms a 5-8 membered heterocyclyl or 5-6 membered heteroaryl; each R2is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and halogen;R3is selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substituted with 1-2 independently selected RE,(iii) C6-C10 aryl optionally substituted with hydroxyl,(iv) C5-C10 cycloalkyl,(v) 5-6 membered heteroaryl optionally substituted with phenyl, and(vi) 5-6 membered heterocyclyl optionally substituted with phenyl; each REis independently selected from:(i) hydroxyl;(ii) C1-C6 alkoxy,(iii) phenyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, and halogen,(iv) 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, and(v) C3-C10 cycloalkyl;Q is selected from:(i) C1-C6 hydroxyalkyl,(ii) -C(=O)OH,(iii) -S(=O)2OH,(iv) cyano,(v) -S(O)2NRA1RB1,(vi) -NRCS(O)2NRA1RB1,(vii) -C(=O)C1-C6 alkoxy optionally substituted with C1-C6 alkoxy optionally substituted with -S(=O)2NRCRD; or 5-6 membered heterocyclyl optionally substituted with C1-C6 alkyl;(viii) -C(=O)C6-C10 aryl oxy;(ix) -C(=O)-(5-6 membered heterocyclyloxy) optionally substituted with 1-4 substituents selected from C1-C6 alkyl, hydroxyl, and -C(=O)OH,(x) -C(=O)NRA2RB2,(xi) C1-C6 haloalkyl optionally substituted with hydroxyl,(xii) 5-6 membered heteroaryl optionally substituted with hydroxyl, and(xiii) -C(=O)NHS(=O)2RF;X is selected from -(CH2)XNRGC(=O)O-, -(CH2)XOC(=O)NRG-, -(CH2)XNRG-, or -CH(OH)-;RA1and RB1are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl;RA2and RB2are independently selected from hydrogen and C1-C6 alkyl optionally substituted with hydroxyl or -S(=O)2NH2;Rcand RDare independently selected from hydrogen and C1-C6 alkyl;RFis selected from:(i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from:(a) hydroxyl,(b) halogen,(c) cyano,(d) C1-C6 alkoxy,(e) 4-6-membered heterocyclyl optionally substituted with C1-C6 alkyl,(f) -C(=O)OH,(g) -OC(=O)C1-C6 alkyl,(h) -S(=O)2Cl-C6 alkyl,(i) -C(=O)NRA1RB1,(j) -NRCRD,(k) -C(=O)C1-C6 aryloxy,(l) C3-C6 cycloalkyl optionally substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy, and(m) -C(=O)C1-C6 alkoxy optionally substituted with -C(=O)C1-C6 alkyl or -OC(=O)C1-C6 alkyl,(ii) C2-C6 alkenyl,(iii) C1-C6 haloalkyl,(iv) phenyl,(v) C3-C6 cycloalkyl optionally substituted with(a) C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxyl, -C(=O)OH, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy,(b) cyano,(c) -C(-O)OH,(d) -C(=O)NRCRD, ore(e) -C(=O)C1-C6 alkoxy optionally substituted with hydroxyl or -C(=O)C1-C6 alkyl, or(f) -NRCRD, and(vi) -NRA3RB3;RA3and RB3are independently selected from hydrogen and C1-C6 alkyl;RGis H or C1-C3 alkyl; and x is 0 or 1.

2. The compound of claim 1 , wherein when Ring B is pyridyl, Ring B and Ring C are connected via a carbon atom of Ring C.

3. The compound of claim 1 or 2, wherein Ring B is 3-7 membered heterocyclylene.

4. The compound of any one of claims 1-3, wherein Ring B is selected from the group consisting of azetidinyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, and azaspiro[3.3 ]heptanyl ..

5. The compound of any one of claims 1-4, wherein Ring B is selected from the group consisting, , wherein indicates the attachment point to Ring A.indicates the attachment point to Ring A.

7. The compound of any one of claims 1-6, wherein Ring C is 5-6 membered heteroarylene.

8. The compound of any one of claims 1-7, wherein Ring C is 5 membered heteroarylene selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.

9. The compound of any one of claims 1 -8, wherein Ring C is selected from the group, p g .

10. The compound of any one of claim 1-9, wherein Ringwherein “* indicates the attachment point to Ring B.

11. The compound of any one of claims 1-7, wherein Ring C is phenylene.

12. The compound of any one of claims 1-11, wherein m is 0.

13. The compound of any one of claims 1-12, wherein n is 1.

14. The compound of any one of claims 1-11 and 13, wherein each R1is an independently selected C1-C6 alkyl.

15. The compound of any one of claims 1-14, wherein at least one R2is C1-C6 alkyl.

16. The compound of any one of claims 1-15, wherein at least one R2is methyl.

17. The compound of any one of claims 1-16, wherein R3is C1-C6 alkyl optionally substituted with 1-2 RE.

18. The compound of any one of claims 1 -17, wherein at least one REis phenyl optionally substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxyl, cyano, or halogen.

19. The compound of any one of claims 1-18, wherein R3iswherein REis phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyalkyl, C1-C63 alkoxy, hydroxyl, cyano, or halogen.

20. The compound of any one of claims 1-19, wherein21. The compound of any one of claims 1-20, wherein Q is selected from -C(=O)OH; -S(=O)2OH; 5-6 membered heteroaryl optionally substituted with hydroxyl; and -C(=O)NHS(=O)2RF.

22. The compound of any one of claims 1-21, wherein Q is -C(=O)OH or -C(=O)NHS(=O)2RF.

23. The compound of any one of claims 1-22, wherein Q is -C(=O)NHS(=O)2RF.

24. The compound of any one of claims 1-24, wherein RFis C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxyl; halogen; cyano; C1-C6 alkoxy; 4-6- membered heterocyclyl optionally substituted with C1 -C6 alkyl; -C(=O)OH; -OC(=O)C1-C6 alkyl; -S(=O)2C1-C6 alkyl; -C(=O)NRA1RB1; -NRCRD; -C(=O)C1-C6 aryloxy; C3-C6 cycloalkyl optionally substituted with -C(=O)OH, cyano, C1-C6 hydroxyalkyl, -C(=O)NRA1RB1, or -C(=O)C1-C6 alkoxy optionally substituted with hydroxyl or -C(=O)C1-C6 alkyl.

25. The compound of any one of claims 1-24, wherein RFis C1-C6 alkyl optionally substituted with C(=O)OH or -C(=O)C1-C6 alkoxy.

26. The compound of any one of claims 1-23, wherein RFis C2-C6 alkenyl.

27. The compound of any one of claims 1-22, wherein Q is -C(=O)OH.

28. The compound of any one of claims 1-22, wherein Q is -NRA3RB3.

29. The compound of any one of claims 1-28, wherein X is -(CH2)xNRGC(=0)0-.

30. The compound of any one of claims 1-29, wherein X is -NHC(=O)O-.

31. The compound of any one of claims 1-28, wherein X is-(CH2)XOC(=O)NRG-.

32. The compound of any one of claims 1-28 or 31, wherein X is -OC(=O)NH-.

33. The compound of any one of claims 1-28, wherein X is -(CH2)xNRG-.

34. The compound of any one of claims 1-28 or 33, wherein X is -NH-.

35. The compound of any one of claims 1-28, wherein X is -CH(OH)-.

36. The compound of Claim 1, wherein Formula (I) is Formula (I-a):or pharmaceutically acceptable salts thereof.

37. The compound of Claim 1, wherein Formula (I) is Formula (I-b):or pharmaceutically acceptable salts thereof.

38. The compound of Claim 1, wherein Formula (I) is Formula (I-c):or pharmaceutically acceptable salts thereof, wherein Z is CH, N, O, or S; V is C or N; and wherein Z is O or S when V is C.

39. The compound of Claim 1, wherein Formula (I) is Formula (I-d):or pharmaceutically acceptable salts thereof, wherein Q is -CO2H or -C(=O)NHS(=O)2RF; and Z is O or S.

40. The compound of Claim 1, wherein Formula (I) is Formula (I-e):'R ,2:(I-e) or pharmaceutically acceptable salts thereof, wherein Q is -CO2H or -C(=O)NHS(=O)2RF; Z is CH, N, O, or S; V is C or N; and wherein Z is O or S when V is C.

41. The compound of Claim 1, wherein Formula (I) is Formula (I-f):140RECTIFIED SHEET (RULE 91) ISA / EPor pharmaceutically acceptable salts thereof, wherein Q is -CO2H or -C(=O)NHS(=O)2RF; Z is CH, N, O, or S; Vis C or N; and wherein Z is O or S when V is C.

42. A compound selected from the group consisting of compounds in Table A, or a pharmaceutically acceptable salt of any of the foregoing.

43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

44. A method of treating a fibrotic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 43.

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