TW202513559A - Compounds for treating fibrotic diseases - Google Patents

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

Compounds for the treatment of fibrotic diseases

The present disclosure relates to the fields of chemistry and biology. More specifically, the present disclosure provides compounds that inhibit lysophosphatidic acid receptor 1 (LPA1) and pharmaceutically acceptable salts thereof. These compounds can be used, for example, to treat diseases associated with LPA1 activity. The present disclosure also provides compositions containing these compounds and methods of using and preparing these compounds.

Lysophospholipids (LPA) are bioactive lipids that regulate various cellular signaling pathways by binding to 7-transmembrane domain G protein-coupled (GPCR) receptors. LPA has long been considered a precursor to phospholipid biosynthesis in eukaryotic and prokaryotic cells, but LPA has only recently emerged as a signaling molecule that is rapidly produced and released by activated cells, especially platelets, to affect target cells by acting on specific cell surface receptors. There are currently six identified LPA receptors, named LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6. These receptors signal through a variety of effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs. LPA receptor-mediated effects have been described in a variety of cell types and model systems in vitro and in vivo through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological effects on nearly every organ system and developmental stage of the organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Perturbations in normal LPA signaling can lead to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity.

Some embodiments provide compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof. In some embodiments, the compound of formula (I) is: (I) or a pharmaceutically acceptable salt thereof, wherein: ^RA is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; Ring B is a 3-7 membered heterocyclic group or a 5-6 membered heteroaryl group; Ring C is a phenyl group or a 5-6 membered heteroaryl group; m is 0 or 1; n is 0, 1, 2 or 3; each ^R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, a 3-7 membered heterocyclic group and a 5-6 membered heteroaryl group; or two ^R1 together with the atoms to which they are attached form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; each ^R2 is independently selected from C1-C6 alkyl, C1-C6 halogenalkyl, C1-C6 alkoxy and halogen; R ^R is selected from: (i) hydrogen, (ii) C1-C6 alkyl optionally substituted with 1-2 independently selected ^RE , (iii) C6-C10 aryl optionally substituted with hydroxy, (iv) C5-C10 cycloalkyl, (v) 5-6 membered heteroaryl optionally substituted with phenyl, and (vi) 5-6 membered heterocyclo optionally substituted with phenyl; each ^RE is independently selected from: (i) hydroxy; (ii) C1-C6 alkoxy, (iii) phenyl optionally substituted with 1-3 substituents selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxy, cyano and halogen, (iv) a 5-10 membered heteroaryl group which is optionally substituted with a C1-C6 alkyl group, and (v) a C3-C10 cycloalkyl group; Q is selected from: (i) a C1-C6 hydroxyalkyl group, (ii) -C(=O)OH, (iii) -S(=O) _2OH , (iv) _a ^{cyano group} , (v) ^-S (O) _2NRA1RB1 , (vi) -NRCS(O) ^2NRA1RB1 , (vii) ^-C (=O)C1- _C6alkoxy ^group which is optionally substituted with -S(=O) ^2NRCRD or a 5-6 membered heterocyclo group which is optionally substituted with a C1-C6 alkyl group; (viii) -C(=O)C6-C10aryloxy group; (ix) -C(=O)-(5-6 membered heterocyclic group) optionally substituted with 1-4 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl and -C(=O)OH, (x) -C(=O)NR ^A2 R ^B2 , (xi) a C1-C6 halogen alkyl optionally substituted with a hydroxyl group, (xii) a 5-6 membered heteroaryl optionally substituted with a hydroxyl group, and (xiii) -C(=O)NHS(=O) ₂ ^RF ; X is selected from -(CH ₂ ) _x NR ^G C(=O)O-, -(CH ₂ ) _x OC(=O)NR ^G -, -(CH ₂ ) _x NR ^G - or -CH(OH)-; ^RA1 and R ^B1 is independently selected from hydrogen and C1-C6 alkyl which is optionally substituted with a hydroxyl group; ^RA2 and ^RB2 are independently selected from hydrogen and C1-C6 alkyl _which is optionally substituted with a hydroxyl group or -S(=O) _2NH2 ; ^RC and ^RD are independently selected from hydrogen and C1-C6 alkyl; ^RF is selected from: (i) C1-C6 alkyl which is optionally substituted with 1-3 substituents selected from the following: (a) hydroxyl, (b) halogen, (c) cyano, (d) C1-C6 alkoxy, (e) a 4-6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl, (f) -C(=O)OH, (g) -OC(=O)C1-C6 alkyl, (h) -S(=O) _2C1 -C6 alkyl, (i) -C(=O)NR ^A1 R ^B1 , (j) -NR ^C R ^D , (k) -C(=O)C1-C6 aryloxy, (l) C3-C6 cycloalkyl substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, and (m) -C(=O)C1-C6 alkoxy 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 substituted with: (a) C1-C6 alkyl which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, -C(=O)OH, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, (b) cyano, (c) -C(=O)OH, (d) -C(=O)NR ^C R ^D , or (e) -C(=O)C1-C6 alkoxy which is optionally substituted with hydroxy or -C(=O)C1-C6 alkyl, or (f) -NR ^C R ^D , and (vi) -NR ^A3 R ^B3 ; ^RA3 and ^RB3 are independently selected from hydrogen and C1-C6 alkyl; ^RG is 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.

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.

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.

Details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of the present disclosure are apparent from the description and the scope of the claims. Additional Definitions

To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meanings as are commonly understood by those skilled in the art to which the disclosure pertains. Each of the patents, applications, published applications, and other publications referred to throughout the specification and appendices is incorporated herein by reference in its entirety. In the event of a conflict, the specification, including definitions, shall prevail.

The term "about" when referring to a number or a numerical range means that the referenced number or numerical range is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary by as much as ±10% of the specified number or numerical range.

The term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, 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.

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 an acid, 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 cases, the pharmaceutically acceptable salt is obtained by reacting the compound having an acidic group described herein with a base to form a salt, such as an ammonium salt, an alkali metal salt (such as a sodium salt or a potassium salt), an alkali earth metal salt (such as a calcium salt or a magnesium salt), a salt of an organic base (such as dicyclohexylamine, N- methyl-D-glucosamine, tris(hydroxymethyl)methylamine), and a salt having an amino acid (such as arginine, lysine and the like), or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited as long as it can be used in a medicament. Examples of salts of the compounds described herein with bases 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 salts. The salt may be an acid addition salt, which is specifically exemplified by an acid addition salt formed with: a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, apple acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; an acidic amino acid such as aspartic acid and glutamic acid.

The term "pharmaceutical composition" refers to a mixture of a compound described herein and other chemical components (collectively referred to herein as "pharmaceutically acceptable excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents and/or thickening agents). Pharmaceutical compositions facilitate administration of the compound to an organism. There are a variety of techniques for administering a compound in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

The term "subject" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein when referring to, for example, a mammalian subject (e.g., a human).

As used herein, the terms "treat" and "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviating in whole or in part symptoms associated with a disease or disorder or condition, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of the disease, improving or reducing the disease state (e.g., one or more symptoms of the disease), and regressing (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival, such as compared to the expected survival if not receiving treatment.

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

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "oxo" refers to a divalent, doubly-bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

The term "hydroxy" refers to an -OH group.

The term "cyano" refers to a -CN group.

The term "alkyl" refers to a saturated acyclic hydrocarbon group that may be straight or branched, containing the indicated number of carbon atoms. For example, _C1-10 indicates that there may be 1 to 10 (including 1 and 10) carbon atoms in the group. The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tertiary butyl, n-hexyl. The term "saturated" as used in this context means that there is only a single bond between the constituent carbon atoms and that the other available valences are 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 the constituent carbon atoms. Non-limiting examples include ethenyl, n-propenyl, isopropenyl, n-butenyl, di-butenyl.

The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with independently selected halogens.

The term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group.

The term "alkoxy" refers to an -O-alkyl group (eg, -OCH ₃ ).

The term "alkoxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected alkoxy groups.

The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic or polycyclic group, wherein at least one ring in the system is aromatic (e.g., a 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 with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl and the like.

The term "aryloxy" refers to an -O-aryl group (eg, phenoxy).

As used herein, the term "cycloalkyl" refers to a cyclic saturated alkyl group having, for example, 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 substituted as appropriate. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and the like. Cycloalkyl also includes spirocycles (e.g., spirobicycles in which the two rings are connected via only one atom). Non-limiting examples of spirocycloalkyl 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 that only a single bond exists between the constituent carbon atoms.

As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic or polycyclic group having 5 to 20 ring atoms, or 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 not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, such as tetrahydroquinolinyl). Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, oxazolyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c ]pyridinyl, pyrazolo[3,4- b ]pyridinyl, pyrazolo[3,4- c ] pyridinyl ]pyridinyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[ b ][1,4]dioxin, benzo[ d ][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ b ][1,4]oxathiophene, isoindoline and other groups. In some embodiments, the heteroaryl group is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindoline, pyranyl, pyrazinyl and pyrimidinyl. For the purpose of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas or vinyl analogs thereof in which each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., , , or ), pyrimidone (e.g., or ), oxazolidinone (e.g., or ), pyrazinones (e.g. or ) and imidazolones (e.g., ), wherein each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., the pendoxyl group (i.e., "=O") herein is part of a heteroaryl ring).

The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic system), if it is monocyclic, it has 1-3 heteroatoms, if it is bicyclic, it has 1-6 heteroatoms, or if it is tricyclic or polycyclic, it has 1-9 heteroatoms, wherein the heteroatoms are selected from O, N or S. (e.g., carbon atoms and 1-3, 1-6 or 1-9 N, O and S heteroatoms (in the case of a monocyclic, bicyclic or tricyclic ring, respectively)), wherein if valence permits, one or more ring atoms may be substituted with 1-3 pendoxy groups (forming, for example, lactam) and one or more N or S atoms may be substituted with 1-2 oxygen ion groups (forming, for example, N-oxides, S-oxides or S,S-dioxides); and wherein 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, fumaryl, tetrahydrofuranyl, tetrahydropyridinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl, and the like. Heterocyclic groups may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 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-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, Cyclo[3.2.1]octane, 2-oxacyclo[1.1.0]butane, 2-oxacyclo[2.1.0]pentane, 2-oxacyclo[1.1.1]pentane, 3-oxacyclo[3.1.0]hexane, 5-oxacyclo[2.1.1]hexane, 3-oxacyclo[3.2.0]heptane oxaherta[4.1.0]heptane, 7-oxaherta[2.2.1]heptane, 6-oxaherta[3.1.1]heptane, 7-oxaherta[4.2.0]octane, 2-oxaherta[2.2.2]octane, 3-oxaherta[3.2.1]octane, and the like. Heterocyclic groups also include spirocyclic groups (e.g., spirobicyclic groups in which the two rings are connected via only one atom). Non-limiting examples of spirocyclic heterocyclic groups include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 2-oxaspiro[3.5 ... [2.2]pentane, 4-oxahistrospiro[2.5]octane, 1-oxahistrospiro[3.5]nonane, 2-oxahistrospiro[3.5]nonane, 7-oxahistrospiro[3.5]nonane, 2-oxahistrospiro[4.4]nonane, 6-oxahistrospiro[2.6]nonane, 1,7-dioxahistrospiro[4.5]decane, 2,5-dioxahistrospiro[3.6]decane, 1-oxahistrospiro[5.5]undecane, 3-oxahistrospiro[5.5]undecane, 3-oxahistrospiro[5.5]undecane and similar groups.

As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, oxazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

The term "heterocyclo" refers to an -O-heterocyclo group.

The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms.

As used herein, when a ring is described as "partially unsaturated," it is meant that the ring has one or more additional unsaturations (in addition to the unsaturation due to the ring itself; e.g., forming one or more double bonds or triple bonds between 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.

For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclo, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic system), it is understood that such rings and cyclic groups encompass those rings and cyclic groups having fused rings, including those rings and cyclic groups wherein the point of fusion is located on: (i) adjacent ring atoms (e.g., a [xx0] ring system where 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro-fused ring system) (e.g., , or ), or (iii) an array of adjacent ring atoms (a bridged ring system with all bridge lengths > 0) (e.g., , or ).

In addition, the atoms making up the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes 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 include ¹³ C and ¹⁴ C.

In addition, compounds disclosed generally or specifically herein are intended to include all tautomeric isomeric forms. Thus, for example, a compound containing part The compounds include some Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxy encompass pyridone or pyrimidone tautomeric forms.

The compounds provided herein may encompass various stereochemical forms. The compounds also encompass mirror image isomers (e.g., R and S isomers), non-mirror image isomers, and mixtures of mirror image isomers (e.g., R and S isomers), including racemic mixtures, and mixtures of non-mirror image isomers, as well as individual mirror image isomers and non-mirror image isomers (due to structural asymmetry in certain compounds). Unless otherwise indicated, when a disclosed compound is named or depicted by a structure that does not specify stereochemistry (e.g., a "planar" structure) and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a designated stereochemical structure (e.g., a structure with "wedge-shaped" and/or "dashed" bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomers of the compound.

The details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of the present disclosure will be apparent from the description and drawings, as well as from the scope of the claims.

LPA signaling promotes normal wound healing and collagen deposition, including fibroblast activation, proliferation, and migration. However, increased LPA levels and LPA1 activation can promote fibrosis as a result of uncontrolled tissue healing processes, leading to excessive accumulation and insufficient resorption of extracellular matrix (ECM), ultimately leading to end-organ failure.

The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof as LPA1 antagonists. These compounds can be used, for example, to treat diseases (e.g., fibrotic diseases) caused by increased (excessive) LPA1 activation, resulting in pathological changes and/or symptoms and/or progression of diseases in individuals (e.g., humans). The present disclosure also provides compositions containing these compounds and methods of using and preparing these compounds. Compounds of formula (I)

Some embodiments provide a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: ^RA is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; Ring B is a 3-7 membered heterocyclic group or a 5-6 membered heteroaryl group; Ring C is a phenyl group or a 5-6 membered heteroaryl group; m is 0 or 1; n is 0, 1, 2 or 3; each ^R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, a 3-7 membered heterocyclic group and a 5-6 membered heteroaryl group; or two ^R1 together with the atoms to which they are attached form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; each ^R2 is independently selected from C1-C6 alkyl, C1-C6 halogenalkyl, C1-C6 alkoxy and halogen; R ^R is selected from: (i) hydrogen, (ii) C1-C6 alkyl optionally substituted with 1-2 independently selected ^RE , (iii) C6-C10 aryl optionally substituted with hydroxy, (iv) C5-C10 cycloalkyl, (v) 5-6 membered heteroaryl optionally substituted with phenyl, and (vi) 5-6 membered heterocyclo optionally substituted with phenyl; each ^RE is independently selected from: (i) hydroxy; (ii) C1-C6 alkoxy, (iii) phenyl optionally substituted with 1-3 substituents selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxy, cyano and halogen, (iv) a 5-10 membered heteroaryl group which is optionally substituted with a C1-C6 alkyl group, and (v) a C3-C10 cycloalkyl group; Q is selected from: (i) a C1-C6 hydroxyalkyl group, (ii) -C(=O)OH, (iii) -S(=O) _2OH , (iv) _a ^{cyano group} , (v) ^-S (O) _2NRA1RB1 , (vi) -NRCS(O) ^2NRA1RB1 , (vii) ^-C (=O)C1- _C6alkoxy ^group which is optionally substituted with -S(=O) ^2NRCRD or a 5-6 membered heterocyclo group which is optionally substituted with a C1-C6 alkyl group; (viii) -C(=O)C6-C10aryloxy group; (ix) -C(=O)-(5-6 membered heterocyclic group) optionally substituted with 1-4 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl and -C(=O)OH, (x) -C(=O)NR ^A2 R ^B2 , (xi) a C1-C6 halogen alkyl optionally substituted with a hydroxyl group, (xii) a 5-6 membered heteroaryl optionally substituted with a hydroxyl group, and (xiii) -C(=O)NHS(=O) ₂ ^RF ; X is selected from -(CH ₂ ) _x NR ^G C(=O)O-, -(CH ₂ ) _x OC(=O)NR ^G -, -(CH ₂ ) _x NR ^G - or -CH(OH)-; ^RA1 and R ^B1 is independently selected from hydrogen and C1-C6 alkyl which is optionally substituted with a hydroxyl group; ^RA2 and ^RB2 are independently selected from hydrogen and C1-C6 alkyl _which is optionally substituted with a hydroxyl group or -S(=O) _2NH2 ; ^RC and ^RD are independently selected from hydrogen and C1-C6 alkyl; ^RF is selected from: (i) C1-C6 alkyl which is optionally substituted with 1-3 substituents selected from the following: (a) hydroxyl, (b) halogen, (c) cyano, (d) C1-C6 alkoxy, (e) a 4-6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl, (f) -C(=O)OH, (g) -OC(=O)C1-C6 alkyl, (h) -S(=O) _2C1 -C6 alkyl, (i) -C(=O)NR ^A1 R ^B1 , (j) -NR ^C R ^D , (k) -C(=O)C1-C6 aryloxy, (l) C3-C6 cycloalkyl substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, and (m) -C(=O)C1-C6 alkoxy 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 substituted with: (a) C1-C6 alkyl which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, -C(=O)OH, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, (b) cyano, (c) -C(=O)OH, (d) -C(=O)NR ^C R ^D , or (e) -C(=O)C1-C6 alkoxy which is optionally substituted with hydroxy or -C(=O)C1-C6 alkyl, or (f) -NR ^C R ^D , and (vi) -NR ^A3 R ^B3 ; ^RA3 and ^RB3 are independently selected from hydrogen and C1-C6 alkyl; ^RG is H or C1-C3 alkyl; and x is 0 or 1.

In some embodiments, formula (I) is formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein: ^RA is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; Ring B is a 3-7 membered heterocyclic group or a 5-6 membered heteroaryl group; Ring C is a phenyl group or a 5-6 membered heteroaryl group; m is 0 or 1; n is 0, 1, 2 or 3; each ^R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, a 3-7 membered heterocyclic group and a 5-6 membered heteroaryl group; or two ^R1 together with the atoms to which they are attached form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; each ^R2 is independently selected from C1-C6 alkyl, C1-C6 halogenalkyl, C1-C6 alkoxy and halogen; R ^R is selected from (i) hydrogen, (ii) C1-C6 alkyl optionally substituted with 1-2 independently selected ^RE , (iii) C6-C10 aryl optionally substituted with hydroxy, (iv) C5-C10 cycloalkyl, (v) 5-6 membered heteroaryl optionally substituted with phenyl, and (vi) 5-6 membered heterocyclo optionally substituted with phenyl; each ^RE is independently selected from (i) hydroxy; (ii) C1-C6 alkoxy, (iii) phenyl optionally substituted with 1-3 substituents selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxy, cyano and halogen, (iv) a 5-10 membered heteroaryl group which is optionally substituted with a C1-C6 alkyl group, and (v) a C3-C10 cycloalkyl group; Q is selected from: (i) a C1-C6 hydroxyalkyl group, (ii) -C(=O)OH, (iii) -S(=O) _2OH , (iv) _a ^{cyano group} , (v) ^-S (O) _2NRA1RB1 , (vi) -NRCS(O) ^2NRA1RB1 , (vii) ^-C (=O)C1- _C6alkoxy group which is optionally substituted with -S(=O) ^2NRCRD or a 5-6 membered ^heterocyclo group which is optionally substituted with a C1-C6 alkyl group, (viii) -C(=O)C6-C10aryloxy group; (ix) -C(=O)-(5-6 membered heterocyclic group) optionally substituted with 1-4 substituents selected from the group consisting of a hydroxyl group and -C(=O)OH, (x) -C(=O)NR ^A2 R ^B2 , (xi) a C1-C6 haloalkyl group optionally substituted with a hydroxyl group, (xii) a 5-6 membered heteroaryl group optionally substituted with a hydroxyl group, and (xiii) -C(=O)NHS(=O) ₂ ^RF ; ^RA1 and ^RB1 are independently selected from hydrogen and a C1-C6 alkyl group optionally substituted with a hydroxyl group; RA2 and ^RB2 are independently selected from hydrogen and a C1-C6 alkyl group optionally substituted with a hydroxyl group or -S(=O) ₂ NH ₂ ; ^RC and ^{R D} is independently selected from hydrogen and C1-C6 alkyl; and ^RF is selected from: (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from the following: (ii) hydroxyl, (iii) halogen, (iv) cyano, (v) C1-C6 alkoxy, (vi) a 4-6 membered heterocyclic group optionally substituted with C1-C6 alkyl, (vii) -C(=O)OH, (viii) -OC(=O)C1-C6 alkyl, (ix) -S(=O) ₂ C1-C6 alkyl, (x) -C(=O)NR ^A1 R ^B1 , (xi) -NR ^C R ^D , (xii) -C(=O)C1-C6 aryloxy, (xiii) C3-C6 cycloalkyl optionally substituted by -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, (xiv) -C(=O)C1-C6 alkoxy optionally substituted by -O(=O)C1-C6 alkyl, (xv) C2-C6 alkenyl, (xvi) C1-C6 halogenalkyl, (xvii) phenyl, (xviii) C3-C6 cycloalkyl optionally substituted by: (a) C1-C6 alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, -C(=O)OH, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, (b) cyano, (c) -C(=O)OH, (d) -C(=O)NR ^C R ^D , or (e) -C(=O)C1-C6 alkoxy which is optionally substituted with a hydroxy group or a -O(=O)C1-C6 alkyl group, or (f) -NR ^C R ^D .

In some embodiments, ^RA is hydrogen.

In some embodiments, ^RA is C1-C6 alkyl. In some embodiments, ^RA is methyl.

In some embodiments, ^RA is C1-C6 alkoxy. In some embodiments, ^RA is methoxy.

In some embodiments, Q is -C(=O)OH. In some embodiments, Q is -S(=O) ₂ OH. 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(O) ₂ NR ^A1 R ^B1 . In some embodiments, Q is -NR ^C S(O) ₂ NR ^A1 R ^B1 . In some embodiments, Q is -C(=O)C1-C6 alkoxy substituted with C1-C6 alkoxy which is optionally substituted with -S(=O) ₂ NR ^C R ^D. In some embodiments, Q is -C(=O)C1-C3 alkoxy, which is 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, which is optionally substituted with -S(=O) ₂ NR ^C R ^D. In some embodiments, Q is C(=O)C1-C6 alkoxy, which is optionally substituted with -S(=O) ₂ NR ^C R ^D. In some embodiments, Q is C(=O)C1-C6 alkoxy, which is substituted with -S(=O) ₂ NR ^C R ^D. In some embodiments, Q is C(=O)C1-C3 alkoxy, which is substituted with -S(=O) 2 NR C R D. In some embodiments, Q is C(=O)C1-C6 alkoxy substituted with a 5-6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl group. In some embodiments, Q is C(=O)C1-C3 alkoxy substituted with a 5-6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl group. In some embodiments, Q is C(=O)C1-C3 alkoxy substituted with a 6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl group. In some embodiments, Q is C(=O)C1-C3 alkoxy substituted with a 5 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl group.

In some embodiments, Q is -C(=O)-(5-6 membered heterocyclic oxy) substituted with 1-4 substituents selected from the following: C1-C6 alkyl, hydroxyl and -C(=O)OH. In some embodiments, Q is -C(=O)-(5 membered heterocyclic oxy) substituted with 1-4 substituents selected from the following: C1-C6 alkyl, hydroxyl and -C(=O)OH. In some embodiments, Q is -C(=O)-(6 membered heterocyclic oxy) substituted with 1-4 substituents selected from the following: C1-C6 alkyl, hydroxyl and -C(=O)OH. In some embodiments, Q is In some embodiments, Q is -C(=O)NR ^{A2 RB2} . In some embodiments, each of ^RA2 and ^RB2 is hydrogen. In some embodiments, one of ^RA2 and ^RB2 is hydrogen and the other of ^RA2 and ^RB2 is a C1-C6 alkyl substituted with a hydroxyl group or -S(=O) ₂ NH ₂ , as the case may be. In some embodiments, one of ^RA2 and ^RB2 is hydrogen and the other of ^RA2 and ^RB2 is a C1-C6 alkyl substituted with a hydroxyl group. In some embodiments, one of ^RA2 and ^RB2 is hydrogen and the other of ^RA2 and ^RB2 is -CH ₂ CH ₂ OH. In some embodiments, one of ^RA2 and ^RB2 is hydrogen and the other of ^RA2 and ^RB2 is C1-C6 alkyl substituted with _-S (=O) _2NH2 . In some embodiments, one of ^RA2 and ^RB2 is hydrogen and the other of ^RA2 and ^RB2 is In some embodiments, one of ^RA2 and ^RB2 is hydrogen and the other of ^RA2 and ^RB2 is an unsubstituted C1-C6 alkyl. In some embodiments, each of ^RA2 and ^RB2 is an independently selected C1-C6 alkyl substituted with hydroxyl or -S(=O) _2NH2 as appropriate. In some embodiments, each of ^RA2 and ^RB2 is _an independently selected unsubstituted C1-C6 alkyl.

In some embodiments, Q is a C1-C6 haloalkyl group which is optionally substituted with a hydroxy group.

In some embodiments, Q is a C1-C6 haloalkyl group substituted with a hydroxy group.

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

In some embodiments, Q is a 5-6 membered heteroaryl group which is optionally substituted with a hydroxyl group.

In some embodiments, Q is a 6-membered heteroaryl group which is optionally substituted with a hydroxyl group.

In some embodiments, Q is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, and triazinyl.

In some embodiments, Q is a 5-membered heteroaryl group which is optionally substituted with a hydroxyl group.

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

In some embodiments, Q is .

In some embodiments, Q is

In some embodiments, Q is an unsubstituted 5-6 membered heteroaryl.

In some embodiments, Q is -C(=O)NHS(=O) ₂ ^RF .

In some embodiments, ^RF is C2-C6 alkenyl.

In some embodiments, ^RF is .

In some embodiments, ^RF is .

In some embodiments, ^RF is C1-C6 haloalkyl.

In some embodiments, ^RF is _-CF3 or _CHF2 .

In some embodiments, ^RF is phenyl.

In some embodiments, ^RF is -NR ^C R ^D .

In some embodiments, ^RF is C1-C6 alkyl which is optionally substituted with 1-3 substituents selected from the following: hydroxyl; halogen; cyano; C1-C6 alkoxy; a 4-6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl; -C(=O)OH; -OC(=O)C1-C6 alkyl; -S(=O) ₂ C1-C6 alkyl; -C(=O)NR ^A1 R ^B1 ; -NR ^C R ^D ; -C(=O)C1-C6 aryloxy; optionally substituted with -C(=O)OH, cyano, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 or C3-C6 cycloalkyl substituted with -C(=O)C1-C6 alkoxy; or -C(=O)C1-C6 alkoxy substituted with -C(=O)C1-C6 alkyl or -OC(=O)C1-C6 alkyl as the case may be.

In some embodiments, ^RF is C1-C6 alkyl substituted with 1-2 hydroxy groups.

In some embodiments, ^RF is selected from the group consisting of: , , , , , , , , , , and .

In some embodiments, ^RF is C1-C6 alkyl substituted with cyano.

In some embodiments, ^RF is .

In some embodiments, ^RF is C1-C6 alkyl substituted with C1-C6 alkoxy.

In some embodiments, ^RF is selected from the group consisting of: , , , , , , and .

In some embodiments, ^RF is C1-C6 alkyl substituted with a 4-6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl group.

In some embodiments, ^RF is .

In some embodiments, ^RF is C1-C6 alkyl substituted with -C(=O)OH.

In some embodiments, ^RF is selected from the group consisting of: , , , , , , and .

In some embodiments, ^RF is C1-C6 alkyl substituted with -OC(=O)C1-C6 alkyl.

In some embodiments, ^RF is .

In some embodiments, ^RF is C1-C6 alkyl substituted with -S(=O) ₂ C1-C6 alkyl.

In some embodiments, ^RF is .

In some embodiments, ^RF is C1-C6 alkyl substituted with -C(=O)NR ^A1 R ^B1 .

In some embodiments, ^RF is selected from the group consisting of: , and In some embodiments, ^RF is .

In some embodiments, ^RF is C1-C6 alkyl substituted with 1-3 substituents selected from halogen, -C(=O)NR ^A1 R ^B1 , and -C(=O)OH.

In some embodiments, ^RF is selected from the group consisting of: , and In some embodiments, ^RF is or .

In some embodiments, ^RF is C1-C6 alkyl substituted with NR ^C R ^D.

In some embodiments, ^RF is C1-C6 alkyl substituted with -C(=O)C1-C6 aryloxy.

In some embodiments, ^RF is C1-C6 alkyl substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 , or -C(=O)C1-C6 alkoxy, which may be C3-C6 cycloalkyl.

In some embodiments, ^RF is C1-C6 alkyl substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 , or -C(=O)C1-C6 alkoxy.

In some embodiments, ^RF is selected from the group consisting of: , , and In some embodiments, ^RF is .

In some embodiments, ^RF is C1-C6 alkyl substituted with -C(=O)C1-C6 alkoxy which is optionally substituted with -C(=O)C1-C6 alkyl.

In some embodiments, ^RF is C1-C6 alkyl substituted with C(=O)C1-C4 alkoxy substituted with -C(=O)C1-C6 alkyl.

In some embodiments, ^RF is C1-C6 alkyl substituted with C(=O)C1-C6 alkoxy.

In some embodiments, ^RF is selected from the group consisting of: , , , , , , , , , , , and .

In some embodiments, ^RF is C1-C6 alkyl optionally substituted with C(=O)OH. In some embodiments, ^RF is C1-C6 alkyl substituted with -C(=O)OH.

In some embodiments, ^RF is unsubstituted C1-C6 alkyl.

In some embodiments, ^RF is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl.

In some embodiments, ^RF is C3-C6 cycloalkyl optionally substituted with: C1-C6 alkyl optionally substituted with 1-3 substituents selected from hydroxy, -C(=O)OH, -C(=O)NR ^A1 R ^B1 , or -C(=O)C1-C6 alkoxy; cyano; -C(=O)OH; -C(=O)NR ^C R ^D ; or -C(=O)C1-C6 alkoxy optionally substituted with hydroxy or -C(=O)C1-C6 alkyl.

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with 1-2 hydroxyl groups.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with 1-2 hydroxyl groups.

In some embodiments, ^RF is cyclopropyl substituted with 1-2 hydroxyl groups.

In some embodiments, ^RF is selected from the group consisting of: , and .

In some embodiments, ^RF is a C3-C6 cycloalkane substituted with a C1-C6 alkyl group substituted with -C(=O)OH.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with C1-C6 alkyl substituted with -C(=O)OH.

In some embodiments, ^RF is cyclopropyl substituted with C1-C6 alkyl substituted with -C(=O)OH.

In some embodiments, ^RF is .

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with -C(=O)NR ^A1 R ^B1 .

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with C1-C6 alkyl substituted with -C(=O)NR ^A1 R ^B1 .

In some embodiments, ^RF is cyclopropyl substituted with C1-C6 alkyl substituted with -C(=O)NR ^A1 R ^B1 .

In some embodiments, ^RF is .

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with -C(=O)C1-C6 alkoxy.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with C1-C6 alkyl substituted with -C(=O)C1-C6 alkoxy.

In some embodiments, ^RF is cyclopropyl substituted with C1-C6 alkyl substituted with -C(=O)C1-C6 alkoxy.

In some embodiments, ^RF is selected from the group consisting of: and .

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with cyano.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with cyano.

In some embodiments, ^RF is .

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with -C(=O)OH.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with -C(=O)OH.

In some embodiments, ^RF is .

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with -C(=O)NR ^C R ^D.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with -C(=O)NR ^C R ^D.

In some embodiments, ^RF is .

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with hydroxy.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with hydroxy.

In some embodiments, ^RF is .

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy.

In some embodiments, ^RF is selected from the group consisting of: and .

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -C(=O)C1-C6 alkyl.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -C(=O)C1-C6 alkyl.

In some embodiments, ^RF is C3-C6 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -OC(=O)C1-C6 alkyl.

In some embodiments, ^RF is C3-C4 cycloalkyl substituted with -C(=O)C1-C6 alkoxy substituted with -OC(=O)C1-C6 alkyl.

In some embodiments, ^RF is .

In some embodiments, ^RF is unsubstituted C3-C6 cycloalkyl.

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

In some embodiments, each of ^RA1 and ^RB1 is hydrogen.

In some embodiments, one of ^RA1 and ^RB1 is hydrogen and the other of ^RA1 and ^RB1 is C1-C6 alkyl which is optionally substituted with hydroxy.

In some embodiments, one of ^RA1 and ^RB1 is hydrogen and the other of ^RA1 and ^RB1 is C1-C3 alkyl.

In some embodiments, one of ^RA1 and ^RB1 is hydrogen and the other of ^RA1 and ^RB1 is methyl.

In some embodiments, each of ^RA1 and ^RB1 is an independently selected C1-C6 alkyl group which is optionally substituted with hydroxy.

In some embodiments, each of ^RA1 and ^RB1 is an independently selected unsubstituted C1-C6 alkyl.

In some embodiments, ^RF is -NR ^{A3 RB3} .

In some embodiments, each of ^RA3 and ^RB3 is hydrogen.

In some embodiments, one of ^RA3 and ^RB3 is hydrogen and the other of ^RA3 and ^RB3 is C1-C6 alkyl.

In some embodiments, one of ^RA3 and ^RB3 is hydrogen and the other of ^RA3 and ^RB3 is C1-C3 alkyl.

In some embodiments, one of ^RA3 and ^RB3 is hydrogen and the other of ^RA3 and ^RB3 is methyl.

In some embodiments, each of ^RA3 and ^RB3 is an independently selected C1-C6 alkyl.

In some embodiments, each of ^RA3 and ^RB3 is an independently selected unsubstituted C1-C6 alkyl.

In some embodiments, Ring B is a 3-7 membered heterocyclic group.

In some embodiments, Ring B is selected from the group consisting of: azetidinyl, oxadiazolyl, pyrrolidinyl, tetrahydrofuranyl, thiacyclopentanyl, pyrazolinyl, oxadiazolyl, isooxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinone, pyrazolidinyl, imidazolinyl, dioxadiazolyl, sulfolane, Thiazolidinedione, succinimidyl, dihydrofuranone, pyrazolidinone, oxazolidinone, isoxazolidinone, hydantoin, thiohydantoin, imidazolidinone, oxazolidinone, thiazolidinone, oxathiocyclopentanone, dioxacyclopentanone, dioxazolidinone, oxadiazolidinone, triazolidinone, triazolidinone sulfinyl , oxadiazolidine sulfinyl, dioxazolidine sulfinyl, dioxacyclopentane sulfinyl, oxazolidine sulfinyl, imidazolidinyl sulfinyl, isothiazolidinone, piperidinyl, tetrahydropyranyl, thiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithiopyranyl, oxazinyl, tetrahydropyranone, piperidone, dioxanone, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinandionyl, dihydropyrimidinedionyl, tetrahydropiperazinonyl, triazinanonyl, oxadiazinandionyl, dioxazinandionyl, morpholinonyl, piperazinedionyl, piperazinetrionyl, triazinandionyl and azaspiro[3.3]heptanyl.

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

In some embodiments, Ring B is selected from the group consisting of: , , , , , and , where “*” indicates the attachment point to ring A.

In some embodiments, Ring B is , where “*” indicates the attachment point to ring A.

In some embodiments, Ring B is a 5-6 membered heteroaryl group.

In some embodiments, Ring B is a 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.

In some embodiments, Ring B is a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, and triazinyl.

In some embodiments, Ring B is pyridinyl.

In some embodiments, Ring B is .

In some embodiments, Ring C is phenylene.

In some embodiments, Ring C is a 5-6 membered heteroaryl.

In some embodiments, Ring C is a 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl.

In some embodiments, Ring C is selected from the group consisting of isoxazolyl, pyrazolyl, triazolyl, thienyl, and isothiazolyl.

In some embodiments, Ring C is selected from the group consisting of: , , , , , , and , where “*” indicates the attachment point to ring B.

In some embodiments, Ring C is , , or , where “*” indicates the attachment point to ring B.

In some embodiments, Ring C is , where “*” indicates the attachment point to ring B.

In some embodiments, Ring C is a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, and triazinyl.

In some embodiments, Ring C is pyrimidinyl.

In some embodiments, each R ¹ is an independently selected C1-C6 alkyl group.

In some embodiments, each R ² is independently selected from C1-C6 alkyl, C1-C6 halogenalkyl, C1-C6 alkoxy and halogen.

In some embodiments, at least one R ² is halogen.

In some embodiments, at least one R ² is chloro.

In some embodiments, at least one R ² is C1-C6 alkyl.

In some embodiments, at least one R ² is methyl.

In some embodiments, at least one R ² is C1-C6 haloalkyl.

In some embodiments, at least one R ² is C1-C6 alkoxy.

In some embodiments, at least one R ² is methoxy.

In some embodiments, X is -(CH ₂ ) _x NR ^G C(=O)O-. In some embodiments, X is -CH ₂ NHC(=O)O-. In some embodiments, X is -NHC(=O)O-. In some embodiments, X is -N(CH ₃ )C(=O)O-.

In some embodiments, X is -(CH ₂ ) _x OC(=O)NR ^G -. In some embodiments, X is -CH ₂ OC(=O)NH-. In some embodiments, X is -OC(=O)NH-.

In some embodiments, X is -(CH ₂ ) _x NR ^G -. In some embodiments, X is -CH ₂ NH-. In some embodiments, X is -NH-.

In some embodiments, ^RG is hydrogen.

In some embodiments, ^RG is C1-C3 alkyl. In some embodiments, ^RG is methyl.

In some embodiments, x is 0.

In some embodiments, x is 1.

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

In some embodiments, R ³ is hydrogen.

In some embodiments, R ³ is C1-C6 alkyl optionally substituted with 1-2 ^RE .

In some embodiments, at least one ^RE is hydroxy.

In some embodiments, at least one ^RE is C1-C6 alkoxy.

In some embodiments, at least one ^RE is phenyl optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxy, cyano or halogen.

In some embodiments, at least one ^RE is a 5-10 membered heteroaryl group which is optionally substituted with a C1-C6 alkyl group.

In some embodiments, at least one ^RE is C3-C10 cycloalkyl.

In some embodiments, ^R3 is selected from the group consisting of: , and .

In some embodiments, ^R3 is .

In some embodiments, ^R3 is , wherein ^RE is phenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 halogenalkyl, C1-C3 alkoxyalkyl, C1-C63 alkoxy, hydroxy, cyano or halogen.

In some embodiments, ^R3 is , wherein ^RE is phenyl substituted with 1-2 substituents selected from the group consisting of methyl, ethyl, isopropyl, chloro, fluoro, cyano, methoxy and trifluoromethyl.

In some embodiments, ^R3 is , or .

In some embodiments, ^R3 is , wherein ^RE is a 5-6 membered heteroaryl group which is optionally substituted with a C1-C6 alkyl group.

In some embodiments, ^R3 is or , wherein ^RE is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, R ³ is C6-C10 aryl which is optionally substituted with hydroxy.

In some embodiments, R ³ is phenyl substituted with hydroxyl.

In some embodiments, R ³ is C5-C10 cycloalkyl.

In some embodiments, R ³ is a 5-6 membered heteroaryl group which is optionally substituted with a phenyl group.

In some embodiments, R ³ is a 5-membered heteroaryl group which is optionally substituted with a phenyl group.

In some embodiments, R ³ is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl and thiatriazolyl, each optionally substituted with phenyl.

In some embodiments, R ³ is pyrazolyl, oxazolyl or oxadiazolyl, each optionally substituted with phenyl.

In some embodiments, ^R3 is selected from the group consisting of: , and .

In some embodiments, R ³ is a 6-membered heteroaryl group which is optionally substituted with a phenyl group.

In some embodiments, R ³ is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl and triazinyl, each optionally substituted with phenyl.

In some embodiments, R ³ is pyridinyl optionally substituted with phenyl.

In some embodiments, ^R3 is or .

In some embodiments, R ³ is unsubstituted 5-6 membered heteroaryl.

In some embodiments, R ³ is a 5-6 membered heterocyclic group which is optionally substituted with phenyl.

In some embodiments, R ³ is a 5-membered heterocyclic group which is optionally substituted with phenyl.

In some embodiments, R ³ is pyrrolidine.

In some embodiments, R ³ is a 6-membered heterocyclic group which is optionally substituted with phenyl.

In some embodiments, R ³ is dihydro-4H-1,3-oxazinyl.

In some embodiments, R ³ is an unsubstituted 5-6 membered heterocyclic group.

In some embodiments, ^RC is hydrogen.

In some embodiments, R ^C is C1-C6 alkyl.

In some embodiments, each of ^RC and ^RD is hydrogen.

In some embodiments, one of ^RC and ^RD is hydrogen and the other of ^RC and ^RD is C1-C6 alkyl.

In some embodiments, each of ^RC and ^RD is an independently selected C1-C6 alkyl.

In some embodiments, R ^D is C1-C3 alkyl.

In some embodiments, R ^D is methyl.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

In some embodiments, Formula (I) is Formula (Ia): (Ia) or a pharmaceutically acceptable salt thereof.

In some embodiments, Formula (I) is Formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof.

In some embodiments, Formula (I) is Formula (Ic): (Ic) or a pharmaceutically acceptable salt thereof, wherein Z is CH, N, O or S; V is C or N; and wherein when V is C, Z is O or S.

In some embodiments, Formula (I) is Formula (Id): (Id) or a pharmaceutically acceptable salt thereof, wherein Q is -CO ₂ H or -C(=O)NHS(=O) ₂ ^RF ; and Z is O or S.

In some embodiments, Formula (I) is Formula (Ie): (Ie) or a pharmaceutically acceptable salt thereof, wherein Q is -CO ₂ H or -C(=O)NHS(=O) ₂ ^RF ; Z is CH, N, O or S; V is C or N; and wherein when V is C, Z is O or S.

In some embodiments, Formula (I) is Formula (If): (If) or a pharmaceutically acceptable salt thereof, wherein Q is -CO ₂ H or -C(=O)NHS(=O) ₂ ^RF ; Z is CH, N, O or S; V is C or N; and wherein when V is C, Z is O or S. Non-limiting exemplary compounds

In some embodiments, the compound is selected from the group consisting of the compounds of Examples 1-31 or pharmaceutically acceptable salts thereof.

In some embodiments, the compound is selected from the group consisting of compounds described in Table A or pharmaceutically acceptable salts thereof. Table A Compound No. Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 F 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 F 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 Pharmaceutical compositions

Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Provided herein are methods for antagonizing the activation of lysophosphatidic acid receptor 1 (LPA1). For example, provided herein are LPA1 antagonists that can be used to treat fibrosis in a subject.

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.

Some embodiments provide a method of treating a fibrotic disease in a subject predicted 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.

Some embodiments provide a method for treating a fibrotic disease in an individual, the method comprising: (a) determining that the individual suffers from a fibrotic disease; and (b) administering to the individual 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 individual is suspected of having a fibrotic disease.

In some embodiments, the subject is at risk for developing a fibrotic disease.

In some embodiments, the fibrotic disease is associated with one or more of the liver, lungs, kidneys, heart, eyes, skin, pancreas, intestines, or bladder. In some embodiments, the fibrotic disease is associated with a cell proliferative disease such as cancer. In some embodiments, the fibrotic disease is associated with nerve damage. In some embodiments, the fibrotic disease is associated with tissue repair.

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

In some embodiments, the fibrotic disease comprises pulmonary fibrosis. In some embodiments, pulmonary 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 pulmonary fibrosis.

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.

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

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

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

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.

Some embodiments provide a method for treating 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.

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 a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having the cell.

The ability of a test compound to act as an LPA1 antagonist can 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 cell lines.

As provided herein, the potency of an LPA1 antagonist can be determined by EC ₅₀ or IC ₅₀ values. A compound having a lower EC ₅₀ or IC ₅₀ value is a more potent antagonist than a compound having a higher EC ₅₀ or IC ₅₀ value, as determined under substantially similar conditions.

When used as medicine, the compounds of formula (I) (including their pharmaceutically acceptable salts) may be administered in the form of pharmaceutical compositions as described herein.

By using standard synthetic methods and procedures known to those skilled in the art or in light of the teachings herein, 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. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein and modifying the specific desired substituents.

Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant technical literature or standard textbooks in this field. Although not limited to any one or more sources, classic textbooks 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 applicable and recognized reference textbooks for organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, the general procedures used to prepare the compounds of the present disclosure.

The synthetic methods disclosed herein are tolerant of a variety of functional groups; therefore, a variety of substituted starting materials can be used. These methods generally provide the desired final compound at or near the end of the overall method, but in some cases it may be necessary to further convert the compound to its pharmaceutically acceptable salt. Synthetic Examples Example 1. Preparation of 1-[4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanesulfonic acid ( Compound 89) 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 ethoxide (3.79 g, 11.13 mmol, 20% purity, 1.5 eq.) at 0°C and the reaction solution was stirred at 0°C for 1 hour. TLC (PE:EA=5:1, Rf= _0.3 ) showed that the starting material was consumed and a new major spot was detected. The residue was dissolved in water (50 mL) and then extracted with _CH2Cl2 (3 x 50 mL) _{. The CH2Cl2} layer was dried ( _Na2SO4 ) and evaporated under vacuum. The residue was purified by silica gel column chromatography (PE:EA=5:1) to obtain ethyl (4-bromophenyl)methanesulfonate (1.8 g, 6.45 mmol, 86.90% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ = 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). Step 2. Preparation of ethyl 1-(4- bromophenyl ) cyclopropanesulfonate

To a solution of ethyl (4-bromophenyl)methanesulfonate (1 g, 3.58 mmol, 1 eq) in THF (30 mL) was added NaHMDS (1 M, 10 mL, 2.79 eq) at -40°C and stirred for 1 hour, then 1,3,2-dioxathiocyclopentane 2,2-dioxide (2A) (1.00 g, 8.06 mmol, 2.25 eq) was added to the resulting mixture at -40°C and then stirred for 1 hour. TLC (PE/EA=5:1, Rf=0.4) showed that a new spot was detected. The reaction mixture was partitioned between EtOAc (130 mL) and NH ₄ Cl (80 mL), washed with brine (90 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography and eluted with PE/EA=50:1 to 5:1 and evaporated under reduced pressure to give 1-(4-bromophenyl)cyclopropanesulfonic acid ethyl ester (400 mg, 1.31 mmol, 36.59% yield) as a white solid. Step 3. Preparation of 1-(4- bromophenyl ) cyclopropanesulfonic acid

To a solution of ethyl 1-(4-bromophenyl)cyclopropanesulfonate (250 mg, 819.17 μmol, 1 eq.) in EtOH (5 mL) /H ₂ O (2.5 mL) was added KOH (140 mg, 2.50 mmol, 3.05 eq.). The reaction solution was stirred at 50° C. for 2 hours. TLC (PE:EA=2:1, Rf=0.02) showed that the starting material was consumed and a new major spot was detected. LCMS showed that the 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 Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a crude product. The crude product was lyophilized to give 1-(4-bromophenyl)cyclopropanesulfonic acid (100 mg, 353.62 μmol, 43.17% yield, 98% purity) as a brown solid. The crude product was used in the next step without further purification. MS m/z: 274.9 ({ ⁷⁹ Br})[MH ^] -Step 4. Preparation of 1-[4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanesulfonic acid

To a mixture of 1-(4-bromophenyl)cyclopropanesulfonic acid (100 mg, 360.84 μmol, 1 eq) in dioxane (1 mL) were added RuPhos Pd G ₃ (100 mg, 119.57 μmol, 3.31e-1 eq), Cs ₂ CO ₃ (200 mg, 613.84 μmol, 1.70 eq) and [(1R)-1-phenylethyl] N-[3-methyl-5-(4-piperidinyl)isoxazol-4-yl]carbamate (160 mg, 485.74 μmol, 1.35 eq), the reaction solution was degassed and purged under N ₂ three times, the reaction solution was stirred at 80° C. for 1 hour. LCMS showed that the desired MS was detected. The pH value of the residue was adjusted to 6 by adding AcOH. The residue was purified by preparative HPLC (column: Shim-pack C ₁₈ 150×25×10 um; mobile phase: [water (FA)-ACN]; B%: 25%-55%, 10 minutes). After preparative HPLC purification, the elution was concentrated to remove the organic solvent. The residual aqueous solution was lyophilized to obtain 1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanesulfonic acid (2 mg, 3.81 μmol, 1.05% yield, 100% purity) as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 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 [MH] ^- Example 2. Preparation of N-[3- methyl -5-[1-[4-[1-(1H -tetrazolyl -5- yl ) cyclopropyl ] phenyl ]-4- piperidinyl ] isoxazol -4- yl ] carbamic acid [(1R)-1- phenylethyl ] ester ( Compound 88) Step 1. Preparation of 1-(4- bromophenyl ) cyclopropanecarbonitrile

To a solution of 2-(4-bromophenyl)acetonitrile (10 g, 51.01 mmol, 1 eq.) and 1-bromo-2-chloro-ethane (10 g, 69.73 mmol, 5.78 mL, 1.37 eq.) in DMF (200 mL) were added Cs ₂ CO ₃ (50 g, 153.46 mmol, 3.01 eq.) and benzyl(triethyl)ammonium chloride (6 g, 26.34 mmol, 5.16e-1 eq.), and the reaction solution was stirred at 110° C. for 12 hours. TLC (PE:EA=10:1, Rf=0.52) showed that the starting material was consumed and a new major spot was detected. The reaction mixture was partitioned between H ₂ O (500 mL) and EtOAc (500 mL). The organic phase was separated, washed with saturated NaCl (500 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. 1-(4-bromophenyl)cyclopropanecarbonitrile (10 g, 45.03 mmol, 88.28% yield) was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ (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). Step 2. Preparation of N-[5-[1-[4-(1- cyanocyclopropyl ) phenyl ]-4 - piperidinyl ]-3 - methyl - isoxazol -4- yl ] carbamic acid [(1R)-1- phenylethyl ] ester

To a solution of [(1R)-1-phenylethyl]N-[3-methyl-5-(4-piperidinyl)isoxazol-4-yl]carbamate (200 mg, 607.18 μmol, 1 eq) and 1-(4-bromophenyl)cyclopropanecarbonitrile (170 mg, 765.49 μmol, 1.26 eq) in dioxane (5 mL) were added RuPhos Pd G ₃ (200 mg, 239.13 μmol, 3.94e-1 eq) and Cs ₂ CO ₃ (400 mg, 1.23 mmol, 2.02 eq), the reaction solution was degassed and purged under N ₂ three times, the reaction mixture was stirred at 80 °C for 1 hour. LCMS showed that the desired MS was detected. TLC (PE/EtOAc=3/1, Rf=0.20) showed that one major spot was observed. The reactant 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 Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue. The crude product was purified by preparative TLC using PE: EtOAc = 3: 1 to give [(1R)-1-phenylethyl]-N-[5-[1-[4-(1-cyanocyclopropyl)phenyl]-4-piperidinyl]-3-methyl-isoxazol-4-yl]carbamate (260 mg, 363.01 μmol, 59.79% yield, 65.7% purity) as a yellow oil. Step 3. Preparation of [(1R)-1- phenylethyl] -N-[3- methyl -5-[1-[4-[1-(1H - tetrazol -5 - yl ) cyclopropyl ] phenyl ] -4- piperidinyl ] isoxazol -4 - yl ] carbamate

To a solution of [(1R)-1-phenylethyl]-N-[5-[1-[4-(1-cyanocyclopropyl)phenyl]-4-piperidinyl]-3-methyl-isoxazol-4-yl]carbamate (200 mg, 425.02 μmol, 1 eq) and NH ₄ Cl (100 mg, 1.87 mmol, 4.40 eq) in DMSO (2 mL) was added NaN ₃ (217 mg, 3.34 mmol, 7.85 eq) and the reaction solution was stirred at 110 °C for 2 hours. LCMS showed that the desired MS was detected. The pH of the reaction solution was adjusted to 9 by adding saturated NaHCO _3. The residue was partitioned between H ₂ O (10 mL) and EtOAc (10×3 mL). The organic layer was dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 _C18 Ultra 150×50 mm×3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 43%-63%, 10 minutes). After preparative HPLC purification, the eluted solution was concentrated to remove the organic solvent. The residual aqueous solution was lyophilized to give (1R)-1-phenylethyl N-[3-methyl-5-[1-[4-[1-(1H-tetrazol-5-yl)cyclopropyl]phenyl]-4-piperidinyl]isoxazol-4-yl]carbamate as a white solid (10 mg, 19.47 μmol, 4.58% yield, 100% purity). ¹ H NMR (400 MHz, methanol-d ₄ ) δ (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[MH] ^- . Example 3. Preparation of methyl 2- methyl -2-[[1-[4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonyl ] propanoate ( Compound 69) Step 1. Preparation of methyl 2-[ bis [(4- methoxyphenyl ) methyl ] sulfamoyl ] acetate

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 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). Step 2. Preparation of 2-[ Bis [(4- methoxyphenyl ) methyl ] sulfonylamine ]-2- methyl - propionic acid methyl ester

To a solution of methyl 2-[bis[(4-methoxyphenyl)methyl]sulfaminyl]acetate (400 mg, 1.02 mmol, 1 eq) in DMF (10 mL) were added K ₂ CO ₃ (480.00 mg, 3.47 mmol, 3.42 eq), MeI (684.00 mg, 4.82 mmol, 0.3 mL, 4.74 eq), and the resulting mixture was stirred at 40° C. for 48 hours. LCMS showed that the desired MS was detected and methyl 2-[bis[(4-methoxyphenyl)methyl]sulfaminyl]acetate was consumed. TLC (PE/EA=3:1, Rf=0.7) showed that a new spot was detected and methyl 2-[bis[(4-methoxyphenyl)methyl]sulfaminyl]acetate was 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 a crude product. The crude product was purified by preparative TLC (PE/EA=3:1, Rf=0.7) to give 2-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-2-methyl-propionic acid methyl ester (250 mg, 593.11 μmol, 58.34% yield) as a white solid.

¹ H NMR (400 MHz, chloroform-d) δ = 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). Step 3. Preparation of 2- methyl -2- sulfaminyl - propionic acid methyl ester

To a solution of 2-[bis[(4-methoxyphenyl)methyl]sulfaminyl]-2-methyl-propionic acid methyl ester (100 mg, 237.24 μmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL), and the resulting mixture was stirred at 25°C for 1 hour. TLC (PE/EA=3:1, Rf=0.1, I ₂ ) showed that a new spot was detected and 2-[bis[(4-methoxyphenyl)methyl]sulfaminyl]-2-methyl-propionic acid methyl ester was consumed. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give crude 2-methyl-2-sulfaminyl-propionic acid methyl ester (80 mg, crude) as a white solid, which was used in the next step without further purification. Step 4. Preparation of methyl 2- methyl -2-[[1-[4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonyl ] propanoate

To a solution of 1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (80 mg, 163.41 μmol, 1 eq) in DCM (2 mL) were added 2-methyl-2-sulfaminyl-propionic acid methyl ester (70 mg, 386.29 μmol, 2.36 eq), DMAP (50 mg, 409.27 μmol, 2.50 eq) and EDCI (50 mg, 260.82 μmol, 1.60 eq), and the resulting mixture was stirred at 25 °C for 12 h. LCMS showed the desired MS was detected and 1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid was consumed. The reaction _mixture was partitioned between EtOAc (70 mL) and water (50 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 preparative HPLC (UniSil 3-100 C ₁₈ UItra (150×25 mm×3 um); mobile phase: [water (FA)-ACN]; B%: 47%-77%, 7 min) and lyophilized to give methyl 2-methyl-2-[[1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]aminosulfonyl]propanoate (5.7 mg, 8.56 μmol, 5.24% yield, 98% purity) as a yellow solid.

¹ H NMR (400 MHz, methanol-d ₄ ) δ = 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] ⁺ Example 4. Preparation of (R)-1-(3- methoxy -4-(4-(3- methyl -4-(((1- phenylethoxy ) carbonyl ) amino ) isoxazol -5 - yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 63) Step 1. Preparation of methyl 1-(4- bromo -3- methoxyphenyl ) cyclopropane -1- carboxylate

To a stirred solution of 1-(4-bromo-3-methoxyphenyl)cyclopropane-1-carboxylic acid (0.500 g, 1.84 mmol) in methanol (0.1 mL) was added sulfuric acid (0.1 mL, 1.84 mmol) at 0 °C, stirred for 10 minutes, and the reaction mixture was maintained at 70 °C for 8 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was concentrated, diluted with water (15 mL), and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with water (2×10 mL), 10% NaHCO ₃ solution (2×7 mL) and brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give methyl 1-(4-bromo-3-methoxyphenyl)cyclopropane-1-carboxylate (0.5 g and 95% yield) as a colorless liquid; MS (ES) m/z 287.0 (M+H) ⁺ . Step 2. Preparation of 5-(1-(2- methoxy- 4-(1-( methoxycarbonyl ) cyclopropyl ) phenyl ) piperidin -4- yl )-3- methylisoxazole -4- carboxylic acid

To a stirred solution of 3-methyl-5-(piperidin-4-yl)-1,2-oxazole-4-carboxylic acid hydrochloride (0.4 g, 1.62 mmol) in dimethylformamide (13.2 mL, 170 mmol) was added cesium carbonate (2.11 g, 4 eq., 6.49 mmol), methyl 1-(4-bromo-3-methoxyphenyl)cyclopropane-1-carboxylate (509 mg, 1.1 eq., 1.62 mmol) and X-phos (77.3 mg, 0.1 eq., 162 µmol) under argon purging for 15 min. Finally Pd ₂ (dba) ₃ (74.2 mg, 0.05 eq., 81.1 µmol) was added and the reaction mixture was heated to 100 °C in a sealed tube for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the 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 the aqueous layer was acidified with 10% citric acid until the pH was acidic, then extracted with ethyl acetate (2×100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 5-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (150 mg, yield 22%) as a dark yellow solid; MS (ES) m/z 415.0 (M+1H) ⁺ Step 3. Preparation of (R)-1-(3- methoxy -4-(4-(3- methyl -4-(((1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane- 1- carboxylic acid methyl ester

To a stirred solution of 5-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (0.100 g, 241 umol) in toluene (10 mL) were added triethylamine (0.1 mL, 3 eq., 719 µmol) and ((1R)-1-phenylethan-1-ol (29.5 mg, 1 eq., 241 umol) and the reaction mixture was heated to 50 °C for 20 min. DPPA (57.5 µL, 1.1 eq., 265 µmol) was then added and heated to 85 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction mass was diluted with water (20 mL) and washed with ethyl acetate (2×25 The combined organic layers were washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 28%) in n-hexane to give (R)-1-(3-methoxy-4-(4-(3-methyl-4-(((1-phenylethoxy)carbonyl)amino)isoxazol-5-yl)piperidin-1-yl)phenyl)cyclopropane-1-carboxylic acid methyl ester (50 mg, yield: 39%) as a light yellow gum; MS (ES) m/z 533.3 (M+H) ⁺ Step 4. Preparation of (R)-1-(3- methoxy -4-(4-(3- methyl -4-(((1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-(3-methoxy-4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (50 mg, 93.7 umol) in THF (3.0 mL), MeOH (3.0 mL) solution was added lithium hydroxide (1+) hydrate (15.7 mg, 375 umol) in water (3.0 mL) and the mixture was stirred at room temperature for 18 hours. The reaction progress was monitored by LCMS and TLC. After the reaction was completed, the reaction mixture was concentrated, diluted with water (10 mL), washed with diethyl ether (2×5 mL), the pH was adjusted to 3-4 with 10% aqueous citric acid solution, a white solid precipitated, filtered on a Buchner funnel, the solid was washed with water (2×5 mL), pentane (2×5 mL) and dried under vacuum to give a crude product (30 mg). It was purified by preparative HPLC to give 1-(3-methoxy-4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (10 mg, 20% yield) as a white solid; MS (ES) m/z 520.3 (M+1H) ⁺ . LC purity 98.72% at 254 nm. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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). Example 5. Preparation of 1-(3- methoxy- 4-{6-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2- azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropane -1- carboxylic acid ( Compound 46) Step 1. Preparation of methyl 1-(4- bromo -3- methoxyphenyl ) cyclopropane -1- carboxylate

To a stirred solution of 1-(4-bromo-3-methoxyphenyl)cyclopropane-1-carboxylic acid (1 g, 3.69 mmol) in methanol (1 mL) was added sulfuric acid (217 uL, 3.69 mmol) at 0 °C, stirred for 10 minutes, and the reaction mixture was maintained at 70 °C for 8 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was concentrated, diluted with water (15 mL), and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with water (2×10 mL), 10% NaHCO3 solution (2×7 mL) and aqueous brine (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give methyl 1-(4-bromo-3-methoxyphenyl)cyclopropane-1-carboxylate (0.8 g and 76% yield) as a colorless liquid. MS (ES) m/z 285.0 (M+H) ⁺ . Step 2. Preparation of 5-(2-{2- methoxy -4-[1-( methoxycarbonyl ) cyclopropyl ] phenyl }-2- azaspiro [3.3] heptane- 6- yl )-3- methyl -1,2- oxazole -4-carboxylic acid

To a stirred solution of 5-{2-azaspiro[3.3]heptane-6-yl}-3-methyl-1,2-oxazole-4-carboxylic acid hydrochloride (350 mg, 1.35 mmol) in dimethylformamide (8.75 mL, 113 mmol) was added cesium carbonate (1.76 g, 4 eq., 5.41 mmol), methyl 1-(4-bromo-3-methoxyphenyl)cyclopropane-1-carboxylate (386 mg, 1.35 mmol) and X-phos (64.5 mg, 0.1 eq., 135 µmol) under argon purging for 15 min. Finally, Pd2(dba)3 (61.9 mg, 0.05 eq., 67.6 µmol) was added and the reaction mixture was heated to 100 °C in a sealed tube for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was cooled to room temperature and filtered through celite, and concentrated, then diluted with water (20 mL) and washed with diethyl ether, then the aqueous layer was acidified with 10% citric acid until the pH was acidic, then extracted with ethyl acetate (2×20 mL), washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get the crude material. The crude product was co-distilled with toluene and washed with ether and pentane to give 5-(2-{2-methoxy-4-[1-(methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptane-6-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (300 mg, 52% yield) as a dark yellow solid; MS (ES) m/z 427.2 (M+1H) ⁺ . Step 3. Preparation of 1-(3- methoxy -4-{6-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2- azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a solution of 5-(2-{2-methoxy-4-[1-(methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptane-6-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (0.3 g, 703 µmol) in toluene (10 mL, 3.26 mmol) was added triethylamine (196 µL, 2 eq., 1.41 mmol), (1R)-1-phenylethan-1-ol (258 µL, 3 eq., 2.11 mmol) and the reaction mixture was stirred at 50 °C. Then, {[azido(phenoxy)phosphatyl]oxy}benzene (303 µL, 2 eq., 1.41 mmol) was added. The mixture was stirred at 85 °C for 3 hours. The reaction progressed under TLC, and the reaction mass was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with water (2×20 mL), brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 50%) in n-hexane to give methyl 1-(3-methoxy-4-{6-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropane-1-carboxylate as a slightly yellow liquid (120 mg, 31%; yield) MS (ES) m/z 546.0 (M+H) ⁺ . Step 4. Preparation of 1-(3- methoxy- 4-{6-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2 -azaspiro [3.3] heptane - 2- yl } phenyl ) cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-(3-methoxy-4-{6-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropane-1-carboxylate (120 mg, 220 µmol) in oxadiazole cyclopentane (2 mL), methanol (2 mL, 156 mmol) was added lithium hydroxide hydrate (36.9 mg, 4 eq, 880 µmol) in water (2 mL) and the mixture was stirred at room temperature for 18 h. The reaction progressed under LCMS and TLC. The reaction mass was concentrated, diluted with water (10 mL), washed with ether (2×10 mL), and the pH was adjusted to 3 to 4 with 10% aqueous citric acid. A white solid precipitated and was filtered on a Buchner funnel and purified by filtration with water (2×10 mL), pentane (2×10 The solid was washed with 1% 4-[(4-[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-yl}phenyl)cyclopropane-1-carboxylic acid (30 mg, 26% yield) as an off-white solid. MS (ES) m/z 532.4 (M+1H) ⁺ . LC purity at 240 nm: 99.62%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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). Example 6. Preparation of (R)-1-(4-(3-(3- methyl -4-(((1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) aziridocyclobutan -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 23) Step 1. Preparation of methyl 3-( methylamino ) but -2- enoate

To a mixture of methyl 3-oxobutyrate (25 g, 215.30 mmol, 23.15 mL, 1 eq.) in MeOH (300 mL) was added 33% aqueous _MeNH2 (31.57 g, 335.45 mmol, 1.56 eq.) dropwise at 0°C over 30 min. The mixture was stirred at 25°C for 1 h. The reaction solution was concentrated under vacuum at 25°C to give methyl 3-(methylamino)but-2-enoate (27.5 g, crude) as a white solid. Step 2. Preparation of tert-butyl 3 -chlorocarbonylazinecyclobutane -1- carboxylate

To a mixture of 1-tert-butyloxycarbonylazacyclobutane-3-carboxylic acid (10 g, 49.70 mmol, 1 eq) and DMF (182 mg, 2.48 mmol, 191 μL, 0.05 eq) in DCM (100 mL) was added acetyl dichloride (6.31 g, 49.70 mmol, 4.35 mL, 1 eq) dropwise at 0°C and the mixture was stirred at 25°C for 16 h. The mixture was concentrated to dryness in vacuo to give tert-butyl 3-chlorocarbonylazacyclobutane-1-carboxylate (5.1 g, 23.22 mmol, 46.72% yield) as a yellow oil. Step 3. Preparation of tert-butyl 3-[(E)-2- methoxycarbonyl -3-( methylamino ) but -2- enyl ] azinecyclobutane -1- carboxylate

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 dropwise 3-chlorocarbonylazinecyclobutane-1-carboxylic acid tributyl ester (5.10 g, 23.23 mmol, 1.2 eq.) at 0°C, and the mixture was stirred at 25°C for 16 hours. The mixture was poured into H ₂ O (30 mL), and the resulting mixture was extracted with EtOAc (40 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1 to 3: 1) to obtain tert-butyl 3-[(E)-2-methoxycarbonyl-3-(methylamino)but-2-enyl]azetidine-1-carboxylate (1.5 g, 4.80 mmol, 24.81% yield) as a yellow oil. Step 4. Preparation of 5-(1- tert-butyloxycarbonylazetidine -3- yl )-3- methyl - isoxazole -4- carboxylate

To a mixture of tributyl 3-[(E)-2-methoxycarbonyl-3-(methylamino)but-2-enyl]azinecyclobutane-1-carboxylate (1.3 g, 4.16 mmol, 1 eq.) in HOAc (5 mL) was added NH ₂ OH⸱HCl (347 mg, 4.99 mmol, 1.2 eq.). The mixture was stirred at 60 °C for 0.5 h. The mixture was concentrated, the residue was dissolved in EtOAc (10 mL), treated with saturated NaHCO ₃ until pH 8, and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by reverse phase MPLC (0.1% FA condition) to give 5-(1-tri-butyloxycarbonylazacyclobutan-3-yl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (585 mg, 1.97 mmol, 47.44% yield) as a yellow oil. Step 5. Preparation of 5-(1- tri-butyloxycarbonylazacyclobutan -3 -yl )-3- methyl - isoxazole -4- carboxylic acid

To a mixture of 5-(1-tributyloxycarbonylazolobutan-3-yl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (585 mg, 1.97 mmol, 1 eq) in MeOH (15 mL) and H ₂ O (1.5 mL) was added LiOH (118 mg, 4.94 mmol, 2.5 eq). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, treated with HCl (1 M) until pH 6, and extracted with EtOAc (5 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuo to give 5-(1 _- tert-butyloxycarbonylazacyclobutane-3-yl)-3-methyl-isoxazole-4-carboxylic acid (480 mg, crude) as a yellow solid. Step 6. Preparation of tert-butyl 3-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ] azacyclobutane -1- carboxylate

To a mixture of 5-(1-tri-butyloxycarbonylazolobutan-3-yl)-3-methyl-isoxazole-4-carboxylic acid (250 mg, 886 μmol, 1 eq) and (1R)-1-phenylethanol (325 mg, 2.66 mmol, 321 μL, 3 eq) in toluene (3 mL) was added DPPA (268 mg, 974 μmol, 211 μL, 1.1 eq) and TEA (179 mg, 1.77 mmol, 247 μL, 2 eq). The mixture was stirred at 80 °C under _N2 atmosphere for 4 h. 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-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]azepanobutane-1-carboxylate (185 mg, 460.82 μmol, 52.03% yield) as a colorless oil. Step 7. Preparation of N-[5-( azepanobutane -3- yl )-3- methyl - isoxazol -4- yl ] carbamate [(1R)-1- phenylethyl ] ester

To a mixture of tert-butyl 3-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]azepanobutane-1-carboxylate (150 mg, 373.64 μmol, 1 equiv) in i-PrOH (5 mL) was added HCl/dioxane (4 M, 1 mL). The mixture was stirred at 25 °C for 17 h. The mixture was concentrated. The residue was purified by reverse phase MPLC (0.1% FA condition) and then lyophilized to give N-[5-(azepanobutan-3-yl)-3-methyl-isoxazol-4-yl]carbamate [(1R)-1-phenylethyl] ester (112 mg, 372 μmol, 99.47% yield) as a colorless oil. Step 8. Preparation of 1-[4-[3-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ] azepanobutan -1- yl ] phenyl ] cyclopropanecarboxylic acid methyl ester

To a mixture of N-[5-(Azocyclobutane-3-yl)-3-methyl-isoxazol-4-yl]carbamic acid [(1R)-1-phenylethyl] ester (72 mg, 239 umol, 1 eq.) in DCM (5 mL) was added Cu(OAc) ₂ (88 mg, 478 umol, 2 eq.), TEA (48 mg, 478 umol, 67 uL, 2 eq.) and [4-(1-methoxycarbonylcyclopropyl)phenyl]boronic acid (105.14 mg, 477.87 umol, 2 eq.). The mixture was stirred at 20 °C under O ₂ atmosphere for 18 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to give methyl 1-[4-[3-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]azepan-1-yl]phenyl]cyclopropanecarboxylate (41 mg, 86 umol, 36% yield) as a yellow oil. Step 9. Preparation of 1-[4-[3-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ] azepan- 1- yl ] phenyl ] cyclopropanecarboxylate

To a mixture of methyl 1-[4-[3-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]azepan-1-yl]phenyl]cyclopropanecarboxylate (41 mg, 86 umol, 1 eq.) in THF (5 mL) and H ₂ O (1 mL) was added LiOH (6 mg, 259 umol, 3 eq.). The mixture was stirred at 25° C. for 16 hours and at reflux for 32 hours. The reaction mixture was cooled to room temperature, treated with 1 N HCl until pH 6, and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 10 minutes) to obtain 1-[4-[3-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]azepan-1-yl]phenyl]cyclopropanecarboxylic acid (7.1 mg, 13.85 umol, 16.06% yield, 90% purity) as an off-white solid. [M+H] ⁺ = 462.2. ¹ H NMR (400 MHz, MeOD-d4) δ = 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)-1-(4-(1-(3- methyl -4-(((1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) piperidin -4- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 8) Step 1. Preparation of 4-( p-tolylsulfonylhydrazono ) piperidine -1- carboxylic acid tert-butyl ester

To a mixture of 4-methylbenzenesulfonylhydrazine (10.84 g, 58.22 mmol, 1 eq.) in MeOH (100 mL) at 25 °C under _N2 was added 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (11.6 g, 58.22 mmol, 1 eq.). The mixture was stirred at 25 °C for 16 h. The mixture was filtered and the filter cake was dried under vacuum to give 4-(p-tolylsulfonylhydrazono)piperidine-1-carboxylic acid tert-butyl ester (17 g, crude) as an off-white solid. Step 2. Preparation of 4-[4-(1- ethoxycarbonylcyclopropyl ) phenyl ] piperidine -1- carboxylic acid tert-butyl ester

To a mixture of tert-butyl 4-(p-tolylsulfonylhydrazono)piperidine-1-carboxylate (5 g, 13.61 mmol, 1 eq) in dioxane (50 mL) were added Cs ₂ CO ₃ (13.30 g, 40.83 mmol, 3 eq) and ethyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (2.5 g, 7.91 mmol, 0.58 eq). The mixture was stirred at 110° C. for 3 hours. Then tert-butyl 4-(p-tolylsulfonylhydrazono)piperidine-1-carboxylate (5.00 g, 13.61 mmol, 1 eq) was added and the mixture was stirred at 110° C. for 32 hours. The mixture was poured into water (50 mL), and the resulting mixture was extracted with EtOAc (50 mL×3). The combined organics were dried over Na ₂ SO ₄ , 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-(1-ethoxycarbonylcyclopropyl)phenyl]piperidine-1-carboxylate (2.3 g, 6.16 mmol, 45.25% yield) as a yellow oil. Step 3. Preparation of ethyl 1-[4-(4- piperidinyl ) phenyl ] cyclopropanecarboxylate

To a mixture of tributyl 4-[4-(1-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 h. The mixture was concentrated to dryness in vacuo, and the residue was redissolved in DCM (30 mL). K ₂ CO ₃ (10 g) was added, and the resulting mixture was stirred at 25 °C for 0.5 h, then filtered, and the filtrate was concentrated to give ethyl 1-[4-(4-piperidinyl)phenyl]cyclopropanecarboxylate (1.6 g, crude) as a yellow solid. Step 4. Preparation of 1-[4-[1-(4- aminoformyl- 3 - methyl - isoxazol -5- yl )-4- piperidinyl ] phenyl ] cyclopropanecarboxylic acid ethyl ester

A mixture of ethyl 1-[4-(4-piperidinyl)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 h. The mixture was cooled to room temperature and HATU (835 mg, 2.19 mmol, 1.2 eq) was added. The resulting mixture was stirred at 25 °C for 10 min and then treated with NH ₄ Cl (196 mg, 3.66 mmol, 2 eq) and stirring was continued at 25 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with EtOAc (5 mL), then filtered, and the filter cake was dried in vacuo to give 1-[4-[1-(4-aminoformyl-3-methyl-isoxazol-5-yl)-4-piperidinyl]phenyl]cyclopropanecarboxylic acid ethyl ester (260 mg, 654 μmol, 35.76% yield) as a white solid. Step 5. Preparation of ethyl 1-[4-[1-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-4- piperidinyl ] phenyl ] cyclopropanecarboxylate

To a mixture of 1-[4-[1-(4-aminomethyl-3-methyl-isoxazol-5-yl)-4-piperidinyl]phenyl]cyclopropanecarboxylic acid ethyl ester (180 mg, 453 μmol, 1 eq) in toluene (5 mL) was added bis(trifluoroacetyloxy)iodo]benzene (390 mg, 905.74 μmol, 2 eq) and pyridine (107 mg, 1.36 mmol, 110 μL, 3 eq). The mixture was stirred at 30 °C for 1 hour under _N2 atmosphere. Then (1R)-1-phenylethanol (277 mg, 2.26 mmol, 274 μL, 5 eq) was added and stirring was continued at 70 °C for 2 hours. The mixture was poured into water (10 mL), and the resulting mixture was extracted with EtOAc (10 mL×3). The combined organic extracts were dried over Na ₂ SO 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 1-[4-[1-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-4-piperidinyl]phenyl]cyclopropanecarboxylic acid ethyl ester (45 mg, 86.94 μmol, 19.20% yield) as a yellow oil. Step 6. Preparation of 1-[4-[1-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-4- piperidinyl ] phenyl ] cyclopropanecarboxylic acid

To a mixture of ethyl 1-[4-[1-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-4-piperidinyl]phenyl]cyclopropanecarboxylate (45 mg, 87 μmol, 1 eq) in THF (5 mL) and H ₂ O (1 mL) was added LiOH (6 mg, 261 μmol, 3 eq). The mixture was stirred at 65° C. for 64 h. Aqueous HCl (1 M, 3 mL) was added to the mixture, and the mixture was extracted with EtOAc (10 mL×3). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 42%-72%, 10 minutes) and then lyophilized to obtain 1-[4-[1-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-4-piperidinyl]phenyl]cyclopropanecarboxylic acid (11.5 mg, 23.26 μmol, 26.75% yield, 99% purity) as an off-white solid. [M+H ⁺ ] = 490.3. ¹ H NMR (400 MHz, CD ₃ OD) δ = 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). Example 8. Preparation of 1-(4-{6-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2- azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropane -1- carboxylic acid ( Compound 54) Step 1. Preparation of 6-(3- ethoxy- 3 -oxopropionyl )-2- azaspiro [3.3] heptane -2- carboxylic acid tributyl ester

To a stirred solution of 2-[(tert-butyloxy)carbonyl]-2-azaspiro[3.3]heptane-6-carboxylic acid (2 g, 8.29 mmol) in acetonitrile (50 mL) was added 2-(1H-imidazole-2-carbonyl)-1H-imidazole (2.02 g, 1.5 eq, 12.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. To a solution of 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+) chloride (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 room temperature for 8 hours, after which the above solution (CDI mixture solution) was added to the reaction mixture at 0°C and stirred at 70°C for 6 hours. The reaction progressed under TLC and LCMS. The reaction mixture was quenched with 1 mol/L hydrochloric acid (50 mL) under ice cooling and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×100 mL), sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 20%) in n-hexane to give tributyl 6-(3-ethoxy-3-oxopropanoyl)-2-azaspiro[3.3]heptane-2-carboxylate (2.4 g, 93% yield) as a viscous liquid; MS (ES) m/z 256.1 (M+1H) ⁺ , -56 De-BOC mass observed. Step 2. Preparation of (Z)-N- Hydroxyethanecarbonimidoyl chloride

To a solution of (E)-N-ethylenehydroxylamine (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 hours. The reaction mass was diluted with water (80 mL) and extracted with diethyl ether (2×100 mL), the combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated to give 2-methylbut-2-ene (yield: 2.8 g, 59%). Step 3. Preparation of tert -butyl 4-[4-( ethoxycarbonyl )-3- methyl -1,2- oxazol -5- yl ] piperidine -1- carboxylate

To a solution of tributyl 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) at 0 °C for 30 min followed by addition of (Z)-N-hydroxyethanecarbonimidoyl chloride (2.4 g, 8 eq, 25.7 mmol) and the resulting mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was diluted with water (80 mL), extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2×50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give the crude material. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 10%) in n-hexane to give tributyl 6-[4-(ethoxycarbonyl)-3-methyl-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-carboxylate as a slightly yellow liquid (yield; 550 mg, 49%) MS (ES) m/z 351 (M+H)+. But m/z 295.1 (-56 De-Boc mass observed). Step 4. Preparation of 5-{2-[( tributyloxy ) carbonyl ]-2- azaspiro [3.3] heptane -6- yl }-3- methyl -1,2- oxazole -4-carboxylic acid

To a solution of tributyl 6-[4-(ethoxycarbonyl)-3-methyl-1,2-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. The reaction progressed under LCMS and TLC. The reaction mass was concentrated and diluted with water (20 mL). The pH was adjusted to 3-4 with 1N HCL. A white solid precipitated and was extracted with DCM (2×30 ml), washed with water (2×15 mL), and dried under vacuum to give 5-{2-[(tert-butyloxy)carbonyl]-2-azaspiro[3.3]heptane-6-yl}-3-methyl-1,2-oxazole-4-carboxylic acid as a colloidal liquid (yield: 450 mg, 89%); MS (ES) m/z 321.2 (MH) ^- . Step 5. Preparation of 5-{2 -azaspiro [3.3] heptane -6- yl }-3- methyl -1,2 - oxazole -4- carboxylic acid hydrochloride

To a stirred solution of 5-{2-[(tributyloxy)carbonyl]-2-azaspiro[3.3]heptane-6-yl}-3-methyl-1,2-oxazole-4-carboxylic acid (410 mg, 1.27 mmol) in dichloromethane (20 mL) was added a solution of dioxane in HCl (4 mL, 8 eq., 10.2 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction material was concentrated, washed with pentane, and dried under vacuum to obtain 5-{2-azaspiro[3.3]heptane-6-yl}-3-methyl-1,2-oxazole-4-carboxylic acid hydrochloride as a white solid (yield: 275 mg, 84%), MS (ES) m/z 221.1 (M+H) ⁺ . Step 6. Preparation of 5-(2-{4-[1-( methoxycarbonyl ) cyclopropyl ] phenyl }-2 -azaspiro [3.3] heptane -6- yl )-3- methyl -1,2- oxazole -4-carboxylic acid

To a stirred solution of 5-{2-azaspiro[3.3]heptane-6-yl}-3-methyl-1,2-oxazole-4-carboxylic acid hydrochloride (275 mg, 1.06 mmol) in dimethylformamide (15 mL, 194 mmol) was added cesium carbonate (1.39 g, 4 eq., 4.25 mmol), methyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (325 mg, 1.2 eq., 1.28 mmol) and X-phos (50.7 mg, 0.1 eq., 106 µmol) under argon purging for 15 min. Finally, Pd2(dba)3 (48.7 mg, 0.05 eq., 53.1 µmol) was added and the reaction mixture was heated to 100 °C in a sealed tube for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the 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 the aqueous layer was acidified with 10% citric acid until pH was acidic, then extracted with ethyl acetate (2×100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 5-(2-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptane-6-yl)-3-methyl-1,2-oxazole-4-carboxylic acid as a dark yellow solid (yield: 325 mg, 77%); MS (ES) m/z 397.2 (M+1H) ⁺ . Step 7. Preparation of 1-(4-{6-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2 -azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropane- 1- carboxylic acid methyl ester

{[azido(phenoxy)phosphatyl]oxy}benzene (163 µL, 2 eq., 757 µmol) and triethylamine (105 µL, 2 eq., 757 µmol) were added to a solution of 5-(2-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptane-6-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (150 mg, 378 µmol) at 50 °C. The mixture was stirred at 50 °C for 30 min. Then (1R)-1-phenylethan-1-ol (139 mg, 3 eq., 1.14 mmol) was added. The mixture was stirred at 80 °C for 3 h. The reaction progressed under TLC and the reaction mass was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 50%) in n-hexane to give methyl 1-(4-{6-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-yl}phenyl)cyclopropane-1-carboxylate (30 mg, 58.2 µmol) (30 mg, 16% yield) as a light yellow solid; MS (ES) m/z 516.3 (M+H) ⁺ . Step 8. Preparation of 1-(4-{6-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2- azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropane -1- carboxylic acid

To a solution of methyl 1-(4-{6-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-yl}phenyl)cyclopropane-1-carboxylate (32 mg, 62.1 µmol) in oxadiazole cyclopentane (4.00 mL), methanol (4.00 mL) was added lithium hydroxide (1+) hydrate (13 mg, 5 eq., 310 µmol) in water (4.00 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction progressed under LCMS and TLC. The reaction mass was concentrated and diluted with water (20 mL). The pH was adjusted to 3-4 with 10% aqueous citric acid solution. A white solid precipitated and was filtered on a Buchner funnel. The solid was washed with water (2×25 mL), pentane (2×25 mL) and dried under vacuum to give 1-(4-{6-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-yl}phenyl)cyclopropane-1-carboxylic acid as a white solid (yield: 15 mg, 48%). MS (ES) m/z 502.4 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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 Example 9. Preparation of 1-(4-((2S,4S)-2- methyl -4-(3- methyl -4-((((R)-1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) piperidin -1 - yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 10) and 1-(4-((2R,4R)-2- methyl -4-(3- methyl -4-((((R)-1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 21) Step 1. Preparation of 2- methylpiperidin -1,4- dicarboxylic acid 1-( tert-butyl ) 4- methyl ester

To a mixture of methyl 2-methylpiperidine-4-carboxylate (6.5 g, 33.56 mmol, 1 eq, HCl) 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) and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo. The residue was purified by flash silica chromatography (ISCO®; 80 g SepaFlash® silica flash column, solvent 0-10% ethyl acetate/petroleum ether) to give 2-methylpiperidine-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-methyl ester (6.9 g, 26.81 mmol, 79.89% yield) as a yellow oil. Step 2. Preparation of 1- tert-butyloxycarbonyl- 2- methyl - piperidine -4- carboxylic acid

To a mixture of 2-methylpiperidine-1,4-dicarboxylic acid O ₁ -tert-butyl O ₄ -methyl ester (6.8 g, 26.43 mmol, 1 eq) in THF (70 mL) and H ₂ O (35 mL) was added LiOH (2.53 g, 105.70 mmol, 4 eq), and the mixture was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo to remove THF, diluted with EtOAc (40 mL) and H ₂ O (40 mL), treated with aqueous HCl (1 M) until pH 5, and extracted with EtOAc (40 mL×3). The combined organic layers were dried _{over Na2SO4} , filtered, and concentrated in vacuo to give 1-tert-butyloxycarbonyl-2-methyl-piperidine-4-carboxylic acid (5.75 g, 23.63 mmol, 89.43% yield) as a yellow solid. Step 3. Preparation of 4- chlorocarbonyl- 2- methyl - piperidine -1- carboxylic acid tert-butyl ester

To a mixture of 1-tert-butoxycarbonyl-2-methyl-piperidine-4-carboxylic acid (2 g, 8.22 mmol, 1 eq.) and DMF (60.00 mg, 820.86 μmol, 63.16 μL, 0.1 eq.) in DCM (40 mL) at 0 °C was added (COCl) ₂ (1.57 g, 12.33 mmol, 1.08 mL, 1.5 eq.) dropwise, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated to give 4-chlorocarbonyl-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (4 g, crude) as a yellow oil. Step 4. Preparation of 4-[(E)-2- methoxycarbonyl- 3-( methylamino ) but -2- enyl ]-2 - methyl - piperidine -1- carboxylic acid tert-butyl ester

To a mixture of (Z)-3-(methylamino)but-2-enoic acid methyl ester (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 4-chlorocarbonyl-2-methyl-piperidine-1-carboxylic acid tributyl ester (2 g, 7.64 mmol, 1 eq) dropwise, and the resulting mixture was stirred at 25 °C for 17 h. The mixture was poured into water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over _Na2SO4 , _filtered and concentrated in vacuo. The residue was purified by flash silica chromatography (ISCO®; 12 g SepaFlash® silica flash column, solvent 0-25% ethyl acetate/petroleum ether) to give 4-[(E)-2-methoxycarbonyl-3-(methylamino)but-2-enyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (2 g, 5.64 mmol, 36.92% yield) as a yellow oil. Step 5. Preparation of 5-(1- tert-butyloxycarbonyl- 2- methyl -4- piperidinyl )-3- methyl - isoxazole -4- carboxylic acid methyl ester

To a mixture of 4-[(E)-2-methoxycarbonyl-3-(methylamino)but-2-enyl]-2-methyl-piperidine-1-carboxylic acid tributyl ester (2 g, 5.64 mmol, 1 eq) in MeOH (20 mL) was added aqueous hydroxylamine solution (1.12 g, 16.93 mmol, 50% purity, 3 eq). The mixture was stirred at 60 °C for 2 h. The mixture was concentrated. The residue was purified by flash silica chromatography (ISCO®; 12 g SepaFlash® silica flash column, solvent 0-10% ethyl acetate/petroleum ether) to give 5-(1-tributyloxycarbonyl-2-methyl-4-piperidinyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (760 mg, 2.25 mmol, 39.80% yield) as a yellow oil. Step 6. Preparation of 3- methyl -5-(2- methyl -4- piperidinyl ) isoxazole -4- carboxylic acid methyl ester HCl salt

To a mixture of 5-(1-tributyloxycarbonyl-2-methyl-4-piperidinyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (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 hour. The mixture was concentrated to give 3-methyl-5-(2-methyl-4-piperidinyl)isoxazole-4-carboxylic acid methyl ester (520 mg, 1.89 mmol, 90.21% yield, HCl) as a white solid. Step 7. Preparation of 5-[1-[4-(1- ethoxycarbonylcyclopropyl ) phenyl ]-2- methyl -4- piperidinyl ]-3- methyl - isoxazole -4 - carboxylic acid methyl ester

To a mixture of methyl 3-methyl- _5- (2-methyl-4-piperidinyl)isoxazole-4-carboxylate (500 mg, 1.82 mmol, 1 eq., HCl) in dioxane (10 mL) was added Cs ₂ CO ₃ (1.78 g, 5.46 mmol, 3 eq.), RuPhos Pd G ₃ (152.21 mg, 181.99 μmol, 0.1 eq.) and ethyl 1-(4-bromophenyl)cyclopropanecarboxylate (979.58 mg, 3.64 mmol, 2 eq.) under N 2, the mixture was stirred at 110 °C for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by flash silica chromatography (ISCO®; 40 g SepaFlash® silica flash column, solvent 0-20% ethyl acetate/petroleum ether) to give 5-[1-[4-(1-ethoxycarbonylcyclopropyl)phenyl]-2-methyl-4-piperidinyl]-3-methyl-isoxazole-4-carboxylic acid methyl ester (420 mg, 984.75 μmol, 54.11% yield) as a yellow oil. Step 8. Preparation of 5-[1-[4-(1- ethoxycarbonylcyclopropyl ) phenyl ]-2- methyl -4- piperidinyl ]-3- methyl - isoxazole -4- carboxylic acid

To a mixture of 5-[1-[4-(1-ethoxycarbonylcyclopropyl)phenyl]-2-methyl-4-piperidinyl]-3-methyl-isoxazole-4-carboxylic acid methyl ester (350 mg, 820.62 μmol, 1 eq) in THF (5 mL) and H ₂ O (2.5 mL) was added LiOH (39.31 mg, 1.64 mmol, 2 eq), and the mixture was stirred at 25° C. for 17 h. Aqueous HCl solution (1 M) was added to adjust the pH to 4, and the resulting mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuo to give 5-[1- _[ 4-(1-ethoxycarbonylcyclopropyl)phenyl]-2-methyl-4-piperidinyl]-3-methyl-isoxazole-4-carboxylic acid (270 mg, crude) as a yellow solid. Step 9. Preparation of 1-[4-[4-[4-(1- hydroxy -4- phenyl - butyl )-3- methyl - isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylic acid

To a mixture of 5-[1-[4-(1-ethoxycarbonylcyclopropyl)phenyl]-2-methyl-4-piperidinyl]-3-methyl-isoxazole-4-carboxylic acid (250.00 mg, 606.09 μmol, 1 eq) and (1R)-1-phenylethanol (222.13 mg, 1.82 mmol, 219.93 μL, 3 eq) in toluene (4 mL) were added DPPA (250.20 mg, 909.14 μmol, 197.00 μL, 1.5 eq) and TEA (122.66 mg, 1.21 mmol, 168.72 μL, 2 eq), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash silica chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate/petroleum ether) to afford ethyl 1-[4-[2-methyl-4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylate (120 mg, 225.72 μmol, 37.24% yield) as a yellow oil. Step 10. Preparation of 1-[4-[(2S,4S)-2- methyl -4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylic acid and 1-[4-[(2R,4R)-2- methyl -4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylic acid

To a mixture of ethyl 1-[4-[2-methyl-4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylate (110 mg, 206.91 μmol, 1 eq) in THF (2 mL), EtOH (1 mL) and H ₂ O (1 mL) was added LiOH (24.78 mg, 1.03 mmol, 5 eq). The mixture was stirred at 60° C. for 3 h. Aqueous HCl solution (1 M) was added to adjust the pH to 5, and the resulting mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 um; mobile phase: [water (FA)-ACN]; B%: 12%-42%, 10 min) to obtain an off-white solid, which was further purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 um); mobile phase: [containing 0.1% NH ₃ H ₂ O in MEOH]; B%: 30%-30%, 3.5 minutes) to obtain 1-[4-[(2S,4S)-2-methyl-4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (12.56 mg, 24.94 μmol, 12.05% yield, 100% purity) and 1-[4-[(2R,4R)-2-methyl-4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (13.1 mg, 26.01 umol, 12.57% yield, 100% purity), all as off-white solids. The absolute configurations of the two chiral centers on the piperidine ring are unknown, and the relative configuration is cis.

1-[4-[(2S,4S)-2-methyl-4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (Compound 10): ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 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.

1-[4-[(2R,4R)-2-methyl-4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (Compound 21): ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 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. Example 10. Preparation of 1-(4-{6-[3- methyl -4-({[(1R)-1-(2- methylphenyl ) ethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2- azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropane -1- carboxylic acid ( Compound 33) Step 1. Preparation of 1-(4-{6-[3- methyl -4-({[(1R)-1-(2- methylphenyl ) ethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2 -azaspiro [3.3] heptane - 2- yl } phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a solution of 5-(2-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}-2-azaspiro[3.3]heptane-6-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (0.3 g, 757 µmol) in toluene (15 mL) was added triethylamine (211 µL, 2 eq., 1.51 mmol), (1R)-1-(2-methylphenyl)ethan-1-ol (309 mg, 3 eq., 2.27 mmol) and the reaction mixture was stirred at 50 °C. Then, {[azido(phenoxy)phosphatyl]oxy}benzene (196 µL, 1.2 eq., 908 µmol) was added. The mixture was stirred at 85 °C for 3 hours. The reaction progressed under TLC, and the reaction mass was diluted with water (20 mL), extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 50%) in n-hexane to give methyl 1-(4-{6-[3-methyl-4-({[(1R)-1-(2-methylphenyl)ethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropane-1-carboxylate as a slightly yellow liquid (yield; 280 mg, 70%). MS (ES) m/z 530.3 (M+H) ⁺ . Step 2. Preparation of 1-(4-{6-[3- methyl -4-({[(1R)-1-(2- methylphenyl ) ethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2 -azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropane -1- carboxylic acid

To a solution of methyl 1-(4-{6-[3-methyl-4-({[(1R)-1-(2-methylphenyl)ethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropane-1-carboxylate (280 mg, 529 µmol) in oxadiazole cyclopentane (4.00 mL), methanol (4.00 mL) was added lithium hydroxide (1+) hydrate (111 mg, 5 eq., 2.64 mmol) in water (4.00 mL) at room temperature and stirred at the same temperature for 18 hours. The reaction progressed under LCMS and TLC. The reaction mass was concentrated and diluted with water (20 mL). The pH was adjusted to 3-4 with 10% aqueous citric acid solution. A white solid precipitated and was filtered on a Buchner funnel. The solid was washed with water (2×25 mL), pentane (2×25 mL) and dried under vacuum to give 1-(4-{6-[3-methyl-4-({[(1R)-1-(2-methylphenyl)ethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-yl}phenyl)cyclopropane-1-carboxylic acid (yield: 40 mg, 15%) as a white solid. (yield: 15 mg, 15%) MS (ES) m/z 516.3 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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, J = 2.8 Hz, 2H), 0.96 (d, J = 1.6 Hz, 2H). Example 11. Preparation of 1-(4-{4-[5- chloro -3-({[(1R)-1- phenylethoxy ] carbonyl } amino ) thiophen- 2- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid ( Compound 92) Step 1. Preparation of 4-(5- chloro -3-( ethoxycarbonyl ) thiophen -2- yl ) piperidine -1- carboxylic acid tributyl ester

To a stirred solution of tributyl 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) in a sealed tube at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice (20 mL), extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 20%) in hexane to afford tri-butyl 4-[5-chloro-3-(ethoxycarbonyl)thiophen-2-yl]piperidine-1-carboxylate (125 mg, 57% yield) as a viscous liquid; MS (ES) m/z 274.1 (M+1H)+ (-100 mass, boc cleavage mass observed in LCMS). ¹ H NMR (400 MHz, CDCl ₃ ): δ 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). Step 2. Preparation of 2-(1-( tributyloxycarbonyl ) piperidin -4- yl )-5- chlorothiophene- 3-carboxylic acid

To a solution of tributyl 4-[5-chloro-3-(ethoxycarbonyl)thiophen-2-yl]piperidine-1-carboxylate (200 mg, 0.535 mmol) in methanol (20 mL) was added water (5 mL) containing sodium hydroxide (64.2 mg, 1.6 mmol) at room temperature and stirred at the same temperature for 18 hours. The reaction progress was monitored by LCMS and TLC. After the reaction was completed, it was concentrated, diluted with water (50 mL), and the pH was adjusted to 3-4 with 10% aqueous citric acid. A white solid precipitated and was filtered on a Buchner funnel. The solid was washed with water (2×15 mL), pentane (2×20 mL) and dried under vacuum to give 2-{1-[(tributyloxy)carbonyl]piperidin-4-yl}-5-chlorothiophene-3-carboxylic acid (160 mg, 86% yield) as a light yellow solid; MS (ES) m/z 246.1 (M+H)+. (-100 mass observed by LCMS). Step 3. Preparation of 5- chloro -2-( piperidin- 4- yl ) thiophene -3- carboxylic acid hydrochloride

To a solution of 2-{1-[(tributyloxy)carbonyl]piperidin-4-yl}-5-chlorothiophene-3-carboxylic acid (0.18 g, 0.52 mmol) in dichloromethane (20 mL) was added 4 M HCl in dioxane (2.6 mL, 10.4 mmol) at 0°C and the resulting mixture was stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated to give 2-(piperidin-4-yl)thiophene-3-carboxylic acid hydrochloride (147 mg, crude) as a light yellow solid. MS (ES) m/z 245.8 (M+1H) ⁺ . (free amine mass). Step 4. Preparation of 5- chloro -2-(1-(4-(1-( methoxycarbonyl ) cyclopropyl ) phenyl ) piperidin -4- yl ) thiophene- 3-carboxylic acid

To _a stirred solution of 5-chloro-2-(piperidin-4-yl)thiophene-3-carboxylic acid hydrochloride (90 mg, 0.31 mmol) and 1-(4-bromophenyl)cyclopropane-1-carboxylic acid methyl ester (89.5 mg, 0.35 mmol) in DMF (8 mL) under N 2 atmosphere was added Cs ₂ CO ₃ (312 mg, 0.95 mmol), followed by purging with N ₂ gas for 3 min, followed by the addition of dicyclohexyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (15.2 mg, 0.032 mmol), tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one)dipalladium (14.6 mg, 0.016 mmol) and the mixture was stirred at 100 °C in a sealed tube for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature and filtered through celite and concentrated, then diluted with water and washed with diethyl ether (2 x 25 mL), then the aqueous layer was acidified to pH 5 with citric acid, then extracted with ethyl acetate (2 x 50 mL), washed with water (25 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 5-chloro-2-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)thiophene-3-carboxylic acid (130 mg, crude) as a light brown gum; MS (ES) m/z 420.1 (M+H)+. Step 5. Preparation of (R)-1-(4-(4-(5- chloro -3-(((1- phenylethoxy ) carbonyl ) amino ) thiophen- 2- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a solution of diphenylphosphinoylazide (0.123 mL, 0.572 mmol) and TEA (0.08 mL, 0.572 mmol) was added 5-chloro-2-(1-{4-[1-(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, followed by the addition of (1R)-1-phenylethan-1-ol (0.235 mL, 1.91 mmol). The mixture was stirred at 90 °C for 8 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, it was diluted with water (30 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 20%) in n-hexane to give methyl 1-(4-{4-[5-chloro-3-({[(1R)-1-phenylethoxy]carbonyl}amino)thiophen-2-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (120 mg, 46% yield) as a light yellow gum; MS (ES) m/z 539.2 (M+H) ⁺ . Step 6. Preparation of (R)-1-(4-(4-(5- chloro -3-(((1- phenylethoxy ) carbonyl ) amino ) thiophen- 2- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid

To a solution of methyl 1-(4-{4-[5-chloro-3-({[(1R)-1-phenylethoxy]carbonyl}amino)thiophen-2-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (100 mg, 0.185 mmol) in THF (7 mL) and methanol (7 mL) was added water (4 mL) containing lithium hydroxide (1+) hydrate (31.1 mg, 0.74 mmol) 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), adjusted to pH 3-4 with 10% aqueous citric acid solution, then extracted with ethyl acetate (2×25 mL), washed with water (20 mL), aqueous brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product, which was purified by combiflash MPLC using ethyl acetate (1% to 70%) in n-hexane to give 1-(4-{4-[5-chloro-3-({[(1R)-1-phenylethoxy]carbonyl}amino)thiophen-2-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (55 mg, 56% yield) as an off-white solid; MS (ES) m/z 525.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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, J = 3.6 Hz, 2H). Example 12. Preparation of (R)-1-(4-(4-(4- methoxy -2-(((1- phenylethoxy ) carbonyl ) amino ) phenyl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 19) Step 1. Preparation of 4-(2- amino- 4- methoxy - phenyl )-3,6- dihydro -2H - pyridine -1- carboxylic acid tributyl ester

To a mixture of 2-bromo-5-methoxy-aniline (1.30 g, 6.43 mmol, 1 eq) and tributyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.99 g, 6.43 mmol, 1 eq) in DMF (20 mL) was added 2 M aqueous NaOH solution (6.43 mL, 12.86 mmol, 2 eq) and Pd(dppf) _Cl2 (471 mg, 643 umol, 0.1 eq) and the mixture was stirred under _N2 at 15 °C for 1 h. H ₂ O (50 mL) was added, and the resulting mixture was extracted with EtOAc (50 mL×3), and the combined organic phases were washed with a saturated NaCl solution (30 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, solvent 0-50% ethyl acetate/petroleum ether) to give 4-(2-amino-4-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tributyl ester (1.7 g, 5.59 mmol, 86.80% yield) as a yellow oil. Step 2. Preparation of 4-(2- amino -4- methoxy - phenyl ) piperidine -1- carboxylate

To a mixture of 4-( ₂ -amino-4-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tributyl ester (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 three times. The mixture was stirred under _H2 (15 Psi) at 40 °C for 36 h. The mixture was filtered and the filtrate was concentrated to give 4-(2-amino-4-methoxy-phenyl)piperidine-1-carboxylic acid ester (1.41 g, crude) as a black oil. Step 3. Preparation of 4-[4- methoxy- 2-( phenoxycarbonylamino ) phenyl ] piperidine -1- carboxylic acid tributyl ester

To a mixture of 4-(2-amino-4-methoxy-phenyl)piperidine-1-carboxylic acid tributyl ester (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 chloroformate (1.07 g, 6.85 mmol, 859 uL, 1.5 eq), and the mixture was stirred at 15 °C for 1 hour. The mixture was poured into water (10 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica chromatography (ISCO®; 40 g SepaFlash® silica flash column, solvent 0-20% ethyl acetate/petroleum ether) to give tert-butyl 4-[4-methoxy-2-(phenoxycarbonylamino)phenyl]piperidine-1-carboxylate (1.6 g, 3.75 mmol, 82.10% yield) as a yellow oil. Step 4. Preparation of tert-butyl 4-[4- methoxy -2-[[(1R)-1- phenylethoxy ] carbonylamino ] phenyl ] piperidine -1- carboxylate

To a mixture of tributyl 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) in portions, the mixture was stirred at 0°C for 0.5 h, then (1R)-1-phenylethanol (0.38 g, 3.11 mmol, 376 uL, 1 eq) was added dropwise at 15°C, the mixture was stirred at 15°C for 0.5 h. The mixture was poured into a saturated NH ₄ Cl solution (40 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica chromatography (ISCO®; 40 g SepaFlash® silica flash column, solvent 0-25% ethyl acetate/petroleum ether) to give tert-butyl 4-[4-methoxy-2-[[(1R)-1-phenylethoxy]carbonylamino]phenyl]piperidine-1-carboxylate as a pink oil (780 mg, 1.72 mmol, 55.17% yield). Step 5. Preparation of [ (1R)-1- phenylethyl ] N-[5- methoxy -2-(4- piperidinyl ) phenyl ] carbamate

To a mixture of tributyl 4-[4-methoxy-2-[[(1R)-1-phenylethoxy]carbonylamino]phenyl]piperidine-1-carboxylate (780 mg, 1.72 mmol, 1 eq.) in i-PrOH (5 mL) was added HCl/dioxane (4 M, 1 mL), and the mixture was stirred at 15°C for 16 hours. The mixture was poured into a saturated solution of NaHCO ₃ (20 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give [(1R)-1-phenylethyl] N-[5-methoxy-2-(4-piperidinyl)phenyl]carbamate (524 mg, crude) as a yellow solid. Step 6. Preparation of ethyl 1-[4-[4-[4- methoxy -2-[[(1R)-1- phenylethoxy ] carbonylamino ] phenyl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylate

To a mixture of [(1R)-1-phenylethyl] N-[5-methoxy-2-(4-piperidinyl)phenyl]carbamate (470 mg, 1.33 mmol, 1 eq) and [4-(1-ethoxycarbonylcyclopropyl)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 under O ₂ atmosphere at 40 °C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase MPLC (0.1% FA condition) to give ethyl 1-[4-[4-[4-methoxy-2-[[(1R)-1-phenylethoxy]carbonylamino]phenyl]-1-piperidinyl]phenyl]cyclopropanecarboxylate (400 mg, 737.10 umol, 55.59% yield) as a yellow oil. Step 7. Preparation of 1-[4-[4-[4- methoxy -2-[[(1R)-1- phenylethoxy ] carbonylamino ] phenyl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylate

To a mixture of ethyl 1-[4-[4-[4-methoxy-2-[[(1R)-1-phenylethoxy]carbonylamino]phenyl]-1-piperidinyl]phenyl]cyclopropanecarboxylate (400 mg, 737.10 umol, 1 eq.) in THF (5 mL) and H ₂ O (5 mL) was added LiOH (53 mg, 2.21 mmol, 3 eq.), and the mixture was stirred at 70° C. for 32 h. Aqueous HCl solution (1 M) was added to the mixture to adjust the pH to 4, and the resulting mixture was extracted with EtOAc (40 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 27%-57%, 10 minutes) and preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 minutes), followed by lyophilization to obtain 1-[4-[4-[4-methoxy-2-[[(1R)-1-phenylethoxy]carbonylamino]phenyl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (93.69 mg, 182.06 umol, 24.70% yield, 100% purity). [M+H] ⁺ = 515.2 ¹ H NMR (400 MHz, MeOD-d4) δ = 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). Example 13. Preparation of (R)-1-(4-(4-(1- methyl -5-(((1- phenylethoxy ) carbonyl ) amino )-1H-1,2,3- triazol - 4- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 60) Step 1. Preparation of tert-butyl 4-(2,2- dibromovinyl ) piperidine -1- carboxylate

To a stirred solution of tetrabromomethane (15.5 g, 2 eq., 46.9 mmol) in dichloromethane (50 mL) was added dropwise a solution of triphenylphosphine (24.6 g, 4 eq., 93.8 mmol) in dichloromethane (50 mL) at 0°C, and the reaction temperature was maintained for 20 minutes. A solution of tributyl 4-formylpiperidine-1-carboxylate (5 g, 23.4 mmol) in dichloromethane (50 mL) was added dropwise at 0°C, and the mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC and LCMS. The solution was diluted with diethyl ether (200 ml), and the precipitate was filtered off. The filtrate was concentrated in vacuo to give a crude substance. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 10%) in n-hexane to afford tri-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (4.5 g, 46% yield) as an off-white solid; MS (ES) m/z 269.0 (M+H) ⁺ , (M-100, boc mass fragmented in LCMS).

¹ H NMR (400 MHz, CDCl ₃ -d): δ 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). Step 2. Preparation of 4-(3- ethoxy- 3 -oxoprop- 1- yn -1- yl ) piperidine -1- carboxylic acid tributyl ester

To a stirred solution of tributyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (5 g, 13.5 mmol) in THF (100 mL) was added butyl lithium (19 mL, 2.1 eq., 28.4 mmol) at -78 °C under nitrogen atmosphere, and the mixture was stirred at -78 °C for 1 hour and at 0 °C for 1 hour. THF (50 mL) containing ethyl chloroformate (4.77 mL, 3.7 eq., 50.1 mmol) was added at -78 °C, and the reaction mixture was allowed to reach room temperature and continued to stir for 8 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the resulting mixture was quenched with ice-cold water (100 mL) 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 (1% to 15%) in n-hexane to give tri-butyl 4-(3-ethoxy-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylate (288 mL, 81% yield) as a light yellow liquid; MS (ES) m/z 182.1 (M+H) ⁺ , (M-100, boc mass of cleavage in LCMS).

¹ H NMR (400 MHz, CDCl _3- d): δ 4.27 - 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). Step 3. Preparation of tributyl 4-(5-( ethoxycarbonyl )-1-(( trimethylsilyl ) methyl )-1H-1,2,3- triazol -4- yl ) piperidine -1- carboxylate

To a stirred solution of tributyl 4-(3-ethoxy-3-oxoprop-1-yn-1-yl)piperidine-1-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) and heated to 110 °C for 8 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by normal phase silica gel column chromatography using ethyl acetate-hexane (10% to 15%) as the eluting solvent to give two major fractions. The distribution regiochemistry was studied by 1H NOE. One fraction was tert-butyl 4-[5-(ethoxycarbonyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (1.2 g, yield 58%) as a light yellow liquid and the other major fraction was tert-butyl 4-[4-(ethoxycarbonyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-5-yl]piperidine-1-carboxylate (1 g, yield 48%) as a white solid; LC-MS (M + H)+ 411.3 (m/e); Step 4. Preparation of tert-butyl 4-(5-( ethoxycarbonyl )-1- methyl -1H-1,2,3- triazol -4- yl ) piperidine -1- carboxylate

To a stirred solution of tributyl 4-[5-(ethoxycarbonyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (2.2 g, 5.36 mmol) in tetrahydrofuran (34.4 mL, 422 mmol) was added water (193 mg, 2 eq., 10.7 mmol) and 1M TBAF in THF (1.68 g, 1.2 eq., 6.43 mmol) at 0°C and maintained at the same temperature for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was purified by combiflash MPLC using ethyl acetate (1% to 25%) in hexane to give tri-butyl 4-[5-(ethoxycarbonyl)-1-methyl-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (666 mg, 36% yield) as a yellow colloidal solid; MS (ES) m/z 339 (M+H) ⁺ but deboc mass observed in LCMS MS (ES) m/z 283.2 (M-56) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ -d): δ 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). Step 5. Preparation of 4-(1-( tributyloxycarbonyl ) piperidin -4- yl )-1- methyl- 1H-1,2,3- triazole -5-carboxylic acid

To a stirred solution of tributyl 4-[5-(ethoxycarbonyl)-1-methyl-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (0.6 g, 1.77 mmol) in ethanol (5 mL, 171 mmol) was added sodium hydroxide (284 mg, 4 eq., 1.77 mmol) dissolved in water (5 mL, 278 mmol) at 0 °C and the reaction mass was maintained at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated to give the crude product. The obtained crude material was acidified with 1 N HCl solution and stirred for 10 min. The product precipitated, filtered, washed with dichloromethane, dried over sodium sulfate, and concentrated to give a crude product of 4-{1-[(tributyloxy)carbonyl]piperidin-4-yl}-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (520 mg, 94% yield) as an off-white solid; MS (ES) m/z 309.1 (M-1H) ⁺ . Step 6. Preparation of 1- methyl -4-( piperidin- 4- yl )-1H-1,2,3- triazole -5- carboxylic acid hydrochloride

To a stirred solution of 4-{1-[(tributyloxy)carbonyl]piperidin-4-yl}-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.6 g, 1.93 mmol) in dichloromethane (20 mL, 312 mmol) was added 1,4-dioxane hydrochloride (1.44 g, 6 eq., 11.6 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the reaction material was concentrated, washed with pentane, and dried under vacuum to obtain the product 1-methyl-4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid hydrochloride (450 mg, crude) as a white solid; MS (ES) m/z 211.1 (M+H) ⁺ . Step 7. Preparation of 4-(1-(4-(1-( methoxycarbonyl ) cyclopropyl ) phenyl ) piperidin -4- yl )-1- methyl -1H-1,2,3- triazole -5-carboxylic acid

To a stirred solution of 1-methyl-4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid hydrochloride (510 mg, 2.07 mmol) in dimethylformamide (15 mL, 194 mmol) was added cesium carbonate (2.69 g, 4 eq., 8.27 mmol), methyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (633 mg, 1.2 eq., 2.48 mmol) and X-phos (98.6 mg, 0.1 eq., 207 µmol) under argon purging for 15 min. Finally, Pd2(dba)3 (94.7 mg, 0.05 eq., 103 µmol) was added and the reaction mixture was heated to 100 °C in a sealed tube for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the 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 the aqueous layer was acidified with 10% citric acid until pH was acidic, then extracted with ethyl acetate (2×100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 4-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (452 mg, yield 56%) as a brown solid; MS (ES) m/z 385.2 (M+1H) ⁺ . Step 8. Preparation of (R)-1-(4-(4-(1- methyl -5-(((1- phenylethoxy ) carbonyl ) amino )-1H-1,2,3- triazol -4- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a stirred solution of 4-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (0.2 g, 520 µmol) in toluene (5 mL) were added triethylamine (79.5 µL, 1.1 eq., 572 µmol) and (1R)-1-phenylethan-1-ol (254 mg, 4 eq., 2.08 mmol) and the reaction mixture was heated to 50 °C for 20 min. Then DPPA (124 µL, 1.1 eq., 572 µmol) was added and heated to 85 °C for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was diluted with water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (41% to 70%) in n-hexane to give methyl 1-(4-{4-[1-methyl-5-({[(1R)-1-phenylethoxy]carbonyl}amino)-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (108 mg, 41% yield); MS (ES) m/z 504.3 (M+H) ⁺ . Step 9. Preparation of (R)-1-(4-(4-(1- methyl -5-(((1- phenylethoxy ) carbonyl ) amino )-1H-1,2,3- triazol -4- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-(4-{4-[1-methyl-5-({[(1R)-1-phenylethoxy]carbonyl}amino)-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (0.1 g, 199 µmol) 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 µmol) in water (1.96 mL, 109 mmol) at 0°C and stirred for 10 minutes. The reaction was finally maintained at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mass was concentrated to give the crude product. The obtained crude material was acidified with 10% citric acid and stirred for 10 minutes. The product was precipitated, filtered and washed with pentane (10 mL) to give the product 1-(4-{4-[1-methyl-5-({[(1R)-1-phenylethoxy]carbonyl}amino)-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (55 mg, crude) as an off-white solid; MS (ES) m/z 430.3 (M+1H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.89 (s, 1H), 7.81 (d, J = 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). Example 14. Preparation of 1-(4-{4-[5-({[(1R)-1-(2- chlorophenyl ) ethoxy ] carbonyl } amino )-1- methyl -1H-1,2,3- triazol -4- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid ( Compound 27) Step 1. Preparation of tert-butyl 4-(2,2- dibromovinyl ) piperidine -1- carboxylate

To a stirred solution of tetrabromomethane (15.5 g, 2 eq., 46.9 mmol) in dichloromethane (50 mL) was added a solution of triphenylphosphine (24.6 g, 4 eq., 93.8 mmol) in dichloromethane (50 mL) dropwise at 0°C, and the same temperature was maintained for 20 minutes, followed by a solution of tributyl 4-formylpiperidine-1-carboxylate (5 g, 23.4 mmol) in dichloromethane (50 mL) dropwise at 0°C, and the mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was diluted with diethyl ether (200 ml), and the precipitate was filtered off. The filtrate was concentrated in vacuo to obtain a crude substance. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 10%) in n-hexane to afford tri-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (4.5 g, 52% yield) as an off-white solid; MS (ES) m/z 269.0 (M+H) ⁺ , (M-100, boc mass fragmented in LCMS).

¹ H NMR (400 MHz, CDCl ₃ ): δ 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). Step 2. Preparation of 4-(3- ethoxy- 3- oxoprop- 1- yn -1- yl ) piperidine -1- carboxylic acid tributyl ester

To a stirred solution of tributyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (5 g, 13.5 mmol) in THF (100 mL) was added 1.6 M n-butyl lithium 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 hour and at 0°C for 1 hour. Ethyl chloroformate (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 at room temperature and continued to stir for 8 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the resulting mixture was quenched with ice-cold water (100 mL) and extracted with ethyl acetate (2×50 mL). The extract was washed with brine, dried and evaporated. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 15%) in n-hexane to give tributyl 4-(3-ethoxy-3-oxoprop-1-yn-1-yl)piperidine-1-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).

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.21 (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). Step 3. Preparation of tributyl 4-(5-( ethoxycarbonyl )-1-(( trimethylsilyl ) methyl )-1H-1,2,3- triazol -4- yl ) piperidine -1- carboxylate

To a stirred solution of tributyl 4-(3-ethoxy-3-oxoprop-1-yn-1-yl)piperidine-1-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 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by normal phase silica gel column chromatography using ethyl acetate-hexane (10% to 15%) as the eluting solvent to give two major fractions. The distribution regiochemistry was studied by 1H NOE. One fraction was tert-butyl 4-[5-(ethoxycarbonyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (324 mg, 44% yield) as a light yellow liquid and the other major fraction was tert-butyl 4-[4-(ethoxycarbonyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-5-yl]piperidine-1-carboxylate (254 mg, 34% yield) as a white solid; LC-MS (M + H) ⁺ 411.3 (m/z). Step 4. Preparation of tert-butyl 4-(5-( ethoxycarbonyl )-1- methyl -1H-1,2,3- triazol -4- yl ) piperidine -1- carboxylate

To a stirred solution of tributyl 4-[5-(ethoxycarbonyl)-1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (320 mg, 779 µmol) in tetrahydrofuran (7 mL, 86 mmol) was added water (28.1 mg, 2 eq., 1.56 mmol) and tetrabutylazonium fluoride (245 mg, 1.2 eq., 935 µmol) at 0°C and maintained at the same temperature for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was purified by combiflash MPLC using ethyl acetate (1% to 25%) in hexane to afford tri-butyl 4-[5-(ethoxycarbonyl)-1-methyl-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (120 mg, 45% yield) as a yellow colloidal solid; MS (ES) m/z 339 (M+H)+ but deboc mass was observed in LCMS MS (ES) m/z 283.2 (M-56) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.34 (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). Step 5. Preparation of 4-(1-( tributyloxycarbonyl ) piperidin -4- yl )-1- methyl -1H-1,2,3- triazole -5-carboxylic acid

To a stirred solution of tributyl 4-[5-(ethoxycarbonyl)-1-methyl-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate (120 mg, 355 µmol) in THF (4 mL) was added lithium hydroxide (1+) hydrate (74.4 mg, 5 eq., 1.77 mmol) dissolved in water (2 mL, 111 mmol) at 0°C and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction material was concentrated to obtain the crude product. The obtained crude material was acidified with 10% citric acid and stirred for 10 minutes. The product precipitated and the precipitated product was filtered and washed with water and pentane. Drying under vacuum gave the product 4-{1-[(tributyloxy)carbonyl]piperidin-4-yl}-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (20 mg, yield 18%) as a white solid; MS (ES) m/z 309.1 (M-1H)+.

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.37 (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). Step 6. Preparation of 1- methyl -4-( piperidin- 4- yl )-1H-1,2,3- triazole -5- carboxylic acid hydrochloride

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

¹ H NMR (400 MHz, CDCl ₃ ): δ 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). Step 7. Preparation of 4-(1-(4-(1-( methoxycarbonyl ) cyclopropyl ) phenyl ) piperidin- 4- yl )-1- methyl -1H-1,2,3- triazole -5- carboxylic acid

To a stirred solution of 1-methyl-4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid hydrochloride (240 mg, 973 µmol) in dimethylformamide (6 mL, 62 mmol) was added cesium carbonate (1.27 g, 4 eq., 3.89 mmol), methyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (298 mg, 1.2 eq., 1.17 mmol) and X-phos (46.4 mg, 0.1 eq., 97.3 µmol) and the mixture was purged under argon for 15 min. Finally Pd ₂ (dba) ₃ (44.5 mg, 0.05 eq., 48.6 µmol) was added and the reaction mixture was heated to 100 °C in a sealed tube for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the 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 the aqueous layer was acidified with 10% citric acid until pH was acidic (3-4), then extracted with ethyl acetate (2×20 mL), washed with water (20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 4-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (232 mg, yield 62%) as a brown gummy solid; MS (ES) m/z 385.2 (M+1H) ⁺ . Step 8. Preparation of 1-(4-{4-[5-({[(1R)-1-(2- chlorophenyl ) ethoxy ] carbonyl } amino )-1- methyl -1H-1,2,3- triazol -4- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a stirred solution of 4-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (230 mg, 598 µmol) in toluene (6 mL, 3.26 mmol) was added TEA (167 µL, 2 eq., 1.2 mmol) and (1R)-1-(2-chlorophenyl)ethan-1-ol (281 mg, 3 eq., 1.79 mmol) and the reaction mixture was heated to 50 °C for 20 min. Then, {[azido(phenoxy)phosphatyl]oxy}benzene (329 mg, 2 eq., 1.2 mmol) was added. The mixture was stirred at 85 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mass was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×10 mL), brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a crude material. The crude product was used in the next step without purification to obtain methyl 1-(4-{4-[5-({[(1R)-1-(2-chlorophenyl)ethoxy]carbonyl}amino)-1-methyl-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (480 mg) as a yellow liquid; MS (ES) m/z 538.2 (M+H)+. Step 9. Preparation of 1-(4-{4-[5-({[(1R)-1-(2- chlorophenyl ) ethoxy ] carbonyl } amino )-1- methyl -1H-1,2,3- triazol -4- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-(4-{4-[5-({[(1R)-1-(2-chlorophenyl)ethoxy]carbonyl}amino)-1-methyl-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (0.5 g, 9.1 eq., 929 µmol) in oxocyclopentane (3 mL), methanol (3 mL, 156 mmol) solution was added lithium hydroxide (1+) hydrate (260 mg, 61 eq., 6.2 mmol) in water (3 mL) and the mixture was stirred at room temperature for 18 h. The reaction progress was monitored by LCMS and TLC. After the reaction was completed, the reaction mixture was concentrated, diluted with water (10 mL), washed with ether (2×10 mL), and the pH was adjusted to 3 to 4 with 10% aqueous citric acid solution. A white solid precipitated and was filtered on a Buchner funnel. The solid was washed with water (2×10 mL), pentane (2×10 mL) and dried under vacuum to obtain a crude material. The crude material was purified by preparative HPLC. Mobile phase (A): water containing 0.1% formic acid

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

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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, J = 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).

Preparative conditions: Column: X-Select C18 (19 mm×250 mm×5 mic), mobile phase (A): water containing 0.1% FA, mobile phase (B): acetonitrile, flow rate: 19 ml/min Example 15. Preparation of (S)-1-(4-(4-(5-(((1-(2-( methoxymethyl ) phenyl ) ethoxy ) carbonyl ) amino ) -1- methyl -1H-1,2,3- triazol -4- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 24) Step 1. Preparation of 2-( methoxymethyl ) benzaldehyde

To a solution of 1-bromo-2-(methoxymethyl)benzene (2 g, 9.95 mmol, 1 eq) in THF (5 mL) was added n-BuLi (2.5 M, 6 mL, 1.51 eq) at -70°C and stirred for 1 hour, then to the resulting mixture was added DMF (1.90 g, 25.99 mmol, 2.00 mL, 2.61 eq) and stirred for 1 hour at -70°C. TLC (PE/EA=3:1, Rf=0.5) showed that a new spot was detected and 1-bromo-2-(methoxymethyl)benzene was consumed. The reaction mixture was quenched by adding saturated NH ₄ Cl (30 mL), partitioned between EtOAc (60 mL×3) and water (80 mL), washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 3/1) to give 2-(methoxymethyl)benzaldehyde (1.2 g, 7.99 mmol, 80.33% yield) as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 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). Step 2. Preparation of 1-[2-( methoxymethyl ) phenyl ] ethanol

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, and the resulting mixture was stirred at 25°C for 1 hour. TLC (PE/EA=3:1, Rf=0.3) showed that a new spot was detected and 2-(methoxymethyl)benzaldehyde was consumed. The reaction mixture was quenched by the addition of saturated NH ₄ Cl (30 mL), partitioned between EtOAc (120 mL) and water (50 mL), washed with brine (70 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 3/1) to give 1-[2-(methoxymethyl)phenyl]ethanol (0.8 g, 4.81 mmol, 60.23% yield) as a colorless oil. ¹ H NMR (400 MHz, chloroform-d) δ = 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, J = 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, J = 6.5 Hz, 3H). Step 3. Preparation of 1-[4-[4-[5-[1-[2-( methoxymethyl ) phenyl ] ethoxycarbonylamino ]-1- methyl - triazol -4- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylic acid ethyl ester

To a solution of 5-[1-[4-(1-ethoxycarbonylcyclopropyl)phenyl]-4-piperidinyl]-3-methyl-triazole-4-carboxylic acid (200 mg, 501.94 μmol, 1 eq) in toluene (10 mL) at 0 °C were added 1-[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), then the resulting mixture was purged with _N2 three times and stirred at 80 °C for 12 h. LCMS showed the desired MS was detected and 5-[1-[4-(1-ethoxycarbonylcyclopropyl)phenyl]-4-piperidinyl]-3-methyl-triazole-4-carboxylic acid was consumed. TLC (PE/EA=1:1, Rf=0.4) showed a new spot was detected and 5-[1-[4-(1-ethoxycarbonylcyclopropyl)phenyl]-4-piperidinyl]-3-methyl-triazole-4-carboxylic acid was consumed. The reaction mixture was partitioned between EtOAc (150 mL) and water (70 mL), washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by flash silica chromatography (ISCO; 12 g SepaFlash@ silica flash column, eluent 0-60% ethyl acetate/petroleum ether gradient, 40 mL/min) to afford ethyl 1-[4-[4-[5-[1-[2-(methoxymethyl)phenyl]ethoxycarbonylamino]-1-methyl-triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylate (180 mg, 320.47 μmol, 63.85% yield, 100% purity) as a yellow solid. MS m/z: 562.6 [M+H] ⁺ Step 4. Preparation of 1-[4-[4-[5-[1-[2-( methoxymethyl ) phenyl ] ethoxycarbonylamino ]-1- methyl - triazol -4- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylic acid

To a solution of ethyl 1-[4-[4-[5-[1-[2-(methoxymethyl)phenyl]ethoxycarbonylamino]-1-methyl-triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylate (150 mg, 267.06 μmol, 1 eq) in EtOH (1 mL) was added LiOH (2 M, 1 mL, 7.49 eq) and the resulting mixture was stirred at 25 °C for 12 h. LCMS showed the desired MS was detected and ethyl 1-[4-[4-[5-[1-[2-(methoxymethyl)phenyl]ethoxycarbonylamino]-1-methyl-triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylate was consumed. The reaction mixture was acidified to pH = 6 by the addition of AcOH. The reaction mixture was purified by preparative HPLC (Phenomenex luna C ₁₈ 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; gradient: 29%-59% B, over 10 min) and lyophilized to give 1-[4-[4-[5-[1-[2-(methoxymethyl)phenyl]ethoxycarbonylamino]-1-methyl-triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (90 mg, 165.29 μmol, 61.89% yield, 98% purity) as a white solid. MS m/z: 534.4 [M+H] ⁺ Step 5. Preparation of 1-[4-[4-[5-[[(1S)-1-[2-( methoxymethyl ) phenyl ] ethoxy ] carbonylamino ]-1- methyl - triazol -4- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarboxylic acid

1-[4-[4-[5-[1-[2-(methoxymethyl)phenyl]ethoxycarbonylamino]-1- _methyl -triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (6) (80 mg, _149.92 μmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm×30 mm, ₁₀ um); mobile phase: [CO 2 -i-PrOH (0.1% NH 3 H 2 O)]; B %: 50%, isocratic elution mode) to give 1-[4-[4-[5-[[(1R)-1-[2-(methoxymethyl)phenyl]ethoxy]carbonylamino]-1-methyl-triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (30.3 mg, 56.78 μmol, 1 eq) as a white solid. μmol, 37.88% yield, 100% purity) (Rt=1.880 min, 30.3 mg) and 1-[4-[4-[5-[[(1S)-1-[2-(methoxymethyl)phenyl]ethoxy]carbonylamino]-1-methyl-triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (41.5 mg, 74.66 μmol, 49.80% yield, 96% purity) (Rt=2.540 min, 41.5 mg) as a white solid.

¹ H NMR (400 MHz, methanol- _{d 4} ) δ = 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, J = 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] ⁺ Example 16. Preparation of (R)-1-(4-(4-(5-(((1- cyclohexylethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 26) Step 1. Preparation of 1- methyl -4-( piperidin -4- yl )-1H-1,2,3- triazole -5- carboxylic acid hydrochloride

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

To a stirred solution of 1-methyl-4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid hydrochloride (410 mg, 1.66 mmol) in dimethylformamide (10 mL, 129 mmol) was added cesium carbonate (2.17 g, 4 eq., 6.65 mmol), methyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (509 mg, 1.2 eq., 1.99 mmol) and X-phos (79.2 mg, 0.1 eq., 166 µmol) under argon purging for 15 min. Finally Pd ₂ (dba) ₃ (76.1 mg, 0.05 eq., 83.1 µmol) was added and the reaction mixture was heated to 100 °C in a sealed tube for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the 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 the aqueous layer was acidified with 10% citric acid until pH was acidic, then extracted with ethyl acetate (2×100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 4-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid as a brown solid (yield: 330 mg, 52%); MS (ES) m/z 385.2 (M+1H) ⁺ . Step 3. Preparation of 1-(4-{4-[5-({[(1R)-1- cyclohexylethoxy ] carbonyl } amino )-1- methyl -1H-1,2,3- triazol -4- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a solution of 4-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (150 mg, 390 µmol) in toluene (15 mL) were added triethylamine (109 µL, 2 eq., 780 µmol), (1R)-1-cyclohexylethan-1-ol (150 mg, 3 eq., 1.17 mmol), and the reaction mixture was stirred at 50°C. Then, {[azido(phenoxy)phosphatyl]oxy}benzene (101 µL, 1.2 eq., 468 µmol) was added. The mixture was stirred at 85°C for 3 hours. The reaction progressed under TLC, and the reaction mass was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 50%) in n-hexane to give methyl 1-(4-{4-[5-({[(1R)-1-cyclohexylethoxy]carbonyl}amino)-1-methyl-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate as a slightly yellow liquid (yield; 80 mg, 40%). MS (ES) m/z 510.3 (M+H) ⁺ . Step 4. Preparation of (R)-1-(4-(4-(5-(((1- cyclohexylethoxy ) carbonyl ) amino )-1- methyl -1H-1,2,3- triazol -4- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-(4-{4-[5-({[(1R)-1-cyclohexylethoxy]carbonyl}amino)-1-methyl-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (80 mg, 157 µmol) in cyclopentane (2 mL), methanol (2 mL, 156 mmol) was added lithium (1+) hydroxide (26.3 mg, 4 eq, 628 µmol) in water (2 mL) and the mixture was stirred at room temperature for 18 h. The reaction progressed under LCMS and TLC. The reaction mass was concentrated, diluted with water (20 mL), washed with ether (2×10 mL), and the pH was adjusted to 3-4 with 10% aqueous citric acid. A white solid precipitated and was filtered on a Buchner funnel. The solid was washed with water (2×10 mL), pentane (2×10 mL) and dried under vacuum to give 1-(4-{4-[5-({[(1R)-1-cyclohexylethoxy]carbonyl}amino)-1-methyl-1H-1,2,3-triazol-4-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (48 mg, 62% yield) as an off-white solid; MS (ES) m/z 496.4 (M+1H) ⁺ . LC purity at 240 nm: 99.52%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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). Example 17. Preparation of (4-{4-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid ( Compound 87) Step 1. Preparation of (R)-1-(4-(4-(3- methyl -4-(((1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid methyl ester

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

To a stirred solution of methyl 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (55 mg, 0.11 mmol) in THF (2 mL) and methanol (2 mL) was added lithium hydroxide monohydrate (30 mg, 6 eq., 0.7 mmol) dissolved in water (2 mL) at 0 °C and the reaction mass was maintained at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mass was concentrated to give the crude product. The obtained crude material was acidified with 10% citric acid and stirred for 10 min. The product precipitated, filtered, washed with water and pentane, and dried under vacuum to obtain the product 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (48 mg, 88% yield) as an off-white solid; MS (ES) m/z 490.0 (M+H)+; LC purity: 99.5%

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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, J = 8.4 Hz, 3H), 1.37-1.36 (t, J = 2.4 Hz, 2H), 1.04-1.01 (t, J = 2.8 Hz, 2H); Example 18. Preparation of (R)-1-(4-(4-(4-(((1-(2- ethylphenyl ) ethoxy ) carbonyl ) amino )-3 -methylisoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid ( Compound 38) Step 1. Preparation of 5-(1-(4-(1-( methoxycarbonyl ) cyclopropyl ) phenyl ) piperidin -4- yl )-3- methylisoxazole -4- carboxylic acid

To a stirred solution of 3-methyl-5-(piperidin-4-yl)-1,2-oxazole-4-carboxylic acid hydrochloride (2 g, 8.11 mmol) in dimethylformamide (30 mL, 387 mmol) was added cesium carbonate (10.6 g, 4 eq., 32.4 mmol), methyl 1-(4-bromophenyl)cyclopropane-1-carboxylate (2.48 g, 1.2 eq., 9.73 mmol) and X-phos (386 mg, 0.1 eq., 811 µmol) under argon purging for 15 min. Finally, Pd2(dba)3 (371 mg, 0.05 eq., 405 µmol) was added and the reaction mixture was heated to 100 °C in a sealed tube for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the 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 the aqueous layer was acidified with 10% citric acid until pH was acidic, then extracted with ethyl acetate (2×100 mL), washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 5-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (2.5 g, 80%) as a light yellow solid; MS (ES) m/z 385.2 (M+1H) ⁺ . Step 2. Preparation of (R)-1-(4-(4-(4-(((1-(2- ethylphenyl ) ethoxy ) carbonyl ) amino ) -3 -methylisoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a solution of 5-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (150 mg, 390 µmol) in toluene (10 mL, 3.26 mmol) were added TEA (109 µL, 2 eq., 780 µmol), (1R)-1-(2-ethylphenyl)ethan-1-ol (117 mg, 2 eq., 780 µmol) and the reaction mixture was stirred at 50 °C. Then DIPEA (168 µL, 2 eq., 780 µmol) was added. The mixture was stirred at 85 °C for 3 h. The reaction progressed under TLC and the reaction mass was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (18% to 30%) in n-hexane to give methyl 1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (76 mg, 36% yield) as a slightly yellow liquid. MS (ES) m/z 532.3 (M+H) ⁺ . Step 3. Preparation of (R)-1-(4-(4-(4-(((1-(2- ethylphenyl ) ethoxy ) carbonyl ) amino )-3 -methylisoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1-carboxylic acid

To a stirred solution of methyl 1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (70 mg, 132 µmol) in tetrahydrofuran (1.3 mL, 15.9 mmol) and methanol (1.3 mL, 32 mmol) was added LiOH.H2O (22.1 mg, 4 eq, 527 µmol) in water (1.3 mL, 72 mmol) at 0°C and stirred for 10 minutes. The reaction was finally maintained at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mass was concentrated to give the crude product. The obtained crude material was acidified with 10% citric acid and stirred for 10 minutes. The product precipitated. The formed product was filtered and washed with water and pentane. It was then dried under vacuum to obtain the product 1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (40 mg, 59%) as a white solid; MS (ES) m/z 518.4 (M+1H) ⁺ . LCMS purity 98.14%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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). Example 19. Preparation of 1-(4-{4-[4-({[(1R)-1-(2- chlorophenyl ) ethoxy ] carbonyl } amino )-3- methyl -1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid ( Compound 74) Step 1. Preparation of (R)-1-(4-(4-(4-(((1-(2- chlorophenyl ) ethoxy ) carbonyl ) amino ) -3 -methylisoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid methyl ester

{[azido(phenoxy)phosphatyl]oxy}benzene (101 µL, 1.2 eq., 468 µmol) and triethylamine (109 µL, 2 eq., 780 µmol) were added to a solution of 5-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (150 mg, 390 µmol) in toluene (10 mL) at 50 °C. The mixture was stirred at 50 °C for 30 min, followed by the addition of (1R)-1-(2-chlorophenyl)ethan-1-ol (244 mg, 4 eq., 1.56 mmol). The mixture was stirred at 90 °C for 8 h. The reaction progressed under TLC, and the reaction mass was diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2 x 50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product. The crude product was purified by combiflash MPLC using ethyl acetate (1% to 20%) in n-hexane to give methyl 1-(4-{4-[4-({[(1R)-1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (90 mg, 42% yield) as an off-white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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%. Step 2. Preparation of (R)-1-(4-(4-(((1-(2- chlorophenyl ) ethoxy ) carbonyl ) amino )-3 -methylisoxazol- 5- yl ) piperidin - 1- yl ) phenyl ) cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-(4-{4-[4-({[(1R)-1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (70.0 mg, 130 µmol) in THF (5.0 mL), MeOH (5.0 mL) was added lithium (1+) hydroxide (31.2 mg, 10 equiv, 1.30 mmol) in water (5.0 mL) and the mixture was stirred at room temperature for 12 h. The reaction progressed under TLC, and the reaction solution was concentrated to remove ethanol and THF, diluted with water (5 mL) and acidified to pH 5 with citric acid solution, and filtered and dried to give 1-(4-{4-[4-({[(1R)-1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (37.0 mg, 54% yield) as an off-white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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 = 7.1 Hz, 4H), 6.97 (d, J = 6.0 Hz, 5H ) ; = 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, J = 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-{1-[( prop -2- ene -1- sulfonyl ) aminoformyl ] cyclopropyl } phenyl ) piperidin -4- yl ]-1,2- oxazol -4 - yl } carbamate ( Compound 2) Step 1. Preparation of 1-(4-{4-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid methyl ester

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

To a stirred solution of methyl 1-(4-{4-[3-methyl-4-({[(1R)-1-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) dissolved in water (5 mL) at 0°C and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mass was concentrated to give the crude product. The obtained crude material was acidified with 10% citric acid and stirred for 10 minutes. The product precipitated, filtered, and washed with water and pentane. Drying under vacuum gave the product 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (950 mg, 88% yield) as an off- white solid ; MS (ES) m/z 490.2 (M+1H) ⁺ ; Step 3. Preparation of (1R)-1 -phenylethyl N-{3- methyl -5-[1-(4-{1-[( prop -2- ene -1- sulfonyl ) aminocarbonyl ] cyclopropyl } phenyl ) piperidin -4- yl ]-1,2- oxazol -4 - yl } carbamate

To a stirred solution of 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (0.2 g, 409 µmol) in dichloromethane (5 mL, 78.1 mmol) at 0°C were added TEA (113 µL, 2 eq., 817 µmol), EDC.HCL (66.5 mg, 1.5 eq., 613 µmol) and HOBT (82.8 mg, 1.5 eq., 613 µmol) and the reaction mixture was stirred at room temperature for 15 minutes. Finally, prop-2-ene-1-sulfonamide (74.2 mg, 1.5 eq., 613 µmol) was added and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with water and extracted with DCM (2 x 20 mL), washed with water (2 x 20 mL) and brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash MPLC using ethyl acetate (75% to 80%) in n-hexane to give (1R)-1-phenylethyl N-{3-methyl-5-[1-(4-{1-[(prop-2-ene-1-sulfonyl)aminocarbonyl]cyclopropyl}phenyl)piperidin-4-yl]-1,2-oxazol-4-yl}carbamate (148 mg, 61% yield) as a yellow colloidal solid; MS (ES) m/z 593.2 (M+H) ⁺ at 240.0 nm.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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 = 4.8 Hz, 3H), 1.36 (bs, 2H), 1.05 (bs, 2H). Example 21. Preparation of 1-[({[1-(4-{4-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ] piperidin- 1- yl } phenyl ) cyclopropyl ] carboxamido } sulfonyl ) methyl ] cyclopropane -1- carboxylic acid ( Compound 82) Step 1. Preparation of 1-[({[1-(4-{4-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) methyl ] cyclopropane -1- carboxylic acid methyl ester

To a stirred solution of 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (0.3 g, 613 µmol) in tetrahydrofuran (6 mL, 73.7 mmol) at room temperature were added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (99.4 mg, 613 µmol) and DMAP (7.49 mg, 0.1 eq, 61.3 µmol) and the reaction mixture was heated at 70 °C for 2 h. Then it was cooled to room temperature and methyl 1-(aminosulfonylmethyl)cyclopropane-1-carboxylate (118 mg, 613 µmol) and DBU (367 µL, 4 eq., 2.45 mmol) were added at 0°C and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water, extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with water (2×10 mL), sodium bicarbonate solution (10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC, mobile phase (A): 0.1% aqueous ammonia solution, mobile phase (B): acetonitrile to give methyl 1-[({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)methyl]cyclopropane-1-carboxylate (240 mg, 58%) as a white solid; MS (ES) m/z 665.6 (M+1H)+. LC purity 99.72%.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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). Step 2. Preparation of 1-[({[1-(4-{4-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) methyl ] cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-[({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)methyl]cyclopropane-1-carboxylate (0.1 g, 1.2 eq., 150 µmol) in methanol (1 mL, 24.7 mmol) and tetrahydrofuran (1 mL, 12.3 mmol) was added lithium (1+) hydroxide (41.1 mg, 8 eq., 980 µmol) in water (1 mL, 55.5 mmol) and the mixture was stirred at room temperature for 18 hours. The progress of the reaction was monitored by LCMS and TLC. After the reaction was completed, the reaction mixture was concentrated, diluted with water (10 mL), washed with ether (2×10 mL), adjusted to pH 3 to 4 with 10% aqueous citric acid solution, and a white solid precipitated, filtered on a Buchner funnel, and washed with water (2×10 mL), pentane (2×10 The solid was washed with 2% 4-(4-[(4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)methyl]cyclopropane-1-carboxylic acid (45 mg, 56%) as a white solid; MS (ES) m/z 651.5 (M+1H) ⁺ . LC purity 97.10%.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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-({[1-(4-{4-[4-({[(1R)-1-(2- ethylphenyl ) ethoxy ] carbonyl } amino )-3- methyl -1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) propanoic acid ( Compound 37) Step 1. Preparation of (R)-1-(4-(4-(4-(((1-(2- ethylphenyl ) ethoxy ) carbonyl ) amino ) -3 -methylisoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carboxylic acid methyl ester

To a solution of 5-(1-{4-[1-(methoxycarbonyl)cyclopropyl]phenyl}piperidin-4-yl)-3-methyl-1,2-oxazole-4-carboxylic acid (0.4 g, 1.04 mmol) in toluene (10 mL, 3.26 mmol) were added TEA (290 µL, 2 eq., 2.08 mmol), (1R)-1-(2-ethylphenyl)ethan-1-ol (313 mg, 2 eq., 2.08 mmol) and the reaction mixture was stirred at 50 °C for 1 hour. Then DPPA (448 µL, 2 eq., 2.08 mmol) was added and the mixture was stirred at 85 °C for 12 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×20 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (18% to 30%) in n-hexane to give methyl 1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (220 mg, 40% yield) as a slightly yellow liquid. MS (ES) m/z 532.3 (M+H) ⁺ . Step 2. Preparation of 1-(4-{4-[4-({[(1R)-1-(2- ethylphenyl ) ethoxy ] carbonyl } amino )-3- methyl -1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropane -1- carboxylic acid

To a stirred solution of methyl 1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylate (270 mg, 508 µmol) in tetrahydrofuran (4.91 mL, 60.3 mmol) and methanol (4.91 mL, 121 mmol) was added LiOH.H ₂ O (128 mg, 6 eq., 3.05 mmol) in water (4.91 mL, 272 mmol) at 0°C and stirred for 10 min. The reaction mixture was then stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated to give the crude product. The obtained crude material was acidified with 10% citric acid solution and stirred for 10 minutes. The product precipitated. It was filtered, washed with water and pentane. It was then dried under vacuum to give the product 1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (190 mg, 72% yield) as a white solid; MS (ES) m/z 518.4 (M+1H) ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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). Step 3. Preparation of methyl 3-({[1-(4-{4-[4-({[(1R)-1-(2- ethylphenyl ) ethoxy ] carbonyl } amino )-3- methyl -1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) propanoate

To a stirred solution of 1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (186 mg, 359 µmol) in dichloromethane (5 mL, 78.1 mmol) at 0 °C were added triethylamine (146 µL, 3 eq., 1.08 mmol), EDC.HCl (115 mg, 3 eq., 1.08 mmol), HOBT (97.1 mg, 2 eq., 719 µmol) and DMAP (4.39 mg, 0.1 eq., 35.9 µmol) and stirred at room temperature for 15 min. Finally, methyl 3-aminosulfonylpropionate (120 mg, 2 eq., 719 µmol) was added and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water, extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2 x 25 mL), sodium bicarbonate solution (15 mL) and brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product, which was purified by combiflash MPLC using methanol in DCM (5% to 15%) to give methyl 3-({[1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoate (210 mg, 87% yield) as a gummy brown solid; MS (ES) m/z 667.1 (M+1H) ⁺ . Step 4. Preparation of 3-({[1-(4-{4-[4-({[(1R)-1-(2- ethylphenyl ) ethoxy ] carbonyl } amino )-3- methyl -1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) propanoic acid

To a stirred solution of methyl 3-({[1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoate (0.1 g, 150 µmol) in tetrahydrofuran (2.5 mL, 30.7 mmol) and methanol (2.5 mL, 61.7 mmol) was added LiOH.H ₂ O (25.2 mg, 4 eq, 0.6 mmol) dissolved 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. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction mass was concentrated to obtain a crude product. The obtained crude material was acidified with 10% citric acid solution and stirred for 10 minutes. The product was precipitated. The precipitate was filtered, washed with water and pentane, and dried under vacuum to obtain a crude product. The crude material was purified by preparative HPLC using mobile phase (A): water containing 0.1% formic acid and mobile phase (B): ACN to give 3-({[1-(4-{4-[4-({[(1R)-1-(2-ethylphenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoic acid (49 mg, 50% yield) as a white solid; MS (ES) m/z 653.6 (M+1H) ⁺ . LCMS purity 98.20% at 254.0 nm.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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). Example 23. Preparation of (1R)-1-phenylethyl N-(5-{1-[4-(1-{[(1- aminoformylcyclopropyl ) sulfonyl ] aminoformyl } cyclopropyl ) phenyl ] piperidin -4- yl }-3- methyl -1,2- oxazol -4 - yl ) carbamate ( Compound 73 ) Step 1. Preparation of 1-({[1-(4-{4-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ] piperidin -1- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) cyclopropane -1- carboxylic acid methyl ester

To a stirred solution of 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (0.3 g, 613 µmol) in tetrahydrofuran (2 mL, 12.3 mmol) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (149 mg, 1.5 eq., 919 µmol) and DMAP (7.49 mg, 0.1 eq., 61.3 µmol) at room temperature and heated to 70 °C for 2 h. Then it was cooled to room temperature and methyl 1-aminosulfonylcyclopropane-1-carboxylate (165 mg, 1.5 eq., 919 µmol) and DBU (367 µL, 4 eq., 2.45 mmol) were added at room temperature and maintained at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction material was quenched with 1.0N HCl solution (5 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with water (2×20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by combiflash MPLC using ethyl acetate (68% to 70%) in n-hexane to give the product methyl 1-({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)cyclopropane-1-carboxylate (370 mg, 93% yield) as a colorless liquid. MS (ES) m/z 651.0 (M+1H) ⁺ . Step 2. Preparation of (1R)-1- phenylethyl N-(5-{1-[4-(1-{[(1- aminoformylcyclopropyl ) sulfonyl ] aminoformyl } cyclopropyl ) phenyl ] piperidin -4- yl }-3- methyl -1,2- oxazol -4- yl ) carbamate

To a stirred solution of methyl 1-({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)cyclopropane-1-carboxylate (0.1 g, 154 µmol) in THF (5 mL) was added aqueous ammonia (15 µL, 4 eq, 615 µmol) and the reaction mixture was stirred at 60 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the resulting mixture was concentrated to give the crude product. The crude material was purified by preparative HPLC, mobile phase (A): 0.1% aqueous ammonia solution, mobile phase (B): acetonitrile to give (1R)-1-phenylethyl N-(5-{1-[4-(1-{[(1-aminoformylcyclopropyl)sulfonyl]aminoformyl}cyclopropyl)phenyl]piperidin-4-yl}-3-methyl-1,2-oxazol-4-yl)carbamate as an off-white solid (10 mg, 10% yield). MS (ES) m/z 636.5 (M+1H) ⁺ . LC purity at 254 nm: 99.08%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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 =6.4 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). Example 24. Preparation of (1R)-1-phenylethyl N-{5-[1-(4-{1-[(3- hydroxy -2 -methylpropanesulfonyl ) carbamyl ] cyclopropyl } phenyl ) piperidin -4- yl ]-3- methyl -1,2- oxazol -4 - yl } carbamate ( Compound 79 ) Step 1. Preparation of methyl 2- methyl - 3-sulfaminyl propionate

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 was purged under ammonia gas for 30 minutes and stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After the reaction was completed, it was filtered and the filtrate was concentrated under reduced pressure to obtain methyl 2-methyl-3-aminosulfonylpropanoate as a colloidal liquid. (450 mg, 100%: yield). Step 2. Preparation of methyl 2- methyl -3-({[1-(4-{4-[3- methyl -4-({[(1R)-1- phenylethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ] piperidin - 1- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) propanoate

To a stirred solution of 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropane-1-carboxylic acid (0.5 g, 1.02 mmol) in THF (5 mL) at 0°C were added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (248 mg, 1.5 eq., 1.53 mmol) and DMAP (62.4 mg, 0.5 eq., 511 µmol) and stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature and finally methyl 2-methyl-3-aminosulfonylpropionate (204 mg, 1.1 eq., 1.12 mmol) and DBU (610 µL, 4 eq., 4.09 mmol) were added at 0°C and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (2×10 mL), sodium bicarbonate solution (10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain the crude product. The crude material was subjected to preparative HPLC, mobile phase (A): 0.1% aqueous ammonia, mobile phase (B): acetonitrile to afford methyl 2-methyl-3-({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoate (550 mg, 82% yield) as a white solid; MS (ES) m/z 653.5 (M+H) ⁺ . Step 3. Preparation of (1R) -1-phenylethyl N-{5-[1-(4-{1-[(3- hydroxy -2- methylpropanesulfonyl ) carbamoyl ] cyclopropyl } phenyl ) piperidin -4- yl ]-3- methyl - 1,2- oxazol - 4- yl } carbamate

To a stirred solution of methyl 2-methyl-3-({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoate (150 mg, 230 µmol) in tetrahydrofuran (10 mL, 123 mmol) was added LAH (16.1 mg, 2 eq., 460 µmol) at 0°C and stirred at the same temperature for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction material was quenched with water and ethyl acetate and filtered through a celite bed and washed with ethyl acetate, dried over sodium sulfate and concentrated to give a crude product. The crude material was subjected to preparative HPLC, mobile phase (A): 0.1% aqueous ammonia, mobile phase (B): acetonitrile, to give (1R)-1-phenylethyl N-{5-[1-(4-{1-[(3-hydroxy-2-methylpropanesulfonyl)aminoformyl]cyclopropyl}phenyl)piperidin-4-yl]-3-methyl-1,2-oxazol-4-yl}carbamate as a white solid (25 mg, 17% yield); MS (ES) m/z 625.5 (M+H) ⁺ . LC purity at 240 nm 99.52%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.93 (s, 1H), 7.39 - 7.07 (m, 5H), 7.31 (d, J =8.4 Hz, 2H), 6.78 (d, J =8.4 Hz, 2H), 5.75 (q, J = 6.4 Hz, 1H), 4.41 (d, J =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). Example 25. Preparation of 1-[[1-[4-[4-[1- methyl - 5-[[(1R)-1 - phenylethoxy ] carbonylamino ] triazol -4- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonyl ] cyclopropanecarboxylic acid ( Compound 57)

To a solution of ethyl 1-[[1-[4-[4-[1-methyl-5-[[(1R)-1-phenylethoxy]carbonylamino]triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonylamine]cyclopropanecarboxylate (85 mg, 127.86 μmol, 1 eq) in EtOH (2 mL) was added LiOH (2 M, 1 mL, 15.64 eq) and the resulting mixture was stirred at 25 °C for 12 h. LCMS showed the desired MS was detected and tributyl 4-(5-propoxycarbonyl-1H-triazol-4-yl)piperidine-1-carboxylate was consumed. The reaction mixture was acidified to pH = 6 by the addition of AcOH. The reaction mixture was purified by preparative HPLC (Phenomenex luna C ₁₈ 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 29%-59%, 10 min) and lyophilized to give 1-[[1-[4-[4-[1-methyl-5-[[(1R)-1-phenylethoxy]carbonylamino]triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonyl]cyclopropanecarboxylic acid (70 mg, 109.94 μmol, 85.98% yield, 100% purity) as a white solid.

¹ H NMR (400 MHz, methanol-d ₄ ) δ = 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] ⁺ Example 26. Preparation of 2-[[1-[4-[4-[1- methyl -5-[[(1R)-1- phenylethoxy ] carbonylamino ] triazol -4- yl ] -1 -piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonylamine ] acetic acid ( Compound 58)

To a solution of methyl 2-[[1-[4-[4-[1-methyl-5-[[(1R)-1-phenylethoxy]carbonylamino]triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonylamine]acetate (25 mg, 40.02 μmol, 1 eq) in MeOH (2 mL) was added LiOH•H ₂ O (2 M, 0.5 mL, 24.99 eq), and the resulting mixture was stirred at 25 °C for 12 h. LCMS showed the desired MS was detected and methyl 2-[[1-[4-[4-[1-methyl-5-[[(1R)-1-phenylethoxy]carbonylamino]triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonylamine]acetate was consumed. The reaction mixture was acidified to pH = 6 by adding AcOH. The crude product was purified by preparative HPLC (Unisil 3-100 C ₁₈ Ultra 150×50 mm×3 um; mobile phase: [water (FA)-ACN]; B%: 24%-54%, 7 minutes) to give 2-[[1-[4-[4-[1-methyl-5-[[(1R)-1-phenylethoxy]carbonylamino]triazol-4-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonylamine]acetic acid (2.7 mg, 4.29 μmol, 10.72% yield, 97% purity) as a white solid.

¹ H NMR (400 MHz, methanol-d ₄ ) δ = 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 1-[[1-[4-[4-[5-[[(1R)-1-(2- chlorophenyl ) ethoxy ] carbonylamino ]-1- methyl - triazol -4- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonyl ] cyclopropanecarboxylic acid ( Compound 39)

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

¹ H NMR (400 MHz, methanol- _{d 4} ) δ = 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-({[1-(4-{6-[3- methyl -4-({[(1R)-1-(2- methylphenyl ) ethoxy ] carbonyl } amino )-1,2- oxazol -5- yl ]-2 -azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) propanoic acid ( Compound 31) Step 1. Preparation of methyl 3-({[1-(4-{6-[3- methyl -4-({[(1R)-1-(2- methylphenyl ) ethoxy ] carbonyl } amino )-1,2- oxazol -5 - yl ]-2 - azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) propanoate

To a stirred solution of 1-(4-{6-[3-methyl-4-({[(1R)-1-(2-methylphenyl)ethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropane-1-carboxylic acid (130 mg, 252 µmol) in DCM (2 mL) were added triethylamine (105 µL, 3 eq., 756 µmol), DMAP (15.4 mg, 0.5 eq., 126 µmol), EDC.HCl (82.1 mg, 3 eq., 756 µmol) and HOBT (68.1 mg, 2 eq., 504 µmol) and stirred at room temperature for 15 min. Finally, methyl 3-aminosulfonylpropionate (126 mg, 3 eq., 756 µmol) was added and stirred at room temperature for 12 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was quenched with ice-cold water, extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×10 mL), sodium bicarbonate solution (10 mL) and brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product methyl 3-({[1-(4-{6-[3-methyl-4-({[(1R)-1-(2-methylphenyl)ethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoate as a white solid (crude); MS (ES) m/z 665.3 (M+1H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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). Step 2. Preparation of 3-({[1-(4-{6-[3- methyl -4-({[(1R)-1-(2- methylphenyl ) ethoxy ] carbonyl } amino )-1,2- oxazol -5 - yl ]-2 -azaspiro [3.3] heptane -2- yl } phenyl ) cyclopropyl ] formamido } sulfonyl ) propanoic acid

To a stirred solution of methyl 3-({[1-(4-{6-[3-methyl-4-({[(1R)-1-(2-methylphenyl)ethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptan-2-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoate (60 mg, 90.3 µmol) in oxadiazole cyclopentane (2 mL), methanol (2 mL, 156 mmol) was added lithium (1+) hydroxide (15.1 mg, 4 eq, 361 µmol) in water (2 mL) and the mixture was stirred at room temperature for 18 h. The reaction progressed under LCMS and TLC. The reaction mass was concentrated, diluted with water (10 mL), washed with ether (2×10 mL), and the pH was adjusted to 3-4 with 10% aqueous citric acid. A white solid precipitated and was filtered on a Buchner funnel. The solid was washed with water (2×10 mL), pentane (2×10 mL) and dried under vacuum to give 3-({[1-(4-{6-[3-methyl-4-({[(1R)-1-(2-methylphenyl)ethoxy]carbonyl}amino)-1,2-oxazol-5-yl]-2-azaspiro[3.3]heptane-2-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoic acid (35 mg, 60% yield) as an off-white solid; MS (ES) m/z 651.3 (M+1H) ⁺ . LC purity 98.42% at 240 nm.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 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). Example 29. Preparation of 3-[[1-[3- methoxy -4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ] -1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonylamine ] propionic acid ( Compound 1) Step 1. Preparation of dimethyl 2-(4- bromo -3- methoxy - phenyl ) malonate

To a solution of 1-bromo-4-iodo-2-methoxy-benzene (2A) (10 g, 31.96 mmol, 1 eq.) and dimethyl malonate (2B) (23.00 g, 174.09 mmol, 20 mL, 5.45 eq.) in dioxane (200 mL) were added CuI (1.2 g, 6.30 mmol, 1.97e-1 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.), and the reaction mixture was stirred at 110°C for 22 hours. TLC (PE/EtOAc=2/1, Rf=0.24) showed that one major spot was observed. The reactant was extracted with EtOAc (500 mL×3). The combined organic phases were washed with saturated brine (500 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, solvent 0-10% ethyl acetate/petroleum ether gradient, 60 mL/min) to give dimethyl 2-(4-bromo-3-methoxy-phenyl)malonate (2C) (10 g, 31.53 mmol, 98.67% yield) as a yellow oil.

¹ H NMR (400 MHz, CHLOROFORM-d) δ = 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). Step 2. Preparation of methyl 2-(4- bromo -3- methoxy - phenyl ) acetate

To a solution of dimethyl 2-(4-bromo-3-methoxy-phenyl)malonate (2C) (7 g, 22.07 mmol, 1 eq.) in DMSO (100 mL), 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.) were added, and the reaction mixture was stirred at 110°C for 12 hours. TLC (PE/EtOAc=5/1, Rf=0.24) showed that one major spot was observed. The reactant was extracted with EtOAc (300 mL×3). The combined organic phases were washed with saturated NH4Cl (100 mL×3) and saturated brine (300 mL×2), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, solvent 0-10% ethyl acetate/petroleum ether gradient, 40 mL/min) to obtain methyl 2-(4-bromo-3-methoxy-phenyl)acetate (2D) (5.4 g, 20.84 mmol, 94.42% yield) as a yellow oil.

¹ H NMR (400 MHz, CHLOROFORM-d) δ = 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). Step 3. Preparation of 1-(4- bromo -3- methoxy - phenyl ) cyclopropanecarboxylic acid methyl ester

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 hour, then 1,3,2-dioxathiocyclopentane 2,2-dioxide (2E) (5.4 g, 43.51 mmol, 2.09 eq.) was added to the resulting mixture at -40°C and stirred for 1 hour. TLC (PE/EtOAc=10/1, Rf=0.58) showed that one major spot was observed. Saturated NH4Cl (10 mL) was added to the solution while maintaining the temperature at 0°C to 5°C, then the reactant was extracted with EtOAc (20 mL×3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, solvent 0-10% ethyl acetate/petroleum ether gradient, 40 mL/min) to obtain 1-(4-bromo-3-methoxy-phenyl)cyclopropanecarboxylic acid methyl ester (1.7 g, 5.96 mmol, 28.61% yield) as a colorless oil.

¹ H NMR (400 MHz, CHLOROFORM-d) δ = 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). Step 4. Preparation of 1-[3- methoxy -4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropane - carboxylic acid methyl ester

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

To a solution of methyl 1-[3-methoxy-4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylate (120 mg, 224.88 μmol, 1 eq) in MeOH (2 mL) was added LiOH (2 M, 1 mL, 8.89 eq) and the resulting mixture was stirred at 25 °C for 12 h. LCMS showed the desired MS was detected and methyl 1-[3-methoxy-4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylate was 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 1-[3-methoxy-4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (100 mg, 192.46 μmol, 85.58% yield) as a yellow oil, which was used in the next step without further purification. MS m/z: 520.3 [M+H]+ Step 6. Preparation of methyl 3-[[1-[3- methoxy -4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5 -yl ] -1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonyl ] propanoate

To a solution of 1-[3-methoxy-4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid (70 mg, 134.72 μmol, 1 eq) in DCM (3 mL) were added methyl 3-sulfaminylpropanoate (50 mg, 299.07 μmol, 2.22 eq), EDCI (120 mg, 625.97 μmol, 4.65 eq) and DMAP (70 mg, 572.98 μmol, 4.25 eq), and the resulting mixture was stirred at 25 °C for 12 h. LCMS showed that the desired MS was detected and 1-[3-methoxy-4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid was consumed. TLC (PE/EA=1:1, Rf=0.3) showed that a new spot was detected and 1-[3-methoxy-4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarboxylic acid was consumed. The reaction mixture was partitioned between EtOAc (70 mL) and HCl (0.1 N, 40 mL), washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by preparative TLC (SiO 2 , PE: EA = 1:1) to give methyl 3-[[1-[3-methoxy-4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]aminosulfonyl]propanoate (45 mg, 63.25 μmol, 46.95% yield, 94% purity) as a white solid. MS m/z: 669.4 [M+H] +. Step 7. Preparation of 3-[[1-[3- methoxy -4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ]-1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonyl ] propanoic acid

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

¹ H NMR (400 MHz, methanol-d ₄ ) δ = 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] ⁺ . Example 30. Preparation of 2- methyl -2-[[1-[4-[4-[3- methyl -4-[[(1R)-1- phenylethoxy ] carbonylamino ] isoxazol -5- yl ] -1- piperidinyl ] phenyl ] cyclopropanecarbonyl ] sulfonyl ] propanoic acid ( Compound 67)

To a solution of methyl 2-methyl-2-[[1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonylamine]propanoate (50 mg, 76.60 μmol, 1 eq) in MeOH (2 mL) was added LiOH•H ₂ O (2 M, 0.5 mL, 13.06 eq), and the resulting mixture was stirred at 25 °C for 12 h. LCMS showed that methyl 2-methyl-2-[[1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonylamine]propanoate (50 mg, 76.60 μmol, 1 eq) was consumed and the desired MS was detected. The reaction mixture was acidified to pH = 6 by adding AcOH. The reaction mixture was purified by preparative HPLC (Unisil 3-100 C ₁₈ Ultra 150×50 mm×3 um; mobile phase: [water (FA)-ACN]; B%: 46%-76%, 7 min) to give 2-methyl-2-[[1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]isoxazol-5-yl]-1-piperidinyl]phenyl]cyclopropanecarbonyl]sulfonylamine]propanoic acid (15.1 mg, 23.64 μmol, 30.86% yield, 100% purity) as a white solid.

¹ H NMR (400 MHz, methanol- _{d 4} ) δ = 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-(1-(4-(4-(3- methyl -4-(((1- phenylethoxy ) carbonyl ) amino ) isoxazol -5- yl ) piperidin -1- yl ) phenyl ) cyclopropane -1- carbonyl ) sulfonylamine ) propanoic acid ( Compound 78)

To a stirred solution of methyl 2,2-dimethyl-3-({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoate (25 mg, 37.5 umol) in THF (3.0 mL), MeOH (3.0 mL) solution was added lithium hydroxide (1+) hydrate (6.29 mg, 150 umol) in water (3.0 mL) and the mixture was stirred at room temperature for 18 hours. The reaction progress was monitored by LCMS and TLC. After the reaction was complete, the reaction mixture was concentrated, diluted with water (10 mL), washed with ether (2×5 mL), adjusted to pH 3-4 with 10% aqueous citric acid, a white solid precipitated, filtered on a Buchner funnel, washed with water (2×5 mL), pentane (2×5 mL) and dried under vacuum to give 2,2-dimethyl-3-({[1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]piperidin-1-yl}phenyl)cyclopropyl]carboxamido}sulfonyl)propanoic acid (5 mg, 21% yield) as an off-white solid; MS (ES) m/z 653.5 (M+1H)+. LC purity at 240 nm: 99.43%. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 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,1H), 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). Additional exemplary compounds of formula (I)

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 similarly 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 with modifications within the purview of one skilled in the art. Biological Examples Ca ²⁺ Flux Analysis Procedure

B103 cells stably expressing hLPAR1 were seeded at a density of 1.0×10 ⁵ cells/well in a clear flat-bottom black 96-well plate and incubated overnight in complete medium. The next day, cells were pre-incubated in serum-free medium for 2 hours to ensure cell equilibrium. To load calcium-sensitive fluorescent dyes, cells were treated with 5 μM concentration of 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 at room temperature (RT) for 40 minutes. Test compounds prepared in DMSO were then added to each well and incubated for 20 minutes at room temperature. To induce calcium release, LPA was introduced at a concentration of 5 μM in HBSS supplemented with 20 mM HEPES and 0.3% fatty acid-free bovine serum albumin. Intracellular calcium mobilization was then quantified by monitoring the fluorescence intensity using a Spark® Multimode Microplate Reader (TECAN).

To monitor cell migration, Neuroprobe ChemoTx® system plates (10 mm pore size, 5.7 mm diameter sites; Gaithersburg, MD, USA) were used. To induce cell migration, LPA or vehicle at a concentration of 5 μM in DMEM was loaded into the bottom chamber. A total of 15,000 A2058 cells (starved for 24 h after treatment with test compounds or vehicle) were then applied to the upper membrane coated with 0.001% fibronectin. The plates were incubated for 4 to 8 h to allow cell migration. After incubation, the plates were disassembled and the migrated cells were visualized by crystal violet staining. The area stained 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) Analysis A. Test Articles 1. Prepare stock solutions of test article (assay agent compound) in DMSO. 2. All final analytical solutions of probe substrate, reference inhibitor, or test article contain 0.5% (v/v) DMSO (vehicle control). 3. The test article concentrations in the transport studies are specified in the Experimental Conditions Summary Table of this protocol. Table 1. Summary of Experimental Conditions: Test system Sf9 insect cell vesicles expressing BSEP Probe substrate (transfer positive control) BSEP: 1 µM [3H]-taurocholic acid Reference inhibitor (positive control of inhibition) BSEP: 300 µM Rifampicin Test article concentration 10 µM Pre-incubation time (minutes) 10 Cultivation time (minutes) 15 B. Materials 1. Bovine serum albumin (BSA) 2. Dimethyl sulfoxide (DMSO) 3. BSEP assay uptake buffer (10 mM HEPES-Tris pH 7.4, 0.1 M KNO ₃ , 12.5 mM Mg(NO ₃ ) ₂ , 50 mM sucrose) 4. BSEP wash buffer (10 mM Tris-HCl pH 7.4, 0.1 M KNO ₃ , 50 mM sucrose) 5. BSEP blocking buffer (BSEP wash buffer + 0.5 mg/mL BSA) 6. 25 mM Mg-ATP solution 7. 25 mM AMP solution 8. Corning Costar 96-well flat-bottom, untreated, white assay plate (Corning catalog number 3912) 9. Millipore Multiscreen _HTS filter plates, glass fiber FB-1.0/0.65 µm (Cat. No. MSFBN6B10 or glass fiber FC-1.2/0.65 µm (Cat. No. MSFCN6B10) 10. Millipore Multiscreen _HTS vacuum manifold (Cat. No. MSVMHTS00) 11. Probe substrates listed in Table 1 12. Reference inhibitors listed in Table 1 13. Test Articles C. Transport Studies of BSEP 1. Test System: a. 96-well flat bottom plates containing vesicle suspension and corresponding 96-well glass fiber filter plates. b. Transport experiments were performed in assay uptake buffer. c. Transport experiments were initiated by adding Mg-ATP or AMP to the appropriate wells. d. Each condition was run in triplicate wells. 2. Prepare a 96-well flat-bottom assay plate. a. Incubate the assay plate with blocking buffer at 37°C for 60 minutes with orbital shaking at approximately 90 rpm. ( Note: This is done to prevent nonspecific binding of vesicles to the polystyrene assay plate ). b. After 60 minutes, completely remove blocking buffer from the assay plate. c. Add assay uptake buffer solution to the wells of the assay plate as follows: i. For probe substrate transport assays, assay uptake buffer contains the specified concentrations of vesicles and probe substrate. ii. For reference inhibition assays, assay uptake buffer contains vesicles, reference inhibitor, and probe substrate at the concentrations specified in Table 1. iii. For test article assays, assay uptake buffer contains vesicles, test article, and probe substrate at the concentrations specified in Table 1. 3. Incubate at 37°C with orbital shaking at approximately 90 rpm for the time periods specified in Table 1 of this protocol. 4. Using a 25 mM Mg-ATP or AMP stock solution, add Mg-ATP or AMP to the assay wells of a flat-bottom assay plate to a final concentration of 5 mM. 5. Incubate at 37°C with orbital shaking at approximately 90 rpm for the time periods specified in Table 1 of this protocol. 6. Prepare 96-well glass fiber filter plates: a. Incubate the filter plate with blocking buffer for 2 minutes at room temperature without vacuum. b. Turn on the vacuum and filter the blocking buffer through the plate. c. With the vacuum turned on, wash the filter plate with ice-cold wash buffer. 7. At the end of the designated incubation time indicated in Table 1 of this protocol, quench vesicle transport by adding ice-cold wash buffer to the samples in the 96-well assay plate. 8. Mix the analytical sample (now diluted in wash buffer) with a pipette and transfer 175 µL to a 96-well glass fiber filter disk to separate the vesicles from the buffer by applying a vacuum. 9. Wash the wells of the filter disk with ice-cold wash buffer. 10. Dry the filter disk under vacuum. 11. Transfer the filter to the scintillation sample disk and add 700 µL of scintillation buffer to the above sample. 12. Count the above sample on a 1450 Microbeta (Perkin-Elmer). D. Analysis, Data Analysis, and Reporting 1. Quantify the amount of substrate by radiometric detection on a 1450 Microbeta (Perkin-Elmer). 2. For transport study samples run in triplicate, report the mean and standard deviation of replicate experiments. 3. For BSEP, calculate the ATP-dependent substrate transport rate (V) in Sf9 vesicles containing the transporter by subtracting the average substrate accumulation in vesicles treated with AMP from the substrate accumulation in vesicles treated with ATP: ATP-dependent transport rate (pmol/min/mg) = ((vesicle accumulation) _ATP - (average vesicle accumulation) _AMP )/incubation time 4. The percent inhibition in the presence of the test article or reference inhibitor is calculated as follows: Percent Inhibition = 100-(100×(ATP-dependent transport rate) _inhibitor /(ATP-dependent transport rate) _{vehicle control} ) 5. For vesicle analysis, statistical analysis was performed using unpaired t-test between transporter-mediated uptake rate or ATP-dependent transport rate of probe substrate in vehicle control and inhibitor. p-values < 0.05 were considered statistically significant. 6. Unless otherwise stated, all reported data are based on the nominal concentrations used. 7. Data and calculated values are presented to 3 significant figures with rounding used only for final presentation. 8. BSEP inhibition % is for 10 µM test compound 9. BSEP inhibition was determined at BioIVT.

The following table (Table B) lists the results of exemplary compounds tested in the Ca2 ⁺ flux and tactility assays as described above, wherein _IC50 values are listed in the following ranges: Ca2 ⁺ assay _IC50 : D ≥ 3000 nM > C ≥ 200 nM > B ≥ 10 nM >A; tactility _IC50 : D ≥ 5000 nM > C ≥ 500 nM > B ≥ 100 nM > A. Liver microsomal stability is the percentage of parent compound remaining after 30 minutes of incubation with mouse (M), rat (R) or human (H) liver microsomes, and the percentage range is D ≤ 25% < C ≤ 50% < B ≤ 75% < A. BSEP inhibition % is at 10 µM test compound, the inhibition percentage range is A ≤ 25% ＜ B ≤ 50% ＜ C ≤ 75% ＜ D ≤ 100%. Table B Compound No. Calcium analysis Trend Liver microsomal stability (%) * Buspirone remaining after 30 minutes % BSEP inhibition at 10 µM IC ₅₀ (nM) IC ₅₀ (nM) Mouse Rat Human R-1 B A A A A D R-2 B C D 1 A A 2 A A 3 A D 4 A C 5 B C 6 B C A A 7 A A D 8 A B B B C 9 A B C 10 B A A A B 11 B B 12 B A B A B 13 D D B D 14 A A 15 C C 16 B C 17 A C A 18 C C 19 A A C 20 B B D twenty one B A A A twenty two B B B B twenty three B C A A B twenty four A B 25 B D A A 26 A C 27 A A 28 B C 29 C C 30 B C 31 B A 32 C D 33 A A D 34 B A 35 A A B C 36 A A 37 A A C 38 A A A C C 39 A A 40 B B 41 A B 42 B A 43 B B 44 B B 45 B B 46 A C 47 C C 48 B A 49 B C 50 A A 51 A C 52 A A 53 A C 54 B A B 55 B B B 56 A B 57 A A 58 B B A 59 A B A 60 B B A 61 A A C 62 B B A A B 63 A A A 64 A A C B D 65 B B C 66 A A 67 A A A A B 68 A A 69 A A 70 A A A A 71 A A B 72 A A A 73 A A 74 A A C 75 A A 76 A B 77 A A 78 A A B 79 A A B 80 A A B A B 81 A A 82 A A 83 A A A A A 84 A B A B A 85 A A B A A 86 A B A A C 87 A A A A B 88 A A 89 A B 90 B B B 91 D B 92 B A D 93 B A C 94 A A B B D 95 B B B 96 B C 97 C C

R-1 and R-2 are selected reference compounds included for comparison.

Claims (44)

A compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: ^RA is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; Ring B is a 3-7 membered heterocyclic group or a 5-6 membered heteroaryl group; Ring C is a phenyl group or a 5-6 membered heteroaryl group; m is 0 or 1; n is 0, 1, 2 or 3; each ^R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, a 3-7 membered heterocyclic group and a 5-6 membered heteroaryl group; or two ^R1 together with the atoms to which they are attached form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group; each ^R2 is independently selected from C1-C6 alkyl, C1-C6 halogenalkyl, C1-C6 alkoxy and halogen; R ^R is selected from: (i) hydrogen, (ii) C1-C6 alkyl optionally substituted with 1-2 independently selected ^RE , (iii) C6-C10 aryl optionally substituted with hydroxy, (iv) C5-C10 cycloalkyl, (v) 5-6 membered heteroaryl optionally substituted with phenyl, and (vi) 5-6 membered heterocyclo optionally substituted with phenyl; each ^RE is independently selected from: (i) hydroxy; (ii) C1-C6 alkoxy, (iii) phenyl optionally substituted with 1-3 substituents selected from the following: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxy, cyano and halogen, (iv) a 5-10 membered heteroaryl group which is optionally substituted with a C1-C6 alkyl group, and (v) a C3-C10 cycloalkyl group; Q is selected from: (i) a C1-C6 hydroxyalkyl group, (ii) -C(=O)OH, (iii) -S(=O) _2OH , (iv) _a ^{cyano group} , (v) ^-S (O) _2NRA1RB1 , (vi) -NRCS(O) ^2NRA1RB1 , (vii) ^-C (=O)C1- _C6alkoxy ^group which is optionally substituted with -S(=O) ^2NRCRD or a 5-6 membered heterocyclo group which is optionally substituted with a C1-C6 alkyl group; (viii) -C(=O)C6-C10aryloxy group; (ix) -C(=O)-(5-6 membered heterocyclic group) which is optionally substituted with 1-4 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl and -C(=O)OH, (x) -C(=O)NR ^A2 R ^B2 , (xi) a C1-C6 halogen alkyl which is optionally substituted with a hydroxyl group, (xii) a 5-6 membered heteroaryl which is optionally substituted with a hydroxyl group, and (xiii) -C(=O)NHS(=O) ₂ ^RF ; X is selected from -(CH ₂ ) _x NR ^G C(=O)O-, -(CH ₂ ) _x OC(=O)NR ^G -, -(CH ₂ ) _x NR ^G - or -CH(OH)-; ^RA1 and R ^B1 is independently selected from hydrogen and C1-C6 alkyl which is optionally substituted with a hydroxyl group; ^RA2 and ^RB2 are independently selected from hydrogen and C1-C6 alkyl _which is optionally substituted with a hydroxyl group or -S(=O) _2NH2 ; ^RC and ^RD are independently selected from hydrogen and C1-C6 alkyl; ^RF is selected from: (i) C1-C6 alkyl which is optionally substituted with 1-3 substituents selected from the following: (a) hydroxyl, (b) halogen, (c) cyano, (d) C1-C6 alkoxy, (e) a 4-6 membered heterocyclic group which is optionally substituted with a C1-C6 alkyl, (f) -C(=O)OH, (g) -OC(=O)C1-C6 alkyl, (h) -S(=O) _2C1 -C6 alkyl, (i) -C(=O)NR ^A1 R ^B1 , (j) -NR ^C R ^D , (k) -C(=O)C1-C6 aryloxy, (l) C3-C6 cycloalkyl substituted with -C(=O)OH, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, and (m) -C(=O)C1-C6 alkoxy 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 substituted with: (a) C1-C6 alkyl which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, -C(=O)OH, -C(=O)NR ^A1 R ^B1 or -C(=O)C1-C6 alkoxy, (b) cyano, (c) -C(=O)OH, (d) -C(=O)NR ^C R ^D , or (e) -C(=O)C1-C6 alkoxy which is optionally substituted with hydroxy or -C(=O)C1-C6 alkyl, or (f) -NR ^C R ^D , and (vi) -NR ^A3 R ^B3 ; ^RA3 and ^RB3 are independently selected from hydrogen and C1-C6 alkyl; ^RG is H or C1-C3 alkyl; and x is 0 or 1. The compound of claim 1, wherein when ring B is pyridyl, ring B and ring C are connected via the carbon atom of ring C. The compound of claim 1 or 2, wherein ring B is a 3-7 membered heterocyclic group. The compound of any one of claims 1 to 3, wherein ring B is selected from the group consisting of azetidinyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl and azetidinyl spiro[3.3]heptanyl. The compound of any one of claims 1 to 4, wherein ring B is selected from the group consisting of: , , , , , and , where “*” indicates the attachment point to ring A. The compound of any one of claims 1 to 5, wherein ring B is , where “*” indicates the attachment point to ring A. The compound of any one of claims 1 to 6, wherein ring C is a 5-6 membered heteroaryl group. The compound of any one of claims 1 to 7, wherein Ring C is a 5-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl and thiatriazolyl. The compound of any one of claims 1 to 8, wherein ring C is selected from the group consisting of: , , , , , , and , where “*” indicates the attachment point to ring B. The compound of any one of claims 1 to 9, wherein ring C is , where “*” indicates the attachment point to ring B. The compound of any one of claims 1 to 7, wherein ring C is phenylene. The compound of any one of claims 1 to 11, wherein m is 0. The compound of any one of claims 1 to 12, wherein n is 1. The compound of any one of claims 1 to 11 and 13, wherein each R ¹ is an independently selected C 1 -C 6 alkyl group. A compound as claimed in any one of claims 1 to 14, wherein at least one R ² is C1-C6 alkyl. The compound of any one of claims 1 to 15, wherein at least one R ² is methyl. The compound of any one of claims 1 to 16, wherein R ³ is C1-C6 alkyl optionally substituted with 1-2 ^RE . The compound of any one of claims 1 to 17, wherein at least one ^RE is phenyl substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 halogenalkyl, C1-C6 alkoxyalkyl, C1-C6 alkoxy, hydroxy, cyano or halogen. The compound of any one of claims 1 to 18, wherein R ³ is , wherein ^RE is phenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 halogenalkyl, C1-C3 alkoxyalkyl, C1-C63 alkoxy, hydroxy, cyano or halogen. The compound of any one of claims 1 to 19, wherein R ³ is , or . The compound of any one of claims 1 to 20, wherein Q is selected from -C(=O)OH; -S(=O) ₂ OH; 5-6 membered heteroaryl optionally substituted with hydroxyl; and -C(=O)NHS(=O) ₂ ^RF . The compound of any one of claims 1 to 21, wherein Q is -C(=O)OH or -C(=O)NHS(=O) ₂ ^RF . The compound of any one of claims 1 to 22, wherein Q is -C(=O)NHS(=O) ₂ ^RF . The compound of any one of claims 1 to 24, wherein ^{RF is} C1-C6 alkyl substituted with 1-3 substituents selected from the group consisting of hydroxyl; halogen; cyano; C1-C6 alkoxy; a 4-6 membered heterocyclic group optionally substituted with a C1-C6 alkyl; -C(=O)OH; -OC(=O)C1-C6 alkyl; -S(=O) ₂ C1-C6 alkyl; -C(=O)NR ^A1 R ^B1 ; -NR ^C R ^D ; -C(=O)C1-C6 aryloxy; optionally substituted with -C(=O)OH, cyano, C1-C6 hydroxyalkyl, -C(=O)NR ^A1 R ^B1 is a C3-C6 cycloalkyl group substituted with a hydroxyl group or a -C(=O)C1-C6 alkyl group, or a -C(=O)C1-C6 alkoxy group substituted with a hydroxyl group or a -C(=O)C1-C6 alkyl group. The compound of any one of claims 1 to 24, wherein ^RF is C1-C6 alkyl substituted with C(=O)OH or -C(=O)C1-C6 alkoxy. The compound of any one of claims 1 to 23, wherein ^RF is C2-C6 alkenyl. The compound of any one of claims 1 to 22, wherein Q is -C(=O)OH. The compound of any one of claims 1 to 22, wherein Q is -NR ^A3 R ^B3 . ^{The compound of any one of claims 1 to 28, wherein X is -(CH2)xNRGC} _{( =} O)O-. The compound of any one of claims 1 to 29, wherein X is -NHC(=O)O-. The compound of any one of claims 1 to 28, wherein X is -(CH ₂ ) _x OC(=O)NR ^G -. The compound of any one of claims 1 to 28 or 31, wherein X is -OC(=O)NH-. The compound of any one of claims 1 to 28, wherein X is -(CH ₂ ) _x NR ^G -. The compound of any one of claims 1 to 28 or 33, wherein X is -NH-. The compound of any one of claims 1 to 28, wherein X is -CH(OH)-. The compound of claim 1, wherein formula (I) is formula (Ia): (Ia) or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein formula (I) is formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein formula (I) is formula (Ic): (Ic) or a pharmaceutically acceptable salt thereof, wherein Z is CH, N, O or S; V is C or N; and wherein when V is C, Z is O or S. The compound of claim 1, wherein formula (I) is formula (Id): (Id) or a pharmaceutically acceptable salt thereof, wherein Q is -CO ₂ H or -C(=O)NHS(=O) ₂ ^RF ; and Z is O or S. The compound of claim 1, wherein formula (I) is formula (Ie): (Ie) or a pharmaceutically acceptable salt thereof, wherein Q is -CO ₂ H or -C(=O)NHS(=O) ₂ ^RF ; Z is CH, N, O or S; V is C or N; and wherein when V is C, Z is O or S. The compound of claim 1, wherein formula (I) is formula (If): (If) or a pharmaceutically acceptable salt thereof, wherein Q is -CO ₂ H or -C(=O)NHS(=O) ₂ ^RF ; Z is CH, N, O or S; V is C or N; and wherein when V is C, Z is O or S. A compound selected from the group consisting of the compounds in Table A or a pharmaceutically acceptable salt of any of the foregoing. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method for 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 to 42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43.