LPAR1 inhibitors

Abstract

To provide LPAR1 inhibitors.SOLUTION: Compounds of Formula (I), compounds of Formula (II), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same are provided herein. Also provided is a method of treating or preventing a disease or condition, the method comprising administering to a subject in need of treatment or prevention of the disease or condition a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II).SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 637,200, filed April 22, 2024, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Lysophosphatidic acid receptor 1 (LPAR1) signaling has been shown to mediate diverse biological functions, including proliferation, platelet aggregation, smooth muscle contraction, inhibition of neuroblastoma cell differentiation, chemotaxis, and tumor cell invasion. Therefore, LPAR1 antagonists may be useful for treating or preventing diseases and disorders associated with LPAR1 signaling. Summary of the Invention [Means for solving the problem]

[0003] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0004] [ka] (In the formula, R a are each independently halo, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -C 1~6 Alkyl, and -C 1~6 haloalkyl; n is 0, 1, or 2; R W are each independently halo, -OR W2 , -NZ2, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or 2 Vicinal RW groups taken together with the atoms to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl; m is 0, 1, 2, or 3; Ring A is an optionally substituted non-aromatic 3- to 7-membered carbocyclylene or non-aromatic 3- to 7-membered heterocyclylene; R W2 is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; Each Z is independently hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl.

[0005] In some embodiments, the A ring is an optionally substituted 4-membered carbocyclyene.

[0006] In some embodiments, each A ring is independently halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C 1~6 alkyl), and -O(C 1~6 haloalkyl).

[0007] In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0008] [ka] (In the formula, Ra are each independently halo, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -C 1~6 Alkyl, and -C 1~6 haloalkyl; n is 0, 1, or 2; R W are each independently halo, -OR W2 , -NZ2, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or 2 Vicinal R W groups taken together with the atoms to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl; m is 0, 1, 2, or 3; X is a bond, or optionally substituted 3- to 7-membered carbocyclylene, 3- to 7-membered heterocyclylene, 3- to 7-membered arylene, 3- to 7-membered heteroarylene, C 1~6 Alkylene, C 2~6 Alkenylene, -CH(3- to 7-membered carbocyclyl)-, -CH(3- to 7-membered heterocyclyl)-, -CH(3- to 7-membered heterocyclyl)alkyl)-, -CH(3- to 7-membered carbocyclyl)alkyl)-, -CH(heteroaryl)-, -CH(aryl)-, -CH(heteroarylalkyl)-, -CH(arylalkyl)-, -CH(C 1~6 alkyl)-, -CH(C 1~6 haloalkyl)-, -CH(C 1~6 hydroxyalkyl)-, -CH(C 1~6 Alkoxy)-, -CH(C 1~6 Alkoxy C 1~6 alkyl)- or -C(OH)(C 1~6 alkyl)-, R W2 is hydrogen, optionally substituted C1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; Each Z is independently hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl.

[0009] In some embodiments, X is an optionally substituted 3- to 7-membered carbocyclylene, 3- to 7-membered heterocyclylene, —CH(3- to 7-membered carbocyclyl)-, —CH(3- to 7-membered heterocyclyl)-, —CH(C 1~6 alkyl), -CH(C 1~6 haloalkyl), or -CH(C 1~6 Alkoxy C 1~6 alkyl).

[0010] In some embodiments, X is an optionally substituted 3- to 7-membered heterocyclylene, —CH(3- to 7-membered heterocyclyl)-, or —CH(C 1~6 Alkoxy C 1~6 alkyl).

[0011] In some embodiments, R a are each independently selected from the group consisting of —Cl and —OCHF2, and n is 2.

[0012] In some embodiments, the compound has the structure of Formula (Ib) or a pharmaceutically acceptable salt thereof:

[0013] [ka] (In the formula, R 1 is hydrogen or C 1~6 is alkyl, R 2 and R3 are each independently hydrogen, halo, optionally substituted (C 1~3 alkyl), or optionally substituted alkoxy (C 1~3 alkyl), or R 2 and R 3 together with the atom to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl.

[0014] In some embodiments, R 1 is hydrogen or methyl.

[0015] In some embodiments, R 2 and R 3 are hydrogen atoms.

[0016] In some embodiments, the compound is selected from the following table:

[0017] [ka]

[0018] In some embodiments, the compound is selected from the following table:

[0019] [ka]

[0020] In some embodiments, the compound is

[0021] [ka] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound is

[0023] [ka] is.

[0024] In some embodiments, the compound is

[0025] [ka] or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compound is

[0027] [ka] is.

[0028] In some embodiments, the compound is a pharmaceutically acceptable salt of the compound.

[0029] [ka]

[0030] In some embodiments, the compound has the structure of Formula (IIb) or a pharmaceutically acceptable salt thereof:

[0031] [ka] (In the formula, R 4 is hydrogen and R 5 is an optionally substituted 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 Alkoxy C 1~6 is alkyl, or R 4 and R 5together with the atoms to which they are attached form an optionally substituted 3- to 7-membered carbocyclylene or an optionally substituted (substituted) 3- to 7-membered heterocyclylene; R 6 and R 7 are each independently hydrogen, halo, optionally substituted (C 1~3 alkyl), or optionally substituted alkoxy (C 1~3 alkyl), or R 6 and R 7 together with the atom to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl.

[0032] In some embodiments, R 4 is hydrogen and R 5 is tetrahydropyranyl or —CH2OCH3, or R 4 and R 5 together with the atoms to which they are attached form a tetrahydropyran ring. 6 and R 7 are each independently hydrogen or fluoro, or R 6 and R 7 together with the atoms to which they are attached form a fused 5-membered heterocyclyl.

[0033] In some embodiments, the compound is selected from the following table:

[0034] [ka] TIFF2025165398000013.tif47170

[0035] In some embodiments, the compound is selected from the following table:

[0036] [ka]

[0037] In some embodiments, the compound is

[0038] [ka] or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the compound is

[0040] [ka] is.

[0041] In some embodiments, the compound is

[0042] [ka] or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the compound is

[0044] [ka] is.

[0045] In some embodiments, the compound is a pharmaceutically acceptable salt of the compound.

[0046] [ka]

[0047] In some embodiments, the compound is

[0048] [ka] or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the compound is

[0050] [ka] is.

[0051] In some embodiments, the compound is a pharmaceutically acceptable salt of the compound.

[0052] [ka]

[0053] In certain aspects, provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a compound of Formula (II) and a pharmaceutically acceptable carrier.

[0054] In some aspects, provided herein are methods for treating or preventing a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II), wherein the disease or condition is treated by inhibition of LPAR1.

[0055] In some aspects, provided herein are methods of treating a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II), wherein the disease or condition is treated by inhibiting LPAR1. In some embodiments, the disease or condition is systemic sclerosis.

[0056] In certain aspects, provided herein are methods of inhibiting LPAR1, comprising administering to a subject an effective amount of a compound of formula (I) or a compound of formula (II).

[0057] In certain aspects, provided herein are methods of treating systemic sclerosis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating systemic sclerosis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, provided herein are methods of treating systemic sclerosis in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutically acceptable salt of a compound of the present disclosure.

[0058] In some embodiments, provided herein are methods of treating systemic sclerosis in a subject in need thereof, comprising administering to the subject an effective amount of Compound 15 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating systemic sclerosis in a subject in need thereof, comprising administering to the subject an effective amount of Compound 15. In some embodiments, provided herein are methods of treating systemic sclerosis in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutically acceptable salt of Compound 15. DETAILED DESCRIPTION OF THE INVENTION

[0059] definition The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0060] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a composition as various stereoisomers, e.g., enantiomers and / or diastereomers and / or geometric (cis / trans or E / Z) isomers. For example, a composition may contain a mixture of stereoisomers, including a racemic (equal) mixture, a mixture enriched in one or more stereoisomers, or may contain an individual stereoisomer in substantially pure (>99%) form. As used herein, "enriched" refers to a composition that contains more than 50% (>50%) of a stereoisomer relative to the total of other stereoisomers that may be present in the composition. In certain embodiments, a composition may contain >60%, >65%, >70%, >75%, >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%, >99.5%, >99.9%, or even up to 100% of one stereoisomer relative to the total amount of other stereoisomers that may be present in the composition. A composition may contain 0%, or less than 0.1% (<0.1%), <0.5%, <1%, <2%, <3%, <4%, <5%, <6%, <7%, <8%, <9%, <10%, <15%, <20%, <25%, <30%, <35%, <40%, <45%, or <50% of one stereoisomer relative to the total of other stereoisomers that may be present in the composition. For simplicity, if any of the stereoisomers is provided as a pharmaceutically acceptable salt in the composition, the enrichment calculation is based on the assumed amount of the free base form. In certain embodiments, the composition is enriched in its (S)-enantiomer. In other embodiments, the composition is enriched in its (R)-enantiomer.

[0061] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms, for example, the replacement of hydrogen with deuterium or tritium; 19 F 18 Replacement of carbon by F 13 C- or 14Replacement of C-enriched carbon and / or oxygen atoms 18 Compounds having the present structure except for the replacement by O are within the scope of this disclosure.

[0062] When various values ​​are listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0063] "Heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or oxygen, nitrogen, or sulfur.

[0064] "Alkyl" refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C for straight chain). 1~30 , C for branched chain 3~30 ), or up to about 20, or up to 10 carbon atoms. In certain embodiments, the term "alkyl" refers to C 1~10 In certain embodiments, the term "alkyl" refers to a C 1~6 Alkyl groups, such as C 1~6 refers to a straight chain alkyl group. In certain embodiments, the term "alkyl" refers to a C 3~12In certain embodiments, the term "alkyl" refers to a C 3~8 This refers to a branched chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0065] "Alkylene" refers to a divalent alkyl group.

[0066] "Haloalkyl" refers to an alkyl group, as defined herein, in which some or all of the hydrogens have been replaced with halogen, such as fluoro, bromo, chloro, or iodo.

[0067] "Carbocyclyl" or "carbocyclic" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon group containing 3 to 12 carbon atoms (i.e., 3-12 members), which is fully saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). In some embodiments, the carbocyclyl is 3-6 members, 3-7 members, 4-6 members, or 4 members. Examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic carbocyclyl ring systems include bridged monocyclic rings, fused bicyclic rings, and spirocyclyl bicyclic rings. Bridged monocyclic rings include monocyclic carbocyclyl rings in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge of an additional 1 to 3 carbon atoms (i.e., —(CH) w-, where w is 1, 2, or 3. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. A fused bicyclic carbocyclyl ring system comprises a monocyclic carbocyclyl ring fused to an aryl, a monocyclic carbocyclyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. A spirocyclyl bicyclic ring system refers to a bicyclic cycloalkyl ring system in which the two rings are joined by a single atom, such as a quaternary carbon atom. A bridged, fused, or spirocyclyl bicyclic carbocyclyl is attached to the parent molecular moiety through any carbon atom contained within the carbocyclyl ring system. Exemplary spirocyclyl bicyclic ring systems include, but are not limited to, spiro[2.2]pentane, spiro[3.3]heptane, spiro[4.4]nonane, spiro[2.3]hexane, and spiro[3.4]octane.

[0068] "Carbocyclylene" refers to a divalent carbocyclyl group.

[0069] "Heterocyclyl" or "heterocyclic" refers to non-aromatic ring systems, including but not limited to monocyclic, bicyclic, and tricyclic rings, having 3 to 12 atoms, including at least one heteroatom such as nitrogen, oxygen, or sulfur, which may be fully saturated or may contain one or more units of unsaturation, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system. In some embodiments, the heterocyclyl is 3 to 6-membered, 3 to 7-membered, 4 to 6-membered, or 4-membered. Bicyclic heterocyclyl ring systems include bridged monocyclic rings, fused bicyclic rings, and spirocyclyl bicyclic rings. Fused bicyclic heterocyclyl ring systems include a monocyclic heterocyclyl ring fused to an aryl, a monocyclic carbocyclyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. A spirocyclyl bicyclic ring system refers to a bicyclic heterocycloalkyl ring system in which the two rings are joined by a single atom, such as a quaternary carbon atom. A bridged or fused or spirocyclyl bicyclic heterocyclyl is attached to the parent molecular moiety through any atom contained within the heterocyclyl ring system.For illustrative purposes, which should not be construed as limiting the scope of the invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolinyl. aryl, isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, trithianyl, and 2-azobicyclo[3.1.0]hexane.

[0070] The term "heterocyclylene" refers to a divalent heterocyclyl group.

[0071] "Aryl" refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene, and pyrene. In some embodiments, an aryl group contains 3 to 7 carbon ring atoms (i.e., a 3- to 7-membered aryl). The term "aryl" also encompasses polycyclic ring systems having two or more cyclic rings, where two or more carbons are shared by two adjacent rings (the rings are "fused rings"), at least one of the rings is aromatic hydrocarbon, and the other cyclic rings can be, for example, carbocyclyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group.

[0072] The term "arylene," as used herein, refers to the diradical obtained by removing two hydrogen atoms from an aryl group, as defined above. Arylene includes, but is not limited to, 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene, as depicted below.

[0073] [ka]

[0074] "Heteroaryl" refers to monocyclic, bicyclic, and polycyclic aromatic groups having a total of 3 to 12 atoms in the ring structure, including one or more heteroatoms such as nitrogen, oxygen, or sulfur. In some embodiments, heteroaryls are 3 to 7 members. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. The term "heteroaryl" also encompasses polycyclic ring systems having two or more cyclic rings, where two or more atoms are shared by two adjacent rings (the rings are "fused rings") and at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, and where the other cyclic rings can be, for example, carbocyclyl, aryl, heteroaryl, and / or heterocyclyl.

[0075] The term "heteroarylene," as used herein, refers to a diradical obtained by removing two hydrogen atoms from a heteroaryl group, as defined above. Heteroarylene includes, but is not limited to, the divalent heteroarylene groups depicted below.

[0076] [ka]

[0077] "Alkenyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 10 carbons and at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond in an alkenyl group can be located anywhere in the moiety and can have either the (Z) or (E) configuration about the double bond.

[0078] "Alkenylene" refers to a divalent alkenyl group.

[0079] "(Heterocyclyl)alkyl" refers to an alkyl group substituted with one or more heterocyclyl groups.

[0080] "(Carbocyclyl)alkyl" refers to an alkyl group substituted with one or more carbocyclyl groups.

[0081] "Arylalkyl" refers to an alkyl group substituted with an aryl group.

[0082] "Heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group.

[0083] "Alkoxy" refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0084] "Hydroxy" refers to --OH.

[0085] "Cyano" refers to -CN.

[0086] "Hydroxyalkyl" refers to at least one hydroxy group appended to the parent molecular moiety through an alkyl group. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0087] "Halo" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0088] Certain compounds contained in the compositions of the present invention can exist as particular geometric or stereoisomers. Furthermore, the compounds of the present invention can also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0089] For example, if a specific enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, and the diastereomers thus formed are then resolved by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0090] "Substituted" or "substituted with" includes the implicit proviso that such substitution is consistent with the substituted atom and the allowed valences of the substituent, and that the substitution results in a stable compound that is not spontaneously altered by, for example, rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0091] "Substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more for appropriate organic compounds and can be the same or different. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0092] In certain embodiments, optional substituents contemplated in the present disclosure include halogen, azide, oxo (=O), alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, (carbocyclyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, carbamato (e.g., -NHC(O)Oalkyl), silyl, ether (e.g., -alkylene-O(alkyl)), alkylthio, sulfonyl, sulfonamido (e.g., -NHSOalkyl), ketone (e.g., -CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano.

[0093] As used herein, the terms "optionally substituted" or "substituted or unsubstituted," when preceding a listed chemical moiety, means that the following listed chemical moiety is substituted or unsubstituted, respectively. For example, "substituted or unsubstituted aryl, heteroaryl, and cycloalkyl" or "optionally substituted aryl, heteroaryl, and cycloalkyl" means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0094] "Salt" refers to any and all salts, including those produced by ionic complexation of a basic compound with an inorganic or organic acid, or an acidic compound with an inorganic or organic base, resulting in an electronically neutral compound. A "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. See also Berge et al., J. Pharmaceutical Sciences (1977) 66:1-19. A "free base" of a compound is the neutral, unsalted form of the compound. In certain embodiments, the compound of Formula (I) can be a salt (e.g., a pharmaceutically acceptable salt). In certain embodiments, for example, when no reference is made to a pharmaceutically acceptable salt, the compound of Formula (I) can exist as a free base.

[0095] Hydroxyl protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3rd Edition, John Wiley & Sons, 1999. As used herein, exemplary "hydroxyl protecting groups" include methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxymethyl), methyltrichloroethoxymethyl, ... (2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), allyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-Dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p Examples of suitable carbonates include, but are not limited to, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, and p-nitrobenzyl carbonate.

[0096] "Subject" refers to mammals, including, but not limited to, humans (i.e., male or female, of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)), and / or other non-human mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cats, and / or dogs.

[0097] "Treate," "treating," and "treatment" refer to an action that occurs while a subject is afflicted with a disease, reducing the severity of the disease, or delaying or slowing the progression of the disease or associated symptoms.

[0098] An "effective amount" of a compound or a pharmaceutically acceptable salt thereof is that amount that alone, or in combination with other therapeutic agents, provides a therapeutic benefit in the treatment of an afflicted disease from which a subject suffers, or that delays or minimizes one or more symptoms associated with a disease from which a subject suffers.

[0099] Detailed Description of the Invention compound In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0100] [ka] (In the formula, R a are each independently halo, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -C 1~6 Alkyl, and -C 1~6 haloalkyl; n is 0, 1, or 2; R W are each independently halo, -OR W2 , -NZ2, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or 2 Vicinal R W groups taken together with the atoms to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl; m is 0, 1, 2, or 3; Ring A is an optionally substituted non-aromatic 3- to 7-membered carbocyclylene or non-aromatic 3- to 7-membered heterocyclylene; R W2 is hydrogen, optionally substituted C1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; Each Z is independently hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl.

[0101] In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0102] [ka] (In the formula, R a are each independently halo, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -C 1~6 Alkyl, and -C 1~6 haloalkyl; n is 0, 1, or 2; R W are each independently halo, -OR W2 , -NZ2, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or 2 Vicinal R W groups taken together with the atoms to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl; m is 0, 1, 2, or 3; X is a bond, or optionally substituted 3- to 7-membered carbocyclylene, 3- to 7-membered heterocyclylene, 3- to 7-membered arylene, 3- to 7-membered heteroarylene, C 1~6 Alkylene, C 2~6 Alkenylene, -CH(3- to 7-membered carbocyclyl)-, -CH(3- to 7-membered heterocyclyl)-, -CH(3- to 7-membered heterocyclyl)alkyl)-, -CH(3- to 7-membered carbocyclyl)alkyl)-, -CH(heteroaryl)-, -CH(aryl)-, -CH(heteroarylalkyl)-, -CH(arylalkyl)-, -CH(C 1~6 alkyl)-, -CH(C 1~6 haloalkyl)-, -CH(C 1~6 hydroxyalkyl)-, -CH(C 1~6 Alkoxy)-, -CH(C 1~6 Alkoxy C 1~6 alkyl)-, or -C(OH)(C 1~6 alkyl)-, R W2 is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; Each Z is independently hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl.

[0103] In some embodiments, the compound is selected from the following table: Nuclear magnetic resonance (NMR) data was experimentally determined for the following synthesized compounds.

[0104] [Table 1] TIFF2025165398000028.tif203169TIFF2025165398000029.tif185169TIFF2025165398000030.tif235169TIFF2025165398000031.tif216169TIFF2025165398000032.tif199169TIFF2025165398000033.tif189169TIFF2025165398000034.tif158169TIFF2025165398000035.tif203169TIFF2025165398000036.tif180169TIFF2025165398000037.tif190169TIFF2025165398000038.tif223169TIFF2025165398000039.tif230169TIFF2025165398000040.tif190169TIFF2025165398000041.tif141169TIFF2025165398000042.tif236169TIFF2025165398000043.tif217169TIFF2025165398000044.tif208169TIFF2025165398000045.tif234169TIFF2025165398000046.tif194169TIFF2025165398000047.tif195169TIFF2025165398000048.tif182169TIFF2025165398000049.tif222169TIFF2025165398000050.tif204169TIFF2025165398000051.tif181169TIFF2025165398000052.tif231169TIFF2025165398000053.tif204169TIFF2025165398000054.tif195169TIFF2025165398000055.tif199169TIFF2025165398000056.tif209169TIFF2025165398000057.tif176169TIFF2025165398000058.tif232169TIFF2025165398000059.tif209170TIFF2025165398000060.tif230170TIFF2025165398000061.tif195170TIFF2025165398000062.tif177170TIFF2025165398000063.tif185170TIFF2025165398000064.tif226170TIFF2025165398000065.tif220170TIFF2025165398000066.tif226170TIFF2025165398000067.tif203170TIFF2025165398000068.tif207170TIFF2025165398000069.tif217170TIFF2025165398000070.tif195170TIFF2025165398000071.tif186170TIFF2025165398000072.tif185170TIFF2025165398000073.tif195170TIFF2025165398000074.tif146170TIFF2025165398000075.tif230170TIFF2025165398000076.tif229170TIFF2025165398000077.tif189170TIFF2025165398000078.tif218170TIFF2025165398000079.tif222170TIFF2025165398000080.tif161170TIFF2025165398000081.tif164170TIFF2025165398000082.tif190170TIFF2025165398000083.tif181170TIFF2025165398000084.tif214170TIFF2025165398000085.tif225170TIFF2025165398000086.tif222170TIFF2025165398000087.tif215170TIFF2025165398000088.tif217170TIFF2025165398000089.tif213170TIFF2025165398000090.tif196170TIFF2025165398000091.tif221170TIFF2025165398000092.tif206170TIFF2025165398000093.tif218170TIFF2025165398000094.tif206170TIFF2025165398000095.tif196170 TIFF2025165398000096.tif195170TIFF2025165398000097.tif189170TIFF202516 5398000098.tif207170TIFF2025165398000099.tif207170TIFF2025165398000100 .tif207170TIFF2025165398000101.tif207170TIFF2025165398000102.tif55170.

[0105] The compounds described herein can be LPAR1 antagonists. By antagonizing LPAR1, the compounds described herein can treat or prevent LPAR1 signaling-related diseases and disorders (e.g., fibrosis).

[0106] In some embodiments, the compounds described herein can be used to treat systemic sclerosis (SSc).Lysophosphatidic acid (LPA) signaling is known to be involved in various forms of tissue fibrosis.Without being bound by any particular theory, research suggests that LPAR inhibition can be used to treat fibrotic diseases such as SSc.

[0107] In certain embodiments, the A ring is an optionally substituted 4-membered carbocyclylene.

[0108] In some embodiments, each A ring is independently halo, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C 1~6 alkyl), and -O(C 1~6 haloalkyl).

[0109] In certain embodiments, X is an optionally substituted 3- to 7-membered carbocyclylene, 3- to 7-membered heterocyclylene, —CH(3- to 7-membered carbocyclyl)-, —CH(3- to 7-membered heterocyclyl)-, —CH(C 1~6 alkyl), -CH(C 1~6 haloalkyl), or -CH(C 1~6 Alkoxy C 1~6 alkyl).

[0110] In some embodiments, X is an optionally substituted 3- to 7-membered heterocyclylene, —CH(3- to 7-membered heterocyclyl)-, or —CH(C 1~6 Alkoxy C 1~6 alkyl).

[0111] In certain embodiments, R a are each independently selected from the group consisting of —Cl and —OCHF2, and n is 2.

[0112] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, which is Compound 96.

[0113] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of Formula (Ib):

[0114] [ka] (In the formula, R 1 is hydrogen or C 1~6 is alkyl, R 2 and R 3 are each independently hydrogen, halo, optionally substituted (C 1~3 alkyl), or optionally substituted alkoxy (C 1~3 alkyl), or R 2 and R 3together with the atom to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl.

[0115] In some embodiments, R 1 is hydrogen or methyl.

[0116] In certain embodiments, R 2 and R 3 are hydrogen atoms.

[0117] In some embodiments, the compound is selected from the following table:

[0118] [ka]

[0119] In some embodiments, the compound is selected from the following table:

[0120] [ka]

[0121] In certain embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIb):

[0122] [ka] (In the formula, R 4 is hydrogen and R 5 is an optionally substituted 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 Alkoxy C 1~6 is alkyl, or R 4 and R 5together with the atoms to which they are attached form an optionally substituted 3- to 7-membered carbocyclylene or an optionally substituted (substituted) 3- to 7-membered heterocyclylene; R 6 and R 7 are each independently hydrogen, halo, optionally substituted (C 1~3 alkyl), or optionally substituted alkoxy (C 1~3 alkyl), or R 6 and R 7 together with the atom to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl.

[0123] In some embodiments, R 4 is hydrogen and R 5 is tetrahydropyranyl or -CH2OCH3, or R 4 and R 5 together with the atoms to which they are attached form a tetrahydropyran ring.

[0124] In certain embodiments, R 6 and R 7 are each independently hydrogen or fluoro, or R 6 and R 7 together with the atoms to which they are attached form a fused 5-membered heterocyclyl.

[0125] In some embodiments, the compound is selected from the following table:

[0126] [ka]

[0127] In some embodiments, the compound is selected from the following table:

[0128] [ka] TIFF2025165398000109.tif109169

[0129] Pharmaceutical Compositions and Methods of Use In certain aspects, provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a compound of Formula (II) and a pharmaceutically acceptable carrier.

[0130] In some aspects, provided herein are methods for treating or preventing a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II), wherein the disease is treated by inhibiting LPAR1. In some embodiments, the disease or condition is systemic sclerosis.

[0131] In certain aspects, provided herein are methods of inhibiting LPAR1, comprising administering to a subject an effective amount of a compound of formula (I) or a compound of formula (II).

[0132] In certain aspects, provided herein are methods of treating systemic sclerosis (SSc) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure.

[0133] Preparation method The compounds described herein may be prepared according to any suitable method known to those skilled in the art. The synthesis of compounds of the present disclosure is described in the Examples below. [Example]

[0134] In order that this disclosure may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0135] Common abbreviations used throughout that are familiar to those skilled in the art include the abbreviations in Table A.

[0136] [Table 2] TIFF2025165398000111.tif89169

[0137] Synthesis of intermediates Preparation #1:INT-1

[0138] [ka]

[0139] Step 1: Di-tert-butyl 1-(1-benzyl-4-(methoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate. To a solution of diisopropylamine (38 mL, 267 mmol) in tetrahydrofuran (THF) (400 mL) under nitrogen at 0° C. was added 2.5 M butyllithium in hexane (100 mL, 250 mmol) dropwise over 10 minutes. After an additional 25 minutes, the mixture was cooled to −60° C., and a solution of methyl 1-benzylpiperidine-4-carboxylate (48 g, 206 mmol) in tetrahydrofuran (THF) (50 mL) was added dropwise over 15 minutes. After 30 minutes, a solution of (E)-di-tert-butyldiazene-1,2-dicarboxylate (66 g, 287 mmol) in tetrahydrofuran (THF) (200 mL) was added over 25 minutes. The resulting orange solution was stirred at −60° C. for 3 hours. After this time, the cooling bath was removed, and the reaction was stirred for 5 minutes. It was then poured into a mixture of saturated aqueous ammonium chloride (800 mL) and ice (300 mL) and stirred vigorously for 60 minutes. The mixture was diluted with ethyl acetate (1000 mL), and the aqueous layer was extracted with TBME (2×200 mL). The organic layers were then combined, washed with additional saturated aqueous ammonium chloride (5×200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, di-tert-butyl 1-(1-benzyl-4-(methoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate (123 g, 212 mmol, 103% yield), as an orange oil, which was used directly in the next step. 1 H NMR (400 MHz, methanol-d4) δ 1.42 - 1.58 (m, 18H), 1.92 - 1.96 (m, 1H), 2.02 - 2.13 (m, 1H), 2.21 - 2.33 (m, 1H), 2.35 - 2.48 (m, 2H), MS (ESI) m / z 464 (M+H) + . Step 2: INT-1. To a solution of di-tert-butyl 1-(1-benzyl-4-(methoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate (42 g, 91 mmol) in methanol (180 mL) was added a solution of 4 N aqueous hydrochloric acid (227 mL, 908 mmol), and the resulting solution was stirred at ambient temperature for 20 hours. The mixture was then concentrated under reduced pressure, and approximately 300 mL of cyclopentyl methyl ether solvent was added. The desired product, methyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate dihydrochloride (INT-1), precipitated from the solution, was collected, and dried under vacuum (34.4 g, 99% yield). 1 H NMR (400 MHz, DMSO-d6) δ 2.00 - 2.18 (m, 2H), 2.28 - 2.46 (m, 2H), 2.94 - 3.25 (m, 4H), 3.73 (s, 3H), 4.30 (d, J = 4.9 Hz, 2H), 6.10 (s, 1H), 7.38 - 7.50 (m, 3H), 7.59 - 7.73 (m, 2H), 9.58 (s, 2H), 11.43 (s, 1H).

[0140] Preparation #2:INT-2

[0141] [ka]

[0142] Step 1: (E)-1-(dimethylamino)-4-methylpent-1-en-3-one. A mixture of 3-methylbutan-2-one (25 g, 290 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (51.9 g, 435 mmol) was stirred at 100 °C for 4 days. TLC showed that the starting material had been consumed and a new spot had been detected. The reaction mixture was then concentrated under reduced pressure to give (E)-1-(dimethylamino)-4-methylpent-1-en-3-one (13.3 g, 29.3% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 0.96 (d, J = 6.8 Hz, 6H), 2.66-3.11 (m, 6H), 3.17 (d, J = 5.3 Hz, 1H), 4.98 (d, J = 12.6 Hz, 1H), 7.46 (d, J = 12.8 Hz, 1H). Step 2: Methyl 1-benzyl-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylate. To a solution of INT-1 (64.5 g, 196 mmol) in methanol (1 L) was added (E)-1-(dimethylamino)-4-methylpent-1-en-3-one (29 g, 205 mmol), and the resulting solution was heated at 65 °C for 20 h. The reaction was then cooled to ambient temperature. The mixture was concentrated under reduced pressure, diluted with ice water (600 mL), and then carefully basified with 2 N aqueous NaOH to pH 8 (approximately 300 mL), extracted with TBME (4 × 200 mL) and 2-methyl THF (200 mL). The combined organic solution was washed with water (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give an orange oil. The crude product was purified by silica gel chromatography using a gradient of methyl tert-butyl ether in hexane to give the title product (48 g, 134 mmol, 64.8% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.11 (d, J = 6.7 Hz, 6H), 2.30 (ddd, J = 13.1, 8.2, 3.9 Hz, 2H), 2.34 - 2.48 (m, 4H), 2.50 - 2.58 (m, 2H), 2.72 - 2.80 (m, 1H), 3.42 (s, 2H), 3.65 (s, 3H), 6.22 (d, J = 1.9 Hz, 1H), 7.20 - 7.26 (m, 1H), 7.27 - 7.33 (m, 4H), 7.36 (d, J = 1.9Hz, 1H).

[0143] Step 3: 1-benzyl-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylic acid. To a solution of methyl 1-benzyl-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (41.47 g, 121 mmol) in MeOH (486 mL) was added 2 M sodium hydroxide (182 mL, 364 mmol). The mixture was stirred at 75° C. for 4 hours, then cooled to ambient temperature and concentrated to remove methanol. 800 mL of ethyl acetate was then added to the mixture, and the solution was adjusted to pH 1 by adding 66 mL of 6 M HCl solution. The resulting solid was filtered and washed with 20 mL of water followed by 100 mL of ethyl acetate to give 1-benzyl-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylic acid. The aqueous filtrate layer was separated and extracted with ethyl acetate (3×300 mL). The combined organic extracts were then dried over NaSO and concentrated to give additional desired product. Total 1-benzyl-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylic acid material (37.0 g, 111 mmol, 92% yield) was obtained as a colorless solid. MS (ESI) m / z 328 (M+H). + .

[0144] Step 4: 1-benzyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide. 1-benzyl-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylic acid (1.69 g, 5.17 mmol) was dissolved in dry DCM (50 ml), and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (1.89 g, 5.68 mmol) was added, followed by Hunig's base (N,N-diisopropylethylamine) (2.71 ml, 15.50 mmol). The mixture was stirred at ambient temperature for 30 minutes. 4-Chloro-2-(difluoromethoxy)aniline (1.0 g, 5.17 mmol) was then added, and the mixture was stirred at ambient temperature for 18 hours. Semi-saturated aqueous ammonium chloride (20 mL) was then added, and the mixture was extracted with DCM (100 mL), separated, and the organic layer was dried, concentrated, and passed through a column using 0-100% ethyl acetate in heptane to give 1-benzyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (1.95 g, 3.88 mmol, 75% yield). MS (ESI) m / z 503.4 (M+H). + .

[0145] Step 5: INT-2. 1-Benzyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (1.95 g, 3.88 mmol) was dissolved in dichloromethane (40 mL), and then 1-chloroethyl chloroformate (0.610 g, 4.26 mmol) was added. The mixture was heated at 80° C. for 1 hour, then cooled to ambient temperature, and the solvent was removed in vacuo. The residue was then dissolved in methanol (40 mL), and the solution was heated at 80° C. for 18 hours. The solution was then concentrated in vacuo, and the residue was passed through a column using 0-40% methanol in dichloromethane to give N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (1.56 g, 3.78 mmol, 97% yield). MS (ESI) m / z 413.3 (M+H). + .

[0146] Synthesis Examples Example #1 Compounds 14 and 15: (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid and (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid

[0147] [ka]

[0148] Step 1: Ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate. To a solution of INT-2 (100 mg, 0.242 mmol) dissolved in DCM (3 ml), ethyl 3-oxo-2-(tetrahydro-2H-pyran-4-yl)propanoate (73 mg, 0.363 mmol) and sodium triacetoxyborohydride (77 mg, 0.363 mmol) were added. The resulting mixture was then stirred at 25° C. for 18 hours. The resulting mixture was diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography using a gradient of 0-100% EA in heptane to give the title compound (120 mg, 83% yield). MS m / z: 597.4 [M+H] + .

[0149] Step 2: rac-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid. Ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate (120 mg, 0.201 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (84 mg, 2.01 mmol) was added, and the mixture was stirred at 50 °C for 18 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography using a gradient of 0 to 20% methanol in dichloromethane to give the racemic material (78 mg, 68% yield). 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.14 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.52 (t, J = 1.9 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.1 Hz, 1H), 6.32 (s, 1H), 3.81 (m, 2H), 3.24 (m, 2H), 2.93 (m, 1H), 2.85 (m, 1H), 2.63 (m, 1H), 2.55 (m, 1H), 2.47 (m, 3H), 2.36 (m, 3H), 2.26 (m, 1H), 1.71 (m, 1H). 1.56 (m, 1H), 1.41 (m, 1H), 1.28 (m, 3H), 1.10 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z 569.4 [M+H] + .

[0150] Step 3: Compounds 14 and 15. rac-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid (75 mg) was subjected to SFC chiral separation using a Whelk-O® (S,S) column using a 7:3 acetonitrile:methanol mixture containing 0.1% diethylamine as the eluent to give the title compound 14 (35 mg) as the first peak (substance) eluting from the column. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.14 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.52 (t, J = 1.9 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.1 Hz, 1H), 6.32 (s, 1H), 3.81 (m, 2H), 3.24 (m, 2H), 2.91 (m, 1H), 2.86 (m, 1H), 2.63 (m, 1H), 2.51 (m, 4H), 2.34 (m, 4H), 1.72 (m, 1H), 1.56 (m, 1H), 1.41 (m, 1H). 1.29 (m, 3H), 1.10 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z 569.4 [M+H] + The second peak eluting from the column gave the other title compound 15 (36 mg). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.14 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.1 Hz, 1H), 6.32 (s, 1H), 3.82 (m, 2H), 3.23 (m, 2H), 2.93 (m, 1H), 2.86 (m, 1H), 2.63 (m, 1H), 2.51 (m, 4H), 2.35 (m, 4H), 1.72 (m, 1H), 1.57 (m, 1H), 1.41 (m, 1H). 1.29 (m, 3H), 1.10 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, dimethyl sulfoxide-d6) δ ppm 175.57, 171.67, 151.56, 143.16, 138.88, 129.44, 128.18, 125.86, 125.06, 119.21, 119.05, 116.62, 114.03, 105.42, 67.41, 66.44, 57.70, 50.10, 49.19, 48.83, 36.09, 33.95, 33.87, 30.77, 25.87, 24.07; 19 F NMR (565 MHz, dimethyl sulfoxide-d6) δ ppm -82.13, -82.26. MS (APCI+) m / z 569.4 [M+H] + .

[0151] Example 2 Compounds 61 and 62: (1s,3s)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]cyclobutanecarboxylic acid and (1r,3r)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]cyclobutanecarboxylic acid

[0152] [ka]

[0153] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)cyclobutane-1-carboxylate. To a solution of INT-2 (200 mg, 0.484 mmol) in DCE (4.5 mL) was added methyl 3-oxocyclobutane-1-carboxylate (124 mg, 0.969 mmol) and sodium triacetoxyborohydride (154 mg, 0.727 mmol). The resulting mixture was then stirred at 25 °C for 18 h. The resulting mixture was diluted with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic phases were dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude desired product as a residue, which was used directly in the next step (254 mg, 100% yield). MS m / z: 525.2 [M+H] + .

[0154] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid. To a solution of methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)cyclobutane-1-carboxylate (254 mg, 0.484 mmol) dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL), lithium hydroxide monohydrate (204 mg, 4.84 mmol) was added, and the mixture was stirred at ambient temperature for 18 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography using a gradient of 0 to 20% methanol in dichloromethane to give the title compound (130 mg, 53% yield). 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.21 (bs, 1H), 7.77 (d, J = 6.2 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.32 (m, 2H), 7.16 (t, J = 73.2 Hz, 1H), 6.33 (d, J = 2.1 Hz, 1H), 3.35 (m, 4H), 2.92 (m, 1H), 2.69 (m, 2H), 2.58 (m, 1H), 2.52 (m, 2H), 2.37 (m, 2H), 2.22 (m, 2H), 1.95 (m, 1H), 1.10 (d, J = 6.6 Hz, 6H). MS (APCI+) m / z: 511.2 [M+H] + .

[0155] Step 3: Compounds 61 and 62. 3-(4-((4-Chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (129 mg) was subjected to SFC separation using a CHIRALPAK® AD-H column using a 7:3 isopropanol:water mixture with 0.1% diethylamine added as eluent to afford the title compound 62 (9 mg, 6% yield). 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.16 (s, 1H), 7.79 (d, J = 6.2 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 2.92 (m, 1H), 2.84 (m, 1H), 2.77 (m, 1H), 2.60 (m, 2H), 2.49 (m, 2H), 2.36 (m, 2H), 2.15 (m, 4H), 2.06 (m, 2H), 1.10 (d, J = 6.6 Hz, 6H); 13C NMR (101 MHz, dimethyl sulfoxide-d6) δ ppm 170.81, 151.61, 143.63, 139.17, 129.83, 127.87, 125.80, 119.20, 119.00, 116.61, 114.02, 105.62, 65.30, 57.63, 45.57, 31.99, 28.62, 25.76, 24.07. 19 F NMR (565 MHz, dimethyl sulfoxide-d6) δ ppm -82.15, -82.29. MS m / z: (APCI+) 511.2 [M+H] + The second peak to elute provided the title compound 61 (79 mg, 61% yield) as the second peak (material) to elute from the column. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.15 (s, 1H), 7.80 (d, J = 6.2 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 2.93 (m, 1H), 2.67 (m, 1H), 2.58 (m, 4H), 2.49 (m, 1H), 2.36 (m, 2H), 2.20 (m, 4H), 1.90 (m, 2H), 1.10 (d, J = 6.6 Hz, 6H). MS (APCI+) m / z: 511.2 [M+H] + .

[0156] [Example #3] Compound 77: (1s,3s)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-1-methyl-cyclobutanecarboxylic acid

[0157] [ka]

[0158] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate. To a solution of INT-2 (200 mg, 0.484 mmol) in DCE (4.5 ml) was added methyl 1-methyl-3-oxocyclobutane-1-carboxylate (103 mg, 0.727 mmol) and sodium triacetoxyborohydride (154 mg, 0.727 mmol). The resulting mixture was then stirred at 25° C. for 18 hours. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL), the combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude desired product as a residue, which was used directly in the next step (261 mg, 100% yield). MS m / z: 539.2 [M+H] + .

[0159] Step 2: Compound 77. To a solution of methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (261 mg, 0.484 mmol) dissolved in a mixture of THF (3 mL), MeOH (3 mL), and water (1 mL) was added lithium hydroxide monohydrate (203 mg, 4.84 mmol), and the solution was stirred at room temperature for 18 h. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phases were dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography using a gradient of 0–20% MeOH in DCM to give a mixture of cis- and trans-cyclobutane isomer products (144 mg, 57% yield). This mixture of cis and trans isomers was then subjected to SFC chiral separation using a ChiralPak IG column to give 71 mg of the cis title compound as the major product. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.81 (m, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.31 (m, 1H), 7.15 (t, J = 73.3 Hz, 1H), 6.32 (d, J = 1.9 Hz, 1H), 2.92 (m, 1H), 2.69 (m, 1H), 2.60 (m, 2H), 2.51 (m, 3H), 2.35 (m, 2H), 2.15 (m, 3H), 1.87 (m, 2H), 1.29 (s, 3H), 1.10 (d, J = 6.6 Hz, 6H); 13 C NMR (101 MHz, DMSO) δ 178.69, 171.71, 151.61, 143.16, 143.13, 138.89, 129.44, 128.25, 125.91, 125.06, 119.11, 116.65, 114.06, 105.43, 66.54, 54.02, 45.70, 36.45, 36.22, 33.58, 25.94, 24.19, 24.11; 19 F NMR (565 MHz, DMSO) δ -82.11, -82.30; MS m / z: 525.0 [M+H]+.

[0160] Example 4: Compound 84: 4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(6,6-dimethyl-4H-furo[3,4-c]pyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-4-carboxylic acid

[0161] [ka]

[0162] Step 1: (E)-4-((dimethylamino)methylene)-2,2-dimethyldihydrofuran-3(2H)-one. A mixture of 1,1-dimethoxy-N,N-dimethylmethanamine (34.1 mL, 250 mmol) and 2,2-dimethyldihydrofuran-3(2H)-one (25 g, 208 mmol) in dimethylformamide (DMF) (416 mL) was stirred at 100° C. for 18 hours. The mixture was then concentrated to give (E)-4-((dimethylamino)methylene)-2,2-dimethyldihydrofuran-3(2H)-one (37.14 g, 198 mmol, 95% yield) as a dark brown solid.

[0163] Step 2: 1-Benzyl-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxylic acid. (E)-4-((dimethylamino)methylene)-2,2-dimethyldihydrofuran-3(2H)-one (34.16 g, 182 mmol), methyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate dihydrochloride (Int-1, 2HCl) (57.5 g, 151 mmol), and acetic acid (AcOH) (505 mL) were heated to 85 °C for 3 h. The solvent was then removed under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of 0 to 10% MeOH in DCM to give the title product (34.19 g, 64.9% yield) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 1.43 (s, 6H), 2.57 - 2.82 (m, 4H), 3.17 (m, 4H), 4.21 (s, 2H), 4.67 (s, 2H), 7.29 (s, 1H), 7.36 - 7.50 (m, 3H), 7.53 - 7.75 (m, 2H), 8.89 (s, 2H), no COOH protons observed; MS m / z: 356 [M+H] + .

[0164] Step 3: 4-(6,6-Dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxylic acid. 1-Benzyl-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxylic acid (34.91 g, 98 mmol), palladium on carbon (1.338 g, 12.57 mmol), and hydrogen chloride (4 M in dioxane) (24.55 mL, 98 mmol) in EtOH (1964 mL) were subjected to hydrogen gas at 5 bar and ambient temperature for 16 hours. The mixture was then filtered through glass fiber paper and washed with methanol (6 × 50 mL). The filtrate was concentrated under reduced pressure to give crude 4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxylic acid as the hydrochloride salt (30 g, 100 mmol, 102% yield). This material was used directly in the next reaction. MS m / z: 266 [M+H] + .

[0165] Step 4: 1-(tert-butoxycarbonyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxylic acid. The crude material, 4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxylic acid hydrochloride, was dissolved in DCM (492 mL), followed by the addition of N-ethyl-N-isopropylpropan-2-amine (86 mL, 492 mmol) and di-tert-butyl dicarbonate (25.8 g, 118 mmol). The resulting reaction was stirred at ambient temperature for 18 hours. The mixture was then acidified with aqueous hydrochloric acid (1 M), and the two phases were separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step. 1H NMR (400 MHz, DMSO) δ 1.42 (d, J = 16.1 Hz, 15H), 2.20 (ddd, J = 13.5, 8.9, 3.9 Hz, 2H), 2.23 - 2.38 (m, 2H), 3.24 (d, J = 8.8 Hz, 2H), 3.52 - 3.70 (m, 2H), 4.66 (s, 2H), 7.24 (s, 1H), 13.41 (s, 1H). MS m / z: 366 [M+H]+.

[0166] Step 5: tert-Butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-1-carboxylate. To a solution of 1-(tert-butoxycarbonyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxylic acid (35.9 g, 98 mmol) and 4-chloro-2-(difluoromethoxy)aniline (20.02 g, 98 mmol) in acetonitrile (491 mL) was added 1-methyl-1H-imidazole (39.2 mL, 491 mmol). After stirring for 10 minutes at room temperature, the flask was placed in an ambient temperature water bath (due to the exothermic reaction), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (41.3 g, 147 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was then concentrated under reduced pressure and then partitioned between a mixture of dichloromethane (600 mL) and water (400 mL). The aqueous phase was extracted with dichloromethane (2 × 400 mL), and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using 0–60% methyl tert-butyl ether in heptane to give the title product (33.80 g, 62.5 mmol, 63.6% yield). 1H NMR (400 MHz, DMSO) δ 1.40 (d, J = 8.1 Hz, 15H), 2.22 - 2.33 (m, 2H), 2.46 (s, 2H), 3.05 (s, 2H), 3.83 (d, J = 13.6 Hz, 2H), 4.67 (d, J = MS (ESI) m / z 485 (M-tBu+H) + .

[0167] Step 6: N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxamide. To a stirred solution of tert-butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-1-carboxylate (33.8 g, 62.5 mmol) in acetonitrile (417 ml) was added hydrochloric acid (4 M in dioxane) (82 ml, 328 mmol), and the solution was stirred at ambient temperature for 18 hours. The solution was then concentrated in vacuo to give N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxamide hydrochloride (29.5 g, 61.8 mmol, 99% yield) as a pale yellow solid. 1 H NMR (500 MHz, DMSO) δ 1.39 (s, 6H), 2.64 (s, 4H), 3.03 (s, 2H), 3.38 (d, J = 6.5 Hz, 2H), 4.70 (s, 2H), 7.05 - 7.36 (m, 2H), 7.37 (d, MS (ESI) m / z: 441 (M+H)+ .

[0168] Step 7: methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate. N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxamide (free base) (19.87 g, 45.1 mmol) was dissolved in dichloroethane (376 mL), and then methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (12.93 g, 67.6 mmol) and sodium triacetoxyborohydride (14.33 g, 67.6 mmol) were added, and the mixture was stirred at ambient temperature for 18 hours. Saturated aqueous sodium carbonate solution (200 mL) was then added, and the solution was extracted with DCM (500 mL). The aqueous layer was extracted again with DCM (200 mL), then the combined DCM layers were washed with brine, dried over NaSO, concentrated and purified by silica gel column chromatography eluting with 0-60% ethyl acetate in heptane to give the title product (24.2 g, 90% yield) as a pink oil. 1H NMR (400 MHz, MeOD) δ 1.48 (s, 6H), 1.61 (ddd, J = 13.6, 11.1, 4.5 Hz, 2H), 2.09 (dq, J = 12.4, 3.5 Hz, 2H), 2.47 (d, J = 8.8 Hz, 4H), 2.56 (s, 4H), 2.80 (dd, J = 7.9, 4.1 Hz, 2H), 3.50 (td, J = 11.5, 2.3 Hz, 2H), 3.76 (s, 3H), 3.83 (dt, J = 11.9, 3.9 Hz, 2H), 4.81 (s, 2H), 6.88 (t, J = 72.8 Hz, 1H), 7.15 - 7.28 (m, 2H), 7.49 (s, 1H), 8.14 - 8.25 (m, 1H), no NH protons observed; MS m / z: 597.5 [M+H] + .

[0169] Step 8: Compound 84. Methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate (24.15 g, 40.4 mmol) was dissolved in a mixture of tetrahydrofuran (173 mL), methanol (173 mL), and water (57.8 mL), and then lithium hydroxide monohydrate (13.58 g, 324 mmol) was added, and the mixture was stirred at 50° C. for 18 hours. The reaction mixture was then concentrated to remove most of the organic solvent, and then DCM (1000 mL) was added, and the pH of the mixture was adjusted to 3 by adding 2.5 N HCl (approximately 130 mL). The two layers were then separated, the aqueous layer was extracted with DCM (2 × 500 mL), and the combined organic extracts were dried over NaSO, filtered, concentrated, and then purified by silica gel chromatography eluting with 0–10% MeOH in DCM to give compound 84 (4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylic acid) (18.0 g, 30.9 mmol, 76% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.80 (m, 1H), 7.49 (s, 1H), 7.35 (m, 1H), 7.20 (t, J = 73.0 Hz, 1H), 4.69 (s, 2H), 3.70 (m, 2H), 3.38 (m, 3H), 2.77 (m, 2H), 2.49 (m, 4H), 2.36 (m, 4H), 1.88 (m, 2H), 1.46 (m, 2H), 1.38 (s, 6H); 13C NMR (101 MHz, DMSO) δ 177.21, 170.90, 163.57, 154.02, 141.62, 141.59, 141.56, 132.74, 128.96, 128.79, 128.36, 126.07, 123.24, 119.24, 119.14, 116.54, 113.94, 80.83, 66.92, 65.76, 64.74, 63.25, 51.02, 45.74, 32.67, 32.56, 27.46; 19 F NMR (565 MHz, DMSO) δ -82.80, -82.99; MS m / z: 583 [M+H]+.

[0170] [Example #5] Compound 169: (2R)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]methyl]-3-methoxy-propanoic acid

[0171] [ka]

[0172] Step 1: 1-(tert-butyl) 4-methyl 4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate. A mixture of methyl 1-benzyl-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylate (17.9 g, 47.2 mmol) (the product of Step 2 in the preparation of INT-2 described above), MeOH (100 mL), concentrated hydrochloric acid (4 mL, 48.0 mmol), and palladium on carbon (JM Type 39L) (1.5 g, 1.410 mmol) was placed in a stainless steel pressure reactor and stirred under a hydrogen atmosphere (5 bar) for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (200 mL), and di-tert-butyl dicarbonate (14.24 mL, 61.3 mmol) and DIPEA (24.72 mL, 142 mmol) were added sequentially. The mixture was stirred at ambient temperature for 18 hours. The mixture was then transferred to a separatory funnel and washed with 1N hydrochloric acid (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% methyl tert-butyl ether in heptane, to afford the title compound (16.86 g, 98% yield) as a colorless oil that solidified upon standing. MS (ESI) m / z 296.2 (M-tBu+H). + .

[0173] Step 2: 1-(tert-butyl) 4-methyl 4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate. To a stirred mixture of 1-tert-butyl 4-methyl 4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate (3.02 g, 8.16 mmol) in MeCN (60 mL) was added Selectfluor™ (4.92 g, 13.88 mmol). The mixture was stirred at ambient temperature for 66 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (80 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 0-100% methyl tert-butyl ether in heptane to give 1-tert-butyl 4-methyl 4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate (1.58 g, 45% yield) as a pale yellow oil. MS (ESI) m / z 314.2 (M-tBu+H). + .

[0174] Step 3: 1-(tert-Butoxycarbonyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylic acid. To a stirred solution of 1-tert-butyl 4-methyl 4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate (1.90 g, 4.37 mmol) in MeOH (15 mL) and THF (30 mL) was added 2 M aqueous lithium hydroxide solution (11 mL, 22.00 mmol). The reaction mixture was stirred at 35 °C for 2 hours. The reaction mixture was then cooled to ambient temperature and concentrated under reduced pressure. The aqueous phase was diluted with water (80 mL) and then carefully acidified to pH 3 with 1 M HCl (aq). The aqueous phase was then extracted with ethyl acetate (3 × 80 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0-10% ethyl acetate in heptane, to give a pale yellow solid. The solid was further purified by triturating it in ice-cold 10% methyl tert-butyl ether:isohexane (10 mL). The solid was filtered and washed with ice-cold 10% methyl tert-butyl ether:isohexane (2 x 5 mL) to give the title product (1.0 g, 61% yield) as a white solid. MS (ESI) m / z 300.2 (M-tBu+H) + .

[0175] Step 4: tert-Butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carboxylate. To a stirred solution of 1-(tert-butoxycarbonyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxylic acid (0.620 g, 1.657 mmol) and 4-chloro-2-(difluoromethoxy)aniline (0.394 g, 1.934 mmol) in acetonitrile (6 mL) was added 1-methylimidazole (0.47 mL, 5.84 mmol). N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (0.697 g, 2.486 mmol) was then added in one portion. An exotherm was observed, and the solution was stirred at ambient temperature for 18 hours. The mixture was partitioned between dichloromethane (20 mL) and water (50 mL). The aqueous phase was extracted with dichloromethane (2 x 20 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 0-100% methyl tert-butyl ether in heptane to afford the title product (1.0 g, 97% yield) as a colorless oil. MS (ESI) m / z 431.0 (M-Boc+H) + .

[0176] Step 5: N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide. To a stirred solution of tert-butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.0 g, 1.601 mmol) in acetonitrile (11 mL) was added 4 M hydrogen chloride in dioxane (2.1 ml, 8.40 mmol), and the solution was stirred at ambient temperature for 1.5 hours. The resulting suspension was cooled in an ice bath, and the solid was filtered and then washed with ice-cold tert-butyl methyl ether (2 x 5 mL) to give N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide, hydrochloride salt (0.715 g, 1.454 mmol, 91% yield) as a white solid. MS (ESI) m / z 431.0 (M+H). + .

[0177] Step 6: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate. N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide hydrochloride (2.0 g, 4.28 mmol) was dissolved in dichloromethane (25 ml) followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (1.935 ml, 12.84 mmol) at 25 °C. Methyl 2-(methoxymethyl)acrylate (1.466 g, 10.70 mmol) CAS [25328-81-8] was then added, and the mixture was stirred at ambient temperature for 18 hours. The solution was then diluted with saturated aqueous sodium bicarbonate (25 mL), then extracted with dichloromethane (3 x 25 mL), combined, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was subjected to silica gel chromatography eluting with 0-75% ethyl acetate in heptane to afford the title product as a viscous pale yellow oil (2.17 g, 90% yield). MS m / z: 561.9 [M+H] + .

[0178] Step 7: Compound 169. To methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate (2.17 g, 3.87 mmol) dissolved in THF (30 mL), MeOH (30.0 mL), and water (10.00 mL) was added lithium hydroxide (0.926 g, 38.7 mmol), and the cloudy mixture was stirred at ambient temperature for 3 hours. The mixture was then diluted with saturated aqueous ammonium chloride (25 mL) and then extracted with dichloromethane (3 × 25 mL). The combined organic extracts were then dried over MgSO, filtered, and concentrated. The resulting residue was subjected to silica gel chromatography eluting with 0–30% MeOH in DCM to afford the racemic product as a colorless solid (1.65 g, 78% yield). This racemic mixture was then subjected to SFC chiral separation using a ChiralPak IC column to give 595 mg of the chiral title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.62 (m, 1H), 7.57 (d, J = 4.1 Hz, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.17 (t, J = 73.4 Hz, 1H), 3.46 (m, 2H), 3.20 (s, 3H), 2.99 (m, 1H), 2.78 (m, 2H), 2.69 (m, 1H), 2.53 (m, 2H), 2.39 (m, 6H), 1.16 (d, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, DMSO) δ 174.68, 171.12, 149.80, 147.37, 144.64, 134.16, 130.29, 127.92, 126.94, 126.14, 125.78, 119.33, 119.07, 116.75, 114.17, 71.91, 66.82, 58.63, 56.60, 49.37, 43.35, 33.61, 25.16, 21.02; 19F NMR (565 MHz, DMSO) δ -81.81, -82.00, -172.02; MS m / z: 547.2 [M+H]+.

[0179] Example 6: Compound 36: 6-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]pyridine-2-carboxylic acid

[0180] [ka]

[0181] Step 1: Compound 36. To a 4 mL vial was added INT-2 (1 equiv., 0.07 mmol, 30 mg) in 1:1 dichloromethane / methanol (0.6 mL), followed by a solution of methyl 6-formylpicolinate (1 equiv., 0.09 mmol, 14.5 mg) in 1:1 dichloromethane / methanol (0.6 mL), acetic acid (5 equiv., 0.36 mmol, 21 μL), and MP-CNBH3 resin (96 mg, 3 equiv., 2.28 loading). The reaction mixture was stirred overnight at room temperature. Upon completion of the reaction, the resin was filtered through an Isolute® single-frit reservoir, and the reaction residue was dried. The dried residue was then dissolved in 1:1 dimethyl sulfoxide / methanol and purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30 mm × 75 mm). A gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) was used. To the purified sample, 1 mL of tetrahydrofuran and 1 mL of ethanol and lithium hydroxide (4 equiv., 0.28 mmol, 280 μL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1 mL of saturated aqueous NH4Cl and extracted with 3:1 CHCl3:IPA (3 mL) using an Isolute® 6 mL phase separator to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.92 (d, J = 9.4 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.30 - 7.25 (m, 2H), 7.14 (t, J = 73.2 Hz, 1H), 6.29 (d, J = 1.9 Hz, 1H), 3.62 (s, 2H), 3.04 - 2.96 (m, 3H), 2.76 (q, J = 9.3 Hz, 2H), 2.61 - 2.52 (m, 2H), 2.47 (m, 2H), 1.11 (d, J = 6.7 Hz, 6H). MS (APCI) m / z: 548.3 [M+H] + .

[0182] Example 7 Compound 37: 2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]thiazole-4-carboxylic acid

[0183] [ka]

[0184] Compound 37 was prepared according to the procedure used in the preparation of Example #36, substituting methyl 2-formylthiazole-4-carboxylate for methyl 6-formylpicolinate. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.17 (s, 1H), 7.93 - 7.88 (m, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.29 (d, J = 1.9 Hz, 1H), 3.80 (s, 2H), 3.00 - 2.95 (m, 3H), 2.85 (dd, J = 10.5, 5.7 Hz, 2H), 2.59 (t, J = 9.8 Hz, 4H), 1.11 (d, J = 6.7 Hz, 6H). MS (APCI) m / z: 554.3 [M+H] + .

[0185] [Example #8] Compound 49: 2-[1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]cyclopropyl]acetic acid

[0186] [ka]

[0187] A mixture of INT-2 (100 mg, 0.242 mmol), methyl 2-(1-(bromomethyl)cyclopropyl)acetate (75 mg, 0.363 mmol), cesium carbonate (395 mg, 1.211 mmol), and potassium iodide (8.04 mg, 0.048 mmol) in tetrahydrofuran (2 mL) was stirred at 60° C. overnight. Potassium trimethylsilanolate (93 mg, 0.727 mmol) was added, and the mixture was stirred at reflux for 1 h. After that, the reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30 mm × 75 mm) using a gradient of acetonitrile and 0.1% trifluoroacetic acid in water to give the title compound. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 7.82 - 7.78 (m, 1H), 7.55 - 7.51 (m, 1H), 7.34 - 7.31 (m, 2H), 7.16 (t, J = 73.2 Hz, 1H), 6.33 (d, J = 1.8 Hz, 1H), 2.94 (p, J = 6.8 Hz, 1H), 2.91 - 2.85 (m, 2H), 2.56 - 2.49 (m, 4H), 2.47 - 2.41 (m, 2H), 2.35 (s, 2H), 2.28 (s, 2H), 1.10 (d, J = 6.7 Hz, 6H), 0.45 - 0.41 (m, 2H), 0.37 - 0.33 (m, 2H). MS (ESI+) m / z: 525.0 [M+H] + .

[0188] [Example #9] Compound 150: (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-morpholino-propanoic acid

[0189] [ka]

[0190] Step 1: Methyl 2-bromo-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)propanoate. To INT-2 (200 mg, 0.484 mmol) in dichloromethane (3 mL) was added methyl 2-bromoacrylate (120 mg, 0.727 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (118 mg, 0.775 mmol). The mixture was stirred at ambient temperature for 2 hours, then diluted with water (3 mL) and the organic phase was collected. The aqueous phase was washed three times with dichloromethane (3 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in heptane) to provide the title compound. MS(APCI+)m / z:577.0, 579.0[M+H] + .

[0191] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-morpholinopropanoic acid. To methyl 2-bromo-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)propanoate (80 mg, 0.138 mmol) in dry acetonitrile (2 mL) was added morpholine (0.060 mL, 0.692 mmol) and potassium phosphate tripotassium (88 mg, 0.415 mmol). The mixture was stirred at ambient temperature for 18 hours, then diluted with water (5 mL), and the organic phase was collected. The aqueous phase was then washed three times with dichloromethane (3 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran (1.5 mL), methanol (1.5 mL), and water (0.5 mL), followed by the addition of lithium hydroxide monohydrate (57.5 mg, 1.370 mmol). The mixture was stirred at ambient temperature for 60 hours, after which saturated aqueous ammonium chloride solution (3 mL) was added, and the organic phase was collected. The aqueous phase was then washed three times with dichloromethane (3 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol in dichloromethane) to give the title compound. MS (APCI+) m / z: 570.8 [M+H] + .

[0192] Step 3: Compound 150. 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-morpholinopropanoic acid (59.5 mg) was separated by preparative chiral supercritical fluid chromatography on a CHIRALPAK® IG column (30 × 250 mm, 5 μm) using a mobile phase of 20% ethanol (0.2% triethylamine):CO at ambient temperature. Fractions were collected based on UV detection at 220 nm with peaks detected at 9.2 and 9.7 minutes to give the two enantiomers. The second-eluting enantiomer was repurified by flash column chromatography (methanol in dichloromethane) and the absolute stereochemistry was arbitrarily assigned to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.19 (s, 1H), 7.82 - 7.75 (m, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.37 - 6.92 (m, 3H), 6.33 (d, J = 1.8 Hz, 1H), 3.57 - 3.49 (m, 4H), 3.30 (dd, J = 9.0, 5.5 Hz, 1H), 2.99 - 2.85 (m, 2H), 2.79 - 2.69 (m, 2H), 2.62 - 2.56 (m, 4H), 2.49 - 2.31 (m, 8H), 1.10 (d, J = 6.6 Hz, 6H). MS (APCI+) m / z: 570.8 [M+H] + .

[0193] [Example #10] Compound 179: 5-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-1-methyl-triazole-4-carboxylic acid

[0194] [ka]

[0195] To a 4 mL vial was added INT-2 (1 equiv., 0.10 mmol, 42 mg) in 0.1 M buffer solution [1 M buffer solution: 36 g sodium acetate, 900 mL methanol, 88–100 mL acetic acid, pH = 4–5], followed by methyl 5-formyl-1-methyl-1H-1,2,3-triazole-4-carboxylate (1.5 equiv., 0.15 mmol, 26 mg) and MP-CNBH3 resin (1 equiv., 42 mg, 2.44 loading) in 0.3 M buffer solution. The vial was stirred overnight at room temperature. Upon completion, the reaction mixture was concentrated under reduced pressure, and 75% lithium hydroxide in methanol was added. The mixture was concentrated under reduced pressure, dissolved in 1:1 dimethyl sulfoxide / methanol, and purified by reverse-phase HPLC. The sample was purified by preparative HPLC in a gradient of acetonitrile and 10 mM ammonium acetate in water to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.90 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.14 (t, J = 73.2 Hz, 1H), 6.30 MS (APCI) m / z: 552.4.

[0196] [Example #11] Compound 192: (2R,5S)-5-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]tetrahydropyran-2-carboxylic acid

[0197] [ka]

[0198] Step 1: Ethyl 5-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydro-2H-pyran-2-carboxylate. To INT-2 (500 mg, 1.208 mmol) dissolved in 1,2-dichloroethane (6 mL) was added ethyl 5-oxotetrahydro-2H-pyran-2-carboxylate (520 mg, 3.02 mmol), and the mixture was stirred at ambient temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride (640 mg, 3.02 mmol). The mixture was stirred for 18 hours. The reaction mixture was then concentrated under reduced pressure to give a residue that was purified by preparative HPLC using a gradient of acetonitrile and 10 mM ammonium acetate in water to give the title compound. MS (ESI+) m / z: 569.2 [M+H] + .

[0199] Step 2: 5-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydro-2H-pyran-2-carboxylic acid. To crude ethyl 5-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydro-2H-pyran-2-carboxylate (600 mg, 1.054 mmol) in tetrahydrofuran (6 mL) was added potassium trimethylsilanolate (406 mg, 3.16 mmol), and the reaction was stirred at ambient temperature for 18 hours before being concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of acetonitrile and 10 mM ammonium acetate in water to provide the title compound.

[0200] Step 3: Compound 192. 5-(4-((4-Chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydro-2H-pyran-2-carboxylic acid (453 mg) was separated by preparative chiral supercritical fluid chromatography on a CHIRALPAK® IC column (30 × 250 mm, 5 μm) using a mobile phase of 40% ethanol (0.25% triethylamine):CO at ambient temperature. Fractions were collected based on UV detection at 220 nm with peaks detected at 2.1, 3.6, 5.4, and 8.9 minutes to give four enantiomers. The third-eluting diastereomer was repurified by flash column chromatography (methanol in dichloromethane) and the diastereomers arbitrarily assigned to give the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.13 (s, 1H), 7.84 - 7.76 (m, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.31 (d, J = 1.9 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.71 - 3.65 (m, 1H), 3.20 (t, J = 10.6 Hz, 1H), 2.98 - 2.88 (m, 1H), 2.81 - 2.74 (m, 2H), 2.61 - 2.43 (m, 4H). 2.40 - 2.25 (m, 3H), 1.98 - 1.88 (m, 2H), 1.45 - 1.37 (m, 2H), 1.09 (d, J = 6.7 Hz, 6H). MS (ESI+) m / z: 541.0 [M+H] + .

[0201] [Example #12] Compound 76: 1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]cyclopropanecarboxylic acid

[0202] [ka]

[0203] Step 1: Methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclopropanecarboxylate. To a solution of INT-2 (100 mg, 0.242 mmol) and methyl 1-formylcyclopropanecarboxylate (46.6 mg, 0.363 mmol) in 1,2-dichloroethane (2 mL) was added sodium triacetoxyhydroborate (77 mg, 0.363 mmol) with stirring at ambient temperature for 10 minutes, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure to give a residue which was purified by preparative HPLC using a gradient of acetonitrile and 10 mM ammonium acetate in water to give the title compound. MS (ESI+) m / z: 525.0 [M+H] + .

[0204] Step 2: Compound 76. To a solution of methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclopropanecarboxylate (110 mg, 0.210 mmol) in dioxane (2 mL) was added potassium trimethylsilanolate (81 mg, 0.629 mmol), and the reaction was stirred at 60° C. overnight and then concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of acetonitrile and 10 mM ammonium acetate in water to provide the title compound. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 7.75 (d, J = 9.1 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.36 - 7.31 (m, 2H), 7.16 (t, J = 73.2 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 3.03 - 2.96 (m, 2H), 2.96 - 2.90 (m, 1H), 2.67 - 2.59 (m, 6H), 2.59 - 2.52 (m, 2H), 2.49 - 2.38 (m, 1H), 1.11 (d, J = 6.7 Hz, 6H), 1.04 (q, J = 3.7 Hz, 2H), 0.67 (q, J = 3.8 Hz, 2H). MS (ESI+) m / z: 511.0 [M+H] + .

[0205] [Example #13] Compounds 137 and 140: (2S,4S)-4-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]tetrahydrofuran-2-carboxylic acid and (2S,4R)-4-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]tetrahydrofuran-2-carboxylic acid

[0206] [ka]

[0207] Step 1: Methyl 4-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydrofuran-2-carboxylate. To a solution of INT-2 (500 mg, 1.211 mmol) in 1,2-dichloroethane (6 mL), methyl 4-oxotetrahydrofuran-2-carboxylate (0.207 mL, 1.817 mmol) was added, and the mixture was stirred at ambient temperature for 18 hours, followed by the addition of sodium triacetoxyborohydride (385 mg, 1.817 mmol). After stirring at ambient temperature for 2 hours, an additional amount of sodium triacetoxyborohydride (385 mg, 1.817 mmol) was added, and the reaction mixture was stirred at ambient temperature for an additional 18 hours. The reaction mixture was concentrated under reduced pressure and purified on a column using ethyl acetate in heptane to provide the title compound. MS(ESI+)m / z:541.0[M+H] + .

[0208] Step 2: 4-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydrofuran-2-carboxylic acid. To crude methyl 4-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydrofuran-2-carboxylate (655 mg, 1.211 mmol) in tetrahydrofuran (6 mL) was added potassium trimethylsilanolate (466 mg, 3.63 mmol) and the reaction was stirred at ambient temperature for 18 hours before being concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of acetonitrile and 10 mM ammonium acetate in water to give the title compound. MS (ESI+) m / z: 511.0 [M+H] + .

[0209] Step 3: Compounds 137 and 140. 4-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)tetrahydrofuran-2-carboxylic acid (250 mg) was separated by preparative chiral supercritical fluid chromatography on a CHIRALPAK® IC column (30 × 250 mm, 5 μm) using a mobile phase of 15% ethanol (0.1% triethylamine):CO at ambient temperature. The sample was dissolved at a concentration of 23 mg / mL in a 1:1:1 ratio of acetonitrile / water / isopropanol, and the injection volume was 0.4 mL. Fractions were collected based on UV detection at 254 nm with peaks detected at 54.1, 63.9, 73.0, and 88.3 minutes to give the four enantiomers. The third eluting peak (compound 137, 73.0 min) and the fourth eluting peak (compound 140, 88.3 min) were isolated and each was separately repurified by flash column chromatography (methanol in dichloromethane) to give compounds 137 and 140. The absolute stereochemistry of both compounds was arbitrarily assigned to give the title compound. Compound 137: 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.18 (s, 1H), 7.87 - 7.72 (m, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.36 - 6.94 (m, 3H), 6.33 (d, J = 1.9 Hz, 1H), 4.31 (t, J = 7.8 Hz, 1H), 3.86 (dd, J = 8.5, 6.3 Hz, 1H), 3.65 (t, J = 7.9 Hz, 1H), 2.97 - 2.73 (m, 3H), 2.71 - 2.59 (m, 1H), 2.49 - 2.31 (m, 7H), 1.84 - 1.73 (m, 1H), 1.10 (d, J = 6.6 Hz, 6H). MS (ESI+) m / z: 527.0 [M+H] + .Compound 140: 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.20 (s, 1H), 7.80 - 7.74 (m, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.38 - 6.94 (m, 3H), 6.33 (d, J = 1.9 Hz, 1H), 4.42 (t, J = 6.6 Hz, 1H), 3.94 (dd, J = 8.6, 6.6 Hz, 1H), 3.71 - 3.59 (m, 1H), 2.97 - 2.88 (m, 1H), 2.77 (m, 1H), 2.69 - 2.47 (m, 5H), 2.45 - 2.31 (m, 3H). 2.10 - 2.07 (m, 2H), 1.10 (d, J = 6.6 Hz, 6H). MS (ESI+) m / z: 527.2 [M+H] + .

[0210] [Example #14] Compound 154: (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-(1-methylpyrazol-4-yl)propanoic acid

[0211] [ka]

[0212] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)propanoate. To N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2, 313 mg, 0.758 mmol) in dichloromethane (8 mL) was added 1-methyl-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (186 mg, 1.213 mmol) and methyl 2-(1-methyl-1H-pyrazol-4-yl)acrylate (126 mg, 0.758 mmol). The reaction was stirred at ambient temperature for 60 hours and then concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate in heptane to give the title compound. MS (ESI+) m / z: 579.0 [M+H] + .

[0213] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)propanoic acid. To methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)propanoate (204 mg, 0.282 mmol) in tetrahydrofuran (3 mL) was added potassium trimethylsilanolate (108 mg, 0.846 mmol), and the reaction was stirred at 60° C. for 15 minutes. The mixture was concentrated, and the residue was purified by flash column chromatography (methanol in dichloromethane) to give the title compound. MS(ESI+)m / z:565.0[M+H] + .

[0214] Step 3: Compound 154. 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)propanoic acid (133 mg) was separated by preparative chiral supercritical fluid chromatography on a Regis Whelk-O® 1(S,S) column (30 × 250 mm, 5 μm) using a mobile phase of 30% ethanol (0.1% triethylamine):CO at ambient temperature. Fractions were collected based on UV detection at 220 nm with peaks detected at 5.2 and 7.5 minutes to give the two enantiomers. The second-eluting enantiomer was repurified by flash column chromatography (methanol in dichloromethane) and the absolute stereochemistry was arbitrarily assigned to give the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.18 (s, 1H), 7.83 - 7.77 (m, 1H), 7.55 (s, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.34 - 6.97 (m, 4H), 6.32 (d, J = 1.8 Hz, 1H), 3.77 (s, 3H), 3.70 (dd, J = 10.4, 5.2 Hz, 1H), 2.98 - 2.82 (m, 3H), 2.77 - 2.66 (m, 1H), 2.61 - 2.44 (m, J = 3.2 Hz, 3H), 2.42 - 2.31 (m, 4H), 1.10 (dd, J = 6.7, 2.0 Hz, 6H). MS (ESI+) m / z: 565.0 [M+H] + .

[0215] [Example #15] Compound 32: (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-(3-methoxyphenyl)propanoic acid

[0216] [ka]

[0217] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(3-methoxyphenyl)propanoate. A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.40 g, 0.969 mmol), methyl 2-(4-methoxyphenyl)acrylate (0.363 g, 1.89 mmol), and DBU (2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine, 0.292 mL, 1.94 mmol) was placed in a 40 mL pressure vial. Dichloromethane (10 mL) was added. The mixture was stirred at 25°C under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 (5 mL) and extracted with dichloromethane (2 x 5 mL). The organic layer was washed with brine (1 x 10 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of ethyl acetate in heptane to give the title compound. MS (ESI) m / z: 605 [M] + .

[0218] Step 2: rac-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(3-methoxyphenyl)propanoic acid. To methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(3-methoxyphenyl)propanoate (0.476 g, 0.787 mmol) was added a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), followed by lithium hydroxide (2.36 mL of a 1 M solution, 2.36 mmol). The reaction mixture was stirred at 25 °C for 1.5 h. Saturated aqueous NH4Cl (10 mL) was added, and the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the racemic title compound. MS (APCI+) m / z: 591 [M+H] + .

[0219] Step 3: Compound 32. The racemic compound (0.359 g) obtained from Step 2 was subjected to preparative supercritical fluid chromatography (SFC) chiral separation using a CHIRALPAK® AD-H column (30 × 250 mm, 5 μm) with a mobile phase of 25% ethanol (containing 0.1% diethylamine):CO at 35 °C. Fractions were collected based on UV detection at 220 nm with peaks detected at 2.98 and 4.67 minutes to give two enantiomers. The first enantiomeric peak (A) eluting at 2.98 minutes was collected and concentrated. This material was purified again by silica gel chromatography (methanol in dichloromethane) to remove traces of diethylamine SFC additive to give the title compound 32. The absolute stereochemistry of the title compound was arbitrarily assigned as (R), >99% ee. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.82 (s, 1H), 7.58 - 7.42 (m, 1H), 7.33 - 7.22 (m, 3H), 7.15 (t, 73.3 Hz, 1H), 7.06 (d, J = 6.0 Hz, 1H), 6.87 (dd, J = 4.5, 2.4 Hz, 3H), 6.80 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 3.78 - 3.74 (m, 3H), 3.67 - 3.57 (m, 2H), 3.24 - 3.04 (m, 5H). 2.98 - 2.87 (m, 4H), 2.75 (d, J = 5.2 Hz, 1H), 1.16 - 1.09 (m, 6H). MS (APCI+) m / z: 591 [M+H] + .

[0220] [Example #16] Compounds 38 and 39: (2R)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-2-carboxylic acid and (2S)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-2-carboxylic acid

[0221] [ka]

[0222] Step 1: Ethyl 2-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carbonyl)tetrahydro-2H-pyran-2-carboxylate. N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.125 g, 0.303 mmol), 2-(ethoxycarbonyl)tetrahydro-2H-pyran-2-carboxylic acid (0.064 g, 0.303 mmol), and HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.138 g, 0.363 mmol). The mixture was combined in a 20 mL pressure vial and charged with N,N-dimethylformamide (5 mL). N-Ethyl-N-isopropylpropan-2-amine (0.159 mL, 0.908 mmol) was added and the mixture was stirred at 25 °C for 17 h. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (2 x 15 mL). The organics were separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 597 [M] + .

[0223] Step 2: 2-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carbonyl)tetrahydro-2H-pyran-2-carboxylic acid. To the product from Step 1 (0.136 g, 0.228 mmol) was added a solvent mixture of tetrahydrofuran (5 mL) and methanol (5 mL), followed by lithium hydroxide (1.14 mL of a 1 M solution, 1.14 mmol). The reaction mixture was stirred at 50 °C for 15 h, diluted with saturated aqueous NH4Cl (10 mL), and extracted with dichloromethane (3 × 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the title compound. MS (APCI+) m / z: 568 [M] + .

[0224] Step 3: 2-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-2-carboxylic acid. To a mixture of the product from Step 2 (0.068 g, 0.120 mmol) in a 20 mL pressure vial was added Vaska's Complex® (carbonylchlorobis(triphenylphosphine)iridium(I)) (0.014 g, 0.018 mmol) and 1,2-dichloroethane (3 mL). To this was added 1,1,3,3-tetramethyldisiloxane (0.161 g, 1.195 mmol) dropwise at 25° C. for 17 hours, during which gas evolution was observed. The reaction mixture was quenched with trifluoroacetic acid (0.028 mL, 0.359 mmol) and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (5 mL). Water (5 mL) was added, and the two-phase aqueous mixture was basified with 2N aqueous NaOH to a pH of approximately 9-10. Saturated aqueous NH4Cl (15 mL) and additional dichloromethane (10 mL) were added, and the organics were dried over MgSO4, filtered, and concentrated to give the crude product. Purification was carried out using a reverse-phase column with a mobile phase of acetonitrile containing 0.1% trifluoroacetic acid to give the racemic title compound. MS (ESI+) m / z: 555 [M+H] + .

[0225] Step 4: Compounds 38 and 39. The racemic product from Step 3 (0.055 g, 0.099 mmol) was separated by preparative chiral supercritical fluid chromatography on a CHIRAL ART cellulose-SC (IC) column (30 × 250 mm, 5 μm) using a mobile phase of 30% ethanol (0.2% diethylamine):CO at 35 °C. Fractions were collected based on UV detection at 220 nm with peaks detected at 4.07 min (A) and 7.39 min (B) to give resolved enantiomeric peaks A and B. Each resolved enantiomeric peak was concentrated to dryness and then purified again by silica gel chromatography to remove residual diethylamine additive. An SFC run using a silica gel column eluted with methanol in dichloromethane afforded chiral compound 38 from peak A. The absolute stereochemistry was arbitrarily assigned as (R) with an ee >99.4%. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.01 (s, 1H), 7.82 (d, J = 9.4 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.44 - 7.14 (m, 2H), 7.07 (s, 1H), 6.88 (s, 0H), 6.34 (d, J = 1.9 Hz, 1H), 3.81 (qt, J = 11.8, 5.2 Hz, 2H), 3.65 - 3.19 (m, 2H), 3.17 - 3.05 (m, 2H), 2.73 - 2.60 (m, 3H), 2.48 (p, J = 1.9 Hz, 7H), 1.56 - 1.40 (m, 3H), 1.12 (dd, J = 6.6, 2.8 Hz, 6H). MS (ESI+) m / z: 555 [M+ H] + The chiral title compound 39 from peak B was purified as described above to give title compound 39. The absolute stereochemistry was arbitrarily assigned as (S) with an ee >99%. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.01 (s, 1H), 7.82 (d, J = 9.4 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.44 - 7.14 (m, 2H), 7.07 (t, J = 73.3 Hz, 1H), 6.88 (s, 1H), 6.34 (d, J = 1.9 Hz, 1H), 3.81 (qt, J = 11.8, 5.2 Hz, 2H), 3.65 - 3.19 (m, 2H), 3.17 - 3.05 (m, 2H), 2.73 - 2.60 (m, 3H), 2.48 (p, J = 1.9 MS (ESI+) m / z: 555 [M+ H] + .

[0226] [Example #17] Compound 108: (1r,3r)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-1-(trifluoromethyl)cyclobutanecarboxylic acid

[0227] [ka]

[0228] Compound 108. A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.20 g, 0.484 mmol) and 3-oxo-1-(trifluoromethyl)cyclobutane-1-carboxylic acid (0.149 g, 0.775 mmol) was combined in a 20 mL pressure vial containing 1,2-dichloroethane (5 mL) and stirred at 25 °C for 1 hour. Sodium triacetoxyborohydride (STAB) (0.164 g, 0.775 mmol) was added to the reaction, and the mixture was stirred for 17 hours. The mixture was quenched by the addition of water (2 mL), followed by saturated aqueous NH4Cl (5 mL) and dichloromethane (2 × 10 mL). The organic phases were combined, dried over MgSO4, then filtered and concentrated to give the crude title product as a mixture of cis and trans isomers (5:1 trans to cis ratio). The crude product was purified by silica gel chromatography using methanol in dichloromethane to separate the cis and trans isomer peaks. The more polar eluting peak was concentrated and confirmed to be the trans title compound by NMR structural analysis. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.42 (s, 1H), 8.22 (s, 1H), 7.80 - 7.75 (m, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.15 (t, J = 73.3 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 3.76 - 3.59 (m, 2H), 3.58 - 3.43 (m, 2H), 3.20 - 2.87 (m, 4H), 2.77 - 2.53 (m, 6H), 1.11 (d, J = 6.6 Hz, 6H). MS (APCI+) m / z: 579 [M+ H] + .

[0229] [Example #18] Compound 164: (1s,3s)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-1-hydroxy-cyclobutanecarboxylic acid

[0230] [ka]

[0231] Compound 164. A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.95 g, 2.30 mmol) and 1-hydroxy-3-oxocyclobutane-1-carboxylic acid (0.479 g, 3.68 mmol) was combined in a 20 mL pressure vial containing 1,2-dichloroethane (12 mL). The mixture was stirred at 25 °C for 1 h, then sodium triacetoxyborohydride (STAB) (0.780 g, 3.68 mmol) was added and the reaction was stirred for 17 h. The reaction was quenched by the addition of water (2 mL) followed by saturated aqueous NH4Cl (5 mL) and dichloromethane (2 × 10 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the crude title product. The crude product was purified using silica gel chromatography eluting with methanol in dichloromethane to give the crude product. The material was then further purified on a reverse phase column using a mobile phase of acetonitrile containing 0.1% ammonium acetate to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.99 (s, 1H), 7.93 - 7.82 (m, 1H), 7.56 - 7.49 (m, 1H), 7.33 - 7.22 (m, 2H), 7.06 (t, J = 73.0 Hz, 1H), 6.32 (d, J = 1.9 Hz, 1H), 3.15 - 2.90 (m, 4H), 2.70 - 2.50 (m, 4H), 2.47 (d, J = 1.9 Hz, 4H), 2.43 - 2.35 (m, 2H), 2.28 - 2.19 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H). MS (APCI+) m / z: 527 [M+ H] + .

[0232] [Example #19] Compound 194: (1r,3r)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-1-methoxy-cyclobutanecarboxylic acid

[0233] [ka]

[0234] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-1-methoxycyclobutane-1-carboxylate. A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.5 g, 1.21 mmol) and methyl 1-methoxy-3-oxocyclobutane-1-carboxylate (0.306 g, 1.94 mmol) was combined in a 40 mL pressure vial with 1,2-dichloroethane (20 mL) and stirred at 25° C. for 1 hour. Sodium triacetoxyborohydride (STAB) (0.411 g, 1.94 mmol) was then added and the reaction was stirred for 17 hours. The reaction was quenched by the addition of water (2 mL) followed by saturated aqueous NH4Cl (5 mL). Dichloromethane (2 x 10 mL) was added. The organic phase was dried over MgSO4, filtered, and concentrated to give the crude title product. The crude product was first purified using silica gel chromatography eluting with ethyl acetate in heptane to give the purified title compound. MS (APCI+) m / z: 555 [M+H] + .

[0235] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-1-methoxycyclobutane-1-carboxylic acid. To the product from Step 1 (0.330 g, 0.594 mmol) was added a solvent mixture of tetrahydrofuran (5 mL) and methanol (5 mL), followed by lithium hydroxide (2.97 mL of a 1 M solution, 2.97 mmol). The reaction mixture was stirred at 25 °C for 16 h, diluted with saturated NH4Cl solution (10 mL), and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the title compound as a cis, trans mixture. MS (APCI+) m / z: 541 [M+H] + .

[0236] Step 3: Compound 194. The cis, trans product mixture from Step 2 (0.286 g) was separated by preparative chiral supercritical fluid chromatography on a CHIRALPAK® (IC) column (30 × 250 mm, 5 μm) using a mobile phase of 20% ethanol (0.1% diethylamine):CO at ambient temperature. Fractions were collected based on UV detection at 254 nm with peaks detected at 11.45 minutes (A) and 25.69 minutes (B) to give resolved isomeric peaks A and B. Peak B was concentrated to dryness and then purified again by silica gel chromatography to remove residual diethylamine additive. SFC run using a silica gel column eluted with methanol in dichloromethane gave the title compound (Compound 194) from peak B, which was assigned a relative cis stereochemistry by NMR structural chemistry. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.42 (s, 1H), 8.22 (s, 1H), 7.80 - 7.75 (m, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.15 (t, J = 73.3 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 3.76 - 3.59 (m, 2H), 3.58 - 3.43 (m, 2H), 3.20 - 2.87 (m, 4H), 2.77 - 2.53 (m, 6H), 1.11 (d, J = 6.6 Hz, 6H). MS (APCI+) m / z: 541 [M+ H] + .

[0237] [Example #20] Compound 40: 6-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-2-oxaspiro[3.3]heptane-6-carboxylic acid

[0238] [ka]

[0239] Step 1: Ethyl 6-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-2-oxaspiro[3.3]heptane-6-carboxylate. A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.4 g, 0.969 mmol) and ethyl 6-formyl-2-oxaspiro[3.3]heptane-6-carboxylate (0.320 g, 1.45 mmol) was combined in a 40 mL pressure vial containing 1,2-dichloroethane (20 mL), and the reaction mixture was stirred at 25 °C for 1 h. Sodium triacetoxyborohydride (STAB) (0.382 g, 1.45 mmol) was added and the reaction was stirred for 17 hours. The reaction mixture was quenched by the addition of water (2 mL) followed by saturated aqueous NH4Cl (5 mL). Dichloromethane (2 x 10 mL) was added and the organic phase was dried over MgSO4, filtered, and concentrated to give the crude title product. The crude product was purified using silica gel chromatography eluting with ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 595 [M] + .

[0240] Step 2: Compound 40. To the product from Step 1 (0.238 g, 0.4 mmol) was added a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), followed by lithium hydroxide (2.00 mL of a 1 M solution, 2.00 mmol). The reaction mixture was stirred at 25 °C for 16 h. Saturated aqueous NH4Cl (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the crude title product. The crude material was purified using silica gel chromatography, eluting with methanol in dichloromethane, to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.07 (s, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.68 - 7.48 (m, 3H), 7.34 - 7.23 (m, 1H), 7.08 (s, 1H), 6.35 (d, J = 1.9 Hz, 1H), 3.36 - 3.25 (m, 1H), 3.08 (t, J = 10.8 Hz, 2H), 2.93 (p, J = 6.7 Hz, 1H), 2.77 - 2.58 (m, 4H), 2.50 - 2.37 (m, 5H), 2.18 - 2.07 (m, 3H), 1.80 - 1.69 (m, 3H), 1.13 (d, J = 6.7 Hz, 6H). MS (ESI) m / z: 567 [M] + .

[0241] [Example #21] Compounds 149, 151 and 152: (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-[(3R)-tetrahydrofuran-3-yl]propanoic acid, (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-[(3S)-tetrahydrofuran-3-yl]propanoic acid and (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-[(3S)-tetrahydrofuran-3-yl]propanoic acid

[0242] [ka]

[0243] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydrofuran-3-yl)propanoate. A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.53 g, 0.1284 mmol) and methyl 3-oxo-2-(tetrahydrofuran-3-yl)propanoate (0.368 g, 1.926 mmol) was combined in a 40 mL pressure vial containing 1,2-dichloroethane (20 mL). The reaction mixture was stirred at 25 °C for 1 hour. Tetramethylammonium triacetoxyborohydride (0.507 g, 1.926 mmol) was added and the reaction was stirred for 17 hours. The reaction was quenched with water (5 mL) and saturated aqueous NH4Cl (5 mL) and dichloromethane (2 x 10 mL) were added. The organic phase was dried over MgSO4, filtered, and concentrated to give the crude title product. The crude product was purified using silica gel chromatography eluting with ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 569 [M] + .

[0244] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydrofuran-3-yl)propanoic acid. To the product from Step 1 (0.703 g, 1.235 mmol) was added a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), followed by lithium hydroxide (6.18 mL of a 1 M solution, 6.18 mmol). The reaction mixture was stirred at 25 °C for 17 h, diluted with saturated aqueous NH4Cl (15 mL), and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the crude racemic title compound, which was used in Step 3. MS (APCI+) m / z: 555 [M] + .

[0245] Step 3: Compounds 149, 151 and 152. The racemic compound (0.551 g) obtained from Step 2 was subjected to a multi-step preparative supercritical fluid chromatography (SFC) chiral separation using three sequential methods: Method 1: Separation used a CHIRALPAK® IC column (30 × 250 mm, 5 μm) using a mobile phase of 25% ethanol:CO at 35° C. Fractions were collected based on UV detection at 220 nm with fraction peaks detected at 4.73 min (A) and 11.50 min (B).

[0246] Method 2: Peak A (0.275 g), first eluting at 4.73 minutes, was then processed in a second preparative SFC method using a CHIRALPAK® AD-H column (30 × 250 mm, 5 μm) with a mobile phase of 20% 2:8 acetonitrile / isopropanol (0.1% diethylamine) / :CO at 35° C. Fractions were collected based on UV detection at 254 nm with the two diastereomeric peaks detected at 10.58 minutes and 14.24 minutes labeled fractions 1 and 2, respectively.

[0247] Method 3: Peak B (0.275 g), eluting second at 11.5 minutes from the initial purification, was subjected to a third SFC purification method to resolve the remaining two diastereomers using a Whelk-O® (S,S) column (30 × 250 mm, 5 μm) with a mobile phase of 25% 1:1 acetonitrile / ethanol (0.1% diethylamine) / :CO at 35°C. Fractions were collected based on UV detection at 254 nm, with two additional diastereomeric peaks detected at 7.08 minutes and 9.32 minutes, labeled fractions 3 and 4, respectively. Four diastereomeric peaks were isolated to elute by these respective methods at 10.58 minutes (1), 14.23 minutes (2), 7.08 minutes (3), and 9.32 minutes (4). Fraction peaks 1, 3, and 4 were concentrated and each re-purified by flash chromatography (methanol in dichloromethane) to remove traces of diethylamine SFC additive to give the title compounds (in fraction peak order 1, 3, and 4) with arbitrarily assigned stereochemistry: Compound 151. (ee>99.5%). 1H NMR (400 MHz, ジメチルスルホキシド-d6) δ ppm 7.91 (dd, J = 9.3, 1.0 Hz, 1H), 7.81 (s, 1H), 7.51 (t, J = 1.8 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.15 (t, J = 73.3 Hz, 1H), 6.28 (t, J = 1.7 Hz, 1H), 3.80 - 3.66 (m, 2H), 3.59 (td, J = 8.1, 7.1 Hz, 1H), 3.37 (dd, J = 8.5, 7.5 Hz, 1H), 2.99 (h, J = 6.7 Hz, 1H), 2.88 (d, J = 6.1 Hz, 1H), 2.86 (s, 1H), 2.71 (dd, J = 10.6, 5.4 Hz, 1H), 2.67 - 2.52 (m, 3H), 2.45 - 2.36 (m, 4H), 2.29 (dt, J = 16.0, 8.0 Hz, 1H), 2.05 - 1.83 (m, 2H), 1.57 (dq, J = 12.2, 8.1 Hz, 2H), 1.11 (dd, J = 6.7, 1.5 Hz, 6H). MS (APCI+) m / z: 566 [M+H] + . Compound 152. (ee>99%). 1H NMR (400 MHz, ジメチルスルホキシド-d6) δ ppm 7.91 (dd, J = 9.3, 1.0 Hz, 1H), 7.81 (s, 1H), 7.51 (t, J = 1.8 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.15 (t, J = 73.3 Hz, 1H), 6.28 (t, J = 1.7 Hz, 1H), 3.79 (dd, J = 8.5, 7.4 Hz, 1H), 3.69 (td, J = 8.3, 4.6 Hz, 1H), 3.59 (q, J = 7.7 Hz, 1H), 3.42 - 3.29 (m, 1H), 2.98 (sevenfold line, J = 6.7 Hz, 1H), 2.83 (td, J = 10.6, 5.1 Hz, 1H), 2.69 (dd, J = 10.6, 5.7 Hz, 1H), 2.62 - 2.50 (m, 5H), 2.43 - 2.33 (m, 4H), 2.33 - 2.23 (m, 2H), 1.92 (dtd, J = 12.3, 7.7, 4.7 Hz, 1H), 1.68 - 1.58 (m, 1H), 1.11 (dd, J = 6.7, 1.6 Hz, 6H). MS (APCI+) m / z: 566 [M+ H] + . Compound 149. (ee>99.6%) 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.91 (dd, J = 9.3, 1.0 Hz, 1H), 7.81 (s, 1H), 7.51 (t, J = 1.8 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.15 (t, J = 73.3 Hz, 1H), 6.28 (t, J = 1.7 Hz, 1H), 3.80 - 3.66 (m, 2H), 3.59 (td, J = 8.1, 7.1 Hz, 1H), 3.37 (dd, J = 8.5, 7.5 Hz, 1H), 2.99 (h, J = 6.7 Hz, 1H), 2.88 (d, J = 6.1 Hz, 1H), 2.86 (s, 1H), 2.71 (dd, J = 10.6, 5.4 Hz, 1H), 2.67 - 2.52 (m, 3H), 2.45 - 2.36 (m, 4H), 2.29 (dt, J = 16.0, 8.0 Hz, MS (APCI+) m / z: 566 [M+ H] + .

[0248] [Example #22] Compound 170: (2S)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]methyl]-3-methoxy-propanoic acid

[0249] [ka]

[0250] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate. (Product of Example #5, Step 5) A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide hydrochloride (2.0 g, 4.28 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (1.94 mL, 12.84 mmol) was combined in a 40 mL pressure vial, followed by the addition of dichloromethane (25 mL) and methyl 2-(methoxymethyl)acrylate (1.466 g, 10.70 mmol). The mixture was stirred at 25 °C for 17 hours, diluted with saturated aqueous NaHCO (20 mL), and extracted with dichloromethane (3 × 25 mL). The organic extracts were combined, washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The crude material was purified by flash silica gel chromatography (ethyl acetate in heptane) to give the title compound. MS (APCI+) m / z: 561 [M+H] + .

[0251] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoic acid. To the product from Step 1 (2.17 g, 3.87 mmol) was added a solvent mixture of tetrahydrofuran (30 mL), methanol (30 mL), and water (10 mL), followed by lithium hydroxide (0.926 g, 38.7 mmol). The reaction mixture was stirred at 25 °C for 2 h, diluted with saturated aqueous NH4Cl (35 mL), and extracted with dichloromethane (3 x 30 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was purified by flash chromatography (methanol in dichloromethane) to give the title compound. MS (APCI+) m / z: 547.2 [M+H] + .

[0252] Step 3: Compound 170. The material from Step 2 (1.65 g) was separated by preparative chiral supercritical fluid chromatography on a CHIRALPAK® (IC) column (30 × 250 mm, 5 μm) using a mobile phase of 15% ethanol (0.1% triethylamine):CO at 35 °C. Fractions were collected based on UV detection at 254 nm with peaks detected at 7.53 minutes (A) and 10.82 minutes (B) to give resolved enantiomeric peaks A and B. Peak B was concentrated to dryness and then repurified by silica gel chromatography to remove residual diethylamine additive, and an SFC run using a silica gel column eluted with a gradient of methanol in dichloromethane gave the chiral title compound with arbitrarily assigned stereochemistry. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.64 (s, 1H), 7.62 (m, 1H), 7.57 (d, J = 4.1 Hz, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.17 (t, J = 73.4 Hz, 1H), 3.46 (m, 2H), 3.20 (s, 3H), 2.99 (m, 1H), 2.78 (m, 2H), 2.69 (m, 1H), 2.53 (m, 2H), 2.39 (m, 6H), 1.16 (d, J = 6.8 Hz, 6H). MS (APCI+) m / z: 547.2 [M+H] + .

[0253] [Example #23] Compounds 184, 185, and 186: (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-((1s,4S)-4-methoxycyclohexyl)propanoic acid, (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-((1r,4R)-4-methoxycyclohexyl)propanoic acid, and (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-((1s,4R)-4-methoxycyclohexyl)propanoic acid

[0254] [ka]

[0255] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(4-methoxycyclohexyl)propanoate. A mixture of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2) (0.8 g, 1.94 mmol) and methyl 2-(4-methoxycyclohexyl)-3-oxopropanoate (0.623 g, 2.91 mmol) was combined in a 40 mL pressure vial with 1,2-dichloroethane (20 mL). The reaction mixture was stirred at 25° C. for 1 hour, then tetramethylammonium triacetoxyborohydride (0.765 g, 2.91 mmol) was added and the reaction mixture was stirred for 17 hours. The reaction mixture was quenched by the addition of water (5 mL), followed by saturated aqueous NH4Cl (15 mL) and dichloromethane (2×20 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the crude title product. The crude product was first purified using silica gel chromatography eluting with ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 612 [M+H] + .

[0256] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(4-methoxycyclohexyl)propanoic acid. To the product from Step 1 (1.04 g, 1.55 mmol) in a 40 mL pressure vial was added a solvent mixture of tetrahydrofuran (8 mL) and methanol (8 mL), followed by lithium hydroxide (8.51 mL of a 1 M solution, 6.94 mmol). The reaction mixture was stirred at 60 °C for 5 h, diluted with saturated aqueous NH4Cl (20 mL), and extracted with dichloromethane (3 × 20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the crude title product. The crude material was purified using silica gel chromatography eluting with methanol in dichloromethane to give the racemic title compound. MS(APCI+)m / z:598[M+H] + .

[0257] Step 3: Compounds 184, 185 and 186. The racemic compound (0.929 g) obtained from Step 2 was then subjected to a multi-step preparative supercritical fluid chromatography (SFC) chiral separation using three sequential methods: Method 1: The compound was first separated into the isomer pair (0.929 g) from Step 2 using a Regis Whelk-O® 1(S,S) column (30 × 250 mm, 5 μm) at 35° C. using a mobile phase of 20% 8:2 isopropanol / acetonitrile / 0.2% diethylamine:CO. Fractions were collected based on UV detection at 220 nm with fraction peaks detected at 10.27 minutes (A) and 13.61 minutes (B), each peak containing one pair of isomers.

[0258] Method 2: Peak A (approximately 0.460 g), first eluting at 10.27 minutes from Method 1, was then processed in a second preparative SFC method using a CHIRALPAK® AD-H column (30 × 250 mm, 5 μm) with a mobile phase of 20% 4:1 isopropanol / acetonitrile (0.2% diethylamine) / :CO at 35° C. Fractions were collected based on UV detection at 254 nm with the two diastereomeric peaks detected at 11.82 minutes and 15.09 minutes labeled Fractions 1 and 2, respectively.

[0259] Method 3: Peak B (approximately 0.460 g), eluting second at 11.5 minutes from Method 1, was subjected to a second SFC purification to resolve the remaining two diastereomers using a CHIRALPAK® IG column (30 × 250 mm, 5 μm) using a mobile phase of 30% isopropanol (0.2% diethylamine) / CO at 35° C. Fractions were collected based on UV detection at 254 nm, with two additional diastereomeric peaks detected at 4.42 minutes and 6.65 minutes, labeled fractions 3 and 4, respectively. Four diastereomeric peaks were isolated to elute by these respective methods at 11.82 minutes (1), 15.09 minutes (2), 4.42 minutes (3), and 6.65 minutes (4). Fraction peaks 1, 2, and 3 were concentrated and each re-purified by flash chromatography (methanol in dichloromethane) to remove traces of diethylamine SFC additive to give the title chiral compounds (in fraction peak order 1, 2, and 3), which were arbitrarily assigned stereochemistry: Compound 184. (>99% ee). 1H NMR (400 MHz, ジメチルスルホキシド-d6) δ ppm 7.90 (dd, J = 9.4, 5.8 Hz, 1H), 7.84 (d, J = 14.4 Hz, 1H), 7.51 (dd, J = 3.3, 1.9 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.17 (t, J = 73.4 Hz, 1H), 6.29 (d, J = 1.9 Hz, 1H), 3.32 (dt, J = 4.5, 2.3 Hz, 1H), 3.18 (s, 3H), 2.98 (p, J = 6.7 Hz, 2H), 2.83 (dd, J = 11.7, 5.5 Hz, 1H), 2.65 (dd, J = 9.2, 4.9 Hz, 1H), 2.50 (s, 3H), 2.44 - 2.27 (m, 5H), 1.77 (d, J = 11.8 Hz, 2H), 1.55 (s, 1H), 1.47 - 1.28 (m, 6H), 1.11 (dd, J = 6.7, 1.7 Hz, 6H). MS (APCI+) m / z: 598 [M+H] + . Compound 185. (>98%ee). (>99%ee). 1H NMR (400 MHz, ジメチルスルホキシド-d6) δ ppm 7.90 (dd, J = 9.4, 5.8 Hz, 1H), 7.84 (d, J = 14.4 Hz, 1H), 7.51 (dd, J = 3.3, 1.9 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.17 (t, J = 73.4 Hz, 1H), 6.29 (d, J = 1.9 Hz, 1H), 3.32 (dt, J = 4.5, 2.3 Hz, 1H), 3.18 (s, 3H), 2.98 (p, J = 6.7 Hz, 2H), 2.83 (dd, J = 11.7, 5.5 Hz, 1H), 2.65 (dd, J = 9.2, 4.9 Hz, 1H), 2.50 (s, 3H), 2.44 - 2.27 (m, 5H), 1.77 (d, J = 11.8 Hz, 2H), 1.55 (s, 1H), 1.47 - 1.28 (m, 6H), 1.11 (dd, J = 6.7, 1.7 Hz, 6H). MS (APCI+) m / z: 598 [M+H] + . Compound 186. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.90 (dd, J = 9.4, 5.8 Hz, 1H), 7.84 (d, J = 14.4 Hz, 1H), 7.51 (dd, J = 3.3, 1.9 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.17 (t, J = 73.4 Hz, 1H), 6.29 (d, J = 1.9 Hz, 1H), 3.32 (dt, J = 4.5, 2.3 Hz, 1H), 3.18 (s, 3H), 2.98 (p, J = 6.7 Hz, 2H), 2.83 (dd, J = 11.7, 5.5 Hz, 1H), 2.65 (dd, J = 9.2, 4.9 Hz, 1H), 2.50 (s, 3H), 2.44 - 2.27 (m, 5H), 1.77 (d, J = 11.8 Hz, 2H), 1.55 (s, 1H), 1.47 - 1.28 (m, 6H), 1.11 (dd, J = 6.7, 1.7 Hz, 6H). MS (APCI+) m / z: 598 [M+H] + .

[0260] [Example #24] Compound 35: 4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(6,6-dimethyl-4,5-dihydrocyclopenta[c]pyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-4-carboxylic acid

[0261] [ka]

[0262] Step 1: (E)-5-((dimethylamino)methylene)-2,2-dimethylcyclopentanone. A mixture of N,N-dimethylformamide dimethyl acetal (7 mL) and 2,2-dimethylcyclopentanone (5 g) in N,N-dimethylformamide (90 mL) was stirred at 100° C. for 18 hours. The resulting mixture was cooled to ambient temperature and then concentrated under reduced pressure to give the title compound. MS (ESI) m / z: 168.3 (M+H).+ .

[0263] Step 2: Methyl 1-benzyl-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-4-carboxylate. To a solution of INT-1 (3 g) in n-butanol (80 mL) was added (E)-5-((dimethylamino)methylene)-2,2-dimethylcyclopentanone (Step 1, 1.8 g) and hydrochloric acid (12 M in water) (1.5 mL), and the reaction was heated at 90° C. for 20 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was partitioned between saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 368.2 (M+H). + .

[0264] Step 3: 1-tert-butyl 4-methyl 4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-1,4-dicarboxylate. A mixture of methyl 1-benzyl-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-4-carboxylate (1.2 g), 10% palladium on activated carbon, type 39 (0.45 g), and hydrogen chloride (4 M in dioxane) (0.8 mL) in methanol (15 mL) was subjected to hydrogen gas at 5 bar and ambient temperature for 5 hours. The mixture was filtered through Whatman GF / F filter paper and washed with methanol (6 × 5 mL). The filtrate was concentrated under reduced pressure, and the crude material was dissolved in dichloromethane (15 mL). N,N-Diisopropylethylamine (3 mL) and di-tert-butyl dicarbonate (0.8 mL) were then added. The resulting reaction mixture was stirred at ambient temperature for 18 hours. The mixture was acidified with aqueous hydrochloric acid (1 M) and the two phases were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 353.2 (M- t Bu+H) + .

[0265] Step 4: 1-(tert-Butoxycarbonyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-4-carboxylic acid. To a solution of 1-tert-butyl 4-methyl 4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-1,4-dicarboxylate (0.83 g) in a solvent mixture of tetrahydrofuran (15 mL) and methanol (2.5 mL) was added 1M aqueous lithium hydroxide monohydrate solution (11 mL). The resulting solution was stirred at 40° C. for 18 hours. The reaction was acidified with saturated aqueous ammonium chloride solution (3 mL) and extracted with ethyl acetate (3×3 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. MS (ESI) m / z: 364.2 (M+H). + .

[0266] Step 5: tert-Butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-1-carboxylate. To a solution of 1-(tert-butoxycarbonyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-4-carboxylic acid (510 mg) in dichloromethane (20 mL) was added 1-(chloro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium hexafluorophosphate (V) (560 mg), 4-chloro-2-(difluoromethoxy)aniline (299 mg), and N,N-diisopropylethylamine (0.8 mL), and the reaction mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between saturated aqueous ammonium chloride (5 mL) and ethyl acetate (5 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 483.2 (M+H). + .

[0267] Step 6: N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-4-carboxamide. To a solution of tert-butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-1-carboxylate (540 mg) in 1,4-dioxane (1.2 mL) was added hydrogen chloride (4 M in 1,4-dioxane) (1.3 mL). The resulting reaction was stirred at ambient temperature for 18 hours. The reaction was concentrated under reduced pressure to provide the title compound as the hydrochloride salt. MS (ESI) m / z: 439.2 (M+H). + .

[0268] Step 7: Methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate. To a solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidine-4-carboxamide, hydrochloride (60 mg) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (25 mg) in 1,2-dichloroethane (1.5 mL) was added tetramethylammonium triacetoxyhydroborate (47 mg), and the resulting suspension was stirred at ambient temperature for 72 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was extracted with ethyl acetate (3 x 4 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 595.2 (M+H). + .

[0269] Step 8: Compound 35. To a solution of methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate (35 mg) in tetrahydrofuran (2 mL) and methanol (0.25 mL) was added lithium hydroxide (20 mg) in water (0.5 mL). The reaction was stirred at 40° C. for 18 hours. The volatiles were removed under reduced pressure. The crude material was dissolved in ethyl acetate (5 mL) and acidified with hydrogen chloride (4 M in 1,4-dioxane) (0.15 mL). The solvent was removed under reduced pressure. The crude product was purified by flash chromatography (acetonitrile / water with 0.1% formic acid) to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.15 (s, 6H), 1.59 - 1.64 (m, 2H), 1.91 - 1.99 (m, 2H), 2.27 (t, J = 6.7 Hz, 2H), 2.54 (d, J = 6.3 Hz, 1H), 2.72 - 2.78 (m, 5H), 3.06 (s, 2H), 3.46 - 3.63 (m, 4H), 3.63 - 3.75 (m, 4H), 7.00 - 7.41 (m, 4H), 7.49 (s, 1H), 8.03 (s, 1H), 13.42 (s, 1H). MS (ESI) m / z: 582.2 (M+H) + .

[0270] [Example #25] Compound 66: 4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-4-carboxylic acid

[0271] [ka]

[0272] Step 1: Methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate. To a stirred solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide hydrochloride (0.31 g) (product of Example 5, Step 5), N,N-diisopropylethylamine (0.17 mL), and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (0.163 g) in dichloromethane (6 mL) was added tetramethylammonium triacetoxyhydroborate (0.249 g). The resulting suspension was stirred at ambient temperature for 18 hours. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (2 x 20 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound. MS (ESI) m / z: 588.2 (M+H). + .

[0273] Step 2: Compound 66. To a stirred solution of methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate (0.395 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 2 M aqueous lithium hydroxide solution (3 mL). The reaction mixture was stirred at 45° C. for 18 hours and then at 60° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material was acidified with 4 M hydrogen chloride in 1,4-dioxane (1 mL) and once again concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.15 (d, J = 6.8 Hz, 6H), 1.41 - 1.50 (m, 2H), 1.86 (d, J = 13.3 Hz, 2H), 2.29 - 2.38 (m, 5H), 2.44 - 2.48 (m, 2H), 2.69 (dd, J = 10.5, 5.1 Hz, 3H), 2.92 - 3.03 (m, 1H), 3.38 (d, J = 11.1 Hz, 2H), 3.65 - 3.72 (m, 2H), 7.17 (t, J = 73.4 Hz, 1H), 7.33 (d, J = 7.0 Hz, MS (ESI) m / z: 574.2 (M+H) + .

[0274] [Example #26] Compound 81: 4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropyl-4-methoxy-pyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-4-carboxylic acid

[0275] [ka]

[0276] Step 1: tert-Butyl 4-hydroxy-1H-pyrazole-1-carboxylate. To a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (45 g) in tetrahydrofuran (300 mL) at 0° C. was added 2 M aqueous sodium hydroxide (153 mL) and hydrogen peroxide (31 mL) sequentially. The resulting reaction mixture was stirred at 0° C. for 10 minutes and then warmed to ambient temperature for an additional 50 minutes. The mixture was then recooled to 0° C. and diluted with dichloromethane (300 mL). Aqueous hydrochloric acid (2 M) was added until a pH of 2 was reached. The organics were then separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. MS (ESI) m / z: 129.1 (M- t Bu+H) + .

[0277] Step 2: tert-Butyl 4-methoxy-1H-pyrazole-1-carboxylate. To a stirred solution of tert-butyl 4-hydroxy-1H-pyrazole-1-carboxylate (36 g) and cesium carbonate (100 g) in anhydrous N,N-dimethylformamide (300 mL) was added methyl iodide (11.5 mL). The reaction mixture was stirred at ambient temperature for 18 hours, then quenched with water (1000 mL) and extracted with methyl tert-butyl ether (3 x 300 mL). The combined organics were washed with brine (500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 143.1 (M- t Bu+H) + .

[0278] Step 3: 4-Methoxy-1H-pyrazole. A mixture of tert-butyl 4-methoxy-1H-pyrazole-1-carboxylate (27 g) in 4 M hydrogen chloride in 1,4-dioxane (150 mL) was heated with stirring at 50° C. for 2 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (100 mL), and the material was collected by filtration and washed with additional amounts of diethyl ether (2×25 mL) to give the title compound as the HCl salt. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.68 (s, 3H), 7.48 (s, 2H), NH not observed.

[0279] Step 4: 1-(tert-butyl) 4-methyl 4-(4-methoxy-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate. To an ice-cooled solution of tert-butyl 4-oxopiperidine-1-carboxylate (22 g) and 4-methoxy-1H-pyrazole, hydrochloride (10 g) in tetrahydrofuran (300 mL) was added sodium hydroxide (15 g). The mixture was stirred for 15 minutes, followed by the addition of a solution of chloroform (30 mL) in tetrahydrofuran (50 mL) at 0° C. over 15 minutes. The reaction mixture was warmed to ambient temperature and stirred for 18 hours. The solvent was removed under reduced pressure, and the material was partitioned between 1N aqueous hydrochloric acid (200 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were washed with water (2 x 50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product which was used in the next step without further purification.

[0280] Cesium carbonate (39.7 g) and methyl iodide (5.0 mL) were added sequentially to a stirred solution of crude 1-(tert-butoxycarbonyl)-4-(4-methoxy-1H-pyrazol-1-yl)piperidine-4-carboxylic acid (33 g) in N,N-dimethylformamide (250 mL). The reaction was stirred at ambient temperature for 1 hour. After this time, the reaction mixture was diluted with water (300 mL) and methyl tert-butyl ether (100 mL), and the aqueous layer was further extracted with methyl tert-butyl ether (2 x 100 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. MS (ESI) m / z: 284.1 (M- t Bu+H) + .

[0281] Step 5: 1-(tert-butyl) 4-methyl 4-(5-bromo-4-methoxy-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate. A 1 L three-neck round-bottom flask was charged with diisopropylamine (14 mL) and tetrahydrofuran (190 mL) and cooled to 0 °C. n-Butyllithium (48 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 45 minutes before being further cooled to -78 °C. A solution of 1-tert-butyl 4-methyl 4-(4-methoxy-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate (11.5 g) in tetrahydrofuran (190 mL) was added over 30 minutes at -78 °C under N. After 10 minutes, 1,2-dibromo-1,1,2,2-tetrachloroethane (20.26 g) was added in one portion, and the mixture was stirred for 10 minutes before warming to ambient temperature for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 362.0 / 364.0 (M+H). + .

[0282] Step 6: 1-(tert-butyl) 4-methyl 4-(4-methoxy-5-(prop-1-en-2-yl)-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate. A flask was charged with 1-tert-butyl 4-methyl 4-(5-bromo-4-methoxy-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate (5.38 g), potassium isopropenyl trifluoroborate (1.71 g), potassium carbonate (2.13 g), bis(triphenylphosphine)palladium(II) dichloride (0.27 g), 1,4-dioxane (30 mL), and water (10 mL). The mixture was degassed by bubbling N for 15 minutes, then heated to 80 °C and stirred for 18 hours. After cooling to ambient temperature, the mixture was partitioned between ethyl acetate (25 mL) and water (50 mL). The layers were separated and the organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 380.1 (M+H). + .

[0283] Step 7: 1-(tert-butyl) 4-methyl 4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate. A glass reactor insert was charged with 1-tert-butyl 4-methyl 4-(4-methoxy-5-(prop-1-en-2-yl)-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate (2.25 g), tris(triphenylphosphine)rhodium(I) chloride (0.494 g), ethanol (15 mL), and acetic acid (1.5 mL). The mixture was placed under a hydrogen atmosphere (5 bar) and stirred at ambient temperature for 18 hours. The mixture was filtered through Whatman GF / F filter paper, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 382.2 (M+H). + .

[0284] Step 8: 1-(tert-Butoxycarbonyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-4-carboxylic acid. To a solution of 1-tert-butyl 4-methyl 4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-1,4-dicarboxylate (1.7 g) in methanol (10 mL) was added 2 M aqueous lithium hydroxide (11 mL), and the mixture was stirred at 45 °C for 18 hours. The reaction mixture was diluted with ethyl acetate (30 mL), acidified with 1 M aqueous hydrochloric acid to pH 3 (approximately 10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organics were washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. MS (ESI) m / z: 312.2 (M- t Bu+H) + .

[0285] Step 9: tert-Butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-1-carboxylate. To a solution of 1-(tert-butoxycarbonyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-4-carboxylic acid (1.4 g) in anhydrous dichloromethane (10 mL) was added 1-(chloro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium hexafluorophosphate (V) (1.25 g) and N,N-diisopropylethylamine (2 mL). 4-Chloro-2-(difluoromethoxy)aniline (0.80 g) was added, and the reaction was stirred at ambient temperature for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 487.1 (M- t Bu+H) + .

[0286] Step 10: N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-4-carboxamide. Hydrogen chloride in 1,4-dioxane (4 M, 5 mL) was added to a stirred solution of tert-butyl 4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.2 g) in 1,4-dioxane (10 mL), and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with dichloromethane (5 mL) and methyl tert-butyl ether (2 x 5 mL). An additional amount of methyl tert-butyl ether (20 mL) was added, and the mixture was filtered. The material was evaporated to dryness in vacuo at 45°C to provide the title compound as the hydrogen chloride salt. MS(ESI)m / z:443.1(M+H) + .

[0287] Step 11: Methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate. To a stirred solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidine-4-carboxamide, hydrochloride (0.05 g) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (0.024 g) in 1,2-dichloroethane (2 mL) was added tetramethylammonium triacetoxyhydroborate (0.074 g), and the resulting suspension was stirred at 45° C. for 18 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (15 mL) and diluted with dichloromethane (10 mL). The aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 599.0 (M+H). + .

[0288] Step 12: Compound 81. To a solution of methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-4-methoxy-1H-pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate (0.025 g) in methanol (0.5 mL) was added 2 M aqueous lithium hydroxide solution (0.1 mL), and the mixture was stirred at 45° C. for 18 hours, then concentrated under reduced pressure. Hydrogen chloride in 1,4-dioxane (4 M, 2 mL) was then added, and the reaction mixture was once again concentrated under reduced pressure. The crude product was purified on a 2 g isolute cartridge eluting with water (5 mL) followed by acetonitrile (2×5 mL) and concentrated under reduced pressure to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.10 (d, J = 6.7 Hz, 6H), 1.40 - 1.50 (m, 2H), 1.81 - 1.90 (m, 2H), 2.28 - 2.36 (m, 6H), 2.4 - 2.49 (m, 2H), 2.67 - 2.74 (m, 2H), 2.83 - 2.90 (m, 1H), 3.38 (d, J = 11.1 Hz, 2H), 3.61 - 3.77 (m, 5H), 6.95 - 7.38 (m, 3H), 7.46 (s, 1H), 7.78 (d, J = 9.2 Hz, 1H), 8.15 (s, 1H), 12.53 (s, 1H). MS (ESI) m / z: 585.1 (M+H) + .

[0289] [Example #27] Compound 97: 3-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-1-ethoxycarbonyl-azetidine-3-carboxylic acid

[0290] [ka]

[0291] Step 1: 1-tert-butyl 3-ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1,3-dicarboxylate. To a solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide, hydrochloride (INT-2, 396 mg) and 1-(tert-butoxycarbonyl)-3-(ethoxycarbonyl)azetidine-3-carboxylic acid (290 mg) in ethyl acetate (5 mL) was added triethylamine (0.3 mL) followed by propanephosphonic anhydride (50% in ethyl acetate) (0.8 mL). The resulting solution was stirred at 60° C. for 90 minutes. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate (10 mL) and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 612.2 (M- t Bu+H) + .

[0292] Step 2: 1-tert-butyl 3-ethyl 3-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidine-1,3-dicarboxylate. To a solution of 1-tert-butyl 3-ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carbonyl)azetidine-1,3-dicarboxylate (250 mg) and 1,1,3,3-tetramethyldisiloxane (1 mL) in dichloromethane (12 mL) was added carbonylchlorobis(triphenylphosphine)iridium(I) (40 mg), and the reaction mixture was stirred at ambient temperature for 4 hours. Trifluoroacetic acid (0.1 mL) was then added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure from toluene (5 mL) twice. The material was partitioned between dichloromethane (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The aqueous phase was extracted with dichloromethane (2 x 10 mL) and the combined organic solution was washed successively with water (10 mL) and brine (10 mL). The mixture was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate (containing 2% triethylamine) / iso-hexane) to give the title compound. MS (ESI) m / z: 654.2 (M+H) + .

[0293] Step 3: Ethyl 3-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidine-3-carboxylate. To a solution of 1-tert-butyl 3-ethyl 3-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidine-1,3-dicarboxylate (102 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) dropwise, and the resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (25 mL) and extracted with dichloromethane (3 x 25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1 mL of 3M hydrogen chloride in cyclopentyl methyl ether and concentrated under reduced pressure to give the title compound. MS (ESI) m / z: 554.2 (M+H) + .

[0294] Step 4: Diethyl 3-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidine-1,3-dicarboxylate. To a solution of ethyl 3-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidine-3-carboxylate (0.090 g) and ethyl carbonochloridate (20 μL) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (60 μL) dropwise, and the reaction was stirred at ambient temperature for 18 hours. The reaction was quenched with methanol (0.5 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (methanol in dichloromethane with 0.7M ammonia) to give the title compound. MS (ESI) m / z: 626.2 (M+H). + .

[0295] Step 5: Compound 97. To a solution of diethyl 3-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidine-1,3-dicarboxylate (88 mg) in tetrahydrofuran (1.5 mL) was added lithium hydroxide (2 M in water) (0.70 mL), and the reaction mixture was stirred at 45° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (2 mL) and acidified with 6 M hydrogen chloride in isopropanol (0.5 mL), followed by concentration under reduced pressure. The crude product was purified by preparative HPLC (acetonitrile in water) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.10 (d, J = 6.6 Hz, 6H), 1.15 (t, J = 7.1 Hz, 3H), 2.22 - 2.39 (m, 2H), 2.42 - 2.48 (m, 2H), 2.61 - 2.76 (m, 2H), 2.83 (s, 2H), 2.87 - 3.02 (m, 1H), 3.34 - 3.43 (m, 2H), 3.76 (s, 2H), 3.99 (q, J = 7.1 Hz, 2H), 4.02 - 4.11 (m, 2H), 6.33 (d, J = 1.9 Hz, 1H), 6.93 - 7.43 (m, 3H), 7.53 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 13.50 (s, 1H). MS (ESI) m / z: 598.5 (M+H) + .

[0296] [Example #28] Compound 103: (1s,3s)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(6,6-dimethyl-5H-furo[3,2-c]pyrazol-1-yl)-1-piperidyl]cyclobutanecarboxylic acid

[0297] [ka]

[0298] Step 1: 3-(Benzyloxy)-4,4-dimethyldihydrofuran-2(3H)-one. Benzyl bromide (22 mL) was added to a suspension of cesium carbonate (100 g) and 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (20 g) in dichloromethane (500 mL). The reaction mixture was stirred at ambient temperature for 18 hours. The crude mixture was filtered, washed with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (methyl tert-butyl ether / iso-hexane) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 0.99 (s, 3H), 1.08 (s, 3H), 3.96 (s, 2H), 4.14 (s, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.91 (d, J = 12.0 Hz, 1H), 7.16–7.54 (m, 5H).

[0299] Step 2: 3-(Benzyloxy)-4,4-dimethyltetrahydrofuran-2-ol. Diisobutylaluminum hydride (150 mL) was added dropwise over 30 minutes via addition funnel to a stirred solution of 3-(benzyloxy)-4,4-dimethyldihydrofuran-2(3H)-one (26.8 g) in dichloromethane (490 mL) at −78° C. under nitrogen. The mixture was stirred for an additional 2 hours at −78° C. before being carefully quenched with 1 M aqueous sulfuric acid (240 mL) and diluted with methyl tert-butyl ether (240 mL) and ethyl acetate (400 mL). The mixture was stirred for 15 minutes before being transferred to a separatory funnel. The layers were separated, and the organic layer was washed with 1 M aqueous sulfuric acid (800 mL), saturated aqueous sodium bicarbonate (500 mL), and brine (500 mL). The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (methyl tert-butyl ether / iso-hexane) to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.00 (s, 3H), 1.04 (s, 3H), 3.41 (d, J = 3.0 Hz, 1H), 3.46 (d, J = 8.3 Hz, 1H), 3.63 (d, J = 8.3 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 4.63 (d, J = 12.2 Hz, 1H), 5.16 (dd, J = 5.3, 3.1 Hz, 1H), 6.36 (d, J = 5.2 Hz, 1H), 7.10 - 7.45 (m, 5H).

[0300] Step 3: 4-(benzyloxy)-3,3-dimethyltetrahydrofuran. Triethylsilane (55 mL) and boron trifluoride diethyl etherate (16 mL) were added sequentially to a stirred solution of 3-(benzyloxy)-4,4-dimethyltetrahydrofuran-2-ol (25.6 g) in anhydrous dichloromethane (450 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 2 hours, then warmed to 0° C. and stirred for an additional 1 hour. The mixture was cooled to −78° C., sodium bicarbonate (50 g) was added, and the mixture was stirred at −78° C. for 15 minutes. Saturated aqueous sodium bicarbonate (250 mL) was added, and the mixture was warmed to ambient temperature over 1 hour and then stirred at ambient temperature for an additional 16 hours. The layers were separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (methyl tert-butyl ether / iso-hexane) to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 0.98 (s, 3H), 1.05 (s, 3H), 3.40 (d, J = 7.8 Hz, 1H), 3.44 (d, J = 7.8 Hz, 1H), 3.61 (dd, J = 5.0, 2.8 Hz, 1H), 3.69 (dd, J = 9.7, 2.8 Hz, 1H), 3.96 (dd, J = 9.7, 5.0 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 7.21 - 7.41 (m, 5H).

[0301] Step 4: 4,4-Dimethyltetrahydrofuran-3-ol. A glass reactor insert was charged with 4-(benzyloxy)-3,3-dimethyltetrahydrofuran (22.7 g), methanol (120 mL), and palladium on carbon (JM Type 39, 2 g). The mixture was transferred to a stainless steel pressure vessel and stirred under a hydrogen atmosphere (5 bar) at ambient temperature for 3 hours. The mixture was filtered through Whatman GF / F filter paper, and the pad was washed with methanol (2 x 25 mL). The filtrate was concentrated under reduced pressure to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 0.91 (s, 3H), 0.94 (s, 3H), 3.34 (d, J = 7.7 Hz, 1H), 3.38 - 3.47 (m, 2H), 3.67 (dd, J = 5.3, 3.2 Hz, 1H), 3.95 (dd, J = 9.1, 5.3 Hz, 1H), 4.87 (s, 1H).

[0302] Step 5: 4,4-Dimethyldihydrofuran-3(2H)-one. Pyridinium chlorochromate (16.33 g) was added to a stirred solution of 4,4-dimethyltetrahydrofuran-3-ol (4.4 g) in dichloromethane (110 mL). The mixture was stirred at ambient temperature for 20 hours. The mixture was filtered through a plug of silica, eluting with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.03 (s, 6H), 3.86 (s, 2H), 3.98 (s, 2H).

[0303] Step 6: (Z)-2-((dimethylamino)methylene)-4,4-dimethyldihydrofuran-3(2H)-one. A mixture of N,N-dimethylformamide dimethyl acetal (5.2 mL) and 4,4-dimethyldihydrofuran-3(2H)-one (3.7 g) in N,N-dimethylformamide (65 mL) was stirred at 100° C. for 18 hours. After this time, the mixture was concentrated under reduced pressure. The residue was co-evaporated with toluene (2×50 mL). The crude product was dissolved in toluene (50 mL), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 0.99 (s, 6H), 3.00 (s, 6H), 3.88 (s, 2H), 6.34 (s, 1H).

[0304] Step 7: Ethyl 2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)acetate. Hydrochloric acid (12N, 5.5 mL) was added to a stirred suspension of ethyl 2-hydrazinyl acetate, hydrochloride salt (2.02 g) and (Z)-2-((dimethylamino)methylene)-4,4-dimethyldihydrofuran-3(2H)-one (2.70 g) in ethanol (45 mL). The mixture was heated to 70° C. and stirred for 30 minutes. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate / iso-hexane) to provide the title compound. MS(ESI)m / z:225.1(M+H) + .

[0305] Step 8: Ethyl 2-allyl-2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)pent-4-enoate. Sodium hydride (60% dispersion in mineral oil) (0.401 g) was added in one portion to a stirred solution of ethyl 2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)acetate (0.75 g) in N,N-dimethylformamide (15 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 10 minutes, after which allyl bromide (1.5 mL) was added. The mixture was warmed to ambient temperature and stirred for an additional 18 hours. The mixture was diluted with water (50 mL) and extracted with methyl tert-butyl ether (3 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (methyl tert-butyl ether / iso-hexane) to give the title compound. MS (ESI) m / z: 305.2 (M+H) + .

[0306] Step 9: 2-Allyl-2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)pent-4-enoic acid. Lithium hydroxide monohydrate (0.520 g) was added to a stirred solution of ethyl 2-allyl-2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)pent-4-enoate (0.754 g) in methanol (10 mL). The mixture was heated to 45° C. and stirred for 18 hours. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. MS (ESI) m / z: 277.2 (M+H). + .

[0307] Step 10: 2-Allyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)pent-4-enamide. Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (0.833 g) was added to a stirred solution of 2-allyl-2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)pent-4-enoic acid (0.72 g), 4-chloro-2-(difluoromethoxy)aniline (0.575 g), and 1-methyl-1H-imidazole (0.7 mL) in acetonitrile (8 mL). The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (10 mL) and 1N aqueous hydrochloric acid (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (methyl tert-butyl ether / iso-hexane) to give the title compound. MS (ESI) m / z: 452.2 (M+H). + .

[0308] Step 11: N-(4-chloro-2-(difluoromethoxy)phenyl)-1-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)cyclopent-3-enecarboxamide. Grubbs' second generation catalyst (0.074 g) was added to a stirred solution of 2-allyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-2-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)pent-4-enamide (0.79 g) in dichloromethane (150 mL). The mixture was heated to 50° C. and stirred for 18 hours. Additional Grubbs II (0.074 g, 0.087 mmol) was added, and the mixture was stirred at 50° C. for an additional 6 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (methyl tert-butyl ether / iso-hexane) to give the title compound. MS (ESI) m / z: 424.3 (M+H) + .

[0309] Step 12: N-(4-chloro-2-(difluoromethoxy)phenyl)-1-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)-3,4-dihydroxycyclopentanecarboxamide. Microencapsulated osmium tetroxide (0.3 mmol / g) (0.467 g) and 4-methylmorpholine 4-oxide (0.450 g) were added to a stirred solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-1-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)cyclopent-3-enecarboxamide (0.60 g) in acetone (14 mL). The mixture was heated to 45° C. and stirred for 18 hours. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 458.1 (M+H) + .

[0310] Step 13: Compound 103. Sodium periodate (144 mg) was added to a stirred solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-1-(6,6-dimethyl-5,6-dihydro-1H-furo[3,2-c]pyrazol-1-yl)-3,4-dihydroxycyclopentanecarboxamide (103 mg) in acetone (2 mL) and water (1 mL) at 0° C. The mixture was warmed to ambient temperature and stirred for 1 hour. The acetone was removed under reduced pressure, and the residue was partitioned between dichloromethane (10 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (3 mL), and cis-3-aminocyclobutanecarboxylic acid (25.9 mg), sodium cyanoborohydride (42.4 mg), and acetic acid (0.02 mL) were added sequentially. The mixture was stirred at ambient temperature for 72 hours. The solvent was removed under reduced pressure, and the residue was directly purified by flash column chromatography (methanol / dichloromethane). The material was further purified by preparative HPLC to give the title compound.1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.21 (s, 6H), 1.84 - 2.05 (m, 4H), 2.13 - 2.25 (m, 2H), 2.25 - 2.39 (m, 2H), 2.45 (d, J = 9.5 Hz, 2H), 2.52 - 2.60 (m, 1H), 2.61 - 2.75 (m, 3H), 4.53 (s, 2H), 7.21 (t, J = 73.1 Hz, 1H), 7.22 (s, 1H), 7.28 - 7.34 (m, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.83 (s, 1H). 8.02 (d, J = 8.8 Hz, 1H). No COOH was observed. MS(ESI) m / z: 539.1 (M+H) + .

[0311] [Example #29] Compound 141: (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid

[0312] [ka]

[0313] Step 1: Ethyl (R)-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate. To a stirred solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide hydrochloride (0.200 g) (product of Example #5, Step 5), N,N-diisopropylethylamine (0.11 mL), and (E)-ethyl 3-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acrylate (0.122 g) in dichloromethane (5 mL) was added tetramethylammonium triacetoxyhydroborate (0.160 g). The resulting suspension was stirred at ambient temperature for 18 hours. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (2 x 20 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound as a racemic mixture. The racemic mixture was then subjected to SFC chiral separation using a CHIRALPAK® IC 10 x 250 mm column to give the title compound. MS (ESI) m / z 616.2 (M+H) + The enantiomer ethyl (S)-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate was also isolated. MS(ESI) m / z 616.2 (M+H) + .

[0314] Step 2: Compound 141. To a stirred solution of ethyl (R)-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate (0.100 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 2 M aqueous lithium hydroxide solution (0.78 mL). The reaction mixture was stirred at 45° C. for 18 hours and at ambient temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the crude material was acidified with 4N hydrogen chloride in 1,4-dioxane (1 mL) and concentrated again under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to provide the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 1.17 (dd, J = 6.9, 3.6 Hz, 6H), 1.22 - 1.40 (m, 3H), 1.36 - 1.47 (m, 1H), 1.49 - 1.59 (m, 1H), 1.70 - 1.86 (m, 1H), 2.39 - 2.49 (m, 2H), 2.51 - 2.62 (m, 2H), 2.66 - 3.16 (m, 6H), 3.07 - 3.29 (m, 3H), 3.75 - 3.88 (m, 2H), 7.19 (t, J = 73.4 Hz, 1H), 7.34 (d, J = 7.4 MS (ESI) m / z: 587.2 (M+H) + .

[0315] [Example #30] Compound 158: (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid

[0316] [ka]

[0317] Compound 158. (S)-ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate (0.100 g) (isolated during Example #29, Step 1) in methanol (2 mL) and tetrahydrofuran (2 mL) was stirred, and a 2 M solution of lithium hydroxide (0.78 mL) was added. The reaction mixture was stirred at 45° C. for 18 hours and then at ambient temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude material was acidified with 4N hydrogen chloride in 1,4-dioxane (1 mL) and concentrated again under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to provide the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 1.13 - 1.18 (m, 6H), 1.17 - 1.37 (m, 3H), 1.38 - 1.45 (m, 1H), 1.53 - 1.60 (m, 1H), 1.63 - 1.76 (m, 1H), 2.20 - 2.41 (m, 7H), 2.50 - 2.65 (m, 2H), 2.74 - 2.87 (m, 1H), 2.98 (p, J = 6.9 Hz, 1H), 3.23 (t, J = 11.6 Hz, 2H), 3.74 - 3.86 (m, 2H), 7.01 - 7.36 (m, 3H). 7.56 (d, J = 4.1 Hz, 1H), 7.58 - 7.63 (m, 1H), 8.61 (s, 1H), 12.08 (s, 1H). MS (ESI) m / z: 589.2 (M+H) + .

[0318] [Example #31] Compounds 161 and 162: (1r,4r)-1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]methyl]-4-hydroxy-cyclohexanecarboxylic acid and (1s,4s)-1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]methyl]-4-hydroxy-cyclohexanecarboxylic acid

[0319] [ka]

[0320] Step 1: Methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4,4-dimethoxycyclohexane-1-carboxylate. To a stirred solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide hydrochloride (0.150 g) (product of Example #5, Step 5), N,N-diisopropylethylamine (0.077 mL), and methyl 1-formyl-4,4-dimethoxycyclohexanecarboxylate (0.102 g) in dichloromethane (5 mL) was added tetramethylammonium triacetoxyhydroborate (0.117 g). The resulting suspension was stirred at ambient temperature for 18 hours. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (2 x 20 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound. MS (ESI) m / z: 646.2 (M+H). + .

[0321] Step 2: Methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexane-1-carboxylate. To a stirred solution of methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4,4-dimethoxycyclohexanecarboxylate (0.245 g) in tetrahydrofuran (2 mL) was added 1 M hydrochloric acid (2 mL), and the solution was stirred at 50° C. for 3 hours. The resulting mixture was cooled to ambient temperature and basified with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (3 x 20 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound. MS (ESI) m / z: 600.2 (M+H). + .

[0322] Step 3: 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexane-1-carboxylic acid. To a stirred solution of methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexanecarboxylate (0.220 g) in methanol (4 mL) and tetrahydrofuran (2 mL) was added 2 M aqueous lithium hydroxide solution (1.4 mL). The reaction mixture was stirred at 35° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The crude material was acidified with 4 N hydrogen chloride in 1,4-dioxane (1 mL) and concentrated under reduced pressure again. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound. MS (ESI) m / z: 586.2 (M+H). + .

[0323] Step 4: Compounds 161 and 162. To a stirred solution of 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexanecarboxylic acid, hydrochloride (60 mg) in methanol (2 mL) was added sodium borohydride (15 mg) and the solution was stirred at ambient temperature for 18 hours. Brine (20 mL) was added and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-hydroxycyclohexanecarboxylic acid as a mixture of cis and trans isomeric products. The cis and trans isomeric mixture was then subjected to achiral separation using a Waters XBridge BEH C18 ODB column to give the title compound. Compound 161. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 1.15 (d, J = 6.8 Hz, 6H), 1.29 - 1.45 (m, 2H), 1.48 - 1.67 (m, 6H), 2.26 - 2.40 (m, 4H), 2.43 - 2.50 (m, 4H), 2.65 - 2.75 (m, 2H), 2.98 (p, J = 7.0 Hz, 1H), 3.55 (s, 1H), 4.34 (s, 1H), 7.00 - 7.36 (m, 3H), 7.56 (d, J = 4.1 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 8.58 (s, 1H), 12.34 (s, 1H). MS (ESI) m / z: 589.2 (M+H) + .Compound 162. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 1.07 - 1.28 (m, 10H), 1.61 - 1.70 (m, 2H), 1.95 - 2.02 (m, 2H), 2.26 - 2.38 (m, 6H), 2.41 - 2.48 (m, 2H), 2.63 - 2.72 (m, 2H), 2.93 - 3.01 (m, 1H), 3.27 - 3.36 (m, 1H), 4.41 (s, 1H), 6.98 - 7.36 (m, 3H), 7.56 (d, J = 4.2 Hz, 1H), 7.59 - 7.64 (m, 1H), 8.56 (s, 1H).COOH was not observed. MS(ESI) m / z: 589.2(M+H) + .

[0324] [Example #32] Compound 176: (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(6,6-dimethyl-4H-furo[3,4-c]pyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid

[0325] [ka]

[0326] Step 1: Ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate. To a stirred solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxamide, hydrochloride (200 mg) (product of Example 4, Step 6) and ethyl 3-oxo-2-(tetrahydro-2H-pyran-4-yl)propanoate (128 mg) in anhydrous dichloromethane (10.0 mL) was added N,N-diisopropylethylamine (0.14 mL) dropwise, followed by tetramethylammonium triacetoxyhydroborate (232 mg). The reaction mixture was stirred at ambient temperature for 16 hours. Additional tetramethylammonium triacetoxyhydroborate (232 mg) and N,N-diisopropylethylamine (0.14 mL) were added to the reaction mixture, and the mixture was stirred at ambient temperature for 48 hours. Upon completion, the reaction mixture was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (methanol / dichloromethane) to give ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate. MS (ESI) m / z: 626.2 (M+H). + .

[0327] Step 2: Compound 176. To a stirred solution of ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate (240 mg) in anhydrous methanol (1 mL) and tetrahydrofuran (1 mL) was added solid lithium hydroxide (46.9 mg). The reaction mixture was stirred at 45° C. for 16 hours. Upon completion, the solvent was removed under reduced pressure, and hydrogen chloride (4 M in 1,4-dioxane) (1.0 mL) was added. The mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (methanol / dichloromethane) to give a racemic mixture. The racemic mixture was then subjected to SFC chiral separation using a CHIRALPAK® IG, 5 μm, 21 mm×250 mm column to give the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 1.06 - 1.48 (m, 10H), 1.56 (d, J = 13.0 Hz, 1H), 1.64 - 1.74 (m, 1H), 2.09 (s, 1H), 2.20 - 2.41 (m, 5H), 2.51 - 2.56 (m, 2H), 2.70 (s, 1H), 2.92 (s, 1H), 3.23 (t, J = 11.5 Hz, 2H), 3.81 (d, J = 11.3 Hz, 2H), 4.68 (s, 2H), 7.05 - 7.33 (m, 2H), 7.36 (d, J = 2.3 Hz, MS (ESI) m / z: 598.2 (M+H) + .

[0328] [Example #33] Compound 195: (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-[(2R,4r,6S)-2,6-dimethyltetrahydropyran-4-yl]propanoic acid

[0329] [ka]

[0330] Step 1: Ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)propanoate. To a solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide, hydrochloride (INT-2, 300 mg), ethyl 2-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-oxopropanoate (230 mg), and N,N-diisopropylethylamine (240 μL) in dichloromethane (3 mL) was added tetramethylammonium triacetoxyhydroborate (350 mg), and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (3×30 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 625.2 (M+H) + .

[0331] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)propanoic acid. To a solution of ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)propanoate (320 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) was added lithium hydroxide (2 M in water) (3 mL), and the reaction mixture was stirred at 45° C. for 18 hours. The reaction was then quenched with 4 M hydrogen chloride in 1,4-dioxane (3 mL) and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound. MS (ESI) m / z: 597.2 (M+H). + .

[0332] Step 3: tert-Butyl (S)-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)propanoate. To a solution of 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)propanoic acid (255 mg) in dichloromethane (5 mL) was added tert-butyl 2,2,2-trichloroacetimidate (300 μL), and the reaction mixture was stirred at ambient temperature under an inert atmosphere for 16 hours. Boron trifluoride etherate (10 μL) and additional tert-butyl 2,2,2-trichloroacetimidate (150 μL) were added, and the reaction mixture was stirred at ambient temperature for an additional 48 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (methanol / dichloromethane) to give a racemic mixture. The racemic mixture was then subjected to SFC chiral separation using a CHIRALPAK® IG, 5 μm, 21 mm×250 mm column to give the title compound. MS (ESI) m / z: 653.2 (M+H). + .

[0333] Step 4: Compound 195. To a stirred solution of (S)-tert-butyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)propanoate (16 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (200 μl) and the reaction was stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (methanol / dichloromethane) to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 0.73 - 0.83 (m, 1H), 0.88 (q, J = 12.3 Hz, 1H), 1.05 (d, J = 6.1 Hz, 6H), 1.07 - 1.13 (m, 6H), 1.45 (d, J = 12.7 Hz, 1H), 1.56 - 1.66 (m, 1H), 1.76 (s, 1H), 2.18 - 2.28 (m, 1H), 2.27 - 2.40 (m, 4H), 2.41 - 2.53 (m, 2H), 2.56 - 2.69 (m, 1H), 2.80 - 2.88 (m, 1H). 2.92 (p, J = 6.6 Hz, 1H), 3.30 - 3.44 (m, 4H), 6.32 (d, J = 1.9 Hz, 1H), 6.94 - 7.36 (m, 1H), 7.32 (dd, J = 6.9, 3.2 Hz, 2H), 7.52 (d, J = 1.9 Hz, 1H), 7.79 (d, J = 9.4 Hz, 1H), 8.16 (s, 1H). No COOH was observed. MS(ESI) m / z: 597.3 (M+H). + .

[0334] [Example #34] Compound 208: (2S)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(6,6-dimethyl-4H-furo[3,4-c]pyrazol-1-yl)-1-piperidyl]methyl]-3-methoxy-propanoic acid

[0335] [ka]

[0336] Step 1: tert-Butyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate. To a solution of N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidine-4-carboxamide, hydrochloride salt (product of Example 4, Step 6) (650 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.620 mL) in dichloromethane (13 mL) was added a solution of tert-butyl 2-(methoxymethyl)acrylate (916 mg) in dichloromethane (4 mL). The mixture was stirred at ambient temperature for 18 hours. Additional 1,8-diazabicyclo[5.4.0]undec-7-ene (0.205 mL) and tert-butyl 2-(methoxymethyl)acrylate (257 mg) were added, and the reaction was heated at 30° C. for 6 hours. Saturated aqueous ammonium chloride (5 mL) was added, and the mixture was extracted with dichloromethane (3×5 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (methanol / dichloromethane) to give the title compound. MS (ESI) m / z: 613.3 (M+H). + .

[0337] Step 2: Compound 208. To a stirred solution of tert-butyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(6,6-dimethyl-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate (0.620 g) in dichloromethane (15 mL) was added trifluoroacetic acid (1.6 mL), and the solution was stirred at 35° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material was purified by flash chromatography (acetonitrile:water with 0.1% formic acid) to give a racemic mixture. The racemic mixture was then subjected to SFC chiral separation using a Phenomenex® Luna®-4, 21×250 mm, 5 μm column to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.38 (s, 6H), 2.10 - 2.41 (m, 5H), 2.79 (d, J = 8.8 Hz, 2H), 2.90 (d, J = 11.6 Hz, 1H), 3.21 (s, 3H), 3.31 - 3.54 (m, 5H), 4.69 (s, 2H), 7.21 (t, J = 73.0 Hz, 1H), 7.31 (dd, J = 8.8, 2.3 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.48 (s, 1H), 7.82 - 7.90 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 12.65 (s, 1H). MS (ESI) m / z: 557.2 (M+H) + .

[0338] [Example #35] Compound 211: (2R)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(6,6-dimethyl-4H-furo[3,4-c]pyrazol-1-yl)-1-piperidyl]methyl]-3-methoxy-propanoic acid

[0339] [ka]

[0340] Compound 211. The racemic mixture (product from Example #34, Step 2) was subjected to SFC chiral separation using a Phenomenex® Luna®-4, 21×250 mm, 5 μm column to afford the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.38 (s, 6H), 2.07 - 2.44 (m, 5H), 2.79 (d, J = 9.2 Hz, 2H), 2.86 - 2.96 (m, 1H), 3.21 (s, 3H), 3.33 - 3.52 (m, 5H), 4.69 (s, 2H), 7.21 (t, J = 73.0 Hz, 1H), 7.31 (dd, J = 8.8, 2.3 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.48 (s, 1H), 7.87 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H).COOH was not observed. MS(ESI) m / z: 557.3(M+H) + .

[0341] [Example #36] Compounds 197 and 198: (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-chloro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid and (2R)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-chloro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]-2-tetrahydropyran-4-yl-propanoic acid

[0342] [ka]

[0343] Step 1: 1-benzyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide. To a stirred mixture of 1-benzyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (Preparation #2, Step 4, 3.00 g, 5.96 mmol) in acetonitrile (39.8 mL) was added HCl (4 M in dioxane) (2.98 mL, 11.93 mmol). The mixture was stirred for 30 minutes, and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (2.75 g, 7.75 mmol) was added. The mixture was stirred at ambient temperature for 4 days. The mixture was quenched with saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (100 mL) was added. The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with ethyl acetate in heptane to give the title compound. 1 H NMR (499 MHz, pyridine-d5) δ ppm 9.10 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 7.51 - 7.36 (m, 5H), 7.35 - 7.26 (m, 3H), 3.48 (s, MS (APCI+) m / z: 538.3 (M+H) + .

[0344] Step 2: N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide. 1-Chloroethyl carbonochloridate (0.699 mL, 6.48 mmol) was added to a solution of 1-benzyl-N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (2.90 g, 5.40 mmol) in 1,2-dichloroethane (DCE, 27.0 mL) at 0° C. The reaction mixture was heated at 83° C. for 16 hours. The mixture was cooled to 60° C., and methanol (approximately 15 mL) was added. The mixture was heated to reflux for 2 hours, cooled to ambient temperature, and concentrated. Methanol (~20 mL) was added and the mixture was heated at reflux for an additional 4 h, cooled to ambient temperature and concentrated to give the crude title compound. MS (APCI+) m / z: 448.2 (M+H). + .

[0345] Step 3: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate. Crude N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (0.974 g, 2.177 mmol) was dissolved in 1,2-dichloroethane (18.15 mL). Methyl 3-oxo-2-(tetrahydro-2H-pyran-4-yl)propanoate (0.631 g, 3.05 mmol) and sodium triacetoxyborohydride (0.692 g, 3.27 mmol) were added, and the mixture was stirred at ambient temperature overnight. Saturated sodium carbonate solution (30 mL) was added, and the mixture was extracted with dichloromethane (150 mL). The dichloromethane layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography eluting with ethyl acetate in heptane to give the title compound. 1H NMR (600 MHz, ジメチルスルホキシド-d6) δ ppm 8.75 (s, 1H), 7.59 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.16 (s, 1H), 3.88 - 3.77 (m, 4H), 3.59 (s, 3H), 3.30 - 3.19 (m, 2H), 3.08 (h, J = 6.9 Hz, 1H), 2.77 (dd, J = 10.0, 5.4 Hz, 1H), 2.58 - 2.51 (m, 1H), 2.36-2.33 (m, 4H), 2.25 (s, 1H), 2.10 - 2.01 (m, 1H), 1.70 (dtt, J = 11.4, 7.5, 3.7 Hz, 1H), 1.57 (ddd, J = 13.2, 3.8, 2.0 Hz, 2H), 1.38-1.15(m, 9H). ). MS (APCI+) m / z: 618.5 (M+H) + .

[0346] Step 4: rac-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoic acid. Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoate (1.30 g, 2.105 mmol) was dissolved in a mixture of tetrahydrofuran (9.02 mL), methanol (9.02 mL), and water (3.01 mL). Lithium hydroxide monohydrate (0.353 g, 8.42 mmol) was added, and the reaction mixture was stirred at 50 °C overnight. The reaction mixture was concentrated to remove some organic solvents. Dichloromethane (100 mL) was added, and the pH was adjusted to approximately 3 by adding 1N aqueous HCl. The aqueous layer was extracted with dichloromethane (2 x 40 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography eluting with ethyl acetate in heptane followed by methanol in ethyl acetate to give the title compound. MS (APCI+) m / z: 604.5 (M+H). + .

[0347] Step 5: Compounds 197 and 198. Racemic 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)propanoic acid was separated by preparative chiral supercritical fluid chromatography (CHIRALPAK® IC, 250 × 30 mm; mobile phase: (A) CO and (B) methanol). Fractions from the first eluting peak were concentrated and dissolved in 400 mL of dichloromethane. Water (10 mL) was added, and the pH was adjusted to approximately 3 with 1 N aqueous HCl. The organics were collected, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol (0-10%) in dichloromethane to give compound 197. 1H NMR (499 MHz, dimethyl sulfoxide-d6) δ ppm 8.81 (s, 1H), 7.61 (s, 1H), 7.58 - 7.52 (m, 1H), 7.36 - 7.30 (m, 1H), 7.32 (s, 1H), 7.17 ( s, 1H), 3.85 - 3.78 (m, 2H), 3.28 - 3.19 (m, 2H), 3.06 (h, J = 7.0 Hz, 1H), 2.86 (s, 1H), 2.66 - 2.56 (m, 2H), 2.43 - 2.34 (m, 8H), 1.71 (dtt, J = 11.2, 7.2, 3.6 Hz, 1H), 1.56 (ddt, J = 11.1, 4.2, 2.2 Hz, 1H), 1.42 (ddd, J = 13.1, 4.1, 2.1 Hz, 1H), 1.38–1.17 (m, 9H). Fractions from the second-eluting peak were concentrated and dissolved in 400 mL of dichloromethane. Water (10 mL) was added, and the pH was adjusted to approximately 3 with 1 N aqueous HCl. The organics were collected, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol in dichloromethane to give compound 198. 1H NMR (499 MHz, dimethyl sulfoxide-d6) δ ppm 8.81 (s, 1H), 7.61 (s, 1H), 7.58 - 7.52 (m, 1H), 7.36 - 7.30 (m, 1H), 7.32 (s, 1H), 7.17(s, 1H), 3.85 - 3.78 (m, 2H), 3.24 (td, J = 11.9, 2.0 Hz, 2H), 3.06 (h, J = 7.0 Hz, 1H), 2.86 (s, 1H), 2.66 - 2.57 (m, 2H), 2.42 - 2.34 (m, 8H), 1.72 (tdt, J = 11.2, 7.1, 3.5 Hz, 1H), 1.56 (ddd, J = 13.2, 4.0, 2.2 Hz, 1H), 1.42 (ddd, J = 13.0, 4.0, 2.1 Hz, 1H), 1.38 - 1.17 (m, 9H).

[0348] [Example #37] Compounds 205 and 206: (2S)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-chloro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]methyl]-3-methoxy-propanoic acid and (2R)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-chloro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]methyl]-3-methoxy-propanoic acid

[0349] [ka]

[0350] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate. Crude N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (Example #36, Step 2, 1.5 g, 2.68 mmol) was dissolved in dichloromethane (16.77 mL). Methyl 2-(methoxymethyl)prop-2-enoate (0.524 g, 4.02 mmol) was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.661 mL, 4.43 mmol), and the mixture was stirred at ambient temperature for 12 hours. Water (15 mL) and dichloromethane (50 mL) were added, and the organics were collected. The aqueous layer was extracted with dichloromethane (30 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate in heptane to provide the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.15 (s, 1H), 7.83 - 7.78 (m, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.34 - 7.29 (m, 2H), 6.32 (d, J = 1.9 Hz, 1H), 3.91-3.2 (br, 6H), 2.93 (septet, J = 6.7 Hz, 1H), 2.70 (p, J = 7.7 Hz, 1H), 2.62 (dt, J = 12.2, 4.5 Hz, 2H), 2.37 (dq, J = 13.4, 4.5 Hz, 2H), 2.20 - 2.17 (m, 2H), 2.17 - 2.11 (m, 2H), 1.88 (ddd, J = 9.7, 7.2, 2.6 Hz, 2H), 1.29 (s, 2H), 1.10 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z: 578.5 (M+H) + .

[0351] Step 2: rac-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoic acid. Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate (1.28 g, 2.217 mmol) was dissolved in a mixture of tetrahydrofuran (9.50 mL), methanol (9.50 mL), and water (3.17 mL). Lithium hydroxide monohydrate (0.372 g, 8.87 mmol) was added, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated to remove some organic solvents, dichloromethane (100 mL) was added, and the pH was adjusted to approximately 3 with 1N aqueous HCl. The aqueous layer was extracted with dichloromethane (2 x 40 mL), and the combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate in heptane followed by methanol in ethyl acetate to give the title compound. MS (APCI+) m / z: 565.4 (M+H). + .

[0352] Step 3: Compounds 205 and 206. Racemic 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-chloro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoic acid was separated by preparative chiral supercritical fluid chromatography (CHIRALCEL® OZ™-H, 250 × 30 mm; mobile phase: (A) CO and (B) methanol). Each pair of peaks was pooled and repurified by column chromatography (methanol in dichloromethane) to give the title compound 206: 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.84 (s, 1H), 7.61 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.17 (s, 1H), 3.46 (qd, J = 9.3, 6.1 Hz, 2H), 3.21 (s, 3H), 3.07 (p, J = 7.0 Hz, 2H), 2.83-2.65 (m,4H), 2.54 (m, 1H), 2.41 - 2.36 (m, 6H), 1.23 (dd, J = 6.9, 1.2 Hz, 6H). MS (APCI+) m / z: 565.4 (M+H) + .Compound 205: 1 H NMR (499 MHz, dimethyl sulfoxide-d6) δ ppm 8.83 (s, 1H), 7.61 (s, 1H), 7.58-7.52 (m, 1H), 7.36-7.30 (m, 2H), 7.17 (s, 1H), 3.45 (qd, J = 9.3, 6.1 Hz, 2H), 3.21 (s, 3H), 3.07 (p, J = 6.9 Hz, 2H), 2.82-2.65 (m, 4H), 2.56-2.51 (m, 1H), 2.38 (q, J = 5.1 Hz, 6H), 1.28-1.17 (m, 6H). MS (APCI+) m / z: 565.4 (M+H) + .

[0353] [Example #38] Compound 51: 2-[4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-4-yl]acetic acid

[0354] [ka]

[0355] Step 1: tert-Butyl 2-(4-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carbonyl)tetrahydro-2H-pyran-4-yl)acetate. To a solution of 4-(2-(tert-butoxy)-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylic acid (110 mg) and N,N-diisopropylethylamine (0.25 mL) in dichloromethane (4 mL) was added 1-(chloro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium hexafluorophosphate (V) (155 mg), and the reaction was stirred at ambient temperature for 3 hours. INT-2 (169 mg) was added, and the reaction was stirred at ambient temperature for an additional 18 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride (5 mL). The mixture was extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate / iso-hexane) to give the title compound. MS (ESI) m / z: 583.2 (M- t Bu+H) + .

[0356] Step 2: Compound 51. 1,1,3,3-Tetramethyldisiloxane (0.4 mL) was added dropwise to a solution of tert-butyl 2-(4-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-1-carbonyl)tetrahydro-2H-pyran-4-yl)acetate (150 mg) and carbonylchlorobis(triphenylphosphine)iridium(I) (17 mg) in dichloromethane (2.5 mL), and the reaction was stirred at ambient temperature for 30 minutes. Trifluoroacetic acid (0.05 mL) was added, and the reaction was stirred at ambient temperature for 45 minutes. The reaction mixture was diluted with toluene (1 mL) and concentrated under reduced pressure. The material was partitioned between dichloromethane (3 mL) and water (1 mL). The pH of the aqueous layer was adjusted to approximately 12 with 2N aqueous sodium hydroxide, and the mixture was washed with saturated aqueous ammonium chloride (5 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3 x 5 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. 1 H NMR (400 MHz, CD3OD) δ ppm 1.22 (d, J = 6.7 Hz, 6H), 1.42 - 1.56 (m, 2H), 1.88 (t, J = 7.5 Hz, 2H), 2.02 - 2.14 (m, 2H), 2.67 - 2.81 (m, 2H), 2.81 - 2.95 (m, 2H), 2.95 - 3.07 (m, 3H), 3.07 - 3.22 (m, 2H), 3.41 - 3.54 (m, 2H), 3.54 - 3.69 (m, 2H), 3.72 - 3.88 (m, 2H), 6.42 (d, J = 2.0 Hz, 1H), 6.83 (t, J = 73.0 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H). No exchangeable protons were observed. MS(ESI) m / z: 569.3 (M+H). + .

[0357] [Example #39] Compound 42: 1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]cyclohexanecarboxylic acid

[0358] [ka]

[0359] Step 1: Ethyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylate. To a solution of INT-2 (200 mg, 0.484 mmol) in dichloromethane (4.5 mL) was added ethyl 1-formylcyclohexane-1-carboxylate (268 mg, 1.45 mmol) and tetramethylammonium triacetoxyborohydride (382 mg, 1.45 mmol). The resulting mixture was then stirred at 25 °C for 18 hours. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS m / z: 581.3 [M+H] + .

[0360] Step 2: Compound 42. To ethyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexane-1-carboxylate (212 mg, 0.365 mmol) dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL) was added lithium hydroxide monohydrate (153 mg, 3.65 mmol). The mixture was stirred at 65° C. for 18 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with half-saturated aqueous ammonium chloride solution (2×5 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to provide the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.11 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.31 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 3.17 (s, 2H), 2.91 (m, 1H), 2.71 (m, 2H), 2.38 (m, 6H), 1.89 (m, 2H), 1.49 (m, 3H), 1.33 (m, 2H), 1.22 (m, 3H), 1.09 (d, J = 6.7 Hz, 6H). MS m / z: 553.1 [M+H] + .

[0361] [Example #40] Compound 45: 1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]cyclobutanecarboxylic acid

[0362] [ka]

[0363] Step 1: Methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclobutane-1-carboxylate. To a solution of INT-2 (200 mg, 0.484 mmol) dissolved in dichloromethane (4.5 mL) was added methyl 1-formylcyclobutane-1-carboxylate (206 mg, 1.45 mmol) and tetramethylammonium triacetoxyborohydride (382 mg, 1.45 mmol). The mixture was then stirred at 25 °C for 18 h. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS m / z: 539.4 [M+H] + .

[0364] Step 2: Compound 45. Methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclobutane-1-carboxylate (260 mg, 0.484 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (203 mg, 4.84 mmol) was added, and the mixture was stirred at 25 °C for 18 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with semi-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to give the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.18 (s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.33 (d, J = 1.8 Hz, 1H), 2.92 (m, 1H), 2.70 (m, 1H), 2.45 (m, 4H), 2.35 (m, 2H), 1.90 (m, 2H), 1.81 (m, 2H), 1.09 (d, J = 6.7 Hz, 6H). MS m / z: 525.2 [M+H] + .

[0365] [Example #41] Compound 52: 3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-methyl-2-tetrahydropyran-4-yl-propanoic acid

[0366] [ka]

[0367] Step 1: Ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-methyl-2-(tetrahydro-2H-pyran-4-yl)propanoate. To a solution of INT-2 (150 mg, 0.363 mmol) dissolved in 1,2-dichloroethane (3 mL), methyl ethyl 2-methyl-3-oxo-2-(tetrahydro-2H-pyran-4-yl)propanoate (117 mg, 0.545 mmol) and sodium triacetoxyborohydride (116 mg, 0.545 mmol) were added. The mixture was then stirred at 25 °C for 18 hours. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 611.3 [M+H] + .

[0368] Step 2: Compound 52. A solution of ethyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-methyl-2-(tetrahydro-2H-pyran-4-yl)propanoate (85 mg, 0.139 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (58 mg, 1.39 mmol) was added, and the solution was stirred at 70 °C for 72 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with semi-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.14 (bs, 1H), 7.80 (m, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.31 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 3.85 (m, 1H), 3.22 (m, 4H), 2.92 (m, 1H), 2.73 (m, 2H), 2.63, (m, 1H), 2.54 (m, 2H), 2.46 (m, 2H), 2.33 (m, 2H), 1.70 (m, 1H), 1.48 (m, 1H), 1.28 (m, 3H), 1.09 (d, J = 6.7 Hz, 6H), 1.05 (s, 3H). MS (APCI+) m / z: 585.2 [M+H] + .

[0369] [Example #42] Compound 63: 2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]indan-2-carboxylic acid

[0370] [ka]

[0371] Step 1: Methyl 2-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-indene-2-carboxylate. To a solution of INT-2 (200 mg, 0.484 mmol) dissolved in 1,2-dichloroethane (4.5 mL) was added methyl 2-formyl-2,3-dihydro-1H-indene-2-carboxylate (396 mg, 1.94 mmol) and tetramethylammonium triacetoxyborohydride (382 mg, 1.45 mmol). The mixture was then stirred at 25 °C for 18 h. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 601.3 [M+H] + .

[0372] Step 2: Compound 63. A solution of methyl 2-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-indene-2-carboxylate (195 mg, 0.324 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (136 mg, 3.24 mmol) was added, and the solution was stirred at 60° C. for 18 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with semi-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to give the title compound. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 12.60 (bs, 1H), 8.13 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.18 (m, 2H), 7.15 (t, J = 73.3 Hz, 1H), 7.10 (m, 2H), 6.32 (d, J = 1.9 Hz, 1H), 3.29 (m, 2H), 2.93 (m, 3H), 2.74 (m, 2H), 2.62 (s, 2H), 2.46 (m, 3H), 2.36 (m, 2H), 1.10 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z: 587.3 [M+H] + .

[0373] [Example #43] Compound 95: (1s,4s)-1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-4-hydroxy-cyclohexanecarboxylic acid

[0374] [ka]

[0375] Step 1: Methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4,4-dimethoxycyclohexane-1-carboxylate. To a solution of INT-2 (1000 mg, 2.42 mmol) dissolved in 1,2-dichloroethane (10 mL) was added methyl 1-formyl-4,4-dimethoxycyclohexane-1-carboxylate (1674 mg, 7.26 mmol) and sodium triacetoxyborohydride (1540 mg, 7.26 mmol). The resulting mixture was then stirred at 25 °C for 18 h. The resulting mixture was diluted with water (25 mL) and extracted with dichloromethane (2 × 25 mL). The combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 627.0 [M+H] + .

[0376] Step 2: Methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexane-1-carboxylate. To a solution of methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4,4-dimethoxycyclohexane-1-carboxylate (1230 mg, 1.961 mmol) dissolved in tetrahydrofuran (25 mL) was added a 1N aqueous solution of the hydrochloride salt (9.81 mL, 9.81 mmol), and the mixture was stirred at room temperature for 22 hours. A solution of half-saturated aqueous sodium bicarbonate (20 mL) was added, and the mixture was extracted with dichloromethane (25 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to give the title material. MS (APCI+) m / z: 581.0 [M+H] + .

[0377] Step 3: 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexane-1-carboxylic acid. To a solution of methyl 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexane-1-carboxylate (380 mg, 0.654 mmol) dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL), lithium hydroxide monohydrate (274 mg, 6.54 mmol) was added, and the solution was stirred at 50° C. for 18 hours. The resulting mixture was diluted with dichloromethane (20 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 × 10 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound. MS (APCI+) m / z: 567.0 [M+H] + .

[0378] Step 4: 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-hydroxycyclohexane-1-carboxylic acid. To 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexane-1-carboxylic acid (315 mg, 0.556 mmol) dissolved in methanol (10 mL) was added solid sodium borohydride (31.5 mg, 0.833 mmol) in portions over 2 minutes at room temperature. The mixture was stirred for 1.5 hours, after which a solution of half-saturated aqueous ammonium chloride (5 mL) was added and the mixture was extracted with dichloromethane (20 mL). The organic extract was then dried over magnesium sulfate, filtered, and concentrated to give the title compound. MS (APCI+) m / z: 569.2 [M+H] + .

[0379] Step 5: Compound 95. 220 mg of 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-hydroxycyclohexane-1-carboxylic acid was subjected to SFC separation using a CHIRAL ART cellulose-SC(IC) column with methanol containing 0.1% diethylamine added as the eluent to give the title compound as the second peak eluting from the column. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.10 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.14 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 4.42 (d, J = 4.5 Hz, 1H), 2.91 (m, 1H), 2.70 (m, 2H), 2.39 (m, 7H), 2.00 (m, 2H), 1.66 (m, 2H), 1.17 (m, 4H), 1.09 (d, J = 6.7 Hz, 6H).MS (APCI+) m / z: 569.2 [M+H] + .

[0380] [Example #44] Compound 175: (1r,4r)-1-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-4-hydroxy-4-methyl-cyclohexanecarboxylic acid

[0381] [ka]

[0382] Compound 175. To a solution of 1-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-4-oxocyclohexane-1-carboxylic acid (Example #43, Step 3, 50 mg, 0.088 mmol) dissolved in tetrahydrofuran (1.5 mL) was added a solution of methylmagnesium bromide (3.0 M in ether, 0.147 mL, 0.441 mmol) at room temperature. The mixture was stirred for 0.5 hours, and then a solution of half-saturated aqueous ammonium chloride (3 mL) was added. The mixture was extracted with dichloromethane (5 mL). The organic extract was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by HPLC to provide the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 7.81 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.31 (m, 2H), 7.14 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 2.91 (m, 1H), 2.75 (m, 2H), 2.54 (m, 2H), 2.46 (m, 4H), 2.35 (m, 2H), 1.91 (m, 2H), 1.38 (m, 4H), 1.31 (m, 2H), 1.08 (d, J = 6.7 Hz, 6H), 1.06 (s, 3H). MS (APCI+) m / z: 567.7 [M+H] + .

[0383] [Example #45] Compound 116: 3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-morpholino-propanoic acid

[0384] [ka]

[0385] Step 1: Methyl 2-bromo-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)propanoate. To a solution of INT-2 (200 mg, 0.484 mmol) dissolved in dichloromethane (3 mL) was added methyl 2-bromoacrylate (120 mg, 0.727 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (118 mg, 0.775 mmol). The mixture was stirred at 25 °C for 2 hours. The resulting mixture was diluted with water (5 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title product. MS(APCI+)m / z:577 / 579[M+H] + .

[0386] Step 2: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-morpholinopropanoate. To a solution of methyl 2-bromo-3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)propanoate (80 mg, 0.138 mmol) dissolved in acetonitrile (2 mL) was added morpholine (0.060 mL, 0.692 mmol) and potassium phosphate tribasic (88 mg, 0.415 mmol). The mixture was stirred at room temperature for 18 hours, after which water (5 mL) was added and the mixture was extracted with dichloromethane (10 mL). The organic extract was then dried over magnesium sulfate, filtered, and concentrated to give the title compound, which was used directly in the next reaction.

[0387] Step 3: Compound 116. To a solution of methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-morpholinopropanoate (80 mg, 0.137 mmol) dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL), lithium hydroxide monohydrate (58 mg, 1.37 mmol) was added. The solution was stirred at ambient temperature for 72 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to provide the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.19 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.33 (d, J = 1.8 Hz, 1H), 3.53 (m, 4H), 3.30 (m, 1H), 2.90 (m, 2H), 2.74 (m, 2H), 2.59 (m, 4H), 2.47 (m, 4H), 2.37 (m, 3H), 1.10 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z: 570.8 [M+H] + .

[0388] [Example #46] Compound 163: (2S)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-3-cyano-propanoic acid

[0389] [ka]

[0390] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(cyanomethyl)propanoate. To a solution of INT-2 (300 mg, 0.727 mmol) dissolved in dichloromethane (10 mL) was added methyl 2-(cyanomethyl)acrylate (272 mg, 2.18 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (354 mg, 2.33 mmol). The mixture was stirred at 25 °C for 48 hours. The resulting mixture was diluted with water (5 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS(APCI+)m / z:538.9[M+H] + .

[0391] Step 2: Compound 163. Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(cyanomethyl)propanoate (285 mg, 0.530 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (222 mg, 5.30 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with semi-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to give the racemic title compound. The racemic title compound (90 mg) was then subjected to SFC separation using a Whelk-O® (S,S) column with 1:1 isopropanol:methanol containing 0.1% diethylamine added as the eluent to give the title compound as the first peak eluting from the column. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.23 ​​(s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.33 (d, J = 1.8 Hz, 1H), 3.17 (s, 1H), 2.93 (m, 2H), 2.80 (m, 2H), 2.69 (m, 2H), 2.58 (m, 2H), 2.50 (m, 4H), 2.41 (m, 2H), 1.10 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z: 524.7 [M+H] + .

[0392] [Example #47] Compound 5: 1-acetyl-4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]piperidine-4-carboxylic acid

[0393] [ka]

[0394] Step 1: 1-(tert-butyl) 4-ethyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-1,4-dicarboxylate. To a solution of INT-2 (500 mg, 1.21 mmol) dissolved in dichloromethane (12 mL) was added 1-(tert-butyl) 4-ethyl 4-formylpiperidine-1,4-dicarboxylate (1036 mg, 3.64 mmol) and sodium triacetoxyborohydride (770 mg, 3.64 mmol). The resulting mixture was then stirred at 25 °C for 48 h. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 15 mL). The combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title product. MS (APCI+) m / z: 682.5 [M+H] + .

[0395] Step 2: 1-(tert-Butoxycarbonyl)-4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-4-carboxylic acid. To a solution of 1-(tert-butyl)4-ethyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-1,4-dicarboxylate (349 mg, 0.512 mmol) dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL) was added lithium hydroxide monohydrate (215 mg, 5.12 mmol), and the solution was stirred at 60° C. for 18 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 x 5 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound. MS (APCI+) m / z: 654.4 [M+H] + .

[0396] Step 3: 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-4-carboxylic acid. To 1-(tert-butoxycarbonyl)-4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-4-carboxylic acid (305 mg, 0.466 mmol) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (1.80 mL, 23.31 mmol), and the mixture was stirred at 25° C. for 1.5 hours. The resulting mixture was concentrated under reduced pressure to provide the title compound as the bistrifluoroacetic acid salt. MS (APCI+) m / z: 554.4 [M+H] + .

[0397] Step 4: Compound 5. To a mixture of 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-4-carboxylic acid bistrifluoroacetate (57 mg, 0.072 mmol) dissolved in tetrahydrofuran (1.5 mL), triethylamine (0.050 mL, 0.361 mmol) and acetic anhydride (0.0102 mL, 0.108 mmol) were added, and the solution was stirred at ambient temperature for 15 minutes. The resulting mixture was diluted with dichloromethane (1 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 × 3 mL). The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography using methanol in dichloromethane to give the title compound. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.12 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.14 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 4.01 (m, 1H), 3.62 (m, 1H), 3.15 (m, 1H), 2.91 (m, 1H), 2.77 (m, 1H), 2.72 (m, 2H), 2.46 (m, 3H), 2.34 (m, 2H), 1.97 (s, 3H), 1.96 (m, 1H), 1.88 (m, 1H), 1.41 (m, 1H), 1.28 (m, 1H), 1.09 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z: 626.4 [M+H] + .

[0398] [Example #48] Compound 119: (2R)-2-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-3-methoxy-propanoic acid

[0399] [ka]

[0400] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate. To a solution of INT-2 (200 mg, 0.484 mmol) dissolved in dichloromethane (3 mL) was added methyl 2-(methoxymethyl)prop-2-enoate (95 mg, 0.727 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (118 mg, 0.775 mmol). The mixture was then stirred at 25 °C for 2.5 h. The resulting mixture was diluted with water (5 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS (APCI+) m / z: 543.7 [M+H] + .

[0401] Step 2: Compound 119. Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-(methoxymethyl)propanoate (205 mg, 0.378 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (158 mg, 3.78 mmol) was added, and the solution was stirred at 25 °C for 24 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with semi-saturated aqueous ammonium chloride solution (2 × 5 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to give the racemic title compound. The racemic title compound was subjected to SFC separation using a CHIRAL ART cellulose SC(IC) column with ethanol containing 0.1% diethylamine added as the eluent to give the title compound as the second peak eluting from the column. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.21 (s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.15 (t, J = 73.2 Hz, 1H), 6.33 (d, J = 1.8 Hz, 1H), 3.48 (m, 4H), 3.21 (s, 3H), 2.93 (m, 1H), 2.83 (m, 1H), 2.75 (m, 2H), 2.49 (m, 3H), 2.38 (m, 3H), 1.10 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z: 529.7 [M+H] + .

[0402] [Example #49] Compound 78: (2S)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]-2-methyl-2-tetrahydropyran-4-yl-propanoic acid

[0403] [ka]

[0404] Step 1: Dimethyl 2-(tetrahydro-2H-pyran-4-yl)malonate. To a solution of potassium tert-butoxide (1.02 g, 9.08 mmol, 1.2 equiv.) in dimethyl sulfoxide (7.6 mL, 1 M) was added dimethyl malonate (1 g, 7.57 mmol, 1 equiv.) and 4-iodotetrahydro-2H-pyran (2.41 g, 11.35 mmol, 1.5 equiv.). The reaction mixture was heated to 80° C. for 16 hours, then cooled to room temperature and poured into 1N aqueous HCl. The mixture was extracted three times with methyl tert-butyl ether and washed with saturated sodium bicarbonate, 10% saturated NaSO, and brine. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography using ethyl acetate in heptane to give the title compound. MS (ESI) m / z 217.0 (M+H).+ .

[0405] Step 2: Dimethyl 2-methyl-2-(tetrahydro-2H-pyran-4-yl)malonate. A solution of dimethyl 2-(tetrahydro-2H-pyran-4-yl)malonate (2.3 g, 10.64 mmol, 1 equiv.) in tetrahydrofuran (42.5 mL, 0.25 M) was cooled to 0 °C. NaH (60% dispersion in mineral oil, 638 mg, 15.96 mmol, 1.5 equiv.) was added, and the mixture was stirred for 30 minutes. Iodomethane (3.02 g, 21.27 mmol, 2 equiv.) was added, and the reaction mixture was warmed to ambient temperature. After 16 hours, saturated aqueous NH4Cl was added, and the mixture was extracted three times with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography using ethyl acetate in heptane to give the title compound. MS (ESI) m / z 231.6 (M+H). + .

[0406] Step 3: Methyl 2-methyl-3-oxo-2-(tetrahydro-2H-pyran-4-yl)propanoate. A solution of dimethyl 2-methyl-2-(tetrahydro-2H-pyran-4-yl)malonate (1 g, 4.34 mmol, 1 equiv.) in dichloromethane (8.7 mL, 0.5 M) was cooled to −78° C. Diisobutylaluminum hydride (1 M in dichloromethane, 8.69 mL, 8.69 mmol, 2 equiv.) was added over 10 min. After 45 min, the reaction mixture was quenched by the addition of 350 μL of water, 350 μL of 15% aqueous NaOH, and then 870 μL of water. The mixture was diluted with methyl tert-butyl ether, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography using ethyl acetate in heptane to provide the title compound.

[0407] Step 4: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-methyl-2-(tetrahydro-2H-pyran-4-yl)propanoate. A solution of methyl 2-methyl-3-oxo-2-(tetrahydro-2H-pyran-4-yl)propanoate (495 mg, 2.47 mmol, 2 equiv.) and INT-2 (510 mg, 1.24 mmol, 1 equiv.) in 1,2-dichloroethane (6.2 mL, 0.2 M) was stirred at room temperature for 90 minutes. Tetramethylammonium triacetoxyborohydride (650 mg, 2.47 mmol, 2 equiv.) was added. After 20 hours, the mixture was poured into saturated NH4Cl and extracted three times with dichloromethane. The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography using ethyl acetate in heptane to give the title compound. MS (ESI) m / z 597.2 (M+H) + .

[0408] Step 5: Compound 78. Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)-2-methyl-2-(tetrahydro-2H-pyran-4-yl)propanoate (161 mg, 0.27 mmol, 1 equiv.) was dissolved in a mixture of tetrahydrofuran (1.2 mL), methanol (1.2 mL), and water (0.385 mL). Lithium hydroxide hydrate (113 mg, 2.7 mmol, 10 equiv.) was added, and the mixture was heated to 70° C. After 24 h, the reaction mixture was poured into saturated aqueous NH4Cl, extracted three times with dichloromethane, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography using methanol in dichloromethane to give a racemic mixture. The enantiomers were separated using chiral SFC using a CHIRALCEL® OZ™-H column. Both fractions were purified again using the original flash chromatography conditions to give the first-eluting peak, arbitrarily assigned as the R isomer, and the second-eluting peak, arbitrarily assigned as S, to give the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 12.47 (br s, 1H), 8.12 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.14 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 3.84 (dt, J = 10.4, 5.1 Hz, 2H), 3.23 (dddd, J = 11.5, 9.8, 7.7, 2.1 Hz, 2H), 2.92 (Septet, J = 6.7 Hz, 1H), 2.73 (ddt, J = 16.4, 10.3, 4.7 Hz, 2H), 2.63 (d, J = 13.4 Hz, 1H), 2.56 - 2.28 (m, 8H), 1.70 (ddt, J = 11.9, 7.0, 3.4 Hz, 1H), 1.48 (d, J = MS (ESI) m / z 583.0 (M+H) + .

[0409] [Example #50] Compound 3: 4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]tetrahydropyran-4-carboxylic acid

[0410] [ka]

[0411] Step 1: Methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate. To a solution of INT-2 (100 mg, 0.242 mmol) dissolved in dichloromethane (3 mL), methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (63 mg, 0.363 mmol) and sodium triacetoxyborohydride (77 mg, 0.363 mmol) were added. The mixture was then stirred at 25 °C for 18 hours. The resulting mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phases were dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate in heptane to give the title compound. MS(APCI+)m / z:569.4[M+H] + .

[0412] Step 2: Compound 3. Methyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-carboxylate (75 mg, 0.132 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL), and lithium hydroxide monohydrate (55 mg, 1.32 mmol) was added. The mixture was stirred at 40° C. for 62 hours. The resulting mixture was diluted with dichloromethane (10 mL) and extracted with semi-saturated aqueous ammonium chloride solution (2×5 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to give the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 12.55 (bs, 1H), 8.11 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.14 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 3.69 (m, 2H), 3.37 (m, 4H), 2.91 (m, 1H), 2.72 (m, 2H), 2.45 (m, 4H), 2.35 (m, 2H), 1.87 (m, 2H), 1.46 (m, 2H), 1.09 (d, J = 6.7 Hz, 6H). MS (APCI+) m / z: 555.4 [M+H] + .

[0413] [Example #51] Compound 123: (1s,3s)-3-[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(4-fluoro-5-isopropyl-pyrazol-1-yl)-1-piperidyl]cyclobutanecarboxylic acid

[0414] [ka]

[0415] Step 1: Methyl 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)cyclobutane-1-carboxylate. (Product of Example #5, Step 5), N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (1.38 g, 3.20 mmol) and methyl 3-oxocyclobutane-1-carboxylate (0.821 g, 6.41 mmol) were combined in a 40 mL pressure vial, followed by the addition of dimethyl sulfoxide (20 mL) and heating at 70 °C for 40 minutes to give a homogeneous solution. Formic acid (1.23 mL, 32.0 mmol) was then added, and the mixture was stirred at 70 °C for 17 hours. The reaction mixture was concentrated to dryness. The residue was purified by flash silica gel chromatography (ethyl acetate in heptane) to give the title compound. MS (APCI+) m / z: 543 [M] + .

[0416] Step 2: 3-(4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(4-fluoro-5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid. The product from Step 1 (1.1 g, 2.03 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of potassium trimethylsilanolate (0.78 g, 6.08 mmol). The reaction mixture was heated to 60° C. for 30 minutes. The reaction mixture was cooled to 25° C. and diluted with dichloromethane (40 mL) followed by saturated ammonium chloride (30 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (methanol in dichloromethane) to give the title compound. MS (APCI+) m / z: 529 [M+H] + .

[0417] Step 3: Compound 123. The cis, trans product mixture from Step 2 (0.721 g) was separated by preparative chiral supercritical fluid chromatography on a CHIRALCEL® OZ™-H column (30 × 250 mm, 5 μm) using a mobile phase of 25% 97:3 methanol (0.5% diethylamine) / water:CO at ambient temperature. Fractions were collected based on UV detection at 254 nm of the desired second-eluting peak (B), detected at 12.65 minutes as the cis isomer. Peak B was concentrated to dryness and then repurified by silica gel chromatography to remove residual diethylamine additive, and an SFC run eluting with methanol in dichloromethane afforded the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 8.62 (s, 1H), 7.63 - 7.59 (m, 1H), 7.56 (d, J = 4.2 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.33 (s, 1H), 7.17 (d, J = 73.2 Hz, 1H), 2.99 (septet, J = 7.0 Hz, 2H), 2.67 (tt, J = 9.8, 8.2 Hz, 2H), 2.57 (ddd, J = 15.3, 7.3, 3.8 Hz, 6H), 2.36 (d, J = 9.9 Hz, 2H), 2.25 - 2.14 (m, 2H), 1.95 - 1.85 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H). MS (APCI+) m / z: 529 [M+H] + .

[0418] [Example #52] Compound 41: 4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-1-propanoyl-piperidine-4-carboxylic acid

[0419] [ka]

[0420] Step 1: Ethyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-4-carboxylate. 1-tert-Butyl 4-ethyl 4-formylpiperidine-1,4-dicarboxylate (83 mg, 0.291 mmol) was added to N-(4-chloro-2-(difluoromethoxy)phenyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidine-4-carboxamide (INT-2, 60 mg, 0.145 mmol) in 1,2-dichloroethane (2 mL), followed by the addition of tetramethylammonium triacetoxyborohydride (76 mg, 0.291 mmol). The mixture was stirred at 40° C. overnight. The reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with brine and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate in hexane) to give 1-tert-butyl 4-ethyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-1,4-dicarboxylate, which was dissolved in dichloromethane (1 mL). 4 M HCl in dioxane (4 mL) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give the crude title compound. MS (APCI+) m / z: 582 (M+H) + .

[0421] Step 2: Compound 41. Triethylamine (0.084 mL, 0.601 mmol) was added to a solution of ethyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-4-carboxylate (70 mg, 0.120 mmol) in dichloromethane (2 mL). Propionyl chloride (11.13 mg, 0.120 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate in hexanes) to give ethyl 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)-1-propionylpiperidine-4-carboxylate, which was dissolved in methanol (2 mL) and 5 N aqueous NaOH (0.5 mL) and stirred at room temperature overnight. The pH was adjusted to approximately 1 by adding 2 N aqueous HCl. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to give the title compound as the trifluoroacetic acid salt. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 7.65 (s, 1H), 7.61 (s, 1H), 7.34 (m, 2H), 7.18 (t, J = 73.2 Hz, 1H), 6.41 (s, 1H), 3.73 (s, 1H), 3.66 - 3.02 (m, 10H), 2.87 (s, 1H), 2.68 (s, 4H), 2.31 (p, J = 6.7 Hz, 2H), 1.95 (dd, J = 45.6, 13.7 Hz, 2H), 1.55 (d, J = 43.2 Hz, 2H), 1.13 (d, J = 6.6 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H). MS (APCI+) m / z 610 (M+H) + .

[0422] [Example #53] Compound 6: 4-[[4-[[4-chloro-2-(difluoromethoxy)phenyl]carbamoyl]-4-(5-isopropylpyrazol-1-yl)-1-piperidyl]methyl]-1-ethoxycarbonyl-piperidine-4-carboxylic acid

[0423] [ka]

[0424] Compound 6. To a solution of 4-((4-((4-chloro-2-(difluoromethoxy)phenyl)carbamoyl)-4-(5-isopropyl-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidine-4-carboxylic acid bistrifluoroacetate (Example #47, Step 3, 57 mg, 0.072 mmol) dissolved in a mixture of dichloromethane (1.5 mL), triethylamine (0.050 mL, 0.361 mmol) and acetic anhydride (0.0078 mL, 0.072 mmol) were added, and the solution was stirred at ambient temperature for 10 minutes. The resulting mixture was diluted with dichloromethane (1 mL) and extracted with half-saturated aqueous ammonium chloride solution (2 × 3 mL). The combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methanol in dichloromethane to provide the title compound. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.11 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.32 (m, 2H), 7.14 (t, J = 73.2 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 4.01 (d, J = 7.1 Hz, 2H), 3.73 (m, 2H), 3.17 (s, 2H), 2.95 (m, 2H), 2.92 (m, 1H), 2.72 (m, 2H), 2.44 (m, 4H), 2.35 (m, 2H), 1.90 (m, MS (APCI+) m / z: 626.4 [M+H] + .

[0425] [Example 54] Inhibitory activity of compounds 15, 62, 77, 84, and 169 against LPAR1 The inhibitory activity of compounds 15, 62, 77, 84, and 169 against LPAR1 was measured in human LPAR1-expressing U2OS cells using an arrestin assay.

[0426] Arrestin Assay Reagents

[0427] [Table 3]

[0428] Arrestin Assay Protocol FreeStyle medium was warmed in a 37°C water bath. A cryovial of TangoEDG2-bla U2OS cells was rapidly thawed in a 37°C water bath. The thawed cells were added to FreeStyle medium, and the cells were pelleted at 300 x g for 5 minutes. The supernatant was aspirated, and the cells were resuspended in FreeStyle medium. The cell density was adjusted to 0.25 x 10 6 The cells (1 × 10 in 40 μL) were adjusted to 1 × 10 cells / mL. 4Cells) were added to each well of a Greiner 384-well black cell plate. The cell plate was placed in a humidified 37°C / 5% CO2 incubator for 18-20 hours. Test compound dilutions were prepared using HH buffer (1x HBSS + 20 mM HEPES) at 6x final concentrations, 12-point, 3-fold dilutions. 6x test compounds were then added to the cell plate at 10 μL / well. Final concentrations ranged from 10 μM to 0.00006 μM. The cell plate was incubated for 1 hour in a humidified 37°C / 5% CO2 incubator. During incubation, 6x LPA was prepared at 1.5 μM in 0.1% BSA HH buffer. After incubating the test compounds with the cells for 1 hour, LPA was added to the cell plate at 10 μL / well (final LPA concentration 0.25 μM). The cell plate was returned to a humidified 37°C / 5% CO2 incubator for 3 hours. Development solution was made according to the LiveBLAzerFRET B / G kit protocol. Development solution was added to the cell plate at 10 μL / well. The cell plate was incubated in the dark at room temperature for 2 hours. The plate was read on an Envision plate reader (Perkin Elmer) to read fluorescence, excitation (409 nm), and emission (460 nm and 530 nm). The raw data for the analysis is the ratio of emission at 460 nm divided by emission at 530 nm. The formula used to determine % inhibition is: (1-(raw data-low average) / (high average-low average)) x 100. Percent inhibition was plotted and the IC was calculated using a variable slope 4-parameter curve fitting analysis in GraphPad Prism 9.5.0 software. 50 value was determined.

[0429] The results are shown below.

[0430] [Table 4]

[0431] [Example #55] Inhibitory activity of compounds against LPAR1 The additional compounds of the present disclosure are synthesized in the same manner as the compounds described above, and are understood by those skilled in the art.The inhibitory activity of the compounds of the present disclosure against LPAR1 is measured using the above-mentioned arrestin assay protocol.The results are shown below.

[0432] [Table 5] TIFF2025165398000170.tif236169TIFF2025165398000171.tif137169

[0433] Example 56: Activity of Compound 15 against skin fibrosis The activity of compound 15 was determined using a bleomycin-induced skin fibrosis model. Model Protocol For the bleomycin model of skin fibrosis, 9- to 11-week-old C57B6J mice were purchased. Upon arrival, mice were group-housed in individually ventilated cages, 10 mice per cage, on a regular 12:12-hour light:12:12-hour dark cycle. Animals were acclimated to the animal facility for at least 10 days before the start of the bleomycin model study. Mice were tagged with ear tags for animal identification. At the start of bleomycin administration, 93M diet gel was also added to all mouse cages and was available ad libitum for the duration of the experiment. All study animals had free access to food and water.

[0434] The upper dorsal region of mice was shaved, and two circles (approximately 1 cm in diameter) were drawn on the skin to identify the location of bleomycin injection. To induce skin fibrosis, mice received subcutaneous injections of bleomycin (10 units / kg) or phosphate-buffered saline (PBS) at two marked injection sites (for a total volume of 200 μL) in a volume of 100 μL on weeks 1 (D0-D4) and 2 (D7-D10). After the final dose of bleomycin, mice were then pseudo-randomized into treatment groups, so that all groups had comparable weight loss before the start of test compound administration. For pharmacological evaluation, mice were orally administered vehicle or compound 15 at 1×, 3×, or 10× mg / kg twice daily from days 10 to 28. On day 28, animals were humanely euthanized, and plasma and 2-8 mm dorsal skin biopsy punches were collected. The ALK5 inhibitor SB-525334 was also included in the study as a positive control. SB-525334 was administered at a single 4.5 mg / kg dose following the same dosing regimen described for compound 15. All treatments were administered at a volume of 1 mL / kg body weight.

[0435] For tissue gene expression measurements, 8 mm skin biopsy punches were homogenized in 300 μL (1:100) of RLT buffer containing β-mercaptoethanol using a QIAgen TissueLyser II. RNA was then extracted using the RNeasy Fibrous Mini Kit, purified, and analyzed for gene expression using a TaqMan Kit (Thermofisher) with the indicated probes (Table B). Expression data for each sample were normalized to the housekeeping gene (Rplp0) and expressed as fold change relative to sham-treated mice.

[0436] [Table 6]

[0437] For protein measurements, one-half of an 8 mm biopsy punch was homogenized in 500 μL of DI water containing extraction buffer and cell extraction enhancer solution using a Ruptor 24 Bead with CryoCool (OMNI). ELISA assays were performed on the lysates to measure fibronectin and procollagen 1a1, and multiplex MSD U-plex assays were performed to measure MCP-1 and CXCL1. All kits were run according to the manufacturer's instructions. Skin protein levels were normalized to the total protein in the lysates and expressed per milligram of total protein.

[0438] Data from gene and protein measurements were analyzed using GraphPad Prism 7 (GraphPad Software, San Diego, CA, USA). Group comparisons were performed by one-way ANOVA followed by Dunnett's multiple comparison test. Results of the bleomycin-induced skin fibrosis model Compound 15 was evaluated in a subcutaneous bleomycin-induced skin fibrosis mouse model after skin fibrosis had developed between days 1 and 10. Compound 15 was administered twice daily by oral gavage from days 10 to 28, as described in Table C.

[0439] [Table 7]

[0440] Treatment of mice with Compound 15 significantly reduced key indicators of dermatitis and fibrosis at tested concentrations of 1×, 3×, and 10× mg / kg. Reduction of disease-associated genes is summarized in Table D.

[0441] [Table 8]

[0442] As shown in Table E, reductions in disease-associated skin proteins were also observed, including decreases in extracellular matrix proteins (procollagen 1 and fibronectin) and inflammatory protein expression (MCP-1 and CXCL6).

[0443] [Table 9]

[0444] Incorporation by Reference All U.S. patents and published U.S. patent applications and international PCT applications cited herein are hereby incorporated by reference, except for any definitions, disclaimers or denials of subject matter, and except to the extent that the incorporated material is inconsistent with the explicit disclosure herein, in which case the language in this disclosure will control.

[0445] equivalent The foregoing written specification is believed to be sufficient to enable one skilled in the art to practice the invention. The present invention is not limited in scope by the described examples, as the examples are intended as single illustrations of one aspect of the invention, and other functionally equivalent embodiments are within the scope of the invention. The foregoing written specification is believed to be sufficient to enable one skilled in the art to practice the invention. The present invention is not limited in scope by the described examples, as the examples are intended as single illustrations of one aspect of the invention, and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and are encompassed by the appended claims. The advantages and objectives of the invention are not necessarily encompassed by each embodiment of the invention. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and are encompassed by the appended claims. The advantages and objectives of the invention are not necessarily encompassed by each embodiment of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R ａ are each independently halo, —O(C １～６ alkyl), —O(C １～６ haloalkyl), -C １～６ Alkyl, and -C １～６ haloalkyl; n is 0, 1, or 2; R Ｗ are each independently halo, -OR Ｗ２ , -NZ ２ , optionally substituted C １～６ Alkyl, optionally substituted C １～６ selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or Two Vicinal R Ｗ groups taken together with the atoms to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl; m is 0, 1, 2, or 3; Ring A is an optionally substituted non-aromatic 3- to 7-membered carbocyclylene or non-aromatic 3- to 7-membered heterocyclylene; R Ｗ２ is hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C １～６ haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; Each Z is independently hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C １～６ is selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl.

2. 10. The compound of claim 1, wherein the A ring is an optionally substituted 4-membered carbocyclylene.

3. A rings each independently represent halo, C １～６ Alkyl, C １～６ haloalkyl, —O(C １～６ alkyl), and —O(C １～６ 3. The compound of claim 1, which is a 4-membered carbocyclylene optionally substituted with 1 to 3 substituents selected from the group consisting of: aryl, aryl haloalkyl, aryl ...

4. A compound of formula (II) or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 (In the formula, R ａ are each independently halo, —O(C １～６ alkyl), —O(C １～６ haloalkyl), -C １～６ Alkyl, and -C １～６ haloalkyl; n is 0, 1, or 2; R Ｗ are each independently halo, -OR Ｗ２ , -NZ ２ , optionally substituted C １～６ Alkyl, optionally substituted C １～６ selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl; or Two Vicinal R Ｗ groups taken together with the atoms to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl; m is 0, 1, 2, or 3; X is a bond, or an optionally substituted 3- to 7-membered carbocyclylene, 3- to 7-membered heterocyclylene, 3- to 7-membered arylene, 3- to 7-membered heteroarylene, C １～６ Alkylene, C ２～６ Alkenylene, —CH(3- to 7-membered carbocyclyl)-, —CH(3- to 7-membered heterocyclyl)-, —CH(3- to 7-membered heterocyclyl)alkyl)-, —CH(3- to 7-membered carbocyclyl)alkyl)-, —CH(heteroaryl)-, —CH(aryl)-, —CH(heteroarylalkyl)-, —CH(arylalkyl)-, —CH(C １～６ alkyl)-, -CH(C １～６ haloalkyl)-, -CH(C １～６ hydroxyalkyl)-, -CH(C １～６ Alkoxy)-, -CH(C １～６ Alkoxy C １～６ alkyl)-, or -C(OH)(C １～６ alkyl)-, R Ｗ２ is hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C １～６ haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; Each Z is independently hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C １～６ is selected from the group consisting of haloalkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 3- to 6-membered heterocyclyl.

5. X is an optionally substituted 3- to 7-membered carbocyclylene, 3- to 7-membered heterocyclylene, —CH(3- to 7-membered carbocyclyl)-, —CH(3- to 7-membered heterocyclyl)-, —CH(C １～６ alkyl), -CH(C １～６ haloalkyl), or —CH(C １～６ Alkoxy C １～６ 5. The compound of claim 4, wherein:

6. X is an optionally substituted 3- to 7-membered heterocyclylene, —CH(3- to 7-membered heterocyclyl)-, or —CH(C １～６ Alkoxy C １～６ 6. The compound of claim 5, wherein:

7. R ａ are each independently —Cl and —OCHF ２ 7. The compound of claim 1, wherein n is 2.

8. The compound of any one of claims 1 to 3 and 7, having the structure of formula (Ib) or a pharmaceutically acceptable salt thereof: 【Transformation 3】 (In the formula, R １ is hydrogen or C １～６ is alkyl, R ２ and R ３ are each independently hydrogen, halo, optionally substituted (C １～３ alkyl), or optionally substituted alkoxy (C １～３ alkyl), or R ２ and R ３ together with the atom to which they are attached form an optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl.

9. R １ The compound of claim 8 , wherein is hydrogen or methyl.

10. R ２ and R ３ 10. The compound of claim 8 or 9, wherein each is hydrogen.

11. A compound according to any one of claims 8 to 10 selected from the following table: 【Chemistry 4】 【change】

12. A compound according to any one of claims 8 to 10 selected from the following table: 【Transformation 5】

13. The compound is 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

14. The compound is 【Transformation 7】 12. The compound of claim 11, wherein:

15. The compound is 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

16. The compound is 【Chemistry 9】 13. The compound of claim 12, wherein:

17. 17. A pharmaceutically acceptable salt of the compound of claim 16.

18. The compound of any one of claims 4 to 7, having the structure of formula (IIb) or a pharmaceutically acceptable salt thereof: 【Chemistry 10】 (In the formula, R ４ is hydrogen, and R ５ is an optionally substituted 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, C １～６ Alkyl, C １～６ Haloalkyl, or C １～６ Alkoxy C １～６ is alkyl, or R ４ and R ５ together with the atom to which they are attached form an optionally substituted 3- to 7-membered carbocyclylene or an optionally substituted 3- to 7-membered heterocyclylene; R ６ and R ７ are each independently hydrogen, halo, optionally substituted (C １～３ alkyl), or optionally substituted alkoxy (C １～３ alkyl), or R ６ and R ７ together with the atoms to which they are attached form a fused optionally substituted 4- to 6-membered carbocyclyl or a fused optionally substituted 4- to 6-membered heterocyclyl.

19. R ４ is hydrogen, and R ５ is tetrahydropyranyl or —CH ２ OCH ３ or R ４ and R ５ 19. The compound of claim 18, wherein together with the atoms to which they are attached form a tetrahydropyran ring.

20. R ６ and R ７ are each independently hydrogen or fluoro; R ６ and R ７ 20. The compound of claim 18 or 19, wherein together with the atoms to which they are attached form a fused 5-membered heterocyclyl.

21. A compound according to any one of claims 18 to 20 selected from the following table: 【Chemistry 11】

22. A compound according to any one of claims 18 to 20 selected from the following table: 【Chemistry 12】 【change】

23. The compound is 【Chemistry 13】 or a pharmaceutically acceptable salt thereof.

24. The compound is 【Chemistry 14】 22. The compound of claim 21, wherein:

25. The compound is 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

26. The compound is 【Chemistry 16】 23. The compound of claim 22, wherein:

27. 27. A pharmaceutically acceptable salt of the compound of claim 26.

28. The compound is 【Chemistry 17】 or a pharmaceutically acceptable salt thereof.

29. The compound is [Chemistry 18] 23. The compound of claim 22, wherein:

30. 30. A pharmaceutically acceptable salt of the compound of claim 29.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 and a pharmaceutically acceptable carrier.

32. 31. A method of treating systemic sclerosis (SSc) 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 30.

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